The Guareschi–Thorpe Cyclization Revisited – An Efficient Synthesis of Substituted 2,6-Dihydroxypyridines and 2,6-Dichloropyridines

Abstract

DBU as base is key in a practical modified Guareschi–Thorpe cyclization of β-keto esters and 2-cyanoacetamide to allow the synthesis of substituted pyridones in good to excellent yields. The chlorination of DBU salts of pyridones with POCl₃ in the presence of a quaternary ammonium salt under standard atmospheric reflux conditions as opposed to the typical pressure equipment led to high yields of substituted 2,6-dichloropyridines.

Key words

fluoroalkyl compounds - β-keto esters - DBU - pyridines - chlorination - Guareschi–Thorpe cyclization

• References and Notes

• 1a Wu J.-P. Fleck R. Brickwood J. Capolino A. Catron K. Chen Z. Cywin C. Emeigh J. Foerst M. Ginn J. Hrapchak M. Hickey E. Hao M.-H. Kashem M. Li J. Liu W. Morwick T. Nelson R. Marshall D. Martin L. Nemoto P. Potocki I. Liuzzi M. Peet GW. Scouten E. Stefany D. Turner M. Weldon S. Zimmitti C. Spero D. Kelly TA. Bioorg. Med. Chem. Lett. 2009; 19: 5547
• 1b Ginn JD. Sorcek RJ. Turner MR. Young ER. R. US 0293533, 2007
• 2 A synthesis of deuterium- and C14-labelled 10b and 1 has been described, see: Latli B. Eriksson M. Hrapchak M. Busacca CA. Senanayake CH. J. Labelled Compd. Radiopharm. 2016; 549: 300
• 3 Jünemann W. Opgenorth H.-J. Scheuermann H. Angew. Chem., Int. Ed. Engl. 1980; 19: 388
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• 5a Guareschi I. Memorie Reale Accad. Sci. Torino II 1896; 46: 7
• 5b Guareschi I. Memorie Reale Accad. Sci. Torino II 1896; 46: 11
• 5c Guareschi I. Memorie Reale Accad. Sci. Torino II 1896; 46: 25

