A new combined source of "cN" from N, N -dimethylformamide and ammonia in the palladium-catalyzed cyanation of aryl C-H bonds

Article abstract of DOI:10.1021/ja104917t

An unprecedented protocol for cyanation at arene C-H bonds has been developed by employing N,N-dimethylformamide and ammonia as a combined source for the cyano "CN" unit. Isotopic incorporation experiments revealed that the carbon and nitrogen of the "CN" originate from the N,N-dimethyl moiety of DMF and ammonia, respectively. The present cyanation reaction shows an excellent degree of regioselectivity, producing only monosubstituted nitriles at the less hindered C-H position, and it allows for the preparation of doubly labeled nitrile compounds for the first time.

Full text of DOI:10.1021/ja104917t

Published on Web 07/13/2010
A New Combined Source of “CN” from N,N-Dimethylformamide and Ammonia
in the Palladium-Catalyzed Cyanation of Aryl C-H Bonds
Jinho Kim and Sukbok Chang*
Molecular-LeVel Interface Research Center and Department of Chemistry, Korea AdVanced Institute of Science and
Technology (KAIST), Daejeon 305-701, Korea
Received June 5, 2010; E-mail: sbchang@kaist.ac.kr
Table 1. Effects of the Reaction Parameters in the Pd-Catalyzed
Abstract: An unprecedented protocol for cyanation at arene C-H
bonds has been developed by employing N,N-dimethylformamide
and ammonia as a combined source for the cyano “CN” unit.
Isotopic incorporation experiments revealed that the carbon and
nitrogen of the “CN” originate from the N,N-dimethyl moiety of
DMF and ammonia, respectively. The present cyanation reaction
shows an excellent degree of regioselectivity, producing only
monosubstituted nitriles at the less hindered C-H position, and
it allows for the preparation of doubly labeled nitrile compounds
for the first time.
Cyanation
entry
change from the “standard conditions”
yield of 2a (%)a
1
2
none
no Pd(OAc)2
85
0
3
4
5
no CuBr2
no NH3(aq)
DMSO instead of DMF
0
0b
0
6
7
8
9
N2 instead of O2 [with 1 equiv of Pd(OAc)2]
0.5 equiv of CuBr2 instead of 1.1 equiv
Cu(OAc)2 instead of CuBr2
CuCN instead of CuBr2
0
49
20
0
Aromatic nitriles possess versatile utilities and are indispensible
not only in organic synthesis but also in chemical industry.1 In
fact, the nitrile group is an important precursor for various functional
groups such as aldehydes, amines, amidines, tetrazoles, amides, and
their carboxyl derivatives.2 Representative methods for the prepara-
tion of organonitriles with cyanide-containing reagents are the
Sandmeyer3 and Rosenmund-von Braun reactions.4 Recently, a
catalytic route to aryl nitriles has been reported on the basis of the
chelation-assisted C-H bond activation5 or metal-catalyzed cya-
nation of haloarenes.6 In those cyanation protocols, the “CN” unit
is provided from metal-bound precursors of MCN (M ) Cu, K,
Na, Zn), TMSCN, or K3Fe(CN)6.6 Additionally, it can be generated
in situ from nitromethane5a or acetone cyanohydrin.7 Herein, we
report the first example of generating “CN” from two different,
readily available precursors, ammonia and N,N-dimethylformamide
(DMF) (Scheme 1). In addition, its synthetic utility is demonstrated
through the Pd-catalyzed cyanation of arene C-H bonds.
10
Pd(OCOCF3)2 instead of Pd(OAc)2
42
a
1H NMR yield (internal standard: 1,1,2,2-tetrachloroethane). b The
2,2′-dimer of 1a was exclusively obtained in 90% yield.
Scheme 2. Cyanation with Different “CN” Sources
Scheme 1
(entries 2 and 3). It was also observed that both DMF solvent and
oxygen atmosphere were essential (entries 5 and 6). While lower
loading of CuBr2 decreased the product yield (entry 7), palladium
or copper species other than Pd(OAc)2 and CuBr2 gave inferior
results (entries 8-10). The reaction was highly regioselective,
affording the cyano product exclusively at the position ortho to
the 2-pyridyl group. On the other hand, when 4-methylbiphenyl
was employed, no cyanated product was observed, suggesting the
importance of a directing group for the conversion.
In order to obtain a clue concerning how the “CN” unit is
provided in this unique cyanation procedure, a series of experiments
were next performed (Scheme 2). When 1a was allowed to react
with 15N-labeled aqueous ammonia under the standard conditions,
almost complete isotopic incorporation into the 2-cyano moiety was
During the course of our studies on the C-H functionalization
of arenes,8 we were interested in the employment of readily
available and nonexpensive reagents such as ammonia.9 With the
use of 2-(p-tolyl)pyridine (1a) as a model substrate, amination of
the tolyl moiety was initially tried using aqueous ammonia.10 Quite
