Aminocyanation by the addition of N-CN bonds to arynes: Chemoselective synthesis of 1,2-bifunctional aminobenzonitriles

Article abstract of DOI:10.1021/ol403346x

An efficient aminocyanation by the direct addition of aryl cyanamides to arynes is described, enabling incorporation of highly useful amino and cyano groups synchronously via cleavage of inert N-CN bonds, affording synthetically useful 1,2-bifunctional aminobenzonitriles. The postsynthetic functionalization of the aminocyanation products allows diverse formation of synthetically important derivatives such as drug molecule Ponstan and fused heterocycles.

Full text of DOI:10.1021/ol403346x

Letter
pubs.acs.org/OrgLett
Aminocyanation by the Addition of N−CN Bonds to Arynes:
Chemoselective Synthesis of 1,2-Bifunctional Aminobenzonitriles
Bin Rao and Xiaoming Zeng*
Center for Organic Chemistry, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi, 710054, P. R.
China
S
* Supporting Information
ABSTRACT: An efficient aminocyanation by the direct
addition of aryl cyanamides to arynes is described, enabling
incorporation of highly useful amino and cyano groups
synchronously via cleavage of inert N−CN bonds, affording
synthetically useful 1,2-bifunctional aminobenzonitriles. The
postsynthetic functionalization of the aminocyanation products
allows diverse formation of synthetically important derivatives
such as drug molecule Ponstan and fused heterocycles.
practical aminocyanation has not been reported to date, despite
the well-known examples of element−CN (E−CN) bond
addition to unsaturated bonds.10
he amino and cyano groups are recognized as among the
Tmost important building blocks and are found in various
bioactive molecules and functionalized materials.1,2 Although
dramatic advances have been achieved in transition-metal-
catalyzed amination3 and cyanation4 for separate formation of
these chemical subunits, a step-economic difunctionalization
reaction that enables synchronous installation of amino and
cyano fragments into one single molecule framework still
remains a significant challenge5 but is a practically useful
strategy to rapid synthesis of important amino nitriles.6 Current
studies in the field focus on the Strecker aminocyanation of
carbonyls7 and the Cu-catalyzed reaction of olefins8 by use of
amine, amide, and cyanide partners (Scheme 1a); thus, limiting
the scope of accessible compounds. Given the atom efficiency,
the use of N−CN bond-containing cyanamides as single amino
and cyano sources is highly attractive. However, because of the
difficulty in cleavage of unreactive N−CN bonds,9 such a
Arynes are synthetically valuable intermediates and have
been widely used in the construction of functionalized arenes.11
In particular, Larock, Yoshida, Stoltz, and others proved that
numerous σ bonds such as C−C, C−N, and C−O enable direct
addition across the high-strain triple bonds of arynes, generally
without the aid of transition metals.11b,12 In an effort to develop
a practically useful synthetic methodology, herein we describe
the first example of aminocyanation by the direct addition of
N−CN bonds of cyanamides to arynes, allowing introduction
of highly useful amino and cyano groups simultaneously to give
synthetically useful 1,2-bifunctional aminobenzonitriles, an
important class of synthons,13 and nonnucleoside reverse
transcriptase inhibitor candidates for HIV-1 infection (Scheme
1b).14
A typical example of a gram-scale reaction by treating 2-
(trimethylsilyl)phenyl trifluoromethanesulfonate (1a) with N-
(4-bromophenyl)cyanamide (2a) illustrates the simplicity of
the protocol (eq 1). A mixture of 1a (1.79 g, 6 mmol), 2a (0.99
Scheme 1. Aminocyanation Reactions
g, 5 mmol), and CsF (1.82 g, 12 mmol) was stirred in THF at
70 °C for 16 h, giving 2-aminobenzonitrile 3a (1.19 g) in
Received: November 19, 2013
Published: December 10, 2013
© 2013 American Chemical Society
314
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Letter
a
satisfactory yield (87%). The structure of 3a was identified by
single-crystal X-ray diffraction (see the Supporting Informa-
tion).
Table 1. Scope of Aryl Cyanamides
It is noteworthy that formation of the corresponding N−H
adduct compound 3a′ was also observed in the reaction (see
the Supporting Information for specific information).15 The
fluoride sources, solvents, and concentration heavily influence
the transformation and chemoselectivity. As compared with
tetrabutylammonium difluorotriphenylsilicate (TBAT), KF/18-
crown-6, and tetrabutylammonium fluoride (TBAF), cesium
fluoride gives the best result, forming 3a in good yield (89%)
and satisfactory chemoselectivity (3a:3a′ = 42:1). The solvent
screening shows that THF is superior to dimethyl ether,
acetonitrile, dioxane, and toluene. Interestingly, low concen-
tration favors the chemoselectivity, which can be significantly
improved to 93:1 in 0.02 M THF (eq 2).
