DOI: 10.1002/chem.201502733
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Synthetic Methods
Cyanoacetic Acid as a Masked Electrophile: Transition-Metal-Free
Cyanomethylation of Amines and Carboxylic Acids
Hongxiang Wang,[a] Ying Shao,*[a, b] Hao Zheng,[b] Hanghang Wang,[a] Jiang Cheng,[b] and
Xiaobing Wan*[a]
Abstract: Using cyanoacetic acid as a masked electrophile,
a new cyanomethylation reaction of amines and carboxylic
acids was developed, producing a variety of a-aminonitriles
and cyanomethyl esters with good yields and excellent func-
tionality tolerance. This protocol features simple manipula-
tion, inexpensive reagents, and a wide substrate scope. Io-
doacetonitrile was generated in situ from the iodination–de-
carboxylation of cyanoacetic acid in this transformation.
Introduction
Cyano groups are commonly found in a variety of natural
products and pharmaceutically active molecules, such as safra-
mycin A and phthalascidin.[1] Additionally, the cyano group can
be further transformed into various functional groups, such as
amino, carboxyl, aldehyde, and ester groups.[2] Therefore,
methods to introduce the cyano group into an organic com-
pound have been a topic of great interest to chemists. In
recent years, following the development of the cyanomethyl-
ation strategy, a series of cyanomethylation agents have been
exploited for use in this method. Cyanomethylation agents in-
clude acetonitrile and acetonitrile derivatives,[3] trimethylsilyla-
cetonitrile (TMSAN),[4] halideacetonitrile,[5] and isoxazole,[2b,6]
which provide new possibilities for the introduction of cyano
groups into organic compounds. However, these methods still
suffer from some inherentlimitations, such as harsh conditions
or a narrow scope of substrates.
Recently, Liu[7a,c] and Tunge[7h,i] et al. developed cyanomethy-
lation reactions by decarboxylation of a-cyanoacetic acids and
its derivatives.[7] This transition-metal-catalyzed reaction gener-
ates metal nucleophiles, which can then react with a variety of
electrophilic reagents, such as aryl halides,[7a,b] aryl triflates,[7a]
benzyl electrophiles,[7c] aldehydes,[7d] imines,[7d,e] and isatin[7f,g]
to construct cyano compounds (Scheme 1a). In sharp contrast
with previous results, cyanoacetic acid is envisioned as
a masked electrophile herein, and used to react with nucleo-
Scheme 1. Cyanomethylation reactions using a-cyanoacetic acids.
philes using Bu4NI as a catalyst and tBuOOH as an oxidant
(Scheme 1b).[8] Mechanistically, iodoacetonitrile is generated in
situ from the oxidative decarboxylation of cyanoacetic acid in
this transformation. This methodology not only provides
a metal-free and practical method to construct a-aminonitriles
and cyanomethyl esters, but also expands the scope of the
transition-metal-catalyzed decarboxylative coupling reactions,
previously studied systematically by Goossen,[9] Myers,[10]
Tunge,[11] and others[12]
.
Results and Discussion
The initial experiment was performed with N-methyl aniline
(1a) and 2-cyanoacetic acid (2) in the presence of Bu4NI
(20 mol%), tert-butyl hydroperoxide (TBHP, 2.2 equiv, 70%
aqueous solution) and NaOAc (2.0 equiv) in water (2.0 mL) at
808C for 12 h (Table 1). Gratifyingly, under such condition,
a high yield of a-aminonitrile (3a; 53%) was obtained (Table 1,
entry 15). No target product was obtained when CH3CN was
used instead of 2 for this transformation. Different oxidants
strongly influenced the reaction, for example, when the reac-
tion was carried out using H2O2, di-tert-butyl peroxide (DTBP),
Oxone, meta-chloroperbenzoic acid (m-CPBA), and K2S2O8 as
oxidants, the desired product (3a) was not detected in signifi-
cant amounts (entries 1–5). Additionally, when Bu4NI was re-
placed with other catalysts, such as I2, N-iodosuccinimide (NIS),
KI, tetrabutylammonium bromide (TBAB), or tetrabutylammoni-
[a] H. Wang, Prof. Dr. Y. Shao, H. Wang, Prof. Dr. X. Wan
Key Laboratory of Organic Synthesis of Jiangsu Province
College of Chemistry, Chemical Engineering and Materials Science
Soochow (Suzhou) University, Suzhou 215123 (P.R. China)
[b] Prof. Dr. Y. Shao, H. Zheng, Prof. Dr. J. Cheng
Jiangsu Key Laboratory of Advanced Catalytic Materials and
Technology Department, Changzhou University
Changzhou, 213164 (P.R. China)
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2015, 21, 18333 – 18337
18333
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