Transamidation of N-Benzyl-N-Boc-amides under Transition Metal-Free and Base-Free Conditions

doi:10.6023/cjoc202009048

Abstract

A new protocol for the transamidation of N-benzyl-N-Boc-amides under transition metal-free and base-free conditions is described. The reaction features high reactivity of N-Boc-imides via direct acyl nucleophilic substitution mechanism, and provides access to a diverse array of substituted amides in good to excellent yields. Notably, the base-free condition preserves enantiopurity with respect to chiral amino-acid-derived nucleophiles, and N-Boc-amides bearing an epimerizable stereocenter. The application of this method is also demonstrated through the synthesis of pro-drugs and antidepressant moclobemide.

Key words: transamidation, N-benzyl-N-Boc-amides, transition metal-free, base-free

Cite this article

Danfeng Ye, Hao Chen, Zhiyuan Liu, Chuanhu Lei. Transamidation of N-Benzyl-N-Boc-amides under Transition Metal-Free and Base-Free Conditions[J]. Chinese Journal of Organic Chemistry, 2021, 41(4): 1658-1669.

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Fig. & Tab. 9

Scheme 1. Methods for the transamidation reaction

Entry	Cs₂CO₃/ equiv.	Solvent	T/℃	Conv./% of 1a^a	Yield^a/% of 3a
1	2.0	DMF	100	41	33
2	1.0	DMF	100	70	48
3	0.2	DMF	100	85	63
4	0	DMF	100	84	81
5	0	THF	Reflux	97	83
6	0	CH₃CN	Reflux	79	78
7	0	Ether	Reflux	93	81
8	0	DCM	Reflux	7	6
9	0	Toluene	100	91	91
10	0	Toluene	80	54	50
11	0	Toluene	Reflux	99	97 (90)^b
12^c	0	Toluene	Reflux	86	79

Table 1. Optimization of the transamidation of N-benzyl-N- Boc-amide (1a) with pyrrolidine 2a

Scheme 2. Effect of N-substituents on amides Reaction conditions: amide (0.1 mmol), 2a (0.15 mmol), and toluene (0.5 mL) were heated with stirring under reflux for 12 h. Yields of the transamidation reaction were determined by GC analysis using an internal standard (yields in parentheses refer to N-activated amide starting material recovered from the reaction mixtures)

Scheme 3. Amide products accessed via the transamidation of the corresponding N-benzyl-N-Boc-amides Reaction conditions: 1 (0.5 mmol), 2a (0.75 mmol), and toluene (2.5 mL) were heated with stirring under reflux for 12 h. Yields refer to isolated yields (the yields in parentheses refer to initial amides recovered in the reaction mixtures)

Scheme 4. Products obtained when N-benzyl-N-Boc-amide (1a) was subject to the present procedure using a variety of amines Reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), and toluene (2.5 mL) were heated with stirring under reflux for 12 h. Yields refer to isolated yield (the yields in parentheses refer to the amide 1a recovered in the reaction mixtures)

Scheme 5. Synthesis of moclobemide and post-transformation of drugs Yields refer to isolated yields after column chromatography

Scheme 6. Transamidation of enantioenriched amino esters and N-activated amides Reaction conditions: 1 (0.5 mmol), amine 4 or 2 (0.75 mmol), and toluene (2.5 mL) were heated with stirring under reflux for 12 h. Yields refer to isolated yields (yields in parentheses are the original N-activated amides recovered in the reaction mixtures). The enantiomeric excess (ee) was determined by HPLC analysis using a stationary phase chiral column

Scheme 7. Selectivity tests involving amide 1x that contains phenolic ester and an N-benzyl-N-Boc Reaction conditions: 1x (0.5 mmol), 2a (0.75 mmol), and toluene (2.5 mL) were heated with stirring under reflux for 12 h. Yields refer to isolated yields

Figure 1. Kinetic profile for test transamidations Reaction of 1a with pyrrolidine 2a(giving product 3a) and n-hexanamine 2k (giving product 3af) under the standard conditions of the present study (top), and reaction of 1a (R=H), 1d (R=4-MeC6H4) and 1n (R=4-NCC6H4) with pyrrolidine 2a at 90 ℃ (bottom)

