Letter pubs.acs.org/OrgLett
Metal-Free Transamidation of Secondary Amides via Selective N−C Cleavage under Mild Conditions Yongmei Liu,‡,†,§ Shicheng Shi,†,§ Marcel Achtenhagen,†,∥ Ruzhang Liu,‡ and Michal Szostak*,† ‡
College of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Road, Yangzhou 225002, China Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
†
S Supporting Information *
ABSTRACT: Nonplanar, electronically destabilized amides have emerged as powerful intermediates in organic synthesis. We report a highly selective method for transamidation of common secondary amides under mild, metal-free conditions that relies on transient N-selective functionalization to weaken amidic resonance. The combination of rational modification of the amide bond with nucleophilic addition mechanism, and the thermodynamic collapse of the resultant tetrahedral intermediate constitutes a two-step procedure to accomplish a challenging transamidation of secondary amides under mild conditions.
D
eveloping methods for the controlled transamidation under mild conditions has become an important goal in organic synthesis.1,2 This broadly applicable process suffers from the high stability of the amide bond through amidic resonance3 and generally requires high temperatures. In contrast to relatively less challenging transamidation of primary amides,4 few methods for transamidation of secondary amides have been developed,5 including enzymatic catalysis.6 This reaction could potentially provide convenient access to a variety of functionalized amides7 and enable the direct conversion of ubiquitous secondary amides in peptides8 and synthetic polyamides.9 In 2016, a breakthrough study was reported by Garg and coworkers (Figure 1A)10 in which a novel two-step mechanism to generate an acyl-nickel intermediate11 catalytically from common secondary benzamides was envisioned. These authors elegantly demonstrated that upon selective N-activation of the amide bond (Figure 1A, Z = Boc),12 the resultant N-acyl-tertbutyl-carbamates undergo highly efficient N−C metal insertion/ cross-coupling. Significant progress has been made in the development of methods for the amide bond cross-coupling via acyl-metal intermediates.13,14 Meanwhile, we have been interested in structural and energetic factors that govern amide reactivity by resonance destabilization.15,16 These N-acyl-Boc-carbamates feature significantly destabilized amide bonds (e.g., Ar = Ph, R = Ph, RE = 7.2 kcal/mol; τ = 29.1°; χN = 8.4°).15a,17 Likewise, selective Nactivation of the amide bond to afford N-acyl-tosylamides (Z = Ts) has emerged as a common tactic to destabilize amidic resonance (e.g., Ar = Ph, R = Ph, RE = 9.7 kcal/mol; τ = 18.8°; χN = 18.9°).15a,13 Expanding upon this topic, we recently hypothesized that common acyclic amides might be directly employed in synthetically valuable transamidation reactions via the use of N-selective amide bond activation/destabilization platform. In contrast to metal-catalyzed cross-coupling of destabilized amides © 2017 American Chemical Society
Figure 1. (a) Ni-catalyzed transamidation of secondary amides (previous work). (b) Metal-free transamidation of secondary amides (this study).
by N−C scission,13,14 studies exploiting nucleophilic addition are noticeably lacking.18 Herein, we describe the successful realization of this strategy and report a highly selective method for transamidation of common secondary amides under mild, metal-free conditions that relies on transient N-selective functionalization of the amide bond to weaken amidic resonance (Figure 1B). Received: February 12, 2017 Published: March 14, 2017 1614
DOI: 10.1021/acs.orglett.7b00429 Org. Lett. 2017, 19, 1614−1617
Letter
Organic Letters
The scope with respect to the amide substitution is also very broad (Scheme 2). Electron-rich (3g) and electron-poor
The challenge in selective transamidation of secondary amides under mild conditions is 2-fold: (1) high energy barrier to nucleophilic addition due to resonance stabilization;2,3 (2) unfavorable thermodynamics of the transamidation process.1a As outlined in Figure 2, our general strategy to achieve trans-
Scheme 2. Metal-Free Transamidation of N-Boc-Activated 2° Amidesa
Figure 2. Proposed mechanism for metal-free transamidation of 2° amides. a
amidation of secondary amides involved site-selective Nactivation of the amide bond, followed by nucleophilic addition to afford tetrahedral intermediate (cf. acyl-metal intermediate in Figure 1A, ref 10). In such a scenario, the reaction is promoted thermodynamically by the properties of the leaving amine (Z = Boc, Ts),19 which is less nucleophilic than the amine participating in transamidation. The site-selective N-Boc activation of secondary amides (Boc2O, CH3CN, rt)10,14q renders these reactions synthetically useful. In addition, selective N-activation of secondary amides using TsCl (NaH, THF, 0 °C to rt) proceeds with high N-selectivity14f and offers a complementary activation method. We determined that transamidation of N-Boc activated secondary benzamide (Scheme 1) proceeds in excellent yield
See Scheme 1.
