Composition, synthesis, and use of new arylsulfonyl isonitriles

Abstract

This invention relates to novel isonitriles, including arylsulfonyl isonitriles, and methods for their synthesis. The isonitriles include a conjugated ring system. The structure is designed with the flexibility to have multiple substitution patterns. The isonitriles may be used in applications including, but not limited to, pharmaceutical compositions.

Claims

1. An isonitrile of a general structure of Formula II: ##STR00089## wherein R.sup.1, R.sup.3 and R.sup.5 are each hydrogen and, R.sup.2 and R.sup.4 are the same and are each selected from halogen excluding Cl, and OX wherein X is selected from alkyl and aryl.

2. An isonitrile of a general structure of Formula III: ##STR00090## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are the same or different and each is hydrogen, or wherein, one of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is selected from halogen, alkyl, haloalkyl and OX wherein X is selected from alkyl and aryl, and each remaining R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 substituent is hydrogen.

3. A method of preparing an arylsulfonyl isonitrile represented by a general structure of Formula II: ##STR00091## wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same and each is hydrogen, or wherein, one of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is alkyl and each remaining R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 substituent is hydrogen, or wherein, one of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is selected from F, Cl, CF.sub.3 and CCl.sub.3, and each remaining R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 substituent is hydrogen, or wherein, two of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OX, wherein X is selected from alkyl and aryl, and each remaining R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 substituent is hydrogen, or wherein, one of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OX, wherein X is aryl, and each remaining R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 substituent is hydrogen, or wherein, one of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OX, wherein X is selected from alkyl and aryl, one of R.sup.1,R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is selected from halogen and haloalkyl, and each remaining R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 substituent is hydrogen, or wherein, each of R.sup.2 and R.sup.4 is the same or different and is selected from halogen and haloalkyl, and each of R.sup.1, R.sup.3 and R.sup.5 is hydrogen, wherein R.sup.1 and R.sup.2, or R.sup.2 and R.sup.3, or R.sup.3 and R.sup.4 , or R.sup.4 and R.sup.5 together form a benzo ring, which forms a naphthalyl group, comprising: reacting an arylsulfinate of the below Formula V with formamide to form an intermediate formamide-containing material of the below Formula VI; and dehydrating the intermediate formamide-containing material of the below Formula VI to form the arylsulfonyl isonitrile of the Formula II: ##STR00092##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The various embodiments of the invention will be better understood when read with reference to the following figures:

(2) FIG. 1 illustrates a condensation/dehydration reaction scheme for synthesis of an arylsulfonyl isonitrile, in accordance with certain embodiments of the invention;

(3) FIG. 2 illustrates a double alkylation reaction scheme for synthesis of an arylsulfonyl isonitrile, in accordance with certain embodiments of the invention;

(4) FIG. 3 illustrates NMR data relating to the synthesis ((isocyanomethyl)sulfonyl) benzene, in accordance with certain embodiments of the invention;

(5) FIGS. 4 and 5 illustrate NMR data relating to the synthesis of 2-((isocyanomethyl)sulfonyl)naphthalene, in accordance with certain embodiments of the invention;

(6) FIGS. 6 and 7 illustrate NMR data relating to the synthesis of 1-fluoro-4-((isocyanomethyl)sulfonyl)benzene, in accordance with certain embodiments of the invention;

(7) FIGS. 8 and 9 illustrate NMR data relating to the synthesis of 1-chloro-4-((isocyanomethyl)sulfortyl)benzene, in accordance with certain embodiments of the invention;

(8) FIGS. 10 and 11 illustrate NMR data relating to the synthesis of 1-((isocyanomethyl)sulfonyl)-4-(trifluoromethyl)benzenesulfinate, in accordance with certain embodiments of the invention;

(9) FIGS. 12 and 13 illustrate NMR data relating to the synthesis of 1,3-dichloro-5-((isocyanomethyl)sulfonyl)benzene, in accordance with certain embodiments of the invention;

(10) FIGS. 14 and 15 illustrate NMR data relating to the synthesis of 1-((isocyanomethyl)sulfonyl)-2-methoxybenzene, in accordance with certain embodiments of the invention;

(11) FIGS. 16 and 17 illustrate NMR data relating to the synthesis of 1-((isocyanoinethyl)sulfonyl)-2-phenoxybenzene, in accordance with certain embodiments of the invention;

(12) FIGS. 18 and 19 illustrates NMR data relating to the synthesis of 4-((isocyanomethypsulfonyl)-1,2-dimethoxybenzene, in accordance with certain embodiments of the invention;

(13) FIGS. 20 and 21 illustrate NMR data relating to the synthesis of 2-((isocyanomethyl)sulfonyl)-1,3-dimethoxybenzene, in accordance with certain embodiments of the invention; and

(14) FIGS. 22 and 23 illustrate NMR data relating to the synthesis of 2-((isocyanomethyl)sulfonyl)-1-methoxy-3-(trifluoromethyl)benzene, in accordance with certain embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

(15) The invention relates in general to novel isonitrile compounds and, in particular, to new arylsulfonyl isonitriles that may be synthesized from readily available materials. The structures of the arylsulfonyl isonitriles are designed with the flexibility to have multiple substitution patterns.

(16) Other than the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, processing conditions and the like used in the specification and claims are to be understood as being modified in all instances by the term about. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

(17) Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical values, however, may contain certain errors, such as, for example, equipment and/or operator error, necessarily resulting from the standard deviation found in their respective testing measurements.

(18) Also, it should be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of 1 to 10 is intended to include all sub-ranges between (and including) the recited minimum value of 1 and the recited maximum value of 10, that is, having a minimum value equal to or greater than 1 and a maximum value of less than or equal to 10.

(19) Any patent, publication, or other disclosure material, in whole or in part, that is said to be incorporated by reference herein is incorporated herein only to the extent that the incorporated material does not conflict with existing definitions, statements, or other disclosure material set forth in this disclosure. As such, and to the extent necessary, the disclosure as explicitly set forth herein supersedes any conflicting material incorporated herein by reference. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material set forth herein will only be incorporated to the extent that no conflict arises between the incorporated material and the existing disclosure material.

(20) The present disclosure describes several different features and aspects of the invention with reference to various exemplary non-limiting embodiments. It is understood, however, that the invention embraces numerous alternative embodiments, which may be accomplished by combining any of the different features, aspects, and embodiments described herein in any combination that one of ordinary skill in the art would find useful.

(21) The new arylsulfonyl isonitrile compounds of the present invention have the general formula I:

(22) ##STR00005##

(23) wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is selected from hydrogen, alkyl, halogen, haloalkyl and OX wherein X is selected from alkyl and aryl, and R.sup.6 is selected from alkyl and cyclic or polycyclic, aromatic or non-aromatic, structure, e.g., one or more rings, such as, but not limited to a cyclic six-membered ring.

(24) In certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is selected from hydrogen, C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 haloalkyl and OX wherein X is selected from C.sub.1-C.sub.6 alkyl and aryl, and R.sup.6 is selected from C.sub.1-C.sub.6 alkyl and cyclic or polycyclic, aromatic or non-aromatic, structure, e.g., one or more rings, such as, but not limited to a cyclic six-membered ring.

(25) Further, in certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is selected from hydrogen, C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 haloalkyl and OX wherein X is selected from C.sub.1-C.sub.4 alkyl and aryl, and R.sup.6 is selected from C.sub.1-C.sub.4 alkyl and cyclic or polycyclic, aromatic or non-aromatic, structure, e.g., one or more rings, such as, but not limited to a cyclic six-membered ring.

(26) Furthermore, in certain embodiments, two of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5, such as, but not limited to R.sup.1 and R.sup.2 or R.sup.2 and R.sup.3, can come together to form a benzo ring.

(27) In certain embodiments, X is phenyl.

(28) In certain embodiments, R.sup.6 is CH.sub.2.

(29) In certain embodiments, halogen is selected from fluoride and chloride.

(30) In certain embodiments, the haloalkyl is CF.sub.3.

(31) In certain embodiments, one of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 haloalkyl or OX and the remaining R substituents are the same and each is hydrogen.

(32) In certain embodiments, R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are the same and each is hydrogen, and R.sup.3 is C.sub.1-C.sub.4 alkyl or halogen.

(33) In certain embodiments, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same and each is hydrogen, and R.sup.5 is C.sub.1-C.sub.4 alkyl or OX.

(34) In certain embodiments, two of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 haloalkyl or OX and the remaining R substituents are each hydrogen.

(35) In certain embodiments, two of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same and each is C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 haloalkyl or OX and the remaining R substituents are the same and each is hydrogen.

(36) In certain embodiments, R.sup.1, R.sup.3 and R.sup.5 are the same and each is hydrogen and, R.sup.2 and R.sup.4 are the same and each is halogen or OX.

(37) In certain embodiments, the new arylsulfonyl isonitrile compounds of the present invention have the general formula II:

(38) ##STR00006##

(39) wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is selected from hydrogen, alkyl, halogen, haloalkyl and OX wherein X is selected from alkyl and aryl.

(40) In certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is selected from hydrogen, C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 haloalkyl and OX wherein X is selected from C.sub.1-C.sub.6 alkyl and aryl.

