Chemoselective esterification and amidation of carboxylic acids with imidazole carbamates and ureas

Article abstract of DOI:10.1021/ol1018882

Imidazole carbamates and ureas were found to be chemoselective esterification and amidation reagents. A wide variety of carboxylic acids were converted to their ester or amide analogues by a simple synthetic procedure in high yields.

Full text of DOI:10.1021/ol1018882

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4572-4575
Chemoselective Esterification and
Amidation of Carboxylic Acids with
Imidazole Carbamates and Ureas
Stephen T. Heller and Richmond Sarpong*
Department of Chemistry, UniVersity of California,
Berkeley, California 94720, United States
rsarpong@berkeley.edu
Received August 11, 2010
ABSTRACT
Imidazole carbamates and ureas were found to be chemoselective esterification and amidation reagents. A wide variety of carboxylic acids
were converted to their ester or amide analogues by a simple synthetic procedure in high yields.
The chemoselective esterification of carboxylic acids is a
ubiquitous synthetic operation. In addition to the venerable
Fischer esterification,1 numerous other methods have been
developed toward this end. Transformations that involve
activation of the carboxylic acid group have become a
mainstay of ester synthesis, and though substantial progress
has been made in this area,2 acid activation often adds an
additional step and can be challenging in the presence of
other reactive functional groups.
diazoalkane analogues have found only limited use as
chemoselective esterification reagents due to the difficulty
associated with their handling and preparation, limiting this
approach to the preparation of methyl esters.4
An alternative strategy for esterification involves depro-
tonation of the carboxylic acid to form a more nucleophilic
carboxylate salt, which can be alkylated in a subsequent
step.5,6 This paradigm has been met with considerable
success in methylation, allylation, and benzylation reactions.
However, acidic or nucleophilic functional groups elsewhere
in the substrate are often incompatible with this approach,
and many of the alkylating agents employed are highly toxic.
Perhaps the most reliable and powerful selective esterifi-
cation method is the methylation of acids with diazomethane,
which activates the carboxylic acid in situ.3 However, this
reagent poses serious health and safety risks. Furthermore,
(4) (a) Diazoethane: Fenton, S. W.; DeWald, A. E.; Arnold, R. T. J. Am.
Chem. Soc. 1955, 77, 979–984. (b) Phenyldiazomethane: Overberger, C. G.;
Anselme, J.-P. J. Org. Chem. 1963, 28, 592–593.
(1) Fischer, E.; Speier, A. Chem. Ber. 1895, 28, 3252–3258.
(2) Methods include: (a) DCC/DMAP: Hassner, A.; Alexanian, V.
Tetrahedron Lett. 1978, 19, 4475–4478. (b) “Mixed anhydride method”:
Kim, S.; Kim, Y. C.; Lee, J. I. Tetrahedron Lett. 1983, 24, 3365–3369. (c)
Mitsunobu (and references therein): Mitsunobu, O. Synthesis 1981, 1–27.
(d) BOPCl: Diago-Meseguer, J.; Palomo-Coll, A. L.; Ferna´ndez-Lizarbe,
J. R.; Zugaza-Bilbao, A. Synthesis 1980, 54, 7–551. (e) DMFDMA:
Brechbu¨hler, H.; Bu¨chi, H.; Hatz, E.; Schreiber, J.; Eschenmoser, A. HelV.
Chim. Acta 1965, 48, 1746–1771. (f) Yamaguchi: Inanaga, J.; Hirata, K.;
Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52,
1989–1993. (g) EEDQ: Zacharie, B.; Connolly, T. P.; Penny, C. L. J. Org.
Chem. 1995, 60, 7072–7074.
(5) Methods include: (a) MeI/Cs2CO3: Pfeffer, P. E.; Silbert, L. S. J.
Org. Chem. 1976, 41, 1373–1379. (b) Me2CO3/K2CO3: Jiang, X.; Tiwari,
A.; Thompson, M.; Chen, Z.; Cleary, T. P.; Lee, T. B. K. Org. Process
Res. DeV. 2001, 5, 604–608. (c) Me2SO4/LiOH: Chakraborti, A. K.; Basak
(ne´e Nandi), A.; Grover, V. J. Org. Chem. 1999, 64, 8014–8017. (d)
Me3OBF4/DIPEA: Raber, D. J.; Gariano, P.; Brod, A. O.; Gariano, A.;
Guida, W. C.; Guida, A. R.; Herbst, M. D. J. Org. Chem. 1979, 44, 1149–
1154
.
(6) Alkylisoureas have been used as in situ alkylating reagents: (a)
Mathias, L. J. Synthesis 1979, 8, 561–576, and references therein. (b)
Crosignani, S.; White, P. D.; Steinauer, R.; Linclau, B. Org. Lett. 2003, 5,
(3) Pizey, J. S. Synthetic Reagents; Horwood: New York, 1974; Vol. 2,
p 65.
853–856
.
10.1021/ol1018882  2010 American Chemical Society
Published on Web 09/21/2010

