Rhodium-catalyzed C-H activation and conjugate addition under mild conditions

Article abstract of DOI:10.1039/c1ob05993a

An efficient rhodium^III-catalyzed C-H activation and subsequent conjugate addition was achieved under mild conditions. The reaction utilized inert arenes to replace stoichiometric organometallic reagents and can tolerate various functional grou

Full text of DOI:10.1039/c1ob05993a

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Rhodium-catalyzed C–H activation and conjugate addition under mild
conditions†
Luo Yang,‡ Camille A. Correia and Chao-Jun Li*
Received 6th May 2011, Accepted 24th June 2011
DOI: 10.1039/c1ob05993a
An efficient rhodiumIII-catalyzed C–H activation and subsequent conjugate addition was achieved
under mild conditions. The reaction utilized inert arenes to replace stoichiometric organometallic
reagents and can tolerate various functional groups as well as air and water.
and zirconium reagents with a,b-unsaturated carbonyl
compounds proceeded under mild conditions with high
regio- and stereoselectivities.1,9 In these reactions, the reactive
organorhodium species are generated by the transmetalation
from the organoboron (and organometallic) reagents.1b,7 Instead
of using organometallic reagents, we envisioned that this active
organorhodium species could also be generated directly from the
inert C–H bonds. While relatively high temperature was required
to realize the ortho group-directed oxidative addition of a low
valent transition metal to the aromatic C–H bonds in the Murai
reaction,4,5 much milder conditions are expected by generation
of organorhodium species through electrophilic substitution of a
high valent rhodium catalyst.8
Introduction
The conjugate addition of organometallic reagents to a,b-
unsaturated carbonyl compounds is one of the most useful
methods for the formation of C–C bonds.1 It generally requires
the pre-generation of organometallic reagents from stoichiometric
aryl halides,2 which lowers the synthetic efficiency and produces
tremendous waste at the same time (Scheme 1, route a). With
the recent great advances in catalytic arene C–H activations,3 the
generation of organometallic reagents in situ from C–H activation
and subsequent conjugate addition with a,b-unsaturated carbonyl
compounds would be an ideal pathway (Scheme 1, route b).
Pioneered by Murai’s research,4 low valent transition metal-
catalyzed hydroarylation of alkenes has been developed into an
efficient strategy for alkylarene synthesis;5 however, relatively high
temperatures (above 120 ◦C) are necessary and only terminal
alkenes can be applied. Recently, Zhao and co-workers reported
the rhodium(I)-catalyzed activation of electron-deficient perfluo-
roarenes and its application to conjugate addition without an ortho
directing group.6 Herein we report an unprecedented rhodium(III)-
catalyzed directed arene C–H activation and subsequent conjugate
addition under very mild reaction conditions.
Results and discussion
With the above analysis in mind, we first examined the reaction
of 2-phenylpyridine (1a) and 2-cyclohexenone (2a) catalyzed
by [CODRhCl]2 and [Cp*RhCl2]2 (Table 1, entry 1) based on
our early work on rhodium-catalyzed conjugate additions with
organometallic compounds in air and water;9 however, the ex-
pected conjugate addition product (3a) was not detected either by
crude 1H NMR or GC-MS analysis. To increase the activity of the
rhodium catalyst, different silver salts were tested as the chloride
abstractor for [Cp*RhCl2]2 (entries 2–4). The yield increased
dramatically to 90% on addition of AgOTf. While AgPF6 was
also effective, AgSbF6 was found to be the best, and the NMR
yield of the conjugate addition product 3a was increased to 94%.
These positive results further prompted us to use the pre-purified
(CH3CN)3Cp*Rh(SbF6)2 (Rh*, Cp* = pentamethylcyclopenta-
dienyl) as the catalyst directly, leading to almost quantitative
formation of product 3a (entry 5). This C–H activation and
conjugate addition can be performed not only in lower polarity
solvent such as CH2Cl2, DCE, toluene and chlorobenzene but
also in much more polar THF and even a protic solvent, tert-
butanol (entries 5–10). It is worth noting that this reaction can
also be performed at room temperature with comparable yields
after a longer reaction time (entry 11). Furthermore, the reaction
was not sensitive to either water or O2, and a similar yield was
Scheme 1 Traditional pathway vs. C–H activation pathway in the
conjugate addition.
