Molecules having pesticidal utility, and intermediates, compositions, and processes, related thereto
09924716 · 2018-03-27
Assignee
Inventors
- Thomas Barton (Indianapolis, IN)
- Xin Gao (Carmel, IN)
- Jim Hunter (Indianapolis, IN)
- Paul R. LePlae, Jr. (Brownsburg, IN)
- William C. Lo (Fishers, IN)
- Joshodeep Boruwa (Noida, IN)
- Raghuram Tangirala (Bengaluru, IN)
- Gerald B. Watson (Zionsville, IN)
- John Herbert (Fishers, IN)
Cpc classification
C07C255/19
CHEMISTRY; METALLURGY
C07C311/09
CHEMISTRY; METALLURGY
A01N37/18
HUMAN NECESSITIES
C07C275/26
CHEMISTRY; METALLURGY
C07C233/66
CHEMISTRY; METALLURGY
C07C233/78
CHEMISTRY; METALLURGY
A01N47/32
HUMAN NECESSITIES
International classification
A01N37/18
HUMAN NECESSITIES
C07C311/09
CHEMISTRY; METALLURGY
C07C233/66
CHEMISTRY; METALLURGY
C07C275/26
CHEMISTRY; METALLURGY
A01N47/32
HUMAN NECESSITIES
C07C255/19
CHEMISTRY; METALLURGY
A01N53/00
HUMAN NECESSITIES
Abstract
This disclosure relates to the field of molecules having pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda, processes to produce such molecules, intermediates used in such processes, compositions containing such molecules, and processes of using such molecules and compositions against such pests. These molecules and compositions may be used, for example, as acaricides, insecticides, miticides, molluscicides, and nematicides. This document discloses molecules having the following formula (Formula One). ##STR00001##
Claims
1. A molecule having the following formula ##STR00307## wherein: (A) R.sup.1, R.sup.5, R.sup.6, R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are each independently selected from the group consisting of H, F, Cl, Br, I, CN, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)haloalkoxy; (B) R.sup.2, R.sup.3, and R.sup.4 are each independently selected from the group consisting of H, F, Cl, Br, I, CN, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)haloalkoxy; (C) R.sup.7 is (C.sub.1-C.sub.6)haloalkyl; (D) R.sup.9 is selected from the group consisting of H, F, Cl, Br, I, CN, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)haloalkoxy; (E) R.sup.10 is selected from the group consisting of F, Cl, Br, I, CN, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)haloalkoxy; (F) R.sup.9 and R.sup.10 together can optionally form a 3- to 5-membered saturated or unsaturated, hydrocarbyl link, wherein said hydrocarbyl link may optionally be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, and CN; (G) L is (C.sub.1-C.sub.6)alkyl; (H) X is selected from the group consisting of C, S, and P(C.sub.1-C.sub.6)alkyl; (I) n is 1 or 2; (J) R.sup.15 is selected from the group consisting of (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.3-C.sub.4)cycloalkyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)haloalkoxy, phenyl, and NH(C.sub.3-C.sub.4)cycloalkyl, wherein each alkyl, alkenyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, and phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, CN, and OH; and agriculturally acceptable acid addition salts, salt derivatives, solvates, ester derivatives, crystal polymorphs, isotopes, resolved stereoisomers, and tautomers, of the molecules of Formula One.
2. A molecule according to claim 1 wherein R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.9, R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are H.
3. A molecule according to claim 1 wherein R.sup.2 is Cl, Br, or CH.sub.3.
4. A molecule according to claim 1 wherein R.sup.3 is F, Cl, Br, or CHCH.sub.2.
5. A molecule according to claim 1 wherein R.sup.4 is Cl, Br, or CH.sub.3.
6. A molecule according to claim 1 wherein R.sup.2, R.sup.3, and R.sup.4 are Cl.
7. A molecule according to claim 1 wherein R.sup.7 is CF.sub.3, CF.sub.2CH.sub.3, or CF.sub.2CH.sub.2CH.sub.3.
8. A molecule according to claim 1 wherein R.sup.10 is Cl, Br, I, CH.sub.3, or CF.sub.3.
9. A molecule according to claim 1 wherein L is CH(CH.sub.3) or CH(CH.sub.2CH.sub.3).
10. A molecule according to claim 1 wherein X is C or S.
11. A molecule according to claim 1 wherein n is 1.
12. A molecule according to claim 1 wherein R.sup.15 is CH.sub.2CH.sub.3, cyclopropyl, CH.sub.2CF.sub.3, CH.sub.2CH.sub.2CF.sub.3, or NHcyclopropyl.
13. A molecule according to claim 1 wherein (A) R.sup.1, R.sup.5, R.sup.6, R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are H; (B) R.sup.2, R.sup.3, and R.sup.4 are each independently selected from the group consisting of H, F, Cl, Br, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl; (C) R.sup.7 is (C.sub.1-C.sub.6)haloalkyl; (D) R.sup.9 is H; (E) R.sup.10 is selected from the group consisting of Cl, Br, (C.sub.1-C.sub.4)alkyl, and (C.sub.1-C.sub.4)haloalkyl; (G) L is (C.sub.1-C.sub.6)alkyl; (H) X is C or S; (I) n is 1 or 2; (J) R.sup.15 is selected from the group consisting of (C.sub.1-C.sub.4)alkyl, (C.sub.3-C.sub.4)cycloalkyl, (C.sub.1-C.sub.4)haloalkyl, and NH(C.sub.3-C.sub.4)cycloalkyl, wherein each alkyl, alkenyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, and phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, CN, and OH.
14. A molecule according to claim 1 wherein said molecule is selected from one of the molecules in the following Table TABLE-US-00018 No. Structure F1
15. A molecule according to claim 1 wherein said molecule is selected from one of the molecules in the following Table TABLE-US-00019 No. Structure P1
16. A pesticidal composition comprising a molecule according to claim 1 further comprising one or more active ingredients.
17. A pesticidal composition according to claim 16 wherein said active ingredient is from AIGA.
18. A process to control a pest, wherein said process comprising applying to a locus, a pesticidally effective amount of a pesticidal composition wherein said pesticidal composition comprises a molecule according to claim 1.
19. A process to control endoparasites and/or ectoparasites, wherein said process comprising applying a molecule according to claim 1 to a locus that includes a non-human animal.
Description
DETAILED DESCRIPTION OF THE DISCLOSURE
(1) This document discloses molecules of Formula One
(2) ##STR00012##
wherein:
(3) (A) R.sup.1, R.sup.5, R.sup.6, R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are each independently selected from the group consisting of H, F, Cl, Br, I, CN, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)haloalkoxy;
(4) (B) R.sup.2, R.sup.3, and R.sup.4 are each independently selected from the group consisting of H, F, Cl, Br, I, CN, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)haloalkoxy;
(5) (C) R.sup.7 is (C.sub.1-C.sub.6)haloalkyl;
(6) (D) R.sup.9 is selected from the group consisting of (F), H, F, Cl, Br, I, CN, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)haloalkoxy;
(7) (E) R.sup.10 is selected from the group consisting of (F), F, Cl, Br, I, CN, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)haloalkoxy;
(8) (F) R.sup.9 and R.sup.10 together can optionally form a 3- to 5-membered saturated or unsaturated, hydrocarbyl link,
(9) wherein said hydrocarbyl link may optionally be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, and CN;
(10) (G) L is (C.sub.1-C.sub.6)alkyl;
(11) (H) X is selected from the group consisting of C, S, and P(C.sub.1-C.sub.6)alkyl;
(12) (I) n is 1 or 2;
(13) (J) R.sup.15 is selected from the group consisting of (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.3-C.sub.4)cycloalkyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)haloalkoxy, phenyl, and NH(C.sub.3-C.sub.4)cycloalkyl, wherein each alkyl, alkenyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, and phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, CN, and OH; and
(14) agriculturally acceptable acid addition salts, salt derivatives, solvates, ester derivatives, crystal polymorphs, isotopes, resolved stereoisomers, and tautomers, of the molecules of Formula One.
(15) In another embodiment R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.9, R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are H. This embodiment may be used in combination with the other embodiments of R.sup.2, R.sup.7, R.sup.10, L, X, n, and R.sup.15.
(16) In another embodiment R.sup.2 is Cl, Br, or CH.sub.3. This embodiment may be used in combination with the other embodiments of R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, L, R.sup.14, X, n, and R.sup.15.
(17) In another embodiment R.sup.3 is F, Cl, Br, or CHCH.sub.2. This embodiment may be used in combination with the other embodiments of R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, L, R.sup.14, X, n, and R.sup.15.
(18) In another embodiment R.sup.4 is Cl, Br, or CH.sub.3. This embodiment may be used in combination with the other embodiments of R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, L, R.sup.14, X, n, and R.sup.15.
(19) In another embodiment R.sup.2, R.sup.3, and R.sup.4 are CL This embodiment may be used in combination with the other embodiments of R.sup.1, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, L, R.sup.14, X, n, and R.sup.15.
(20) In another embodiment R.sup.7 is (C.sub.1-C.sub.6)haloalkyl. This embodiment may be used in combination with the other embodiments of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, L, R.sup.14, X, n, and R.sup.15.
(21) In another embodiment R.sup.7 is CF.sub.3, CF.sub.2CH.sub.3, or CF.sub.2CH.sub.2CH.sub.3 This embodiment may be used in combination with the other embodiments of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, L, R.sup.14, X, n, and R.sup.15.
(22) In another embodiment R.sup.10 is Cl, Br, I, CH.sub.3, or CF.sub.3. This embodiment may be used in combination with the other embodiments of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.11, R.sup.12, R.sup.13, L, R.sup.14, X, n, and R.sup.15.
(23) In another embodiment L is CH(CH.sub.3) or CH(CH.sub.2CH.sub.3). This embodiment may be used in combination with the other embodiments of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, X, n, and R.sup.15.
(24) In another embodiment X is C or S. This embodiment may be used in combination with the other embodiments of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, L, R.sup.14, n, and R.sup.15.
(25) In another embodiment n is 1 or 2. This embodiment may be used in combination with the other embodiments of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, L, R.sup.14, X, and R.sup.15.
(26) In another embodiment R.sup.15 is CH.sub.2CH.sub.3, cyclopropyl, CH.sub.2CF.sub.3, CH.sub.2CH.sub.2CF.sub.3, or NHcyclopropyl. This embodiment may be used in combination with the other embodiments of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, X, and n.
(27) In another embodiment:
(28) (A) R.sup.1, R.sup.5, R.sup.6, R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are H;
(29) (B) R.sup.2, R.sup.3, and R.sup.4 are each independently selected from the group consisting of H, F, Cl, Br, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl;
(30) (C) R.sup.7 is (C.sub.1-C.sub.6)haloalkyl;
(31) (D) R.sup.9 is H;
(32) (E) R.sup.10 is selected from the group consisting of Cl, Br, (C.sub.1-C.sub.4)alkyl, and (C.sub.1-C.sub.4)haloalkyl;
(33) (G) L is (C.sub.1-C.sub.6)alkyl;
(34) (H) X is C or S;
(35) (I) n is 1 or 2;
(36) (J) R.sup.15 is selected from the group consisting of (C.sub.1-C.sub.4)alkyl, (C.sub.3-C.sub.4)cycloalkyl, (C.sub.1-C.sub.4)haloalkyl, and NH(C.sub.3-C.sub.4)cycloalkyl,
(37) wherein each alkyl, alkenyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, and phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, CN, and OH.
(38) Preparation of Benzyl Halides
(39) Benzyl alcohol 1-3, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are as previously disclosed, may be prepared in several ways. Ketones 1-1 may be prepared by treating bromobenzenes with a lithium base such as n-butyllithium in a polar, aprotic solvent preferably diethyl ether at temperatures from about 78 C. to about 0 C. followed by treatment with esters R.sup.7C(O)O(C.sub.1-C.sub.4)alkyl, wherein R.sup.7 is as previously disclosed, such as ethyl 2,2-difluoropropanoate (not shown). Treatment of ketones 1-1, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.7 are as previously disclosed, with a reducing agent such as sodium borohydride, in the presence of a base, such as aqueous sodium hydroxide, in a polar, protic solvent preferably methanol at about 10 C. to about 10 C. may provide benzyl alcohols 1-3 (Scheme 1, step a). Alternatively, aldehydes 1-2, wherein R.sup.6 is H and R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as previously disclosed, may be allowed to react with trifluorotrimethylsilane in the presence of a catalytic amount of tetrabutylammonium fluoride in a polar, aprotic solvent preferably tetrahydrofuran (Scheme 1, step b) to provide benzyl alcohols 1-3, wherein R.sup.7 is CF.sub.3. Subsequently, benzyl alcohols 1-3 may be converted into benzyl halides 1-4, wherein E is Br, CI, or I, and R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are as previously disclosed, by treatment with a halogenating reagent, such as N-bromosuccinimide, and triethylphosphite in a solvent that does not react with the reagentspreferably dichloromethaneat about 40 C. to provide benzyl halides 1-4, E is Br (Scheme 1, step c). Alternatively, benzyl alcohols 1-3 may be converted into benzyl halides 1-4, where E is Br by treatment with a sulfonyl chloride such as methanesulfonyl chloride in the presence of a base such as triethylamine and subsequent treatment of the resultant sulfonate with a transition metal bromide such as iron(III) bromide. Additionally, treatment with chlorinating reagents such as thionyl chloride in the presence of a base such as pyridine in a hydrocarbon solvent such as toluene at about 110 C. may provide benzyl halides 1-4, where E is Cl (Scheme 1, step c).
(40) ##STR00013##
Preparation of Fluorinated Vinylbenzoic Esters and Acids
(41) Halobenzoic acids 2-1, wherein R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are as previously disclosed may be converted to halobenzoic acid esters 2-2, wherein R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are as previously disclosed. Halobenzoic acids 2-1, may be treated with an acid, such as sulfuric acid, in the presence of a (C.sub.1-C.sub.8)alcohol such as ethanol, to provide halobenzoic acid ethyl esters 2-2 (Scheme 2, step a). Fluorinated vinylbenzoic acid esters 2-3 may be accessed via reaction of 2-2 with a fluorinated vinyl silane in the presence of a palladium catalyst such as tetrakis(triphenylphospine)palladium(0), a copper additive such as copper(I) iodide, and a fluoride source, such as cesium fluoride in a polar, aprotic solvent preferably 1,3-dimethyl-2-imidazolidinone at temperatures ranging from about ambient temperature to about 45 C., to provide fluorinated vinyl benzoic acid esters 2-3 (Scheme 2, step b). Fluorinated vinyl benzoic acid esters 2-3 may be treated with a metal hydroxide source such as lithium hydroxide in a mixed solvent system comprising a polar, aprotic solvent preferably tetrahydrofuran and polar, protic solvents preferably methanol and water at about ambient temperature to provide fluorinated vinyl benzoic acids 2-4 (Scheme 2, step c).
(42) ##STR00014##
(43) Alternatively, halobenzoic acids 2-1 may be directly treated with a vinyl borane source such as vinyltrifluoroborate or 3-hydroxy-2,3-dimethylbutan-2-yl hydrogen vinylboronate in the presence of a palladium catalyst such as 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride, and a base such as potassium carbonate, in a polar, aprotic solvent preferably dimethylsulfoxide at temperatures ranging from about 80 C. to about 140 C., to provide vinyl benzoic acids 3-1, wherein R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are as previously disclosed (Scheme 3, step a). Vinyl benzoic acids 3-1 may be treated with a bromine source such as N-bromosuccinimide, and a fluorine source such as triethylamine trihydrofluoride, in a polar, aprotic solvent preferably dichloromethane at about 0 C., to provide bromofluoroalkyl benzoic acids 3-2, wherein R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are as previously disclosed (Scheme 3, step b). Bromofluoroalkyl benzoic acids 3-2 may be treated with a base such as potassium tert-butoxide, in a polar, protic solvent preferably methanol, at temperatures ranging from about 0 C. to about ambient temperature, to provide fluorinated vinyl benzoic acids 2-4 (Scheme 3, step c).
(44) ##STR00015##
Preparation of Fluorinated Phenyl Allylbenzoic Acids
(45) Benzyl halides 1-4 and fluorinated vinylbenzoic acids 2-4 may be treated with a copper(I) source such as copper(I) chloride or copper(I) bromide and a pyridine ligand such as 2,2-bipyridyl in a polar, aprotic solvent preferably N-methyl-2-pyrrolidone, at a temperature between about 100 C. to about 180 C. to provide fluorinated phenyl allylbenzoic acids 4-1, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are as previously disclosed (Scheme 4, step a).
(46) ##STR00016##
Preparation of Diacylamines
(47) Diacylamines 5-3, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, L, R.sup.13, R.sup.14, X, n, and R.sup.15 are as previously disclosed, may be prepared by treatment with acylamino salts 5-2, wherein L, R.sup.13, R.sup.14, X, n, and R.sup.15 are as previously disclosed, and activated carboxylic acids 5-1, wherein A is an activating group, and R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are as previously disclosed, with a base, such as potassium bicarbonate, triethylamine, diisopropylethylamine, or preferably 4-methylmorpholine in an anhydrous aprotic solvent such as dichloromethane, tetrahydrofuran, 1,2-dichioroethane, N,N-dimethylformamide, or any combination thereof, at temperatures between about 0 C. and about 120 C. (Scheme 5, step a).
(48) Activated carboxylic acids 5-1 may be an acid halide such as an acid chloride, an acid bromide, or an acid fluoride; a carboxylic ester such as a para-nitrophenyl ester, a pentafluorophenyl ester, an ethyl (hydroxyimino)cyanoacetate ester, a methyl ester, an ethyl ester, a benzyl ester, an N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1-yl ester, or a hydroxypyridyltriazol-1-yl ester; an O-acylisourea; an acid anhydride; or a thioester. Acid chlorides may be prepared from the corresponding carboxylic acids by treatment with a dehydrating, chlorinating reagent such as oxalyl chloride or thionyl chloride. Activated carboxylic acids 5-1 may be prepared from carboxylic acids in situ with a uronium salt such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU), or (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholine-carbenium hexafluorophosphate (COMU). Activated carboxylic esters 5-1 may also be prepared from carboxylic acids in situ with a phosphonium salt such as benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop). Activated carboxylic acids 5-1 may also be prepared from carboxylic acids in situ with a coupling reagent such as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide (EDC), or dicyclohexylcarbodiimide (DCC) in the presence of a triazole such as hydroxybenzotriazolemonohydrate (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt). O-Acylisoureas may be prepared with a dehydrating carbodimide such as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide or dicyclohexylcarbodiimide. Activated carboxylic acids 5-1 may also be prepared from carboxylic acids in situ with a coupling reagent such as 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) in the presence of a triazole such as 1-hydroxy-7-azabenzotriazole (HOAt).
(49) ##STR00017##
(50) Diacylamines 5-3, wherein R.sup.15 contains a sulfide may be oxidized to the corresponding sulfoxide and sulfone by treatment with one equivalent of sodium perborate in a protic solvent such as acetic acid (sulfoxide) or two equivalents of sodium perborate (sulfone). Preferably, the oxidation will be performed at temperatures between about 40 C. to about 100 C. using 1.5 equivalents of sodium perborate to provide chromatographically separable mixtures of sulfoxide and sulfone diacylaminals 5-3, wherein R.sup.15 contains a sulfoxide or sulfone.
(51) Diacylamines 5-3 may also be prepared by treatment of acylamine salts 6-1, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, L and R.sup.14 are as previously disclosed, with activated coupling partners 6-2, wherein A is an activated group, and X, n, and R.sup.15 are as previously disclosed, with a base, such as potassium bicarbonate, triethylamine, diisopropylethylamine, or preferably 4-methylmorpholine in a polar, aprotic solvent such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, or any combination thereof, at temperatures between about 0 C. and about 120 C. (Scheme 6, step a).
(52) Activated coupling partners 6-2, wherein A is an activated group, wherein X is C, n is 1, and R.sup.15 is as previously disclosed, may be an acid halide, such as an acid chloride, an acid bromide, or an acid fluoride; a carboxylic ester, such as a para-nitrophenyl ester, a pentafluorophenyl ester, an ethyl (hydroxyimino)cyanoacetate ester, a methyl ester, an ethyl ester, a benzyl ester, a N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1-yl ester, or a hydroxypyridyltriazol-1-yl ester; an O-acylisourea; an acid anhydride; or a thioester. Acid chlorides may be prepared from the corresponding carboxylic acids by treatment with a dehydrating, chlorinating reagent such as oxalyl chloride or thionyl chloride. Activated coupling partners 6-2 that are activated carboxylic esters may be prepared from carboxylic acids in situ with a uronium salt such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (H BTU), or (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU). Activated coupling partners 6-2 that are activated carboxylic esters may also be prepared from carboxylic acids in situ with a phosphonium salt such as benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop). Activated coupling partners 6-2 that are activated carboxylic esters may also be prepared from carboxylic acids in situ with a coupling reagent such as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide (EDC), or dicyclohexylcarbodiimide (DCC) in the presence of a triazole such as hydroxybenzotriazolemonohydrate (HOBO or 1-hydroxy-7-azabenzotriazole (HOAt). O-Acylisoureas may be prepared with a dehydrating carbodimide such as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide or dicyclohexylcarbodiimide. Activated coupling partners 6-2 that are activated carboxylic esters may also be prepared from carboxylic acids in situ with a coupling reagent such as 2-chloro-1,3-dirnethylimidazolidinium hexafluorophosphate (CIP) in the presence of a triazole such as 1-hydroxy-7-azabenzotriazole (HOAt).
(53) ##STR00018##
(54) Activated coupling partners 6-2, wherein A is an activated group, wherein X is P(C.sub.1-C.sub.4)alkyl, n is 1, and R.sup.15 is as previously disclosed, may be a phosphinic halide, such as a phosphinic chloride. Activated coupling partners 6-2, wherein A is an activated group, wherein X is S, n is 2, and R.sup.15 is as previously disclosed, may be a sulfonyl halide, such as a sulfonyl chloride.
(55) Precursors to and activated coupling partners 6-2, wherein R.sup.15 contains a sulfide may be oxidized to the corresponding sulfoxide or sulfone by treatment with one equivalent of sodium perborate in a protic solvent such as acetic acid (sulfoxide) or two equivalents of sodium perborate (sulfone). Preferably, the oxidation will be performed at temperatures between about 40 C. to about 100 C. using 1.5 equivalents of sodium perborate to provide chromatographically separable mixtures of sulfoxide and sulfone precursors to and activated coupling partners 6-2, containing a sulfoxide or sulfone.
(56) Diacylamines 7-2, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, L, R.sup.13, R.sup.14, and R.sup.15 are as previously disclosed, may also be prepared by treatment of acylamine salts 6-1 with isocyanates 7-1, wherein R.sup.15 is as previously disclosed, with a base, such as potassium bicarbonate, triethylamine, diisopropylethylamine, 4-methylmorpholine, or 2,6-dimethylpyridne in a polar, aprotic solvent such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, pyridine, or any combination thereof, at temperatures between about 0 C. and about 120 C., heated conventionally or by microwave (Scheme 7, step a).
