Direct amination of azoles via catalytic C-H, N-H Coupling

Article abstract of DOI:10.1021/ol900298e

C-H, N-H Coupling of azoles takes place with several amines in the presence of a copper catalyst to undergo amination at the 2-position. The reaction of benzothiazole with N-methylaniline in the presence of sodium acetate and 20 mol % Cu(0Ac)₂

Full text of DOI:10.1021/ol900298e

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1607-1610
Direct Amination of Azoles via Catalytic
C-H, N-H Coupling
Daiki Monguchi, Taiki Fujiwara, Hirotoshi Furukawa, and Atsunori Mori*
Department of Chemical Science and Engineering, Kobe UniVersity, 1-1 Rokkodai,
Nada, Kobe 657-8501, Japan
amori@kobe-u.ac.jp
Received February 11, 2009
ABSTRACT
C-H, N-H Coupling of azoles takes place with several amines in the presence of a copper catalyst to undergo amination at the 2-position.
The reaction of benzothiazole with N-methylaniline in the presence of sodium acetate and 20 mol % Cu(OAc)2 in xylene under an oxygen
atmosphere afforded the aminated product in 81% yield.
Transition-metal-catalyzed C-H functionalization reactions
are of great interest in organic synthesis because the reaction
shows an advantage in atom efficiency compared to related
cross-coupling with organometallic compounds.1 The reac-
tion of heteroaromatic compounds is particularly important
because of their wide utilities in the synthesis of biologically
active molecules and advanced organic materials.2 The
catalytic carbon-carbon bond-forming reaction via C-H
functionalization has been achieved by the reaction of aryl
halides3,4 or simple arenes at the carbon-hydrogen bond.5
(Buchwald-Hartwig reactions)6 and organometallic com-
pounds (oxidative coupling)7 have been developed so far.
In contrast, limited examples are shown for intra-8 and
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Chem. Soc. 2006, 128, 10930. (f) Arai, N.; Takahashi, M.; Mitani, M.; Mori,
A. Synlett 2006, 3170. (g) Mori, A.; Shikuma, J.; Kinoshita, M.; Ikeda, T.;
Misaki, M.; Ueda, Y.; Komura, M.; Asaoka, S.; Iyoda, T. Chem. Lett. 2008,
37, 272. (h) Arai, N.; Miyaoku, T.; Teruya, S.; Mori, A. Tetrahedron Lett.
2008, 49, 1000. (i) Miyaoku, T.; Mori, A. Heterocycles 2009, 77, 151.
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In addition to such carbon-carbon bond-forming reactions,
carbon-heteroatom bond formation is also an important
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81, 548. (b) Campeau, L. C.; Stuart, D. R.; Fagnou, K. Aldrichimica Acta
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10.1021/ol900298e CCC: $40.75
Published on Web 03/02/2009
2009 American Chemical Society

