Selective C-4 alkylation of pyridine by nickel/Lewis acid catalysis

Article abstract of DOI:10.1021/ja106514b

Direct C-4-selective addition of pyridine across alkenes and alkynes is achieved for the first time by nickel/Lewis acid cooperative catalysis with an N-heterocyclic carbene ligand. A variety of substituents on both alkenes and pyridine are tolerated to give linear 4-alkylpyridines in modest to good yields. The addition across styrene, on the other hand, gives branched 4-alkylpyridines. A single example of C-4-selective alkenylation is also described.

Full text of DOI:10.1021/ja106514b

Published on Web 09/07/2010
Selective C-4 Alkylation of Pyridine by Nickel/Lewis Acid Catalysis
Yoshiaki Nakao,* Yuuya Yamada, Natsuko Kashihara, and Tamejiro Hiyama*,†
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity, Kyoto 615-8510, Japan
Received July 22, 2010; E-mail: yoshiakinakao@npc05.mbox.media.kyoto-u.ac.jp; thiyama@kc.chuo-u.ac.jp
Scheme 1. Strategies for Catalytic Direct Metalation of Pyridine
Abstract: Direct C-4-selective addition of pyridine across alkenes
and alkynes is achieved for the first time by nickel/Lewis acid
cooperative catalysis with an N-heterocyclic carbene ligand. A
variety of substituents on both alkenes and pyridine are tolerated
to give linear 4-alkylpyridines in modest to good yields. The
addition across styrene, on the other hand, gives branched
4-alkylpyridines. A single example of C-4-selective alkenylation
is also described.
A pyridine core plays a key role in a number of natural products,
pharmaceuticals, ligands, and functional materials. Because a wide
variety of pyridine derivatives are available, a strategy to install
activated pyridines to nickel, rather than η1-coordination of the sp2
substituents directly into a preformed pyridine core has advantages
in terms of step economy as well as versatility. Nevertheless, the
low reactivity of pyridine and its derivatives toward aromatic
electrophilic substitution reactions such as halogenation and the
Friedel-Crafts reaction due to the presence of electron-withdrawing
and Lewis-basic sp2 nitrogen limits a repertoire of methods to
decorate the heteroaromatic ring.1 It has been known that some
strong nucleophiles and radicals can react with pyridines at the C-2
position selectively to introduce a C-2 substituent.1 In addition, the
C(2)-H bond can be metalated by a strong base and functionalized
by subsequent reactions with electrophile.1,2 More recently, C-2-
selective functionalizations have been effected in a catalytic manner
through C(2)-H activation of pyridines by transition metal com-
plexes.3 The high C-2 selectivity observed in these protocols can
be ascribed to the coordination of Lewis-basic sp2 nitrogen to a
metal, which then directs C-2 functionalization due to proximity
(Scheme 1). In contrast, direct C-3 and C-4 functionalizations of
pyridines have been scarcely achieved, although the acidity of
C(2)-H is estimated to be lower than that of C(3)-H and C(4)-H
by theoretical calculation.4 Such transformations have met with
limited success using pyridines having a directing group to control
both stoichiometric5 and catalytic6 metalation at the C-3 or C-4
position. Classically, C-3-selective sulfonation and nitration can
proceed under harsh reaction conditions.1 On the other hand, C-4
functionalization of pyridines has relied on indirect processes that
include formation of pyridinium species such as N-oxides, N-alkyl-,
or N-acylpyridiniums followed by subsequent reactions with
electrophiles or nucleophiles to install a C-4 substituent.1,7
nitrogen atom, precedes the C(2)-H functionalization in our
protocol, size and/or electronic factors of the two catalysts can direct
regioselectivity of the pyridine metalation (Scheme 1). Herein, we
report realization of such control by nickel/Lewis acid (LA)
cooperative catalysis. The use of highly bulky N-heterocyclic
carbene (NHC) ligands allows direct C-4 alkylation and alkenylation
of pyridine.9
We first examined C-4 alkylation of pyridine with 1-alkenes
(Table 1). The reaction of pyridine (1a, 1.0 mmol) and 1-tridecene
(2a, 1.5 mmol) in the presence of Ni(cod)2 (5 mol %), 1,3-(2,6-
diisopropylphenyl)imidazol-2-ylidene (IPr, 5 mol %), and AlMe3
(20 mol %) in toluene at 130 °C for 3 h gave 4-tridecylpyridine
(3aa) in 70% yield after isolation by flash chromatography on silica
gel (entry 1). A small amount of 3-tridecylpyridine was also
obtained in 7% yield. Phosphorus ligands including P(i-Pr)3, a ligand