(41) Further, in certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is selected from hydrogen, C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 haloalkyl and OX wherein X is selected from C.sub.1-C.sub.4 alkyl and aryl.

(42) Furthermore, in certain embodiments, two of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5, such as, but not limited to R.sup.1 and R.sup.2 or R.sup.2 and R.sup.3, can come together to form a benzo ring.

(43) In certain embodiments, X is phenyl.

(44) In certain embodiments, halogen is selected from fluoride and chloride.

(45) In certain embodiments, the haloalkyl is CF.sub.3.

(46) In certain embodiments, one of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 haloalkyl or OX and the remaining R substituents are the same and each is hydrogen.

(47) In certain embodiments, R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are the same and each is hydrogen, and R.sup.3 is C.sub.1-C.sub.4 alkyl or halogen.

(48) In certain embodiments, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same and each is hydrogen, and R.sup.5 is C.sub.1-C.sub.4 alkyl or OX.

(49) In certain embodiments, two of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 haloalkyl or OX and the remaining R substituents are each hydrogen.

(50) In certain embodiments, two of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same and each is C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 haloalkyl or OX and the remaining R substituents are the same and each is hydrogen.

(51) In certain embodiments, R.sup.1, R.sup.3 and R.sup.5 are the same and each is hydrogen and, R.sup.2 and R.sup.4 are the same and each is halogen or OX.

(52) In certain other embodiments, the new arylsulfonyl isonitrile compounds of the present invention have the general formula III:

(53) ##STR00007##

(54) wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is selected from hydrogen, alkyl, halogen, haloalkyl and OX wherein X is selected from alkyl and aryl.

(55) In certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is selected from hydrogen, C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 haloalkyl and OX wherein X is selected from C.sub.1-C.sub.6 alkyl and aryl.

(56) Further, in certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is selected from hydrogen, C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 haloalkyl and OX wherein X is selected from C.sub.1-C.sub.4 alkyl and aryl.

(57) Furthermore, in certain embodiments, two of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5, such as, but not limited to R.sup.1 and R.sup.2 or R.sup.2 and R.sup.3, can come together to form a benzo ring.

(58) In certain embodiments, X is phenyl.

(59) In certain embodiments, halogen is selected from fluoride and chloride.

(60) In certain embodiments, the haloalkyl is CF.sub.3.

(61) In certain embodiments, one of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 haloalkyl or OX and the remaining R substituents are the same and each is hydrogen.

(62) In certain embodiments, R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are the same and each is hydrogen, and R.sup.3 is C.sub.1-C.sub.4 alkyl or halogen.

(63) In certain embodiments, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same and each is hydrogen, and R.sup.5 is C.sub.1-C.sub.4 alkyl or OX.

(64) In certain embodiments, two of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same or different and each is C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 haloalkyl or OX and the remaining R substituents are each hydrogen.

(65) In certain embodiments, two of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are the same and each is C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 haloalkyl or OX and the remaining R substituents are the same and each is hydrogen.

(66) In certain embodiments, R.sup.1, R.sup.3 and R.sup.5 are the same and each is hydrogen and, R.sup.2 and R.sup.4 are the same and each is halogen or OX.

(67) For example, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 can include the following combinations.

(68) TABLE-US-00001 R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 H H H H H H H CH.sub.3 H H H H H H CH.sub.3 H H F H H H H Cl H H H H CF.sub.3 H H H Cl H Cl H H H H H OCH.sub.3 H H H H OPh H H OCH.sub.3 OCH.sub.3 H OCH.sub.3 H H H OCH.sub.3 OCH.sub.3 H H CF.sub.3 H CH.sub.3 H H H H H H CH.sub.3 H H

(69) In certain other embodiments, the new arylsulfonyl isonitrile compounds of the present invention have the general formula IV:

(70) ##STR00008##

(71) wherein R.sup.6 is as defined for Formula I.

(72) The compounds of the invention may be readily synthesized using organic chemistry techniques. The syntheses of various embodiments of the isonitrile precursors and products are described herein. It should be noted that the featured embodiments are intended to be exemplary and are in no way limiting to the scope of the isonitrile precursors and products as described herein. For example, the compounds of Formulas I and II can be prepared according to certain embodiments of the invention. In general, condensation and dehydration reactions may be conducted to form the compounds of Formulas I and II. These compounds then may be used as precursors or building blocks to form other arylsulfonyl isonitriles. In certain embodiments, compounds represented by Formula I and Formula II can be subjected to double alkylation reactions to form the arylsulfonyl isonitrile represented by Formula III. Further, the compounds of Formulas III and IV may be used as precursors or building blocks to form other isonitrile compounds, such as by exchange reactions.

(73) Certain specific synthesis examples are discussed in detail in FIGS. 1 and 2.

(74) FIG. 1 shows a reaction scheme for preparing arylsulfonyl isonitrile of Formula II, in accordance with certain embodiments of the invention. Compounds represented by the general structure of Formula II herein can be prepared by known organic reactions, such as, Mannich condensation reactions. As shown in FIG. 1, alkyl sulfonate (i.e., methyl benzenesulfonate) is reacted with formamide in formic acid, paraformaldehyde and toluene to form an intermediate (sulfonyl formamide) product. The reaction can be conducted at various temperatures and typically ranges from about 50 C. to about 110 C., and preferably from about 90 C. to about 110 C. The temperature can be achieved using conventional methods and apparatus in the art. In certain embodiments, microwave heating is employed.

(75) It is contemplated that other suitable acids and solvents known in the art can be used. Non-limiting examples of suitable acids include, but are not limited to, formic acid, acetic acid, proprionic acid, trifluoroacetic acid, chloroacetic acid, toluenesulfonic acid, camphor sulfonic acid, and mixtures thereof. Non-limiting examples of suitable solvents include, but are not limited to, toluene, formaldehyde, paraformaldehyde, dimethyl formamide, dimethylacetamide, hexamethylphosphoramide, dimethylsulphoxide, tetrahydrofuran and mixtures thereof.

(76) The intermediate (formamide) product then undergoes a dehydration reaction to remove the water molecule, such that NHCHO group in the intermediate product is NC in the final isonitrile product. Various dehydration methods and processes can be used. In accordance with certain embodiments of the invention and as shown in FIG. 1, the intermediate (sulfonyl formamide) product is reacted with a dehydrating agent to form an arylsulfonyl isonitrile product, i.e., ((isocyanomethyl)sulfonyl)benzene (represented by the general structure of Formula II herein, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each hydrogen). It is contemplated that other suitable solvents and dehydrating agents known in the art can be used. Non-limiting examples of suitable solvents include, but are not limited to, dichloromethane, toluene, chloroform and mixtures thereof. Non-limiting examples of suitable dehydrating agents include, but are not limited to, phosphoryl chloride, triphenylphosphine dichloride, triphenylphosphine dibromide, triphenylphosphinelcarbon tetrabromide, sulfonyl chloride, oxalyl chloride and mixtures thereof. The dehydration step can be conducted at various temperatures and is typically carried out at a temperature within a range from 30 C. to 0 C.

(77) The resulting product may be purified by conventional purification methods and processes known in the art such as, but not limited to, vacuum distillation, flash chromatography, preparative thin layer chromatography and radial chromatography.

(78) As shown in FIG. 2, compounds represented by the general structure of Formula II herein may be used as precursors or building blocks to form other arylsulfonyl isonitriles. For example, compounds of Formula II can be used to prepare arylsulfonyl isonitriles represented by the general structure of Formula III herein. In particular, in FIG. 2, a sulfonylmethyl isonitrile product as shown in FIG. 1, i.e., ((isocyanomethyl)sulfonyl)benzene, undergoes an alkylation reaction to replace the CH.sub.2 group bridging the arylsulfonyl and the isonitrile to form a sulfonyl isonitrile product (represented by the general structure of Formula III herein, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are each hydrogen). As shown in FIG. 2, the sulfonylmethyl isonitrile reactant is reacted with the dihalide 1,5-dibromopentane in sodium hydride and dimethyl formamide (DMF). The sodium hydride is typically present in an amount in the range from 2 to 5 equivalents. The alkylation reaction can be conducted at various temperatures and typically the temperature is in the range from 10 C. to room temperature. The time for carrying out the alkylation can also vary and typically is carried out in a time period in the range from 10 hours to 72 hours. It is contemplated that other bases known in the art for use in organic synthesis can be used, such as but not limited to, sodium hydroxide, potassium hexamethyldisilazide, lithium amide, sodium amide and mixtures thereof. Further, it is contemplated that any solvent can be used that is compatible with the base, e.g., sodium hydride, such as but not limited to, dimethylacetamide, hexamethylphosphoramide, dimethylsulphoxide, tetrahydrofuran, toluene and mixtures thereof. It is also contemplated that other dihalide compounds known in the art can be used. Non-limiting examples of suitable dihalides include, but are not limited to, 1,3-dihalopropane, 1,4-dihalobutane, 1,5-dihalopentane, 1,6-dihalohexane and mixtures thereof.

(79) The resulting product may be purified by conventional purification methods and processes known in the art such as, but not limited to, vacuum distillation, flash chromatography, preparative thin layer chromatography and radial chromatography.

