Skip to main content
NCBI home page
International Journal of Molecular Sciences logoLink to International Journal of Molecular Sciences
. 2012 Apr 23;13(4):5035–5047. doi: 10.3390/ijms13045035

A Novel and Expedient Approach to New Thiazoles, Thiazolo[3,2-a]pyridines, Dihydrothiophenes, and Hydrazones Incorporating Thieno[2,3-b]thiophene Moiety

Yahia Nasser Mabkhot 1,*, Assem Barakat 1,*, Abdullah Mohammad Al-Majid 1, Abdullah Saleh Alamary 1, Taleb T Al-Nahary 2
PMCID: PMC3344264  PMID: 22606028

Abstract

This paper reports details about the synthesis of a series of novel functionalized symmetrical bis-heterocyclic compounds containing a thieno[2,3-b]thiophene motif. Bis-thiazole derivatives 2, 3a-c and thiazolo[3,2-a]pyridine derivatives 4a-c are achieved. The hitherto unknown dihydrothiophene derivatives 6a-d via bis-pyridimium salt 5 are obtained. Additionally, the novel hydrazonothieno[2,3-b]thiophene derivatives 10a-c are obtained via bis-tosylacetylthieno[2,3-b]thiophene derivative 9. All compounds are characterized by 1H-, 13C-NMR, GCMS, IR, and UV-vis spectrometry. These compounds represent a new class of sulfur and nitrogen containing heterocycles that should also be of interest as new materials.

Keywords: thiazolo[3,2-a]pyridine; dihydrothiphene; thieno[2,3-b]thiophene; symmetrical bis-heterocycle

1. Introduction

Thienothiophene derivatives have been developed for different purposes in the pharmaceutical field and have been tested as potential antitumor, antiviral, antibiotic, and antiglaucoma drugs, or as inhibitors of platelet aggregation [1–5]. We have been interested for some time in the chemical and biological properties of thienothiophene derivatives [6–12]. On the other hand thiophene derivatives represent a class of important and well-studied heterocycles [13,14]. Thiazoles and their derivatives have attracted continuing interest over the years because of their diverse biological activities [15,16]. They have found application in drug development for the treatment of allergies [15], hypertension, inflammation, schizophrenia, bacterial and HIV infections [17–21]. On the other hand substituted thiazolo pyridines represent an important class of annulated heterocycles with diverse types of pharmaceutical [22] and pesticide activity [23–28]. We have found that the bis-2-bromoacetylthieno[2,3-b]thiophene derivative 1, is a versatile, readily accessible building block for the synthesis of several new heterocyclic compounds of biological potency.

2. Results and Discussion

Refluxing of equimolar amounts of the bis-2-bromoacetylthieno[2,3-b]thiophene derivative 1 and cyanothioacetamide in ethanol and in the presence of a catalytic amount of TEA, afforded the corresponding bis-thiazole derivative 2. The structure of the isolated cycloadduct was identified as 2,2′-(4,4′-(3,4′-dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(thiazole-4,2-diyl))diacetonitrile (2) on the basis of its elemental analyses and spectral data. The IR spectrum of the reaction product exhibited absorption bands at 2259 cm−1 due to the nitrile group. The 1H-NMR spectrum of compound 2 revealed three singlets at δ 2.21, 3.79 and 7.80 due to methyl, methelene and CH thiazol protons, respectively. The reactivity of compound 2 towards some heterocyclic aldehydes was also investigated. Thus, the treatment of compound 2 with aldehyde derivatives in ethanol and in the presence of a catalytic amount of TEA afforded bis-thiazole derivatives 3a-c. The 1H-NMR spectrum of 3a showed three singlets at δ 2.28, 8.50 and 8.84 due to CH3, CH and CH thiazol protons respectively, in addition to an aromatic multiplet in the region 6.99–7.40. Compounds 3a-c were alternatively obtained by the reaction of the treatment of bis-2-bromoacetylthieno[2,3-b]thiophene derivative 1 with 2-cyano-2-arylmethylene-thioacetamide derivatives in ethanol/DMF (Scheme 1). Treatment of the bis-thiazole derivatives 3a-c with malononitrile afforded the corresponding thiazolo pyridine derivatives 4a-c (Scheme 1). Compounds 4a-c were alternatively obtained by reaction of the treatment of bis-thiazole derivative 2 with 2-cyano-2-arylmethylenethioacetamide derivatives in ethanol/DMF (Scheme 1). On the other hand, compounds 4a-c underwent a thermal intramolecular cyclization reaction via an initial Michael type adduct. The IR spectrum of compound 4b, taken as a typical example of the prepared series, revealed absorption bands at 2241, 2193, and 3383–3320 cm−1 corresponding to two nitrile and amino functions, respectively. Its 1H-NMR spectrum showed signals at δ 2.31, 4.57, 4.72, and 9.23, due to CH3, CH2, NH2 and CH thiazol protons respectively, in addition to an aromatic multiplet in the region 6.99–7.40. An aromatic multiplet in the region δ 7.49–7.60 was also found. Its mass spectrum revealed a molecular ion peak at m/z 789.

Scheme 1.

Scheme 1

Open in a new tab

Synthesis of thiazolo[3,2-a]pyridine derivatives 4a-c.

