A β-keto ester as a novel, efficient, and versatile ligand for copper(I)-catalyzed C-N, C-O, and C-S coupling reactions

Article abstract of DOI:10.1021/jo070443m

(Formula Presented) Employing ethyl 2-oxocyclohexanecarboxylate as a novel, efficient, and versatile ligand, the copper-catalyzed coupling reactions of various N/O/S nucleophilic reagents with aryl halides could be successfully carried out under mild conditions. A variety of products including N-arylamides, N-arylimidazoles, aryl ethers, and aryl thioethers were synthesized in good to excellent yields.

Full text of DOI:10.1021/jo070443m

A â-Keto Ester as a Novel, Efficient, and Versatile Ligand for
Copper(I)-Catalyzed C-N, C-O, and C-S Coupling Reactions
Xin Lv and Weiliang Bao*
Department of Chemistry, Xixi Campus, Zhejiang UniVersity, Hangzhou 310028,
People’s Republic of China
wlbao@css.zju.edu.cn
ReceiVed March 3, 2007
Employing ethyl 2-oxocyclohexanecarboxylate as a novel, efficient, and versatile ligand, the copper-
catalyzed coupling reactions of various N/O/S nucleophilic reagents with aryl halides could be successfully
carried out under mild conditions. A variety of products including N-arylamides, N-arylimidazoles, aryl
ethers, and aryl thioethers were synthesized in good to excellent yields.
Introduction
Taillefer ligands) were used.2g In 2002, Buchwald et al. found
that several diamino-type ligands could greatly facilitate the
reactions between aryl halides and amides at low temperatures.2j
Recently, they reported the copper-catalyzed C-N coupling
reactions of aliphatic amines with aryl iodides promoted by
â-diketone at room temperature, and satisfying results were
achieved in relatively shorter reaction times.5 Very recently,
BINOL was used as a new ligand for copper-catalyzed N-
arylation of aliphatic amines at room temperature by Fu and
co-workers.6 Ma et al. reported a C-C bond formation at
surprisingly low temperatures facilitated by trans-4-hydroxy-
L-proline, and they extended the Ullmann coupling to the area
of enantioselective synthesis.7 The above reports revealed that
proper ligands could obviously accelerate the reaction rates and
substantially lower the reaction temperatures. However, the
applications of these Ullmann methods might be limited in a
certain degree by the high expense, unavailability, or specificity
N-Arylamides, N-arylimidazoles, aryl ethers, and aryl thio-
ethers are valuable compounds widely employed in organic
synthesis, pharmaceutical, or biological areas.1 One of the most
common synthetic protocols for their preparation is copper-
catalyzed Ullmann coupling. However, classic Ullmann reac-
tions are usually conducted under harsh conditions, and
therefore, their applications would be restricted. Recently, much
enthusiasm has been paid to the improvement of Ullmann
coupling, and significant progress has been made.2-4 In 2001,
Taillefer et al. discovered that pyrazoles were successfully
N-arylated when several oxime/imine-type ligands (Cristau-
* To whom correspondence should be addressed. Tel/Fax: +86 571
88273814. E-mail: wlbao@css.zju.edu.cn.
(1) For reviews, see: (a) Barchechath, S. D.; Tawatao, R. I.; Corr, M.;
Carson, D. A.; Cottam, H. B. J. Med. Chem. 2005, 48, 6409. (b) Zhong,
C.; He, J.; Xue, C.; Li, Y. Bioorg. Med. Chem. 2004, 12, 4009. (c) Theil,
F. Angew. Chem., Int. Ed. 1999, 38, 2345. (d) Buckingham, J. B. In
Dictionary of Natural Products; CRC Press: Boca Raton, FL, 1994;
Vol. 1.
(2) For recent copper-catalyzed C-N coupling reactions, see: (a)
Taillefer, M.; Xia, N.; Ouali, A. Angew. Chem. 2007, 46, 934. (b) Chen,
Y-J.; Chen, H.-H. Org. Lett. 2006, 8, 5609. (c) Buchwald, S. L.; Altman,
R. A. Org. Lett. 2006, 8, 2779. (d) Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.;
Chen, H.; Wan, B. Tetrahedron 2006, 62, 4435. (e) Zhang, H.; Cai, Q.;
Ma, D. W. J. Org. Chem. 2005, 70, 5164. (f) Buchwald, S. L.; Antilla, J.
C.; Baskin, J. M.; Barder, T. E. J. Org. Chem. 2004, 69, 5578. (g) Cristau,
H.-J.; Cellier, P.; Spindler, J.-F.; Taillefer, M. Eur. J. Org. Chem. 2004,
695. The related applications were earlier reported in a patent in 2001 (FR
01 16547). (h) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (i)
Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793. (j) Buchwald, S.
L.; Klapars, A.; Huang, X. H. J. Am. Chem. Soc. 2002, 124, 7421.
(3) For recent C-O coupling reactions, see: (a) Ouali, A.; Spindler, J.-
F.; Jutand, A.; Taillefer, M. Organometallics 2007, 26, 65. (b) Ouali, A.;
Spindler, J.-F.; Cristau, H. J.; Taillefer, M. AdV. Synth. Catal. 2006, 348,
499. (c) Cristau, H. J.; Cellier, P. P.; Hamada, S.; Spindler, J.-F.; Taillefer,
M. Org. Lett. 2004, 6, 913. (d) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799.
(e) Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 10770. (f) Gujadhur, R. K.; Bates, C. G.; Venkataraman,
D. Org. Lett. 2001, 3, 4315.
(4) For recent C-S coupling reactions, see: (a) Itoh, T.; Mase, T. Org.
Lett. 2004, 6, 4587. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4,
3517.
(5) Shafir, S.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(6) Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007, 72, 672.
(7) Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050.
10.1021/jo070443m CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/14/2007
J. Org. Chem. 2007, 72, 3863-3867
3863

