Synthesis of substituted salicylaldehyde derivatives

Abstract

Among other things, the present invention encompasses methods of synthesizing salicylaldehyde derivatives comprising the steps of: a) providing salicylaldehyde or a derivative thereof, b) forming an anhydro dimer of the provided salicylaldehyde compound, c) performing one or more chemical transformations on the anhydro dimer and d) hydrolyzing the anhydro dimer to provide a salicylaldehyde derivative different from that provided in step (a).

Claims

1. A compound of any one of formulae D2-D8, D10, or D13: ##STR00056## ##STR00057## wherein Z is nitrogen or phosphorus, wherein the formal charge on Z satisfies valency requirements; X is halogen; C.sub.6-C.sub.20 aryloxy; C.sub.1-C.sub.20 carboxy; C.sub.1-C.sub.20 alkoxy; C.sub.1-C.sub.20 alkylsulfonato; or C.sub.1-C.sub.20 amido; R.sup.11, R.sup.12, R.sup.13, R.sup.21, R.sup.22, R.sup.23, R.sup.24 and R.sup.25 are each independently hydrogen; C.sub.1-C.sub.20 alkyl; C.sub.2-C.sub.20 alkenyl; C.sub.7-C.sub.20 alkylaryl; or C.sub.7-C.sub.20 arylalkyl; or two of R.sup.11, R.sup.12 and R.sup.13, or two of R.sup.21, R.sup.22, R.sup.23, R.sup.24 and R.sup.25 being optionally fused together to form a bridged structure; R.sup.31, R.sup.32 and R.sup.33 are each independently hydrogen; C.sub.1-C.sub.20 alkyl; C.sub.2-C.sub.20 alkenyl; C.sub.7-C.sub.20 alkylaryl; or two of R.sup.31, R.sup.32 and R.sup.33 being optionally fused together to form a bridged structure; R.sup.62 is hydrogen, methyl, ethyl, n-propyl, isopropyl or tert-butyl; n is from 1 to 20; X is oxygen, sulfur or NR; and R is hydrogen; C.sub.1-C.sub.20 alkyl; C.sub.2-C.sub.20 alkenyl; C.sub.7-C.sub.20 alkylaryl; or C.sub.7-C.sub.20 arylalkyl.

2. The compound of claim 1, wherein the compound is of formula D5.

3. The compound of claim 1, wherein the compound is of formula D8.

4. The compound of any one of claim 1, wherein each Z is nitrogen.

5. The compound of any one of claim 1, wherein R.sup.11, R.sup.12, R.sup.13, R.sup.21, R.sup.22, R.sup.23, R.sup.24 and R.sup.25 are each independently C.sub.1-C.sub.20 alkyl.

6. The compound of any one of claim 1, wherein R.sup.62 is hydrogen.

7. The compound of any one of claim 1, wherein R.sup.62 is methyl, ethyl, n-propyl, isopropyl or tert-butyl.

8. The compound of claim 7, wherein R.sup.62 is methyl.

9. The compound of claim 7, wherein R.sup.62 is tert-butyl.

10. The compound of claim 1, wherein the compound is any one of formulae D9 or D11 through D13: ##STR00058##

11. The compound of claim 10, wherein the compound is of formula D11.

12. The compound of claim 10, wherein the compound is of formula D12.

13. The compound of claim 10, wherein the compound is of formula D13.

14. The compound of any one of claim 10, wherein R.sup.62 is hydrogen.

15. The compound of any one of claim 10, wherein R.sup.62 is methyl, ethyl, n-propyl, isopropyl or tert-butyl.

16. The compound of claim 15, wherein R.sup.62 is methyl.

17. The compound of claim 15, wherein R.sup.62 is tert-butyl.

Description

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

(1) In one aspect, the present invention encompasses methods of synthesizing salicylaldehyde derivatives comprising the steps of: a) providing salicylaldehyde or a derivative thereof, b) forming an anhydro dimer of the provided salicylaldehyde compound, c) performing one or more chemical transformations on the anhydro dimer and d) hydrolyzing the anhydro dimer to provide a salicylaldehyde derivative different from that provided in step (a).

(2) In some embodiments, a provided method comprises the steps of a) providing salicylaldehyde or a derivative thereof, and b) forming an anhydro dimer of a provided salicylaldehyde compound. In certain embodiments, a provided method further comprises the step of performing one or more chemical transformations on an anhydro dimer. In some embodiments, a provided method further comprises the step of hydrolyzing an anhydro dimer to provide a salicylaldehyde derivative different from that provided in step (a).