substituents (3h) on the aromatic ring had no impact on the reaction outcome (however, see mechanistic studies, Scheme 5). Notably, the reaction tolerates several substituents that would be problematic using nickel catalysis such as bromo (3i), ester (3j),20 and electron-rich five-membered heterocycles bearing the amide bond at the conjugating position (3k,l). Note that the presence of allyl N-amide substitution would also likely be problematic using metal catalysis. Pleasingly, the two-step activation/nucleophilic addition process is compatible with secondary anilide substrates14a (Scheme 3). These examples also include sensitive sterically hindered amines (3q) and substrates containing internal olefins (3p) that would likely isomerize under metal-catalysis. These
Scheme 1. Metal-Free Transamidation of N-Boc-Activated 2° Amidesa
Scheme 3. Metal-Free Transamidation of N-Boc-Activated 2° Amidesa
a
Conditions: amide (1.0 equiv), amine (3.0 equiv), Et3N (3.0 equiv), CH2Cl2 (1.0 M), 23 °C, 15 h. Isolated yields. b76% yield (amine, 1.2 equiv). cTHF (1.0 M), 80 °C.
at room temperature (Et3N, CH2Cl2, amine, 3.0 equiv). Amine stoichiometry could be decreased to 1.2 equiv with minimum decrease of the reaction efficiency (>90%, not shown). Among other solvents tested toluene, THF and CH3CN provided the transamidation product with similar efficiency. Importantly, the reaction accommodates simple alkyl (3a,b), allyl (3c), sterically hindered α-branched amines (3d), benzyl (3e), and secondary amines (3f). The reactions of α-branched and secondary amines were conducted at 80 °C in THF to afford optimum results.
a
See Scheme 1. b96% yield (amine, 1.2 equiv). c95% yield (amine, 1.2 equiv). 1615
DOI: 10.1021/acs.orglett.7b00429 Org. Lett. 2017, 19, 1614−1617
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Organic Letters mild conditions can also be readily applied to N-Ts-activated secondary amides (Scheme 4) to give the corresponding
consistent with amine nucleophilicity of the driving force for addition to the resonance weakened amide bond, as expected. In situ N-activation/transamidation is feasible (Scheme 6). This formal amide exchange highlights the synthetic potential of
Scheme 4. Metal-Free Transamidation of N-Ts-Activated 2° Amidesa
Scheme 6. In Situ N-Activation/Transamidation
the current method. Preliminary studies indicate that transamidation of aliphatic N-activated amides is also feasible (Scheme 7). Of note, transamidation of aliphatic amides under Scheme 7. Transamidation of Aliphatic Amides
a
Ni-catalysis represents a major challenge,10,14e pointing at the complementary substrate scope of these reactions of N-activated amides (vide infra). Moreover, it should be noted that while the substrate scope of the metal-free transamidation is broad, less nucleophilic amine substrates such as anilines are incompatible with the reaction conditions. In contrast, these substrates have been demonstrated as excellent nucleophiles in the Ni-catalyzed amide transamidation by Garg and co-workers.10 Table 1
See Scheme 1. b95% yield (amine, 1.2 equiv). cR = Me (86% yield).
transamidation products in high yields. At present, the yield using Et2NH is modest due to low conversions. Importantly, the activating group removal (N−Z cleavage), a common side reaction in metal catalyzed cross-coupling of these amides (i.e., deactivating scission of the alternative N−C or N−S bond),13 is not observed under these conditions. Studies have been carried out to gain preliminary insight into the reaction mechanism (Scheme 5). The presence of an
Table 1. Transamidation of N-Activated 2° Amides Using [Ni] Catalysis and Metal-Free Conditions [Boc], [Ts]
Scheme 5. Mechanistic Studies a
ref 10. bThis study. nd = not determined.
presents a summary of viable nucleophiles in Ni-catalyzed and metal-free transamidation of secondary N-activated amides. The successful transamidation of a range of secondary amides using these two methods highlights the efficiency of the amide bond resonance destabilization in organic synthesis using complementary reaction manifolds. In summary, amide bond destabilization has been leveraged for the development of a highly selective transamidation of common secondary amides under mild, metal-free conditions. This process relies on a transient N-selective functionalization of the amide bond to weaken amidic resonance. This protocol bears analogy to the Ni-catalyzed amide transamidation and is characterized by lower cost, operational-simplicity, and complementary reaction scope to the Ni-catalyzed transamidation. Given the challenges in transamidation of secondary amides, we anticipate that this mild, versatile method will find broad applications in organic synthesis. Studies directed toward expansion of the scope of this metal-free amide N−C bond functionalization are underway in our laboratories.
