Cobalt-catalyzed ortho -arylation of aromatic imines with aryl chlorides

Article abstract of DOI:10.1021/ol301934y

An ortho-arylation reaction of aromatic imines with aryl chlorides has been achieved using a cobalt-N-heterocyclic carbene catalyst in combination with a neopentyl Grignard reagent. The reaction takes place at room temperature to afford biaryl products in moderate to good yields.

Full text of DOI:10.1021/ol301934y

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4234–4237
Cobalt-Catalyzed Ortho-Arylation of
Aromatic Imines with Aryl Chlorides
Ke Gao, Pin-Sheng Lee, Chong Long, and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
nyoshikai@ntu.edu.sg
Received July 12, 2012
ABSTRACT
An ortho-arylation reaction of aromatic imines with aryl chlorides has been achieved using a cobaltÀN-heterocyclic carbene catalyst in
combination with a neopentyl Grignard reagent. The reaction takes place at room temperature to afford biaryl products in moderate to good yields.
Biaryls are key structural units in numerous functional
molecules relevant to medicinal chemistry and materials
science. While their syntheses have heavily relied on transi-
tion-metal-catalyzed cross-coupling between halogenated
arenes and metalated arenes,1 the past decade has wit-
nessed significant advances in a more straightfoward and
atom-economical alternative, that is, direct arylation via
aromatic CÀH bond activation.2 Among several types of
CÀH arylation reactions, arylation of arenes bearing
ortho-directing groups features high efficiency and perfect
regiocontrol of the CÀH bond activation. While the
majority of catalysts for ortho-arylation reactions are
based on palladium, rhodium, and ruthenium,2,3 recent
studies have demonstrated promising catalytic activities of
inexpensive first-row transition metals.4 Nakamura and
co-workers developed iron-catalyzed oxidative arylation
of 2-arylpyridines and aryl imines using arylzinc or aryl
Grignard reagents in combination with a dichloroalkane
oxidant, which takes placeat a temperature aslow as0 °C.5
Wang, Shi, and co-workers reported that cobalt also
catalyzes a similar reaction of 2-arylpyridines with aryl
Grignard reagents at room temperature (Scheme 1a).6
Despite the inexpensive catalysts and the mild reaction
conditions, the requirement of a large amount (typically
3À4 equiv) of a preformed arylmetal reagent constitutes
a major drawback in these arylation reactions.7,8 Here,
we report that cobalt-catalyzed ortho-arylation of aryl
imines can be achieved using an aryl chloride as a readily
(5) (a) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E.
J. Am. Chem. Soc. 2008, 130, 5858. (b) Yoshikai, N.; Matsumoto, A.;
Norinder, J.; Nakamura, E. Angew. Chem., Int. Ed. 2009, 48, 2925.
(c) Yoshikai, N.; Matsumoto, A.; Norinder, J.; Nakamura, E. Synlett 2010,
313. (d) Ilies, L.; Asako, S.; Nakamura, E. J. Am. Chem. Soc. 2011, 133,
7672. (e) Yoshikai, N.; Asako, S.; Yamakawa, T.; Ilies, L.; Nakamura, E.
Chem.;Asian J. 2011, 6, 3059. (f) Ilies, L.; Kobayashi, M.; Matsumoto, A.;
Yoshikai, N.; Nakamura, E. Adv. Synth. Catal. 2012, 354, 593.
(6) Li, B.; Wu, Z.-H.; Gu, Y.-F.; Sun, C.-L.; Wang, B.-Q.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2011, 50, 1109.
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004. (b) Modern Arylation
Methods; Ackermann, L., Ed.; Wiley-VCH: Weinheim, 2009.
(2) For selected reviews, see: (a) Yeung, C. S.; Dong, V. M. Chem.
Rev. 2011, 111, 1215. (b) Daugulis, O. Top. Curr. Chem. 2010, 292, 57.
(c) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211.
(d) Bouffard, J.; Itami, K. Top. Curr. Chem. 2010, 292, 231. (e) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (f) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624.
(g) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed.
2009, 48, 9792.
(3) For latest examples of ortho-arylation reactions with second-row
transition metal catalysts, see: (a) Wencel-Delord, J.; Nimphius, C.;
Patureau, F. W.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 2247.
(b) Kalyani, D.; McMurtey, K. B.; Neufeldt, S. R.; Sanford, M. S. J. Am.
Chem. Soc. 2011, 133, 18566. (c) Wang, X.; Leow, D.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 13864.
(7) These reactions intrinsically require 2 equiv of the arylmetal
reagent because 1 equiv of the reagent is used for the removal of the
ortho-hydrogen atom and another 1 equiv for the arylation.
(8) Nakamura et al. demonstrated, for their iron-catalyzed reaction,
that preparation of an aryl Grignard reagent can be bypassed by the
direct use of an aryl bromide and metallic magnesium (see ref 5f).
(9) For direct arylation of aryl imines with aryl electrophiles, see:
(a) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y. Org. Lett. 2002, 4, 1783.
(b) Ackermann, L. Org. Lett. 2005, 7, 3123. (c) Ackermann, L.; Althammer,
A.; Born, R. Tetrahedron 2008, 64, 6115. (d) Kim, M.; Kwak, J.; Chang, S.
Angew. Chem., Int. Ed. 2009, 48, 8935.
(4) (a) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
(b) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010, 75, 6061.
(c) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087.
r
10.1021/ol301934y
Published on Web 08/08/2012
2012 American Chemical Society

