Cobalt-catalyzed directed alkylation of olefinic C-H bond with primary and secondary alkyl chlorides

Article abstract of DOI:10.1055/s-0034-1379247

A cobalt-N-heterocyclic carbene catalytic system promotes pyridine-directed olefinic C-H alkylation reactions using a variety of primary and secondary alkyl chlorides under mild conditions. Radical clock experiments suggest that the reaction involves single-electron transfer from the cobalt intermediate to the alkyl chloride.

Full text of DOI:10.1055/s-0034-1379247

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 340–344
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Cobalt-Catalyzed Directed Alkylation of Olefinic C–H Bond with
Primary and Secondary Alkyl Chlorides
Cobalt-Catalyzed Alkylation of Olefins
Takeshi Yamakawa
cat. Co–NHC
Yuan Wah Seto
t-BuCH2MgBr
TMEDA
N
N
Naohiko Yoshikai*
+
Cl
THF, r.t., 12 h
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
nyoshikai@ntu.edu.sg
+
6
5
6
7
9
1
1
9
6
1
92%
Received: 28.08.2014
Accepted: 15.09.2014
Published online: 15.10.2014
tempt to apply these catalytic systems to the reaction of
2-(cyclohex-1-en-1-yl)pyridine (1a) and chlorocyclohexane
(2a). The catalytic system consisting of CoBr2 (10 mol%), L1
(10 mol%), and neopentylmagnesium bromide (2 equiv)
promoted the desired reaction to afford the cyclohexylation
product 3aa in a moderate yield of 63%, along with a small
amount of a byproduct 4a arising from vinylic C–H alkyla-
tion with the Grignard reagent (Table 1, entry 1). The use of
L2 instead of L1 gave a comparable result, while the forma-
tion of 4a was slightly suppressed (Table 1, entry 2). Popu-
lar NHC precursors such as 1,3-bis(2,4,6-trimethylphe-
nyl)imidazolium chloride (IMes·HCl) and 1,3-bis(2,6-diiso-
propylphenyl)imidazolium chloride (IPr·HCl) exhibited
much poorer performances (Table 1, entries 3 and 4).
DOI: 10.1055/s-0034-1379247; Art ID: st-2014-r0719-c
Abstract A cobalt–N-heterocyclic carbene catalytic system promotes
pyridine-directed olefinic C–H alkylation reactions using a variety of pri-
mary and secondary alkyl chlorides under mild conditions. Radical clock
experiments suggest that the reaction involves single-electron transfer
from the cobalt intermediate to the alkyl chloride.
Key words cobalt, C–H activation, alkylations, alkyl halides, alkenes
Transition-metal-catalyzed,
directing-group-assisted
alkylation of aromatic compounds with alkyl halides allows
the introduction of a variety of alkyl groups into the aro-
matic ring with predictable regioselectivity,1 and thus
serves as a complementary tool to the classical Friedel–
Crafts alkylation as well as transition-metal-catalyzed C–H
alkylation through hydroarylation of alkenes.2 Over the past
several years, a significant progress has been made for this
type of reaction with the development of catalytic systems
based on ruthenium,3 palladium,4 nickel,5 cobalt,6 and iron.7
Analogous alkylation on an olefinic substrate is also con-
ceivable and appears attractive for the stereoselective syn-
thesis of multisubstituted olefins. Thus far, such reactions
have been achieved only for acrylamide derivatives bearing
a bidentate 8-aminoquinoline directing group under nickel
or iron catalysis.5a,7a,c As a part of our continuing research
on cobalt-catalyzed C–H functionalization reactions,8 we
report here that olefinic C–H alkylation of a 2-alkenylpyri-
dine derivative can be achieved using primary and second-
ary alkyl chlorides with the aid of a cobalt–N-heterocyclic
carbene (NHC) catalyst and a neopentyl Grignard re-
agent.9,10
Table 1 Optimization of Reaction Conditionsa
CoBr2 (10 mol%)
ligand (10 mol%)
RMgX (2 equiv)
N
N
N
+
+
R
Cl
THF, r.t., 6 h
1a
2a (1.5 equiv)
3aa
4a
N
N+
N
N+
–
BF4
Br–
L1
L2
Entry
Ligand
RMgX
3aa (%)b
4a (%)b
1
2
3
4
5
6
L1
t-BuCH2MgBr
t-BuCH2MgBr
t-BuCH2MgBr
t-BuCH2MgBr
Me3SiCH2MgCl
n-BuMgBr
63
65
12
23
14
21
6
We recently developed cobalt–NHC catalytic systems
that allow ortho-alkylation of aryl imines and 2-arylpyri-
dines with primary and secondary alkyl halides, identifying
1,3-diisopropyl-2,5-dihydro-1H-imidazol-3-ium tetrafluo-
roborate (L1) and its benzo-fused analogue L2 as effective
NHC preligands.6a,c The present study began with an at-
L2
2
IMes·HCl
IPr·HCl
L2
2
9
9
L2
26
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T. Yamakawa et al.
