* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2005, vol. 44, # 11, p. 2367 - 2371
[2] Synthetic Communications, 1997, vol. 27, # 3, p. 473 - 482
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 13, p. 3562 - 3569
[4] Pharmazie, 1980, vol. 35, # 5-6, p. 326 - 327
[5] Tetrahedron, 2008, vol. 64, # 7, p. 1430 - 1434
[6] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 7, p. 2358 - 2365
[7] Organic and Biomolecular Chemistry, 2016, vol. 14, # 25, p. 6119 - 6133
[8] Patent: WO2006/52722, 2006, A1, . Location in patent: Page/Page column 44
[9] Synthetic Communications, 2011, vol. 41, # 19, p. 2811 - 2821
[10] Patent: WO2015/158908, 2015, A1, . Location in patent: Page/Page column 50
[11] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 38 - 50
[12] Patent: CN107253944, 2017, A, . Location in patent: Paragraph 0071; 0072; 0073
2
[ 6802-76-2 ]
[ 4506-71-2 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1986, vol. 23, p. 129 - 134
[2] Synlett, 2010, # 9, p. 1351 - 1354
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1994, vol. 33, p. 298 - 301
[4] Letters in Drug Design and Discovery, 2011, vol. 8, # 4, p. 330 - 338
[5] Turkish Journal of Chemistry, 2014, vol. 38, # 4, p. 650 - 660
[6] Patent: CN107253944, 2017, A, . Location in patent: Paragraph 0071; 0072; 0073
3
[ 108-94-1 ]
[ 105-56-6 ]
[ 4506-71-2 ]
Yield
Reaction Conditions
Operation in experiment
98%
With morpholine; sulfur In ethanol at 0℃;
General procedure: A mixture of cyclohexanone (1 mmol), an activated nitrile(1 equiv), morpholine (1 equiv) and elemental sulfur (1 equiv) in5 ml of ethanol was stirred at 0 C overnight. After, the solvent was evaporated at reduced pressure and the crude product was extracted with ethyl acetate thrice. The organic layer was treated with anhydrous sodium sulphate and evaporated again. Finally the final compounds were purified by recrystallization from MeOH/water. Yellow crystalline solid. Yield: 98percent, mp 134-135 °C. 1H NMR (400 MHz, DMSO-d6) δ 1.20 (3H, t, J = 7.1, CH3), 1.60-1.65 (4H, m, CH2), 2.35-2.37 (2H, m, CH2), 2.55-2.56 (2H, m, CH2), 4.11 (2H, q, J = 7.3, CH2CH3), 7.14 (2H, br s, NH2). 13C NMR (100 MHz, DMSO-d6) δ 14.18 (CH3), 22.34 (CH2), 22.76 (CH2), 23.88 (CH2), 26.49 (CH2), 58.71 (OCH2), 103.16 (Cq), 115.96 (Cq), 131.50 (Cq), 163.19 (Cq), 165.32 (C=O).
96%
With sulfur In ethanol at 77℃; for 0.333333 h; Microwave irradiation
General procedure: A mixture of the respective aldehyde or ketone (4mmol), ethylcyanoacetate (4mmol), S8 (0.14g, 4.4mmol), and morpholine or diethylamine (5mL) in EtOH (7mL) was put in a vial (G30 size) and submitted to microwave irradiation for 20min at 77°C (Pmax=80W). After cooling, the solution was poured onto 50mL ice water to yield a precipitate which was filtered, washed with water and dried under vacuum. The solid was used without further purification. 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (2b) [30] Yellow powder, 96percent; MS (HR-ESI) m/z calcd for C11H15NNaO2S (M + Na)+: 248.0716, found: 248.0709.
88%
at 60℃; for 2 h; Ionic liquid; Green chemistry
General procedure: For the synthesis of 4,5-alkyl-2-aminothiophenes (2a–2j), the general procedures are the same as those of compound 2i. A mixture of N-benzyl-4-piperidone (1i, 380 mg, 2 mmol), malononitrile (132 mg, 2 mmol), sulfur (64 mg, 2 mmol), and basic ionic liquid (bmIm)OH (380 mg, 2.4 equiv.) was heated to 60°C for 2 h. The reaction mixture was cooled to room temperature and washed with diethyl ether or ethyl acetate (340 mL),and the organic layers were concentrated under vacuum to obtain an oily crude product. The crude product was dissolved in ether/hexane (3:1, 50 mL) mixture, insoluble material was decanted, and the organic layer was concentrated to 1/4 of the volume and kept in a refrigerator. The precipitate that formed was filtered and dried.
85%
With sulfur; triethylamine In ethanol for 24 h; Reflux
General procedure: To a mixture of ketone (1 eq.), ethyl cyanoacetate (4) (1 eq.), and elemental sulfur (1 eq.) in absolute ethanol (1.7 mL/mmol eq.) was added triethylamine (1.5 eq.), and the mixture was refluxed for 24 h. The reaction mixture was then concentrated and the residue was partitioned between water (10 mL/mmol eq.)and ethyl acetate (10 mL/mmol eq.). The organic layer was separated, dried over MgSO4, and concentrated, and the crude product was purified by crystallization from EtOH/H2O unless otherwise stated. S.1.1 Ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (5a) [S1]. Obtained in 85percent yield as an off-white solid. 1H-NMR (CDCl3), δ: 1.35 (t, J= 7.1 Hz, 3H), 1.77 (m, 4H),2.51 (m, 2H), 2.72 (m, 2H), 4.27 (q, J= 7.1 Hz, 2H), 5.98 (bs, 2H). 13C-NMR (CDCl3), δ: 14.4, 22.8,23.2, 24.5, 26.9, 59.3, 105.7, 117.6, 132.46, 161.7, 166.1.
83%
With sulphur; diethylamine In ethanol at 20℃;
Example 13; Preparation of 7-bromo- N-(3-chloro-4-[(3-fluorobenzyl)oxyl phenyl ) [1]benzothieno[2,3-d]pyrimidin-4-amine; EPO <DP n="55"/> Step 1; Preparation of ethyl 2-amino-4,5.6.7-tetrahydro-l-benzothiophene-3- carboxylate; Cyclohexanone (200 g, 2.04 mol), ethyl cyanoacetate (231 g, 204 mol), diethylamine (149 g, 204 mol), sulfur (65.3 g, 2.04 mol) and ethanol were combined and stirred at room temperature over the weekend. The reaction mixture containing crystalline product was concentrated to -50percent of the original volume on a rotavap.The slurry was filtered and the collected solid was dried on the filter overnight to yield 381 g (83percent). 1H NMR (DMSO-d6) δ 7.18 (s, 2H), 4.12 (q, 2H), 2.57 (t, 2H), 2.40 (t, 2H), 1.66 (m, 4H), 1.23 (t, 3H); LCMS RT = 3.36 min' [M+H]+ = 226.0.