Our study was extended to include the synthesis of new bis-dihydrothiophene derivatives 6a-d. Thus, the bis-2-bromoacetylthieno[2,3-b]thiophene 1 was refluxed in a mixture of absolute ethanol, pyridine and THF for 1 h to give a single product of bis-pyridimium salt 5 as examined by TLC. Elemental analyses and mass spectrum analysis of the isolated product were completely in agreement with the molecular formula C22H20Br2N2O2S2. The structure of the product is assumed to be 5 according to the rationale outlined in Scheme 2 in 95% yield. The compound reacts with (E)-3-amino-2-benzyl-3-mercaptoacrylonitrile which is in resonating structure with (E)-2-cyano-3-phenylprop-2-enethioamide in refluxing ethanol which undergoes intramolecular cyclization to give compound 6a in 86% yield. The 1H-NMR of compound 6a was free of pyridine protons and exhibited two characteristic doublet signal at 4.40, 4.70 pmm integrated for 2H (for the C–H proton of the dihydrothiophene moiety). In addition, one broad signal at 4.19 ppm was integrated for 2H proton (for the NH2). Furthermore, CN and NH absorption appeared at 2187, 3450 cm−1, respectively, in the IR.

Scheme 2.

Scheme 2

Open in a new tab

Synthesis of dihydrothiophene derivatives 6a-d.

It is noteworthy to mention here that the bis-dihydrothiophene derivatives 6b-d with different moieties were also prepared from bis-pyridimium salt 5 and the corresponding aryl-mercaptoacrylonitrile derivatives but in very good yield, as depicted in Scheme 2.

There has been continuous interest in the synthesis of a new hydrazono system containing sulfone moiety because it holds considerable interest relative to the preparation of organic intermediates and physiologically active compounds. Thus, when the bis-2-bromoacetylthieno[2,3-b]thiophene 1 was treated with sodium 4-methylbenzenesulfinate in a mixture of absolute ethanol and DMF under reflux for 4 h, it afforded a white crystalline product, namely the bis-tosylacetylthieno[2,3-b]thiophene derivative 9 in a 97% yield, and its use as key intermediate for the synthesis of a wide variety of bis-(hydrazones) derivative 10 is shown in Scheme 3.

Scheme 3.

Scheme 3

Open in a new tab

Synthesis of hydrazonothieno[2,3-b]thiophene derivatives 10a–c.

When bis-tosylacetylthieno[2,3-b]thiophene derivative 9 were allowed to react with benzenediazoniumchloride, which had been prepared in situ from the corresponding aniline in hydrochloric acid with aqueous sodium nitrite in dioxane at 0–5 °C, it resulted in a single product as examined by TLC. Elemental analyses and mass spectrum analysis of the isolated product were completely in agreement with the molecular formula C40H32O6S4. The structure of the product is assumed to be 10a according to the rationale outlined in Scheme 3 in a 76% yield. The structure of compound 10a was substantiated from its elemental and spectral analyses. Its IR spectrum showed the presence of an absorption band characteristic for NH as well as the presence of C=N absorption at 3217, and 1627 cm−1, respectively. The fact that the 1H NMR of compound 10a was free of tosylacetyl protons in the 1H NMR spectrum strongly supported this assignment.

Finally, having now available the new bis-tosylacetylthieno[2,3-b]thiophene derivative 9 prompted us to study its synthetic utility as a key intermediate for novel symmetrical bis-(hydrazono) heterocycles 10b,c. Following the same methodology as described for 10a resulted in the formation of the bis-(hydrazone) derivatives 10b and 10c in 81% and 77% yield, respectively, and as depicted in Scheme 3. The structures of compounds 10b,c were inferred from different spectroscopic and analytical data.

3. Experimental Section

All melting points were measured on a Gallenkamp melting point apparatus. IR spectra were measured as KBr pellets on a Pye-Unicam SP 3–300 spectrophotometer. The NMR spectra were recorded on a Varian Mercury VX-400 NMR spectrometer. 1H-NMR and 13C-NMR (400 MHz) were run in dimethylsulphoxide (DMSO-d6). Chemical shifts were related to that of the solvent. Mass spectra were recorded on a Shimadzu GCMS-QP 1000 EX mass spectrometer at 70 eV. Elemental analyses was carried out on an Elementar Vario EL analyzer.

3.1. 2,2′-(4,4′-(3,4′-Dimethylthieno[2,3-b]thiophene-2,5-diyl)Bis(thiazole-4,2 diyl))diacetonitrile (2)

To a solution of 1 (0.41 g, 1 mmol, 1.0 equiv) in absolute ethanol (20 mL, 99.9%), 2-cyanoethanethioamide (0.20 g, 2.0 mmol, 2.0 equiv) and TEA (triethylamine) were added (few drops) and the resulting mixture was refluxed for 6 h. The solution was allowed to cool to room temperature. The formed solid product was filtered off and recrystallized from EtOH/DMF to afford the compound 2 as black needle crystals; Yield (88%); m.p. 270–272 °C; IR νmax (KBr) 2259 (CN), 1529 (C=N) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.21 (s, 6H, CH3), 3.79 (s, 4H, CH2), 7.80 (s, 2H, Thiazol); 13C-NMR: δ 14.8, 22.0, 117.4, 116.8, 128.8, 159.3, 134.3, 136.0, 148.1, 148.8; MS m/z (%): 412 (M+, 100); Anal. for C18H12N4S4 (412.05) calcd; C, 52.40; H, 2.93; N, 13.58; S, 31.09. Found: C, 52.10; H, 2.71; N, 13.28; S, 31.42.

