Chelation-assisted palladium-catalyzed direct cyanation of 2-arylpyridine C-H bonds

Article abstract of DOI:10.1021/ol9017529

A chelation-assisted palladium-catalyzed ortho-cyanation of the sp ² C-H bond by CuCN provided aromatic nitriles In moderate to good yields. Notably, the reaction could be conducted on a 10 mmol scale. The key Intermediate of the natural produc

Full text of DOI:10.1021/ol9017529

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4716-4719
Chelation-Assisted Palladium-Catalyzed
Direct Cyanation of 2-Arylpyridine C-H
Bonds
Xiaofei Jia,† Dongpeng Yang,† Shouhui Zhang,† and Jiang Cheng*,†,‡
College of Chemistry & Materials Engineering, Wenzhou UniVersity,
Wenzhou 325027, P. R. China, and State Key Laboratory of Coordination Chemistry,
Nanjing UniVersity, Nanjing 210093, P. R. China
jiangcheng@wzu.edu.cn
Received July 31, 2009
ABSTRACT
A chelation-assisted palladium-catalyzed ortho-cyanation of the sp2 C-H bond by CuCN provided aromatic nitriles in moderate to good yields.
Notably, the reaction could be conducted on a 10 mmol scale. The key intermediate of the natural product of Menispermum dauricum DC was
concisely synthesized by the procedure. This new approach represents an exceedingly practical method for the synthesis of aromatic nitriles
and offers an attractive alternative to the traditional Sandmeyer reaction.
Aromatic nitriles are not only key components of numerous
commercial compounds, including pharmaceuticals, agro-
chemicals, pigments, and dyes,1 but also valuable in the
installation of functional groups, such as aldehydes, amines,
amidines, tetrazoles, carboxylic acids, and carboxylic acid
derivatives.2 The Sandmeyer reaction is a powerful method
for the synthesis of aromatic nitriles, but the multiple-step
procedure limits its application (Path a, Scheme 1). Alterna-
tive transformations involve the palladium-catalyzed cyana-
tion of aryl halides with cyanating reagents, such as KCN,
Over the past several decades, extensive efforts have been
directed toward a transition-metal-catalyzed C-H function-
alization.4 The combination of transition metals and directing
groups has been a useful strategy to facilitate the transforma-
tion of C-H bonds into C-C5 and C-hetero bonds,6 which
suffered from the limited scope of reaction partners. From
the synthetic point of view, the direct and catalytic cyanation
via C-H bond cleavage is attractive in organic chemistry
(Path c, Scheme 1); nevertheless, to the best of our
knowledge, few examples have been reported to access
3
Zn(CN)2, TMSCN, and K3Fe(CN)6 (Path b, Scheme 1).
(3) (a) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 1388.
(b) Cristau, H.-J.; Ouali, A.; Spindler, J.-F.; Taillefer, M. Chem.sEur. J.
2005, 11, 2483. (c) Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.;
Sans, J.; Weiss, S.; Beller, M. Chem.sEur. J. 2003, 9, 1828. (d) Zhu, Y.-
Z.; Cai, C. Eur. J. Org. Chem. 2007, 2401. (e) Weissman, S. A.; Zewge,
D.; Chen, C. J. Org. Chem. 2005, 70, 1508. (f) Marcantonio, K. M.; Frey,
L. F.; Liu, Y.; Chen, Y.; Strine, J.; Phenix, B.; Wallace, D. J.; Chen, C.
Org. Lett. 2004, 6, 3723. (g) Yang, C.; Williams, J. M. Org. Lett. 2004, 6,
2867. (h) Littke, A.; Soumeillant, M.; Kaltenbach, R. F., III; Cherney, R. J.;
Tarby, C. M.; Kiau, S. Org. Lett. 2007, 9, 1711. (i) Chidambaram, R.
Tetrahedron Lett. 2004, 45, 1441. (j) Srivastava, R. R.; Collibee, S. E.
Tetrahedron Lett. 2004, 45, 8895. (k) Jin, F.; Confalone, P. N. Tetrahedron
Lett. 2000, 41, 3271. (l) Schareina, T.; Zapf, A.; Beller, M. Tetrahedron
Lett. 2004, 45, 4576. (m) Sundermeier, M.; Mutyala, S.; Zapf, A.;
Spannenberg, A.; Beller, M. J. Organomet. Chem. 2003, 684, 50. (n)
Schareina, T.; Zapf, A.; Ma¨gerlein, W.; Mu¨ller, N.; Beller, M. Tetrahedron
Lett. 2007, 48, 1087. (o) Okano, T.; Iwahara, M.; Kiji, J. Synlett 1998,
243.
However, prefunctionalization, mostly bromination, is re-
quired in this cyanation reaction.
† Wenzhou University.
‡ Nanjing University.
(1) (a) Uehling, D. E.; Nanthakumar, S. S.; Croom, D.; Emerson, D. L.;
Leitner, P. P.; Luzzio, M. J.; McIntyre, G.; Morton, B.; Profeta, S.; Sisco,
J.; Sternbach, D. D.; Tong, W.-Q.; Vuong, A.; Besterman, J. M. J. Med.
Chem. 1995, 38, 1106. (b) Nagamura, S.; Kobayashi, E.; Gomi, K.; Saito,
H. Bioorg. Med. Chem. 1996, 4, 1379. (c) Kleemann, A.; Engel, J.; Kutscher,
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Transformations; Wiley-VCH: New York, 1988.
10.1021/ol9017529 CCC: $40.75
Published on Web 09/18/2009
 2009 American Chemical Society

