Cobalt-catalyzed chelation-assisted alkylation of arenes with primary and secondary alkyl halides

Article abstract of DOI:10.1055/s-0033-1338658

Cobalt-N-heterocyclic carbene catalytic systems have been developed for chelation-assisted ortho-alkylation of aromatic compounds with alkyl halides. Aryl imines can be selectively monoalkylated at room temperature by various primary or secondary alkyl chlorides or bromides. The catalytic system can also be applied to 2-arylpyridine derivatives, which in the absence of steric hindrance are amenable to dialkylation by an excess of the alkyl halide. Mechanistic experiments, including reactions of stereochemical probes and radical clocks, indicate that the reaction involves single-electron transfer from the cobalt center to the alkyl halide to form the corresponding alkyl radical, which has a finite lifetime before it undergoes C-C bond formation. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1338658

2024▌
FEATURE ARTICLE
feature article
Cobalt-Catalyzed Chelation-Assisted Alkylation of Arenes with Primary and
Secondary Alkyl Halides
Cobalt-Catalyzed Alkylation of Arenes
Ke Gao, Takeshi Yamakawa, Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore
637371, Singapore
Fax +65(6791)1961; E-mail: nyoshikai@ntu.edu.sg
Received: 07.04.2014; Accepted after revision: 12.06.2014
metal complexes to undergo β-hydride elimination
Abstract: Cobalt–N-heterocyclic carbene catalytic systems have
(Scheme 1, a).
been developed for chelation-assisted ortho-alkylation of aromatic
compounds with alkyl halides. Aryl imines can be selectively
monoalkylated at room temperature by various primary or second-
ary alkyl chlorides or bromides. The catalytic system can also be ap-
plied to 2-arylpyridine derivatives, which in the absence of steric
hindrance are amenable to dialkylation by an excess of the alkyl ha-
lide. Mechanistic experiments, including reactions of stereochemi-
cal probes and radical clocks, indicate that the reaction involves
single-electron transfer from the cobalt center to the alkyl halide to
form the corresponding alkyl radical, which has a finite lifetime be-
fore it undergoes C–C bond formation.
We have recently been interested in cobalt catalysis for
C–H bond-functionalization reactions, including those in-
volving chelation-assisted C–H activation.11 In the course
of our research program, we recently found that a cobalt–
N-heterocyclic carbene (NHC) catalyst, in combination
with a neopentyl Grignard reagent, efficiently promotes
ortho-alkylation of aromatic ketimines by alkyl chlorides
or bromides (Scheme 1, b).12 The reaction permits the in-
troduction of a variety of primary or secondary alkyl
groups under mild conditions. In this article, we report the
full details of this reaction, along with the results of an ex-
panded investigation of the substrate scope and the reac-
tion mechanism.
Key words: functionalization, catalysis, cobalt, alkylations, alkyl
halides, radical reaction
1
Introduction
[M]
(a)
R
The alkylation of aromatic compounds is among the most
important C–C bond-forming transformations in organic
synthesis. Since the discovery by Murai et al.1 of the ru-
thenium-catalyzed ortho-alkylation of aromatic ketones
with olefins, the chelation-assisted hydroarylation of al-
kenes in the presence of transition-metal catalysts has
evolved into a versatile approach that complements the
classical Friedel–Crafts alkylation.2,3 However, unlike
Friedel–Crafts chemistry, this approach has met with lim-
ited success in the introduction of secondary alkyl groups.
There are several reasons for this, including the anti-
Markovnikov selectivity of terminal alkenes,4,5 the low re-
activity of internal alkenes, and the isomerization of al-
kenes bearing allylic hydrogens. In addition, some
alkenes, such as cyclobutene, are not readily available
from commercial sources, despite their potential utility.
L
L
H
R
[M]
R
X
often limited to
1° alkyl groups
base
(b)
Co–NHC (cat.)
t-BuCH2MgBr
N
N
R2
R2
+
H
THF, r.t.
R3
X
R3
R1
X = Br or Cl
broad range of
1° and 2° alkyl groups
Scheme 1 Cobalt-catalyzed ortho-alkylation of arenes with alkyl ha-
lides
Recently, ortho-alkylation with alkyl halides as alkylating
agents has attracted significant attention as an alternative
to the hydroarylation approach.6,7 Nevertheless, this ap-
proach has also met with limited success in the introduc-
tion of secondary alkyl groups, with a few exceptions.7h
Only a handful of examples of alkylation with secondary
alkyl halides have been reported in the literature,8–10 pre-
sumably because of their low reactivity toward transition-
metal catalysts and the propensity of secondary alkyl–
2
Ortho-Alkylation of Aryl Imines
We previously developed cobalt–NHC catalytic systems
for ortho C–H functionalization with an aryl aldimine or
an aryl chloride as the electrophile. Cobalt catalysts gen-
erated from a cobalt salt, an imidazolium salt, and neopen-
tylmagnesium bromide promote the addition of 2-
arylpyridines to aryl aldimines,13 as well as the ortho-aryl-
ation of aryl ketimines with aryl chlorides.14 Ackermann
and co-workers had also developed cobalt–NHC systems
SYNTHESIS 2014, 46, 2024–2039
Advanced online publication: 09.07.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338658; Art ID: ss-2014-z0228-fa
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Cobalt-Catalyzed Alkylation of Arenes
2025
for ortho-arylation of 2-arylpyridines or N-pyridylindoles Whereas the unsaturated analogue L2 and the tert-butyl
with aryl sulfamates or carbamates;15 the scope of this re- analogue L3 gave poorer results (entries 5 and 6, respec-
action was later extended to include ortho-arylations and tively), the benzo-fused analogue L4 further improved the
ortho-alkylations of the same substrates with the corre- yield to 82% (entry 7). As we observed in our previous
sponding chlorides.16 We therefore surmised that a similar studies,13,14 neopentylmagnesium bromide was the
catalytic system might also permit ortho C–H alkylation Grignard reagent of choice among other primary and sec-
with an alkyl halide as the electrophile.
ondary Grignard reagents, as it caused ortho-neopentyl-
ation to only a small extent (< 2% in most cases).
To test this hypothesis, we chose the acetophenone imine
1a and 1-chlorooctane (2a) as model reactants for screen- With L1 and L4 as preligands, we next examined the ef-
ing the reaction conditions (Table 1). A catalytic system fects of the leaving group. Whereas the reaction of 1-bro-
consisting of cobalt(II) bromide (10 mol%), 1,3-bis(2,4,6- mooctane (2a′) proceeded smoothly using both L1 and L4
trimethylphenyl)imidazolium chloride (IMes·HCl; 10 (entries 8 and 9), 1-iodooctane (2a′′) gave only low yields
mol%), and neopentylmagnesium bromide (2 equiv), of product 3aa (entries 10 and 11) because of an undesir-
which is effective for ortho-arylation, promoted the reac- able dehydrohalogenation side reaction. Octyl tosylate
tion to afford the alkylation product 3aa in a moderate (2a*) took part in the reaction at an elevated temperature
yield of 38% (Table 1, entry 1). Other typical NHC preli- of 60 °C, giving 3aa in moderate yields (entries 12 and
gands such as 1,3-bis(2,6-diisopropylphenyl)imidazolium 13). However, we found that by simply mixing 2a* and
chloride hydrochloride (IPr·HCl) and 1,3-bis(2,4,6- neopentylmagnesium bromide, substantial displacement
trimethylphenyl)-4,5-dihydroimidazolium
chloride of the tosyloxy group with the bromide anion occurred,
(SIMes·HCl) were less effective (entries 2 and 3). Further even at room temperature. This observation suggests that
screening showed that 1,3-diisopropyl-2,5-dihydro-1H- the alkylation with 2a* involves prior conversion of 2a*
imidazol-3-ium tetrafluoroborate (L1) gave rise to a high- into 2a′.
er catalytic activity, improving the yield to 64% (entry 4).
Biographical Sketches█
Ke Gao received his B.Sc. at Nanyang Technological pursuing his postdoctoral
(2006) and M.Sc. (2009) de- University where he recent- studies in Professor Atsuhiro
grees from Fudan Universi- ly completed his Ph.D. stud- Osuka and Professor Hideki
ty under the supervision of ies, which focused on the Yorimitsu’s group at Kyoto
Professor Jie Wu. He subse- development of cobalt-cata- University.
quently moved to Professor lyzed C–H bond functional-
Naohiko Yoshikai’s group izations. He is currently
Takeshi Yamakawa re- grees from The University studies. His current research
ceived his B.Sc. (2008; su- of Tokyo. In 2010, he is focused on the develop-
pervised by Professor Eiichi joined Professor Naohiko ment of C–H functionaliza-
Nakamura) and M.Sc. Yoshikai’s group at Nan- tion reactions catalyzed by
(2010; supervised by Pro- yang Technological Univer- cobalt and other transition
fessor Shu Kobayashi) de- sity to pursue his Ph.D. metals.
Naohiko Yoshikai received Singapore to join the faculty Japan Award for Young
his B.Sc. (2000), M.Sc. of Nanyang Technological Chemists (2014). His re-
(2002), and Ph.D. (2005) University as a Nanyang search interests focus on the
degrees from the University Assistant Professor and a development and mechanis-
of Tokyo under the guid- Research Fellow of the Sin- tic study of new transition
ance of Professor Eiichi gapore National Research metal-catalyzed reactions
Nakamura, and then served Foundation. He has been and on the synthetic applica-
as an Assistant Professor at awarded the Thieme Chem- tions of such reactions.
the same institution (2005– istry Journal Award (2011)
2009). In 2009, he moved to and the Chemical Society of
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2024–2039

2026
K. Gao et al.
FEATURE ARTICLE
Table 1 Screening of NHC Preligands and Leaving Groupsa
bromide exchange between the major product 3ag and
neopentylmagnesium bromide (see above). Dihalogenat-
ed substrates containing both alkyl–Cl and aryl–X (X = F
or Cl) moieties underwent chemoselective activation of
the former, affording the ketones 3ah and 3ai in good
yields (entries 8 and 9). Alkyl halides hindered at the β-
position, such as 1-bromo-2,2-dimethylpropane, (chloro-
methyl)(trimethyl)silane, or (bromomethyl)cyclopentane,
participated smoothly in the reaction (entries 10–12). The
presence of acetal or secondary amide groups in the alkyl
bromide was tolerated (entries 13 and 14). An alkyl chlo-
ride containing a pyridine ring reacted rather sluggishly,
presumably as a result of coordination of the pyridine ni-
trogen atom to the catalyst (entry 15).
PMP
N
CoBr2 (10 mol%)
NHC•HX (10 mol%)
t-BuCH2MgBr (2 equiv)
O
H+
n-C8H17
+
n-C8H17
X
THF, r.t., 6 h
2a (X = Cl)
2a' (X = Br)
2a'' (X = I)
3aa
2a* (X = OTs)
1a
N
N+
N
N+
i-Pr
i-Pr
i-Pr
i-Pr
–
–
BF4
BF4
L1
L2
Br–
N
N+
The present catalytic system also allowed alkylation of
imine 1a with a broad range of secondary alkyl chlorides
or bromides, as summarized in Table 3. Four-membered
to twelve-membered cycloalkyl halides participated in the
reaction to afford the corresponding products 3ap–at in
moderate to good yields (Table 3, entries 1–7). tert-Bu-
toxycarbonyl-protected 4-bromopiperidine also gave the
corresponding product 3au, albeit in moderate yield (en-
try 8). With the Co–L1 catalyst, acyclic secondary alkyl
halides such as 1-chloro- or 1-bromopropane or 2-bro-
mobutane gave the alkylation products 3av and 3aw in
moderate yields and with high ratios of the secondary to
primary isomers (i/n ≤ 99:1; entries 9–11). In these cases,
the Co–L4 catalyst improved the product yields by about
10–20%, but caused a deterioration in the secondary-to-
primary ratios (i/n = 8:2 to 7:3). With 3-bromopentane as
the substrate, the 3-pentylation product 3ax was formed
exclusively (entry 12). Secondary alkyl chlorides contain-
ing aromatic moieties, including one bearing a para-chlo-
rophenyl group, were also amenable to the reaction
(entries 13–15). The reaction of exo-2-chloronorbornane
resulted in predominant formation of the exo-arylation
product (entry 16).
t-Bu
t-Bu
N
N+
–
i-Pr
i-Pr
BF4
L3
L4
Entry
X
NHC·HX
Yieldb (%)
1
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
I
IMes·HCl
38
13
20
64
38
14
82c
79c
57
14
6
IPr·HCl
SIMes·HCl
L1
3
4
5
L2
6
L3
7
L4
8
L1
9
L4
10
11
12
13
L1
I
L4
OTs
OTs
L1
64c
49c
L4
Next, we explored the scope of the aromatic imines by us-
ing randomly chosen cycloalkyl halides as the reaction
partners (Figure 1). Imines derived from para-substituted
(methoxy, fluoro, chloro, or phenyl) acetophenones gave
the corresponding products 3br, 3co, 3dq, and 3eq in
moderate to good yields, whereas p-bromoacetophenone
imine gave a complex mixture of products arising from
ortho-alkylation and cross-coupling on the C–Br bond.