83.5%
With sulfur; diethylamine In ethanol at 20℃; for 0.5 h;
Some Formula (II) compounds can be synthesized, in some embodiments, as summarized in Scheme 2. This Scheme begins with the preparation of the 2-amino-4,5,6,7- tetrahydrobenzo[b]thienophene-3-carboxylic acid ethyl ester by using the Gewald reaction and then preparing the cyclic pyrimidinone compound F, by reacting the 2-aminothiophene carboxylic ester with excess of formamide. Compound F undergoes chlorination using phosphorus oxychloride (POCI3) yielding the suitable electrophile for the nucleophilic displacement using aqueous hydrazine generating the corresponding aromatic hydrazine derivative compound G (which is also referred to as PC for precursor). The Scheme concludes with the synthesis of the Formula (II) compounds by forming the Schiff base upon reaction of compound G with the corresponding aromatic aldehyde.
82%
With sulfur; diethylamine In ethanol at 20℃; for 1.25 h;
General procedure: Diethylamine (0.1mol) was added dropwise for 30min to a suspension of the appropriate ketone (0.1mol), ethyl cyanacetate 0.1mol (11ml) and 3.2g sulfur in 30ml ethanol and the reaction mixture was stirred at room temperature for about 75min. When the synthesis was completed the mixture was cooled. The obtained 2-aminothiophene crystalized in the form of yellow powder. The precipitate was filtrated, washed with water and recrystallized from ethanol to give the 2-aminothiophene derivatives [27].6.1.3 Еthyl 2-amino-4,5,6,7-tetrahydrothiophene-3-carboxylate (1c) Yield: 82percent; Mp. 114-115 °C [1] ; IR (KBr): 3300 cm-1 (NH), 2920 cm-1 (CH3), 2800 cm-1 (CH2), 1640 cm-1 (C=O), 1260 cm-1 (C-O); Analysis: Calc. for C11H15NO2S: C, 58.64; H, 6.71; N, 6.22; O, 14.20; S, 14.23; Found: C, 58.74; H, 6.73; N, 6.26; O, 14.19; S, 14.29.
80%
With sulfur; diethylamine In ethanol at 20℃; for 24 h;
A solution of cyclohexanone (9.8 g, 99.85 mmol, 1.00 equiv) in ethanol (50 mL) was added ethyl 2-cyanoacetate (11.3 g, 99.90 mmol, 1.00 equiv), diethylamine (7.3 g, 99.81 mmol, 1.00 equiv) and S (3.2 g, 0.10 mol, 1.00 equiv) was stirred for 24 h at room temperature. The solids formed were collected by filtration and then washed with EtOAc (20 mL). The solid was dried in an oven at 45 °C for 2 h to give 18 g (80percent) of the desired ethyl 2-amino-4,5,6,7- tetrahydro-l-benzothiophene-3-carboxylate as a yellow solid.
79%
With morpholine; cyanoacetic acid tert-butyl ester; sulfur In ethanol at 40℃; for 4 h;
General procedure: A mixture of ketone (1.0 eq.), sulfur powder (1.0 eq.) and t-butyl cyanoacetate, ethyl cyanoacetate or malononitrile (1.0 eq.) in EtOH (2mL/mmol) was prepared before morpholine (1.0 eq.) was added dropwise, ensuring that the reaction did not heat up above 60°C during the addition. The mixture was then heated at 40°C and stirred for 4–20h.
78%
With morpholine; sulfur In ethanol at 25℃; for 20 h; Inert atmosphere
General procedure: A mixture of ethyl cyanoacetate (5.43 mL, 50.95 mmol), the ketone (5.28 mL, 50.95 mmol), sulfur (1.74g, 50.95 mmol) and morpholine (4.44 mL, 50.95 mmol) in ethanol (100 mL) was allowed to stir for 20 h at 25 oC. 5percent Sodium chloride solution (100 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic layer was dried (MgSO4) and then concentrated in vacuo. The resulting residue was triturated with a mixture of diethyl ether (20 mL) and petroleum ether (40 mL) and the solid was filtered off to obtain a pale yellow solid (9.0 g, 78 percent).
77%
With sulfur; triethylamine In ethanol; water at 3 - 5℃; Reflux
EXAMPLE 1 Preparation of 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (IV) 1 mol cyclohexanone and 1 mol cyano-acetic acid ethyl ester were solved in 800 milliliter ethyl alcohole, 1 mol sulphur and 35 milliliter distilled water were added to the solution. The mixture was cooled down between to 3-5° C. and 35 milliliter triethyl-amine was added to it. The reaction mixture was stirred for 2 hours at reflux temperature then it was allowed to cool down to room temperature. The precipitated solid was wiltered off, washed with water and n-hexane, then dried. Yield: 77percent.
77%
With octasulfur; bovine serum albumin In N,N-dimethyl-formamide at 50℃; for 12 h;
General procedure: A mixture of 1 (1 mmol), 2 (1 mmol), elemental sulfur (1 mmol)and BSA (20 mg) was added to 1 mL of DMF. The reaction was incubatedat 50 C and 200 rpm. After the required time, the BSA wasfiltered off to terminate the reaction. For the products with highyields, the solid crude products precipitated in water, and then followedby filtration and drying. For the products with low yields,the crude residues were purified by flash column chromatographyon silica gel using petroleum/ethyl acetate.
77%
With sulfur; triethylamine In ethanol; water at 3 - 5℃; Reflux
Example 1; Preparation of 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (IV) <n="11"/>; 1 mol cyclohexanone and 1 mol cyano-acetic acid ethyl ester were solved in 800 milliliter ethyl alcohole, 1 mol sulphur and 35 milliliter distilled water were added to the solution. The mixture was cooled down between to 3 - 5 0C and 35 milliliter triethyl-amine was added to it. The reaction mixture was stirred for 2 hours at reflux temperature then it was allowed to cool down to room temperature. The precipitated solid was wiltered off, washed with water and n-hexane. then dried. Yield: 77 percent.
77%
With sulfur; triethylamine In ethanol; water at 100℃; for 2 h;
Example 1; The production of compounds marked with 1-12.; Ia.; The compound of the formula (III) is produced as follows: 1 mole of cyclohexanone and 1 mole of cyan-acetic acid ethylester are dissolved in 00 milliliter of ethyl alcohol, 1 mole of sulfur powder 35 milliliter of distilled water <n="9"/>and 35 milliliter of triethylamine are added. The reaction mixture is mixed at 100 centigrades during two hours then let to cool to room temperature. The precipitated crystalline material is filtered then washed with water and n-hexane. The yield is 60 to 77percent.