available arylating agent under mild room-temperature
conditions.9À13
assumption, we envisioned that interception of a cobalta-
cycle species such as II with an aryl electrophile would
result in an ortho-arylation product (catalytic cycle B).18
With this hypothesis, we commenced our study with the
reaction of acetophenone imine 1a with 4-chloroanisole 2a
(Table 1). The CoÀIPrÀtBuCH2MgBr system we used for
the reaction of a 2-arylpyridine with an aldimine
(Scheme 1b)16 promoted the desired reaction to a small
extent at room temperature (25 °C), affording the biaryl
product 3aa in 3% yield (entry 1). Use of IMes•HCl
instead of IPr•HCl significantly enhanced the reaction
efficiency to afford 3aa in 65% yield (entry 2), which was
accompanied by a byproduct arising from cross-coupling
of 2a and tBuCH2MgBr (17% yield). No diarylation
product was observed. According to the hypothetical
catalytic cycle (Scheme 1c), we surmise that the cross-
coupling byproduct has formed via direct reaction of the
alkylcobaltspecies I and 2a. In line with this conjecture, the
use of 4-bromoanisole in place of 2a produced the cross-
coupling product as the major product, with only a trace
amount of 3aa.
Scheme 1
The neopentyl Grignard reagent was noted to play a
critical role, because other Grignard reagents such as
Me3SiCH2MgCl, EtMgBr, iPrMgBr, and PhMgBr poorly
promoted the reaction (entries 3À6). Further efforts to
improve the CoÀIMesÀtBuCH2MgBr system by modifi-
cation of various reaction parameters (e.g., stoichiometry,
temperature) were not fruitful. For example, the reaction
at an elevated temperature (80 °C) resulted in a lower yield
of 3aa (entry 7) and an increase of the undesirable coupling
product between 2a and tBuCH2MgBr (37%). While other
ligands including mono- and bidentate phosphines and
As a part of our continuing studies on cobalt-catalyzed
ortho CÀH bond functionalization,14,15 we recently re-
portedon a coupling reaction of a 2-arylpyridine derivative
with an aldimine promoted by a cobaltÀN-heterocyclic
carbene catalyst and tBuCH2MgBr (Scheme 1b).16
A
putative mechanism for this reaction involves cyclometa-
lation of 2-arylpyridine withan alkylcobalt species I togive
a cobaltacycle species II (Scheme 1c).17 The intermediate II
would then undergo nucleophilic attack on the aldimine,
which is followed by transmetalation with the Grignard
reagent to afford the addition product and regenerate the
species I (catalytic cycle A). Based on this mechanistic
Table 1. Screening of Reaction Conditionsa
(10) For direct arylation of aryl imines with aryl nucleophiles, see ref
5 and the following: Tredwell, M. J.; Gulias, M.; Bremeyer, N. G.;
Johansson, C. C. C.; Collins, B. S. L.; Gaunt, M. J. Angew. Chem., Int.
Ed. 2011, 50, 1076.
ligand
temp
yield
(%)b
entry
(mol %)
RMgX
(°C)
(11) For cobalt-catalyzed nondirected CÀH arylation reactions with
aryl halides, see: (a) Liu, W.; Cao, H.; Xin, J.; Jin, L.; Lei, A. Chem.;
Eur. J. 2011, 17, 3588. (b) Li, H.; Sun, C.-L.; Yu, M.; Yu, D.-G.; Li, B.-J.;
Shi, Z.-J. Chem.;Eur. J. 2011, 17, 3593.
1
IPr•HCl (10)
IMes•HCl (10)
IMes•HCl (10)
IMes•HCl (10)
IMes•HCl (10)
IMes•HCl (10)
IMes•HCl (10)
PEt3 (30)
tBuCH2MgBr
tBuCH2MgBr
Me3SiCH2MgCl
EtMgBr
25
25
25
25
25
25
80
80
80
80
80
3
2
65c
0
3
(12) For a review on mild metal-catalyzed CÀH bond functionaliza-
4
0
€
tion, see: Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc.
5
iPrMgBr
1
Rev. 2011, 40, 4740.
6
PhMgBr
6
(13) During submission of this manuscript, a similar cobalt-catalyzed
ortho-arylation reaction of 2-arylpyridines and N-pyridylindoles with
aryl sulfamates and carbamates was reported: Song, W.; Ackermann, L.
Angew. Chem., Int. Ed. 2012, 51, 8251.
7
tBuCH2MgBr
tBuCH2MgBr
tBuCH2MgBr
tBuCH2MgBr
tBuCH2MgBr
41
63c
35
<1
17
8d
9d
10d
11d
PMe3 (30)
(14) Yoshikai, N. Synlett 2011, 1047.
PPh3 (30)
(15) (a) Gao, K.; Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem.
Soc. 2010, 132, 12249. (b) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2011,
133, 400. (c) Gao, K.; Yoshikai, N. Angew. Chem., Int. Ed. 2011, 50,
6888. (d) Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2011, 133,
17283. (e) Ding, Z.; Yoshikai, N. Angew. Chem., Int. Ed. 2012, 51, 4698.
(16) Gao, K.; Yoshikai, N. Chem. Commun. 2012, 48, 4305.
PCy3 (30)
a Unless otherwise noted, the reaction was performed using 0.3 mmol
of 1a and 0.6 mmol of 2a. PMP = p-An = 4-MeOC6H4. b Determined
by GC using n-tridecane as an internal standard. c Isolated yield. d 0.36
mmol of 2a was used.
€
(17) Klein, H.-F.; Camadanli, S.; Beck, R.; Leukel, D.; Florke, U.
Angew. Chem., Int. Ed. 2005, 44, 975.
Org. Lett., Vol. 14, No. 16, 2012
4235

