Carbamoylimidazolium salts as diversification reagents: An application to the synthesis of tertiary amides from carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2003.08.026

An efficient method for the preparation of tertiary amides from carbamoylimidazolium salts and carboxylic acids is described. The transformation occurs at room temperature and under relatively mild conditions. The carbamoylimidazolium salts are obtained from the reaction of secondary amines with N,N′-carbonyldiimidazole, followed by methylation with methyl iodide. The utility of this reaction was demonstrated in the formation of Weinreb amides and in a short synthesis of fused bicyclic amides. The introduction of this reaction now permits carbamoylimidazolium salts to be utilized in the formation of tertiary amides, ureas, carbamates and thiocarbamates under a single set of conditions.

Full text of DOI:10.1016/j.tetlet.2003.08.026

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7485–7488
Carbamoylimidazolium salts as diversification reagents:
an application to the synthesis of tertiary amides from
carboxylic acids
Justyna A. Grzyb and Robert A. Batey*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto,
Ontario, M5S 3H6, Canada
Received 22 July 2003; revised 5 August 2003; accepted 7 August 2003
Abstract—An efficient method for the preparation of tertiary amides from carbamoylimidazolium salts and carboxylic acids is
described. The transformation occurs at room temperature and under relatively mild conditions. The carbamoylimidazolium salts
are obtained from the reaction of secondary amines with N,N%-carbonyldiimidazole, followed by methylation with methyl iodide.
The utility of this reaction was demonstrated in the formation of Weinreb amides and in a short synthesis of fused bicyclic amides.
The introduction of this reaction now permits carbamoylimidazolium salts to be utilized in the formation of tertiary amides, ureas,
carbamates and thiocarbamates under a single set of conditions.
© 2003 Elsevier Ltd. All rights reserved.
Carbamoylimidazolium salts
1
are versatile elec-
generates tetra- or trisubstituted ureas 3.1 Reaction of 1
with phenols or the alkoxides of aliphatic alcohols
generates carbamates 4.2 In each of these reactions the
carbamoylimidazolium salt acts as a disubstituted car-
bamoyl cation equivalent. A further advantage of this
protocol, is that carbamoylimidazolium salts are readily
prepared by the sequential treatment of secondary
amines with the commercially available crystalline solid
N,N%-carbonyldiimidazole (CDI)3 and iodomethane.
The reactivity of 1 is significantly enhanced over that of
the corresponding carbamoyl imidazoles, as a result of
the methylation of the imidazole ring.4 This method
avoids the direct use of phosgene or triphosgene that is
required for the synthesis of carbamoyl chlorides (the
most commonly employed disubstituted carbamoyl
cation equivalent). The salts 1 are more readily handled
than carbamoyl chlorides, and in most cases are stable
crystalline solids that can be stored in sealed vessels for
extended periods. By contrast, carbamoyl chlorides
often display poor stability and are difficult to obtain as
high purity samples, a feature that has limited their use
and, in all but the simplest cases, their commercial
availability.
trophiles in organic synthesis, reacting with a variety of
nucleophiles (Scheme 1).1,2 Treatment of the salts 1
with thiols results in the formation of thiocarbamates
2,2 whereas reaction with secondary or primary amines
Scheme 1. Synthesis and reactivity of carbamoylimidazolium
salts 1 with various nucleophiles.
As part of a study into the reactivity patterns of
carbamoylimidazolium salts, we now report their reac-
tion with carboxylic acids for the generation of tertiary
amides. The experimental protocol is quite straightfor-
ward, with treatment of 1 with carboxylic acids in the
Keywords: carbamoyl imidazolium salts; amides; Weinreb amides;
parallel synthesis.
* Corresponding author. Tel./fax: +1-416-978-5059; e-mail:
rbatey@chem.utoronto.ca
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.026

