Transition-Metal-Free Esterification of Amides via Selective N-C Cleavage under Mild Conditions

Article abstract of DOI:10.1021/acs.orglett.8b02323

A general, transition-metal-free, and operationally simple method for esterification of amides by a highly selective cleavage of N-C(O) bonds under exceedingly mild conditions is reported. The reaction is characterized by broad substrate scope and excellent functional group tolerance. The potential of this mild esterification is highlighted by late-stage diversification of natural products and pharmaceuticals. Conceptually, the metal-free acyl functionalization of amides represents a significant step forward as a practical alternative to ligand exchange in acylmetal intermediates.

Full text of DOI:10.1021/acs.orglett.8b02323

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transition-Metal-Free Esterification of Amides via Selective N−C
Cleavage under Mild Conditions
Guangchen Li,† Peng Lei,†,‡ and Michal Szostak*,†
†Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
‡Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China
S
* Supporting Information
ABSTRACT: A general, transition-metal-free, and operationally
simple method for esterification of amides by a highly selective
cleavage of N−C(O) bonds under exceedingly mild conditions is
reported. The reaction is characterized by broad substrate scope and
excellent functional group tolerance. The potential of this mild
esterification is highlighted by late-stage diversification of natural
products and pharmaceuticals. Conceptually, the metal-free acyl functionalization of amides represents a significant step forward
as a practical alternative to ligand exchange in acylmetal intermediates.
he direct functionalization of amides represents a highly
1−5
Tattractive strategy in organic synthesis.
Given that
amides are among the most ubiquitous functional groups in
pharmaceuticals,6 natural products,7 and polymers8 as well as
constitute the key linkage in peptides and proteins,9 the
development of new strategies for the conversion of amides
into other functional groups provides powerful transformations
for practitioners of organic synthesis.10 The major challenge in
the functional group interconversion of amides stems from
amidic resonance (15−20 kcal/mol, nN → π*CO conjuga-
tion),11−13 which prohibits functionalization of the N−C(O)
bond under mild, functional-group-tolerant, and operationally
practical conditions.14 In particular, the direct conversion of
amides to esters represents a synthetic challenge that has been
met with limited success to date owing to the high reactivity of
the ester group under the conditions required to directly break
the amide bond.
In 2015, a breakthrough study by Garg and co-workers
reported the amide to ester interconversion15 using Ni-catalyzed
Figure 1. (a) Metal-catalyzed esterification of amides (previous work).
(b) Transition-metal-free esterification of amides (this study).
activation of the amide bond to produce a versatile acyl-Ni
intermediate (Figure 1A).16 Later, Danoun and co-workers
demonstrated Co-catalyzed esterification of amides,17 thus
context, N-acyl-Boc-carbamates (e.g., Ar = Ph, R = Ph, RE =
7.2 kcal/mol; τ = 29.1°; χN = 8.4°)12a and N-acyl-tosylamides
introducing cobalt catalysis into field of amide bond activation
(Figure 1A). Recently, a fluoride-catalyzed method18 for
esterification of amides at high temperature has been
reported.19,20 All of these elegant methods rely on the intrinsic
properties of the amide bond to undergo controlled twisting and
resonance destabilization from planarity to enable previously
elusive synthetic transformations.12
(e.g., Ar = Ph, R = Ph, RE = 9.7 kcal/mol; τ = 18.8°; χN =
18.9°)12a have emerged as broadly useful resonance destabilized
amides that have significantly improved the utility of amide bond
interconversion tactics in transition-metal catalysis.5,15,16,17−21
We recognized that if a direct, transition-metal-free esterification
manifold could be realized,23 the reaction would represent a
valuable addition to the synthetic toolbox available for
interconversion of the ubiquitous amide bond endowed with
all the advantages inherent to transition-metal-free reactions24
and could stimulate the development of new methods for acyl
Meanwhile, we have been interested in metal-catalyzed21 and
metal-free22 activation of amides. We recognized that
implementation of common acyclic amides, after a suitable N-
activation12d in a fashion similar to the previous meth-
ods,15,16,17−20 should enable a mild, transition-metal-free
esterification of amides with broad substrate scope by exploiting
amide bond destabilization platform (Figure 1B). In this
Received: July 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02323
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
functionalization5,16 of amides under attractive transition-metal-
free conditions.
Scheme 1. Transition-Metal-Free Esterification of N-Boc-
Activated 2° Amides
a
Herein, we describe the successful development of this
process and report a general, transition-metal-free, and opera-
tionally simple method for esterification of amides by a highly
selective N−C(O) bond cleavage under exceedingly mild room
temperature conditions (Figure 1B). The reaction is charac-
terized by broad substrate scope and excellent functional group
tolerance enabled by mild activation of the amide bond.
