CuBr-catalyzed reaction of N,N-dimethylanilines and silyl enol ethers: An alternative route to β-arylamino ketones

Article abstract of DOI:10.1021/ol901347t

Image Presented A wide range of silyl enol ethers undergo the reactions with N,N-dimethylanilines in the presence of transition metal catalysts under mild conditions to give β-arylamino ketones. In the cases of silyl enol ethers derived from unsymmetrical ketones, regiospecific addition of carbonyl compounds was obtained at the olefinic position of silyl enol ether.

Full text of DOI:10.1021/ol901347t

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3730-3733
CuBr-Catalyzed Reaction of
N,N-Dimethylanilines and Silyl Enol
Ethers: An Alternative Route to
ꢀ-Arylamino Ketones
Lehao Huang, Xunbin Zhang, and Yuhong Zhang*
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, People’s Republic of China
yhzhang@zju.edu.cn
Received June 16, 2009
ABSTRACT
A wide range of silyl enol ethers undergo the reactions with N,N-dimethylanilines in the presence of transition metal catalysts under mild
conditions to give ꢀ-arylamino ketones. In the cases of silyl enol ethers derived from unsymmetrical ketones, regiospecific addition of carbonyl
compounds was obtained at the olefinic position of silyl enol ether.
The investigation of new reactions of C-H activation in
searching for high efficiencies and high selectivities has
aroused a lot of attention in recent years because of
economical and environmental importance.1 In these efforts,
transition metal catalysis has featured prominently in the past
decades, leading to the establishment of a range of new types
of reactions that offer the powerful tools for the synthesis
of complex frameworks without utilizing the prefunctional-
ization of C-X or C-M bonds.2 Amines are common
structural units of natural products, pharmaceuticals, and
functional materials. Consequently, the selective C-H bond
functionalization of amines has been extensively explored,
and some promising catalytic systems for sp3 C-H bond
activation adjacent to the nitrogen atom have been reported.3
For instance, ruthenium-catalyzed intramolecular olefin-
iminium ion cyclization4 and oxidative cyanation of tertiary
amines,5 ruthenium-catalyzed alkylation of amines from the
addition of alkenes,6 iridium-catalyzed approach of pyrroliz-
(2) (a) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005,
127, 13148. (b) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2008, 47, 4882. (c) Tobisu, M.; Yamaguchi, S.; Chatani,
N. Org. Lett. 2007, 9, 3351. (d) Do, H.-Q.; Daugulis, O. J. A. J. Am. Chem.
Soc. 2007, 129, 12404. (e) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am.
Chem. Soc. 2008, 130, 2448. (f) Colby, D. A.; Bergman, R. G.; Ellman,
J. A. J. Am. Chem. Soc. 2008, 130, 3645. (g) Li, Y.-Z.; Li, B.-J.; Lu, X.-
Y.; Lin, S.; Shi, Z.-J. Angew. Chem., Int. Ed. 2009, 48, 3817. (h) Dwsai,
L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285.
(i) Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2007, 9, 3813. (j)
Fleming, J. J.; Fiori, K. W.; Bois, J. D. J. Am. Chem. Soc. 2003, 125, 2028.
(k) Mousseau, J. J.; Larive, A.; Charette, A. B. Org. Lett. 2008, 10, 1641.
(3) (a) Davies, H. M. L.; Hansen, T.; Hopper, D. W.; Panaro, S. A.
J. Am. Chem. Soc. 1999, 121, 6509. (b) Liu, X.; Zhang, Y.; Wang, L.; Fu,
H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008, 73, 6207.
(4) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.;
Murai, S. J. Am. Chem. Soc. 2001, 123, 10935.
(1) (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731.
(b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (c)
Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698. (d) Li, C.-J. Acc. Chem.
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10.1021/ol901347t CCC: $40.75
Published on Web 07/22/2009
 2009 American Chemical Society