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Table 2 Alkylation of 1a with Various Alkyl Chloridesa
Table 1 (continued)
Entry
Ligand
RMgX
3aa (%)b
4a (%)b
CoBr2 (10 mol%)
L2 (10 mol%)
t-BuCH2MgBr (2 equiv)
TMEDA (2 equiv)
7
L2
L2
L2
L2
L2
L2
i-PrMgBr
1
29
–
N
N
8
CyMgCl
1
+
Alkyl Cl
9c
t-BuCH2MgBr
t-BuCH2MgBr
t-BuCH2MgBr
t-BuCH2MgBr
85
73
7
4
Alkyl
THF, r.t., 12 h
10c,d
11c,e
12c,f
4
1
1a
2a–k (1.5 equiv)
3aa–ak
39
2
a The reaction was performed on a 0.3 mmol scale.
b Determined by GC using n-tridecane as an internal standard.
c TMEDA (2 equiv) was added.
Entry Alkyl chloride
Product
Yield
(%)b
d The loadings of CoBr2 and L2 were reduced to 5 mol%.
e The reaction was performed at 0 °C.
1
2a
2b
2c
2d
2e
2f
c-C6H11Cl
c-C4H7Cl
c-C5H9Cl
c-C7H13Cl
i-C3H7Cl
3aa
92
76
90
93
85
86
f Bromocyclohexane was used instead of 2a.
2
3ab
3
3ac
4c
5d
6
3ad
Using L2, we further examined other reaction parame-
ters. Replacement of neopentylmagnesium bromide with
other primary or secondary Grignard reagent resulted in a
diminished yield of 3aa (Table 1, entries 5–8), while in
some cases substantial formation of the undesirable alkyla-
tion product 4a was observed (Table 1, entries 6 and 7). The
addition of TMEDA (2 equiv) considerably improved the ef-
ficiency of the reaction, thus affording 3aa in 85% yield (Ta-
ble 1, entry 9).11 With TMEDA as the additive, the catalyst
loading could be reduced to 5 mol% albeit with a decrease in
the product yield by ca. 10% (Table 1, entry 10), while the
reaction became markedly sluggish at 0 °C (Table 1, entry
11). Note that the use of bromocyclohexane instead of 2a
afforded 3aa in only 39% yield (Table 1, entry 12).
With the optimized conditions (Table 1, entry 9) in
hand, we explored the scope of the vinylic C–H alkylation
reaction. We first examined the reaction of 1a with various
alkyl chlorides (Table 2). Cycloalkyl chlorides of various ring
sizes smoothly participated in the reaction to afford the
corresponding products 3aa–3ad in good to excellent yields
(entries 1–4). The reaction of isopropyl chloride was effi-
ciently achieved at 40 °C with a high ratio of the isopropyla-
tion product to the n-propylation product (entry 5). A (3-
chlorobutyl)benzene derivative 2f was also amenable to the
present reaction, while the ratio of the secondary to prima-
ry isomers degraded slightly (entry 6). The reactions using
primary alkyl chlorides such as n-butyl, n-octyl, and
phenethyl chlorides proceeded at room temperature to af-
ford the desired products 3ag–3aj in moderate to good
yields (entries 7–10). Note that the reaction of phenethyl
chloride was accompanied by the formation of a minor
amount of the branched isomer (entry 9). The reaction of
neopentyl chloride required an elevated temperature of
60 °C, presumably due to the steric hindrance at the β-posi-
tion (entry 11).