Notably, in contrast to transition-metal-catalyzed ap-
proaches,15,16,17−20 these mild conditions are particularly
effective for esterification of amides with phenols, a previously
elusive transformation in metal-catalyzed activation of the amide
bond, thus enabling direct access to valuable aromatic esters
from amides.23 The potential of this mild esterification method
is highlighted by late-stage diversification of natural products
and pharmaceuticals (Figure 2). Conceptually, the transition-
Figure 2. Proposed mechanism for metal-free esterification of amides.
metal-free acyl functionalizations of amides with ample substrate
scope represent a significant step forward in the conversion of
amides by N−C(O) bond activation as a practical alternative to
ligand exchange in acylmetal intermediates.
a
Conditions: amide (1.0 equiv), ROH (1.2 equiv), K3PO4 (3.0
After extensive optimization, we determined that esterifica-
tion of N-Boc-activated amide 1a proceeds in excellent 90%
yield at room temperature using inexpensive K3PO4 as a base
and THF as a solvent (Scheme 1, 3a). The reaction requires only
a close to stoichiometric amount of PhOH (1.2 equiv),
consistent with the efficient direct O-addition to the activated
amide bond under these conditions. Optimization studies (see
the Supporting Information (SI)) revealed that other bases
(K2CO3, KO-t-Bu, KF, KOH, Cs2CO3) and solvents (DMF,
CH3CN, acetone, CH2Cl2) are less effective in promoting the
reaction. The base is required for the reaction, with modest
conversion observed with close to stoichiometric amount of the
base (55%, K3PO4, 1.2 equiv). Importantly, under the optimized
conditions, cleavage of the N-Boc group deactivating the amide
was not observed.
With optimal conditions in hand, the substrate scope was next
examined (Scheme 1). Importantly, the reaction readily
accommodates a broad range of phenols including simple
(3a), electron-rich (3b), electron-deficient (3c), and sterically
hindered (3d) as well as those bearing sensitive functional
groups such as bromo (3e) and aldehyde (3f). Note that these
substituents are often problematic in transition-metal-catalyzed
protocols, showing the advantage of these mild conditions.
The scope with respect to the amide substitution is also broad
(Scheme 1) and accommodates amides bearing both electron-
rich (3g,h) and electron-deficient (3i,j) substituents. Fluorine-
containing amides relevant from a medicinal chemistry stand-
point (3k), and heterocyclic amides bearing a deactivating
heteroatom at the conjugating position (3l) are well-tolerated.
Perhaps most notably, the reaction readily accommodates
b
equiv), THF (1.0 M), 23 °C, 15 h. Isolated yields. ROH (3.0 equiv).
c
ROH (2.0 equiv).
aliphatic amides with systematic variation of sterics at the α-
position (3m−o). In contrast, transition-metal-catalyzed
esterification typically requires extensive ligand optimization
to provide reactivity of aliphatic amides.15b Finally, although we
were primarily interested in the synthesis of aromatic esters
because such method has been elusive using transition
metals,15,16,17−20 the present conditions can also be readily
applied to esterification with aliphatic alcohols without
modification of the reaction conditions (3p).
Pleasingly, this new method is also compatible with N-Ts-
activated amides to give the corresponding esterification
products in high yields (Scheme 2). These examples include
electronically differentiated (3a−c), sterically hindered (3d),
halide-containing (3e), aldehyde-containing (3f), and aliphatic
alcohols (3l). Importantly, removal of the activating N−S group
is not observed under these conditions. In this case, selective N-
activation of secondary amides using TsCl offers a comple-
mentary activation method.5,12,16
Notably, the reaction could be extended to a variety of amide
activating groups (Table 1). N-Ts-anilides (entry 1), N-
acylglutarimides (entry 2), N-alkylcarbamates (entry 3), as
well as readily prepared from 1° carboxamides12d,14 N,N-Boc2
amides (entries 4−6) underwent smooth esterification to
provide C−O interconversion products in high yields. It is
particularly noteworthy that esterification using electron-
deficient 4-nitrophenol proceeded in high yield (3q), albeit at
B
DOI: 10.1021/acs.orglett.8b02323
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Transition-Metal-Free Esterification of N-Ts-
Activated 2° Amides
Scheme 3. Amide to Thioester Conversion
a
a
Scheme 4. Late-Stage Diversification
a
See Scheme 1.
a
Table 1. Transition-Metal-Free Esterification of Amides
a
b
See Scheme 1. ROH (1.5 equiv).
delivered the esterification products in high to excellent yields,
demonstrating a synthetic advantage of this protocol.