References 50

[1]	(a) Greenberg, A.R.; Breneman, C.M.; Liebman, J.F. The Amide Linkage: Structural Significance in Chemistry, Biochemistry, and Materials Science, Wiley-VCH, New York, 2003.
	(b) Hua, X.; Liu, N.; Fan, Z.; Zong, G.; Ma, Y.; Lei, K.; Yin, H.; Wang, G. Chin. J. Org. Chem. 2019, 39,2581. (in Chinese)
	( 华学文, 刘南南, 范志金, 宗广宁, 马翼, 雷康, 殷昊, 王桂清, 有机化学, 2019, 39,2581.)
	(c) Zhong, L.; Jiang, T.; Zhang, F.; Fu, Q.; Liu, X.; Xu, T.; Ding, C.; Chen, J.; Yuan, J.; Tan, C. Chin. J. Org. Chem. 2019, 39,2655. (in Chinese)
	( 钟良坤, 江涛, 张帆, 付庆, 刘幸海, 许天明, 丁成荣, 陈杰, 袁静, 谭成侠, 有机化学, 2019, 39,2655.)
[2]	For reviews, see: (a) Allen, C. L; Williams, J. M. J. Chem. Soc. Rev. 2011, 40,3405. pmid: 27934465
	(b) Pattabiraman, V.R.; Bode, J.W. Nature 2011, 480,471. pmid: 27934465
	(c) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Chem. Soc. Rev. 2014, 43,2714. pmid: 27934465
	(d) Wan, J.-P.; Jing, Y. Beilstein J. Org. Chem. 2015, 11,2209. pmid: 27934465
	(e) de Figueiredo, R.M.; Suppo, J.-S.; Campagne, J.-M. Chem. Rev. 2016, 116,12029. doi: 10.1021/acs.chemrev.6b00237 pmid: 27934465
	(f) Ojeda-Porras, A.; Gamba-Sánchez, D. J. Org. Chem. 2016, 81,11548. pmid: 27934465
	For recent examples on the synthesis of amide, see: (g) Wang, Z.; Yang, L.; Liu, H.; Bao, W.; Tan, Y.; Wang, M.; Tang, Z.; He, W. Chin. J. Org. Chem. 2018, 38,2639. (in Chinese) pmid: 27934465
	( 王峥, 杨柳, 刘慧兰, 谭英芝, 包文虎, 汪明, 唐子龙, 何卫民, 有机化学, 2018, 38,2639.) pmid: 27934465
	(h) Xie, L.Y.; Peng, S.; Liu, F.; Yi, J.Y.; Wang, M.; Tang, Z.L.; Xu, X.H.; He, W.M. Adv. Synth. Catal. 2018, 360,4259. pmid: 27934465
	(i) Dissanayake, D. M., M.M.; Melville, A.D.; Vannucci, A.K. Green Chem. 2019, 21,3165. pmid: 27934465
	(j) Tu, Z.; Du, Y.; Cao, X.; Liu, Y. Adv. Synth. Catal. 2019, 361,4989. pmid: 27934465
	(k) Xie, L.-Y.; Hu, J.-L.; Song, Y.-X.; Jia, G.-K.; Lin, Y.-W.; He, J.-Y.; Cao, Z.; He, W.-M. ACS Sustainable Chem. Eng. 2019, 7,19993. pmid: 27934465
	(l) Yue, H.; Bao, P.; Wang, L.; Lü, X.; Yang, D.; Wang, H.; Wei, W. Chin. J. Org. Chem. 2019, 39,463. (in Chinese) pmid: 27934465
	( 岳会兰, 鲍鹏丽, 王雷雷, 吕晓霞, 杨道山, 王桦, 魏伟, 有机化学, 2019, 39,463.) pmid: 27934465
	(m) Sheng, R.; Li, P.; Zhou, Z.; Hu, G.; Zhang, X. Chin. J. Org. Chem. 2020, 40,462. (in Chinese) pmid: 27934465
	( 圣戎, 李萍, 周志强, 胡贵文, 张小祥, 有机化学, 2020, 40,462.) pmid: 27934465
[3]	(a) Lanigan, R.M.; Sheppard, T.D. Eur. J. Org. Chem. 2013,7453. pmid: 23473076
	(b) Zheng, J.-F.; Jin, L.-R.; Huang, P.-Q. Org. Lett. 2004, 6,1139. doi: 10.1021/ol049887k pmid: 23473076