Rhodium-catalyzed conjugate addition reactions of
organoboron, zinc, tin, silicon, bismuth, lead, titanium
Department of Chemistry, McGill University, Montreal, QC, Canada H3A
2K6. E-mail: cj.li@mcgill.ca; Fax: +01-514-398-8457; Tel: +01-514-398-
3797
† Electronic supplementary information (ESI) available: Experimental
details and spectral data. See DOI: 10.1039/c1ob05993a
‡ Present address: College of Chemistry, Xiangtan University, Xiangtan,
411105, China.
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Table 1 Optimization of the C–H activation and conjugate additiona
Entry
Rh (mol%)
Additive
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
[Cp*RhCl2]2 (2.5)
[Cp*RhCl2]2 (2.5)
[Cp*RhCl2]2 (2.5)
[Cp*RhCl2]2 (2.5)
(CH3CN)3Cp*Rh(SbF6)2 (5)
(CH3CN)3Cp*Rh(SbF6)2 (5)
(CH3CN)3Cp*Rh(SbF6)2 (5)
(CH3CN)3Cp*Rh(SbF6)2 (5)
(CH3CN)3Cp*Rh(SbF6)2 (5)
(CH3CN)3Cp*Rh(SbF6)2 (5)
(CH3CN)3Cp*Rh(SbF6)2 (5)
(CH3CN)3Cp*Rh(SbF6)2 (5)
[Cp*RuCl2]2 (2.5)
—
AgOTf
AgPF6
AgSbF6
—
—
—
—
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
Toluene
PhCl
THF
0
90
70
94
97
96
66
83
89c
63
93d
92e
0
9
—
—
—
10
11
12
13
14
15
16
tBuOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
H2O (20 mL)
AgSbF6
—
—
—
Pd(TFA)2 (5.0)
Cu(OTf)2 (5.0)
In(OTf)3 (5.0)
0
0
0
a Conditions: 1a (0.1 mmol), 2a (0.2 mmol), [Rh], additives (10 mol%), CH2Cl2 (0.5 mL), reacted for 48 h at 40 ◦C under argon, unless otherwise noted.
b
1H NMR yields. c Reacted for 24 h. d Reacted at r.t. for 10 days. e Reacted for 72 h under air.
obtained when the reaction was performed in the presence of water
and under air atmosphere (entry 12). Under similar conditions,
[Cp*RuCl2]2/AgSbF6, Pd(TFA)2, Cu(OTf)2 and In(OTf)3 were all
found to be ineffective catalysts, which differentiated this C–H
activation and conjugate addition from the normal Lewis acid-
promoted Friedel–Crafts reaction. The Rh* catalyst played a
unique role in the activation of both the inert C–H bonds and
2-cyclohexenone (2a).
Under the optimized conditions, the substrate scope of this
novel C–H activation and conjugate addition was explored. As
shown by the results in Table 2, all the 2-phenylpyridine analogs
tested (1a–1i) reacted with 2-cyclohexenone (2a) smoothly to
produce the corresponding conjugate addition product efficiently,
regardless of the electronic nature of the substituents. The
influence of substituents at different positions of the phenyl
ring was also examined. The ortho-methyl substrate 1c reacted
with 2-cyclohexenone in high yield. 2-b-Naphthylpyridine 1f was
also applicable to this reaction and only the less hindered C–H
bond was activated to give the corresponding conjugate addition
product. Substituted by an electron withdrawing acetyl group,
the substrate 1i was also reactive, which further differentiates this
reaction from the classical Friedel–Crafts reaction. However, the
C–H activation and conjugate addition process cannot stop at
the mono-alkylation step and almost a quantitative yield of the
corresponding di-alkylation product 3i was obtained.
corresponding conjugate addition products 3m–3o were obtained
in medium to high yields when reacted at a slightly higher
temperature.
Then, we explored the substrate scope of the Michael acceptor
in this C–H activation and conjugate addition process (Table 4).
Besides 2-cyclohexenone (2a), the reaction of 2-phenylpyridine
with 2-cyclopentenone (2b) and trans-4-hexen-3-one (2c) pro-
ceeded smoothly to afford 3p and 3q, respectively, in good yields.
a,b-Unsaturated aldehydes such as trans-2-pentenal (2d) and
cinnaldehyde derivatives (2e–2h) were found to be good substrates
in this reaction. When the cinnaldehyde was substituted by an
electron withdrawing nitro or ethoxyl carbonyl group (2g–h), a
higher yield was obtained due to their stronger electrophilicity.
