Rh(I)-catalyzed direct arylation of pyridines and quinolines

Article abstract of DOI:10.1021/ja8059396

A Rh(I)-catalyzed direct arylation of pyridine and quinoline heterocycles has been developed. The method provides rapid entry into an important class of substituted heterocycles employing inexpensive and readily available starting materials. Copyright

Full text of DOI:10.1021/ja8059396

Published on Web 10/15/2008
Rh(I)-Catalyzed Direct Arylation of Pyridines and Quinolines
Ashley M. Berman, Jared C. Lewis, Robert G. Bergman,* and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California, and DiVision of Chemical Sciences, Lawrence Berkeley National
Laboratory, Berkeley, California 94720
Received July 29, 2008; E-mail: jellman@berkeley.edu; rbergman@berkeley.edu
Table 2. Investigation of Scope in Heterocycle
Pyridine and quinoline nuclei are privileged scaffolds that occupy
a central role in many medicinally relevant compounds.1 Conse-
quently, methods for their expeditious functionalization are of
immediate interest. However, despite the immense importance of
transition-metal-catalyzed cross-coupling for the functionalization
of aromatic scaffolds, general solutions for coupling 2-pyridyl
organometallics with aryl halides have only recently been pre-
sented.2 Direct arylation at the ortho position of pyridine would
constitute an even more efficient approach because it eliminates
the need for the stoichiometric preparation and isolation of 2-pyridyl
organometallics.3,4 Progress toward this goal has been achieved
by activation of the pyridine nucleus for arylation via conversion
to the corresponding pyridine N-oxide5 or N-iminopyridinium
ylide.6 However, this approach necessitates two additional steps:
activation of the pyridine or quinoline starting material, and then
unmasking the arylated product. The use of pyridines directly would
clearly represent the ideal situation in terms of both cost and
simplicity. We now wish to document our efforts in this vein,
culminating in an operationally simple Rh(I)-catalyzed direct
arylation of pyridines and quinolines.
We recently developed an electron-rich Rh(I) system for catalytic
alkylation at the ortho position of pyridines and quinolines with
alkenes.7,8 Therefore, we initially focused our attention on the use
of similarly electron-rich Rh(I) catalysts for the proposed direct
arylation. After screening an array of electron-rich phosphine ligands
and Rh(I) salts, only marginal yields (<20%) of the desired product
were obtained. Much more efficient was an electron-poor Rh(I)
system with [RhCl(CO)2]2 as precatalyst (Table 1).9,10 For the direct
a Isolated yield of analytically pure product; 0.4 mmol scale in ArBr;
0.8 M absolute concentration in ArBr. b Reaction run at 175 °C and 0.3
M absolute concentration in ArBr.
Table 1. Direct Arylation of 2-Methyl Pyridine
arylation of picoline with 3,5-dimethylbromobenzene, addition of
P(OiPr)3 afforded a promising 40% yield of the cross-coupled
product 1a (entry 1). The exclusion of phosphite additive proved
even more effective, with the yield of 1a improving to 61% (entry
2). Further enhancement in yield was not observed upon the
inclusion of other additives such as MgO (entry 3), various organic
bases (entries 4 and 5) and inorganic bases (entry 6), or a protic
acid source (entry 7). Absolute concentration proved very important,
with the best results being obtained at relatively high concentrations
of the aryl bromide (compare entries 8 and 9). A marginal
improvement was observed upon running the reaction with 6 equiv
of 2-methylpyridine (entry 10).11,12 The reaction temperature could
also be increased to 175 or 190 °C while maintaining reaction yield,
to enable the reaction time to be reduced to 24 h (entries 11 and
12).
entry
additive (equiv)
concn (M)a
temp (°C)
yield (%)b,c
1
2
3
4
5
6
7
8
P(OiPr)3 (0.30)
none
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.15
1.1
0.8
0.8
0.8
165
165
165
165
165
165
165
165
165
165
175
190
40
61
33
0
47
0
55
34
61
63d
60d,e
62d,e
MgO (3.0)
i
NiPr2 Bu (3.0)
2,6-lutidine (3.0)
K2CO3 (3.0)
2,6-lut ·HCl (0.25)
none
none
none
9
10
11
12
none
none
With a set of optimized conditions in hand, we next set out to
investigate the generality of the catalytic direct arylation with a
variety of substituted pyridine derivatives (Table 2). Good arylation
yields were observed for pyridine derivatives with straight-chain
(entries 1 and 2), ꢀ-branched (entry 3), and R-branched (entry 4)
a Refers to the absolute concentration in aryl bromide. b Determined
by GC analysis with hexamethylbenzene as an internal standard. c The
reaction time was 48 h unless otherwise indicated. d 6.0 equiv of
2-methylpyridine was employed. e The reaction time was 24 h.
9
14926 J. AM. CHEM. SOC. 2008, 130, 14926–14927
10.1021/ja8059396 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Investigation of Scope in Aryl Bromide
Studies exploring reaction scope were conducted using 5 mol
% of the Rh(I) catalyst. However, the reaction can be performed
with comparable efficiency employing only 1 mol % of the catalyst.
In this case, the reaction was run neat, resulting in complete
