Efficient copper(II)-catalyzed addition of activated methylene compounds to alkenes

Article abstract of DOI:10.1021/jo800836g

(Chemical Equation Presented) Efficient regioselective addition of β-diketones to styrenes, norbornene, cyclic enol ether, and diene has been realized by means of copper(II) triflate as the catalyst. The solvent effect is prominent on the reactions, and the desired addition products were obtained in good to excellent yields only in dioxane or ionic liquid [bmim]PF₆. The mechanism suggests that copper(II) triflate activates the enolic O-H bond of a β-diketone substrate to initiate the addition reaction.

Full text of DOI:10.1021/jo800836g

documented with palladium(II) catalysts.5 Lewis acidic indium
triflate-catalyzed vinylation of ꢀ-ketoesters with acetylene gas
occurred efficiently under atmospheric pressure.6 Recently,
inexpensive FeCl3-catalyzed addition of 1,3-dicarbonyl com-
pounds to styrenes has been developed.7 Cationic ruthenium(II)
is also effective to catalyze the addition of ꢀ-diketones to
alcohols and styrenes.8 Catalytic addition of 1,3-dicarbonyl
compounds to alkynes was promoted with palladium,9 rhe-
nium,10 or nickel/Yb.11 Ni(II)-catalyzed addition of 1,3-dicar-
bonyl compounds to conjugated nitroalkenes12 and base-
mediated addition of ꢀ-diesters to allenes13 have been explored.
Copper(II) triflate has recently been documented to catalyze the
addition of O-H bonds to norbornene14 and N-H bonds to
norbornene, vinyl arenes, and 1,3-cyclohexadiene.15 Cu(OTf)2-
catalyzed intramolecular hydroamination of γ- and δ-alkenyl
sulfonamides were reported by Takaki et al.16 Very recently,
Li’s group reported Cu(OTf)2-catalyzed hydroalkylation of
alkenes in neat liquids (12 examples):2 only in the reactions of
dibenzoylmethane with styrene or 4-chlorostyrene the desired
products were collected in 85% yields, and in other cases, the
hydroalkylation products were obtained in 5-58% yields. In
SnBr4-catalyzed hydroalkylation of the same alkenes in ionic
liquid [bmim]OTf (bmim ) 1-butyl-3-methylimidazolium),2 the
products were usually formed in poor yields (0-41%), and only
in the reactions of dibenzoylmethane with styrene or 4-chlo-
rostyrene the desired products were afforded in 60-61% yields.
Keeping this in mind, we became interested in copper(II) triflate-
catalyzed reactions of alkenes and substrates with activated C-H
bonds that are similar in acidity to the N-H bonds of amines,17
that is, ꢀ-diketones, and found that Cu(OTf)2-catalyzed addition
reactions of ꢀ-diketones to alkenes are very sensitive to the
reaction media. Herein, we wish to report Cu(OTf)2-catalyzed
intermolecular hydroalkylation of alkenes by activated meth-
ylene compounds (i.e., ꢀ-diketones) in dioxane and ionic liquid
[bmim]PF6.
Efficient Copper(II)-Catalyzed Addition of
Activated Methylene Compounds to Alkenes
Yu Li,† Zhengkun Yu,*,†,‡ and Sizhong Wu†
Dalian Institute of Chemical Physics, Chinese Academy of
Sciences, 457 Zhongshan Road,
Dalian, Liaoning 116023, PR China, and State Key
Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354
Fenglin Road, Shanghai 200032, PR China
zkyu@dicp.ac.cn
ReceiVed April 16, 2008
Efficient regioselective addition of ꢀ-diketones to styrenes,
norbornene, cyclic enol ether, and diene has been realized
by means of copper(II) triflate as the catalyst. The solvent
effect is prominent on the reactions, and the desired addition
products were obtained in good to excellent yields only in
dioxane or ionic liquid [bmim]PF6. The mechanism suggests
that copper(II) triflate activates the enolic O-H bond of a
ꢀ-diketone substrate to initiate the addition reaction.