(57) ##STR00019##
(58) Diacylamines 5-3 may be prepared by treating acylamines 8-1, wherein R.sup.14 is H, and R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, L, X, n, and R.sup.15 are as previously disclosed, with an alkylating reagent R.sup.14Z, wherein R.sup.14 is not H and is as previously disclosed, and Z is a leaving group, such as a halogen or a sulfonate, wherein R.sup.14Z is an alkyl halide, such as iodomethane, or an activated alcohol, such as ethyltriflate in the presence of a base, such as sodium hydride, cesium carbonate, silver oxide, potassium hydride, tetrabutylammonium fluoride, or potassium carbonate in a polar, aprotic solvent such as N,N-dimethylformamide, tetrahydrofuran, acetone, acetonitrile, dimethylsulfoxide, or glyme. Alternatively, the alkylation of acylamines 8-1 may be conducted in a biphasic manner using an alkali metal hydroxide base, such as sodium hydroxide, in water, a phase-transfer catalyst, such as a tetraalkylammonium salt, in an organic solvent such as toluene or dichloromethane at temperatures ranging from about 0 C. and about 120 C. (Scheme 8, step a).
(59) ##STR00020##
Preparation of Acylamine Salt Precursors
(60) Amides 9-2, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, and L are as previously disclosed, are novel intermediates which may be used in the preparation of acylamine salts 6-1. Amides 9-2 may be prepared by reacting alpha-amino amides 9-1, wherein R.sup.13 and L are as previously disclosed, and an activated carboxylic acid 5-1 with a base, such as potassium bicarbonate, triethylamine, diisopropylethylamine, or preferably 4-methylmorpholine in an polar, aprotic solvent such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, or any combination thereof, at temperatures between about 0 C. and about 120 C. (Scheme 9, step a).
(61) ##STR00021##
Preparation of Acylamine Salts
(62) Acylamines 6-1, wherein R.sup.14 is H, may be prepared from amides 9-2 by conversion of the primary amide nitrogen to a nitrene-like species, resulting in nitrogen migration, followed by isocyanate formation. Hydrolysis of the intermediate isocyanate with aqueous acid, such as hydrochloric acid may provide acylamine salts 6-1 (Scheme 10, step a). When an acid weaker than aqueous hydrochloric acid is employed, anion exchange may be achieved by treatment with hydrochloric acid to provide acylamine salts 6-1. Preferably amide 9-2 may be treated with iodobenzene bis(trifluoroacetate) in a solvent mixture consisting of about two parts acetonitrile and about one part deionized water at temperatures between about 0 C. and about 120 C. The resulting trifluoroacetate salt may be converted to the chloride salt by the addition of hydrochloric acid followed by evaporation of volatiles.
(63) ##STR00022##
Preparation of Acylamine Salts
(64) Acylamine salts 10-3, wherein R.sup.14 and R.sup.15 are as previously disclosed, may be prepared according to those reactions outlined in Scheme 11, Scheme 12, and Scheme 13. Treatment of carboxylic acids 10-1, wherein A is OH, R.sup.14, R.sup.15, and L are as previously disclosed, or the corresponding activated acids 10-1, wherein A is an activating group as previously described may be reacted with a nitrogen nucleophile to provide amides and amide derivatives 10-2, wherein Z.sup.2 is H, N.sub.2, NH tert-butoxycarbonyl, or OH, R.sup.14, R.sup.15, and L are as previously disclosed. The resultant amides and amide derivatives 10-2 may be converted to acylamine salts 10-3 by the formation of the corresponding nitrene-like species, resulting in nitrogen migration, and subsequent hydrolysis of the resultant isocyanate.
(65) Activated amido acids 10-1 may be treated with ammonia (Scheme 11, step a) to provide carboxamides 10-2, wherein Z.sup.2 is H. Carboxamides 10-2, wherein Z.sup.2 is H, may be converted to acylamines 10-3 via the Hoffman rearrangement followed by acidification with hydrochloric acid or preferably by treatment with iodobenzene bis(trifluoroacetate) in a solvent mixture consisting of about one part acetonitrile and about one part deionized water at temperatures between about 0 C. and about 120 C. (Scheme 11, step e). The resulting trifluoroacetate salt may be converted to the chloride salt by the addition of hydrochloric acid followed by the evaporation of volatiles.
(66) Amido acids 10-1, wherein A is OH, may be treated with an azide source such as diphenylphosphoryl azide in the presence of a base, such as proton sponge or triethylamine (Scheme 11, step b) to provide acyl azides 10-2, wherein Z.sup.2 is N.sub.2. Alternatively, amido acids 10-1, wherein A is an activating group as described above, may be treated with an azide source, such as sodium azide (Scheme 11, step b) to provide acyl azides 10-2, wherein Z.sup.2 is N.sub.2. Acyl azides 10-2, may be heated to about 40 C. to about 110 C. in a polar, aprotic solvent, such as acetonitrile, toluene, 1,2-dichloroethane, tetrahyrofuran, or 1,4-dioxane to affect a Curtius rearrangement resulting in the formation of a non-isolated isocyanate that may be treated with aqueous hydrochloric acid to provide acylamine salts 5-2. Alternatively, the isocyanate may be treated with an alcohol, such as tert-butanol, para-methoxybenzyl alcohol, or benzyl alcohol to provide an acid labile carbamate, which after purification may be decomposed under acidic conditions to provide acylamine salts 10-3 (Scheme 11, step f).
(67) ##STR00023##
(68) Activated amido acids 10-1 may be treated with protected hydrazines (Scheme 11, step c), such as tert-butyl carbazate in the presence of a base, such as 4-methylmorpholine, to provide protected hydrazides 10-2, wherein Z.sup.2 is NHtert-butoxycarbonyl. Protected hydrazides 10-2 may be deprotected by treatment with acids such as hydrochloric acid or trifluoroacetic acid in aprotic solvents such as 1,4-dioxane or dichloromethane. The resulting hydrazide salts 10-2, wherein Z.sup.2 is NH.sub.3Cl, may be neutralized to provide hydrazide 10-2, wherein Z.sup.2 is NH.sub.2. Hydrazides 10-2 may then be diazotized with reagents such as nitric acid or isobutyl nitrite to produce isocyanates that may be converted to acylamine salts 10-3 (Scheme 11, step g).
(69) Activated amido acids 10-1 are as previously disclosed, may be treated with hydroxylamine (Scheme 11, step d) to provide hydroxamic acids 10-2, wherein Z.sup.2 is OH. Hydroxamic acids 10-2 may be acylated with activated carboxylic acids, wherein activated carboxylic acids are as previously disclosed, to provide the O-acyl hydroxamic acids 10-2, wherein Z.sup.2 is O-acyl, which may be converted to isocyanates by treatment with heat or the addition of base to produce isocyanates that may be converted to acylamine salts 10-3 (Scheme 11, step h).
(70) Carbamate acids 11-1, wherein R.sup.14 is H and L is as previously disclosed, may be treated with an alkylating reagent R.sup.14Z, wherein R.sup.14 is not H and is as previously disclosed and Z is a leaving group, such as a halogen or sulfonate, wherein R.sup.14Z is an alkyl halide, such as iodomethane, or an activated alcohol, such as ethyltriflate, in the presence of a base, such as sodium hydride, cesium carbonate, silver oxide, potassium hydride, tetrabutylammonium fluoride, or potassium carbonate in a polar, aprotic solvent such as N,N-dimethylformamide, tetrahydrofuran, acetone, acetonitrile, dimethylsulfoxide, or glyme. Alternatively, the alkylation of carbamate acids 11-1 may be conducted in a biphasic manner using an alkali metal hydroxide base, such as sodium hydroxide, in water, a phase-transfer catalyst, such as a tetraalkylammonium salt, in an organic solvent such as toluene or dichloromethane at temperatures ranging from about 0 C. to about 120 C. (Scheme 12, step a).
(71) ##STR00024##
(72) The resultant carbamate acids 11-2, wherein R.sup.14 and L are as previously disclosed, may be treated with an azide source such as diphenylphosphoryl azide in the presence of a base, such as proton sponge or triethylamine (Scheme 12 step b) to provide an acyl azide which may in turn be heated from about 40 C. to about 110 C. in a polar, aprotic solvent, such as acetonitrile, toluene, 1,2-dichioroethane, tetrahydrofuran, or 1,4-dioxane to affect a Curtius rearrangement resulting in the formation of an isocyanate (Scheme 12, step c). Treatment of the resultant isocyanate with benzyl alcohol may provide a differentially protected diamine (Scheme 12, step d). Removal of the tert-butylcarbamate may be achieved by treatment with an acid, such as hydrochloric acid or trifluoroacetic acid, in a polar, aprotic solvent, such as 1,4-dioxane or dichloromethane, at temperatures between about 0 C. and about 65 C., to provide benzyl carbamate amine salts 11-3, wherein R.sup.14 and L are as previously disclosed (Scheme 12, step e).
(73) Benzyl carbamate amine salts 11-3 may be treated with activated carboxylic acids 6-2, wherein X is C, in the presence of a base, such as potassium bicarbonate, triethylamine, diisopropylethylamine, or preferably 4-methylmorpholine in a polar, aprotic solvent such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, or any combination thereof, at temperatures between about 0 C. and about 120 C. (Scheme 12, step f). The resultant carbamate acylamine may be treated with a source of hydrogen and a transition metal catalyst, such as palladium on carbon to provide acylamine salts 10-3 (Scheme 12, step g).
(74) Carbamate acids 11-1 may be treated with an alkylating reagent R.sup.16Z, wherein R.sup.16 is (C.sub.1-C.sub.8)alkenyl and Z is a leaving group, such as a halogen or a sulfonate, wherein R.sup.16Z is an alkenyl halide, such as allyl bromide, or an activated alcohol, such as crotyltriflate in the presence of a base, such as sodium hydride, cesium carbonate, silver oxide, potassium hydride, tetrabutylammonium fluoride, or potassium carbonate in a polar, aprotic solvent such as N,N-dimethylformamide, tetrahydrofuran, acetone, acetonitrile, dimethylsulfoxide, or glyme. Alternatively, the alkylation of carbamate acids 11-1 may be conducted in a biphasic system using an alkali metal hydroxide base, such as sodium hydroxide, in water, a phase-transfer catalyst, such as a tetraalkylammonium salt, in an organic solvent such as toluene or dichloromethane at temperatures ranging from about 0 C. to about 100 C. (Scheme 13, step a).
(75) The resultant carbamate acids 12-1, wherein R.sup.16 and L are as previously disclosed, may be treated with an azide source such as diphenylphosphoryl azide in the presence of a base, such as proton sponge or triethylamine (Scheme 13, step b) to provide an acyl azide which may in turn be heated to about 40 C. to about 110 C. in an aprotic solvent, such as acetonitrile, toluene, 1,2-dichloroethane, tetrahydrofuran, or 1,4-dioxane to affect a Curtius rearrangement resulting in the formation of an isocyanate (Scheme 13, step c). Treatment of the resultant isocyanate with benzyl alcohol may provide a differentially protected diamine (Scheme 13, step d). Removal of the tert-butylcarbamate may be achieved by treatment with an acid, such as hydrochloric acid or trifluoroacetic acid, in a polar, aprotic solvent, such as 1,4-dioxane or dichloromethane, at temperatures between about 0 C. and about 65 C., to provide benzyl carbamate aminal salts 12-2, wherein R.sup.16 and L are as previously disclosed (Scheme 13, step e).
(76) ##STR00025##
(77) Benzyl carbamate amine salts 11-3 may be treated with activated carboxylic acids 10-3 in the presence of a base, such as potassium bicarbonate, triethylamine, diisopropylethylamine, or preferably 4-methylmorpholine in an anhydrous, aprotic solvent such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, or any combination thereof, at temperatures between about 0 C. and about 120 C. (Scheme 13, step f). The resultant carbamate acylaminal may be treated with a source of hydrogen and a transition metal catalyst, such as palladium on carbon to provide acylamine salts 10-3 (Scheme 13, step g).
(78) Preparation of Amido Acids
(79) Esters 13-2, wherein A is O(C.sub.1-C.sub.8)alkyl or O(C.sub.1-C.sub.8)alkylphenyl, and L, X, n, and R.sup.15 are as previously disclosed may be prepared by treating amino esters 13-1, wherein A is O(C.sub.1-C.sub.8)alkyl or O(C.sub.1-C.sub.8)alkylphenyl, and L is as previously disclosed, with activated coupling partners 6-2, a base, such as potassium bicarbonate, triethylamine, diisopropylethylamine, or preferably 4-methylmorpholine in an anhydrous, aprotic solvent such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, or any combination thereof, at temperatures between about 0 C. and about 120 C. (Scheme 14, step a).
(80) ##STR00026##
(81) Esters 13-2 may be treated with an alkylating reagent R.sup.14Z, wherein R.sup.14 is not H and is as previously disclosed, and Z is a leaving group, such as a halogen or a sulfonate, wherein R.sup.14Z is an alkyl halide, such as iodomethane or an activated alcohol, such as ethyltriflate in the presence of a base, such as sodium hydride, cesium carbonate, silver oxide, potassium hydride, tetrabutylammonium fluoride, or potassium carbonate in a polar, aprotic solvent such as N,N-dimethylformamide, tetrahydrofuran, acetone, acetonitrile, dimethylsulfoxide, or glyme. Alternatively, the alkylation of esters 13-2 may be conducted in a biphasic system using an alkali metal hydroxide base, such as sodium hydroxide, in water, a phase-transfer catalyst, such as a tetraalkylammonium salt, in an organic solvent such as toluene or dichloromethane at temperatures ranging from about 0 C. to about 120 C. (Scheme 14, step b).
(82) The resultant alkylated esters, when A is O(C.sub.1-C.sub.8)alkyl, may be treated with an acid, such as aqueous hydrochloric acid, in a polar, aprotic solvent, such as 1,4-dioxane, at about 100 C. to provide acids 13-4, wherein L, R.sup.14, X, n, and R.sup.15 are as previously disclosed. Alternatively, alkylated esters, when A is O-tea-butyl, may be treated with hydrochloric acid in 1,4-dioxane. Alkylated esters, when A is O(C.sub.1-C.sub.8)alkyl may be treated with an alkali base, such as lithium hydroxide, in a polar solvent, such as 1,4-dioxane, tetrahydrofuran, methanol, water, or mixtures thereof, at temperatures between 0 C. and about 140 C. to provide acids 13-4. The alkylated esters, when A is O(C.sub.1-C.sub.8)alkylphenyl may be treated with a source of hydrogen and a transition metal catalyst, such as palladium on carbon to provide acids 13-4 (Scheme 14, step c).
(83) Acids 13-4 may be prepared in alternate sequences to the sequence discussed above. Step b may be initially performed to provide substituted esters 13-3, wherein A is O(C.sub.1-C.sub.8)alkyl or O(C.sub.1-C.sub.8)alkylphenyl, and R.sup.14 and L are as previously disclosed, before steps a and steps c are performed to provide acids 13-4.
(84) Substituted esters 13-3 may be prepared by treating esters 13-1 with R.sup.16C(O)H or R.sup.16C(O)(C.sub.1-C.sub.8)alkyl, wherein R.sup.16 is not H, in the presence of a reductant, such as sodium borohydride or sodium cyanoborohydride, in protic solvents such as methanol or ethanol in the presence of weak organic acids, such as acetic acid. Alternatively, the imine intermediate resulting from condensation of the amine and the carbonyl may be reduced by a source of hydrogen and a transition metal catalyst, such as palladium on carbon to provide substituted esters 13-3, when A is O(C.sub.1-C.sub.5)alkyl (Scheme 14, step d).
(85) Acids 13-4 may be prepared in a two-step sequence, by first treating substituted esters 13-3 with activated coupling partners 6-2, with a base, such as potassium bicarbonate, triethylamine, diisopropylethylamine, or preferably 4-methylmorpholine in an anhydrous aprotic solvent such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, or any combination thereof, at temperatures between about 0 C. and about 120 C. (Scheme 14, step e).
(86) Secondly, the resultant esters, when A is O(C.sub.1-C.sub.8)alkyl may be treated with an acid, such as aqueous hydrochloric acid, in a polar, aprotic solvent, such as 1,4-dioxane, at about 100 C. to provide amido acids 13-4. Alternatively, esters, when A is Otert-butyl, may be treated with hydrochloric acid in 1,4-dioxane. Esters, when A is O(C.sub.1-C.sub.8)alkyl may be treated with an alkali base, such as lithium hydroxide, in a polar solvent, such as 1,4-dioxane, tetrahydrofuran, methanol, water, or mixtures thereof, at temperatures between 0 C. and about 100 C. to provide acids 13-4. Finally, acylated esters, when A is O(C.sub.1-C.sub.8)alkylphenyl may be treated with a source of hydrogen and a transition metal catalyst, such as palladium on carbon to provide acids 13-4 (Scheme 14, step f).
(87) Acids 13-2 may be prepared by treating amino esters 13-1 with activated coupling partners 6-2, a base, such as potassium bicarbonate, triethylamine, diisopropylethylamine, or preferably 4-methylmorpholine in an anhydrous, aprotic solvent such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, or any combination thereof, at temperatures between about 0 C. and about 120 C. (Scheme 14, step a).
(88) ##STR00027##
(89) Esters 13-2 may be treated with an alkylating reagent R.sup.16Z, wherein R.sup.16 is (C.sub.1-C.sub.8)alkenyl and Z is a leaving group, such as a halogen or a sulfonate, wherein R.sup.16Z is an alkyl halide, such as allyl bromide, or an activated alcohol, such as crotyltriflate in the presence of a base, such as sodium hydride, cesium carbonate, silver oxide, potassium hydride, tetrabutylammonium fluoride, or potassium carbonate in a polar, aprotic solvent such as N,N-dimethylformamide, tetrahydrofuran, acetone, acetonitrile, dimethylsulfoxide, or glyme. Alternatively, the alkylation of esters 13-2 may be conducted in a biphasic system using an alkali metal hydroxide base, such as sodium hydroxide, in water, a phase-transfer catalyst, such as a tetraalkylammonium salt, in an organic solvent such as toluene or dichloromethane at temperatures ranging from about 0 C. to about 100 C. (Scheme 15, step b). The alkene present in R.sup.16 may be subsequently reduced by a source of hydrogen and a transition metal catalyst, such as palladium on carbon. In alkylated esters when A is O(C.sub.1-C.sub.8)alkylphenyl reduction of the alkene may also lead to concomitant reduction of the ester to provide amido acids 13-4 (Scheme 15, step c).
(90) Alkylated amido esters, when A is O(C.sub.1-C.sub.8)alkyl may be treated with an acid, such as aqueous hydrochloric acid, in a polar, aprotic solvent, such as 1,4-dioxane, at about 100 C. to provide amido acids 13-4. Alternatively, esters, when A is Otert-butyl, may be treated with hydrochloric acid in 1,4-dioxane. Alkylated esters, when A is O(C.sub.1-C.sub.8)alkyl may be treated with an alkali base, such as lithium hydroxide, in a polar solvent, such as 1,4-dioxane, tetrahydrofuran, methanol, water, or mixtures thereof, at temperatures between 0 C. and about 100 C. to provide acids 13-4 (Scheme 15, step d).
(91) Acids 13-4 may be prepared in alternate sequences to the sequence discussed above. Step b may be initially performed to provide substituted esters 13-1, wherein A is O(C.sub.1-C.sub.8)alkyl or O(C.sub.1-C.sub.8)alkylphenyl, and L and R.sup.15 are as previously disclosed, before steps a and steps c, or steps a, steps c, and steps d are performed to provide 13-4.
EXAMPLES
(92) These examples are for illustration purposes and are not to be construed as limiting this disclosure to only the embodiments disclosed in these examples.
(93) Starting materials, reagents, and solvents that were obtained from commercial sources were used without further purification. Anhydrous solvents were purchased as Sure/Seal from Aldrich and were used as received. Melting points were obtained on a Thomas Hoover Unimelt capillary melting point apparatus or an OptiMelt Automated Melting Point System from Stanford Research Systems and are uncorrected. Examples using room temperature were conducted in climate controlled laboratories with temperatures ranging from about 20 C. to about 24 C. Molecules are given their known names, named according to naming programs within ISIS Draw, ChemDraw, or ACD Name Pro. If such programs are unable to name a molecule, such molecule is named using conventional naming rules. .sup.1H NMR spectral data are in ppm () and were recorded at 300, 400, 500, or 600 MHz; .sup.13C NMR spectral data are in ppm () and were recorded at 75, 100, or 150 MHz, and .sup.19F NMR spectral data are in ppm () and were recorded at 376 MHz, unless otherwise stated.
Example 1
Preparation of (Z)-2-bromo-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (C1)
(94) ##STR00028##
(95) To a 25 mL round-bottomed flask were added 2,2-bipyridine (0.255 g, 1.63 mmol), 2-bromo-4-(1-fluorovinyl)benzoic acid (C24) (1.00 g, 4.08 mmol), and 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (2.79 g, 8.16 mmol) in N-methylpyrrolidone (2.0 mL) to give a yellow solution. Copper(I) bromide (0.117 g, 0.816 mmol) was added and the reaction mixture was purged with nitrogen for 5 minutes. The reaction was then heated to 150 C. for 3 hours. The reaction mixture was poured into ice water (100 mL). The water was filtered and the resultant black gum was dissolved in ethyl acetate (800 mL), washed with brine (2200 mL), and water (2200 mL), dried over magnesium sulfate, filtered, and concentrated to provide the title compound as a brown oil (1.40 g, 64%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.03 (d, J=8.2 Hz, 1H), 7.89 (d, J=1.8 Hz, 1H), 7.59 (dd, J=8.3, 1.8 Hz, 1H), 7.43 (s, 2H), 5.83 (dd, J=32.4, 9.6 Hz, 1H), 4.60 (p, J=8.8 Hz, 1H); .sup.19F NMR (376 MHz, CDCl.sub.3) 69.32 (d, J=2.3 Hz), 108.70-119.01 (m); ESIMS m/z 505 ([MH].sup.).
(96) The following compounds were prepared in like manner to the procedure outlined in Example 1:
(Z)-4-(1,4,4,4-Tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C2)
(97) ##STR00029##
(98) Isolated as a yellow oil (7.6 g, 68%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.04 (d, J=8.2 Hz, 1H), 7.99-7.94 (m, 1H), 7.84 (dd, J=8.2, 1.8 Hz, 1H), 7.44 (s, 2H), 5.90 (dd, J=32.4, 9.6 Hz, 1H), 4.62 (p, J=8.9 Hz, 1H); .sup.19F NMR (376 MHz, CDCl.sub.3) 59.60, 69.28 (d, J=2.3 Hz), 112.11; ESIMS m/z 493 ([MH].sup.).
(Z)-4-(1,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)pent-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C3)
(99) ##STR00030##
(100) Isolated as a yellow foam (0.628 g, 60%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.00 (d, J=8.2 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.42 (s, 2H), 5.96 (dd, J=33.6, 9.8 Hz, 1H), 4.29 (td, J=14.3, 9.8 Hz, 1H), 1.65 (t, J=18.4 Hz, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 59.61, 92.97-97.35 (m), 114.82; ESIMS m/z 491 ([MH].sup.).
(Z)-2-Chloro-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (C4)
(101) ##STR00031##
(102) Isolated as a white solid (4.27 g, 88%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.07 (d, J=8.2 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.54 (dd, J=1.8 Hz, 1H), 7.43 (s, 2H), 5.85 (dd, J=32.4, 9.6 Hz, 1H), 4.60 (p, J=8.8 Hz, 1H); .sup.19F NMR (376 MHz, CDCl.sub.3) 69.33 (d, J=2.2 Hz), 112.18 (d, J=2.4 Hz); ESIMS m/z 461 ([MH].sup.).
(Z)-4-(3-(3,5-Dibromo-4-chlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C5)
(103) ##STR00032##
(104) Isolated as a brown gum (2.00 g, 37%): ESIMS m/z 583 ([MH].sup.).