Alkylation of m-tolyl, 2-naphthyl, or 3-fluorenyl groups
occurred at the less-hindered position with exclusive
regioselectivity to give the products 3fq, 3gq, and 3ho, re-
spectively. On the other hand, a methylenedioxy group
exhibited a directing effect so that alkylation took place at
the proximate carbon atom, giving the product 3ip and its
regioisomer in a ratio of 84:16. Tetralone- and propiophe-
none-derived imines also participated smoothly in the re-
action to give products 3jr and 3kq, respectively. The C2
positions of thiophene and indole were also amenable to
the alkylation, giving the corresponding cyclohexylated
products 3lo and 3mq in modest yields.
a 0.3 mmol scale; Me(CH2)7X (1.2–1.5 equiv).
b Determined by GC with tridecane as an internal standard.
c Isolated yield.
d The reaction was performed at 60 °C.
Next, we explored the scope of the Co–L1 and Co–L4 cat-
alytic systems for the alkylation of imine 1a with a variety
of primary alkyl chlorides or bromides (Table 2). The re-
action of 1-bromohexane on a 10 mmol scale gave ketone
3ab in 77% yield (Table 2, entry 1). 5-Bromopent-1-ene
gave the expected alkylation product 3ad as the major
product, accompanied by a small amount of the isomer
3ad′ arising from olefin isomerization (entry 4). Che-
moselective C–Br bond cleavage/alkylation was achieved
for 1-bromo-4-fluorobutane and 1-bromo-4-chlorobutane
(entries 5 and 6). On the other hand, 6-bromohexyl tosyl-
ate gave the expected product 3ag, along with a minor
product 3ag′ bearing a 6-bromohexyl group (entry 7). The
latter product appears to have formed through tosylate–
Synthesis 2014, 46, 2024–2039
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Cobalt-Catalyzed Alkylation of Arenes
2027
um-catalyzed intramolecular C–H insertion gave inde-
O
O
O
none 7 in 27% overall yield (unoptimized).
3
Ortho-Alkylation of 2-Arylpyridines
OMe
F
Cl
3br (X = Cl, L4), 81%a 3co (X = Br, L1), 53%
3dq (X = Br, L1), 65%b
The present catalytic system can also be used in the ortho-
alkylation of 2-arylpyridine derivatives with primary and
secondary alkyl chlorides or bromides (Scheme 3). The
reaction of 2-phenylpyridine (8a) with 1-chlorooctane
(2a; 1.5 equiv) in the presence of the Co–L1 catalytic sys-
tem gave the monoalkylation product 9aa in 71% yield,
accompanied by the dialkylation product 10aa in 16%
yield. A similar result was obtained in the reaction of 8a
with neopentyl bromide (see 9aj). The formation of dial-
kylation product 10aa was noteworthy because the reac-
tion of aryl imines does not produce any dialkylation
products (see above), and also because the Ackermann
catalytic system [Co(acac)3, IMes·HCl, CyMgBr, in 1,3-
dimethyltetrahydropyrimidin-2(1H)-one (DMPU)] did
not cause dialkylation of the same substrate.16 When the
reaction was performed with increased amounts of 1-chlo-
rooctane (2a; 2.5 equiv) and t-BuCH2MgBr (3 equiv),
10aa was obtained as the dominant product in 76% yield.
ortho-Dialkylation was also possible with secondary alkyl
halides as the alkylating agents. Thus, para-substituted 2-
arylpyridine derivatives reacted with 2.5 equivalents of 2-
chloropropane, cyclobutyl bromide, or cyclohexyl chlo-
ride to afford the dialkylation products 10bv, 10cp, and
10dr, respectively, in moderate to good yields, accompa-
nied by a small amount of the corresponding monoalkyl-
ation products. Exclusive monoalkylation was achieved
by using 2-arylpyridine derivatives bearing a meta-sub-
stituent on the aryl moiety or a 3-substituent on the pyri-
dine ring (see 10ep, 10fr, and 10gp). Of note was the
substrate bearing a meta-chlorophenyl group, which un-
derwent cyclohexylation at the more hindered ortho-posi-
tion (10fr), presumably because of secondary directing
effect of the lone pair of the chlorine atom.18 Similar sec-
ondary directing effects have also been observed in
O
O
O
Ph
3ep (X = Cl, L1), 85%b 3fq (X = Br, L1), 81%b,c
3gq (X = Cl, L4), 56%
O
O
O
O
O
3ip (X = Cl, L4), 45%d
3ho (X = Br, L1), 78%
3jr (X = Cl, L4), 81%
H
O
O
O
NMe
S
3kq (X = Br, L1), 80%b,c
3lo (X = Br, L1), 24%
3mq (X = Br, L1), 45%
Figure 1 Products of cycloalkylation of various aryl imines (0.3
mmol scale; reaction time = 24 h). a Reaction time 6 h. b Additional t-
BuCH2MgBr (1 equiv) was added after 2, 4, or 5 h. c Two equivalents
of the alkyl halide were used. d Obtained as a mixture with its regioi-
somer in a ratio of 84:16.
The present cycloalkylation products can be transformed
into unique benzo-fused spirocycles through manipula-
tion of the acetyl and cycloalkyl groups (Scheme 2). Con-
version of the acetyl group of 3br into an ethynyl group
was followed by platinum-catalyzed carbocyclization17 to
afford indene 5 in a moderate yield. Alternatively, diazo
transfer to the acetyl group of 3br and subsequent rhodi-
O
O
N2
c, d
a
MeO
MeO
MeO
4
6
3br
b
e
O
MeO
MeO
5
7
Scheme 2 Transformations of cycloalkylation product 3br into benzo-fused spirocycles. Reaction conditions: (a) LDA, ClP(O)(OEt)2, THF,
–78 °C to r.t., then LDA, –78 °C to r.t., 56%; (b) PtCl2, CuBr, toluene, 100 °C, 77%; (c) LiHMDS, THF, –78 °C, then F3CCO2CH2CF3, –78 °C
to r.t.; (d) 4-AcNHC6H4SO2N3, H2O, Et3N, MeCN, r.t., 75% (two steps); (e) Rh2(OAc)4, CH2Cl2, r.t., 36%.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2024–2039

2028
K. Gao et al.
FEATURE ARTICLE
Table 2 Alkylation of Imine 1a with Primary Alkyl Halidesa
PMP
CoBr2 (10 mol%)
L (10 mol%)
O
N
H+
t-BuCH2MgBr (2 equiv)
+
X
R
R
THF, r.t., 4–24 h
2
(1.5 equiv)
3
1a
Entry
Substrate
Ligand
Time (h)
Product(s)
Yieldb (%)
1c
2
2b′
L1
L4
L1
6
24
24
3ab
3ac
3ac
77
73
82
Br
Ph
Cl
2c
Ph
Br
3
2c′
3ad [R = (CH2)3CH=CH2]
3ad′ [R = (CH2)2CH=CHMe] 6d
66d
4
2d′
L1
6
Br
F
5
6
2e′
2f′
L1
L1
24
24
3ae [R = (CH2)4F]
3af [R = (CH2)4Cl]
73
80
Br
Cl
Br
3ag [R = (CH2)6OTs]
3ag′ [R = (CH2)6Br]
71
18
TsO
7
2g′
L1
4
Br
Cl
8
9
2h
L4
24
3ah
77
X
(X = F)
2i
(X = Cl)
L4
L1
L1
L1
24
13
24
14
3ai
3aj
3ak
3al
61
86
65
87
Br
10
2j′
2k
2l′
11
12
TMS
Cl
Br
Br
O
O
13
14e
15
2m′
2n′
2o
L4
L1
L1
24
24
24
3am [R = (CH2)3COMe]
69
N
3an
3ao
41f
19g
Br
O
Cl
N
a Unless otherwise noted, the reaction was performed on a 0.3 mmol scale.
b Isolated yield.
c 10 mmol scale.
d Obtained as a mixture. The ratio was determined by 1H NMR.
e Two equivalents of 2n′ were used, and an additional one equivalent of t-BuCH2MgBr was added after 2 h.
f Obtained as a mixture with 2n′ and its β-elimination product.
g Obtained as a mixture with 4-MeO(C6H4)NH2.
Ackermann’s cobalt-catalyzed ortho-arylation of 2-aryl- The high catalytic activity of the present system allowed
pyridines with meta-alkoxy and -fluoro substituents.15,16 the sequential introduction of different alkyl groups onto
Arylpyridine derivatives having only one reactive site 2-phenylpyridine in a one-pot operation (Scheme 4).
also participated in the reaction with secondary alkyl ha- Thus, the reaction of 8a and 2-phenylethyl bromide (1.5
lides (see 10hv, 10iq, and 10jq).
equiv) was performed under the standard monoalkylation
conditions, followed by addition of excess amounts of 1-
chlorooctane (2a; 3.0 equiv) and t-BuCH2MgBr (3.5
Synthesis 2014, 46, 2024–2039
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Cobalt-Catalyzed Alkylation of Arenes
2029
Table 3 Alkylation of 1a with Secondary Alkyl Halidesa
PMP
CoBr2 (10 mol%)
L (10 mol%)
t-BuCH2MgBr (2 equiv)
N
O
R1
H+
R1
+
R2
X
R2
THF, r.t., 6–24 h
2
(1.5 equiv)
1a
3
Entry
Alkyl halide
L
Time (h) Product
Yield (%)b
1
2p
2p′
2q
2r
c-C4H7Cl
c-C4H7Br
c-C5H9Cl
c-C6H11Cl
c-C6H11Br
c-C7H13Cl
c-C12H23Cl
L4
L1
L1
L4
L1
L4
L1
24
24
24
12
6
3ap
3ap
3aq
3ar
3ar
3as
3at
51
75
78
73
90
84
65
2
3c
4
5
2r′
2s
6
24
24
7c,d
2t
8c,d
9
2u
L1
24
3au
42
BocN
Br
2v
i-C3H7Cl
i-C3H7Br
s-C4H9Br
L1
L1
L1
6
6
6
3av (i/n = 99:1)e
3av (i/n = 93:7)e
3aw (i/n = 94:6)e
65
68
56
10
2v′
2w′
11
12
Br
2x′
L1
24
3ax
63
Cl
13
14
15
2y (R = H)
2z (R = OMe)
2aa (R = Cl)
L1
L1
L1
24
24
12
3ay (i/n = 94:6)e
3az (i/n = 94:6)e
3aaa (i/n = 86:14)e
76
61
75
R
16
2ab
L1
24
3aab (exo/endo = 90:10)
82
Cl
a The reaction was performed on a 0.3 mmol scale.
b Isolated yield.
c An additional one equivalent of t-BuCH2MgBr was added after 2 or 5 h.
d Two equivalents of the alkyl halide were used.
e The ratio of the secondary and primary alkylation products.
equiv) to afford the unsymmetrically substituted dialkyl- catalyzed cross-coupling reactions of alkyl halides and
ation products 11 in 50% isolated yield, along with the aryl Grignard reagents developed by Yorimitsu and
symmetric dialkylation products derived from 1-chloro- Oshima and their co-workers,20 and by Cahiez and co-
octane and 2-phenylethyl bromide as byproducts (19% workers.21 However, the scopes of the alkyl halides for
and 4% GC yields, respectively).19
these reactions do not completely overlap with those for
the present reaction. The cross-coupling reaction can be
applied to primary and secondary alkyl iodides and bro-
mides, but not to chlorides. We therefore became particu-
larly interested in the carbon–halogen bond-activation
4
Mechanistic Investigations
Having established the synthetic scope of the ortho-alkyl- step of the present reaction. Below, we describe a series of
ation reaction, we turned our attention to its mechanism. experiments that we performed to gain insight into this
The reaction appears to have some relevance to the cobalt- step.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2024–2039

2030
K. Gao et al.
FEATURE ARTICLE
The chemoselective activation of the alkyl bromide moi-
ety over the alkyl chloride moiety in the reaction of 1-bro-
mo-4-chlorobutane prompted us to investigate the
chemoselectivity of the reaction systematically by means
of intermolecular competition experiments (Table 4). Not
unexpectedly, competition between 1-bromodecane and
1-chlorooctane in the reaction with imine 1a resulted in
predominant formation of the alkylation product of the
former (Table 4, entry 1). In a similar manner, the reaction
using a mixture of 2-bromopropane-d7 and 2-chloropro-
pane resulted in predominant incorporation of the deuter-
ated isopropyl group (entry 2). Interestingly, a primary
and a secondary alkyl bromide (1-bromodecane and bro-
mocyclohexane, respectively) exhibited a similar reactiv-
ity, and produced the corresponding products in ~1:1 ratio
(entry 3). We also examined the effect of the ring size of
the cycloalkyl halide on its relative reactivity. Chlorocy-
clohexane reacted in preference to chlorocyclobutane
(entry 4), whereas it was less reactive than chlorocyclo-
pentane or chlorocycloheptane (entries 5 and 6, respec-
tively).
