Synlett 2018; 29(02): 246-250
DOI: 10.1055/s-0036-1589115
letter
© Georg Thieme Verlag Stuttgart · New York

l-Phenylalanine Triflate as Organocatalyst for Divergent ­Approaches to Trisubstituted Hexahydroimidazo[1,2-a]pyridine and 1,4-Diazepane Derivatives

Jun Jiang
a  National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: [email protected]
b  Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
,
Miao Zhang
a  National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: [email protected]
,
Wen-Biao Wu
b  Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
,
Hai-Bo Lu
a  National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: [email protected]
b  Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
,
Yu-Long Shi
b  Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
,
Jian-Jun Li*
a  National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China   Email: [email protected]
b  Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
› Author Affiliations
We are grateful to the National Natural Science Foundation of China (No. 21776254 and 21406203) for financial support.
Further Information

Publication History

Received: 02 July 2017

Accepted after revision: 11 September 2017

Publication Date:
11 October 2017 (online)


Abstract

The convergent synthesis of two biologically significant classes of trisubstituted hexahydroimidazo[1,2-a]pyridine and 1,4-diazepane derivatives from readily available aromatic aldehydes, ketones, and ethane-1,2-diamine is reported. This protocol is promoted by the highly effective l-phenylalanine triflate catalyst through intermolecular annulation, and tolerates a variety of functional groups with excellent yields.

