A Cyanide-Free Synthesis of Acylcyanides through Ru-Catalyzed C(sp3)-H-Oxidation of Benzylic Nitriles

Article abstract of DOI:10.1002/open.201900130

A practical method for generation of acylcyanides devoid of any external cyanide sources is presented that relies on a mild Ru-catalyzed selective C?H-oxidation of benzylic nitriles. The starting materials are smoothly generated through condensation of the corresponding carboxylic acid amides using silanes. The obtained acylcyanides can be employed in a plethora of transformation as exemplified to some larger extend in the sequence of C?H-oxidation-Tischenko-rearrangement for the generation of structurally diverse benzoyloxycyanohydrines.

Full text of DOI:10.1002/open.201900130

DOI: 10.1002/open.201900130
Communications
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A Cyanide-Free Synthesis of Acylcyanides through
Ru-Catalyzed C(sp3)-H-Oxidation of Benzylic Nitriles
Pascal Eisele, Michael Bauder, Shih-Fan Hsu, and Bernd Plietker*[a]
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A practical method for generation of acylcyanides devoid of any
external cyanide sources is presented that relies on a mild Ru-
catalyzed selective CÀ H-oxidation of benzylic nitriles. The
starting materials are smoothly generated through condensa-
tion of the corresponding carboxylic acid amides using silanes.
The obtained acylcyanides can be employed in a plethora of
transformation as exemplified to some larger extend in the
sequence of CÀ H-oxidation-Tischenko-rearrangement for the
generation of structurally diverse benzoyloxycyanohydrines.
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Acylcyanides are versatile building blocks in Organic synthesis.[1]
They can be used as both acylating reagents but also in cross-
couplings[2] and addition reactions[3] but also in carbonylcyana-
tion of alkynes[4] or the formation of cyanohydrines (Figure 1).[5]
At the outset of our studies 4-methoxyphenylacetonitrile
and the conditions for the previously reported benzylic CÀ H
oxidation were chosen for the initial experiments and further
optimized. We were delighted to find that after a slight
modification of the previously established reactions conditions
the corresponding acylcyanide 2 was obtained in 97% yield. As
expected, electron-rich acetonitriles give higher yields but
moderately electron withdrawing groups like halides are
tolerated as well. Interestingly, even acetals are stable under
the conditions, neither hydrolysis nor oxidation to the corre-
sponding carbonates were observed. As acylcyanides are highly
reactive,[1] the crude acylcyanides were trapped as t-butylesters
by simple treatment with t-butanol in the presence of base
(Table 1).
Figure 1. Ru-catalyzed selective CÀ H-oxidation of benzylnitriles.
Table 1. Ru-catalyzed oxidation of benzylnitriles and in-situ trapping.
As pointed out above, acylcyanides are highly reactive
intermediates which are difficult to isolate. In the fate of
practicability we subsequently wondered, whether the reaction
mixture could be quenched through the addition of
nucleophiles.[11] While in the case of t-butanol a switch of
solvents proved necessary, both secondary and primary alco-
hols could be added directily after full conversion in the
[a] M. Sc. P. Eisele, M. Sc. M. Bauder, Dr. S.-F. Hsu, Prof. Dr. B. Plietker
Institute of Organic Chemistry
University of Stuttgart
Pfaffenwaldring 55, DE-70569 Stuttgart, Germany
E-mail: bernd.plietker@oc.uni-stuttgart.de
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/open.201900130
© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This
is an open access article under the terms of the Creative Commons Attri-
bution Non-Commercial NoDerivs License, which permits use and distribu-
tion in any medium, provided the original work is properly cited, the use is
non-commercial and no modifications or adaptations are made.
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Table 2. Sequential CÀ H oxidation-nucleophilic substitution.
Table 3. Sequential CÀ H oxidation-acylcyanide rearrangement.
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catalytic CÀ H-oxidation to obtain the corresponding esters in
good to excellent yields (Table 2). Moreover, thiols but also
amines can be employed. Deterious side reaction due to
remainding catalyst and/or oxidant were not observed.
Apart from the use of acylcyanides as acylating agents, their
transformation into acylcyanohydrins through base-mediated
reaction with aldehydes is an important application (Table 3).
Knowing that the in-situ trapping experiments provide
access to different ester, thioesters, and amides (Table 2), we
became interested in tying up both processes. Indeed, upon
addition of 0.4 equiv. of triethylamine and 1 equiv. of aldehyde
to the in-situ formed acylcyanide delivered the corresponding
cyanohydrines in good to excellent yields (Table 3). Both
aromatic and aliphatic aldehydes were tolerated and converted
in good yields. α,β-unsaturated aldehydes like Cinnamaldehyde
(Table 3, compound 34) or Citral (Table 3; compounds 39) were
converted without observation of the 1,4-addition product. In
case of (S)-(À )-citronellal retention of the stereocenter and a
single diastereomer was observed (Table 3, compound 38).
A variety of methods for the synthesis of nitriles has been
reported in the literature.[12] Apart from the classical preparation
via nucleophilic substitution using cyanide salts,[13] the dehy-
dration of carboxylic acid amides is the most prominent
synthetic approach.[14] Classical methods for the dehydration
rely on the use of dehydrating agents like P2O5, PCl5, etc. under
high temperature.[15] Most recently, catalytic versions for amide
Scheme 1. Cyanide-free synthesis of acylcyanohydrinesters starting from
carboxylic acid amides.
oxidized and after addition of butyraldehyde and amine base
transferred into the benzoylcyanohydrine in about 75% yield.
In summary we were able to develop a convenient cyanide
salt free method for the preparation of benzoyl cyanides which
are versatile and reactive compounds. Conversion of those
benzoyl cyanides into the valuable cyanohydrin esters is
possible under these conditions in a one-pot sequence.
dehydration to nitriles were described.[16] To showcase the Acknowledgements
synthetic utility of the oxidative preparation of acylcyanides, we
coupled both processes (Scheme 1). The fluoride-catalyzed
dehydration delivered after filtration over Alox-N (removal of
silicon by-products) a solution of the nitrile which was directly
Financial support by the Deutsche Forschungsgemeinschaft (DFG),
the Landesgraduiertenstiftung Baden-Württemberg (Ph.D.-grant
for P.E. as part of the cooperative graduate school “Windy Cities”),
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Plietker, Angew. Chem. Int. Ed. 2017, 56, 15852–15856; Angew. Chem.
and the Deutscher Akademischer Austauschdienst (DAAD) (Ph.D.-
grant for S.-F.H.) is gratefully acknowledged.
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T. Kuwabara, Synlett 1989, 62–63; b) For a Ru-catalyzed synthesis of
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Conflict of interest
The authors declare no conflict of interest.
Keywords: acylcyanides
· oxidation reactions · catalysis ·
ruthenium · cyanohydrines
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Manuscript received: April 9, 2019
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Communications
COMMUNICATIONS
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M. Sc. P. Eisele, M. Sc. M. Bauder,
Dr. S.-F. Hsu, Prof. Dr. B. Plietker*
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A Cyanide-Free Synthesis of Acyl-
cyanides through Ru-Catalyzed C
(sp3)-H-Oxidation of Benzylic
Nitriles
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Three on one strike: The Ru-catalyzed
CÀ H-oxidation of benzylnitrile deriva-
tives provides access toward reactive
acylcyanides which can be trans-
formed in-situ into esters, amides, but
also into acylcyanohydrines. Upon
coupling the process to a fluoride-
catalyzed dehydrogenation of carbox-
ylic acid amides allows for a three-
step, one-pot preparation of acylcya-
nohydrines without the need to
employ cyanide salts.