3.2. General Procedure for the Synthesis of Compounds 3a-c (GP1)

3.2.1. 4,4′-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(thiazole-4,2-Diyl))bis (3-aryle acrylonitrile) (3a–c)

Method A: To a solution of 1 (0.41 g, 1 mmol, 1.0 equiv.) in mixture of absolute ethanol (20 mL, 99.9%) and DMF (5 mL), 3-aryle-2-cyanoprop-2-enethioamide (2.0 mmol, 2.0 equiv.) was added, and the reaction mixture was then heated under reflux for 6 h. The solution was allowed to cool to room temperature. The solid product was collected by filtration and recrystallized from EtOH/DMF to afford the compound 3a–c.

Method B: To a solution of 2 (0.41 g, 1 mmol, 1.0 equiv) in mixture of absolute ethanol (20 mL, 99.9%) and DMF (5 mL), aromatic aldehyde derivatives (2 mmol, 2.0 equiv) were added, the reaction mixture was then heated under reflux for 6–7 h. The solution was allowed to cool to room temperature. The solid product was collected by filtration and recrystallized from EtOH/DMF to afford the compound 3a–c.

3.2.2. 2,2′-(4,4′-(3,4-Dimethylthieno[2,3-b]thiophene-2,5- diyl)bis(triazole -4,2-diyl))bis (3-phenylacrylonitrile) (3a)

3a was prepared according to method A or method B, dark yellow crystals; yield (81a, 67b %); m.p. 300–302 °C; IR νmax (KBr) 2214 (CN), 1591 (C=N) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.28 (s, 6H, CH3), 6.99–7.40 (m, 10H, ArH’s), 8.50 (s, 2H, Ar–CH=C), 8.84 (s, 2H, Thiazol); 13C-NMR: δ 15.5, 118.0, 113.2, 135.9, 164.5, 106.1, 154.0, 124.0, 125.2, 128.0, 132.0, 138.5, 141.4, 147.6, 148.2; MS m/z (%): 588 (M+, 100); Anal. for C32H20N4S4 (588.79) calcd; C, 65.28; H, 3.42; N, 9.52; S, 21.78. Found: C, 65.06; H, 3.18; N, 9.23; S, 21.12.

3.2.3. 2,2′-(4,4′-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(thiazole-4,2-Diyl))bis (3-(4-chlorophenyl)acrylonitrile (3b)

3b was prepared according to method A or method B, brown needle crystals, yield (75a, 48b %); m.p. >320 °C; IR νmax (KBr) 2119 (CN), 1570 (C=N) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.36 (s, 6H, CH3), 6.44 (d, 2H, J = 8.4 Hz, ArH’s), (d, 2H, J = 8.4 Hz, ArH’s), 8.48 (s, 2H, Ar–CH=C), 8.82 (s, 2H, Thiazol), 13C-NMR: δ 14.1, 117.7, 111.1, 149.5, 162.3, 104.8, 153.2, 122.4, 125.8, 127.3, 131.2, 134.2, 138.1, 142.5, 147.9; MS m/z (%): 658 (M++2, 62); Anal. for C32H18N4S4 Cl2 (657.68) calcd; C, 58.44; H, 2.76; N, 8.52; S, 19.50. Found: C, 58.14; H, 2.46; N, 8.82; S, 19.20.

3.2.4. 2,2′-(4,4′-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(thiazole-4,2-diyl))bis (3-(4-methoxyphenyl)acrylonitrile (3c)

3c was prepared from according to method A or method B (GP1), dark brown powder crystals; yield (88a, 55b %); m.p. 282–284 °C; IR νmax (KBr) 2188 (CN), 1579 (C=N) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.36 (s, 6H, CH3), 3.86 (s, 6H, OCH3), 6.57 (d, 2H, J = 8.4 Hz, ArH’s), 7.21 (d, 2H, J = 8.4 ArH’s) 8.43 (s, 2H, Ar–CH=C), 8.87 (s, 2H, Thiazol); 13C-NMR: δ 14.6, 116.4, 112.45, 148.7, 164.2, 102.1, 155.8, 123.4, 125.1, 128.8, 129.3, 55.4, 133.8, 137.6, 141.9, 146.3; MS m/z (%): 648 (M+, 100); Anal. for C32H18N4S4 Cl2 (648.84) calcd; C, 62.94; H, 3.73; N, 8.63; S, 19.77. Found: C, 62.64; H, 3.43; N, 8.93; S, 19.47.

3.3. General Procedure for the Synthesis of Compounds 4a-c (GP2)

3.3.1. 3,3′-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(5-amino-7-aryle-7H-thiazolo[3,2-a]pyridine-6,8-dicarbonitrile) (4a-c)

Method A: To a solution of 2 (0.41 g, 1 mmol, 1.0 equiv) in mixture of absolute ethanol (20 mL, 99.9%) and DMF (5 mL), 2-arylidenemalo nonitril derivatives (2 mmol, 2.0 equiv) were added, the reaction mixture was then heated under reflux for 4 h. The solution was allowed to cool to room temperature. The solid product was collected by filtration and recrystallized from EtOH/DMF to afford the compound 4a-c.

Method B: To a solution of 3a-c (1.0 mmol, 1.0 equiv) in mixture of absolute ethanol (20 mL, 99.9%) and DMF (5 mL), malononitrile (0.13 mL, 2.0 mmol, 2 equiv) was added, the reaction mixture was then heated under reflux for 4–6 h. The solution was allowed to cool to room temperature. The solid product was collected by filtration and recrystallized from EtOH/DMF to afford the compound 4a-c.

