Cobalt-catalyzed C4-selective direct alkylation of pyridines

Article abstract of DOI:10.1002/anie.201208666

How pyridine got its tail: A new catalyst for the atom-economical C4-selective direct alkylation of pyridines is described. A combination of CoBr₂ and LiBEt₃H catalyzes the reaction of pyridines with 1-alkenes at 70 °C to give alkylation products with C4/C2 ratios of >20:1. Substrate/catalyst ratios of up to 4000, and a turnover number of 3440 were achieved.

Full text of DOI:10.1002/anie.201208666

Angewandte
Chemie
DOI: 10.1002/anie.201208666
Regioselective Catalysis
Cobalt-Catalyzed C4-Selective Direct Alkylation of Pyridines**
Takashi Andou, Yutaka Saga, Hirotomo Komai, Shigeki Matsunaga,* and Motomu Kanai*
A pyridine core is a ubiquitous structural motif found in many
biologically active natural products and pharmaceuticals. The
regioselective functionalization of pyridines,[1] such as the C2-
selective addition of highly reactive nucleophiles and C2-
selective deprotonation with a strong base followed by
reactions with electrophiles,[2] has long been investigated by
À
many researchers. Catalytic C H bond functionalization of
pyridines provides atom-[3] and step-economical[4] methods
for accessing various functionalized pyridines, and thus has
attracted recent interest.[5–16] In many reports, a Lewis basic
Scheme 1. Working hypothesis for the atom-economic catalytic C4-
selective alkylation of pyridines.
sp2 nitrogen atom in the pyridine ring was utilized as the
À
directing group, and C H bond activation by transition-metal
catalysts occurred selectively at the C2 position.[5,7] In
(II) has sufficient nucleophilicity, its addition to pyridine may
afford a dihydropyridine intermediate (III). To realize an
atom-economical catalytic process, rearomatization of pyri-
dine without any oxidants and regeneration of the metal-
hydride catalyst (I) are required.
We first screened various metal salts and hydride sources
that fulfilled the requirements for Scheme 1. Selected results
from the optimization studies are summarized in Table 1.
À
contrast, reports on the C3- or C4-selective catalytic C H
bond functionalization of pyridines without an additional
directing group are limited.[8–11] Thus, further studies into the
development of new catalysts for C3- or C4-selective direct
functionalization of pyridines are highly desirable. In 2010,
Nakao, Hiyama, and co-workers,[10a] and Ong et al.[10b] inde-
pendently reported the first C4-selective direct functionaliza-
tion of pyridines through an oxidative addition/insertion/
reductive elimination sequence catalyzed by Ni0 and bulky
Lewis acids. There remains room for improvement in the C4-
selective direct functionalization of pyridines, however,
especially in terms of catalyst loading.
Table 1: Optimization studies.
To realize the C4-selective alkylation of pyridines, we
searched for a new catalyst system based on a different
strategy, catalytic nucleophilic addition/rearomatization.[14–16]
Our working hypothesis is shown in Scheme 1. Hydrometa-
lation of alkenes with a metal hydride catalyst (I) would
afford an alkyl–metal species (II). If the alkyl–metal species
Entry Metal
Additive
(x mol%)
[HÀ]
Yield
[%][a]
Product ratio[b]
(C4/C2/double)
1
2
3
4
FeBr2
NiBr2
MnBr2
CuBr
none
none
none
none
none
none
none
none
none
none
PCy3 (3)
IMes (3)
Et3B (20)
Et3B (20)
LiBEt3H 10
LiBEt3H 24
LiBEt3H 22
LiBEt3H
LiBEt3H 77
NaBEt3H 10
KBEt3H
DIBAL-H
none
>20:1:0
>20:1:0
>20:1:0
>20:1:0
1.8:1:0.2
1.3:1:0
3
[*] Dr. T. Andou,[+] Y. Saga,[+] H. Komai, Dr. S. Matsunaga,
Prof. Dr. M. Kanai
5
6
7
8
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
none
CoBr2
CoBr2
CoBr2
CoCl2
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: smatsuna@mol.f.u-tokyo.ac.jp
kanai@mol.f.u-tokyo.ac.jp
Y. Saga,[+] H. Komai, Prof. Dr. M. Kanai
2
2
0
4
>20:1:0
0:1.3:1
9
–
10
11
12
13
14
15
16
LiBEt3H
>20:1:0
1.3:1:0
2.5:0:1
7.0:1:0.52
6.7:1:0.25
7.4:1:0.26
>20:1:0.38
LiBEt3H 77
LiBEt3H 34
LiBEt3H 95[c]
LiBEt3H 82
LiBEt3H 88
LiBEt3H 91[c]
JST, ERATO, Kanai Life Science Catalysis Project
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Dr. S. Matsunaga
JST, ACT-C, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
[+] These authors contributed equally to this work.
