Synthesis of the Novel Tetrahydropyrazolo[3,4-c]pyridin-5-one Scaffold

We report an efficient synthesis of the novel 1,4,6,7-tetrahydropyrazolo[3,4-c]pyridin-5-one scaffold with the potential for incorporation of alkyl or aryl substituents at the C-3 and N-6 positions. The route utilises a Dieckmann condensation to install the lactam ring, followed by a hydrazine cyclisation to build the fused pyrazole ring.

Key words

pyrazole - lactam - Dieckmann condensation - hydrazine

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References

References and Notes

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8 Wang Y, Przyuski K, Roemmele RC, Hudkins RL, Bakale RP. Org. Process Res. Dev. 2013; 17: 846 ; Pd-catalysed coupling gave the desired γ-keto ester in 63% yield (Scheme 4); however, on 10-fold scale-up to 13 mmol, the yield dropped to 39%. We were unable to obtain a robust, scalable procedure by using this methodology

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10 Shi L, Chu Y, Knochel P, Mayr H. J. Org. Chem. 2009; 74: 2760 ; In this paper, they report that 50% Br–Mg exchange with i-PrMgCl·LiCl at 0 °C occurs in 2.3 min for 3-bromobenzonitrile, 1.9 days for bromobenzene and 2.4 days for 4-bromotoluene
11 For conditions for lactam N-alkylation and N-arylation, see Ref. 6. For the conversion of silyl-protected lactams into N-alkyl cyclic imines, see: Hua DH, Miao SW, Bharathi SN, Katsuhira T, Bravo AA. J. Org. Chem. 1990; 55: 3682
12 Formation of γ-Keto Esters; Typical Procedure for Ethyl 4-Oxo-4-phenylbutanoate(9a): A multi-necked round-bottomed flask was dried with a hot-air gun under vacuum and then purged with nitrogen and cooled. To this flask was added (3-ethoxy-3-oxopropyl)zinc(II) bromide (0.5 M in THF, 7.50 mL, 3.75 mmol), which was cooled to –15 °C under nitrogen. Benzoyl chloride (0.419 mL, 3.57 mmol) was added followed by copper(I) dilithium dichloride cyanide (1 M in THF, 3.75 mL, 3.75 mmol). The reaction mixture was warmed to r.t. and stirred at this temperature for 3 h. The reaction was quenched by addition of sat. aq NH₄Cl (80 mL) and filtered. The filtrate was extracted with EtOAc (2 × 50 mL) and the combined organics were washed with brine (40 mL), dried (MgSO₄), filtered, and concentrated under vacuum to afford an orange oil (900 mg). The crude product was purified by flash silica chromatography (EtOAc–heptane, 0 to 30%). Pure fractions were evaporated to dryness to afford ethyl 4-oxo-4-phenylbutanoate (0.53 g, 71%) as a colourless liquid. ¹H NMR (400 MHz, CDCl₃): δ = 1.26 (t, J = 7.2 Hz, 3 H), 2.76 (t, J = 6.7 Hz, 2 H), 3.31 (t, J = 6.7 Hz, 2 H), 4.16 (q, J = 7.1 Hz, 2 H), 7.43–7.50 (m, 2 H), 7.53–7.60 (m, 1 H), 7.95–8.01 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 14.2, 28.4, 33.4, 60.6, 128.1, 128.6, 133.2, 136.7, 172.9, 198.1. HRMS: m/z calcd for C₁₂H₁₄O₃: 206.0943; found: 206.0926.Methyl 4-(3-Cyanophenyl)-4-oxobutanoate(9c): To dried glassware was added 3-bromobenzonitrile (400 mg, 2.20 mmol) in anhydrous THF (5 mL) under nitrogen. This was cooled to –10 °C and isopropylmagnesium lithium chloride (1.3 M in THF, 2.54 mL, 3.30 mmol) was added over 10 min. The mixture was stirred at 0 °C for 3 h, monitoring for completion of magnesiation