Copper-catalyzed amidation of sp3 C - H bonds adjacent to a nitrogen atom

Article abstract of DOI:10.1021/ol701715m

We have developed a novel copper-catalyzed amidation of unactivated sp ³ C - H bonds adjacent to a nitrogen atom by using an inexpensive catalyst - oxidant (CuBr/^tBuOOH) system under mild conditions. The dephenylation was first found

Full text of DOI:10.1021/ol701715m

ORGANIC
LETTERS
Copper-Catalyzed Amidation of sp3 C
Bonds Adjacent to a Nitrogen Atom
−H
2007
Vol. 9, No. 19
3813-3816
Yongming Zhang,† Hua Fu,*,† Yuyang Jiang,†,‡ and Yufen Zhao†
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Ministry
of Education, Department of Chemistry, Tsinghua UniVersity, Beijing 100084,
P. R. China, and Key Laboratory of Chemical Biology, Guangdong ProVince,
Graduate School of Shenzhen, Tsinghua UniVersity, Shenzhen 518057, P. R. China
fuhua@mail.tsinghua.edu.cn
Received July 19, 2007
ABSTRACT
We have developed a novel copper-catalyzed amidation of unactivated sp3
catalyst
oxidant (CuBr/tBuOOH) system under mild conditions. The dephenylation was first found for N-benzylaniline, and the new class of
products provide diverse structures for pharmaceuticals and combinatorial chemistry.
C−H bonds adjacent to a nitrogen atom by using an inexpensive
−
Direct and selective formation of C-C, C-O, and C-N
bonds from unactivated carbon-hydrogen bonds is an
important and long-standing goal in chemistry. These
conversions have wide potential in synthetic organic chem-
istry because C-H bonds are ubiquitous in organic mol-
ecules. However, achieving selectivity among many different
C-H bonds remains a challenge.1 The formation of C-N
bonds is very important in organic synthesis because many
bioactive and medicinal molecules are nitrogen-containing
compounds.2 The vast majority of methods for the introduc-
tion of C-N bonds depends on functional group intercon-
versions for their synthesis, thus the direct utilization of only
C-H bonds is highly desirable.3 In the past several years,
great achievements have been made on amidation via a C-H
activation strategy, particularly with regards to allylic and
benzylic C-H bonds,4-6 and most of them were performed
through the metal-nitrene-type amidation. Although great
(3) Davies, H. M. L.; Long, M. S. Angew. Chem., Int. Ed. 2005, 44,
3518-3520.
(4) Representative intramolecular metal-nitrene-type amidations: (a)
Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett. 2006, 8,
1073-1076. (b) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005,
127, 14198-14199. (c) Cui, Y.; He, C. Angew. Chem., Int. Ed. 2004, 43,
4210-4212. (d) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am.
Chem. Soc. 2004, 126, 15378-15379. (e) Liang, J.-L.; Yuan, S.-X.; Huang,
J.-S.; Yu, W.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2002, 41, 3465-
3468. (f) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem.
Soc. 2001, 123, 6935-6936. (g) Espino, C. G.; Du Bois, J. Angew. Chem.,
Int. Ed. 2001, 40, 598-600.
† Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology.
‡ Key Laboratory of Chemical Biology.
(1) (a) Godula, K.; Sames, D. Science 2006, 312, 67-72. (b) Bergman,
R. G. Nature 2007, 446, 391-393. (c) Cho, J.-Y.; Tse, M. K.; Holmes, D.;
Maleczka, R. E., Jr.; Smith, M. R., III. Science 2002, 295, 305-307. (d)
Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287,
1995-1997. (e) Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507-
514.
(2) (a) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439-2463.
(b) Du Bois, J. Chemtracts 2005, 18, 1-13. (c) Espino, C. G.; Du Bois, J.
In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-
VCH: Weinheim, 2005; pp 379-416. (d) Halfen, J. A. Curr. Org. Chem.
2005, 9, 657-669.
(5) Representative intermolecular metal-nitrene-type amidations: (a)
Fructos, M. R.; Trofimenko, S.; D´ıaz-Requejo, M. M.; Pe´rez, P. J. J. Am.
Chem. Soc. 2006, 128, 11784-11791. (b) Thu, H.-Y.; Yu, W.-Y.; Che,
C.-M. J. Am. Chem. Soc. 2006, 128, 9048-9049. (c) Leung, S. K.-Y.; Tsui,
W.-M.; Huang, J.-S.; Che, C.-M.; Liang, J.-L.; Zhu, N. J. Am. Chem. Soc.
2005, 127, 16629-16640. (d) Pelletier, G.; Powell, D. A. Org. Lett. 2006,
8, 6031-6034.
(6) For other strategies for the amidation of allylic and benzylic C-H
bonds, see: (a) Adam, W.; Krebs, O. Chem. ReV. 2003, 103, 4131-4146.
(b) Johannsen, M.; Jørgensen, K. A. Chem. ReV. 1998, 98, 1689-1708.
10.1021/ol701715m CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/16/2007

