(3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2- dioxide hydrobromide

(3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2- dioxide hydrobromide; (2b)
 


Synthesis of substituent R² (3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2- dioxide hydrobromide; (2b) was carried out as shown in Scheme-4 and the stepwise procedure is depicted below:
Scheme-4:

Bz-NH

Substitued R² (2b)
Step-1 : 2,3-dimethylbuta-L3-diene (14)
To 2,3-dimethylbutane-2,3-diol (13, 85g), 48% aqueous HBr was added to get the colorless solution. Mixture was fractionally distilled, washed twice with water and dried over anhydrous CaCl₂. Mixture was redistilled and the fraction of 69-70 °C was collected to get 2,3-dimethylbuta-l,3-diene (14, 38g. 64%yield). 1H NMR: (CDCl₃, 400 MHz): δ 5.06 (2H, s), 4.97 (2H, s), 1.92 (6H, s); ESI-MS: (+ve mode) 83.3 (M+H)⁺ (70 %).


Step-2: 3,4-dimethyl-2,5-dihydrothiophene 1,1 -dioxide (15)
A mixture of hydroquinone (492mg) and 2,3-dimethylbuta-l ,3-diene (14, 31.96 ml) was placed in sealed tube and a solution of sulfur dioxide in MeOH (140 ml) was added. Reaction mixture was heated at 85 °C for 4 h and cooled to room temperature. Crystals obtained was filtered, washed with cold methanol and dried to get 3,4- dimethyl-2,5-dihydrothiophene 1,1 -dioxide (15) as white crystalline solid (30 gm, 72% yield).
lH NMR: (CDCl_3, 400 MHz): δ 3.73 (4H, d, J = 1.2 Hz), 1.78 (6H, t, J = 1.2 Hz); ESI- MS: (+ve mode) 147.2 (M+H)⁺ (70 %), 169.1 (M+Na)⁺ (40%).


Step-3: 3,4-bis(bromomethyl)-2,5-dihydrothiophene 1,1 -dioxide (16)
A mixture of 3,4-dimethyl-2,5-dihydrothiophene 1,1-dioxide (15, 20g), 1- bromopyrrolidine-2,5-dione (53.5g), and AIBN (400mg) in CHC1₃ was heated for 15 hr. After completion of reaction, filtrate was evaporated under reduced pressure. The residue obtained was recrystallize from methanol to get 3,4-bis(bromomethyl)-2,5- dihydrothiophene 1,1-dioxide as a white crystals (16, 19 g, 45% yield).
1H NMR: (CDC1_3> 400 MHz): δ 4.06 (4H, s), 4.01 (4H, s); ESI-MS: (+ve mode) 303.8 (M+H)⁺ (90 %), 305.7 (M+2H)⁺ (70%).


Step-4: 5-benzyl-3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2-dioxide (17)
Mixture of 3,4-bis(bromomethyl)-2,5-dihydrothiophene 1,1-dioxide (16, 12g) and phenylmethanamine (10.84ml) in acetonitrile was stirred at 25 °C for 2 hr. After completion of reaction, solvent was removed under reduced pressure, ethyl acetate and IN NaOH were added, organic layer was separated and aq layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to give 5-benzyI-3,4,5,6-tetrahydro- lH-thieno[3,4-c]pyrrole 2,2-dioxide (17) as a solid compound (3.7 g, 38% yield).
1H NMR: (CDCI_3, 400 MHz): δ 7.34-7.29 (5H, m), 3.88 (2H, s), 3.77 (4H,s), 3.61 (4H, s); ESI-MS: (+ve mode) 250.3 (M+H)⁺ (100 %).

Step-5: benzyl 4,6-dihvdro-lH-thieno[3,4-clpyrrole-5(3H^")-carboxylate 2,2-dioxide (IS) A mixture of 5-benzyl-3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2-dioxide (17, 3.6g) and CBZ-C1 (13.5 ml) in toluene was stirred for 3 hr. After completion of reaction, diethyl ether was added till solid precipitated out. Solid was filtered and dried under reduced pressure to get benzyl 4,6-dihydro-lH-thieno[3,4-c]pyrrole-5(3H)- carboxylate 2,2-dioxide (18, 2.7 g, 64% yield). ^lH NMR: (CDC1_3, 400 MHz): δ 7.38-7.35 (5H, m), 5.19 (2H, s), 4.31 (4H, s), 3.88 (4H, d, J = 13.6 Hz); ESI-MS: (+ve mode) 294.4 (M+H)⁺ (80 %).


