A new entry of amination reagents for heteroaromatic C-H bonds: Copper-catalyzed direct amination of azoles with chloroamines at room temperature

Article abstract of DOI:10.1021/ja101939r

Chloroamine serves as an efficient amination reagent to the heteroaromatic C-H bond of azole under copper catalysis even at room temperature. This catalysis enables a rapid and concise construction of aminoazoles of great interest in biological and medicinal chemistry.

Full text of DOI:10.1021/ja101939r

Published on Web 05/03/2010
A New Entry of Amination Reagents for Heteroaromatic C-H Bonds:
Copper-Catalyzed Direct Amination of Azoles with Chloroamines at Room
Temperature
Tsuyoshi Kawano, Koji Hirano, Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity, Suita, Osaka 565-0871, Japan
Received March 8, 2010; E-mail: miura@chem.eng.osaka-u.ac.jp
A metal-mediated sp2 C-N bond forming reaction is of great
interest in organic synthesis since the molecules containing aryl-
and heteroarylamine units are prevalent in biological and pharma-
ceutical sciences.1 The palladium-catalyzed amination of aryl
halides, that is Buchwald-Hartwig amination,2 as well as a copper-
mediated one3,4 is now the most powerful and reliable method for
the synthesis of these target structures. On the other hand, transition-
metal-catalyzed direct amination of arenes and heteroarenes has
received much attention as a complementary and potentially more
efficient route to the above amines. Although palladium5 and
rhodium6 complexes are known to catalyze this type of transforma-
tions, most of them are restricted in an intramolecular fashion.5a,c-e,6
The efforts by several groups have overcome the limitation and
achieved the intermolecular versions using the copper7 and silver8
salts. However, these processes still suffer from harsh conditions
such as higher reaction temperature7c,d and use of a stoichiometric
amount of metal oxidant.7a,b,8 Thus, further development for direct
C-H amination is strongly desired.
metals, ligands, and bases, we were pleased to find that a
combination of Cu(acac)2/bpy (bpy ) 2,2′-bipyridine) catalyzed
the amination of 1a with 2a in the presence of LiO-t-Bu as a base
to furnish 3aa in 81% yield (Table 1, entry 1).12 Notably, the
reaction completed within 2 h even at room temperature. The
oxadiazoles bearing electron-donating methyl 1b and methoxy
groups 1c as well as the simple one underwent the amination very
smoothly (entries 2 and 3). The electron-withdrawing trifluoro-
methyl and chloro substituents did not interfere with the reaction
(entries 4 and 5). In particular, 1e was transformed to 3ea in good
yield with the carbon-chloride moiety left intact, which could enjoy
further elaboration. A bulky naphthalene motif was also compatible
toward the reaction (entry 6). Moreover, the aliphatic phenethyl-
substituted 1g coupled with 2a to form the heteroarylamine 3ga in
an acceptable yield (entry 7).
Under the standard reaction conditions, a variety of N,N-
dialkylchloroamines 2 were examined for the direct amination of
1a (Table 2). The reactions with cyclic 2b and acyclic chloroamines
2c proceeded without any difficulties to afford amino-1,3,4-
oxadiazoles 3ab and 3ac (entries 1 and 2). Benzyl and Boc
protections on nitrogen were tolerant so that the orthogonal
additional functionalization after their appropriate deprotection
would be possible (entries 3 and 4). In addition, the chloroamine
2f containing two C-Cl bonds was also available for use (entry
Herein, we introduce chloroamine9 as a readily available and
effective nitrogen source for heteroaromatic C-H functionalization:
the copper-catalyzed direct amination of azoles with chloroamines
is described. Use of this type of reagent under copper catalysis
enables the formation of heteroaryl-amino linkages even at room
temperature so as to provide a rapid and straightforward access to
the heteroarylamines of quite importance in biological and medicinal
chemistry.10
Table 2. Copper-Catalyzed Direct Amination of
2-Phenyl-1,3,4-oxadiazole (1a) with Various Chloroamines 2a
Table 1. Copper-Catalyzed Direct Amination of Various
1,3,4-Oxadiazoles 1 with 4-Chloromorpholine (2a)a
entry
R 1
3, yield (%)b
1
2
3
4
5
6
7
Ph (1a)
3aa, 81
3ba, 70
3ca, 72
3da, 62
3ea, 84
3fa, 83
3ga, 63
4-MeC6H4 (1b)
4-MeOC6H4 (1c)
4-CF3C6H4 (1d)
4-ClC6H4 (1e)
1-naphthyl (1f)
Ph(CH2)2 (1g)
a A mixture of Cu(acac)2 (0.050 mmol), bpy (0.050 mmol), 1 (0.50
mmol), 2a (0.75 mmol), and LiO-t-Bu (1.0 mmol) in toluene (3.0 mL)
was stirred at room temperature for 2 h under N2. b Yield of isolated
product.
Initially, we selected 2-phenyl-1,3,4-oxadiazole (1a) and 4-chlo-
romorpholine (2a) as the starting materials because the expected
product skeleton, amino-1,3,4-oxadiazole, is among the most
interesting heteroarylamines exhibiting a broad spectrum of biologi-
cal activity.11 After the extensive screening of various transition
a See Table 1 for the reaction conditions. b Yield of isolated product.
c Chloroamine 2f as the limiting reagent. With 20 mol % of Cu(acac)2/
bpy, 2.4 equiv of 1a, and 4.8 equiv of LiO-t-Bu.
9
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10.1021/ja101939r  2010 American Chemical Society