(Z)-4-(3-(3,5-Dichlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C6)
(105) ##STR00033##
(106) Isolated as a brown gum (0.50 g, 43%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) 13.9 (br s, 1H), 8.16 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.82 (s, 2H), 7.64 (t, J=6.0 Hz, 1H), 6.90 (dd, J=36.0, 10.4 Hz, 1H), 5.26-5.17 (m, 1H); IR (thin film) 3416, 2926, 1716, 1119 cm.sup.1; ESIMS m/z 449 ([M+H].sup.+).
(Z)-4-(3-(3,4-Dichlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C7)
(107) ##STR00034##
(108) Isolated as a brown gum (2.50 g, 56%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) 13.9 (br s, 1H), 8.16 (s, 1H), 8.09 (d, J=10.8 Hz, 1H), 8.08 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.75-7.65 (m, 2H), 6.90 (dd, J=36.0, 10.4 Hz, 1H), 5.22-5.16 (m, 1H); IR (thin film) 3440, 2927, 1716, 1175 cm.sup.1; ESIMS m/z 459 ([MH].sup.6).
(Z)-4-(3-(3,5-Dibromophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C8)
(109) ##STR00035##
(110) Isolated as a brown gum (2.20 g, 39%): .sup.1H NMR (300 MHz, CDCl.sub.3) 8.05-7.95 (m, 2H), 7.84 (d, J=7.2 Hz, 1H), 7.69-7.68 (m, 1H), 7.49 (s, 2H), 5.95 (dd, J=32.7, 9.6 Hz, 1H), 4.64-4.58 (p, 1H); IR (thin film) 3439, 2925, 1714, 1118, 746 cm.sup.1; ESIMS m/z 549 ([MH].sup.).
(Z)-4-(3-(3,5-Dichloro-4-fluorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C9)
(111) ##STR00036##
(112) Isolated as a brown gum (1.20 g, 54%): .sup.1H NMR (300 MHz, CDCl.sub.3) 7.88 (s, 2H), 7.76-7.75 (m, 1H), 7.37 (d, J=6.0 Hz, 2H), 5.90 (dd, J=32.1, 9.0 Hz, 1H), 4.62-4.56 (p, 1H); IR (thin film) 3445, 2926, 1698, 1260, 750 cm.sup.1; ESIMS m/z 477 ([MH].sup.).
(Z)-4-(3-(4-Chloro-3,5-dimethylphenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C10)
(113) ##STR00037##
(114) Isolated as a yellow gum (2.20 g, 53%): .sup.1H NMR (300 MHz, CDCl.sub.3) 8.01 (d, J=8.1 Hz, 1H), 7.94 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.11 (s, 2H), 6.00 (dd, J=33.0, 9.9 Hz, 1H), 4.58-4.55 (m, 1H), 2.40 (s, 6H); IR (thin film) 3445, 1713, 852 cm.sup.1; ESIMS m/z 453 ([MH].sup.),
(Z)-4-(3-(4-Bromo-3,5-dichlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C11)
(115) ##STR00038##
(116) Isolated as a brown solid (1.50 g, 65%): mp 78-81 C.; .sup.1H NMR (300 MHz, CDCl.sub.3) 8.09-7.99 (m, 2H), 7.83-7.81 (m, 1H), 7.42 (s, 2H), 5.95 (dd, J=32.4 Hz, 9.6 Hz, 1H), 4.63-4.57 (m, 1H); IR (thin film) 3445, 1713, 852 cm.sup.1; ESIMS m/z 538 ([M+H].sup.+).
(Z)-4-(3-(3-Bromo-5-chlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C12)
(117) ##STR00039##
(118) Isolated as a brown gum (2.0 g, 62%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) 13.80 (br s, 1H), 8.15 (s, 1H), 8.09 (d, J=8.1 Hz, 1H), 7.93-7.78 (m, 4H), 6.91 (dd, J=35.7, 10.2 Hz, 1H), 5.27-5.14 (m, 1H); IR (thin film) 3081, 2927, 1714, 776 cm.sup.1; ESIMS m/z 503 ([MH].sup.).
(Z)-4-(3-(3,4-Dibromophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C13)
(119) ##STR00040##
(120) Isolated as a yellow gum (2.1 g, 78%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.02 (d, J=8.4 Hz, 1H), 7.94 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.26-7.21 (m, 1H), 5.96 (dd, J=32.4, 9.2 Hz, 1H), 4.67-4.58 (p, 1H); IR (thin film) 3426, 2925, 1714, 1115 cm.sup.1; ESIMS m/z 547 ([MH].sup.).
(Z)-2-Methyl-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (C14)
(121) ##STR00041##
(122) Isolated as an orange oil (0.94 g, 61%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.09 (d, J=8.8 Hz, 1H), 7.49-7.45 (m, 2H), 7.44 (s, 2H), 5.80 (dd, J=32.7, 9.6 Hz, 1H), 4.60 (p, J=8.9 Hz, 1H), 2.69 (s, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 69.40 (d, J=2.3 Hz), 108.40-115.65 (m); ESIMS m/z 441 ([MH].sup.).
(Z)-2-Methyl-4-(1,4,4-trifluoro-3-(3,4,5-trichlorophenyl)pent-1-en-1-yl)benzoic acid (C15)
(123) ##STR00042##
(124) Isolated as an orange foam (0.204 g, 51): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.07 (d, J=8.8 Hz, 1H), 7.49-7.40 (m, 4H), 5.86 (dd, J=33.9, 9.9 Hz, 1H), 4.27 (td, J=14.3, 9.7 Hz, 1H), 2.68 (s, 3H), 1.65 (t, J=18.4 Hz, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 95.11, 95.18, 114.57; ESIMS m/z 437 ([MH].sup.).
(Z)-4-(1,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)hex-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C16)
(125) ##STR00043##
(126) Isolated as an orange foam (0.136 g, 63%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.99 (dd, J=8.4, 4.0 Hz, 1H), 7.93 (s, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.42 (d, J=2.6 Hz, 2H), 6.08-5.87 (m, 1H), 4.32 (td, J=14.6, 9.8 Hz, 1H), 1.87 (ddt, J=21.6, 15.4, 8.0 Hz, 2H), 1.07 (t, J=7.4 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) 170.72, 156.96 (d, J.sub.CF=253.0 Hz), 136.85, 135.06, 134.53, 133.75, 131.90, 131.19, 130.18, 129.17, 128.60, 128.05, 127.29, 124.11, 123.36-122.67 (m), 121.39, 104.66 (d, J.sub.CF=18.0 Hz), 46.46, 29.70-27.14 (m), 6.40-5.44 (m); ESIMS m/z 503 ([MH].sup.).
(Z)-4-(3-(3,4-Dichlorophenyl)-1,4,4-trifluoropent-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C17)
(127) ##STR00044##
(128) Isolated as an orange glass (0.495 g, 51%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.01 (d, J=8.2 Hz, 1H), 7.94 (d, J=1.6 Hz, 1H), 7.80 (dd, J=8.2, 1.8 Hz, 1H), 7.49 (d, J=2.1 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.26 7.22 (m, 1H), 6.00 (dd, J=33.9, 9.8 Hz, 1H), 4.32 (ddd, J=15.8, 13.0, 9.8 Hz, 1H), 1.62 (t, J=18.4 Hz, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 59.58, 89.79-99.81 (m), 115.63; IR (thin film) 3008, 1711 cm.sup.1; ESIMS m/z 455 ([MH].sup.).
(Z)-4-(3-(3,4-Dichlorophenyl)-1,4,4-trifluoropent-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C18)
(129) ##STR00045##
(130) Isolated as a brown gum (2.5 g, 46%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) 13.79 (br s, 1H), 8.15-8.06 (m, 3H), 7.91 (d, J=8.1 Hz, 1H), 7.71 (s, 2H), 6.90 (dd, J=36.0, 10.2 Hz, 1H), 5.21-5.15 (m, 1H); IR (thin film) 3431, 2924, 1623, 597 cm.sup.1; ESIMS m/z 503 ([MH].sup.).
(Z)-4-(3-(3-Chloro-4-fluorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C19)
(131) ##STR00046##
(132) Isolated as a yellow gum (1.50 g, 57%): .sup.1H NMR (300 MHz, CDCl.sub.3) 8.01 (d, =8.1 Hz, 2H) 7.94 (s, 2H), 7.76-7.75 (m, 1H), 7.37 (d, J=6.0 Hz, 2H), 5.90 (dd, J=32.1, 9.0 Hz, 1H); IR (thin film) 3445, 2926, 1698, 1260, 750 cm.sup.1; ESIMS m/z 443 ([MH].sup.).
(Z)-4-(3-(4-Chloro-3-fluorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C20)
(133) ##STR00047##
(134) Isolated as a brown gum (0.50 g, 48%): .sup.1H NMR (300 MHz, CDCl.sub.3) 8.03 (d, J=8.1 Hz, 1H), 7.94 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.46-7.44 (m, 1H), 7.23-7.13 (m, 2H), 5.98 (dd, J=34.2, 9.9 Hz, 1H), 4.69-4.63 (m, 1H); IR (thin film) 3092, 1751, 750 cm.sup.1; ESIMS m/z 443 ([MH].sup.).
(Z)-4-(1,4,4,4-Tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (CC1)
(135) ##STR00048##
(136) Isolated as a yellow gum (1.1 g, 56%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.15 (d, J=8.2 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.44 (s, 2H), 5.84 (dd, J=32.6, 9.6 Hz, 1H), 4.61 (p, J=8.9 Hz, 1H); .sup.19F NMR (376 MHz, CDCl.sub.3) 69.38 (d, J=2.2 Hz), 109.75-116.47 (m); ESIMS m/z 427 ([MH].sup.).
Example 2
Preparation of (Z)-2-iodo-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (C21)
(137) ##STR00049##
(138) To a 25 mL vial were added (Z)-2-bromo-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (C1) (0.500 g, 0.987 mmol), copper(I) iodide (0.00940 g, 0.0490 mmol), and 1,4-dioxane (4.9 mL) to form a yellow suspension. Sodium iodide (0.296 g, 1.97 mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.0140 g, 0.0990 mmol) were added, and the reaction mixture was stirred at 110 C. for 3.5 hours. The reaction mixture was concentrated and purified by flash column chromatography to provide the title compound as a brown oil (0.247 g, 43%): .sup.1H NMR (300 MHz, CDCl.sub.3) 8.21 (d, J=1.7 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.62 (dd, J=8.3, 1.7 Hz, 1H), 7.43 (s, 2H), 5.82 (dd, J=32.5, 9.6 Hz, 1H), 4.59 (p, J=8.9 Hz, 1H); .sup.19F NMR (471 MHz, CDCl.sub.3) 69.32, 112.14 (d, J=20.8 Hz); ESIMS m/z 553 ([MH].sup.).
Example 3
Preparation of (Z)-2-iodo-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (C22)
(139) ##STR00050##
(140) Tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol) was added to a solution of (Z)-4-(3-(4-bromo-3,5-dichlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C11) (1.4 g, 2.6 mmol) in toluene (10 mL) at room temperature. The reaction mixture was degassed by purging with nitrogen (310 minutes). Tributyl vinyl stannane (0.82 g, 2.6 mmol) was added to the reaction mixture. The reaction mixture was again degassed by purging with nitrogen (310 minutes) and stirred at 120 C. for 3 hours. The reaction mixture was quenched with water and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography using 30% ethyl acetate/hexanes provided the title compound as a pale yellow gum (0.80 g, 63%); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.85 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.37 (s, 1H), 6.72-6.65 (dd, J=17.6 Hz, 11.6 Hz, 1H), 5.86-5.73 (m, 3H), 4.61-4.56 (m, 1H); IR (thin film) 3445, 2925, 1646, 1275, 749 cm.sup.1; ESIMS m/z 488 ([M+H].sup.+).
Example 4
Preparation of (Z)-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoyl chloride (C23)
(141) ##STR00051##
(142) To a 25 mL vial was added (Z)-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C2) (0.200 g, 0.404 mmol), oxalyl chloride (0.095 mL, 1.09 mmol), and N,N-dirnethylformamide (catalytic amount) in dichloromethane (1.3 mL) to give a yellow solution. The reaction was stirred for 15 hours at room temperature. The solvent was removed under vacuum providing the title compound as a yellow gum (0.220 g, 95%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.99 (d, J=8.2 Hz, 1H), 7.92 (d, J=1.7 Hz, 1H), 7.81 (dd, J=8.2, 1.8 Hz, 1H), 7.44 (5, 2H), 5.88 (dd, J=32.5, 9.6 Hz, 1H), 4.73-4.50 (m, 1H); .sup.19F NMR (376 MHz, CDCl.sub.3) 59.58, 69.32, 109.75-113.19 (m); IR (thin film) 3445, 2925, 1646, 1275, 749 cm.sup.1; ESIMS m/z 476 ([MCl].sup.+).
Example 5
Preparation of 2-bromo-4-(1-fluorovinyl)benzoic acid (C24)
(143) ##STR00052##
(144) To a 250 mL round-bottomed flask were added methyl 2-bromo-4-(1-fluorovinyl)benzoate (C29) (1.8 g, 7.0 mmol), lithium hydroxide hydrate (0.88 g, 21 mmol), methanol (7.0 mL), tetrahydrofuran (21 mL), and water (7.0 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated, quenched with a pH 4 buffer, and extracted with ethyl acetate to provide the title compound as a white solid (1.0 g, 56%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.01 (d, J=8.2 Hz, 1H), 7.89 (d, J=1.8 Hz, 1H), 7.57 (dd, J=8.3, 1.8 Hz, 1H), 5.21 (dd, J=48.6, 4.0 Hz, 1H), 5.06 (dd, J=17.3, 3.9 Hz, 1H); .sup.19F NMR (471 MHz, CDCl.sub.3) 108.71 (d, J=1.4 Hz); ESIMS m/z 244 ([MH].sup.).
(145) The following compounds were prepared in like manner to the procedure outlined in Example 5:
4-(1-Fluorovinyl)-2-(trifluoromethyl)benzoic acid (C25)
(146) ##STR00053##
(147) Isolated as a white solid (1.9 g, 93%): .sup.1H NMR (400 MHz, methanol-d.sub.4) 7.95 (d, J=1.5 Hz, 1H), 7.95-7.91 (m, 1H), 7.90-7.86 (m, 1H), 5.46 (dd, J=50.0, 4.1 Hz, 1H), 5.09 (dd, J=18.0, 4.1 Hz, 1H); .sup.19F NMR (376 MHz, methanol-d.sub.4) 61.04 (d, J=1.1 Hz), 110.93; ESIMS m/z 233 ([MH].sup.).
2-Chloro-4-(1-fluorovinyl)benzoic acid (C26)
(148) ##STR00054##
(149) Isolated as a white solid (3.5 g, 75%): .sup.1H NMR (400 MHz, acetone-d.sub.6) 7.97 (dd, J=8.2, 0.9 Hz, 1H), 7.76 (d, J=1.7 Hz, 1H), 7.70 (dd, J=8.2, 1.7 Hz, 1H), 5.68-5.45 (m, 1H), 5.11 (dd, J=18.2, 4.1 Hz, 1H); .sup.19F NMR (376 MHz, acetone-d.sub.6) 108.71; ESIMS m/z 200 ([MH].sup.).
4-(1-Fluorovinyl)-2-methylbenzoic acid (C27)
(150) ##STR00055##
(151) Isolated as a white solid (0.550 g, 89%): .sup.1H NMR (400 MHz, methanol-d.sub.4) 7.92 (d, J=8.1 Hz, 1H), 7.59-7.52 (m, 1H), 7.52-7.44 (m, 1H), 5.29 (dd, J=50.1, 3.7 Hz, 1H), 4.93 (dd, J=18.1, 3.7 Hz, 1H), 2.60 (s, 3H); .sup.19F NMR (376 MHz, methanol-d.sub.4) 110.32 (d, J=2.1 Hz); ESIMS m/z 181 ([M+H].sup.+).
Example 6
Preparation of methyl 4-(1-fluorovinyl)-2-(trifluoromethyl)benzoate (C28)
(152) ##STR00056##
(153) To a 100 mL round-bottomed flask was added methyl 4-bromo-2-(trifluoromethyl)benzoate (2.25 g, 8.00 mmol), fluorovinyl)(methyl)diphenylsilane (3.58 g, 14.8 mmol), and 1,3-dimethylimidazolidin-2-one (40 mL). Tetrakis(triphenylphosphine)palladium(0) (0.459 g, 0.400 mmol), copper(I) iodide (0.0760 mg, 0.400 mmol), and cesium fluoride (3.62 g, 23.9 mmol) were added and the reaction was stirred at room temperature for 24 hours under a nitrogen atmosphere. Water was added to the mixture and the mixture was diluted with 3:1 hexanes/diethyl ether. The layer was separated, and the organic layer was dried over sodium sulfate, concentrated, and the residue was purified by flash column chromatography provided the title compound as a colorless oil (2.00 g, 96%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.96-7.87 (m, 1H), 7.83 (dq, J=8.1, 0.7 Hz, 1H), 7.77 (dd, J=8.2, 1.7 Hz, 1H), 5.23 (dd, J=48.6, 4.0 Hz, 1H), 5.07 (dd, J=17.4, 4.0 Hz, 1H), 3.95 (s, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 59.92, 108.73 (d, J=1.4 Hz); EIMS m/z 248 ([M].sup.+).
(154) The following compounds were prepared in like manner to the procedure outlined in Example 6:
Methyl 2-bromo-4-(1-fluorovinyl)benzoate (C29)
(155) ##STR00057##
(156) Isolated as a colorless oil (1.8 g, 93%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.84 (d, J=1.7 Hz, 1H), 7.82 (dd, J=8.2, 0.9 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 5.16 (dd, J=48.7, 3.9 Hz, 1H), 5.01 (dd, J=17.3, 3.9 Hz, 1H), 3.94 (d, J=2.2 Hz, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 108.61 (d, J=1.5 Hz); ESIMS m/z 258 ([MH].sup.).
Methyl 2-chloro-4-(1-fluorovinyl)benzoate (C30)
(157) ##STR00058##
(158) Isolated as a colorless oil (2.1 g, 99%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.86 (dd, J=8.2, 0.9 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.48 (dd, J=8, 3, 1.8 Hz, 1H), 5.17 (dd, J=48.7, 3.8 Hz, 1H), 5.02 (dd, J=17.3, 3.9 Hz, 1H), 3.94 (s, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 108.63 (d, J=1.4 Hz); ESIMS m/z 214 ([MH].sup.).
Methyl 2-chloro-4-(1-fluorovinyl)benzoate (C31)
(159) ##STR00059##
(160) Isolated as a colorless oil (0.5 g, 85%): .sup.1H NMR (400 MHz, methanol-d.sub.4) 7.90 (d, J=8.2 Hz, 1H), 7.51 (s, 1H), 7.49 (dd, J=8.0, 1.6 Hz, 1H), 5.30 (dd, J=50.1, 3.7 Hz, 1H), 4.95 (dd, J=18.0, 3.7 Hz, 1H), 3.88 (d, J=5.9 Hz, 3H), 2.59 (s, 3H); .sup.19F NMR (376 MHz, methanol-d.sub.4) 110.41 (d, J=1.3 Hz); ESIMS m/z 195 ([M+H].sup.+).
Example 7
Preparation of 4-(1-fluorovinyl)-2-(trifluoromethyl)benzoic acid (C25)
(161) ##STR00060##
Step 1: 4-(2-bromo-1-fluoroethyl)-2-(trifluoromethyl)benzoic acid (C32) 2-(Trifluoromethyl)-4-vinylbenzoic acid (5.3 g, 24 mmol) was dissolved in dichloromethane (123 mL) at 0 C., triethylamine trihydrofluoride was added (8.0 mL, 49 mmol) followed by N-bromosuccinimide (8.7 g, 49 mmol). The reaction mixture was stirred for 16 hours while warming to room temperature. Water was then added to the mixture, washed with dichloromethane, dried over sodium sulfate, filtered, and concentrated providing the title compound as a yellow oil which was used without further purification (5.0 g, 65%).
Step 2: 4-(1-fluorovinyl)-2-(trifluoromethyl)benzoic acid (C25) 4-(2-Bromo-1-fluoroethyl)-2-(trifluoromethyl)benzoic acid (4.3 g, 14 mmol) was dissolved in methanol (68 mL) at 0 C. and potassium tert-butoxide (4.6 g, 41 mmol) was added as a solid while stirring. The reaction mixture was allowed to slowly warm to 23 C. and then stirred for 4 hours. Hydrochloric acid (1 N) was slowly added, and the mixture was extracted with ethyl acetate. Purification by flash column chromatography using 0-40% acetone/hexanes provided the title compound as an off-white solid (1.7 g, 53%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.02 (d, J=8.2 Hz, 1H), 8.00 7.93 (m, 1H), 7.82 (dd, J=8.2, 1.8 Hz, 1H), 5.27 (dd, J=48.5, 4.1 Hz, 1H), 5.11 (dd, J=17.3, 4.1 Hz, 1H).
(162) The following compounds were prepared in like manner to the procedure outlined in Example 7:
4-(1-Fluorovinyl)benzoic acid (C33)
(163) ##STR00061##
(164) Isolated as a white solid (6.5 g, 86%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.13 (d, J=8.2 Hz, 2H), 7.69-7.62 (m, 2H), 5.21 (dd, J=49.0, 3.7 Hz, 1H), 5.02 (dd, J=17.5, 3.7 Hz, 1H); .sup.19F NMR (376 MHz, CDCl.sub.3) 108.35; ESIMS m/z 165 ([MH].sup.).
4-(1-Fluorovinyl)-2-methylbenzoic acid (C27)
(165) ##STR00062##
(166) Isolated as a colorless oil (0.165 g, 89%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.12-8.03 (m, 1H), 7.46 (dd, J=5.8, 2.1 Hz, 2H), 5.17 (dd, =49.1, 3.7 Hz, 1H), 4.98 (dd, J=17.5, 3.7 Hz, 1H), 2.68 (s, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 108.50.
Example 8
Preparation of 5-(1-bromo-2,2-difluoropropyl)-1,2,3-trichlorobenzene (C34)
(167) ##STR00063##
(168) N-bromosuccinimide (12.0 g, 67.5 mmol) was added to a solution of 2,2-difluoro-1-(3,4,5-trichlorophenyl)propan-1-ol (C43) (6.00 g, 21.8 mmol) in dichloromethane (72.6 mL). To this stirred solution was added triphenyl phosphite (17.1 mL, 65.3 mmol) slowly, dropwise, and the reaction mixture became dark brown. The reaction mixture was then heated at reflux for 3 hours. The solvent was concentrated, and the residue was triturated with diethyl ether. The solid was filtered, the filtrate was concentrated and the resultant oil was purified by flash column chromatography using hexanes as eluent to provide the title compound as a clear and colorless oil (2.20 g, 25%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.52 (s, 2H), 4.85 (dd, J=12.3, 10.4 Hz, 1H), 1.77 (t, J=18.2 Hz, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 92.14-95.01 (m); EIMS m/z 338 ([M].sup.+).
(169) The following compounds were prepared in like manner to the procedure outlined in Example 8:
1,3-Dibromo-5-(1-bromo-2,2,2-trifluoroethyl)-2-chlorobenzene (C35)
(170) ##STR00064##
(171) Isolated as a clear oil (28 g, 56%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.01-7.97 (m, 2H), 6.26-6.20 (m, 1H); IR (thin film) 1168, 736, 557 cm.sup.1; ESIMS m/z 428 ([M+H].sup.+).