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J. A. Grzyb, R. A. Batey / Tetrahedron Letters 44 (2003) 7485–7488
Table 1. Synthesis of tertiary amides 5 from carbamoyl-
imidazolium salts 1a
presence of 1 equivalent of triethylamine in acetonitrile
at room temperature for 16 h resulting in the formation
of amides 5 in excellent yields (Table 1).5 Stronger
bases, such as potassium carbonate also give high yields
of the product. However, with weaker bases such as
pyridine or resin-supported bases like poly(4-
vinylpyridine) and Amberlyst® A-21 the yields are very
low. In the absence of base, the product yields are
negligible. Amide 5a was isolated with yields of 71 and
85% when the reaction was worked up after 1 and 5 h,
respectively. Other solvents such as chloroform may be
used as a suitable substitute for acetonitrile. The
methylimidazole byproduct is easily removed by wash-
ing the organic layer with dilute acid. The tertiary
amide products are generally of high enough purity
after aqueous work-up that chromatographic purifica-
tion is not required. Reaction with simple carboxylic
acids resulted in good to excellent yields of amides
5a–h. Reaction with Cbz-protected a-amino acids also
worked well, as illustrated by the examples of N-CBz-
glycine and N-CBz-phenylalanine (Table 1, 5i–k). In
the latter case, racemization was not detected to have
occurred under the reaction conditions by HPLC analy-
sis, and the purity of the product 5k was 97% without
column chromatography.
This approach also provides a very convenient way of
generating N-methoxy-N-methyl amides (5l–p, Table
1), otherwise known as Weinreb amides, which are
widely used in the synthesis of ketones from Grignard
and organolithium reagents.6,7 The N-methoxy-N-
methyl carbamoylimidazolium salt reacts with one
equivalent of carboxylic acid and triethylamine to
afford the Weinreb amides in excellent yields without
the need for further purification. Although the precur-
sor imidazolium salt is less stable than most other salts
that we have studied, it can be stored for several
months at −20°C without noticeable decomposition.
The N-methoxy-N-methyl carbamoylimidazolium salt
is also more reactive towards carboxylic acids, and
generates the amides in good yields, even when weaker
bases such as pyridine are used.
The formation of the tertiary amides, presumably pro-
ceeds by reaction of the carboxylate anion with the
carbamoylimidazolium salt to generate the correspond-
ing mixed anhydride, with concomitant release of N-
methylimidazole.
Subsequent
attack
of
the
N-methylimidazole then generates an acylimidazolium
species with release of carbon dioxide and the free
amine. The amine then reacts with the acylimidazolium
species to form the final product. Thus, the car-
bamoylimidazolium salt serves as both the source of the
amine donor and as the activation reagent for the
carboxylic acid acceptor. The activation step is similar
to the use of both CDI8 and N,N%-carbonylbis(3-
methylimidazolium) triflate9 for carboxyl activation of
carboxylic acids and a-amino acids. The overall trans-
formation is analogous, and complementary, to the
conversion of isocyanates with carboxylic acids into
secondary amides,10 a process that is known to proceed
via a mixed acid anhydride, which subsequently under-
goes decarboxylation to give the product at elevated
temperatures. A modification of this process utilizes
imidazole as an additive, which initially attacks the
isocyanate to form a corresponding azolide intermedi-
ate, which is then transformed into the secondary
amide.11
While numerous methods are known for the direct or
indirect transformation of carboxylic acids into amides,
this operationally straightforward method provides
potentially useful opportunities in organic synthesis.

