Cobalt-catalyzed ortho alkylation of aromatic imines with primary and secondary alkyl halides

Article abstract of DOI:10.1021/ja403759x

We report here cobalt-N-heterocyclic carbene catalytic systems for the ortho alkylation of aromatic imines with alkyl chlorides and bromides, which allows the introduction of a variety of primary and secondary alkyl groups at room temperature. The stereochemical outcomes of the reaction of secondary alkyl halides suggest that the present reaction involves single-electron transfer from a cobalt species to the alkyl halide to generate the corresponding alkyl radical. A cycloalkylated product obtained by this method can be transformed into unique spirocycles through manipulation of the directing and cycloalkyl groups.

Full text of DOI:10.1021/ja403759x

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Communication
Cobalt-Catalyzed ortho-Alkylation of Aromatic
Imines with Primary and Secondary Alkyl Halides
Ke Gao, and Naohiko Yoshikai
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja403759x • Publication Date (Web): 12 Jun 2013
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Cobalt-Catalyzed ortho-Alkylation of Aromatic Imines with
Primary and Secondary Alkyl Halides
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Ke Gao and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371, Singapore
Supporting Information Placeholder
[M]
(a)
ABSTRACT: We report here cobalt–N-heterocyclic carbene
catalytic systems for the ortho-alkylation of aromatic imines
with alkyl chlorides and bromides, which allows introduction
of a variety of primary and secondary alkyl groups at room
temperature. Stereochemical outcomes of the reaction of sec-
ondary alkyl halides suggest that the present reaction involves
single-electron transfer from a cobalt species to the alkyl hal-
ide to generate the corresponding alkyl radical. A cycloalkyl-
ated product obtained by this method can be transformed into
unique spirocycles through manipulation of the directing and
the cycloalkyl groups.
R
R1
L
L
H
[M]
X
R
base
(b)
NPMP
H
Co–NHC
O
R1
H+
R1
tBuCH2MgBr
+
R2
X
R2
THF, rt
X = Br or Cl
With our recent development of cobalt/NHC/Grignard cata-
lytic systems for ortho C–H functionalization using aldimine11
and aryl chloride12 as electrophiles, we conceived that a simi-
lar system would allow ortho-alkylation with alkyl halides,
and thus commenced the present study with the reaction of
acetophenone imine 1 with n-octyl chloride (Table 1). The
catalytic system consisting of CoBr2 (10 mol %), IMes•HCl
(10 mol %), and tBuCH2MgBr (2 equiv), which we employed
for the ortho-arylation,12a was only modestly effective, afford-
ing the alkylation product 2a in 38% yield (entry 1). Other
popular bulky NHC preligands, such as IPr•HCl and
SIMes•HCl, exhibited poorer performances (entries 2 and 3).
Upon further screening, we found that a simple N,N'-
diisopropylimidazolinium salt L1 improved the yield to 64%
(entry 4). While the unsaturated analogue L2 and t-butyl ana-
logue L3 were less effective (entries 5 and 6), the benzo-fused
analogue L4 further improved the yield to 82% (entry 7). As
was the case in our previous studies,11,12a tBuCH2MgBr per-
formed best among a series of alkyl Grignard reagents (prima-
ry, secondary, and those without β-hydrogen), causing ortho-
neopentylation to only a small extent (< 2% for most cases).
The discovery of the ruthenium-catalyzed ortho-alkylation
of aromatic ketones with olefins by Murai et al. in 1993
brought about a new paradigm in regioselective aromatic al-
kylations (Scheme 1a, top).1 Since then, a series of catalytic
systems have been developed for the chelation-assisted alkyla-
tion using terminal olefins.2,3 However, this strategy has been
less successful in the introduction of a secondary alkyl group
for various reasons, such as anti-Markovnikov selectivity with
terminal olefins, low reactivity of internal olefins, and isomer-
ization of internal acyclic olefins, with limited exceptions.4,5
More recently, ortho-alkylation employing alkyl halides as
alkylating agents has emerged as an alternative strategy
(Scheme 1a, bottom).6,7 Nevertheless, while successful for
primary alkyl halides, this strategy has been practiced with
only a handful of secondary alkyl halides.7a,d,f,8-10 Here, we
report a significant expansion of the scope of the latter strate-
gy achieved with a cobalt–N-heterocyclic carbene (NHC) cata-
lyst system, which allows ortho-alkylation of aromatic imines
using a variety of primary and secondary alkyl halides under
room-temperature conditions (Scheme 1b). The activation of
the alkyl halide is proposed to occur through single-electron
transfer from a cobalt species, generating the corresponding
alkyl radical.