(3) In some embodiments, a provided method comprises the steps of a) dehydrating a salicylaldehyde to form an anhydro dimer, b) alkylating at least one aromatic ring of the anhydro dimer in one or more positions; and c) hydrolyzing the alkylated anhydro dimer to recover an alkylated salicyladehyde derivative.

(4) The formation of an anhydro dimer may be performed using any suitable conditions such as those known in the art. Typical conditions employ acid catalysis in the presence of a dehydrating agent. One such method employs an acid anhydride in the presence of sulfuric or alkyl sulfonic acid catalyst. It will be apparent to the skilled artisan that many other methods can be employed including those based on other dehydrating reagents such as thionyl chloride, phosphorous oxides, dialkyldicarbonates and the like, as well as dehydrating reaction conditions that remove water via azeotroping (Dean Stark or the like) or that rely on adsorbants to physically sequester water (such as molecular sieves, anhydrous salts or the like).

(5) Similarly, hydrolysis of an anhydro dimer to recover the substituted salicylaldehyde may be performed using literature procedures. These normally employ acidic treatment in protic solvents such aqueous mineral acids, but it will be apparent to the skilled artisan that other hydrolysis conditions can be employed. Many examples are available from the literature describing the hydrolysis of acetals and ketals and any of these conditions may be employed in embodiments of the present invention.

(6) Chemical transformations performed at the anhydro-dimer stage can be quite varied, the only limitations being the practical ones requiring that the reagents and conditions employed do not cause a substantial degree of undesirable reaction on the bicyclic acetal moiety of the anhydro dimer and that any functional groups introduced are substantially compatible with the chemistry employed in hydrolysis of the dimers to recover the salicylaldehyde products. In some embodiments, several such reactions are performed on the anhydro dimers prior to recovery of the final substituted salicylaldehyde derivatives by hydrolysis of the dimers.

(7) In certain embodiments, the methods and compounds described herein are useful in the synthesis of known metal complexes and/or ligands thereof. In some embodiments, methods and compounds described herein are useful in the synthesis of compounds described in WO2008136591, WO2010013948, WO2010022388, WO2009137540, WO2008150033, US2010029896, U.S. Pat. Nos. 6,870,004, 7,304,172, JP2010001443A, CN101020747, CN10229276, J. Am. Chem. Soc., 2007, 129, p. 8082-83, Bull. Korean Chem. Soc., 2009, Vol. 30, No. 3 p. 745-748, Angew. Chem. Int. Ed. 2008, 47, 7306-9, Angew. Chem. Int. Ed. 2006, 45, 7274-7277, J. Am. Chem. Soc. 2009, p. 11509, and Macromolecules, 2010, 43 (3), p. 1396-1402, the entire contents of each of which are hereby incorporated by reference.

(8) I. Carbon-Carbon Bond Forming Reactions

(9) In certain embodiments, a step of performing one or more chemical transformations on an anhydro dimer comprises performing a carbon-carbon bond forming reaction on at least one aromatic ring of the anhydro dimer in one or more positions. In certain embodiments, a carbon-carbon bond forming reaction on at least one aromatic ring of the anhydro dimer comprises alkylating at least one aromatic ring of the anhydro dimer in one or more positions.

(10) In certain embodiments, an alkylation occurs equally on both salicylaldhyde molecules comprising the anhydro dimer. In certain embodiments, this process entails replacing a non-carbon substituent (Q) on the aryl ring with a carbon atom. In certain embodiments, such a method proceeds according Scheme 1:

(11) ##STR00002##
wherein R.sub.1 represents one or more non-hydrogen substituents optionally present at one or more positions of the aryl ring(s), where each R.sub.1 group is independently selected and is as defined hereinbelow; -Q represents one or more substitutable groups present on the aryl ring(s) and -alkyl, represents one or more moieties that is linked to the aryl ring through a carbon atom (including aliphatic, acyl, aryl, etc.) and which is introduced on the aryl ring in place of one or more of the -Q groups.

(12) In certain embodiments, -Q groups in Scheme 1 are selected from the group consisting of H, F, Cl, Br, I, B(OR.sup.y).sub.2, OSO.sub.2R.sup.y, and combinations of two or more of these.

(13) In certain embodiments, a -Q group in Scheme 1 is H. In certain embodiments, an H at the ortho, para or ortho and para positions is replaced with a carbon atom.

(14) In certain embodiments, an alkylation occurs at an unsubstituted aromatic ring position ortho to the hydroxyl group of the starting salicylaldehyde.

(15) ##STR00003##

(16) wherein the R.sub.x groups are as defined hereinbelow and -alkyl represents any moiety linked to the aryl ring through a carbon atom (including aliphatic, acyl, aryl, etc.).

