Bronsted acid enhanced rhodium-catalyzed conjugate addition of aryl C-H bonds to α,β-unsaturated ketones under mild conditions

Article abstract of DOI:10.1002/chem.201201348

Acid test: With a Bronsted acid as the solvent, the rhodium-catalyzed direct addition of aryl C-H bonds to α,β- unsaturated ketones was realized under mild reaction conditions (see scheme). The acid may assist by interceding in the conflict of the two proton-transfer events and averting the substrate inhibition involved in this type of C-H addition reaction. Copyright

Full text of DOI:10.1002/chem.201201348

COMMUNICATION
DOI: 10.1002/chem.201201348
Brønsted Acid Enhanced Rhodium-Catalyzed Conjugate Addition of Aryl
À
C H Bonds to a,b-Unsaturated Ketones under Mild Conditions
Lei Yang,[a] Bo Qian,[a] and Hanmin Huang*[a, b]
À
Transition-metal-catalyzed C H additions to unsaturated
À
C=X (X=C, O, N) bonds by C H bond activation has
À
become an important strategy for the construction of C C
bonds.[1–3] Although only a few examples of reactions involv-
À
ing addition of C H bonds to the highly electrophilic unsa-
À
turated substrates by C H bond activation could be per-
formed in relative milder reaction conditions, the catalytic
À
conjugate addition of C H bonds to a,b-unsaturated car-
bonyl compounds usually require harsh reaction conditions,
such as high reaction temperature, long reaction time or ad-
À
Scheme 1. Transition-metal-catalyzed C H activation/addition.
ditional ligands.[4] In general, in the area of C C bond form-
are involved. As shown in Scheme 1, the first proton-trans-
fer event occurred in the C H activation step, which indi-
À
À
ing processes that proceed through a transition-metal-cata-
lyzed 1,4-conjugate addition reaction, a fast proton transfer
step proved to be vital for excellent catalyst turnover.[5]
Compared with the more often reported C–C bond-forming
cates that quick removal of the generated proton in basic
conditions would facilitate the reversible arene metalation
process. Subsequent conjugate addition with a,b-unsaturated
ketone substrate 2 forms a metal–enolate B, which releases
the desired product 3 upon protonation. This step would be
favored in acidic conditions and substrate inhibition would
occur if nitrogen-containing substrates were used.[3f] Based
on this consideration, we anticipated that the success of this
strategy lies in the identification of a catalytic system effi-
À
processes, the effect of the proton transfer in such a C H
activation triggered conjugate addition reaction is still elu-
sive. Thus, it is both synthetically and mechanistically impor-
tant to investigate the proton effect of this type of transfor-
À
mation to develop an efficient C H addition reaction under
mild conditions.
À
The rhodium-catalyzed conjugate addition of organome-
tallic reagents to a,b-unsaturated ketones is a well-studied
and effective transformation, the key catalytic nucleophilic
active species generated in these reactions proceeded by the
transmetalation of organometallic reagents, which results in
cient for both the C H activation and proton transfer steps.
Herein, we demonstrate an efficient and atom-economical
À
protocol for the rhodium-catalyzed C H activation/addition
process under milder conditions.
To validate our hypothesis, 2-phenylpyridine (1a) and
chalcone 2a were used in the rhodium-catalyzed model re-
action (Table 1). After extensive screening of the reaction
parameters,[9] we found that by using the combination of
[Cp*RhCl2]2 and AgSbF6 as the catalyst, the desired product
3aa could be obtained in 63% yield with PhOCH3 as the
solvent (Table 1, entries 1–6). Other silver additives with dif-
ferent anions produced less satisfactory results (Table 1, en-
tries 7 and 8), indicating that the anion plays an important
role in the present transformation. Lewis acids, such as
FeCl3 and AlCl3, as well as a catalytic amount of AgSbF6
and AgCl, are ineffective as catalysts. These results indicate
that the reaction is most likely not a simple Lewis acid cata-
lyzed Friedel–Crafts reaction. The choice of solvent is cru-
cial for the success of the present catalytic reaction (Table 1,
entries 9–13). Although all of the solvents examined here
could give the desired product with comparable results, the
reaction conducted in CH3CO2H produced the desired prod-
uct 3aa in excellent yield at lower temperature (Table 1,
entry 16). Other solvents such as PhOCH3 gave the desired
product in lower yield when the reaction was conducted at
the unwanted formation of stoichiometric amounts of metal
[7]
salts.[6] Recent advances in catalytic C H activation and
À
our own research contributions in this area[8,3c] have promot-
À
ed us to investigate the possibility of using aromatic C H
substrates in place of organometallic reagents to circumvent
À
this problem. In contrast, such a C H activation triggered
reaction pathway is distinct from the conventional organo-
metallic reagents involved in a catalyzed conjugate addition
reaction, in which two incompatible proton-transfer steps
[a] Dr. L. Yang, B. Qian, Prof. Dr. H. Huang
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences
Lanzhou, 730000 (P.R. China)
Fax : (+86)931-496-8129
E-mail: hmhuang@licp.cas.cn
[b] Prof. Dr. H. Huang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University Lanzhou, 730000 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201348.
