Synthesis and chemical characterisation of some new diheteroaryl thienothiophene derivatives.

Treatment of 1-(5-acetyl-3,4-dimethythieno[2,3-b]thiophene-2yl)ethanone (1) with dimethylformamide dimethyl acetal afforded enaminone derivative 2, which reacted with amino derivatives to give the corresponding bis-pyrimidine, bis-pyrazole, bis-triazolo-pyrimidine and bis-benzoimidazopyrimidine derivatives.

1. Introduction

In the last 30 years, annulated heterocyclic systems have attracted considerable attention both from a theoretical standpoint and in view of their various practical applications [1,2,3,4,5,6,7,8,9,10,11,12,13,14]. Enaminones are valuable intermediates in synthetic organic chemistry [15,16,17,18], and Mabkhot and others [19,20,21,22,23,24,25,26] have reported a variety of syntheses of heteroaromatics developed using functionally substituted enaminones as readily obtainable building blocks possessing multiple electrophilic and nucleophilic moieties. This study was undertaken in continuation of our interest in the chemical and biological properties of thienothiophene derivatives [27,28,29] and our work aimed at the synthesis of a variety of heterocyclic systems for biological and pharmacological evaluation, we have found that 1-(5-acetyl-3,4-dimethylthieno[2,3-b]-thiophene-2-yl) ethanone (1) is a versatile, readily accessible building block for the synthesis of several new bis-heterocyclic compounds.

2. Results and Discussion

Treatment of 1-(5-acetyl-3,4-dimethythieno[2,3-b]thiophene-2-yl)ethanone (1) with dimethylformamide dimethylacetal (DMF-DMA) in refluxing ethanol afforded 1,1-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)-bis(3(dimethylamino)prop-2-en-1-one (2) in high yield (Scheme 1). The 13C-NMR spectrum of compound 2, revealed ten carbon types. The 1H-NMR spectrum displayed a singlet at δ 2.22 due to methyl protons, a singlet at δ 2.82 due to the N,N-dimethyl protons and at δ 5.36, 5.40 (d, 2H, CH, J = 16), 7.62, 7.66 (d, 2H, CH, J = 1) due to olefinic protons. The mass spectrum revealed a molecular ion peak at m/z 363, corresponding to C18H22N2O2S2. When compound 2 was treated with hydrazine hydrate or phenylhydrazine in refluxing ethanol/DMF the novel products 3a,b were obtained, respectively, which then undergo intramolecular cyclization and subsequent aromatization via the loss of dimethylamine and water molecules (Scheme 1). The structures of the latter products were deduced from their elemental analyses and spectral data. The H-NMR spectrum of compound 3a, for example, revealed signals at δ 5.47 (d, 2H, CH, J = 5.5), 7.86 (d, 2H, CH, J = 5.5) and 13.20 characteristic of pyrazole CH protons and a NH proton, respectively.

Scheme 1

Synthesis of enaminone 2 and pyrazole thienothiophene derivatives 3a,b.

When compound 2 was treated with guanidine, thiourea and or urea in refluxing EtOH/DMF, the the expected derivatives 4a-c were not obtained, and rather the novel bis-thienothiophene derivatives 5a-c were formed, which then undergo intramolecular cyclization and subsequent aromatization via the loss of dimethylamine and water molecules under the reaction conditions to give 5a-c, as depicted in Scheme 2.

Scheme 2

Synthesis of pyrimidine thienothiophene derivatives 5a-c.

The structures of the latter products were deduced from their elemental analyses and spectral data. The IR spectrum of compound 5a, for example, showed, the absence of carbonyl bands and revealed the appearance of bands in the 3,417 and 3,100 cm−1 region due to NH2 groups. The structure of product 5a was confirmed by the 1H-NMR spectrum, which displayed a new pair of doublet signals at δ 7. 83, 8.37 with J = 12 Hz corresponding to pyrimidine CH protons, as reported for such E-coupled protons [30,31,32]. The 1H-NMR spectrum also revealed one singlet corresponding to a methyl group at δ 2.21, in additionto the NH2 protons at δ 4.83 in Scheme 2. The formation of compound 5a would involve an initial addition of the amino group in guanidine to the activated double bond in enaminone derivative 2, followed by deamination to an intermediate which then undergoes cyclization and aromatization via loss of water affording the final isolable product (Scheme 2).