Catalytic alkylation of 1,3-dicarbonyl compounds is consid-
ered as one of the most promising atom-economical organic
processes for C-C bond formation because use of a stoichio-
metric amount of base and an organic halide can be avoided.1
Catalytic addition to alkenes is extremely attractive for alkylation
of 1,3-dicarbonyl compounds and has recently been paid
considerable attention.2 Highly efficient addition of activated
methylene compounds to alkenes was reported by means of
AuCl3 catalyst in the presence of AgOTf in CH2Cl2.3 In solvent
CH3NO2 and at elevated temperature such as 100 °C, inter- and
intramolecular alkylation of 1,3-dicarbonyl compounds by
alkenes can be catalyzed by AgOTf.4 Intramolecular hydro-
alkylation of alkenyl-1,3-dicarbonyl compounds was also
(5) (a) Pei, T.; Widenhoefer, R. A. J. Am. Chem. Soc. 2001, 123, 11290–
11291. (b) Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2003, 125, 2056–
2057. (c) Wang, X.; Pei, T.; Han, X.-Q.; Widenhoefer, R. A. Org. Lett. 2003, 5,
2699–2701. (d) Han, X.-Q.; Wang, X.; Pei, T.; Widenhoefer, R. A. Chem.—Eur.
J. 2004, 10, 6333–6342. (e) Qian, H.; Pei, T.; Widenhoefer, R. A. Organome-
tallics 2005, 24, 287–301. (f) Li, J.-H.; Zhu, Q.-M.; Liang, Y.; Yang, D. J. Org.
Chem. 2005, 70, 5347–5349.
(6) Nakamura, M.; Endo, K.; Nakamura, E. Org. Lett. 2005, 7, 3279–3281.
(7) (a) Kischel, J.; Michalik, D.; Zapf, A.; Beller, M. Chem. Asian J. 2007,
2, 909–914. (b) Duan, Z.; Xuan, X. J.; Wu, Y. J. Tetrahedron Lett. 2007, 48,
5157–5159.
(8) Liu, P. N.; Zhou, Z. Y.; Lau, C. P. Chem.—Eur. J. 2007, 13, 8610–
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2188.
† Dalian Institute of Chemical Physics.
‡ Shanghai Institute of Organic Chemistry.
(12) Evans, D. A.; Seidel, D. J. Am. Chem. Soc. 2005, 127, 9958–9959.
(13) Xu, L. B.; Huang, X.; Zhong, F. R. Org. Lett. 2006, 8, 5061–5064.
(14) Taylor, J. G.; Whittall, N.; Hii, K. K. Chem. Commun. 2005, 5103–
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(1) (a) Trost, B. M. Science 1991, 254, 1471–1477. (b) Trost, B. M Angew.
Chem., Int. Ed. Engl. 1995, 34, 259–281. (c) Trost, B. M. Acc. Chem. Res. 2002,
35, 695–705.
(2) Lanman, H. E.; Nguyen, R.-V.; Yao, X. Q.; Chan, T.-H.; Li, C.-J. J.
Mol. Catal. A: Chem. 2008, 279, 218–222.
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10.1021/jo800836g CCC: $40.75
Published on Web 06/18/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5647–5650 5647

TABLE 1. Catalytic Addition of Dibenzoylmethane to Styrene
(Conditions: dibenzoylmethane, 1 mmol; styrene, 1.5 mmol; solvent,
5 mL; 20 h)
The catalytic efficiency of various copper reagents was
initially tested in the addition of dibenzoylmethane to styrene
(Table 1). Because styrene dimer can be easily formed as the
side product in all the cases, excess of styrene (1.5 equiv) was
used in the reactions. At 75 °C in dioxane, Cu(I) and Cu(II)
halides such as CuI, CuBr, and CuCl2 exhibited no catalytic
activity to the alkylation of dibenzoylmethane (1c) by styrene
(2a), while CuBr2 showed low catalytic activity with a poor
conversion of the ꢀ-diketone substrate (Table 1, entries 1-4).
