Metal-Free Transamidation of Secondary Amides via Selective N-C Cleavage under Mild Conditions

Article abstract of DOI:10.1021/acs.orglett.7b00429

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.

Full text of DOI:10.1021/acs.orglett.7b00429

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.
eveloping methods for the controlled transamidation
Dunder 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 co-
workers (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-tert-
butyl-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
Figure 1. (a) Ni-catalyzed transamidation of secondary amides
(previous work). (b) Metal-free transamidation of secondary amides
(this study).
Meanwhile, we have been interested in structural and energetic
factors that govern amide reactivity by resonance destabiliza-
tion.15,16 These N-acyl-Boc-carbamates feature significantly
destabilized amide bonds (e.g., Ar = Ph, R = Ph, RE = 7.2
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).
kcal/mol; τ = 29.1°; χN = 8.4°).15a,17 Likewise, selective N-
activation 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
Received: February 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00429
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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-
The scope with respect to the amide substitution is also very
broad (Scheme 2). Electron-rich (3g) and electron-poor
Scheme 2. Metal-Free Transamidation of N-Boc-Activated 2°
a
Amides
Figure 2. Proposed mechanism for metal-free transamidation of 2°
amides.
a
See Scheme 1.
amidation of secondary amides involved site-selective N-
activation 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.
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
We determined that transamidation of N-Boc activated
secondary benzamide (Scheme 1) proceeds in excellent yield
Scheme 1. Metal-Free Transamidation of N-Boc-Activated 2°
a
Amides
Scheme 3. Metal-Free Transamidation of N-Boc-Activated 2°
a
Amides
a
Conditions: amide (1.0 equiv), amine (3.0 equiv), Et3N (3.0 equiv),
b
CH2Cl2 (1.0 M), 23 °C, 15 h. Isolated yields. 76% yield (amine, 1.2
equiv). THF (1.0 M), 80 °C.
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
b
c
See Scheme 1. 96% yield (amine, 1.2 equiv). 95% yield (amine, 1.2
equiv).
B
DOI: 10.1021/acs.orglett.7b00429
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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°
a
Amides
Scheme 6. In Situ N-Activation/Transamidation
the current method. Preliminary studies indicate that trans-
amidation of aliphatic N-activated amides is also feasible
(Scheme 7). Of note, transamidation of aliphatic amides under
Scheme 7. Transamidation of Aliphatic Amides
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
a
b
c
See Scheme 1. 95% yield (amine, 1.2 equiv). R = 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.
Table 1. Transamidation of N-Activated 2° Amides Using [Ni]
Catalysis and Metal-Free Conditions [Boc], [Ts]
Studies have been carried out to gain preliminary insight into
the reaction mechanism (Scheme 5). The presence of an
Scheme 5. Mechanistic Studies
a
b
ref 10. This 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 comple-
mentary 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 comple-
mentary 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
C
DOI: 10.1021/acs.orglett.7b00429
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(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.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
■
S
ACS Publications website at DOI: 10.1021/acs.orglett.7b00429.
(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.
Experimental procedures and characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michal.szostak@rutgers.edu.
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.
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 Depart-
ment (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).
(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.; Aube, 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.
REFERENCES
■
(1) (a) Gonzalez-Rosende, M. E.; Castillo, E.; Lasri, J.; Sepulveda-
Arques, 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.
(17) Amide resonance energies have been calculated at the B3LYP/6-
311++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.
́
(2) Aube, 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.
D
DOI: 10.1021/acs.orglett.7b00429
Org. Lett. XXXX, XXX, XXX−XXX