Direct arylation of pyridines without the use of a transition metal catalyst

Article abstract of DOI:10.1039/c4cc02546f

A method for achieving the direct arylation of pyridines with phenylhydrazine hydrochloride was developed in this study. This new reaction proceeds readily at room temperature without the use of any transition metal catalysts. This method allows rapid access to various arylated heterocycles that are more difficult to access through traditional methods.

Full text of DOI:10.1039/c4cc02546f

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Direct arylation of pyridines without the use of a
transition metal catalyst†
Yahui Li,ab Wei Liuab and Chunxiang Kuang*ab
Cite this: Chem. Commun., 2014,
50, 7124
Received 7th April 2014,
Accepted 11th May 2014
DOI: 10.1039/c4cc02546f
www.rsc.org/chemcomm
A method for achieving the direct arylation of pyridines with phenyl-
hydrazine hydrochloride was developed in this study. This new
reaction proceeds readily at room temperature without the use of
any transition metal catalysts. This method allows rapid access to
various arylated heterocycles that are more difficult to access
through traditional methods.
Pyridine nuclei are among the most important heterocyclic
structural motifs and are found in a large number of natural
products and in many medicinally relevant compounds.1 Examples
of such compounds include preclamol,2a which is used as an
antipsychotic, and altinicline,2b,c which is used in the treatment
of Parkinson’s disease (Scheme 1).2 However, despite the numerous
applications of the arylation of pyridines, their preparation remains
a difficult challenge because pyridines are electron-poor and have
a tendency to adopt a non-productive N-bound coordination
mode with metal centers.3,4 Significant developments have recently
been made in the direct arylation of pyridine (Scheme 2). Several
C2-selective arylation reactions of pyridines (eqn (1)) via conversion
to N-oxides and N-iminopyridinium ylides have been developed.5
Significant research studies on the C2-selective arylation of
unprotected 2-methylpyridine (eqn (2))6 and the Ag-catalyzed
arylation of pyridine have also been conducted (eqn (3)).7
However, transition metal complexes, especially Pd, Rh, Ag,
and Cu complexes, play a key role in these reactions. To avoid the
drawbacks of metal usage, such as toxicity and heavy transition
metal impurities in the final products, transition-metal-free cross-
coupling reactions must be developed. Therefore, a new method
Scheme 1 Pharmaceutical drugs containing pyridine.
Scheme 2 Transition metal catalyst direct arylation of pyridine.
Significant progress has recently been made in the direct
that does not need a noble metal catalyst, a ligand and any additive arylation of C–H bonds in the absence of a transition metal
would be ideal in terms of both cost and simplicity.
catalyst.8 Hayashi,8a Shi,8b and Lei et al.8c reported the base-
mediated arylation of benzene with aryl halides in the presence
of 1,10-phenanthroline or N,N0-dimethyl-ethylene diamine.
Herein, we report the first direct arylation of pyridines using
phenylhydrazine hydrochloride (a readily available and stable
reagent) at room temperature and without any additive.
Initially, pyridine and 4-methoxyphenylhydrazine hydro-
chloride were chosen as the substrates for the model reaction
in the presence of 5 mol% of Pd(OAc)2 and 2 equiv. of K2CO3 in
a Department of Chemistry, Tongji University, Siping Road 1239, Shanghai 200092,
China. E-mail: kuangcx@tongji.edu.cn; Tel: +86-21-6598319
b Key Laboratory of Yangtze River Water Environment, Ministry of Education,
Siping Road 1239, Shanghai 200092, China
† Electronic supplementary information (ESI) available: Characterization data,
and 1H and 13C NMR spectra. See DOI: 10.1039/c4cc02546f
7124 | Chem. Commun., 2014, 50, 7124--7127
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Table 1 Influence of reaction conditions on the reaction of 1a with 2aa
Table 2 The reaction of arylhydrazines with pyridinea
Entry
Catalyst
Base
Solvent
Yieldb
1
2
3
4
5
6
7
Pd(AcO)2 (5 mol%)
PdCl2 (5 mol%)
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
NaOH
—
—
—
—
—
—
—
—
—
—
—
—
DCE
Toluene
DMF
DMF
14
12
18
22
14
Trace
76
33
37
—
—
—
—
—
—
—
—
—
8c
9c
10c
11d
46
39
a
Reaction conditions: pyridine (2 mL), 2a (0.2 mmol) in air, RT, 24 h,
b
c
sealed tube. Isolated yields (total yields of all isomers). Pyridine
(0.4 mL, 5.0 mmol) with solvent (1 mL) was used. Pyridine (0.1 mL,
d
1.25 mmol) with DMF (1 mL) was used, RT, 48 h, sealed tube.