of choice for C-2 alkenylation,8b were completely ineffective. Use
of other aluminum-based LAs including AlMe2Cl and AlMeCl2
gave lower yields, whereas BEt3 and BPh3 showed comparable
activity with slightly decreased yields of 3aa. Diorganozincs, the
best LA catalysts for the C-2 alkenylation,8b were ineffective. A
reduced amount of the LA catalyst gave lower yields, whereas use
of a higher amount showed no significant improvement. While use
of other NHC ligands did not improve the regioselectivity (C-4 vs
C-3), very bulky (2,6-t-Bu2-4-Me-C6H2O)2AlMe (MAD)10 as a LA
catalyst effected exclusive C-4 alkylation of pyridine, albeit with
contamination of branched adduct 3′aa in a small amount (entry
2). These reaction conditions were examined for aliphatic 1-alkenes
having a phenyl-, silyl- or pivaloyl-protected hydroxy group and a
terminal or internal double bond as well as a vinylsilane to give
respective products in good yields (entries 3-8). No detectable
second addition of pyridine was observed across 3ae and 3af (entries
6 and 7). On the other hand, branched C-4-alkylated pyridine 3′ah
was obtained exclusively by the addition reaction across styrene
(entry 9), probably through migratory insertion of the vinylarene
in a manner different from that of aliphatic alkenes to give a
stabilized benzylic nickel intermediate (Vide infra).11 Use of 1,3-
(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes, 5 mol %) instead
We and others have recently uncovered that an electron-rich
nickel catalyst can introduce an alkenyl or aryl group into pyridine
derivatives selectively at the C-2 position.8 Our own strategy
involves stoichiometric or catalytic activation of pyridines to form
pyridinium species, the C(2)-H of which is metalated by a nickel
catalyst with an electron-donating phosphine ligand, possibly
through oxidative addition.8a,b Because η2-coordination of the
† Present address: Research & Development Initiative, Chuo University, Bunkyo-
ku, Tokyo 112-8551, Japan.
9
13666 J. AM. CHEM. SOC. 2010, 132, 13666–13668
10.1021/ja106514b  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. C-4 Alkylation of Pyridine Derivatives Catalyzed by
Ni/MAD
Scheme 2. Plausible Catalytic Cycle
methyl nicotinate (1d), and quinoline (1e) were also alkylated with
2a at the C-4 position (entries 11-14), while no reaction was
observed with pyridines having a C-4 substituent. We also examined
C-4-selective alkenylation of pyridine (eq 1). After brief screening
of reaction parameters, use of IMes as a ligand and slow addition
of an excess amount (3.0 equiv) of 4-ocytne were found effective
to minimize unwanted tri- and oligomerization of the alkyne, giving
a mixture of C-4 and C-3 cis-alkenylated pyridines 4 and 5.
To gain mechanistic insights, the reaction of 1a-d5 (>99.5%D)
with 2a was examined under the standard reaction conditions (eq
2).
This reaction for 9 h gave 3aa with some loss of deuterium at the
C-2 and C-3 positions, whereas the identical reaction quenched after
3 min showed almost no incorporation of hydrogen at these
positions (values in parentheses). The source of the incorporated
hydrogen should be 2a employed in an excess amount. These results
imply a catalytic cycle initiated by oxidative addition of the C(4)-H
bond of pyridine coordinating to MAD,12 which is kinetically
favored over that of the C(2)-H and C(3)-H bonds, through η2-
arenenickel species A (Scheme 2). Coordination and migratory
insertion of alkenes into the Ni-H bond of nickel(II) intermediate
B takes place to give alkylnickel D through C, and subsequent
reductive elimination gives C-4-alkylated pyridines and regenerates
A. We observed an equilibrium between 1a-MAD and 3aa-MAD
in C6D6, suggesting that the turnover of the LA catalyst can be
operative. The results shown in eq 2 suggest that this catalysis works
irreversibly at the C-4 position and that the C-2 and C-3 positions
are also activated reversibly to give the corresponding alkylnickel
a Isolated yields based on 1. b Estimated by GC of crude products. c Run
with AlMe3 (20 mol %) instead of MAD. d C-3-alkylated pyridine (7%)
was also obtained. e Run with IMes as a ligand. f 2-Methyl-1-hexene.
g Quinoline.
of IPr was found more effective for this particular alkene substrate.
The exo-methylene of 2-methyl-1-hexene (2i) was also hydroary-
lated with pyridine regioselectively, albeit in modest yield (entry
10). Pyridine derivatives such as 2-picoline (1b), 2,6-lutidine (1c),
9
J. AM. CHEM. SOC. VOL. 132, NO. 39, 2010 13667