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Table 1. Optimization of the reaction conditions.[a]
Entry Catalyst (mol%)
Solvent
T [8C] Yield [%][b]
1
2
2
4
5
6
7
8
Pd
RuCl3·3H2O (5)
Rh2A(OAc)4 (2.5)
[Cp*RhCl2]2 (2.5)
[Rh(COD)2]BF4 (5)
G
PhOCH3
PhOCH3
PhOCH3
PhOCH3
PhOCH3
120
120
120
120
120
120
120
120
120
120
120
120
0
0
0
E
0
<5
63
59
45
45
48
54
48
64
65
79
82
19
88
89
70
72
67
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9
ACHTUNGTRENNUNG
10
11
12
13
14
15
16
17
18[c]
19[d]
20[d,e]
21[d]
22[d,f]
ACHTUNGTRENNUNG
Figure 1. X-ray crystal structure of 3aa.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
in a decreased the yield of 3am, whereas the reaction
worked well with 2i–2l, substituted with an electron-with-
drawing group at R2, furnishing the expected products 3ai-
3al in high yields. Substrates 1n and 1o having a naphthyl
group and heteroaromatic ring afforded the desired prod-
ucts 3an and 3ao in high yields. Notably, in some cases, the
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
À
C H activation/addition could be realized smoothly at room
ACHTUNGTRENNUNG
temperature. Benzalacetones showed a high compatibility
with the present reaction conditions, affording the desired
products (3ap, 3aq, and 3ar) in good yields. It was notewor-
thy that the Michael acceptors could be extended to aliphat-
ic a,b-unsaturated ketones, to give the products in excellent
yields at room temperature.[11] The substrate scope of arenes
was then investigated. To our satisfaction, both para-substi-
tuted electron-rich and electron-deficient arylpyridine deriv-
atives (1b, 1c, 1d, and 1e) worked well with 2a, and gave
the desired products 3ba, 3ca, 3da, and 3ea in good to ex-
cellent yields. Some steric effect was observed when using
1 f as the substrate. Other heterocyclic directing groups at-
tached to the arenes, such as 2-arylquinoline compounds
(1g, 1h, 1i, and 1j), could also be used in this reaction. In
addition, we were pleased to find that pyrazole 1k, a com-
monly encountered motif in medicinal chemistry, could also
be used in this transformation. Exploring the practicality of
the present reaction was also investigated. The reaction of
2a with 1.5 equivalents of 1a in the presence of 1.25 mol%
of [Cp*RhCl2]2 and 5 mol% of AgSbF6 was carried out on
a 4 mmol scale of 2a. The desired product 3aa was obtained
on a gram scale with 96% isolated yield.[9]
We then conducted a series of experiments to uncover the
reaction mechanism of this reaction. First, intermolecular
competition experiments were carried out between the 2-ar-
ylpyridine 1c (4-OMe) and 1e (4-F). The fact that adduct
3ea was preferentially formed revealed that an electrophilic
deprotonation mechanism was less likely to have occurred
(Scheme 2). Reactions with isotopically labeled solvent
CD3CO2D and substrate 1a were then studied (Scheme 3).
When the reaction of 1a was performed in CD3CO2D in the
absence of chalcone 2a, 67% deuterium incorporation was
[a] General conditions: catalyst, 1a (0.20 mmol), 2a (0.20 mmol), solvent
(1.0 mL), under argon for 24 h, unless otherwise noted. [b] Isolated yield.
[c] 1a (0.20 mmol), 2a (0.30 mmol). [d] 1a (0.30 mmol), 2a (0.20 mmol).
[e] The reaction was carried out under air. [f] The reaction was carried
out for 48 h.