In the poor polar solvent, such as toluene, copper(II) triflate
demonstrated negligible catalytic activity (entry 5). However,
in refluxing THF (66 °C) or in DCE at 75 °C, Cu(OTf)2 showed
a better catalytic activity, and the desired product was isolated
in 26-40% yields (entries 6 and 7). In dioxane at 75 °C, the
catalytic activity of Cu(OTf)2 was remarkably improved,
promoting the formation of 3i in 72% yield (entry 8). With a
lower loading of the catalyst (i.e., 15 mol % Cu(OTf)2), the
desired product was isolated in 68% yield (entry 9). With 15
mol % of the catalyst and increasing the reaction temperature
to 90 °C, the same reaction afforded 3i in 76% yield (entry
10). Using ionic liquid [bmim]PF6 as the reaction medium,
Cu(OTf)2-catalyzed alkylation of 1c by 2a also worked very
well (entry 11). It is obvious that the reaction is very sensitive
to the reaction media and temperature. The Cu(II) catalyst may
be additionally stabilized by the oxygen or nitrogen donor atoms
in dioxane or [bmim]PF6 because it has showed very good
catalytic activity in the addition of dibenzoylmethane to styrene
in these solvents. The reaction can not be efficiently carried
out at temperatures above 90 °C due to obvious dimerization
or polymerization of styrene.
entry
catalyst (mol %)
solvent
temp (°C)
yield (%)a
1
2
3
4
5
6
7
8
9
CuI (25)
CuBr (25)
CuCl2 ·2H2O (25)
CuBr2 (25)
Cu(OTf)2 (25)
Cu(OTf)2 (25)
Cu(OTf)2 (25)
Cu(OTf)2 (25)
Cu(OTf)2 (15)
Cu(OTf)2 (15)
Cu(OTf)2 (25)
dioxane
dioxane
dioxane
dioxane
toluene
THF
75
75
75
75
75
65
75
75
75
90
90
0
0
0
18b
<5
26
40
72
68
76
52
DCEc
dioxane
dioxane
dioxane
[bmim]PF6
10
11
a Isolated yields of 3i. b 30% conversion for 1c. c DCE
dichloroethane.
)
its reaction with 2b only produced 3j in 29% yield (entries
11-14). The desired product 3l was also formed in a high yield
(96%) in the ionic liquid (entry 15). As discussed for the
configuration of 3d, the H-H COSY spectrum of 3l also
revealed exclusive formation of the exo-isomer. However, in
other cases, ionic liquid [bmim]PF6 or [bmim]BF4 did not
improve formation of the expected addition products. It should
be noted that because 3,4-dihydro-2H-pyran (2e) and cyclo-
pentadiene (2f) can be easily polymerized at elevated temper-
ature, their reactions were carried out under rather mild
conditions. At ambient temperature (25 °C), ꢀ-diketones 1a and
1d demonstrated no obvious reactivity to alkenes 2e and 2f,
while the addition products 3n-q were isolated in 27-73%
yields from the reactions of 1b,c with 2e,f (entries 17-20),
respectively.
A mechanism for the present Cu(OTf)2-catalyzed addition
reactions is proposed in Scheme 1. The catalyst reacts with the
enolized form of a ꢀ-diketone to generate copper(II) intermediate
4 and release of triflic acid (HOTf) which then protonates the
alkene, furnishing a carbocation 5. The carbocation reacts with
intermediate 4 to yield the desired addition product 3 and/or it
reacts with another molecule of alkene to form a dimer and/or
higher oligomers as the side products.
Subsequently, the optimized reaction conditions were applied
in the alkylation of a variety of ꢀ-diketones by alkenes (Table
2). Most of the 1,3-dicarbonyl compounds were effectively
added to styrenes, norbornene, cyclic enol ether, and diene, but
no desired product was detected from the reactions of dimethyl
malonate with alkenes (Table 2, entry 16), which might be
attributed to the incapability of dimethyl malonate to be enolized
during the reaction. The addition of 2,4-pentanedione (1a) to
styrenes (2a-c) and norbornene (2d) in dioxane formed the
desired products (3a-d) in 42-69% yields (Table 2, entries
1-4). Unexpectedly, the reaction of 1a and norbornene in ionic
liquid [bmim]PF6 afforded product 3d in 94% yield (entry 5).
