Copper-catalyzed highly regioselective oxidative c-h bond amidation of 2-arylpyridine derivatives and 1-methylindoles

Article abstract of DOI:10.1002/adsc.200900775

Copper(I) bromide-catalyzed amidation of 2-arylpyridine derivatives and 1-methylindoles with a variety of amides was achieved by employing teri-butyl peroxide (TBP) as oxidant. Aryl halides could be tolerated under the reaction conditions. Neither a special ligand nor a base was required for this amidation process.

Full text of DOI:10.1002/adsc.200900775

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DOI: 10.1002/adsc.200900775
À
Copper-Catalyzed Highly Regioselective Oxidative C H Bond
Amidation of 2-Arylpyridine Derivatives and 1-Methylindoles
Qi Shuai,a Guojun Deng,a Zhijie Chua,a D. Scott Bohle,a and Chao-Jun Lia,*
a
Department of Chemistry, McGill University, Montreal, QC, H3A 2K6, Canada
Fax : (+1)-514-398-3797; e-mail: cj.li@mcgill.ca
Received: November 6, 2009; Revised: January 25, 2010; Published online: March 4, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900775.
Abstract: Copper(I) bromide-catalyzed amidation
of 2-arylpyridine derivatives and 1-methylindoles
with a variety of amides was achieved by employing
tert-butyl peroxide (TBP) as oxidant. Aryl halides
could be tolerated under the reaction conditions.
Neither a special ligand nor a base was required for
this amidation process.
lyzed direct and highly site-selective amidation of 2-
arylpyridine derivatives and 1-methylindoles through
a cross-dehydrogenative–coupling (CDC) process,[1i]
which can serve as a novel approach to modify
amides and directly produce various biologically
useful arylamide derivatives.
We began our studies by examining the reaction of
2-phenylpyridine (1a) with acetanilide (2a) in dioxane
by using CuBr (20 mol%) as catalyst and tert-butyl
peroxide (TBP) as oxidant. To our delight, the desired
ortho- amidated product (3a) was isolated in fair yield
(Table 1, entry 1) and its molecular structure was con-
firmed by X-ray crystallography (Figure 1). Oxygen
was also found to be an effective oxidant, although
Keywords: amidation; copper; 1-methylindoles; 2-
phenylpyridines; regioselectivity
À
Over the past decade, transition metal-catalyzed C H the yield was only moderate (entry 3). Later, when
functionalization, a powerful and efficient strategy to the reaction was performed in benzene, it afforded
À
À
construct C C bonds and C heteroatom bonds has the corresponding amidation product in 56% yield
attracted significant interest.[1] Specifically, palladium (entry 4). Increasing the substrate concentration im-
has been reported predominantly as a versatile cata- proved the yield to 67% (entry 5). A higher tempera-
À
À
lyst for constructing C N bonds through a C H acti- ture led to a decreased yield possibly due to the de-
vation.[2] In addition, Chang et al. demonstrated a composition of product (entry 6), whereas a longer re-
silver-mediated amination of benzoxazoles with acid action time at a lower temperature did not significant-
additives.[3]
ly improve the yield (entry 7). To further optimize the
Recently, explorations toward more economical reaction conditions, we decided to change the ratio of
and environmentally benign catalysts have led to vari- the two substrates, since the ortho-bromination prod-
ous pioneering advances in Cu-mediated and -cata- uct of 2-phenylpyridine was found to be a major side
[4]
À
À
lyzed C N bond formation processes. Direct C N product (see supporting information). When
À
bond formation based on Cu-mediated Ar H func- 1.5 equivalents of 1a was used, the yield was increased
tionalization was recently reported by Yu and co- up to 80% (entry 8). When the reaction was carried
workers,[5] employing 2-arylpyridines as the substrates out in other solvents, no good results were obtained
and requiring a stoichiometric amount of CuACTHNUTRGNEUNG(OAc)2. (entries 9–12). An excellent yield (92%) was obtained
Similar results were also found by Chatani et al.[6] An when the reaction was carried out under neat condi-
improved Cu-catalyzed intramolecular version was tions (entry 13).
later achieved by Buchwald and co-workers.[7] More
With the optimal reaction conditions in hand, we
recently, Cu-catalyzed direct aminations/amidations of then explored the scope and generality of this trans-
À
aromatic C H bonds, in the presence of a special formation (Table 2). Both 18 and 28 amides were
ligand and a base were reported by Mori[8] and found to be effective substrates for the ortho-amida-
Schreiber.[9] Meanwhile, the arylamide moiety has tion of 1. With an ortho-methoxy-substituted phenyl
been recognized as an important structural motif for ring, the amide (2b) gave a resonable yield of the ary-
biological studies.[10] Herein, we present a Cu-cata- lation product, although it is more sterically hindered
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Adv. Synth. Catal. 2010, 352, 632 – 636