Co(acac)2 Et3B (20)
CoBr2
Et3B (20)
+HMPA (30)
[**] We thank Mr. Shohei Yamamoto for fruitful discussions and
experimental support. This work was supported in part by ERATO
from JST (M.K.), a Grant-in-Aid for Scientific Research on Innovative
Areas “Molecular Activation Directed toward Straightforward Syn-
thesis” from MEXT (S.M.), the ACT-C program from JST (S.M.) and
the Naito Foundation. T.A. thanks JSPS for a postdoctoral fellow-
ship.
[a] Combined yield of alkylated products based on pyridine 1a.
Determined by 1H NMR analysis of the crude mixture using 1,2-
dibromoethane as an internal standard. [b] Determined by 1H NMR
analysis of the crude mixture. [c] Combined yield of alkylated products
after purification by silica gel column chromatography. acac=acetyl-
acetonate, Cy=cyclohexyl, DIBAL-H=diisobutylaluminum hydride,
HMPA=hexamethylphosphoramide, IMes=1,3-bis(2,4,6-trimethylphe-
nyl)imidazol-2-ylidene.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208666.
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Table 2: Cobalt-catalyzed direct C4-selective alkylation of pyridines with
Catalytic amounts of Fe, Ni, Mn, and Cu salts in the presence
of LiBEt3H (20 mol%) resulted in unsatisfactory yields
(entries 1–4). In contrast, CoBr2 (1 mol%) promoted the
reaction of pyridine 1a with styrene 2a, affording alkylation
product 3aa in 77% yield and with a branched/linear
selectivity of > 20:1, but low C4/C2 selectivity (1.8:1;
entry 5). We also screened other hydride sources (entries 6–
8), but LiBEt3H was crucial for obtaining product 3aa in good
yield. Control experiments using either CoBr2 alone (entry 9)
or LiBEt3H alone (entry 10) gave poor results. Thus, the
combination of CoBr2 and LiBEt3H was important for
obtaining high reactivity. To improve C4/C2 selectivity, we
investigated ligands such as phosphines and N-heterocyclic
carbenes, but observed no improvement (entries 11 and 12).
On the other hand, the addition of Et3B effectively improved
C4/C2 selectivity, and the alkylation adduct was obtained in
95% yield, and with branched/linear=> 20:1 and C4/C2 =
7.0:1 selectivities (entry 13). Other cobalt salts, such as CoCl2
and [Co(acac)2] (acac = acetylacetonate) gave comparable
C4/C2 selectivity (entries 14 and 15), but the reactivity was
slightly lower than with CoBr2. Hexamethylphosphoramide
(HMPA; 30 mol%) in combination with Et3B further
improved the C4/C2 selectivity to > 20:1 (entry 16).[17]
The substrate scope of the C4-selective direct pyridine
alkylation is summarized in Table 2. The reaction of pyridine
and its derivatives 1a–1d with styrene derivatives 2a–2 f
(1.05 equiv) proceeded smoothly when using CoBr2
(1 mol%), LiBEt3H (20–30 mol%), and Et3B (20 mol%).
Good to high branched selectivity (> 20:1–7.4:1) and C4
selectivity (> 20:1 for all entries)[18] were observed for
entries 1–5 and 9–17. Aliphatic 1-alkenes 2g, 2h, and 2i
were also applicable, but the reactivity of 2g–2i was much
lower than that of the styrene derivatives. An increase in the
loading of CoBr2 (6 or 9 mol%) and LiBEt3H (200 or
300 mol%) and the use of excess aliphatic alkenes were
required to promote alkylation. As shown in entries 6–8,
linear products 4ag–4ai (branched/linear= 1: > 20) were
obtained in 58–86% yield with high C4 selectivity
(> 20:1).[19] When using bipyridine 1e, a product doubly
alkylated at the C4 and C4ꢀ positions was obtained in 85%
yield by performing the reaction with styrene (5.0 mol equiv;
entry 18). Notably, the reaction of 3-picoline 1b with styrene
2a proceeded smoothly on a gram scale with as little as
0.025 mol% of CoBr2, which equates to a substrate/catalyst
(s/c) ratio of 4000 (Scheme 2). The high turnover number
(TON; 3440) of the reaction is also noteworthy.