(17) In certain embodiments, an alkylation occurs at the aromatic ring position para to the hydroxyl group of the starting salicylaldehyde. In certain embodiments, this process proceeds according to the following scheme:

(18) ##STR00004##
wherein the R.sub.x groups are as defined hereinbelow and -alkyl is as defined above.

(19) In some embodiments, bis alkylation occurs at aromatic ring positions ortho and para to the hydroxyl group of the starting salicylaldehyde. In certain embodiments, this process proceeds according to the following scheme:

(20) ##STR00005##
wherein the R.sub.x groups are as defined hereinbelow and -alkyl is as defined above.

(21) In certain embodiments, a provided method comprises a first alkylating step using a first alkylating reagent and a second alkylating step using a second alkylating reagent wherein the first and second alkylating reagents are different. In certain embodiments, the first alkyating step introduces a substituent at the aryl position para to the phenol hydroxy group of the starting salicylaldehyde and the second alkylating step introduces a different substituent at the aryl position ortho to the phenol hydroxy group of the starting salicylaldehyde. In other embodiments, the first alkyating step introduces a substituent at the aryl position ortho to the phenol hydroxy group of the starting salicylaldehyde and the second alkylating step introduces a different substituent at the aryl position para to the phenol hydroxy group of the starting salicylaldehyde. In certain embodiments, these processes proceed according to the following schemes:

(22) ##STR00006## ##STR00007##
wherein the R.sub.x groups are as defined hereinbelow and -alkyl is as defined above.

(23) In some embodiments, a starting salicylaldehyde is substituted at the aryl position ortho to the phenol and an alkylation step introduces a substituent at the aryl position para to the phenol hydroxyl group.

(24) In some embodiments, a starting salicylaldehyde is substituted at the aryl position para to the phenol and an alkylation step introduces a substituent at the aryl position ortho to the phenol hydroxyl group.

(25) In certain embodiments, an alkylation transforms R.sub.3 of an anhydro dimer from H to an optionally substituted aliphatic group. In certain embodiments, an optionally substituted aliphatic group introduced at R.sub.3 is selected from the group consisting of optionally substituted C.sub.1-20 aliphatic, and optionally substituted aryl.

(26) In certain embodiments, a step of alkylating the aromatic ring comprises reacting the anhydro dimer under Friedel Crafts conditions. In certain embodiments, a step of alkylating the aromatic ring comprises reacting the anhydro dimer under Friedel Crafts alkylating or acylating conditions. Suitable reagents and conditions for Friedel Crafts reactions are well known in the art. Exemplary conditions for such transformations include, but are not limited to, those found in: ADVANCED ORGANIC CHEMISTRY, 4.sup.th Ed. by Jerry March, pp 534-552 and the references cited therein.

(27) In certain embodiments, the Friedel Crafts alkylating conditions comprise reacting the anhydro dimer with at least one compound selected from the group consisting of: alkenes, alcohols, alkyl halides, and mixtures of two or more of these in the presence of a promoter selected from the group consisting of Lewis acids and proton acids.

(28) In certain embodiments, the step of performing a carbon-carbon bond forming reaction comprises reacting the anhydro dimer with a transition metal catalyst and a suitable reagent to introduce a new carbon-linked substituent. In certain embodiments, such transitional metal catalyzed carbon-carbon bond forming reactions take place between the anhydro dimer and a suitable reagent, wherein the anhydro dimer and reagent bear complementary coupling groups. Suitable coupling reactions are well known to one of ordinary skill in the art and typically involve either the anydro dimer or reagent bear an electron-withdrawing group (EWG) (e.g., Cl, Br, I, OTf, OTs, OMs etc.), such that the resulting polar carbon-EWG bond is susceptible to oxidative addition by an electron-rich metal (e.g., a low-valent palladium or nickel species), and the complementary coupling group being an electropositive group (e.g., boronic acids, boronic esters, boranes, stannanes, silyl species, zinc species, aluminum species, magnesium species, zirconium species, etc.), such that the carbon which bears the electropositive coupling group is susceptible to transfer to other electropositive species (e.g., a Pd.sup.II-IV species or a Ni.sup.II-IV species).

(29) In certain embodiments, the step of performing a transition metal-catalyzed carbon-carbon bond forming reaction comprises reacting a position on the anhydro dimer substituted with a halogen, or similar group (i.e. a sulfonate ester or other leaving group) with a transition metal catalyst and a suitable reagent to introduce a new substituent at that position. In certain embodiments, the step of performing a transition metal-catalyzed carbon-carbon bond forming reaction comprises reacting a position on the anhydro dimer substituted with an atom from groups 1-2 or 12-14 (IA-IIA and IIB-IVA) of the periodic table. In certain embodiments, the atom is selected from the group consisting of, boron, tin, silicon, magnesium, or zinc atom with a transition metal catalyst and a suitable reagent to introduce a new carbon-linked substituent at that position. Suitable conditions, catalysts and reagents for performing such transformations are well known in the art. Suitable conditions can be found in ADVANCED ORGANIC CHEMISTRY, 4.sup.th Ed. by Jerry March and references cited therein.