3.3.2. 3,3′-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(5-amino-7-phenyl-7H-thiazolo [3,2-a]pyridine-6,8-dicarbonitrile (4a)

4a was prepared according to method A or method B (GP2), black light needle crystals; yield (73a, 56b %); m.p. >302 °C; IR νmax (KBr) 3444–3361(NH2 ), 2202, 2188.8 (4CN) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.21 (s, 6H, CH3), 4.37 (br, 4H, NH2), 5.02 (s, 2H, pyridine), 7.04–7.70 (m, 10H, ArH’s), 9.08 (s, 2H, Thiazol); 13C-NMR: δ 13.8, 115.7, 116.9, 112.1, 153.9, 155.0, 33.0, 56.4, 71.5, 159.8, 123.0, 126.0, 128.9, 134.3, 141.5, 141.9, 148.1, 148.8; MS m/z (%):720 (M+, 100); Anal. for C38H24N8S (720.91) calcd; C, 63.31; H, 3.36; N, 15.54; S, 17.79. Found: C, 63.01; H, 3.06; N, 15.24; S, 17.49.

3.3.3. 3,3′-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(5-amino-7-(4-chlorophenyl)-7Hthiazolo[ 3,2-a]pyridine-6,8-dicarbonitrile (4b)

4b was prepared according to method A or method B (GP2), greenish yellow scale crystals; yield (85a, 62b %); m.p. >302 °C; IR νmax (KBr) 3383–3320 (NH2 ), 2241, 2193.2 (4CN) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.31 (s, 6H, CH3), 4.57 (br,4H, NH2), 4.72 (s, 2H, pyridine), 7.17 (d, 2H, J = 8.8 Hz, ArH’s), 7.65 (d, 2H, J = 8.8 Hz, ArH’s), 9.23 (s, 2H, Thiazol); 13C-NMR: δ 15.2, 117.6, 118.4, 114.6, 152.5, 155.2, 32.3, 58.2, 73.8, 158.5, 122.7, 125.1, 127.6, 132.3, 142.7, 142.8, 147.5, 148.1; MS m/z (%):790 (M+, 18); Anal. for C38H22N8S4 Cl2 calcd; C, 57.79; H, 2.81; N, 14.19; S, 16.24. Found: C, 57.49; H, 2.51; N, 13.97; S, 16.54.

3.3.4. 3,3′-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(5-amino-7-(4-methoxyphenyl)-7Hthiazolo[ 3,2-a]pyridine-6,8-dicarbonitrile) (4c)

4c was prepared according to method A or method B (GP2), black shiny powder crystals; yield (68a, 44b %); m.p. >302 °C; IR νmax (KBr) 3410–3315(NH2 ), 2288, 2245 (4CN) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.28 (s, 6H, CH3), 3.85 (s, 6H, OCH3), 4.18 (br,4H, NH2), 5.23 (s, 2H, pyridine), 6.87 (d, 2H, J = 8.8 Hz, ArH’s), 7.12 (d, 2H, J = 8.8 Hz, ArH’s), 9.15 (s, 2H, Thiazol); 13C-NMR: δ 13.4, 117.48, 119.11, 111.1, 154.3, 156.09, 34.0, 57.1, 75.1, 159.6, 122.7, 125.1, 127.6, 132.3, 51.3, 141.2, 142.3, 148.2, 148.4; MS m/z (%): 780 (M+, 100); Anal. for C40H28N8O2S4 calcd; C, 61.52; H, 3.61; N, 14.35; S, 16.42. Found: C, 61.22; H, 3.31; N, 14.65; S, 16.20.

3.4. 1,1′-(2,2′-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(2-oxoethane-2,1-diyl))dipyridinium Bromide (5)

To a solution of 1 (0.41 g, 1.0 mmol, 1.0 equiv) in a mixture of absolute ethanol (20 mL, 99.9%) and THF (5 mL), pyridine (0.16 mL, 2 mmol, 2.0 equiv) was added, the reaction mixture was then heated under reflux for 1 h. The solution was allowed to cool to room temperature. The solid product was collected by filtration and recrystallized from EtOH/DMF to afford the compound 5. White needles crystals; yield (95 %); m.p. 265–267 °C; IR νmax (KBr) 1636 (C=O ), 1580 (C=N) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.14 (s, 6H, CH3), 4.81 (s,4H, CH2), 8.27–9.06 (m, 10H, pyridine); 13C-NMR: δ 15.6, 67.6, 128.1, 128.9, 140.8, 141.6, 146.7, 146.9, 147.5, 147.9; MS m/z (%): 569 (M+ +4, 18); Anal. for C22H20Br2N2O2S2 calcd; C, 46.49; H, 3.55; N, 4.63 S, 11.28. Found: C, 46.19; H, 3.25; N, 4.63; S, 11.08.

3.5. General Procedure for the Synthesis of Compounds 6a-d (GP3)

3.5.1. 5,5′-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-dicarbonyl)bis(2-amino-4-aryl-4, 5-dihydrothiophene-3-carbonitrile) (6a-d)

To a solution of 5 (0.57 gm, 1.0 mmol, 1.0 equiv) in mixture of absolute ethanol (20 mL, 99.9%) and DMF (5 mL), 2-cyano-3-aryle prop-2-enethioamide derivatives (2 mmol, 2.0 equiv) were added; the reaction mixture was then heated under reflux for 4 h. The solution was allowed to cool to room temperature. The solid product was collected by filtration and recrystallized from EtOH/DMF to afford the compound 6a-d.