Having identified L1 and L4 as promising preligands, we
examined the effect of the leaving group. The reaction of n-
octyl bromide took place smoothly with both L1 and L4 (en-
tries 8 and 9), while n-octyl iodide underwent substantial de-
hydrohalogenation (as judged by GC analysis), and thus pro-
duced 2a in only low yield (entries 10 and 11). n-Octyl tosyl-
ate participated in the reaction at an elevated temperature of
60 °C to afford 2a in moderate yields (entries 12 and 13).
However, control experiments showed that n-octyl tosylate
and tBuCH2MgBr undergo substantial displacement of the
tosyloxy group with the bromide anion at room temperature in
the absence of the cobalt catalyst and 1, thus suggesting that
this alkylation reaction does not occur directly from n-octyl
tosylate but goes through n-octyl bromide.
Scheme 1. ortho-Alkylation of Arenes with Olefins or Alkyl
Halides
Table 1. Screening of Reaction Conditionsa
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reaction rather sluggish (entry 15).14 The reaction of cyclo-
propylmethyl bromide resulted in a complex mixture (entry
16); we failed to detect either of the possible products arising
from simple alkylation (i.e., cyclopropylmethylation) and ring
opening followed by alkylation (i.e., homoallylation). The
results in entries 5 and 16 will be discussed again later in a
mechanistic context.
CoBr2 (10 mol %)
preligand (10 mol %)
tBuCH2MgBr (2 equiv)
NPMP
H
O
1
2
H+
nC8H17
+
nC8H17
X
THF, rt, 6 h
3
1
(1.2–1.5 equiv)
2a
4
5
6
7
N
N+
N
N+
N
N+
–
Br–
N+
–
–
BF4
BF4
BF4
N
L1
L2
L3
L4
Table 2. Alkylation of 1 with Primary Alkyl Halidesa
8
9
entry
1
X
preligand
yield (%)b
38
CoBr2 (10 mol %)
NPMP
H
L (10 mol %)
tBuCH2MgBr (2 equiv)
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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56
57
58
59
60
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
I
IMes•HCl
IPr•HCl
H+
+
R
R
X
2
13
THF, rt, 4–24 h
1
(1.5 equiv)
R–X
2
3
SIMes•HCl
20
entry
1c
L
yield (product)b
77% (2b)
4
64
L1
L2
L3
L4
L1
L4
L1
L4
L1
L4
nC6H13 Br
L1
5
38
Cl
2
3
L4
L1
73% (2c)
Ph
6
14
Br
82% (2c)
Ph
7
82c
79c
57
66% (2d, R = -(CH2)3CH=CH2)
Br
Br
Br
Br
4
5
L1
L1
6% (2d', R = -(CH2)2CH=CHCH3)d
8
85% (2e, R = -(CH2)4CH=CH2)
12% (2e', R = -(CH2)3CH=CHCH3)d
9
6
7
L1
L1
73% (2f, R = -(CH2)4F)
80% (2g, R = -(CH2)4Cl)
F
10
11
12d
14
Cl
I
6
71% (2h, R = -(CH2)6OTs)
18% (2h', R = -(CH2)6Br)
Br
Cl
8
L1
OTs
OTs
64c
49c
TsO
9
L4
L4
L1
L1
77% (2i, X = F)
61% (2j, X = Cl)
86% (2k)
13d
10
X
a
Reaction was performed on a 0.3 mmol scale. PMP = p-
tBu
Br
Cl
11
12
b
methoxyphenyl. Determined by GC using n-tridecane as an in-
ternal standard. c Isolated yield. d Performed at 60 °C.