air. The target product was obtained with a yield of 14%. As
such, various conditions were screened, and the results are
summarized in Table 1. First, some catalysts, such as Pd(OAc)2
and PdCl2, were screened (Table 1, entries1 and 2). Further
investigation demonstrated that a higher yield was obtained in
the absence of a base or a catalyst (Table 1, entries 1–6). Under
the best conditions, excess pyridine substrate was needed to
obtain practical yields. Moreover, the yield decreased signifi-
cantly from 76% to 22% when pyridine was reduced to 6 equiv.
in 1 mL of N,N-dimethylformamide (DMF) (entry 9). The use of
25 equiv. of pyridine in 1 mL of DMF, however, afforded the
arylated product in a 46% yield (entry 10). The compatibility of
this catalytic reaction with DMF solvent is important in further
development for reducing the amount of the pyridine substrate
to 1 equiv. It is of note that this reaction can occur at room
temperature. These results indicate that this transformation is
facile and practical, as it did not require the use of an expensive
a
Reaction conditions: pyridine (2 mL), 2a (0.2 mmol), in air, RT, 24 h,
b
c
sealed tube. Isolated yields (total yields of all isomers). 3x1 represent
the product of C2 and 3x2 represent the product of C3. Pyridine (320 mg,
4 mmol) with DMF (1 mL) was used. Trace of C3 product was obtain.
d
e
catalyst, any additive and rigorous exclusion of air. Thus, this High chemoselectivities were observed when 2,4-dichlorophenyl-
feature is expected to have numerous important applications in hydrazine hydrochloride (3j, Table 2) and 4-bromophenyl-hydrazine
medicine and in materials chemistry.
hydrochloride (3g, Table 2) were used in this coupling reaction. Aryl
Under these optimized reaction conditions, the general halides were tolerated, providing handles for further functionalization
application of this novel process was investigated using various (e.g., with a Suzuki reaction). We note that this reaction substantially
arylhydrazines, and the results are summarized in Table 2. The reduced the cost of these compounds compared to known methods.
regioselectivity of the heterocycle that was predominantly for To further illustrate the efficacy of this coupling reaction,
the 2-, 3-, and 4- positions was proven to be minimal. The the scope of pyridine substrates was also briefly surveyed. For
generality of this novel process was explored using various example, 4-methoxyphenyl-hydrazine hydrochloride reacted with
phenylhydrazine hydrochlorides, and the results are summar- 3-methylpyridine to produce the product with a yield of 53% (3p,
ized in Table 2. As outlined, a wide range of phenylhydrazine Table 2), and the reaction between 4-methoxyphenylhydrazine
hydrochloride compounds that incorporate electron-donating hydrochloride and 4-methylpyridine resulted in a yield of 52%.
and electron-withdrawing groups into the ortho-, meta-, and The reaction proved to be fairly general for other electron-poor
para-positions gave the desired products in good yields (3a–3l, heterocycles, such as pyrazine (3q, Table 2), which also proved to
Table 2). The ortho-substituted phenylhydrazine hydrochloride be viable substrates, as well as pyridine derivatives.
also reacted readily to give the desired product in good yields
To demonstrate the applicability of this method in the synthesis
(3d and 3j, Table 2). A functional group, such as cyano, was of these types of molecules, we prepared 2-(4-fluoro-phenyl)-pyridine
noted to be compatible in this reaction (3h and 3m, Table 2). on the gram scale using the optimized conditions (Scheme 3).
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 7124--7127 | 7125

View Article Online
ChemComm
Communication
Scheme 6 Plausible mechanism.
Scheme 3 Prepared arylation of pyridines on a gram scale.
This result demonstrated that hydrochloride plays an impor-
tant role in the reaction. And traces of the desired product were
observed when we used Tempo (1.0 eq.). Subsequently, the
kinetic isotope effect (KIE) was investigated with regard to the
Compared with previous approaches requiring expensive air-
sensitive organometallic reagents, harsh reaction conditions,
and having toxic and heavy transition metal impurities in final
products, this new method is expected to have numerous
important applications in medicine and in materials chemistry.