J. A. Grzyb, R. A. Batey / Tetrahedron Letters 44 (2003) 7485–7488
7487
strate, and was about 50-fold more reactive than cyclo-
hexanethiol, which was the next most reactive
nucleophile examined. Aliphatic alcohols or anilines
were unreactive under these conditions, and require
much stronger bases for reaction to occur. The reactiv-
ity differences between primary and secondary aliphatic
amines (e.g. n-butylamine, tetrahydroisoquinoline), car-
boxylic acids and phenols were moderate, and useful
selectivity levels cannot be assured in substrates bearing
these competing functionalities.
In particular, a single reagent is now available for the
formation of tertiary amides, ureas, carbamates and
thiocarbamates. These divergent transformations occur
under a unified set of conditions, a feature that should
allow for their use in parallel synthesis or combinatorial
chemistry applications. Indeed, carbamoylimidazolium
salts have already been applied to the synthesis of urea
libraries, using both parallel solution-phase synthesis
and solid-phase synthesis techniques.12
The multifarious reactivity of carbamoylimidazolium
salts presents potential chemoselectivity problems for
those substrates containing multiple functional groups
capable of reacting with these salts. A competition
study of the reaction of 1a with carboxylic acids,
amines, anilines, thiols, phenols and alcohols was
undertaken to establish an approximate guide to their
reactivity. NMR analysis of the crude product ratios
from the reaction of 1a with an excess of pairs of
nucleophiles (5 equivalents) and triethylamine (10
equivalents) in acetonitrile at room temperature, pro-
vided a reactivity profile as indicated in Figure 1.
Thiophenol was found to be the most reactive sub-
The reactivity profile allows the rational planning of
chemoselective transformations of bifunctional sub-
strates (Scheme 2). Thus, using 1a as a model substrate,
p-cresol was converted into carbamate 6 in 88% yield,
without any evidence of reaction of the aniline func-
tionality. The reaction of N-acetyl- -cysteine with 1a
L
resulted in the clean reaction of the thiol group over the
carboxylic acid, and an isolated 81% yield of thiocarba-
mate 7. Finally, reaction with p-aminobenzoic acid led
to the corresponding amide 8 in 81% yield.
To demonstrate the synthetic utility of the tertiary
amide formation, the reaction was applied to the syn-
thesis of fused bicyclic lactams 9a and 9b (Scheme 3).
The key reactions in these approaches are the forma-
Figure 1. Relative reactivities of various nucleophiles and
carboxylic acids towards carbamoylimidazolium salt 1a.
Scheme 3. Reagents and conditions: (a) TBDMSCl, pyr,
CH2Cl2, rt, 4 h. (b) CDI, CH2Cl2, rt, 1 day. (c) MeI, MeCN,
rt, 1 day. (d) Diethyl phosphonoacetic acid, NEt3, MeCN,
50°C,
1
day. (e) TBAF, THF, rt, 30 min. (f)
Scheme 2. Examples of chemoselective transformations of 1a
with bifunctional substrates.
C6H4COOI(OAc)3 (i.e. Dess–Martin periodinane reagent),
CH2Cl2, rt, overnight. (g) NaH, THF, 0°C, 40 min.

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J. A. Grzyb, R. A. Batey / Tetrahedron Letters 44 (2003) 7485–7488
tion and intramolecular Wadsworth–Horner–Emmons
of a phosphonate amide substrate using the car-
bamoylimidazolium salt protocol. Bicyclic lactam 9a is
an intermediate in the synthesis of indolizidines such as
2-epilentiginosine and lentiginosine,13 while 9b can be
used in the synthesis of quinolizidine ring systems and
is an intermediate in the synthesis of leontiformine and
leontiformidine.14 The synthesis began with the protec-
tion of 2-piperidinemethanol 10a or 2-piperidineethanol
10b with TBDMSCl in essentially quantitative yields.
The resultant amines 11a and 11b, used without purifi-
cation, were reacted with CDI in CH2Cl2 at room
temperature to generate the carbamoyl imidazoles in
greater then 95% yield after column chromatography.
Activation of 12a and 12b through methylation with
methyl iodide, according to the standard procedure,
generated the carbamoylimidazolium salts 13a and 13b
in quantitative yields. The phosphonate moiety neces-
sary for the Wadsworth–Horner–Emmons reaction was
accomplished through the amide bond forming reaction
between 13a and 13b and commercially available
diethyl phosphonoacetic acid at 50°C to give 14a and
14b in 92 and 91% yield, respectively. Deprotection
with TBAF occurred in 90% yield for the formation of
both 15a and 15b, and was followed by oxidation with
the Dess–Martin reagent to give 16a and 16b in 90 and
87% yields, respectively. Aldehydes 16a and 16b had to
be chromatographed through a very short silica column
to minimize decomposition, with impurities at this stage
leading to poor yields in the next step. The final
intramolecular Wadsworth–Horner–Emmons cycliza-
tion was carried out with sodium hydride in THF at
0°C to give the products 9a and 9b in 82 and 75% yield,
respectively.
lence Award. We thank Dr. A. B. Young for mass
spectrometric analysis.
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Crompton Co., the Natural Sciences and Engineering
Research Council of Canada (NSERC), the Ontario
Research and Development Challenge Fund, and the
Environmental Science and Technology Alliance of
Canada supported this work. We would also like to
thank Ms. Chiaki Yoshina-Ishii for preliminary experi-
ments, and Dr. Ming Shen for the synthesis of some of
the carbamoyl imidazolium salts. R.A.B gratefully
acknowledges receipt of a Premier’s Research Excel-