Thiol-catalyzed synthesis of thioamides

Abstract

This disclosure relates to processes for the synthesis of organic compounds, and more particularly to methods for the synthesis of thioamides from nitriles using a thiol catalyst.

Description

[0001] THIOL-CATALYZED SYNTHESIS OF THIOAMIDES

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims priority to U.S. Provisional Patent Application No. 63 / 556,563 filed on February 22, 2024, the contents of which is incorporated herein by reference in its entirety for all purposes.

[0004] STATEMENTREGARDING FEDERALLYSPONSORED RESEARCH OR DEVELOPMENT

[0005] This invention was made with government support under Grant No. 1724099 awarded by the National Science Foundation. The Government has certain rights in the invention.

[0006] TECHNICAL FIELD

[0007] This disclosure relates to processes for the synthesis of organic compounds and more particularly to methods for the synthesis of thioamides.

[0008] BACKGROUND

[0009] Thioamide compounds find use as fungicides or herbicides or may be used as intermediates in the synthesis of pharmaceuticals or crop protection agents. Thioamide moieties are commonly encountered in synthetic intermediates due to their unique reactivity and ability to serve as building blocks in the synthesis of heterocycles (such as thiazoles or thioazolines). Further, thioamides are considered bioisosteres of amides, showing improved resistance to enzymatic hydrolysis (which may lead to improved biological activity in pharmaceuticals, for example). Thioamide bonds are also important intermediates in prebiotic chemistry. In cyanosulfidic metabolism, they serve as crucial intermediates in the pathways that lead to the formation of many important biomolecules (e.g., amino acids). Indeed, in cyanosulfidic metabolism, thioamides participate in the formation of a-hydroxythioamides, which is integral in the synthesis of amino acids from cyanohydrins (see Patel, B.H., Percivalle, C., Ritson, D.J., Duffy, C.D., Sutherland, J.D.: Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism. Nature Chemistry 7(4), 301-307 (2015)). They can also serve as purine and pyrimidine precursors, the two classes of heterocycle employed in genetic molecules. Indeed, recent work has demonstrated that thioamides can function as important intermediates in the formation of pyrimidines from cyanoacetylene (see Okamura, H., Becker, S., Tiede, N., Wiedemann, S., Feldmann, J., Carell, T.: A one-pot, water compatible synthesis of pyrimidine nucleobases under plausible prebiotic conditions. Chemical Communications 55(13), 1939-1942 (2019)).

[0010] Despite their importance, the formation of thioamide bonds from nitriles under prebiotic conditions has required large excesses of sulfide or compounds with unknown prebiotic sources. Other processes for the synthesis of thioamides often require the use large quantities of toxic reagents or require intensive conditions (such as elevated temperatures or pressures) to facilitate the formation of the desired products, often limiting the substrate scope which may be used in such reactions. Further, many processes often lead to the formation of several byproducts in addition to the desired thioamide products, leading to associated difficulties with purification. Recent work has demonstrated that thiophosphate (PSO33-) can efficiently facilitate the thiolysis of nitriles to form thioamides (see Ritson, D., Xu, J., Sutherland, J.: Thiophosphate A Versatile Prebiotic Reagent? Synlett 28(01 ), 64-67 (2016)). However, a prebiotic source of thiophosphates remains uncertain.

[0011] Thus, there is a clear need for mild processes which may be used for the synthesis of thioamide-containing compounds.

[0012] SUMMARY

[0013] The present disclosure provides processes for the synthesis of thioamides from nitriles under mild conditions and without the formation of significant quantities of byproducts. The present processes utilize a thiol catalyst to cleanly facilitate the reaction of nitrile compounds with sulfides under mild temperature and pressure conditions.

[0014] Thus, one aspect of the present disclosure is a process for the synthesis of a compound containing one or more thioamide groups having the structure, the process comprising: reacting a mixture comprising a compound containing one or more nitrile groups and a catalyst with a sulfide to form the compound containing one or more thioamide groups, wherein the catalyst comprises a compound containing one or more thiol groups or salts thereof.

[0015] Another aspect of the present disclosure is a compound containing one or more thioamide groups, wherein the compound is prepared by a process described herein.

[0016] Yet another aspect of the present disclosure is a composition comprising any one of the compounds disclosed herein containing one or more thioamide groups, wherein the composition is a pesticide, a herbicide, or a fungicide. In a first aspect, a process for the synthesis of a compound containing one or more thioamide groups having the structure , the process comprising: reacting a mixture comprising a compound containing one or more nitrile groups and a catalyst with a sulfide to form the compound containing one or more thioamide groups, wherein the catalyst comprises a compound containing one or more thiol groups or salts thereof.

[0017] In a second aspect, the compound can contain one or more thioamide groups comprises a compound of Formula I: wherein:

[0018] R1is selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(Co- C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Z groups as allowed by valency;

[0019] Z is independently selected at each occurrence from halo, cyano, azido, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8- membered monocyclic or bicyclic heterocycle)-(Co-C3 alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, RxO-(Co-C3 alkyl)-, RxS-(Co-C3 alkyl)-, (RxRyN)- (C0-C3 alkyl)-, RXO-C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN) C(0)-(Co-C3alkyl)-, RXO-S(0)2-(CO-C3alkyl)-, (RxRyN) S(0)2-(Co-C3alkyl)-, RzC(O)-O-(C0-C3alkyl)-, RZC(O)-(RXN)-(C0-C3alkyl)-, RzS(0)2-0-(Co-C3alkyl)-, RzS(0)2-(RxN)-(Co-C3alkyl)-, RZC(0)-(CO-C6alkyl)-, RzS(O)-(C0-C3alkyl)-, and RzS(0)2-(Co-C3alkyl)- wherein each Z may be optionally substituted with one or more groups selected from Y as allowed by valency;

[0020] Rxand Ryare independently selected at each occurrence from hydrogen, Ci-Ce alkyl, C1 - C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)-, (4- to 6-membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; Rzis independently selected at each occurrence from hydrogen, halo, Ci-Ce alkyl, C1 - C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)- (C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, -ORX, -SRX, and -Rx, each of which may be optionally substituted with one or more Y groups as allowed by valency; and

[0021] Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol. In a third aspect, the compound containing one or more nitrile groups can include a compound of Formula II: wherein:

[0022] R1is selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(Co- C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Z groups as allowed by valency;

[0023] Z is independently selected at each occurrence from halo, cyano, azido, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8- membered monocyclic or bicyclic heterocycle)-(Co-C3 alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, RxO-(Co-C3 alkyl)-, RxS-(Co-C3 alkyl)-, (RxRyN)- (C0-C3 alkyl)-, RXO-C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN)C(O)-(C0-C3 alkyl)-, RXO-S(0)2-(CO-C3alkyl)-, (RxRyN)S(0)2-(Co-C3 alkyl)-, RzC(O)-O-(C0-C3alkyl)-, RZC(O)-(RXN)-(C0-C3alkyl)-, RzS(O)2-O-(C0-C3 alkyl)-, RzS(O)2-(RxN)-(C0-C3 alkyl)-, RZC(0)-(CO-C6alkyl)-, RzS(O)-(C0-C3alkyl)-, and RzS(0)2-(Co-C3alkyl)- wherein each Z may be optionally substituted with one or more groups selected from Y as allowed by valency;

[0024] Rxand Ryare independently selected at each occurrence from hydrogen, Ci- Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)- , (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)- (C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;

[0025] Rzis independently selected at each occurrence from hydrogen, halo, Ci-Ce alkyl, C1 - C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)- (Co-C3 alkyl)-, -ORX, -SRX, and -NRxRy, each of which may be optionally substituted with one or more Y groups as allowed by valency; and

[0026] Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

[0027] In a fourth aspect, the sulfide comprises hydrogen sulfide, an alkali metal sulfide, an ammonium sulfide, or a substituted ammonium sulfide. In other embodiments, the sulfide can be selected from the group consisting of hydrogen sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide, ammonium sulfide, disodium hydrogen sulfide, dipotassium hydrogen sulfide, and concentrations thereof.

[0028] In a fifth aspect, the catalyst comprises an alkyl thiol or an aryl thiol, or salts thereof. In other embedments, the catalyst comprises a compound of Formula III: or salts thereof, wherein:

[0029] R1is selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(Co- C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Z groups as allowed by valency;

[0030] Z is independently selected at each occurrence from halo, cyano, azido, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8- membered monocyclic or bicyclic heterocycle)-(Co-C3 alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, RxO-(Co-C3 alkyl)-, RxS-(Co-C3 alkyl)-, (RxRyN)- (C0-C3 alkyl)-, RXO-C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN) C(0)-(Co-C3alkyl)-, RXO-S(0)2-(CO-C3alkyl)-, (RxRyN) S(O)2-(C0-C3 alkyl)-, RzC(O)-O-(C0-C3alkyl)-, RZC(O)-(RXN)-(C0-C3alkyl)-, RzS(O)2-O-(C0-C3 alkyl)-, RzS(O)2-(RxN)-(C0-C3 alkyl)-, RZC(0)-(CO-C6alkyl)-, RzS(O)-(C0-C3alkyl)-, and RzS(0)2-(Co-C3alkyl)- wherein each Z may be optionally substituted with one or more groups selected from Y as allowed by valency;

[0031] Rxand Ryare independently selected at each occurrence from hydrogen, Ci- Ce alkyl, C1- C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; Rzis independently selected at each occurrence from hydrogen, halo, Ci-Ce alkyl, C1- C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, -ORX,-SRX, and -Rx, each of which may be optionally substituted with one or more Y groups as allowed by valency; and

