Base-Promoted Coupling of Carbon Dioxide, Amines, and N -Tosylhydrazones: A Novel and Versatile Approach to Carbamatesby Wenfang Xiong, Chaorong Qi, Haitao He, Lu Ouyang, Min Zhang, Huanfeng Jiang

Angewandte Chemie International Edition


Chemistry (all) / Catalysis


LXVIII. The Abbot and Convent of Woburn to the King

Thabbot and convent of Woburn

Regulatory approaches to the control of environmental mutagens and carcinogens

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Occupational safety and health standards adopted for fourteen carcinogens

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Stephen N. Steen and Robert Crane


Multicomponent Reactions Hot Paper

DOI: 10.1002/anie.201410605

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 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.

Organic carbamates constitute an important class of biologically and pharmaceutically interesting compounds that frequently occur in numerous natural products,[1] agrochemicals,[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, organic carbamates can also serve as key reagents, targetspecific 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 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-carbonylsubstituted phenols,[12] have also been developed.

From the viewpoints of natural abundance, cost effectiveness, 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 halogenated 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.

In recent years, N-tosylhydrazones have been extensively employed as useful building blocks to construct complex molecules by transition-metal-catalyzed or metal-free crosscoupling 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 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 knowledge, 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.

Figure 1. Representative pharmaceuticals containing the carbamate motif.

Figure 2. The decomposition of tosylhydrazones and their application in organic synthesis. [*] 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: [**] We thank the National Natural Science Foundation of China (21172078), the National Basic Research Program of China (973

Program; 2011CB808600), the Guangdong Natural Science Foundation (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


Chemie 1Angew. Chem. Int. Ed. 2015, 54, 1 – 5  2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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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 120 8C 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 basepromoted 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).

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–3 ia), 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 electron-withdrawing groups furnished the desired products (3aa–3 fa) in higher yields than those with electron-neutral or electron-donating substituents (3ga–3 ia). 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 disubstituted and 1-naphthyl-substituted N-tosylhydrazones smoothly underwent the coupling reaction to afford the desired products 3 la and 3ma in 77% and 71% yield, respectively. Interestingly, organic carbamates with heterocyclic substituents, such as benzofuryl, thiophenyl, or pyridyl groups (3na–3pa), could also be obtained from the corresponding N-tosylhydrazones, albeit in moderate yields.