2. Results and Discussion
We recently [
5] confirmed that in fact the product generated in the reaction of
1b with malononitrile is
3b by X-ray crystallographic analysis of the thiazolylpyrazolo[1,5-
a]pyrimidine derivative
7 [
6], which was produced
via reaction of
3b with hydrazine hydrate to yield the diaminopyrazole
5b and subsequent reaction of
5b with enaminone
6 (
Figure 1).
Although the diaminopyrazole
5a, produced by Salah Eldine [
4] through the reaction of hydrazine hydrate with
3a, proved to be identical with the substance we produced by reaction of
1a with malononitrile, it was claimed that both
2 and
3 can be formed in this process. Consequently, we thought that a further effort aimed at confirming the structures of
5a,
b was in order since Abdelrazek has reported that
2a can be utilized as a precursor in syntheses of several heterocyclic substances. Thus, if
2a is really
3a the structures of products claimed to be formed from
2a in the earlier investigations need to be reassigned [
1,
3,
7,
8,
9].
In the current work, we explored the reaction of diaminopyrazole
5a with benzylidenemalononitrile
8. This process generates a product, resulting from sequential addition and molecular hydrogen elimination, that could be assigned as either
11 or
14. These substances would be produced
via the respective initially formed adducts
9 or 12 (
Scheme 2).
Cyclization of these intermediates would form 10 or 13, which then aromatize to generate 11 or 14, respectively The actual structure of the final product was shown to be compound 11, based on an analysis of 15N HMBC results. These results showed that the amino nitrogen at δ = 30 ppm is coupled to the bridgehead nitrogen at δ = 211 ppm.
Diaminopyrazole
5a reacts with enaminonitrile
15 to yield the pyrazolo[1,5-
a] pyrimidinediamine
17 (
Scheme 3). The isomeric adduct
16 was also excluded as the product based on the results of
15N HMBC and the X-ray crystallographic analyses (
Figure 2) [
10].
The combined observations made in this investigation confirm the structural assignment of
3a. Moreover, thiazole
3a undergoes a coupling reaction with benzenediazonium chloride to yield the aryldiazo derivative
18. Compound
18 was reduced by treatment with Zn metal in acetic acid to yield the amide
19 rather than the isomeric substance
20. This assignment is based on the absence of amine signals in both the IR and
1H-NMR spectra of
19. In addition, treatment of
3a with sulfuric acid in acetic acid led to production of the amide
21. Although
21 can exist in either a
E- or
Z-isomeric form, the
E-stereoisomer appears to be generated selectively, as indicated from NOE difference experiments thus irradiating NH at δ = 12.46 ppm has enhanced amide NH
2 at δ = 6.64 ppm and
vice versa, such enhancement cannot occur with
Z-isomeric. Clearly the claim [
3] that pyrrole
23 and thiophene
24 are produced from a substance assumed to be
2 must be subjected to more concrete verification (
Scheme 4).
Finally, in an attempt to extend the Salah Eldine [
4] reaction of
3a with furfurylidine malononitrile to its reaction with benzylidenemalononitrile
8, only
27 was generated via the intermediacy of adduct
26. The elimination of active methylene carbanions from substances analogous to
26 is well known [
11] (
Scheme 5).
Abdelrazek has also reported [
12] that 1-phenyl-2-thiocyanatoethanone (
1a) reacts with ethyl cyanoacetate to yield either the alkylidene or the thiazole adducts
29 or
30, respectively. Again, analysis of the reaction mixture formed by carrying out this process under a variety of conditions revealed that
29 was not formed and only
30 was produced when potassium hydroxide was present (
Scheme 6).
Our attention next shifted to an exploration of condensation reactions of
1a with other active methylene reagents. However, in our hands
1a failed to produce adducts with acetylacetone, ethyl acetoacetate and the malononitrile dimer. under a variety of conditions reactions. Only the self tricondensation of
31 ocurred in the case of reaction of cyanoketone
31 with
1a. Although the tricondensation product is well known, Briel
et al. [
13] recently assigned structure
32 to this substance. In contrast, Elnagdi
et al. [
14] have assigned the structure of this product as
33, a substance which in fact can also be formed by cyclization of
32. Again, Abdelrazek [
15] has incorrectly claimed that this product is
33. Of course, MS analysis shows that
33 differs from both
32 and
34 (
Scheme 7). It is possible that Briel’s structural assignement is correct since heating the tricondensation product with zeolites affords an isomeric product that has been assigned as
33.
