Cobalt-catalyzed arylation of aldimines via directed C-H bond functionalization: Addition of 2-arylpyridines and self-coupling of aromatic aldimines

Article abstract of DOI:10.1039/c2cc31114c

A cobalt-N-heterocyclic carbene catalyst, in combination with an appropriate Grignard reagent, promotes a chelation-assisted aromatic C-H functionalization reaction via addition to an aromatic aldimine. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc31114c

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COMMUNICATION
Cobalt-catalyzed arylation of aldimines via directed C–H bond
functionalization: addition of 2-arylpyridines and self-coupling of
aromatic aldiminesw
Ke Gao and Naohiko Yoshikai*
Received 15th February 2012, Accepted 9th March 2012
DOI: 10.1039/c2cc31114c
A cobalt–N-heterocyclic carbene catalyst, in combination with
an appropriate Grignard reagent, promotes a chelation-assisted
aromatic C–H functionalization reaction via addition to an
aromatic aldimine.
Transition metal-catalyzed aromatic C–H bond functionalization
Scheme 1 Addition of 2-phenylpyridine 1a to benzaldimine 2a.
with olefins and alkynes has provided a number of straightforward
and regioselective methods for introduction of alkyl and alkenyl
groups onto aromatic compounds.1 On the other hand, a relatively
Our initial study was focused on the reaction of 2-phenyl-
pyridine 1a with N-phenyl benzaldimine 2a (Scheme 1). After
limited number of C–H functionalization reactions via addition to
extensive screening of the reaction conditions (see ESIw for
details), we found that 1a and 2a (1.2 equiv.) reacted in the
presence of CoBr2 (10 mol%), IPrÁHCl (10 mol%), and
tBuCH2MgBr (1.8 equiv.) at 60 1C to afford, after aqueous
workup, diarylmethylamine 3a in 84% yield. The use of
sterically less demanding NHC precursors resulted in lower yields,
while none of the other types of ligands, such as phosphines and
phenanthroline derivatives, promoted the reaction. The amount of
the Grignard reagent could be reduced to 1.6 equiv. with only a
slight decrease in the product yield, while further decrease caused a
significant drop. The choice of the Grignard reagent was critical,
as the use of alkyl Grignard reagents such as MeMgCl, nBuMgBr,
iPrMgBr, and Me3SiCH2MgCl resulted in much lower yields.
Note that addition of tBuCH2MgBr to the aldimine was not
observed. Unlike the rhodium(III)-catalyzed reactions reported
recently by the groups of Bergman–Ellman and Shi,6a,b aldimines
bearing Boc and Ts groups did not participate in the reaction.
Table 1 summarizes the scope of 2-arylpyridines and aldimines.
A series of 2-arylpyridines participated in the reaction with
benzaldimine bearing an N-p-methoxyphenyl group to afford
adducts 3b–3j in moderate to good yields. With a 3-methyl
substituent on the benzene ring, C–H functionalization took
place exclusively at the less hindered position (3f). A methoxy
group at the 2-position of the benzene ring did not cause
apparent inhibition of the reaction (3g). The 3-position of
thiophene could be functionalized in a moderate yield (3h).
The substrate with a 4-methyl group on the pyridine ring
afforded adduct 3i in excellent yield, while the presence of a
3-methyl group slowed the reaction (3j). A pyrazolyl group
also served as a directing group, affording adduct 3k in 61%
yield. Electron-rich aldimines smoothly participated in the
reaction, affording adducts 3l and 3m in good yields, while the
reaction of an electron-poor aldimine was rather sluggish (3n).
polar C–O and C–N multiple bonds have been known to date,
regardless of their potential as alternative methods to nucleophilic
addition of preformed organometallic reagents.2 Thus far, such
reactions have been sporadically achieved for aldehydes,3 ketones,4
carbon dioxide,5 imines,6 isocyanates,7 and nitriles8 by the
ad hoc use of manganese, rhenium, rhodium, iridium, or
palladium catalysts.
In pursuit of the development of C–H functionalization
with first-row transition metal catalysts,9 we have recently
demonstrated that low-valent cobalt species generated under
reductive conditions serve as effective catalysts for aromatic
and heteroaromatic C–H functionalization with alkynes and
alkenes.10,11 On our way to expand the scope of the cobalt
catalysis, we became interested in possible exploitation of a
putative arylcobalt species generated via directed aromatic
C–H activation as a nucleophilic aryl donor to a polar
unsaturated substrate. We report here that a cobalt–N-heterocyclic
carbene (NHC) catalyst, in combination with a Grignard
reagent, promotes ortho-functionalization of a 2-arylpyridine
derivative with an aromatic aldimine to afford a diarylmethyl-
amine product.6a,b Furthermore, the same catalytic system
allows self-coupling of an aromatic aldimine to afford an
isoindole derivative,12 which is unstable toward oxidation
but can be efficiently intercepted by an aldehyde to afford an
indenone product in a regiocontrolled manner.
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore. E-mail: nyoshikai@ntu.edu.sg;
Fax: +65-6791-1961; Tel: +65-6592-7768
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for new compounds. See DOI:
10.1039/c2cc31114c
c
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Chem. Commun., 2012, 48, 4305–4307 4305