5-(1-Bromo-2,2,2-trifluoroethyl)-2-chloro-1,3-dimethylbenzene (C36)
(172) ##STR00065##
(173) Isolated as a clear oil (6.32 g, 89%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) 7.39 (s, 2H), 6.17-6.09 (m, 1H), 2.35 (s, 6H); IR (thin film) 1114, 754 cm.sup.1; ESIMS m/z 302 ([M+H].sup.+).
2-Bromo-5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichlorobenzene (C37)
(174) ##STR00066##
(175) Isolated as a clear oil (19 g, 46%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.54-7.51 (m, 2H), 5.03-4.98 (m, 1H); .sup.19F NMR (376 MHz, CDCl.sub.3) 70.38.
4-(1-Bromo-2,2-difluoropropyl)-4,2-dichlorobenzene (C38)
(176) ##STR00067##
(177) Isolated as a colorless liquid (1.40 g, 65%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) 7.76-7.70 (m, 2H), 7.54 (dd, J=8.4, 1.8 Hz, 1H), 5.81-5.73 (m, 1H), 1.67 (d, J=18.9 Hz, 3H); IR (thin film) 1118, 800, 499 cm.sup.1; EIMS m/z 304 ([M].sup.+).
2-Bromo-4-(1-bromo-2,2,2-trifluoroethyl)-1-chlorobenzene (C39)
(178) ##STR00068##
(179) Isolated as a colorless liquid (10.5 g, 54%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.76 (d, J=1.2 Hz, 1H), 7.49-7.47 (m, 1H), 7.41-7.39 (m, 1H), 5.07-5.02 (m, 1H); IR (thin film) 3437, 2924, 1631, 1114 cm.sup.1; EIMS m/z 350 ([M].sup.+).
4-(1-Bromo-2,2,2-trifluoroethyl)-2-chloro-1-fluorobenzene (C40)
(180) ##STR00069##
(181) Isolated as a colorless oil (8.0 g, 73%): .sup.1H NMR (300 MHz, CDCl.sub.3) 7.59-7.57 (m, 1H), 7.42-7.33 (m, 1H), 7.20-7.14 (m, 1H), 5.10-5.03 (m, 1H); IR (thin film) 3429, 2926, 1502, 750 cm.sup.1; ESIMS m/z 292 ([M+H].sup.+).
4-(1-Bromo-2,2,2-trifluoroethyl)-1-chloro-2-fluorobenzene (C41)
(182) ##STR00070##
(183) Isolated as a yellow oil (1.1 g, 45%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.44 (dd, J=8.3, 7.5 Hz, 1H), 7.34 (dd, J=9.5, 1.9 Hz, 1H), 7.26-7.22 (m, 1H), 5.08 (q, J=7.1 Hz, 1H); EIMS m/z 291 ([M].sup.+).
Example 9
Preparation of 5-(1-bromo-2,2-difluorobutyl)-1,2,3-trichlorobenzene (C42)
(184) ##STR00071##
(185) Triethylamine (2.46 mL, 17.6 mmol) and methanesulfonyl chloride (1.10 mL, 14.1 mmol) were added to a solution of 2,2-difluoro-1-(3,4,5-trichlorophenyl)butan-1-ol (C44) (3.40 g, 11.7 mmol) in dichloromethane (58.7 mL). The reaction mixture was stirred for 1 hour, and then pentane was added. Filtration followed by concentration of the filtrate under vacuum provided a white solid. The solid was dissolved in dichloromethane (58.7 mL) to which iron(III) bromide (6.94 g, 23.5 mmol) was added. The reaction mixture was stirred overnight. The mixture was poured into water and then extracted with dichloromethane. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography using hexanes as eluent provided the title compound as a white solid (3.52 g, 72%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.51 (s, 2H), 4.85 (t, J=12.1 Hz, 1H), 2.14-1.91 (m, 2H), 1.06 (t, J=7.5 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) 135.55, 134.39, 132.52, 129.48, 120.25 (t, J=249.0 Hz), 49.76 (t, J=30.3 Hz), 28.03 (t, J=25.2 Hz), 6.06 (t, J=5.1 Hz); ESIMS m/z 351 ([MH].sup.).
Example 10
Preparation of 2,2-difluoro-1-(3,4,5-trichlorophenyl)propan-1-ol (C43)
(186) ##STR00072##
(187) 2,2-Difluoro-1-(3,4,5-trichlorophenyl)propan-1-one (C52) (1.75 g, 6.40 mmol) was dissolved in methanol (64.0 mL) at room temperature and sodium borohydride (0.290 g, 7.68 mmol) was added. The reaction stirred at room temperature for 1 hour, until gas evolution ceased. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography using 0-30% acetone/hexanes as eluent provided the title compound as a clear, colorless oil (1.60 g, 91%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.50 (d, J=0.9 Hz, 2H), 4.81 (td, J=8.7, 3.8 Hz, 1H), 1.65-1.41 (m, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 98.54-101.73 (m); IR (thin film) 3405, 1555, 1389 cm.sup.1.
(188) The following compounds were prepared in like manner to the procedure outlined in Example 10:
2,2-Difluoro-1-(3,4,5-trichlorophenyl)butan-1-ol (C44)
(189) ##STR00073##
(190) Isolated as a clear and colorless oil (3.4 g, 48%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.48 (d, J=0.9 Hz, 2H), 4.87-4.70 (m, 1H), 2.54 (dt, J=4.0, 1.0 Hz, 1H), 2.06-1.82 (m, 1H), 1.82-1.63 (m, 1H), 1.02 (t, J=7.5 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) 136.85, 134.20, 131.60, 127.54123.19 (t, J=248.0 Hz), 73.71 (t, J=30.0 Hz), 25.05 (t, J=24.6 Hz), 5.35 (t, J=5.2 Hz); EIMS m/z 287 ([M].sup.+).
1-(3,4-Dichlorophenyl)-2,2-difluoropropan-1-ol (C45)
(191) ##STR00074##
(192) Isolated as a clear and colorless oil (2.78 g, 89%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.57 (dd, J=2.0, 0.9 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.33-7.27 (m, 1H), 4.83 (td, J=8.9, 3.7 Hz, 1H), 2.55 (dt, J=3.8, 1.1 Hz, 1H), 1.50 (t, J=18.9 Hz, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 99.52 (d, J=249.6 Hz), 101.09 (d, J=249.4 Hz); IR (thin film) 3417 cm.sup.1.
Example 11
Preparation of 1-(3-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (C46)
(193) ##STR00075##
(194) Trimethyl(trifluoromethyl)silane (10.1 mL, 68.4 mmol) and tetrabutylammonium fluoride (1.44 g, 4.56 mmol) were added to a stirred solution of 3-bromo-4-chloro-benzaldehyde (10.0 g, 45.6 mmol) in tetrahydrofuran (150 mL) at room temperature and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with dichloromethane and washed with hydrochloric acid (2 N). The separated organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound as a brown liquid that was used without further purification (13.2 g, 94%):
(195) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.76 (s, 1H), 7.50-7.48 (m, 1H), 7.38-7.35 (m, 1H), 5.03-4.97 (m, 1H), 2.95 (br s, 1H); IR (thin film) 3406, 2881, 1469, 814 cm.sup.1; EIMS m/z 288 ([M].sup.+).
(196) The following compounds were prepared in like manner to the procedure outlined in Example 11:
1-(3,5-Dibromo-4-chlorophenyl)-2,2,2-trifluoroethanol (C47)
(197) ##STR00076##
(198) Isolated as a pale yellow liquid (7.4 g, 85%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.90 (s, 2H), 7.24 (d, J=5.2 Hz, 1H), 5.33 (d, J=6.4 Hz, 1H); IR (thin film) 3370, 1175, 735, 541 cm.sup.1; EIMS m/z 366 ([M].sup.+).
1-(4-Chloro-3,5-dimethylphenyl)-2,2,2-trifluoroethanol (C48)
(199) ##STR00077##
(200) Isolated as a clear liquid (5.0 g, 70%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.18 (s, 2H), 4.95-4.92 (m, 1H), 2.40 (s, 6H); IR (thin film) 3378, 1124, 833 cm.sup.1; EIMS m/z 238 ([M].sup.+).
1-(4-Bromo-3,5-dichlorophenyl)-2,2,2-trifluoroethanol (C49)
(201) ##STR00078##
(202) Isolated as a clear oil (33 g, 86%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.51 (s, 2H), 5.01-4.96 (m, 1H), 4.14-4.09 (m, 1H); .sup.19F NMR (376 MHz, CDCl.sub.3) 78.32.
1-(3-Chloro-4-fluorophenyl)-2,2,2-trifluoroethanol (C50)
(203) ##STR00079##
(204) Isolated as a clear and brown gum (7.0 g, 97%): .sup.1H NMR (300 MHz, CDCl.sub.3) 7.58-7.55 (m, 1H), 7.38-7.33 (m, 1H), 7.20-7.15 (m, 1H), 5.03-4.97 (m, 1H); EIMS m/z 228 ([M].sup.+).
1-(4-Chloro-3-fluorophenyl)-2,2,2-trifluoroethanol (C51)
(205) ##STR00080##
(206) Isolated as a clear and colorless oil (1.97 g, 75%); .sup.1H NMR (400 MHz, CDCl.sub.3) 7.52-7.37 (m, 1H), 7.32 (d, J=9.6 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 5.03 (dd, J=6.3, 3.6 Hz, 1H), 2.62 (d, J=4.0 Hz, 1H); .sup.13C NMR (101 MHz, CDCl.sub.3) 158.06 (d, J.sub.CF=250.4 Hz), 134.40 (d, J.sub.CF 6.6 Hz), 130.79, 123.83 (d, J.sub.CF=3.5 Hz), 122.4 (q, J.sub.CF=188.9 Hz), 115.8 (d, J=25.3 Hz), 71.65 (q, J.sub.CF=31.6 Hz); EIMS m/z 228 ([M].sup.+).
Example 12
Preparation of 2,2-difluoro-1-(3,4,5-trichlorophenyl) propan-1-one (C52)
(207) ##STR00081##
(208) To 5-bromo-1,2,3-trichlorobenzene (2.28 g, 8.76 mmol) dissolved in diethyl ether (39.8 mL) at 78 C. under nitrogen was added n-butyllithium (3.50 mL, 8.76 mmol). The solution was stirred for 30 minutes. To this was added ethyl 2,2-difluoropropanoate (1.10 g, 7.96 mmol, as a 20% w/w solution in toluene) dropwise over 10 minutes, and the reaction mixture was stirred for an additional hour. Saturated aqueous ammonium chloride solution was added to the mixture and stirring was continued as the reaction flask warmed to room temperature. The reaction mixture was then extracted with diethyl ether, washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography provided the title compound as a pale yellow oil (1.76 g, 73%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.11 (d, J=0.9 Hz, 2H), 1.89 (t, J=19.6 Hz, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 92.66; ESIMS m/z 271 ([MH].sup.).
(209) The following compounds were prepared in like manner to the procedure outlined in Example 12:
2,2-Difluoro-1-(3,4,5-trichlorophenyl)butan-1-one (C53)
(210) ##STR00082##
(211) Isolated as an oil (2.3 g, 68%) and used without further purification or characterization.
1-(3,4-Dichlorophenyl)-2,2-difluoropropan-1-one (C54)
(212) ##STR00083##
(213) Isolated as a colorless oil (3.89 g, 71%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.21-8.18 (m, 1H), 7.99-7.93 (m, 1H), 7.59 (dd, =8.4, 4.2 Hz, 1H), 1.89 (t, J=19.6 Hz, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 92.08-93.21 (m); EIMS m/z 238/240 ([M].sup.+).
Example 13
Preparation of 4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (F16)
(214) ##STR00084##
(215) Diisopropylethylamine (0.20 mL, 1.1 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.22 g, 0.41 mmol), and (S)- N-(1-aminoethyl)-4,4,4-trifluorobutanamide hydrochloride (C55) (0.086 g, 0.41 mmol) were added to a solution of (Z)-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C2) (0.18 g, 0.37 mmol) in dichloromethane. The reaction was stirred for 6 hours at room temperature. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography using 30% ethyl acetate/petroleum ether as eluent provided the title compound as a pale yellow solid (0.17 g, 62%).
Example 14
Preparation of 4-((Z)-3-(3,5-dichlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F11)
(216) ##STR00085##
(217) Diisopropylethylamine (0.19 mL, 1.1 mmol), 1-hydroxy-7-azabenzotriazole (0.059 g, 0.43 mmol), and 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (0.12 g, 0.43 mmol) were added to a solution of (Z)-4-(3-(3,5-dichlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C6) (0.20 g, 0.43 mmol) and (S)N-(1-aminoethyl)-3,3,3-trifluoropropanamide hydrochloride (C56) (0.099 g, 0.48 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with dichloromethane and washed sequentially with hydrochloric acid (2 N) and aqueous sodium bicarbonate. The organic layer was separated, washed with water, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography provided the title compound as a white solid (0.11 g, 40%).
(218) The following compounds were prepared in like manner to the procedure outlined in Example 14:
4-((Z)-3-(3,5-Dichlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (F12)
(219) ##STR00086##
(220) Isolated as a yellow gum (0.190 g, 61%).
4-((Z)-3-(3,4-Dichlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F13)
(221) ##STR00087##
(222) Isolated as a yellow gum (0.170 g, 59%).
4-((Z)-3-(3,4-Dichlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (F14)
(223) ##STR00088##
(224) Isolated as a yellow gum (0.140 g, 48%).
4-((Z)-3-(4-Bromo-3,5-dichlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (F15)
(225) ##STR00089##
(226) Isolated as a yellow gum (0.115 g, 45%).
4-((Z)-3-(3,5-Dichloro-4-fluorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (F17)
(227) ##STR00090##
(228) Isolated as a yellow solid (0.125 g, 44%).
4-((Z)-3-(3,5-Dichloro-4-vinylphenyl)-1,4,4,4-tetrafluorobut-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F18)
(229) ##STR00091##
(230) Isolated as an off-white solid (0.130 g, 49%).
4-((Z)-3-(3,5-Dichloro-4-vinylphenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (F19)
(231) ##STR00092##
(232) Isolated as an off-white solid (0.073 g, 27%).
4-((Z)-3-(3,5-Dibromophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F22)
(233) ##STR00093##
(234) Isolated as a pale yellow solid (0.156 g, 61%).
4-((Z)-3-(3,5-Dibromophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (F23)
(235) ##STR00094##
(236) Isolated as a yellow solid (0.155 g, 56%).
4-((Z)-3-(4-Chloro-3,5-dimethylphenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F24)
(237) ##STR00095##
(238) Isolated as an off-white solid (0.170 g, 55%).
4-((Z)-3-(4-Chloro-3,5-dimethylphenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (F25)
(239) ##STR00096##
(240) Isolated as a yellow gum (0.170 g, 50%).
4-((Z)-3-(3,5-Dibromo-4-chlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F26)
(241) ##STR00097##
(242) Isolated as a brown solid (0.120 g, 31%).
4-((Z)-3-(3,5-Dibromo-4-chlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (F30)
(243) ##STR00098##
(244) Isolated as a brow gum (0.100 g, 27%).
4-((Z)-3-(4-Bromo-3,5-dichlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F31)
(245) ##STR00099##
(246) Isolated as a yellow gum (0.109 g, 51%).
4-((Z)-3-(3,4-Dibromophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F32)
(247) ##STR00100##
(248) Isolated as a yellow solid (0.155 g, 58%).
4-((Z)-3-(3-Bromo-5-chlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F36)
(249) ##STR00101##
(250) Isolated as a yellow solid (0.094 g, 42%).
4-((Z)-3-(3-Bromo-4-chlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F37)
(251) ##STR00102##
(252) Isolated as a yellow gum (0.105 g, 49%).
Example 15
Preparation of 4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (F1)
(253) ##STR00103##
(254) To a 25 mL vial was added (Z)-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoyl chloride (C23) (0.073 g, 0.14 mmol), (S)N-(1-aminoethyl)-4,4,4-trifluorobutanamide hydrochloride (C55) (0.063 g, 0.28 mmol), and 1,2-dichloroethane (0.71 mL). 4-Methylmorpholine (0.070 mL, 0.64 mmol) was added, and the reaction was allowed to stir for two hours at room temperature. Direct purification of the reaction mixture by flash column chromatography provided the title compound as a colorless oil (0.046 g, 47%).
(255) The following compounds were prepared in like manner to the procedure outlined in Example 15:
2-Methyl-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)benzamide (F2)
(256) ##STR00104##
(257) Isolated as an off-white gum (0.026 g, 25%).
2-Bromo-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)benzamide (F3)
(258) ##STR00105##
(259) Isolated as an off-white gum (0.050 g, 37%).
2-Bromo-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F4)
(260) ##STR00106##
(261) Isolated as a yellow gum (0.047 g, 35%).
4-((Z)-1,4,4,4-Tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F5)
(262) ##STR00107##
(263) Isolated as an off-white solid (0.061 g, 58%).
2-Methyl-4-((Z)-1,4,4-trifluoro-3-(3,4,5-trichlorophenyl)pent-1-en-1-yl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F6)
(264) ##STR00108##
(265) Isolated as an orange gum (0.028 g, 52%).
2-Chloro-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F7)
(266) ##STR00109##
(267) Isolated as a yellow gum (0.078 g, 51%).
4-((Z)-1,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)pent-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F8)
(268) ##STR00110##
(269) Isolated as a white gum (0.062 g, 63%).
2-Chloro-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)benzamide
(270) ##STR00111##
(271) Isolated as a white solid (0.056 g, 37%).
4-((Z)-1,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)pent-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (F10)
(272) ##STR00112##
(273) Isolated as a white foam (0.049 g, 61%).
4-((Z)-1,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)hex-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F20)
(274) ##STR00113##
(275) Isolated as a white foam (0.044 g, 56%).
4-((Z)-1,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)hex-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (F21)
(276) ##STR00114##
(277) Isolated as a white foam (0.051 g, 64%).
2-Methyl-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F33)
(278) ##STR00115##
(279) Isolated as a yellow gum (0.053 g, 36%).
4-((Z)-1,4,4,4-Tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (FC1)
(280) ##STR00116##
(281) Isolated as a white foam (0.030 g, 37%).
4-((Z)-1,4,4,4-Tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)benzamide (FC2)
(282) ##STR00117##
(283) Isolated as a white foam (0.035 g, 42%).
Example 16
Preparation of N((R)-1-(cyclopropanecarboxamido)ethyl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (F27)
(284) ##STR00118##
(285) To a 5 mL vial were added cyclopropanecarboxylic acid (0.0337 g, 0.392 mmol) and 1,2-dichloroethane (1.3 mL). Oxalyl dichloride (0.0350 mL, 0.409 mmol) and N,N-dimethylformamide (0.986 mg, 0.0130 mmol) were added, and the reaction was stirred at room temperature for 3 hours. N((R)-1-aminoethyl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide hydrochloride (C59) (0.150 g, 0.261 mmol) and 4-methylmorpholine (0.0890 mL, 0.809 mmol) were added, and the reaction was capped, vortexed, and left to stir. Direct purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent followed by purification by reverse phase high pressure liquid chromatography provided the title compound as a colorless glass (0.088 g, 50%).
Example 17
Preparation of N((R)-1-propionamidoethyl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (F34)
(286) ##STR00119##
(287) To a 5 mL vial were added N((R)-1-aminoethyl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide hydrochloride (C59) (0.125 g, 0.218 mmol) and 1,2-dichloroethane (1.3 mL). Propionyl chloride (0.0302 mL, 0.327 mmol) and 4-methylmorpholine (0.0718 mL, 0.653 mmol) were added and the reaction was capped, vortexed, and left to stir. Direct purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a white wax (0.038 g, 27%).
(288) The following compounds were prepared in like manner to the procedure outlined in Example 17:
4-((Z)-1,4,4,4-Tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)propyl)benzamide (F35)
(289) ##STR00120##
(290) Isolated as a white solid (0.045 g, 12%).
Example 18
Preparation of 4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N((S)-1-(2,2,2-trifluoroethylsulfonamido)ethyl)-2-(trifluoromethyl)benzamide (F28)
(291) ##STR00121##
(292) To a 25 mL vial were added N((R)-1-aminoethyl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide hydrochloride (C59) (0.150 g, 0.261 mmol), 2,2,2-trifluoroethanesulfonyl chloride (0.0572 g, 0.314 mmol), and dioxane (3 mL). 4-Methylmorpholine (0.0720 mL, 0.653 mmol) was added, and the reaction was vertexed several times over a five minute period. A magnetic stir bar was introduced into the vial, and the reaction was left to stir for 48 hours. Direct purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent followed by purification by reverse phase high pressure liquid chromatography provided the title compound as a colorless glass (0.0280 g, 15%).
Example 19
Preparation of N((S)-1-(3-cyclopropylureido)ethyl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (F29)
(293) ##STR00122##
(294) N((R)-1-Aminoethyl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide hydrochloride (C59) (0.100 g, 0.174 mmol), isocyanatocyclopropane (0.200 g, 2.41 mmol), 2,6-dimethylpyridine (0.0500 mL, 0.429 mmol), and pyridine (0.400 mL) were capped in a 2 mL vial and heated at 80 C. for 6 minutes in a Biotage Initiator microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. Direct purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent followed by purification by reverse phase high pressure liquid chromatography provided the title compound as a colorless glass (0.040 g, 35%).
Example 20
Preparation of (S)N-(1-aminoethyl)-4,4,4-trifluorobutanamide hydrochloride (C55)
(295) ##STR00123##
(296) (S)N-(1-Amino-1-oxopropan-2-yl)-4,4,4-trifluorobutanamide (C57) (3.00 g, 14.1 mmol) was dissolved in a mixture of water and acetonitrile (1:1, 42 mL). [Bis(trifluoroacetoxy)iodo]benzene (6.08 g, 14.1 mmol) was added, and the reaction mixture was stirred in a flask wrapped in aluminum foil overnight. The reaction mixture was poured into hydrochloric acid (1 N, 35 mL) and diethyl ether (35 mL). The organic layer was separated, and the aqueous layer was azeotroped with isopropanol (2125 mL). Purification by reverse phase flash column chromatography using 0-100% acetonitrile/water as eluent provided the title compound as a white solid (1.50 g, 48%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.11 (d, J=7.4 Hz, 1H), 8.36 (s, 3H), 4.94 (p, J=6.6 Hz, 1H), 2.66-2.32 (m, 4H), 1.40 (d, J=6.5 Hz, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) 65.19; ESIMS m/z 185 ([M+H].sup.+).
(297) The following compounds were prepared in like manner to the procedure outlined in Example 20:
(S)N-(1-Aminoethyl)-3,3,3-trifluoropropanamide hydrochloride (C56)
(298) ##STR00124##
(299) Isolated as a white solid (0.300 g, 29%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.40 (dd, J=12.1, 6.8 Hz, 1H), 8.38 (s, 3H), 4.97 (p, J=6.6 Hz, 1H), 3.52-3.39 (m, 2H), 1.41 (d, J=6.4 Hz, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) 61.32; ESIMS m/z 171 ([M+H].sup.+).
Example 21
Preparation of (S)N-(1-amino-1-oxopropan-2-yl)-4,4,4-trifluorobutanamide (C57)
(300) ##STR00125##
(301) L-Alaninamide.2H.sub.2O (17.7 g, 97.0 mmol) was dissolved in dioxane (162 mL) to which 4,4,4-trifluorobutanoyl chloride (2.86 mL, 24.2 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and the solids were dissolved in water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered, and concentrated to provide the desired compound as a white solid (3.00 g, 58%): .sup.1H NMR (400 MHz, CDCl.sub.3) 8.15 (d, J=7.6 Hz, 1H), 7.32 (s, 1H), 6.97 (s, 1H), 4.20 (p, J=7.2 Hz, 1H), 2.53-2.37 (m, 7H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) 65.18; ESIMS m/z 213 ([M+H].sup.+).