Step-6: 3 A5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2-dioxide hydrobromide (2b)
To a solution of benzyl 4,6-dihydro-lH-thieno[3,4-c]pyrrole-5(3H)-carboxylate 2,2-dioxide (18, 3.7 g) in glacial acetic acid, HBr in glacial acetic acid was added and the reaction mixture was stirred at 2 °C for 3h. After completion of reaction, diethyl ether was added to afford sticky solid, solvent was decanted and added minimum amount of methanol to get the crystalline solid as 3,4,5,6-tetrahydro-lH-thieno[3,4- c]pyrrole 2,2-dioxide hydrobromide as a hydrobromide salt (2b, 1.5 g, 50% yield). 1H NMR: (CDCI₃, 400 MHz): δ 9.43 (2H, bs), 4.08 (4H, s), 4.02 (4H, s); ESI-MS: (+ve mode) 160.4 (M+H)⁺ (88 %).


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Hexahydro-lH-furo[3,4-c]pyrrole

 

 

 

hexahydro-lH-furo[3,4-c]pyrrole; (2a)

 

 

Synthesis of substituent R (hexahydro-lH-furo[3,4-c]pyrrole; 2a) was out as shown in Scheme-3 and the stepwise procedure is depicted below:
Schem -3:

Substituted R² (2a)


Step-1 : 1 -Benzyl -pyrrolidine-3,4-dicarbQxylic acid dimethyl ester (10
N-benzyl-l-methoxy-N-((trimethylsilyl)methyl)methanamine (8, 21.4g) and dimethyl maleate (9, lOg) were dissolved in DCM (200 ml). To the reaction mixture TFA (0.54ml, 6.94mmol) was added and stirred for 3h. After completion of reaction, reaction mixture was neutralized with saturated NaHC0₃ solution (100 ml). Organic layer was washed with water, brine solution, dried over anhydrous Na₂S0₄ and evaporated under reduced pressure to get l-Benzyl-pyrrolidine-3,4-dicarboxylic acid dimethyl ester (10) as a light yellow color oil (16.7g, 87% yield).
lH NMR: (CDC1₃, 400 MHz): 6 7.25-7.13 (m, 5H), 3.72 (s, 2H), 3.58 (s, 6H), 3.26- 3.20 (m, 2H), 3.08-3.04 (m, 2H), 3.04-2.63 (m, 2H); ESI-MS: (+ve mode) 277.9 (M+H)⁺ (60 %), 299.9 (M+Na) (80 %).; HPLC: 90 %.


Step-2: (l-Benzylpyn:olidine-3,4-divOdimethanol (11)
l-Benzyl-pyrrolidine-3,4-dicarboxylic acid dimethyl ester (10, 15g), dissolved in THF (30 ml) was added to a suspension of LiAlH₄ (4.3g) and stirred for 2h at 25 °C. Reaction mixture was quenched with water (2 ml) and 2N NaOH solution (2 ml). The reaction mixture was filtered, dried over anhydrous Na₂S0₄ and evaporated under reduced pressure to get (l-Benzylpyrrolidine-3,4-diyl)dimethanol (11) as a yellow color oil (1 1.6 g, 97% yield).
1H NMR: (CDCI3, 400 MHz): δ 7.25-7.13 (m, 5H), 3.67 (s, 2H), 3.64-3.47 (m, 4H), 2.70-2.65 (m, 2H), 2.44-2.39 (m, 2H), 2.15-2.1 l(m, 2H); ESI-MS: (+ve mode) 222.1 (M+H)⁺ (85%); HPLC: 94 %.


Step-3: 5-Benzyl-hexahvdro-furo[^"3,4-c pyrrole (12) A mixture of l-Benzylpyrrolidine-3,4-diyl)dimethanol (11, lOg) and PTSA
(1.94g) in dry toluene (100 ml) was refluxed at 140 °C for 16h. The reaction mixture was cooled and basified with IN NaOH solution (100 ml), organic layer was separated off, washed with water, brine solution and dried to yield 5-Benzyl-hexahydro-furo[3,4- cjpyrrole (12) as an oil (5.9 g, 64% yield).
1H NMR: (CDCI3_, 400 MHz): δ 7.05-7.23 (m, 5H), 3.77-3.67 (s, 4H), 3.49 (s, 2H), 2.27-2.25 (m, 4H) 2.26-2.25 (m, 2H); ESI-MS: (+ve mode) 204.2 (M+H)⁺ (89%); HPLC: 84 %.


Step-4: hexahydro-lH-furo|^"3,4-c|pyrrole (2a)
5-Benzyl-hexahydro-furo[3,4-c]pyrrole (12, 5g) was dissolved in EtOH (50 ml) and hydrogenated in presence of 10 % Pd/C (0.5 g) at 60 psi. Filtered the reaction mixture was filtered, evaporated to dryness to get hexahydro-lH-furo[3,4-c]pyrrole (2a) as a colorless oil (2.56g, 92% yield). 1H NMR: (CDCI3_, 400 MHz): δ 3.67-3.58 (m, 4H) 3.43-3.33 (m, 2H), 2.97-2.88 (m, 4H); ESI-MS: (+ve mode) 1 13.8 (M+H)⁺ (55%); GC: 92 %.

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