We have also investigated the reactivity of
1a with phenylhydrazine. This reaction has been reported by Abdelrazek
et al. [
8] to yield the hydrazone
35. In our hands, only the thiazole
36 was isolated from the reaction mixture (
Scheme 8).
3. Experimental
3.1. General
Melting points are reported uncorrected and were determined with a Sanyo (Gallaenkamp) instrument. Infrared spectra were recorded using KBr pellets and a Perkin-Elmer 2000 FT–IR instrument. 1H- and 13C-NMR spectra were determined by using a Bruker DPX instrument at 400 MHz for 1H-NMR and 100 MHz for 13C-NMR and either CDCl3 or DMSO-d6 solutions with TMS as internal standards. Chemical shifts are reported in δ (ppm). Mass spectra were measured using VG Autospec Q MS 30 and MS 9 (AEI) spectrometer, with the EI (70 EV) mode. Elemental analyses were carried out by using a LEOCHNS-932 Elemental Analyzer.
3.2. General Procedure for the Syntheses of 3a,b
Solutions of malononitrile (0.66 g, 0.01 mol) and α-thiocyanatoketones 1a,b (0.01 mol) in ethanol (15 mL) containing piperidine (5 drops) were stirred at reflux for 1–2 h. (completion assessed by TLC, 1:1 ethyl acetate-petroleum ether). The solid products, isolated by pouring the reaction mixtures into ice-water and subsequent separation by filtration, were crystallized from EtOH to afford green crystals.
2-(4-Phenylthiazol-2(3H)-ylidene)malononitrile (3a). Yield 93%; m.p. 275–276 °C; Anal. calcd. for C12H7N3S (225.27): C, 63.98; H, 3.13; N, 18.65; S, 14.23. Found: C, 63.94; H, 3.31; N; 18.45; S, 13.92; IR (KBr): υmax 3147 (NH), 2210 (CN), 2175 (CN); 1H-NMR (DMSO): δ, ppm 7.33 (s, 1H, CH), 7.45–7.49 (m, 3H, Ar-H), 7.71–7.72 (m, 2H, Ar-H), 13.23 (br, 1H, NH, D2O exchangeable); 13C-NMR (DMSO): δ, ppm 172.27, 143.70, 130.01, 129.12(2C), 128.92, 127.51 (2C), 127.64, 117.75, 105.93 (2CN). MS: m/z (%) 225 (M+, 100), 180 (20), 134 (45), 108 (10), 102 (15), 89 (15), 77 (10).
2-(4-Methylthiazol-2(3H)-ylidene)malononitrile (3b). Yield 85%; m.p. 290–291 °C; Anal. calcd. for C7H5N3S (163.2): C, 51.52; H, 3.09; N, 25.75; S, 19.64. Found: C, 51.26; H, 3.12; N; 25.54; S, 19.27; IR (KBr): υmax 3160 (NH), 2179 (2CN); 1H-NMR (DMSO): δ, ppm 2.17 (s, 3H, CH3), 6.71 (s, 1H, CH), 13.1 (br, 1H, NH, D2O exchangeable); 13C-NMR (DMSO): δ, ppm 170.10, 142.54, 105.93 (2CN), 95.23, 87.68, 16.54. MS: m/z (%) 163 (M+, 100), 136 (20), 118 (30), 98 (10), 71 (50).
3.3. General Procedure for the Syntheses of 5a,b
Mixtures of 3a,b (0.01 mol) and hydrazine monohydrate (0.50 g, 0.01 mol) in DMF (10 mL) were stirred at reflux for 20 h. (completion assessed by TLC analysis using ethyl acetate-petroleum ether 1:1). The mixtures were cooled and poured into ice-water. The solid products, collected by filtration, were crystallized from DMF to give light yellow crystals.
4-(4-Phenylthiazol-2-yl)-1H-pyrazole-3,5-diamine (5a). Yield 78%; m.p. 322–323 °C; Anal. calcd. for C12H11N5S (257.31): C, 56.01; H, 4.31; N, 27.22; S, 12.41. Found: C, 55.80; H, 4.41; N; 26.88; S, 11.99; IR (KBr): υmax 3372, 3256 (NH2), 3176, 3112 (NH2), 3132 (NH); 1H-NMR (DMSO): δ, ppm 5.39 (br, 4H, 2NH2, D2O exchangeable), 7.31–7.46 (m, 3H, Ar-H), 7.75 (s, 1H, CH), 7.96–7.98 (m, 2H, Ar-H), 10.73 (br, 1H, NH, D2O exchangeable); 13C-NMR (DMSO): δ, ppm 166.29, 162.08, 152.30 (2C), 134.31, 128.69 (2C), 127.69, 125.89 (2C), 107.48, 87.97. MS: m/z (%) 257 (M+, 100), 226 (10), 200 (5), 134 (35), 128 (10), 90 (10).
