Copper-mediated amidation of heterocyclic and aromatic C-H bonds

Article abstract of DOI:10.1021/ol902079g

A copper-mediated aerobic coupling reaction enables direct amidation of heterocycles or aromatics having weakly acidic C-H bonds with a variety of nitrogen nucleophiles. These reactions provide efficient access to many biologically important skeletons, in

Full text of DOI:10.1021/ol902079g

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5178-5180
Copper-Mediated Amidation of
Heterocyclic and Aromatic C-H Bonds
Qiu Wang and Stuart L. Schreiber*
Howard Hughes Medical Institute, Broad Institute, Cambridge, Massachusetts 02142,
and Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
stuart_schreiber@harVard.edu
Received September 9, 2009
ABSTRACT
A copper-mediated aerobic coupling reaction enables direct amidation of heterocycles or aromatics having weakly acidic C-H bonds with a
variety of nitrogen nucleophiles. These reactions provide efficient access to many biologically important skeletons, including ones with the
potential to serve as inhibitors of HMTs.
The methylation marks on chromatin established by histone
methyltransferases (HMTs) are key elements of heritable cell
states and can lead to disease when disregulated.1,2 Thus, it
was of interest that a compound containing a 2-amidoben-
zimidazole skeleton was reported to inhibit several HMTs.3
Methods to synthesize this skeleton require multiple-step
sequences that do not easily lend themselves to syntheses
of many structural analogues.4 To overcome this obstacle,
we describe here the direct C-H functionalization of
benzimidazoles with nitrogen-containing reagents via a
copper(II)-mediated oxidative coupling that affords 2-ami-
dobenzimidazoles.
We anticipated that the aerobic cross-coupling of heterocycles
(I) with nucleophiles would lead to the 2-amido-substituted
heterocycles (III) through the organocopper intermediate (II)
in analogy to the Chan-Lam oxidative coupling of arylboronic
acids and nucleophiles (Scheme 1).5-7
(1) (a) Schreiber, S. L.; Bernstein, B. E. Cell 2002, 111, 771–778. (b)
Bernstein, B. E.; Mikkelsen, T. S.; Xie, X.; Kamal, M.; Huebert, D. J.;
Cuff, J.; Fry, B.; Meissner, A.; Wernig, M.; Plath, K.; Jaenisch, R.;
Wagschal, A.; Feil, R.; Schreiber, S. L.; Lander, E. S. Cell 2006, 125, 315–
326. (c) Kouzarides, T. Cell 2007, 128, 693–705
.
(2) (a) Cole, P. A. Nat. Chem. Biol. 2008, 4, 590–597. (b) Marks, P. A.;
Breslow, R. Nat. Biotechnol. 2007, 25, 84–90. (c) Copeland, R. A.; Solomon,
M. E.; Richon, V. M. Nat. ReV. Drug DiscoV. 2009, 8, 724–732
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(3) (a) Kubicek, S.; O’Sullivan, R. J.; August, E. M.; Hickey, E. R.;
Zhan, Q.; Teodoro, M. L.; Rea, S.; Mechtler, K.; Kowalski, J. A.; Homon,
C. A.; Kelly, T. A.; Jenuwein, T. Mol. Cell 2007, 25, 473–481. Other
recently reports on biological activities of 2-aminobenzimidazole cores: (b)
Winters, M. P.; Robinson, D. J.; Khine, H. H.; Pullen, S. S.; Woska, J. R.;
Raymond, E. L.; Sellati, R.; Cywin, C. L.; Snow, R. J.; Kashem, M. A.;
Wolak, J. P.; King, J.; Kaplita, P. V.; Liu, L. H.; Farrell, T. M.; DesJarlais,
R.; Roth, G. P.; Takahashi, H.; Moriarty, K. J. Bioorg. Med. Chem. Lett.
2008, 18, 5541–5544. (c) Powers, J. P.; Li, S. Y.; Jaen, J. C.; Liu, J. Q.;
Walker, N. P. C.; Wang, Z. L.; Wesche, H. Bioorg. Med. Chem. Lett. 2006,
16, 2842–2845. (d) Kim, R. M.; Chang, J.; Lins, A. R.; Brady, E.; Candelore,
M. R.; Dallas-Yang, Q.; Ding, V.; Dragovic, J.; Iliff, S.; Jiang, G. Q.; Mock,
S.; Qureshi, S.; Saperstein, R.; Szalkowski, D.; Tamvakopoulos, C.; Tota,
L.; Wright, M.; Yang, X. D.; Tata, J. R.; Chapman, K.; Zhang, B. B.;
Parmee, E. R. Bioorg. Med. Chem. Lett. 2008, 18, 3701–3705.
Scheme 1
.
Copper-Mediated C-H Functionalization of
Heterocyclic C-H Bonds
We first examined the reaction of N-methylbenzimida-
zole (1) with pyrrolidinone (2a) in the presence of catalytic
copper salts under 1 atm of O2. In the initial screening of
Cu sources, Brønsted bases, and solvents, optimal results
were observed with 0.2 equiv of Cu(OAc)2 and 2 equiv
(4) (a) Carpenter, R. D.; DeBerdt, P. B.; Lam, K. S.; Kurth, M. J.
J. Comb. Chem. 2006, 8, 907–914. (b) Perkins, J. J.; Zartman, A. E.;
Meissner, R. S. Tetrahedron Lett. 1999, 40, 1103–1106. (c) Seth, P. P.;
Robinson, D. E.; Jefferson, E. A.; Swayze, E. E. Tetrahedron Lett. 2002,
43, 7303–7306.
10.1021/ol902079g CCC: $40.75
Published on Web 10/27/2009
 2009 American Chemical Society