idinones from N-acylated pyrrolidines,7 and copper-catalyzed
reactions of tertiary amines with alkynes, indoles, ni-
tromethane, and malonates8 have been developed to synthe-
size R-substitued amines. Very recently, the copper-catalyzed
oxidative difluoromethylation of tertiary amines was de-
scribed.9 As our ongoing research program toward the
development of catalytic systems for the direct functional-
ization of C-H bonds,10 we have been interested with
employing amines as useful substrates. Herein, we describe
our results concerning the unique copper-catalyzed coupling
of silyl enol ethers with N,N-dimethylanilines to give
ꢀ-arylamino ketones by the cleavage of R-sp3 C-H bond of
nitrogen in the presence of TBHP under mild conditions
(Scheme 1, A).
formation of iminium ion intermediates.14 These conclusions
led us to the assumption that the nucleophilic attack of silyl
enol ethers, which are widely used in organic synthesis as
more reactive analogues of ketones, to these iminium ion
intermediates may be feasible to give ꢀ-arylamino ketones
directly, which would be extremely valuable from the
synthetic point of view.
To test our hypothesis, we examined the reaction of
cyclohexynyloxytrimethylsilane and N,N-dimethyl- ben-
zenamine in the presence of metal catalysts under oxida-
tive conditions, and a selection of examples are presented
in Table 1. The nature of catalysts, oxidants, and solvents
Table 1. Effect of Metals, Oxidants, and Solvents on the
Reactiona
Scheme 1. Strategies for Preparation of ꢀ-Amino Ketones
ꢀ-Amino ketones are highly valuable molecules consider-
ing their numerous applications for building blocks of drugs
and biologically active compounds.11 Traditionally, ꢀ-amino
ketones are synthesized by the Mannich reaction or the aza-
Michael addition reaction (Scheme 1, B and C). Although
these methods are widely used in organic synthesis, they
often suffer from long reaction time and harsh reaction
conditions.12 In particular, it has been difficult to achieve
ꢀ-arylamino ketones from Mannich reaction or aza-Michael
addition reaction using arylamines because of their reduced
nucleophilic reactivity.13 Recent studies established that the
coordination of nitrogen to metal and overlap of the metal
obital with the R-C-H bond in amines would induce the
(7) DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126,
6556.
(8) (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810. (b) Niu,
M.; Yin, Z.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008, 73, 3961. (c)
Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968. (d) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2005, 127, 3672. (e) Li, Z.; Li, C.-J. Eur. J. Org. Chem.
2005, 3173.
a Reaction conditions: N,N-dimethylbenzenamine (122 mg, 1 mmol),
cyclohexenyloxytrimethylsilane (85 mg, 0.5 mmol), catalyst (0.025 mmol),
oxidant (1 equiv), TBHP (1-1.2 equiv), 0.10 mL, 5-6 M in decane, CH3CN
(5 mL), 50 °C, 12 h. b Isolated yields. c 1.5 mmol of N,N-dimethylbenze-
namine was used. d 1.2 equiv of 2ꢀ-di-tert-butyl-4-methylphenol (BHT)
was added.
(9) Chu, L.; Zhang, X.; Qing, F.-L. Org. Lett. 2009, 11, 2197.
(10) (a) Cheng, K.; Yao, B.; Zhao, J.; Zhang, Y. Org. Lett. 2008, 10,
5309. (b) Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428.
(c) Cheng, K.; Huang, L.; Zhang, Y. Org. Lett. 2009, 11, 2908.
(11) (a) Traxler, P.; Trinks, U.; Buchdunger, E.; Mett, H.; Meyer, T.;
Mu¨ller, M.; Regenass, U.; Ro¨sel, J.; Lydon, N. J. Med. Chem. 1995, 38,
2441. (b) Dimmock, J. R.; Sidhu, K. K.; Chen, M.; Reid, R. S.; Allen,
T. M.; Kao, G. Y.; Truitt, G. A. Eur. J. Med. Chem. 1993, 28, 313.
(12) (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem.,Int. Ed.
1998, 37, 1044. (b) Tramontini, M. Synthesis 1973, 703.
(13) (a) Craig, J. C.; Moyle, M.; Johnson, L. F. J. Org. Chem. 1964,
29, 410. (b) Danishefsky, S.; Kitahara, T.; McKee, R.; Schuda, P. F. J. Am.
Chem. Soc. 1976, 98, 6715. (c) Varala, R.; Alam, M. M.; Adapa, S. R.
Synlett 2003, 720.
was crucial for the activation of sp3 C-H bond of
dimethylbenzenamine. No reaction was examined in the
absence of catalysts or oxidants (entries 1 and 2). The
reaction was found to occur in the presence of TBHP with
several metals such as RuCl3, Pd(OAc)2, FeCl3, and FeCl2,
Org. Lett., Vol. 11, No. 16, 2009
3731