4-(4-Methylthiazol-2-yl)-1H-pyrazole-3,5-diamine (5b). Yield 76%; m.p. 330–332 °C; Anal. calcd. for C7H9N5S (195.24): C, 43.06; H, 4.65; N, 35.87; S, 16.42. Found: C, 42.89; H, 4.73; N; 35.60; S, 15.98; IR (KBr): υmax 3371, 3275 (NH2), 3255, 3180 (NH2), 3118 (NH); 1H-NMR (DMSO): δ, ppm 2.23 (s, 3H, CH3), 5.62 (br, 4H, 2NH2, D2O exchangeable), 6.86 (s, 1H, CH), 10.67 (br, 1H, NH, D2O exchangeable); 13C-NMR (DMSO): δ, ppm 164.33, 161.56, 150.03 (2C), 106.88, 87.68, 16.84. MS: m/z (%) 195 (M+, 100), 164 (20), 138 (10), 123 (15), 112 (5), 72 (15).
3.4. Synthesis of 2,7-diamino-5-phenyl-3-(4-phenylthiazol-2-yl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile (11)
A mixture of 5a (2.57 g, 0.01 mol) and benzylidenemalononitrile (8, 1.54 g, 0.01 mol) in DMF (10 mL) was stirred at reflux for 10 h (completion assessed by TLC analysis using ethyl acetate-petroleum ether 1:1 as eluent). The reaction mixture was cooled and poured into ice-water giving a solid which was collected by filtration and crystallized from DMF to give a the product as yellow crystals in a yield of 75%; m.p. 298–300 °C; Anal. calcd. for C22H15N7S (409.47): C, 64.53; H, 3.69; N, 23.94; S, 7.83. Found: C, 64.61; H, 3.69; N; 23.79; S, 7.59; IR (KBr): υmax 3430, 3318 (NH2), 3429, 3315 (NH2), 2211 (CN); 1H-NMR (DMSO): δ, ppm 6.85 (br, 2H, NH2, D2O exchangeable), 7.35–8.03 (m, 11H, Ar-H, thiazole-H), 8.57 (br, 2H, NH2, D2O exchangeable); 13C-NMR (DMSO): δ, ppm 195.47, 159.46, 157.98, 152.59, 148.91, 145.21, 137.10, 133.97, 130.37 (2C), 128.77 (2C), 128.70 (2C), 128.38 (2C), 127.89, 125.93, 116.48, 111.39, 92.24, 73.15. MS: m/z (%) 409 (M+, 100), 333 (5), 204 (15), 195 (5), 134 (30), 90(5).
3.5. Synthesis of 3-(4-phenylthiazol-2-yl)pyrazolo[1,5-a]pyrimidine-2,7-diamine (17)
A mixture of 5a (2.57 g, 0.01 mol) and 3-(piperidin-1-yl)acrylonitrile (15, 1.36 g, 0.01 mol) in DMF (10 mL) was stirred at reflux for 10 h (completion assessed by TLC analysis using ethyl acetate-petroleum ether 1:1 as eluent). The reaction mixture was cooled and poured into ice-water giving a solid which was collected by filtration and crystallized from DMF to give a the product as yellow crystals in a yield of 70%; m.p. 329–330 °C; Anal. calcd. for C15H12N6S (308.36): C, 58.43; H, 3.92; N, 27.25; S, 10.40. Found: C, 58.33; H, 3.79; N; 27.20; S, 10.37; IR (KBr): υmax 3443, 3305 (NH2), 3355, 3263 (NH2); 1H-NMR (DMSO): δ, ppm 6.13 (d, 1H, J = 6 Hz, CH), 6.62 (br, 2H, NH2, D2O exchangeable), 7.33–7.47 (m, 3H, Ar-Hs), 7.61 (br, 2H, NH2, D2O exchangeable), 7.85 (s, 1H, thiazole-H), 8.01 (m, 2H, Ar-Hs), 8.07 (d, 1H, J = 6 Hz, CH); 13C-NMR (DMSO): δ, ppm 160.59, 156.98, 152.22, 149.36, 147.14, 146.94, 134.31, 128.75 (2C), 127.72, 125.90 (2C), 109.66, 89.99, 88.59. MS: m/z (%) 308 (M+, 100), 268 (30), 175 (5), 154 (5), 134 (30), 102 (5), 89(5), 77 (5).