(30) In some embodiments, the coupling is a Suzuki coupling. Suzuki coupling of boronic acids with different aryl halides is typically conducted using palladium catalysts tetrakis(triphenylphosphine) palladium (0) or another suitable source such as trans-dichlorobis(tri-o-tolylphosphine)palladium (II), Pd(II)Cl.sub.2(PPh.sub.3).sub.2, Pd(II)Cl.sub.2(dppb).sub.2, Pd(II)(OAc).sub.2+PPh.sub.3, Pd(II)(OAc).sub.2+tri(o-tolyl)phosphine (palladacycle), or Pd/C under basic conditions. Typically, the reaction base is sodium or potassium or barium hydroxide, sodium or potassium bicarbonate, sodium, potassium, cesium or thallium carbonate, cesium or potassium fluoride sodium or potssium tert-butoxide, potassium phosphate or triethylamine and the solvent includes DMF, ethanol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, water, toluene/benzene and mixtures thereof and with phase transfer reagents, such as Bu.sub.4NCl or 18-crown-6. Exemplary reactions include those described in Metal-Catalyzed Cross-Coupling Reactions, A. de Meijere and F. Diederich, Eds., 2.sup.nd Edition, John Wiley & Sons, 2004; and Handbook of Organopalladium Chemistry for Organic Synthesis, Negishi, E., de Meijere, A. Editors, Wiley: New York, N.Y., 2002.

(31) II. Carbon-Heteroatom Bond Forming Reactions

(32) In other embodiments, a step of performing one or more chemical transformations on an anhydro dimer comprises performing a carbon-heteroatom bond forming reaction on at least one aromatic ring of an anhydro dimer in one or more positions.

(33) In certain embodiments, a carbon-heteroatom bond forming reaction is selected from the group consisting of halogenation, or introduction of a group linked via an atom selected from the group consisting of: oxygen, nitrogen, sulfur, phosphorous, boron, tin, silicon, lithium, magnesium, or combinations of two or more of these.

(34) In certain embodiments, the anhydro dimer formed in step (a) has a formula:

(35) ##STR00008##

(36) wherein at least one of R.sub.1, R.sub.2, R.sub.3, and R.sub.4 is H, and the remainder are each independently selected from the group consisting of halogen, NO.sub.2, CN, Si(R.sup.y).sub.3, SR.sup.y, S(O)R.sup.y, S(O).sub.2R.sup.y, NR.sup.yC(O)R.sup.y, OC(O)R.sup.y, CO.sub.2R.sup.y, NCO, N.sub.3, OR.sup.y, OC(O)N(R.sup.y).sub.2, N(R.sup.y).sub.2, NR.sup.yC(O)R.sup.y, NR.sup.yC(O)OR.sup.y; or an optionally substituted radical selected from the group consisting of C.sub.1-20 aliphatic; C.sub.1-20 heteroaliphatic; phenyl; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7-14 carbon saturated or partially unsaturated carbocycle; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3- to 8-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 6- to 12-membered polycyclic saturated or partially unsaturated heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 8- to 14-membered aryl; or an 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; where each occurrence of R.sup.y is independently H, or an optionally substituted radical selected from the group consisting of C.sub.1-6 aliphatic, 3- to 7-membered heterocyclic, phenyl, and 8- to 10-membered aryl, and where two or more adjacent R.sup.y groups can be taken together to form an optionally substituted saturated, partially unsaturated, or aromatic 5- to 12-membered ring containing 0 to 4 heteroatoms.

(37) In certain embodiments, R.sub.3 is H in a provided salicylaldehyde derivative from which an anhydro dimer is formed.

(38) In certain embodiments, R.sub.1 in a provided salicylaldehyde derivative selected from the group consisting of optionally substituted C.sub.1-20 aliphatic, and optionally substituted aryl.

(39) In certain embodiments, R.sub.1 in the provided salicylaldehyde derivative from which the anhydro dimer is formed is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, isoamyl, tert-amyl, and substituted phenyl.