The compound 7,7'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl) bis-[1,2,4]triazolo[1,5-a] pyrimidine (6) was formed initially via Michael type addition followed by elimination of dimethylamine and water molecules when treatment of compound 2 with 5-amino-1,2,4-triazole in refluxing ethanol/DMF afforded in (Scheme 3).

Scheme 3

Synthesis of triazolo and benzoimidazolo pyrimidine thienothiophenederivatives 6 and 7.

In the 1H-NMR spectra of compound 6 the CH proton appeared as a pair of doublets at 7.66/7.69 ppm (d, 2H, CH, J = 12 Hz), and 9.09/9.12 ppm (d, 2H, CH, J = 12 Hz) due to vicinal coupling with the two magnetically non-equivalent protons of the methylene group at position 5 and 6 of the pyrimidine ring. Also, the 1H-NMR spectrum showed one singlet corresponding to a methyl group at δ 2.24, in addition to the CH proton of triazole at δ 8.62. The mass spectrum revealed a molecular ion peak at m/z 404, corresponding to C18H12N8S2. In a similar manner, when 2 was treated with 2-aminobenzimidazole, the corresponding compound 7 was obtained in high yield.

3. Experimental

3.1. General

All melting points were measured on a Gallenkamp melting point apparatus. The infrared spectra were recorded in potassium bromide disks on a Pye Unicam SP 3300 or Shimadzu FT IR 8101 PC infrared spectrophotometers. The NMR spectra were recorded on a Varian Mercury VX-400 NMR spectrometer. 1H spectra were run at 400 MHz and 13C spectra were run at 75.46 MHz in dimethyl sulphoxide (DMSO-d). Chemical shifts were related to that of the solvent. Mass spectra were recorded on a Shimadzu GCMS-QP 1000 EX mass spectrometer at 70 e.V. Elemental analyses were carried out at the Microanalytical Center of King Saud University, Riyadh, Saudi Arabia.

1,1'-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(3-(dimethylamino)prop-2-en-1-one (2): A mixture of compound 1 (10 mmol, 0.252 mg) and DMF-DMA (20 mmol, 5 mL) in 99.9% EtOH (20 mL) was refluxed for 8 h, then left to cool to room temperature. The reddish-brown precipitate was filtered off, washed with petroleum ether, and dried. Recrystallization from DMF/EtOH afforded the enaminone derivative 2 in 97% yield, mp. 270–272 °C; IR 1620 (C=O) 1546 (C=C) cm−1; 1H-NMR δ 2.22 (s, 6H, 2CH3), 2.82 (12H, 2CH3), 5.36, 5.40 (d, 2H, CH, J = 16), 7.62, 7.66 (d, 2H, CH, J = 16); 13C-NMR δ 15.6, 44.3, 90.4, 136.0, 138.6, 141.5, 147.7, 186.9, 155.3; MS m/z (%): 363 (M+1, 37), 362 (M, 100), 347 (84), 318 (10), 284 (6), 98 (100). Anal. Calcd for C18H22N2O2S2 (362.51); C, 59.64; H, 6.12; N, 7.73; S, 17.69. Found: C, 59.58; H, 5.82; N, 7.44; S, 17.39.

3.2. General Procedure for the Reaction of Compound with Hydrazine Derivatives

Treatment of compounds 2 (1 mmol) with hydrazine hydrate or phenyl hydrazine (0.1 mL) in dry ethanol (20 mL) under reflux for 7 h afforded the corresponding derivatives 3a and 3b, respectively. The solid products were collected by filteration, washed with ethanol, dried and recrystallized from DMF/EtOH.