75%
With sulfur; choline chloride; urea; sodium hydroxide In water at 60℃; Green chemistry
General procedure: A mixture of 0.070 g 4-propylcyclohexanone (0.5 mmol),0.030 g malononitrile (0.5 mmol), 0.019 g sulfur powder(0.6 mmol), and 0.1 cm3 NaOH (4 mol dm-3 aqueoussolution) in 1 cm3 choline chloride/urea was stirred at 60°C for 2–3 h. After completion of the reaction, indicated by TLC monitoring, 5 cm3 water was added. The solid product was separated by filtration and if necessary the precipitate recrystallized from EtOH to afford the corresponding pure product
74%
Stage #1: With sulfur In ethanol at 50 - 60℃; Stage #2: With diethylamine In ethanol at 50 - 60℃; for 0.25 h;
The mixture of cyclohexanone, ethyl cyanoacetate and sulphur in ethanol was stirred at 50–60 °C, followed by addition of diethylamine dropwise over 15 minutes. The reaction mixture was stirred at same temperature for 2 hours, monitored by TLC. After completion of the reaction, the mixture was cooled to rt, solid precipitate was filtered at vacuum pump and washed with 2x5 ml ethanol. A yellow colored solid was recrystallized from ethanol to yield 74percent product 1.
73%
With morpholine; sulfur In ethanol at 90℃;
General procedure: A mixture of cyclohexanone (1.06 mL, 10 mmol), ethyl cyanoacetate (1.15 mL, 10 mmol), morpholine (0.90 mL, 10 mmol), sulphur (0.32 g, 10 mmol) in ethanol (10 mL) was stirred and refluxed for overnight. After completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The crude solid was washed with cold ethanol and filtered though sintered funnel, dried under vacuum. The crude product was dissolved in dichloromethane and washed with brine. The organic layer was collected and concentrated under low vacuum to give the compound 2a; yield: 73percent (1.83 g); brown solid; mp: 116.2-117.2 °C; 1H NMR (400 MHz, CDCl3) δ: 1.33 (t, J = 7.3 Hz, 3H), 1.74-1.80 (m, 4H), 2.47-2.51 (m, 2H), 2.68-2.71(m, 2H), 4.25 (q, J = 7.3 Hz, 2H), 5.93 (s, 2H); 13C NMR (100 MHz, CDCl3) δ: 14.4, 22.8, 23.2, 24.5, 26.9, 59.3, 105.7, 117.6, 132.4, 162.6, 166.1; IR (KBr) vmax (cm-1): 3408, 3300, 2938, 1646, 639; MS (ESI) m/z : 226.2 [M + H].
73%
With morpholine; sulfur In ethanol at 20℃; for 48 h;
EXAMPLE 209 - PREPARATION OF INTERMEDIATE Ethyl 2-amino- 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylateTo a solution of ethyl cyanoacetate (42.68 ml 400 mmol) in dry ethanol (400 ml_) were added cyclohexanone (62.18 ml 600 mmol), morpholine (52.8 ml 600 mmol) and sulfur (19.24 g; 600 mmol). The reaction mixture was stirred at room temperature for 48 h and the resulting suspension was filtered, washed with a small volume of cold ethanol and dried to furnish 66 g (73percent) of the title compound as a white powder. ESI/APCI(+): 226 (M+H).
66%
With morpholine; sulfur In ethanol at 20 - 50℃; for 0.333333 h;
Morpholine (20.4 g, 0.234 mol) was added dropwise to a mixture of cyclohexanone (10.0 g, 0.102 mol), ethyl cyanoacetate (11.53 g, 0.102 mol), and sulfur (2.9 g, 0.094 mol) in 30mL of ethanol at ambient temperature in 20 min. The reaction was exothermic, so the temperature increased to 50°C, and a clear solution was obtained. It was filtered from solids and cooled to 0–5°C. After stirring for 1h the product was filtered off, washed with chilled ethanol (15 mL) and sucked dry. The obtained cake was dried in an oven at 50°C for 3h to obtain 14g of the title product. Yield: 66.0percent.1H NMR (ppm): 1.23 (3H, t), 1.61– 1.72 (4H, m), 2.38–2.41 (2H, m), 2.56–2.61 (2H, m), 4.13 (2H, d), 7.21 (2H, br.s).
55%
With morpholine; sulfur In ethanol at 20℃; for 8 h;
Example 1: Intermediate A.[00245] Synthesis of compound 3. In to a mixture of cyclohexanone (compound 1) (49 g, 0.5 mol, 1.0 eq), ethyl 2-cyanoacetate (compound 2) (56 g, 0.5 mol, 1.0 eq), and sulphur (16 g, 0.5 mol, 1.0 eq) in 150 mL of ethanol was added morpholine (44 g, 0.5 mol, 1.0 eq). The mixture was stirred for 8 h at room temperature. The reaction mixture was diluted with water and the precipitate was collected by filtration and recrystallized from ethanol to afford compound 3 as yellow solid (62 g, 55percent).
55%
With morpholine; sulfur In ethanol for 8 h;
To a mixture of cyclohexanone (49 g, 0.5 mol), ethyl2-cyanoacetate (56 g, 0.5 mol), and sulphur (16 g, 0.5 mol)in 150 ml of ethanol was added morpholine (44 g, 0.5 mol).The mixture was stirred for 8 h at room temperature. Thereaction mixture was diluted with water and the precipitatewas collected by filtration and recrystallized from ethanol.Compound 2 as yellow solid (62 g, 55 percent); m.p. = 115 °C;1H NMR (CDCl3, 400 MHz) δ 5.94(s, 2H, Ar–NH2), 4.25 (q, 2H, J = 7 Hz, –O–CH2–), 2.69–2.60 (m, 2H, –CH2–CH2–CH2–), 2.49–2.43(m, 2H, –CH2–CH2–CH2–), 1.76–1.66 (m, 4H, –CH2–CH2–CH2–), 1.33(t, 3H, J = 7 Hz, –OCH2–CH3); ES-MS: m/z 226.3 (M+H)+.
50%
With sulfur; triethylamine In N,N-dimethyl-formamide at 55℃; for 12 h;
A mixture of ethyl cyanoacetate (1.15 g, O.Olmol), sulphur (0.32 g, 0.01 mol), triethyl amine (0.52 g, 0.005 mol) and cyclohexanone (1.0 g, 0.01 mol) in DMF (10 ml) was stirred at 55 0C for 12 hours. It was cooled, diluted with water (80 ml), extracted with ethyl acetate (2 x 100 ml), dried, concentrated and purified by column chromatography to obtain the pure ethyl 2-amino-4, 5, 6, 7- tetrahydrobenzo[b]thiophene-3-carboxylate of Formula (2h) (1.13 gm, 50percent).1HNMR (CDCl3, 200 MHz): δ 1.27 (t, JM7 Hz, 3H)5 1.62-1.78 (m, 4H), 2.35-2.50 (m, 2H), 2.54-2.70 (m, 2H), 4.19 (q, J=7 Hz, 2H).