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Copper-Catalyzed Highly Regioselective Oxidative C H Bond Amidation
Table 1. Optimization of reaction conditions.[a]
Entry
Solvent
Temp. [8C]
Yield[b] [%]
1
dioxane
dioxane
dioxane
benzene
benzene
benzene
benzene
benzene
DMSO
DMF
120
120
120
120
120
130
100
120
120
120
120
120
120
45 (32)
trace
31
56
67
27
50
80 (71)
trace
0
2[c]
3[d]
4
5[e]
6[e]
7[e,f]
8[g]
9
10
11
12
13[h]
toluene
xylene
neat
44
25
92 (87)
Figure 1. ORTEP representation of the molecular structure
of 3a with H atoms omitted for clarity.
[a]
Unless otherwise noted, all reactions were performed
under standard reaction conditions: 2-phenypyridine (1a,
31 mg, 0.2 mmol), acetanilide (2a, 54 mg, 0.4 mmol), TBP
(74 mL, 0.4 mmol), solvent (0.6 mL), oil bath for 16 h.
NMR yields using an internal standard; isolated yields
are given in parenthesis.
Oxidant: tert-butyl hydroperoxide (5.0–6.0M solution in
decane, 73 mL, 0.4 mmol).
Oxidant: O2 (1 atm).
Reactions in benzene (0.2 mL).
48 h.
1a (47 mg, 0.3 mmol), 2a (27 mg, 0.2 mmol), benzene
(0.1 mL).
1a (47 mg, 0.3 mmol), 2a (27 mg, 0.2 mmol).
ployed as solvent (entries 12 and 13). This might be
explainedby the fact that the nucleophilicity of 18
amides is not as good as that of 28 amides.
[b]
[c]
À
Although a Cu-catalyzed site-selective C H aryla-
tion of indole has been reported,[11] the corresponding
amidation is very rare. To our surprise, when applying
the modified reaction conditions (see supporting in-
formation) to 1-methylindole without a directing
group, the desired amidation product 6a was obtained
in 60% yield (Table 3, entry 1) with extremely high C-
2 selectivity.[12] We then examined the scope of this
amidation process. The methoxy group at an ortho-
position of the phenyl bearing amide facilitated the
[d]
[e]
[f]
[g]
[h]
(entry 2, 3b). It is possible that coordination of the formation of amidation product (entry 3) while no sig-
methoxy group to Cu facilitated the amidation pro- nificant effect was observed with the para-substituted
cess. The amide bearing phenyl with an electron-with- derivative 2k (entry 2). 1,3-Dimethyindole (4b) also
drawing group at para- position formed the product served as a suitable substrate, affording amidation
in good yield (entry 3, 3c). Notably, the chloro, bromo product 6d in reasonable yield (entry 4). Similar to
and iodo moieties on arylamides were all well tolerat- the amidation of 2-arylpyridine, halide moieties of
ed under these reaction conditions and afforded the amides were unaffected under these conditions (en-
target products in good yields (entries 4–8), which tries 5–8). However, an electron-withdrawing cyano
makes further elaborations of the corresponding ami- group either on the phenyl ring of the acetanilide or
dation products readily. Substituents either on the on that of 1-methylindole suppresses the reaction
pyridine ring or phenyl ring of 1 did not significantly completely (see Supporting Information). In addition,
affect the efficiency of the transformation (entries 8 simple 18 amides, 2i and 2j, as well as N-methylbenza-
and 9). The desired product was obtained in excellent mide (2h) were not reactive.
yield with sterically hindered benzoquinoline (1d)
In terms of the mechanism of the amidation of 2-ar-
with a rigid skeleton (entry 10). N-Methylbenzamide ylpyridine, since 2-(2-bromophenyl)pyridine 1e was
2h also turned out to be a suitable substrate isolated as a major side product, and it also served as
(entry 11). Simple 18 amides (2i and 2j) were not a good substrate for this process under the same reac-
good substrates under neat conditions. However, the tion conditions (see Supporting Information), it was
amidation products (3l and 3m) were obtained in proposed that a bromination of 2-phenylpyridine oc-
comparatively lower yields when benzene was em- curred first through a single electron transfer pro-
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Qi Shuai et al.
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Table 2. Amidation of 2-arylpyridine.[a]
Table 3. Amidation of 1-methylindole.[a]
[a]
All reactions were performed under standard reaction
conditions: 1-methylindole (4, 0.6 mmol), amide (2,
0.4 mmol), TBP (148 mL, 0.8 mmol), benzene (0.2 mL),
1208C for 16 h.
[b]
Isolated yields based on amides.
À
À
tive Ar H and N H coupling is not clear, based on
previous studies of Cu-mediated amination,[8] aryla-
tion,[11] and CDC reactions,[1i,14] a tentative mechanism
was proposed to rationalize this Cu-catalyzed oxida-
tive amidation process (Scheme 1). Low oxidation
À
state Cu(I) A first inserts into the weak O O bond of
TBP to generate intermediate B, which reacts with
amide 6 to form CuACTHNUTRGNE(NUG III) species C and alcohol. Reac-
tion of C with 1-methylindole 4a leads to the forma-
tion of another equivalent of alcohol and species D,
which undergoes reductive elimination to generate
the final amidation product 7 and Cu(I) A. However,
the reason for high C-2 selectivity of this process is
still not clear at this stage. It seems that C-3 is not re-
active to amide, since no amidation product was ob-
tained when 1,2-dimethyl-1H-indole 4d was tested as
a substrate (see Supporting Information).
[a]
All reactions performed under standard reaction condi-
tions: 2-arylpyridine (1, 0.6 mmol), amide (2, 0.4 mmol),
TBP (148 mL, 0.8 mmol), 1208C for 16 h.
Isolated yields based on amides.
In benzene (0.2 mL).
[b]
[c]
In conclusion, we have developed a novel method
for the direct and highly regioselective amidation of
cess,[5] followed by an Ullmann-type coupling with 2-arylpyridine derivatives and 1-methylindoles in the
amide to form the final product.[13] The observed high absence of a specialized ligand or a base. This new
ortho-selectivity was achieved through chelation method requires only inexpensive CuBr as catalyst,
methodology in the presence of a directing group and can tolerate aryl halides. Further investigation of
and, notably, no diamidation product was observed. the scope, mechanism and its application to construct-
Although the mechanism of the Cu-catalyzed oxida- ing complex molecules is in progress.
634
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Adv. Synth. Catal. 2010, 352, 632 – 636