electron-withdrawing group on the aromatic ring favors transamidation (Scheme 5A), consistent with the relative electrophilicity of the amide bond. Moreover, O-nucleophiles such as alcohols (Scheme 5B) and water (not shown) are ineffective as nucleophiles under the developed conditions, resulting in recovery of the amide starting materials. This result is 1616
DOI: 10.1021/acs.orglett.7b00429 Org. Lett. 2017, 19, 1614−1617
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Organic Letters
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(13) Reviews on N−C amide cross-coupling: (a) Meng, G.; Shi, S.; Szostak, M. Synlett 2016, 27, 2530. (b) Liu, C.; Szostak, M. Chem. - Eur. J. 2017, DOI: 10.1002/chem.201605012. (c) Dander, J. E.; Garg, N. K. ACS Catal. 2017, 7, 1413. (14) (a) Hie, L.; Nathel, N. F. F.; Shah, T. K.; Baker, E. L.; Hong, X.; Yang, Y. F.; Liu, P.; Houk, K. N.; Garg, N. K. Nature 2015, 524, 79. (b) Weires, N. A.; Baker, E. L.; Garg, N. K. Nat. Chem. 2016, 8, 75. (c) Simmons, B. J.; Weires, N. A.; Dander, J. E.; Garg, N. K. ACS Catal. 2016, 6, 3176. (d) Dander, J. E.; Weires, N. A.; Garg, N. K. Org. Lett. 2016, 18, 3934. (e) Hie, L.; Baker, E. L.; Anthony, S. M.; Desrosiers, J. N.; Senanayake, C.; Garg, N. K. Angew. Chem., Int. Ed. 2016, 55, 15129. (f) Li, X.; Zou, G. Chem. Commun. 2015, 51, 5089. (g) Meng, G.; Szostak, M. Org. Lett. 2015, 17, 4364. (h) Meng, G.; Szostak, M. Org. Biomol. Chem. 2016, 14, 5690. (i) Shi, S.; Szostak, M. Chem. - Eur. J. 2016, 22, 10420. (j) Meng, G.; Szostak, M. Angew. Chem., Int. Ed. 2015, 54, 14518. (k) Shi, S.; Meng, G.; Szostak, M. Angew. Chem., Int. Ed. 2016, 55, 6959. (l) Meng, G.; Szostak, M. Org. Lett. 2016, 18, 796. (m) Meng, G.; Shi, S.; Szostak, M. ACS Catal. 2016, 6, 7335. (n) Shi, S.; Szostak, M. Org. Lett. 2016, 18, 5872. (o) Liu, C.; Meng, G.; Liu, Y.; Liu, R.; Lalancette, R.; Szostak, R.; Szostak, M. Org. Lett. 2016, 18, 4194. (p) Liu, C.; Meng, G.; Szostak, M. J. Org. Chem. 2016, 81, 12023. (q) Lei, P.; Meng, G.; Szostak, M. ACS Catal. 2017, 7, 1960. (r) Hu, J.; Zhao, Y.; Liu, J.; Zhang, Y.; Shi, Z. Angew. Chem., Int. Ed. 2016, 55, 8718. (s) Cui, M.; Wu, H.; Jian, J.; Wang, H.; Liu, C.; Daniel, S.; Zeng, Z. Chem. Commun. 2016, 52, 12076. (t) Wu, H.; Cui, M.; Jian, J.; Zheng, Z. Adv. Synth. Catal. 2016, 358, 3876. (u) Wu, H.; Liu, T.; Cui, M.; Li, Y.; Jian, J.; Wang, H.; Zeng, Z. Org. Biomol. Chem. 2017, 15, 536. (v) Dey, A.; Sasmai, S.; Seth, K.; Lahiri, G. K.; Maiti, D. ACS Catal. 2017, 7, 433. (w) Liu, L.; Chen, P.; Sun, Y.; Wu, Y.; Chen, S.; Zhu, J.; Zhao, Y. J. Org. Chem. 2016, 81, 11686. (15) (a) Szostak, R.; Shi, S.; Meng, G.; Lalancette, R.; Szostak, M. J. Org. Chem. 2016, 81, 8091. (b) Pace, V.; Holzer, W.; Meng, G.; Shi, S.; Lalancette, R.; Szostak, R.; Szostak, M. Chem. - Eur. J. 2016, 22, 14494. (c) Szostak, R.; Aubé, J.; Szostak, M. Chem. Commun. 2015, 51, 6395. (16) For seminal studies on amide bond destabilization, see: (a) Greenberg, A.; Venanzi, C. A. J. Am. Chem. Soc. 1993, 115, 6951. (b) Greenberg, A.; Moore, D. T.; DuBois, T. D. J. Am. Chem. Soc. 1996, 118, 8658. (c) Tani, K.; Stoltz, B. M. Nature 2006, 441, 731. (d) Kirby, A. J.; Komarov, I. V.; Wothers, P. D.; Feeder, N. Angew. Chem., Int. Ed. 1998, 37, 785. (17) Amide resonance energies have been calculated at the B3LYP/6311++G(d,p) level using the COSNAR method.16a This method has been found reliable in predicting resonance energies of destabilized amides. See, refs 15a, 15b, and 16a for details. (18) (a) Liu, Y.; Meng, G.; Liu, R.; Szostak, M. Chem. Commun. 