progress has been made in intramolecular4 amidation reac-
tions, intermolecular5 couplings remain limited, and some
expensive metal catalysts, such as Ru and Rh, were generally
used. Herein, we report an efficient copper-catalyzed ami-
dation of sp3 C-H bonds adjacent to a nitrogen atom.
Since tert-butyl hydroperoxide (tBuOOH) is a suitable
oxidant in the copper-catalyzed formation of C-C bonds
by directly using C-H bonds,7 we first chose N,N-dimethyl-
p-toluidine and benzoylamide as the model substrates and
Table 2. Copper-Catalyzed Amidation of N,N-Dimethylaniline
Derivativesa
t
1.5 equiv of BuOOH (relative to benzoylamide) in decane
as the oxidant to optimize the catalysis conditions, including
optimization of the copper catalysts and solvents in amidation
at 80 °C as shown in Table 1. Several copper salts, CuCl,
Table 1. Copper-Catalyzed Amidation of sp3 C-H Bonds:
Optimization of Conditionsa
entry
catalyst
additional solvent
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CuCl
CuBr
CuI
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
CH3CN
CH2Cl2
CH3OH
THF
20
61
52
16
3
48
25
35
25
42
82 (77c)
0d
0e
57f
60g
CuO
CuSO4
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
DMSO
DMSO
CuBr
CuBr
CuBr
a Reaction conditions: under nitrogen atmosphere, N,N-dimethyl-p-
toluidine (2 mmol), benzoylamide (1 mmol), tBuOOH (1.5 mmol, 5-6 M
in decane), catalyst (0.05 mmol), solvent (0.5 mL). b Reported yields were
determined by NMR using THF or CH3CN as internal standard, and were
based on benzoylamide. c Isolated yield. d No addition of copper-catalyst
t
t
or BuOOH. e Room temperature. f Pure BuOOH was used as a dehydro-
genative reagent instead of BuOOH in decane. g Without nitrogen atmo-
t
sphere.
CuBr, CuI, CuO, and CuSO4 (5 mol % catalytic amount
relative to benzoylamide), were tested in DMSO, and CuBr
was found to be the most effective catalyst in this amidation.
The reaction did not proceed in the absence of either a copper
t
catalyst or BuOOH (entry 12). We also studied the effect
a Reaction conditions: under nitrogen atmosphere, anilines (4 mmol for
of solvents (compare entries 1, 6-10). Decane provided the
highest yield (see entry 11); DMSO (see entry 14) and mixed
solvents (mixture of decane and other solvents) gave lower
yields. When the reaction temperature was lowered to room
entries 1-3, 6, 8, 10-11, 13, 14; 3 mmol for others), amides (2 mmol),
t
CuBr (0.1 mmol), BuOOH (3 mmol, 5-6 M in decane). b Isolated yield.
c DMSO (1 mL) as the additional solvent.
(7) (a) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006,
103, 8928-8933. (b) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997-4999. (c)
Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810-11811. (d) Li, Z.; Li,
C.-J. J. Am. Chem. Soc. 2005, 127, 3672-3673.
temperature, no product was found (entry 13). The amidation
led to a lower yield in the absence of a nitrogen atmosphere
(entry 15). The use of 2 equiv of aniline increased the amide
3814
Org. Lett., Vol. 9, No. 19, 2007