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Copper-Catalyzed Highly Regioselective Oxidative C H Bond Amidation
Scheme 1. A tentative mechanism for the amidation of 1-methylindole.
References
Experimental Section
[1] For recent reviews, see: a) G. Dyker, Angew. Chem.
1999, 111, 1808; Angew. Chem. Int. Ed. 1999, 38, 1698;
b) V. Ritleng, C. Sirlin, M. Pfeffer, Chem. Rev. 2002,
102, 1731; c) D. Alberico, M. E. Scott, M. Lautens,
Chem. Rev. 2007, 107, 174; d) L.-C. Campeau, D. R.
Stuart, K. Fagnou, Aldrichimica Acta 2007, 40, 35;
e) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007,
36, 1173; f) F. Kakiuchi, T. Kochi, Synthesis 2008, 3013;
g) B. J. Li, S. D. Yang, Z. J. Shi, Synlett 2008, 949;
h) G. P. McGlacken, L. M. Bateman, Chem. Soc. Rev.
2009, 38, 2447; i) C.J. Li, Acc. Chem. Res. 2009, 42, 335.
[2] For selected examples, see: a) W. C. Peter Tsang, N.
Zheng, S. L. Buchwald, J. Am. Chem. Soc. 2005, 127,
14560; b) W. C. Peter Tsang, R. H. Munday, G. Bra-
sche, N. Zheng, S. L. Buchwald, J. Org. Chem. 2008, 73,
7603; c) H.-Y. Thu, W.-Y. Yu, C.-M. Che, J. Am. Chem.
Soc. 2006, 128, 9048; d) J.-J. Li, T.-S. Mei, J.-Q. Yu,
Angew. Chem. 2008, 120, 6552; Angew. Chem. Int. Ed.
2008, 47, 6452; e) M. Wasa, J. Q. Yu, J. Am. Chem. Soc.
2008, 130, 14058; f) J. A. Jordan-Hore, C. C. C. Johans-
son, M. Gulias, E. M. Beck, M. J. Gaunt, J. Am. Chem.
Soc. 2008, 130, 16184.
Typical Procedure
A mixture of 2-phenylpyridine (1a, 93 mg, 0.6 mmol), CuBr
(11.5 mg, 0.08 mmol, 20 mol%), acetanilide (2a, 54 mg,
0.4 mmol) and tert-butyl peroxide (TBP, 148 mL, 0.8 mmol)
was combined and sealed in a 5 mL conical vial with a
Teflon lined cap. The vial was heated at 1208C in an oil
bath for 16 h and then cooled down to room temperature.
The resulting mixture was diluted with EtOAc and filtered
through a plug of silica gel eluting with EtOAc. The filtrate
was concentrated under vacuum with a rotary evaporator
and the residue was purified by column chromatography
(hexane: EtOAc=2:1) on silica gel. Product 3a (mixture of
two rotamers) was obtained as a light orange solid; yield:
100 mg (87%).
CCDC 766957 contains the supplementary crystallograph-
ic data for compound 3a in this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
[3] S. H. Cho, J. Y. Kim, S. Y. Lee, S. Chang, Angew. Chem.
2009, 121, 9291; Angew. Chem. Int. Ed. 2009, 48, 9127.
[4] For recent reviews, see: a) I. P. Beletskaya, A. V. Che-
prakov, Coord. Chem. Rev. 2004, 248, 2337; b) G.
Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108,
3054; c) S. V. Ley, A. W. Thomas, Angew. Chem. 2003,
115, 5558; Angew. Chem. Int. Ed. 2003, 42, 5400; d) F.
We are grateful to the Canada Research Chair (Tier I) foun-
dation (to DSB and CJL), NESERC, and McGill University
for their support of our research.
Adv. Synth. Catal. 2010, 352, 632 – 636
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635