consumption of the aryl bromide after 24 h and a 68% isolated
yield of the arylated product 1e (eq 1).
In summary, we have developed a Rh(I)-catalyzed strategy for
the direct arylation of pyridines and quinolines. The heterocycle is
used without the need for prefunctionalization, and all reaction
components are inexpensive and readily available. The strategy
represents an expeditious route to an important class of substituted
heterocycles and should be of broad utility.14
Acknowledgment. This work was supported by NIH Grant
GM069559 to J.A.E. and the Office of Basic Energy Sciences,
Chemical Sciences Division, U.S. Department of Energy, under
Contract DE-AC03-76SF00098 to R.G.B. A.M.B. was supported
by a NRSA postdoctoral fellowship (GM082080).
Supporting Information Available: Experimental procedures and
analytical data for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) For an analysis of heterocycles used in the preparation of drug candidates,
see: Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol.
Chem. 2006, 4, 2337.
a Isolated yield of analytically pure product; 0.4 mmol scale in ArBr;
0.3 M absolute concentration in ArBr.
(2) Billingsley, K. L.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 4695.
(3) For a recent comprehensive review on direct arylation, see: Alberico, D.;
Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174.
(4) Excess Zn and catalytic Pd/C have been used to prepare 2-phenylpyridine
in 52% yield from pyridine and phenyl chloride: Mukhopadhyay, S.;
Rothenberg, G.; Gitis, D.; Baidossi, M.; Ponde, D. E.; Sasson, Y. Perkin
Trans. 2 2000, 9, 1809.
substituents at the C-2 position. Tetrahydroquinoline also provided
the arylated product in good yield (entry 5), as did 2,4-dimeth-
ylpyridine (entry 6). In contrast, when a substituent at the C-2
position is not present, arylation does not occur (entry 7). This result
parallels our previous studies on Rh-catalyzed pyridine alkylation.7,13
The steric interactions provided by a substituent at this position
may reduce the energy difference between the N-bound complex
and the C-H activation intermediate. Consistent with the require-
ment for C-2 substitution, quinoline is also a highly effective
substrate for direct arylation (entry 8). As illustrated in entry 9,
the compatibility of the reaction conditions with chloro substitution
should enable efficient further elaboration of the arylation product
by standard cross-coupling methods. However, no arylation was
observed for 2-fluoropyridine or 2-chloropyridine.
The substrate scope in aryl bromide was also evaluated with
quinoline as the coupling partner (Table 3). Both electron-rich and
electron-poor aryl bromides are accommodated with equal efficiency
(compare, for example, entries 4 and 11). A variety of useful
functional groups are tolerated, including aryl and alkyl ethers
(entries 3 and 4), chloride (entry 8), fluoride (entry 9), and ketone
functionality (entry 10). While cross-coupling proceeds smoothly
with meta substitution on the aryl bromide ring (see, for example,
entry 1), attempted cross-coupling with 2-methylbromobenzene
failed to afford product, with only unreacted starting material
recovered.
(5) (a) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,
127, 18020. (b) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006,
45, 7781. (c) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008,
130, 9254.
(6) Larivee, A.; Mousseau, J. J.; Charette, A. B. J. Am. Chem. Soc. 2008, 130,
52.
(7) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129,
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(8) For Ni- and Lewis acid-catalyzed C-2 alkenylation of pyridines with alkynes,
see: Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130,
2448.
(9) The direct arylation of azoles proceeds most efficiently with Rh(I) salts
containing alkene rather than CO ligands and requires the addition of either
an electron-rich trialkylphosphine or a phosphepine, see: Lewis, J. C.;
Berman, A. M.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008,
130, 2493.
(10) For use of [RhCl(CO)2]2 in a different type of C-H bond functionalization
reaction, see: Zhao, X.; Yu, Z. J. Am. Chem. Soc. 2008, 130, 8136.
(11) The role of excess heterocycle may be to both stabilize the Rh catalyst
and act as an acid scavenger.
(12) Mass balance experiments indicate <10% unproductive loss of the
heterocycle after complete consumption of the aryl bromide. For all of the
aryl bromides investigated, neither hydrodehalogenation nor dimerization
was observed.
(13) For relevant studies on the impact of pyridyl C-2 substitution on C-H
bond activation, see the following. (a) Iridium complexes: Alvarez, E.;
Conejero, S.; Paneque, M.; Petronilho, A.; Poveda, M. L.; del Rio, D.;
Serrano, O.; Carmona, E. J. Am. Chem. Soc. 2006, 128, 13060. (b) Osmium
complexes: Buil, M. L.; Esteruelas, M. A.; Garce´s, K.; Oliva´n, M.; On˜ate,
E. J. Am. Chem. Soc. 2007, 129, 10998.
(14) For several mechanistic possibilities, please see the Supporting Information.
JA8059396
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