3ae (i/n = 97:3)e
3af (i/n = 91:9)e
Cl
MeO
7
2g
2h
2i
n-C4H9Cl
n-C8H17Cl
Ph(CH2)2Cl
3ag
81
85
70
65
8
3ah
9
3ai (i/n = 5:95)e
10
2j
3aj
Cl
F
11f
2k
t-BuCH2Cl
3ak
72
a The reaction was performed on a 0.3 mmol scale.
b Isolated yield.
c Alkyl chloride (2 equiv) and t-BuCH2MgBr (2.5 equiv) were used.
d The reaction was performed at 40 °C.
e The ratio of the secondary and primary alkylation products.
f The reaction was performed at 60 °C.
Next, different olefinic substrates were subjected to the
reaction with 2a (Table 3). Five- and seven-membered cy-
clic 2-alkenylpyridines 1b and 1c afforded the correspond-
ing tetrasubstituted olefins 3ba and 3ca, respectively, in
good yields (entries 1 and 2). Analogous acyclic 2-alken-
ylpyridine 1d also participated in the reaction to afford the
product 3da in a modest yield of 41% (entry 3). The reaction
of 2-alkenylpyridine 1e bearing a tert-butyl group at the α-
position took place at 60 °C with moderate efficiency (entry
4). With a methyl group instead of the tert-butyl group at
the α-position, the reaction became complicated and af-
forded an intractable mixture, in which the desired product
was not detected (entry 5). A pyrazolyl group proved to
serve as a directing group for the present reaction, albeit
with low efficiency (entry 6). Unfortunately, α,β-unsaturat-
ed imines, even with a geometrically favorable cyclohexenyl
skeleton (1h), failed to participate in the reaction (entry 7).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 340–344

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T. Yamakawa et al.
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Table 3 Reaction of Different Olefins with 2aa
With several lines of evidence, including results of radi-
cal clock experiments, we previously proposed that the co-
balt–NHC-catalyzed ortho-alkylation of an aryl imine with
an alkyl halide involves single-electron transfer from the
cobalt center to the alkyl halide to generate the alkyl radi-
cal.6a,c To examine whether the present reaction also pro-
ceeds through a similar process, we performed radical clock
experiments using 1a and 6-halohex-1-ene (2l) as the sub-
strates (Scheme 1). The reaction of 1a with 6-chlorohex-1-
ene afforded the expected direct alkylation product 3al and
the ring-closing alkylation product 3al′ in 16% and 3%
yields, respectively, along with another two alkylation
products 5 (26%) and 6 (9%). The product 5 appears to have
been formed through the insertion of the C=C double bond
of 2l into the vinylic C–H bond of 1a, with the C–Cl bond
untouched. Participation of both the C–Cl and C=C bond of
2l in the vinylic C–H functionalization should have resulted
in the dimeric product 6. The distribution of the four prod-
ucts was very different when 6-bromohex-1-ene was used
instead of the corresponding chloride. The reaction afforded
a near equimolar mixture of 3al and 3al′ in an overall yield
of 58%. The olefin insertion product 5 was not detected,
while the formation of a minor amount of the double al-
kylation product 6 was observed.
CoBr2 (10 mol%)
L2 (10 mol%)
DG
t-BuCH2MgBr (2 equiv)
DG
TMEDA (2 equiv)
+
R1
R1
Cl
R2
1b–h
Entry
THF, 12 h
R2
3ba–ha
Product Yield (%)b
2a (1.5 equiv)
Olefin
Temp (°C)
40
N
1
2
3
1b
3ba
3ca
3da
77c
68c
41c
N
1c
40
r.t.
N
1d
CoBr2 (10 mol%)
L2 (10 mol%)
t-BuCH2MgBr (2 equiv)
N
N
TMEDA (2 equiv)
+
C6H11
X
THF, r.t., 12 h
N
4
5
1e
1f
60
r.t.
3ea
3fa
46
3ala
16% (X = Cl)
25% (X = Br)
1a
2l (1.5 equiv)
t-Bu
N
N
N.D.
N
N
N
+
+
+
(CH2)6X
(CH2)3
N
2
6d
1g
1h
60
60
3ga
3ha
7
3al'
5
6
3% (X = Cl)
33% (X = Br)
26% (X = Cl)
0% (X = Br)
8% (X = Cl)
9% (X = Br)
PMP
N
Scheme 1 Radical clock experiments. The yields were estimated by GC
using n-tridecane as an internal standard. The reaction also afforded C–H
neopentylation product (9%). a Obtained as a mixture of four or five dif-
ferent isomers. The position of the double bond of each isomer was not
determined.
7
N.D.
a The reaction was performed on a 0.3 mmol scale.
b Isolated yield.