CoBr2 (10 mol%)
L1 (10 mol%)
t-BuCH2MgBr
N
N
N
R2
X
+
+
R2
R2
R2
THF, r.t., 14–24 h
2
R1
R1
R1
8a
9
10
N
N
N
n-C8H17
n-C8H17
n-C8H17
t-Bu
9aa (X = Cl), 71%a,b
10aa (X = Cl), 76%c
9aj (X = Br), 72%a,b
N
N
N
CF3
OMe
F
Table 4 Intermolecular Competition of Two Alkyl Halidesa
10bv (X = Cl), 86%c,d
10cp (X = Br), 70%c,d
10dr (X = Cl), 39%c,d
standard
R1
(1.5 equiv)
X
O
O
conditions
H+
N
(L1)
N
N
+
R1
+
R2
1a
r.t., 4 h
R2
Y
(1.5 equiv)
P1
P2
Cl
OMe
Entry
R1X
R2Y
Yieldb (%)
10ep (X = Br), 86%a
10fr (X = Br), 47%a
10gp (X = Br), 86%a
P1
P2
N
N
N
1
2
3
4
5
6
n-C10H21Br
i-C3D7Br
n-C8H17Cl
64
74
36
35
10
11
2
i-C3H7Cl
c-C6H11Br
c-C4H7Cl
c-C5H11Cl
c-C7H13Cl
6
S
n-C10H21Br
c-C6H11Cl
c-C6H11Cl
c-C6H11Cl
33
12
58
64
10hv (X = Cl), 89%a
10iq (X = Cl), 80%a
10jq (X = Cl), 23%a
Scheme 3 ortho-Alkylation of 2-arylpyridines with alkyl halides.
a 1.5 equivalents of alkyl halide and two equivalents of t-BuCH2MgBr
b
were used. Dialkylation products were obtained as byproducts
(<20% yield). c 2.5 equivalents of alkyl halide and three equivalents
a The reaction was performed on a 0.3 mmol scale.
d
of t-BuCH2MgBr were used. Monoalkylation products were ob-
tained as byproducts (<10% yield).
b Estimated by GC using tridecane as an internal standard.
CoBr2 (10 mol%)
L1 (10 mol%)
t-BuCH2MgBr (2 equiv)
Ph(CH2)2Br (1.5 equiv)
N
Ph
N
t-BuCH2MgBr (3.5 equiv)
n-C8H17Cl (3 equiv)
n-C8H17
r.t., 14 h
THF, r.t., 5 h
8a
11, 50%
Scheme 4 Sequential ortho-alkylation with different alkyl halides
Synthesis 2014, 46, 2024–2039
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Cobalt-Catalyzed Alkylation of Arenes
2031
The exo/endo selectivity of 90:10 in the reaction of exo-2-
chloronorbornane (Table 3, entry 16) shows that the reac-
tion is not stereospecific. Given this result, we examined
the stereochemical course of the reaction by using several
probes (Scheme 5). Reactions of imine 1a with the trans-
and cis-isomers of 1-chloro-4-tert-butylcyclohexane
(2ac) resulted in the formation of the corresponding alkyl-
ation product 3aac with the same trans/cis ratio of ~8:2
(Scheme 5, a and b). Therefore, the diastereochemical in-
formation present in the starting materials was completely
lost during the reaction. Furthermore, the reaction of im-
ine 1a with (2R)-2-bromooctane 2ad (> 98% ee) gave the
product 3aad as a virtually racemic mixture, clearly
showing involvement of a stereochemical mutation pro-
cess (Scheme 5, c).
(a)
standard
O
t-Bu
conditions
t-Bu
H+
(L4)
+
+
+
1a
r.t., 24 h
Cl
trans-2ac
3aac, 31%
(trans/cis = 79:21)
(trans/cis = 91:9)
(b)
standard
conditions
(L4)
O
t-Bu
H+
t-Bu
1a
r.t., 24 h
Cl
cis-2ac
3aac, 30%
(trans/cis = 79:21)
(trans/cis = 4:96)
standard
conditions
(L1)
(c)
1a
O
H+
The results described above are indicative of a radical pro-
cess in the reaction. To probe this possibility further, we
performed radical clock experiments (Scheme 6). The re-
action of imine 1a with (bromomethyl)cyclobutane (2ae′)
under the standard conditions afforded a direct alkylation
product 3aae in 60% yield along with the ring-opening al-
kylation byproducts 3ad and 3ad′ (Scheme 6, a). The
identity of the byproducts was confirmed by comparison
with authentic samples (Table 2, entry 4). The formation
of 3ad and 3ad′ suggests that the reaction involves a cy-
clobutylmethyl radical, which can undergo ring-opening
to give a 4-pentenyl radical at a rate of 5 × 103 s–1.22 An-
other probe substrate, 6-bromohex-1-ene (2af′), showed
somewhat puzzling behavior (Scheme 6, b). In three runs
performed under the standard conditions at room temper-
ature, the direct alkylation products 3aaf/3aaf′ were ob-
n-C6H13
r.t., 24 h
Br
n-C6H13
(R)-2ad'
(> 98% ee)
3aad, 63%
(< 5% ee)
Scheme 5 Reactions with stereochemistry probes
tained in a modest overall yield of ~40%, accompanied by
a various amounts (5–16%) of the ring-closing alkylation
product 3al. The identity of 3al was confirmed by com-
parison with an authentic sample (Table 2, entry 12).23 We
observed a certain correlation between the reaction tem-
perature and the fate of 2af′. Thus, whereas formation of
the direct alkylation products was favored at a low tem-
perature (0 °C), ring-closing alkylation overrode direct al-
(a)
standard
conditions
(L1)
O
O
H+
Br
+
+
1a
r.t., 12 h
3aae, 60%a
3ad (terminal)
+
2ae'
3ad' (internal)
5% (43:57)a
(b)
standard
conditions
(L1)
O
O
H+
+
+
1a
12 h
Br
2af'
3aaf (terminal)
+
3aaf' (internal)
3al
r.t.:
38–42%b,c
51%b
26%b
5–16%b,c
12%b
30%b
0 °C:
40 °C:
standard
conditions
(L1 or L4)
(c)
H+
complex
mixture
Br
+
1a
2ag'
Scheme 6 Radical clock experiments. a Isolated yield. b Determined by GC using tridecane as an internal standard. c Results from three runs.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2024–2039

2032
K. Gao et al.
FEATURE ARTICLE
kylation at a higher temperature (40 °C). Although we
have not identified the factors that are responsible for the
irreproducibility and the varying yield, our observations
support the formation of a 5-hexenyl radical and its cycli-
zation to form a cyclopentylmethyl radical (rate constant =
2.3 × 105 s–1)22 in the cobalt-catalyzed reaction. Note that,
for unknown reasons, the reaction using (bromometh-
yl)cyclopropane (2ag′) gave a complex mixture, in which
we could detect neither a direct alkylation product nor a
ring-opening alkylation product (Scheme 6, c).
CoBr2, NHC•HX
MgX
R
L
H
R
[Co]
MgX2
MgX
trans-
metalation
cyclo-
metalation
R
R
H
L
[Co]
X
[Co]
Finally, we performed control experiments using alkenes
instead of alkyl halides (Scheme 7). The reaction of imine
1a with oct-1-ene gave the ortho-octylation product 3aa
in 28% yield (Scheme 7, a), which was significantly lower
than that obtained using 1-bromooctane (Table 1, entry 8).
Furthermore, cyclohexene failed to give the correspond-
ing cyclohexylated product 3ar (Scheme 7, b). These ob-
servations indicate that the major pathway of the present
reaction does not involve the formation of an alkene
through dehydrohalogenation of alkyl halide.
radical
PMP
N
coupling
SET
Alkyl
X
L
[Co]
Alkyl•
X
Alkyl
Scheme 8 Proposed catalytic cycle
(a)
features mild reaction temperatures, a broad scope of pri-
mary and secondary alkyl halides, and useful chemoselec-
tivity. Mechanistic experiments indicate that the reaction
involves a unique combination of cobalt-mediated cyclo-
metalation and single-electron transfer processes. Explo-
ration of other electrophilic reaction partners for cobalt-
catalyzed ortho C–H functionalization is currently ongo-
ing.
O
standard
conditions (L1)
H+
n-C6H13
n-C8H17
+
+
1a
1a
THF, r.t., 12 h
(1.5 equiv)
3aa, 28%
(b)
O
standard
conditions (L1)
H+
Cy
THF, r.t., 24 h
All reactions involving air- or moisture-sensitive compounds were
performed by standard Schlenk techniques in oven-dried reaction
vessels under N2. Analytical TLC was performed on Merck 60 F254
silica gel plates. Flash chromatography was performed on 40–63
μm silica gel (Si 60, Merck). 1H and 13C NMR spectra were record-
ed on JEOL ECA-400 (400 MHz) or Bruker AV-400 (400 MHz)
(1.5 equiv)
3ar, 0%
Scheme 7 Control experiments using olefins as reaction partners
1
spectrometers. H and 13C NMR spectra are reported in parts per
Although further experiments are necessary to completely
characterize the reaction mechanism of the C–X cleavage
step and the C–H activation step, we propose the catalytic
cycle outlined in Scheme 8. The first step is assumed to be
cyclometalation of the aryl imine or 2-arylpyridine with
an organocobalt species.24 The resulting cobaltacycle in-
termediate undergoes single-electron transfer to the alkyl
halide,25 resulting in the formation of the corresponding
alkyl radical and one-electron oxidation of the cobalt cen-
million (ppm) downfield from TMS (0 ppm) or CHCl3 (77.0 ppm),
respectively, as internal standards. GC analysis was performed on a
Shimadzu GC-2010 system equipped with an FID detector and an
Agilent J&W DB-5 capillary column (0.25 mm i.d. × 30 m, 0.25 μm
film thickness). HPLC analysis was performed by using a Shimadzu
LC-20 AD system equipped with Shimadzu SPD-20A UV–vis de-
tector and a Daicel Chiralpak IC column. High-resolution mass
spectra were obtained with a Waters Q-Tof Premier LC HR mass
spectrometer. Unless otherwise noted, reagents were purchased
from Aldrich, Alfa Aesar, or other commercial suppliers, and were
ter. The alkyl radical then undergoes radical coupling with used as received. THF was distilled over Na/benzophenone. 1,3-Di-
isopropyl-1H-benzimidazol-3-ium bromide (L4) was synthesized
the aryl group on the cobalt center to afford the ortho-al-
kylation product. Transmetalation between the resulting
cobalt halide and the Grignard reagent regenerates the al-
kylcobalt species. The radical clock experiments suggest
that the radical coupling process should occur at a rela-
tively fast rate.
according to the procedure described in the literature.26 Neopentyl-
magnesium bromide was prepared from neopentyl bromide and Mg
turnings in anhyd THF, and titrated before use. Aryl imines and 2-
arylpyridines were synthesized according to the literature proce-
dures.27,28 Alkyl halides 2h,12 2i,12 2n′,12 2o,12 2t,29 2y,30 2z,30 2aa,30
trans/cis-2ac,31 and (R)-2ad′32 were synthesized according to the
procedures described in the literature. Characterization data for ha-
lides 2z and 2aa are given in the Supporting Information.
5
Conclusions
1-(2-Octylphenyl)ethanone (3aa): Typical Procedure
A 10 mL Schlenk tube was charged with CoBr2 (6.6 mg, 0.03
mmol), 1,3-diisopropyl-1H-benzimidazol-3-ium bromide (L4; 8.5
mg, 0.03 mmol), 4-methoxy-N-[(1E)-1-phenylethylidene]aniline
(1a, 67.6 mg, 0.30 mmol), 1-chlorooctane (2a, 76.5 µL, 0.45
We have developed cobalt-based catalytic systems for im-
ine- and pyridine-directed ortho-alkylation of aromatic
compounds with alkyl chlorides or bromides. The reaction
Synthesis 2014, 46, 2024–2039
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Cobalt-Catalyzed Alkylation of Arenes
2033
mmol), and THF (0.69 mL). A 1.92 M solution of t-BuCH2MgBr in
THF (0.31 mL, 0.60 mmol) was added dropwise at 0 °C, and the
mixture was stirred at r.t. for 6 h. The reaction was quenched by the
addition of 3 M aq HCl (1.0 mL), and the mixture was stirred at r.t.
for 1 h, then extracted with EtOAc (3 × 10 mL). The organic layers
were combined, dried (MgSO4), and concentrated under reduced
pressure. The crude product was purified by chromatography [silica
gel, hexane–EtOAc (40:1)] to give a light-yellow oil: yield; 57.3 mg
(82%).
1H NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 7.2 Hz, 3 H), 1.26–1.35
(m, 10 H), 1.53–1.59 (m, 2 H), 2.57 (s, 3 H), 2.83 (t, J = 8.0 Hz, 2
H), 7.22–7.26 (m, 2 H), 7.36–7.40 (m, 1 H), 7.60–7.62 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 29.3, 29.4, 29.7, 29.9,
31.9 (two signals overlapping), 34.0, 125.5, 128.9, 131.1, 131.2,
138.0, 142.9, 202.3.
1-[2-(4-Chlorobutyl)phenyl]ethanone (3af)
Light-yellow oil; yield: 50.4 mg (80%).
1H NMR (400 MHz, CDCl3): δ = 1.70–1.75 (m, 2 H), 1.81–1.86 (m,
2 H), 2.58 (s, 3 H), 2.87 (t, J = 7.6 Hz, 2 H), 3.55 (t, J = 6.8 Hz, 2
H), 7.25–7.29 (m, 2 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.66 (d, J = 8.0 Hz,
1 H).
13C NMR (100 MHz, CDCl3): δ = 28.9, 29.8, 32.5, 33.2, 44.8, 125.9,
129.3, 131.2, 131.5, 137.6, 142.1, 201.9.
HRMS (ESI): m/z [M + H]+ calcd for C12H16ClO: 211.0890; found:
211.0887.
6-(2-Acetylphenyl)hexyl 4-Methylbenzenesulfonate (3ag)
Brown oil; yield: 80.4 mg (71%).
