Base-promoted coupling of carbon dioxide, amines, and N-tosylhydrazones: A novel and versatile approach to carbamates

Article abstract of DOI:10.1002/anie.201410605

A base-promoted three-component coupling of carbon dioxide, amines, and N-tosylhydrazones has been developed. The reaction is suggested to proceed via a carbocation intermediate and constitutes an efficient and versatile approach for the synthesis of a wide range of organic carbamates. The advantages of this method include the use of readily available substrates, excellent functional group tolerance, wide substrate scope, and a facile work-up procedure.

Full text of DOI:10.1002/anie.201410605

Angewandte
Chemie
DOI: 10.1002/anie.201410605
Multicomponent Reactions
Hot Paper
Base-Promoted Coupling of Carbon Dioxide, Amines, and
N-Tosylhydrazones: A Novel and Versatile Approach to Carbamates**
Wenfang Xiong, Chaorong Qi,* Haitao He, Lu Ouyang, Min Zhang, and Huanfeng Jiang*
Abstract: A base-promoted three-component coupling of
carbon dioxide, amines, and N-tosylhydrazones has been
developed. The reaction is suggested to proceed via a carbo-
cation intermediate and constitutes an efficient and versatile
approach for the synthesis of a wide range of organic
carbamates. The advantages of this method include the use of
readily available substrates, excellent functional group toler-
ance, wide substrate scope, and a facile work-up procedure.
of carbamates is restricted.[8] Recently, elegant phosgene-free
methods, including the catalytic reductive carbonylation of
nitro compounds,[9] the oxidative carbonylation of amines,[10]
the Hofmann and Curtius rearrangements,[11] and oxidative
couplings of formamides with b-ketoesters or 2-carbonyl-
substituted phenols,[12] have also been developed.
From the viewpoints of natural abundance, cost effective-
ness, toxicity, and sustainability, the use of carbon dioxide as
an alternative to phosgene for the direct synthesis of organic
carbamates is highly desirable.[13] Despite of remarkable
advances achieved in the past decades, many of these methods
suffer from the use of less environmentally benign halogen-
ated reagents, a limited substrate scope, harsh reaction
conditions, and poor chemoselectivity or yields. Therefore,
the development of greener methods for the versatile
incorporation of CO2 to yield organic carbamates still remains
a demanding goal.
Organic carbamates constitute an important class of
biologically and pharmaceutically interesting compounds
that frequently occur in numerous natural products,[1] agro-
chemicals,[2] and medicines.[3] Representative examples,
namely Prezista,[4] Lunesta,[5] and VESIcare,[6] which are
used for the treatment of HIV, insomnia, and overactive
bladders, respectively, are shown in Figure 1. Moreover,
In recent years, N-tosylhydrazones have been extensively
employed as useful building blocks to construct complex
molecules by transition-metal-catalyzed or metal-free cross-
coupling reactions.[14] It is known that the diazo compound,
which is generated in situ from the N-tosylhydrazone through
a Bamford–Stevens process, can decompose to the carbene in
aprotic media (Figure 2, path a) or to the carbocation in protic
Figure 1. Representative pharmaceuticals containing the carbamate
motif.
organic carbamates can also serve as key reagents, target-
specific intermediates, and removable protecting groups in
organic synthesis.[7] Conventional methods for accessing such
compounds are mainly based on the use of toxic phosgene and
isocyanates, which can easily have a detrimental influence on
the environment, and their use for the large-scale production
Figure 2. The decomposition of tosylhydrazones and their application
in organic synthesis.
media (path b).[15] Thus far, most of the cross-coupling
reactions using N-tosylhydrazones as coupling partners are
designed to proceed through the former intermediate
whereas the corresponding carbocation has been scarcely
investigated in organic synthesis. To the best of our knowl-
edge, its application to the fixation of CO2 has not been
explored yet.[16] As part of our continuing studies on the
transformation of CO2 into useful chemicals,[17] combined
with our interest in the development of new synthetic
methods based on N-tosylhydrazones,[18] we herein present
an unprecedented strategy for the synthesis of organic
carbamates by a three-component coupling reaction of CO2,
amines, and N-tosylhydrazones under transition-metal-free
conditions.