(80) Table 1 shows suitable alkyl sulfonates for use in the invention and, arylsulfonyl isonitriles synthesized by suitable formamide synthesis and dehydration methods.

(81) TABLE-US-00002 TABLE 1 Alkyl Sulfonates 4a 0 4b 4c 4d 4e 4f 4g 4h 4i t1 4j 0 4k 4l 4m 4n 4o s1 s2 11p 11q 11r Formamide/Dehydration Synthesis Of Arylsulfonyl Isonitriles 0 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 0 3k 3l 3m 3n Oxidizing Formamides 3p 3q 3r 3s 3t

(82) Moreover, other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification be considered as exemplary only. Furthermore, the following examples are meant to be illustrative of certain embodiments of the invention and are not intended to be limiting as to the scope of the invention.

EXAMPLES

(83) General Experimental Conditions:

(84) Tetrahydrofuran (THE) was freshly distilled from Na/benzophenone ketyl prior to use. Dichloromethane and acetonitrile were dried by passing through an alumina and molecular sieve drying train, commercially available from Innovative Technology Inc. (Model: PS-MD-7). Isopropanol, ethanol and toluene were used as received. Other reagents were purchased at analytical or ACS grade, and used without further purification unless otherwise stated. A Biotage microwave reactor (Model: Initiator) and 2-20 mL reaction tubes were employed (with the irradiation absorption parameter set to NORMAL). Thin layer chromatography (TLC) was performed with UV active (w/F-254) glass backed silica gel plates (Dynamic Adsorbents Inc.). TLC plates were visualized by exposure to short wavelength UV light (254 inn) and/or staining with a phosphomolybdic acid solution (20% in ethanol) or iodine. Flash chromatography was performed using SiliaFlash silica gel P60 (30-400 mesh) purchased from Silicycle, Florisil (100-200 mesh) purchased from Alfa Aesar, or SiliaBond Diol purchased from Silicycle. Radial chromatography was performed on a Harrison Research Chromatotron using rotors covered with SiO.sub.2 and leveled to 1, 2, and 4 mm thickness. .sup.1H NMR and .sup.13C NMR high resolution nuclear magnetic resonance spectra were obtained on a Bruker Avance 400 or Bruker Avance 500 spectrometers. .sup.1H NMR data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, quin=quintet, dd=doublet of doublet, dt=doublet of triplet, ddd=doublet of doublet of doublets, td=triplet of doublets, qd=quartet of doublets, m=multiplet, etc.), integration, and coupling constants (Hz). .sup.13C NMR data are reported in parts per million (ppm) on the scale. High resolution mass spectra (HRMS) were recorded on a 6500 Series Accurate Mass Quadrupole Time of Flight LC/MS using a nano ESI. Infrared spectra were recorded on a Perkin Elmer Frontier FT-IR spectrometer with a universal ATR sampling accessory.

(85) General Sulfinate Synthesis from Thiols

(86) Solid N-bromosuccinimide powder (2 equiv) was added in one portion to a 0 C., methanol:dichloromethane solution (1:1 by volume) of the thiol (1 equiv). The cold bath was removed and, after 1 hour, the mixture was poured into 0 C., saturated NaHCO.sub.3 solution. The biphasic mixture was transferred to a separation funnel and shaken until discoloration. The phases were separated and the aqueous layer was extracted with dichloromethane (3). The combined organic extract was washed with brine, dried (Na.sub.2SO.sub.4), and concentrated to afford a yellowish crude sulfinate. The crude sulfinate was purified by filtration through a SiO.sub.2 plug (1050 mm) to afford pure methyl sulfinate.

Example 1

(87) ##STR00049##

(88) Methyl benzenesulfinate (compound 4a) was prepared from thiophenol (4 g, 36.4 mmol) according to the general sulfinate synthesis affording 5.27 g of compound 4a (93%) as a colorless oil after purification by SiO.sub.2 flash chromatography (hexanes:Et.sub.2O gradient, 100:0 to 90:10).

Example 2

(89) ##STR00050##

(90) Methyl 4-methylbenzenesulfinate (compound 4b) was prepared from 4-methylbenzenethiol (4 g, 32.2 mmol) according to the general sulfinate procedure to afford 5.3 g of compound 4b (97%) as a colorless oil after purification by filtration on a SiO.sub.2 plug (1050 mm) using hexanes:ethyl ether (90:10) as the eluent.

Example 3

(91) ##STR00051##

(92) Methyl 2-methylbenzenesulfinate (compound 4c) was prepared from 2-methylbenzenethiol (2 g, 16.1 mmol) according to the general sulfinate procedure to afford 2.7 g of compound 4c (99%) as a slightly amber oil after purification by SiO.sub.2 radial chromatography (4 mm rotor using hexanes:EtOAc, 98:2 as the eluent).

Example 4

(93) ##STR00052##

(94) Methyl naphthalene-2-sulfinate (compound 4d) was prepared from 2-naphtalenethiol (2 g. 12.48 mmol) according to the general sulfinate procedure to afford 2.48 g of compound 4d (96%) as slightly yellow crystals after purification by SiO.sub.2 column chromatography (hexanes:acetone gradient, 90:10 to 80:20).

Example 5

(95) ##STR00053##

(96) Methyl 4-fluorobenzenesulfinate (compound 4e) was prepared from 4-fluorothiophenol (400 mg, 3.1 mmol) according to the general sulfinate procedure to afford 500 mg of compound 4e (92%) as a colorless oil after purification by SiO.sub.2 radial chromatography (2 mm rotor using hexanes:EtOAc:acetone, 80:10:10 as the eluent).

Example 6

(97) ##STR00054##

(98) Methyl 4-chlorobenzenesulfinate (compound 4f) was prepared from 4-chlorothiophenol (2 g, 13.8 mmol) according to the general sulfinate procedure to afford 2.3 g of compound 4f (87%) as a colorless oil after purification by SiO.sub.2 radial chromatography (4 mm rotor using hexanes:EtOAc, 80:20 as the eluent).

Example 7

(99) ##STR00055##

(100) Methyl 4-(trifluoromethyl)benzenesulfinate (compound 4g) was prepared from 4-trifluoromethylbenzenethiol (400 mg, 2.25 mmol) according to the general sulfinate procedure to afford 410 mg of compound 4g (82%) as a colorless oil after purification by SiO.sub.2 radial chromatography (1 mm rotor using a hexanes:EtOAc as eluent with a gradient ranging from 90:10 to 80:20). .sup.1H NMR (400 MHz, benzene-d.sub.6) 7.32 (d, J=7.8 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 2.94 (s, 2H). .sup.13C NMR (100 MHz, benzene-do) 148.53 (s), 133.52 (q, J=32.5 Hz), 126.24, 126.06 (q, J=3.7 Hz), 124.15 (q, J=272.8 Hz), 48.98. IR (ATR) 2949, 1320, 1125, 1058, 959, 698 cm.sup.1. HRMS calculated for C.sub.8H.sub.7F.sub.3O.sub.2S, 225.0192. found 225.0190 (M+Na).sup.+.

Example 8

(101) ##STR00056##

(102) Methyl 3,5-dichlorobenzenesulfinate (compound 4h) was prepared according to a published method: Na.sub.2CO.sub.3 (2.98 g, 28.1 mmol) was added to a cold (0 C.) of 1,2-bis(3,5-dichlorophenyl)disulfane (2 g, 5.62 mmol) in MeOH (112 mL). Bromine (870 L, 16.8 mmol) was then added dropwise via syringe. After stirring at rt for 3 h, the volatiles were removed in vacuo, the residue was diluted with cold water (100 mL) and EtOAc (100 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2100 mL). The combined organic extract was washed with brine, dried (Na.sub.2SO.sub.4), and concentrated to afford 2.09 g of compound 4h (100%) as a colorless oil which crystallized after purification by filtration through a SiO.sub.2 plug using hexanes:Et.sub.2O:dichloromethane (90:5:5) as eluent. Mp 55 C. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.58 (d, J=1.9 Hz, 1H), 7.54 (t, J=1.9 Hz, 1H), 3.53 (s, 1H). .sup.13C NMR (125 MHz, CDCl.sub.3) 147.37, 136.34, 132.38, 124.12, 50.35. IR (ATR): 3068, 1566, 1132, 958 cm.sup.1. HRMS calculated for C.sub.7H.sub.6Cl.sub.2O.sub.2S, 224.9538. found 224.9534 (MH).sup.+.

Example 9

(103) ##STR00057##

(104) Methyl 2-methoxybenzenesulfinate (compound 4i) was prepared from 2-methoxybenzenethiol (8 g, 57.1 mmol) according to the general sulfinate procedure to afford 10.8 g of compound 4i (100%) as a slightly yellow oil after purification by SiO.sub.2 column chromatography (hexanes:acetone, 50:50 to 0:100).

Example 10

(105) ##STR00058##

(106) 2-Phenoxythiophenol (compound t1) was prepared as follows. Elemental sulfur (565 mg, 17.6 mmol) was added in one portion, under a N.sub.2 blanket, to a 0 C., Et.sub.2O solution of (2-phenoxyphenyl)lithium. The cooling bath was removed and after 30 min, the mixture was diluted with cold water (100 mL) and then acidified with 2M aqueous HCl until the pH1. The mixture was left in a freezer (30 C.) for 20 min and then filtered to afford 2.3 g of a white solid (65%). The crude product was recrystallized from MeOH, to afford 1.7 g (48%) of compound ti as white crystals (mp 63 C.).