With the above observations, we suggest that the pres-
ent reaction features a catalytic cycle similar to that pro-
posed for the ortho-alkylation (Scheme 2). An organocobalt
species A generated from the cobalt precatalyst and the
Grignard reagent undergoes cyclometalation of 2-alkenyl-
c The product was obtained as a mixture with the C–H neopentylation
product.
d With 4.5 equiv of 2a and 5 equiv of t-BuCH2MgBr.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 340–344

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T. Yamakawa et al.
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pyridine through vinylic C–H oxidative addition and reduc-
tive elimination of alkane R–H to give a cobaltacycle C.12
Single-electron transfer from the intermediate C to the alkyl
halide is followed by the coupling of the resulting alkenyl-
cobalt species and alkyl radical (D),13 thus affording the al-
kylation product.14,15 Transmetalation of the cobalt halide E
and the Grignard reagent regenerates the initial species A.
In light of the ratio of 3al and 3al′ (Scheme 1), the C–C bond
formation would occur at a relatively fast rate. The putative
C–H oxidative addition intermediate B may be responsible
for the formation of the olefin insertion products 5 and 6.
References and Notes
(1) Ackermann, L. Chem. Commun. 2010, 46, 4866.
(2) For selected reviews, see: (a) Kakiuchi, F.; Kochi, T. Synthesis
2008, 3013. (b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem.
Rev. 2010, 110, 624. (c) Ackermann, L. Chem. Rev. 2011, 111,
1315. (d) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev.
2012, 112, 5879.
(3) Ackermann, L.; Novák, P.; Vicente, R.; Hofmann, N. Angew.
Chem. Int. Ed. 2009, 48, 6045.
(4) (a) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem. Int. Ed. 2009,
48, 6097. (b) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010,
132, 3965. (c) Zhao, Y.-S.; Chen, G. Org. Lett. 2011, 13, 4850.
(5) (a) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2013, 135, 5308.
(b) Song, W.; Lackner, S.; Ackermann, L. Angew. Chem. Int. Ed.
2014, 53, 2477.
CoBr2, NHC⋅HX
RMgBr
N
(6) (a) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 9279.
(b) Punji, B.; Song, W. F.; Shevchenko, G. A.; Ackermann, L.
Chem. Eur. J. 2013, 19, 10605. (c) Gao, K.; Yamakawa, T.;
Yoshikai, N. Synthesis 2014, 46, 2024.
(7) (a) Ilies, L.; Matsubara, T.; Ichikawa, S.; Asako, S.; Nakamura, E.
J. Am. Chem. Soc. 2014, 136, 13126. (b) Fruchey, E. R.; Monks, B.
M.; Cook, S. P. J. Am. Chem. Soc. 2014, 136, 13130. (c) Monks, B.
M.; Fruchey, E. R.; Cook, S. P. Angew. Chem. Int. Ed. 2014, 53,
11065.
(8) Gao, K.; Yoshikai, N. Acc. Chem. Res. 2014, 47, 1208.
(9) For an example of cobalt-catalyzed olefinic C–H functionaliza-
tion, see: Yamakawa, T.; Yoshikai, N. Org. Lett. 2013, 15, 196.
(10) For examples of other types of olefinic C–H functionalization of
2-alkenylpyridines, see: (a) Oi, S.; Sakai, K.; Inoue, Y. Org. Lett.
2005, 7, 4009. (b) Ackermann, L.; Born, R.; Alvarez-Bercedo, P.
Angew. Chem. Int. Ed. 2007, 46, 6364. (c) Kuninobu, Y.; Fujii, Y.;
Matsuki, T.; Nishina, Y.; Takai, K. Org. Lett. 2009, 11, 2711.
(d) Ilies, L.; Asako, S.; Nakamura, E. J. Am. Chem. Soc. 2011, 133,
7672. (e) Li, Y.; Zhang, X.-S.; Zhu, Q.-L.; Shi, Z.-J. Org. Lett. 2012,
14, 4498.
MgBrX
[Co]
R
A
RMgBr
[Co]
X
N
E
[Co]
R
H
N
B
Alkyl
R
H
N
N
[Co]
X
[Co]
Alkyl•
C
Alkyl
X
D
Scheme 2 Proposed catalytic cycle
(11) (a) Li, B.; Wu, Z.-H.; Gu, Y.-F.; Sun, C.-L.; Wang, B.-Q.; Shi, Z.-J.