1H NMR (400 MHz, CDCl3): δ = 1.31–1.40 (m, 4 H), 1.50–1.53 (m,
2 H), 1.62–1.66 (m, 2 H), 2.44 (s, 3 H), 2.57 (s, 3 H), 2.79 (t, J = 7.6
Hz, 2 H), 4.01 (t, J = 6.4 Hz, 2 H), 7.21–7.27 (m, 2 H), 7.34 (d, J =
8.0 Hz, 2 H), 7.37 (td, J = 7.2 Hz, J = 1.2 Hz, 1 H), 7.64 (dd, J = 8.0
Hz, J = 1.2 Hz, 1 H), 7.79 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.6, 25.1, 28.7, 28.9, 29.9, 31.5,
33.8, 70.6, 125.7, 127.8, 129.1, 129.8, 131.1, 131.4, 133.2, 137.7,
142.6, 144.6, 202.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H25O: 233.1905; found:
233.1903.
1-(2-Hexylphenyl)ethanone (3ab)
The reaction was performed on a 10-mmol scale in a 100-mL two-
necked flask to give a light-yellow oil; yield: 1.58 g (77%).
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.28–1.38
(m, 6 H), 1.54–1.58 (m, 2 H), 2.57 (s, 3 H), 2.83 (t, J = 8.0 Hz, 2 H),
7.22–7.26 (m, 2 H), 7.35–7.39 (m, 1 H), 7.60–7.62 (m, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C21H27O4S: 375.1630; found:
375.1632.
13C NMR (100 MHz, CDCl3): δ = 14.0, 22.6, 29.4, 29.9, 31.7, 31.8,
34.0, 125.5, 128.9, 131.1, 131.2, 138.1, 142.8, 202.3.
1-[2-(6-Bromohexyl)phenyl]ethanone (3ag′)
Light-yellow oil; yield: 15.0 mg (18%).
HRMS (ESI): m/z [M + H]+ calcd for C14H21O: 205.1592; found:
205.1594.
1H NMR (400 MHz, CDCl3): δ = 1.41–1.49 (m, 4 H), 1.54–1.63 (m,
2 H), 1.83–1.90 (m, 2 H), 2.84 (s, 3 H), 2.84 (t, J = 7.6 Hz, 2 H),
3.40 (t, J = 6.8 Hz, 2 H), 7.24–7.27 (m, 2 H), 7.39 (td, J = 7.6 Hz,
J = 1.2 Hz, 1 H), 7.64 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 28.0, 28.8, 29.9, 31.5, 32.7, 33.89,
33.93, 125.7, 129.1, 131.1, 131.3, 137.8, 142.7, 202.1.
1-[2-(2-Phenylethyl)phenyl]ethanone (3ac)33
Light-yellow oil; yield: 48.9 mg (73%).
1H NMR (400 MHz, CDCl3): δ = 2.58 (s, 3 H), 2.96 (t, J = 8.0 Hz,
2 H), 3.22 (t, J = 8.0 Hz, 2 H), 7.24–7.35 (m, 7 H), 7.44 (td, J = 7.5
Hz, 1.3 Hz, 1 H), 7.72 (dd, J = 7.7 Hz, 1.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 29.6, 36.3, 38.2, 125.8, 125.9
(two signals overlapping), 128.2, 128.6, 129.2, 131.42, 131.45,
137.8, 141.9, 201.9.
HRMS (ESI): m/z [M + H]+ calcd for C14H20BrO: 283.0698; found:
283.0697.
1-{2-[3-(4-Fluorophenyl)propyl]phenyl}ethanone (3ah)
Light-yellow oil; yield: 59.2 mg (77%).
1H NMR (400 MHz, CDCl3): δ = 1.85–1.93 (m, 2 H), 2.57 (s, 3 H),
2.67 (t, J = 7.6 Hz, 2 H), 2.89 (t, J = 7.6 Hz, 2 H), 6.96 (t, J = 8.4
Hz, 2 H), 7.13–7.17 (m, 2 H), 7.23–7.29 (m, 2 H), 7.40 (t, J = 7.6
Hz, 1 H), 7.66 (d, J = 7.6 Hz, 1 H).
1-(2-Pent-4-en-1-ylphenyl)ethanone (3ad)
Obtained as a mixture with 1-{2-[(3E)-pent-3-en-1-yl]phenyl}etha-
none (3ad′) as a light-yellow oil; yield: 40.9 mg (72%; 3ad/3ad′ =
92:8).
1H NMR (400 MHz, CDCl3): δ = 1.64–1.71 (m, 2 H), 2.10–2.15 (m,
2 H), 2.57 (s, 3 H), 2.86 (t, J = 6.0 Hz, 2 H), 4.97 (ddt, J = 10.2 Hz,
2.0 Hz, 1.1 Hz, 1 H), 5.02 (ddt, J = 17.1 Hz, 1.7 Hz, 1.6 Hz, 1 H),
5.85 (ddt, J = 17.0 Hz, 10.3 Hz, 6.6 Hz, 1 H), 7.24–7.28 (m, 2 H),
7.39 (td, J = 7.4 Hz, 1.2 Hz, 1 H), 7.64 (dd, J = 8.4 Hz, 1.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 29.8, 33.4, 33.7, 35.0, 118.9 (d,
2JC–F = 21 Hz), 125.8, 129.2, 129.6 (d, 3JC–F = 8 Hz), 131.1, 131.4,
4
1
137.7, 137.9 (d, JC–F = 4 Hz), 142.3, 161.1 (d, JC–F = 241 Hz),
202.0.
HRMS (ESI): m/z [M + H]+ calcd for C17H18FO: 257.1338; found:
13C NMR (100 MHz, CDCl3): δ = 29.9, 30.9, 33.5, 33.7, 114.6,
257.1342.
125.7, 129.1, 131.2, 131.3, 137.9, 138.6, 142.5, 202.1.
HRMS (ESI): m/z [M + H]+ calcd for C13H17O: 189.1279; found:
1-{2-[3-(4-Chlorophenyl)propyl]phenyl}ethanone (3ai)
Light-yellow oil; yield: 49.9 mg (61%).
189.1280.
1H NMR (400 MHz, CDCl3): δ = 1.82–1.93 (m, 2 H), 2.57 (s, 3 H),
2.66 (t, J = 7.6 Hz, 2 H), 2.88 (t, J = 7.6 Hz, 2 H), 7.13 (d, J = 8.4
Hz, 2 H), 7.22–7.29 (m, 4 H), 7.39 (td, J = 7.6 Hz, 1.2 Hz, 1 H), 7.66
(dd, J = 7.6 Hz, 1.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 29.8, 33.2, 33.7, 35.2, 125.9,
128.3, 129.3, 129.8, 131.2, 131.4, 131.5, 137.7, 140.8, 142.3, 202.0.
1-[2-(4-Fluorobutyl)phenyl]ethanone (3ae)
Light-yellow oil; yield: 42.5 mg (73%)
1H NMR (400 MHz, CDCl3): δ = 1.67–1.82 (m, 4 H), 2.58 (s, 3 H),
2.89 (t, J = 7.6 Hz, 2 H), 4.46 (dt, 1JC–F = 47.2 Hz, J = 5.6 Hz, 2 H),
7.25–7.29 (m, 2 H), 7.40 (td, J = 7.4 Hz, J = 1.2 Hz, 1 H), 7.66 (d,
J = 7.6 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C17H18ClO: 273.1045; found:
13C NMR (100 MHz, CDCl3): δ = 27.3 (d, 3JC–F = 5.2 Hz), 29.8, 30.3
(d, JC–F = 19.2 Hz), 33.5, 84.0 (d, JC–F = 163 Hz), 125.9, 129.3,
131.2, 131.4, 137.7, 142.3, 201.9.
HRMS (ESI): m/z [M + H]+ calcd for C12H16FO: 195.1185; found:
273.1046.
2
1
1-[2-(2,2-Dimethylpropyl)phenyl]ethanone (3aj)
Light-yellow oil; yield: 49.3 mg (86%).
1H NMR (400 MHz, CDCl3): δ = 0.84 (s, 9 H), 2.56 (s, 3 H), 2.94
(s, 2 H), 7.19 (d, J = 7.6 Hz, 1 H), 7.23–7.27 (m, 1 H), 7.35 (td, J =
7.6 Hz, J = 1.2 Hz, 1 H), 7.54 (dd, J = 7.6 Hz, J = 0.8 Hz, 1 H).
195.1185.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2024–2039

2034
K. Gao et al.
FEATURE ARTICLE
13C NMR (100 MHz, CDCl3): δ = 29.4, 30.2, 32.6, 44.4, 125.7,
127.9, 130.0, 133.3, 138.5, 140.4, 203.6.
HRMS (ESI): m/z [M + H]+ calcd for C16H18NO: 240.1388; found:
240.1386.
HRMS (ESI): m/z [M + H]+ calcd for C13H19O: 191.1436; found:
191.1431.
1-(2-Cyclobutylphenyl)ethanone (3ap)
Light-yellow oil; yield: 26.5 mg (51%).
1H NMR (400 MHz, CDCl3): δ = 1.69–1.82 (m, 1 H), 1.96–2.17 (m,
3 H), 2.32–2.38 (m, 2 H), 2.54 (s, 3 H), 4.02 (m, 1 H), 7.21–7.25 (m,
1 H), 7.40–7.46 (m, 2 H), 7.51 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 18.1, 29.4, 30.0, 38.1, 125.4,
127.2, 127.8, 131.0, 138.2, 144.9, 203.0.
1-{2-[(Trimethylsilyl)methyl]phenyl}ethanone (3ak)
Light-yellow oil; yield: 40.4 mg (65%).
1H NMR (400 MHz, CDCl3): δ = –0.05 (s, 9 H), 2.56 (s, 3 H), 2.62
(s, 2 H), 7.06 (d, J = 7.6 Hz, 1 H), 7.14 (t, J = 6.8 Hz, 1 H), 7.30 (td,
J = 7.2 Hz, J = 1.2 Hz, 1 H), 7.69 (dd, J = 7.6 Hz, J = 0.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = –1.6, 25.2, 29.5, 123.7, 130.0,
HRMS (ESI): m/z [M + H]+ calcd for C12H15O: 175.1123; found:
131.0, 131.3, 135.5, 142.3, 201.4.
175.1125.
HRMS (ESI): m/z [M + H]+ calcd for C12H19OSi: 207.1205; found:
207.1201.
1-(2-Cyclopentylphenyl)ethanone (3aq)34
Light-yellow oil; yield: 35.7 mg (63%).
1H NMR (400 MHz, CDCl3): δ = 1.54–1.62 (m, 2 H), 1.66–1.71 (m,
2 H), 1.78–1.83 (m, 2 H), 2.03–2.09 (m, 2 H), 2.57 (s, 3 H), 3.43–
3.48 (m, 1 H), 7.19–7.23 (m, 1 H), 7.39–7.41 (m, 2 H), 7.45 (d, J =
7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 25.8, 30.7, 35.1, 41.5, 125.2,
127.1, 127.3, 130.9, 139.9, 145.2, 204.0.
1-[2-(Cyclopentylmethyl)phenyl]ethanone (3al)
Yellow oil; yield: 52.7 mg (87%).
1H NMR (400 MHz, CDCl3): δ = 1.13–1.21 (m, 2 H), 1.47–1.54 (m,
2 H), 1.57–1.69 (m, 4 H), 2.00–2.08 (m, 1 H), 2.57 (s, 3 H), 2.89 (d,
J = 7.3 Hz, 2 H), 7.22–7.26 (m, 2 H), 7.37 (t, J = 7.8 Hz, 1 H), 7.60
(d, J = 7.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 25.0, 30.3, 32.7, 39.5, 42.1, 125.8,
129.0, 131.2, 131.7, 138.5, 142.3, 202.8.
HRMS (ESI): m/z [M + H]+ calcd for C14H19O: 203.1436; found:
203.1436.
1-(2-Cyclohexylphenyl)ethanone (3ar)34
Light-yellow oil; yield: 44.2 mg (73%).
1H NMR (400 MHz, CDCl3): δ = 1.15–1.21 (m, 1 H), 1.39–1.44 (m,
4 H), 1.73–1.85 (m, 5 H), 2.57 (s, 3 H), 3.00–3.07 (m, 1 H), 7.20–
7.24 (m, 1 H), 7.37–7.40 (m, 2 H), 7.47 (d, J = 7.2 Hz, 1 H).
5-(2-Acetylphenyl)pentan-2-one (3am)
Orange oil; yield: 42.1 mg (69%).
13C NMR (100 MHz, CDCl3): δ = 26.2, 26.9, 30.8, 34.5, 40.0, 125.3,
127.1, 127.6, 130.9, 139.1, 146.6, 203.8.
1H NMR (400 MHz, CDCl3): δ = 1.83–1.89 (m, 2 H), 2.12 (s, 3 H),
2.47 (t, J = 7.6 Hz, 2 H), 2.56 (s, 3 H), 2.82 (t, J = 7.6 Hz, 2 H), 7.24–
7.28 (m, 2 H), 7.37 (td, J = 7.6 Hz, J = 1.2 Hz, 1 H), 7.64 (d, J = 8.0
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 25.6, 29.7, 29.8, 33.1, 43.3, 125.9,
129.3, 131.2, 131.5, 137.6, 141.9, 201.9, 208.9.
1-(2-Cycloheptylphenyl)ethanone (3as)
Light-yellow oil; yield: 54.6 mg (84%).
1H NMR (400 MHz, CDCl3): δ = 1.53–1.71 (m, 8 H), 1.76–1.80 (m,
2 H), 1.87–1.92 (m, 2 H), 2.57 (s, 3 H), 3.15–3.20 (m, 1 H), 7.17–
7.22 (m, 1 H), 7.35–7.41 (m, 2 H), 7.45 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 27.4, 27.7, 30.7, 36.9, 41.6, 125.0,
127.37, 127.42, 131.0, 138.2, 148.7, 203.6.