50%
With sulfur; triethylamine In N,N-dimethyl-formamide at 55℃; for 12 h;
A mixture of ethyl cyanoacetate (1.15 g, O.Olmol), sulphur (0.32 g, 0.01 mol), triethyl amine (0.52 g, 0.005 mol) and cyclohexanone (1.0 g, 0.01 mol) in DMF (10 ml) was stirred at 55 0C for 12 hours. It was cooled, diluted with water (80 ml), extracted with ethyl acetate (2 x 100 ml), dried, concentrated and purified by column chromatography to obtain the pure ethyl 2-amino-4, 5, 6, 7-tetrahydrobenzo[b]thiophene-3-carboxylate of Formula (3-A09) (1.13 gm, 50percent).IHNMR (CDC13, 200 MHz): 1.27 (t, J=7 Hz, 3H), 1.62-1.78 (m, 4H), 2.35-2.50 (m, 2H), 2.54-2.70 (m, 2H), 4.19 (q, J=7 Hz, 2H)
44%
for 0.25 h; Microwave irradiation
General procedure: A one-neck 50-mL flask containing cyclohexanone (2.4 g, 20 mmol), ethyl cyanoacetate (3.4 g, 30 mmol), sulphur (0.96 g, 30 mmol), basic Al2O3 (1.8 g), and morpholine (2.6 g, 30 mmol) was placed into a microwave oven and irradiated at the power of 140W for 15 min. After cooling, the residue was separated by column chromatography with silica gel using petroleum ether/ethyl acetate (10/1) as eluting solution, to afford 8a (2.0 g, 44percent) as a off-white solid: mp 112-115 °C; 1H NMR (CDCl3, 400 MHz) δ 1.37 (t, 3H), 1.80 (m, 4H), 2.53 (m, 2H), 2.73 (m, 2H), 4.30 (q, 2H), 6.00 (br, 2H).
36%
With morpholine; sulfur In ethanol at 20 - 40℃;
General procedure: A mixture of the ketone (1 eq.), cyanoacetate (1 eq.), and elemental sulphur (1eq.) in ethanol were combined and heated at 40-70 °C. Morpholine or diethylamne (1 eq.) was added dropwise. The reaction was stirred at 40-70 °C for 1-4 hours, and then stirred at room temperature overnight. The resulting precipitate was typically collected by filtration and recrystallised from ethanol or toluene.
30%
With morpholine; sulfur In ethanol at 50℃; for 18 h;
Preparation 1 : Ethyl 2-amino-4.5.6.7-tetrahydro-1-benzothiophene-3-carboxylateTo a solution of ethyl cyanoacetate (427 mL, 4 mol) in ethanol (4 L) was added sulfur (153.88 g, 4.80 mol), morpholine (422 mL, 4.80 mol) and cyclohexanone (497 mL, 4.80 mol) and the resulting solution was stirred at 50°C for 18 hours. The reaction was cooled to room temperature and filtered to remove solids. The filter cake was washed with cold ethanol and then dried to give the title compound as a pale yellow solid, 608.4 g. The mother liquors were cooled in an ice bath and the resulting precipitate was collected by filtration. The solid was purified by dry flash chromatography eluting with ethyl acetate in heptane (20 - 30percent) to yield a further 38.62 g of the title compound. The two solids were combined to give 647.02 g of the title compound in a 72percent yield. 1H NMR (400 MHz, CDCI3) δ ppm 1.34 (t, 3 H), 1.73-1.75 (m, 4 H), 2.46-2.49 (m, 2 H), 2.63-2.69 (m, 2 H), 4.25 (q, 2 H), 5.92 (br s, 2 H).
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With trichlorophosphate In 1,2-dichloro-ethane Heating;
90%
Stage #1: caprolactam; ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate With trichlorophosphate In 1,2-dichloro-ethane Heating / reflux;
Stage #2: With potassium hydroxide In water
1.2a EXAMPLE 1; General procedure for the synthesis of 2a-i; 2a 2,3,4,7,8,9,10,11-octahydro[1]benzothieno[2',3':4,5]pyrimido-[1,2-a]azepin-13(1H)-one
To ethyl 2-amino-4,5, 6,7-tetrahydrobenzo (b) THIOPHENE-3-CARBOXYLATE 1b (0. 22MOL) and E- caprolactam (0. 33MOL) in dry DICHLOROETHANE (1500ML), POCI3 (0. 27MOL) was added dropwise. The mixture was heated under reflux until no starting material was detected on TLC after which 4/5 of the solvent was evaporated. Water (200MOI) was added and the solution was made basic with 20% KOH. The solution was extracted with CH2CI2 washed with brine and water and dried with NA2SO4. After filtration the solvent was evaporated. Recrystallisation from ethanol afforded 2a as white crystals in 90% yield. 'H NMR 8 1. 85 (10H, M), 2.75 (2H, M), 3.00 (4H, M), 4.35 (2H, m)
90%
With trichlorophosphate In 1,2-dichloro-ethane Reflux;
(i) POCl3, 1,2-dichloro-ethane, (ii) aq. NaOAc; Multistep reaction;
With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h;
8%
With triethylamine In benzene for 4h; Reflux;
Synthesis of (6):
A mixture of 1 (3.8 mmol), benzoyl chloride (4.3 mmol), and few drops oftriethylamine was refluxed for 4 h in dry benzene. The reaction mixture was concentrated andcooled at room temperature. The formed ppt was collected and recrystallized from ethanol to obtainyellow crystals.Ethyl 2-benzamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (6)Yield: 8%, m.p. 170-172 C; 1H NMR (400 MHz, DMSO-d6): 12.03 (s, 1H, D2O exchangeable,NH), 7.64±7.93 (m, 5H, phenyl), 4.35 (q, 2H, OCH2CH3), 2.66, 2.76 (2brs, 4H, 2 CH2cyhex), 1.76 (brs, 4H,2 CH2cyhex), 1.35 (t, 3H, CH2CH3); 13C NMR (100 MHz, DMSO-d6): 166.23, 163.06 (2 C=Oester+amide),147.01, 133.21, 132.54, 131.21, 129.64, 127.46, 127.03 (4 Cthiophene, 6 Cphenyl), 61.04 (OCH2CH3), 26.29,24.27, 22.97, 22.75 (4 CH2cyhex), 14.52 (OCH2CH3); CHN calcd. for: C18H19NO3S [329.41]: C, 65.63; H,5.81; N, 4.25; S, 9.73; found: C, 65.60; H, 5.84; N, 4.15; S, 9.5.