surprisingly, instead of the anticipated product 5-methyl-2-(pyridin-
2-yl)aniline (3a), its cyano variant 2a was obtained in 85% NMR
yield under the standard conditions (Table 1, entry 1). Both
palladium and copper species were required for the cyanation
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10.1021/ja104917t  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Pd-Catalyzed Cyanation with NH3(aq) and DMFa
Scheme 3. Mechanistic Proposal for the “CN” Formation
observed (combination 1),11 strongly indicating that ammonia serves
as the nitrogen source of “CN”. It was interesting to note that the
carbon source of “CN” was supplied from the dimethylamino
moiety rather than formyl group of DMF (combinations 2 and 3).12
In addition, while the use of N,N-dimethylacetamide resulted in
just a moderate product yield relative to that for DMF, its
diethylamino derivative did not afford 2a (combinations 4 and 5),
implying that the N,N-dimethylamino moiety of amides is an
efficient carbon source of “CN” in the present cyanation protocol.
Although the details of this way of generating the cyano unit
“CN” are not clear at the present stage, it is proposed that the copper
complex is presumably involved in the single electron transfer (SET)
step to give an imine species A, which is attacked by ammonia to
provide an amidine intermediate B (Scheme 3).13 C-N bond
cleavage in B is envisioned to occur under the aerobic conditions,
leading to “CN” (major pathway).14 It was observed that the reaction
is completely inhibited in the presence of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO).15 On the basis of the above isotope
experiments (Scheme 2), a path generating “CN” from the formyl
group of DMF and ammonia can be regarded as a minor contribu-
tion. However, an alternative route to cyanation that, instead of
using prior-generated “CN”, proceeds via reaction of the substrate
with proposed amidine species such as B to form an intermediate
D cannot be completely ruled out at the moment. On the other hand,
it is postulated that the palladium catalyst is involved only in the
C-H bond activation of 1a, and a large intramolecular kinetic
isotope effect (kH/kD ) 3.3) was observed from 1a-d.16
Irrespective of the exact mechanistic path offering the “CN” unit,
the standard cyanation conditions were briefly applied to a range
of substrates (Table 2). 2-(2-Pyridyl)arenes bearing various sub-
stitutents at the para, meta, or ortho position were readily cyanated,
although electron-deficient groups led to slightly lower product
yields (2a-j). A substituted pyridyl group did not cause any
difficulties (2k). Cyanation of arenes containing other pyridine-
like directing groups also proceeded smoothly. In fact, the reactions
of 1-phenylisoquinoline (2l), benzo[h]quinoline (2m), and 2-phe-
nylpyrimidine (2n) afforded the corresponding cyanated products
in high efficiency. It should be noted that the reaction is highly
regioselective, affording only one isomeric product in cases where
two different reacting sites are present (e.g., 2h, 2i, and 2j).
Since the present cyanation protocol employs two different
sources for the in situ generation of “CN”, it was envisioned that
doubly labeled benzonitriles could readily be obtained. Indeed, when
isotopic aqueous ammonia (15NH3) and N,N-dimethyl-13C2 DMF
were used under our conditions, a doubly labeled product was
isolated in 40% yield17 with >96% isotopic incorporation at each
carbon and nitrogen of “CN” (eq 1), representing to the best of
our knowledge the first example of making such nitriles.
a Substrate (0.3 mmol), NH3(aq, 28%), DMF (1.5 mL), and O2 (1
atm). b Reaction time 48 h. c Using 2.2 equiv of CuBr2 and 8.8 equiv of
NH3(aq) for 48 h.
In summary, we have discovered a new protocol for generating
a cyano “CN” unit from two readily available precursors, NH3(aq)
and DMF. Its synthetic utility has been demonstrated in the Pd-
catalyzed cyanation of aryl C-H bonds. Mechanistic studies on
the detailed path of generating the cyano group are underway.
Acknowledgment. Dedicated with respect to the memory of
Prof. Chi Sun Hahn. This research was supported by the Korea
Research Foundation (KRF-2008-C00024, Star Faculty Program)
and MIRC (NRF-2010-0001957).
1
Supporting Information Available: Experimental details and H,
13C, and 15N NMR spectra of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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(16) See the Supporting Information for details.
(17) The lower yield is presumably due to the lower concentration of aqueous
ammonia employed. See the Supporting Information for details.
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