3.5.2. 4,4′-5,5′(3,4-Dimethylthieno[2,3-b]thiophene-2,5-dicarbonyl)bis(2-amino-4-phenyl-4, 5-dihydrothiphene-3-corbonitrile (6a)

6a was prepared according to (GP3), red light powder crystals; yield (86%); m.p. 300–302 °C; IR νmax (KBr) 3450–3348(NH2), 1651 (C=O) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.25 (s, 6H, CH3), 4.19 (br, 4H, NH2), 4.40 (d, 2H, J = 4.80 Hz, dihydrothiophene), 4.70 (d, 2H, J = 4.20 Hz, dihydrothiophene), 7.26–7.39 (m, 10H, ArH’s); 13C-NMR: δ 14.8, 54.0, 55.2, 72.3, 159.3, 116.8, 123.6, 124.06, 128.8, 134.3, 136.0, 142.0, 148.1, 148.8, 191.0; MS m/z (%):624 (M+, 29); Anal. for C32H24N4O2S4 calcd; C, 61.51; H, 3.87; N, 8.97; S, 20.53. Found: C, 61.21; H, 3.57; N, 8.67; S, 20.83.

3.5.3. 4,4′-5,5′(3,4-Dimethylthieno[2,3-b]thiophene-2,5-dicarbonyl)bis(2-amino-4-(4-chlorophenyl)-4,5-dihydrothiphene-3-corbonitrile (6b)

6b was prepared according to (GP3), dark brown powder crystals; yield (78%); m.p. >320 °C; IR νmax (KBr) 3438–3320 (NH2), 1686 (C=O) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.37 (s, 6H, CH3), 4.42 (br, 4H, NH2), 4.39 (d, 2H, J = 4.80 Hz, dihydrothiophene), 4.82 (d, 2H J = 4.20 Hz, dihydrothiophene), 7.12 (d, 2H, J = 8.0 Hz, ArH’s), 7.42 (d, 2H, J = 8.0 Hz, ArH’s); 13C-NMR: δ 15.6, 54.6, 56.1, 73.6, 161.1, 117.2, 122.3, 126.1, 133.8, 134.4, 139.6, 146.8, 147.1, 148.4, 188.7; MS m/z (%):694 (M+ +2, 19); Anal. for C32H22Cl2N4O2S4 calcd; C, 55.40; H, 3.20; N, 8.08; S, 18.49. Found: C, 55.10; H, 3.50; N, 7.88; S, 18.19.

3.5.4. 4,4′-5,5′(3,4-Dimethylthieno[2,3-b]thiophene-2,5-dicarbonyl)bis(2-amino-4-(4-hydroxyphenyl)-4,5-dihydrothiphene-3-corbonitrile (6c)

6c was prepared according to (GP3), red blessed scale crystals; yield (79%); m.p. >320 °C; IR νmax (KBr) 3420–3382(NH2), 1633 (C=O) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.81 (s, 6H, CH3), 5.02 (br, 4H, NH2), 4.30 (d, 2H, J = 4.8 Hz, dihydrothiophene), 4.79 (d, 2H, J= 4.2 Hz, dihydrothiophene), 7.26 (d, 2H, J = 8.0 Hz, ArH’s), 7.57 (d, 2H, J = 8.0 Hz, ArH’s), 11.32 (br, 2H, OH); 13C-NMR: δ 15.4, 55.6, 56.6, 74.0, 152.7, 116.2, 123.2, 127.7, 134.5, 136.8, 142.2, 146.3, 148.1, 148.8, 190.4; MS m/z (%): 656 (M+, 100); Anal. for C32H24N4O4S4 calcd; C, 58.52; H, 3.68; N, 8.53; S, 19.53. Found: C, 58.22; H, 3.38; N, 8.23; S, 19.23.

3.5.5. 4,4′-5,5′(3,4-Dimethylthieno[2,3-b]thiophene-2,5-dicarbonyl)bis(2-amino-4-(4-methoxyphenyl)-4,5-dihydrothiphene-3-corbonitrile (6d)

6c was prepared according to (GP3), dark yellow powder crystals; yield (81%); m.p. >320 °C; IR νmax (KBr) 3433–3364 (NH2), 1710 (C=O) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.33 (s, 6H, CH3), 3.81 (s, 6H, OCH3), 4.88 (br, 4H, NH2), 4.32 (d, 2H, J = 4.8 Hz, dihydrothiophene), 4.66 (d, 2H J = 4.2 Hz, dihydrothiophene), 6.85 (d, 2H, J = 8.0 Hz, ArH’s), 7.31 (d, 2H, J = 8.0 Hz, ArH’s); 13C-NMR: δ 15.3, 52.3, 56.2, 57.3, 74.24, 158.50, 115.9, 122.7, 128.5, 134.4, 135.8, 143.9, 147.0, 148.1, 148.5, 192.1; MS m/z (%):684 (M+, 100); Anal. for C34H28N4O4S4 calcd; C, 59.63; H, 4.12; N, 8.18; S, 18.73. Found: C, 59.33; H, 4.42; N, 8.48; S, 18.43.