	(c) Tyrrell, E.; Brawn, P.; Carew, M.; Greenwood, I. Tetrahedron Lett. 2011, 52,369. pmid: 23473076
	(d) Allen, C.L.; Atkinson, B.N.; Williams, J.M. J. Angew. Chem. Int. Ed. 2012, 51,1383. pmid: 23473076
	(e) Rao, S.N.; Mohan, D.C.; Adimurthy, S. Org. Lett. 2013, 15,1496. doi: 10.1021/ol4002625 pmid: 23473076
[4]	(a) Eldred, S.E.; Stone, D.A.; Gellman, S.H.; Stahl, S.S. J. Am. Chem. Soc. 2003, 125,3422. doi: 10.1021/ja028242h pmid: 12643691
	(b) Hoerter, J.M.; Otte, K.M.; Gellman, S.H.; Cui, Q.; Stahl, S.S. J. Am. Chem. Soc. 2008, 130,647. pmid: 12643691
[5]	Bon, E.; Bigg, D.C. H.; Bertrand, G. J. Org. Chem. 1994, 59,4035.
[6]	(a) Gotor, V.; Brieva, R.; González, C.; Rebolledo, F. Tetrahedron 1991, 47,9207.
	(b) Sergeeva, M.V.; Mozhaev, V.V.; Rich, J.O.; Khmelnitsky, Y.L. Biotechnol. Lett. 2000, 22,1419.
[7]	(a) Hie, L.; Fine Nathel, N.F.; Shah, T.K.; Baker, E.L.; Hong, X.; Yang, Y.-F.; Liu, P.; Houk, K.N.; Garg, N.K. Nature 2015, 524,79. pmid: 26673267
	(b) Weires, N.A.; Baker, E.L.; Garg, N.K. Nat. Chem. 2016, 8,75. doi: 10.1038/nchem.2388 pmid: 26673267
[8]	(a) Baker, E.L.; Yamano, M.M.; Zhou, Y.; Anthony, S.M.; Garg, N.K. Nat. Commun. 2016, 7,11554. doi: 10.1038/ncomms11554 pmid: 29163929
	(b) Dander, J.E.; Baker, E.L.; Garg, N.K. Chem. Sci. 2017, 8,6433. doi: 10.1039/c7sc01980g pmid: 29163929
[9]	(a) Meng, G.; Lei, P.; Szostak, M. Org. Lett. 2017, 19,2158. pmid: 28397498
	(b) Shi, S.; Szostak, M. Chem. Commun. 2017, 53,10584. pmid: 28397498
[10]	Li, G.; Szostak, M. Chem. Rec. 2020, 20,649. doi: 10.1002/tcr.201900072 pmid: 31833633
[11]	(a) Liu, Y.; Shi, S.; Achtenhagen, M.; Liu, R.; Szostak, M. Org. Lett. 2017, 19,1614. doi: 10.1021/acs.orglett.7b00429 pmid: 31203613
	(b) Li, G.; Szostak, M. Nat. Commun. 2018, 9,4165. pmid: 31203613
	(c) Liu, Y.; Achtenhagen, M.; Liu, R.; Szostak, M. Org. Biomol. Chem. 2018, 16,1322. pmid: 31203613
	(d) Li, G.; Ji, C.-L.; Hong, X.; Szostak, M. J. Am. Chem. Soc. 2019, 141,11161. doi: 10.1021/jacs.9b04136 pmid: 31203613
[12]	Guo, W.; Huang, J.; Wu, H.; Liu, T.; Luo, Z.; Jian, J.; Zeng, Z. Org. Chem. Front. 2018, 5,2950.
[13]	Verho, O.; Pourghasemi Lati, M.; Oschmann, M. J. Org. Chem. 2018, 83,4464.
[14]	Rahman, M.M.; Li, G.; Szostak, M. J. Org. Chem. 2019, 84,12091. pmid: 31430149
[15]	Ramkumar, R.; Chandrasekaran, S. Synthesis 2018, 51,921.
[16]	Other recent methods referring to the transamidation of amides (a) Cheung, C.W.; Ploeger, M. L.; Hu, X.; ACS Catal. 2017, 7,7092. pmid: 32298591