[*] W. Xiong, Dr. C. Qi, H. He, L. Ouyang, Prof. Dr. M. Zhang,
Prof. Dr. H. Jiang
School of Chemistry and Chemical Engineering
South China University of Technology
Guangzhou 510640 (P.R. China)
E-mail: crqi@scut.edu.cn
jianghf@scut.edu.cn
[**] We thank the National Natural Science Foundation of China
(21172078), the National Basic Research Program of China (973
Program; 2011CB808600), the Guangdong Natural Science Foun-
dation (10351064101000000), and the Fundamental Research
Funds for the Central Universities (2013M0061) for financial
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410605.
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At the outset of this investigation, we explored the
coupling of N-tosylhydrazone 1a, pyrrolidine (2a), and CO2
for the synthesis of 3aa under different reaction conditions,[19]
and the optimized reaction conditions included the use of
K2CO3 as the base in a mixed MeCN/H2O (15:1) solvent
system at 1208C under CO2 atmosphere (4 MPa) for 24 hours
(Scheme 1).
With the optimized reaction conditions in hand, we turned
our attention to the scope and limitations of this base-
promoted transformation. Gratifyingly, a wide range of
N-tosylhydrazones with different substitution patterns could
be used in this reaction, affording the corresponding organic
carbamates in moderate to excellent yields (Scheme 1).
(3aa–3 fa) in higher yields than those with electron-neutral
or electron-donating substituents (3ga–3ia). Interestingly,
3- and 4-substituted substrates gave better yields than
2-substituted substrates (products 3aa, 3ja, and 3ka), which
might be attributed to steric hindrance effects. Both disub-
stituted and 1-naphthyl-substituted N-tosylhydrazones
smoothly underwent the coupling reaction to afford the
desired products 3la and 3ma in 77% and 71% yield,
respectively. Interestingly, organic carbamates with hetero-
cyclic substituents, such as benzofuryl, thiophenyl, or pyridyl
groups (3na–3pa), could also be obtained from the corre-
sponding N-tosylhydrazones, albeit in moderate yields.
N-Tosylhydrazones
derived
from
cyclopropyl-
(phenyl)methanone, benzophenone, and 3,4-dihydronaphtha-
len-1(2H)-one were also suitable substrates for this trans-
formation, giving the desired products in good to excellent
yields (3qa–3sa). Pleasingly, N-tosylhydrazones derived from
various benzaldehydes were compatible with the reaction
conditions and were efficiently converted into the corre-
sponding products 3ta–3va in good yields. However,
N-tosylhydrazones derived from aliphatic ketones or alde-
hydes failed to yield even a trace of the desired products;
presumably, the lack of a stabilizing group disfavors the
formation of essential reaction intermediates.
Subsequently, we turned our attention to the utilization of
various secondary and primary aliphatic amines (Scheme 2).
Scheme 1. Synthesis of organic carbamates from a variety of
N-tosylhydrazones. Reaction conditions: N-Tosylhydrazone
1 (0.5 mmol), pyrrolidine (5 mmol), K2CO3 (1.5 mmol), CO2 (4 MPa),
MeCN/H2O (3 mL, 15:1 v/v), 1208C, 24 h. Yields of isolated products
are given. Ts=para-toluenesulfonyl.
Scheme 2. Synthesis of organic carbamates from a variety of amines.
Reaction conditions: N-Tosylhydrazone 1a (0.5 mmol), amine
(5 mmol), K2CO3 (1.5 mmol), CO2 (4 MPa), MeCN/H2O (3 mL, 15:1
v/v), 1208C, 24 h. Yields of isolated products are given.
Notably, the reaction system tolerates a variety of valuable
functional groups on the aryl ring of the N-tosylhydrazones,
including Cl, Br, I, NO2, CF3, and CN substituents (products
3aa–3ia), providing ample potential for further synthetic
elaborations. The electronic nature of the substituents on the
aryl ring of the N-tosylhydrazone influences the product
yields significantly. In general, N-tosylhydrazones with elec-
tron-withdrawing groups furnished the desired products
To our delight, all of the coupling reactions proceeded
smoothly and furnished the corresponding products in
moderate to good yields under the standard reaction con-
ditions. However, the reaction using aniline as a coupling
partner gave rise to a complex mixture, and the desired
product was not observed, which could be ascribed to the low
basicity and nucleophilicity of aniline.