608C (Table 1, entry 17). A variable substrate ratio was also
examined (Table 1, entries 18 and 19), with the excellent
yield being achieved by using 1.5 equivalents of 1a and the
excess 1a could be recovered. Notably, the reaction could
be operational at a lower catalyst loading (1.25 mol%) or
under air (Table 1, entries 20 and 21). It was noteworthy
that the corresponding product 3aa could be obtained in
good yield even at room temperature when CH3CO2H
served as the solvent (Table 1, entry 22). The structure of
the corresponding product 3aa was unambiguously identi-
fied by X-ray single-crystal analysis (Figure 1).[10]
Under the optimized reaction conditions, a number of
a,b-unsaturated ketones were successfully employed in this
transformation (Table 2). Treatment of 2-phenylpyridine
(1a) with a series of chalcones 2a–o afforded the corre-
sponding products 3aa–3ao in good to excellent yields. It
appeared that the electronic nature of the para and meta
substituents on the phenyl ring R1 of 2 had no strong influ-
ence on the reactivity. But a steric effect was observed in
this reaction when R1 has a substituent in the ortho position
the reaction gave a lower yield in comparison with that
bearing a substituent in the para position (3ae vs. 3ah). The
electronic characteristics of R2 exerted an obvious influence
on the yields of product 3. For example, the substrate 2m
that has an electron-donating group (-OMe) at R2 resulted
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Brønsted Acid Enhanced Rhodium Catalysis
COMMUNICATION
[a]
À
Table 2. Scope of the rhodium-catalyzed C H addition.
observed at the two ortho positions (Scheme 3a). If
the same reaction was conducted in the presence of
2a, the desired product 3aa was obtained with 84%
deuterium incorporation at the a-position of the
ketone moiety and 53% deuterium incorporation at
the ortho position of phenylpyridine moiety
(Scheme 3b). Furthermore, the reaction of 2a and
isotopically labeled 1a was conducted in CH3CO2H,
no deuterium incorporation was detected in both
unreacted 1a and the product 3aa (Scheme 3c).
À
These experiments suggest that the C H bond met-
alation step is reversible, and the solvent CH3CO2H
indeed participates in the proton-transfer step in
this reaction.
To reveal the role of acids in the present conju-
À
gate C H addition reaction, a series of organic
acids with different pKa values were employed as
solvents in the model reaction under identical con-
ditions.[9] As shown in Figure 2, the reactivity of the
reaction was dramatically affected by the acid. The
strong acids with lower pKa values inhibited the de-
sired reaction completely. This finding suggests that
stronger acids[12] may slow the C H bond metala-
À
tion step resulting from the inhibition of the first
proton transfer event (see Scheme 1). Meanwhile,
the weaker acids with pKa values higher than 4.8
also decreased the reactivity of the desired reaction,
presumably because that the weaker acids might
decrease the rate of the protonolysis step.
[a] General conditions: [Cp*RhCl2]2 (2.5 mol%), AgSbF6 (10 mol%), 1a (0.30 mmol),
2 (0.20 mmol), CH3CO2H (1.0 mL), under argon, 608C, 24 h. Product was purified by
column chromatography. [b] The data in parentheses were obtained at 258C for 60 h.
[c] Reactions were conducted at 258C for 30 h. [d] The reactions were carried out at
1208C for 48 h.
CH3CO2H,
iPrCO2H,
and
PhCH2CO2H with appropriate
pKa could give comparably
good results. These data clearly
indicate that careful control of
the acid property is vital to this
rhodium-catalyzed
conjugate
À
C H addition reaction. We
speculate that the acids with ap-
propriate pKa values could
finely settle the conflict of the
two proton-transfer events in-
Scheme 2. Intermolecular competition experiment with 2-arylpyridine 1.
À
volved in this type of C H ad-
dition reaction.
Finally, to eliminate the solu-
bility effect created by different
acids for the present reaction,
we conducted control experi-
ments by using CH3CO2H and
CD3CO2D as solvents, and the
kinetic reaction profiles were
obtained under other identical
reaction conditions. The dra-
matic effect of acids was further
demonstrated by the kinetic re-
action
profiles
shown
in
Figure 3. These data presented
here offer further valuable in-
Scheme 3. Experiments with isotopically labeled compounds.
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H. Huang et al.
Figure 2. The pKa values of the acids and their effects on the reactivity of
À
C H addition reaction of 1a with 2a.
Scheme 4. Proposed catalytic cycle.
accelerating the last protonation step of the rhodium-cata-
lyzed conjugate reaction.
In summary, we have developed a rhodium-catalyzed se-
À
lective C H activation and subsequent conjugate addition
to a,b-unsaturated ketones under mild reaction conditions.
Vital to the success of this approach is the rational analysis
of the proton-transfer effect involved in this conjugate addi-
tion reaction. With CH3CO2H as the solvent, the inherent
substrate inhibition effect of this type of reaction could be
successfully overcome allowing the reaction proceed
smoothly under mild reaction conditions. This approach pro-
À
vides a new strategy to accomplish this type of C H activa-
tion/addition process.