Table 1. Amination of Benzothiazole (1) with 2a
entry
reagents (equiv)a
yieldb (%)
1
CuI (0.2), PPh3 (0.4), NaOAc (4), O2
0
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
CuCl2 (0.2), PPh3 (0.4), NaOAc (4), O2
Cu(OAc)2 (0.2), PPh3 (0.4), NaOAc (4), O2
Cu(OAc)2 (0.2), NaOAc (4), O2
23
82
39c
tr
52
42
68
46
tr
51
51
33
52
29
70d
Cu(OAc)2 (0.2), 2,2′-bipyridyl (0.2), NaOAc (4), O2
Cu(OAc)2 (0.2), N,N′-dimethylethylenediamine (0.2), NaOAc (4), O2
Cu(OAc)2 (0.2), dppe (0.2), NaOAc (4), O2
Cu(OAc)2 (0.2), XANTPHOS (0.2), NaOAc (4), O2
Cu(OAc)2 (0.2), PPh3 (0.4), NaOAc (4), air
Cu(OAc)2 (0.2), PPh3 (0.4), NaOAc (4), N2
Cu(OAc)2 (0.2), PPh3 (0.4), Na2CO3 (4), O2
Cu(OAc)2 (0.2), PPh3 (0.4), NaHCO3 (4), O2
Cu(OAc)2 (0.2), PPh3 (0.4), NEt3 (4), O2
Cu(OAc)2 (0.2), PPh3 (0.4), NaF (4), O2
Cu(OAc)2 (0.2), PPh3 (0.4), KF (4), O2
Cu(OAc)2 (0.1), PPh3 (0.2), NaOAc (4), O2
a Unless noted, the reaction was performed with 1 (0.2 mmol) and 2a (0.8 mmol) in 1 mL of xylene at 140 °C for 20 h under O2 (1 atm). b Yield
estimated by H NMR analysis. c Reaction period of 18 h. d Reaction period of 40 h.
1
intermolecular9 C-H functionalization with amines.10 The
reaction of azoles at the 2-position, which possess an sp2
C-H bond, still remains to be exploited, and thereby it is
intriguing whether the reaction takes place by transition metal
catalysis. Herein, we report catalytic oxidative amination of
azoles via C-H, N-H coupling in the presence of a copper
salt as a catalyst.
Benzothiazole 1 (0.2 mmol) and N-mehylaniline 2a (0.8
mmol) were first chosen as a substrate. As summarized in
Table 1, the reaction was performed at 140 °C for 20 h in
xylene with a copper catalyst. The reaction in the presence
of copper(II) chloride (20 mol %)/PPh3 (40 mol %) and
sodium acetate (0.8 mmol) under an oxygen atmosphere
afforded the amination product 3a in 23% yield, whereas
the use of copper(I) iodide (20 mol %) resulted in no reaction
(entries 1 and 2). An improved yield (82%) was obtained
when the catalyst was switched to Cu(OAc)2 (entry 3). The
addition of PPh3 is not crucial to the amination; 3a was
afforded in slightly inferior yield when the reaction was
carried out without the phosphine ligand (entry 4). Although
the reaction with several bidentate nitrogen and phosphine
ligands was also examined, drastic improvement in the yield
was not observed (entries 5-8). It appeared to be important
to carry out the reaction under oxygen. The yield was, indeed,
decreased to 46% when the reaction was performed under
an aerobic condition, and no reaction was observed under a
nitrogen atmosphere (entries 9 and 10). The use of other
organic and inorganic bases, including Na2CO3, NaHCO3,
NEt3, NaF, and KF, was found to promote the reaction,
although the yield was inferior to that using NaOAc (entries
11-15). Lower catalyst loading (10 mol %) also afforded
3a in 70% yield with a longer reaction period (40 h, entry
16).
With the reaction conditions for the catalytic C-H
amination in hand, several amines were employed for the
reaction of benzothiazole 1. As summarized in Table 2,
N-methylaniline 2a and diphenyl amine 2b were found to
react with 1 to afford the corresponding amination product
3 in 47-81% yield. Furthermore, sulfonamide 2c also
underwent the reaction to give 3c in 65% yield.
(8) (a) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932. (b) Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett. 2008,
10, 5147. (c) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006,
128, 9048. (d) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058.
(e) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127, 14198.
(9) (a) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
833. (b) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6791. (c) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem.
Soc. 2006, 128, 9048.
In addition to benzothiazole 1, several azoles were
subjected to the amination reactions. The scope with respect
to the heteroaromatic compounds is presented in Table 3.
The reaction of 4,5-dimethylthiazole 4 with N-methylaniline
2a afforded 5a in 73% yield (entry 1). Benzoxazole 6 with
2a and diphenylamine 2b also afforoded 7a and 7b in 73%
and 66% yield, respectively (entries 2 and 3). The reaction
of 6 was found to take place with several aliphatic amines
(10) Insertion of a carbene complex into N-H bond: (a) Liang, C.; Collet,
F.; Robert-Peillard, F.; Mu¨ller, P.; Dodd, R. H.; Dauban, P. J. Am. Chem.
Soc. 2008, 130, 343. (b) Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2007,
129, 562. (c) Badiei, Y. M.; Dinescu, A.; Dai, X.; Palomino, R. M.;
Heinemann, F. W.; Cundari, T. R.; Warren, T. H. Angew. Chem., Int. Ed.
2008, 47, 9961. (d) Shen, M.; Leslie, B. E.; Driver, T. G. Angew. Chem.,
Int. Ed. 2008, 47, 5056. (e) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois,
J. J. Am. Chem. Soc. 2004, 126, 15378. (f) Li, Z.; Capretto, D. A.; Rahaman,
R. O.; He, C. J. Am. Chem. Soc. 2007, 129, 12058. (g) Fraunhoffer, K. J.;
White, M. C. J. Am. Chem. Soc. 2007, 129, 7275.
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Org. Lett., Vol. 11, No. 7, 2009