[0032] Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

[0033] In yet other embodiments, the catalyst is selected from the group consisting of methanethiol, ethanethiol, thiophenol, benzyl mercaptan, 2-methyl-2- propanethiol, 1 -butanethiol, 4-methoxythiophenol, triphenylmethanethiol, 2- naphthalenethiol, 4-bromothiophenol, 4-chlorothiophenol, 4-fluorothiophenol, cyclohexanethiol, 2-phenylethanethiol, 4-nitrothiophenol, 2,2,2- trifluoroethanethiol, 2- propanethiol, 2-propene-1 -thiol, 4-tert-butylbenzenethiol, 2-bromothiophenol, 2,4- dimethylbenzenethiol, 4-tert-butylbenzyl mercaptan, 4- methoxy-2-methylthiophenol, 2- (trimethylsilyl)ethanethiol, 2,6- dimethylbenzenethiol, 2-(2-methoxyethoxy)ethanethiol, 2- methylbenzenethiol, 2- methyl-1 -propanethiol, 2-methoxythiophenol, 1 -hexadecanethiol, 3- bromothiophenol, cyclopentanethiol, 3-methoxythiophenol, 3,5- bis(trifluoromethyl)benzenethiol, 3-methylbenzenethiol, 3,5- dimethylbenzenethiol, 2- chlorothiophenol, 2-fluorothiophenol, (4- nitrobenzyl)mercaptan, 3,4-dimethoxythiophenol, 4-chlorobenzenemethanethiol, 4- fluorobenzyl mercaptan, 1 -phenylethyl mercaptan, 2,5- dimethylbenzenethiol, 2,3,5,6-tetrafluorobenzenethiol, 3,4-dimethylbenzenethiol, 3,4- difluorothiophenol, 4-trifluoromethylbenzyl mercaptan, 4-bromobenzyl mercaptan, 2,5- dimethoxythiophenol, 2-(trifluoromethyl)benzenethiol, 4- trifluoromethyl-2,3,5,6- tetrafluorothiophenol, 2,5-dicluorobenzenethiol, 3- ethoxythiophenol, (3- nitrobenzyl)mercaptan, 1 -isopropylbenzenethiol, 4- (trifluoromethoxy)benzyl mercaptan, 3,4-difluorobenzyl mercaptan, 3-bromo-4- fluorothiophenol, 2,5-difluorothiophenol, 3,5- difluorobenzyl mercaptan, 4-chloro- 2-fluorobenzyl mercaptan, 2,6-difluorobenzyl mercaptan, 3,5-difluorobenzyl mercaptan, 3,5-difluorothiophenol, 2-(trifluoromethoxy)thiophenol, 3- (trifluoromethoxy)thiophenol, 2-bromobenzyl mercaptan, 2,4-difluorothiophenol, and 2,4-dichlorobenzenethiol, or salts thereof. For example, in some embodiments, the catalysts comprises methanethiol, ethanethiol, or salts thereof.

[0034] In a sixth aspect, the reaction mixture can also comprise a solvent. In some embodiments, the solvent can include an aqueous solvent, such as water or a buffered aqueous solution. As another example, the solvent can include a mixture of an organic solvent and an aqueous solvent. In some embodiments, the organic solvent is selected from pentane, hexane, heptane, cyclohexane, 1 ,4- dioxane, p-xylene, benzene, m-xylene, toluene, o-xylene, diethyl ether, chloroform, chlorobenzene, diglyme, 1 ,2-dimethoxyethane, tetrahydrofuran, methylene chloride, or 1 ,2-dichloroethane.

[0035] In a seventh aspect, the process can be performed at a pH from about 7 to about 12.

[0036] In an eighth aspect, the process can be performed at a temperature of about 0 degree Celsius to about 30 degrees Celsius.

[0037] In a ninth aspect, a compound is provided. The compounds can include one or more thioamide groups prepared by an embodiment of the process. In some embodiments, the compound is of Formula I: wherein:

[0038] R1is selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(Co- C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Z groups as allowed by valency;

[0039] Z is independently selected at each occurrence from halo, cyano, azido, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8- membered monocyclic or bicyclic heterocycle)-(Co-C3 alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, RxO-(Co-C3 alkyl)-, RxS-(Co-C3 alkyl)-, (RxRyN)- (C0-C3 alkyl)-, RXO-C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN) C(0)-(Co-C3alkyl)-, RXO-S(0)2-(CO-C3alkyl)-, (RxRyN) S(0)2-(Co-C3alkyl)-, RzC(O)-O-(C0-C3alkyl)-, RZC(O)-(RXN)-(C0-C3alkyl)-, RzS(0)2-0-(Co-C3alkyl)-, RzS(0)2-(RxN)-(Co-C3alkyl)-, RZC(0)-(CO-C6alkyl)-, RzS(O)-(C0-C3alkyl)-, and RZS(O)2-(C0-C3 alkyl)-, wherein each Z may be optionally substituted with one or more groups selected from Y as allowed by valency;

[0040] Rxand Ryare independently selected at each occurrence from hydrogen, Ci- Ce alkyl, Ci- Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;

[0041] Rzis independently selected at each occurrence from hydrogen, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)- (C0-C3 alkyl)-, -ORX, -SRX, and -Rx, each of which may be optionally substituted with one or more Y groups as allowed by valency; and

[0042] Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

[0043] In some embodiments, the compounds can be for use in a pesticide, a herbicide or a fungicide or can be a pesticide, a herbicide, or a fungicide.

[0044] In other embodiments, the compound can adapted for use as an intermediate used in an industrial process.

[0045] The details of one or more embodiments of the present disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the present disclosure will be apparent from the description and drawings, and from the claims.

[0046] BRIEF DESCRIPTION OF THE DRAWINGS

[0047] FIG. 1 provides13C NMR spectra for reducing spark discharge experiment (H2 - N2 -13CO2). Spectrum A shows the spark discharge mixture. Spectrum B shows the spark discharge mixture after 48 hours of incubation with methanethiol at room temperature. The peak corresponding to the carbonyl carbon of thioformamide is highlighted.

[0048] FIG. 2 provides13C NMR spectra for neutral spark discharge experiment (N2 -13CO2). Spectrum A shows the spark discharge mixture. Spectrum B shows the spark discharge mixture after 48 hours of incubation with methanethiol. The peak corresponding to the carbonyl carbon of thioformamide is highlighted.

[0049] FIG. 3 provides13C NMR spectra for reactions of cyanide and sulfide with methane- and ethanethiol. Spectrum A shows the methanethiol-catalyzed formation of thioformamide at pH 8; spectrum B corresponds to this reaction at pH 11. Spectrum C shows the ethanethiol-catalyzed formation of thioformamide at pH 8; spectrum D shows the reaction at pH 11. The peak corresponding to the carbonyl carbon of thioformamide is highlighted.

[0050] FIG. 4 provides13C NMR spectrum for the formation of thioformamide from hydrogen cyanide and sodium thiophosphate. The peak observed in these reactions (<513C = 193.6 ppm) is identical to those in the reactions of cyanide, sulfide, with an alkyl thiol catalyst. The peak corresponding to the carbonyl carbon of thioformamide is highlighted.

[0051] FIG. 5 provides13C NMR spectra showing the formation of thioformamide from HCN and sulfide using different alkyl thiol catalysts. The top figure and middle spectra show the formation of thioformamide with different alkyl thiol catalysts. The bottom spectrum shows the reaction in the absence of catalyst. The stars indicate the carbonyl carbon of thioformamide.

[0052] FIG. 6 provides13C NMR spectra showing the formation of thionicotinamide from 3-cyanopyridine and sulfide using a methanethiol catalyst.

[0053] FIG. 7 provides13C NMR spectrum for the formation of thionicotinamide from 3-cyanopyridine and Na2S with a CHsSH catalyst. Reactions were carried out for 72 hours at room temperature. Peaks corresponding to the carbons on the pyridine ring are labeled in both A and B. Unlabelled peaks in spectrum B correspond to carbons on the 3-cyanopyridine ring. In the presence of the thiol- catalyst, a near complete conversion of 3-cyanopyridine was observed (spectrum A). In the absence of the catalyst, some conversion is still observed, but not to the same extent (spectrum B).

[0054] FIG. 8 provides a proposed mechanism for the thiol-catalyzed formation of thioamides from nitriles and sulfide. Two subsequent nucleophilic attacks yield a thiolimine which tautuomerizes to form a thioamide. The reaction is illustrated here with HCN to yield thioformamide as the end product.

[0055] FIG. 9 provides Gibbs energy of reaction (AG°) for the hydrolysis of thioformamide to yield either thioformic acid or formamide. Gibbs energy values were computed with B3LYP / 6- 311 ++g(3df,3pd) / scrf=(iefpcm, solvent=water).

[0056] FIG. 10 provides Gibbs energy of reaction (AGr) for the hydrolysis of thioformamide to yield formamide.

[0057] FIG. 11 provides representative reactions of the present disclosure for the synthesis of thioformamide from hydrogen cyanide and sodium sulfide.

[0058] FIG. 12 summarizes reaction schemes demonstrated hereinbelow that thioformamide can be formed from HCN and H2S with a thiol-catalyst (highlighted in square). Thioformamide also reacts with the HCN polymer aminomalononitrile to form purine precursors.

[0059] FIG. 13 depicts13C NMR spectrum (DEPT-135) for the reducing spark discharge incubation. The peak corresponding to thioformamide (193.6 ppm) is phased up, indicating that the carbon is either a methine or methyl carbon.

[0060] FIG. 14 depicts13C NMR spectrum (jmod) for the reducing spark discharge incubation. The peak corresponding to thioformamide (193.6 ppm) is phased down, indicating that the carbon is either a methine or methyl carbon.

[0061] FIG. 15 depicts13C NMR spectrum (DEPT-135) for the reaction of HCN, CHsSH, and HS_. The peak corresponding to thioformamide (193.6 ppm) is phased up, indicating that the carbon is either a methine or methyl carbon.

[0062] FIG. 16 depicts13C NMR spectrum (jmod) for the reaction of HCN, CHsSH, and HS_. The peak corresponding to thioformamide (193.6 ppm) is phased up, indicating that the carbon is either a methine or methyl carbon.

[0063] FIG. 17 depicts13C NMR spectrum (proton-decoupled) for the reaction of HCN, CHsSH, and HS_in carbonate buffer at pH 11. The peak observed at 193.6 ppm corresponds to the carbonyl carbon on thioformamide.