Qi Shuai et al.
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Monnier, M. Taillefer, Angew. Chem. 2009, 121, 7088;
Angew. Chem. Int. Ed. 2009, 48, 6954.
[5] X. Chen, X.-S. Hao, C. E. Goodhue, J.-Q. Yu, J. Am.
[10] G. N. Tew, D. Liu, B. Chen, R. J. Doerksen, J. Kaplan,
P. J. Carroll, M. L. Klein, W. F. DeGrado, Proc. Natl.
Acad. Sci. USA 2002, 99, 5110.
Chem. Soc. 2006, 128, 6790.
[6] T. Uemura, S. Imoto, N. Chatani, Chem. Lett. 2006, 35,
842.
[7] G. Brasche, S. L. Buchwald, Angew. Chem. 2008, 120,
1958; Angew. Chem. Int. Ed. 2008, 47, 1932.
[8] D. Monguchi, T. Fujiwara, H. Furukawa, A. Mori, Org.
Lett. 2009, 11, 1607.
[11] R. J. Phipps, N. P. Grimster, M. J. Gaunt, J. Am. Chem.
Soc. 2008, 130, 8172.
[12] Only one isomer was isolated, and neither NMR nor
GC-MS could detect the presence of other isomers.
[13] F. Y. Kwong, A. Klapars, S. L. Buchwald, Org. Lett.
2002, 4, 581.
[14] Y. Zhang, J. Feng, C.-J. Li, J. Am. Chem. Soc. 2008,
130, 2900.
[9] Q. Wang, S. L. Schreiber, Org. Lett. 2009, 11, 5178.
636
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