Synthesis and reactivity of monothio-oxamides

A convenient method has been developed for the synthesis of monothio-oxamides by the reaction of chloroacetamides with a previously prepared solution of elemental sulfur in amines. Oxalic acid derivatives and heterocyclic compounds were synthesized from the monothiooxamides obtained.


Introduction
The combination of amide species in close proximity in the same molecule of monothiooxamides imparts unexpected properties to these compounds and makes them of considerable interest for the synthesis of various substances, including heterocyclic structures.Monothiooxamide fragments are found in natural compounds, 1 and are under intensive study as biologically active substances. 2,3Also, monothio-oxamides are of special interest as complexforming structures. 4However, despite their high synthetic potential, the chemistry of these compounds has been studied insufficiently prior to our studies, 5 mainly because convenient methods for their synthesis were unavailable.

Results and Discussion
In our opinion, the most attractive method for the synthesis of the monothio-oxamides is based on the reaction of chloroacetamides with elemental sulfur and amines.A few examples of this approach have been described in the literature, 6,7 but they have substantial disadvantages, one of the main being the necessity of prolonged heating of the reaction mixture.It is known that sulfur, when heated, reacts with amines to form a complicated mixture of products, 8 which can impede the process of monothio-oxamide preparation.We have shown that the reaction under the conditions of the published procedure, in which elemental sulfur and the amine are simultaneously added to chloroacetamide, produces a large amount of α-aminoacetamides, which then react with sulfur only on prolonged heating.It is known 9 that when amines react with elemental sulfur for a rather long time, a considerable amount of polysulfide anion accumulates in the solution.These are formed by cleavage of the eight-membered cyclic molecule of elemental sulfur under the action of amines.It is most likely that at a sufficiently high concentration the polysulfide anions might react preferentially with chloroacetamides instead of the amines.The nucleophilic substitution of the chlorine atom affords the corresponding polysulfide, in which the amine molecules induce elimination of a proton simultaneously with the cleavage of the sulfide bond to form the thioaldehyde fragment.The reaction of thioaldehyde with amine affords the imine, which is oxidized further by sulfur to the corresponding thioamide fragment.

Scheme 2
We have established that monothio-oxamides are formed under mild conditions, in high yields, at room temperature using a solution of sulfur prepared previously in the corresponding amine (by stirring the components for 20-30 min).We have also studied the influence of solvents, the nature of the substituent in the α-position of the amides, and the nature of substituents in the "acetamide" and "amine" components.The S-functionalization of chloroacetamides and their pyridinium salts occurs most smoothly.The most convenient solvents for the reaction are DMF, pyridine, or the amine itself.We have shown that the mild conditions of the reactions make it possible to use DMF, while heating of a mixture of chloroacetamide and sulfur in DMF results in the corresponding monothiooxamides containing the dimethylamino group in the thioamide fragment.

Scheme 4
The nature of the substituent in the acetamide fragment has no substantial effect on the sulfurization of chloroacetamides.Acetamides containing electron-withdrawing and electrondonating substituents react almost in the same manner with the previously prepared solution of elemental sulfur in amides.

Scheme 5
Our method also allows the synthesis of bis-substituted monothio-oxamides.

Scheme 6
The effect of substituents in the "amine" component of the reaction is substantial.When anilines having a lower basicity than aliphatic amines are used, triethylamine should be added to the reaction mixture.We have also demonstrated that heteroaromatic monothio-oxamides can be synthesized by the reaction of chloroacetamide with sulfur and heteroaromatic amines in the presence of triethylamine.The use of aromatic, unlike aliphatic amines, makes it possible to perform the reaction at a single amino group.In several cases where the chloroacetamides did not react, it was necessary to use the corresponding pyridinium salts in the reactions with aromatic amines.This approach was useful for the synthesis of aminothiazole derivatives, as shown in Scheme 10.

Scheme 12
Steric effects do not substantially affect the reaction, and this allows one to use hindered amines, including amino-adamantane.Unstable amines, for example cyclopropyl-and allylamines or aziridines, can be used in the reaction, owing to the mild conditions of the process.
The method also allows the possibility of synthesizing isomers of monothio-oxamides, which can be obtained by the replacement of the "amine" and "acetamide" components of the reaction.
Thus, we have shown that the use of the previously prepared solution of sulfur in amines is a convenient method for the S-functionalization of α-chloroacetamides.The monothio-oxamides synthesized are convenient starting compounds for syntheses of various oxalic acid derivatives.

Scheme 13
It should be noted that the reaction with O-methylhydroxylamine, which most likely possesses reducing properties (to a lesser extent than in hydroxylamine), 10 occurs less unambiguously than is the case with hydroxylamine, and depends on the substituents in the phenyl ring.Electron-donating substituents decrease the probability of reduction of the Nmethoxy group to an amino group, and in the absence of substituents in the benzene ring, this group is hydrolyzed to some extent to form the hydroxamic acid 21.It is noteworthy that the dimethoxyamide group (in compound 19) has not been described previously.