(302) The following compounds were prepared in like manner to the procedure outlined in Example 21:
(S)N-(1-Amino-1-oxopropan-2-yl)-3,3,3-trifluoropropanamide (C58)
(303) ##STR00126##
(304) Isolated as a white solid (0.9 g, 60%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.38 (d, J=7.6 Hz, 1H), 7.43 (s, 1H), 7.04 (s, 1H), 4.25 (p, J=7.2 Hz, 1H), 3.32 (q, J=11.4 Hz, 2H), 1.20 (d, J=7.0 Hz, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) 61.44; IR (thin film) 3396, 3304, 3206, 2979, 1711, 1670, 1645, 1622, 1546 cm.sup.1.
Example 22
Preparation of N((R)-1-aminoethyl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide hydrochloride (C59)
(305) ##STR00127##
(306) To a 25 mL vial were added N((R)-1-amino-1-oxopropan-2-yl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (C62) (1.13 g, 2.00 mmol), acetonitrile (6.7 mL), water (3.3 mL), and bis(trifluoroacetoxy)iodobenzene (0.687 g, 1.60 mmol) and the reaction mixture was stirred protected from light for 80 minutes. Hydrochloric acid (concentrated, 1 mL) was added, and the reaction was concentrated under a stream of nitrogen gas. Purification by reverse phase chromatography using 10-100% acetonitrile/water as eluent provided the title compound as a pale yellow amorphous solid (0.478 g, 42%): mixture of diastereomers .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.61 (d, J=7.4 Hz, 1H), 8.56 (s, 3H), 8.18 (d, J=1.7 Hz, 1H), 8.13 (dd, J=8.0, 1.6 Hz, 1H), 8.06 (s, 2H), 7.75 (d, J=8.1 Hz, 1H), 6.84 (dd, J=35.7, 10.1 Hz, 1H), 5.27 (p, J=9.4 Hz, 1H), 5.15 (t, J=7.5 Hz, 1H), 1.47 (d, J=6.4 Hz, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) 57.88, 57.88, 68.57, 68.58, 113.68, 113.71; ESIMS m/z 535 ([MH].sup.).
(307) The following compounds were prepared in like manner to the procedure outlined in Example 22:
N((R)-1-Aminopropyl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide hydrochloride (C60)
(308) ##STR00128##
(309) Isolated as a pale yellow solid (0.210 g, 24%): mixture of diastereomers .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.65-9.44 (m, 1H), 8.44 (s, 3H), 8.25-8.18 (m, 1H), 8.19-8.11 (m, 1H), 8.07 (s, 2H), 7.70 (d, J=8.1 Hz, 1H), 6.85 (dd, J=35.7, 10.1 Hz, 1H), 5.28 (p, J=9.4 Hz, 1H), 5.01 (dq, J=9.0, 5.2 Hz, 1H), 1.97-1.68 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) 57.95, 68.59, 113.64, 113.67; ESIMS m/z 551 ([MH].sup.).
Example 23
Preparation of N((R)-1-amino-1-oxobutan-2-yl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (C61)
(310) ##STR00129##
(311) To a 25 mL vial were added (Z)-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C2) (1.0 g, 2.0 mmol), oxalyl chloride (0.26 g, 2.0 mmol), and dichloromethane (13 mL). To this solution was added N,N-dimethylformamide (0.015 mL) and the reaction was stirred while gas evolved. After 2 hours, (R)-ethyl glycinal sodium chloride (0.32 g, 2.0 mmol; Prepared by the addition of sodium hydroxide (1 equivalent) to (R)-ethylglycinamide hydrochloride and concentrated.) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with hydrochloric acid (0.2 M, 3200 mL). The organic solution was dried over magnesium sulfate, filtered, and concentrated to provide the title compound as an orange foam (0.82 g, 60%): .sup.1H NMR (500 MHz, CDCl.sub.3) 7.82 (d, J=1.8 Hz, 1H), 7.76-7.67 (m, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.44 (s, 2H), 7.13-7.03 (m, 1H), 6.84 (s, 1H), 6.06 (s, 1H), 5.83 (dd, J=32.6, 9.6 Hz, 1H), 4.72 (dt, J=7.8, 6.6 Hz, 1H), 4.60 (p, J=8.9 Hz, 1H), 1.93 (ddd, J=13.8, 7.6, 6.2 Hz, 1H), 1.77 (dp, J=14.4, 7.3 Hz, 1H), 0.98 (t, J=7.4 Hz, 3H); .sup.19F NMR (471 MHz, CDCl.sub.3) 59.29, 69.36 (t, J=7.3 Hz), 112.12 (dd, J=32.7, 8.2 Hz); ESIMS m/z 579 ([MH].sup.).
(312) The following compounds were prepared in like manner to the procedure outlined in Example 23:
N((R)-1-Amino-1-oxopropan-2-yl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (C62)
(313) ##STR00130##
(314) Isolated as an orange foam (1.13 g, 89%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.86-7.82 (m, 1H), 7.74 (dd, J=8.1, 1.7 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.44 (s, 2H), 6.94 (dd, J=7.5, 2.9 Hz, 1H), 6.64 (s, 1H), 5.91-5.74 (m, 2H), 4.79 (p, J=7.1 Hz, 1H), 4.61 (p, J=8.9 Hz, 1H), 1.50 (d, J=7.0 Hz, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) 59.18, 69.34 (m), 112.05; ESIMS m/z 565 ([MH].sup.).
(315) The following molecules in Table 0.1 may be prepared according to the procedures disclosed: P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P20, P21, P22, P23, P24, P25, P26, P27, P28, P29, P30, and P31.
(316) TABLE-US-00002 TABLE 1 Structure and Preparation Method for Prophetic Molecules No. Structure P1
(317) The following compounds were prepared in like manner to the procedure outlined in Example 1:
(Z)-4-(1,4,4,4-Tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-1-naphthoic acid (C63)
(318) ##STR00162##
(319) Isolated as a yellow solid (0.85 g, 5): .sup.1H NMR (300 MHz, CDCl.sub.3) 8.30 (d, J=7.5 Hz, 1H), 8.07-8.05 (m, 1H), 7.70-7.61 (m, 4H), 7.49 (s, 2H), 5.69 (dd, 1=9.9, 31.2 Hz, 1H), 4.75-4.69 (m, 1H); IR (thin film) 3445, 1684, 1260, 750 cm.sup.1; ESIMS m/z 475.23 ([M].sup.).
(Z)-4-(3-(3,4-Dichloro-5-methylphenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C64)
(320) ##STR00163##
(321) Isolated as a brown gum (1.7 g, 42%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) 13.80 (s, 1H), 8.14 (s, 1H), 8.09 (d, J=8.1 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.83 (s, 1H), 7.65 (s, 1H), 6.87 (dd, J=9.9, 36.0 Hz, 1H), 5.13-5.07 (m, 1H), 2.42 (s, 3H); IR (thin film) 3446, 2928, 1716 cm.sup.1; ESIMS m/z 473.10 ([MH].sup.).
(Z)-4-(3-(4-Bromo-3-chlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C65)
(322) ##STR00164##
(323) Isolated as a brown gum (2.5 g, 68%): .sup.1H NMR ((400 MHz, CDCl.sub.3) 8.02 (d, J=8.4 Hz, 1H), 7.94 (s, 1H), 7.83 (d, J=7.2 Hz, 1H), 7.66 (d, =8.4 Hz, 1H), 7.50 (s, 1H), 7.17 (dd, =8.4 Hz, 1H), 5.96 (dd, J=9.2, 32.0 Hz, 1H), 4.65-4.61 (m, 1H); IR (thin film) 3447, 2927, 1715, 750 cm.sup.1; ESIMS m/z 504.4 ([MH].sup.).
(324) The following compounds were prepared in like manner to the procedure outlined in Example 7:
(4-(1-Fluorovinyl)-1-naphthoic acid (C66)
(325) ##STR00165##
(326) Isolated as an off-white solid (0.70 g, 52%): mp 154-156 C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 13.40 (br s, 1H), 8.88-8.84 (m, 1H), 8.17-8.10 (m, 2H), 7.75-7.66 (m, 3H), 5.39 (dd, J=3.6, 17.2 Hz, 1H), 5.23 (dd, J=36.0, 50.4 Hz, 1H); ESIMS m/z 215.20 ([MH].sup.).
(327) The following compounds were prepared in like manner to the procedure outlined in Example 8:
1-Bromo-4-(1-bromo-2,2,2-trifluoroethyl)-2-chlorobenzene (C67)
(328) ##STR00166##
(329) Isolated as a colorless oil (TO g, 51%); .sup.1H NMR (400 MHz, CDCl.sub.3) 7.75-7.72 (m, 1H), 7.65-7.61 (m, 1H), 7.26-7.21 (m, 1H), 5.08-5.02 (m, 1H); ESIMS m/z 350.0 ([M].sup.+).
5-(1-Bromo-2,2,2-trifluoroethyl)-1,2-dichloro-3-methylbenzene (C70)
(330) ##STR00167##
(331) Isolated as a clear oil (6.7 g, 67%): .sup.1H NMR (300 MHz, CDCl.sub.3) 7.46 (s, 1H), 7.28 (s, 1H), 5.02 (q, J=7.2 Hz, 1H), 2.45 (s, 3H); IR (thin film) 1260, 1113, 750 cm.sup.1; EIMS m/z 322 ([M].sup.+).
(332) The following compound was prepared in like manner to the procedure outlined in Example 10:
1-(3,4-Dichloro-5-methylphenyl)-2,2,2-trifluoroethan-1-ol (C71)
(333) ##STR00168##
(334) Isolated as a pale yellow oil (4.6 g, 79%): .sup.1H NMR (300 MHz, CDCl.sub.3) 7.44 (s, 1H), 7.26 (s, 1H), 4.97 (q, J=6.6 Hz, 1H), 2.44 (s, 3H); IR (thin film) 3428, 1275, 1262, 750 cm.sup.1; EIMS m/z 258 ([M].sup.+).
(335) The following compounds were prepared in like manner to the procedure outlined in Example 11:
1-(4-Bromo-3-chlorophenyl)-2,2,2-trifluoroethan-1-ol (C68)
(336) ##STR00169##
(337) Isolated as a brown gum (12 g, 77%): .sup.1H NMR (400 MHz, CDCl.sub.3) 7.65-7.60 (m, 1H), 7.59 (s, 1H), 7.23-7.19 (m, 1H), 5.09-5.01 (m, 1H), 2.86 (br s, 1H); ESIMS m/z 289.90 ([M].sup.+).
(338) The following compounds were prepared in like manner to the procedure outlined in Example 14:
4-((Z)-1,4,4,4-Tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)-1-naphthamide (PF1)
(339) ##STR00170##
(340) Isolated as a yellow solid (0.128 g, 64%).
4-((Z)-3-(4-Chloro-3-fluorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (PF2)
(341) ##STR00171##
(342) Isolated as a yellow solid (0.120 g, 50%).
4-((Z)-3-(3-Chloro-4-fluorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (PF3)
(343) ##STR00172##
(344) Isolated as a yellow gum (0.090 g, 36%).
4-((Z)-3-(3,4-Dichloro-5-methylphenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (PF4)
(345) ##STR00173##
(346) Isolated as a brown gum (0.180 g, 66%).
4-((Z)-3-(4-Bromo-3-chlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (PF8)
(347) ##STR00174##
(348) Isolated as an off-white solid (0.050 g, 21%).
4-((Z)-3-(3-Bromo-4-chlorophenyl)-1,4,4,4-tetrafluorobut-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (PF13)
(349) ##STR00175##
(350) Isolated as a yellow gum (0.090 g, 32%).
(351) The following compounds were prepared in like manner to the procedure outlined in Example 16:
4-((Z)-3-(3,4-Dichlorophenyl)-1,4,4-trifluoropent-1-en-1-yl)-2-(trifluoromethyl)-N((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (F39)
(352) ##STR00176##
(353) Isolated as a white foam (0.099 g, 83%).
4-((Z)-3-(3,4-Dichlorophenyl)-1,4,4-trifluoropent-1-en-1-yl)-N((R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (F40)
(354) ##STR00177##
(355) Isolated as a white foam (0.077 g, 62.8%).
N((R)-1-(3-Cyanopropanamido)ethyl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide(F41)
(356) ##STR00178##
(357) Isolated as a colorless glass (0.049 g, 29%).
N((S)-1-(1-Cyanocyclopropane-1-carboxamido)ethyl)-4-((Z)-1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (PF31)
(358) ##STR00179##
(359) Isolated as a colorless foam (0.15 g, 82%).
Example 24
Preparation of 4-vinyl-1-naphthoic acid (C69)
(360) ##STR00180##
(361) To a stirred solution of 4-bromo-1-naphthoic acid (2.50 g, 9.98 mmol) in dimethyl sulfoxide (32.3 mL) was added potassium vinyltrifluoroborate (1.33 g, 9.96 mmol), potassium carbonate (3.85 g, 27.9 mmol) and [1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.364 g, 0.498 mmol). The reaction mixture was heated in an 80 C. bath for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with 1 N aqueous hydrochloric acid solution (150 mL) and water (150 mL). The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO.sub.2, eluting with 0-100% ethyl acetate in hexanes) to afford the title compound as a bright yellow solid (1.36 g, 62%): mp 147-155 C.; .sup.1H NMR (300 MHz, acetone-d.sub.6) 11.42 (s, 1H), 9.16-9.03 (m, 1H), 8.31-8.25 (m, 2H), 7.77 (dd, J=7.7, 0.7 Hz, 1H), 7.70-7.57 (m, 3H), 5.95 (dd, J=17.2, 1.5 Hz, 1H), 5.62 (dd, J=11.1, 1.5 Hz, 1H); ESIMS m/z 197.1 ([MH].sup.).
Example 25
Preparation of 1-(3,4-dichloro-5-methylphenyl)-2,2,2-trifluoroethan-1-one (C72)
(362) ##STR00181##
(363) To 5-bromo-1,2-dichloro-3-methylbenzene (6.9 g, 29 mmol) in tetrahydrofuran (65 mL) cooled in an ice bath under nitrogen was added isopropylmagnesium chloride lithium chloride complex in tetrahydrofuran (26.8 mL, 34.8 mmol). After 1 hour methyl 2,2,2-trifluoroacetate (3.79 mL, 37.7 mmol) was added. After 30 minutes, the ice bath was removed, and the solution was stirred for 1 hour. The reaction mixture was quenched with aqueous hydrochloric acid (2 N). The mixture was concentrated and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (SiO.sub.2, petroleum ether) provided the title compound as a white solid (5.9 g, 80%); .sup.1H NMR (400 MHz, CDCl.sub.3) 8.00 (s, 1H), 7.83 (s, 1H), 2.51 (s, 3H); EIMS m/z 256 ([M].sup.+).
(364) Biological Assays
(365) The following bioassays against Beet Armyworm (Spodoptera exigua), Cabbage Looper (Trichoplusia ni), Corn Earworm (Helicoverpa zea), Green Peach Aphid (Myzus persicae), and Yellow Fever Mosquito (Aedes aegypti), are included herein due to the damage they inflict. Furthermore, the Beet Armyworm, Corn Earworm, and Cabbage Looper are three good indicator species for a broad range of chewing pests. Additionally, the Green Peach Aphid is a good indicator species for a broad range of sap-feeding pests. The results with these four indicator species along with the Yellow Fever Mosquito show the broad usefulness of the molecules of Formula One in controlling pests in Phyla Arthropoda, Mollusca, and Nematoda (For further information see Methods for the Design and Optimization of New Active Ingredients, Modern Methods in Crop Protection Research, Edited by Jeschke, P., Kramer, W., Schirmer, U., and Matthias W., p. 1-20, 2012).
Example A
Bioassays on Beet Armyworm (Spodoptera exigua, LAPHEG) (BAW), Corn Earworm (Helicoverpa zea, HELIZE) (CEW), and Cabbage Looper (Trichoplusia ni, TRIPNI) (CL)
(366) Beet army worm is a serious pest of economic concern for alfalfa, asparagus, beets, citrus, corn, cotton, onions, peas, peppers, potatoes, soybeans, sugar beets, sunflowers, tobacco, tomatoes, among other crops. It is native to Southeast Asia but is now found in Africa, Australia, Japan, North America, and Southern Europe. The larvae may feed in large swarms causing devastating crop losses. It is known to be resistant to several pesticides.
(367) Cabbage Looper is a serious pest found throughout the world. It attacks alfalfa, beans, beets, broccoli, Brussel sprouts, cabbage, cantaloupe, cauliflower, celery, collards, cotton, cucumbers, eggplant, kale, lettuce, melons, mustard, parsley, peas, peppers, potatoes, soybeans, spinach, squash, tomatoes, turnips, and watermelons, among other crops. This species is very destructive to plants due to its voracious appetite. The larvae consume three times their weight in food daily. The feeding sites are marked by large accumulations of sticky, wet, fecal material. It is known to be resistant to several pesticides.
(368) Corn earworm is considered by some to be the most costly crop pest in North America. It often attacks valuable crops, and the harvested portion of the crop. This pest damages alfalfa, artichoke, asparagus, cabbage, cantaloupe, collard, corn, cotton, cowpea, cucumber, eggplant, lettuce, lima bean, melon, okra, pea, pepper, potato, pumpkin, snap bean, soybean, spinach, squash, sugarcane, sweet potato, tomato, and watermelon, among other crops. Furthermore, this pest is also known to be resistant to certain insecticides.
(369) Consequently, because of the above factors control of these pests is important. Furthermore, molecules that control these pests (BAW, CEW, and CL), which are known as chewing pests, are useful in controlling other pests that chew on plants.
(370) Certain molecules disclosed in this document were tested against BAW, CEW, and CL using procedures described in the following examples. In the reporting of the results, the BAW, CEW, & CL Rating Table was used (See Table Section).
(371) Bioassays on BAW
(372) Bioassays on BAW were conducted using a 128-well diet tray assay. one to five second instar BAW larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 g/cm.sup.2 of the test molecule (dissolved in 50 L of 90:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover and held at 25 C., 14:10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells was then averaged. The results are indicated in the table entitled Table ABC: Biological Results (See Table Section).
(373) Bioassays on CL
(374) Bioassays on CL were conducted using a 128-well diet tray assay. one to five second instar CL larvae were placed in each well (3 mL) of the diet tray that had been previously filled with 1 mL of artificial diet to which 50 g/cm.sup.2 of the test molecule (dissolved in 50 L of 90:10 acetone-water mixture) had been applied (to each of eight wells) and then allowed to dry. Trays were covered with a clear self-adhesive cover and held at 25 C., 14:10 light-dark for five to seven days. Percent mortality was recorded for the larvae in each well; activity in the eight wells was then averaged. The results are indicated in the table entitled Table ABC: Biological Results (See Table Section).
Example B
Bioassays on Green Peach Aphid (Myzus persicae, MYZUPE) (GPA)
(375) GPA is the most significant aphid pest of peach trees, causing decreased growth, shriveling of the leaves, and the death of various tissues. It is also hazardous because it acts as a vector for the transport of plant viruses, such as potato virus Y and potato leafroll virus to members of the nightshade/potato family Solanaceae, and various mosaic viruses to many other food crops. GPA attacks such plants as broccoli, burdock, cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce, macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress, and zucchini, among other crops. GPA also attacks many ornamental crops such as carnation, chrysanthemum, flowering white cabbage, poinsettia, and roses. GPA has developed resistance to many pesticides. Consequently, because of the above factors control of this pest is important. Furthermore, molecules that control this pest (GPA), which is known as a sap-feeding pest, are useful in controlling other pests that feed on the sap from plants.
(376) Certain molecules disclosed in this document were tested against GPA using procedures described in the following example. In the reporting of the results, the GPA & YFM Rating Table was used (See Table Section).
(377) Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) true leaves, were used as test substrate. The seedlings were infested with 20-50 GPA (wingless adult and nymph stages) one day prior to chemical application. Four pots with individual seedlings were used for each treatment. Test molecules (2 mg) were dissolved in 2 mL of acetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm test molecule. The stock solutions were diluted 5 with 0.025% Tween 20 in water to obtain the solution at 200 ppm test molecule. A hand-held aspirator-type sprayer was used for spraying a solution to both sides of cabbage leaves until runoff. Reference plants (solvent check) were sprayed with the diluent only containing 20% by volume of acetone/methanol (1:1) solvent. Treated plants were held in a holding room for three days at approximately 25 C. and ambient relative humidity (RH) prior to grading. Evaluation was conducted by counting the number of live aphids per plant under a microscope. Percent Control was measured by using Abbott's correction formula (W. S. Abbott, A Method of Computing the Effectiveness of an Insecticide J. Econ. Entomol. 18 (1925), pp. 265-267) as follows.
Corrected % Control=100*(XY)/X where X=No. of live aphids on solvent check plants and Y=No. of live aphids on treated plants
(378) The results are indicated in the table entitled Table ABC: Biological Results (See Table Section).
Example C
Bioassays on Yellow Fever Mosquito (Aedes aegypti, AEDSAE) (YFM)
(379) YFM prefers to feed on humans during the daytime and is most frequently found in or near human habitations. YFM is a vector for transmitting several diseases. It is a mosquito that can spread the dengue fever and yellow fever viruses. Yellow fever is the second most dangerous mosquito-borne disease after malaria. Yellow fever is an acute viral hemorrhagic disease and up to 50% of severely affected persons without treatment will die from yellow fever. There are an estimated 200,000 cases of yellow fever, causing 30,000 deaths, worldwide each year. Dengue fever is a nasty, viral disease; it is sometimes called breakbone fever or break-heart fever because of the intense pain it can produce. Dengue fever kills about 20,000 people annually. Consequently, because of the above factors control of this pest is important. Furthermore, molecules that control this pest (YFM), which is known as a sucking pest, are useful in controlling other pests that cause human and animal suffering.
(380) Certain molecules disclosed in this document were tested against YFM using procedures described in the following paragraph. In the reporting of the results, the GPA & YFM Rating Table was used (See Table Section).
(381) Master plates containing 400 g of a molecule dissolved in 100 L of dimethyl sulfoxide (DMSO) (equivalent to a 4000 ppm solution) are used. A master plate of assembled molecules contains 15 L per well. To this plate, 135 L of a 90:10 water:acetone mixture is added to each well. A robot (Biomek NXP Laboratory Automation Workstation) is programmed to dispense 15 L aspirations from the master plate into an empty 96-well shallow plate (daughter plate). There are 6 reps (daughter plates) created per master. The created daughter plates are then immediately infested with YFM larvae.
(382) The day before plates are to be treated, mosquito eggs are placed in Millipore water containing liver powder to begin hatching (4 g. into 400 mL). After the daughter plates are created using the robot, they are infested with 220 L of the liver powder/larval mosquito mixture (about 1 day-old larvae). After plates are infested with mosquito larvae, a non-evaporative lid is used to cover the plate to reduce drying. Plates are held at room temperature for 3 days prior to grading. After 3 days, each well is observed and scored based on mortality. The results are indicated in the table entitled Table ABC: Biological Results (See Table Section).
(383) Agriculturally Acceptable Acid Addition Salts, Salt Derivatives, Solvates, Ester Derivatives, Polymorphs, Isotopes, and Radionuclides
(384) Molecules of Formula One may be formulated into agriculturally acceptable acid addition salts. By way of a non-limiting example, an amine function can form salts with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic, hydroxyl-methanesulfonic, and hydroxyethanesulfonic acids. Additionally, by way of a non-limiting example, an acid function can form salts including those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Examples of preferred cations include sodium, potassium, and magnesium.