With triethylamine In dichloromethane at 20℃;
In acetone Reflux;
With triethylamine In dichloromethane at 20℃; for 4h; Inert atmosphere;
Ethyl 2-benzamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (5)
To a 250 mL RBF were added 4 (6.08 g, 27.0 mmol), DCM (60 mL), benzoyl chloride (4.18 g, 29.7mmol), the RBF was capped with a septum and purged with N2 flow for 5 min. The mixture was cooled in ice/water bath and triethylamine (3.28 g, 32.4 mmol) was added dropwise. The mixture wasstirred at r.t. for 4 h until TLC indcated full conversion. N,N-Dimethylethylenediamine (0.3 mL, 2.7mmol) was added to scavenge residual benzoyl chloride, and the mixture was stirred at r.t. for anadditional 20 min. The mixture was then washed with sat. ammonium chloride, water, and then brine.The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to give 5 as ayellow powder (8.4732 g, 95%).
With triethylamine In dichloromethane at 20℃; for 3h; Cooling with ice;
1.2
Weigh 1 eq of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester, add dichloromethane and 2 eq of triethylamine, and stir under ice bath. The above-mentioned benzoyl chloride solution was added dropwise, and after the dropping was completed, the mixture was stirred at room temperature for 3 hours until the reaction was completed as detected by TLC. Dichloromethane and dilute hydrochloric acid were added to the reaction solution to wash 3 times, the organic layer was collected, and then washed 3 times with saturated sodium bicarbonate solution and once with saturated brine. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and reduced. Press and concentrate to obtain crude product. Add ethanol to the crude product, heat and reflux until all the solids are dissolved, then slowly drop to room temperature, and filter under reduced pressure to obtain the intermediate 2-benzamide-4,5,6,7-tetrahydrobenzo[b]thiophene -3-carboxylic acid ethyl ester derivative.
A suspension of ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (10 g) in 100 ml_ 2.5 N sodium hydroxide (NaOH) solution (1 :1 water/ethanol) was heated at 80 C overnight. After the mixture was cooled and filtered to remove unreacted starting material, the solution was concentrated in vacuo. The residue was acidified to pH 3 by addition of 6N HCI and then filtered, resulting in a light brown solid (7.43 grams, ESMS [M+H]+m/z 198.3 ).
With water; potassium hydroxide; In tetrahydrofuran; ethanol; at 90℃; for 48.0h;
To a stirred solution of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (300 mg, 1.33 mmol) in H20 (4.0 mL) and EtOH (1.0 mL) was added KOH (746 mg, 10.0 mmol). The reaction mixture was stirred at 90 C for 12 h and treated with KOH (10.0 mmol) again. The reaction mixture was further stirred overnight at 90 C and needed additional KOH (10.0 mmol). After reaction was completed, solvents were removed under reduced pressure. No further purification was performed.
With sodium hydroxide; In ethanol; for 2.5h;Reflux;
General procedure: The relevant ester was refluxed in 2M NaOH (10mL) or (5mL) with ethanol (5mL) for the period of time specified. The solution was cooled, acidified to pH 3 with concentrated HCl and the precipitate was filtered off and dissolved in acetone (12.5 or 6.5mL). The solution was dried (MgSO4), filtered and the solvent evaporated at 20C. The resulting solid was treated with 2-propanol (3 or 1.5mL) and anhydrous oxalic acid (1 or 0.6g) at 38C for 45min. The mixture was cooled, diluted with ether, the solid filtered off and washed with ether and dried. The salt was dissolved in water, basified with conc. ammonia. The mixture was extracted with CH2Cl2 (3×5mL), the combined extracts were dried (MgSO4) and the solvents removed. The material was redissolved in CH2Cl2 (10mL) before an appropriate quantity of each of the following were added sequentially, based on the mass of the crude dicationic salt: 62 (2.4 eq.), TEA (8.0 eq) and HgCl2 (3.0 eq.). The solution was stirred for 2 days, was filtered through a pad of celite and washed with EtOAc. The filtrate was washed with brine before being dried over MgSO4 and the solvents removed. The resulting material was purified on using column chromatography on a Biotage (hexane/EtOAc 1%/CV over 20 CV).
With sodium hydroxide; In water; acetone; at 40℃; for 2.0h;
Cyclohexanone (0.1 mol) and ethyl 2-nitrileacetate (0.1 mol) in ethanol (25 mL) to give compound 3 '(wherein R1' is ethoxycarbonyl)To the reaction solution was added sulfur powder (0.1-0.11 mol), diethylamine (10 mL) was added dropwise and the reaction temperature was maintained at no more than 50 C. 3h after the reaction to ice salt bath, so that the reaction liquid crystallization, if not Crystallization The reaction solution was poured into 100 mL of water and filtered to give compound 4 '.The obtained solid product compound 4 'was dissolved in 30 mL of acetone solution, and 1 mL of NaOH aqueous solution (1 mol / L) was added thereto, followed by heating at 40C for 2 hours. After the end of the reaction, adjust with dilute hydrochloric acidpH = 1, extracted with dichloromethane and evaporated to give the desired product, namely compound 5 '(wherein R1 is carboxy) in a yield of 29%
2-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With hydrogenchloride In 1,4-dioxane at 0℃; for 10h; Heating;
74%
With hydrogenchloride In 1,4-dioxane at 20℃; for 18h;
2.2.1. General Procedure for the Synthesis of thieno[2,3-d]pyrimidin-4-ones 2-14
General procedure: Compound 1 (0.0094 mol) and the appropriate cyano derivative R-CN (0.018 mol) were dissolved in 10 ml dioxane in a round-bottom flask. Dry hydrogen chloride gas was passed through the solution for 6 h. This reaction mixture was allowed to stay 12 h at room temperature. It was then poured into a beaker containing crushed ice and 10%NH4OH was added to pH~8. The precipitate was filtered, washed many times with water and dried.
Stage #1: ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate With hydrogenchloride; acetic acid; sodium nitrite at 0 - 5℃;
Stage #2: ethyl acetoacetate In ethanol at 20℃; for 1h;
9
2-Amino-4,5,6,7-tetrahydrobenzothiophene-3-carboxylic acid ethyl ester (Compound A) (4.0 g) was dissolved in anhydrous methylene chloride (40.0 ml). Subsequently, pyridine (2.8 ml) and 3-(chloromethyl) benzoyl chloride (compound B) (3.0 ml) were added at 0°C, and the mixture was stirred at 0°C for one hr. After the completion of the reaction, distilled water was added, and the mixture was subjected to separatory extraction with chloroform, and the organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated to give 2-(3-chloromethyl-benzoylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester as a useful intermediate (7.42 g, yield 100%).
With hydrogenchloride In 1,4-dioxane at 20℃; for 18h;
2.2.1. General Procedure for the Synthesis of thieno[2,3-d]pyrimidin-4-ones 2-14
General procedure: Compound 1 (0.0094 mol) and the appropriate cyano derivative R-CN (0.018 mol) were dissolved in 10 ml dioxane in a round-bottom flask. Dry hydrogen chloride gas was passed through the solution for 6 h. This reaction mixture was allowed to stay 12 h at room temperature. It was then poured into a beaker containing crushed ice and 10%NH4OH was added to pH~8. The precipitate was filtered, washed many times with water and dried.