The effect of arylhydrazine hydrochlorides on the reaction
was investigated through a competition experiment (Scheme 4).
Under the reaction conditions, pyridine was treated with both
4-methoxyphenylhydrazine hydrochloride and 4-cyanophenyl-
hydrazine hydrochloride. The yields from the competition
experiment indicate that there is no significant difference in
the yield between phenylhydrazine hydrochloride bearing
electron-donating groups and phenylhydrazine hydrochloride
bearing electron-withdrawing groups in this system.
C–H/D bonds for pyridine. No significant KIE value (kH/kD
=
1.12) was obtained. Based on the results of the reaction in the
experiment and previous literature,9 we outlined a plausible
reaction mechanism as shown in Scheme 6. The results have
shown that in the presence of pyridines, phenylhydrazine
hydrochloride disproportionates into aryl radicals. The aryl
radical C reacts with the protonated heterocycle B to form the
radical cation E, which in turn is re-oxidized by O2, producing
the desired product F.
Despite the generality and practicality of the reaction, there are
several apparent limitations. First, the regioselectivity is not governed
by the reagents but by the inherent reactivity of the substrates. Second,
the yields are mediocre in some cases. In addition to carrying out a
detailed investigation of the mechanism of this reaction, future
studies should aim to overcome these limitations.
To obtain some insights into the mechanism of this novel
method, the following experiments were conducted Scheme 5.
Trace amounts of the desired product were obtained when we
used phenylhydrazine instead of phenylhydrazine hydrochloride.
In summary, a reaction to achieve the direct coupling of
phenylhydrazine hydrochloride (ca. 3 cent per g) to electron-
deficient heterocycles without any catalyst and co-oxidant has
been developed. The reaction proceeds under mild conditions
(room temperature) and does not require pre-functionalization of
the heterocycle. The reaction did not require excessive time, harsh
reaction conditions, catalyst, and exclusion of air. This cost-
effective methodology will be very attractive to both academia
and industry because commercially available arylhydrazines are
used as coupling partners. Lastly, this work sets a precedent for the
mild generation of highly reactive species (tentatively assumed to
be radicals) from phenylhydrazine hydrochloride, a platform that
may find use in other areas of reaction design.
Scheme 4 Competition experiment.
We thank the Natural Science Foundation of China
(No. 21272174), the Key Projects of Shanghai in Biomedicine
(No. 08431902700), and the Scientific Research Foundation of
the State Education Ministry for Returned Overseas Chinese
Scholars for the support of this research.
Notes and references
1 (a) M. G. P. Buffat, Tetrahedron, 2004, 60, 1701; (b) F.-X. Felpin and
J. M. Lebreton, Eur. J. Org. Chem., 2003, 3693; (c) P. M. Weintraub,
J. S. S. abol, J. M. Kane and D. R. Borcherding, Tetrahedron, 2003, 59, 2953.
2 (a) M.-C. Ye, G.-L. Gao, A. J. F. Edmunds, P. A. Worthington, J. A. Morris
and J.-Q. Yu, J. Am. Chem. Soc., 2011, 133, 19090; (b) N. D. P. Cosford,
et al., Pharm. Acta Helv., 2000, 74, 125; (c) F. F. Wagner and D. L. Comins,
J. Org. Chem., 2006, 71, 8673–8675; (d) W. Masayuki, T. W. Brady and
J.-Q. Yu, Angew. Chem., Int. Ed., 2010, 49, 1275.
Scheme 5 Hydrochloride, tempo and isotope effect.