3.6. 1,1′-(3,4-Dimethyl-5-(2-tosylacetyl)thieno[2,3-b]thiophen-2-yl)-2-tosylethanone (9)

To a solution of 8 (0.41 gm, 1.0 mmol, 1.0 equiv) in mixture of absolute ethanol (20 mL, 99.9%) and DMF (5 mL), sodium 4-methylbenzenesulfinate (0.35 g, 2 mmol, 2.0 equiv) was added; the reaction mixture was then heated under reflux for 4 h. The solution was allowed to cool to room temperature. The solid product was collected by filtration and recrystallized from EtOH/DMF to afford the compound 9. White cubes crystals; yield (97%); m.p. 263–265 °C; IR νmax (KBr) 2980 (CH2), 1653 (C=O) cm−1; 1H-NMR (40 0 MHz, DMSO-d6) (ppm): 1.50 & 2.73 (s, 12H, CH3), 3.90 (s, 4H, Methylene), 6.93 (d, 2H, J = 7.3 Hz, ArH’s), 6.99 (d, 2H, J = 7.3 Hz, ArH’s); 13C-NMR: δ 15.6, 20.6, 69.2, 122.0, 122.5, 128.2, 132.0, 138.6, 141.5, 146.0, 147.7, 190.1; MS m/z (%): 560 (M+, 52); Anal. for C26H24O6S4 calcd; C, 55.69; H, 4.31; S, 22.87. Found C, 55.39; H, 4.61; S, 22.67.

3.7. General Procedure for the Synthesis of Compounds 10a-c (GP4)

3.7.1. 2-(2-Arylhydrazono)-1-(5-((Z)-2-(2-chlorohydrazono)-2-tosylacetyl)-3,4-dimethylthieno [2,3-b]thiophen-2-yl)-2-tosylethanone (10a–c)

A stirred soln. of 9 (0.5 mmol, 0.28 g) in ethanol (15 mL) was cooled in an ice bath at 0–5 °C, and then a soln. of the benzenediazonium chloride [freshly prepared by diazotizing aniline (1 mmol) in HCl (0.28 mL) with NaNO2 (2 mmol) in H2O (4 mL)] was added drop-wise over a period of 20 min. The reaction mixture was kept in a refrigerator overnight. The solid product was collected by filtration, and recrystallized from Et-OH/DMF. Thus pure crystals of the desired compounds 10a–c were obtained in a good yield that ranged from 76 to 81%.

3.7.2. 1-(3,4-Dimethyl-5-2-(2-phenylhydrazono)-2-tosylacetyl)thieno[2,3-b]thiophen-2-yl)-2-(2- phenylhydrazono)-2-tosylethanone (10a)

10a was prepared according to (GP4), red light powder crystals; yield (76%); m.p.295–297 °C; IR νmax (KBr) 3217 (NH), 1669 (C=O), 1595 (C=N) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.14, 2.79 (s, 12H, CH3), 7.48–7.58 (m, 10H, aromatic), 7.83 (d, 2H, J = 7.3 Hz, ArH’s), 7.85 (d, 2H, J = 7.3 Hz, ArH’s), 8.25 (br, 2H, NH); 13C-NMR: δ 15.5, 21.6, 119.8, 119.8, 120.0, 120.2, 128.7, 130.2, 135.1, 138.0, 141.5, 145.3, 148.1, 148.6, 169.0, 185.3; MS m/z (%):768 (M+, 19); Anal. for C38H32N4O6S4 calcd; C, 59.35; H, 4.19; N, 7.29; S, 16.68. Found: C, 59.05; H, 4.49; N, 6.99; S, 16.48.

3.7.3. 2-(2-(4-Chlorophenyl) hydrazono)-1-(5-2-(2-(4-chlorophenyl) hydrazono)-2-tosylacetyl)-3, 4-dimethylthieno[2,3-b]thiophen-2-yl)-2-tosylethanone (10b)

10b was prepared according to (GP4), yellow powder crystals; yield (81%); m.p. >320 °C; IR νmax (KBr) 3288 (NH), 1720 (C=O), 1565 (C=N) cm−1; 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.10, 2.86 (s, 12H, CH3), 7.19 (d, 2H, J = 8.8Hz, ArH’s), 7.28 (d, 2H, J = 8.8 Hz, ArH’s), 7.67 (d, 2H, J = 7.3 Hz, ArH’s), 7.80 (d, 2H, J = 7.3 Hz, ArH’s), 12.8 (br, 2H, NH); 13C-NMR: δ 14.8, 23.5, 121.2, 123.0, 123.9, 124.0, 126.3, 128.8, 132.4, 136.5, 140.9, 147.5, 147.7, 154.3, 165.2, 190.1; MS m/z (%): 838 (M+, 39); Anal. for C38H30Cl2N4O6S4 calcd; C, 54.47; H, 3.61; N, 6.69; S, 15.31. Found: C, 54.17; H, 3.31; N, 6.39; S, 15.01.