[0064] FIG. 18 depicts13C NMR spectrum (proton-decoupled) for the reaction of HCN, CHsSH, and HS_in water at pH 11. The peak observed at 193.6 ppm corresponds to the carbonyl carbon on thioformamide.

[0065] FIG. 19 depicts13C NMR spectrum (proton-decoupled) for the reaction of HCN and CHsSH with a N2 / H2S headspace at pH 11. The peak observed at 193.6 ppm corresponds to the carbonyl carbon on thioformamide.

[0066] FIG. 20 depicts13C NMR spectrum (proton-decoupled) for the reaction of formamide and CHsSH at pH 11 . No thioformamide was observed in this reaction.

[0067] FIG. 21 depicts13C NMR spectrum (proton-decoupled) for the reaction of SCN- and CHsSH at pH 11 . No thioformamide was observed in this reaction.

[0068] Like reference symbols in the various drawings indicate like elements.

[0069] DETAILED DESCRIPTION

[0070] The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known embodiments. Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0071] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0072] As can be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0073] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non- express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0074] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0075] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It can be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0076] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.

[0077] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, nonlimiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.

[0078] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound”, “a solvent”, or “a catalyst”, includes, but is not limited to, two or more such compounds, solvents, or catalysts, and the like.

[0079] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It can be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it can be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0080] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as we II as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0081] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub- range is explicitly recited. To illustrate, a numerical range of “about 0.1 % to 5%” should be interpreted to include not only the explicitly recited values of about 0.1 % to about 5%, but also include individual values (e.g., about 1 %, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1 %; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0082] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0083] Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0084] A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH2 is attached through the carbon of the keto (C=O) group.

[0085] The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a moiety selected from the indicated group, provided that the designated atom’s normal valence is not exceeded and the resulting compound is stable. For example, when the substituent is oxo (i.e., =0) then two hydrogens on the atom are replaced. For example, a pyridyl group substituted by oxo is a pyridine. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable active compound refers to a compound that can be isolated and can be formulated into a dosage form with a shelf life of at least one month. A stable manufacturing intermediate or precursor to an active compound is stable if it does not degrade within the period needed for reaction or other use. A stable moiety or substituent group is one that does not degrade, react or fall apart within the period necessary for use. Non-limiting examples of unstable moieties are those that combine heteroatoms in an unstable arrangement, as typically known and identifiable to those of skill in the art.

[0086] Any suitable group may be present on a “substituted” or “optionally substituted” position that forms a stable molecule and meets the desired purpose of the invention and includes, but is not limited to: alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

[0087] “Alkyl” is a straight chain or branched saturated aliphatic hydrocarbon group. In certain embodiments, the alkyl is C1-C2, C1-C3, or Ci-Ce (i.e. , the alkyl chain can be 1 , 2, 3, 4, 5, or 6 carbons in length). The specified ranges as used herein indicate an alkyl group with length of each member of the range described as an independent species. For example, Ci-Ce alkyl as used herein indicates an alkyl group having from 1 , 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and C1-C4 alkyl as used herein indicates an alkyl group having from 1 , 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. When Co-Cn alkyl is used herein in conjunction with another group, for example (C0-C3 cycloalkyl)Co-C4 alkyl, or -Co-C4(Co-C3 cycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (Co alkyl), or attached by an alkyl chain, in this case 1 , 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms, as in -O-C0-C4 alkyl(Co-C3 cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2- dimethylbutane, and 2,3-dimethylbutane. In one embodiment, the alkyl group is optionally substituted as described herein.

[0088] “Cycloalkyl” is a saturated mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused or bridged fashion. Non-limiting examples of typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In one embodiment, the cycloalkyl group is optionally substituted as described herein.

[0089] “Alkenyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, each of which is independently either cis or trans, that may occur at a stable point along the chain. Non-limiting examples include C2-C4 alkenyl and C2-C6 alkenyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. In one embodiment, the alkenyl group is optionally substituted as described herein.

[0090] “Alkynyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C2-C4 alkynyl or C2-C6 alkynyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1 -pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. In one embodiment, the alkynyl group is optionally substituted as described herein.

[0091] “Alkoxy” is an alkyl group as defined above covalently bound through an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2- pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly, an “alkylthio” or “thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound through a sulfur bridge (-S-). In one embodiment, the alkoxy group is optionally substituted as described herein.

[0092] “Alkanoyl” is an alkyl group as defined above covalently bound through a carbonyl (C=O) bridge. The carbonyl carbon is included in the number of carbons, for example C2 alkanoyl is a CHs(C=O)- group. In one embodiment, the alkanoyl group is optionally substituted as described herein.

[0093] “Halo” or “halogen” indicates, independently, any of fluoro, chloro, bromo or iodo.

[0094] “Aryl” indicates an aromatic group containing only carbon in the aromatic ring or rings. In one embodiment, the aryl group contains 1 to 3 separate or fused rings and is 6 to 14 or 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 4- to 7- or 5- to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1 , 2, or 3 heteroatoms independently selected from N, O, B, P, Si and S, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1 -naphthyl and 2- naphthyl. In one embodiment, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In one embodiment, the aryl group is optionally substituted as described herein.

[0095] The term “heterocycle” refers to saturated and partially saturated heteroatom- containing ring radicals, where the heteroatoms may be selected from N, O, and S. The term heterocycle includes monocyclic 3-12 members rings, as well as bicyclic 5-16 membered ring systems (which can include fused, bridged, or spiro bicyclic ring systems). It does not include rings containing -O-O- , -0-S-, and -S-S- portions. Examples of saturated heterocycle groups including saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl]; saturated 4- to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; and saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl], Examples of partially saturated heterocycle radicals include, but are not limited, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocycle groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro- benzo[1 ,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1 ,2- dihydroquinolyl, 1 ,2,3,4-tetrahydro-isoquinolyl, 1 ,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1 H-3-aza-fluorenyl, 5,6,7-trihydro-1 ,2,4-triazolo[3,4- a]isoquinolyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl, benzo[1 ,4]dioxanyl, 2,3,- dihydro-1 H-benzo[d]isothazol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Bicyclic heterocycle includes groups wherein the heterocyclic radical is fused with an aryl radical wherein the point of attachment is the heterocycle ring. Bicyclic heterocycle also includes heterocyclic radicals that are fused with a carbocyclic radical. Representative examples include, but are not limited to, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example indoline and isoindoline, partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms.

[0096] “Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring which contains from 1 to 4, or in some embodiments 1 , 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 4, or in some embodiments from 1 to 3 or from 1 to 2, heteroatoms selected from N, O, S, B, or P, with remaining ring atoms being carbon. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have from 5 to 6 ring atoms. In some embodiments, bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, that is groups containing 8 or 10 ring atoms in which one 5-, 6-, or 7- membered aromatic ring is fused to a second aromatic or non-aromatic ring, wherein the point of attachment is the aromatic ring. When the total number of S and O atoms in the heteroaryl group excess 1 , these heteroatoms are not adjacent to one another. In one embodiment, the total number of S and O atoms in the heteroaryl group is not more than 2. In another embodiment, the total number of S and O atoms in the heteroaryl group is not more than 1 . Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

[0097] “Protecting group”, as used herein, refers to any convenient functional group that allows one to obtain chemoselectivity in a subsequent reaction. Protecting groups are described, for example, in Peter G. M. Wuts, ed. “Greene’s Protecting Groups in Organic Synthesis”, 5thed. New York; John Wiley & Sons, Inc., 2014. For a particular compound and / or a particular chemical reaction, a person skilled in the art knows how to select and implement appropriate protecting groups and synthetic methods. Examples of amine protecting groups include acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl (BOC), and [2- (trimethylsilyl)ethoxy]methyl (SEM). Examples of carboxyl protecting groups include (1-6C) alkyl groups, such as methyl, ethyl, and t-butyl. Examples of alcohol protecting groups include benzyl, trityl, silyl ethers, and the like.

[0098] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0099] As used herein, substantially pure means sufficiently homogenous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), nuclear magnetic resonance (NMR), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), gas chromatography mass spectrometry (GC-MS), and the like, used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties of the substance. Both traditional and modern methods for purification of compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers.

[0100] The compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates and other isomers, such as rotamers, as if each is specifically described, unless otherwise indicated or otherwise excluded by context. It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R-) or (S-) configuration. The compounds provided herein may either be enantiomerically pure, or be diastereomeric or enantiomeric mixtures. Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture.

[0101] In one aspect, a process is provided for the synthesis of a compound containing one or more thioamide groups having the structure , the process comprising: reacting a mixture comprising a compound containing one or more nitrile groups and a catalyst with a sulfide to form the compound containing one or more thioamide groups, wherein the catalyst comprises a compound containing one or more thiol groups or salts thereof.

