Liu et al.
chloramines-T,7a–c,8 bromamine-T,9 and tosyloxycarbamates10
as the primary nitrogen sources. Inspired by the previous good
results, we are searching for a convenient, efficient, and general
copper catalyst/oxidant system to reach the selective amidation
of C-H bonds. Fortunately, an excellent CuBr/NXS (X ) Br,
Cl) system has been developed for amidations of saturated C-H
bonds.
TABLE 1. Copper-Catalyzed Amidation of Benzylic sp3 C-H
Bond: Optimization of Conditionsa
entry
catalyst
CuO
Cu(OAc)2
CuSO4
CuCl
NXS
solvent
yieldb (%)
1
2
3
4
5
6
7
8
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NCS
NBS
NBS
NBS
NBS
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
hexane
ClC2H4Cl
CH3OH
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
22
34
15
40
56
51
18
64
Results and Discussion
Copper-Catalyzed Amidation of Benzylic C-H Bonds.
Because N-halosuccinimides (such as N-bromosuccinimide
(NBS) and N-chlorosuccinimide (NCS)) are the oxidants11 and
free radical triggers,12 we first chose diphenylmethane and
benzamide as the model substrates and NBS or NCS as the
oxidant to optimize the catalysis conditions, including optimiza-
tion of copper catalysts, oxidants, and solvents at 40 °C without
exclusion of air as shown in Table 1. Several copper salts, CuO,
Cu(OAc)2, CuSO4, CuCl, CuBr, and CuI, were tested in CH2Cl2;
Cu(I) salts showed better activity than Cu(II) salts in this
amidation (see entries 1-6), and CuBr was found to be the most
effective catalyst. The effect of solvents (CH2Cl2, hexane, 1,2-
dichloroethane, CH3OH, and EtOAc) (without any previous
procedure for the commercial available solvents) was also
investigated (compare entries 5 and 7-10); ethyl acetate
provided the highest yield (see entry 10). In order to export
whether the amidation reaction in entry 10 is from the catalysis
of Cu(II) salt (oxidation of CuBr), we investigated the effect of
CuBr2 in ethyl acetate, and only 36% yield of product was
obtained (entry 11). Slightly lower yields were given when NCS
replaced NBS as the oxidant (see entry 12). Only a trace amount
of amidation product was observed in the absence of copper
catalyst (entry 13). The amidation led to a lower yield when a
base (such as K2CO3) was added to the reaction system (entry
14). When the reaction temperature was increased to 60 °C,
the reaction yield was slightly improved (compare entries 10
and 15). The use of excess of diphenylmethane (2 equiv)
improved amide conversion and improved the yield of 3a
(compare entries 10 and 16). After the optimization process of
catalysts, oxidants, solvents, and temperature, the following
amidations were carried out under our standard conditions: CuBr
as the catalyst, NBS as the oxidant (NCS was used as the oxidant
for amidation of isochroman), and ethyl acetate as the solvent.
CuBr
CuI
CuBr
CuBr
CuBr
CuBr
CuBr2
CuBr
9
trace
75 (64c)
36
10
11
12
13
14
15
16
68
traced
63e
78f
CuBr
CuBr
CuBr
34g
a Reaction conditions: diphenylmethane (1 mmol), benzamide (0.5
mmol), catalyst (0.1 mmol), NBS or NCS (0.55 mmol), solvent (3 mL).
b Determined by 1H NMR using THF as the internal standard. c Isolated
yield. d No addition of catalyst. e K2CO3 was used as the base.
f Reaction temperature was maintained at 60 °C. g 0.55 mmol of
diphenylmethane was used.
The amidation temperature of benzylic sp3 C-H bonds was
maintained between room temperature and 80 °C without
exclusion of air.
The scope of CuBr/NBS-mediated amidation of benzylic sp3
C-H bonds was investigated under our standard conditions.