To gain preliminary insight into the reaction mechanism, we
conducted competition experiments (Scheme 5). We found that
Scheme 5. Competition Experiments
a
b
c
See Scheme 1. ROH (2.0 equiv). ROH, K3PO4 (3.0 equiv), 110
°C.
elevated temperature. This reaction establishes primary amide to
activated 4-NO2-ester interconversion.25 Given the broad utility
of such activated esters in cross-coupling reactions,25 this
protocol may find utility in sequential strategies for manipu-
lation of common amide bonds.
Importantly, the present method can be applied directly to
effect transition-metal-free amide to thioester [CO−N → CO−
S] interconversion without modification of the reaction
conditions (Scheme 3). This protocol further expands the
range of downstream transformations of amides enabled by a
versatile thioester functional group handle.26
The broad synthetic utility of this process is further
highlighted by the late-stage diversification of natural products
and pharmaceuticals (Scheme 4). We were pleased to find that
the direct esterification of eugenol (3s), a naturally occurring
guaiacol with a sensitive double bond, estrone (3t), an estrogen
receptor agonist, and α-tocopherol (3u), an essential vitamin,
electron-deficient amides are inherently more reactive, con-
sistent with the relative electrophilicity of the amide bond
(Scheme 5A). Furthermore, electron-rich alcohols were found
to react preferentially (Scheme 5B). Finally, aliphatic alcohols
are inherently more reactive than their aromatic counterparts
(Scheme 5C). Overall, these results emphasize the challenge of
selective nucleophilic addition of phenols to the amide bond and
are consistent with alcohol nucleophilicity in the metal-free
activation pathway (Figure 1B).
C
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Organic Letters
Letter
(10) (a) Larock, R. C. Comprehensive Organic Transformations; Wiley:
New York, 1999. (b) Zabicky, J. The Chemistry of Amides; Interscience:
New York, 1970.
(11) Pauling, L. The Nature of the Chemical Bond; Oxford University
Press: London, 1940.
(12) For pertinent studies on amide destabilization in N−C cross-
coupling, see: (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.; Meng, G.; Szostak, M. J. Org. Chem. 2017, 82,
6373. (d) Meng, G.; Shi, S.; Lalancette, R.; Szostak, R.; Szostak, M. J.
Am. Chem. Soc. 2018, 140, 727.
(13) For selected theoretical studies, see: (a) Kemnitz, C. R.; Loewen,
M. J. J. Am. Chem. Soc. 2007, 129, 2521. (b) Mujika, J. I.; Mercero, J. M.;
Lopez, X. J. Am. Chem. Soc. 2005, 127, 4445. (c) Glover, S. A.; Rosser,
A. A. J. Org. Chem. 2012, 77, 5492. (d) Morgan, J.; Greenberg, A.;
Liebman, J. F. Struct. Chem. 2012, 23, 197.
A summary of state-of-the-art methods in metal-catalyzed and
transition-metal-free esterification of amides is presented in the
SI (Table SI-1). The successful esterification of a broad range of
amides establishes a unique approach to deploying amide bond
functional group interconversion by complementary reaction
mechanisms.
In summary, we have reported a transition-metal-free
platform for esterification of amides by highly selective N−
C(O) bond cleavage under exceedingly mild conditions. The
reaction demonstrates a broad substrate scope and excellent
functional group tolerance. This operationally simple, mild, and
practical method establishes the first general interconversion of
amides to aromatic esters that were previously elusive in
transition-metal-catalyzed N−C amide bond activation. The
potential of this method has been highlighted by late-stage
diversification of natural products and pharmaceuticals. We fully
expect that the transition-metal-free esterification will be of great
interest for manipulation of amides in organic synthesis. In a
broader context,5,16,21 it becomes crystal clear that both metal-
catalyzed and transition-metal-free approaches should be
considered in acyl conversion of the historically inert amide
bond with wide-ranging implications in chemistry.
(14) For a study on metal-free amide bond interconversion in polymer
synthesis, see: Larsen, M. B.; Herzog, S. E.; Quilter, H. C.; Hillmyer, M.
A. ACS Macro Lett. 2018, 7, 122.
(15) (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.
(b) Hie, L.; Baker, E. L.; Anthony, S. M.; Desrosiers, J. N.; Senanayake,
C.; Garg, N. K. Angew. Chem., Int. Ed. 2016, 55, 15129.
(16) (a) Dander, J. E.; Garg, N. K. ACS Catal. 2017, 7, 1413. (b) See
refs 5a−c.
ASSOCIATED CONTENT
* Supporting Information
■
(17) Bourne-Branchu, Y.; Gosmini, C.; Danoun, G. Chem. - Eur. J.
2017, 23, 10043.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02323.
