Previously we carried out the interaction of hetarylacetonitriles 1a,b with acetylmercaptoacetyl chloride (2) and studied the spectroscopic properties of the 3-cyano-3-hetarylylidene-2-oxopropyl ethanethioates 3a,b obtained. In the present work we have broadened the series acylated substrates; in the reactions we have involved hetarylacetonitriles 1c-e (Scheme 1) and also hetarylideneacetonitriles 4a-f (Table 1) obtained by alkylation of compounds 1a-c,f with dialkyl sulfates with subsequent treatment with aqueous NaOH solution (Scheme 2). Compounds 4a,c,d were previously obtained by a method described elsewhere [46].

Scheme 1
scheme 1

 

Table 1 Characteristics of Compounds Synthesized
Scheme 2
scheme 2

 

The electronegativity of the substituents on the nitrogen atoms and in the aromatic ring, and also the nature of the heteroatom in X affected the ratio of the (Z)- and (E)-isomers formed.

The structures of the isomers and their ratios were determined by 1H NMR spectra. Thus the products 4c,d were formed exclusively as the (Z)-isomers in which the CN groups are in trans position relative to the NR2 unit. From compound 1a a symmetrical product 4a is formed, while the remaining unsymmetrical nitrogen-containing hetarylylidene acetonitriles were isolated as mixtures: 4e 1:1.67 (E:Z), 4b 1:1.46 (E:Z), and 4f 1:1.1 (E:Z), in which the isomers with the nitrile trans to the NR2 predominated.

In the IR spectra of compounds 4a-f intense absorption bands are present in the 2175-2150 cm-1 region, characteristic of a conjugated nitrile group [7], and also stretching bands of a conjugated C=C bond at 1600-1588 cm-1. Sharp singlets of the proton of the =CHCN group were observed in the 3.53-4.15 ppm region in the 1H NMR spectra, recorded in DMSO-d6.

A single product, either the (Z)- or the (E)-isomer, 5a-f, was obtained by acylation of compounds 4a-f with the acyl chloride 2 (Scheme 3).

Scheme 3
scheme 3

 

Scheme 4
scheme 4

 

The configurations of 3-cyano-3-hetarylylidene-2-oxopropyl ethanethioates were established through 1H NMR spectroscopy using lanthanide shift reagents (LSR).

Thus the use of Eu(FOD)3 Footnote 1 showed that in these compounds the CN group is in a trans position relative to the fragment X (cf. formulas 5a-f in Scheme 3). The similarity in structure of compounds 5b,d and 5c,f respectively permits the supposition that the latter have similar configurations.

S-acyl derivatives of compounds 3a-e and 5a,b,e,f under influence of bases (alkalis, primary and secondary amines) undergo deacetylation and the mercaptonitriles formed undergo intramolecular cyclization.

In this way the corresponding substituted oxothiophenes 6a-e were prepared from compounds 3a-e (with the fragment N(3)H), and in the case of compounds 5a,b,e,f (with the fragment N(3)R2) the products of cyclization 7a-d were isolated as salts.

We had prepared compounds 6a and 6b previously [2, 3].

Deacetylation of compounds 5c,d, in contrast to compound 3c, was not accompanied by cyclization. On acidification of the basic solutions 2-hetarylylidene-3-oxo-4-sulfanylbutanenitriles 8a,b were isolated (Scheme 5).

Scheme 5
scheme 5

 

Scheme 6
scheme 6

 

These differences are apparently determined by the different spatial dispositions of the CN and SH groups in the initially formed thiols, which are determined by the nature of the fragment X and the substituent at the atom N(3). For example with X = NMe or NCHF2 (in the thiols from compounds 5a,b,e,f) this position is favorable for cyclization, whereas with X = S (in the thiols from compounds 5c,d) it is unfavorable. The ease of formation of the cyclic products 6a-e from compounds 3a-e with the fragment N(3)H (and with X= S in compound 3b) shows the decisive influence of this fragment for cyclization, probably because of the production of a intramolecular hydrogen bond between it and the C=O group, which is possible with the cis position of the CN fragment relative to the X fragment.

The structures of compounds 8a,b were confirmed from their spectral characteristics (Table 2). In their 1H NMR spectra are signals of protons of the CH2 group of the thioglycolic group (doublet at 3.65 ppm) and the proton of the SH group (triplet at 2.55-2.60 ppm). In the IR spectra there are weak stretching vibrations of the SH group at 2565 cm-1. Also treatment of compounds with acetyl chloride gave acyl derivatives 5c,d, and treatment of the thiol 8a with ethyl iodide gave the product of alkylation, 9.

Table 2 Spectral Characteristics of the Compounds Synthesized

Compound 3a is capable of alkylation at the NH group with alkyl halides (MeI, EtI) in DMF in the presence of K2CO3 to give compounds 5a,b respectively.

Interaction of the hetarylacetonitriles 1a and 10 with 3-acetylmercaptopropionyl chloride 11 gave the 4-cyano- 4-hetarylylidene-3-oxobutyl ethanethioates 12a,b (Scheme 7).

Scheme 7
scheme 7

 

Like 3-cyano-3-hetarylylidene-2-oxopropyl ethanethioates 3a-e, compounds 12a,b exist in tautomeric forms with intramolecular hydrogen bonding between the NH fragment of the heterocycle and the conjugated carbonyl group of the acyl fragment CH2COCH2.