Herein, we wish to report that alkyl imidazole carbamates
and ureas efficiently mediate the chemoselective esterification
and amidation of carboxylic acids. These inexpensive
reagents are easily prepared, can be stored on scale, and do
not appear to pose a safety risk.7 Despite operating in a
manifold seemingly similar to 1,1′-carbonyldiimidazole-
mediated esterification or amidation,8 these reagents obviate
the need for multi-operation synthetic procedures as well as
monitoring of the acid activation step.
During the course of a synthesis of a complex molecule,
we observed that the alkoxy group of imidazole carbamates
was rapidly acetylated when dissolved in acetic acid.
Intrigued by this previously unreported reactivity, we treated
1 (Table 1) with methyl imidazole carbamate (MImC)9 at
accelerated imidazole alkylation. Thus, a balance between
these two pathways was negotiated by reducing the concen-
tration, using 2 equiv of MImC and running the reaction at
relatively high temperature (entry 15).
Importantly, the typical reaction products of a MImC
esterification are imidazole, N-methylimidazole, and the
desired ester. As such, a simple aqueous workup provides
pure ester products.11
A variety of esters could be prepared by treatment of a
carboxylic acid substrate (e.g., 1) with the appropriate
imidazole carbamate (Table 2).12,13 The preparation of
Table 2. Alkyl Group Scopea
Table 1. Optimization of Methylation of 1 with MImCa
entry
R
% yield
1
2
3
4
5
6
7
8
methyl
93
89
70b
91
81c
87
84
85
ethyl
isopropyl
allyl
benzyl
propargyl
trans-crotyl
3-butenyl
entry solvent temp (°C) MImC (equiv) [1] (M) % yield
1
CDCl3
CDCl3
DCE
25
60
80
80
80
80
60
60
60
60
60
60
60
80
80
1.5
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.0
3.0
4.0
1.2
2.0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.5
1.0
2.0
0.5
0.5
0.5
0.5
0.5
0
33
63
58
66
72
47
70
74
69
72
80
83
85
93
2
3
4
toluene
EtOAc
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
a All reactions were run for 24 h, except entries 3 and 8, which were
run for 48 h. b The reaction did not reach completion. c Chromatography
was required to remove benzyl carbonate.
5
6
7
8
9
10
11
12
13
14
15
secondary esters from simple aliphatic alkoxy groups was
somewhat less efficient (entry 3). However, secondary allyl
esters were synthesized without event (entry 8). No loss of
regiochemical information was observed when substituted
allyl imidazole carbamates were employed (entries 7 and 8).
Investigation of several glycine and glycolic acid deriva-
tives demonstrated the high degree of chemoselectivity
provided by esterification with MImC (Table 3). Relatively
a All reactions were performed in sealed vials under a nitrogen
atmosphere and run for 18 h.
room temperature for 18 h but observed only starting
materials. However, heating the mixture to 60 °C resulted
in clean but partial conversion to 2.
Using more polar solvents had a dramatic positive effect
on the reaction (entries 3-6), as did raising the reaction
temperature (entries 6 and 7). Increasing the amount of the
MImC reagent (entries 11-13) led to improved conversion
but also to substantially higher levels of N-methylimidazole
as a byproduct.10 Because the esterification reaction produces
imidazole, significant amounts of N-methylimidazole begin
to form once the majority of the carboxylic acid substrate
has been consumed. Higher reaction concentrations also
Table 3. Chemoselectivity of MImC-Mediated Esterification
entry
R
% yield
1
2
3
4
5
6
7
8
NHCbz
NHBoc
NHFmoc
NHTs
NHAc
NPth
93
93
NDa
83b
92
92
(7) A full safety evaluation has yet to be performed. MImC was stable
for weeks at -20 °C and could be stored for prolonged periods at 4 °C.
All other prepared imidazole carbamates could be stored at room temperature
without observable decomposition.
OBz
90
OPMP
94
a The Fmoc group was cleaved. b A 7% yield of the N-acylated methyl
ester was obtained.
(8) Staab, H. A. Angew. Chem., Int. Ed. 1962, 1, 351–367.
(9) (a) Crumbie, R. L.; Nimitz, J. S.; Mosher, H. S. J. Org. Chem. 1982,
47, 4040–4045. (b) Trost, B. M.; Zhang, Y.; Zhang, T. J. Org. Chem. 2009,
74, 5115–5117.
acidic protected amines were well-tolerated (entries 1 and
2), though very acidic functional groups such as tosylamides
(10) Subjecting MImC to 2 equiv of imidazole in MeCN at 60 °C for
16 h led to nearly quantitative conversion to 1-methylimidazole.
Org. Lett., Vol. 12, No. 20, 2010
4573