Me3Si
65% (2l)
69%
O
N
O
O
13
L4
L1
The present catalytic systems were applicable to ortho-
alkylation of 1 with a variety of primary alkyl chlorides and
bromides (Table 2). The reaction of n-hexyl bromide could be
performed on a 10 mmol scale in 77% yield (entry 1). 5-
Bromo-1-pentene and 6-bromo-1-hexene afforded the ex-
pected alkylation products along with small amounts of minor
isomers arising from terminal-to-internal olefin isomerization
(entries 4 and 5).13 The C–F and C–Cl bonds remained intact
in the reaction of 1-bromo-4-fluorobutane and 1-bromo-4-
chlorobutane, respectively (entries 6 and 7). The chemoselec-
tivity in the latter case was consistent with an intermolecular
competition reaction of n-bromodecane and n-chlorooctane
with 1, which predominantly afforded the n-decylation prod-
uct (eq 1). On the other hand, the reaction of 6-bromohexyl
tosylate was accompanied by a minor product 2h' with a C–Br
bond at the alkyl terminus, which presumably formed through
displacement of the tosyloxy group of the major product 2h by
the bromide anion (entry 8; vide supra). Chemoselective acti-
vation of alkyl chloride was achieved in the presence of an
aryl fluoride or chloride moiety (entries 9 and 10).
(2m, R = -(CH2)3C(=O)CH3)
Br
14e
41% (2n)f
Br
Cl
L4
19% (2o)g
15
16
N
L1/L4
complex mixture
Br
a
Unless otherwise noted, the reaction was performed on a 0.3
b
c
d
mmol scale. Isolated yield. 10 mmol scale. Obtained as a
mixture, and the ratio was determined by H NMR. 2 equiv of
alkyl bromide was used, and an additional equiv of
1
e
1
f
tBuCH2MgBr was added at the reaction time of 2 h. Obtained as
g
a mixture with the alkyl bromide and its β-elimination product.
Obtained as a mixture with p-anisidine.
Gratifyingly, the present reaction was also applicable to a
variety of secondary alkyl chlorides and bromides (Table 3).
Cycloalkyl halides with different ring size (4 to 12) afforded
the corresponding alkylation products in moderate to good
yields (entries 1–7). The reaction also allowed alkylation with
Boc-protected 4-bromopiperidine (entry 8). Linear secondary
alkyl halides were also amenable to the reaction. With the Co–
L1 catalyst, isopropyl chloride, bromide, and sec-butyl bro-
mide afforded the corresponding alkylation products with only
a small degree of secondary-to-primary isomerization (entries
9–11). The use of the Co–L4 catalyst improved the yields by
10–20% but reduced the regioselectivity (i:n = 8:2 to 7:3). The
reaction of 3-bromopentane exclusively afforded the 3-
pentylation product (entry 12). The reaction of exo-2-
norbornane took place smoothly with an exo/endo ratio of
90:10 (entry 13). Trans- and cis-isomers of 1-chloro-4-tert-
nC10H21 Br
O
O
standard
conditions (L1)
H+
(1.5 equiv)
nC10H21
+
nC8H17
+
(1)
1
THF, rt, 4 h
nC8H17 Cl
(1.5 equiv)
64% (GC)
2% (GC)
The steric hindrance of neopentyl bromide and trimethylsi-
lylmethyl chloride did not interfere with the reaction (entries
11 and 12). Acetal protection was necessary for introducing an
alkyl chain with a ketone moiety (entry 13), while secondary
amide was tolerable albeit with a modest reaction efficiency
(entry 14). A pyridyl moiety in the alkyl chloride made the
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O
standard
butylcyclohexane both afforded the product 2v with the same
H+
conditions (L1)
trans/cis ratio of 79:21 (entries 14 and 15).14 tert-Butyl bro-
mide and chloride decomposed under the reaction conditions,
and afforded neither the tert-butylation nor the isobutylation
products.
+
1
2
3
4
nC6H13
nC8H17
1
(2)
(3)
THF, rt, 12 h
(1.5 equiv)
28% (GC)
O
standard
conditions (L1)
H+
5
c-C6H11
+
1
THF, rt, 24 h
Table 3. Alkylation of 1 with Secondary Alkyl Halidesa
6
7
(1.5 equiv)
0%
CoBr2 (10 mol %)
8
9
NPMP
H
L (10 mol %)
tBuCH2MgBr (2 equiv)
O
The absence of cyclopentylmethylated product in the reac-
tion of 6-bromo-1-hexene (Table 2, entry 5) may be interpret-
ed as a consequence of faster recombination of the 5-hexenyl
radical with the cobalt center than its 5-exo-trig cyclization.17
The failure of cyclopropylmethylation (Table 2, entry 16) may
be explained by rapid ring opening of a cyclopropylmethyl
radical (which is much faster than cyclization of the 5-hexenyl
radical),18 while the reason for the further complication of the
reaction (i.e., absence of homoallylation product) is not clear
at present.