Lv and Bao
TABLE 1. N-Arylation of 2-Pyrrolidinone in Different Conditionsa
FIGURE 1. The effect of the ligand in the N-arylation of 2-pyrroli-
dinone.
entry
cat/L
base
solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
NMP
dioxane
[Bmim]BF4
DMSO
DMSO
DMSO
DMSO
yield %b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CuI/A
CuI/B
CuI/C
CuI/D
CuI/E
CuI/F
CuI/-
CuI/D
CuI/D
CuI/D
CuI/D
CuI/D
CuI/D
CuI/D
CuBr/D
CuCl/D
Cu2O/D
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
trace
36
30
78
trace
34
trace
16
55
83
70
22
trace
93
96
11
to not be suitable for this coupling either (entry 3). Another
cyclic â-keto ester D was tested, and moderate result was
achieved (entry 4). Interestingly, an R-substituted cyclic â-keto
ester E was introduced into the reaction to compare with ligand
D, but it seemed to be inefficient (entry 5). Maybe the Et group
blocked the formation of the enolate. An amino acid N,N-
dimethyl glycine (ligand F), once reported as a good ligand for
vinyl C-N coupling, was examined.9 However, low yield
revealed that F was inefficient in this reaction condition
(entry 6). Finally, a blank test without any ligand was carried
out, and almost no product was detected in the same condition
(entry 7). The effects of these ligands on the reaction were
clearly demonstrated by Figure 1.
A brief study of several other reaction conditions was carried
out after the best ligand was determined. As shown in Table 1
(entries 4, 8, and 9), with their basicities increasing, K2CO3,
K3PO4, and Cs2CO3 led to sharply ascending efficiencies in the
arylation of pyrrolidin-2-one. Cs2CO3 was found to be the most
appropriate base (entry 4). Then the effect of solvent was
evaluated (Table 1, entries 4 and 10-14). Dioxane was not
suitable as a solvent. To our surprise, the reaction in the RTIL
(room-temperature ionic liquid) gave a disappointing result
(entry 13). DMSO performed as the prime solvent; DMF, CH3-
CN, and NMP were fairish, but were not as good as DMSO.
The copper(I) resources also were proved to have remarkable
effects on the reaction (entries 14-17). Both CuI and CuBr
were satisfying, whereas CuBr was a little better than CuI. CuCl
and Cu2O performed improperly for the coupling reaction.
Therefore, the optimized conditions employed 10 mol % of
CuBr, 20 mol % of ligand D, and 2.1 equiv of Cs2CO3 in
DMSO.
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
7
a Reaction conditions: iodobenzene (1.0 mmol), amide (1.2 mmol), Cu(I)
catalyst (0.1 mmol), ligand (0.2 mmol), and Cs2CO3 (2.1 mmol) in indicated
solvent (1.0 mL) at rt (∼25 °C) under N2 for 22 h. b Isolated yields.
of the ligands. Recently, several examples have been presented
to apply the same ligands for various carbon-heteroatom
coupling reactions, and their applications seem to be of more
and more importance.2d,e,3d,8 Therefore, more efficient, versatile,
and facile ligands for facilitating these coupling reactions under
relatively milder conditions are still in demand.
Inspired by Buchwald’s active â-diketone-type ligands, we
examined more commercially available and facile â-keto esters
as ligands. Fortunately, we found one of them could facilitate
various copper(I)-catalyzed carbon-heteroatom coupling reac-
tions. Herein we report that, promoted by ethyl 2-oxocyclo-
hexanecarboxylate, aryl halides could successfully couple with
N/O/S nucleophilic reagents at relatively lower temperatures
(no higher than 80 °C).
Coupling Reactions of Aryl Halides with Amides under
the Catalysis of CuBr/Ethyl 2-Oxocyclohexanecarboxylate.
After the best reaction condition was set, we screened different
aryl halides and amides to explore the scope of the C-N
coupling reactions. The p-Cl and p-Br groups on the aryl iodides
were tolerated, and good results could be obtained at room
temperature (Table 2, entries 2 and 3). Electron-donating groups
on the aryl halides usually depressed the efficiencies of the
reactions to a certain extent. Those halides with a p-Me group
generally required higher temperatures (entries 4 and 10). Para-
methoxy aryl halides gave the worst results and needed higher
temperatures and longer reaction time (entries 5 and 11).
Coupling Reactions of Aryl Halides with Imidazoles under
the Catalysis of CuBr/Ethyl 2-Oxocyclohexanecarboxylate.
The C-N coupling reactions between aryl halides and imida-
Results and Discussion
Optimization of the Coupling Condition. Initially, we tried
to seek the optimal ligand from compounds A-F for Cu(I)-
catalyzed C-N bond formation. Iodobenzene and 2-pyrrolidi-
none were chosen as the model substrates with CuI as the
catalyst. The linear â-keto esters A and B were employed
(Table 1, entries 1 and 2). However, there was only a trace
amount of the product detected in the presence of A; the reaction
promoted by B gave low yield. The cyclic â-keto ester C seemed
(8) (a) Ouali, A.; Laurent, R.; Caminade, A.-M.; Majoral, J.-P.; Taillefer,
M. J. Am. Chem. Soc. 2006, 128, 15990. (b) Ouali, A.; Renard, B.; Spindler,
J.-F.; Taillefer, M. Chem.sEur. J. 2006, 20, 5301. (c) Rao, H.; Jin, Y.; Fu,
H.; Jiang, Y.; Zhao, Y. Chem.sEur. J. 2006, 12, 3636. (d) Cristau, H.-J.;
Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.sEur. J. 2004, 10, 5607.
(e) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4,
2803.
(9) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809.
3864 J. Org. Chem., Vol. 72, No. 10, 2007