were partially acylated by MImC, presumably via initial
deprotonation by imidazole.
MImC also efficiently mediates the esterification of
benzoic acids under the standard conditions using DMF as
solvent (Table 4).14 With this modification, excellent yields
Table 4. Methylation of Benzoic Acids
entry
R
% yield
1
2
3
4
5
6
7
4-Br
94
94
91a
82
83
90
84
4-OMe
4-NO2
4-Ac
4-NHAc
2-Me
2-I
a 5% conversion to the corresponding N,N-dimethylbenzamide was
observed.
were obtained for most benzoic acid substrates. Carboxylic
acids of varied acidity reacted comparably (entries 1-3).
However, steric hindrance of the carboxylic acid group led
to slightly lower yields (entries 6 and 7).
Figure 1.
Substrate scope of methylation with MimC. aA 12% yield
of the N-acylated product was obtained. bNMR yield using
piperonylonitrile as an internal standard. cThe remainder of the crude
material was the product of conjugate addition by imidazole.
dExtensive racemization was observed.
As shown in Figure 1, the esterification proved to be
general for a range of substrates. For example, branching at
the R-position is tolerated, as are a variety of functional group
arrays and heterocyclic scaffolds. Notably, mildly basic
functionality such as a quinoline did not have a negative
impact on the esterification. N-Protected amino acids such
as Boc-Phe-OH or Boc-Cys(Trt)-OH were also esterified in
good yield but were partially racemized. Therefore, the use
of MImC with carboxylic acids bearing epimerizable ste-
reocenters is not recommended at the present time.15
We propose that esterification with imidazole carbamates
proceeds by a mechanism similar to that postulated by Staab
for the formation of acylimidazoles from carboxylic acids
and CDI (Scheme 1).16 Specifically, an imidazolium car-
boxylate ion pair (3) decomposes to an acylcarbonate (4)
that can be intercepted at either carbonyl by imidazole. In
the productive pathway, an acylimidazole intermediate (5)
forms along with a carbonic ester, which presumably
undergoes decarboxylation. The liberated alcohol then
scavenges the acylimidazole (5), providing the ester product.
This proposal is supported by the isolation of an acylimi-
Scheme 1
.
Proposed Mechanism of Esterification by Imidazole
Carbamate Reagents
(11) Unless a minor product is reported, all yields reported herein are
for reactions purified only by aqueous workup to give analytically pure
products.
(12) Imidazole carbamates were prepared either by treating imidazole
(2 equiv) with the appropriate alkyl chloroformate (1 equiv) or by treating
1,1′-carbonyldiimidazole (1.05 equiv) with the appropriate alcohol (1 equiv).
See the Supporting Information for details.
(13) All esterification reactions were run for 24 h. No attempt was made
to optimize reaction time for individual substrates.
(14) In some cases, small amounts of N,N-dimethylbenzamide byprod-
ucts were observed. Using freshly distilled DMF usually suppressed this
side reaction except in the case of very electron-poor benzoic acids such as
4-nitrobenzoic acid.
(15) Efforts to mitigate amino acid racemization are underway.
(16) For a discussion see, ref 8.
dazole intermediate (such as 5) when the MImC-mediated
esterification was conducted in an open vessel so that
methanol vapor was released as the reaction proceeded.
At this stage, other mechanistic hypotheses cannot be
discarded since initial results suggest that the mechanism of
esterification may depend on the type of carbamate used.17
4574
Org. Lett., Vol. 12, No. 20, 2010