Example 11

(107) ##STR00059##

(108) Methyl 2-phenoxybenzensulfinate (compound 4j) was prepared from 2-phenoxythiophenol (1.63 g, 8.06 mmol) according to the general sulfinate procedure to afford 1.81 g of compound 4j (91%) as a colorless oil after purification by filtration through a SiO.sub.2 plug (1050 mm, using a hexanes:dichloromethane:Et.sub.2O gradient 90:5:5 to 80:10:10). .sup.1H NMR (500 MHz, Chloroform-d) 7.94 (dd, J=7.8, 1.7 Hz, 1H), 7.50-7.42 (m, 1H), 7.37 (dd, J=8.6, 7.3 Hz, 2H), 7.27 (td, J=7.6, 1.0 Hz, 1H), 7.20-7.15 (m, 1H), 7.04 (d, J=7.9 Hz, 2H), 6.89 (d, J=8.1 Hz, 1H), 3.59 (s, 3H). .sup.13C NMR (125 MHz. Chloroform-d) 156.16, 155.52, 134.17, 133.84, 130.07, 126.25, 124.47, 123.35, 119.44, 118.27, 51.36. IR (ATR) 2940, 1581, 1465, 1227, 1120, 965, 691. HRMS calculated for C.sub.13H.sub.12O.sub.3S, 271.0399. found 271.0401 (M+Na)+.

Example 12

(109) ##STR00060##

(110) Methyl 3,4-dimethoxybenzenesulfinate (compound 4k) was prepared as follows. Methanol (8.8 mL) and dry pyridine (3.5 mL, 43.4 mmol) were added sequentially to a flask immersed in an ice bath containing freshly prepared 3,4-dimethoxybenzenesulfinyl chloride (1.6 g, 7.24 mmol). After 2 h, the reaction was diluted with cold aqueous NaHCO.sub.3 and extracted with dichloromethane (410 mL). After removal of the volatiles, 1.21 g (77%) of relatively pure compound 4k were recovered as a slightly yellow oil: .sup.1H NMR (400 MHz, Chloroform-d) 7.28 (dd, J=8.3, 2.0 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.48 (s, 3H). .sup.13C NMR (100 MHz, Chloroform-d) 152.18, 149.48, 135.60, 118.91, 110.87, 107.27, 56.13, 56.12, 49.28. IR (ATR) 2940, 2839, 1504, 1256, 1231, 1117, 1019, 957, 672 cm.sup.1. HRMS calculated for C.sub.9H.sub.12O.sub.4S, 239.0348. found 239.0350 (M+Na).sup.+.

Example 13

(111) ##STR00061##

(112) Methyl 2-methylpropane-1-sulfinate (compound 4l) was prepared from isobutyl mercaptan (3 g, 33.27 mmol) according to the general sulfinate procedure to afford 3.97 g of compound 4l (88%) as a colorless oil after purification by SiO.sub.2 flash chromatography (hexanes:dichloromethane, 90:10 as eluent): .sup.1H NMR (500 MHz, Chloroform-d) 3.78 (s, 3H), 2.69 (dd, J=13.2, 7.6 Hz, 1H), 2.61 (dd, J=13.2, 6.6 Hz, 1H), 2.14 (nontuplet, J=6 Hz, 1H), 1.07 (d, J=3.0 Hz, 3H), 1.06 (d, J=2.9 Hz, 3H); .sup.13C NMR (125 MHz, Chloroform-d) 65.89, 54.41, 23.61, 22.68, 22.33. IR (ATR): 2962, 1125, 992, 684 cm; HRMS calculated for C.sub.5H.sub.12O.sub.2S, 159.0450. found 159.0444 (M+Na).sup.+.

Example 14

(113) ##STR00062##

(114) Methyl cyclohexanesulfinate (compound 4m) was prepared from cyclohexanethiol (2 g, 17.2 mmol) according to the general sulfinate procedure to afford 2.92 g of compound 4m (quant.) as a colorless oil after purification by SiO.sub.2 flash chromatography (hexanes:Et.sub.2O:dichloromethane, 90:5:5 as eluent). .sup.1H NMR (500 MHz, Chloroform-d) 3.78 (s, 3H), 2.56 (tt, J=11.7, 3.7 Hz, 1H), 2.06-1.94 (m, 2H), 1.93-1.81 (m, 1H), 1.74-1.65 (m, 1H), 1.46-1.18 (m, 6H); .sup.13C NMR (125 MHz, Chloroform-d) 63.44, 54.95, 25.56, 25.12, 25.03, 24.42, 24.03. IR (ATR): 2930, 1450, 1129, 689 cm; HRMS calculated for C.sub.7H.sub.14O.sub.2S, 163.0787. found 163.0790 (M+H).sup.+.

Example 15

(115) ##STR00063##

(116) Methyl phenylmethanesulfinate (compound 4n) was prepared from benzylmercaptan (3 g, 24.15 mmol) according to the general sulfinate procedure to afford 3.41 g of compound 4n (83%) as a colorless oil after purification by SiO.sub.2 flash chromatography (hexanes:dichloromethane 95:5 then hexanes:dichloromethane:Et.sub.2O 90:5:5).

Example 16

(117) ##STR00064##

(118) Phenethyl 4-methylbenzenesulfinate (compound 4o) Dicyclohexylcarbodiimide (0.436 g, 2.11 mmol), 2-phenylethanol (250 L, 21.11 mmol) and were sequentially added to a rt, dichloromethane solution (2.1 mL) of p-toluenesulfinic acid (0.33 g, 2.11 mmol). After 4 h, the mixture was diluted with aqueous NaHCO.sub.3 (4 mL) and Et.sub.2O (4 mL). The mixture was filtered and the solid was washed with Et.sub.2O (2 mL). The organic layer was collected and the aqueous was extracted with Et.sub.2O (24 mL). The organic extracts were dried (Na.sub.2SO.sub.4) and concentrated and the crude sulfinate purified by SiO.sub.2 flash chromatography (hexanes:EtOAc, gradient 90:10 to 85:15) to afford 501 mg (91%) of compound 4o as a clear, colorless oil.

Example 17

(119) ##STR00065##

(120) Ethyl 4-methylbenzenesulfinate (compound s1) was prepared from 4-methylbenzenethiol (2.33 g, 18.8 mmol) according to the general sulfinate procedure with the modification of using ethanol instead of methanol, to afford 3.38 g of compound s1 (98?/o) as a colorless oil after purification by SiO.sub.2 flash chromatography (hexanes:Et.sub.2O:CH.sub.2Cl.sub.2 gradient (95:5:5 to 70:20:10).

Example 18

(121) ##STR00066##

(122) Isopropyl 4-methylbenzenesulfinate (compound s2) was prepared from 4-methylbenzenethiol (2.18 g, 17.6 mmol) according to the general sulfinate procedure with the modification of using i-PrOH instead of methanol, adding K.sub.2CO.sub.3 (2.43 g, 17.6 mmol) immediately prior to the NBS, and extending the reaction time to 2.5 h. The modified procedure afforded 2.32 g (67%) of compound s3 as a colorless oil after SiO.sub.2 flash chromatography (hexanes:Et.sub.2O:CH.sub.2Cl.sub.2 95:5:5, then Et.sub.2O: CH.sub.2Cl.sub.2 50:50).

Example 19

(123) ##STR00067##

(124) 2,6-dimethoxybenzenethiol (compound 11p) was prepared as follows. Elemental sulfur (2.09 g, 65.1 mmol) was added in one portion, under a N.sub.2 12 blanket, to a 0 C. suspension of (2,6-dimethoxyphenyl)lithium in hexanes. After stirring the mixture overnight at rt, the mixture was diluted with water (100 mL) and then acidified with 1M aqueous HCl until a pH 1. The mixture was cooled to 0 C. and after 30 min the solid was filtered and collected. The material was recrystallized from MeOH to afford 9.48 g (77%) of compound 11p.

Example 20

(125) ##STR00068##

(126) 2-methoxy-6-(trifluoromethyl)benzenethiol (compound 11 q) Elemental sulfur (2.73 g, 85.16 mmol) was added in small portions, under a N.sub.2 blanket, to a 0 C., THF solution of (2-methoxy-6-(trifluoromethyl)phenyl)lithium. After 30 min, the reaction was diluted with cold water (25 mL) and then acidified with 2M aqueous HCl until a pH 1. The phases were separated, the aqueous was extracted with dichloromethane (330 mL), and the extracts were then combined. The crude thiol was concentrated and was then purified by filtration on a SiO.sub.2 plug using hexanes as the eluant to afford 9.62 g (81%) of 11q as a slightly yellow oil.

