Synthesis of 4,4′-Disubstituted and Spiro-tetrahydroquinolines via Photochemical Cyclization of Acrylanilides and the First Synthesis of (±)-trans-Vabicaserin

Abstract

The synthesis of vabicaserin analogues bearing a quaternary center or spiro substitution at the 4-position has been studied via a [6π]-acrylanilide cyclization employing flow photochemistry in a mesoscale and microfluidic flow photoreactor. The method is also used to synthesize 4,4′-disubstituted tetrahydroquinolines and, furthermore, enables the first synthesis of (±)-trans-vabicaserin.

Key words

flow photochemistry - photocyclization - electrocyclization - electrocyclic reactions - tetrahydroquinoline - vabicaserin

• References and Notes

• 1a Sridharan V, Suryavanshi PA, Menendez JC. Chem. Rev. 2011; 111: 7157
• 1b Katritzky AR, Rachwal S, Rachwal B. Tetrahedron 1996; 52: 15031
• 1c Nammalwar B, Bunce RA. Molecules 2014; 19: 204
• 2 Ferrari ML. A, Coelho PM. Z, Antunes CM. F. Tavares C. A. P, da Cunha AS. Bull. W.H.O. 2003; 81: 190
• 3 Imanishi S, Kimura T, Arita M. Cardiovasc. Drug Rev. 1991; 9: 223

For recent relevant examples, see:
• 4a Chu DT. W, Chen J, Zhang W, Li X, Song J, Wang B, Cong Q, James DR. US 20060128790, 2006 ; Chem. Abstr. 2006, 145, 62795
• 4b Frackenpohl J, Bojack G, Helmke H, Lehr S, Mueller T, Willms L, Dietrich H, Schmutzler D, Baltz R, Bickers U. WO 2015155154, 2015 ; Chem. Abstr. 2015, 163, 628222
• 4c Feng L, Huang M, Liu Y, Wu G, Yan S, Yun H, Zhou M. US 20120190677, 2012 ; Chem. Abstr. 2012, 157, 294945
• 5 Fauber BP, Gobbi A, Savy P, Burton B, Deng Y, Everett C, La H, Johnson AR, Lockey P, Norman M, Wong H. Bioorg. Med. Chem. Lett. 2015; 25: 4109
• 6 Homan KT, Larimore KM, Elkins JM, Szklarz M, Knapp S, Tesmer JJ. G. ACS Chem. Biol. 2015; 10: 310
• 7 Parmenon C, Guillard J, Caignard D.-H, Hennuyer N, Staels B, Audinot-Bouchez V, Boutin J.-A, Ktorza A, Dacquet C, Viaud-Massuard M.-C. Bioorg. Med. Chem. Lett. 2008; 18: 1617
• 8 Venier O, Pascal C, Braun A, Namane C, Mougenot P, Crespin O, Pacquet F, Mougenot C, Monseau C, Onofri B, Dadji-Faïhun R, Leger C, Ben-Hassine M, Van-Pham T, Ragot JL, Philippo C, Güssregen S, Engel C, Farjot G, Noah L, Maniani K, Nicolaï E. Bioorg. Med. Chem. Lett. 2011; 21: 2244
• 9 Dunlop J, Watts SW, Barrett JE, Coupet J, Harrison B, Mazandarani H, Nawoschik S, Pangalos MN, Ramamoorthy S, Schechter L, Smith D, Stack G, Zhang J, Zhang G, Rosenzweig-Lipson S. J. Pharm. Exp. Tech. 2011; 337: 673
• 10a Megati S, Bhansali S, Dehnhardt C, Deshmukh S, Fung P, Macewan M, Tinder RJ. WO 2009039362, 2009 ; Chem. Abstr. 2009, 150, 329853
• 10b Dragan V, McWilliams JC, Miller R, Sutherland K, Dillon JL, O'Brien MK. Org. Lett. 2013; 15: 2942
• 10c Dziechciejewski WJ, Weber R, Sowada O, Boysen MM. K. Org. Lett. 2015; 17: 4132

It is noteworthy, that the commonly employed approach, a Pd-catalyzed amidation of aryl halides, should allow the synthesis of dihydroquinolinones bearing a quarternary center in the 4-position if a suitable precursor is employed. Until now, this has not been shown. For the underlying chemistry, see:
• 11a Zhang L, Qureshi Z, Sonaglia L, Lautens M. Angew. Chem. Int. Ed. 2014; 53: 13850

