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Synlett 2015; 26(02): 228-232
DOI: 10.1055/s-0034-1379504
DOI: 10.1055/s-0034-1379504
letter
Synthesis of the Novel Tetrahydropyrazolo[3,4-c]pyridin-5-one Scaffold
Further Information
Publication History
Received: 09 October 2014
Accepted after revision: 30 October 2014
Publication Date:
02 December 2014 (online)
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Abstract
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.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0034-1379504.
- Supporting Information
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References and Notes
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- 2 ClogP values were calculated by using clogPv4.3 (Biobyte), see: Leo AJ. Chem. Rev. 1993; 93: 1281
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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
- 9a For transmetallation of ArMg species with CuCN·2LiCl, see: Krasovskiy A, Knochel P. Angew. Chem. Int. Ed. 2004; 43: 3333
- 9b For transmetallation of ArZn species with CuCN·2LiCl, see: Kneisel FF, Dochnahl M, Knochel P. Angew. Chem. Int. Ed. 2004; 43: 1017
- 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.
For examples, see:
For examples, see: