A novel method for heterocyclic amide–thioamide transformations

In this paper, we introduce a novel and convenient method for the transformation of heterocyclic amides into heteocyclic thioamides. A two-step approach was applied for this transformation: Firstly, we applied a chlorination of the heterocyclic amides to afford the corresponding chloroheterocycles. Secondly, the chloroherocycles and N-cyclohexyl dithiocarbamate cyclohexylammonium salt were heated in chloroform for 12 h at 61 °C to afford heteocyclic thioamides in excellent yields.


Results and Discussion
Many synthetic methods related to thiation of heterocyclic amides have been reported to date. Most methods suffer from Scheme 2: The two-step thiation of quinazolin-4-one A1-6 and phthalazin-1-ones A7 and A8. the employment of expensive specific reagents, high temperature, use of strong basic conditions, ultra-dry solvents, bad smell, low yield, difficulties in work-up procedures or from a narrow substrate scope. Therefore, the development of a more efficient method for the transformation of heterocyclic amides to heterocyclic thioamides gained great attention.
The reaction of three molar equivalents of cyclohexylamine (1) with one molar equivalent of carbon disulfide in water typically afforded N-cyclohexyl dithiocarbamate cyclohexylammonium salt (2) as an excellent new thiating reagent in high yield, Scheme 1.
The structure assignment of the prepared N-cyclohexyl dithiocarbamate cyclohexylammonium salt (2) is based on 1 H and 13 C NMR spectral and physicochemical analysis. The 1 H NMR spectrum displays a broad singlet signal at 8.01 ppm associated with three NH protons. The 1 H NMR spectrum also shows three multiplet signals at 4.15-3.95 and 3.05-2.96 and 1.98-0.96 ppm corresponding to two CH and 10 CH 2 groups, respectively. The 13 C NMR spectrum of 2 displays signals at δ 212.4, 55.3 and 50.0 ppm associated with (C=S) and two CH groups, respectively. The 13 C NMR spectrum of 2 also shows signals at 32.3, 30.9, 25.8, 25.5, 25.1, and 24.3 ppm due to cyclohexyl CH 2 groups.
Heterocyclic amides A1-13 used in this context were prepared as described in literature expanding simple one-step procedures to multi-step sequential reactions. Quinazoline-4-one (A1) [18] was prepared by Niementowski reaction by fusion of anthranilic acid with formamide at 120 °C for 5 h. A number of quinazoline derivatives A2-A6 [19][20][21] were prepared via sequential steps starting from easily available carboxylic acid chlorides. The acid chlorides reacted with anthranilic acid to afford benzoxazines, followed by sequential reaction with ammonia to afford the benzanilide derivatives and finally, benzanilides were cyclized by heating in sodium hydroxide solution and gave quinazolines A2-A6. Methyl 1,2-dihydro-2-oxoquinoline-4carboxylate (A9) [22,23] was prepared by heating isatine with malonic acid followed by esterification of the produced quinoline carboxylic acid with methanol in the presence of sulfuric acid at 80 °C for 6 h. 4-Arylphthalazin-1(2H)-ones A7 and A8 [24,25] were prepared by Friedel-Crafts acylation reaction of N-aminophthalimide with either benzene or toluene in the presence of AlCl 3 , respectively. A number of quinoxalin-2-one derivatives A10-13 [26][27][28][29] were prepared by the reaction of o-phenylenediamine with oxoacids or oxoesters either in HCl solution or in ethanol.
The synthetic procedure for the formation of C1-13 reported herein have the advantage of operational simplicity and availability of both the substrate and the reagents giving a series of 78% a Reaction conditions as described before. b Yields refer to isolated pure product of the reaction from B to C.
Scheme 3: Thiation of quinoline A9 and quinoxalinone A10-13.  very interesting compounds. This method also was adjusted to involve a one-pot strategy starting from heterocyclic amides A1-13 to directly afford the heterocyclic thioamides C1-13.
Thus, 2-phenylquinazolin-4(3H)-one (A2) was heated with phosphorous oxychloride for 2 h. The reaction mixture was evaporated and poured in ice-cold ammonia solution, then extracted with chloroform and dried over sodium sulfate. N-cyclohexyl dithiocarbamate cyclohexylammonium salt (2) was added to the chloroform solution of chloroquinazoline B2 and heated at 61 °C for 12 h. The reaction mixture was evapourated and ethanol was added successively to give the desired product C2.
The structure assignment of the prepared heterocyclic thioamides C1-13 is based on 1 H and 13 C NMR spectral and physicochemical analyses. The 1 H NMR spectrum of 2-(4methoxyphenyl)quinazoline-4(3H)-thione (C5) gave a broad singlet and a singlet signal at δ 13.71 and 3.87 ppm, associated with NH and OCH 3 groups, respectively. The significant downfield shift of the NH proton is probably due to intermolecular hydrogen bond interactions of the type NH···S=C. All the isolated thioureas C1-13 exhibited similar 1 H NMR spectral patterns with the NH protons at similar chemical shifts and they adopt paired thioamide structures (vide infra A mechanistic rationalization for this interesting rearrangement is given in Scheme 4. The reaction of 4-chloro-2-phenylquinazoline (B2) with N-cyclohexyl dithiocarbamate cyclohexylammonium salt (2) in CHCl 3 at 61 °C for 12 h was principally expected to give 2-phenylquinazolin-4-yl cyclohexylcarbamodithioate (I) and cyclohexylamine hydrochloride. Cyclohexylamine hydrochloride under heating conditions will eliminate an HCl molecule forming the free cyclohexylamine base.
Cyclohexylamine will further abstract a proton from I followed by electron delocalization and the overall formation of cyclohexyl isothiocyanate (4) via C-S bond cleavage and the formation of quinazoline thiol anion II having a negative charge concerted on the nitrogen atom. The protonated cyclohexylamine in the previous step will transfer this extra proton to II to afford the quinazoline thione C2. On the other hand the free cyclohexylamine will add to cyclohexyl isothiocyanate (4) to form the thiourea 3. Similar results were obtained by Furumoto [40], and Sun [41] reported the application of cyanuric chloride (2,4,6-trichloro-1,3,5-triazine, TCT) as a desulfurylation reagent in the synthesis of carbodiimides or alkyl isothiocyanates from thioureas under mild conditions.

Conclusion
Several synthetic procedures related to thiation of heterocyclic amides have been reported to date. The drawback of the existing methods is the use of expensive specific reagents, high temperature, use of strong basic conditions, ultra-dry solvents, bad smell, low yield, difficulties in work-up procedures or from a narrow substrate scope. In this work, we successfully developed a facile and convenient general method for the transformation of heterocyclic amides into heterocyclic thioamides. Generally, in the proposed technique we transformed heterocyclic amides to chloroheterocyclic compounds by the action of phosphorous oxychloride. Subsequently, chloroheterocyclic derivatives reacted with N-cyclohexyl dithiocarbamate cyclohexylammonium salt in chloroform at 61 °C for 12 h to finally afford the heterocyclic thioamides in excellent yields. Furthermore, this method is advantageous over existing methods in the matter of simplicity of the work-up procedure, higher yield, odorless, lower reaction temperature and finally the availability of both precursors and reagent.

Supporting Information
Supporting Information File 1 Additional experimental and analytical data.