Cu/â-Keto Ester-Catalyzed C-X Bond Coupling
TABLE 2. CuBr/Ethyl 2-Oxocyclohexanecarboxylate-Catalyzed N-Arylation of Amidea
a Reaction conditions: halide (1.0 mmol), amide (1.2 mmol), CuBr (0.1 mmol), ligand D (0.2 mmol), and Cs2CO3 (2.1 mmol) in DMSO (1.0 mL) under
N2. b Isolated yields.
zoles were examined. The CuBr/â-keto ester-catalyzed protocol
could also facilitate this type of C-N coupling efficiently
(Table 3). The reactions of imidazole with some aryl iodides
successfully occurred at an especially low temperature (45 °C,
entries 1 and 2). It was found that they could handle the
electronic effects (entries 2, 6, and 8). Unfortunately, the
reactions seemed to be sensitive to the steric hindrance on the
nucleophilic reagents. 1H-Benzoimidazole seemed to be more
difficult to react with aryl halides compared to imidazole, but
once higher temperatures were provided, moderate to good
results were achieved (entries 3 and 7).
Coupling Reactions of Aryl Halides with Phenols under
the Catalysis of CuBr/Ethyl 2-Oxocyclohexanecarboxylate.
We also applied this ligand to the copper-catalyzed C-O
coupling reactions of phenols with aryl halides. Fortunately, the
catalysis system was found to be efficient in the aryl C-O bond-
forming reactions. The diaryl ether products from the coupling
between phenols and aryl iodides were obtained in good to
excellent yields (Table 4, entries 1-4 and 8). While higher
temperature and longer reaction times were employed, three aryl
bromides also gave good yields (entries 5-7).
work: C-S bond formations via coupling of thiols with aryl
iodides. The results showed that this ligand also could success-
fully promote these reactions, and the desired products were
gained in good to excellent yields (Table 5).
In summary, we found that the novel and commercially
available ethyl 2-oxocyclohexanecarboxylate was an efficient
and facile ligand. It could promote CuBr-catalyzed C-N, C-O,
and C-S coupling reactions. Generally, good to excellent yields
of the desired products could be successfully obtained. Note-
worthy was that the readily available ligand would be versatilely
used, and the coupling reactions promoted by this ligand
occurred under mild conditions. Given these advantages, this
method would have wilder implications for further development
of Ullmann reactions.
Experimental Section
General Consideration. All reactions were carried out in
Schlenk or test tubes, and run under an atmosphere of N2. All of
the copper sources, ligands, and bases were commercially available.
Organic solvents, also were commercially available, were dried over
4 Å molecular sieves before being used. All amides, imidazoles,
phenols, and thiols were used as received. Thin-layer chromatog-
raphy (TLC) was carried out with 0.2 mm thick silica gel plates
(GF 254) and visualized by UV light. The columns were packed
Coupling Reactions of Aryl Iodides with Thiols under the
Catalysis of CuBr/Ethyl 2-Oxocyclohexanecarboxylate. The
same catalytic system was applied for the last portion of our
J. Org. Chem, Vol. 72, No. 10, 2007 3865