HRMS (ESI): m/z [M + H]+ calcd for C13H17O2: 205.1229; found:
205.1224.
HRMS (ESI): m/z [M + H]+ calcd for C15H21O: 217.1592; found:
217.1593.
1-[2-(6-Oxo-6-pyrrolidin-1-ylhexyl)phenyl]ethanone (3an)
Obtained as a mixture with 1-(6-bromohexanoyl)pyrrolidine and 1-
[(4E)-hex-4-enoyl]pyrrolidine; yield: 41% (by weight and 1H NMR
analysis).
1H NMR (400 MHz, CDCl3): δ = 1.38–1.45 (m, 2 H), 1.55–1.70 (m,
4 H), 1.82–1.87 (m, 2 H), 1.90–1.95 (m, 2 H), 2.26 (t, J = 8.0 Hz, 2
H), 2.56 (s, 3 H), 2.83 (t, J = 8.0 Hz, 2 H), 3.40 (t, J = 6.8 Hz, 2 H),
3.45 (t, J = 6.8 Hz, 2 H), 7.23–7.25 (m, 2 H), 7.38 (t, J = 7.6 Hz, 1
H), 7.61 (d, J = 7.2 Hz, 1 H).
1-(2-Cyclododecylphenyl)ethanone (3at)
Light-yellow oil; yield: 55.9 mg (65%).
1H NMR (400 MHz, CDCl3): δ = 1.36–1.75 (m, 20 H), 1.75–1.82
(m, 2 H), 2.56 (s, 3 H), 3.39–3.42 (m, 1 H), 7.18–7.22 (m, 1 H),
7.38–7.43 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 22.9, 23.0, 23.2, 24.0 (two signals
overlapping), 30.8, 31.8, 34.1, 125.1, 126.9, 128.0, 130.6, 140.3,
146.1, 204.2.
13C NMR (100 MHz, CDCl3): δ = 24.4, 24.8, 26.1, 29.5, 29.9, 31.5,
33.9, 34.7, 45.6, 46.6, 125.6, 129.0, 131.2, 131.3, 137.9, 142.6,
171.9, 202.2.
HRMS (ESI): m/z [M + H]+ calcd for C20H31O: 287.2375; found:
HRMS (ESI): m/z [M + H]+ calcd for C18H26NO2: 288.1964; found:
287.2377.
288.1965.
tert-Butyl 4-(2-Acetylphenyl)piperidine-1-carboxylate (3au)
Brown oil; yield: 38.4 mg (42%).
1-[2-(3-Pyridin-3-ylpropyl)phenyl]ethanone (3ao)
Obtained as a mixture with 4-methoxyaniline; yield: 19% (by
weight and 1H NMR analysis).
1H NMR (400 MHz, CDCl3): δ = 1.89–1.95 (m, 2 H), 2.57 (s, 3 H),
2.69 (t, J = 8.0 Hz, 2 H), 2.90 (t, J = 8.0 Hz, 2 H), 7.18–7.30 (m, 3
H), 7.40 (td, J = 7.6 Hz, 1.2 Hz, 1 H), 7.51 (dd, J = 7.6 Hz, 1.0 Hz,
1 H), 7.68 (dd, J = 7.6 Hz, 1.2 Hz, 1 H), 8.43 (d, J = 4.0 Hz, 1 H),
8.45 (s, 1 H).
1H NMR (400 MHz, CDCl3): δ = 1.47 (s, 9 H), 1.58–1.63 (m, 2 H),
1.77–1.80 (m, 2 H), 2.57 (s, 3 H), 2.73–2.84 (m, 2 H), 3.29 (tt, J =
12.0 Hz, 3.3 Hz, 1 H), 4.18–4.23 (br s, 2 H), 7.26 (t, J = 7.4 Hz, 1
H), 7.35 (d, J = 8.0 Hz, 1 H), 7.41 (t, J = 7.2 Hz, 1 H), 7.57 (d, J =
7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 28.5, 30.4, 33.2, 38.0, 44.5, 79.4,
125.8, 127.2, 128.4, 131.4, 138.4, 145.0, 154.9, 203.0.
13C NMR (100 MHz, CDCl3): δ = 29.7, 33.0 (two signals overlap-
ping), 33.8, 123.2, 126.0, 129.4, 131.2, 131.5, 135.8, 137.5, 139.9,
147.2, 149.9, 152.8, 201.8.
HRMS (ESI): m/z [M + H]+ calcd for C18H26NO3: 304.1913; found:
304.1916.
1-(2-Isopropylphenyl)ethanone (3av)35
Light-yellow oil; yield: 31.5 mg (65%).
Synthesis 2014, 46, 2024–2039
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Cobalt-Catalyzed Alkylation of Arenes
2035
1H NMR (400 MHz, CDCl3): δ = 1.24 (d, J = 6.8 Hz, 6 H), 2.57 (s,
3 H), 3.47 (septet, J = 6.8 Hz, 1 H), 7.22–7.25 (m, 1 H), 7.41–7.43
(m, 2 H), 7.48 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.1, 29.2, 30.7, 125.3, 126.5,
127.6, 131.0, 138.9, 147.6, 203.7.
HRMS (ESI): m/z [M + H]+ calcd for C18H20ClO: 287.1203; found:
287.1203.
1-[2-(exo-Bicyclo[2.2.1]heptan-2-yl)phenyl]ethanone (3aab)3c
Light-yellow oil; yield: 52.6 mg (82%).
1H NMR (400 MHz, CDCl3): δ = 1.21–1.32 (m, 2 H), 1.37–1.43 (m,
1 H), 1.47–1.51 (m, 1 H), 1.53–1.61 (m, 3 H), 1.68–1.86 (m, 1 H),
2.35 (d, J = 18.4 Hz, 2 H), 2.56 (s, 3 H), 3.19 (dd, J = 8.9 Hz, 6.0
Hz, 1 H), 7.20 (td, J = 8.0 Hz, J = 1.6 Hz, 1 H), 7.36–7.42 (m, 2 H),
7.49 (d, J = 7.2 Hz, 1 H).
1-(2-(sec-Butyl)phenyl)ethanone (3aw)
Light-yellow oil; yield: 29.6 mg (56%).
1H NMR (400 MHz, CDCl3): δ = 0.81 (t, J = 7.6 Hz, 3 H), 1.23 (d,
J = 6.8 Hz, 3 H), 1.53–1.67 (m, 2 H), 2.56 (s, 3 H), 3.17 (app. sextet,
J = 7.0 Hz, 1 H), 7.22 (td, J = 7.6 Hz, J = 1.6 Hz, 1 H), 7.35 (d, J =
7.6 Hz, 1 H), 7.39–7.46 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 28.7, 30.4, 30.6, 36.6, 37.0, 40.2,
42.6, 43.4, 125.0, 126.4, 128.0, 130.7, 139.3, 146.2, 203.7.
13C NMR (100 MHz, CDCl3): δ = 12.2, 22.0, 30.8, 31.1, 36.2, 125.3,
126.8, 127.3, 130.8, 139.8, 146.4, 203.9.
HRMS (ESI): m/z [M + H]+ calcd for C12H17O: 177.1279; found:
1-(2-Cycloheptyl-4-methoxyphenyl)ethanone (3br)
The reaction was performed on a 10 mmol scale to give a light-
yellow oil; yield: 2.10 g (85%).
1H NMR (400 MHz, CDCl3): δ = 1.56–1.63 (m, 6 H), 1.69–1.78 (m,
4 H), 1.87–1.92 (m, 2 H), 2.54 (s, 3 H), 3.45–3.50 (m, 1 H), 3.83 (s,
3 H), 6.70 (dd, J = 8.8 Hz, J = 2.8 Hz, 1 H), 6.88 (d, J = 2.8 Hz, 1
H), 7.59 (d, J = 8.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 27.5, 27.7, 30.0, 36.9, 41.1, 55.2,
109.6, 113.3, 129.9, 131.2, 153.0, 161.9, 201.0.
177.1274.
1-[2-(1-Ethylpropyl)phenyl]ethanone (3ax)
Light-yellow oil; yield: 36.1 mg (63%).
1H NMR (400 MHz, CDCl3): δ = 0.77 (t, J = 7.4 Hz, 6 H), 1.52–1.61
(m, 2 H), 1.63–1.72 (m, 2 H), 2.54 (s, 3 H), 2.94–3.02 (m, 1 H), 7.22
(td, J = 7.6 Hz, J = 1.2 Hz, 1 H), 7.31 (d, J = 7.6 Hz, 1 H), 7.38–7.44
(m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C16H23O2: 247.1698; found:
247.1693.
13C NMR (100 MHz, CDCl3): δ = 12.0, 29.3, 31.1, 43.2, 125.2,
126.9, 127.0, 130.6, 141.2, 144.4, 204.1.
HRMS (ESI): m/z [M + H]+ calcd for C13H19O: 191.1436; found:
1-(2-Cyclobutyl-4-fluorophenyl)ethanone (3co)
Light-yellow oil; yield: 30.4 mg (53%).
1H NMR (400 MHz, CDCl3): δ = 1.77–1.80 (m, 1 H), 1.80–1.81 (m,
3 H), 1.98–2.39 (m, 2 H), 2.53 (s, 3 H), 4.04–4.08 (m, 1 H), 6.90 (td,
J = 8.0 Hz, J = 2.4 Hz, 1 H), 7.09 (dd, J = 10.8 Hz, J = 2.4 Hz, 1 H),
7.57 (dd, J = 8.8 Hz, J = 6.0 Hz, 1 H).
191.1438.
1-[2-(1-Methyl-3-phenylpropyl)phenyl]ethanone (3ay)
Light-yellow oil; yield: 57.8 mg (76%).
1H NMR (400 MHz, CDCl3): δ = 1.31 (d, J = 6.8 Hz, 3 H), 1.86–
2.02 (m, 2 H), 2.46–2.52 (m, 1 H), 2.53 (s, 3 H), 2.57–2.62 (m, 1 H),
3.33–3.89 (m, 1 H), 7.12–7.14 (m, 2 H), 7.17 (d, J = 7.6 Hz, 1 H),
7.24–7.28 (m, 3 H), 7.42–7.45 (m, 2 H), 7.50 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 22.5, 30.6, 34.0, 34.3, 40.0, 125.5,
125.6, 126.8, 127.5, 128.2 (two signals overlapping), 131.0, 139.6,
142.4, 146.1, 203.5.
13C NMR (100 MHz, CDCl3): δ = 17.9, 29.3, 29.8, 38.1, 112.1 (d,
2
3
2JC–F = 21 Hz), 114.6 (d, JC–F = 21 Hz), 130.9 (d, JC–F = 9 Hz),
134.0, 149.2 (d, 3JC–F = 8 Hz), 164.4 (d, 1JC–F = 250 Hz), 200.9.
HRMS (ESI): m/z [M + H]+ calcd for C12H14FO: 193.1029; found:
193.1032.
1-(4-Chloro-2-cyclohexylphenyl)ethanone (3dq)
Orange oil; yield: 45.9 mg (65%).
HRMS (ESI): m/z [M + H]+ calcd for C18H21O: 253.1592; found:
1H NMR (400 MHz, CDCl3): δ = 1.23–1.29 (m, 1 H), 1.36–1.43 (m,
4 H), 1.73–1.83 (m, 5 H), 2.55 (s, 3 H), 3.08–3.11 (m, 1 H), 7.20
(dd, J = 8.4 Hz, 2.0 Hz, 1 H), 7.35 (d, J = 2.0 Hz, 1 H), 7.44 (d, J =
8.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 26.1, 26.7, 30.6, 34.4, 39.8, 125.5,
127.6, 129.3, 137.0, 137.1, 149.1, 202.2.
253.1594.
1-{2-[3-(4-Methoxyphenyl)-1-methylpropyl]phenyl}ethanone
(3az)
Light-yellow oil; yield: 51.4 mg (61%).
1H NMR (400 MHz, CDCl3): δ = 1.29 (d, J = 6.8 Hz, 3 H), 1.87–
1.95 (m, 2 H), 2.37–2.45 (m, 1 H), 2.48–2.56 (m, 4 H), 3.30–3.36
(m, 1 H), 3.78 (s, 3 H), 6.80 (d, J = 8.4 Hz, 2 H), 7.03 (d, J = 8.4 Hz,
2 H), 7.25–7.27 (m, 1 H), 7.42–7.44 (m, 2 H), 7.49 (d, J = 7.6 Hz, 1
H).
13C NMR (100 MHz, CDCl3): δ = 22.6, 30.7, 33.2, 34.4, 40.3, 55.3,
113.7, 125.5, 126.9, 127.6, 129.2, 131.1, 134.6, 139.7, 146.2, 157.7,
203.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H18ClO: 237.1046; found:
237.1041.
1-(3-Cyclopentylbiphenyl-4-yl)ethanone (3ep)
Yellow solid; yield: 67.6 mg (85%); mp 78.5–79.6 °C.
1H NMR (400 MHz, CDCl3): δ = 1.65–1.75 (m, 4 H), 1.84–1.87 (m,
2 H), 2.13–2.15 (m, 2 H), 2.62 (s, 3 H), 3.07–3.63 (m, 1 H), 7.39 (t,
J = 7.6 Hz, 1 H), 7.44–7.49 (m, 3 H), 7.58–7.65 (m, 3 H), 7.60 (s, 1
H).