R1
R1
H+
+
R2
X
R2
THF, rt, 6–24 h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(1.5 equiv)
2
entry
R–X
L
yield (product)b
1
2
c-C4H7 Cl
L4
L1
51% (2p)
75% (2p)
c-C4H7 Br
c-C5H9 Cl
c-C6H11 Cl
c-C6H11 Br
3c
4
L1
L4
L1
78% (2q)
73% (2r)
90% (2r)
5
The scope of aromatic imines was explored using cycloalkyl
chloride or bromide as the alkylating agent (Table 4). Imines
bearing methoxy, fluoro, chloro, and phenyl substituents at the
para-position afforded the products 3–6 in moderate to good
yields, while a bromo-substituted analogue afforded a com-
plex mixture of products arising from ortho-alkylation and
cross-coupling on the C–Br bond. Alkylation of meta-tolyl, 2-
naphthyl, and 3-fluorenyl imines took place exclusively at the
less hindered position (see products 7–9), with tolerance of the
acidic C9-H site in the latter case. On the other hand, a meth-
ylenedioxy group at the 3,4-position directed the reaction to
take place preferentially at the proximal position, affording the
product 10 and its regioisomer 10' in a ratio of 84:16. Imines
derived from tetralone and propiophenone afforded the prod-
ucts 11 and 12 in good yields. Cyclohexylation of the C2 posi-
tion of thiophene and indole rings was also achieved, albeit in
modest yields (see products 13 and 14).
6
c-C7H13 Cl
c-C12H23 Cl
L4
L1
84% (2s)
65% (2t)
7c,d
8c,d
L1
42% (2u)
BocN
Br
65% (2v, i:n = 99:1)e
68% (2v, i:n = 93:7)e
9
10
i-C3H7 Cl
i-C3H7 Br
L1
L1
56% (2w, i:n = 94:6)e
63% (2x)
11
12
13
Br
Br
L1
L1
82% (2y, exo:endo = 90:10)e
31% (2z, trans:cis = 79:21)f
L1
L4
Cl
14
15
tBu
Cl
(trans:cis = 91:9)
L4
tBu
Cl
30% (2z, trans:cis = 79:21)f
(trans:cis = 4:96)
a
b
Table 4. Products of Cycloalkylation of Different Iminesa
The reaction was performed on a 0.3 mmol scale. Isolated
c
yield. An additional 1 equiv of tBuCH2MgBr was added at the
reaction time of 2 h or 5 h. d 2 equiv of alkyl halide was used. e i:n
refers to the ratio of the secondary and primary alkylation prod-
ucts, which was determined by H NMR. The ratio was deter-
mined by GC.
O
O
O
O
1
f
OMe
F
Cl
Ph
3 (X = Cl, L4)
81% [10 mmol scale]b
4 (X = Br, L1)
5 (X = Br, L1)
6 (X = Cl, L1)
65%c
85%c
53%
With some of the results in Tables 2 and 3, we speculate
that a radical-type mechanism operates in the present reaction
(see Scheme S1 for a possible catalytic cycle). The stereo-
chemical outcomes in Table 3, entries 13–15 suggest that the
reaction involves, as has been proposed for the cobalt-
catalyzed cross-coupling reaction of alkyl halides,15,16 for-
mation of a secondary alkyl radical through single-electron
transfer from a cobalt species followed by recombination of
the cobalt and the radical centers. The resulting alkylcobalt
species may undergo β-hydride elimination/re-insertion prior
to C–C bond formation, which would have caused partial
isomerization of the acyclic secondary alkyl groups to the pri-
mary alkyl groups (Table 3, entries 9–11). While the present
catalytic system caused formation of olefin byproducts via β-
elimination of the alkyl halide (e.g., 1-octene and its isomers
from n-octyl halide), control experiments showed that a termi-
nal olefin is much less reactive than a primary alkyl halide (eq
2), and that a cyclic olefin is entirely unreactive (eq 3). Thus,
olefins would not be involved in the major productive path-
way of the present reaction.