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Table
1
Addition of 2-arylpyridine derivatives to aromatic
Table 2 Indenone synthesis via self-coupling of aryl aldimine followed
by condensation with aldehydea
aldiminesa
a
Reaction conditions: 2-arylpyridine (0.3 mmol), aldimine (1.2 equiv.),
CoCl2 (10 mol%), IPrÁHCl (10 mol%), tBuCH2MgBr (1.8 equiv.),
THF, 60 1C, 14–48 h. PMP = p-methoxyphenyl.
Substituents at the 2- and 3-positions of the aldimine could be
tolerated (3o–3r).
When the cobalt-catalyzed reaction of aldimine 2c was
performed in the absence of 2-phenylpyridine 1a, a self-coupling
reaction of 2c took place (Scheme 2). Thus, the reaction of
2c afforded, after quenching and acidic workup under air,
isoindolinones 5 and 6 in 16% and 49% yields, respectively.
Although we observed formation of isoindole 4 as an inter-
mediate for 5 and 6 by GC–MS analysis, its low stability
toward oxidation precluded isolation.13 The self-coupling
reaction took place even at room temperature, and when the
crude reaction mixture was treated with p-anisaldehyde under
acidic conditions, indenone 7a was obtained in 71% yield. The
formation of the indenone may be explained by a mechanism
a
The reactions were performed on 0.6–1.2 mmol scale. See ESI for
b
detailed reaction conditions. Regioselectivity was 2.7 : 1.
similar to that proposed for the reaction of isobenzofuran
and benzaldehyde, which also affords an indenone derivative
(see ESIw).14
The one-pot condensation of two aldimine molecules and an
aldehyde allows regiocontrolled synthesis of 2,3-diaryl indenones,
which is complementary to other transition metal-catalyzed
reactions for indenone synthesis (Table 2).15 A variety of
aromatic and heteroaromatic aldehydes participated in the
condensation reaction to afford indenones 7b–7p in moderate
to good yields with tolerance of functional groups such as
iodo, hydroxy, cyano, and ester groups and heterocycles such
as pyridine and furan. The reaction of ethyl glyoxylate also
afforded indenone 7i in 41% yield. Note that the 3-methyl-
benzaldehyde imine exhibited a modest level of regioselectivity
(2.7 : 1), where C–H bond cleavage at the less hindered site was
preferred (7l). Twofold condensation using isophthalaldehyde
was achieved to afford the bis-indenone product 7p in 69%
yield. A condensation reaction using pivalaldehyde resulted in
the formation of diketone 7q rather than an indenone, which
would support our mechanistic proposal (see ESIw). An attempted
condensation with a primary alkyl aldehyde afforded a mixture of
intractable products.
Considering that the present reactions require the use of a
stoichiometric amount of the Grignard reagent, their mechanisms
Scheme 2 Self-coupling of aryl aldimine.
c
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Scheme 3 Possible catalytic cycle.
are likely to be different from that of the cobalt-catalyzed C–H
functionalization with olefins and alkynes,11 as well as of
the rhodium(III)-catalyzed reaction of 2-arylpyridines with
aldimines.6a,b We tentatively suggest a mechanism analogous
to that proposed for rhodium(I)-catalyzed ortho-carboxylation of
2-arylpyridine with carbon dioxide by Iwasawa et al. (Scheme 3).5
First, a neopentylcobalt species A would be generated from the
cobalt precatalyst and tBuCH2MgBr. Species A would then
react with the aromatic substrate to produce a cyclometalated
species C via chelation-assisted C–H oxidative addition
followed by reductive elimination of neopentane.16 Nucleophilic
attack of species C on the aldimine and subsequent transmetala-
tion of the resulting cobalt amide D and the Grignard reagent
would afford a magnesium amide E and regenerate species A.
When the directing group is an imino group, intramolecular
addition of magnesium amide to the CQN bond takes place to
give an aminal F, which undergoes deamination upon aqueous
workup to afford an isoindole.
11 (a) K. Gao, P.-S. Lee, T. Fujita and N. Yoshikai, J. Am. Chem.
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2011, 133, 17283.
In summary, we have demonstrated that a polar CQN bond
can serve as a reaction partner for cobalt-catalyzed C–H bond
functionalization. Thus, ortho-functionalization of 2-arylpyridines
with aldimines and self-coupling of aromatic aldimines
have been achieved using a cobalt–NHC catalyst. The latter
reaction, in combination with subsequent condensation with
aldehydes, offers a unique method for the regiocontrolled
synthesis of 2,3-diarylindenone derivatives. Further effort will
be focused on elucidation of the reaction mechanism and
expansion of the scope of reaction partners for the cobalt-
catalyzed C–H bond functionalization.
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This work was supported by Singapore National Research
Foundation (NRF-RF-2009-05), Nanyang Technological
University, and JST, CREST.
Notes and references
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c
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Chem. Commun., 2012, 48, 4305–4307 4307