(385) Molecules of Formula One may be formulated into salt derivatives. By way of a non-limiting example, a salt derivative may be prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt. A free base may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia, and sodium bicarbonate. As an example, in many cases, a pesticide, such as 2,4-D, is made more water-soluble by converting it to its dimethylamine salt.
(386) Molecules of Formula One may be formulated into stable complexes with a solvent, such that the complex remains intact after the non-complexed solvent is removed. These complexes are often referred to as solvates. However, it is particularly desirable to form stable hydrates with water as the solvent.
(387) Molecules of Formula One may be made into ester derivatives. These ester derivatives can then be applied in the same manner as the molecules disclosed in this document is applied.
(388) Molecules of Formula One may be made as various crystal polymorphs. Polymorphism is important in the development of agrochemicals since different crystal polymorphs or structures of the same molecule can have vastly different physical properties and biological performances.
(389) Molecules of Formula One may be made with different isotopes. Of particular importance are molecules having .sup.2H (also known as deuterium) or .sup.3H (also known as tritium) in place of 1H. Molecules of Formula One may be made with different radionuclides. Of particular importance are molecules having .sup.14C. Molecules of Formula One having deuterium, tritium, or .sup.14C may be used in biological studies allowing tracing in chemical and physiological processes and half-life studies, as well as, MoA studies.
(390) Stereoisomers
(391) Molecules of Formula One may exist as one or more stereoisomers. Thus, certain molecules may be produced as racemic mixtures. It will be appreciated by those skilled in the art that one stereoisomer may be more active than the other stereoisomers. Individual stereoisomers may be obtained by known selective synthetic procedures, by conventional synthetic procedures using resolved starting materials, or by conventional resolution procedures. Certain molecules disclosed in this document can exist as two or more isomers. The various isomers include geometric isomers, diastereomers, and enantiomers. Thus, the molecules disclosed in this document include geometric isomers, racemic mixtures, individual stereoisomers, and optically active mixtures. It will be appreciated by those skilled in the art that one isomer may be more active than the others. The structures disclosed in the present disclosure are drawn in only one geometric form for clarity, but are intended to represent all geometric forms of the molecule.
(392) Combinations
(393) In another embodiment of this invention, molecules of Formula One may be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more active ingredients.
(394) In another embodiment of this invention, molecules of Formula One may be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more active ingredients each having a MoA that is the same as, similar to, but more likelydifferent from, the MoA of the molecules of Formula One.
(395) In another embodiment, molecules of Formula One may be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more molecules having acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, and/or virucidal properties.
(396) In another embodiment, the molecules of Formula One may be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more molecules that are antifeedants, bird repellents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, plant activators, plant growth regulators, and/or synergists.
(397) In another embodiment, molecules of Formula One may also be used in combination (such as in a compositional mixture, or a simultaneous or sequential application) with one or more biopesticides.
(398) In another embodiment, in a pesticidal composition combinations of a molecule of Formula One and an active ingredient may be used in a wide variety of weight ratios. For example, in a two component mixture, the weight ratio of a molecule of Formula One to an active ingredient, may be from about 100:1 to about 1:100; in another example the weight ratio may be about 50:1 to about 1:50; in another example the weight ratio may be about 20:1 to about 1:20; in another example the weight ratio may be about 10:1 to about 1:10; in another example the weight ratio may be about 5:1 to 1:5; in another example the weight ratio may be about 3:1 to about 1:3; in another example the weight ratio may be about 2:1 to about 1:2; and in a final example the weight ratio may be about 1:1 (See Table B). However, in general, weight ratios less than about 10:1 to about 1:10 are preferred. It is also preferred sometimes to use a three or four component mixture comprising a molecule of Formula One and one or more active ingredients.
(399) TABLE-US-00003 TABLE B Weight Ratios Molecule of the Formula One:active ingredient 100:1 to 1:100 50:1 to 1:50 20:1 to 1:20 10:1 to 1:10 5:1 to 1:5 3:1 to 1:3 2:1 to 1:2 1:1
(400) Weight ratios of a molecule of Formula One to an active ingredient may also be depicted as X:Y; wherein X is the parts by weight of a molecule of Formula One and Y is the parts by weight of active ingredient. The numerical range of the parts by weight for X is 0<X100 and the parts by weight for Y is 0<Y100 and is shown graphically in TABLE C. By way of non-limiting example, the weight ratio of a molecule of Formula One to an active ingredient may be 20:1.
(401) TABLE-US-00004 TABLE C active 100 X, Y X, Y X, Y ingredient 50 X, Y X, Y X, Y X, Y X, Y (Y) 20 X, Y X, Y X, Y X, Y X, Y Parts by 15 X, Y X, Y X, Y X, Y X, Y weight 10 X, Y X, Y 5 X, Y X, Y X, Y X, Y 3 X, Y X, Y X, Y X, Y X, Y X, Y X, Y 2 X, Y X, Y X, Y X, Y X, Y 1 X, Y X, Y X, Y X, Y X, Y X, Y X, Y X, Y X, Y 1 2 3 5 10 15 20 50 100 molecule of Formula One (X) Parts by weight
(402) Ranges of weight ratios of a molecule of Formula One to an active ingredient may be depicted as X.sub.1:Y.sub.1 to X.sub.2:Y.sub.2, wherein X and Y are defined as above.
(403) In one embodiment, the range of weight ratios may be X.sub.1:Y.sub.1 to X.sub.2:Y.sub.2, wherein X.sub.1>Y.sub.1 and X.sub.2<Y.sub.2. By way of non-limiting example, the range of a weight ratio of a molecule of Formula One to an active ingredient may be between 3:1 and 1:3, inclusive of the endpoints.
(404) In another embodiment, the range of weight ratios may be X.sub.1:Y.sub.1 to X.sub.2:Y.sub.2, wherein X.sub.1>Y.sub.1 and X.sub.2>Y.sub.2. By way of non-limiting example, the range of weight ratio of a molecule of Formula One to an active ingredient may be between 15:1 and 3:1, inclusive of the endpoints.
(405) In another embodiment, the range of weight ratios may be X.sub.1:Y.sub.1 to X.sub.2: Y.sub.2, wherein X.sub.1<Y.sub.1 and X.sub.2<Y.sub.2. By way of non-limiting example, the range of weight ratios of a molecule of Formula One to an active ingredient may be between about 1:3 and about 1:20, inclusive of the endpoints.
(406) Formulations
(407) A pesticide is rarely suitable for application in its pure form. It is usually necessary to add other substances so that the pesticide may be used at the required concentration and in an appropriate form, permitting ease of application, handling, transportation, storage, and maximum pesticide activity. Thus, pesticides are formulated into, for example, baits, concentrated emulsions, dusts, emulsifiable concentrates, fumigants, gels, granules, microencapsulations, seed treatments, suspension concentrates, suspoemulsions, tablets, water soluble liquids, water dispersible granules or dry flowables, wettable powders, and ultra-low volume solutions.
(408) Pesticides are applied most often as aqueous suspensions or emulsions prepared from concentrated formulations of such pesticides. Such water-soluble, water-suspendable, or emulsifiable formulations are either solids, usually known as wettable powders, or water dispersible granules, or liquids usually known as emulsifiable concentrates, or aqueous suspensions. Wettable powders, which may be compacted to form water dispersible granules, comprise an intimate mixture of the pesticide, a carrier, and surfactants. The concentration of the pesticide is usually from about 10% to about 90% by weight. The carrier is usually selected from among the attapulgite clays, the montmorillonite clays, the diatomaceous earths, or the purified silicates. Effective surfactants, comprising from about 0.5% to about 10% of the wettable powder, are found among sulfonated lignins, condensed naphthalenesulfonates, naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, and non-ionic surfactants such as ethylene oxide adducts of alkyl phenols.
(409) Emulsifiable concentrates of pesticides comprise a convenient concentration of a pesticide, such as from about 50 to about 500 grams per liter of liquid dissolved in a carrier that is either a water miscible solvent or a mixture of water-immiscible organic solvent and emulsifiers. Useful organic solvents include aromatics, especially xylenes and petroleum fractions, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as the terpenic solvents including rosin derivatives, aliphatic ketones such as cyclohexanone, and complex alcohols such as 2-ethoxyethanol. Suitable emulsifiers for emulsifiable concentrates are selected from conventional anionic and non-ionic surfactants.
(410) Aqueous suspensions comprise suspensions of water-insoluble pesticides dispersed in an aqueous carrier at a concentration in the range from about 5% to about 50% by weight. Suspensions are prepared by finely grinding the pesticide and vigorously mixing it into a carrier comprised of water and surfactants. Ingredients, such as inorganic salts and synthetic or natural gums may also be added, to increase the density and viscosity of the aqueous carrier. It is often most effective to grind and mix the pesticide at the same time by preparing the aqueous mixture and homogenizing it in an implement such as a sand mill, ball mill, or piston-type homogenizer.
(411) Pesticides may also be applied as granular compositions that are particularly useful for applications to the soil. Granular compositions usually contain from about 0.5% to about 10% by weight of the pesticide, dispersed in a carrier that comprises clay or a similar substance. Such compositions are usually prepared by dissolving the pesticide in a suitable solvent and applying it to a granular carrier which has been pre-formed to the appropriate particle size, in the range of from about 0.5 to about 3 mm. Such compositions may also be formulated by making a dough or paste of the carrier and molecule and crushing and drying to obtain the desired granular particle size.
(412) Dusts containing a pesticide are prepared by intimately mixing the pesticide in powdered form with a suitable dusty agricultural carrier, such as kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1% to about 10% of the pesticide. Dusts may be applied as a seed dressing or as a foliage application with a dust blower machine.
(413) It is equally practical to apply a pesticide in the form of a solution in an appropriate organic solvent, usually petroleum oil, such as the spray oils, which are widely used in agricultural chemistry.
(414) Pesticides can also be applied in the form of an aerosol composition. In such compositions the pesticide is dissolved or dispersed in a carrier, which is a pressure-generating propellant mixture. The aerosol composition is packaged in a container from which the mixture is dispensed through an atomizing valve.
(415) Pesticide baits are formed when the pesticide is mixed with food or an attractant or both. When the pests eat the bait they also consume the pesticide. Baits may take the form of granules, gels, flowable powders, liquids, or solids. Baits may be used in pest harborages.
(416) Fumigants are pesticides that have a relatively high vapor pressure and hence can exist as a gas in sufficient concentrations to kill pests in soil or enclosed spaces. The toxicity of the fumigant is proportional to its concentration and the exposure time. They are characterized by a good capacity for diffusion and act by penetrating the pest's respiratory system or being absorbed through the pest's cuticle. Fumigants are applied to control stored product pests under gas proof sheets, in gas sealed rooms or buildings or in special chambers.
(417) Pesticides may be microencapsulated by suspending the pesticide particles or droplets in plastic polymers of various types. By altering the chemistry of the polymer or by changing factors in the processing, microcapsules may be formed of various sizes, solubility, wall thicknesses, and degrees of penetrability. These factors govern the speed with which the active ingredient within is released, which in turn, affects the residual performance, speed of action, and odor of the product.
(418) Oil solution concentrates are made by dissolving pesticide in a solvent that will hold the pesticide in solution. Oil solutions of a pesticide usually provide faster knockdown and kill of pests than other formulations due to the solvents themselves having pesticidal action and the dissolution of the waxy covering of the integument increasing the speed of uptake of the pesticide. Other advantages of oil solutions include better storage stability, better penetration of crevices, and better adhesion to greasy surfaces.
(419) Another embodiment is an oil-in-water emulsion, wherein the emulsion comprises oily globules which are each provided with a lamellar liquid crystal coating and are dispersed in an aqueous phase, wherein each oily globule comprises at least one molecule which is agriculturally active, and is individually coated with a monolamellar or oligolamellar layer comprising: (1) at least one non-ionic lipophilic surface-active agent, (2) at least one non-ionic hydrophilic surface-active agent and (3) at least one ionic surface-active agent, wherein the globules having a mean particle diameter of less than 800 nanometers.
(420) Other Formulation Components
(421) Generally, when the molecules disclosed in Formula One are used in a formulation, such formulation can also contain other components. These components include, but are not limited to, (this is a non-exhaustive and non-mutually exclusive list) wetters, spreaders, stickers, penetrants, buffers, sequestering agents, drift reduction agents, compatibility agents, anti-foam agents, cleaning agents, and emulsifiers. A few components are described forthwith.
(422) A wetting agent is a substance that when added to a liquid increases the spreading or penetration power of the liquid by reducing the interfacial tension between the liquid and the surface on which it is spreading. Wetting agents are used for two main functions in agrochemical formulations: during processing and manufacture to increase the rate of wetting of powders in water to make concentrates for soluble liquids or suspension concentrates; and during mixing of a product with water in a spray tank to reduce the wetting time of wettable powders and to improve the penetration of water into water-dispersible granules. Examples of wetting agents used in wettable powder, suspension concentrate, and water-dispersible granule formulations are: sodium lauryl sulfate; sodium dioctyl sulfosuccinate; alkyl phenol ethoxylates; and aliphatic alcohol ethoxylates.
(423) A dispersing agent is a substance which adsorbs onto the surface of particles and helps to preserve the state of dispersion of the particles and prevents them from reaggregating. Dispersing agents are added to agrochemical formulations to facilitate dispersion and suspension during manufacture, and to ensure the particles redisperse into water in a spray tank. They are widely used in wettable powders, suspension concentrates and water-dispersible granules. Surfactants that are used as dispersing agents have the ability to adsorb strongly onto a particle surface and provide a charged or steric barrier to reaggregation of particles. The most commonly used surfactants are anionic, non-ionic, or mixtures of the two types. For wettable powder formulations, the most common dispersing agents are sodium lignosulfonates. For suspension concentrates, very good adsorption and stabilization are obtained using polyelectrolytes, such as sodium naphthalene sulfonate formaldehyde condensates. Tristyrylphenol ethoxylate phosphate esters are also used. Non-ionics such as alkylarylethylene oxide condensates and EO-PO block copolymers are sometimes combined with anionics as dispersing agents for suspension concentrates. In recent years, new types of very high molecular weight polymeric surfactants have been developed as dispersing agents. These have very long hydrophobic backbones and a large number of ethylene oxide chains forming the teeth of a comb surfactant. These high molecular weight polymers can give very good long-term stability to suspension concentrates because the hydrophobic backbones have many anchoring points onto the particle surfaces. Examples of dispersing agents used in agrochemical formulations are: sodium lignosulfonates; sodium naphthalene sulfonate formaldehyde condensates; tristyrylphenol ethoxylate phosphate esters; aliphatic alcohol ethoxylates; alkyl ethoxylates; EO-PO block copolymers; and graft copolymers.
(424) An emulsifying agent is a substance which stabilizes a suspension of droplets of one liquid phase in another liquid phase. Without the emulsifying agent the two liquids would separate into two immiscible liquid phases. The most commonly used emulsifier blends contain alkylphenol or aliphatic alcohol with twelve or more ethylene oxide units and the oil-soluble calcium salt of dodecylbenzenesulfonic acid. A range of hydrophile-lipophile balance (HLB) values from 8 to 18 will normally provide good stable emulsions. Emulsion stability can sometimes be improved by the addition of a small amount of an EO-PO block copolymer surfactant.
(425) A solubilizing agent is a surfactant which will form micelles in water at concentrations above the critical micelle concentration. The micelles are then able to dissolve or solubilize water-insoluble materials inside the hydrophobic part of the micelle. The types of surfactants usually used for solubilization are non-ionics, sorbitan monooleates, sorbitan monooleate ethoxylates, and methyl oleate esters.
(426) Surfactants are sometimes used, either alone or with other additives such as mineral or vegetable oils as adjuvants to spray-tank mixes to improve the biological performance of the pesticide on the target. The types of surfactants used for bioenhancement depend generally on the nature and mode of action of the pesticide. However, they are often non-ionics such as: alkyl ethoxylates; linear aliphatic alcohol ethoxylates; aliphatic amine ethoxylates.
(427) A carrier or diluent in an agricultural formulation is a material added to the pesticide to give a product of the required strength. Carriers are usually materials with high absorptive capacities, while diluents are usually materials with low absorptive capacities. Carriers and diluents are used in the formulation of dusts, wettable powders, granules and water-dispersible granules.
(428) Organic solvents are used mainly in the formulation of emulsifiable concentrates, oil-in-water emulsions, suspoernulsions, and ultra-low volume formulations, and to a lesser extent, granular formulations. Sometimes mixtures of solvents are used. The first main groups of solvents are aliphatic paraffinic oils such as kerosene or refined paraffins. The second main group (and the most common) comprises the aromatic solvents such as xylene and higher molecular weight fractions of C9 and C10 aromatic solvents. Chlorinated hydrocarbons are useful as cosolvents to prevent crystallization of pesticides when the formulation is emulsified into water. Alcohols are sometimes used as cosolvents to increase solvent power. Other solvents may include vegetable oils, seed oils, and esters of vegetable and seed oils.
(429) Thickeners or gelling agents are used mainly in the formulation of suspension concentrates, emulsions and suspoemulsions to modify the rheology or flow properties of the liquid and to prevent separation and settling of the dispersed particles or droplets. Thickening, gelling, and anti-settling agents generally fall into two categories, namely water-insoluble particulates and water-soluble polymers. It is possible to produce suspension concentrate formulations using clays and silicas. Examples of these types of materials, include, but are not limited to, montmorillonite, bentonite, magnesium aluminum silicate, and attapulgite. Water-soluble polysaccharides have been used as thickening-gelling agents for many years. The types of polysaccharides most commonly used are natural extracts of seeds and seaweeds or are synthetic derivatives of cellulose. Examples of these types of materials include, but are not limited to, guar gum; locust bean gum; carrageenam; alginates; methyl cellulose; sodium carboxymethyl cellulose (SCMC); hydroxyethyl cellulose (HEC). Other types of anti-settling agents are based on modified starches, polyacrylates, polyvinyl alcohol and polyethylene oxide. Another good anti-settling agent is xanthan gum.
(430) Microorganisms can cause spoilage of formulated products. Therefore preservation agents are used to eliminate or reduce their effect. Examples of such agents include, but are not limited to: propionic acid and its sodium salt; sorbic acid and its sodium or potassium salts; benzoic acid and its sodium salt; p-hydroxybenzoic acid sodium salt; methyl p-hydroxybenzoate; and 1,2-benzisothiazolin-3-one (BIT).
(431) The presence of surfactants often causes water-based formulations to foam during mixing operations in production and in application through a spray tank. In order to reduce the tendency to foam, anti-foam agents are often added either during the production stage or before filling into bottles. Generally, there are two types of anti-foam agents, namely silicones and non-silicones. Silicones are usually aqueous emulsions of dimethyl polysiloxane, while the non-silicone anti-foam agents are water-insoluble oils, such as octanol and nonanol, or silica. In both cases, the function of the anti-foam agent is to displace the surfactant from the air-water interface.
(432) Green agents (e.g., adjuvants, surfactants, solvents) can reduce the overall environmental footprint of crop protection formulations. Green agents are biodegradable and generally derived from natural and/or sustainable sources, e.g. plant and animal sources. Specific examples are: vegetable oils, seed oils, and esters thereof, also alkoxylated alkyl polyglucosides.
(433) Applications
(434) Molecules of Formula One may be applied to any locus. Particular crop loci to apply such molecules include loci where alfalfa, almonds, apples, barley, beans, canola, corn, cotton, crucifers, lettuce, oats, oranges, pears, peppers, potatoes, rice, sorghum, soybeans, strawberries, sugarcane, sugar beets, sunflowers, tobacco, tomatoes, wheat, and other valuable crops are growing or the seeds thereof are going to be planted.
(435) Molecules of Formula One may also be applied where plants, such as crops, are growing and where there are low levels (even no actual presence) of pests that can commercially damage such plants. Applying such molecules in such locus is to benefit the plants being grown in such locus. Such benefits, may include, but are not limited to: helping the plant grow a better root system; helping the plant better withstand stressful growing conditions; improving the health of a plant; improving the yield of a plant (e.g. increased biomass and/or increased content of valuable ingredients); improving the vigor of a plant (e.g. improved plant growth and/or greener leaves); improving the quality of a plant (e.g. improved content or composition of certain ingredients); and improving the tolerance to abiotic and/or biotic stress of the plant.
(436) Molecules of Formula One may be applied with ammonium sulfate when growing various plants as this may provide additional benefits.
(437) Molecules of Formula One may be applied on, in, or around plants genetically modified to express specialized traits, such as Bacillus thuringiensis or other insecticidal toxins, or those expressing herbicide resistance, or those with stacked foreign genes expressing insecticidal toxins, herbicide resistance, nutrition-enhancement, or any other beneficial traits.
(438) Molecule of Formula One may be applied to the foliar and/or fruiting portions of plants to control pests. Such molecules will either come in direct contact with the pest, or the pest will consume such molecules when eating the plant or while extracting sap from the plant.
(439) Molecule of Formula One may also be applied to the soil, and when applied in this manner, root and stem feeding pests may be controlled. The roots may absorb such molecules thereby taking it up into the foliar portions of the plant to control above ground chewing and sap feeding pests.
(440) Systemic movement of pesticides in plants may be utilized to control pests on one portion of the plant by applying (for example by spraying a locus) a molecule of Formula One to a different portion of the plant. For example, control of foliar-feeding insects may be achieved by drip irrigation or furrow application, by treating the soil with for example pre- or post-planting soil drench, or by treating the seeds of a plant before planting.
(441) Molecules of Formula One may be used with baits. Generally, with baits, the baits are placed in the ground where, for example, termites can come into contact with, and/or be attracted to, the bait. Baits can also be applied to a surface of a building, (horizontal, vertical, or slant surface) where, for example, ants, termites, cockroaches, and flies, can come into contact with, and/or be attracted to, the bait.
(442) Molecules of Formula One may be encapsulated inside, or placed on the surface of a capsule. The size of the capsules can range from nanometer size (about 100-900 nanometers in diameter) to micrometer size (about 10-900 microns in diameter).
(443) Molecules of Formula One may be applied to eggs of pests. Because of the unique ability of the eggs of some pests to resist certain pesticides, repeated applications of such molecules may be desirable to control newly emerged larvae.
(444) Molecules of Formula One may be applied as seed treatments. Seed treatment may be applied to all types of seeds, including those from which plants genetically modified to express specialized traits will germinate. Representative examples include those expressing proteins toxic to invertebrate pests, such as Bacillus thuringiensis or other insecticidal toxins, those expressing herbicide resistance, such as Roundup Ready seed, or those with stacked foreign genes expressing insecticidal toxins, herbicide resistance, nutrition-enhancement, drought resistance, or any other beneficial traits. Furthermore, such seed treatments with molecules of Formula One may further enhance the ability of a plant to better withstand stressful growing conditions. This results in a healthier, more vigorous plant, which can lead to higher yields at harvest time. Generally, about 1 gram of such molecules to about 500 grams per 100,000 seeds is expected to provide good benefits, amounts from about 10 grams to about 100 grams per 100,000 seeds is expected to provide better benefits, and amounts from about 25 grams to about 75 grams per 100,000 seeds is expected to provide even better benefits.
(445) Molecules of Formula One may be applied with one or more active ingredients in a soil amendment.
(446) Molecules of Formula One may be used for controlling endoparasites and ectoparasites in the veterinary medicine sector or in the field of non-human-animal keeping. Such molecules may be applied by oral administration in the form of, for example, tablets, capsules, drinks, granules, by dermal application in the form of, for example, dipping, spraying, pouring on, spotting on, and dusting, and by parenteral administration in the form of, for example, an injection.
