Palladium-Catalyzed Aerobic Oxidative Cyclization of Aliphatic Alkenyl Amides for the Construction of Pyrrolizidine and Indolizidine Derivatives

Published as part of the Cluster Catalytic Aerobic Oxidations

Abstract

An efficient palladium-catalyzed aerobic oxidative cyclization has been developed to synthesize a variety of pyrrolizidine and indolizidine derivatives from simple aliphatic alkenyl amides in moderate to good yields. The reaction features the capability of accessing various N-heterocycles and the use of molecular oxygen (1 atm) as the green oxidant.

Key words

palladium catalysis - aerobic oxidation - cascade cyclization - aminopalladation - N-heterocycles

• References and Notes


For selected reviews of transition-metal-catalyzed aerobic oxidation, see:
• 1a Punniyamurthy T. Velusamy S. Iqbal J. Chem. Rev. 2005; 105: 2329
• 1b Piera J. Bäckvall J.-E. Angew. Chem. Int. Ed. 2008; 47: 3506
• 1c Shi Z. Zhang C. Tang C. Jiao N. Chem. Soc. Rev. 2012; 41: 3381
• 1d McCann SD. Stahl SS. Acc. Chem. Res. 2015; 48: 1756

For selected reviews, see:
• 2a Stahl SS. Angew. Chem. Int. Ed. 2004; 43: 3400
• 2b Stahl SS. Science 2005; 309: 1824
• 2c Sigman MS. Jensen DR. Acc. Chem. Res. 2006; 39: 221
• 2d Gligorich KM. Sigman MS. Chem. Commun. 2009; 3854

For representative examples, see:
• 2e Nishimura T. Onoue T. Ohe K. Uemura S. J. Org. Chem. 1999; 64: 6750
• 2f Fix SR. Brice JL. Stahl SS. Angew. Chem. Int. Ed. 2002; 41: 164
• 2g Andappan MM. S. Nilsson P. Larhed M. Chem. Commun. 2004; 218
• 2h Mitsudome T. Umetani T. Nosaka N. Mori K. Mizugaki T. Ebitani K. Kaneda K. Angew. Chem. Int. Ed. 2006; 45: 481
• 2i Zhu J. Liu J. Ma R. Xie H. Li J. Jiang H. Wang W. Adv. Synth. Catal. 2009; 351: 1229
• 2j Campbell AN. White PB. Guzei IA. Stahl SS. J. Am. Chem. Soc. 2010; 132: 15116
• 2k Izawa Y. Pun D. Stahl SS. Science 2011; 333: 209
• 2l White PB. Jaworski JN. Zhu GH. Stahl SS. ACS Catal. 2016; 6: 3340

For selected reviews, see:
• 3a McDonald RI. Liu G. Stahl SS. Chem. Rev. 2011; 111: 2981

For representative examples, see:
• 3b Schultz MJ. Sigman MS. J. Am. Chem. Soc. 2006; 128: 1460
• 3c Zhu M.-K. Zhao J.-F. Loh T.-P. J. Am. Chem. Soc. 2010; 132: 6284
• 3d Scarborough CC. Stahl SS. Org. Lett. 2006; 8: 3251
• 3e Wang A. Jiang H. Chen H. J. Am. Chem. Soc. 2009; 131: 3846
• 3f Shi Z. Ding S. Cui Y. Jiao N. Angew. Chem. Int. Ed. 2009; 48: 7895
• 3g Ji X. Huang H. Wu W. Jiang H. J. Am. Chem. Soc. 2013; 135: 5286
• 3h Li J. Grubbs RH. Stoltz BM. Org. Lett. 2016; 18: 5449
• 4a Yip KT. Yang M. Law KL. Zhu NY. Yang D. J. Am. Chem. Soc. 2006; 128: 3130
• 4b Yip KT. Zhu NY. Yang D. Org. Lett. 2009; 11: 1911
• 4c He W. Yip KT. Zhu NY. Yang D. Org. Lett. 2009; 11: 5626
• 4d Yip KT. Yang D. Chem. Asian J. 2011; 6: 2166
• 4e Yip K.-T. Yang D. Org. Lett. 2011; 13: 2134
• 4f Xing D. Yang D. Org. Lett. 2013; 15: 4370
• 4g Du W. Gu Q. Li Z. Yang D. J. Am. Chem. Soc. 2015; 137: 1130
• 4h Ye L. Lo K.-Y. Gu Q. Yang D. Org. Lett. 2017; 19: 308
• 5a Larock RC. Hightower TR. Hasvold LA. Peterson KP. J. Org. Chem. 1996; 61: 3584
• 5b Cacchi S. Fabrizi G. Chem. Rev. 2005; 105: 2873