by LC-MS of NH₄Cl solution-quenched aliquots. Transmetallation was carried out by addition of copper(I) dilithium dichloride cyanide (1 M in THF, 3.74 mL, 3.74 mmol) at 0 °C, with stirring at this temperature for 10 min and then the mixture was cooled to –50 °C under nitrogen and methyl 4-chloro-4-oxobutanoate (0.418 mL, 3.30 mmol) in anhydrous THF (2 mL) was added. The reaction was stirred at –50 °C for 10 min and then warmed to r.t. gradually overnight. The reaction mixture was quenched by addition of sat. aq NH₄Cl (30 mL) and then extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with water (20 mL), brine (20 mL), dried (MgSO₄), filtered and concentrated under vacuum to afford a brown oil (1.0 g). The crude product was purified by flash silica chromatography (EtOAc–heptane, 0 to 100%). Pure fractions were evaporated to dryness to afford methyl 4-(3-cyanophenyl)-4-oxobutanoate (395 mg, 84%) as a white foamy solid. ¹H NMR (400 MHz, CDCl₃): δ = 2.80 (t, J = 6.5 Hz, 2 H), 3.30 (t, J = 6.5 Hz, 2 H), 3.71 (s, 3 H), 7.59–7.65 (m, 1 H), 7.85 (dt, J = 7.7, 1.4 Hz, 1 H), 8.20 (dt, J = 7.9, 1.4 Hz, 1 H), 8.24–8.28 (m, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 27.9, 33.5, 51.9, 113.4, 117.9, 129.7, 131.8, 132.0, 136.1, 137.4, 173.0, 196.1. HRMS: m/z calcd for C₁₂H₁₁NO₃: 217.0739; found: 217.0753.
13 Dieckmann Condensation and Subsequent Hydrazine Cyclisation; Typical Procedure for 3-Phenyl-6-propyl-6,7-di-hydro-1H-pyrazolo[3,4-c]pyridin-5(4H)-one (8e): (i) Lithium bis(trimethylsilyl)amide (1 M in THF, 1.46 mL, 1.46 mmol) was added to a solution of methyl 2-(4-oxo-4-phenyl-N-propylbutanamido)acetate (386 mg, 1.32 mmol) in anhydrous THF (4 mL) under nitrogen. The reaction mixture was heated at reflux for 30 min. After cooling to r.t., the reaction was diluted with 1 M citric acid (20 mL) and CH₂Cl₂ (50 mL). The organics were washed with brine (50 mL), dried (MgSO₄), filtered, and the crude product was purified by flash silica chromatography (MeOH–CH₂Cl₂, 0 to 8%). Pure fractions were evaporated to dryness to afford 4-benzoyl-5-hydroxy-1-propyl-1,6-dihydropyridin-2(3H)-one (13e; 272 mg, 79%) as a pale-yellow oil, which solidified on standing. (ii) Hydrazine hydrate (0.097 mL, 2.01 mmol) was added to a solution of 4-benzoyl-5-hydroxy-1-propyl-1,6-dihydropyridin-2(3H)-one (260 mg, 1.00 mmol) in ethanol (5 mL). The reaction was heated to reflux for 24 h. After cooling to r.t., the solvent was removed under vacuum to afford a pale-brown solid, which was triturated with EtOAc–Et₂O (1:1), filtered, and dried to afford 3-phenyl-6-propyl-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-5(4H)-one (213 mg, 83%) as a beige powder. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.88 (t, J = 7.4 Hz, 3 H), 1.53–1.67 (m, 2 H), 3.37–3.47 (m, 2 H), 3.62 (t, J = 1.9 Hz, 2 H), 4.54 (s, 2 H), 7.25–7.78 (m, 5 H), 13.17 (s, 1 H). ¹³C NMR (176 MHz, DMSO-d ₆ + CD₃CO₂D): δ = 11.0, 19.5, 29.8, 45.0, 48.5, 107.9, 125.7, 127.5, 128.8, 130.6, 139.2, 140.5, 166.5. HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₈N₃O: 256.1450; found: 256.1460.
14 For full experimental procedures and analytical data, please refer to the Supporting Information.

Supplementary Material

Supporting Information