but with low yields (entries 3-6). An improvement was
presented by using copper catalysts such as CuI, CuCl,
CuBr2, and CuCl2, and the combination of CuBr and TBHP
provided the best result (entries 7-11). Other oxidants
including benzoic peroxyanhydride and 2-(tert-butylper-
oxyl)-2-methyl- propane were less efficient (entries 12 and
13). A study of the reaction in various solvents identified
acetonitrile as suitable alternatives to CH2Cl2 and toluene
(entries 14 and 15). The use of excess anilines could be
beneficial and provided improved yield (entry 16). Cy-
clohexanone was inactive under the reaction conditions,
showing that silyl enol ethers are better nucleophiles than
corresponding carbonyl derivatives. Notably, the reaction
was completely chemoselective and no traces of product
resulting from second coupling were detected.
Table 2. Reaction of N,N-Dimethylanilines with Silyl Enol
Ethersa
The generality of this transformation was examined under
the optimized reaction conditions, and the results are
summarized in Table 2. A broad range of N,N-dimethyla-
nilines could be coupled with silyl enol ethers. N,N-
Dimethylanilines bearing both electron-donating and electron-
withdrawing substituents on the aryl ring could be successfully
used in the direct reaction with silyl enol ethers to synthesis
the desired ꢀ-arylamino ketones (Table 2, entries 1-8).
However, the substituent at ortho-position drastically slowed
the reaction (Table 2, entry 12). Very poor reactivity of other
hindered tertiary amines and anilines such as N-phenyl-
1,2,3,4-tetrahydroisoquinoline and N,N-diethylbenzenamine
was also observed, indicating that the steric hindance
successively decreased the reactivity. Both acyclic and cyclic
silyl enol ethers, which were easily prepared through a
stirring of ketones with CH3SiCl in the presence of Et3N
and NaI in CH3CN at room temperature,15 were found to
serve as good substrates (Table 2, entries 1-25). In the case
of cyclic silyl enol ethers, the size of cycle has an significant
effect on the efficiency of the reaction. Cyclohexenyloxy-
trimethylsilane and cycloheptenyloxytrimethylsilane were
active substrates and gave the desired ꢀ-amino ketones
efficiently (Table 2, entries 9-20). Cyclopentenyloxytrim-
ethylsilane, however, was found to be less active to afford
lower yields (Table 2, entry 21). The aryl silyl enol ether
were also applicable to the present reaction to give the
corresponding ꢀ-arylamino ketones smoothly (Table 2,
entries 22-25).
a Reaction conditions: N,N-dimethylanilines (1.5 mmol), CuBr (4 mg,
0.025 mmol), silyl enol ethers (0.5 mmol), TBHP (1-1.2 equiv), 0.10 mL,
5-6 M in decane, CH3CN (5 mL), 50 °C, 12 h. b Isolated yields. c 1 mmol
of N,N-dimethylbenzenamine was used.
We extended the reaction to unsymmetrical silyl enol
ethers. It is known that the regioselectivity of ketones in
Mannich reaction is difficult to control to any significant
extent. With the aid of strong lithium base (LDA),16 we
prepared the less substituent kinetically favored silyl enol
ether 1f from 2-methylcyclohexanone. In addition, under the
conventional equilibrium conditions, we obtained the more
stable silyl enol ether 1g via the removing of C-2 proton in
2-methylcyclohexanone. Notably, during the course of this
transformation the reaction of N,N-dimethylbenzenamine
took place regioselectively at the olefinic position of the silyl
enol ethers, and the regiochemical feature was retained. As
we expected, the reactivity of silyl enol ether 1g was slightly
decreased due to the steric hindrance (Scheme 2). This
reaction provided an alternative method for regioselective
synthesis of ꢀ-arylamino ketones.
Encouraged by the successful reaction between silyl enol
ethers and N,N-dimethylanilines, we next attempted the
reaction of enol ethers with N,N-dimethylanilines. Signifi-
cantly, N,N-dimethylbenzenamine was directly converted to
(14) (a) Murahashi, S.-I.; Takaya, H. Acc. Chem. Res. 2000, 33, 225.
(b) Campos, K. R. Chem. Soc. ReV. 2007, 36, 1069.
(15) (a) Rathore, R.; Kochi, J. K. J. Org. Chem. 1996, 61, 627. (b)
Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.; Dunogues, J. Tetrahedron
1987, 43, 2075.
(16) House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org. Chem.
1969, 34, 2324.
3732
Org. Lett., Vol. 11, No. 16, 2009

