Advanced Catalyst-Free Pseudo-Six-Component Synthesis of Tetrahydrodipyrazolopyridines in Water by Using Ammonium Carbonate as an Ecofriendly Source of Nitrogen

Fatemeh Tamaddon; Ali Khorram

doi:10.1055/s-0039-1691600

Synlett, Inhaltsverzeichnis

Synlett 2020; 31(07): 691-694
DOI: 10.1055/s-0039-1691600

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Advanced Catalyst-Free Pseudo-Six-Component Synthesis of Tetrahydrodipyrazolopyridines in Water by Using Ammonium Carbonate as an Ecofriendly Source of Nitrogen

Fatemeh Tamaddon∗

Department of Chemistry, Faculty of Science, Yazd University, Yazd 89195-741, Iran eMail: ftamaddon@yazd.ac.ir eMail: khorramali58@gmail.com

,

Ali Khorram

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Abstract

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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.

Keywords

dipyrazolopyridines - water-based synthesis - catalyst-free synthesis - multicomponent reaction - green chemistry - ammonium carbonate

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References and Notes

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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, H_arom), 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, H_arom), 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, H_arom), 7.3 (d, J = 8 Hz, 2 H, H_arom), 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, H_arom), 8.1 (d, J = 8 Hz, 2 H, H_arom), 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.