alkenes.[a]
Entry
1
LiBEt3H
[mol%]
2
Yield 3,4 Branched/linear C4/C2/double
[%][b] product ratio[c] product ratio[c]
1[d]
2[d]
3
1a 20
1a 30
1a 30
1a 30
1a 30
1a 200
1a 200
1a 300
1b 20
1b 20
1b 20
1b 20
1c 30
1c 30
1c 30
1c 30
2a 91
2b 87
2c 83
2d 77
2e 60
2g 71
2h 86
2i 58
2a 89
2b 97
2c 84
2 f 87
2a 96
2b 88
2c 86
2 f 81
2a 63
2a 85
3aa
3ab
3ac
3ad
3ae
4ag
4ah
4ai
3ba
3bb
3bc
3bf
3ca
3cb
3cc
3cf
>20:1
>20:1
>20:1
>20:1
7.4:1
>20:1:0.38
>20:1:1.1
>20:1:trace
>20:1:0
>20:1:0
>20:1:0
>20:1:0
>20:1:0
>20:1:trace
>20:1:0
>20:1:0
>20:1:0
>20:1:0
>20:1:0
>20:1:trace
>20:1:0
4
5
6[e]
7[e]
8[f]
9
1:>20
1:>20
1:>20
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
10
11
12
13
14
15
16
17[g] 1d 30
18[h] 1e 30
3da
3ea
>20:1:trace
C4 only
[a] The reaction was run using 1 (0.90 mmol), 2 (1.05 equiv), CoBr2
(1 mol%) and Et3B (20 mol%) in toluene (0.3m) at 708C, unless
otherwise noted. [b] Combined yield of alkylated products based on
1 after purification by silica gel column chromatography. [c] Determined
by 1H NMR analysis of the crude mixture. [d] HMPA (30 mol%) was
added. [e] CoBr2 (6.0 mol%) and excess alkenes (2g: 12 equiv, 2h:
13.5 equiv) were used. [f] CoBr2 (9.0 mol%) and excess 2i (15.2 equiv)
were used. [g] Reaction was run in the absence of Et3B. [h] 5.0 mol equiv
of 2a was used and a product doubly alkylated at the C4 and C4’
positions was obtained.
To obtain preliminary insights into the reaction mecha-
nism, we performed control experiments (Schemes 3–5).
First, to assess the catalyst turnover process, the reaction
was performed starting from a cobalt amide species 5
(a model for III in Scheme 1), which was generated by the
procedure shown in Scheme 3. Pyridine (0.2 equiv) was first
reacted with PhLi (0.2 equiv), and CoBr2 (1 mol%) was
added to the mixture to generate proposed cobalt amide 5. An
active cobalt–hydride species [Co–H] would then be gener-
ated from 5 by b-hydride elimination. With the presumed
cobalt hydride catalyst generated in situ in the absence of
LiBEt3H and Et3B, the alkylation of pyridine indeed pro-
ceeded to give 3aa in 70% yield.[20] The observed C4/C2
Scheme 2. Gram-scale reaction with reduced catalyst loading
(s/c=4000).
selectivity was similar to that in Table 1, entry 5, thus
supporting the intermediacy and regeneration of the cobalt–
hydride species[21] in the actual catalytic cycle of the reactions
in Table 2.
2
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Scheme 5. H/D scrambling experiment with [D5]pyridine.
suggest that the present cobalt-catalyzed C4-selective alkyla-
tion of pyridines would proceed through a pathway that does
not involve oxidative addition.
Scheme 3. In situ generation of the active cobalt species in the
absence of LiBEt3H and Et3B.
In summary, we have developed a new catalyst for the
atom-economical C4-selective direct alkylation of pyridines.
A catalytic amount of CoBr2 in combination with LiBEt3H
gave branched adducts from styrene derivatives, and linear
adducts from aliphatic alkenes. The high catalyst turnover
numbers (up to 3440; s/c = 4000) observed in the reaction with
styrene are noteworthy. Further studies to expand the
substrate scope to other heterocyclic compounds and to
clarify the reaction mechanism in more detail are ongoing in
our group.