HRMS (ESI): m/z [M + H]+ calcd for C18H21O: 283.1698; found:
283.1703.
1-{2-[3-(4-Chlorophenyl)-1-methylpropyl]phenyl}ethanone
(3aaa)
13C NMR (100 MHz, CDCl3): δ = 25.8, 30.5, 35.1, 41.5, 124.0,
126.0, 127.2, 127.8, 128.3, 128.8, 138.3, 140.5, 143.8, 146.2, 203.2.
HRMS (ESI): m/z [M + H]+ calcd for C19H21O: 265.1592; found:
265.1591.
Light-yellow oil; yield: 64.5 mg (75%).
1H NMR (400 MHz, CDCl3): δ = 1.29 (d, J = 6.8 Hz, 3 H), 1.83–
1.95 (m, 2 H), 2.39–2.47 (m, 1 H), 2.51–2.59 (m, 4 H), 3.33–3.38
(m, 1 H), 7.04 (d, J = 8.4 Hz, 2 H), 7.10 (d, J = 8.4 Hz, 2 H), 7.23–
7.27 (m, 1 H), 7.39–7.47 (m, 2 H), 7.50 (dd, J = 1.2 Hz, 7.6 Hz, 1 H).
1-(2-Cyclohexyl-5-methylphenyl)ethanone (3fq)
Light-yellow oil; yield: 38.1 mg (53%).
1H NMR (400 MHz, CDCl3): δ = 1.22–1.29 (m, 1 H), 1.34–1.45 (m,
4 H), 1.73–1.83 (m, 5 H), 2.34 (s, 3 H), 2.55 (s, 3 H), 2.97–3.01 (m,
1 H), 7.21 (d, J = 8.0 Hz, 1 H), 7.26 (s, 1 H), 7.27 (d, J = 8.4 Hz, 1
H).
13C NMR (100 MHz, CDCl3): δ = 22.5, 30.6, 33.4, 34.2, 39.9, 125.5,
126.7, 127.7, 128.3, 129.6, 131.1, 131.3, 139.4, 140.9, 146.0, 203.4.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2024–2039

2036
K. Gao et al.
FEATURE ARTICLE
13C NMR (100 MHz, CDCl3): δ = 20.8, 26.2, 26.9, 30.7, 34.6, 39.6,
127.0, 128.1, 131.6, 134.8, 139.1, 143.5, 203.9.
1-(2-Cyclobutyl-3-thienyl)ethanone (3lo)
Light-yellow oil; yield: 15.1 mg (24%).
1H NMR (400 MHz, CDCl3): δ = 1.84–1.90 (m, 1 H), 1.98–2.12 (m,
3 H), 2.48 (s, 3 H), 2.49–2.53 (m, 2 H), 4.34–4.40 (m, 1 H), 7.06 (d,
J = 5.6 Hz, 1 H), 7.35 (d, J = 5.6 Hz, 1 H)
13C NMR (100 MHz, CDCl3): δ = 18.1, 29.8, 31.2, 36.0, 121.1,
129.4, 134.6, 160.3, 193.5.
HRMS (ESI): m/z [M + H]+ calcd for C10H13OS: 181.0687; found:
181.0692.
HRMS (ESI): m/z [M + H]+ calcd for C15H21O: 217.1592; found:
217.1593.
1-(3-Cyclohexylnaphthalen-2-yl)ethanone (3gq)
Yellow oil; yield: 42.6 mg (56%).
1H NMR (400 MHz, CDCl3): δ = 1.26–1.35 (m, 1 H), 1.42–1.55 (m,
4 H), 1.78–1.98 (m, 5 H), 2.70 (s, 3 H), 3.21–3.27 (m, 1 H), 7.46 (td,
J = 8.0 Hz, J = 1.2 Hz, 1 H), 7.53 (td, J = 8.0 Hz, J = 1.2 Hz, 1 H),
7.78 (s, 1 H), 7.83 (t, J = 8.0 Hz, 2 H), 8.03 (s, 1 H).
2-Cyclohexyl-1-methyl-1H-indole-3-carbaldehyde (3mq)
Brown oil; yield: 32.4 mg (45%).
13C NMR (100 MHz, CDCl3): δ = 26.3, 27.0, 30.6, 34.9, 39.6, 125.7,
1H NMR (400 MHz, CDCl3): δ = 1.26–1.47 (m, 3 H), 1.84–2.05 (m,
7 H), 3.20–3.26 (m, 1 H), 3.80 (s, 3 H), 7.28–7.29 (m, 3 H), 8.36–
8.38 (m, 1 H), 10.4 (s, 1 H).
125.9, 127.4, 127.6, 128.2, 128.6, 130.6, 134.5, 137.9, 143.7, 203.2.
HRMS (ESI): m/z [M + H]+ calcd for C18H21O: 253.1592; found:
253.1591.
13C NMR (100 MHz, CDCl3): δ = 25.8, 27.0, 30.9, 32.9, 37.4, 109.3,
114.0, 121.7, 122.9, 123.2, 126.1, 136.9, 155.2, 184.8.
HRMS (ESI): m/z [M + H]+ calcd for C16H20NO: 242.1545; found:
242.1545.
1-(2-Cyclobutyl-9H-fluoren-3-yl)ethanone (3ho)
Light-yellow oil; yield: 59.2 mg (75%).
1H NMR (400 MHz, CDCl3): δ = 1.85–1.90 (m, 1 H), 2.02–2.19 (m,
1 H), 2.14–2.19 (m, 2 H), 2.41–2.48 (m, 2 H), 2.61 (s, 3 H), 3.88 (s,
2 H), 4.13–4.18 (m, 1 H), 7.35 (t, J = 6.8 Hz, 1 H), 7.42 (t, J = 7.2
Hz, 1 H), 7.56 (d, J = 7.6 Hz, 1 H), 7.71 (s, 1 H), 7.80 (s, 1 H), 7.86
(d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 18.1, 29.6, 29.9, 36.5, 38.4, 118.4,
120.4, 124.8, 125.1, 126.8, 127.5, 136.5, 139.9, 140.8, 144.30,
144.33, 144.4, 202.6.
(2-Ethynyl-5-methoxyphenyl)cycloheptane (4)
A solution of LDA in THF (10 mL) was prepared from i-PrNH2
(148.7 mg, 1.47 mmol) and a 1.6 M solution of BuLi hexane (1.30
mL, 1.47 mmol) at 0 °C. A solution of ketone 3br (350 mg, 1.4
mmol) in THF (5 mL) was added dropwise to the LDA solution at
–78 °C, and the resulting mixture was stirred for 1 h. ClP(O)(OEt)2
(265.7 mg, 1.54 mmol) was added, and the mixture was gradually
warmed to r.t. and then added dropwise to a solution of LDA (3.15
mmol) in THF (prepared as above) at –78 °C. The resulting mixture
was warmed to r.t. over 3 h and the reaction was quenched with
H2O. The mixture was extracted with hexane (3 × 10 mL) and the
extracts were washed successively with 1 M HCl (10 mL), H2O (10
mL), and aq NaHCO3 (10 mL). The organic phase was dried
(MgSO4) and concentrated under reduced pressure. The crude prod-
uct was purified by chromatography [silica gel, hexane–EtOAc
(10:1)] to give a yellow oil; yield: 181.7 mg (56%).
HRMS (ESI): m/z [M + H]+ calcd for C19H19O: 263.1436; found:
263.1435.
1-(4-Cyclopentyl-1,3-benzodioxol-5-yl)ethanone (3ip)
Pale-yellow solid; obtained partially in a pure form [yield: 17.2 mg
(25%)] and partially as a mixture with its regioisomer [yield: 13.9
mg (20%), ratio = 64:36]; mp 65.8–66.9 °C.
1H NMR (400 MHz, CDCl3): δ = 1.60–1.64 (m, 2 H), 1.80–1.93 (m,
6 H), 2.53 (s, 3 H), 3.45–3.54 (m, 1 H), 5.98 (s, 2 H), 6.68 (d, J =
8.0 Hz, 1 H), 7.12 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 26.4, 30.4, 31.9, 38.6, 101.0,
105.3, 123.5, 128.4, 134.6, 146.4, 149.7, 201.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H17O3: 233.1178; found:
1H NMR (400 MHz, CDCl3): δ = 1.60–1.66 (m, 6 H), 1.70–1.74 (m,
2 H), 1.78–1.84 (m, 2 H), 1.91–1.96 (m, 2 H), 3.18 (s, 1 H), 3.20–
3.25 (m, 1 H), 3.80 (s, 3 H), 6.66 (dd, J = 8.4 Hz, 2.4 Hz, 1 H), 6.77
(d, J = 2.4 Hz, 1 H), 7.40 (d, J = 8.4 Hz, 1 H).
233.1178.
13C NMR (100 MHz, CDCl3): δ = 27.5, 27.8, 35.8, 43.8, 55.2, 79.2,
82.6, 110.4, 111.9, 112.8, 134.2, 154.1, 160.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H21O: 229.1592; found:
8-Cycloheptyl-3,4-dihydronaphthalen-1(2H)-one (3jr)
Orange oil; yield: 59.4 mg (81%).
1H NMR (400 MHz, CDCl3): δ = 1.55–1.65 (m, 6 H), 1.70–1.82 (m,
4 H), 1.88–1.91 (m, 2 H), 2.03–2.10 (m, 2 H), 2.66 (t, J = 6.8 Hz, 2
H), 2.92 (t, J = 6.0 Hz, 2 H), 3.84–3.89 (m, 1 H), 7.04 (d, J = 7.6 Hz,
1 H), 7.27 (d, J = 6.4 Hz, 1 H), 7.34 (t, J = 6.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 22.9, 27.7, 27.8, 31.2, 37.0, 40.8,
41.3, 125.8, 125.9, 130.3, 132.2, 145.1, 153.2, 200.6.
229.1593.
6′-Methoxyspiro[cycloheptane-1,1′-indene] (5)
A mixture of alkyne 4 (68.5 mg, 0.30 mmol), CuBr (86.1 mg, 0.60
mmol), and PtCl2 (8.0 mg, 0.03 mmol) in toluene (3 mL) was stirred
at 100 °C for 24 h. When the reaction was complete, the dark solid
was removed from the mixture by filtration through a pad of Celite,
which was then washed with Et2O (3 × 5 mL). The combined filtrate
was dried (MgSO4) and concentrated under reduced pressure. The
crude product was purified by chromatography [silica gel, hexane–
EtOAc (10:1 to 5:1)] to give a yellow oil; yield: 53.0 mg (77%).
HRMS (ESI): m/z [M + H]+ calcd for C17H23O: 243.1749; found:
243.1750.
1-(2-Cyclohexylphenyl)propan-1-one (3kq)
Light-yellow oil; yield: 51.8 mg (80%).
1H NMR (400 MHz, CDCl3): δ = 1.20 (t, J = 7.2 Hz, 3 H), 1.22–1.30
(m, 1 H), 1.37–1.44 (m, 4 H), 1.73–1.84 (m, 5 H), 2.86 (q, J = 7.2
Hz, 2 H), 2.83–2.89 (m, 1 H), 7.19–7.23 (m, 1 H), 7.37–7.39 (m, 3
H).
1H NMR (400 MHz, CDCl3): δ = 1.55–1.60 (m, 2 H), 1.67–1.79 (m,
6 H), 1.81–1.85 (m, 4 H), 3.83 (s, 3 H), 6.51 (d, J = 5.6 Hz, 1 H),
6.59 (d, J = 5.6 Hz, 1 H), 6.75 (dd, J = 8.0 Hz, 2.4 Hz, 1 H), 6.96 (d,
J = 2.0 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 25.5, 29.9, 36.9, 55.5, 56.8, 108.8,
110.9, 121.3, 127.6, 135.4, 143.8, 156.9, 158.0.
13C NMR (100 MHz, CDCl3): δ = 8.4, 26.2, 26.8, 34.6, 36.3, 40.2,
HRMS (ESI): m/z [M + H]+ calcd for C16H21O: 229.1592; found:
229.1592.
125.3, 126.7, 127.0, 130.4, 139.6, 146.0, 207.3.
HRMS (ESI): m/z [M + H]+ calcd for C15H21O: 217.1592; found:
217.1595.
Synthesis 2014, 46, 2024–2039
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Cobalt-Catalyzed Alkylation of Arenes
2037
1-(2-Cycloheptyl-4-methoxyphenyl)-2-diazoethanone (6)
A solution of ketone 3br (289 mg, 1.2 mmol) in THF (5 mL) was
added over 1 min to a 1.0 M solution of LiHMDS (1.30 mL) in THF
(10 mL) at –78 °C. The mixture was stirred for 30 min and then
F3CCO2CH2CF3 (282.3 mg, 1.44 mmol) was added over 2–3 min.
The mixture was stirred for a further 3 h, allowed to warm to r.t., and
poured into a separatory funnel together with Et2O (10 mL) and 5%
aq HCl (20 mL). The separated aqueous layer was extracted with
Et2O (30 mL), and the organic layers were combined, washed with
brine, dried (MgSO4), and concentrated under reduced pressure to
give a yellow oil. This oil was placed in a dry, 50 mL, three-necked,
round bottomed flask under N2 and dissolved in MeCN (10 mL).