(40) III. Functional Group Manipulations

(41) It will be appreciated that, in addition to reactions that add or modify substituents on the anhydo dimers, the present invention encompasses chemical manipulations to the anhydro dimer substituent groups themselves. In certain embodiments, the step of performing one or more chemical transformations on the anhydro dimer comprises performing one or more chemical reactions to manipulate functional groups already present on the anhydro dimer. Such reactions can include those commonly performed in organic synthesis such as reductions, oxidations, additions, protections, deprotections, cycloadditions, aminations, decarboxylations, halogenations, transition metal-catalyzed carbon-carbon bond couplings, Click reactions, ring-closing or cross metathesis reactions, and the like. The functional groups thus manipulated may be those attached to the aryl ring of the salicaldehyde or may be present on substituents attached to the aryl rings.

(42) The following schemes represent non-limiting examples of chemical syntheses embodying certain methods of the present invention. Such chemical transformations and useful reagents for carrying out such reactions will be known to the skilled artisan, and are also available in the literature (e.g., March, vide supra).

(43) ##STR00009##

(44) ##STR00010##

(45) ##STR00011##

(46) ##STR00012##

(47) ##STR00013##

(48) ##STR00014##

(49) ##STR00015##

(50) ##STR00016##

(51) ##STR00017##

(52) ##STR00018##

(53) ##STR00019##

(54) ##STR00020##

(55) ##STR00021##

(56) ##STR00022##

(57) ##STR00023##

(58) ##STR00024##

(59) ##STR00025##

(60) ##STR00026##

(61) ##STR00027##

(62) ##STR00028##

(63) ##STR00029##

(64) ##STR00030##

(65) ##STR00031##

(66) ##STR00032##

(67) ##STR00033##

(68) ##STR00034##

(69) ##STR00035##

(70) ##STR00036##

(71) ##STR00037##

(72) ##STR00038##

(73) ##STR00039##

(74) ##STR00040##

(75) ##STR00041##

(76) ##STR00042##
IV. Compositions of Matter

(77) In certain embodiments, the present invention encompasses novel compositions of matter with utility in the production of substituted salicylaldehyde compounds. In certain embodiments, the present invention provides the anhydro dimers disclosed in the schemes and descriptions hereinabove.

(78) In certain embodiments, the present invention encompasses anhydro dimers with utility in the production of salen catalysts. In certain embodiments, such compounds have a structure D1:

(79) ##STR00043##
wherein, R.sub.1 and R.sub.2 are independently selected from the group consisting of hydrogen, halogen, NO.sub.2, CN, Si(R.sup.y).sub.3, SR.sup.y, S(O)R.sup.y, S(O).sub.2R.sup.y, NR.sup.yC(O)R.sup.y, OC(O)R.sup.y, CO.sub.2R.sup.y, NCO, N.sub.3, OR.sup.y, OC(O)N(R.sup.y).sub.2, N(R.sup.y).sub.2, NR.sup.yC(O)R, NR.sup.yC(O)OR.sup.y; or an optionally substituted radical selected from the group consisting of C.sub.1-20 aliphatic; C.sub.1-20 heteroaliphatic; phenyl; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7-14 carbon saturated or partially unsaturated polycyclic carbocycle; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3- to 8-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 6- to 12-membered polycyclic saturated or partially unsaturated heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 8- to 14-membered aryl; or an 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; where each occurrence of R.sup.y is independently H, or an optionally substituted radical selected from the group consisting of C.sub.1-6 aliphatic, 3- to 7-membered heterocyclic, phenyl, and 8- to 10-membered aryl, and where two or more adjacent R.sup.y groups can be taken together to form an optionally substituted saturated, partially unsaturated, or aromatic 5- to 12-membered ring containing 0 to 4 heteroatoms, with the proviso that R.sub.1 and R.sup.2 are not both hydrogen.

(80) In certain embodiments, in compounds of formula D1, at least one of R.sub.1 and R.sub.2 is an optionally substituted radical selected from the group consisting of C.sub.1-20 aliphatic and C.sub.1-20 heteroaliphatic. In certain embodiments, for compounds of formula D1, R.sub.1 and R.sub.2 are independently optionally substituted radicals selected from the group consisting of C.sub.1-20 aliphatic and C.sub.1-20 heteroaliphatic.

(81) In certain embodiments, for compounds of formula D1, at least one of R.sub.1 and R.sub.2 is t-butyl. In certain embodiments, for compounds of formula D1, R.sub.1 and R.sub.2 are both t-butyl.