Scheme 2
.
Regioselective Synthesis of ꢀ-Arylamino Ketones
Scheme 4. Plausible Mechanism
the derivatives of quinonlines via the intramolecular annu-
lation in a single step (Scheme 3), although the efficiency
Scheme 3. Synthesis of Quinoline Derivatives
give the annulated products. Another possible pathway is
that the free radicals generated by TBHP with the accelera-
tion of transition metals result in the formation of intermedi-
ate B,17 which undergoes the addition reaction to give the
products. We performed the reaction in the presence of 1.2
equiv of free-radical scavenger 2ꢀ-di-tert-butyl-4-methylphe-
nol (BHT) and found that the yield was decreased to 46%
(Table 1, entry 17). This result illustrates that a radical
pathway is not able to be fully excluded. Further research is
required for the elucidation of the detailed mechanism.
In summary, we have demonstrated the application of sp3
C-H bond activation for various N,N-dimethylanilines in
the synthesis of ꢀ-arylamino ketones under mild conditions.
The method is compatible with a wide range of silyl enol
ethers/enol ethers and the regiospecific additions typically
take place at the olefinic position of silyl enol ethers.
of the reaction required further improvement. Thus, cyclic
enol ether such as 2,3-dihydrofuran and 3,4-dihydro-2H-
pyran underwent the annulation process to provide the fused
heterocycles with cis-stereoisomers. The reaction demon-
strates the potential power for the construction of a C-C
bond in which the sp3 C-H activation occurs with concomi-
tant ring closure under catalytic mild conditions.
Based on the mechanistic findings of previous studies,5 a
plausible scenario that could account for the formation of
these compounds is illustrated in Scheme 4. The oxidative
addition of copper to the R-C-H bond of amine to give the
R-metalated intermediate A, which generates the η2-iminium
metal complex B.14 The nucleophilic attack of silyl enol ether
on iminium ion complex B affords the corresponding
ꢀ-amino ketones and librates the copper catalyst. In the case
of enol ethers, the nucleophilic attack of enol ether on the
iminium ion intermediate B results in the intermediate C,
which undergoes electrophilic addition to the phenyl ring to
Acknowledgment. Funding from Natural Science Foun-
dation of China (20872126) and Zhejiang Provincial Natural
Science Foundation of China (R407106) is acknowledged.
Supporting Information Available: Experimental pro-
cedure and characterization of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL901347T
(17) (a) Fayadh, J. M.; Jessop, D. W.; Swan, G. A. J. Chem. Soc. C
1966, 1605. (b) Murahashi, S.-I.; Naota, T.; Yonemura, K. J. Am. Chem.
Soc. 1988, 110, 8256.
Org. Lett., Vol. 11, No. 16, 2009
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