The presence of catalytic Et3B was key to improving the
C4-selectivity (Table 1, entry 5 vs. entry 13).[22] To assess the
possible role of Et3B, reactions of 4-substituted pyridine 1 f
with styrene 2a in the presence and absence of Et3B were
conducted (Scheme 4). C2-alkylated product 3 fa was
Received: October 29, 2012
Revised: December 12, 2012
Published online: && &&, &&&&
Scheme 4. Reactions of C4-substituted pyridine 1 f in the presence and
absence of Et3B.
Keywords: alkylation · atom economy · catalysis ·
heterocyclic compounds · synthetic methods
.
obtained in 68% yield in the presence of Et3B, whereas the
yield increased to 92% in the absence of Et3B. Thus, Et3B
does not seem to act as a simple Lewis acid to increase the
electrophilicity of pyridines, but may selectively decelerate
the C2 alkylation pathway, resulting in an increase in the C4
selectivity for C4-unsubstituted pyridines.[23]
[1] Reviews: a) J. A. Joule, K. Mills, Heterocyclic Chemistry, 4th ed.,
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Although there is no direct evidence to exclude a reaction
mechanism involving oxidative addition/insertion/reductive
elimination promoted by a low valent cobalt species gener-
ated in situ,[24,25] a mechanism involving hydrometalation/
nucleophilic addition/rearomatization (Scheme 1) appears to
be more plausible for the present reaction, based on the
following observations: 1) The low-valent cobalt catalyst
[2] Review: P. C. Gros, Y. Fort, Eur. J. Org. Chem. 2009, 4199.
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reported by Yoshikai et al[25a] for C H bond functionalization
À
by oxidative addition was not effective in the present pyridine
alkylation reaction.[26] 2) The C3-alkylation adduct was not
detected at all under the present conditions. C3 functional-
ization was, however, the major side reaction in the Ni0/Al
system used by the groups of Nakao/Hiyama and Ong,[10]
which proceeds through oxidative addition. 3) Profiles of H/D
scrambling when using [D5]pyridine as a substrate under the
present cobalt-catalyzed conditions and the Ni0/Al system
were markedly different. Under the present conditions, the H/
D scrambling selectively occurred at the electrophilic C2
positions (Scheme 5), possibly through the reversible addi-
tion/elimination of a cobalt–hydride species. In contrast,
under the Ni0/Al system, which proceeds by oxidative
addition, H/D scrambling occurred at both the C2 and C3
positions.[10,27] Altogether, these contrasting observations
[7] For selected examples of the C2-selective catalytic direct
alkylation of pyridines without prior activation, see: a) R. F.
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d) B.-T. Guan, Z. Hou, J. Am. Chem. Soc. 2011, 133, 18086, and
references therein. For other examples of the C2-selective
functionalization of pyridines and pyridine N-oxides through CH
activation, see the reviews in Refs [1] and [5].
À
[8] For C3-selective catalytic C C bond formation with pyridines,
see: a) M. Ye, G.-L. Gao, A. J. F. Edmunds, P. A. Worthington,
J. A. Morris, J.-Q. Yu, J. Am. Chem. Soc. 2011, 133, 19090; b) M.
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À
[9] C3-selective catalytic C C bond formation with pyridines was
also achieved under Ir catalysis, see: a) B.-J. Li, Z.-J. Shi, Chem.
Sci. 2011, 2, 488; for a review on Ir-catalyzed regioselective
borylation, see: b) J. F. Hartwig, Chem. Soc. Rev. 2011, 40, 1992.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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[10] For the C4-selective catalytic alkylation/alkenylation of pyri-
dines, see: a) Y. Nakao, Y. Yamada, N. Kashihara, T. Hiyama, J.
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[11] For the C4-Selective catalytic silaboration/rearomatization of
pyridines, see: K. Oshima, T. Ohmura, M. Suginome, J. Am.
Chem. Soc. 2011, 133, 7324.
[12] For the directing-group-assisted C3- or C4-selective catalytic
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dron Lett. 1997, 38, 5737.
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electron-deficient substituents at the C3-position, see: a) P.
Guo, J. M. Joo, S. Rakshit, D. Sames, J. Am. Chem. Soc. 2011,
133, 16338; for the functionalization of 2,3,5,6-F4-pyridine, see:
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metric amount of oxidants, see: a) I. B. Seiple, S. Su, R. A.
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[17] HMPA without Et3B was not effective, giving alkylated products
with modest selectivity (87% yield, C4/C2/double = 3.2:1:0.1).
[18] In Table 2, HMPA (30 mol%) was added only when there
remained room for improvement in the C4 selectivity.