3.6. Synthesis of 2-(4-Phenyl-5-phenylazo-3H-thiazol-2-ylidene)malononitrile (18a)
A cold solution of benzenediazonium chloride (0.01 mol) was prepared by adding a solution of sodium nitrite (0.7 g in 10 mL H2O) to a cold solution of aniline hydrochloride (0.93 g, 0.01 mol of aniline in 5 mL concentrated HC1) with stirring at room temperature. The resulting solution was then added to cold solutions of 3a (2.25 g, 0.01 mol) in ethanol (50 mL) containing sodium acetate (2 g). The reaction mixtures was stirred for 1 h and then filtered. The solid products were crystallized from EtOH to give the products as red crystals, yield 85%; m.p. 198–200 °C; Anal. calcd. for C18H11N5S (329.38): C, 65.64; H, 3.37; N, 21.26; S, 9.73. Found: C, 65.49; H, 3.51; N; 21.15; S, 9.39; IR (KBr): υmax 3180 (NH), 2216 (2CN); 1H-NMR (DMSO): δ, ppm 5.03 (br, 1H, NH, D2O exchangeable), 7.25–7.60 (m, 8H, Ar-H), 8.22–8.24 (m, 2H, Ar-H); 13C-NMR (DMSO): δ, ppm 175.46, 147.29, 138.67, 131.79, 131.47, 130.73 (2C), 130.70 (2C), 129.59 (2C), 128.63 (2C), 127.05, 118.96, 117.71, 115.70 (2CN). MS: m/z (%) 329 (M+, 100), 301 (20), 237 (15), 225 (25), 153 (5), 103 (20), 92 (25), 77 (65).
3.7. Synthesis of N-(2-Dicyanomethylene-4-phenyl-2,3-dihydro-thiazol-5-yl)-acetamide (19)
A mixture of 18a (3.29 g, 0.01 mol) and Zn dust (1 g) in AcOH (10 mL) was stirred at reflux for 1 hr (completion assessed by TLC analysis using ethyl acetate-petroleum ether 1:1 as eluent). The reaction mixture was cooled and poured into ice-water giving a solid which was collected by filtration and crystallized from EtOH to give the product as faint green coloured crystals in a yield of 70%; m.p. 335–338 °C; Anal. calcd. for C14H10N4OS (282.32): C, 59.56; H, 3.57; N, 19.85; S, 11.36. Found: C, 59.61; H, 3.44; N; 19.75; S, 11.42; IR (KBr): υmax 3057 (NH), 3027 (NH), 2204 (CN), 2178 (CN); 1H-NMR (DMSO): δ, ppm 2.02 (s, 3H, CH3), 7.21–7.76 (m, 6H, Ar-Hs, NH, D2O exchangeable), 10.07 (br, 1H, NH, D2O exchangeable); 13C-NMR (DMSO): δ, ppm 169.86, 169.04, 164.93, 163.14, 128.69, 128.28 (2C), 128.09, 127.89 (2C), 127.73, 119.92, 117.67, 22.39. MS: m/z (%) 282 (M+, 60), 257 (20), 240 (100), 215 (85), 180 (10), 148(30), 121 (40), 104 (75), 93 (40), 77 (65), 73 (40).
3.8. Synthesis of 2-cyano-2-(4-phenylthiazol-2(3H)-ylidene)acetamide (21)
A mixture of 3a (2.25 g, 0.01 mol) and H2SO4 (3 mL) in AcOH (10 mL) was stirred at reflux for 1 h. The reaction mixture was cooled and poured into ice-water giving a solid which was collected by filtration and crystallized from AcOH to give the product as white coloured crystals a yield of 80%; m.p. 229–231 °C; Anal. calcd. for C12H9N3OS (243.28): C, 59.24; H, 3.73; N, 17.27; S, 13.18. Found: C, 59.15; H, 3.58; N; 17.34; S, 13.32; IR (KBr): υmax 3305, 3236 (NH2), 3126 (NH), 2184 (CN); 1H-NMR (DMSO): δ, ppm 6.64 (br, 2H, NH2, D2O exchangeable), 7.15 (s, 1H, thiazole-H), 7.43–7.68 (m, 5H, Ar-H), 12.46 (br, 1H, NH, D2O exchangeable); 13C-NMR (DMSO): δ, ppm 169.77, 139.49, 129.37, 129.27, 128.93 (2C), 126.83 (2C), 126.07, 125.22, 118.94, 106.97. MS: m/z (%) 243 (M+, 90), 226 (100), 200 (45), 171 (5), 134 (40), 102 (45), 98 (10), 77 (5).