[0102] In some embodiments, the compound containing one or more thioamide groups comprises a compound of Formula I: wherein:

[0103] R1is selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(Co- C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Z groups as allowed by valency;

[0104] Z is independently selected at each occurrence from halo, cyano, azido, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8- membered monocyclic or bicyclic heterocycle)-(Co-C3 alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, RxO-(Co-C3 alkyl)-, RxS-(Co-C3 alkyl)-, (RxRyN)- (C0-C3 alkyl)-, RXO-C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN) C(0)-(Co-C3alkyl)-, RXO- S(0)2-(Co-C3alkyl)-, (RxRyN) S(0)2-(Co-C3alkyl)-, RzC(O)-O-(C0-C3alkyl)-, RZC(O)- (RxN)-(C0-C3alkyl)-, RzS(O)2-O-(C0-C3alkyl)-, RzS(O)2-(RxN)-(C0-C3alkyl)-, RZC(0)-(CO-C6alkyl)-, RzS(O)-(C0-C3alkyl)-, and RzS(O)2-(C0-C3alkyl)-, wherein each Z may be optionally substituted with one or more groups selected from Y as allowed by valency;

[0105] Rxand Ryare independently selected at each occurrence from hydrogen, Ci- Ce alkyl, Ci-Ce haloalkyl, C2-Ce alkenyl, C2-Ce alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)- , (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)- (C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;

[0106] Rzis independently selected at each occurrence from hydrogen, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-Ce alkenyl, C2-Ce alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)- (C0-C3 alkyl)-, -ORX, -SRX, and -Rx, each of which may be optionally substituted with one or more Y groups as allowed by valency; and

[0107] Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

[0108] In some embodiments, the compound containing one or more nitrile groups comprises a compound of Formula II: wherein:

[0109] R1is selected from hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(Co- C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Z groups as allowed by valency;

[0110] Z is independently selected at each occurrence from halo, cyano, azido, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8- membered monocyclic or bicyclic heterocycle)-(Co-C3 alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, RxO-(Co-C3 alkyl)-, RxS-(Co-C3 alkyl)-, (RxRyN)- (C0-C3 alkyl)-, RXO-C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN) C(0)-(Co-C3alkyl)-, RXO- S(0)2-(Co-C3alkyl)-, (RxRyN) S(0)2-(Co-C3alkyl)-, RzC(O)-O-(C0-C3alkyl)-, RZC(O)- (RxN)-(C0-C3alkyl)-, RzS(0)2-0-(Co-C3alkyl)-, RzS(0)2-(RxN)-(Co-C3alkyl)-, RZC(0)-(CO-C6alkyl)-, RzS(O)-(C0-C3alkyl)-, and RzS(0)2-(Co-C3alkyl)- wherein each Z may be optionally substituted with one or more groups selected from Y as allowed by valency;

[0111] Rxand Ryare independently selected at each occurrence from hydrogen, Ci- Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)- , (4- to 6-membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;

[0112] Rzis independently selected at each occurrence from hydrogen, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)-, (4- to 6-membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)- (C0-C3 alkyl)-, -ORX,-SRX, and -Rx, each of which may be optionally substituted with one or more Y groups as allowed by valency; and

[0113] Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

[0114] The disclosed processes comprise the reaction of a nitrile with a sulfide. A “sulfide” as used herein refers to a compound containing or comprising the sulfide anion (S2-) or its conjugate acids thereof, such as hydrogen sulfide (H2S) and bisulfide (SH_). In some embodiments, the sulfide comprises hydrogen sulfide, an alkali metal sulfide, an ammonium sulfide, or a substituted ammonium sulfide. Representative examples of sulfides which may be used in the disclosed processes include, but are not limited to, hydrogen sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide, ammonium sulfide, disodium hydrogen sulfide, dipotassium hydrogen sulfide, and concentrations thereof.

[0115] The disclosed processes make use of a catalyst which comprises a thiol. As used herein, the term “thiol” refers to any organic compound containing the functional group -S-H. The catalyst may be present in the reaction mixture in an amount ranging from about 0.1 mol % to about 50 mol % based on the molar mass of the nitrile.

[0116] In some embodiments, the catalyst is present in the reaction mixture in an amount ranging from about 0.1 mol % to about 45 mol %, from 0.1 mol % to about 40 mol %, from 0.1 mol % to about 35 mol %, from 0.1 mol % to about 30 mol %, from 0.1 mol % to about 25 mol %, from 0.1 mol % to about 20 mol %, from 0.1 mol % to about 15 mol %, from 0.1 mol % to about 10 mol %, from 0.1 mol % to about 5 mol %, from 0.1 mol % to about 4 mol %, from 0.1 mol % to about 3 mol %, from 0.1 mol % to about 2 mol %, from 0.1 mol % to about 1 mol %, from 0.1 mol % to about 0.5 mol %, about 0.5 to about 50 mol %, about 0.5 mol % to about 45 mol %, from 0.5 mol % to about 40 mol %, from 0.5 mol % to about 35 mol %, from 0.5 mol % to about 30 mol %, from 0.5 mol % to about 25 mol %, from 0.5 mol % to about 20 mol %, from 0.5 mol % to about 15 mol %, from 0.5 mol % to about 10 mol %, from 0.5 mol % to about 5 mol %, from 0.5 mol % to about 4 mol %, from 0.5 mol % to about 3 mol %, from 0.5 mol % to about 2 mol %, from 0.5 mol % to about 1 mol %, about 1 to about 50 mol %, about 1 mol % to about 45 mol %, from 1 mol % to about 40 mol %, from 1 mol % to about 35 mol %, from 1 mol % to about 30 mol %, from 1 mol % to about 25 mol %, from 1 mol % to about 20 mol %, from 1 mol % to about 15 mol %, from 1 mol % to about 10 mol %, from 1 mol % to about 5 mol %, from 1 mol % to about 4 mol %, from

[0117] 1 mol % to about 3 mol %, from 1 mol % to about 2 mol %, about 2 to about 50 mol %, about 2 mol % to about 45 mol %, from 2 mol % to about 40 mol %, from

[0118] 2 mol % to about 35 mol %, from 2 mol % to about 30 mol %, from 2 mol % to about 25 mol %, from 2 mol % to about 20 mol %, from 2 mol % to about 15 mol %, from 2 mol % to about 10 mol %, from 2 mol % to about 5 mol %, from 2 mol % to about 4 mol %, from 2 mol % to about 3 mol %, about 3 to about 50 mol %, about 3 mol % to about 45 mol %, from 3 mol % to about 40 mol %, from 3 mol % to about 35 mol %, from 3 mol % to about 30 mol %, from 3 mol % to about 25 mol %, from 3 mol % to about 20 mol %, from 3 mol % to about 15 mol %, from 3 mol % to about 10 mol %, from 3 mol % to about 5 mol %, from 3 mol % to about 4 mol %, about 4 to about 50 mol %, about 4 mol % to about 45 mol %, from 4 mol % to about 40 mol %, from 4 mol % to about 35 mol %, from 4 mol % to about 30 mol %, from 4 mol % to about 25 mol %, from 4 mol % to about 20 mol %, from 4 mol % to about 15 mol %, from 4 mol % to about 10 mol %, from 4 mol % to about 5 mol %, about 5 to about 50 mol %, about 5 mol % to about 45 mol %, from 5 mol % to about 40 mol %, from 5 mol % to about 35 mol %, from 5 mol % to about 30 mol %, from 5 mol % to about 25 mol %, from 5 mol % to about 20 mol %, from 5 mol % to about 15 mol %, from 5 mol % to about 10 mol %, about 10 to about 50 mol %, about 10 mol % to about 45 mol %, from 10 mol % to about 40 mol %, from 10 mol % to about 35 mol %, from 10 mol % to about 30 mol %, from 10 mol % to about 25 mol %, from 10 mol % to about 20 mol %, from 10 mol % to about 15 mol %, about 15 to about 50 mol %, about 15 mol % to about 45 mol %, from 15 mol % to about 40 mol %, from 15 mol % to about 35 mol %, from 15 mol % to about 30 mol %, from 15 mol % to about 25 mol %, from 15 mol % to about 20 mol %, about 20 to about 50 mol %, about 20 mol % to about 45 mol %, from 20 mol % to about 40 mol %, from 20 mol % to about 35 mol %, from 20 mol % to about 30 mol %, from 20 mol % to about 25 mol %, about 25 to about 50 mol %, about 25 mol % to about 45 mol %, from 25 mol % to about 40 mol %, from 25 mol % to about 35 mol %, from 25 mol % to about 30 mol %, about 30 to about 50 mol %, about 30 mol % to about 45 mol %, from 30 mol % to about 40 mol %, from 30 mol % to about 35 mol %, about 35 to about 50 mol %, about 35 mol % to about 45 mol %, from 35 mol % to about 40 mol %, about 40 to about 50 mol %, about 40 mol % to about 45 mol %, or about 45 to about 50 mol %, based on the molar mass of the nitrile. In some embodiments, the catalyst is present in the reaction mixture in an amount of about 0.1 mol %, about 0.5 mol %, about 1 mol %, about 2 mol %, about 3 mol %, about 4 mol %, about 5 mol %, about 10 mol %, about 15 mol %, about 20 mol %, about 25 mol %, about 30 mol %, about 35 mol %, about 40 mol %, about 45 mol %, or about 50 mol %, based on the molar mass of the nitrile.

[0119] In some embodiments, the catalyst comprises an alkyl thiol or an aryl thiol, or salts thereof. In some embodiments, the catalyst comprises a compound of Formula III: or salts thereof, wherein:

[0120] R1is selected from Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(Co- C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Z groups as allowed by valency;

[0121] Z is independently selected at each occurrence from halo, cyano, azido, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(Co-C3 alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, RxO-(Co-C3 alkyl)-, RxS-(Co-C3 alkyl)-, (RxRyN)- (C0-C3 alkyl)-, RXO-C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN) C(0)-(Co-C3alkyl)-, RXO-S(0)2-(CO-C3alkyl)-, (RxRyN)S(O)2-(C0-C3 alkyl)-, RzC(O)-O-(C0-C3alkyl)-, RZC(O)- (RxN)-(C0-C3alkyl)-, RzS(O)2-O-(C0-C3 alkyl)-, RzS(O)2-(RxN)-(C0-C3 alkyl)-, RZC(0)-(CO-C6alkyl)-, RzS(O)-(C0-C3alkyl)-, and RzS(0)2-(Co-C3alkyl)- wherein each Z may be optionally substituted with one or more groups selected from Y as allowed by valency;

[0122] Rxand Ryare independently selected at each occurrence from hydrogen, Ci- Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)- , (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)- (C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; Rzis independently selected at each occurrence from hydrogen, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-Ce alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)- (C0-C3 alkyl)-, -ORX, -SRX, and -Rx, each of which may be optionally substituted with one or more Y groups as allowed by valency; and