of Na2CO3 with pyridine as additive in toluene.8 The
dimeric product 4 was observed in many conditions, but
its formation was suppressed and the yield of 3a was
increased by using 5 equiv of nucleophile (Table 1, entry
similar reaction conditions. A wide range of primary
amides was found to undergo the reaction (Table 1, entries
8-16). The reaction with benzamide 2h using a catalytic
amount of Cu(OAc)2 formed product 3h; however, the
starting material 1 was not effectively consumed. This may
be due to the binding of Cu(II) to the carbonyl oxygen
and imino nitrogen in the product. This problem was
circumvented by using 2 equiv of Cu(OAc)2 (entry 8).
Both electron-withdrawing and electron-donating func-
tional groups are tolerated well on the aryl ring of the
amides (entries 9-12). Simple alkyl primary amides are
also substrates (entries 13 and 14), even ones with steric
bulk on the amide. Reactions of 1 with sulfonamides
resulted in excellent yields (entries 15 and 16), including
one with a bromine substituent on the aryl group. Although
reactions with amines under the same conditions provided
the desired products, the formation of the dimeric product
4 was significant, most likely due to strong electron
donation by the amine and the unfavorable deprotonation.
We also investigated the scope of this reaction with
other heterocyclic and aromatic C-H bonds (Table 2). In
the amidation reactions with pyrrolidinone 2a, the het-
erocyclic C-H bonds of benzothiazole, caffeine, and
oxazole all underwent oxidative coupling (entries 1-3).
Similar reactions with primary amide 2i were successful
(entries 4 and 5), and intramolecular reactions delivered
cyclic products with excellent yields (entries 6 and 7).
The reaction condition was also effective for the direct
amidation of C-H bonds in fluorinated aromatic rings,
albeit in diminished yields (entries 8-10). These trans-
formations offer successful examples of challenging
intermolecular C-N bond formation using aromatic C-H
and amide N-H groups. These amidation reactions
(entries 8-10) indicate the potential of this method in the
synthesis of fluorobenzene derivatives.
Although mechanisms of copper-catalyzed oxidative
C-N couplings have been proposed,6 the details remain
uncertain. A proposed mechanism for this amidation
reaction is outlined in Scheme 2. In the presence of Cu(II)
and base, we imagine that organocopper intermediate 1a
from the heterocycle (e.g., 1) is formed. Ligand exchange
with the deprotonated nucleophile would yield intermedi-
ate 1b. C-N reductive elimination and aerobic reoxidation
of the catalyst would complete the catalytic cycle.
Since the formation of 1b can compete with the formation
of 1c, dimer 4 will form when 1b is disfavored by slow
deprotonation (e.g., pKa > 25 or amine) or steric hindrance
(e.g., primary vs secondary amides). Reactions with pyridone
(pKa ) 17) and phthalimide (pKa ) 8.3) only resulted in the
Table 1. Cu(II)-Mediated Oxidative Coupling of 1 with
N-Nucleophilesa
a Reaction conditions for 2a-2g. Condition A: 1 (0.3 mmol), 2 (1.5
mmol), pyridine (6.0 mmol), Cu(OAc)2 (0.06 mmol), Na2CO3 (0.6 mmol),
toluene (10 mL), O2 (balloon), 120-140 °C, 12-30 h. For 2h-2p.
Condition B: 1 (0.3 mmol), 2 (1.5 mmol), pyridine (6.0 mmol), Cu(OAc)2
(0.6 mmol), Na2CO3 (0.9 mmol), toluene (10 mL), O2 (balloon), 120-140
°C, 12-30 h. b Yields correspond to isolated products. c Cu(OAc)2 (0.3
mmol). d 2g (0.6 mmol), pyridine (1.5 mmol). e Yield of product 3h under
condition A.
1). Among the Cu sources tested, Cu(OAc)2 generally
performed better than CuCl2, CuBr2, Cu(OTf)2, and
Cu(O2CCF3)2.
We next varied the nucleophiles in this reaction (Table
1). Cyclic amide (entries 2 and 3), urea and carbamate
(entries 4-6) nucleophiles, and N-methyl benzenesulfona-
mide (entry 7) provided the desired products effectively,
while acyclic secondary amides were not effective under
(7) For examples involving transition-metal-directed functionalization
of C-H bonds with heteroatoms, see: (a) Chen, X.; Hao, X.-S.; Goodhue,
C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790–6791. (b) Uemura, T.;
Imoto, S.; Chatani, N. Chem. Lett. 2006, 35, 842–843. Intramolecular: (c)
Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932–1934.
(d) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048–
9049. (e) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058–14059.
(f) Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10,
5147–5150. (g) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck,
E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184–16186. (h) Ueda,
S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411–6413. (i) Mei,
T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 10806–10807.
(5) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933–2936. (b) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.
Tetrahedron Lett. 1998, 39, 2941–2944. (c) Evans, D. A.; Katz, J. L.; West,
T. R. Tetrahedron Lett. 1998, 39, 2937–2940.
(6) For a related reaction involving directed functionalization of C-H
bond with N-nucleophiles, see: (a) Hamada, T.; Ye, X.; Stahl, S. S. J. Am.
Chem. Soc. 2008, 130, 833–835. (b) Balsamo, A.; Macchia, B.; Macchia,
F.; Rossello, A.; Domiano, P. Tetrahedron Lett. 1985, 26, 4141–4144. (c)
King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131,
5044–5045.
Org. Lett., Vol. 11, No. 22, 2009
5179