Example 21

(127) ##STR00069##

(128) 2-Methoxynaphthalene-1-thiol (compound 11r) was prepared as follows. (Preparation of (2-methoxynaphthalen-1-yl)magnesium bromide) A THF solution (8 mL) of 1-bromo-2-methoxynaphtalene (4 g, 16.87 mmol) was added, dropwise, to a THF slurry (17 mL) of magnesium turnings (533 g, 21.93 mmol) that had been previously activated through the addition of 1,2-dibromoethane (150 L, 1.69 mmol). The flask was gently heated with a heat gun, while avoiding boiling. After 30 min, the flask was irradiated at rt in an ultrasonic cleaning bath for 2.5 h to afford a THF solution of the Grignard reagent. Elemental sulfur (0.757 g, 23.62 mmol) was added in one portion, under a N.sub.2 blanket, to the 0 C. solution of (2-methoxynaphtalen-1-yl)magnesium bromide (vide supra). After 30 min, lithium aluminum hydride powder (0.32 g, 8.44 mmol) was added in very small portions. After 30 min, the reaction was diluted with cold, aqueous, saturated NH.sub.4Cl (20 mL) and then aqueous citric acid 2M (5 mL). The mixture was extracted with dichloromethane (330 mL) and, after the removal of volatiles, the resulting slightly yellow solid was partially dissolved with pentane. The pentane solution was cooled by immersion into a 78 C. cooling bath and after 5 min the temperature was raised to 0 C. After 15 min the solution was filtered to afford 3.01 g (94%) of compound 11r as a white crystalline solid: Mp 66-67 C. (lit. 65-68 C.). .sup.1H NMR (400 MHz, Chloroform-d) 7.98 (dd, J=8.5, 0.9 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H), 7.49 (ddd, J=8.4, 6.8, 1.3 Hz, 1H), 7.34 (ddd, J=8.0, 6.8, 1.1 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 4.39 (s, 1H), 3.95 (s, 3H); .sup.13C NMR (100 MHz, Chloroform-d) 151.51, 132.01, 129.28, 128.43, 126.64, 126.28, 124.04, 123.98, 114.72, 112.71, 56.82; IR (ATR) 3052, 2937, 2838, 2579, 1506, 1265, 1247, 1075, 797, 767, 741 cm.sup.1; HRMS calculated for C.sub.22H.sub.18O.sub.2S.sub.2 (disulfide) 401.0640. found 401.0648 (M+Na).sup.+.

(129) General Formamide Synthesis AConventional Heating

(130) Paraformaldehyde (4 eq), formamide (7.5 eq) and formic acid (5 eq) were sequentially added to neat methyl sulfinate (1 eq) and then the flask was immersed in a pre-heated oil bath (90-100 C.). After 2-3 h the mixture was diluted with cold water and extracted with EtOAc (4). The combined organic extract was washed once with brine, dried (Na.sub.2SO.sub.4), and concentrated to afford the crude formamide. The material was dried for 2 h under high vacuum before performing the dehydration.

(131) General Formamide Synthesis BMicrowave Heating

(132) A Biotage Microwave vial was charged sequentially with paraformaldehyde (5 eq), formamide (6 eq), formic acid (5 eq) and toluene (5 eq). The vial was capped, purged three times with N.sub.2 by a gas inlet and a needle vent, and then the flask was heated at 100 C. After 3 h, the mixture was allowed to cool, diluted with cold water, and extracted with EtOAc (4). The combined organic extract was washed once with brine, dried (Na.sub.2SO.sub.4), and concentrated to afford the crude formamide. The material was dried for 2 h under high vacuum before performing the dehydration.

(133) General Dehydration Method

(134) Dry diisopropylamine or dry triethylamine (9.3 equiv) were sequentially added dropwise to a 20 C., THF:acetonitrile solution (0.3 M, 2:1 mixture) of the crude formamide (1 eq). After 1 h, while maintaining the temperature below 10 C., the reaction was diluted with cold, aqueous NaHCO.sub.3 and then the phases were separated. The mixture was extracted with dichloromethane (4), the combined organic extract was washed with brine, dried (Na.sub.2SO.sub.4), and concentrated to afford the crude isonitrile. The crude isonitrile was filtered through a SiO.sub.2 plug (1050 mm) and then purified by SiO.sub.2 flash chromatography or SiO.sub.2 radial chromatography to afford the pure isonitrile.

Example 22

(135) ##STR00070##

(136) ((Isocyanomethyl)sulfonyl)benzene (compound 3a) was prepared as follows. The sulfonyl formamide 2a was prepared from methyl benzenesulfinate 4a (500 mg, 3.2 mmol) following the general method B. Subsequent dehydration following the general method with i-Pr.sub.2NH afforded 419 mg (72%) of compound 3a as a white solid after purification by SiO.sub.2 radial chromatography (2 mm rotor, hexanes:EtOAc 90:10 to hexanes:EtOAc:dichloromethane 60:20:20): Mp 89-90 C. (lit. 88 C.); .sup.1H NMR (500 MHz, Chloroform-d) 8.03 (d, J=7.2 Hz, 2H), 7.80 (t, J=7.6 Hz, 1H), 7.67 (t, J=7.8 Hz, 2H), 4.62 (s, 2H); .sup.13C NMR (125 MHz, Chloroform-d) 166.38, 135.58, 135.14, 129.88, 129.54, 61.13; IR (ATR) 3058, 2985, 2933, 2151 (lit. 2150 cm.sup.1), 1583, 1158; FIRMS calculated for C.sub.8H.sub.7NO.sub.2S, 204.0090. found 204.0091 (M+Na).sup.+. See FIG. 3.

Example 23

(137) ##STR00071##

(138) 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) (compound 3b) was prepared as follows. The sulfonyl formamide 2b was prepared from methyl 4-methylbenzenesulfinate 4b (0.5 g, 2.94 mmol) following the general method B. Subsequent dehydration of 2b following the general method with i-Pr.sub.2NH afforded 0.406 g (71%) of compound 3b as a white solid after purification by SiO.sub.2 radial chromatography (2 mm rotor, hexanes:EtOAc, 70:30, as eluent): Mp 112-113 C. (lit. 116-117 C.).

Example 24

(139) ##STR00072##

(140) 1-((isocyanomethyl)sulfonyl-2-methylbenzene (compound 3c) was prepared as follows. The sulfonyl formamide 2c was prepared from methyl 2-methylbenzenesulfinate 4c (0.5 g, 2.94 mmol) according to the general method B. Subsequent dehydration of 2c with i-Pr.sub.2NH following the general dehydration method afforded 325 mg (57%) of compound 3c as a yellowish oil after purification by SiO.sub.2 radial chromatography (2 mm thickness rotor, hexanes:EtOAc, gradient 90:10 to 60:40): .sup.1H NMR (400 MHz, Chloroform-d) 8.08 (dd, J=8.0, 1.4 Hz, 1H), 7.63 (td, J=7.6, 1.4 Hz, 1H), 7.46 (tdd, =7.4, 1.3, 0.6 Hz, 1H), 7.42 (ddt, J=7.6, 1.3, 0.6 Hz, 1H), 4.66 (s, 2H), 2.74 (s, 3H); .sup.13C NMR (100 MHz, Chloroform-d) 166.23, 139.30, 135.46, 133.42, 133.18, 132.18, 127.20, 60.55, 20.83; IR (ATR) 2936, 2146, 1330, 1152, 748; HRMS calculated for C.sub.9H.sub.9NO.sub.2S, 218.0246. found 218.0244 (M+Na).sup.+.

Example 25

(141) ##STR00073##

(142) 2-((isocyanomethyl)sulfonyl)naphthalene (compound 3d) was prepared as follows. The sulfonyl formamide 2d was prepared from methyl 2-naphthylsulfinate 4d (0.5 g, 2.42 mmol) following general method A and with the modification of heating for 2 h at 90 C. The resulting formamide 2d was dehydrated following the general method with i-Pr.sub.2NH to afford 390 mg (70%) of compound 3d as a white solid after purification by SiO.sub.2 radial chromatography (hexanes:EtOAc 90:10 to hexanes:EtOAc/dichloromethane 60:20:20): Mp 104-105 C.; .sup.1H NMR (500 MHz, Chloroform-d) 8.61 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.94 (dd, J=8.7, 1.9 Hz, 1H), 7.74 (t, J=6.9 Hz, 1H), 7.68 (t, J=7.0 Hz, 1H), 4.69 (s, 3H); .sup.13C NMR (125 MHz, Chloroform-d) 166.32, 136.09, 132.17, 132.11, 131.90, 130.35, 130.22, 129.84, 128.29, 128.20, 123.11, 61.16; IR (ATR) 3059, 2989, 2934, 2146, 1330, 1129, 1072, 754; HRMS calculated for C.sub.12H.sub.9NO.sub.2S, 232.0427. found 232.0431 (M+H).sup.+. See FIGS. 4 and 5.