3.7.4. 1-(3,4-Dimethyl-5-2-(2-(p-tolyl)hydrazono)-2-tosylacetyl)thieno[2,3-b]thiophen-2-yl)-2-(2- (p-tolyl)hydrazono)-2-tosylethanone (10c)

10b was prepared according to (GP4), dark yellow needles crystals; yield (77%); m.p. 300–302 °C; IR νmax (KBr) 3356 (NH), 1652 (C=O), 1582 (C=N) cm−1; 1H-NMR (400 MHz, DMSO-d6) (ppm): 2.05, 2.10, 2.86 (s, 18H, CH3), 6.67 (d, 2H, J = 8.8 Hz, ArH’s), 6.81 (d, 2H, J = 8.8 Hz, ArH’s), 7.62 (d, 2H, J = 7.3 Hz, ArH’s), 7.79 (d, 2H, J = 7.3 Hz, ArH’s), 9.52 (br, 2H, NH); 13C-NMR: δ 16.0, 24.2, 24.1, 120.1, 120.9, 122.4, 123.9, 127.8, 128.2, 134.1, 137.6, 142.0, 143.8, 146.6, 152.9, 163.3, 188.0; MS m/z (%): 796 (M+, 28); Anal. for C40H36N4O6S4 calcd; C, 60.28; H, 4.55; N, 7.03; S, 16.09. Found: C, 60.08; H, 4.25; N, 7.33; S, 16.29.

4. Conclusions

In conclusion, the present investigation describes an efficient method for access toward novel bis-heterocycles containing biologically active moieties. We believe that these new series of symmetrical bis-hetrocycles may exhibit potentially diverse useful applications in the field of medicinal chemistry.

Acknowledgments

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project No. RGP-VPP-007.