such example in metal-catalyzed direct amidation of C-H
bonds reported thus far.
We also attempted intramolecular amidation under our
standard coupling conditions as shown in Scheme 1, and the
Table 3. Copper-Catalyzed Amidation of
N-Methyl-N-benzylanilinea
Scheme 1. Synthesis of the Six-Membered Cyclic Compound
six-membered cyclic compound 5 was obtained in 59% yield.
This might be a favorable process to construct complex
nitrogen-containing heterocycles in pharmaceuticals and
combinatorial chemistry.
A tentative mechanism for product formation is proposed
in Scheme 2. Reaction of the N-substituted aniline with
Scheme 2. Tentative Mechanism for the Direct Oxidative
Coupling of N-Substituted Aniline with Amide
a Reaction conditions: under nitrogen atmosphere, anilines (4 mmol),
amides (2 mmol), CuBr (0.1 mmol), tBuOOH (3 mmol, 5-6 M in decane).
b Isolated yield.
conversion and improved the yield. After the optimization
process for catalysts, solvents and temperature, we decided
to carry out the following reactions under our standard
conditions: 5 mol % CuBr as the catalyst relative to amides
and decane or decane/DMSO mixture as the solvent (the
mixed solvent was used for insoluble substrates in decane)
at 80 °C.
The scope of the copper-catalyzed amidation was explored
under our standard conditions. As shown in Table 2, the
coupling reactions could be performed for all of the substrates
examined, and the desired amidation products were obtained
in various yields. The substituted anilines containing electron-
rich groups showed higher reactivity than those containing
electron-deficient groups. The ortho-substituted aniline (1c)
gave a low yield (entry 10) because of steric hindrance.
However, the electron-deficient amides gave higher reaction
yields than the electron-rich ones, the primary amides
provided higher reaction activity than the secondary ones,
and N-arylamide was a poor substrate (entry 5).
tBuOOH under catalysis of CuBr produced the free radical
A through a single-electron transfer. The resulting iminium
type intermediate B or C was then generated, leaving a
hydrogen7,8 or phenyl free radical. Combination of B or C
and amide with copper formed the complex D or E, and
removal of the copper catalyst yielded the amidation product
3 (dehydrogenative product or dephenylation product).
In summary, we have developed a novel copper-catalyzed
amidation of unactivated sp3 C-H bonds adjacent to a
nitrogen atom via cross-dehydrogenative-coupling reaction
by using an inexpensive catalyst-oxidant (CuBr/tBuOOH)
system under mild conditions. The dephenylation of N-
benzylaniline first was disclosed, and the new products may
provide diverse structures for pharmaceuticals and combi-
Interestingly, reactions of amides with N-methyl-N-ben-
zylaniline led to both dehydrogenative and dephenylation
coupling products, and the latter product was major (see
Table 3). To our knowledge, the dephenylation is the first
(8) (a) Wang, F.; Sayre, L. M. J. Am. Chem. Soc. 1992, 114, 248-255.
(b) Leonard, N. J.; Leubner, G. W. J. Am. Chem. Soc. 1949, 71, 3408-
3411.
Org. Lett., Vol. 9, No. 19, 2007
3815

natorial chemistry. The scope, mechanism, and synthetic
application of this reaction is under investigation.
IRT0404) in China, and the Key Subject Foundation from
Beijing Department of Education (XK100030514).
Supporting Information Available: Synthetic proce-
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (Grant Nos.
20472042 and 20672065), Programs for New Century
Excellent Talents in University (NCET), Changjiang Scholars
and Innovative Research Team in University (PCSIRT) (No.
1
dures, characterization data, and H and 13C NMR spectra
of these synthesized compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL701715M
3816
Org. Lett., Vol. 9, No. 19, 2007