Table 2. Amination of Benzothiazolea
Table 3. Amination of Azolesa
a Reaction conditions: 1 (0.2 mmol), 2 (0.8 mmol), Cu(OAc)2 (20 mol
%), and PPh3 (40 mol %), under 1 atm of O2, in 1 mL of xylene, at 140 °C
for 20 h. b Isolated yield. c The reaction was carried out with 0.8 mmol of
1 and 0.2 mmol of 2c. The yield was based on the amount of 2c.
such as piperidine (2d) and diethylamine (2e) in 72% and
47% yields (entry 4 and 5). N-Methylbenzoimidazole (8) was
found to be a favorable substrate to undergo the amination
reaction with 2a.
Although the mechanism of copper-catalyzed oxidative
C-H, N-H coupling is still unclear, the reaction would
proceed under a similar pathway to the reaction of terminal
alkynes reported by Stahl.9a As shown in Scheme 1, the C-H
bond of the azole would be replaced with Cu(II), to form
organocopper 10. The X group of 10 would be replaced with
amine to give 11. A following reductive elimination produces
the coupling product 3 along with a copper species of the
lower oxidation state, which would be oxidized to give Cu(II)
by oxygen to complete the catalytic cycle.
a Reaction conditions: 1 (0.2 mmol), 2 (0.8 mmol), Cu(OAc)2 (20 mol
%), and PPh3 (40 mol %), under 1 atm of O2, in 1 mL of xylene, at 140 °C
for 20 h. b Isolated yield.
Since we have recently shown that the masked thiazole
12 induces catalytic C-H arylation at the 5-position of the
thiazole ring to obtain 5-arylthiazole 13 after removal of the
masked group by treatment of base,11 13 is an avail-
able thiazole derivative for catalytic C-H amination at the
2-position, which leads to the N-analogue of donor-acceptor-
type 2,5-disubstituted thiazole.12 Introduction of an electron-
deficient aryl group to 12 following removal of the masked
group was performed as reported to afford 5-arylthiazole 13,
which was reacted with N-methylaniline 2a and diphenyl-
amine 2b at 140 °C for 3-5 h under the optimized conditions
to give 14 in 68% and 48% yields, respectively. Despite the
use of secondry amines, the ester group of 13 was found to
be tolerant under the reaction conditions and no exchange
Scheme 1
(11) Furukawa, H.; Matsumura, S.; Sugie, A.; Monguchi, D.; Mori, A.
Heterocycles 2009, in press.
(12) (a) Masui, K.; Mori, A.; Okano, K.; Takamura, K.; Kinoshita, M.;
Ikeda, T. Org. Lett. 2004, 6, 2011. (b) Shikuma, J.; Mori, A.; Masui, K.;
Matsuura, R.; Sekiguchi, A.; Ikegami, H.; Kawamoto, M.; Ikeda, T. Chem.
Asian J. 2007, 2, 301.
Org. Lett., Vol. 11, No. 7, 2009
1609

of ester with amines was observed.13 Spectroscopic and
electronic properties of thus obtained 13 will be performed
in due course (Scheme 2).
bearing an amino substituent at the 2-position, the method
is a powerful tool for synthesizing such a molecule ef-
ficiently.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research on Priority Areas,
“Advanced Molecular Transformation of Carbon Resources”
by Ministry of Education, Culture, Sports, Science and
Technology (MEXT), Japan.
Scheme 2
Supporting Information Available: Experimental de-
tails.14 This material is available free of charge via the
Internet at http://pubs.acs.org.
OL900298E
In conclusion, we have demonstrated the C-H, N-H
coupling of azoles with a variety of nitrogen nucleophiles
in the presence of a copper catalyst. Since a number of
biologically active compounds are found in azole derivatives
(13) No reaction was confirmed to take place by mixing 13 and 2a in
xylene at 140 °C for 3 h.
(14) The authors thank Nara Institute of Science and Technology, Kyoto-
Advanced Nanotechnology Network, supported by MEXT for measurements
of high resolution mass spectra.
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Org. Lett., Vol. 11, No. 7, 2009