	(b) Cheung, C.W.; Ma, J.-A.; Hu, X. J. Am. Chem. Soc. 2018, 140,6789. doi: 10.1021/jacs.8b03739 pmid: 32298591
	(c) Mishra, A.; Singh, S.; Srivastava, V. Asian J. Org. Chem. 2018, 7,1600. pmid: 32298591
	(d) Ghosh, T.; Jana, S.; Dash, J. Org. Lett. 2019, 21,6690. pmid: 32298591
	(e) Sureshbabu, P.; Azeez, S.; Chaudhary, P.; Kandasamy, J. Org. Biomol. Chem. 2019, 17,845. doi: 10.1039/c8ob03010c pmid: 32298591
	(f) Chen, J.; Xia, Y.; Lee, S. Org. Lett. 2020, 22,3504. doi: 10.1021/acs.orglett.0c00958 pmid: 32298591
[17]	Ye, D.; Liu, Z.; Chen, H.; Sessler, J.L.; Lei, C. Org. Lett. 2019, 21,6888.
[18]	(a) Galli, C. Org. Prep. Proced. Int. 1992, 24,285. pmid: 11856006
	(b) Salvatore, R.N.; Nagle, A.S.; Jung, K.W. J. Org. Chem. 2002, 67,674. pmid: 11856006
[19]	(a) Meng, G.; Szostak, M. Angew. Chem., nt. Ed. 2015, 54,14518. pmid: 27304392
	(b) Meng, G.; Szostak, M. Org. Lett. 2015, 17,4364. doi: 10.1021/acs.orglett.5b02209 pmid: 27304392
	(c) Shi, S.; Meng, G.; Szostak, M. Angew. Chem., nt. Ed. 2016, 55,6959. pmid: 27304392
	(d) Shi, S.; Szostak, M. Chem.-Eur. J. 2016, 22,10420. pmid: 27304392
[20]	Graton, J.; Berthelot, M.; Laurence, C. J. Chem. Soc., erkin Trans. 2 2001,2130.
[21]	The pK_a of protonated N-methyl-4-methoxybenzylamine was 9.97 from website: http://ibond.nankai.edu.cn/pka/.
[22]	Bonnet, U. CNS Drug Rev. 2002, 8,283. pmid: 12353059
[23]	Dworkin, R.H.; Kirkpatrick, P. Nat. Rev. Drug Discovery 2005, 4,455. doi: 10.1038/nrd1756 pmid: 15959952
[24]	Sheraz, M.A.; Ahsan, S.F.; Khan, M.F.; Ahmed, S.; Ahmad, I. J. Pharm. 2016, 2016,8961621.
[25]	Bryans, J.S.; Williams, S.C.; Blakemore, D.C. EP 1178034, 2001.
[26]	(a) Yamada, S.; Hongo, C.; Yoshioka, R.; Chibata, I. J. Org. Chem. 1983, 48,843.
	(b) Harry, L.G.; Pugnière, M.; Castro, B.; Previero, A. Int. J. Peptide Prorein Res. 1993, 41,323.
	(c) Ramachandran, U.; Kumar, S.; Chawla, H.P. S. Org. Prep. Proced. Int. 2003, 35,616.
	(d) Wang, S.M.; Zhao, C.; Zhang, X.; Qin, H.L. Org. Biomol. Chem. 2019, 17,4087.
[27]	(a) Cheung, C.W.; Ploeger, M.L.; Hu, X. Nat. Commun. 2017, 8,14878. doi: 10.1038/ncomms14878 pmid: 28345585
	(b) Halima, T.B.; Masson-Makdissi, J.; Newman, S.G. Angew. Chem. Int. Ed. 2018, 57,12925. pmid: 28345585
[28]	(a) D, H.A.; Hang, Y. EP 20050713917, 2005. pmid: 16634594
	(b) Abergel, R.J.; Raymond, K.N. Inorg. Chem. 2006, 45,3622. pmid: 16634594
[29]	Kanzian, T.; Nigst, T.A.; Maier, A.; Pichl, S.; Mayr, H. Eur. J. Org. Chem. 2009,6379.