[0123] Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

[0124] In some embodiments, representative examples of catalysts which may be used include, but are not limited to, methanethiol, ethanethiol, thiophenol, benzyl mercaptan, 2- methyl-2 -propanethiol, 1 -butanethiol, 4-methoxythiophenol, triphenylmethanethiol, 2- naphthalenethiol, 4-bromothiophenol, 4- chlorothiophenol, 4-fluorothiophenol, cyclohexanethiol, 2-phenylethanethiol, 4- nitrothiophenol, 2,2,2-trifluoroethanethiol, 2- propanethiol, 2-propene-1 -thiol, 4-tert- butylbenzenethiol, 2-bromothiophenol, 2,4- dimethylbenzenethiol, 4-tert-butylbenzyl mercaptan, 4-methoxy-2-methylthiophenol, 2- (trimethylsilyl)ethanethiol, 2,6- dimethylbenzenethiol, 2-(2-methoxyethoxy)ethanethiol, 2- methylbenzenethiol, 2- methyl-1 -propanethiol, 2-methoxythiophenol, 1 -hexadecanethiol, 3-bromothiophenol, cyclopentanethiol, 3-methoxythiophenol, 3,5- bis(trifluoromethyl)benzenethiol, 3- methylbenzenethiol, 3,5-dimethylbenzenethiol, 2- chlorothiophenol, 2- fluorothiophenol, (4-nitrobenzyl)mercaptan, 3,4-dimethoxythiophenol, 4- chlorobenzenemethanethiol, 4-fluorobenzyl mercaptan, 1 -phenylethyl mercaptan, 2,5- dimethylbenzenethiol, 2,3,5,6-tetrafluorobenzenethiol, 3,4-dimethylbenzenethiol, 3,4-difluorothiophenol, 4-trifluoromethylbenzyl mercaptan, 4-bromobenzyl mercaptan, 2,5- dimethoxythiophenol, 2-(trifluoromethyl)benzenethiol, 4- trifluoromethyl-2,3,5,6- tetrafluorothiophenol, 2,5-dicluorobenzenethiol, 3- ethoxythiophenol, (3- nitrobenzyl)mercaptan, 1 -isopropylbenzenethiol, 4- (trifluoromethoxy)benzyl mercaptan, 3,4-difluorobenzyl mercaptan, 3-bromo-4- fluorothiophenol, 2,5-difluorothiophenol, 3,5-difluorobenzyl mercaptan, 4-chloro-2- fluorobenzyl mercaptan, 2,6-difluorobenzyl mercaptan, 3,5-difluorobenzyl mercaptan, 3,5-difluorothiophenol, 2-(trifluoromethoxy)thiophenol, 3- (trifluoromethoxy)thiophenol, 2-bromobenzyl mercaptan, 2,4-difluorothiophenol, and 2,4-dichlorobenzenethiol, or salts thereof.

[0125] In particular embodiments, the catalyst comprises methanethiol, ethanethiol, or salts thereof.

[0126] In some embodiments, the reaction mixture further comprises a solvent. Suitable solvents for use in the processes described herein may be readily identified by a person of skill in the art based upon the particular nitrile, sulfide, and thiol components used therein. In some embodiments, the solvent comprises an aqueous solvent, such as water or a buffered aqueous solution. In some embodiments, the solvent comprises a mixture of an organic solvent and an aqueous solvent. Representative examples of suitable organic solvents for use in the processes described herein include, but are not limited to, pentane, hexane, heptane, cyclohexane, 1 ,4-dioxane, p-xylene, benzene, m-xylene, toluene, o-xylene, diethyl ether, chloroform, chlorobenzene, diglyme, 1 ,2- dimethoxyethane, tetrahydrofuran, methylene chloride, or 1 ,2-dichloroethane.

[0127] In some embodiments, the process is performed at a pH from about 7 to about 12, for example a pH from about 7 to about 11 .5, about 7 to about 11 , about 7 to about 10.5, about 7 to about 10, about 7 to about 9.5, about 7 to about

[0128] 9, about 7 to about 8.5, about 7 toabout 8, about 7 to about 7.5, about 7.5 to about 12, about 7.5 to about 11.5, about 7.5 to about 11 , about 7.5 to about 10.5, about 7.5 to about 10, about 7.5 to about 9.5, about 7.5 to about 9, about 7.5 to about 8.5, about 7.5 to about 8, about 8 to about 12, about 8 to about 11.5, about 8 to about 11 , about 8 to about 10.5, about 8 to about 10, about 8 to about 9.5, about 8 to about 9, about 8 to about 8.5, about 8.5 to about 12, about 8.5 to about 11 .5, about 8.5 to about 11 , about 8.5 to about 10.5, about 8.5 to about

[0129] 10, about 8.5 to about 9.5, about 8.5 to about 9, about 9 to about 12, about 9 to about 11 .5, about 9 to about 11 , about 9 to about 10.5, about 9 to about 10, about 9 to about 9.5, about 9.5 to about 12, about 9.5 to about 11 .5, about 9.5 to about 11 , about 9.5 to about 10.5, about 9.5 to about 10, about 10 to about 12, about 10 to about 11 .5, about 10 to about 11 , about 10 to about 10.5, about 10.5 to about 12, about 10.5 to about 11.5, about 10.5 to about 11 , about 11 to about 12, about 11 to about 11 .5, and about 11 .5 to about 12. In some embodiments, the process is performed at a pH of about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11 , about 11 .5, or about 12.

[0130] In some embodiments, the process is performed at a temperature of about 0 degree Celsius to about 30 degrees Celsius. In some embodiments, the process is performed at a temperature of about 0 degree Celsius, about 5 degrees Celsius, about 10 degrees Celsius, about 15 degrees Celsius, about 20 degrees Celsius, about 25 degrees Celsius, or about 30 degrees Celsius.

[0131] In another aspect, a compound containing one or more thioamide groups formed by a process as described herein. In some embodiments, the compound formed by the described processes is a compound of Formula I: wherein:

[0132] R1is selected from hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(Co- C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Z groups as allowed by valency;

[0133] Z is independently selected at each occurrence from halo, cyano, azido, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8- membered monocyclic or bicyclic heterocycle)-(Co-C3 alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, RxO-(Co-C3 alkyl)-, RxS-(Co-C3 alkyl)-, (RxRyN)- (C0-C3 alkyl)-, RXO-C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN) C(0)-(Co-C3alkyl)-, RXO- S(O)2-(C0-C3 alkyl)-, (RxRyN)S(O)2-(C0-C3 alkyl)-, RzC(O)-O-(C0-C3alkyl)-, RZC(O)- (RxN)-(C0-C3alkyl)-, RzS(O)2-O-(C0-C3 alkyl)-, RzS(O)2-(RxN)-(C0-C3 alkyl)-, RZC(0)-(CO-C6alkyl)-, RzS(O)-(C0-C3alkyl)-, and RZS(O)2-(C0-C3 alkyl)- wherein each Z may be optionally substituted with one or more groups selected from Y as allowed by valency;

[0134] Rxand Ryare independently selected at each occurrence from hydrogen, Ci- Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)- , (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)- (C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;

[0135] Rzis independently selected at each occurrence from hydrogen, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)- (C0-C3 alkyl)-, -ORX, -SRX, and -NRxRy, each of which may be optionally substituted with one or more Y groups as allowed by valency; and

[0136] Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

[0137] Kits for practicing the processes described herein are further provided. By “kit” is intended any manufacture (e.g., a package or a container) comprising at least one reagent, e.g., a thiol catalyst and / or sulfide as described herein. The kit can be promoted, distributed, or sold as a unit for performing the processes described herein. Additionally, the kits can contain a package insert describing the kit and processes for its use. Any or all of the kit reagents can be provided within containers that protect them from the external environment, such as in sealed containers or pouches.

[0138] Also disclosed are kits that comprise a composition comprising a sulfide and / or thiol catalyst disclosed herein in one or more containers. The disclosed kits can optionally include solvents as appropriate for the particular process. In one embodiment, a kit includes instructions or packaging materials that describe how to perform the processes described herein. Containers of the kit can be of any suitable material, e.g., glass, plastic, metal, etc., and of any suitable size, shape, or configuration.

[0139] Variations on compounds of Formula II or Formula III as used in the processes described herein can include the addition, subtraction, or movement of the various constituents as described for each compound. Similarly, when one or more chiral centers is present in a molecule, the chirality of the molecule can be changed. Additionally, the synthesis of the compounds of Formula II or Formula III for use in the process can involve the protection of various chemical groups, and further the compounds of Formula I prepared by the disclosed process may be subsequently deprotected as appropriate. The use of protection and deprotection, and the selection of appropriate protecting groups, would be readily known to one skilled in the art. The chemistry of protecting groups can be found, for example, in Peter G. M. Wuts, Green’s Protecting Groups in Organic Synthesis, 5thed., Wiley & Sons, 2014.

[0140] The described processes, or reactions used to produce the compounds in the described processes, can be carried out in solvents indicated herein, or in solvents which can be selected by one of skill in the art of organic synthesis. Solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products underthe conditions at which the reactions are carried out, i.e. , temperature and pressure. Reactions can be carried out in one solvent or a mixture of more than one solvent. Product or intermediate formation can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,1H or13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0141] A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

[0142] By way of non-limiting illustration, examples of certain embodiments of the present disclosure are given below.

[0143] EXAMPLES

[0144] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the scope of the present disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in degrees Celsius or is at ambient temperature, and pressure is at or near atmospheric pressure.

[0145] Example 1: Formation of Thioamides from Nitriles and Sulfide with a Thiol- catalyst

[0146] Thioamide compounds are crucial intermediates in several plausible prebiotic chemical networks (see Patel, B.H., Percivalle, C., Ritson, D.J., Duffy, C.D., Sutherland, J.D.: Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism. Nature Chemistry 7(4), 301-307 (2015)) and are important heterocycle precursors (see Okamura, H., Becker, S., Tiede, N., Wiedemann, S., Feldmann, J., Carell, T.: A one-pot, water compatible synthesis of pyrimidine nucleobases under plausible prebiotic conditions. Chemical Communications 55(13), 1939-1942 (2019)). Their synthesis from nitriles usually requires activation by acetylation of Strecker precursors (see P. Canavelli, S. Islam, M. W. Powner, Peptide ligation by chemoselective aminonitrile coupling in water. Nature. 571 , 546-549 (2019); C. S. Foden, S. Islam, C. Fernandez-Garcia, L. Maugeri, T. D. Sheppard, M. W. Powner, Prebiotic synthesis of cysteine peptides that catalyze peptide ligation in neutral water. Science. 370, 865-869 (2020)), reactions with excesses of sulfide (see Patel, B.H., Percivalle, C., Ritson, D.J., Duffy, C.D., Sutherland, J.D.: Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism. Nature Chemistry 7(4), 301-307 (2015); Tull, R., Weinstock, L.M.: A New Synthesis of Thioformamide. Agnew. Chem. International Edition 8(4), 278-279 (1969)), or compounds lacking a known geochemical source (see Ritson, D., Xu, J., Sutherland, J.: Thiophosphate A Versatile Prebiotic Reagent? Synlett 28(01 ), 64-67 (2016)). The formation of thioamides from nitriles and sulfide with a thiol- catalyst was investigated.