References

  • 1.Jarak I., Kralj M., Piantanida I., Suman L., Zinic M., Pavelic K., Karminski-Zamola G. Novel cyano- and amidino-substituted derivatives of thieno[2,3-b]- and thien-o[3,2-b]thiophene-2-carboxanilides and thieno[30,20:4,5]thieno- and thieno[20,30:4,5]thieno[2,3-c]quinolones: Synthesis, photochemical synthesis, DNA binding, and antitumor evaluation. Bioorg. Med. Chem. 2006;14:2859–2868. doi: 10.1016/j.bmc.2005.12.004. [DOI] [PubMed] [Google Scholar]
  • 2.Peters D., Hornfeldt A.B., Gronowitz S. Synthesis of various 5-substituted uracils. J. Heterocycl. Chem. 1990;27:2165–2173. [Google Scholar]
  • 3.Kukolja S., Draheim S.E., Graves B.J., Hunden D.C., Pfeil J.L., Cooper R.D.G., Ott J.L., Couter F.T. Orally absorbable cephalosporin antibiotics. 2. Structure-activity studies of bicyclic glycine derivatives of 7-aminodeacetoxycephalosporanic acid. J. Med. Chem. 1985;28:1896–1903. doi: 10.1021/jm00150a023. [DOI] [PubMed] [Google Scholar]
  • 4.Prugh J.D., Hartman G.D., Mallorga P.J., McKeever B.M., Michelson S.R., Murcko M.A., Schwam H., Smith R.L, Sondey J.M., Springer J.P., et al. 5-substituted thieno[2,3-b]thiophene-2-sulfonamides. J. Med. Chem. 1991;34:1805–1818. doi: 10.1021/jm00110a008. [DOI] [PubMed] [Google Scholar]
  • 5.Hartman G.D., Ansdale P.A. Substituted thieno[2,3-b]thiophene-2-sulfonamides as antiglaucoma agents. 4,806,562. U.S. Patent. 1989 Feb 21;
  • 6.Mabkhot N.Y., Barakat A., Al-Majid A.M., Al-Othman Z.A., Alamary A.S. A facile and convenient synthesis of some novel hydrazones, schiff’s base and pyrazoles incorporating thieno[2,3-b]thiophenes. Int. J. Mol. Sci. 2011;12:7824–7834. doi: 10.3390/ijms12117824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Mabkhot Y.N., Kheder N.A., Al-Majid A.M. Facile and convenient synthesis of new thieno[2,3-b]thiophene derivatives. Molecules. 2010;15:9418–9426. doi: 10.3390/molecules15129418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Mabkhot Y.N. synthesis and chemical characterisation of new bis-thieno[2,3-b]thiophene derivatives. Molecules. 2010;15:3329–3337. doi: 10.3390/molecules15053329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Mabkhot Y.N. Synthesis and analysis of some bis-heterocyclic compounds containing Sulphur. Molecules. 2009;14:1904–1914. doi: 10.3390/molecules14051904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Mabkhot Y.N., Al-Majid A.M., Barakat A., Alshahrani S., Siddiqui Y. 1,1′-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)diethanone as building block in heterocyclic synthesis. Novel synthesis of some pyrazoles, and pyrimidines derivatives. Molecules. 2011;16:6502–6511. doi: 10.3390/molecules16086502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Mabkhot Y.N., Al-Majid A.M., Alamary A.S. Synthesis and chemical characterisation of some new diheteroaryl thienothiophene derivatives. Molecules. 2011;16:7706–7714. doi: 10.3390/molecules16097706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Mabkhot N.Y., Barakat A., Al-Majid A.M., Alshahrani S.A. Comprehensive and facile synthesis of some functionalized bis-heterocyclic compounds containing a thieno[2,3-b]thiophene motif. Int. J. Mol. Sci. 2012;13:2263–2275. doi: 10.3390/ijms13022263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Mabkhoot Y.N. Synthesis and analysis of some bis-heterocyclic compounds containing sulphur. Molecules. 2009;14:1904–1914. doi: 10.3390/molecules14051904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Eicher T., Hauptmann S., Speicher A. The Chemistry of Heterocycles. Wiley-VCH; New York, NY, USA: 2003. Five-Membered Heterocycle. [Google Scholar]
  • 15.Gronowitz S. In: The Chemistry of Heterocyclic Compounds: Thiophene and Its Derivatives. Gronowitz S., editor. Vol. 44. Wiley; New York, NY, USA: 1991. Part 3, Chapter 2. [Google Scholar]
  • 16.Quiroga J., Hernandez P., Insuasty B., Abonia R., Cobo J., Sanchez A., Nogueras M., Low J.N. Control of the reaction between 2-aminobenzothiazoles and mannich bases: Synthesis of pyrido[2,1-b][1,3]benzothiazoles versus [1,3]benzothiazolo[2,3-b]quinazolines. J. Chem. Soc. Perkin Trans. 1. 2002;4:555–559. [Google Scholar]
  • 17.Hutchinson I., Jennings S.A., Vishnuvajjala B.R., Westwell A.D., Stevens M.F.G. Antitumor benzothiazoles: 16 synthesis and pharmaceutical properties of antitumor 2-(4-aminophenyl)benzothiazole amino acid prodrugs. J. Med. Chem. 2002;45:744–747. doi: 10.1021/jm011025r. [DOI] [PubMed] [Google Scholar]
  • 18.Hargrave K.D., Hess F.K., Oliver J.T. N-(4-Substituted-thiazolyl)oxamic acid derivatives, new series of potent, orally active antiallergy agents. J. Med. Chem. 1983;26:1158–1163. doi: 10.1021/jm00362a014. [DOI] [PubMed] [Google Scholar]
  • 19.Patt W.C., Hamilton H.W., Taylor M.D., Ryan M.J., Taylor D.G., Jr, Connolly C.J.C., Doherty A.M., Klutchko S.R., Sircar I, Steinbaugh B.A., et al. Structure-activity relationships of a series of 2-amino-4-thiazole containing renin inhibitors. J. Med. Chem. 1992;35:2562–2572. doi: 10.1021/jm00092a006. [DOI] [PubMed] [Google Scholar]
  • 20.Sharma R.N., Xavier F.P., Vasu K.K., Chaturvedi S.C., Pancholi S.S. Synthesis of 4-benzyl-1,3-thiazole derivatives as potential anti-inflammatory agents: An analogue-based drug design approach. J. Enzym. Inhib. Med. Chem. 2009;24:890–897. doi: 10.1080/14756360802519558. [DOI] [PubMed] [Google Scholar]
  • 21.Jaen J.C., Wise L.D., Caprathe B.W., Tecle H, Bergmeier S., Humblet C.C., Heffner T.G., Meltzner L.T., Pugsley T.A. 4-(1,2,5,6-Tetrahydro-1-alkyl-3-pyridinyl)-2-thiazolamines: A novel class of compounds with central dopamine agonist properties. J. Med. Chem. 1990;33:311–317. doi: 10.1021/jm00163a051. [DOI] [PubMed] [Google Scholar]
  • 22.Tsuji K., Ishikawa H. Synthesis and anti-pseudomonal activity of new 2-isocephems with a dihydroxypyridone moiety at C-7. Bioorg. Med. Chem. Lett. 1994;4:1601–1606. [Google Scholar]
  • 23.Bell F.W., Cantrell A.S., Hogberg M., Jaskunas S.R., Johansson N.G., Jordon C.L., Kinnick M.D., Lind P., Morin J.M., Jr, Noreen R., et al. Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1: Synthesis and basic structure-activity relationship studies of PETT analogs. J. Med. Chem. 1995;38:4929–4936. doi: 10.1021/jm00025a010. [DOI] [PubMed] [Google Scholar]
  • 24.Lin R., Johnson S.G., Connolly P.J., Wetter S.K., Binnun E., Hughes T.V., Murray W.V., Pandey N.B., Moreno-Mazza S.J., Adams M., et al. Synthesis and evaluation of 2,7-diamino-thiazolo[4,5-d] pyrimidine analogues as anti-tumor epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett. 2009;19:2333–2337. doi: 10.1016/j.bmcl.2009.02.067. [DOI] [PubMed] [Google Scholar]
  • 25.Kulkarni S.S., Newman A.H. Discovery of heterobicyclic templates for novel metabotropic glutamate receptor subtype 5 antagonists. Bioorg. Med. Chem. Lett. 2007;17:2987–2991. doi: 10.1016/j.bmcl.2007.03.066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Komoriya S., Kobayashi S., Osanai K., Yoshino T., Nagata T., Haginoya N., Nakamoto Y., Mochizuki A., Nagahara T., Suzuki M., et al. Design, synthesis, and biological activity of novel factor Xa inhibitors: Improving metabolic stability by S1 and S4 ligand modification. Bioorg. Med. Chem. 2006;14:1309–1330. doi: 10.1016/j.bmc.2005.09.056. [DOI] [PubMed] [Google Scholar]
  • 27.Walczynski K., Zuiderveld O.P., Timmerman H. Non-imidazole histamine H3 ligands. Part III. New 4-n-propylpiperazines as non-imidazole histamine H3-antagonists. Eur. J. Med. Chem. 2005;40:15–23. doi: 10.1016/j.ejmech.2004.09.010. [DOI] [PubMed] [Google Scholar]
  • 28.Litvinov V.P., Dozenko V.V., Krivokolysko S.G. The Chemistry of Thienopyridines. In: Katritzky A.R., editor. Advances in Heterocyclic Chemistry. Vol. 93. Elsevier Academic; Amsterdam, The Netherlands: 2007. pp. 117–178. [Google Scholar]

Articles from International Journal of Molecular Sciences are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

RESOURCES