Supporting Information

 
  • References and Notes

    • 1a Deiters A. Martin SF. Chem. Rev. 2004; 104: 2199
    • 1b Zhao W. Chem. Rev. 2010; 110: 1706
    • 2a Cheng D. Croft L. Abdi M. Lightfoot A. Gallagher T. Org. Lett. 2007; 9: 5175
    • 2b Andrews MD. af Forselles K. Beaumont K. Galan SR. Glossop PA. Grenie M. Jessiman A. Kenyon AS. Lunn G. Maw G. Owen RM. Pryde DC. Roberts D. Tran TD. ACS Med. Chem. Lett. 2015; 6: 419
    • 2c Enguehard-Gueiffier CE. Fauvelle F. Debouzy JC. Peinnequin A. Thery I. Dabouis V. Gueiffier A. Eur. J. Pharm. Sci. 2005; 24: 219
    • 2d Hamdouchi C. de Blas J. del Prado M. Gruber J. Heinz BA. Vance L. J. Med. Chem. 1999; 42: 50
    • 2e Srivastava P. Pandey VC. Misra AP. Gupta P. Raj K. Bhaduri AP. Bioorg. Med. Chem. 1998; 6: 181
    • 2f Badawey E. Kappe T. Eur. J. Med. Chem. 1995; 30: 327
    • 2g Kaminski JJ. Doweyko AM. J. Med. Chem. 1997; 40: 427
    • 2h Gueiffier A. Mavel S. Lhassani M. Elhakmaoui A. Snoeck R. Andrei G. Chavignon O. Teulade J.-C. Witvrouw M. Balzarini J. De Clercq E. Chapat JP. J. Med. Chem. 1998; 41: 5108
  • 3 Okubo T. Yoshikawa R. Chaki S. Okuyama S. Nakazato A. Bioorg. Med. Chem. 2004; 12: 423
  • 4 Almirante L. Polo L. Mugnaini A. Provinciali E. Rugarli P. Biancotti A. Gamba A. Murmann W. J. Med. Chem. 1965; 8: 305
    • 5a Katritzky AR. Xu Y.-J. Tu H. J. Org. Chem. 2003; 68: 4935
    • 5b Hanson SM. Morlock EV. Satyshur KA. Czajkowski C. J. Med. Chem. 2008; 51: 7243
  • 6 Kukla MJ. Breslin HJ. J. Org. Chem. 1987; 52: 5046
  • 7 Márton-Merész M. Zára-Kaczián E. Boros S. Mátyus P. J. Heterocycl. Chem. 1997; 34: 1033
    • 8a Santra S. Bagdi AK. Majee A. Hajra A. Adv. Synth. Catal. 2013; 355: 1065
    • 8b Monir K. Bagdi AK. Ghosh M. Hajra A. Org. Lett. 2014; 16: 4630
    • 9a Bagdi AK. Rahman M. Santra S. Majee A. Hajra A. Adv. Synth. Catal. 2013; 355: 1741
    • 9b Mohan DC. Donthiri RR. Rao SN. Adimurthy S. Adv. Synth. Catal. 2013; 355: 2217
    • 9c Cai Z.-J. Wang S.-Y. Ji S.-J. Adv. Synth. Catal. 2013; 355: 2686
  • 10 Wang R.-L. Zhu P. Lu Y. Huang F.-P. Hui X.-P. Adv. Synth. Catal. 2013; 355: 87
    • 11a Li J. Lu L. Su W. Tetrahedron Lett. 2010; 51: 2434
    • 11b Ramalingan C. Park S.-J. Lee I.-S. Kwak Y.-W. Tetrahedron 2010; 66: 2987
  • 12 Li J. He P. Yu C. Tetrahedron 2012; 68: 4138
  • 13 Trisubstituted hexahydroimidazo[1,2-a] pyridines 4ar; General ProcedureThe appropriate aldehyde (1.0 mmol), ketone (2.5 mmol), H2N(CH2)2NH2 (1.0 mmol), and MeOH (5.0 mL) were mixed with LPAT (10 mol%), and the mixture was refluxed for 24 h. The solvent was evaporated and the residue was crystallized.5,7,8a-Triphenyl-1,2,3,7,8,8a-hexahydroimidazo[1,2-a]pyridine (4a)White solid; yield: 320.5 mg (91%); mp 133.5–134.5 °C. 1H NMR (400 MHz, CDCl3): δ = 7.68–7.61 (m, 4 H), 7.39–7.16 (m, 11 H), 4.97 (s, 1 H), 3.62–3.56 (m, 1 H), 3.18–3.05 (m, 2 H), 3.00–2.94 (m, 2 H), 2.45 (dd, J = 12.4, 5.6 Hz, 1 H), 2.17 (s, 1 H), 1.87 (t, J = 12.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 145.7, 145.4, 144.9, 139.7, 128.4, 128.3, 127.9, 127.4, 127.2, 126.2, 125.9, 107.5, 80.8, 52.5, 44.4, 41.8, 39.4. MS (ESI): m/z = 353.2 [M + 1]+.7-(3,4-Dimethylphenyl)-5,8a-diphenyl-1,2,3,7,8,8a-hexahydroimidazo[1,2-a]pyridine (4c)Pale-yellow solid; yield: 353.6 mg (93%); mp 122.8–123.6 °C. 1H NMR (400 MHz, CDCl3): δ = 7.64 (dd, J = 16.0, 7.2 Hz, 4 H), 7.38–7.27 (m, 6 H), 7.05–6.96 (m, 3 H), 4.96 (s, 1 H), 3.61–3.55 (m, 1 H), 3.17–3.04 (m, 2 H), 3.00–2.89 (m, 2 H), 2.42 (dd, J = 12.0, 5.6 Hz, 1 H), 2.24 (s, 3 H), 2.23 (s, 3 H), 2.13 (s, 1 H), 1.86 (t, J = 12.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 145.4, 145.0, 142.8, 139.7, 136.5, 134.4, 129.7, 128.8, 128.4, 128.2, 127.8, 127.4, 127.2, 126.0, 124.8, 108.1, 80.8, 52.5, 44.4, 41.7, 39.0, 20.1, 19.6. MS (ESI): m/z = 381.2 [M + 1]+. HRMS-ESI: m/z calcd for C27H29N2: 381.2325; found: 381.2345.
  • 14 Fujioka H. Murai K. Kubo O. Ohba Y. Kita Y. Org. Lett. 2007; 9: 1687
    • 15a Murai K. Nakatani R. Kita Y. Fujioka H. Tetrahedron 2008; 64: 11034
    • 15b Sotoca E. Allais C. Constantieux T. Rodriguez J. Org. Biomol. Chem. 2009; 7: 1911
    • 15c Lal M. Basha RS. Sarkar S. Khan AT. Tetrahedron Lett. 2013; 54: 4264
  • 16 1,4-Diazepane 6ah; General Procedure Aromatic aldehyde (1.0 mmol), ethyl acetoacetate (1.2 mmol), H2N(CH2)2NH2 (1.0 mmol), and toluene (5.0 mL) were mixed with LPAT (10 mol%), and the mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure to afford the crude compound, which was purified by flash chromatography (silica gel).Ethyl (2Z)-(7-Phenyl-1,4-diazepan-5-ylidene)acetate (6a)Yellow oil; yield: 161.2 mg (62%). 1H NMR (400 MHz, CDCl3): δ = 8.90 (br s, 1 H), 7.35–7.24 (m, 5 H), 4.45 (s, 1 H), 4.09 (q, J = 7.2 Hz, 2 H), 3.75 (d, J = 10.0 Hz, 1 H), 3.62–3.55 (m, 1 H), 3.42–3.35 (m, 1 H), 3.16 (dd, J = 12.8, 4.4 Hz, 1 H), 2.98–2.82 (m, 2 H), 2.34 (d, J = 14.4 Hz, 1 H), 1.93 (br s, 1 H), 1.25 (t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 170.6, 165.4, 145.0, 128.8, 127.7, 126.4, 82.5, 62.8, 58.7, 51.0, 46.5, 46.2, 14.9. MS (ESI): m/z = 261.0 [M + 1]+.
  • 17 CCDC 1422263 contains the supplementary crystallographic data for compound 4a. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.