Selective α‐Deuteration of Cinnamonitriles using D2O as Deuterium Source

Beibei Guo,Johannes G De Vries,Edwin Otten

doi:10.1002/adsc.202101093

Beibei Guo, Johannes G De Vries + Show 1 more

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https://doi.org/10.1002/adsc.202101093

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Abstract

AbstractThe selective α‐deuteration of α,β‐unsaturated nitriles using the strong base tBuOK or a metal‐ligand cooperative Ru pincer catalyst is described. With D2O as deuterium source and glyme as solvent at 70 °C, tBuOK is an efficient catalyst for deuteration at the α‐C(sp2) position of cinnamonitriles, providing access to a broad range of deuterated derivatives in good to excellent yields and with very high levels of deuterium incorporation. While the tBuOK‐catalysed protocol does not tolerate base‐sensitive functional groups, cinnamonitrile derivatives containing a benzylic bromide or ester moiety were deuterated in excellent yields using Milstein's ruthenium PNN pincer catalyst. Moreover, the activity for H/D exchange of the metal‐ligand cooperative Ru catalyst is found to be significantly higher than that of tBuOK, allowing reactions to proceed well even at room temperature. A mechanistic proposal is put forward that involves deprotonation of the cinnamonitrile α‐CH position when using tBuOK as catalyst, whereas H/D exchange catalysis with the Ru PNN pincer likely proceeds via (reversible) oxa‐Michael addition of D2O.magnified image

Highlights

Labelled compounds in which one or more hydrogen (1H) atoms are substituted for the heavier isotopes deuterium (2H or D) or tritium (3H or T) are of interest in a wide variety of contexts
No H/D exchange was observed in the absence of APNN
The related PNP-pincer catalyst APNP instead resulted in a mixture of nitrile and the corresponding amide product, which indicates that under these conditions APNP is active for both H/D exchange and nitrile hydration.[19]

Summary

Introduction

Labelled compounds in which one or more hydrogen (1H) atoms are substituted for the heavier isotopes deuterium (2H or D) or tritium (3H or T) are of interest in a wide variety of contexts. The use of glyme (dimethoxyethane) as a solvent resulted in 95% deuteration under these conditions (rt, 24 h; entry 7 in Table 1), which indicates H/D exchange to approach the expected statistical distribution based on the amount of deuterium present

Results

Conclusion