C O M M U N I C A T I O N S
5). Thus, a symmetrical N,N′-bis(heteroaryl)piperazine 2af was
easily prepared.13
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(4a) (Table 3).14 Under the same conditions as those shown in
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delight, the simple replacement of LiO-t-Bu with NaO-t-Bu
significantly improved the reaction efficiency to afford 5aa in 76%
yield (entry 2). By using the modified protocol, benzoxazoles 4b-d
having the substitutions at the 5-position were aminated effectively
(entries 3-5), and the piperizine and dibutylamine moieties also
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Table 3. Copper-Catalyzed Direct Amination of Various
Benzoxazoles 4a
entry
R 4
2
5, yield (%)b
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1c
2
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H (4a)
4a
Ph (4b)
Me (4c)
Cl (4d)
4a
2a
2a
2a
2a
2a
2b
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5aa, 17d
5aa, 76
5ba, 62
5ca, 53
5da, 73
5ab, 66
5ac, 38
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4a
a A mixture of Cu(acac)2 (0.050 mmol), bpy (0.050 mmol), 4 (0.50
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was stirred at room temperature for 2 h under N2. b Yield of isolated
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While the present chloroamines are readily accessible from the
corresponding amines and bleach,16 a more convenient chlorination/
direct amination sequence is operative.9b Namely, upon the exposure
of 2a generated in situ through the chlorination of morpholine with
N-chlorosuccinimide (NCS) in toluene to a mixture of 1a, Cu(acac)2/
bpy, and LiO-t-Bu, 3aa was produced in a slightly lower yield
(Scheme 1). Amino-1,3,4-oxazole 3ea was also synthesized in the
same manner.
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Scheme 1
(12) See Supporting Information for the detailed optimization studies.
(13) The direct coupling with the chloroamide such as N-chloroacetanilide was
unsuccessful, and the starting materials were recovered unchanged.
(14) 2-Aminobenzoxazoles in medicinal chemistry: (a) Sato, Y.; Yamada, M.;
Yoshida, S.; Soneda, T.; Ishikawa, M.; Nizato, T.; Suzuki, K.; Konno, F.
J. Med. Chem. 1998, 41, 3015. (b) Yoshida, S.; Watanabe, T.; Sato, Y.
Bioorg. Med. Chem. 2007, 15, 3515.
(15) Among other azoles tested, 5-(4-methoxyphenyl)oxazole reacted with 2a
in the presence of the same Cu(acac)2/bpy catalyst and LiHMDS as the
base to give the aminated product in 30% yield. The reactions with thiazole
and imidazole were unsuccessful.
(16) Zhong, Y.-L.; Zhou, H.; Gauthier, D. R.; Lee, J.; Askin, D.; Dolling, U. H.;
Volante, R. P. Tetrahedron Lett. 2005, 46, 1099.
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(18) Regardless of the valency of copper precursors, a small amount of
homocoupling product of azole was detected in all cases by GC-MS. The
result is suggestive of the existence of Cu species of a higher oxidation
state in the catalytic cycle. (a) Huffman, L. M.; Stahl, S. S. J. Am. Chem.
Soc. 2008, 130, 9196. (b) Srieter, E. R.; Bhayana, B.; Buchwald, S. L.
J. Am. Chem. Soc. 2009, 131, 78. (c) King, A. E.; Brunold, T. C.; Stahl,
S. S. J. Am. Chem. Soc. 2009, 131, 5044. Also see ref 17d. See Supporting
Information for the detailed discussion.
Although the exact reaction mechanism still remains unclear,
the most plausible pathway would involve (i) base-assisted cupration
of azole,17 (ii) subsequent oxidative addition of the chloroamine
to the resulting (heteroaryl)Cu(I) intermediate, and (iii) productive
reductive elimination from the Cu(III) complex.18 Ongoing work
seeks to uncover the detailed mechanism and expand the reaction
scope with chloroamines of high potential in direct C-H amination
chemistry.
Acknowledgment. This work was supported by Grants-in-Aid
for Scientific Research from MEXT and JSPS, Japan.
Supporting Information Available: Experimental details and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA101939R
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