O
O
O
O
O
O
Me
8 (X = Cl, L4)
9 (X = Br, L1)
7 (X = Br, L1)
81%c,d
10 (X = Cl, L4)
56%
78%
45%e
H
O
O
O
O
NMe
S
11 (X = Cl, L4)
12 (X = Br, L1)
13 (X = Br, L1)
14 (X = Br, L1)
80%c,d
81%
24%
45%
a
The product was obtained after acidic hydrolysis of the reac-
tion of PMP imine (0.3 mmol) under the standard conditions for
24 h. The leaving group and the ligand used are indicated for each
b
c
case. The reaction time was 6 h. An additional 1 equiv of
d
tBuCH2MgBr was added at the reaction time of 2, 4, or 5 h.
2
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e
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(15) (a) Ohmiya, H.; Wakabayashi, K.; Yorimitsu, H.; Oshima, K.
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(16) Cahiez, G.; Moyeux, A. Chem. Rev. 2010, 110, 1435.
(17) Even in cross-coupling reactions proposed to involve radical
mechanisms, the fate of this radical probe depends on each case. For
examples, see: (a) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J.
Am. Chem. Soc. 2001, 123, 5374. (b) Nakamura, M.; Matsuo, K.; Ito,
S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686. (c) Bedford, R.
B.; Bruce, D. W.; Frost, R. M.; Hird, M. Chem. Commun. 2005,
4161. (d) Bedford, R. B.; Betham, M.; Bruce, D. W.; Davis, S. A.;
Frost, R. M.; Hird, M. Chem. Commun. 2006, 1398. (e) Yasuda, S.;
Yorimitsu, H.; Oshima, K. Bull. Chem. Soc. Jpn. 2008, 81, 287. (f)
Vechorkin, O.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131,
9756.
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regioisomer 10' in a ratio of 84:16.
Further manipulation of the directing group and the newly
introduced cycloalkyl group allows construction of unique
benzo-fused spirocycles (Scheme 2). Conversion of the acetyl
group of 3 to an ethynyl group was followed by platinum-
catalyzed carbocyclization19 to afford indene 16 in a moderate
yield. In another example, diazo transfer to the acetyl group of
3 and subsequent rhodium-catalyzed intramolecular C–H in-
sertion furnished indenone 18 in 27% overall yield (unopti-
mized).
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Scheme 2. Transformation of ortho-Cycloalkylation Product
to Spirocyclesa
O
O
N2
c, d
a
MeO
MeO
MeO
3
15
17
b
e
O
MeO
MeO
16
18
a
Reaction conditions: a) LDA, ClP(O)(OEt)2, THF, –78 °C to
rt, then LDA, –78 °C to rt, 56%; b) PtCl2, CuBr, toluene, 100 °C,
77%; c) LiHMDS, THF, –78 °C, then CF3CO2CH2CF3, –78 °C to
rt; d) 4-acetamidobenzenesulfonyl azide, H2O, Et3N, MeCN, rt,
75% (two steps); e) Rh2(OAc)4, CH2Cl2, rt, 36%.
In summary, we have developed a cobalt–NHC-catalyzed
ortho-alkylation reaction of aromatic imines with a broad
range of primary and secondary alkyl chlorides and bromides
under mild room-temperature conditions. It may be noted that
the present reaction and the cobalt-catalyzed aryl–alkyl cross-
coupling reaction are markedly different with respect to the
scope of alkyl halides, the latter being applicable to alkyl io-
dides and bromides but not to alkyl chlorides,15,16 while these
reactions appear to share the feature of a single-electron trans-
fer from a cobalt species to alkyl halide. The proposed radical
process will be further investigated from mechanistic and syn-
thetic points of view.
ASSOCIATED CONTENT
Supporting Information. Detailed experimental procedures and
characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
nyoshikai@ntu.edu.sg
ACKNOWLEDGMENT
We thank the National Research Foundation Singapore (NRF-RF-
2009-05), Nanyang Technological University, and JST, CREST
for financial support.
(18) For examples of cross-couplings involving ring opening of
this probe, see ref 17c,d,f and the following: Fürstner, A.; Martin, R.;
Krause, H.; Seidel, G.; Goddard, R.; Lehmann, C. W. J. Am. Chem.
Soc. 2008, 130, 8773.
REFERENCES
(1) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529.
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(19) Yang, S.; Li, Z.; Han, X.; He, C. Angew. Chem., Int. Ed.
2009, 48, 3999.
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O
cat. Co–NHC
tBuCH2MgBr
NPMP
H
Cl
H+
+
MeO
THF, rt, 6 h
MeO
10 mmol
15 mmol
81%
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