92.35%
With hydrogenchloride In 1,4-dioxane at 0℃; for 10h; Heating;
Stage #1: ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 0 - 20℃; for 2h; Inert atmosphere;
Stage #2: With hydrogenchloride In water; acetonitrile Inert atmosphere;
Ethyl 2-bromo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (5)
General procedure: Anhydrous copper bromide (12mmol), tert-butyl nitrite (15mmol), and anhydrous acetonitrile (40mL) were added at 0 oC to a three necked round bottom flask that was equipped with a reflux condenser, addition funnel or solid inlet tube, and a gas outlet tube. The coresponding amine (10mmol) in 5mL of acetonitrile or as a solid was slowly added over a period of 5 min to the reaction solution. During this addition, the reaction solution turned completely black from the initial green color and nitrogen was evolved. After gas evolution had been ceased the reaction mixture was stiered at r.t. for 2 hours. Then the mixture was poured into 100 mL of 10% aqueous hydrochlroic acid and extracted with 100 mL of ether; organic layer was washed once with 100 mL of 10% aqueous hydrochloric acid. The resulting ether solution was dried over anhydrous Na2SO4 and the ether was removed under reduce prussure. The product was then purified by silca gel column chromatography.
81%
With 2-Methyl-2-nitropropane; copper(ll) bromide In acetonitrile at 20℃; for 5h; Cooling with ice;
1.30.2.1
Under ice-cooling, to a suspension of CuBr2 (1.19 g, 5.326 mmol) in MeCN (40 mL) was added tert-butyl nitrate (0.69 g, 6.657 mmol). And ethyl 2-amino-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (1.0 g, 4.438 mmol) was added portion wise thereto, followed by stirring under ice-cooling for 2 h and then at room temperature for 3 h. To the reaction mixture was poured 50 mL of lOpercent aqueous HC1 solution, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The organic layer was washed with water and brine in this order, dried over MgS04, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient 0-25 percent, ethyl acetate in hexane) to afford 1 - 72 (1.05 g, 81%) as a brown oil.
70%
With tert.-butylnitrite In acetonitrile at 0 - 25℃; Inert atmosphere;
Synthesis of ethyl 2-iodothiophene-3-carboxylate (20)
General procedure: CuI (0.84 g, 4.44 mmol) was dissolved in 10 mL of acetonitrile and the resulting mixture was placed into an ice-bath. tert-Butyl nitrite (0.73 g, 7.10 mmol) was added dropwise into the mixture and the resulting mixture was kept at this temperature for additional 10 minutes. Then, compound 30 (0.76 g, 4.44 mmol) was dissolved in 5 mL of acetonitrile and added dropwise into the reaction mixture which was slowly brought to room temperature. Reaction was monitored via TLC. After the completion of the reaction, the mixture was filtered through celite, then solvent was evaporated under vacuum. 25 mL of 10 % HCl solution was added to the residue and then extracted with EtOAc (2 x 25 mL). Organic phases were collected and were washed with brine and then dried over MgSO4. After removal of solvent, the residue was purified over silica gel eluting with hexanes/ethylacetate (50:1) to give the product 20 as a light brown viscous liquid (120 mg, 10 % yield).
44%
With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 0 - 20℃; for 5h;
2 Step 2. Ethyl 2-bromo-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate
To a solution of tert-butyl nitrite (4.09 ml, 34.4 mmol) in MeCN (58 ml) cooled to 0° C was addd CuBr2 (8.54 g, 38.2 mmol). To this mixture was added portionwise ethyl 2-amino- 4,5,6,7-tetrahydrobenzothiophene-3-carboxylate (6.24 g, 27.7 mmol). The resulting mixture was stirred at 0° C for 2 h, then allowed to warm to rt and stirred for 3 h. The RM was concentrated under reduced pressure to remove MeCN. The residue was diluted with H2O (40 ml) and extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (3 x 20 ml), dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica, Petroleum ether: Ethyl acetate = 5:1) to give the title compound as a white solid. Y = 44 %. 1H NMR (400 MHz, MeOD) d 4.30 (q, J = 7 Hz, 2H), 2.70 (t, J = 7 Hz, 2H), 2.63 (t, J = 7 Hz, 2H), 1.80 - 1.74 (m, 4H), 1.36 (t, J = 7 Hz, 3H).
General procedure: A mixture of cyclohexanone (0.196 g,2.0 mmol), methyl cyanoacetate (0.198 g, 2.0 mmol),elemental sulfur (0.064 g, 2.0 mmol) and morpholine (0.174g, 2.0 mmol) was heated at 75 C for 1 h. After nearlycomplete conversion to the corresponding 2-aminothiophene, as was indicated by TLC monitoring, thereaction mixture was cooled to r.t. and the solid residue wasrecrystallized from EtOH to afford methyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (6a). Then asolution of 6a (0.211 g, 1 mmol) in benzonitrile (2 mL) washeated within a flask equipped with an air-filled balloon at200 C for 24 h in a silicone oil bath. Progress of the reactionwas monitored by TLC. After completion of the reaction, the mixture was cooled to r.t. and the excess of benzonitrile wasremoved under the reduced pressure. The crude product waspurified by column chromatography using n-hexane-EtOAc(8:1) as eluent. The solvent was evaporated under thereduced pressure and the residue was crystallized from nhexane-EtOAc (5:1) to afford the pure product 7a as paleyellow crystals. Yield: 0.188 g, 91% (on the basis of 6a
93%
With benzonitrile; at 200℃; for 24.0h;
General procedure: A mixture of cyclohexanone (0.196 g,2.0 mmol), methyl cyanoacetate (0.198 g, 2.0 mmol),elemental sulfur (0.064 g, 2.0 mmol) and morpholine (0.174g, 2.0 mmol) was heated at 75 C for 1 h. After nearlycomplete conversion to the corresponding 2-aminothiophene, as was indicated by TLC monitoring, thereaction mixture was cooled to r.t. and the solid residue was recrystallized from EtOH to afford methyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (6a). Then asolution of 6a (0.211 g, 1 mmol) in benzonitrile (2 mL) was heated within a flask equipped with an air-filled balloon at 200 C for 24 h in a silicone oil bath. Progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to r.t. and the excess of benzonitrile was removed under the reduced pressure. The crude product was purified by column chromatography using n-hexane-EtOAc(8:1) as eluent. The solvent was evaporated under the reduced pressure and the residue was crystallized from nhexane-EtOAc (5:1) to afford the pure product 7a as paleyellow crystals.