Figure 3. Kinetics curves of the yields of 3aa in CH3CO2H and
CD3CO2D.
Experimental Section
General procedure: An oven-dried Schlenk tube was charged with
[Cp*RhCl2]2 (2.5 mol%), AgSbF6 (10 mol%), 1a (0.30 mmol), and 2a
(0.20 mmol) in CH3CO2H (1.0 mL) under argon. The reaction mixture
was stirred vigorously at 608C in the dark for 24 h. After cooling to room
temperature, the reaction mixture was diluted with CH2Cl2 (15 mL) and
quenched with aq NaHCO3 (30 mL). The organic layer was separated
and the water phase was extracted with CH2Cl2 (2ꢁ15 mL), the com-
bined organic phases were dried over anhydrous Na2SO4. After filtration
and evaporation of the solvents under reduced pressure, the crude resi-
due was purified by column chromatography on silica gel (ethyl acetate/
petroleum 1:20 to 1:5) to afford the desired product 3aa as a white solid
(64.6 mg, 89%).
sight into the comparison of these two proton-transfer
events. The higher reactivity observed in CD3CO2D provides
evidence that the rate of the last protonation step is faster
À
than that of the C H bond metalation step in our catalytic
system (Scheme 1).
On the basis of the results that we obtained here and pre-
viously,[3f–g,6,13] a plausible pathway is proposed (Scheme 4).
The rhodium catalyst reacts with 2-phenylpyridine 1a to
generate a cationic intermediate A. Coordination of the
chalcone 2a produces arylrhodium complex B, which is fol-
lowed by conjugate addition to form (oxa-p-allyl) rhodium
species C or rhodium enolate D. The rhodium complex C or
D is protonated by the solvent CH3CO2H and regenerates
the active rhodium catalyst. In the non-acidic reaction
À
medium, the proton produced in the first C H bond metala-
Acknowledgements
tion step would be captured by the basic substrate 1a, which
will inhabit the last protonolysis step. Thus, the reaction
would be slowed and harsh reaction conditions required. In
contrast, the free proton source existed in the presence of
an acidic reaction medium would suppress the substrate in-
hibition effect, and thus facilitate catalytic turnover through
This work was supported by the Chinese Academy of Sciences and the
National Natural Science Foundation of China (21173241, 21172226, and
21133011).
À
Keywords: C H activation · conjugate addition · ketones ·
proton transfer · rhodium
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Brønsted Acid Enhanced Rhodium Catalysis
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À
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À
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[10] CCDC-860608 (3aa) contains the supplementary crystallographic
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[11] When we were preparing this manuscript, Li and co-workers report-
À
ed the direct addition of aryl C H bonds to several aliphatic a,b-un-
saturated ketones, trans-2-pentenal, and cinnaldehyde derivatives,
but relatively harsh reaction conditions and longer reaction times
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[12] When the reaction of 1a was performed in CF3COOD in the pres-
ence of 2.5 mol% of [Cp*RhCl2]2 and 10 mol% of AgSbF6 for 16 h,
only <2% deuterium incorporation was observed at the two ortho
positions.
À
[13] A control experiment revealed that a slight reversibility of this C H
[6] For selected reviews, see: a) K. Fagnou, M. Lautens, Chem. Rev.
2003, 103, 169; b) T. Hayashi, K. Yamasaki, Chem. Rev. 2003, 103,
2829.
activation/addition reaction was observed by subjecting 3aa to the
standard reaction conditions. Please see the Supporting Information
for details.
À
[7] For recent selected reviews on C H activation, see: a) L.-C. Cam-
peau, D. R. Stuart, K. Fagnou, Aldrichimica Acta 2007, 40, 35;
b) Y. J. Park, J.-W. Park, C.-H. Jun, Acc. Chem. Res. 2008, 41, 222;
Received: April 20, 2012
Published online: && &&, 0000
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H. Huang et al.
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C H Functionalization
L. Yang, B. Qian,
H. Huang* .................... &&&& — &&&&
Brønsted Acid Enhanced Rhodium-
Catalyzed Conjugate Addition of Aryl
Acid test: With a Brønsted acid as the
solvent, the rhodium-catalyzed direct
scheme). The acid may assist by inter-
ceding in the conflict of the two
proton-transfer events and averting the
substrate inhibition involved in this
À
C H Bonds to a,b-Unsaturated
À
addition of aryl C H bonds to a,b-
Ketones under Mild Conditions
unsaturated ketones was realized
under mild reaction conditions (see
À
type of C H addition reaction.
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