The reaction favors exclusive formation of the exo-isomer
(coupling between the endo-proton and its adjacent bridgehead
methane proton is conspicuously absent from the H-H COSY
spectrum of 3d).15 The addition of a more reactive unsym-
metrical ꢀ-diketone, such as 1-phenyl-1,3-butanedione (1b), to
2a-d produced the desired products 3e-h as two diastereomers
in 72-82% yields (entries 6-9). The diastereoselectivity of the
products is presumably attributed to the two enolizable forms
of the 1,3-diketone substrate and introduction of two different
chiral centers to the product molecules. In the same fashion,
the reaction of 1b with norbornene in [bmim]PF6 afforded the
desired product 3h in 99% yield (entry 10). The reactions of
symmetrical ꢀ-diketone 1c and alkenes 2a, 2c, and 2d formed
products 3i, 3k, and 3l in 76-79% yields, respectively, while
SCHEME 1. A Proposed Mechanism for
Cu(OTf)2-Catalyzed Addition Reactions
In conclusion, efficient regioselective addition of ꢀ-diketones
to styrenes, norbornene, cyclic enol ether, and diene has been
5648 J. Org. Chem. Vol. 73, No. 14, 2008

TABLE 2. Copper(II)-Catalyzed Addition of ꢀ-Diketones to
Alkenes (Conditions: ꢀ-diketone, 1 mmol; alkene, 1.5 mmol;
Cu(OTf)2, 0.15 mmol; dioxane, 5 mL, 90 °C, 20 h)
realized with a remarkable solvent effect by means of copper(II)
triflate as the catalyst. The mechanism suggests that copper(II)
triflate activates the enolic O-H bond of a ꢀ-diketone to initiate
the reaction.
Experimental Section
Typical Procedure for Cu(OTf)2-Catalyzed Addition
Reactions in Dioxane: A mixture of the catalyst Cu(OTf)2 (54
mg, 0.15 mmol) and 5 mL of dioxane was stirred under nitrogen
at 90 °C for 10 min, and then a ꢀ-diketone 1 (1 mmol) and alkene
2 (1.5 mmol) were introduced. The resulting mixture was stirred
at 90 °C for 20 h. After cooling to ambient temperature, all the
volatiles were removed under reduced pressure. Purification of the
resultant residue by flash silica gel column chromatography
(petroleum ether (60-90 °C)/ethyl acetate, v/v ) 50/1) afforded
the desired product 3. All the addition products were >98% pure
1
by HPLC determination and identified by comparison of their H
NMR features with the reported authentic NMR data for the known
compounds, and the new compounds 3f, 3j, and 3pwere further
characterized by HRMS analysis.
Synthesis of 1-Phenyl-2-(1-p-tolylethyl)butane-1,3-dione
(3f): A mixture of 1-phenyl-1,3-butanedione 1b (0.162 g, 1 mmol),
4-methylstyrene 2b (0.177 g, 1.5 mmol), and Cu(OTf)2 (0.054 g,
0.15 mmol) in 5.0 mL of dioxane was stirred at 90 °C for 20 h.
