Vinylogous Blaise Reaction: Conceptually New Synthesis of Pyridin-2-ones

Abstract

A conceptually new synthesis of pyridine rings by a [C₄ + CN] assembly has been developed by applying a vinylogous version of the classic Blaise reaction. The zinc-mediated reaction of (het)aryl or alkyl nitriles with ethyl-4-bromocrotonate provided a variety of C(6)-substituted pyridin-2-ones in a single-step.

Key words

vinylogous Blaise reaction - pyridinones - pyridine ring ­synthesis - zinc catalysis - bromoalkenoates

• References

• 1 Murugan R. Scriven EF. V. In Pyridines: From Lab to Production . Scriven EF. V. Academic Press; Oxford: 2013. Chap. 1
• 2 Anderson T. Justus Liebigs Ann. Chem. 1846; 60: 86
• 3 Pozharskiĭ AF. Soldatenkov AT. Katritzky AR. Heterocycles in Life and Society: An Introduction to Heterocyclic Chemistry, Biochemistry and Applications . Wiley; Chichester: 2011. 2nd ed
• 4 Hamama WS. Waly M. El-Hawary I. Zoorob HH. Synth. Commun. 2014; 44: 1730
• 5a Mitscher LA. Chem. Rev. 2005; 105: 559
• 5b Li Q. Mitscher LA. Shen LL. Med. Res. Rev. 2000; 20: 231
• 6a Wall ME. Wani MC. Cook CE. Palmer KH. McPhail AT. Sim GA. J. Am. Chem. Soc. 1966; 88: 3888
• 6b Ljungman M. Hanawalt PC. Carcinogenesis 1996; 17: 31
• 6c Efferth T. Fu Y.-J. Zu Y.-G. Schwarz G. Konkimalla VS. B. Wink M. Curr. Med. Chem. 2007; 14: 2024
• 7a Aly R. Katz HI. Kempers SE. Lookingbill DP. Lowe N. Menter A. Morman M. Savin RC. Wortzman M. Int. J. Dermatol. 2003; 42 (01) : 19
• 7b Niewerth M. Kunze D. Seibold M. Schaller M. Korting HC. Hube B. Antimicrob. Agents Chemother. 2003; 47: 1805
• 8 Tang X. Liu P. Li R. Jing Q. Lv J. Liu L. Liu Y. Basic Clin. Pharmacol. Toxicol. 2015; 117: 186
• 9a Litvinov VP. Krivokolysko SG. Dyachenko VD. Chem. Heterocycl. Compd. (Engl. Transl.) 1999; 35: 509
• 9b Mijin D. Ž. Ušćumlić GS. Valentić NV. Marinković AD. Hem. Ind. 2011; 65: 517 ;
• 10a Jessen HJ. Gademann K. Nat. Prod. Rep. 2010; 27: 1168
• 10b Wang S. Cao L. Shi H. Dong Y. Sun J. Yuefei H. Chem. Pharm. Bull. 2005; 53: 67
• 11 Rawson JM. Winpenny RE. P. Coord. Chem. Rev. 1995; 139: 313
• 12a Imase H. Noguchi K. Hirano M. Tanaka K. Org. Lett. 2008; 10: 3563
• 12b Zhang H. Chen B.-C. Wang B. Chao ST. Zhao R. Lim N. Balasubramanian B. Synthesis 2008; 1523
• 12c Smith AB. III. Atasoylu O. Beshore DC. Synlett 2009; 2643
• 12d Patel BH. Mason AM. Barrett AG. M. Org. Lett. 2011; 13: 5156
• 12e Mijin D. Ž. Marković JM. Brković DV. Marinković AD. Hem. Ind. 2014; 68: 1
• 13 Keller PA. Abdel-Hamid MK. Abdel-Megeed AM. Pyridines: From Lab to Production . Scriven EF. V. Academic Press; Oxford: ; Chap. 2; 15
• 14 Kröhnke F. Zecher W. Curtze J. Drechsler D. Pfleghar K. Schnalke KE. Weis W. Angew. Chem. Int. Ed. Engl. 1962; 1: 626
• 15a Guareschi I. Mem. Reale Accad. Sci. Torino II 1896; 46: 7,11,25
• 15b Guareschi I. Atti Accad. Sci. Torino 1900; 36: 443
• 15c Baron H. Remfry FG. P. Thorpe JF. J. Chem. Soc. Trans 1904; 85: 1726 ;
• 16 Hantzsch A. Justus Liebigs Ann. Chem. 1882; 215: 1
• 17 Chichibabin AE. Russ. J. Phys. Chem. 1905; 37: 1229
• 18 Petrenko-Kritschenko P. J. Prakt. Chem. 1912; 85: 1