Example 26

(143) ##STR00074##

(144) 1-fluoro-4-((isocyanomethyl)sulfonyl)benzene (compound 3e) was prepared as follows. The sulfonyl formamide 2e was prepared from methyl 4-fluorobenzenesulfinate 4e (0.2 g, 1.15 mmol) following general method B with the modification of heating for 3 h at 100 C. Crude 2e was dehydrated following the general method with i-Pr.sub.2NH to afford 0.155 g (81%) of compound 3e as a slight amber solid after purification on SiO.sub.2 (radial chromatography, 1 mm rotor, hexanes:EtOAc gradient 90:10 to 80:20): Mp 63 C.; .sup.1H NMR (400 MHz, Chloroform-d) 8.09-8.01 (m, 2H), 7.40-7.30 (m, 2H), 4.63 (s, 2H); .sup.13C NMR (100 MHz, Chloroform-d) 167.03 (d, J=259.6 Hz), 166.62, 132.66 (d, J=10.1 Hz), 131.06 (d, J=3.2 Hz), 117.40 (d, J=22.9 Hz), 61.21; IR (ATR) 2992, 2147, 1338, 1147 cm.sup.1; HRMS calculated for C.sub.8H.sub.6FNO.sub.2S, 200.0176. found 200.0174 (M+Na).sup.+. See FIGS. 6 and 7.

Example 27

(145) ##STR00075##

(146) 1-Chloro-4-((isocyanomethyl)sulfonyl)benzene (compound 3f) was prepared as follows. The sulfonyl formamide 2f was prepared from methyl 4-chlorobenzenesulfinate 4f (500 mg, 2.62 mmol) following general method B with the modification of heating for 3 h at 105 C. The crude formamide 2f was dehydrated following the general method with i-Pr.sub.2NH to afford 399 mg (71%) of compound 3f as a white solid after purification on SiO.sub.2 (radial chromatography, 2 mm rotor, hexanes:Et.sub.2O:dichloromethane gradient 90:5:5 to 60:20:20); mp. 109-110 (dec); .sup.1H NMR (500 MHz, Chloroform-d) 7.96 (d, J=8.7 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H), 4.64 (s, 1H); .sup.13C NMR (126 MHz, Chloroform-d) 166.67, 142.69, 133.43, 130.98, 130.27, 61.12. IR (ATR) 3006, 2152, 1323, 1151, 1082 cm.sup.1; HRMS calculated for C.sub.8H.sub.6C.sub.1NO.sub.2S, 237.9702. found 237.9702 (M+Na).sup.+. See FIGS. 8 and 9.

Example 28

(147) ##STR00076##

(148) 1-((isocyanomethypsulfonyl)-4-(trifluoromethyl)benzenesulfinate (compound 3g) was prepared as follows. The sulfonyl formamide 2g was prepared from methyl 4-(trifluoromethyl)benzene sulfinate 4g (500 mg, 2.23 mmol) following general method A. Crude 2g was dehydrated following the general method with Et.sub.3N to afford 316 mg (57%) of compound 3g as a white solid after purification on SiO.sub.2 (flash chromatography using hexanes:Et.sub.2O gradient 90:10 to 80:20); mp. 104-105 C. (dec); .sup.1H NMR (500 MHz, Chloroform-d) 8.18 (d, J=8.2 Hz, 2H), 7.95 (d, J=8.2 Hz, 2H), 4.67 (s, 3H); .sup.13C NMR (125 MHz, Chloroform-d) 167.31, 138.59, 137.18 (q, J=33.5 Hz), 130.30, 127.07 (q, J=3.7 Hz), 122.95 (q, J=274.5 Hz), 61.03; IR (ATR) 2987, 2933, 2149, 1323, 1165, 1134, 1147, 1108, 843 cm.sup.1; HRMS calculated for C.sub.9H.sub.6F.sub.3NO.sub.2S, 271.9964. found 271.9964 (M+Na).sup.+. See FIGS. 10 and 11.

Example 29

(149) ##STR00077##

(150) 1,3-dichloro-5-((isocyanomethyl)sulfonyl)benzene (compound 3h) was prepared as follows. The sulfonyl formamide 2h was prepared from 3,5-dichlorobenzenesulfinate 411 (0.4 g, 1.77 mmol) following general method A with the modification of heating for 2 h at 90 C. Crude 2h was dehydrated following the general method with Et.sub.3N to afford 249 mg (89%) of compound 3h as a white solid after purification by column chromatography using SiliaBond Diol matrix (hexanes:Et.sub.2O 70:30 as eluent): mp 82-83 C.; .sup.1H NMR (400 MHz, Chloroform-d) 7.90 (d, J=1.9 Hz, 1H), 7.76 (t, J=1.9 Hz, 1H), 4.66 (s, 1H); .sup.13C NMR (100 MHz, Chloroform-d) 167.66, 137.82, 137.13, 135.70, 127.81, 61.01; IR (ATR) 3079, 2145, 1570, 1344, 1161, 1135, 804, 666; HRMS calculated for C.sub.8H.sub.6FNO.sub.2S, 287.9050. found 287.9052 (M+K).sup.+. An analogous reaction using procedure B gave 87% of compound 3h. See FIGS. 12 and 13.

Example 30

(151) ##STR00078##

(152) 1-((Isocyanomethyl)sulfonyl)-2-methoxybenzene (compound 3i) was prepared as follows. The sulfonyl formamide 2i was prepared from methyl 2-methoxybenzenesulfinate 4i (2 g, 10.74 mmol) following general method B with the modification of heating for 2.5 h at 90 C. Crude 2i was dehydrated following the general method with i-Pr.sub.2NH to afford 1.49 g (66%) of compound 3i as a slightly amber solid after purification on SiO.sub.2 (radial chromatography, 4 mm rotor, hexanes:acetone gradient 80:20 to 40:60). The pure product exhibited spectral data identical to that exhibited from previously reported material: .sup.1H NMR (500 MHz, Chloroform-d) 8.03 (dd, J=7.9, 1.8 Hz, 1H), 7.71 (ddd, J=8.4, 7.4, 1.8 Hz, 1H), 7.19 (td, J=7.7, 1.0 Hz, 1H), 7.12 (dd, J=8.4, 0.9 Hz, 1H), 4.89 (s, 2H), 4.02 (s, 3H); .sup.13C NMR (125 MHz, Chloroform-d) 165.69, 157.60, 137.40, 132.32, 122.85, 121.37, 112.71, 59.51, 56.72. See FIGS. 14 and 15.

Example 31

(153) ##STR00079##

(154) 1-((Isocyanomethypsulfonyl)-2-phenoxybenzene (compound 3j) was prepared as follows. The sulfonyl formamide 2j was prepared from methyl 2-phenoxybenzenesulfinate 4j (1 g, 4 mmol) following general method A with the modification of heating for 2.5 h at 90 C. Crude 2j was dehydrated following the general method using i-Pr.sub.2NH to afford 685 mg (71%) of compound 3j as a white solid after purification on SiO.sub.2 (radial chromatography, 4 mm rotor, hexanes:EtOAc 70:30: mp 67-68 C.; .sup.1H NMR (500 MHz, Chloroform-d) 8.12 (dd, J=7.9, 1.7 Hz, 1H), 7.62 (ddd, J=8.8, 7.4, 1.8 Hz, 1H), 7.47-7.40 (m, 2H), 7.32-7.24 (m, 2H), 7.13 (d, J=7.6 Hz, 2H), 6.94 (d, J=8.4 Hz, 1H), 4.97 (s, 2H); .sup.13C NMR (125 MHz, Chloroform-d) 166.10, 156.45, 154.71, 137.07, 132.16, 130.51, 125.79, 124.81, 123.32, 120.41, 118.30, 59.95; IR (ATR) 3001, 2146, 1583, 1467, 1336, 1148, 749; HRMS calculated for C.sub.14H.sub.11NO.sub.3S, 312.0091. found 312.0092 (M+K).sup.. See FIGS. 16 and 17.

Example 32

(155) ##STR00080##

(156) 4-((isocyanomethyl)sulfonyl)-1,2-dimethoxybenzene (compound 3k) was prepared as follows. The sulfonyl formamide 2k was prepared from 3,4-dimethoxybenzenesulfinate 4k (200 mg, 0.925 mmol) following the general method A with the modification of heating for 2 h at 90 C. Crude 2k was dehydrated following the general method with i-Pr.sub.2NH to afford 105 mg (45%) of compound 3k as a yellowish solid after purification on SiO.sub.2 (flash chromatography using hexanes:Et.sub.2O (80:20) as eluent): mp 101-102 C.; .sup.1H NMR (500 MHz, Chloroform-d) 7.63 (dd, J=8.5, 2.2 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 4.61 (s, 2H), 3.99 (s, 3H), 3.97 (s, 3H); .sup.13C NMR (125 MHz, Chloroform-d) 165.88, 154.84, 149.56, 126.22, 124.01, 111.19, 111.04, 61.25, 56.43, 56.42; IR (ATR) 2937, 2147, 1508, 1262, 1133, 728 cm.sup.1; HRMS calculated for C.sub.10H.sub.11NO.sub.4S, 264.0301. found 264.0329 (M+Na).sup.+. See FIGS. 18 and 19.

Example 33

(157) ##STR00081##

(158) 1-((isocyanomethyl)sulfonyl)-2-methylpropane (compound 31) was prepared as follows. The sulfonyl formamide 21 was prepared from methyl 2-methylpropane-1-sulfinate 41 (500 mg, 3.67 mmol) following the general method B with the modification of heating for 3 h at 100 C. Crude 21 was dehydrated following the general method with i-Pr.sub.2NH to afford 276 mg (45%) of compound 31 as a white solid after purification on SiO.sub.2 (radial chromatography, 2 mm rotor, hexanes:Et.sub.2O:dichloromethane 60:20:20): mp 59-60 C.; NMR (500 MHz, Chloroform-d) 4.54 (s, 2H), 3.13 (d, J=6.6 Hz, 2H), 2.43 (nontuplet, J=6.7 Hz, 1H), 1.19 (d, J=6.7 Hz, 6H); .sup.13C NMR (125 MHz, Chloroform-d) 166.69, 59.24, 58.16, 23.74, 22.69; IR (ATR) 2970, 2147, 1319, 1136 cm.sup.1; HRMS calculated for C.sub.8H.sub.13NO.sub.2S, 210.0559. found 210.0561 (M+Na).sup.+.