7126 | Chem. Commun., 2014, 50, 7124--7127
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
3 (a) I. B. Seiple, S. Su, R. A. Rodriguez, R. Gianatassio, Y. Fujiwara, 7 (a) F. Minisci, E. Vismara and F. Fontana, Heterocycles, 1989, 28, 489;
L. Sobel and P. S. Baran, J. Am. Chem. Soc., 2010, 132, 13194; (b) M. Li
and R. Hua, Tetrahedron Lett., 2009, 50, 1478; (c) O. Kobayashi,
D. Uraguchi and T. Yamakawa, Org. Lett., 2009, 11, 2679;
(d) S. Yanagisawa, K. Ueda, T. Taniguchi and K. Itami, Org. Lett.,
2008, 10, 4673; (e) S. Mukhopadhyay, G. Rothenberg, D. Gitis,
(b) F. Minisci, F. Fontana and E. J. Vismara, Heterocycl. Chem., 1990,
27, 79; (c) D. C. Harrowven and B. J. Prog. Sutton, Heterocycl. Chem.,
2004, 16, 27; (d) B. Seiple, S. Su, R. A. Rodriguez, R. Gianatassio,
Y. Fujiwara, A. L. Sobel and P. S. Baran, J. Am. Chem. Soc., 2010, 132,
13194–13196.
M. Baidossi, D. E. Ponde and Y. J. Sasson, J. Chem. Soc., Perkin 8 (a) E. Shirakawa, K.-I. Itoh, T. Higashino and T. Hayashi, J. Am. Chem. Soc.,
Trans. 2, 2000, 1809.
4 For a recent review of CH functionalization of pyridines, see:
Y. Nakao, Synthesis, 2011, 3209.
2010, 132, 15537; (b) C.-L. Sun, H. Li, D.-G. Yu, M. Yu, X. Zhou, X.-Y. Lu,
K. Huang, S.-F. Zheng, B.-J. Li and Z.-J. Shi, Nat. Chem., 2010, 2, 1044;
(c) W. Liu, H. Cao, H. Zhang, H. Zhang, K. H. Chung, C. He, H. Wang,
F. Y. Kwong and A. Lei, J. Am. Chem. Soc., 2010, 132, 16737; (d) O. Vakuliuk,
B. Koszarna and D. T. Gryko, Adv. Synth. Catal., 2011, 353, 925;
(e) S. Yanagisawa, K. Ueda, T. Taniguchi and K. Itami, Org. Lett., 2008,
10, 4673; ( f) S. Yanagisawa and K. Itami, ChemCatChem, 2011, 3, 827;
(g) N. E. Leadbeater, Nat. Chem., 2010, 2, 1007; (h) D. S. Roman, Y. Takahashi
and A. B. Charette, Org. Lett., 2011, 13, 3242; (i) Y. Qiu, Y. Liu, K. Yang,
W. Hong, Z. Li, Z. Wang, Z. Yao and S. Jiang, Org. Lett., 2011, 13, 3556;
( j) T. Truong and O. Daugulis, J. Am. Chem. Soc., 2011, 133, 4243.
5 (a) L. C. Campeau, S. Rousseaux and K. J. Fagnou, J. Am. Chem. Soc.,
2005, 127, 18020; (b) K. S. Kanyiva, Y. Nakao and T. Hiyama, Angew.
Chem., Int. Ed., 2007, 46, 8872; (c) S. H. Cho, S. J. wang and S. Chang,
J. Am. Chem. Soc., 2008, 130, 9254; (d) J. Wu, X. Cui, L. Chen, G. Jiang
and Y. J. Wu, J. Am. Chem. Soc., 2009, 131, 13888; (e) P. Xi, F. Yang,
S. Qin, D. Zhao, J. Lan, G. Gao, C. Hu and J. S. You, J. Am. Chem. Soc.,
2010, 132, 1822; ( f ) A. Lariv, J. J. Mousseau and A. B. Charette, J. Am.
Chem. Soc., 2008, 130, 52.
6 (a) A. M. Berman, J. C. Lewis, R. G. Bergman and J. A. Ellman, J. Am. 9 (a) A. G. Myers, M. Movassaghi and B. Zheng, Tetrahedron Lett., 1997,
Chem. Soc., 2008, 130, 14926; (b) T. Kawashima, T. Takao and
H. J. Suzuki, J. Am. Chem. Soc., 2007, 129, 11006; (c) M. Tobisu,
I. Hyodo and N. Chatani, J. Am. Chem. Soc., 2009, 131, 12070.
38, 6569; (b) E. M. Kosower, P.-K. C. Huang and T. Tsuji, J. Am. Chem.
Soc., 1969, 91, 2325; (c) J. Hofmann, H. Jasch and M. R. Heinrich,
J. Org. Chem., 2014, 79, 2314.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 7124--7127 | 7127