Pd0/PR3-catalyzed arylation of nicotinic and isonicotinic acid derivatives

Article abstract of DOI:10.1002/anie.200906104

(Chemical Eqation Presented) Good for your health: Intermolecular C-H functionalization of pyridine rings at the 3- and 4-positions is described using a Pd⁰/PR₃/ArBr catalytic system. This reaction provides a powerful method for the preparation of structurally diverse nicotinic and isonicotinic acids that are of great importance in drug discovery.

Full text of DOI:10.1002/anie.200906104

Angewandte
Chemie
DOI: 10.1002/anie.200906104
À
C H Activation
Pd0/PR3-Catalyzed Arylation of Nicotinic and Isonicotinic Acid
Derivatives**
Masayuki Wasa, Brady T. Worrell, and Jin-Quan Yu*
Owing to the prominence of azaheterocycles in natural
products and pharmaceuticals,[1,2] diverse synthetic methods
have been developed to construct substituted pyridines and
quinolines.[3] Most syntheses of pyridine rings rely upon one
of two approaches: condensation of amines and carbonyl
compounds or cycloaddition reactions.[3] Further decoration
of pyridine rings often involves transition-metal-catalyzed
cross-coupling reactions of their halogenated analogues.[4]
also been achieved.[8] Herein, we report the selective palla-
dium(0)-catalyzed arylation reactions at the 3- or 4-positions
of nicotinic and isonicotinic acids using a simple amide
directing group [Scheme 1, Eq. (7), (8)]. Notably, this is the
first example of a directing group activating the pyridine
ring.[9]
Arylated derivatives of nicotinic and isonicotinic acids are
widely used as building blocks for pharmaceuticals owing to
their diverse biological activity.[10a–c] For instance, studies have
shown that compounds 1, 2, and 3 are a serine protease
inhibitor,[10a] an a,b-3-adrenoceptor agonist,[10b] and a liver X-
receptor modulator for the treatment of LXR-mediated
diseases,[10c] respectively (Scheme 2). We envision that the
palladium-catalyzed functionalization of nicotinic and isoni-
À
Therefore, the direct functionalization of pyridine C H
bonds using transition metal catalysis is an attractive alter-
native to typical cross-coupling reactions. A number of groups
have reported the selective transition-metal-catalyzed direct
functionalization at the 2-position of pyridine or pyridine N-
oxides [Scheme 1, Eq. (1)–(6)],[5] and the intramolecular
Scheme 2. Pharmaceutical drugs containing nicotinic or isonicotinic
acid frameworks.
Scheme 1. Direct arylation, alkylation or vinylation reactions of pyridine
or pyridine N-oxide. LA=Lewis acid.
arylation at the 3- or 4-position of substituted pyridines.[6]
The palladium-catalyzed intermolecular arylation of 2,3,5,6-
tetrafluoropyridine[7] at the 4-position and the copper(I)-
catalyzed arylation of 3-fluoropyridine at the 4-position have
cotinic acids will be a powerful method for accessing a large
family of biologically useful compounds. Our previous failed
À
attempts to functionalize pyridine rings using directed C H
activation point to two inherent difficulties: first, the palla-
À
dium-catalyzed C H functionalization of pyridines is ham-
pered by the poor electron density of the ring; second, the
pyridyl group favorably competes with the directing groups
for binding to the palladium catalysts. We recently reported
the palladium(0)-catalyzed intermolecular arylation of sp3 b-
[*] M. Wasa, B. T. Worrell, Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2409
E-mail: yu200@scripps.edu
[11]
À
C H bonds using a novel amide directing group.
This
[**] We gratefully acknowledge The Scripps Research Institute, the
National Institutes of Health (NIGMS, 1 R01 GM084019-02),
Amgen, and Eli Lilly for financial support. We thank the A. P. Sloan
Foundation for a fellowship (J.-Q.Y.), and the Bristol Myers Squibb
for a graduate fellowship (M.W.).
development, with the pioneering report on amide-directed
arylation by Miura and co-workers[12] and other related
work[13] prompted us to investigate the intermolecular aryla-
tion of pyridine at the 3- and 4-positions using an amide
directing group and a suitable ligand via the ArX/Pd0/PR3
catalytic system.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906104.
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Communications
We were pleased to find that using our previously
reaction. Of the directing groups tested, N-phenyl amide gave
an excellent overall yield, albeit with poor selectivity for the
monoarylated product. The N-2,6-dimethylphenyl amide
group significantly improved the mono selectivity, but in
lower yield. The N-3,5-dimethylphenyl amide protecting
group significantly improved the yield of the monoarylated
product to 87% (Table 1). This auxiliary was then used for
further ligand screening (Table 2). We found that the
PCy2tBu-HBF4 ligand reported by Fu and Netherton[14] was
the most effective, giving the highest yield of 87% (Table 2,
entry 4). It is worth noting that the use of freshly prepared
phosphonium salts gave better yields.