We first tested the cyanation of 2-phenylpyridine with
CuCN. To our delight, cyanation took place in the presence
of Pd(OAc)2 (10 mol %) with Cu(OAc)2 (0.4 equiv) in DMF
under air (Table 1, entry 1). Among the Cu(II) catalysts
Scheme 1. Three Pathways to Access Aromatic Nitrile
Table 1. Selected Results of Screening the Optimal Conditionsa
entry
palladium
oxidant (equiv)
solvent
yield (%)b
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Cu(OAc)2 (0.4) DMF
34
25
81(85)c
20
16
42
60
<5
<5
<5
8
11
<5
32
47
<5
13
<5
CuCl2 (0.4)
CuBr2 (0.4)
CuSO4 (0.4)
Cu(OTf)2 (0.4)
DMF
DMF
DMF
DMF
aromatic nitriles via C-H bond cleavage employing TMSCN
as the cyanating reagent.7 The general problem of these
cyanation reactions is the deactivation of the transition-metal
catalyst by formation of highly stable cyano complexes.8
Thus, the concentration of dissolved cyanide ions is crucial
for the direct cyanation of C-H bonds. Herein, we report
the palladium-catalyzed ortho-cyanation of aromatic C-H
bonds employing CuCN as a cyanating reagent.
Cu(acac)2 (0.4) DMF
CuBr2 (0.2)
K2S2O8 (1.0)
DMF
DMF
9
PhI(OAc)2 (1.0) DMF
10
11
12
13
14
15
16
17
18
Oxone (1.0)
CuBr2 (0.4)
CuBr2 (0.4)
CuBr2 (0.4)
CuBr2 (0.4)
CuBr2 (0.4)
CuBr2 (0.4)
DMF
toluene
xylene
1,4-dioxane
DMSO
DMF
(4) For representative reviews on C-H functionalization, see: (a) Dyker,
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Pd(dba)2
DMF
Pd(OCOCF3)2 CuBr2 (0.4)
CuBr2 (0.4)
DMF
DMF
a 2-Phenylpyridine (0.2 mmol), CuCN (0.24 mmol), Pd (10 mol %),
indicated oxidant, dry solvent (1 mL), 130 °C, under air, 24 h. b Isolated
yield. c Pd(OAc)2 (5 mol %), 36 h.
tested, CuBr2 was the best, and the yield was sharply
increased to 81% by employing 0.4 equiv of CuBr2 at 130
°C in DMF for 24 h (entry 3). In the case of employing 5
mol % of Pd(OAc)2, the cyanation product was isolated in
85% yield with elongated reaction time (36 h). Other
oxidants, such as K2S2O8 and PhI(OAc)2, were totally
ineffective for this transformation. The use of toluene, xylene,
and 1,4-dioxane as solvents resulted in lower yields or no
reaction (entries 11-13, Table 1). Gratifyingly, the mono-
cyanated product was obtained as a major product, probably
because the electron-withdrawing cyanogen group attached
to the aryl ring inhibited further reaction. Under an O2
atmosphere, a comparable result was obtained, providing the
cyanation products in 75% yield. Under N2, only 27% of
the desired product was isolated, indicating that air may serve
as a terminal oxidant in the procedure. Further studies
revealed that Pd(OAc)2 was superior to other Pd(II) catalysts
and Pd(0) was totally ineffective. No product was formed
in the absence of Pd(II). Importantly, this transformation is
very practical as it does not require the use of strong bases
or expensive ligands, and the rigorous exclusion of air/
moisture is not required.
(8) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2003,
42, 1661, and references cited therein.
Org. Lett., Vol. 11, No. 20, 2009
4717