[0147] Methods

[0148] Unless stated otherwise, all reactions were carried out in an N2-sparged phosphate- buffer (0.1 M) with an N2-headspace at room temperature. Degassed HCI or NaOH was used to adjust the pH.

[0149] Spark discharge experiments Spark discharge experiments were carried out under a mildly reducing atmosphere (H2 - N2 -13CO2; 0.33 bar each). Gaseous13CO2 was generated from sodium bicarbonate (NaH13COs(s), Cambridge Isotope Laboratories) and degassed hydrochloric acid (4 N; HCI). Excess HCI was added to NaH13COs in a 1100-mL round-bottom flask under vacuum. The reaction was allowed to proceed for 30 minutes at room temperature, after which residual acid and water was removed before proceeding. The same procedure was used to generate a neutral atmosphere (N2 -13CO2; 0.5 bar each).

[0150] Phosphate buffer (0.2 M; pH 8; VWR) and sodium sulfide nonahydrate (0.1 M; Na2S 9H2O; EMD Millipore) were added as the aqueous phase in a 1100-mL round- bottom flask. An Electrotechnics BD50E Tesla coil and two tungsten electrodes were used to generate a spark for 72 hours. During this time, the flask was kept in a water bath at ~ 5°C to maintain a consistent temperature in the flask. After 72 hours, the aqueous phase was incubated with sodium thiomethoxide (20 mM; CHsSNa) at room temperature for 48 hours.

[0151] Each reaction was carried out with equimolar amounts of nitrile (either13C- potassium cyanide or 3-cyanopyridine), sodium sulfide (Na2S*9H2O) and alkyl thiol (either sodium methanethiolate or ethanethiol). Final concentrations of 20 mM of each reactant was placed into a serum vial and dissolved in anoxic 0.1 M phosphate buffer (sparged with N2) and under an N2 headspace.

[0152] HCN reactions

[0153] Reactions with HCN were carried out with isotopically labeled potassium cyanide (20 mM, K13CN; Cambridge Isotope Laboratories), sodium sulfide (20 mM, Na2S 9H2O); Sigma Aldrich). Alkyl thiol was also added as either methanethiolate (20 mM, CHsSNa; Sigma Aldrich) or ethanethiol (50 mM, CH3CH2SH; Sigma Aldrich). Initial reactions were carried out with a ratio of 2:5:5 HCN:sulfide:thiol, but subsequent reactions were carried out with equimolar amounts of each reactant. Each reactant was placed into a serum vial and dissolved in degassed phosphate buffer (0.1 M) and under an N2 headspace.

[0154] Reactions with a headspace containing H2S (g) were carried out in a manner similar to those above, with equimolar amounts of K13CN and CHsSNa (20 mM). Gaseous H2S was generated by placing Na2S 9H2O (s) under vacuum and adding degassed 4 N HCI. This reaction was allowed to proceed for 24 hours at room temperature. After 24 hours, 7.5 mL of H2S (g) (1 .5 bar) was added to a reaction of K13CN and CHsSNa (20 mM) in degassed phosphate buffer with an N2-headspace.

[0155] Non-alkyl thiols were screened for their ability to catalyze the formation of thioformamide. Reactions containing cysteamine (2-aminoethanethiol hydrochloride) and N- acetyl cysteamine were carried out in the same manner as the thioformam ide-forming reactions above.

[0156] To confirm the identity of thioformamide, reactions were also carried out to form thioformamide from HCN and sodium thiophosphate (Na2PO3S; Sigma-Aldrich) following the methods of Ritson (see Ritson, D., Xu, J., Sutherland, J.: Thiophosphate A Versatile Prebiotic Reagent? Synlett 28(01 ), 64-67 (2016)).

[0157] Further reactions were conducted to determine if compounds other than HCN present in the spark discharge mixture could serve as precursors to thioformamide. Reactions with formamide (HCONH2; 20 mM; Acres Organics) and sodium thiocyanate (NaSCN; 20 mM; Acres Organics) carried out in a manner similar to those described above, replacing K13CN with either formamide or sodium thiocyanate. To determine whether or not alkyl thiols were serving as catalysts themselves via the mechanism proposed below or just acting as an acid, imidazole (20 mM; Thermo Scientific) was reacted with K13CN and Na2S 9H2O and the production of thioformamide was not detected.

[0158] 3-cyanopyridine reactions

[0159] Thionicotinamide-forming reactions were carried out with 3-cyanopyridine (25 mM; Sigma-Aldrich), sodium sulfide (50 mM), and methanethiolate (50 mM; Sigma Aldrich).

[0160] Nuclear magnetic resonance spectroscopy

[0161] Samples were prepared for nuclear magnetic resonance spectroscopy (NMR) by adding 0.1 mL of deuterium oxide (D2O, 99.8 atom % D; Acres Organics) to 0.5 mL of the reaction mixture. NMR spectra were collected on either a Broker Avance- lll-HD- 500 or a Broker NEO-400 spectrometer. Spectra for1H (500 MHz, 400 MHz) were collected using solvent suppression (zgesgp). Proton-decoupled spectra for13C (125 MHz, 100 MHz) were collected using the pulse program zgpg30. Yield determinations for HCN reactions were carried out by increasing the ti relaxation time (ti = 30 s; zgig). The optimal ti relaxation time was determined using inversion recovery experiments. Spectra were also collected for Distortionless Enhancement by Polorization Transfer (DEPT 135; deptsp135) and J modulation (jmod) in initial experiments when determining the structure of thioformamide. All spectra were processed using the MestReNova software suite (see Willcott, M.R.: MestRe Nova. Journal of the American Chemical Society 131 (36), 13180-13180 (2009)).

[0162] Thermodynamics and kinetics

[0163] Density functional theory calculations

[0164] To compute the thermochemical properties of the compounds involved in the hydrolysis of thioformamide, we employed Gaussian 16 (Frisch, M., Trucks, G., Schlegel, H.B., Scuseria, G., Robb, M., Cheeseman, J., Scalmani, G., Barone, V., Petersson, G., Nakatsuji, H., et al.: Gaussian 16. Gaussian, Inc. Wallingford, CT (2016)) to perform ab initio density functional theory calculations. B3LYP level of theory (Becke-style 3-parameter density functional theory with the Lee-Yang-Parr correlation functional) was used with the basis set 6- 311 ++g(3df,3pd), which have been previously used to study thioformamide (Bernhardt, B., Dressier, F., Eckhardt, A.K., Becker, J., Schreiner, P.R.: Characterization of the Simplest Thiolimine: The Higher Energy Tautomer of Thioformamide. Chemistry - A European Journal 27(22), 6732-6739 (2021 )). Solvation effects were taken into account with a self-consistent reaction field (SCRF) and a polarizable continuum model (with integral equation formalism; IEFPCM).

[0165] Standard state enthalpy (AH°) and Gibbs energy (AG°) of reaction were calculated from thermochemical output using the equations below:

[0166] Where £o is the total electronic energy of a compound and Hcorr and Geon- are the thermal corrections to enthalpy and free energies, respectively.

[0167] Kinetic rate constants

[0168] Kinetic rate constants for the formation of thioformamide were determined from reaction yields from quantitative13C NMR. The formation of thioformamide was assumed to follow a second-order rate law and the kinetic rate constant (k) was determined from the below equation.

[0169] The concentration of HCN was equal to the concentration of HS_. The hydrolysis of thioformamide was determined in previous work to have a half-life (fi / 2) of 3 days (see Sanchez, R.A., Ferbis, J.P., Orgel, L.E.: Studies in Prebiotic Synthesis II. Synthesis of purine precursors and amino acids from aqueous hydrogen cyanide. Journal of Molecular Biology 30(2), 223-253 (1967)). Taken to be a pseudo-first order reaction (where the rate of reaction is only dependent on the concentration of thioformamide) the kinetic rate constant can be calculated from:

[0170] Results

[0171] Thioformamide-forming reactions

[0172] Spark-discharge experiments

[0173] Carbon-13 NMR spectra for the mildly reducing (H2 - N2 -13CO2) spark discharge mixture indicated that a variety of organics were produced (see FIG. 1 ). When this solution was incubated with methanethiol and / or ethanethiol, a peak corresponding to a carbonyl carbon was detected (513C = 193.6ppm) (see FIG. 2 and FIG. 3). Spectra collected using the DEPT135 and JMOD pulse programs indicated that this corresponded to a carbon with one proton attached. A lower diversity of organic compounds was detected in the neutral spark discharge mixture but after incubation with methanethiol, the same peak (513C = 193.6ppm) was again detected with13C NMR.

[0174] Isolated HCN reactions

[0175] Several reactions were investigated for their ability to reproduce the compound detected in the spark discharge incubations. Reactions of cyanide, methanethiol, and sulfide produced thioformamide at 4°C and room temperature, as well as at pH of about 7 and pH of about 11 . Quantitative13C NMR indicated about a 33% yield of thioformamide from HCN at pH of about 7. The phosphate buffer did not have any influence on the reaction. To prove this point, the same reaction was conducted in carbonate buffer and in water. Both of these reactions produced thioformamide. Reactions of formamide and sodium thiocyanate in place of cyanide did not produce any detectable thioformamide.

[0176] Hydrogen cyanide was then reacted with sodium thiophosphate to confirm the production of thioformamide. Carbon-13 NMR spectra from this reaction showed an identical chemical shift (513C = 193.6ppm), confirming the production of thioformamide (see FIG. 4).