See also:
• 5d Guareschi I. Ber. Dtsch. Chem. Ges. 1896; 29: 654
• 5e Thole FB. Thorpe JF. J. Chem. Soc., Trans. 1911; 99: 422
• 5f Guareschi I. Atti R. Accad. Sci. Torino 1900; 36: 443
• 6 Representative Procedure for the Formation of Alkyl γ,γ-Difluoro β-Keto Esters 8 Sodium hydride (7.43 g, 60%, 1.25 equiv, 185.6 mmol) was charged to a 500 mL flask fitted with mechanic stirrer, thermocouple, reflux condenser, and nitrogen outlet. Tetrahydrofuran (150 mL) was added, and the mixture stirred at room temperature. Butyl 2,2-difluorobutyrate (7b, 30 g, 89.2 wt%, 1.0 equiv, 148.5 mmol) was followed by butyl acetate (26.4 mL, 200.5 mmol, 1.35 equiv) The resulting white slurry was stirred under nitrogen at 25 °C for 5 min and then at 40 °C for 6 h. GC analysis indicated 90% conversion. Additional sodium hydride (1.188 g, 60%, 0.2 equiv) and butyl acetate (5.87 mL, 200.5 mmol, 0.3 equiv) were added. GC analysis 1 h later showed full conversion. The reaction mixture was cooled to room temperature and quenched carefully with aq. NH₄Cl (150 mL) followed by conc. HCl (16.0 mL, 1.29 equiv) to adjust pH to 5–6. The layers were separated and the light yellow aqueous layer was extracted with EtOAc (100 mL). The combined red-orange organic layer (261.2 g, ca. 300 mL) was concentrated on Rotavapor at 60 °C to give an orange oil that was purified by fractional distillation under reduced pressure (bp 62–69 °C, 5 mmHg) to give 8b as a colorless oil (29.5 g, 89% yield). ¹H NMR indicated a mixture of about 1:1 of the keto ester and the enol ester. LC–MS (medium polar method), R _t = 1.08 min, MH⁺ (100%) = 223.0. ¹H NMR (500 MHz, CDCl₃): δ = 11.98 (s, 1 H), 5.50 (s, 1 H), 4.19 (t, J = 6.75 Hz, 2 H), 3.70 (s, 3 H), 2.01–2.18 (m, 2 H), 1.6–1.71 (m, 2 H), 1.32–1.45 (m, 2 H), 1.01 (t, J = 7.69 Hz, 3 H), 0.95 (t, J = 7.48 Hz, 2 H). ¹³C NMR (125 MHZ, CDCl₃): δ = 193.62, 172.30, 167.47 (m), 165.91, (121.26, 120.74), (118.84, 118.24), (116.43, 115.74), 90.33 (t, J = 5.21 Hz), (65.64, 64.82), 43.45, (30.63, 30.43), 27.99 (t, J = 25.4 Hz), 25.75 (t, J = 23.2 Hz), (19.09, 18.95), 13.62, 6.08 (t, J = 5.03 Hz), 5.39 (t, J = 5.51 Hz). ¹⁹F NMR (470 MHz, CDCl₃): δ: –108.23, –108.32.
• 7 Mišić-Vuković M. Radojković-Veličković M. J. Chem. Soc., Perkin Trans. 2 1992; 1965
• 8a Faty RA. M. Youssef AM. S. Curr. Org. Chem. 2009; 13: 1577
• 8b Sarkar TK. Panda N. Basak S. J. Org. Chem. 2003; 68: 6919
• 8c Portnoy S. J. Org. Chem. 1965; 30: 3377
• 8d Roch J. Muller E. Narr B. Nickl J. Haarmann W. DE 264375, 1978
• 8e Grozinger KG. Hargrave KD. Adams J. US 5200522, 1993
• 9a Bobbitt JM. Scola DA. J. Org. Chem. 1960; 25: 560
• 9b Stevens JR. Beutel RH. J. Am. Chem. Soc. 1943; 449
• 9c Ziener U. Breuning E. Lehn J.-M. Wegelius E. Rissanen K. Baum G. Fenske D. Vaughan G. Chem. Eur. J. 2000; 6: 4132
• 10 The predicted pKa for R = CH₃CF₂ and R = C₈H₁₇CF₂ is 8.95±0.46 according to SciFinder literature search. No predicted pKa for R = CH₃CH₂CF₂ is available but it is reasonable to expect that it would be similar.
• 11 Representative Procedure for the Cyclization of β-Keto Esters to Pyridine DBU Salts 9 Butyl 4,4-difluoro-3-ketohexanoate (8b, 11.3 g, 48.1 mmol) was added to a suspension of 2-cyanoacetamide (4.29 g, 50.5 mmol) in propanol (50 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 7.69 mL, 50.5 mmol) was added and the mixture heated at reflux for 20 h to afford a dark brown solution. The solution was concentrated on Rotavapor to an oil that was stirred at room temperature for 16 h with a ca. 20% propanol/methylcyclohexane (v/v) solution (60 mL) to afford 9b as a light brown solid in 87% yield (15.2 g); mp 133–135 °C. ¹H NMR (500 MHz, DMSO-d⁶): δ = 10.1 (br s, 1 H), 9.55 (br s, 1 H), 5.13 (s, 1 H), 3.52–3.58 (m, 2 H), 3.48 (t, J = 5.8 Hz, 2 H), 3.26 (t, J = 5.8 Hz, 2 H), 2.62–2.67 (m, 2 H), 2.08–2.23 (m, 2 H), 1.88–1.96 (m, 2 H), 1.56–1.72 (m, 6 H), 0.92 (t, J = 7.4 Hz, 3 H). ¹³C NMR (125 MHz, DMSO-d⁶); 165.6, 165.4, 164.3, 149.9 (t, J_C-F = 25 Hz), 122.4 (t, J_C-F = 243 Hz), 120.3, 96.03 (t, J_C-F = 8.0 Hz), 69.73, 53.40, 47.87, 37.62, 29.53 (t, J_C-F = 27 Hz), 28.22, 25.89, 23.29, 18.85, 6.53 (t, J_C-F = 5.0 Hz). ¹⁹F-NMR (470 MHz, DMSO-d⁶); –98.6.
• 12 Heravi MM. Tahershamsi L. Oskooie HA. Baghernejad B. Chin. J. Chem. 2010; 28: 670
• 13 Roch J. Muller E. Narr B. Nickl J. Haarmann W. DE 264375, 1978
• 14 Achmatowicz MM. Thiel OR. Colyer JT. Hu J. Elipe MV. S. Tomaskevitch J. Tedrow JS. Larsen RD. Org. Process Res. Dev. 2010; 14: 1490
• 15 Representative Procedure for the Chlorination of Pyridine DBU Salts to 2,6-Dichloropyridines 10 5-Cyano-4-(1,1-difluoro-propyl)-6-oxo-1,6-dihydropyridin-2-olate2,3,4,6,7,8,9,10-octahydro-pyrimido[1,2-a]azepin-5-ium (9b, 20.0 g, 54.6 mmol), benzyltrimethylammonium chloride (10.5 g, 54.6 mmol), and phosphorous oxychloride (30.8 mL, 327 mmol) were added to a 100 mL flask fitted with a stir bar and a reflux condenser connected to an argon bubbler. The mixture was stirred and heated in an oil bath (120 °C) for about 8 h and then cooled to 20–25 °C. The mixture was diluted with toluene (200 mL) and quenched by careful slow addition of water (200 mL), keeping internal temperature <40 °C. The two-layer mixture was stirred vigorously for about 20 min and the layers allowed to separate. The aqueous layer was drained and the small ‘rag’ layer was left with the organic layer. The organic layer was washed with dilute (4–5 wt%) aq. sodium carbonate (2 × 200 mL) followed by water (200 mL), leaving any ‘rag’ layer with the organic. The organic layer was filtered through Celite and the pad rinsed with toluene (40 mL). The filtrate was concentrated to dryness on a Rotavapor to afford 13.4 g (97%) light brown solid with 99.4 wt% purity. The solid was recrystallized from 2.5% n-propanol/methylcyclohexane (27 mL, v/v) to afford 11.4 g (83%) light tan solid with 99.9 wt% purity; mp 68–70 °C. ¹H NMR (DMSO-d⁶): δ = 7.98 (s, 1 H), 2.34 (m, 2 H), 1.03 (t, J = 7.4 Hz, 3 H). ¹³C NMR (DMSO-d⁶): δ = 153.7, 153.2, 152.1 (t, J_C-F = 28 Hz), 121.4 (t, J_C-F = 7 Hz), 120.9 (t, J_C-F = 246 Hz), 112.7, 106.0 (t, J_C-F = 3.5 Hz), 29.94 (t, J_C-F = 25 Hz), 5.84 (t, J_C-F = 5.0 Hz). ¹⁹F NMR (DMSO-d⁶); –97.2.