As in the case of compounds 5c,d, deacetylation of compounds 12a,b is not accompanied by cyclization, but 2-hetarylylidene-3-oxo-5-sulfanylpentanenitriles 13a,b are formed (Scheme 8). The 1H NMR spectra of compounds 13a,b, like those of compounds 8a,b, contain the characteristic signal of the SH proton (a triplet in the 2.0-2.1 ppm range), and a weak stretching band of the SH group is observed at 2560 cm-1 in the IR spectra. Completely analogously, treatment of the mercapto derivatives 13a,b with acetyl chloride in DMF leads to acetylation of the sulfhydryl group, regenerating the initial structures of compounds 12a,b .

Scheme 8
scheme 8

 

Thus increasing the hydrocarbon chain of the acylating agent with a protected mercapto group in the end leads to the impossibility of intramolecular cyclization of the thiols produced.

Experimental

Monitoring of the course of experiments and of the purity of the compounds synthesized was carried out by TLC on Silufol UV-254 plates with 9:1 chloroform–methanol. 1H NMR spectra of DMSO-d6 solutions with TMS as internal standard were measured with a Varian Mercury 400 (400 MHz) instrument. IR spectra of KBr tablets were obtained with a Perkin-Elmer BX instrument, mass spectra were observed with an Agilent 1100 Series instrument with and Agilent LC/MSD SL detector. Melting points were measured with a small laboratory Boetius heating plate with a VEB Analytic PNMK 05 observation device.

3-Cyano-3-hetarylylidene-2-oxopropyl Ethanethioates 3a-e, 5a-f, and 4-Cyano-4-hetarylylidene-3-oxobutyl Ethanethioates 12a,b (General Method). Acetylmercaptoacetyl chloride 2 (5.5 mmol) or 3-acet-oxymercaptopropionyl chloride 11 (5.5 mmol) was added to a solution of hetarylacetonitrile 1a-e, 10, or hetarylylideneacetonitrile 4a-f (5 mmol) in DMF (5 ml) at 25°C. The reaction mixture was kept at room temperature for 12 h, then the precipitate was filtered off, washed with water, dried and recrystallized from a suitable solvent (Table 1).

Hetarylylideneacetonitriles 4a-f (General Method). A mixture of hetarylacetonitrile 1a-c, f (10 mmol) and the corresponding dialkyl sulfate (11 mmol) was stirred for 40 min at 70°C. Then the reaction mixture was poured into water (10 ml) and a solution of NaOH (25 mmol) in water (20 ml) was added with stirring. The precipitate formed was filtered off, washed with cold water, dried and recrystallized.

2-Amino-3-hetaryl-4(5H)-oxothiophenes 6a-c (General Method). Aqueous ammonia (10 mmol) was added to a solution of compound 3a-e (5 mmol) in DMF (5 ml) and the mixture was kept at 30-40°C for 24 h. The precipitate was filtered off, washed with water, dried, and recrystallized.

2-Amino-4(5H)-oxothiophenehetaren-3-ium Chlorides 7a-d (General Method). An aqueous solution of NaOH (10 mmol) in water (2 ml) was added to a solution of compound 5a,b,e,f (5 mmol) in DMF (10 ml) and kept at 30-40°C for 24 h. Aqueous HCl was added until the mixture was slightly acidic, evaporated, and the residue was recrystallized.

2-(3-Alkyl-2,3-dihydro-1,3-benzothiazol-2-ylidene)-3-oxo-4-sulfanylbutanenitriles 8a,b and 2-Het-arylylidene-3-oxo-5-sulfanylpentanenitriles 13a,b (General Method). MeONa (10 mmol) in MeOH (10 ml) was added with stirring at 60°C to a suspension of 6e,f or 12a,b (5 mmol) in MeOH (15 ml). After the reaction mixture had become homogeneous, aqueous HCl was added to an acid reaction, the precipitate was filtered off, washed with water, dried, and recrystallized.

2-(3-Methyl-2,3-dihydro-1,3-benzothiazol-2-ylidene)-3-oxo-4-ethylsulfanylbutanenitrile (9). MeONa (10 mmol) in MeOH (10 ml) was added with stirring at 60°C to a suspension of compound 8a (5 mmol) in MeOH (15 ml). After the reaction mixture was completely homogenized and cooled, ethyl iodide (10 mmol) was added with stirring. Product 9 precipitated over 8 h, was filtered off, washed with methanol, dried and recrystallized.

Acylation of 2-(3-Alkyl-2,3-dihydro-1,3-benzothiazol-2-ylidene)-3-oxo-4-sulfanylbutanenitriles 8a,b and 2-Hetarylylidene-3-oxo-5-sulfanylpentanenitriles 13a,b (General Method). AcCl (5.5 mmol) was added to a solution of nitrile 8a,b or 13a,b (5 mmol) in DMF (5 ml). The reaction mixture was kept for 12 h at room temperature, the precipitate was filtered off, washed with water, dried and recrystallized. Compounds 5c,d or 12a,b obtained respectively were identical with samples synthesized as described above. No depression of the melting point was observed with mixed samples.

Alkylation of 3-Cyano-3-(1-methyl-2,3-dihydro-1H-benzoimidazol-2-ylidene)-2-oxopropyl Ethane- thioate 3a (General Method). Finely dispersed K2CO3 (20 mmol) and the corresponding alkyl iodide (10 mmol) were added to a solution of compound 3a (5 mmol) in DMF (20 ml). The reaction mixture was stirred for 12 h at a temperature of 50°C, cooled to room temperature, filtered, the filtrate evaporated, and the residue was recrystallized. The compounds 5a,b obtained were identical to samples synthesized as described above. No depressions of mixed melting points were observed.