H2O (0.02 mL) and Et3N (0.25 mL) were added, followed by drop-
wise addition of a solution of 4-AcNHC6H4SO2N3 (432.4 mg, 1.8
mmol) in MeCN (10 mL). The resulting solution was stirred at r.t.
for 8 h, then poured into a separatory funnel with Et2O (20 mL). The
organic layer was washed successively with 5% aq NaOH (3 × 20
mL), H2O (3 × 20 mL), and brine, then dried (MgSO4) and concen-
trated under reduced pressure. The crude product was purified by
chromatography [silica gel, hexane–EtOAc (30:1 to 5:1)] to give a
yellow oil; yield: 240.9 mg (75%).
13C NMR (100 MHz, CDCl3): δ = 14.2, 22.8, 29.3, 29.4, 29.7, 31.3,
32.0, 33.8, 121.7, 125.2, 126.7, 128.1, 135.9, 140.0, 140.1, 149.5,
159.9.
HRMS (ESI): m/z [M + H]+ calcd for C27H42N: 380.3317; found:
380.3316.
2-[2-(2,2-Dimethylpropyl)phenyl]pyridine (9aj)7a
Colorless oil; yield: 48.4 mg (72%).
1H NMR (400 MHz, CDCl3): δ = 0.64 (s, 9 H), 2.88 (s, 2 H), 7.19–
7.39 (m, 6 H), 7.71 (td, J = 7.8 Hz, 1.8 Hz, 1 H), 8.66–8.68 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 29.7, 33.0, 45.1, 121.6, 125.0,
126.2, 127.6, 130.3, 132.6, 136.2, 137.7, 141.7, 149.1, 161.5.
2-(2,6-Diisopropyl-4-methoxyphenyl)pyridine (10bv)
Light-yellow solid; yield: 69.3 mg (86%); mp 81.6–82.5 °C.
1H NMR (400 MHz, CDCl3): δ = 1.07 (d, J = 6.8 Hz, 6 H), 1.11 (d,
J = 6.8 Hz, 6 H), 2.47–2.54 (m, 2 H), 3.85 (s, 3 H), 6.75 (s, 2 H),
7.24 (t, J = 7.6 Hz, 2 H), 7.68–7.73 (m, 1 H), 8.69–8.71 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 23.7, 24.0, 55.1, 108.1, 121.4,
125.4, 131.7, 135.6, 148.1, 149.3, 159.6, 159.9.
HRMS (ESI): m/z [M + H]+ calcd for C18H24NO: 270.1858; found:
270.1859.
1H NMR (400 MHz, CDCl3): δ = 1.53–1.61 (m, 6 H), 1.63–1.70 (m,
2 H), 1.72–1.77 (m, 2 H), 1.87–2.00 (m, 2 H), 3.24–3.37 (m, 1 H),
3.77 (s, 3 H), 5.52 (s, 1 H), 6.64 (dd, J = 2.4 Hz, 8.4 Hz, 1 H), 6.84
(d, J = 2.4 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H).
2-(2,6-Dicyclobutyl-4-fluorophenyl)pyridine (10cp)
Yellow solid; yield: 59.2 mg (70%); mp 62.3–63.6 °C.
13C NMR (100 MHz, CDCl3): δ = 27.2, 27.6, 36.7, 41.3, 55.0, 56.1,
1H NMR (400 MHz, CDCl3): δ = 1.63–1.69 (m, 3 H), 1.71–1.82 (m,
5 H), 1.91 (t, J = 9.2 Hz, 2 H), 1.97–2.06 (m, 2 H), 3.26–3.33 (m, 2
H), 6.93 (d, JH-F = 10.0 Hz, 2 H), 7.15 (d, J = 7.6 Hz, 1 H), 7.23–
7.26 (m, 1 H), 7.68–7.72 (m, 1 H), 8.68 (d, J = 5.2 Hz, 1 H).
109.8, 113.0, 128.8, 129.1, 151.2, 161.4, 189.6.
HRMS (ESI): m/z [M + H]+ calcd for C16H21N2O2: 273.1602; found:
273.1603.
6′-Methoxyspiro[cycloheptane-1,1′-inden]-3′(2′H)-one (7)
A solution of diazo compound 6 (81.7 mg, 0.30 mmol) in CH2Cl2
(22.5 mL) was added dropwise to a suspension of Rh2(OAc)4 (2.7
mg, 6 μmol) in CH2Cl2 (7.5 mL) at r.t. over 6 h by using a syringe
pump. The resulting mixture was stirred for an additional 3 h and
then concentrated under reduced pressure. The crude product was
purified by chromatography [silica gel, hexane–EtOAc (10:1)] to
give a yellow oil; yield: 26.2 mg (36%).
1H NMR (400 MHz, CDCl3): δ = 1.56–1.62 (m, 2 H), 1.65–1.72 (m,
6 H), 1.75–1.79 (m, 2 H), 1.90 (t, J = 12.0 Hz, 2 H), 2.60 (s, 2 H),
3.89 (s, 3 H), 6.87 (dd, J = 8.0 Hz, 2.4 Hz, 1 H), 6.93 (d, J = 2.4 Hz,
1 H), 7.62 (d, J = 8.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 17.9, 29.2, 29.8, 38.4 (d, 4JC–F
=
2
1 Hz), 110.3 (d, JC–F = 21 Hz), 121.7, 125.3, 134.1, 135.7, 146.1
(d, 3JC–F = 8 Hz), 149.3, 158.8, 163.0 (d, 1JC–F = 243 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C19H21FN: 282.1658; found:
282.1657.
2-[2,6-Dicyclohexyl-4-(trifluoromethyl)phenyl]pyridine (10dr)
White solid; yield: 45.4 mg (39%); mp 140.8–142.2 °C.
1H NMR (400 MHz, CDCl3): δ = 0.94–1.06 (m, 4 H), 1.12–1.23 (m,
2 H), 1.31–1.43 (m, 4 H), 1.58–1.70 (m, 8 H), 1.82 (d, J = 12.4 Hz,
2 H), 2.08 (tt, J = 3.0 Hz, 11.6 Hz, 2 H), 7.20 (d, J = 8.0 Hz, 1 H),
7.29–7.32 (m, 1 H), 7.38–7.46 (m, 2 H), 7.72–7.78 (m, 1 H), 8.71
(d, J = 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.6, 28.5, 41.9, 45.8, 50.3, 55.6,
107.6, 114.7, 125.1, 128.2, 165.4, 168.2, 204.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H21O2: 245.1542; found:
245.1544.
13C NMR (100 MHz, CDCl3): δ = 25.9, 26.6, 26.7, 33.8, 34.3, 41.2,
3
1
120.3 (q, JC–F = 4 Hz), 122.0, 124.4, 127.0 (q, JC–F = 248 Hz),
130.3 (q, 2JC–F = 31 Hz), 135.8, 142.3, 146.6, 149.4, 158.7.
HRMS (ESI): m/z [M + H]+ calcd for C24H29F3N: 388.2252; found:
388.2255.
2-(2-Octylphenyl)pyridine (9aa)2d
Yellow oil; yield: 57.3 mg (71%).
1H NMR (400 MHz, CDCl3): δ = 0.86 (t, J = 7.2 Hz, 3 H), 1.17–1.26
(m, 10 H), 1.43–1.47 (m, 2 H), 2.70 (t, J = 8.0 Hz, 2 H), 7.23–7.39
(m, 6 H), 7.71–7.76 (m, 1 H), 8.69 (d, J = 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 29.1, 29.2, 29.4, 31.2,
31.8, 32.9, 121.5, 124.1, 125.7, 128.2, 129.66, 129.68, 136.0, 140.3,
140.8, 149.1, 160.3.
2-(2-Cyclobutyl-5-methylphenyl)pyridine (10ep)
Yellow oil; yield: 57.9 mg (86%).
1H NMR (400 MHz, CDCl3): δ = 1.71–1.73 (m, 1 H), 1.82–1.87 (m,
1 H), 1.98–2.06 (m, 4 H), 2.37 (s, 3 H), 3.76–3.81 (m, 1 H), 7.17 (s,
1 H), 7.19–7.25 (m, 2 H), 7.32–7.35 (m, 2 H), 7.68–7.73 (m, 1 H),
8.67–8.69 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 18.2, 20.9, 30.0, 37.7, 121.5,
124.1, 126.5, 129.0, 130.1, 135.1, 135.8, 139.6, 140.7, 149.2, 160.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H18N: 224.1439; found:
224.1441.
2-(2,6-Dioctylphenyl)pyridine (10aa)
Obtained as a mixture with 2-[2-(2,2-dimethylpropyl)-6-(2-phenyl-
ethyl)phenyl]pyridine; yield: 76% (by weight and 1H NMR analy-
sis).
1H NMR (400 MHz, CDCl3): δ = 0.85 (t, J = 7.3 Hz, 6 H), 1.11–1.16
(m, 16 H), 1.21–1.25 (m, 4 H), 1.37–1.42 (m, 4 H), 2.29 (t, J = 7.8
Hz, 4 H), 7.11 (d, J = 7.8 Hz, 2 H), 7.22–7.26 (m, 3 H), 7.72 (td, J =
7.8, 1.8 Hz, 1 H), 8.69–8.71 (m, 1 H).
2-(3-Chloro-2-cyclohexylphenyl)pyridine (10fr)
Light-yellow oil; yield: 38.3 mg (47%).
1H NMR (400 MHz, CDCl3): δ = 1.13–1.23 (m, 3 H), 1.35–1.44 (m,
2 H), 1.65–1.80 (m, 5 H), 2.70 (tt, J = 2.8 Hz, 11.6 Hz, 1 H), 7.26–
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2024–2039

2038
K. Gao et al.
FEATURE ARTICLE
7.29 (m, 1 H), 7.30–7.34 (m, 4 H), 7.73–7.77 (m, 1 H), 8.69–8.70
(m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 26.1, 26.7, 34.3, 39.5, 122.0,
124.1, 127.9, 128.4, 129.6, 131.1, 136.1, 141.5, 144.1, 149.4, 158.9.
HRMS (ESI): m/z [M + H]+ calcd for C17H19ClN: 272.1206; found:
H), 2.57–2.76 (m, 4 H), 6.91 (d, J = 7.0 Hz, 2 H), 7.09–7.19 (m, 6
H), 7.27 (t, J = 7.5 Hz, 2 H), 7.71 (td, J = 7.7 H, 1.8 Hz, 1 H), 8.73
(d, J = 4.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.3, 22.8, 29.3, 29.4, 29.7, 31.3,
32.0, 33.7, 36.3, 38.0, 121.9, 125.2, 125.9, 126.8, 127.1, 128.3,
128.38, 128.44, 136.0, 139.8, 140.2, 141.1, 142.3, 149.6, 159.7.
272.1205.
HRMS (ESI): m/z [M + H]+ calcd for C27H34N: 372.2691; found:
372.2689.
2-(2-Cyclobutyl-4-methoxyphenyl)-3-methylpyridine (10gp)
Light-yellow oil; yield: 57.9 mg (86%).
1H NMR (400 MHz, CDCl3): δ = 1.65–1.78 (m, 3 H), 1.82–2.09 (m,
3 H), 2.09 (s, 3 H), 3.38–3.47 (m, 1 H), 3.85 (s, 3 H), 6.77 (dd, J =
2.4 Hz, 8.4 Hz, 1 H), 6.94 (d, J = 2.4 Hz, 1 H), 7.04 (d, J = 8.4 Hz,
1 H), 7.15 (dd, J = 4.8 Hz, 7.6 Hz, 1 H), 7.53 (d, J = 6.8 Hz, 1 H),
8.46–8.48 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 18.0, 19.3, 29.3, 38.1, 55.2, 110.3,
112.3, 121.9, 129.6, 131.8, 131.9, 137.4, 145.2, 146.4, 159.3, 159.5.
1-[2-(4-tert-Butylcyclohexyl)phenyl]ethanone (3aac)
Light-yellow oil; yield: 23.8 mg (31%; trans/cis = 79:21).
1H NMR (400 MHz, CDCl3): δ (trans) = 0.88 (s, 9 H), 1.08–1.22
(m, 3 H), 1.35–1.48 (m, 2 H), 1.79–1.93 (m, 4 H), 2.57 (s, 3 H), 2.98
(tt, J = 12.0 Hz, 3.2 Hz, 1 H), 7.20–7.24 (m, 1 H), 7.37–7.40 (m, 2
H), 7.47–7.48 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ (trans) = 27.6, 27.7, 30.8, 32.5,
34.8, 40.0, 47.9, 125.3, 127.0, 127.7, 130.9, 139.3, 146.4, 203.8.
HRMS (ESI): m/z [M + H]+ calcd for C18H27O: 259.2062; found:
HRMS (ESI): m/z [M + H]+ calcd for C17H20NO: 254.1545; found:
254.1541.
259.2057.
2-(2-Isopropyl-6-methylphenyl)pyridine (10hv)
Obtained as a mixture with 2-(4-tolyl)pyridine (8h); yield: 89% (by
weight and 1H NMR analysis).
1H NMR (400 MHz, CDCl3): δ = 1.12 (d, J = 4.8 Hz, 3 H), 1.13 (d,
J = 4.8 Hz, 3 H), 2.00 (s, 3 H), 2.57–2.64 (m, 1 H), 7.10 (d, J = 7.2
Hz, 1 H), 7.11–7.31 (m, 4 H), 7.72–7.77 (m, 1 H), 8.72–8.73 (m, 1
H).
13C NMR (100 MHz, CDCl3): δ = 20.4, 23.91, 23.94, 30.1, 121.5,
122.7, 124.5, 127.2, 128.2, 135.6, 136.0, 139.5, 146.4, 149.5, 159.9.