[0177] Notably, reactions of cyanide and sulfide alone did not lead to the production of thioformamide indicating that methanethiol is acting as a catalyst in the formation of thioformamide. Indeed, reactions of cyanide and sulfide with ethanethiol also lead to the production of thioformamide, signifying that these alkyl thiols are likely acting to catalyze the formation of thioamide bonds in the presence of sulfide (see FIG. 5). The formation of thioformamide also proceeded in a carbonate buffer, as opposed to a phosphate buffer, demonstrating that, aside from the intended effect of buffering the pH of the reaction, the phosphate played no role in this reaction.

[0178] Additionally, a few reactions where non-alkyl thiols were used in place of methane- or ethanethiol failed to produce thioformamide. These reactions seemed to have preferentially formed other products instead of thioformamide. For example, cysteamine, a thiol-containing precursor to coenzyme A, reacted with cyanide to form a thiazole (a nitrogen- and sulfur-containing five-membered heterocycle). Reactions using cysteine, a thiol-containing a-amino acid, also did not catalyze the formation of thioformamide. This was suspected to be caused by the formation of cyanohydrins, a favorable product of the reaction of amino acids and cyanide.

[0179] Thionicotinamide-forming reactions

[0180] To test whether thiols can catalyze the formation of other thioamides, the reaction of 3-cyanopyridine and sulfide with methanethiol as a catalyst was examined. This reaction resulted in the near complete conversion of 3- cyanopyridine to thionicotinamide at a pH of about 7 (see FIG. 6 and FIG. 7). In one experiment, visual precipitation of thionicotinamide was observed in the reaction vial. Thionicotinamide is far less soluble than 3-cyanopyridine in water at 25°C (0.02 g L-1compared to 140 g L-1for thionicotinamide and 3- cyanopyridine, respectively). This reaction did not produce thionicotinamide at higher pH values. Reactions of 3-cyanopyridine with sulfide in the absence of a thiol catalyst still produced thionicotinamide, but not in the amounts produced in the presence of a thiol catalyst.

[0181] Proposed mechanism

[0182] The formation of thioamide bonds from nitriles is proposed to proceed through two subsequent nucleophilic substitution reactions (see FIG. 8). The catalytic thiol initially attacks the nitrile carbon (reducing the triple bond) to form a thioimidate intermediate. Bisulfide then attacks the carbonyl carbon of the thioimidate to yield a tetrahedral intermediate. While this conversion was efficient at neutral pHs, no detectable thionicotinamide was produced at higher (about 11 ) pHs. This intermediate collapses to reform the C=N double bond as the thiol catalyst leaves to form the thiolimine which subsequently tautomerizes to form the more thermodynamically stable thioformamide.

[0183] Alternatively, the thiol could be protonating the nitrile nitrogen, making it more electrophilic and thus susceptible to nucleophilic attack by sulfide. To examine this possibility, cyanide and sulfide was reacted with imidazole, which could act as an acid (pKa of about 7). No production of thioformamide was observed in these reactions. Accordingly, the proposed mechanism is a likely explanation for the thiol-catalyze formation of thioamide bonds.

[0184] Density functional theory calculations and Gibbs energy of reaction Thioformamide can potentially hydrolyze to form either formamide or thioformic acid. To study the energetics of these reactions, density functional theory (DFT) calculations were performed in Gaussian. Thermochemical output was used to calculate the standard enthalpy of reaction (AH°r) and Gibbs energy of reaction (AG°r) for these reactions. For the formation of thioformic acid, AH°rwas calculated to equal 27.728 kJ mol-1and AG°r was calculated to equal 23.593 kJ mol-1. The hydrolysis of thioformamide to yield formamide had an enthalpy of reaction of AH°requal to -25.0158 kJ mol-1and a Gibbs energy of reaction of AG°r equal to -27.350 kJ mol-1. Thus, under standard state conditions, the hydrolysis of thioformamide to formamide is significantly more favorable than the hydrolysis to thioformic acid (see FIG. 9).

[0185] Next, a Gibbs energy of reaction (AGr) for varying concentrations of thioformamide and formamide under plausible prebiotic conditions was calculated. Previous estimates of steady-state concentrations of formamide depended largely on the pH and temperature but ranged from about 10-13- 10-9M, assuming the main source of formamide is the hydrolysis of HCN. While there was not enough information to estimate a steady-state concentration of thioformamide, the hydrolysis of thioformamide proceeded spontaneously under a wide range of formamide and thioformamide concentrations (see FIG. 10).

[0186] Kinetic rate constants

[0187] The rate of thioformamide formation was initially expected to be quite high given that product was observed in experiments after just one hour at room temperature. Quantitative13C NMR and Equation 3 was used to determine the kinetic rate constant for the thiol-catalyzed formation of thioformamide (kf), which was found to be about 5.8 x 10-4L mol-1s-1(at 25°C). This rate of formation was compared to the rate of hydrolysis measured in previous studies. The kinetic rate constant for the hydrolysis of thioformamide to formamide (kh) is equal to 2.7 x 10-6s-1(at 25°C). Given that kf » kh, it seems likely that, absent a significant sink, thioformamide would accumulate in a prebiotic environment. While this neglects any utility thioformamide might have in prebiotic reactions, it illustrates that thioformamide could have accumulated in potentially quite large quantities on early Earth.

[0188] Conclusion

[0189] Overall, the formation of thioformamide and thionicotinamide from hydrogen cyanide and 3-cyanopyridine, respectively, was discovered. It was also found that the formation of thioamides proceeded readily at room temperature in the presence of a thiol-catalyst. Two different nitriles were used: hydrogen cyanide, and 3-cyanopyridine to form thioformamide, and thionicotinamide, respectively. The catalytic ability of thiols using two alkyl thiols: methane- and ethanethiol was investigated and show to promote the formation of thioamides (see FIG. 11 ).

[0190] These reactions represent a form of catalysis that might have facilitated reactions important in prebiotic chemistry, such as the formation of 4- aminoimidazole-5-carboxamide (AICA), an adenine precursor, from diaminomalononitrile (see FIG. 12).

[0191] Without wishing to be bound by any theory, it is proposed that the formation of thioamides from nitriles proceeds through two subsequent nucleophilic substitution reactions. The catalytic thiol initially attacks the nitrile carbon (reducing the triple bond) to form the thioimidate intermediate. Bisulfide (HS-) then attacks the carbonyl carbon of the thioimidate to yield a tetrahedral intermediate. This intermediate collapses to reform the C=N double bond as the thiol catalyst leaves to form the thiolimine which then tautomerizes to form the more thermodynamically stable thioamide (see Bernhardt, B., Dressier, F., Eckhardt, A.K., Becker, J., Schreiner, P.R.: Characterization of the Simplest Thiolimine: The Higher Energy Tautomer of Thioformamide. Chemistry - A European Journal 27(22), 6732- 6739 (2021 )).

[0192] Supplemental Data for Example 1

[0193] Additional 13C spectra were collected for spark discharge experiments to aide in the identification of the compound of interest (thioformamide). Dimensionless Enhancement by Polarization Transfer (DEPT-135) helped elucidate the multiplicity of the carbon atoms (methine and methyl groups have a positive phase, methylene groups have a negative phase, and quaternary carbons do not have peaks). Similarly, the pulse program jmod showed methine and methyl groups with a negative phase and showed methene and quaternary carbons with a positive phase. These spectra are shown in FIG. 13 and FIG. 14.

[0194] DEPT-135 and jmod pulse programs were also used to characterize the reaction of HCN, CHsSH, and HS_. These specta are shown in FIG. 15 and FIG. 16. The impact of the phosphate buffer on the formation of thioformamide was also investigated by using both a carbonate buffer (see FIG. 17) and carrying out an unbuffered reaction (see FIG. 18). Both of these showed the formation of thioformamide.

[0195] Additional experiments were performed by injecting H2S into a N2 headspace in the presence of aqueous HCN and CH3SH. This also resulted in the formation of thioformamide (See FIG. 19). Furthermore, whether formamide and thiocyanate could serve as precursors to thioformamide was investigated. These compounds were reacted with HS_in the presence of CH3SH in different reaction experiments and the production of a detectable quantity of thioforamide was not observed (see FIG. 20 and FIG. 21 ).

[0196] The inventors of the present application have found that the formation of thioforamide via an embodiment of the process of making thioforamide, as disclosed hereinabove, can be utilized to facilitate the formation of pesticides, herbicides, fungicides, or intermediates that can be used in industrial processing. Embodiments of the process for the synthesis of a compound containing one or

[0197] S u more thioamide groups having the structure can also be utilized to form a compound that can be adapted for use in pesticides, herbicides, fungicides, or intermediates that can be used in industrial processing. Compounds made via an embodiment of such processes can also be suitable for use in pesticides, herbicides, fungicides, or intermediates that can be used in industrial processing.

[0198] The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

[0199] The term “comprising”, and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, nonlimiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of’ can be used in place of “comprising” and “including” to provide for more specific embodiments of the invention and are also disclosed. Other than in the examples, or where otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches.

Claims

WHAT IS CLAIMED IS:

1. A process for the synthesis of a compound containing one or moreSthioamide groups having the structure , the process comprising: reacting a mixture comprising a compound containing one or more nitrile groups and a catalyst with a sulfide to form the compound containing one or more thioamide groups, wherein the catalyst comprises a compound containing one or more thiol groups or salts thereof.