Table 2. Cu(II)-Mediated Amidations of Aromatic C-H Bondsa
Scheme 2. Proposed Mechanism for Copper-Mediated C-H
Functionalization of Heterocyclic C-H Bonds
the reaction, presumably by facilitating the C-N reductive
elimination step.
In conclusion, we have developed a copper-mediated
method for aerobic coupling of 2-benzimidazoles and other
heterocycles or aromatics having acidic C-H bonds with a
variety of nitrogen nucleophiles. These reactions provide
efficient access to many biologically important skeletons,
including ones with the potential to serve as inhibitors of
HMTs.9
Acknowledgment. We gratefully acknowledge the Na-
tional Cancer Institute (NCI-PO1-CA078048) for support of
this research. S.L.S. is a Howard Hughes Medical Institute
Investigator.
Supporting Information Available: Experimental pro-
cedures, additional screening data, and characterization data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
a Standard reaction condition: heterocycle (1.0 equiv), nucleophile (5.0 equiv),
Cu(OAc)2 (0.2 equiv), Na2CO3 (2.0 equiv), pyridine (20.0 equiv), toluene, O2
(balloon), 120-140 °C, 12-30 h. Yields correspond to isolated products.
b Cu(OAc)2 (2.0 equiv), Na2CO3 (3.0 equiv). c Cu(OAc)2 (1.0 equiv), pyridine (5.0
equiv). d Cu(OAc)2 (1.0 equiv), K2CO3 (2.0 equiv) instead of Na2CO3. e 14 (5.0
equiv), 2a (1.0 equiv), pyridine (5.0 equiv), K2CO3 (2.0 equiv).
OL902079G
(8) See Supporting Information.
(9) During the preparation of this paper, a related study of C-H
amination of benzothiazoles, benzimidazoles, benzoxazoles, and thiazoles
was reported: Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org.
Lett. 2009, 11, 1607–1610.
recovery of starting material, which suggests that the
nucleophilicity of the substrates plays an important role in
5180
Org. Lett., Vol. 11, No. 22, 2009