(447) Molecules of Formula One may also be employed advantageously in livestock keeping, for example, cattle, sheep, pigs, chickens, salmon and geese. They may also be employed advantageously in pets such as, horses, dogs, and cats. Particular pests to control would be fleas and ticks that are bothersome to such animals. Suitable formulations are administered orally to the animals with the drinking water or feed. The dosages and formulations that are suitable depend on the species.
(448) Molecules of Formula One may also be used for controlling parasitic worms, especially of the intestine, in the animals listed above.
(449) Molecules of Formula One may also be employed in therapeutic methods for human health care. Such methods include, but are limited to, oral administration in the form of, for example, tablets, capsules, drinks, granules, and by dermal application.
(450) Molecules of Formula One may also be applied to invasive pests. Pests around the world have been migrating to new environments (for such pest) and thereafter becoming a new invasive species in such new environment. Such molecules may also be used on such new invasive species to control them in such new environments.
(451) Consequently, in light of the above and the Tables in the Table Section, the following items are provided. 1. A molecule having the following formula
(452) ##STR00182##
wherein:
(453) (A) R.sup.1, R.sup.5, R.sup.6, R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are each independently selected from the group consisting of H, F, Cl, Br, I, CN, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)haloalkoxy
(454) preferably, R.sup.1, R.sup.5, R.sup.6, R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are H;
(455) (B) R.sup.2, R.sup.3, and R.sup.4 are each independently selected from the group consisting of H, F, Cl, Br, I, CN, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)haloalkoxy
(456) preferably, R.sup.2, R.sup.3, and R.sup.4 are H, F, Cl, Br, CH.sub.3, or CHCH.sub.2;
(457) (C) R.sup.7 is (C.sub.1-C.sub.6)haloalkyl
(458) preferably R.sup.7 is CF.sub.3, CF.sub.2CH.sub.3, or CF.sub.2CH.sub.2CH.sub.3;
(459) (D) R.sup.9 is selected from the group consisting of (F), H, F, Cl, Br, I, CN, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)haloalkoxy
(460) preferably R.sup.9 is H;
(461) (E) R.sup.10 is selected from the group consisting of (F), F, Cl, Br, I, CN, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, and (C.sub.1-C.sub.4)haloalkoxy
(462) preferably R.sup.10 is Cl, Br, I, CH.sub.3, or CF.sub.3;
(463) (F) R.sup.9 and R.sup.10 together can optionally form a 3- to 5-membered saturated or unsaturated, hydrocarbyl link,
(464) wherein said hydrocarbyl link may optionally be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, and CN;
(465) (G) L is (C.sub.1-C.sub.6)alkyl
(466) preferably L is CH(CH.sub.3) or CH(CH.sub.2CH.sub.3);
(467) (H) X is selected from the group consisting of C, S, and P(C.sub.1-C.sub.6)alkyl
(468) preferably X is C or S;
(469) (I) n is 1 or 2;
(470) (J) R.sup.15 is selected from the group consisting of (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, (C.sub.3-C.sub.4)cycloalkyl, (C.sub.1-C.sub.4)haloalkyl, (C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)haloalkoxy, phenyl, and NH(C.sub.3-C.sub.4)cycloalkyl,
(471) wherein each alkyl, alkenyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, and phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, CN, and OH
(472) preferably R.sup.15 is CH.sub.2CH.sub.3, cyclopropyl, CH.sub.2CF.sub.3, CH.sub.2CH.sub.2CF.sub.3, or NHcyclopropyl; and
(473) agriculturally acceptable acid addition salts, salt derivatives, solvates, ester derivatives, crystal polymorphs, isotopes, resolved stereoisomers, and tautomers, of the molecules of Formula One. 2. A molecule according to 1 wherein
(474) (A) R.sup.1, R.sup.5, R.sup.6, R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are H;
(475) (B) R.sup.2, R.sup.3, and R.sup.4 are each independently selected from the group consisting of H, F, Cl, Br, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl;
(476) (C) R.sup.7 is (C.sub.1-C.sub.6)haloalkyl;
(477) (D) R.sup.9 is H;
(478) (E) R.sup.19 is selected from the group consisting of Cl, Br, (C.sub.1-C.sub.4)alkyl, and (C.sub.1-C.sub.4)haloalkyl;
(479) (G) L is (C.sub.1-C.sub.6)alkyl;
(480) (H) X is C or S;
(481) (I) n is 1 or 2;
(482) (J) R.sup.15 is selected from the group consisting of (C.sub.1-C.sub.4)alkyl, (C.sub.3-C.sub.4)cycloalkyl, (C.sub.1-C.sub.4)haloalkyl, and NH(C.sub.3-C.sub.4)cycloalkyl,
(483) wherein each alkyl, alkenyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, and phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, CN, and OH. 3. A molecule according to 1 wherein said molecule is selected from one of the molecules in Table 2. 4. A molecule according to 1 wherein said molecule is selected from one of the molecules in Table 1. 5. A pesticidal composition comprising a molecule according to any one of 1, 2, 3, or 4, further comprising one or more active ingredients. 6. A pesticidal composition according to 5 wherein said active ingredient is from AIGA. 7. A pesticidal composition according to 5 wherein said active ingredient is selected from the group consisting of AI-1, 1,3-dichloropropene, chlorpyrifos, chlorpyrifos-methyl, hexaflumuron, methoxyfenozide, noviflumuron, spinetoram, spinosad, sulfoxaflor, and sulfuryl fluoride. 8. A pesticidal composition comprising a molecule according to any one of 1, 2, 3, or 4, further comprising a MoA Material. 9. A pesticidal composition according to 7 wherein said MoA Material is from MoAMGA. 10. A pesticidal composition according to any one of 5, 6, 7, 8, or 9, wherein the weight ratio of the molecule according to Formula One to said active ingredient is selected from Table B. 11. A process to control a pest said process comprising applying to a locus, a pesticidally effective amount of a molecule according to any one of the 1, 2, 3, or 4. 12. A process to control a pest said process comprising applying to a locus, a pesticidally effective amount of a pesticidal composition according to any one of the 5, 6, 7, 8, 9, or 10. 13. A molecule according to any one of 1, 2, 3, or 4, or a pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said molecule is in the form of agriculturally acceptable acid addition salt. 14. A molecule according to any one of 1, 2, 3, or 4, or a pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said molecule is in the form of a salt derivative. 15. A molecule according to any one of 1, 2, 3, or 4, or a pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said molecule is in the form of solvate. 16. A molecule according to any one of 1, 2, 3, or 4, or a pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said molecule is in the form of an ester derivative. 17. A molecule according to any one of 1, 2, 3, or 4, or a pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said molecule is in the form of a crystal polymorph. 18. A molecule according to any one of 1, 2, 3, or 4, or a pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said molecule has deuterium, tritium, and or .sup.14C. 19. A molecule according to any one of 1, 2, 3, or 4, or a pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said molecule is in the form of one or more stereoisomers. 20. A molecule according to any one of 1, 2, 3, or 4, or a pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said molecule is in the form of a resolved stereoisomer. 21. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said pesticidal composition further comprises another active ingredient. 22. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said pesticidal composition further comprises two more active ingredients. 23. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said active ingredient has a MOA different from the MoA of said molecule of Formula One. 24. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said pesticidal composition comprises an active ingredient having acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, and/or virucidal properties. 25. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said pesticidal composition comprises an active ingredient that is an antifeedant, bird repellent, chemosterilant, herbicide safener, insect attractant, insect repellent, mammal repellent, mating disrupter, plant activator, plant growth regulator, and/or synergist. 26. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said pesticidal composition comprises an active ingredient that is a biopesticide. 27. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said weight ratio of a molecule of Formula One to an active ingredient is 100:1 to 1:100. 28. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said weight ratio of a molecule of Formula One to an active ingredient is 50:1 to 1:50. 29. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said weight ratio of a molecule of Formula One to an active ingredient is 20:1 to 1:20. 30. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said weight ratio of a molecule of Formula One to an active ingredient is 10:1 to 1:10. 31. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said weight ratio of a molecule of Formula One to an active ingredient is 5:1 to 1:5. 32. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said weight ratio of a molecule of Formula One to an active ingredient is 3:1 to 1:3. 33. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said weight ratio of a molecule of Formula One to an active ingredient is 2:1 to 1:2. 34. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said weight ratio of a molecule of Formula One to an active ingredient is 1:1. 35. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said weight ratio of a molecule of Formula One to an active ingredient is depicted as X:Y; wherein X is the parts by weight of a molecule of Formula One and Y is the parts by weight of active ingredient; further wherein the numerical range of the parts by weight for X is 0<X100 and the parts by weight for Y is 0<Y100; and further wherein X and Y are selected from Table C. 36. A pesticidal composition according to 35 wherein a range of weight ratios of a molecule of Formula One to an active ingredient is depicted as X.sub.1: Y.sub.1 to X.sub.2: Y.sub.2; further wherein X.sub.1>Y.sub.1 and X.sub.2<Y.sub.2. 37. A pesticidal composition according to 35 wherein a range of weight ratios of a molecule of Formula One to an active ingredient is depicted as X.sub.1: Y.sub.1 to X.sub.2: Y.sub.2; further wherein X.sub.1>Y.sub.1 and X.sub.2>Y.sub.2. 38. A pesticidal composition according to 35 wherein a range of weight ratios of a molecule of Formula One to an active ingredient is depicted as X.sub.1:Y.sub.1 to X.sub.2:Y.sub.2; further wherein X.sub.1<Y.sub.1 and X.sub.2<Y.sub.2. 39. A pesticidal composition according to 35 wherein said composition is is synergistic. 40. A process according to 12 wherein said pest is from Phylum Arthropoda. 41. A process according to 12 wherein said pest is from Phylum Mollusca. 42. A process according to 12 wherein said pest is from Phylum Nematoda. 43. A process according to 12 wherein said pests are are ants, aphids, beetles, bristletails, cockroaches, crickets, earwigs, fleas, flies, grasshoppers, leafhoppers, lice (including sea lice), locusts, mites, moths, nematodes, scales, symphylans, termites, thrips, ticks, wasps, and/or whiteflies. 44. A process according to 12 wherein said locus is where alfalfa, almonds, apples, barley, beans, canola, corn, cotton, crucifers, lettuce, oats, oranges, pears, peppers, potatoes, rice, sorghum, soybeans, strawberries, sugarcane, sugar beets, sunflowers, tobacco, tomatoes, wheat, and other valuable crops are growing or the seeds thereof are planted. 45. A pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, wherein said pesticidal composition further comprises ammonium sulfate. 46. A process according to 12 wherein said locus is where plants genetically modified to express specialized traits are planted. 47. A process according to 12 wherein said applying is done to the foliar and/or fruiting portions of plants. 48. A process according to 12 wherein said applying is done to the soil. 49. A process according to 12 wherein said applying is done by drip irrigation, furrow application, or pre- or post-planting soil drench. 50. A process according to 12 wherein said applying is done to the foliar and/or fruiting portions of plants, or by treating the seeds of a plant before planting. 51. A pesticidal composition comprising a molecule according to any one of 1, 2, 3, or 4, and a seed. 52. A process comprising applying a molecule according to any one of 1, 2, 3, or 4, or a pesticidal composition according to any of 5, 6, 7, 8, 9, or 10, to a seed. 53. A process comprising applying a molecule according to 1, 2, 3, or 4, to a locus that includes a non-human animal to control endoparasites and/or ectoparasites. 54. A process to produce a pesticidal composition, said process comprising mixing a molecule according to any one of claim 1, 2, 3, or 4, with one or more active ingredients.
(484) The headings in this document are for convenience only and must not be used to interpret any portion hereof.
(485) Table Section
(486) TABLE-US-00005 TABLE 2 Structure and Preparation Method for F Series Molecules No. Structure Prep.* F1
(487) TABLE-US-00006 TABLE 3 Structure and Preparation Method for C Series Molecules No Structure Prep.* C1
(488) TABLE-US-00007 TABLE 4 Analytical Data for Molecules in Table 2 Mp .sup.13C NMR; No. ( C.) Mass (m/z) .sup.1H NMR .sup.19F NMR; IR F1 663 .sup.1H NMR (400 MHz, .sup.19F NMR (376 ([M + H].sup.+) CDCl.sub.3) 7.81 (d, MHz, CDCl.sub.3) J = 1.6 Hz, 1H), 59.30, 66.87, 7.71 (dd, J = 8.1, 69.36 (d, J = 2.2 1.7 Hz, 1H), 7.49 Hz), 112.02 (t, (d, J = 8.1 Hz, J = 14.4 Hz) 1H), 7.43 (s, 2H), 7.29 (s, 1H), 7.17 (d, J = 7.6 Hz, 1H), 5.81 (dd, J = 32.6, 9.6 Hz, 1H), 5.47 (q, J = 7.2 Hz, 1H), 4.60 (p, J = 8.8 Hz, 1H), 2.46-2.27 (m, 4H), 1.65 (d, J = 6.8 Hz, 3H) F2 609 .sup.1H NMR (400 MHz, .sup.19F NMR (376 ([M + H].sup.+) CDCl.sub.3) 7.42 (s, MHz, CDCl.sub.3) 2H), 7.34 (s, 1H), 66.80, 69.48, 7.30 (d, J = 2.6 111.78 Hz, 2H), 7.28 (s, 1H), 5.69 (dd, J = 32.9, 9.6 Hz, 1H), 5.58 (p, J = 7.1 Hz, 1H), 4.57 (p, J = 8.9 Hz, 1H), 2.45-2.29 (m, 7H), 1.61 (d, J = 6.7 Hz, 3H) F3 671 .sup.1H NMR (400 MHz, .sup.19F NMR (376 ([M H].sup.) CDCl.sub.3) 7.70 (d, MHz, CDCl.sub.3) J = 7.9 Hz, 1H), 66.81, 67.67- 7.64 (d, J = 1.6 72.15 (m), Hz, 1H), 7.52- 112.14 7.44 (m, 1H), 7.41 (d, J = 3.1 Hz, 3H), 7.36 (d, J = 8.1 Hz, 1H), 5.84-5.56 (m, 2H), 4.56 (p, J = 8.9 Hz, 1H), 2.51- 2.15 (m, 4H), 1.63-1.53 (m, 3H) F4 657 .sup.1H NMR (400 MHz, .sup.19F NMR (376 ([M H].sup.) CDCl.sub.3) 8.25 (d, MHz, CDCl.sub.3) J = 8.5 Hz, 1H), 62.97, 68.04- 8.22-8.07 (m, 70.81 (m), 1H), 7.41 (d, J = 112.29 2.0 Hz, 2H), 7.25 (d, J = 9.5 Hz, 1H), 7.16 (dd, J = 7.8, 1.5 Hz, 1H), 5.93 (q, J = 7.9 Hz, 1H), 5.67 (ddd, J = 32.7, 9.6, 4.8 Hz, 1H), 4.52 (p, J = 8.9 Hz, 1H), 3.25- 2.86 (m, 2H), 1.52 (d, J = 6.6 Hz, 3H) F5 649 .sup.1H NMR (400 MHz, .sup.19F NMR (376 ([M + H].sup.+) CDCl.sub.3) 8.44 (s, MHz, CDCl.sub.3) 1H), 8.29 (s, 1H), 59.85, 63.33 (d, 7.50 (dd, J = 3.8, J = 2.4 Hz), 1.7 Hz, 1H), 7.47- 69.48, 110.42- 7.33 (m, 3H), 114.23 (m) 7.17 (d, J = 7.9 Hz, 1H), 5.95 (d, J = 7.9 Hz, 1H), 5.71 (ddd, J = 32.6, 9.6, 5.6 Hz, 1H), 4.54 (p, J = 8.9 Hz, 1H), 3.04 (dd, J = 15.4, 10.1 Hz, 1H), 2.90 (t, J = 12.4 Hz, 1H), 1.41 (d, J = 6.5 Hz, 3H) F6 591 .sup.1H NMR (400 MHz, .sup.19F NMR (376 ([M + H].sup.+) CDCl.sub.3) 8.06 (d, MHz, CDCl.sub.3) - J = 7.3 Hz, 1H), 63.07, 94.11- 7.90 (s, 1H), 7.42 96.32 (m), (d, J = 1.3 Hz, 114.28 2H), 7.18 (s, 1H), 7.16-7.07 (m, 2H), 5.88-5.63 (m, 2H), 4.25 (td, J = 14.2, 9.7 Hz, 1H), 3.18-3.02 (m, 1H), 2.93 (m, 1H), 2.12 (s, 3H), 1.64 (t, J = 18.4 Hz, 3H), 1.51 (d, J = 6.6 Hz, 3H) F7 615 .sup.1H NMR (400 MHz, .sup.19F NMR (376 ([M + H].sup.+) CDCl.sub.3) 8.41 (d, MHz, CDCl.sub.3) J = 8.6 Hz, 1H), 63.05, 69.49, 8.27 (d, J = 8.2 112.31 Hz, 1H), 7.40 (d, J = 1.7 Hz, 2H), 7.27 (d, J = 1.3 Hz, 1H), 7.21 (t, J = 5.4 Hz, 2H), 5.98 (q, J = 7.9 Hz, 1H), 5.68 (ddd, J = 32.7, 9.6, 4.5 Hz, 1H), 4.53 (p, J = 8.9 Hz, 1H), 3.24- 2.87 (m, 2H), 1.49 (d, J = 6.5 Hz, 3H) F8 645 .sup.1H NMR (400 MHz, .sup.19F NMR (376 ([M + H].sup.+) CDCl.sub.3) 7.83 (s, MHz, CDCl.sub.3) - 1H), 7.74 (d, J = 59.43, 63.18, 8.6 Hz, 1H), 7.51 93.17-97.04, (d, J = 8.1 Hz, 114.80 1H), 7.42 (s, 2H), 6.99 (d, J = 7.4 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 5.88 (dd, J = 33.8, 9.8 Hz, 1H), 5.46 (q, J = 7.1 Hz, 1H), 4.27 (td, J = 14.3, 9.7 Hz, 1H), 3.06 (q, J = 10.4 Hz, 2H), 1.71 (d, J = 6.8 Hz, 3H), 1.62 (d, J = 18.5 Hz, 3H) F9 629 .sup.1H NMR (400 MHz, .sup.19F NMR (376 ([M + H].sup.+) CDCl.sub.3) 7.83 (d, MHz, CDCl.sub.3) J = 7.9 Hz, 1H), 66.84, 69.44 (d, 7.54-7.48 (m, J = 2.4 Hz), 1H), 7.47-7.43 110.87-113.41 (m, 2H), 7.41 (s, (m) 2H), 7.40-7.35 (m, 1H), 5.81- 5.61 (m, 2H), 4.56 (p, J = 8.9 Hz, 1H), 2.46- 2.14 (m, 4H), 1.57 (d, J = 6.6 Hz, 3H) F10 659 .sup.1H NMR (400 MHz, .sup.13C NMR (101 ([M + H].sup.