(18) Wu, H.; Guo, W.; Daniel, S.; Li, Y.; Liu, C.; Zeng, Z. Chem. - Eur.
J. 2018, 24, 3444.
(19) For a biomimetic esterification by N−C activation, see: Wybon,
C. C. D.; Mensch, C.; Hollanders, K.; Gadais, C.; Herrebout, W. A.;
Ballet, S.; Maes, B. U. W. ACS Catal. 2018, 8, 203.
Experimental procedures and characterization data
(PDF)
(20) For a pertinent review on functional group interconversion, see:
Guo, L.; Rueping, M. Acc. Chem. Res. 2018, 51, 1185.
(21) (a) Meng, G.; Szostak, M. Angew. Chem., Int. Ed. 2015, 54, 14518.
(b) Shi, S.; Meng, G.; Szostak, M. Angew. Chem., Int. Ed. 2016, 55, 6959.
(c) Liu, C.; Szostak, M. Angew. Chem., Int. Ed. 2017, 56, 12718. (d) Lei,
P.; Meng, G.; Shi, S.; Ling, Y.; An, J.; Szostak, R.; Szostak, M. Chem. Sci.
2017, 8, 6525 and references cited therein.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michal.szostak@rutgers.edu.
ORCID
Michal Szostak: 0000-0002-9650-9690
Notes
(22) Liu, Y.; Shi, S.; Achtenhagen, M.; Liu, R.; Szostak, M. Org. Lett.
2017, 19, 1614 and references cited therein.
(23) For leading examples of using aryl esters as electrophiles in cross-
coupling reactions, see: (a) Amaike, K.; Muto, K.; Yamaguchi, J.; Itami,
K. J. Am. Chem. Soc. 2012, 134, 13573. (b) Muto, K.; Yamaguchi, J.;
Musaev, D. G.; Itami, K. Nat. Commun. 2015, 6 (7508), 1−8. (c) See
refs 20 and 21d.
(24) Summerton, L.; Sneddon, H. F.; Jones, L. C.; Clark, J. H. Green
and Sustainable Medicinal Chemistry: Methods, Tools and Strategies for
the 21st Century Pharmaceutical Industry; RSC: Cambridge, 2016.
(25) (a) Gooßen, L. J.; Paetzold, J. Angew. Chem., Int. Ed. 2002, 41,
1237. (b) John, A.; Hogan, L. T.; Hillmyer, M. A.; Tolman, W. B. Chem.
Commun. 2015, 51, 2731. (c) John, A.; Dereli, B.; Ortuno, M. A.;
Johnson, H. E.; Hillmyer, M. A.; Cramer, C. J.; Tolman, W. B.
Organometallics 2017, 36, 2956.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Rutgers University and the NSF (CAREER CHE-1650766) are
gratefully acknowledged for support. P.L. thanks the China
Scholarship Council (No. 201606350069) for a fellowship.The
Bruker 500 MHz spectrometer used in this study was supported
by the NSF-MRI grant (CHE-1229030).
REFERENCES
■
(1) Greenberg, A.; Breneman, C. M.; Liebman, J. F. The Amide
Linkage: Structural Significance in Chemistry, Biochemistry and Materials
Science; Wiley-VCH: New York, 2003.
(26) For a review, see: (a) Hirschbeck, V.; Gehrtz, P. H.; Fleischer, I.
Chem. - Eur. J. 2018, 24, 7092. For a recent example, see: (b) Liu, C.;
Szostak, M. Chem. Commun. 2018, 54, 2130.
(2) Tani, K.; Stoltz, B. M. Nature 2006, 441, 731.
́
(3) Aube, J. Angew. Chem., Int. Ed. 2012, 51, 3063.
(4) Ruider, S.; Maulide, N. Angew. Chem., Int. Ed. 2015, 54, 13856.
(5) For reviews on N−C functionalization of amides, see: (a) Takise,
R.; Muto, K.; Yamaguchi, J. Chem. Soc. Rev. 2017, 46, 5864. (b) Liu, C.;
Szostak, M. Chem. - Eur. J. 2017, 23, 7157. (c) Meng, G.; Shi, S.;
Szostak, M. Synlett 2016, 27, 2530. (d) See ref 16.
(6) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
(7) (a) Kudo, F.; Miyanaga, A.; Eguchi, T. Nat. Prod. Rep. 2014, 31,
1056. (b) Walsh, C. T.; O’Brien, R. V.; Khosla, C. Angew. Chem., Int. Ed.
2013, 52, 7098.
(8) Marchildon, K. Macromol. React. Eng. 2011, 5, 22.
(9) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471.
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DOI: 10.1021/acs.orglett.8b02323
Org. Lett. XXXX, XXX, XXX−XXX