With the optimized conditions in hand, the scope of
substrates was further explored as shown in Figure 1. As
hindrance of the aryl group of 2-arylpyridine had a limited
effect on the reaction. For example, the ortho-substituted
substrate delivered a 76% yield of 2d. When 2-(naphthalen-
1-yl)pyridine was subjected to the procedure, the cyanation
product 2k was isolated in 65% yield. Interestingly, 2-(naph-
thalen-2-yl)pyridine produced the ꢀ-cyanation product 2l in
70% yield. Benzo[h]quinoline and 1-p-tolyl-1H-pyrazole
were good reaction partners, delivering the corresponding
cyanation product in 56% and 36% yields along with the
recovered substrates, respectively (Figure 1, 2m and 2n).
Experiments to gain a preliminary understanding of the
mechanism revealed that 2-(2-bromophenyl)pyridine 1o did
not appear to be an intermediate in the reaction since the
product 2o was isolated in 71% yield under the standard
reaction condition (Scheme 2, eq 1). This result ruled out
Scheme 2. Preliminary Studies on the Mechanism
the possibility of a tandem C-H bond halogenation/cyanation
pathway. Palladacycle A was prepared (see Supporting
Information).11 and A could catalyze the formation of 2a in
77% isolated yield. Moreover, A reacted with CuCN cleanly
forming the cyanated pyridine in 83% yield, indicating that
palladacycle A may be an intermediate during this catalytic
cycle (Scheme 2, eq 2). Additionally, the reaction exhibited
a kinetic isotope effect (kH/kD ) 3.0), indicating slow C-H
bond activation (Scheme 2, eq 3).
Upon the basis of these experimental results, a plausible
mechanism is outlined in Scheme 3. Step (i) involves the
chelate-directed C-H activation of 2-phenylpyridine to
afford a cyclopalladated intermediate A. The high ortho-
selectivity as well as preliminary mechanistic experiments
(Scheme 2, eq 2) have provided strong evidence to support
this step. Step (ii) of the proposed catalytic cycle involves
ligand exchange of CN- to form Pd(II) species B. In the
final step (iii), intermediate B undergoes carbon-carbon
bond-forming reductive elimination to deliver the product
along with a Pd(0) species, which is oxidized to Pd(II) by
Cu(II) and/or air.
Figure 1.
Palladium-catalyzed cyanation of C-H bonds.a
a2-Arylpyridine (0.2 mmol), CuCN (0.24 mmol), Pd(OAc)2 (10
mol %), CuBr2 (40 mol %), dry DMF (1 mL), air, 130 °C, 24 h.
b
c
d
Isolated yield. 18 h. 36 h. 48 h.
expected, a variety of functional groups, including methoxy,
chloro, fluoro, vinyl, and cyanogen, were well tolerated.
Compared with electron-deficient analogues (Figure 1, 2a-2f
vs 2i), electron-rich arenes exhibited high reactivity in the
procedure. Notably, the regioselectivity of meta-substituted
substrate was dominated by steric effects, and only the less
hindered ortho-cyanated 2-arylpyridine (2c) was produced.
Regioisomeric products were not observed by GC-MS and
1H NMR spectroscopy. The observed selectivity is at least
partly linked to the regioselectivity of the cyclopalladation
step9 which is known to be sterically sensitive.10 The
(9) (a) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149. (b) Kalyani,
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4718
Org. Lett., Vol. 11, No. 20, 2009

Scheme 3
.
Plausible Mechanism
Scheme 4. Concise Pathway to a Key Intermediate of 3p
present cyanating procedure, the cyclic imine motif in 1p
was directly converted to the pyridine ring.
We next turned our efforts toward investigation of the
practicality of the direct cyanation reaction of the C-H bond.
The reaction conducted on a 10 mmol scale formed the
cyanation product 2a in an acceptable 61% yield.
5,6,9-Trimethoxy-7H-dibenzo[de,h]quinolin-7-one (3p) is
a known base from Menispermum dauricum DC (Menisper-
maceae). Some alkaloids possessing the 7H-dibenzo-
[de,h]quinoline skeleton isolated from Menispermum dau-
ricum DC have exhibited cytotoxic activities against a small
panel of cancer cell lines.12 The key intermediate (2p) for
the synthesis of 3p was concisely synthesized under the
standard procedure (Scheme 4). Importantly, under the
In conclusion, we have demonstrated an efficient pal-
ladium-catalyzed direct cyanation of arene C-H bonds. The
reaction represents a convenient and atom economic method
for the synthesis of aromatic nitriles. Ongoing work seeks
to gain further insights into the mechanism of this reaction
and to expand the scope of the cyanation of unactivated sp3
C-H bonds.
Acknowledgment. We thank the Key Project of Chinese
Ministry of Education (No. 209054) and State Key Labora-
tory of Coordination Chemistry of Nanjing University and
Graduate Scientific Innovation Program of Zhejiang Province
(No. Yk2008093) for financial support.
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(b) Kunitomo, J.-I.; Satoh, M.; Shingu, T. Tetrahedron 1983, 39, 3261. (c)
Takani, M.; Takasu, Y.; Takahashi, K. Chem. Pharm. Bull. 1983, 31, 3091.
(d) Kunitomo, J.-I.; Kaede, S.; Satoh, M. Chem. Pharm. Bull. 1985, 33,
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Supporting Information Available: Experimental pro-
cedures along with copies of spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL9017529
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