C O M M U N I C A T I O N S
intermediates like D. However, the final irreversible reductive elimina-
tion does not operate at these positions, presumably due to steric
hindrance and competition with ꢀ-hydride elimination, which should
account for the observed loss of deuterium. Use of sterically highly
demanding NHC ligands and MAD is apparently crucial to induce
the C-4 selectivity on both the oxidative addition and the reductive
elimination steps, while the exact rationale is under investigation.
Regarding the effect of LA on the latter step, Hartwig and Shen have
reported that the reductive elimination of aryl(pyridyl)palladium(II)
complexes is accelerated by LA with 4-pyridyl derivatives better than
with 3- or 2-pyridyl ones.13
In conclusion, we have demonstrated that direct C-4-selective
alkylation of pyridines is achieved for the first time by nickel/LA
catalysis. Combined with our previous report,8b we have shown
that ligands and LA cocatalyts indeed effect the nickel-catalyzed
regioselective functionalizations of pyridines. Current efforts are
directed to understanding the reaction mechanism in detail and C-3-
selective variants of these transformations.
References
(1) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Publishing:
Oxford, 2000; pp 63-120.
(2) For reviews, see: (a) Gros, P.; Fort, Y. Eur. J. Org. Chem. 2002, 3375. (b)
Gros, P.; Fort, Y. Eur. J. Org. Chem. 2009, 4199.
(3) (a) Jordan, R. F.; Taylor, D. F. J. Am. Chem. Soc. 1989, 111, 778. (b)
Moore, E. J.; Pretzer, W. R.; O’Connell, T. J.; Harris, J.; LaBounty, L.;
Chou, L.; Grimmer, S. S. J. Am. Chem. Soc. 1992, 114, 5888. (c)
Mukhopadhyay, S.; Rothenberg, G.; Gitis, D.; Baidossi, M.; Ponde, D. E.;
Sasson, Y. J. Chem. Soc., Perkin Trans. 2000, 2, 1809. (d) Murakami, M.;
Hori, S. J. Am. Chem. Soc. 2003, 125, 4720. (e) Lewis, J. C.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 5332. (f) Kawashima,
T.; Takao, T.; Suzuki, H. J. Am. Chem. Soc. 2007, 129, 11006. (g) Berman,
A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2008, 130, 14926. (h) Yotphan, S.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2010, 12, 2978.
(4) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007, 63,
1568.
(5) For a review, see: Snieckus, V. Chem. ReV. 1990, 90, 879.
(6) (a) Grigg, R.; Savic, V. Tetrahedron Lett. 1997, 38, 5737. (b) Wasa, M.;
Worrell, B. T.; Yu, J.-Q. Angew. Chem., Int. Ed. 2010, 49, 1275.
(7) For a review, see: Lavilla, R. J. Chem. Soc., Perkin Trans. 2002, 1, 1141.
(8) (a) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem., Int. Ed. 2007,
46, 8872. (b) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc.
2008, 130, 2448. (c) Tobisu, M.; Hyodo, N.; Chatani, N. J. Am. Chem.
Soc. 2009, 131, 12070.
(9) A part of this work was presented at the 90th annual meeting of the
Chemical Society of Japan on March 28, 2010 (No. 3F2-15). After
submission of this manuscript, closely related direct C-4 alkenylation of
pyridine by a nickel/NHC/AlMe3 catalyst and characterization of a Lewis
acid adduct of an η2-pyridine-nickel complex (like A in Scheme 2) as a
reaction intermediate were reported: Tsai, C.-C.; Shih, W.-C.; Fang, C-.H.;
Ong, T.-G.; Yap, G. P. A. J. Am. Chem. Soc. 2010, 132, 11887.
Acknowledgment. We thank Dr. Kyalo Stephen Kanyiva for
some initial experiments. This work has been supported financially
by a Grant-in-Aid for Scientific Research (S) (to T.H., No.
21225005) and Scientific Research on Innovative Areas “Molecular
Activation Directed toward Straightforward Synthesis” (to Y.N.,
No. 22105003) from JSPS and MEXT, respectively.
(10) Saito, S.; Yamamoto, H. Chem. Commun. 1997, 1585.
(11) Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. Angew. Chem., Int.
Ed. 2010, 49, 4451.
(12) Treatment of pyridine with 1.0 equiv of MAD showed upfield shifts of the
1H NMR signals for the aromatic hydrogens of pyridine that were possibly
shielded by the arene rings of MAD through complexation.10
Note Added after ASAP Publication. In the version published
ASAP September 7, 2010, Table 1, entry 9 contained an error; the
correct version reposted September 9, 2010.
Supporting Information Available: Detailed experimental proce-
dures; spectroscopic and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7734.
JA106514B
9
13668 J. AM. CHEM. SOC. VOL. 132, NO. 39, 2010