2. The process of claim 1 , wherein the compound containing one or more thioamide groups comprises a compound of Formula I:wherein:R1is selected from hydrogen, Ci-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C3 alkyl)- , (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more Z groups as allowed by valency;Z is independently selected at each occurrence from halo, cyano, azido, Ci-C6alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8- membered monocyclic or bicyclic heterocycle)-(C0-C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, RxO-(C0-C3alkyl)-, RxS-(C0-C3alkyl)-, (RxRyN)-(C0-C3alkyl)-, RXO- C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN) C(O)-(C0-C3alkyl)-, RxO-S(O)2-(C0-C3alkyl)-, (RxRyN) S(O)2-(C0-C3alkyl)-, RzC(O)-O-(C0-C3alkyl)-, RzC(O)-(RxN)-(C0-C3alkyl)-, RZS(O)2-O-(C0-C3alkyl)-, RzS(O)2-(RxN)-(C0-C3alkyl)-, RzC(O)-(C0-C6alkyl)-, RzS(O)-(C0-C3alkyl)-, and RzS(O)2-(C0-C3alkyl)-, wherein each Z may be optionally substituted with one or more groups selected from Y as allowed by valency;Rxand Ryare independently selected at each occurrence from hydrogen, Ci-C6alkyl, C1-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(C0-C3 alkyl)-, (4- to 6-membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; Rzis independently selected at each occurrence from hydrogen, halo, Ci-C6alkyl, C1- C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -ORX, -SRX, and -Rx, each of which may be optionally substituted with one or more Y groups as allowed by valency; andY is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

3. The process of claim 1 or 2, wherein the compound containing one or more nitrile groups comprises a compound of Formula II:wherein:R1is selected from hydrogen, Ci-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C3 alkyl)- , (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more Z groups as allowed by valency;Z is independently selected at each occurrence from halo, cyano, azido, Ci-C6alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8- membered monocyclic or bicyclic heterocycle)-(C0-C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, RxO-(C0-C3alkyl)-, RxS-(C0-C3alkyl)-, (RxRyN)-(C0-C3alkyl)-, RXO- C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN)C(O)-(C0-C3alkyl)-, RxO-S(O)2-(C0-C3alkyl)-, (RxRyN)S(O)2-(C0-C3alkyl)-, RzC(O)-O-(C0-C3alkyl)-, RzC(O)-(RxN)-(C0-C3alkyl)-, RZS(O)2-O-(C0-C3alkyl)-, RzS(O)2-(RxN)-(C0-C3alkyl)-, RzC(O)-(C0-C6alkyl)-, RzS(O)-(C0-C3alkyl)-, and RzS(O)2-(C0-C3alkyl)-, wherein each Z may be optionally substituted with one or more groups selected from Y as allowed by valency;Rxand Ryare independently selected at each occurrence from hydrogen, Ci-C6alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;Rzis independently selected at each occurrence from hydrogen, halo, Ci-C6alkyl, C1- C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, -ORX, -SRX, and -NRxRy, each of which may be optionally substituted with one or more Y groups as allowed by valency; andY is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

4. The process of any one of claims 1-3, wherein the sulfide comprises hydrogen sulfide, an alkali metal sulfide, an ammonium sulfide, or a substituted ammonium sulfide.

5. The process of any one of claims 1-4, wherein the sulfide is selected from the group consisting of hydrogen sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide, ammonium sulfide, disodium hydrogen sulfide, dipotassium hydrogen sulfide, and concentrations thereof.

6. The process of any one of claims 1-5, wherein the catalyst comprises an alkyl thiol or an aryl thiol, or salts thereof.

7. The process of any one of claims 1-6, wherein the catalyst comprises a compound of Formula III:or salts thereof, wherein:R1is selected from Ci-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl) (C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, each of which may be optionally substituted with one or more Z groups as allowed by valency;Z is independently selected at each occurrence from halo, cyano, azido, Ci-C6alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8- membered monocyclic or bicyclic heterocycle)-(C0-C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, RxO-(C0-C3alkyl)-, RxS-(C0-C3alkyl)-, (RxRyN)-(C0-C3alkyl)-, RXO- C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN) C(O)-(C0-C3alkyl)-, RxO-S(O)2-(C0-C3alkyl)-, (RxRyN) S(O)2-(C0-C3alkyl)-, RzC(O)-O-(C0-C3alkyl)-, RzC(O)-(RxN)-(C0-C3alkyl)-, RZS(O)2-O-(C0-C3alkyl)-, RzS(O)2-(RxN)-(C0-C3alkyl)-, RzC(O)-(C0-C6alkyl)-, RzS(O)-(C0-C3alkyl)-, and RzS(O)2-(C0-C3alkyl)-, wherein each Z may be optionally substituted with one or more groups selected from Y as allowed by valency;Rxand Ryare independently selected at each occurrence from hydrogen, Ci-C6alkyl, C1- C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; Rzis independently selected at each occurrence from hydrogen, halo, Ci-C6alkyl, C1- C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (Co- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, -ORX,-SRX, and -Rx, each of which may be optionally substituted with one or more Y groups as allowed by valency; andY is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

8. The process of any one of claims 1-7, wherein the catalyst is selected from the group consisting of methanethiol, ethanethiol, thiophenol, benzyl mercaptan, 2- methyl-2-propanethiol, 1-butanethiol, 4-methoxythiophenol, triphenylmethanethiol, 2- naphthalenethiol, 4-bromothiophenol, 4-chlorothiophenol, 4-fluorothiophenol, cyclohexanethiol, 2-phenylethanethiol, 4-nitrothiophenol, 2,2,2-trifluoroethanethiol, 2- propanethiol, 2-propene-1 -thiol, 4-tert-butylbenzenethiol, 2-bromothiophenol, 2,4-dimethylbenzenethiol, 4-tert-butylbenzyl mercaptan, 4-methoxy-2-methylthiophenol, 2- (trimethylsilyl)ethanethiol, 2,6-dimethylbenzenethiol, 2-(2-methoxyethoxy)ethanethiol, 2- methylbenzenethiol, 2-methyl-1-propanethiol, 2-methoxythiophenol, 1 -hexadecanethiol, 3- bromothiophenol, cyclopentanethiol, 3-methoxythiophenol, 3,5- bis(trifluoromethyl)benzenethiol, 3-methylbenzenethiol, 3,5-dimethylbenzenethiol, 2- chlorothiophenol, 2-fluorothiophenol, (4-nitrobenzyl)mercaptan, 3,4-dimethoxythiophenol, 4- chlorobenzenemethanethiol, 4- fluorobenzyl mercaptan, 1-phenylethyl mercaptan, 2,5- dimethylbenzenethiol, 2,3,5,6-tetrafluorobenzenethiol, 3,4-dimethylbenzenethiol, 3,4- difluorothiophenol, 4-trifluoromethylbenzyl mercaptan, 4-bromobenzyl mercaptan, 2,5- dimethoxythiophenol, 2-(trifluoromethyl)benzenethiol, 4-trifluoromethyl-2, 3,5,6- tetrafluorothiophenol, 2,5-dicluorobenzenethiol, 3-ethoxythiophenol, (3- nitrobenzyl)mercaptan, 1-isopropylbenzenethiol, 4-(trifluoromethoxy)benzyl mercaptan,3.4-difluorobenzyl mercaptan, 3-bromo-4-fluorothiophenol, 2,5-difluorothiophenol, 3,5- difluorobenzyl mercaptan, 4-chloro-2-fluorobenzyl mercaptan, 2,6-difluorobenzyl mercaptan, 3,5-difluorobenzyl mercaptan, 3,5-difluorothiophenol, 2- (trifluoromethoxy)thiophenol, 3-(trifluoromethoxy)thiophenol, 2-bromobenzyl mercaptan,2.4-difluorothiophenol, and 2,4-dichlorobenzenethiol, or salts thereof.

9. The process of any one of claims 1-8, wherein the catalysts comprises methanethiol, ethanethiol, or salts thereof.

10. The process of any one of claims 1-9, wherein the reaction mixture further comprises a solvent.

11. The process of claim 10, wherein the solvent comprises an aqueous solvent, such as water or a buffered aqueous solution.

12. The process of any one claims 10 or 11 , wherein the solvent comprises a mixture of an organic solvent and an aqueous solvent.

13. The process of claim 12, wherein the organic solvent is selected from pentane, hexane, heptane, cyclohexane, 1,4-dioxane, p-xylene, benzene, m-xylene, toluene, o-xylene, diethyl ether, chloroform, chlorobenzene, diglyme, 1 ,2- dimethoxyethane, tetrahydrofuran, methylene chloride, or 1,2-dichloroethane.

14. The process of any one of claims 1-13, wherein the process is performedat a pH from about 7 to about 12.

15. The process of any one of claims 1-14, wherein the process is performed at a temperature of about 0 degree Celsius to about 30 degrees Celsius.

16. A compound containing one or more thioamide groups prepared by a process of any one of claims 1-15.

17. The compound of claim 16, wherein the compound is of Formula I:wherein:R1is selected from hydrogen, Ci-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C3 alkyl)- , (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, and (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more Z groups as allowed by valency;Z is independently selected at each occurrence from halo, cyano, azido, Ci-C6alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8- membered monocyclic or bicyclic heterocycle)-(C0-C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, RxO-(C0-C3alkyl)-, RxS-(C0-C3alkyl)-, (RxRyN)-(C0-C3alkyl)-, RXO- C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN) C(O)-(C0-C3alkyl)-, RxO-S(O)2-(C0-C3alkyl)-, (RxRyN) S(O)2-(C0-C3alkyl)-, RzC(O)-O-(C0-C3alkyl)-, RzC(O)-(RxN)-(C0-C3alkyl)-, RZS(O)2-O-(C0-C3alkyl)-, RzS(O)2-(RxN)-(C0-C3alkyl)-, RzC(O)-(C0-C6alkyl)-, RzS(O)-(C0-C3alkyl)-, and RZS(O)2-(C0-C3alkyl)-, wherein each Z may be optionally substituted with one or more groups selected from Y as allowed by valency;Rxand Ryare independently selected at each occurrence from hydrogen, Ci-C6alkyl, Ci- C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C0-C3 cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;Rzis independently selected at each occurrence from hydrogen, halo, Ci-C6alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-Ce alkynyl, (C0-C3 cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, -ORX, -SRX, and -Rx, each of which may be optionally substituted with one or more Y groups as allowed by valency; andY is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

18. The compound of claim 16 for use in a pesticide, a herbicide or a fungicide.

19. A composition comprising the compound of claim 16, wherein the composition is a pesticide, a herbicide, or a fungicide.

20. The compound of claim 16, wherein the compound is adapted for use as an intermediate used in an industrial process.

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