Example 34

(159) ##STR00082##

(160) ((Isocyanomethyl)sulfonyl)cyclohexane (compound 3m) was prepared as follows. The sulfonyl formamide 2m was prepared from methyl cyclohexansulfinate 4m (400 mg, 2.5 mmol) following general method A with the modification of adding three additional portions of paraformaldehyde, HCONH.sub.2 and HCO.sub.2H, at 2.5 h intervals with a total reaction time of 9 hours. Crude 2m was then dehydrated following the general method with i-Pr.sub.2NH to afford 238 mg (51%) of compound 3m as a white solid after purification by filtration through a SiO.sub.2 plug (hexanes:Et.sub.2O 70:30 as eluent): mp. 73-74 C.; .sup.1H NMR (400 MHz, Chloroform-d) 4.56 (s, 2H), 3.31 (tt, J=12.3, 3.7 Hz, 1H), 2.18 (d, J=12.8 Hz, 2H), 1.98 (d, J=11.7 Hz, 2H), 1.77 (d, J=11.8 Hz, 1H), 1.63 (qd, J=12.6, 3.8 Hz, 2H), 1.38 (qt, J=12.6, 3.4 Hz, 2H), 1.26 (qt, J=12.8, 3.2 Hz, 1H); .sup.13C NMR (100 MHz, Chloroform-d) 166.53, 59.77, 55.56, 24.88, 24.86; IR (ATR) 2933, 2148, 1320, 1129, 906, 732 cm.sup.1; HRMS calculated for C.sub.6H.sub.11NO.sub.2S, 184.0403. found 184.0383 (M+Na).sup.+.

Example 35

(161) ##STR00083##

(162) ((Isocyanomethyl)sulfonyl)methyl)benzene (compound 3n) was prepared as as follows. The sulfonyl formamide 2n was prepared from methyl phenylmethanesulfinate 4n (0.5 g, 2.94 mmol) following the general method A with the modification of heating for 2.5 h at 90 C. Crude 2n was dehydrated following the general dehydration method with i-Pr.sub.2NH to afford 324 mg (57%) of compound 3n as a white solid after purification on SiO.sub.2 (radial chromatography, 2 mm rotor, hexanes:Et.sub.2O 70:30 then hexanes:Et.sub.2O:acetone 40:30:30): mp 105-106 C. (lit. 103-106 C.); NMR (500 MHz, Chloroform-d) 7.46 (s, 5H), 4.49 (s, 2H) (lit. 4.50), 4.31 (s, 2H); .sup.13C NMR (125 MHz, Chloroform-d) 166.99, 130.74, 129.97, 129.65, 126.29, 57.07, 55.62. IR (ATR) 3007, 2141, 1303, 1133 cm.sup.1; HRMS calculated for C.sub.9H.sub.9NO.sub.2S, 233.9986. found 233.9988 (M+Kr.

(163) General Oxidation Method of Formamides

(164) Solid m-CPBA (2.2 equiv) was added to a 0 C., dichloromethane solution (0.5 M) of the crude sulfanyl formamide (1 eq) in three portions at 10 min intervals. After 2.5 h, the reaction was diluted with cold, saturated NaHCO.sub.3, the phases were separated and the aqueous phase was then extracted with dichloromethane (5). The combined organic extract was washed with 0 C., saturated aqueous NaHCO.sub.3 and then with 0 C., 5% aqueous Na.sub.2SO.sub.3. The aqueous layer was re-extracted once with dichloromethane. The organic extract was dried (Na.sub.2SO.sub.4) and concentrated to afford the crude sulfonyl formamide (a-z) that was sufficiently pure to use in the following dehydration.

Example 36

(165) ##STR00084##

(166) 2-((Isocyanomethyl)sulfonyl)-1,3-dimethoxybenzene (compound 3p) was prepared as follows. The sulfanyl formamide 12p was prepared from 2,6-dimethoxybenzenethiol 11p (1 g, 5.88 mmol) following general method A with the modification of heating for 3 h at 100 C. Crude 12p was filtered through a plug of Florisil (toluene/EtOAc 70:30 as eluant) to afford 1.3 g of sulfanyl formamide 12p after removal of the volatiles. For the major rotamer: .sup.1H NMR (500 MHz, Chloroform-d) 8.07 (d, J=1.6 Hz, 1H), 7.29 (t, J=8.4 Hz, 1H), 6.60 (d, J=8.4 Hz, 2H), 4.59 (d, J=6.0 Hz, 2H), 3.90 (s, 6H). Oxidation of 12p (1.3 g, 5.72 mmol) following the general m-CPBA method afforded 1.154 g of 13p as a white solid: .sup.1H NMR (500 MHz, Chloroform-d) 8.10 (d, J=1.2 Hz, 1H), 7.47 (t, J=8.5 Hz, 1H), 7.01 (bs, 1H), 6.63 (d, J=8.5 Hz, 2H), 4.98 (d, J=6.9 Hz, 2H), 3.94 (s, 6H). After drying 13p (1.154 g, 4.45 mmol) under vacuum (ca. 2 h), the formamide was dehydrated following the general method using i-Pr.sub.2NH to afford 572 mg (40%, 3 steps) of compound 3p as a white solid after purification on SiO.sub.2 (radial chromatography, 2 mm rotor, using a hexanes:dichloromethane:acetone gradient 80:10:10 to 60:20:20): mp 90-91 C.; .sup.1H NMR (500 MHz, Chloroform-d) 7.55 (t, J=8.5 Hz, 1H), 6.69 (d, J=8.5 Hz, 2H), 4.87 (s, 2H), 3.95 (s, 6H); .sup.13C NMR (125 MHz, Chloroform-d) 165.08, 160.22, 136.66, 112.65, 105.41, 62.29, 56.99; IR (ATR) 2944, 2148, 1582, 1476, 1331, 1253, 1146, 1099, 779 cm.sup.1; HRMS calculated for C.sub.10H.sub.11NO.sub.4S, 280.0040. found 280.0061 (M+K).sup.+. See FIGS. 20 and 21.

Example 37

(167) ##STR00085##

(168) 2-((Isocyanomethypsulfonyl)-1-methoxy-3-(trifluoromethyl)benzene (compound 3q) was prepared as follows. The sulfanyl formamide 12q was prepared from 2-methoxy-6-(trifluoromethyl)benzenethiol 11q (1 g, 4.8 mmol) following the general method A with the modification of heating for 2 h at 90 C. and then, after allowing the reaction to cool, adding cold water (0 C., 10 mL). Crude 12q was filtered and then left in a freezer (30 C.) for 15 min. The slightly pink solid was washed with copious cold water, cold hexanes (5 mL), and refiltered. The solid was then washed with cold hexanes/Et.sub.2O (50:50, 10 mL) and dried under vacuum for 2 h to afford 1.083 g of formamide as a solid. .sup.1H NMR for the major rotamer: .sup.1H NMR (500 MHz, Chloroform-d) 8.02 (s, 1H), 7.44 (t, J=8.1 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 5.87 (bs, 1H), 4.72 (d, J=6.4 Hz, 2H), 4.00 (s, 3H). Formamide 12q (220 mg, 8.29 mmol) was oxidized to the sulfonyl formamide 13q following the general m-CPBA method with the modification of performing the reaction for 3 h at rt until complete conversion was determined as judged by .sup.1H NMR: .sup.1H NMR (500 MHz, Chloroform-d) 8.01 (s, 1H), 7.69 (t, J=8.2 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 6.76 (s, 1H), 5.06 (d, J=7.0 Hz, 2H), 4.14 (s, 3H). After drying under vacuum (ca. 2 h), the crude 13q was dehydrated following the general method with Et.sub.3N to afford 124 mg (46%, 3 steps) of compound 3q as a slightly yellow solid after purification on SiO.sub.2 (column chromatography, hexanes:EtOAc 80:20 to 70:30): mp 84-85 C.; .sup.1H NMR (500 MHz, Chloroform-d) 7.79 (t, J=8.1 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 4.97 (s, 3H), 4.09 (s, 3H); .sup.13C NMR (125 MHz, Chloroform-d) 166.57, 159.47, 136.23, 132.29 (q, J=33.5 Hz), 123.54, 122.06 (q, J=274.9 Hz), 121.26 (q, J=7.4 Hz), 117.73, 62.21, 57.83. IR (ATR) 2947, 2148, 1587, 1349, 1305, 1142, 1099, 1022, 800 cm.sup.1; HRMS calculated for C.sub.10H.sub.8F.sub.3NO.sub.3S, 317.9809. found 317.9816 (M+K).sup.+. See FIGS. 22 and 23.