• 19a Blaise EE. C. R. Hebd. Seances Acad. Sci. 1901; 132: 478
• 19b Blaise EE. C. R. Hebd. Seances Acad. Sci. 1901; 132: 987
• 19c Blaise EE. Bull. Soc. Chim. Fr. 1906; 35: 589
• 19d For reviews, see: Rao HS. P. Rafi S. Padmavathy K. Tetrahedron 2008; 64: 8037
• 19e Kim JH. Ko YO. Bouffard J. Lee S.-g. Chem. Soc. Rev. 2015; 44: 2489
• 20 Rao HS. P. Muthanna N. Eur. J. Org. Chem. 2015; 1525
• 21 Rao HS. P. Muthanna N. Synlett. 2016; 27: 2014
• 22 Rao HS. P. Rafi S. Padmavathy K. Lett. Org. Chem. 2008; 5: 527
• 23 Detailed information on the optimization of the reaction conditions is given in Table 1 of the Supplementary Information.
• 24 Kröhnke F. Zecher W. Angew. Chem. 1962; 74: 811
• 25 Smith CL. Hirschhäuser C. Malcolm GK. Nasrallah DJ. Gallagher T. Synlett. 2014; 25: 1904
• 26a Arendt J. Rajaratnam SM. Br. J. Psychiatry 2008; 193: 267
• 26b Zlotos DP. Arch. Pharm. (Weinheim) 2005; 338: 229
• 27a Rice LE. Boston MC. Finklea HO. Suder BJ. Frazier JO. Hudlicky T. J. Org. Chem. 1984; 49: 1845
• 27b Fürstner A. Synthesis 1989; 571
• 28 Pyridin-2-ones 13a–m; General Procedure A solution of TMSCl (3 mol%) in anhyd 1,4-dioxane (1 mL) was added to a suspension of Zn dust (2 equiv) in anhyd 1,4-dioxane (3 mL), and the resulting suspension was refluxed with vigorous stirring for 25 min. The appropriate nitrile (2 mmol) in dry 1,4-dioxane (1 mL) and ethyl (E)-4-bromobut-2-enoate (12; 2 equiv) in dry 1,4-dioxane (1 mL) were simultaneously added dropwise to the refluxing suspension during 10 min by using two syringes. The resulting light-green mixture was refluxed until all the starting material was consumed and the color changed to brown (TLC; 3–6 h). The mixture was cooled to r.t. then centrifuged (700 rpm). The upper solution was decanted and the remaining solid was washed with 1,4-dioxane (4 × 1 mL). The 1,4-dioxane solutions were combined and concentrated to about 1 mL under reduced pressure in a rotatory evaporator. The residue was treated with 50% aq K₂CO₃ until the pH reached 13 (~5 mL). The resulting mixture was stirred for 30 min at r.t. (30 °C) then diluted with CH₂Cl₂ (10 mL) and H₂O (10 mL). The organic layer was separated, washed sequentially with H₂O (2 × 10 mL) and brine (10 mL), dried (Na₂SO₄), and evaporated under reduced pressure to give a crude product that was purified by column chromatography [silica gel (100–200 mesh); 15–60% EtOAc–hexane]. 6-Phenylpyridin-2(1H)-one (13a) By following the general procedure, the reaction of PhCN (5a; 201 mg, 1.94 mmol) with crotonate 12 (374 mg, 1.94 mmol) in the presence of Zn (252 mg, 3.88 mmol) and TMSCl (7 mg, 3 mol %) in 1,4-dioxane (6 mL) for 4 h, followed by hydrolysis with 50% aq K₂CO₃ (5 mL) gave a light-yellow solid; yield: 205 mg (62%); mp 194–195 °C; R_f = 0.5 (hexanes–EtOAc, 2:1). IR (KBr): 2904, 1643, 1612, 1550, 1493, 990, 921, 795, 761 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 12.49 (br s, 1 H), 7.72 (d, J = 6.9 Hz, 2 H), 7.59–7.40 (m, 4 H), 6.55–6.47 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.4, 147.1, 141.5, 133.6, 130.1, 129.2, 126.8, 118.7, 105.0. HRMS (ESI): m/z [M + H] calcd for C₁₁H₉NO: 172.0762; found: 172.0750.