phenanthroline derivatives were poorly effective at 25 °C,
use of PEt3 (30 mol %) provided a comparable reaction
efficiency at 80 °C, affording 3aa in 63% yield (entry 8).
Other monodentate phosphines such as PMe3, PPh3, and
PCy3 were much less effective (entries 9À11). Note that, in
contrast to the CoÀIMes system, the CoÀPEt3 system did
not produce the cross-coupling byproduct.
Scheme 2. Scope of Aryl Iminesa
With the CoÀIMes and its alternative (i.e., CoÀPEt3)
systems in hand, we first explored the scope of aromatic
imines using 2a as the arylating agent (Scheme 2). Imines
bearing para-methoxy, phenyl, and fluoro groups
smoothly participated in the reaction to afford the pro-
ducts 3baÀ3da in good yields. Incontrast, an imine derived
from para-trifluoromethyl acetophenone failed to react
under the CoÀIMes system, while the CoÀPEt3 system
afforded the arylation product 3ea in 20% yield. With a
meta-methyl substituent, the less hindered position was
selectively arylated (see 3fa), while poor regioselectivity
was observed for an imine derived from 2-acetonaphthone
(see 3ga). On the other hand, methylenedioxy and fluoro
groupsdirectedthereaction totake placeintheir proximity
(see 3ha and 3ia), presumably because of their ability to
direct the CÀH metalation process by coordination or to
stabilize the resulting carbonÀmetal bond.15d,19À21 An
imine derived from 3,5-difluoroacetophenone produced a
substantial amount of the diarylation product 4ja. In addi-
tion to the acetophenone derivatives, imines derived from
propiophenone, tetralone, and indole-3-carbaldehyde were
also arylated in moderate to good yields (3kaÀ3ma).22
We next explored the reaction of the imine 1a or 1b with
a variety of aryl chlorides (Table 2). The CoÀIMes system
tolerated aryl chlorides bearing electronically different
para-substituents including dimethylamino, siloxy, and
fluoro groups (entries 1À6) but did not promote the
reaction of p-chlorobenzotrifluoride at all.23 The reaction
of this highly electron-poor substrate was achieved with
the CoÀPEt3 system in a moderate yield of 47% (entry 7).
Under either catalytic systems, p-chlorothioanisole and
p-chlorostyrene reacted rather sluggishly (entries 8 and 9),
presumably because the desired reaction was inhibited by
a The reaction was performed on a 0.3 mmol scale. b The reaction was
performed under the CoÀPEt3 system (Table 1, entry 7). c The product
ratio was determined by 1H NMR. d The product was isolated without
acidic hydrolysis.
coordination of the thioether and vinyl moieties, respec-
tively, to the catalyst. The reaction also tolerated meta-
substituted (entries 10À12) and ortho-substituted aryl
chlorides (entries 13À15), among which m-chlorobenzo-
trifluoride and 1-chloronaphthalene required the use of the
CoÀPEt3 system (entries 12 and 15).
Notably, the present cobalt catalysis allowed a twofold
CÀH/CÀCl coupling reaction. Thus, the reaction of 1a
(2.2 equiv) with p-dichlorobenzene under the CoÀPEt3
system afforded the terphenyl derivative 3aq in a modest
yield of 49% (Scheme 3).
(18) For cobalt-catalyzed ortho CÀH functionalization with alkyl
chlorides, see: Chen, Q.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2011,
133, 428.
(19) (a) Ackermann, L.; Diers, E.; Manvar, A. Org. Lett. 2012, 14,
1154. (b) Ackermann, L.; Vicente, R.; Potukuchi, H. K.; Pirovano, V.
Org. Lett. 2010, 12, 5032. (c) Campeau, L. C.; Parisien, M.; Jean, A.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (d) Sonoda, M.; Kakiuchi,
F.; Chatani, N.; Murai, S. Bull. Chem. Soc. Jpn. 1997, 70, 3117.
(20) (a) Clot, E.; Megret, C.; Eisenstein, O.; Perutz, R. N. J. Am.
Chem. Soc. 2009, 131, 7817. (b) Clot, E.; Eisenstein, O.; Jasim, N.;
Macgregor, S. A.; Mcgrady, J. E.; Perutz, R. N. Acc. Chem. Res. 2011,
44, 333.
(21) Deuterium-labeling experiments suggested the reversible nature
of the cyclometalation process, while its detailed mechanism remains
unclear (see the Supporting Information).
(22) Acetophenone failed to participate in the arylation reaction but
underwent aldol reaction, while a small amount (3% by GC) of an
arylation product was observed with N-methylbenzamide. For cobalt-
catalyzed ortho CÀH functionalization of benzamides, see ref 18 and the
following: (a) Ilies, L.; Chen, Q.; Zeng, X.; Nakamura, E. J. Am. Chem.
Soc. 2011, 133, 5221. (b) Chen, Q.; Ilies, L.; Yoshikai, N.; Nakamura, E.
Org. Lett. 2011, 13, 3232.
The present ortho-arylation reaction represents a rare
example of biaryl coupling reactions involving cobalt-
mediated activation of unactivated aryl chlorides.11a,24,25
To gain preliminary insight into the nature of the CÀCl
bond activation step, we performed competition experiments
using electronically different aryl chlorides (Scheme 4).
The competition of chlorobenzene and an aryl chloride
bearing a dimethylamino, methoxy, or fluoro group under
CoÀIMes catalysis resulted in the preferential reaction of the
(24) Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.; Nakamura, M.
J. Am. Chem. Soc. 2009, 131, 11949.
(25) For reviews on cobalt-catalyzed cross-coupling reactions, see:
(a) Cahiez, G.; Moyeux, A. Chem. Rev. 2010, 110, 1435. (b) Hess, W.;
Treutwein, J.; Hilt, G. Synthesis 2008, 3537. (c) Gosmini, C.; Begouin,
J. M.; Moncomble, A. Chem. Commun. 2008, 3221.
(23) The reason why the CoÀIMes system was not effective remains
unclear. The aryl chloride did not undergo any side reactions (e.g., cross-
coupling with tBuCH2MgBr) but was recovered almost completely.
4236
Org. Lett., Vol. 14, No. 16, 2012