3,3'-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(1H-pyrazole) (3a): White crystals; yield 92%; mp > 320 °C; IR 3186 (NH), 1549 (C=N) cm−1; 1H-NMR δ 2.10 (s, 6H, 2CH3), 5.47, 5.50 (d, 2H, CH, J = 5.5), 7.83, 7.86 (d, 2H, CH, J = 5.5), 13.20 (2H, pyrazole N-H); 13C-NMR δ 14.3, 103.2, 127.2, 130.2, 133.5, 145.7, 148.3, 161.9; MS m/z (%): 301 (M+1, 24), 300 (M, 100), 284 (19), 233 (68). Anal. Calcd for C14H12N4S2 (300.40); C, 55.97; H, 4.03; N, 18.65; S, 21.35. Found: C, 55.67; H, 3.73; N, 18.38; S, 21.05.

3,3'-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(1-phenyl-1H-pyrazole) (3b): Red crystals; yield (87%); mp > 320 °C; IR 1568 (C=N) cm−1; 1H-NMR δ 2.18 (s, 6H, 2CH3), 6.28, 7.16, 7.42 (5H, ArH’s), 6.77, 6.80 (d, 2H, CH, J = 12), 8,20, 8.23 (d, 2H, CH, J = 12); 13C-NMR δ 15.5, 105.5, 120.3, 121.8, 123.6, 125.4, 128.1, 131.5, 135.1, 146.8, 149.3, 162.1; MS m/z (%): 453 (M+1, 91), 452 (M, 100), 437 (39), 375 (25). Anal. Calcd for C26H20N4S2 (452.11); C, 69.00; H, 4.45; N, 12.38; S, 14.17. Found: C, 68.70 H, 4.18; N, 12.08; S, 13.88.

3.3. General Procedure for the Reaction of Compound with Guanidine, Thiourea and Urea

Treatment of compound 2 (1 mmol) with guanidine, thiourea or urea (2 mmol) after making sure they dissolve in DMF (2 mL) in dry ethanol (20 mL, 99.9%), under reflux for 6-8 h. afforded the corresponding derivatives 5a-c respectively. After the solid products were collected by filtration, washed with ethanol, dried and recrystallized from DMF/EtOH.

4,4'-(3,4-Dimethylthieno[2,3-b]thiophen-2,5-diyl)bis(pyrimidine-2-amine) (5a): Brown crystals; yield 71%; mp. 304–306 °C; IR 3417, 3326 (NH2), 1556 (C=N) cm−1; 1H-NMR δ 2.21 (s, 6H, CH3), 4.83 (s, 4H, NH2), 7.83 (d, 2H, CH, J = 5.5 Hz), 8.37 (d, 2H, CH, J = 5.5 Hz); 13C-NMR δ 14.92, 102.6, 126.9, 134.1, 135.9, 144.5, 148.2, 158.5, 162.1; MS m/z (%): 355 (M+1, 7), 354 (M, 18), 339 (21), 322 (16). Anal. Calcd for C16H14N6S2 (354.07); C, 54.22; H, 3.98; N, 23.71; S, 18.09. Found: C, 53.92 H, 3.68; N, 23.68; S, 17.82.

4,4'-(3,4-Dimethylthieno[2,3-b]thiophen-2,5-diyl)bis(pyrimidine-2-thiol) (5b): Dark yellow crystals; Yield (88%); mp. > 320 °C; IR 3282 (SH), 1622 (C=N) cm−1; 1H-NMR δ 2.28 (s, 6H, CH3), 7.12, (d, 2H, CH, J = 5.5 Hz), 8.35 (d, 2H, CH, J = 5.5 Hz), 11.82 (2H, SH); 13C-NMR δ 16.3, 107.7, 125.6, 136.3, 137.1, 144.8, 149.1, 159.7, 161.1; MS m/z (%): 389 (M+1, 67), 388 (M, 78), 354 (6), 277 (31). Anal. Calcd for C16H12N4S4 (388.55); C, 49.46; H, 3.11; N, 14.42; S, 33.01. Found: C, 49.93; H, 2.82; N, 14.32; S, 32.92.