reported N-perfluorophenyl amide[11] as a directing group
afforded monoarylated (14%) and diarylated (8%) products
for isonicotinic acid (Table 1). During our preliminary screen-
ing of different directing groups, it occurred to us that the
strongly electron-withdrawing N-perfluorophenyl amide
group would render the pyridine ring more electronically
deficient, thus retarding the reaction. Therefore, we inves-
tigated the effect that the different substituents on the phenyl
ring of the amide directing group have on the arylation
Table 1: Directing group screening.[a,b]
Table 3: Arylation of nicotinic and isonicotinic derivatives.[a,b]
X=
X=
OMe
4a 27% mono
4b 51% di
5a 86% mono
trace di
6a 58% para
6b 5% ortho
a 0%
b 0%
a 34%
b 52%
a 38%
b 2%
7a 89%
8a 63%
9a 50% para
9b 14% ortho
a 2%
b 0%
a 24%
b 21%
a 12%
b 11%
X=
10a 58%
11a 62%
a 14%
b 8%
a 24%
b 26%
a 87%
b 4%
[a] Conditions: 0.2 mmol of substrate, 10 mol% Pd(OAc)2, 10 mol%
ligand, 3.0 equiv of Cs2CO3, 1.5 equiv of aryl bromide, 100 mg 3 ꢀ M.S.,
1 mL toluene, 1308C, N2, 48 h. [b] Yield was determined by 1H NMR
analysis of the crude product using CH2Br2 as an internal standard.
Table 2: Ligand screening.[a,b]
6c 44% para
trace ortho
6d 60% para
6e 9% ortho
7b 82%
Entry PR3
Yield [%] Entry PR3
Yield [%]
1
2
3
4
5
6
7
PPh3
PiPr3·BF4
PCy3·BF4
PCy2tBu·BF4
PtBu3·BF4
3
51
71
87
50
60
64
8
9
PCy2(o-Tol)·BF4
Cy-JohnPhos·BF4
MePhos·BF4
DavePhos·BF4
SPhos·BF4
0
12
10
19
9
10
11
12
13
14
7c 88%
7d 94%
7e 71%
PtBu2Me·BF4
PAd2nBu·BF4
RuPhos·BF4
XPhos·BF4
15
8
[a] For reaction conditions, see: Table 1, footnote [a]. [b] Yield was
determined by 1H NMR analysis of the crude product using CH2Br2 as an
internal standard.
7 f 92%
7g 68%
7h 83%
[a] Conditions: 0.2 mmol of substrate, 10 mol% Pd(OAc)2, 10 mol%
PCy2tBu·HBF4, 3.0 equiv of Cs2CO3, 1.5 equiv of aryl bromide, 100 mg 3 ꢀ
M.S., 1 mL toluene, 1308C, N2, 48 h. [b] Yield of isolated product.
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[4] a) V. N. Kalinin, Synthesis 1992, 413; b) W. M. Albers, G. W.
With these optimized conditions in hand, we began to test
this reaction with commercially available nicotinic and
isonicotinic acids (Table 3). Mono selective arylation of
isonicotinic acid was successfully performed using the bulky
N-3,5-dimethylphenyl amide as the directing group, whilst the
simple N-phenyl amide give a mixture of monoarylated and
diarylated products (4a, 4b, and 5a). This reaction provides a
potentially efficient route to structurally diverse nicotinic
acids that are highly desirable in medicinal chemistry. At
present, a commercial route typically involves a lengthy
amide-directed lithiation/iodination/cross-coupling reaction
sequence.[15]
Canters, J. Reedijk, Tetrahedron 1995, 51, 3895; For recent
advances, see: c) B. Bhayana, B. P. Fors, S. L. Buchwald, Org.
Lett. 2009, 11, 3954.
[5] a) E. J. Moore, W. R. Pretzer, T. J. OꢀConnell, J. Harris, L.
LaBounty, L. Chou, S. S. Grimmer, J. Am. Chem. Soc. 1992, 114,
5888; b) L. S. Campeau, S. Rousseaux, K. Fagnou, J. Am. Chem.
Soc. 2005, 127, 18020; c) J. C. Lewis, R. G. Bergman, J. A.
Ellman, J. Am. Chem. Soc. 2007, 129, 5332; d) A. Larivꢁe, J. J.
Mousseau, A. B. Charette, J. Am. Chem. Soc. 2008, 130, 52; e) Y.
Nakao, K. S. Kanyiva, T. Hiyama, J. Am. Chem. Soc. 2008, 130,
2448; f) S. H. Cho, S. J. Hwang, S. Chang, J. Am. Chem. Soc.
2008, 130, 9254; g) A. M. Berman, J. C. Lewis, R. G. Bergman,
J. A. Ellman, J. Am. Chem. Soc. 2008, 130, 14926; h) L. C.
Campeau, D. R. Stuart, J. P. Leclerc, M. Bertrand-Laperle, E.