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Considering that the N-tosylhydrazones are easily
obtained by condensation reactions between tosylhydrazides
and carbonyl compounds, we then wished to develop a one-
pot synthesis of the organic carbamates through the use of
N-tosylhydrazones generated in situ (Scheme 3). Therefore,
Scheme 3. One-pot synthesis of 3ac. Reaction conditions: 1) 4
(0.5 mmol), tosylhydrazide (0.5 mmol), reflux, 2 h; 2) diethylamine
(5 mmol), K2CO3 (1.5 mmol), CO2 (4 MPa), MeCN/H2O (3 mL, 15:1
v/v), 1208C, 24 h.
Scheme 5. Proposed reaction mechanism.
tions, a plausible mechanism is proposed in Scheme 5.
Initially, N-tosylhydrazone 1w undergoes thermal decompo-
sition in the presence of K2CO3 to generate diazo compound
A, which could be protonated by carbonic acid formed from
water and CO2 to provide diazonium ion B. Then, the
thermodynamically favorable liberation of dinitrogen gives
allylic carbocation species C,[15b] which can be described by
a resonance hybrid of D and E. Finally, the carbamate anion,
which is generated from the reaction of the amine with
CO2,[13] undergoes nucleophilic attack to C, which affords the
desired products 3wc or 3wc’. It should be pointed out that
the final step could also be promoted by K2CO3.[13e]
a solution of 1-(4-bromophenyl)ethanone (4) and tosylhy-
drazide in methanol was heated to reflux and stirred for two
hours, followed by removal of the solvent, and the remaining
crude mixture was then treated with K2CO3, pyrrolidine, and
CO2 under the standard reaction conditions. Gratifyingly, the
desired product 3ac could also be obtained in a similar yield
to that described in Scheme 2. This reaction demonstrates the
potential of this method for the convenient synthesis of
various carbamates directly from readily available carbonyl
compounds.
To gain further insights into the nature of this trans-
formation, we conducted the three-component reaction of
N-tosylhydrazone 1w, diethylamine (2c), and CO2 under the
optimized reaction conditions. Upon isolation, two regioisom-
ers (3wc and 3wc’) were obtained in 43% and 14% yield,
respectively (Scheme 4).[20] These results indicate that the
In summary, we have developed a novel and versatile
reaction of CO2 with N-tosylhydrazones and amines to yield
organic carbamates, offering an attractive method for the
straightforward synthesis of various carbamates, a privileged
motif found in a number of natural and synthetic compounds
with extraordinary biological and pharmaceutical properties.
Further investigations to extend the substrate scope of this
reaction and to deepen our mechanistic understanding of this
transformation are ongoing in our laboratory.
Received: October 31, 2014
Revised: December 7, 2014
Published online: && &&, &&&&
Keywords: amines · carbamates · carbon dioxide ·
.
multicomponent reactions · tosylhydrazones
Scheme 4. The three-component reaction of N-tosylhydrazone 1w,
diethylamine, and CO2. Reaction conditions: 1) 1w (0.5 mmol), diethyl-
amine (5 mmol), K2CO3 (1.5 mmol), CO2 (4 MPa), MeCN/H2O (3 mL,
15:1 v/v), 1208C, 24 h.
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[20] 5-Phenyl-1H-pyrazole as the major side product was also
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Multicomponent Reactions
W. Xiong, C. Qi,* H. He, L. Ouyang,
M. Zhang, H. Jiang*
&&& — &&&
Carbene intermediate? No! An unprece-
dented strategy for the synthesis of
a range of organic carbamates through
the coupling of carbon dioxide, amines,
and N-tosylhydrazones is reported. The
base-promoted reaction is proposed to
Base-Promoted Coupling of Carbon
Dioxide, Amines, and
N-Tosylhydrazones: A Novel and Versatile
Approach to Carbamates
proceed via a carbocation intermediate
and is characterized by excellent func-
tional group tolerance and a wide sub-
strate scope.
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