4,4'-(3,4-Dimethylthieno[2,3-b]thiophen-2,5-diyl)bis(pyrimidine-2-ol) (5c): Dark brown crystals; yield 79%; mp > 320 °C; IR 3480 (OH), 1587 (C=N) cm−1; 1H-NMR δ 2.26 (s, 6H, CH3), 8.18(d, 2H, CH, J = 5.5 Hz), 8.42 (d, 2H, CH, J = 5.5 Hz), 12.62 (2H, OH); 13C-NMR δ 15.9, 112.5, 126.3, 134.8, 136.1, 145.6, 147.4, 160.4, 162.5; MS m/z (%): 357 (M+1, 58), 356 (M, 18), 355 (2.5), 261 (11). Anal. Calcd for C16H12N4O2S2 (356.42); C, 53.92; H, 3.39; N, 15.72; S, 17.99. Found: C, 54.00; H, 3.55; N, 15.64; S, 17.78.

3.4. General Procedure for the Synthesis of Compounds and

Compound 2 (0.362 g, 1 mmol) in dry DMF (2 mL) was added to 4-amino-1,2,4-triazole (2 mmol, 0.168 gm) or 2-aminobenzimidazole (2 mmol, 0.266 mg), respectively, in dry 99.9% ethanol (20 mL) under reflux for 6–7 h. Then the solid product were collected by filtration, washed with ethanol, dried and recrystallized from (DMF/EtOH) to give 6 or 7.

7,7'-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis-[1,2,4]triazolo[1,5-a]pyrimidine (6): Light yellow crystals; yield 88%; mp > 320 °C; IR 1548, (C=N) cm−1; 1H-NMR δ 2.24 (s, 6H, 2CH3),7.66, 7.69 (d, 2H, CH, J = 12), 9.09, 9.12 (d, 2H, CH, J = 12), 8.62 (2H, =CH, triazole); 13C-NMR δ 16.3, 117.2, 128.8, 134.3, 142.0, 145.8, 148.2, 158.7,159.3, 162.1; MS m/z (%): 406 (M+2, 41), 405 (M+1, 56), 404 (100), 389 (14), 285 (31). Anal. Calcd for C18H12N8S2 (404.06); C, 53.45; H, 2.99; N, 27.70; S, 15.86. Found: C, 53.44; H, 2.81; N, 27.76; S, 15.67.

2,2'-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(benzo[4,5]imidazo[1,2-a]pyrimidine) (7): Dark yellow crystals; yield 82%; mp > 320 °C; IR 1529 (C=N) cm−1; 1H-NMR δ 2.18 (s, 6H, 2CH3), 7.56, 7.59 (d, 2H, CH, J = 12), 8.37, 8.40 (d, 2H, CH, J = 12), 8.12, 8.86 (4H, CH, pyrimidine); 13C-NMR δ 15.81, 100.0, 112.1, 115.1, 122.5, 127.1, 131.3, 135.9, 139.1, 142.0, 148.0, 148.4, 156.0, 162.78; MS m/z (%): 503 (M+1, 67), 502 (M, 100), 487 (9), 334 (12). Anal. Calcd for C28H18N6S2 (502.61); C, 66.91; H, 3.61; N, 16.72; S, 12.76. Found: C, 66.86; H, 3.57; N, 16.86; S, 12.61

4. Conclusions

In summary, the reactivity of 1-(5-acetyl-3,4-dimethythieno[2,3-b]thiophene-2-yl)ethanone (1) as a versatile and readily accessible building block for the synthesis of new bis-heterocycles incorporating thieno[2,3-b]thiophene was investigated.