Subsequently, the scope of cyanamides was next explored by
treatment with o-silyl aryl triflate 1a (Table 1). Various
electron-donating (entries 2−5) and electron-withdrawing
(entries 6−16) substituted aromatic cyanamides are suitable
with the formation of the corresponding aminocyanation
products in good yields (64−86%). A broad range of functional
groups, including fluoride, chloride, bromide, iodide, trifluor-
omethyl, alkoxyl, alkoxycarbonyl, nitro, and cyano, are well
tolerated. Notably, pyridyl-substituted cyanamide can be
employed in the reaction (entry 17). Interestingly, synthetically
important allyl and propargyl are successfully introduced into
the scaffolds of 2-aminobenzonitriles (entries 18 and 19).
Unfortunately, the transformations using N-alkyl- and N,N-
diaryl-substituted cyanamides, including N-benzylcyanamide,
N-methyl-N-phenylcyanamide, and N,N-diphenylcyanamide,
do not give the desired aminocyanation products.
The influence of substituents on the arynes was then studied
(Table 2). Both electron-poor (entry 1) and electron-rich
(entries 2 and 3) symmetric arynes allow easy access to the
desired products in moderate to good yields (42−75%).
Interestingly, introducing the inductively electron-withdrawing
methoxy group at the C3 and C5 positions of benzyne favors
the nucleophilic attack at C1 site, giving the 2-amino-
benzonitrile 3x as a single product (entry 4).11g It should be
mentioned that formation of a mixture in a nearly 1:1
regioisomeric ratio was observed using C4-methyl-substituted
aryne (entry 5). In addition to benzynes, the reaction of 1,2-
naphthalyne also takes place leading to two regioisomers (entry
6).
a
Reaction conditions: 1a (0.3 mmol), 2 (0.25 mmol), CsF (0.6
b
c
mmol), THF (2.5 mL), 70 °C, 16 h. Isolated yield. 1a (0.5 mmol), 2
(0.25 mmol), CsF (1.0 mmol), THF (12.5 mL).
a direct nucleophilic attack of cyanamide to benzyne without
the deprotonation cannot be excluded.
In view of the easily modified feature of the aminocyanation
products, the postsynthetic functionalization was explored.
Diversely functionalized derivatives, including 2-amino-sub-
stituted benzylamine (5), benzamide (6), ketone (7), and
benzaldehyde (8), can be readily accessed by the trans-
formation of the cyano scaffold while leaving NH and bromide
intact (Scheme 3). In particular, the application of our method
in transition-metal-free synthesis of the nonsteroidal anti-
inflammatory drug molecule Ponstan (9) was successfully
through two-step operations.18 The synchronous difunctional-
ization of the cyano and amino moieties was realized giving
diphenylamino-substituted benzamide derivative 10.19 In
addition, fused heterocyclic carbazole 11 and bioactive
acridanone 12 can also be easily produced. Obviously, the
diversely functionalization of the resulting 2-aminobenzonitriles
dramatically improves the practicality of the synthetic method-
ology.
To gain insight into the reaction pathway, a preliminary
mechanistic study was performed by treatment of N-(2-
bromophenyl)-N-phenylcyanamide (4) with n-BuLi and then
quenching with water (Scheme 2). The reaction furnishes the
2-aminobenzonitrile 3b in 62% yield. This indicates that a
phenyl anion derived from a nucleophilic attack of deproto-
nated cyanamide to benzyne can be considered in the
transformation,16 which may undergo a cyclization leading to
the four-membered intermediate B, followed by a ring-opening
and protonation giving the final product.17 On the other hand,
In summary, we have developed an operationally simple,
transition-metal-free, and highly efficient aminocyanation of
arynes through the direct addition of N−CN bonds of aryl
cyanamides. The protocol enables facile access to synthetically
and biologically interesting 1,2-bifunctional aminobenzonitriles
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Letter
a
Table 2. Variation of Substituents on the Arynes
Scheme 3. Postsynthetic Functionalization
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed optimization data; experimental procedures; character-
ization data of all new compounds; ORTEP drawing of 3a and
3z′; and crystallographic data (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zengxiaoming@mail.xjtu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for this work by XJTU from a start-up fund and the
National Natural Science Foundation of China [No. 21202128
(X.Z.)] is gratefully acknowledged. We are grateful to Prof.
Yan-Zhen Zheng (XJTU) for X-ray crystallographic analysis.
a
Reaction conditions: 1 (0.3 mmol), 2a (0.25 mmol), CsF (0.6
b
c
mmol), THF (2.5 mL), 70 °C, 16 h. Isolated yield. The ratio was
determined by H NMR analysis. 1g (0.5 mmol), 2a (0.25 mmol),
d
1
CsF (1.0 mmol), THF (12.5 mL).
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Scheme 2. Proposed Mechanism
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