[30]	Fox, J.M.; Dmitrenko, O.; Liao, L.-a.; Bach, R.D. J. Org. Chem. 2004, 69,7317. doi: 10.1021/jo049494z pmid: 15471486
[31]	Adachi, S.; Kumagai, N.; Shibasaki, M. Tetrahedron Lett. 2018, 59,1147.
[32]	Kumar, V.; Connon, S.J. Chem. Commun. 2017, 53,10212.
[33]	Wang, X.-F.; Yu, S.-S.; Wang, C.; Xue, D.; Xiao, J. Org. Biomol. Chem. 2016, 14,7028. doi: 10.1039/c6ob00736h pmid: 27363514
[34]	Chardon, A.; Mohy El Dine, T.; Legay, R.; De Paolis, M.; Rouden, J.; Blanchet, J. Chem.-Eur. J. 2017, 23,2005. pmid: 27930832
[35]	Ning, X.-Q.; Lou, S.-J.; Mao, Y.-J.; Xu, Z.-Y.; Xu, D.-Q. Org. Lett. 2018, 20,2445. doi: 10.1021/acs.orglett.8b00793 pmid: 29634276
[36]	Zhang, B.; Feng, P.; Cui, Y.; Jiao, N. Chem. Commun. 2012, 48,7280.
[37]	Chaudhari, M.B.; Bisht, G.S.; Kumari, P.; Gnanaprakasam, B. Org. Biomol. Chem. 2016, 14,9215.
[38]	Mondal, A.; Subaramanian, M.; Nandakumar, A.; Balaraman, E. Org. Lett. 2018, 20,3381. doi: 10.1021/acs.orglett.8b01305 pmid: 29791162
[39]	Qian, C.; Zhang, X.; Zhang, Y.; Shen, Q. J. Organomet. Chem. 2010, 695,747.
[40]	Zhu, M.; Fujita, K.-i.; Yamaguchi, R. J. Org. Chem. 2012, 77,9102. doi: 10.1021/jo301553v pmid: 23006061
[41]	Sawant, D.N.; Bagal, D.B.; Ogawa, S.; Selvam, K.; Saito, S. Org. Lett. 2018, 20,4397. pmid: 30020789
[42]	Zhu, J.; Zhang, Y.; Shi, F.; Deng, Y. Tetrahedron Lett. 2012, 53,3178.
[43]	Soulard, V.; Villa, G.; Vollmar, D.P.; Renaud, P. J. Am. Chem. Soc. 2018, 140,155. doi: 10.1021/jacs.7b12105 pmid: 29240406
[44]	Zhao, Q.; Li, H.; Wang, L. Org. Biomol. Chem. 2013, 11,6772. pmid: 23999992
[45]	Hamada, S.; Sugimoto, K.; Iida, M.; Furuta, T. Tetrahedron Lett. 2019, 60,151277.
[46]	Rossi, S.A.; Shimkin, K.W.; Xu, Q.; Mori-Quiroz, L.M.; Watson, D.A. Org. Lett. 2013, 15,2314. doi: 10.1021/ol401004r pmid: 23611591
[47]	Yuan, Y.-C.; Kamaraj, R.; Bruneau, C.; Labasque, T.; Roisnel, T.; Gramage-Doria, R. Org. Lett. 2017, 19,6404. pmid: 29152976
[48]	Chernykh, A.V.; Melnykov, K.P.; Tolmacheva, N.A.; Kondratov, I.S.; Radchenko, D.S.; Daniliuc, C.G.; Volochnyuk, D.M.; Ryabukhin, S.V.; Kuchkovska, Y.O.; Grygorenko, O.O. J. Org. Chem. 2019, 84,8487. doi: 10.1021/acs.joc.9b00719 pmid: 30990713
[49]	Tran, B.L.; Li, B.; Driess, M.; Hartwig, J.F. J. Am. Chem. Soc. 2014, 136,2555. pmid: 24405209
[50]	Wang, Y.; Hu, X.; Morales-Rivera, C.A.; Li, G.-X.; Huang, X.; He, G.; Liu, P.; Chen, G. J. Am. Chem. Soc. 2018, 140,9678. doi: 10.1021/jacs.8b05753 pmid: 29983059

无过渡金属及无碱参与的N-苄基-N-叔丁基羰基酰胺的转酰胺化