A tentative mechanism to rationalize this novel rhodium-
catalyzed C–H activation and subsequent conjugate addition
is illustrated in Scheme 2. First, the coordination of rhodium
catalyst (Rh*) to 2-phenylpyridine and subsequent electrophilic
substitution8 generates the arylrhodium complex 5, releasing
one equivalent of proton at the same time. Then, the carbon–
carbon double bond of 2-cyclohexenone (2a) coordinates to the
arylrhodium complex 5 to produce arylrhodium complex 6, which
is followed by the 1,4-conjugate addition of the arylrhodium
species to the activated double bond to yield the rhodium-oxa-p-
allyl species 7.1b,7 Protonolysis of 7 releases the conjugate addition
product and regenerates the rhodium catalyst (Rh*).
Next, the use of various nitrogen-containing heterocyclic sub-
stituents as directing groups was investigated (Table 3). Pyridinyl
groups with a methyl substituent at C-3 (1j, 1k) or C-4 (1l) showed
good reactivity. It is worth noting that the 2-phenylpyridine analog
1k bearing a free hydroxyl group reacted with 2-cyclohexenone
to afford 3k in 88% yield. Besides the pyridinyl group, other
nitrogen-containing heterocyclic substituents such as quinolinyl,
pyrimidinyl and pyrazolyl can also act as the directing group; the
Conclusions
In summary, we have developed an efficient rhodium-catalyzed
C–H activation and subsequent conjugate addition under mild
conditions. Unlike the previous rhodium catalyzed conjugate
addition, the current process does not require pre-generation of a
stoichiometric quantity of organometallic reagents. The reaction
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Table 2 The reaction of 2-phenylpyridine analogs with 2-cyclohexenonea
Table 3 Pyridine analogs as the directing groups in the C–H activation
and conjugate additiona
a Conditions: 1j–o (0.2 mmol), 2a (0.4 mmol), (CH3CN)3Cp*Rh(SbF6)2
(Rh*, 5 mol%, 0.01 mmol), CH2Cl2 (1.0 mL), reacted at 40 ◦C under
argon, unless otherwise noted. The yield of isolated product is reported.
b Reacted at 50 ◦C.
a Conditions: 1a–i (0.2 mmol), 2a (0.4 mmol), (CH3CN)3Cp*Rh(SbF6)2
(Rh*, 5 mol%, 0.01 mmol), CH2Cl2 (1.0 mL), reacted at 40 ◦C under
argon, unless otherwise noted. The yield of isolated product is reported.
can tolerate a wide range of functional groups such as ketones,
esters, halide, nitro, and unprotected hydroxyl groups as well as
air and water. The scope, mechanism, application and asymmetric
introduction of this novel reaction are under investigation.
Experimental section
General experimental procedure
A
general experimental procedure is described as fol-
lowing: an oven-dried reaction vessel was charged with
(CH3CN)3Cp*Rh(SbF6)2 (Rh*, 8.4 mg, 5 mol%, 0.01 mmol),
CH2Cl2 (1 mL, dried by CaH2), 2-phenylpyridine (1a, 31 mg, 0.2
mmol) and 2-cyclohexenone (2a, 0.4 mmol, 38.4 mg, 40.2 mL)
under argon. The vessel was sealed and heated at 40 ◦C (oil bath
temperature) for 48 h. The resulting mixture was cooled to room
temperature, filtered through a short silica gel pad, transferred to
silica gel column directly and eluted with hexanes and ethyl acetate
(2 : 1) to give products 3a (47.6 mg, 95% yield) as a light yellow
solid.
Scheme 2 Tentative mechanism for the C–H activation and subsequent
conjugate addition.
7.26–7.36 (m, 4H), 3.27–3.33 (m, 1H), 2.53 (d, J = 8.5 Hz, 2H),
2.30–2.39 (m, 2H), 2.04–2.09 (m, 2H), 1.79–1.87 (m, 1H), 1.53–
1.62 (m, 1H); 13C NMR (125 MHz, CDCl3, TMS) d 211.4, 159.8,
149.2, 142.4, 140.0, 136.8, 130.4, 129.0, 126.6, 126.3, 124.4, 122.2,
49.1, 41.4, 40.3, 33.0, 25.7. HRMS (ESI) m/z: [M + H]+ calc’d for
C17H18ON, 252.1383; found: 252.1376.
3a. 1H NMR (500 MHz, CDCl3, TMS) d 8.67 (ddd, J = 1.0,
2.0, 5.0 Hz, 1H), 7.76 (td, J = 2.0, 8.0 Hz, 1H), 7.40–7.44 (m, 2H),
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Table 4 The substrate scope of the Michael acceptor in the C–H
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The Royal Society of Chemistry 2011
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