(82) In certain embodiments, the present invention provides anhydro dimers with utility in the production of salen catalysts. In certain embodiments, such compounds have any of structures D2 through D8:

(83) ##STR00044## wherein Z is nitrogen or phosphorus, wherein the formal charge on Z satisfies valency requirements; X is halogen; C.sub.5-C.sub.20 aryloxy; C.sub.5-C.sub.20 aryloxy having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; C.sub.1-C.sub.20 carboxy; C.sub.1-C.sub.20 carboxy having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; C.sub.1-C.sub.20 alkoxy; C.sub.1-C.sub.20 alkoxy having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; C.sub.1-C.sub.20 alkylsulfonato; C.sub.1-C.sub.20 alkylsulfonato having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; C.sub.1-C.sub.20 amido; or C.sub.1-C.sub.20 amido having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; R.sup.11, R.sup.12, R.sup.13, R.sup.21, R.sup.22, R.sup.23, R.sup.24 and R.sup.25 are each independently hydrogen; oxo; C.sub.1-C.sub.20 alkyl; C.sub.1-C.sub.20 alkyl having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; C.sub.2-C.sub.20 alkenyl; C.sub.2-C.sub.20 alkenyl having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; C.sub.7-C.sub.20 alkylaryl; C.sub.7-C.sub.20 alkylaryl having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; C.sub.7-C.sub.20 arylalkyl; C.sub.7-C.sub.20 arylalkyl having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; or a metalloid radical of group XIV metal substituted by hydrocarbyl, two of R.sup.11, R.sup.12 and R.sup.13, or two of R.sup.21, R.sup.22, R.sup.23, R.sup.24 and R.sup.25 being optionally fused together to form a bridged structure; R.sup.31, R.sup.32 and R.sup.33 are each independently hydrogen; C.sub.1-C.sub.20 alkyl; C.sub.1-C.sub.20 alkyl having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; C.sub.2-C.sub.20 alkenyl; C.sub.2-C.sub.20 alkenyl having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; C7-C.sub.20 alkylaryl; C.sub.7-C.sub.20 alkylaryl having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; C.sub.7-C.sub.20 arylalkyl; C.sub.7-C.sub.20 arylalkyl having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; or a metalloid radical of group XIV metal substituted by hydrocarbyl, two of R.sup.31, R.sup.32 and R.sup.33 being optionally fused together to form abridged structure; R.sup.62 is hydrogen, methyl, ethyl, n-propyl, isopropyl or tert-butyl; n is from 1 to 20; X is oxygen, sulfur or NR; and R is hydrogen; C.sub.1-C.sub.20 alkyl; C.sub.1-C.sub.20 alkyl having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; C.sub.2-C.sub.20 alkenyl; C.sub.2-C.sub.20 alkenyl having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; C.sub.7-C.sub.20 alkylaryl; C.sub.7-C.sub.20 alkylaryl having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus; C.sub.7-C.sub.20 arylalkyl; C.sub.7-C.sub.20 arylalkyl having one or more functional moieties selected from the group consisting of halogen, nitrogen, oxygen, silicon, sulfur and phosphorus.

(84) In certain embodiments, the invention encompasses anhydro dimers with any of structures D9 through D13:

(85) ##STR00045## wherein X, n, and R.sup.62 are as defined above.

(86) In certain embodiments, the invention encompasses anhydro dimers with any of structures D14 through D18:

(87) ##STR00046## wherein, R.sup.26 the group consisting of: hydrogen, halogen, optionally substituted C.sub.1-20 aliphatic, and optionally substituted aryl; R.sup.a and R.sup.b are, independently at each occurrence, selected from the group consisting of hydrogen, halogen, and optionally substituted C.sub.1-4 aliphatic; Q is selected from the group consisting of: halogen, hydroxyl, sulfonate ester, a neutral or cationic nitrogen-containing functional group, and a neutral or cationic phosphorous-containing functional group; and m is from 1 to 10.

(88) In certain embodiments, for compounds of formulae D14-D18, Q is selected from the group consisting of: bromine, chlorine, iodine, OH, OSO.sub.2R, N(R).sub.2, N(R).sub.3.sup.+, P(R).sub.3.sup.+, substituted guanidine, guanidinium, and amidine. In certain embodiments, in compounds of formulae D14-D18, Q is hydroxyl. In certain embodiments, in compounds of formulae D14-D18, Q is bromine. In certain embodiments, for compounds of formulae D14-D18, Q is a guanidine. In certain embodiments, for compounds of formulae D14-D18, Q is TBD. In certain embodiments, for compounds of formulae D14-D18, Q is [N-methyl TBD].sup.+. In certain embodiments, for compounds of formulae D14-D18, Q is trialkylammonium.

(89) In certain embodiments, for compounds of formulae D14-D18, R.sup.26 is selected from the group consisting of: H, halogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, and t-butyl. In certain embodiments, for compounds of formulae D14-D18, R.sup.26 is t-butyl.