HRMS (ESI): m/z [M + H]+ calcd for C15H18N: 212.1439; found:
212.1440.
1-[2-(1-Methylheptyl)phenyl]ethanone (3aad)
Obtained as a mixture with the linear isomer 3aa and the ortho-neo-
pentylation product 3aj; yield: 63% (by weight and 1H NMR anal-
ysis). See the Supporting Information for the determination of the
enantiomeric excess.
1H NMR (400 MHz, CDCl3): δ = 0.83–0.85 (m, 3 H), 1.09–1.26 (m,
11 H), 1.46–1.66 (m, 2 H), 2.52 (s, 3 H), 3.23 (sextet, J = 7.3 Hz, 1
H), 7.18–7.23 (m, 1 H), 7.34–7.45 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 14.3, 22.7, 22.8, 27.9, 29.6, 31.0,
32.0, 34.7, 38.6, 125.5, 127.1, 127.5, 131.1, 139.9, 146.9, 204.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H25O: 233.1905; found:
233.1908.
10-Cyclopentylbenzo[h]quinoline (10iq)
Light-yellow oil; yield: 59.5 mg (80%).
1H NMR (400 MHz, CDCl3): δ = 1.74–1.81 (m, 2 H), 1.86–1.96 (m,
4 H), 2.37–2.43 (m, 2 H), 5.71–5.75 (m, 1 H), 7.47 (dd, J = 4.4 Hz,
8.0 Hz, 1 H), 7.62–7.67 (m, 2 H), 7.79 (t, J = 8.4 Hz, 2 H), 7.85 (d,
J = 7.6 Hz, 1 H), 8.14 (dd, J = 2.0 Hz, 8.0 Hz, 1 H), 9.02–9.03 (m,
1 H).
13C NMR (100 MHz, CDCl3): δ = 25.7, 34.7, 43.5, 120.5, 125.3,
126.0, 126.5, 127.4, 127.6, 129.1, 129.4, 135.3, 135.4, 146.9, 147.2,
148.7.
1-[2-(Cyclobutylmethyl)phenyl]ethanone (3aae)
Obtained as a mixture with the ring-opening alkylation products
3ad and 3ad′; yield: 60% (by weight and 1H NMR analysis).
1H NMR (400 MHz, CDCl3): δ = 1.67–1.74 (m, 2 H), 1.77–1.85 (m,
2 H), 1.95–2.02 (m, 2 H), 2.52–2.60 (m, 4 H), 2.97 (d, J = 7.6 Hz, 2
H), 7.21 (d, J = 7.6 Hz, 1 H), 7.25 (d, J = 7.6 Hz, 1 H), 7.34–7.38
(m, 1 H), 7.60 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 18.3, 28.3, 30.0, 37.1, 40.3, 125.6,
128.8, 130.9, 131.0, 138.2, 140.8, 202.5.
HRMS (ESI): m/z [M + H]+ calcd for C13H17O: 189.1279; found:
HRMS (ESI): m/z [M + H]+ calcd for C18H18N: 248.1439; found:
248.1437.
189.1274.
2-(3-Cyclopentyl-2-thienyl)pyridine (10jq)
Brown oil; yield: 15.7 mg (23%).
1-(2-Hex-5-en-1-ylphenyl)ethanone (3aaf)
Obtained as an 88:12 mixture with 1-{2-[(4E)-hex-4-en-1-yl]phe-
nyl}ethanone (3aaf′) as a yellow oil; yield: 58.6 mg (97%).
1H NMR (400 MHz, CDCl3): δ = 1.63–1.70 (m, 4 H), 1.82–1.83 (m,
2 H), 2.03–2.09 (m, 2 H), 3.49–3.53 (m, 1 H), 7.06 (d, J = 5.6 Hz,
1 H), 7.16–7.19 (m, 1 H), 7.32 (d, J = 5.6 Hz, 1 H), 7.50 (d, J = 8.0
Hz, 1 H), 7.69–7.23 (m, 1 H), 8.64–8.65 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 25.7, 34.9, 39.3, 121.4, 122.6,
126.0, 127.6, 136.3, 137.6, 144.8, 149.7, 153.7.
1H NMR (400 MHz, CDCl3): δ = 1.44–1.50 (m, 2 H), 1.55–1.61 (m,
2 H), 2.06–2.11 (m, 2 H), 2.58 (s, 3 H), 2.85 (t, J = 7.6 Hz, 2 H),
4.94 (ddt, J = 10.2 Hz, 2.0 Hz, 1.1 Hz, 1 H), 5.00 (ddt, J = 17.1 Hz,
1.9 Hz, 1.6 Hz, 1 H), 5.81 (ddt, J = 17.0 Hz, 10.2 Hz, 6.7 Hz, 1 H),
7.24–7.27 (m, 2 H), 7.39 (td, J = 7.6 Hz, 1.2 Hz, 1 H), 7.63 (dd, J =
7.6 Hz, 1.2 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C14H16NS: 230.1003; found:
230.1004.
13C NMR (100 MHz, CDCl3): δ = 28.9, 29.9, 31.3, 33.6, 33.8, 114.3,
125.6, 129.0, 131.1, 131.2, 137.9, 138.9, 142.7, 202.2.
HRMS (ESI): m/z [M + H]+ calcd for C14H19O: 203.1436; found:
203.1437.
2-[2-Octyl-6-(2-phenylethyl)phenyl]pyridine (11)
Colorless oil; yield: 55.6 mg (50%)
1H NMR (400 MHz, CDCl3): δ = 0.86 (t, J = 7.2 Hz, 3 H), 1.13–1.16
(m, 8 H), 1.20–1.25 (m, 2 H), 1.40–1.41 (m, 2 H), 2.28–2.34 (m, 2
Synthesis 2014, 46, 2024–2039
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Acknowledgment
Cobalt-Catalyzed Alkylation of Arenes
2039
J. Am. Chem. Soc. 2012, 134, 7325. (b) Deng, G.-J.; Zhao,
L.; Li, C.-J. Angew. Chem. Int. Ed. 2008, 47, 6278.
(11) (a) Yoshikai, N. Synlett 2011, 1047. (b) Gao, K.; Yoshikai,
N. Acc. Chem. Res. 2014, 47, 1208.
(12) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 9279.
(13) Gao, K.; Yoshikai, N. Chem. Commun. 2012, 48, 4305.
(14) Gao, K.; Lee, P.-S.; Long, C.; Yoshikai, N. Org. Lett. 2012,
14, 4234.
This work was supported by Singapore National Research Founda-
tion (NRF-RF2009-05), Nanyang Technological University, and
JST, CREST.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
(15) Song, W.; Ackermann, L. Angew. Chem. Int. Ed. 2012, 51,
8251.
10.1055/s-00000084.SunpfgIpi
m
o
nr
i
(16) Punji, B.; Song, W. F.; Shevchenko, G. A.; Ackermann, L.
Chem. Eur. J. 2013, 19, 10605.
(17) Yang, S.; Li, Z.; Han, X.; He, C. Angew. Chem. Int. Ed.
2009, 48, 3999.
(18) Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2011,
133, 17283.
References
(1) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani,
A.; Sonoda, M.; Chatani, N. Nature 1993, 366, 529.
(2) For recent 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) For recent examples, see: (a) Kakiuchi, F.; Kochi, T.;
Mizushima, E.; Murai, S. J. Am. Chem. Soc. 2010, 132,
17741. (b) Ilies, L.; Chen, Q.; Zeng, X.; Nakamura, E. J. Am.
Chem. Soc. 2011, 133, 5221. (c) Gao, K.; Yoshikai, N.
Angew. Chem. Int. Ed. 2011, 50, 6888. (d) Schinkel, M.;
Marek, I.; Ackermann, L. Angew. Chem. Int. Ed. 2013, 52,
3977. (e) Rouquet, G.; Chatani, N. Chem. Sci. 2013, 4, 2201.
(4) For branched-selective reaction with styrene derivatives,
see: (a) Uchimaru, Y. Chem. Commun. 1999, 1133. (b) Gao,
K.; Yoshikai, N. J. Am. Chem. Soc. 2011, 133, 400. (c) Pan,
S.; Ryu, N.; Shibata, T. J. Am. Chem. Soc. 2012, 134, 17474.
(d) Lee, P.-S.; Yoshikai, N. Angew. Chem. Int. Ed. 2013, 52,
1240. (e) Dong, J.; Lee, P.-S.; Yoshikai, N. Chem. Lett.
2013, 42, 1140.
(5) For Markovnikov-selective reaction of phenol derivatives
with alkyl olefins, see: (a) Lewis, L. N.; Smith, J. F. J. Am.
Chem. Soc. 1986, 108, 2728. (b) Dorta, R.; Togni, A. Chem.
Commun. 2003, 760. (c) Kuninobu, Y.; Matsuki, T.; Takai,
K. J. Am. Chem. Soc. 2009, 131, 9914. (d) Oyamada, J.;
Hou, Z. Angew. Chem. Int. Ed. 2012, 51, 12828.
(6) Ackermann, L. Chem. Commun. 2010, 46, 4866.
(7) (a) Ackermann, L.; Novák, P.; Vicente, R.; Hofmann, N.
Angew. Chem. Int. Ed. 2009, 48, 6045. (b) Zhang, Y.-H.;
Shi, B.-F.; Yu, J.-Q. Angew. Chem. Int. Ed. 2009, 48, 6097.
(c) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010,
132, 3965. (d) Chen, Q.; Ilies, L.; Nakamura, E. J. Am.
Chem. Soc. 2011, 133, 428. (e) Ackermann, L.; Hofmann,
N.; Vicente, R. Org. Lett. 2011, 13, 1875. (f) Zhao, Y. S.;
Chen, G. Org. Lett. 2011, 13, 4850. (g) Aihara, Y.; Chatani,
N. J. Am. Chem. Soc. 2013, 135, 5308. (h) Song, W.;
Lackner, S.; Ackermann, L. Angew. Chem. Int. Ed. 2014, 53,
2477.
(19) The use of smaller amounts of Me(CH2)7Cl (1.5 equiv) and
t-BuCH2MgBr (2 equiv) did not effect full conversion of the
monoalkylation product formed in the first step, thereby
giving the desired product in a lower yield (~30%).
(20) (a) Ohmiya, H.; Wakabayashi, K.; Yorimitsu, H.; Oshima,
K. Tetrahedron 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.
(21) 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.; Bégouin, J. M.; Moncomble, A.
Chem. Commun. 2008, 3221. (d) Yorimitsu, H.; Oshima, K.
Pure Appl. Chem. 2006, 78, 441.
(22) Newcomb, M. Tetrahedron 1993, 49, 1151.
(23) The higher yield reported in our earlier communication
(3aaf/3aaf' with 97% yield and an 88:12 ratio; see ref. 12)
could not be reproduced in this study.
(24) Klein, H.-F.; Camadanli, S.; Beck, R.; Leukel, D.; Flörke, U.
Angew. Chem. Int. Ed. 2005, 44, 975.
(25) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem.
Soc. 2001, 123, 5374.
(26) Huynh, H. V.; Han, Y.; Ho, J. H. H.; Tan, G. K.
Organometallics 2006, 25, 3267.
(27) (a) Mršić, N.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G.
J. Am. Chem. Soc. 2009, 131, 8358. (b) Gautier, F.-M.;
Jones, S.; Martin, S. J. Org. Biomol. Chem. 2009, 7, 229.
(28) Mongin, F.; Mojovic, L.; Guillamet, B.; Trécourt, F.;
Quéguiner, G. J. Org. Chem. 2002, 67, 8991.
(29) Yasuda, M.; Yamasaki, S.; Onishi, Y.; Baba, A. J. Am.
Chem. Soc. 2004, 126, 7186.
(30) (a) Jaegar, D. A.; Ward, M. D.; Martin, C. A. Tetrahedron
1984, 40, 2691. (b) Hochstein, F. A.; Brown, W. G. J. Am.
Chem. Soc. 1948, 70, 3484. (c) Guthrie, R. W.; Kierstead, R.
W.; Mullin, J. G.; Tilley, J. W. US 4927838, 1990.
(31) Roberts, B. P.; Steel, A. J. J. Chem. Soc., Perkin Trans. 2
1994, 2411.
(32) Cahiez, G.; Gager, O.; Moyeux, A.; Delacroix, T. Adv.
Synth. Catal. 2012, 354, 1519.
(33) Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N.; Murai, S. Bull. Chem. Soc. Jpn. 1995, 68,
62.
(8) For examples of nondirected alkylation of heteroarenes with
secondary alkyl halides, see: (a) Xiao, B.; Liu, Z.-J.; Liu, L.;
Fu, Y. J. Am. Chem. Soc. 2013, 135, 616. (b) Ren, P.; Salihu,
I.; Scopelliti, R.; Hu, X. Org. Lett. 2012, 14, 1748.
(9) For meta-selective alkylation with secondary alkyl halides
through cyclometalation process, see: Hofmann, N.;
Ackermann, L. J. Am. Chem. Soc. 2013, 135, 5877.
(10) For ortho-alkylations using different sources of secondary
alkyl groups, see: (a) Lee, D.-H.; Kwon, K.-H.; Yi, C. S.
(34) Savarin, C. G.; Grisé, C.; Murry, J. A.; Reamer, R. A.;
Hughes, D. L. Org. Lett. 2007, 9, 981.
(35) Cahiez, G.; Luart, D.; Lecomte, F. Org. Lett. 2004, 6, 4395.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2024–2039