3.9. Synthesis of 2-(5-benzylidene-4-phenylthiazol-2(5H)-ylidene)malononitrile (27)
A mixture of 3a (2.25 g, 0.01 mol) and benzylidenemalononitrile (8, 1.54 g, 0.01 mol) in EtOH (20 mL) in presence of piperidine (1 mL) was stirred at reflux for 3 h. The reaction mixture was cooled and poured into ice-water giving a solid which was collected by filtration and crystallized from EtOH to give the product as faint yellow coloured crystals in a yield of 77%; m.p. 280–282 °C; Anal. calcd. for C19H11N3S (313.38): C, 72.82; H, 3.54; N, 13.41; S, 10.23. Found: C, 12.94; H, 3.32; N; 13.31; S, 10.19; IR (KBr): υmax 22.7 (CN), 2179 (CN); 1H-NMR (DMSO): δ, ppm 5.84 (s, 1H, CH), 7.15–7.42 (m, 10H, Ar-H); 13C-NMR (DMSO): δ, ppm 169.07, 141.21, 140.04, 131.24, 130.57, 129.69, 129.21 (2C), 128.91 (2C), 128.45 (2C), 128.21, 127.94, 127.61 (2C), 124.62, 122.00, 117.17. MS: m/z (%) 313 (M+, 80), 285 (10), 235 (90), 225 (100), 178 (10), 134 (60), 98 (20).
3.10. Synthesis of ethyl 2-cyano-2-(4-phenylthiazol-2(3H)-ylidene)acetate (30)
Solutions of ethyl cyanoacetate (1.13 g, 0.01 mol) and α-thiocyanatoketone 1a (0.01 mol) in ethanol (15 mL) containing KOH (1 g) were stirred at room temperature for 1–2 h (completion assessed by TLC, 1:1 ethyl acetate- petroleum ether). The solid products, produced by pouring the reaction mixtures into ice-water containing HCl (2 mL) and subsequent separation by filtration, were crystallized from EtOH to give the product as white crystals in a yield of 90 %; m.p. 157–159 °C; Anal. calcd. for C14H12N2O2S (272.32): C, 61.75; H, 4.44; N, 10.29; S, 11.77. Found: C, 61.71; H, 4.32; N; 10.18; S, 11.98; IR (KBr): υmax 3152 (NH), 2211 (CN); 1H-NMR (DMSO): δ, ppm 1.23 (t, 3H, J = 6 Hz, CH3), 4.16 (q, 2H, J = 6 Hz, CH2), 7.15 (s, 1H, thiazole-H), 7.43–7.71 (m, 5H, Ar-H), 12.99 (br, 1H, NH, D2O exchangeable); 13C-NMR (DMSO): δ, ppm 169.23, 166.55, 140.68, 129.31 (2C), 128.75, 128.75 (2C), 127.00, 117.54, 107.49, 62.93, 59.68, 14.55. MS: m/z (%) 272 (M+, 90), 226 (100), 200 (50), 172 (10), 153 (5), 134 (50), 102 (40), 89 (10), 77 (10).
3.11. Synthesis of 1-phenyl-2-(4-phenylthiazol-2-yl)hydrazine (36)
A mixture of 1a (1.77 g, 0.01 mol), phenyl hydrazine (1.80 g, 0.02 mol), in EtOH (20 mL) was refluxed for 3–4 h (completion assessed by TLC analysis using ethyl acetate-petroleum ether 1:1 as eluent). The reaction mixture was cooled and poured into ice-water giving a solid which was collected by filtration and crystallized from EtOH to give the product as white crystals in a yield of 75%; m.p. 216–218 °C; Anal. calcd. for C15H13N3S (267.35): C, 67.39; H, 4.90; N, 15.72; S, 11.99. Found: C, 67.17; H, 4.88; N; 15.58; S, 12.12; IR (KBr): υmax 3239 (NH), 3089 (NH); 1H-NMR (DMSO): δ, ppm 6.47–7.61 (m, 11H, Ar-H, thiazole-H), 9.08 (br, 1H, NH, D2O exchangeable), 12.60 (br, 1H, NH, D2O exchangeable); 13C-NMR (DMSO): δ, ppm 163.35, 147.00, 130.91, 128.94 (2C), 128.54 (2C), 128.01, 127.91, 126.59 (2C), 119.59, 112.59 (2C), 111.19. MS: m/z (%) 267 (M+, 100), 234 (5), 207 (5), 175 (15), 148 (5), 117 (70), 93 (50), 77 (10).