Table 2. Scope of Aryl Chloridesa
Scheme 4. Competition Experiments
under the CoÀPEt3 system preferentially produced the
arylation product of the latter (Scheme 4b). These results
suggest higher reactivity of electron-poor aryl chlo-
rides toward the putative cobaltacycle intermediate II
(Scheme 1c). Note, however, that the aryl electrophile
should not be too reactive as an aryl bromide, because
the cross-coupling with tBuCH2MgBr overrides the desired
direct arylation (vide supra).
In summary, we have developed CoÀIMes and CoÀPEt3
catalytic systems for the ortho-arylation of aromatic
imines with aryl chlorides. The former system allows
arylation to take place at room temperature, while the
latter complements some limitations of the former.
Further efforts will be focused on the development of
more robust and broadly applicable catalytic systems
and the mechanistic investigation.
a The reaction was performed on a 0.3 mmol scale. b Isolated yield.
c The siloxy group was converted to a hydroxy group by the hydrolysis.
d The acetal moiety was converted to a formyl group by the hydrolysis.
e The reaction was performed under the CoÀPEt3 system (Table 1, entry 7).
f GC yield.
Acknowledgment. We thank Singapore National Re-
search Foundation (NRF-RF2009-05 to N.Y.), Nanyang
Technological University, and JST, CREST for generous
financial support.
Scheme 3. Twofold Coupling Reaction
Supporting Information Available. Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
electron-poorer aryl chloride (Scheme 4a). Likewise, the
competition of p-chloroanisole and p-chlorobenzotrifluoride
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
4237