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Synlett 2020; 31(07): 691-694
DOI: 10.1055/s-0039-1691600
DOI: 10.1055/s-0039-1691600
letter
Advanced Catalyst-Free Pseudo-Six-Component Synthesis of Tetrahydrodipyrazolopyridines in Water by Using Ammonium Carbonate as an Ecofriendly Source of Nitrogen
We gratefully thank the Yazd University Research Council for financial support.Further Information
Publication History
Received: 16 October 2019
Accepted after revision: 04 January 2020
Publication Date:
04 February 2020 (online)
Abstract
This work describes an improved environmentally friendly method for the synthesis of tetrahydrodipyrazolopyridines (THDPPs) in water through a catalyst-free pseudo-six-component reaction of alkyl acetoacetates, hydrazine hydrate, and ammonium carbonate with an aldehyde in a mole ratio of 2:2:1:1 at room temperature. The ammonium carbonate serves as a green source of nitrogen for the central 1,4-dihydropyridine ring in the THDPPs. Methyl acetoacetate reacts faster than either ethyl or propyl acetoacetate in this method. The product precipitates during the reaction and is simply collected by filtration. Advantages of this environmentally benign method include no use of an organic solvent, no hazardous waste, rapid clean reactions, and excellent yields of products.
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- 21 Tetrahydrodipyrazolopyridines; General Procedure (NH4)2CO3 (2.0 mmol) was added to a stirred mixture of the appropriate aldehyde (2.0 mmol), alkyl acetoacetate (4.0 mmol), and hydrazine hydrate (4.0 mmol) in H2O (1.0 mL), and the mixture was stirred vigorously at r.t. for the appropriate time (Table 3). The precipitated product was separated by simple filtration. 4-(3,5-Dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridin-4-yl)phenol (Table [3], Entry 3) White solid; yield: 244.1 mg (92%); mp 267–269 °C (Lit.15 267–268 °C). FTIR (KBr): 3234 (overlapped NH and OH stretching), 2935 (CH stretching), 1600 cm–1 (C=N stretching). 1H NMR (400 MHz, DMSO-d 6): δ = 2.05 (s, 6 H, 2 CH3), 4.68 (s, 1 H, CH), 6.57 (d, J = 8 Hz, 2 H, Harom), 6.89 (d, J = 8 Hz, 2 H, ArH), 9.15 (s, OH), 11.52 (s, 3 H, 3 NH). 13C NMR (100 MHz, DMSO-d 6): δ = 10.35, 31.76, 104.51, 114.45, 128.25, 133.36, 139.75, 155.05, 161.05. 3,5-Dimethyl-4-(4-tolyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridine (Table [3], Entry 5) White solid: 245.8 mg (88%); mp 244–246 °C (Lit.15 244–246 °C). FTIR (KBr): 3170 (NH stretching), 2920 (CH stretching), 1610 (C=N stretching), 1520 (C=C aromatic), 1139 cm–1 (C–N stretching). 1H NMR (400 MHz, DMSO-d 6): δ = 2.1 (s, 6 H, 2 CH3), 2.20 (s, 3 H, p-CH3), 4.78 (s, 1 H, CH), 6.99–7.00 (m, 4 H, Harom), 11.25 (s, 3 H, 3 NH). 13C NMR (100 MHz, DMSO-d 6): δ = 10.85, 20.98, 32.85, 104.85, 127.82, 128.83, 134.70, 140.20, 140.75, 161.50. [4-(3,5-Dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridin-4-yl)phenyl]dimethylamine (Table [3], Entry 9) Yellow-orange solid: 299.1mg (97%); mp 250–252 °C. FTIR (KBr): 3514, 3168 (NH stretching), 2942 (CH stretching), 1608 (C=N stretching), 1520 (C=C arom), 1139 cm–1 (C–N stretching). 1H NMR (400 MHz, DMSO-d 6): δ = 2.26 (s, 6 H, 2 CH3), 2.91 (s, 6 H, 2 p-CH3), 4.9 (s, 1 H, CH), 6.75 (d, J = 8 Hz, 2 H, Harom), 7.3 (d, J = 8 Hz, 2 H, Harom), 11.54 (s, 3 H, 3 NH). 3,5-Dimethyl-4-(4-nitrophenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4′,3′-e]pyridine (Table [3], Entry 11) Cream solid: 291.7 mg (94%); mp 333–335 °C (Lit.15 >300 °C). FTIR (KBr): 3250 (NH stretching), 2985 (CH stretching), 1605 (C=N stretching), 1489 (overlapped asymm stretching NO2 with C=C arom), 1352 (NO2 symm stretching), 753 cm–1 (out-of-plane bending C–H, para-substituted). 1H NMR (400 MHz, DMSO-d 6): δ = 2.1 (s, 6 H, 2 CH3), 4.95 (s, 1 H, CH), 7.35 (d, J = 8 Hz, 2 H, Harom), 8.1 (d, J = 8 Hz, 2 H, Harom), 11.20 (s, 3 H, 3 NH). 13C NMR (100 MHz, DMSO-d 6): δ = 10.70, 33.40, 103.60, 123.40, 129.20, 140.20, 146.1, 152.25, 161.35.