[19] The observed branched/linear selectivity difference between the
styrene derivatives and aliphatic alkenes can be ascribed to the
relative stability differences in the alkylcobalt intermediates (II
in Scheme 1 vs. its linear alkylmetal counterpart). Because H/D
scrambling was observed at both the a- and b-positions of
styrene in Scheme 5, the hydrometallation step should be
reversible, at least for styrenes. The reaction between styrenes
and pyridines would proceed through the thermodynamically
more stable p-conjugated benzylic – cobalt intermediate,
whereas the reaction of aliphatic alkenes may proceed from
the kinetically favored linear alkylcobalt intermediate. For
a similar discussion, see: Y. Nakao, N. Kashihara, K. S. Kanyiva,
T. Hiyama, Angew. Chem. 2010, 122, 4553; Angew. Chem. Int.
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[22] To avoid oxygen contamination of the reaction vial, all experi-
ments were performed in a glove box (O2: < 0.5 ppm). Thus, the
possibility of Et3B acting as a radical initiator is less probable.
[23] Although any proposal at the current stage is too speculative,
and further studies are required to precisely clarify the role of
Et3B, we assume that Et3B would competitively prevent the
cobalt species from being coordinated by the sp2 nitrogen atom
in the pyridine ring, which may lead to undesirable C2
alkylation. Alternatively, Et3B may form an organocobalate
species, which would act as a soft nucleophile and prefer addition
at the C4 position. For a discussion on soft and hard nucleophile
properties affecting site selectivity in additions to pyridines, see
the review in Ref. [1e]. For representative catalytic reactions
through organocobalates, see: a) K. Wakabayashi, H. Yorimitsu,
K. Oshima, J. Am. Chem. Soc. 2001, 123, 5374; b) W. M. Czaplik,
M. Mayer, A. Jacobi von Wangelin, Synlett 2009, 2931; c) Z.-H.
Ding, N. Yoshikai, Org. Lett. 2010, 12, 4180.
À
[24] For a review on Co-catalyzed C H activation, see: a) N.
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Moyeux, Chem. Rev. 2010, 110, 1435.
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Gao, P.-S. Lee, T. Fujita, N. Yoshikai, J. Am. Chem. Soc. 2010,
132, 12249; For selected recent examples of other Co-catalyzed
À
C H functionalization reactions, see: c) Q. Chen, L. Ilies, E.
Nakamura, J. Am. Chem. Soc. 2011, 133, 428; d) B. Li, Z.-H. Wu,
Y.-F. Gu, C.-L. Sun, B.-Q. Wang, Z.-J. Shi, Angew. Chem. 2011,
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Ed. 2012, 51, 8251; for early examples, see the review in
Ref. [24].
[26] The reaction of 1a with 2a at 708C using CoBr2 (10 mol%),
PCy3 (10 mol%), and Me3SiCH2MgCl (80 mol%, see Ref. [25a])
did not afford 3aa.
[27] The deuterium scrambling experiment in Ref. [10a] was per-
formed with [D5]pyridine and 1-tridecene, not with styrene. To
precisely compare the results of deuterium scrambling experi-
ments, we additionally performed the experiment using
[D5]pyridine and styrene under the reported Ni0 and bulky Al
Lewis acid conditions. H/D scrambling at the C3 position was
also observed in the reaction with styrene (MAD = (2,6-tBu2-4-
Me-C6H2O)2AlMe;
zoyl-2-ylidene):
IMes = 1,3-(2,4,6-trimethylphenyl)imida-
À
[20] To exclude the possibility of Co H generation from the ethyl
groups in Et3B, the reaction in Scheme 3 was performed in the
absence of Et3B. When Et3B (20 mol%) was added, C4
selectivity improved to C4/C2/double = 12:1:trace.
4
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Regioselective Catalysis
How pyridine got its tail: A new catalyst
for the atom-economical C4-selective
direct alkylation of pyridines is described.
A combination of CoBr2 and LiBEt3H
catalyzes the reaction of pyridines with 1-
alkenes at 708C to give alkylation prod-
ucts with C4/C2 ratios of >20:1. Sub-
strate/catalyst ratios of up to 4000, and
a turnover number of 3440 were achieved.
T. Andou, Y. Saga, H. Komai,
S. Matsunaga,* M. Kanai*
&&& — &&&
Cobalt-Catalyzed C4-Selective Direct
Alkylation of Pyridines
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!