Angew. Chem. Int. Ed. 2011, 50, 1109. (b) Yamakawa, T.;
Yoshikai, N. Chem. Asian J. 2014, 9, 1242.
(12) Klein, H.-F.; Camadanli, S.; Beck, R.; Leukel, D.; Flörke, U. Angew.
Chem. Int. Ed. 2005, 44, 975.
(13) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2001, 123, 5374.
(14) (a) Ohmiya, H.; Wakabayashi, K.; Yorimitsu, H.; Oshima, K. Tet-
rahedron 2006, 62, 2207. (b) Ohmiya, H.; Yorimitsu, H.; Oshima,
K. J. Am. Chem. Soc. 2006, 128, 1886. (c) Cahiez, G.; Chaboche, C.;
Duplais, C.; Moyeux, A. Org. Lett. 2009, 11, 277.
In summary, we have demonstrated that the cobalt–
NHC catalytic system is capable of promoting olefinic C–H
alkylation with primary and secondary alkyl chlorides, pre-
sumably through single-electron transfer as one of the key
steps.16 The present study has also indicated the potential
of cobalt catalysis for olefinic C–H alkylation through the
insertion of simple olefins.17
(15) For reviews on cobalt-catalyzed cross-coupling reactions, see:
(a) Cahiez, G.; Moyeux, A. Chem. Rev. 2010, 110, 1435. (b) Hess,
W.; Treutwein, J.; Hilt, G. Synthesis 2008, 3537. (c) Gosmini, C.;
Begouin, J. M.; Moncomble, A. Chem. Commun. 2008, 3221.
(d) Yorimitsu, H.; Oshima, K. Pure Appl. Chem. 2006, 78, 441.
(16) General Procedure for 2-{[1,1′-Bi(cyclohexan)]-1-en-2-
yl}pyridine (3aa): In a 10-mL Schlenk tube were placed CoBr2
(0.3 M in THF, 0.10 mL, 0.030 mmol), 1,3-diisopropylbenzimid-
azolium bromide (L2; 8.5 mg, 0.030 mmol), 2-(cyclohex-1-en-
1-yl)pyridine (1a; 47.8 mg, 0.30 mmol), chlorocyclohexane (2a;
53.6 μL, 0.45 mmol), TMEDA (90 μL, 0.60 mmol) and THF (0.28
mL). To the mixture was added a THF solution of t-BuCH2MgBr
(0.96 M, 0.63 mL, 0.60 mmol) dropwise at 0 °C. The reaction
mixture was stirred at r.t. for 6 h, and then quenched by the
addition H2O (1.0 mL). The resulting mixture was extracted
with EtOAc (3 × 3 mL). The combined organic layer was dried
Acknowledgment
This work was supported by the Singapore National Research Founda-
tion (NRF-RF2009-05), Nanyang Technological University, and JST,
CREST.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379247.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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T. Yamakawa et al.
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over Na2SO4 and concentrated under reduced pressure. The
crude product was purified by silica gel chromatography (elu-
ent: hexane–EtOAc, 100:12) to afford a mixture of 3aa and 2-(2-
neopentylcyclohex-1-en-1-yl)pyridine in a ratio of 30:1 (deter-
mined by 1H NMR) as a yellow solid (69.2 mg, 92% yield for 3aa).
1H NMR (400 MHz, CDCl3): δ = 1.00–1.09 (m, 3 H), 1.27–1.37 (m,
2 H), 1.48–1.55 (m, 3 H), 1.62–1.74 (m, 6 H), 2.05–2.12 (m, 3 H),
2.30–2.33 (m, 2 H), 7.09–7.11 (m, 2 H), 7.58–7.63 (m, 1 H),
8.56–8.60 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 23.2, 23.3,
24.5, 26.3, 26.6 (2 × C), 31.0, 31.2 (2 × C), 42.1, 121.0, 123.4,
131.2, 136.0, 140.0, 149.5, 162.9. HRMS (ESI): m/z [M + H]+ calcd
for C17H24N: 242.1909; found: 242.1908.
(17) (a) Ilies, L.; Chen, Q.; Zeng, X.; Nakamura, E. J. Am. Chem. Soc.
2011, 133, 5221. (b) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2011,
133, 400. (c) Gao, K.; Yoshikai, N. Angew. Chem. Int. Ed. 2011, 50,
6888. (d) Lee, P.-S.; Yoshikai, N. Angew. Chem. Int. Ed. 2013, 52,
1240.
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