+) CDCl.sub.3) 8.05 (d, MHz, CDCl.sub.3) J = 8.1 Hz, 1H), 169.85, 166.53, 7.83 (t, J = 5.8 161.53-153.79 Hz, 1H), 7.67- (m), 136.96, 7.60 (m, 1H), 135.96, 134.51, 7.52 (d, J = 8.2 132.74, 131.21, Hz, 1H), 7.41 (s, 129.10, 128.60, 2H), 7.33-7.24 127.91, 127.29, (m, 1H), 5.96- 125.17, 122.19, 5.69 (m, 2H), 103.44 (d, J = 4.33-4.15 (m, 16.0 Hz), 99.98, 1H), 2.35-2.05 53.81-52.37 (m, 4H), 1.71- (m), 48.64- 1.57 (m, 3H), 47.20 (m), 29.79- 1.45 (d, J = 6.6 28.88 (m), Hz, 3H) 28.27, 23.34- 21.75 (m), 19.91 F11 613 .sup.1H NMR (400 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.98 3239, 2928, (d, J = 7.2 Hz, 1674, 1119 cm.sup.1 1H), 8.66 (d, J = 6.8 Hz 1H), 8.11 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.81 (s, 2H), 7.68 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 6.84 (dd, J = 35.6, 9.6 Hz, 1H), 5.60-5.55 (m, 1H), 5.23-5.18 (m, 1H), 3.31- 3.22 (m, 2H), 1.36 (d, J = 6.4 Hz, 3H) F12 627 .sup.1H NMR (400 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.85 3439, 3300, (d, J = 6.8 Hz, 1669, 749 cm.sup.1 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.81 (s, 2H), 7.68 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 6.84 (dd, J = 36.0, 10.4 Hz, 1H), 5.60-5.55 (m, 1H), 5.23- 5.18 (m, 1H), 2.50-2.33 (m, 4H), 1.34 (d, J = 6.4 Hz, 3H) F13 613 .sup.1H NMR (400 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.98 3439, 3302, (d, J = 7.6 Hz, 1676, 750 cm.sup.1 1H), 8.66 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 8.05- 8.03 (m, 1H), 8.00 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.68-7.65 (m, 1H), 7.56 (d, J = 8.0 Hz, 1H), 6.83 (dd, J = 36.0, 10.4 Hz, 1H), 5.60-5.55 (m, 1H), 5.20- 5.15 (m, 1H), 3.31-3.22 (m, 2H), 1.34 (d, J = 6.8 Hz, 3H) F14 627 .sup.1H NMR (400 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.85 3439, 3300, 1669, (d, J = 6.8 Hz, 749 cm.sup.1 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 8.04- 7.99 (m, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.72- 7.65 (m, 1H), 7.56 (d, J = 8.0 Hz, 1H), 6.84 (dd, J = 35.6, 10.0 Hz, 1H), 5.60-5.55 (m, 1H), 5.20- 5.15 (m, 1H), 2.51-2.33 (m, 4H), 1.34 (d, J = 6.4 Hz, 3H) F15 705 .sup.1H NMR (300 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.86 3423, 1667 cm.sup.1 (d, J = 7.2 Hz, 1H), 8.43 (d, J = 7.2 Hz, 1H), 8.09 (s, 1H), 8.04- 8.00 (m, 3H), 7.57 (d, J = 8.1 Hz, 1H), 6.86 (dd, J = 35.7, 9.9 Hz, 1H), 5.61-5.54 (m, 1H), 5.25- 5.19 (m, 1H), 2.50-2.30 (m, 4H), 1.34 (d, J = 6.6 Hz, 3H) F16 631 .sup.1H NMR (400 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.95 3302, 1672, (d, J = 7.2 Hz, 1120, 714 cm.sup.1 1H), 8.64 (d, J = 7.2 Hz, 1H), 8.09 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 6.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 35.6, 10.4 Hz, 1H), 5.61-5.55 (m, 1H), 5.23- 5.22 (m, 1H), 3.30-3.22 (m, 2H), 1.36 (d, J = 6.4 Hz, 3H) F17 645 .sup.1H NMR (300 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.86 3741, 3309, (d, J = 6.9 Hz, 2935, 1670, 1132 1H), 8.43 (d, J = cm.sup.1 7.2 Hz, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 8.00 (d, J = 6.3 Hz, 2H), 7.57 (d, J = 7.8 Hz, 1H), 6.84 (dd, J = 36.0, 10.2 Hz, 1H), 5.61-5.54 (m, 1H), 5.24- 5.23 (m, 1H), 2.45-2.30 (m, 4H), 1.34 (d, J = 6.6 Hz, 3H) F18 98- 639 .sup.1H NMR (300 MHz, 100 ([M + H].sup.+) CDCl.sub.3) 7.84 (s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 6.81- 6.72 (m, 1H), 5.94-5.65 (m, 3H), 5.49-5.31 (m, 1H), 4.64- 4.60 (m, 1H), 3.12 (q, J = 10.5 Hz, 2H), 1.72 (d, J = 6.9 Hz, 3H) F19 56- 653 .sup.1H NMR (300 MHz, 58 ([M + H].sup.+) CDCl.sub.3) 7.85 (s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.43 (s, 1H), 7.37 (s, 1H), 7.01- 6.92 (dd, J = 17.7, 11.4 Hz, 1H), 5.94-5.65 (m, 3H), 5.47- 5.31 (m, 1H), 4.67-4.60 (m, 1H), 2.50-2.43 (m, 4H), 1.70 (d, J = 6.9 Hz, 3H) F20 659 .sup.1H NMR (400 MHz, .sup.19F NMR (471 ([M + H].sup.+) CDCl.sub.3) 7.81 (s, MHz, CDCl.sub.3) - 1H), 7.72 (d, J = 59.15, 63.05, 8.0 Hz, 1H), 7.48 102.66-106.98 (d, J = 8.0 Hz, (m), 114.95 1H), 7.41 (s, 2H), 7.21 (s, 1H), 6.99 (s, 1H), 6.00- 5.78 (m, 1H), 5.44 (h, J = 7.0 Hz, 1H), 4.30 (td, J = 14.5, 9.8 Hz, 1H), 3.06 (q, J = 10.4 Hz, 2H), 1.94- 1.79 (m, 2H), 1.70 (d, J = 6.8 Hz, 3H), 1.07 (t, J = 7.5 Hz, 3H) F21 673 .sup.1H NMR (400 MHz, .sup.19F NMR (471 ([M + H].sup.+) CDCl.sub.3) d 7.80 (s, MHz, CDCl.sub.3) -.sup.19F 1H), 7.70 (dd, J = NMR (471 MHz, 8.2, 2.8 Hz, 1H), CDCl.sub.3) 59.15, 7.48 (dd, J = 8.1, 66.78, 102.42- 3.6 Hz, 1H), 7.41 107.74 (m), (s, 2H), 7.07 (s, 115.03 2H), 5.88 (ddd, J = 33.9, 9.7, 3.3 Hz, 1H), 5.50- 5.37 (m, 1H), 4.30 (td, J = 14.6, 9.8 Hz, 1H), 2.41 (br s, 4H), 2.00- 1.78 (m, 2H), 1.70-1.63 (m, 3H), 1.07 (t, J = 7.4 Hz, 3H) F22 135- 699 .sup.1H NMR (300 MHz, 137 ([M H].sup.) DMSO-d.sub.6) 8.98 (d, J = 7.5 Hz, 1H), 8.66 (d, J = 7.2 Hz, 1H), 8.11 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.96 (s, 2H), 7.90 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 6.86 (dd, J = 35.7, 9.9 Hz, 1H), 5.61-5.54 (m, 1H), 5.22-5.21 (m, 1H), 3.28- 3.21 (m, 2H), 1.36 (d, J = 6.3 Hz, 3H) F23 130- 713 .sup.1H NMR (300 MHz, 132 ([M H].sup.) DMSO-d.sub.6) 8.86 (d, J = 6.9 Hz, 1H), 8.43 (d, J = 7.5 Hz, 1H), 8.10 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.96 (s, 2H), 7.91- 7.90 (m, 1H), 7.57 (d, J = 8.1 Hz, 1H), 6.86 (dd, J = 36.0, 10.2 Hz, 1H), 5.59-5.54 (m, 1H), 5.22- 5.21 (m, 1H), 2.43-2.32 (m, 4H), 1.34 (d, J = 6.6 Hz, 3H) F24 605 .sup.1H NMR (300 MHz, IR (thin film) ([M H].sup.) DMSO-d.sub.6) 8.97 3423, 2924, (d, J = 7.2 Hz, 1674, 714 cm.sup.1 1H), 8.66 (d, J = 6.9 Hz, 1H), 8.07 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.45 (s, 2H), 6.77 (dd, J = 35.4, 9.6 Hz, 1H), 5.59-5.56 (m, 1H), 4.95-4.85 (m, 1H), 3.31- 3.21 (m, 2H), 2.36 (s, 6H), 1.36 (d, J = 8.1 Hz, 3H) F25 619 .sup.1H NMR (300 MHz, IR (thin film) ([M H].sup.) DMSO-d.sub.6) 8.85 3308, 2925, 1668 (d, J = 6.9 Hz, cm.sup.1 1H), 8.42 (d, J = 7.2 Hz, 1H), 8.06 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.45 (s, 2H), 6.77 (dd, J = 36.3, 10.2 Hz, 1H), 5.58-5.56 (m, 1H), 4.95- 4.88 (m, 1H), 2.50-2.40 (m, 4H), 2.35 (s, 6H), 1.29-1.21 (d, J = 6.9 Hz, 3H) F26 733 .sup.1H NMR (300 MHz, IR (thin film) ([M H].sup.) DMSO-d.sub.6) 8.98 3308, 1674 cm.sup.1 (d, J = 7.2 Hz, 1H), 8.67 (d, J = 7.2 Hz, 1H), 8.17- 8.03 (m, 4H), 7.57 (d, J = 8.1 Hz, 1H), 6.86 (dd, J = 35.7, 10.2 Hz, 1H), 5.61-5.54 (m, 1H), 5.25- 5.19 (m, 1H), 3.31-3.21 (m, 2H), 1.36 (d, J = 6.3 Hz, 3H) F27 605 .sup.1H NMR (500 MHz, .sup.19F NMR (471 ([M H].sup.) CDCl.sub.3) 7.87- MHz, CDCl.sub.3) 7.82 (m, 1H), 59.18, 69.32 (d, 7.74 (dd, J = 8.1, J = 8.4 Hz), 1.7 Hz, 1H), 7.54 111.89 (d, J = (d, J = 8.1 Hz, 32.5 Hz) 1H), 7.43 (s, 2H), 7.01 (d, J = 7.3 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 5.81 (dd, J = 32.5, 9.6 Hz, 1H), 5.42 (h, J = 7.0 Hz, 1H), 4.60 (p, J = 8.9 Hz, 1H), 1.70 (d, J = 6.7 Hz, 3H), 1.36 (tt, J = 7.9, 4.6 Hz, 1H), 1.00-0.86 (m, 2H), 0.77 (dt, J = 7.9, 3.4 Hz, 2H) F28 150- 683 .sup.1H NMR (300 MHz, 152 ([M H].sup.) Acetonitrile-d.sub.3) 8.10-8.01 (m, 1H), 7.94 (dd, J = 8.1, 1.8 Hz, 1H), 7.71 (s, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.62-7.56 (m, 1H), 6.27 (dd, J = 34.2, 9.8 Hz, 1H), 5.51 (dq, J = 7.9, 6.6 Hz, 1H), 4.91 (p, J = 9.2 Hz, 1H), 4.41- 4.13 (m, 2H), 1.50 (d, J = 6.6 Hz, 3H) F29 158- 620 .sup.1H NMR (300 MHz, 162 ([M H].sup.) Acetonitrile-d.sub.3) 7.91 (d, J = 1.7 Hz, 1H), 7.85- 7.77 (m, 1H), 7.70 (s, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 6.22 (dd, J = 34.2, 9.8 Hz, 1H), 5.91 (d, J = 8.4 Hz, 1H), 5.80-5.69 (m, 1H), 5.69-5.55 (m, 1H), 4.88 (p, J = 9.1 Hz, 1H), 2.42 (dtd, J = 9.2, 6.6, 3.6 Hz, 1H), 1.43 (d, J = 6.5 Hz, 3H), 0.74- 0.52 (m, 2H), 0.51-0.29 (m, 2H) F30 749 .sup.1H NMR (300 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.86 3320, 2925, (d, J = 6.9 Hz, 1663, 1138 cm.sup.1 1H), 8.43 (d, J = 7.5 Hz, 1H), 8.17 (s, 2H), 8.10- 7.96 (m, 2H), 7.57 (d, J = 8.1 Hz, 1H), 6.86 (dd, J = 36.0, 10.5 Hz, 1H), 5.59-5.56 (m, 1H), 5.22- 5.19 (m, 1H), 2.45-2.32 (m, 4H), 1.34 (d, J = 6.6 Hz, 3H) F31 691 .sup.1H NMR (300 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.98 3302, 1678, 1119 (d, J = 7.5 Hz, cm.sup.1 1H), 8.67 (d, J = 7.2 Hz, 1H), 8.11- 8.00 (m, 4H), 7.57 (d, J = 8.1 Hz, 1H), 6.86 (dd, J = 36.3, 10.2 Hz, 1H), 5.61-5.56 (m, 1H), 5.25- 5.19 (m, 1H), 3.31-3.21 (m, 2H), 1.37 (d, J = 6.6 Hz, 3H F32 701 .sup.1H NMR (400 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.97 3415, 2925, (d, J = 7.6 Hz, 1663, 1114 cm.sup.1 1H), 8.66 (d, J = 7.2 Hz, 1H), 8.11 (s, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.62- 7.59 (m, 1H), 7.56 (d, J = 7.6 Hz, 1H), 6.82 (dd, J = 36.0, 9.6 Hz, 1H), 5.60-5.55 (m, 1H), 5.18- 5.13 (m, 1H), 3.31-3.22 (m, 2H), 1.36 (d, J = 6.4 Hz, 3H) F33 615 .sup.1H NMR (400 MHz, .sup.19F NMR (376 ([M + Na].sup.+) CDCl.sub.3) 8.26 (dd, MHz, CDCl.sub.3) J = 39.4, 8.3 Hz, 63.18 (d, J = 54.7 2H), 7.41 (s, 2H), Hz), 69.55 (d, 7.14 (d, J = 19.5 J = 2.9 Hz), Hz, 3H), 5.94 (q, 111.92 (d, J = J = 7.5 Hz, 1H), 39.2 Hz); 5.65 (ddd, J = IR (thin film) 32.9, 9.6, 2.1 Hz, 3291, 1673, 1H), 4.55 (p, J = 1112, 727 cm.sup.1 8.8 Hz, 1H), 3.25- 3.04 (m, 1H), 2.97 (p, J = 10.5 Hz, 1H), 2.11 (s, 3H), 1.48 (d, J = 6.6 Hz, 3H) F34 593 .sup.1H NMR (400 MHz, .sup.19F NMR (376 ([M H].sup.) CDCl.sub.3) 7.87- MHz, CDCl.sub.3) 7.79 (m, 1H), 59.21, 69.32, 7.74 (dd, J = 8.1, 111.91 1.7 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.43 (s, 2H), 7.05 (d, J = 7.2 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 5.81 (dd, J = 32.5, 9.6 Hz, 1H), 5.42 (h, J = 7.0 Hz, 1H), 4.60 (p, J = 8.9 Hz, 1H), 2.21 (q, J = 7.6 Hz, 2H), 1.69 (d, J = 6.7 Hz, 3H), 1.13 (t, J = 7.6 Hz, 3H) F35 661 .sup.1H NMR (400 MHz, .sup.19F NMR (376 ([M H].sup.) CDCl.sub.3) 7.76- MHz, CDCl.sub.3) 7.51 (m, 3H), 59.52, 63.24, 7.42 (s, 2H), 7.36 69.39, 112.22 (d, J = 8.1 Hz, 1H), 5.76 (ddd, J = 32.6, 9.6, 2.1 Hz, 1H), 5.39 (q, J = 8.3 Hz, 1H), 4.57 (p, J = 8.8 Hz, 1H), 3.02 (dtt, J = 20.8, 15.0, 10.5 Hz, 2H), 1.91 (q, J = 7.5 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H) F36 657 .sup.1H NMR (300 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.98 3297, 2919, (d, J = 7.2 Hz, 1674, 1118 cm.sup.1 1H), 8.66 (d, J = 7.8 Hz, 1H), 8.11- 8.03 (m, 2H), 7.93 (s, 1H), 7.84- 7.79 (m, 2H), 7.57 (d, J = 7.8 Hz, 1H), 6.86 (dd, J = 35.7, 9.9 Hz, 1H), 5.61-5.54 (m, 1H), 5.23- 5.16 (m, 1H), 3.31-3.19 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H) F37 657 .sup.1H NMR (400 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.98 3330, 1673, 1132 (d, J = 7.2 Hz, cm.sup.1 1H), 8.66 (d, J = 7.2 Hz, 1H), 8.11 (s, 2H), 8.05 (d, J = 8.0 Hz, 1H), 7.73-7.68 (m, 2H), 7.56 (d, J = 8.4 Hz, 1H), 6.83 (dd, J = 35.6, 9.6 Hz, 1H), 5.60- 5.55 (m, 1H), 5.20-5.15 (m, 1H), 3.31-3.22 (m, 2H), 1.36 (d, J = 6.8 Hz, 3H) F39 609.4 .sup.1H NMR (400 MHz, .sup.19F NMR (376 ([M + H].sup.+) CDCl.sub.3) 7.82 (s, MHz, CDCl.sub.3) 1H), 7.72 (d, J = 59.20, 63.09, 7.9 Hz, 1H), 7.51- 90.39-101.60 7.47 (m, 2H), (m), 115.42 7.45 (d, J = 8.3 Hz, 1H), 7.23 (dd, J = 8.3, 1.7 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 7.4 Hz, 1H), 5.92 (dd, J = 33.9, 9.8 Hz, 1H), 5.53-5.37 (m, 1H), 4.30 (td, J = 14.2, 9.7 Hz, 1H), 3.06 (q, J = 10.4 Hz, 2H), 1.74- 1.57 (m, 6H) F40 623.4 .sup.1H NMR (400 MHz, .sup.19F NMR (376 (M + H].sup.+) CDCl.sub.3) 7.82 (s, MHz, CDCl.sub.3) 1H), 7.73 (d, J = 59.12, 66.80, 8.1 Hz, 1H), 7.56- 93.09-97.12 7.42 (m, 3H), (m), 115.40 7.23 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 5.92 (dd, J = 34.0, 9.8 Hz, 1H), 5.50-5.36 (m, 1H), 4.39- 4.20 (m, 1H), 2.54-2.37 (m, 4H), 1.69 (d, J = 6.8 Hz, 3H), 1.62 (t, J = 18.4 Hz, 3H) F41 620 .sup.1H NMR (500 MHz, .sup.19F NMR (471 ([M + H].sup.+) CDCl.sub.3) 7.77 (s, MHz, CDCl.sub.3) 1H), 7.70-7.66 59.24, 69.35 (m, 1H), 7.48 (d, (d, J = 8.6 Hz), J = 8.1 Hz, 1H), 112.20 (dd, J = 7.47-7.40 (m, 32.7, 7.5 Hz) 4H), 5.81 (dd, J = 32.6, 9.6 Hz, 1H), 5.53 (h, J = 7.1 Hz, 1H), 4.59 (p, J = 8.9 Hz, 1H), 2.61-2.49 (m, 4H), 1.61 (d, J = 6.7 Hz, 3H)
(489) TABLE-US-00008 TABLE 5 Structure and Preparation Method for FC Series Compounds No. Structure Prep.* FC1
(490) TABLE-US-00009 TABLE 6 Structure and Preparation Method for CC Series Molecules No. Structure Prep.* CC1
(491) TABLE-US-00010 TABLE 7 Analytical Data for Compounds in Table 5 Mp Mass .sup.13C NMR; No. ( C.) (m/z) .sup.1H NMR .sup.19F NMR; IR FC1 581 .sup.1H NMR (300 MHz, .sup.19F NMR (471 ([M + H].sup.+) CDCl.sub.3) 7.79 (d, J = MHz, CDCl.sub.3) 8.3 Hz, 2H), 7.62 (d, 63.01, 63.03, J = 8.5 Hz, 2H), 7.43 63.05, 69.39, (s, 2H), 7.30 (d, J = 69.40, 111.70, 7.7 Hz, 1H), 7.08 (d, 111.77 J = 7.4 Hz, 1H), 5.78 (dd, J = 32.7, 9.6 Hz, 1H), 5.52 (q, J = 7.1 Hz, 1H), 4.59 (p, J = 9.0 Hz, 1H), 3.05 (q, J = 10.4 Hz, 2H), 1.73 (d, J = 6.8 Hz, 3H) FC2 595 .sup.1H NMR (300 MHz, .sup.19F NMR (471 ([M + H].sup.+) CDCl.sub.3) 7.80 (d, J = MHz, CDCl.sub.3) 8.1 Hz, 2H), 7.65 66.75, 66.76, 7.57 (m, 2H), 7.51 (d, 66.77, 66.80, J = 7.4 Hz, 1H), 7.43 69.40, 69.42, (s, 2H), 7.06 (d, J = 111.72, 111.79 7.5 Hz, 1H), 5.78 (dd, J = 32.8, 9.6 Hz, 1H), 5.52 (h, J = 7.0 Hz, 1H), 4.59 (p, J = 8.9 Hz, 1H), 2.56 2.39 (m, 3H), 1.70 (d, J = 6.8 Hz, 3H)
(492) TABLE-US-00011 TABLE 8 Structure and Preparation Method for PF Series Molecules No. Structure Prep.* PF1
(493) TABLE-US-00012 TABLE 9 Analytical Data for Molecules in Table 8 Mp Mass .sup.13C NMR; No. ( C.) (m/z) .sup.1H NMR .sup.19F NMR; IR PF1 629.06 .sup.1H NMR (300 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 9.02 (d, 3310, 1671, J = 7.8 Hz, 1H), 8.72 1114, 765 cm.sup.1 (d, J = 6.9 Hz, 1H), 8.21 (d, J = 6.9 Hz, 1H), 8.07 (s, 2H), 7.97 (d, J = 6.3 Hz, 1H), 7.73-7.68 (m, 1H), 7.65 (s, 2H), 7.58 (d, J = 7.2 Hz, 1H), 6.29 (dd, J = 10.2, 33.9 Hz, 1H), 5.75-5.70 (m, 1H), 5.35-5.28 (m, 1H), 3.30-3.25 (m, 2H), 1.42 (d, J = 6.3 Hz, 3H) PF2 595.30 .sup.1H NMR (400 MHz, IR (thin film) ([M H].sup.) DMSO-d.sub.6) 8.98 (d, 3432, 2925, J = 7.2 Hz, 1H), 8.66 1673 cm.sup.1 (d, J = 7.2 Hz, 1H), 8.11 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 10.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.56-7.53 (m, 2H), 6.80 (dd, J = 10.0, 36.0 Hz, 1H), 5.59-5.57 (m, 1H), 5.17-5.15 (m, 1H), 3.31-3.22 (m, 2H), 1.36 (d, J = 6.4 Hz, 3H) PF3 611.14 .sup.1H NMR (400 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.85 3429, 2916, (d, J = 7.2 Hz, 1H), 1652, 1025 cm.sup.1 8.42 (d, J = 7.2 Hz, 1H), 8.10 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 6.8 Hz, 1H), 7.68 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 6.82 (dd, J = 10.0, 36.0 Hz, 1H), 5.60-5.55 (m, 1H), 5.18-5.13 (m, 1H), 2.41-2.33 (m, 4H), 1.34 (d, J = 8.0 Hz, 3H) PF4 627.00 .sup.1H NMR (300 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.98 3309, 2926, (d, J = 7.2 Hz, 1H), 1678 cm.sup.1 8.66 (d, J = 7.2 Hz, 1H), 8.09 (s, 1H), 8.07 (d, J = 6.0 Hz, 1H), 7.83 (s, 1H), 7.64 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 6.82 (dd, J = 9.9, 35.4 Hz, 1H), 5.61-5.54 (m, 1H), 5.12-5.05 (m, 1H), 3.31-3.21 (m, 2H), 2.49 (s, 3H), 1.39 (d, J = 6.0 Hz, 3H) PF8 84-86 659.20 .sup.1H NMR (300 MHz, ([M + H].sup.+) DMSO-d.sub.6) 8.98 (d, J = 7, 2 Hz, 1H), 8.66 (d, J = 7.5 Hz, 1H), 8.11 (s, 1H), 8.05- 7.98 (m, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.58 (t, J = 6.0 Hz, 2H), 6.84-6.69 (dd, J = 9.9 Hz, 1H), 5.61- 5.54 (m, 1H) 5.19- 5.13 (m, 1H), 3.31 (s, 2H), 1.36 (d, J = 6.0 Hz, 3H) PF13 671.10 .sup.1H NMR (300 MHz, IR (thin film) ([M + H].sup.+) DMSO-d.sub.6) 8.85 (d, 3284, 2925, J = 6.9 Hz, 1H), 8.42 1665, 1136 cm.sup.1 (d, J = 7.2 Hz, 1H), 8.11-8.10 (m, 2H), 8.04 (d, J = 8.4 Hz, 1H), 7.71 (s, 2H), 7.56 (d, J = 8.1 Hz, 1H), 6.84 (dd, J = 9.9, 36.0 Hz, 1H), 5.61-5.54 (m, 1H), 5.20-5.14 (m, 1H), 2.50-2.32 (m, 4H), 1.34 (d, J = 6.6 Hz, 3H) PF31 630.7 .sup.1H NMR (500 MHz, .sup.19F NMR (471 ([M H].sup.) CDCl.sub.3) 7.83 (d, J = MHz, CDCl.sub.3) 1.7 Hz, 1H), 7.75 59.02, 69.32 (dd, J = 8.1, 1.7 Hz, (d, J = 8.6 Hz), 1H), 7.56 (d, J = 8.0 111.99 (dd, J = Hz, 1H), 7.44 (s, 2H) 32.5, 7.2 Hz) 7.33 (d, J = 7.1 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 5.82 (dd, J = 32.5, 9.6 Hz, 1H), 5.64 (h, J = 6.9 Hz, 1H), 4.68-4.55 (m, 1H), 1.72-1.65 (m, 4H), 1.57-1.49 (m, 2H), 1.26 (t, J = 7.2 Hz, 1H)
(494) TABLE-US-00013 BAW, CEW & CL Rating Table % Control (or Mortality) Rating 50-100 A More than 0-Less than 50 B Not Tested C No activity noticed in this bioassay D
(495) TABLE-US-00014 GPA & YFM Rating Table % Control (or Mortality) Rating 80-100 A More than 0-Less than 80 B Not Tested C No activity noticed in this bioassay D
(496) TABLE-US-00015 TABLE ABC Biological Results Pests No. BAW CL GPA YFM F1 A A C C F2 A A C C F3 A A C C F4 A A C C F5 A A C C F6 A A C C F7 A A C C F8 A A C C F9 A A C C F10 A A C C F11 A A C A F12 A A C A F13 A A C A F14 A A C A F15 A A C A F16 A A C B F17 A A B A F18 A A C A F19 A A C A F20 A A C C F21 A A C C F22 A A C A F23 A A C A F24 A A C A F25 A A C A F26 A A C A F27 A A C C F28 A A C C F29 A A C C F30 A A C A F31 A A B A F32 A A C A F33 A A C C F34 A A C C F35 A A C C F36 A A C A F37 A A C C F39 A A C C F40 A A C C F41 A A C A PF1 A A C B PF2 A A C A PF3 A A C B PF4 A A C B PF8 A A C C PF13 A A C C PF31 A A C C
Comparative Data
(497) Bioassays on BAW and CL were conducted according to the procedures outlined in Example A: Bioassays on Beet Armyworm (BAW) and Cabbage Looper (CL) using the indicated concentrations. The results are indicated in Table CD1 and Table CD2.
(498) TABLE-US-00016 TABLE CD1
(499) TABLE-US-00017 TABLE CD2