For the synthesis of such precursors, the purposive Rh-based conjugate addition of ortho-halo-arylboronic acids onto β-substituted acrylamides, however, fails even if only a tertiary center is attempted, as stated in:
• 11b Zhang L, Sonaglia L, Stacey J, Lautens M. Org. Lett. 2013; 15: 2128 ; and references cited therein
• 12 Parmenon C, Guillard J, Caignard D.-H, Hennuyer N, Staels B, Audinot-Bouchez V, Boutin J.-A, Dacquet C, Ktorza A, Viaud-Massuard M.-C. Bioorg. Med. Chem. Lett. 2008; 18: 1617
• 13 Bunce RA, Cain NR, Cooper JG. Org. Prep. Proced. Int. 2013; 45: 28
• 14a Pereira J, Barlier M, Guillou C. Org. Lett. 2007; 9: 3101
• 14b Koolman HF, Braje WM, Mack H, Haupt A, Relo AL, Drescher K, Bakker MH. M, Lakics V, Hoft C, Xu R, Zhao X. WO 2014041131, 2014 ; Chem. Abstr. 2014, 160, 457941
• 15 Dressel M, Bach T. Org. Lett. 2006; 8: 3145
• 16 Horn J, Li HY, Marsden SP, Nelson A, Shearer RJ, Campbell AJ, House D, Weingarten GG. Tetrahedron 2009; 65: 9002
• 17 Linsenmeier AM, Braje WM. Tetrahedron 2015; 71: 6913
• 18a Povarov LS. Russ. Chem. Rev. 1967; 36: 656
• 18b Xie M, Liu X, Zhu Y, Zhao X, Xia Y, Lin L, Feng X. Chem. Eur. J. 2011; 17: 13800
• 19 Pigge FC, Fang S, Rath NP. Tetrahedron Lett. 1999; 40: 2251
• 20a For a general review, see: Laarhoven WH. Org. Photochem. 1989; 10: 163
• 20b Barbera C, Garcia H, Miranda MA, Primo J. An. Quim. 1995; 91: 95
• 20c Bach T, Grosch B, Strassner T, Herdtweck E. J. Org. Chem. 2003; 68: 1107
• 21 The pharmacologic activities and the relevance of the final compounds presented herein will be published elsewhere.
• 22 Typical Procedure for the Preparation of tert-Butyl 8,8-Dimethyl-6-oxo-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate (10) A degassed solution of 0.33 g (1.0 mmol) of tert-butyl 1-(3-methylbut-2-enoyl)-2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate (9) in acetone (20 mL), 0.05 M) was continuously irradiated with a 150 W Hg lamp in a mesoscale photochemical flow reactor (5 mL reactor volume, FEP-tubing) equipped with a Pyrex^® filter at 10–15 °C until completion of the reaction monitored by liquid chromatography. The solution was concentrated in vacuo, and the residue was directly purified by column chromatography on silica (eluent: 10–30% EtOAc in heptane) to yield 202 mg (61%) of 10 as a beige solid. ESI-MS: m/z (%) = 275 (80) [M – C₄H₉ + 2H]⁺, 331 (20) [M + H]⁺. ¹H NMR (500 MHz, CDCl₃): δ = 7.23–7.15 (m, 1 H), 7.13–6.99 (m, 2 H), 4.68 (s, 1 H), 4.54 (s, 1 H), 4.18–4.09 (m, 2 H), 3.82–3.66 (m, 2 H), 2.43 (d, J = 8.8 Hz, 2 H), 1.41 (s, 6 H), 1.27 (s, 9 H).

For a review on effective space time yields (STY_eff) to compare efficiencies of reactors with different geometries see:
• 23a Shvydkiv O, Yavorskyy A, Tan SB, Nolan K, Hoffmann N, Youssef A, Oelgemöller M. Photochem. Photobiol. Sci. 2011; 10: 1399
• 23b The flow reaction (Table 1, entry 6) has a STY_eff = 0.21 mmol L^–1 min^–1 (based on a 5 mL volume), whereas the batch reaction (Table 1, entry 7) has a STY_eff = 7.1·10^–3 mmol L^–1 min^–1 (based on a 250 mL volume) and is thus considered less efficient.
• 24 Vasudevan A, Villamil C, Trumbull J, Olson J, Sutherland D, Pan J, Djuric S. Tetrahedron Lett. 2010; 51: 4007
• 25 For example via a known Pictet–Spengler-type cyclization, see: Neelamegam R, Hellenbrand T, Schroeder FA, Wang C, Hooker JM. J. Med. Chem. 2014; 57: 1488
• 26 The [6π]-acrylanilide cyclization of dimethylphenyl-acrylamide is known and described in ref. 20b but the yield reported therein is elusive.
• 27 Acetone has a UV cutoff of ca. 330 nm (although this effect is diminished in a microfluidic setup with very short path lengths), see: Reichardt C. Solvents and Solvent Effects in Organic Chemistry . Wiley-VCH; Weinheim: 2003. 3rd ed., 482
• 28 See ref. 24 for the setup of the flow cell.