(90) In certain embodiments, for compounds of formulae D14-D18, n is an integer between 1 and 6. In certain embodiments, for compounds of formulae D14-D18, n is an integer between 2 and 5. In certain embodiments, for compounds of formulae D14-D18, n is 3 or 4.

EXAMPLES

Example 1

(91) ##STR00047##

(92) A mixture of 5-tert-butyl-2-hydroxy-3-iodobenzaldehyde (8.5 g, 28.1 mmol) and Eaton's reagent (7.5% w/w, 30 mL) was stirred at ambient temperature for 2.5 h. The reaction mixture was added dropwise to a cold (0-5 C.) solution of NaOH (24 g, 600 mmol) in water (45 mL). After the addition was complete, the solid that formed was collected by vacuum filtration and the filter cake was washed well with water (330 mL). The anhydro dimer was obtained as a tan powder after drying (5.4 g, 65%). .sup.1H NMR (400 MHz, CDCl.sub.3): 1.27 (s, 18H), 6.37 (s, 2H), 7.32 (d, 2H, J=2.2 Hz), 7.71 (d, 2H, J=2.2 Hz).

Example 2

(93) ##STR00048##

(94) A mixture of 5-tert-butyl-3-bromo-2-hydroxybenzaldehyde (5 g, 19.4 mmol) and Eaton's reagent (7.5% w/w, 20 mL) was stirred at ambient temperature for 5 h. The reaction mixture was added dropwise to a cold (0-5 C.) solution of NaOH (16 g, 400 mmol) in water (35 mL). After the addition was complete, the solid that formed was collected by vacuum filtration and the filter cake was washed well with water (330 mL). The anhydro dimer was obtained as a tan powder in quantitative yield after drying (4.83 g, 100%). .sup.1H NMR (400 MHz, CDCl.sub.3): 1.27 (s, 18H), 6.42 (s, 2H), 7.30 (d, 2H, J=2.2 Hz), 7.51 (d, 2H, J=2.2 Hz).

Example 3

(95) ##STR00049##

(96) To a solution of 5-tert-butyl-3-(3-bromopropyl)-2-hydroxybenzaldehyde (5 g, 16.8 mmol) in EtOAc (9 mL) was added Eaton's reagent (5.5 mL). The reaction mixture was heated at 65 C for 4.5 h and then cooled to 0-5 C. Cold MeOH (10 mL) was added and the resulting slurry was filtered. The filter cake was washed with cold MeOH (210 mL) and the filter cake was dried to give the anhydro dimer as a white powder (3.25 g, 67%). .sup.1H NMR (300 MHz, CDCl.sub.3): 1.27 (s, 18H), 2.07 (m, 2H), 2.71 (m, 2H), 3.29 (m, 2H), 6.32 (s, 2H), 7.13 (d, 2H, J=2.4 Hz), 7.15 (d, 2H, J=2.4 Hz).

Example 4

(97) ##STR00050##

(98) Zinc powder (1.28 g, 19.6 mmol) suspended in DMF (7 mL) was treated with I.sub.2 (0.21 g, 1 mmol) under nitrogen at ambient temperature. When the red color dissipated, the mixture was warmed to 50 C., and a charge of 1-chloro-4-iodobutane (2 mL, 16.3 mmol) was added. After two hours, the anhydro dimer of 5-tert-butyl-3-bromo-2-hydroxybenzaldehyde (2.3 g, 4.6 mmol) and PdCl.sub.2-dppf-CH.sub.2Cl.sub.2 (0.37 g, 0.45 mmol) were added. Heating at 60 C. was continued for 17 h. Afterwards, water was added (20 mL) and a precipitate formed. The material was collected by vacuum filtration and dried to give the desired product in high yield (2.18 g, 90%). .sup.1H NMR (400 MHz, CDCl.sub.3): 1.26 (s, 18H), 1.65 (m, 2H), 1.76 (m, 2H), 2.58 (m, 2H), 3.49 (t, 2H, J=6.5 Hz), 6.32 (s, 2H), 7.08 (d, 2H, J=2.4 Hz), 7.12 (d, 2H, J=2.4 Hz).

Example 5

(99) ##STR00051##

(100) A flask was charged with Pd(OAc).sub.2 (2.2 mg, 0.01 mmol), neomenthyldiphenylphosphine (13 mg, 0.04 mmol)), methyl acrylate (55 mg, 0.64 mmol), Et.sub.3N (55 mg, 0.54 mmol), and the anhydro dimer of 5-tert-butyl-3-bromo-2-hydroxybenzaldehyde (55 mg, 0.11 mmol). The contents were suspended in ACN (1.25 mL) under N.sub.2 and heated at 95 C. for 14 h. The mixture was cooled to ambient temperature and the resulting slurry was filtered. The filter cake was washed with heptane (0.5 mL) and dried to provide the desired product as a white solid (42 mg, 0.083 mmol, 75%). .sup.1H NMR (400 MHz, CDCl.sub.3): 1.26 (s, 18H), 3.82 (s, 6H), 6.41 (s, 2H), 6.57 (d, 2H, J=16 Hz), 7.35 (d, 2H, J=2.4 Hz), 7.50 (d, 2H, J=2.4 Hz), 7.88 (d, 2H, J=16 Hz).