41%
With palladium 10% on activated carbon; In toluene; for 120.0h;Reflux;
A mixture of 5a (1.8 g, 7.9 mmol) and 10% Pd/C (1.8 g) in toluene (130 mL) was stirred under refluxfor 5 days. The reaction mixture was then cooled to r.t. and filtered over celite. The filtrate was concentrated at reduced pressure to afford a yellow solid residue, which was purified was by flash column chromatography (n-hexane-EtOAc 100:0 v/v increasing to n-hexane-EtOAc 90:10 v/v) to give pure a white solid in 41% yield. TLC (9:1 n-hexane-EtOAc, Rf: 0.28). 1H-NMR (CDCl3), δ: 1.49 (t, J= 7.1 Hz,3H), 4.44 (q, J= 7.1 Hz, 2H), 6.54 (bs, 2H), 7.14-7.17 (m, 1H), 7.32-7.35 (m, 1H), 7.51-7.53 (m, 1H),8.12-8.14 (m, 1H). 13C-NMR (CDCl3), δ: 14.5, 59.8, 99.8, 121.2, 122.3, 122.5, 125.4, 128.8, 137.4,164.3, 166.3.
With triethylamine; In benzene; at 50℃; for 0.333333h;
General procedure: A solution of 0.05 mol of triphenylphosphine in 100 mL of anhydrous benzenewas cooled to 5C, a solution of 0.05 mol of brominein 30 mL of anhydrous benzene was added dropwise under stirring, and the mixture was stirred for 3 h at room temperature. A solution of 0.1 mol of triethylaminein 30 mL of anhydrous benzene was added to the resulting suspension of dibromo(triphenyl)-lambda5-phosphane, a solution of 0.05 mol of nitrile 6 or ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylatein 50 mL of anhydrous benzene was added, and the mixture was stirred for 20 min at 50C. After cooling, the precipitate of triethylamine hydrobromide was filtered off, the filtrate was evaporated under reduced pressure, and the residue was purified by recrystallization
Stage #1: ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate; 4-cyanophenol In 1,4-dioxane at 80℃; for 0.166667h;
Stage #2: With hydrogenchloride In 1,4-dioxane; water at 80℃; for 6h;
3.1.2. General Procedure for the Synthesis of A1-6
General procedure: One gram of intermediate 1 and 2 molar equivalents of an appropriately substituted nitrile were dissolved in 15 mL dioxane, and the mixture was stirred at 80 °C for 10 min, then 20 mL hydrochloric acid was added. The reaction continued for 6 h, and was cooled to ambient temperature, poured into ice water, and adjusted to slightly basic using ammonia. The precipitate was suction-filtered to afford the crude product. Silica gel column chromatography using 3:1 petroleum ether:ethyl acetate as eluent yielded compounds A1-6.
57.3%
With hydrogenchloride In 1,4-dioxane at 100℃;
45%
With hydrogenchloride In 1,4-dioxane at 25℃; for 48h;
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 18h;
General procedure: Compound 1 (0.0094 mol) and the appropriate cyano derivative R-CN (0.018 mol) were dissolved in 10 ml dioxane in a round-bottom flask. Dry hydrogen chloride gas was passed through the solution for 6 h. This reaction mixture was allowed to stay 12 h at room temperature. It was then poured into a beaker containing crushed ice and 10%NH4OH was added to pH~8. The precipitate was filtered, washed many times with water and dried.
2-[4-chloro-[1,2,3]dithiazol-(5Z)-ylideneamino]-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With pyridine In dichloromethane at 20℃; Inert atmosphere;
General procedure for the synthesis of imino-1,2,3-dithiazoles 3, 9, 11 and 12 from starting amino ester derivatives.
General procedure: Under an inert atmosphere (argon), dithiazolium salt 1 (0.208 g,1 mmol) was added to a solution of amino ester (1 mmol) in dichloromethane (5 mL). Pyridine (2 mmol) was slowly added. The mixture was stirred until all of the amine had been consumed (tlc control). The mixture was warmed to room temperature and the reaction mixture filtered through acidic alumina and pour into ice water and the organic layer was separated and the aqueous phase extracted with dichloromethane. The crude product was purified by column chromatography using petroleum ether/DCM as the eluent.Orange solid; Yield: 68% ; mp 130 °C ; 1H NMR (400 MHz, CDCl3) d : 4.38 (q, 2H, J 7.2 Hz, CH2),2.72-2.92 (m, 4H, 2 CH2), 1.73-2.00 (m, 4H, 2 CH2), 1.41 (t, 3H, J 7.2 Hz, CH3).13C NMR (100 MHz, CDCl3) d :164.0; 152.0; 149.2; 148.9; 136.4; 133.1; 127.2; 60.8; 25.7; 25.6; 22.9; 22.3; 14.3. υmax (ATR) / cm-1 : 2929,1665, 1545, 1268, 1146, 779. HRMS (ESI) m/z [M+H]+: calcd for C13H1335ClN2O2S3 : 359.98277; found :359.9853.
ethyl (E)-2-((4-amino-5-cyano-3-methyl-6-oxo-6,7-dihydrothieno[2,3-b]pyridin-2-yl)azo)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67.3%
Stage #1: ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 0.5h;
Stage #2: 2-amino-4-methylthiophene-3-carbonitrile With sodium acetate In ethanol at 0 - 5℃; for 2h;
3.6.4. General Procedure for Synthesis of thienopyridyl-azo-tetrahydrothiophene Derivatives (6a-c)
General procedure: Molar quantities of thiophenes 4a-c (2.25 g, 1.96 g, 1.78 g, respectively, 10 mmol) in (3 mL) conc.HCl and (5 mL) of an aqueous NaNO2 solution (10 mmol, 0.69 g) were mixed and well stirred at 0-5 °C for 30 min. The freshly prepared diazonium salts (5a-c) were added afterwards to (20 mL) of ethanolic solution for the coupling of component 2-aminothiazole 1 (2.05 g, 10 mmol) containing sodium acetate (3 g) with slow and continuous stirring at 0-5 °C for 2 h. The resulting products (6a-c) were collected,dried and recrystallized from MeOH/Dioxan.