Example 38

(169) ##STR00086##

(170) 2-((isocyanomethypsulfonyl)-3-methoxynaphthalene (compound 3r) was prepared as follows. The sulfanyl formamide 12r was prepared from 2-methoxynaphtalene-1-thiol 11r (1.5 g, 7.89 mmol) following the general method A with the modification of heating for 3 h at 105 C. Crude 12r was recrystallized from benzene/hexanes and filtered to yield 1.53 g crystalline material. .sup.1H NMR for major rotamer: .sup.1H NMR (500 MHz, Chloroform-d) 8.57 (d, J=8.7 Hz, 1H), 7.99 (d, J=1.5 Hz, 1H), 7.90 (d, J=9.1 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.55 (ddd, J=8.6, 7.0, 1.4 Hz, 1H), 7.39 (ddd, J=8.1, 6.8, 1.2 Hz, 1H), 7.32 (d, J=9.0 Hz, 1H), 6.22 (bs, 1H), 4.66 (d, J=6.3 Hz, 2H), 4.07 (s, 3H). Sulfanyl formamide 12r (1.53 g, 6.19 mmol) was oxidized to the sulfonyl formamide 13r following the general m-CPBA method to afford, after removal of volatiles, 1.85 g of 13r as a white solid: .sup.1H NMR (500 MHz, Chloroform-d) 9.27 (d, J=9.2 Hz, 1H) 8.09 (d, J=9.3 Hz, 1H), 7.93 (d, J=1.2 Hz, 1H), 7.80 (dd, J=8.2, 1.5 Hz, 1H), 7.60 (ddd, J=8.7, 6.8, 1.6 Hz, 1H), 7.44 (ddd, J=8.0, 6.8, 1.1 Hz, 1H), 7.34 (d, J=9.1 Hz, 1H), 6.38 (bs, 1H), 5.09 (d, J=6.9 Hz, 2H), 4.19 (s, 3H). After drying 13r under vacuum (ca. 2 h), the crude sulfonyl formamide (1 g, 3.58 mmol) was dehydrated following the general method with i-Pr.sub.2NH to afford 850 mg (56%, 3 steps) of compound 3r as a slightly yellow solid after purification on SiO.sub.2 (radial chromatography, 4 mm rotor, hexanes:dichloromethane:acetone 40:30:30): mp 100-102 C. (dec); .sup.1H NMR (500 MHz, Chloroform-d) 9.24 (dq, J=9.0, 0.9 Hz, 1H), 8.14 (d, J=9.1 Hz, 1H). 7.82 (d, J=8.1 Hz, 1H), 7.66 (ddd, J=9.0, 6.9, 1.5 Hz, 1H), 7.47 (ddd, J=8.0, 6.9, 1.1 Hz, 1H), 7.34 (d, J=9.1 Hz, 1H), 4.98 (s, 2H), 4.12 (s, 3H); .sup.13C NMR (125 MHz, Chloroform-d) 165.56, 159.05, 138.71, 132.16, 130.01, 129.41, 128.99, 125.36, 123.42, 116.56, 113.05, 62.03, 57.89; IR (ATR) 2990, 2144, 1597, 1509, 1338, 1331, 1142, 908, 815, 730 cm.sup.1; HRMS calculated for C.sub.13H.sub.11NO.sub.3S, 284.0352. found 284.0353 (M+Na).sup.+.

Example 39

(171) ##STR00087##

(172) (1R,2S,4R)-2-((isocyanomethyl)sulfonyl)-4-isopropyl-1-methylcyclohexane (compound 3s) was prepared as follows. The sulfanyl formamide 12s was prepared from neomenthyl thiol (0.2 g, 1.16 mmol) according to the general method A with the modification of heating for 3 h at 110 C. Crude 12s was filtered through a florisil plug (toluene/EtOAc 90:10 as eluent) to obtaining 0.18 g of partially purified material. .sup.1H NMR for the major rotamer: .sup.1H NMR (500 MHz, Chloroform-d) 8.21 (s, 1H), 5.81 (bs, 1H), 4.60 (dd, J=14.1, 7.3 Hz, 1H), 4.22 (dd, J=14.1, 5.3 Hz, 1H), 3.28 (m, 1H), 2.04-1.94 (m, 1H), 1.94-1.82 (m, 2H), 1.75-1.69 (m, 1H), 1.65-1.53 (m, 1H), 1.25 (ddd, =13.7, 11.8, 3.1 Hz, 1H), 1.13-1.00 (m, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.90 (d, J=3.3 Hz, 3H), 0.89 (d, J=3.2 Hz, 3H). Sulfanyl formamide 12s (0.18 g, 78.5 mmol) was oxidized to the sulfonyl formamide 13s following the general m-CPBA method to afford 0.25 g of compound 13s as a semisolid: .sup.1H NMR (500 MHz, Chloroform-d) 8.28 (s, 1H), 6.70 (s, 2H), 4.90 (dd, J=14.4, 7.6 Hz, 2H), 4.25 (dd, J=14.4, 5.9 Hz, 2H), 3.54 (bs, 1H), 2.32 (d, 1H), 2.23-2.07 (m, 2H), 1.95-1.84 (m, 1H), 1.84-1.70 (m, 2H), 1.04 (d, J=6.4 Hz, 3H), 0.97-0.92 (m, 1H), 0.95 (d, J=6.4 Hz, 3H), 0.90 (d, J=6.5 Hz, 3H). After drying under vacuum (ca. 2 h), crude 13s (250 mg, 1.09 mmol) was dehydrated following the general method with i-Pr.sub.2NH to afford 154 mg (55%, 3 steps) of compound 3s as a colorless oil after purification on SiO.sub.2 (radial chromatography, 1 mm rotor, hexanes:EtOAc 90:10). An analytically pure sample was obtained by crystallization from pentane: mp 62-63 C., [].sub.D +40.2 (lit. 68 C. and [].sub.D+42.7 respectively); IR (ATR) 2954, 2143, 1328, 1127 cm.sup.1; .sup.1H NMR (500 MHz, Chloroform-d) 4.59 (d, J=15.4 Hz, 1H), 4.39 (d, J=15.4 Hz, 1H), 3.94-3.87 (m, 1H), 2.25 (ddt, J=15.0, 3.3, 2.4 Hz, 1H), 2.13-2.01 (m, 2H), 1.96-1.86 (m, 1H), 1.86-1.80 (m, 2H), 1.47-1.37 (m, 2H), 1.10 (d, J=6.5 Hz, 3H), 1.03-0.95 (m, 1H), 0.97 (d, J=6.5 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H); .sup.13C NMR (125 MHz, Chloroform-d) 166.42, 59.60, 59.00, 49.33, 36.57, 34.98, 29.67, 26.78, 24.94, 22.29, 21.95, 21.80. HRMS calculated for C.sub.12H.sub.21NO.sub.2S, 266.1185. found 266.1185 (M+Na).sup.+.

Example 40

(173) ##STR00088##

(174) 1-((Isocyanomethypsulfonyl)adamantane (compound 3t) was prepared as follows. The sulfanyl formamide 12t was prepared from 1-adamantanethiol following a modification of general method A: A toluene:formamide (1:6) solution (0.6 mL) of 1-adamantanethiol (300 mg, 1.78 mmol) was slowly added to the formic acid-formaldehyde solution over a 3 h period through the assistance of a syringe pump. 0.5 h after the addition, the reaction was worked up as described in general method A. Crude 12t was filtered through a florisil column (hexanes:EtOAc 60:40 as eluent) to afford 252 mg of partially purified 12t. .sup.1H NMR for the major rotamer: .sup.1H NMR (400 MHz, Chloroform-d) 8.12 (s, 1H), 5.67 (bs, 1H), 4.44 (d, J=5.7 Hz, 2H), 2.06 (bs, 3H), 1.96-1.82 (m, 6H), 1.76-1.65 (m, 6H). Sulfanyl formamide 12t (200 mg, 0.89 mmol) was oxidized to the sulfonyl formamide 13t following the general m-CPBA method to afford 217 mg of compound 13t as a solid: .sup.1H NMR (400 MHz, Chloroform-d) 8.22 (s, 1H), 7.28 (bs, 1H), 4.68 (d, J=6.7 Hz, 2H), 2.18 (bs, 3H), 2.12-2.05 (m, 6H), 1.82-1.67 (m, 6H). After drying under vacuum (ca. 2 h), crude compound 13t (217, 0.84 mmol) was dehydrated following the general method with i-Pr.sub.2NH to afford 106 mg (32%, 3 steps) of compound 3p as a white solid after purification on SiO.sub.2 (flash chromatography, hexanes:EtOAc 75:25): mp 110-111 C.; .sup.1H NMR (500 MHz, Chloroform-d) 4.58 (s, 1H), 2.24 (s, 2H), 2.14 (d, J=3.0 Hz, 4H), 1.77 (q, J=12.6 Hz, 5H); .sup.13C NMR (125 MHz, Chloroform-d) 166.56, 64.60, 53.01, 35.51, 35.24, 28.14; IR (ATR) 2918, 2857, 2146, 1455, 1297, 1142 cm.sup.1. HRMS calculated for C.sub.12H.sub.17NO.sub.2S, 278.0612. found 278.0639 (M+K).sup.+.