Scheme 14
The monothio-oxamides have been used in syntheses of heterocyclic compounds.For example, iso-thioamides, prepared by the reaction of monothio-oxamides with dimethyl sulfate were used in a reaction with phenylthiosemicarbazide to afford the novel 2-carbamoyl-5-phenyl-1,3,4-thiadiazoles.
A wide range of thiadiazoles can be prepared by the heterocyclization of oxamic thiohydrazides followed by their chemical modification.

Scheme 16
The reactions of aromatic and cyclic vicinal diamines with chloroacetamides form the monothio-oxamide at one of the amino groups, followed by a rapid heterocyclization involving the second amino group.

Scheme 18
The intramolecular ring closure of a monothio-oxamide of the thiophene series occurs at 20°C under the action of K 3 Fe(CN) 6 and is accompanied by hydrolysis of the amide group to form 2-carboxythieno [3,2-d]

Conclusions
Our study shows that monothio-oxamides are convenient starting compounds in the syntheses of a variety of oxamic acid derivatives and various mono-and di-heterocyclic compounds.

Experimental Section
General Procedures.The 1 H NMR spectra were measured on Bruker WM-250 instrument (250 MHz) in DMSO-d 6 .Mass spectra (EI) were obtained on Kratos MS-30 instrument with a direct inlet of the sample into the ion source: the ionizing voltage was 70 eV, and the emission current, 0.1 mA.Melting points were determined on a Boetius stage and were not corrected.Column chromatography used silica gel (Merck 60, 70-230 mesh).Commercial reagents were purchased from Aldrich.RT denotes room temperature.
Synthesis of monothio-oxamides 3a,b according to a reported procedure. 6Chloroacetamide 1a (5.3 mmol), sulfur (0.7 g), and the amine (10 ml) were mixed and heated under reflux.The mixture was partitioned between ethyl acetate and water, and the organic phase washed with water, dried and evaporated.The reaction gave 3a (28%), mp 58-60°C (lit. 7

Synthesis of monothio-oxamides (General Procedure A)
Chloroacetamide 1 (5 mmol) was added to a mixture of the appropriate amine (5.5 mmol) and sulfur (0.7 g) in 5 ml DMF.The reaction mixture was stirred at ca. 20°C for 8 h and diluted with water.The precipitate that formed was filtered off, washed with water, and dried.The resulting product was dissolved in acetone (10 ml), the solution filtered, the acetone removed and the residue crystallized from 95% EtOH.The reaction gave 3a (88%), mp 58-60°C (lit. 7

Synthesis of the hydroxamic acid 21
O-Methylhydroxylamine (0.42 g, 5 mmol) was added to a solution of the monothio-oxamide 3b (0.25 g, 1 mmol) in pyridine (7 mL).The mixture was heated at reflux for 7 h, cooled, and diluted with water.The precipitate was filtered off, washed with 2% HCl, and dried to give the product (0.15 g).This was purified by column chromatography using ethyl acetate-hexane (1:1) as eluent to give the product (0.

Synthesis of 22a,b
A mixture of monothio-oxamide 3b (0.8 mmol) and dimethyl sulfate (2.4 mmol) was heated for 45 min at 100°C followed by cooling to RT.The resulting mixture was dissolved in DMF (5 ml), the amine (2 mmol) was added, the mixture was stirred for 2 h, poured into water, and the precipitate filtered off and recrystallized from ethanol.

Synthesis of 23
A mixture of monothio-oxamide 3b (0.2 g, 0.8 mmol) and dimethyl sulfate (0.4 ml, 0.3 g, 2.4 mmol) was heated for 45 min at 100°C followed by cooling to RT.Then H 2 S was passed through the mixture for 7 h, and the mixture poured into water.The precipitate was filtered off and recrystallized from ethanol.Yield of 23 32%, mp 78-80°C (lit. 1278-80°C).

Synthesis of 25a,b
A mixture of monothio-oxamide 3b (or 3j) (0.8 mmol) and dimethyl sulfate (2.4 mmol) was heated for 45 min at 100°C, then cooled to RT.The mixture was then dissolved in DMF (5 ml), the amine (2 mmol) was added, and the mixture stirred for 2 h, then poured into water, and the precipitate formed was filtered off and recrystallized from ethanol.

Synthesis of 27c,d
A mixture of sulfur (1 mmol) and triethylamine (0.5 ml) in DMF (1 ml) was stirred for 30 min.Then a solution of 27a (or 27b) 13 (0.3 mmol) in DMF (1 ml) was added, the mixture stirred for 1.5 h at RT, and then MeI (4 mmol) was added.After 3 h, the mixture was poured into water, and the precipitate filtered off and dried.To remove unreacted sulfur, the product was dissolved in acetone, the solution separated, and the solvent evaporated in vacuo.

Synthesis of 32a,b and 35a,b
Chloroacetamide 1 (5 mmol) was added to a prepared mixture of the aromatic amine (5.5 mmol), sulfur (0.7 g) and Et 3 N (1 mL) in 5 ml DMF.The reaction mixture was stirred at 40-50°C for 8 h, diluted with water, and extracted with ethyl acetate.The organic layer was washed with water and dried.After removal of solvent, the residue was purified by column chromatography using ethyl acetate-hexane (1:1) as eluent.32a.Yield 42%, mp ~300°C (lit.