Lv and Bao
TABLE 3. CuBr/Ethyl 2-Oxocyclohexanecarboxylate-Catalyzed N-Arylation of Imidazolea
a Reaction conditions: halide (1.0 mmol), imidazole (1.2 mmol), CuBr (0.1 mmol), ligand D (0.2 mmol), and Cs2CO3 (2.1 mmol) in DMSO (1.0 mL)
under N2. b Isolated yields.
TABLE 4. CuBr/Ethyl 2-Oxocyclohexanecarboxylate-Catalyzed O-Arylation of Phenola
a Reaction conditions: halide (1.0 mmol), phenol (1.2 mmol), CuBr (0.1 mmol), ligand D (0.2 mmol), and Cs2CO3 (2.1 mmol) in DMSO (1.0 mL) under
N2. b Isolated yields.
1
with silica gel 60 (200-300). All products were confirmed by H
NMR and 13C NMR. An unknown compound was additionally
confirmed by IR and elemental analysis.
General Procedure. An oven-dried Schlenk tube equipped with
a Teflon valve was charged with a magnetic stir bar, Cs2CO3 (684
mg, 2.1 mmol), CuBr (15 mg, 0.10 mmol, 10 mol %), and ethyl
2-oxocyclohexanecarboxylate (34 mg, 0.20 mmol, 20 mol %). The
tube was evacuated and backfilled with N2 (this procedure was
repeated three times). Under a counter flow of N2, DMSO (0.5
mL) was added by syringe and pre-stirred for 0.5 h at room
3866 J. Org. Chem., Vol. 72, No. 10, 2007

Cu/â-Keto Ester-Catalyzed C-X Bond Coupling
TABLE 5. CuBr/Ethyl 2-Oxocyclohexanecarboxylate-Catalyzed S-Arylation of Thiola
a Reaction conditions: halide (1.2 mmol), thiol (1.0 mmol), CuBr (0.1 mmol), ligand D (0.2 mmol), and Cs2CO3 (2.1 mmol) in DMSO (1.0 mL) under
N2. b Isolated yields.
temperature. Then a solution of halide (1.0 mmol for C-N and
C-O coupling; 1.2 mmol for C-S coupling) and nucleophilic
reagent (1.2 mmol for C-N and C-O coupling; 1.0 mmol for C-S
coupling) in DMSO (0.5 mL) was added via syringe under a counter
flow of N2. The tube was sealed, and the mixture was allowed to
stir at the temperature indicated in Tables 2-5. The reaction was
monitored by TLC. After the starting material was completely
consumed, the reaction was stopped and the mixture was cooled
to room temperature. The reaction mixture was directly passed
through Celite. After being rinsed with another 60 mL of ethyl
acetate, the combined filtrate was washed with saturated brine
(10 mL × 2). After the organic layer was dried by Na2SO4, it was
concentrated by rotatory evaporation. The residue was purified by
column chromatography on silica gel using hexane/ethyl acetate
as eluent to give the pure product.
(1:1) as eluent to give a white solid of 1-phenylpyrrolidin-2-one
(155 mg, 96%): white solid; H NMR (400 MHz, CDCl3) δ 7.60
(2 H, d, J ) 8.0 Hz), 7.36 (2 H, t, J ) 7.8 Hz), 7.13 (1 H, t, J )
7.4 Hz), 3.82-3.86 (2 H, m), 2.57-2.61 (2 H, m), 2.10-2.17
(2 H, m); 13C NMR (50 MHz, CDCl3) δ 174.4, 139.6, 129.0, 124.7,
120.2, 49.0, 33.0, 18.3 (CDCl3 δ 77.3).
1
Acknowledgment. This work was financially supported by
the Natural Science Foundation of China (No. 20372058).
Supporting Information Available: Typical experimental
1
procedure, characterization data, and copies of H and 13C NMR
spectra for all of the coupling products with additional IR spectra
for the unknown compound. This material is available free of charge
via the Internet at http://pubs.acs.org.
1-Phenylpyrrolidin-2-one (1a):8d The residue was purified by
column chromatography on silica gel using hexane/ethyl acetate
JO070443M
J. Org. Chem, Vol. 72, No. 10, 2007 3867