Cascade Regioselective Heterocyclization of 2-Acyl-1,1,3,3-tetracyanopropenides: Synthesis of Pyrrolo[3,4-c]pyridine and Pyrrolo[3,4-d]thieno[2,3-b]pyridine Derivatives

Abstract

2-Acyl-1,1,3,3-tetracyanopropenides (ATCN) undergo cascade heterocyclization under the action of aliphatic thiols, resulting in the formation of 6-(alkylthio)-4-amino-1-aryl(alkyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitriles. The involvement of methyl mercaptoacetate to this reaction leads to the formation of the methyl 4,8-diamino-1-aryl-1-hydroxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-d]thieno[2,3-b]pyridine-7-carboxylates, containing a new fused heterocyclic scaffold.

Key words

tetracyanopropenide - heterocyclization - fused heterocycles

• References and Notes

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• 7 CCDC 1522443 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 8 Typical Procedure for the Preparation of 6-(Alkylthio)-4-amino-1-aryl(alkyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-7-carbonitriles 2a–l via the Reaction of ATCN 1 with Aliphatic Thiols ATCN (10 mmol) was dissolved in 80% aq pyridine (20 mL), then the aliphatic thiol (12 mmol) was added. The resulting mixture was heated to reflux for 1–2 h (TLC monitoring) then cooled to r.t. and poured into water (80 mL). The white precipitate thus formed was filtered, recrystallized from 2-PrOH and dried in vacuo. Compound 2d: 64% yield (2.18 g), white solid, mp 248–250 °С. ¹H NMR (500.13 MHz, DMSO-d ₆): δ = 1.27 (3 Н, t, ³ J = 7.1 Hz, CH₂СH ₃), 2.29 (3 Н, s, СH₃), 3.17 (2 H, q, ³ J = 7.2 Hz, CH ₂СH₃), 7.09 (1 Н, br s, NH₂), 7.17 (2 H, d, ³ J = 8.1 Hz, Ar), 7.19 (1 Н, s, OH), 7.33 (2 H, d, ³ J = 8.2 Hz, Ar), 8.07 (1 Н, br s, NH₂), 9.14 (1 Н, s, NH). ¹³C NMR (125.77 MHz, DMSO-d ₆): δ = 14.4, 20.6, 24.0, 86.5, 87.3, 103.2, 113.8, 125.9, 128.5, 135.6, 137.5, 155.5, 163.3, 166.7, 167.5. IR (mineral oil): 3633 (OH), 3481, 3277 (NH₂), 2216 (CN), 1689 (C=O) cm^–1. MS (EI, 70 eV): m/z (%) = 341 (16) [М + 1]⁺, 340 (25) [М]⁺, 249 (100) [М – Ar]⁺, 119 (50) [ArCO]⁺, 91 (67) [Ar]⁺. Anal. Calcd for C₁₇H₁₆N₄O₂S: C, 59.98; H, 4.74; N, 16.46. Found: C, 60.21; H, 4.73; N, 16.40.
• 9 Typical Procedure for the Preparation of Methyl 4,8-Diamino-1-(aryl)-1-hydroxy-3-oxo-2,3-dihydro-1H-pyrrolo-[3,4-d]thieno[2,3-b]pyridine-7-carboxylates 3a–d via the Reaction of ATCN 1 with Methyl Thioglycolate ATCN (10 mmol) was dissolved in 80% aq pyridine (20 mL), then methyl thioglycolate (10 mmol) was added. The resulting mixture was heated to reflux for 1–2 h (TLC monitoring) then cooled to r.t. and poured into water (80 mL). The yellow precipitate this formed was filtered, recrystallized from MeCN and dried in vacuo. Compound 3d: 55% yield (2.07 g), yellow solid, mp 247–250 °С. ¹H NMR (500.13 MHz, DMSO-d ₆): δ = 3.69 (3 Н, s, OCH₃), 6.66 (2 Н, br s, NH₂ (Tf)), 6.90 (1 Н, br s, NH₂ (Py)), 6.91–6.93 (1 Н, m, Ar), 6.93–6.96 (1 Н, m, Ar), 7.50 (1 Н, d, ³ J = 5.0 Hz, Ar), 7.63 (1 Н, br s, NH₂ (Py)), 8.32 (1 Н, s, OH), 9.45 (1 Н, s, NH). ¹³C NMR (125.77 MHz, DMSO-d ₆): δ = 51.1, 85.7, 88.6, 105.7, 111.9, 124.9, 126.4, 127.0, 144.1, 147.7, 155.8, 156.4, 164.5, 165.0, 167.9. IR (mineral oil): 3653 (OH), 3441, 3284 (NH₂), 1685(C=O) cm^–1. MS (EI, 70 eV): m/z (%) = 377 (19) [М + 1]⁺, 376 (100) [М]⁺, 358 (17) [М – H₂O]⁺, 326 (49) [М – H₂O – CH₃OH]⁺, 325 (64) [М – H₂O – CH₃OH₂]⁺, 298 (68), 111 (28) [ArCO]⁺. Anal. Calcd for C₁₅H₁₂N₄O₄S₂: C, 47.86; H, 3.21; N, 14.88. Found: C, 47.68; H, 3.22; N, 14.85.