Example 6

(101) ##STR00052##

(102) The anhydro dimer of 5-tert-butyl-2-hydroxy-3-iodobenzaldehyde (150 mg, 0.25 mmol) was dissolved in THF (0.25 mL) and treated with a solution of iPrMgCl in THF (2 M, 0.66 mmol) at ambient temperature under nitrogen. Within 0.5 h, a solution of CuCN-2LiCl in THF (1 M, 0.5 mmol) was added and the mixture was allowed to stir another 0.5 h. A charge of 1,3-dibromopropane (0.067 mL, 0.66 mmol) was added and the mixture was heated to 60 C. After 2 h, an HPLC aliquot showed formation of the desired product as determined by comparison with the HPLC chromatogram of an authentic sample.

Example 7

(103) ##STR00053##

(104) The anhydro dimer of 5-tert-butyl-2-hydroxybenzaldehyde (630 mg, 1.9 mmol) and N-bromosuccinamide (665 mg, 3.7 mmol) was dissolved in DMF (4 mL) at room temperature. After 3 h, the temperature was gradually increased to 60 C. More NBS (1.75 g, 9.7 mmol) was added to the reaction over 7 h. The reaction was diluted with water and the precipitate that formed was collected by vacuum filtration and washed well with water. After drying, the desired product was obtained as a powder (710 mg, 76%). .sup.1H NMR (400 MHz, CDCl.sub.3): 1.27 (s, 18H), 6.42 (s, 2H), 7.3 (d, J=2.1 Hz, 2H), 7.51 (d, J=2.1 Hz, 2H).

Example 8

(105) ##STR00054##

(106) The anhydro dimer of 5-tert-butyl-3-(3-bromopropyl)-2-hydroxybenzaldehyde (1 g, 1.7 mmol) was combined with 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) (0.53 g, 3.8 mmol) in 10 mL acetonitrile. The mixture was heated to 65 C. and held for 16 h. The solution was then washed with hexanes (110 mL) and concentrated to an oil. The oil was taken up in EtOH and treated with 1 M HCl (20 mL) at 65 C. After 1 h, conc. HCl (2 mL) was added. After 3 h, conc. H.sub.2SO.sub.4 (1 mL) was added and the reaction was stirred at 65 C. for another 3 h. The solvent was then removed and EtOAc was added to give a biphasic mixture. The aqueous layer was adjusted to pH 7 with aq. NaOH. The layers were separated and the aqueous was extracted again with dichloromethane. The organic extracts were concentrated to yield an oil (1.22 g). .sup.1H NMR (400 MHz, CDCl.sub.3): 1.23 (s, 9H), 1.89 (m, 4H), 1.99 (m, 2H), 2.69 (dd, J=7.5, 8.9 Hz, 2H), 3.27 (m, 6H), 3.41 (t, J=7.3 Hz, 2H), 3.57 (t, J=7.3 Hz, 2H), 7.32 (d, J=2.5 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H), 9.90 (s, 1H).

Example 9

(107) ##STR00055##

(108) The anhydro dimer of 5-tert-butyl-3-(3-bromopropyl)-2-hydroxybenzaldehyde (0.5 g, 0.86 mmol) was combined with 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MeTBD) (0.37 g, 2.6 mmol) in 1.5 mL acetonitrile. The mixture was heated to 70 C. and held for 5 h. The reaction was then allowed to cool to room temperature overnight. Concentrated HCl (0.8 mL, 9.9 mmol) was added and the mixture was heated over the range of 50-65 C. for 8 h with an additional charge of conc. HCl (0.4 mL, 4.9 mmol) after 5 h. The reaction yielded the desired product as a solution in aq. HCl and ACN. Low resolution mass spec (m/z): [M.sup.+] 372.3, [(2M-H).sup.+] 743.0.

OTHER EMBODIMENTS

(109) The foregoing has been a description of certain non-limiting embodiments of the invention. Accordingly, it is to be understood that the embodiments of the invention herein described are merely illustrative of the application of the principles of the invention. Reference herein to details of the illustrated embodiments is not intended to limit the scope of the claims, which themselves recite those features regarded as essential to the invention.