Villemure, H. Y. Sun, S. Lasserre, N. Guimond, M. Lecavallier,
K. Fagnou, J. Am. Chem. Soc. 2009, 131, 3291; i) M. Tobisu, I.
Hyodo, N. Chatani, J. Am. Chem. Soc. 2009, 131, 12070; j) J. Wu,
X. Cui, L. Chen, G. Jiang, Y. Wu, J. Am. Chem. Soc. 2009, 131,
13888 – 13889.
[6] J. Roger, A. L. Gottumukkala, H. Doucet, ChemCatChem 2009,
DOI: 10.1002/cctc.200900074, and references therein.
[7] a) M. Lafrance, C. N. Rowley, T. K. Woo, K. Fagnou, J. Am.
Chem. Soc. 2006, 128, 8754; b) M. Lafrance, D. Shore, K. Fagnou,
Org. Lett. 2006, 8, 5097.
[8] H. Q. Do, O. Daugulis, J. Am. Chem. Soc. 2008, 130, 1128.
[9] X. Chen, K. M. Engle, D. H. Wang, J. Q. Yu, Angew. Chem. 2009,
121, 5196; Angew. Chem. Int. Ed. 2009, 48, 5094.
Interestingly, other substrates are also mono selectively
arylated, even using only the simple N-phenyl amide directing
group (6a, 6c, 6d, 9a), presumably because the two available
À
ortho-C H bonds have drastically different reactivities.
Arylation of the more-hindered fluorinated substrates
afforded lower yields (8a, 11a). Importantly, the aryl
bromides could tolerate substituents such as fluorine atoms
(6d, 7b, 7c), methoxy groups (7d, 7e), and ester groups (7h).
Following completion of the reaction, the amide group could
be converted to the corresponding acid by treatment with 4m
HCl (see the Supporting Information).[15]
In summary, we have developed a Pd0/PR3-catalyzed
arylation procedure for nicotinic and isonicotinic acid deriv-
atives, the first example of directed transition-metal-catalyzed
[10] a) Y. S. Babu, R. S. Rowland, P. Chand, P. L. Kotian, Y. El-
Kattan, S. Niwas, U.S. Patent No. 6699994, 2004; b) K. H.
Donaldson, B. G. Shearer, D. E. Uehling, W.O Patent No. 01/
42217, 2001; c) R. C. Bernotas, R. R. Singhaus, J. W. Ullrich,
D. H. Kaufman, R. L. Morris, J. E. Wrobel, B. Hu, J. W. Jetter,
M. D. Collini, J. M. Travins, R. L. Magolda, W.O. Patent No.
2008/049047, 2008.
À
C H functionalizations of a pyridine ring at the 3- or 4-
positions. This procedure allows us to rapidly generate a
library of arylated nicotinic and isonicotinic acid derivatives
that are of tremendous importance in medicinal chemistry.
[11] M. Wasa, K. M. Engle, J. Q. Yu, J. Am. Chem. Soc. 2009, 131,
9886.
[12] Y. Kametani, T. Satoh, M. Miura, M. Nomura, Tetrahedron Lett.
2000, 41, 2655.
Received: October 30, 2009
Published online: January 15, 2010
À
Keywords: arylation · C H activation · homogeneous catalysis ·
palladium · quinolines
[13] For recent examples of palladium(0)-catalyzed intermolecular
.
2
À
arylation of sp C H bonds, see: a) M. Lafrance, K. Fagnou, J.
Am. Chem. Soc. 2006, 128, 16496; b) I. V. Seregin, V. Gevorgyan,
Chem. Soc. Rev. 2007, 36, 1173; c) H. A. Chiong, Q. N. Pham, O.
Daugulis, J. Am. Chem. Soc. 2007, 129, 9879; d) J. Roger, H.
Doucet, Org. Biomol. Chem. 2008, 6, 169; e) L. Ackermann, A.
Althammer, S. Fenner, Angew. Chem. 2009, 121, 207; Angew.
Chem. Int. Ed. 2009, 48, 201.
[1] For recent reviews, see: a) G. D. Henry, Tetrahedron 2004, 60,
6043; b) J. P. Michael, Nat. Prod. Rep. 2005, 22, 627.
[2] a) G. Jones, Comprehensive Heterocyclic Chemistry II, Vol. 5
(Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven, A. McKil-
lop), Pergamon, Oxford, 1996, p. 167; b) R. C. Larock, Compre-
hensive Organic Transformations: A Guide to Functional Group
Preparations, Wiley-VCH, New York, 1999.
[3] For reviews on metal-catalyzed heterocycle synthesis, see: a) I.
Nakamura, Y. Yamamoto, Chem. Rev. 2004, 104, 2127; b) G.
Zeni, R. C. Larock, Chem. Rev. 2006, 106, 4644, and references
therein.
[14] For HBF4 salts of phosphine ligands, see: M. R. Netherton, G. C.
Fu, Org. Lett. 2001, 3, 4295. For earlier uses of HBF4 salts of
À
phosphine ligands in C H arylation, see references [5b] and
[11c].
[15] J. W. B. Cooke, B. N. Glover, R. M. Lawrence, M. J. Sharp, M. F.
Tymoschenko, W.O. Patent No. 02/066418, 2002.
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