Elsevier

Tetrahedron Letters

Volume 57, Issue 44, 2 November 2016, Pages 4890-4892
Tetrahedron Letters

One-pot synthesis of carbamates and thiocarbamates from Boc-protected amines

https://doi.org/10.1016/j.tetlet.2016.09.038Get rights and content

Highlights

  • One-pot reaction for the synthesis of carbamates and thiocarbamates using Boc-protected amines was realized.

  • In situ-generated isocyanates react with relatively weak nucleophiles such as alcohols and thiols.

  • The reactivity of alcohols was improved by changing the reaction conditions.

Abstract

A highly efficient one-pot procedure for the synthesis of carbamates and thiocarbamates has been described. In the presence of 2-chloropyridine and trifluoromethanesulfonyl anhydride, the isocyanate intermediates were generated in situ for further reactions with alcohols and thiols to afford the desired carbamates and thiocarbamates in high yields.

Introduction

Carbamates and thiocarbamates are found in numerous bioactive compounds such as agrochemicals and pharmaceutical candidates. For example, they have been applied in various commodity chemicals such as herbicides,1 pesticides,1b bactericides,2 and antiviral agents.3 Given the importance of this class of biologically active compounds, the synthesis of carbamates and thiocarbamates is a high-value endeavor.

Numerous preparations of carbamates and thiocarbamates have been reported. The traditional method involves the use of toxic phosgene or triphosgene and transition metal species such as palladium,4 nickel,5 and rhodium.1(b), 6 Recently, more environmentally benign procedures also have been developed. For example, carbonates,7 N-N′-carbonyldiimidazole,8 1,1′-carbonylbisbenzotriazole,9 S,S-dimethylthiocarbonate,10 and S-methylthiocarbamate11 have been used for the synthesis of carbamates and thiocarbamates. In addition, the isocyanate group has been widely employed as a precursor for carbamate moieties. There are various procedures for generating the desired isocyanate intermediates. Transformation of carboxylic acid derivatives to the corresponding isocyanates has been achieved via oxidative rearrangements such as Hofmann or Curtius rearrangements.12 However, there are certain limitations in oxidative rearrangements such as the use of strong hypervalent iodine reagents (Hofmann rearrangement) and potentially explosive azides (Curtius rearrangement).12b The Lossen rearrangement generates isocyanates under relatively mild reaction conditions.13 Hydroxamic acids have been employed for the synthesis of carbamates via this process.1(b), 14 However, the formation of by-products during the Lossen rearrangement would be problematic for making this a green alternative.1(b), 13

Alternatively, the isocyanate intermediate could be generated in situ under mild reaction conditions in the presence of a base and trifluoromethanesulfonyl anhydride. This strategy has been employed in several reactions. For example, 2-chloropyridine and trifluoromethanesulfonyl anhydride have been used to generate the isocyanate intermediate in Friedel–Crafts acylation,15 cyclodehydration reactions,16 and urea synthesis.17 Encouraged by these reports and our continuing interest in the synthesis of bioactive-relevant compounds, we explored a one-pot reaction for the synthesis of carbamates and thiocarbamates. Herein we report the first one-pot protocol of carbamates and thiocarbamates from Boc-protected amines (Scheme 1).

Section snippets

Results and discussion

The main problem in the synthesis of carbamates starting from Boc-protected amines is the relatively weak nucleophilicity of the alcohols which react with in situ-generated isocyanates to afford the desired carbamates.

We hypothesized that the weak nucleophiles (e.g., alcohols) could be activated by changing the reaction conditions. To test our hypothesis, we chose the reaction of Boc-protected amine 1a and isobutanol as our model (Table 1). Various amines were tested in the reaction. The

Conclusion

We have developed a highly efficient one-pot reaction for the synthesis of carbamates and thiocarbamates from Boc-protected amines. The in situ-generated isocyanates react successfully with relatively weak nucleophiles such as alcohols and thiols, producing the resulting carbamates and thiocarbamates in high yields. This one-pot process facilitates rapid access to carbamates and thiocarbamates and further studies on the synthesis of biologically active compounds via in situ-generated isocyanate

Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A1A2057943).

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