After quenching the reaction and workup, purification by silica gel
column chromatography (petroleum ether (60-90 °C)/ethyl acetate,
v/v ) 50/1) afforded 3f as a colorless oil (0.201 g, 72%): 1H NMR
(400 MHz, CDCl3) δ 8.09 (d, J ) 7.4 Hz, 2H), 7.62-6.97 (m,
7H), 4.89 (d, J ) 11.0 Hz, 1H), 3.87-3.81 (m, 1H), 2.38 (s, 3H),
1.92 (m, 3H), 1.20 (d, J ) 6.8 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 203.5, 195.5, 140.2, 137.4, 136.7, 133.9, 129.6, 129.0,
128.6, 127.3, 71.2, 40.7, 27.9, 21.9, 21.0. The other diastereomer
(from the mixture of two isomers and some peaks are difficult to
be distinguished.): 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J ) 7.4
Hz, 2H), 7.62-6.97 (m, 7H), 4.82 (d, J ) 11.0 Hz, 1H), 3.87-3.81
(m, 1H), 2.23 (s, 3H), 2.21 (s, 3H), 1.29 (d, J ) 7.0 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 204.0, 195.5, 140.6, 137.2,
136.2, 133.5, 129.3, 128.7, 128.5, 126.6, 71.8, 40.0, 27.6, 21.2,
20.5; HRMS (EI) m/z calcd for C19H20O2 (M+) 280.1463, found
280.1473.
Synthesis of 1,3-Diphenyl-2-(1-p-tolylethyl)propane-1,3-di-
one (3j): A mixture of dibenzoylmethane 1c (0.224 g, 1 mmol),
4-methylstyrene 2b (0.177 g, 1.5 mmol), and Cu(OTf) (0.054 g,
2
0.15 mmol) in 5.0 mL of dioxane was stirred at 90 °C for 20 h.
After quenching the reaction and workup, purification by silica gel
column chromatography (petroleum ether (60-90 °C)/ethyl acetate,
v/v ) 50/1) afforded 3j as a white solid (0.100 g, 29%): mp 98-100
°C; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J ) 7.44 Hz, 2H), 7.78
(d, J ) 7.4 Hz, 2H), 7.58- 7.27 (m, 6H), 7.18 (d, J ) 7.8 Hz,
2H), 7.00 (d, J ) 7.8 Hz, 2H), 5.64 (d, J ) 10.1 Hz, 1H), 4.10-4.06
(m, 1H), 2.22 (s, 3H), 1.36-1.34 (m, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 195.2, 194.7, 140.9, 137.3, 137.0, 136.2, 133.6,
133.1, 129.2, 128.9, 128.6, 128.5, 127.6, 65.1, 40.9, 21.0, 20.5;
HRMS (EI) m/z calcd for C24H22O2 (M+) 342.1620, found 342.1626.
Typical Procedure for Cu(OTf)2-Catalyzed Addition Reac-
tions in [bmim]PF6—Synthesis of 3-Bicyclo[2.2.1]hept-2-yl-pen-
tane-2,4-dione (3d): A mixture of 2,4-pentanedione 1a (0.101 g, 1
mmol), norbornene 2d (0.141 g, 1.5 mmol), and Cu(OTf)2 (0.054
g, 0.15 mmol) in 5.0 g of [bmim]PF6 was stirred at 90 °C for 20 h.
After cooling to ambient temperature, the resulting mixture was
extracted with diethyl ether (4 × 5 mL). The ether phase was
concentrated under reduced pressure and further purified by silica
gel column chromatography (petroleum ether (60-90 °C)/ethyl
acetate, v/v ) 50/1) to afford 3d as a colorless oil (0.184 g, 94%).
Compound 3d was identified by comparison of its 1H NMR features
with the reported authentic NMR data,16 and its configuration was
a Isolated yields, isomer ratios (in parentheses) determined by 1H
NMR. b The exo product was determined by H-H COSY analysis. c 5 g
of [bmim]PF6 was used as the solvent. d 38% conversion for 1c. e 25 °C,
20 h.
J. Org. Chem. Vol. 73, No. 14, 2008 5649

determined by H-H COSY NMR analysis (see the Supporting
Supporting Information Available: Experimental details,
spectroscopic data, and copies of 1H, 13C{1H} NMR and HRMS
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
Information).
Acknowledgment. We are grateful to the “Hundred Talented
Program” Funding of CAS and the National Natural Science
Foundation of China (Nos. 20406020, 20501018, 20772124)
for financial support of this research.
JO800836G
5650 J. Org. Chem. Vol. 73, No. 14, 2008