2016, 52, 6841. (b) Liu, Y.; Liu, R.; Szostak, M. Org. Biomol. Chem. 2017, 15, 1780. (19) Mucsi, Z.; Chass, G. A.; Csizmadia, I. G. J. Phys. Chem. B 2008, 112, 7885. (20) (a) Hie, L.; Nathel, N. F. F.; Hong, X.; Yang, Y. F.; Houk, K. N.; Garg, N. K. Angew. Chem., Int. Ed. 2016, 55, 2810. (b) Pu, X.; Hu, J.; Zhao, Y.; Shi, Z. ACS Catal. 2016, 6, 6692.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00429. Experimental procedures and characterization data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Ruzhang Liu: 0000-0002-9569-2622 Michal Szostak: 0000-0002-9650-9690 Present Address ∥ Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States.
Author Contributions §
These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support was provided by Rutgers University. Y.L. is thankful for a scholarship from the National Natural Science Foundation of China (21472161) and the Priority Academic Program Development of Jiangsu Higher Education-Yangzhou University (BK2013016). M.A. thanks the Chemistry Department (Rutgers University) for a Summer Undergraduate Fellowship. The Bruker 500 MHz spectrometer used in this study was supported by the NSF-MRI grant (CHE-1229030).
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REFERENCES
(1) (a) Gonzalez-Rosende, M. E.; Castillo, E.; Lasri, J.; SepulvedaArques, J. Prog. React. Kinet. Mech. 2004, 29, 311. (b) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471. (c) Loomis, W. D.; Stumpf, P. K. Transamination and Transamidation. In Nitrogen Metabolism; Allen, E. K.; et al., Eds.; Springer: Heidelberg, 1958. (d) Ojeda-Porras, A.; Gamba-Sanchez, D. J. Org. Chem. 2016, 81, 11548. (2) Aubé, J. Angew. Chem., Int. Ed. 2012, 51, 3063. (3) Greenberg, A., Breneman, C. M., Liebman, J. F., Eds. The Amide Linkage: Structural Significance in Chemistry, Biochemistry, and Materials Science; Wiley: New York, 2000. (4) For leading examples of transamidation of primary amides, see: (a) Dineen, T. A.; Zajac, M. A.; Myers, A. G. J. Am. Chem. Soc. 2006, 128, 16406. (b) Allen, A. C.; Atkinson, B. N.; Williams, J. M. Angew. Chem., Int. Ed. 2012, 51, 1383. (5) (a) Bon, E.; Bigg, D. C. H.; Bertrand, G. J. Org. Chem. 1994, 59, 4035. (b) Eldred, S. E.; Stone, D. A.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 3422. (6) Sergeeva, M. V.; Mozhaev, V. V.; Rich, J. O.; Khmelnitsky, Y. L. Biotechnol. Lett. 2000, 22, 1419. (7) Trost, B. M.; Fleming, I. Comprehensive Organic Synthesis; Pergamon Press: Oxford, 1991. (8) Eisenberg, K. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 11207. (9) Marchildon, K. Macromol. React. Eng. 2011, 5, 22. (10) Baker, E. L.; Yamano, M. M.; Zhou, Y.; Anthony, S. M.; Garg, N. K. Nat. Commun. 2016, 7, 11554. (11) (a) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299. (b) Mesganaw, T.; Garg, N. K. Org. Process Res. Dev. 2013, 17, 29. (c) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A. M.; Garg, N. K.; Perec, V. Chem. Rev. 2011, 111, 1346. (12) Davidsen, S. K.; May, P. D.; Summers, J. B. J. Org. Chem. 1991, 56, 5482. 1617
DOI: 10.1021/acs.orglett.7b00429 Org. Lett. 2017, 19, 1614−1617