The pK_aof the anilido proton is about 21.5, see:
• 6a Bordwell FG. Ji GZ. J. Am. Chem. Soc. 1991; 113: 8398

The pK _αof the aliphatic amide proton is about 26.5; see:
• 6b Bordwell FG. Fried HE. J. Org. Chem. 1991; 56: 4218
• 7a Ramalingan C. Takenaka K. Sasai H. Tetrahedron 2011; 67: 2889
• 7b Du W. Gu Q. Li Y. Lin Z. Yang D. Org. Lett. 2017; 19: 316
• 8 Jung ME. Piizzi G. Chem. Rev. 2005; 105: 1735
• 9 Romanelli MN. Galeotti N. Ghelardini C. Manetti D. Martini E. Gualtieri F. CNS Drug Reviews 2006; 12: 39

For examples of cis-aminopalladation, see:
• 10a Negishi E.-I. Handbook of Organopalladium Chemistry for Organic Synthesis. Wiley; New York: 2002
• 10b Kočovsy P. Bäckvall J.-E. Chem. Eur. J. 2015; 21: 36
• 10c Neukom JD. Perch NS. Wolfe JP. J. Am. Chem. Soc. 2010; 132: 6276
• 10d Neukom JD. Perch NS. Wolfe JP. Organometallics 2011; 30: 1269
• 10e Liu G. Stahl SS. J. Am. Chem. Soc. 2007; 129: 6328
• 10f Mai DN. Wolfe JP. J. Am. Chem. Soc. 2010; 132: 12157

For examples of trans-aminopalladation, see:
• 11a Weinstein AB. Stahl SS. Angew. Chem. Int. Ed. 2012; 51: 11505
• 11b Mai DN. Wolfe JP. J. Am. Chem. Soc. 2006; 128: 2893
• 12a Konnick MM. Gandhi BA. Guzei IA. Stahl SS. Angew. Chem. Int. Ed. 2006; 45: 2904
• 12b Popp BV. Stahl SS. J. Am. Chem. Soc. 2007; 129: 4410
• 12c Popp BV. Stahl SS. Chem. Eur. J. 2009; 15: 2915
• 13 General Procedure To a well-stirred solution of Pd(TFA)₂(33.2 mg, 0.1 mmol) in toluene (5 mL) were added pyridine (32.3 μL, 0.4 mmol) and DABCO (44.9 mg, 0.4 mmol). The mixture was stirred continuously until the solid dissolved. The reaction solution was oxygenated for 15 min, then amide 1a (139.2 mg, 1.0 mmol) and toluene (5 mL) were added. The resulting solution was stirred under an O₂ atmosphere for 15 min, then heated at 95 °C with an air condenser under an O₂ atmosphere for 21 h. The reaction mixture was filtered through a short pad of Celite, then concentrated in vacuo. The residue was purified by flash column chromatography to afford 2a (101.5 mg, 0.74 mmol, 74% yield) as a yellow oil. 2-Methylenehexahydro-3H-pyrrolizin-3-one (2a) Yellow liquid; analytical TLC (silica gel 60), 50% EtOAc in n-hexane, R _f = 0.18. ¹H NMR (400 MHz, CDCl₃): δ = 5.93 (t, J = 2.7 Hz, 1 H), 5.28 (t, J = 2.2 Hz, 1 H), 3.77 (tt, J = 7.2, 4.9 Hz, 1 H), 3.67 (dt, J = 12.0 Hz, 8.1 Hz, 1 H), 3.21 (ddd, J = 12.3, 9.6, 3.0 Hz, 1 H), 3.00 (ddt , J = 17.0 Hz, 7.4 Hz, 2.1 Hz, 1 H), 2.50 (ddd, J = 17.0 Hz, 7.4 Hz, 3.1 Hz, 1 H), 2.26–1.93 (m, 3 H), 1.30–1.21 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.3 (C), 143.0 (C), 115.2 (CH₂), 58.5 (CH), 41.4 (CH₂), 31.9 (CH₂), 31.4 (CH₂), 25.9 (CH₂); IR (CH₂Cl₂) 3048, 2981, 2888, 1692, 1659, 1445, 1244, 1208, 1156 cm^–1. LRMS (EI, 20 eV): m/z = 137 (100) [M⁺]. HRMS (EI): m/z calcd for C₈H₁₁NO [M⁺]: 137.0841; found: 137.0843.