We can, however, discount an SN1 process (via decarboxy-
lation of ion pair intermediates such as 3) because of the
regiospecificity observed with substituted allyl carbamates
(Table 2, entries 7 and 8). Rather, this result lends some
support to a potential SNi mechanism (see Scheme 1) in the
case of allylic carbamates because of the qualitative observa-
tion that but-3-en-2-yl imidazole carbamate mediates esteri-
fication much faster than isopropyl imidazole carbamate
(Table 2, entry 3).18 In addition, esterification of benzoic
acid with enantioenriched imidazole carbamate 6 (eq 1) was
found to proceed through a retentive process to afford 7.19,20
quantitative conversion to the desired amide. Functionalized
carboxylic acids could also be transformed into their corre-
sponding Weinreb amide analogues in excellent yield (Figure
2). Amidation proceeded with a high degree of chemoselectivity
Figure 2. Substrate scope of amidation with WImC.
Given the proposed mechanistic hypotheses (Scheme 1), it
is perhaps unsurprising that MImC reacts sluggishly with
phenols.21 Intriguingly, more acidic phenols were methylated
less efficiently, and the use of either ethyl or allyl imidazole
carbamate led to only trace O-alkylation.22 As a representative
example, 4-hydroxy-3-nitrobenzoic acid was treated with a
variety of imidazole carbamates (eq 2) under standard conditions
to demonstrate the chemoselectivity of these reagents toward
phenolic acids.23 Analysis of the reaction mixture revealed that
no phenol methylation had taken place. However, the presence
of the highly acidic phenol group impeded esterification.24
Presumably, the additional acidic functionality sequestered some
amount of the MImC in an unproductive equilibrium.
in cases where multiple electrophilic carbonyls were present
and appears to be tolerant of sterically congested carboxylic
acids as well.27
In conclusion, we have developed practical and highly
chemoselective esterification and amidation reactions using
imidazole carbamates and ureas. In particular, we have
demonstrated the utility of imidazole carbamates as powerful
and chemoselective esterification reagents. We believe these
reagents will be a useful alternative to diazoalkanes for the
synthesis of esters. In addition, we have demonstrated the
utility of an imidazole urea reagent for direct Weinreb amide
formation. Efforts to elucidate the mechanisms by which
these transformations occur, suppress racemization, and
expand the utility of this methodology are underway.
Acknowledgment. The authors are grateful to the NSF
for financial support (CAREER: CHE-0643264 and predoc-
toral fellowship for STH).
Supporting Information Available: Experimental details
and characterization for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Finally, Weinreb amides can also be prepared directly from
carboxylic acids using imidazole urea 825 (WImC).26 Treating
4-bromophenylacetic acid with 2 equiv of WImC led to
OL1018882
(17) In many regards, MImC is unique among the imidazole carbamates
investigated. It is easily hydrolyzed by water and seems to be a competent
electrophile in the methylation of imidazole, whereas ethyl imidazole
carbamate (EImC) can be purified by aqueous extraction and does not act
as an ethylating agent toward imidazole. As such, a simple SN2 displacement
mechanism cannot be excluded.
(22) Mixing ethyl and allyl imidazole carbamates (EImC and AllImC)
with p-cresol led to <1% and 6% conversion to p-ethoxytoluene and
p-allyloxytoluene, respectively.
(23) When 4-hydroxy-3-nitrobenzoic acid was treated with 1 equiv of
TMSCHN2 in CH2Cl2/MeOH for 4 h at room temperature, only the methyl
ester was observed.
(18) Cowdrey, W. A.; Hughes, E. D.; Ingold, C. K.; Masterman, S.;
Scott, A. D. J. Chem. Soc. 1937, 1271–1277.
(24) 4-Hydroxy-3-nitrobenzoic acid was obtained in 31% isolated yield
when using MImC (eq 2, top entry).
(19) The product ester was assigned as the R enantiomer by comparison
of its optical rotation with literature values: Cheˆnevert, R.; Pelchat, N.;
(25) Grzyb, J. A.; Shen, M.; Yoshina-Ishii, C.; Chi, W.; Brown, R. S.;
Batey, R. A. Tetrahedron 2005, 61, 7153–7175.
Morin, P. Tetrahedron: Asymmetry 2009, 20, 1191–1196
.
(26) Other methods for the direct conversion of carboxylic acids to
Weinreb amides include: (a) Niu, T.; Zhang, W.; Huang, D.; Xu, C.; Wang,
H.; Hu, Y. Org. Lett. 2009, 11, 4474–4477. (b) Tunoori, A. R.; White,
J. M.; Georg, G. I. Org. Lett. 2000, 2, 4091–4093.
(20) Retentive and regiospecific esterification can also be explained by
a mechanism involving an acylimidazole intermediate. Further experimenta-
tion to delineate these mechanisms is underway.
(21) 11% conversion to 4-methoxytoluene anisole was observed when
MImC was mixed with p-cresol under the standard esterification
conditions.
(27) The transformation of hindered acids can be problematic when
standard conditions are used. See: Woo, J. C. S.; Fenster, E.; Dake, G. R.
J. Org. Chem. 2004, 69, 8984–8986.
Org. Lett., Vol. 12, No. 20, 2010
4575