As shown in Table 2, the coupling reactions could be performed
for the substrates examined, and the desired amidation products
were obtained in moderate to good yields. The activity order
of the benzylic reagents is triphenylmethane > diphenylmethane
> ethylbenzene > 4-bromoethylbenzene. For example, the
amidation of triphenylmethane could be carried out at room
temperature (entry 14), while the coupling reactions of 4-bro-
moethylbenzene with amides were not performed until the
temperature was raised to 80 °C (entries 11 and 12). We also
investigated amidation of isochroman; interestingly, NCS is a
more effective oxidant than NBS, and the reactions selectively
occurred on the benzylic C-H bond adjacent to the oxygen
atom (entries 15-17). For the carboxamides and sulfonamides,
the electron effect of the substrates are prime, the substrates
containing the stronger electron-withdrawing groups showed
higher reactivity, and their order of activity is sulfonamides >
benzamides > aliphatic amides. In addition, the benzamides
containing electron-withdrawing groups usually showed higher
reactivity than those containing electron-donating groups (com-
pare entries 1-5).
(7) (a) Fructos, M. R.; Trofimenko, S.; D´ıaz-Requejo, M. M.; Pe´rez, P. J.
J. Am. Chem. Soc. 2006, 128, 11784–11791. (b) Bhuyan, R.; Nicholas, K. M.
Org. Lett. 2007, 9, 3957–3959. (c) Albone, D. P.; Challenger, S.; Derrick, A. M.;
Fillery, S. M.; Irwin, J. L.; Parsons, C. M.; Takada, H.; Taylor, P. C.; Wilson,
D. J. Org. Biomol. Chem. 2005, 3, 107–111. (d) Pelletier, G. ; Powell, D. A.
Org. Lett. 2006, 8, 6031–6034. (e) Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org.
Lett. 2007, 9, 3813–3816.
(8) (a) Albone, D. P.; Challenger, S.; Derrick, A. M.; Fillery, S. M.; Irwin,
J. L.; Parsons, C. M.; Takada, H.; Taylor, P. C.; Wilson, D. J. Org. Biomol.
Chem. 2005, 3, 107–111. (b) Simkhovich, L.; Gross, Z. Tetrahedron Lett. 2001,
42, 8089–8092. (c) Albone, D. P.; Aujla, P. S.; Taylor, P. C.; Challenger, S.;
Derrick, A. M. J. Org. Chem. 1998, 63, 9569–9571.
A possible mechanism for the amidation of benzylic sp3 C-H
bonds is proposed in Scheme 1. Reaction of carboxamide or
sulfonylamide with NBS yields N-bromocarboxamide or N-
bromosulfonamide (A),13 exchange of copper(I) ion with proton
in A gives B, and the exchange pathway of metal ion with proton
in sulfonamides was proposed in the previous catalytic cycle.14
It is worthwhile to note that B is similar to chloramines-T,7a–c,8
(9) (a) Gao, G.-Y.; Harden, J. D.; Zhang, X. P. Org. Lett. 2005, 7, 3191–
3993. (b) Harden, J. D.; Ruppel, J. V.; Gao, G.-Y.; Zhang, X. P. Chem. Commun.
2007, 4644–4646. (c) Chanda, B. M.; Vyas, R.; Bedekar, A. V. J. Org. Chem.
2001, 66, 30–34. (d) Vyas, R.; Gao, G.-Y.; Harden, J. D.; Zhang, X. P. Org.
Lett. 2004, 6, 1907–1910.
(10) (a) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127,
14198–14199. (b) Lebel, H.; Huard, K. Org. Lett. 2007, 9, 639–642. (c) Lebel,
H.; Leogane, O.; Huard, K.; Lectard, S. Pure Appl. Chem. 2006, 78, 363–375.
(11) (a) Kim, D. W.; Choi, H. Y.; Lee, K. J.; Chi, D. Y. Org. Lett. 2001, 3,
445–447. (b) Krishnaveni, N. S.; Surendra, K.; Rao, K. R. AdV. Synth. Catal.
2004, 346, 346–350.
(12) Sharma, V. B.; Jain, S. L.; Sain, B. J. Mol. Catal. A: Chem. 2005, 227,
47–49.
(13) (a) Thakur, V. V.; Talluri, S. K.; Sudalai, A. Org. Lett. 2003, 5, 861–
864. (b) Talluri, S. K.; Sudalai, A. Org. Lett. 2005, 7, 855–857.
6208 J. Org. Chem. Vol. 73, No. 16, 2008