With hydrogenchloride In 1,4-dioxane; water at 20℃; Sonication; Sealed tube;
2-(Pyridin-4-yl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (4; Scheme 1)
The following is a modification of a literature preparation37: To anice-cold solution of 4 M HCl in p-dioxane (12 mL) in a sealed tube wasadded ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate(2; 1.02 g, 4.53 mmol). The stirred suspension was then treatedwith isonicotinonitrile (3; 613 mg, 5.9 mmol) followed by 4 mL ofadditional 4 M HCl in p-dioxane. The tube was capped and the suspensionwas placed in a sonicator bath for 1 h during which a brilliantyellow precipitate formed while the temperature reached 40 °C. Thesuspension was stirred at room temperature for 16 h and then sonicatedagain (2 h). TLC (ethyl acetate) showed complete consumption ofstarting thiophene with clean generation of product and a trace of ahigher Rf fluorescent impurity. The suspension was diluted with 20 mLof ether and the solids were collected, washed well with ether and driedto leave 1.87 g of a bright yellow cake-like solid. The solids were suspendedin cold water followed by vigorous stirring to leave a thicksuspension that was treated dropwise with con. ammonium hydroxideuntil all yellow color had discharged to provide an off-white suspension.The solids were collected, washed thoroughly with water, andvacuum dried to leave an off-white solid that was suspended in ethylacetate (~20 mL). The suspension was sonicated for 5 min and thenheated to reflux. The solids were collected by filtration and then vacuum dried at 80 °C to leave 4 (1.06 g, 83%) as an insoluble, off whitepowdery solid
With pyridine; trichlorophosphate In dichloromethane at 0 - 20℃; for 16h;
40.1 Step 1: Synthesis of Ethyl 2-benzamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate
Pyridine (1.25 mL) and benzoic acid (542 mg, 4.438 mmol) were added to a solution of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (500 mg, 2.219 mmol) in dichloromethane (10 mL) at 0° C. After 10 min, phosphorus(V) oxychloride, (1.25 mL) was added. The mixture was allowed to slowly warm to room temperature and stirring continued for 16 h. Ice water (50 mL) was added and the crude mixture was extracted with dichloromethane (3*50 mL). The organic layer was dried over sodium sulphate and concentrated. The crude residue was purified by column chromatography eluting with ethyl acetate:hexane to give ethyl 2-benzamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (200 mg, 27.4% yield) as off white solid. LCMS: 57.85% (RT: 2.427, 230.0 nm) (MS: ESI+ve 330.08 [M+H])
2-(2,4-dimethyl)benzamide-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine In dichloromethane at 20℃; for 3h; Cooling with ice;
14.2
Weigh 1 eq of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester, add dichloromethane and 2 eq of triethylamine, and stir under ice bath. The above-mentioned benzoyl chloride solution was added dropwise, and after the dropping was completed, the mixture was stirred at room temperature for 3 hours until the reaction was completed as detected by TLC. Dichloromethane and dilute hydrochloric acid were added to the reaction solution to wash 3 times, the organic layer was collected, washed 3 times with saturated sodium bicarbonate solution, and washed once with saturated brine. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and reduced. After pressing and concentrating, the crude product is obtained. Add ethanol to the crude product, heat and reflux until all the solids are dissolved, then slowly drop to room temperature, and filter under reduced pressure to obtain the intermediate 2-(2,4-dimethyl)benzamide-4,5,6,7 -Tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester derivative.
2-(2-fluoro-5-chloro)benzamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine In dichloromethane at 20℃; for 3h; Cooling with ice;
17.2
Weigh 1 eq of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester, add dichloromethane and 2 eq of triethylamine, and stir in an ice bath. The above-mentioned benzoyl chloride solution was added dropwise, and after the dropping was completed, the mixture was stirred at room temperature for 3 hours until the reaction was completed as detected by TLC. Dichloromethane and dilute hydrochloric acid were added to the reaction solution and washed 3 times. The organic layer was collected, washed 3 times with saturated sodium bicarbonate solution and once with saturated brine. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and reduced. After pressing and concentrating, the crude product is obtained. Add ethanol to the crude product, heat and reflux until all the solids are dissolved, then slowly drop to room temperature, and filter under reduced pressure to obtain the intermediate 2-(2-fluoro-5-chloro)benzamide-4,5,6,7-Tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester derivative.
With triethylamine In dichloromethane at 20℃; for 3h; Cooling with ice;
5.2
Weigh 1 eq of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester, add dichloromethane and 2 eq of triethylamine, and stir in an ice bath. The above-mentioned benzoyl chloride solution was added dropwise, and after the dropping was completed, the mixture was stirred at room temperature for 3 hours until the reaction was completed as detected by TLC. Dichloromethane and dilute hydrochloric acid were added to the reaction solution to wash 3 times, the organic layer was collected, and then washed 3 times with saturated sodium bicarbonate solution and once with saturated brine. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and reduced. After pressing and concentrating, the crude product is obtained. Add ethanol to the crude product, heat and reflux until all the solids are dissolved, then slowly drop to room temperature, and filter under reduced pressure to obtain the intermediate2-(4-Bromo)benzamide-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester derivative.
With triethylamine In dichloromethane at 20℃; for 3h; Cooling with ice;
6.2
Weigh 1 eq of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester, add dichloromethane and 2 eq of triethylamine, and stir under ice bath. The above benzoyl chloride solution was added dropwise, and after the dropping was completed, the mixture was stirred at room temperature for 3 hours until the reaction was completed as detected by TLC. Dichloromethane and dilute hydrochloric acid were added to the reaction solution to wash 3 times, the organic layer was collected, and then washed 3 times with saturated sodium bicarbonate solution and once with saturated brine. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and reduced. After pressing and concentrating, the crude product is obtained. Add ethanol to the crude product, heat and reflux until all the solids are dissolved, then slowly drop to room temperature, and filter under reduced pressure to obtain the intermediate2-(4-nitro)benzamide-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester derivative.
ethyl 2-({2-[(4-chloro-2-nitrophenyl)amino]-2-oxoethyl}amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.2%
With triethylamine In 1,4-dioxane for 2h; Reflux;
2.1.4. Step 3: Synthesis of ethyl 2-({2-[(substituted phenyl)amino]-2-oxoethyl}amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (RCA1-RCA9)
General procedure: In 15 mL of 1,4-dioxane, equimolar proportions (0.05 mol) of 3 and different N-substituted α-chloro acetanilides (6A1-A9) were mixed. The reaction mixture was refluxed for 2 hrs. after adding 0.005 mol triethylamine solution. Upon cooling, the reaction mixture was poured over crushed ice. The precipitate was filtered, washed with potassium bicarbonate (1%), and dried. Rf values for RCA1- RCA9 were calculated using the solvent system, ethyl acetate/n-hexane (1:2).
86.2%
With triethylamine In 1,4-dioxane for 2h; Reflux;
2.1.4. Step 3: Synthesis of ethyl 2-({2-[(substituted phenyl)amino]-2-oxoethyl}amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (RCA1-RCA9)
General procedure: In 15 mL of 1,4-dioxane, equimolar proportions (0.05 mol) of 3 and different N-substituted α-chloro acetanilides (6A1-A9) were mixed. The reaction mixture was refluxed for 2 hrs. after adding 0.005 mol triethylamine solution. Upon cooling, the reaction mixture was poured over crushed ice. The precipitate was filtered, washed with potassium bicarbonate (1%), and dried. Rf values for RCA1- RCA9 were calculated using the solvent system, ethyl acetate/n-hexane (1:2).
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