Copper-catalyzed direct amination of benzoxazoles using primary amines as nitrogen sources

Article abstract of DOI:10.1055/s-0034-1379886

A facile, efficient, and simple protocol for direct oxidative C-H amination of benzoxazoles with primary amines through copper-catalyzed C-H bond activation using tert-butyl peroxide (TBP) as oxidant under air has been developed. The reaction proceeds smoothly at ambient temperature to furnish the products. A variety of substituted aminobenzoxazoles were synthesized with good to excellent yields.

Full text of DOI:10.1055/s-0034-1379886

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 639–642
letter
639
J. Gu, C. Cai
Letter
Synlett
Copper-Catalyzed Direct Amination of Benzoxazoles Using
Primary Amines as Nitrogen Sources
Jian Gu
O
R1
NH
O
N
Cu(cat), AcOH
R2
R1NH2
R2
Chun Cai*
+
TBP, toluene, 80 °C
N
Chemical Engineering College, Nanjing University of Science
and Technology, Nanjing, Jiangsu 210094, P. R. of China
c.cai@mail.njust.edu.cn
Received: 30.10.2014
Accepted after revision: 01.12.2014
Published online: 22.01.2015
use of stoichiometric amounts of catalyst, a large amount of
strong base, and toxic ligand. Many groups have accom-
plished excellent results that address the drawbacks men-
tioned above. Duan and Yu independently provided a cop-
per-catalyzed and iron-catalyzed amination of azoles with
formamides or secondary amines.9 Huang developed a cop-
per-catalyzed route to heteroarylamines by using tertiary
amines as nitrogen sources10 and then they developed aero-
bic oxidative C–H amination of azoles with secondary
amines at room temperature under cooperative catalysis
with aldehydes and copper.11 In these methods, the nitro-
gen sources are usually secondary or tertiary amines and
the reaction does not occur when primary amines are used.
In this context, we have developed a facile, efficient, and
simple protocol for direct oxidative C–H amination of ben-
zoxazoles with primary amines through copper-catalyzed
C–H bond activation (Scheme 1).
DOI: 10.1055/s-0034-1379886; Art ID: st-2014-w0906-l
Abstract A facile, efficient, and simple protocol for direct oxidative C–H
amination of benzoxazoles with primary amines through copper-cata-
lyzed C–H bond activation using tert-butyl peroxide (TBP) as oxidant
under air has been developed. The reaction proceeds smoothly at ambi-
ent temperature to furnish the products. A variety of substituted ami-
nobenzoxazoles were synthesized with good to excellent yields.
Key words C-H activation, amination, copper catalysis, benzoxazole
The transition-metal-catalyzed selective C–N bond for-
mation of azoles is an important reaction in synthetic
chemistry, because the molecules containing heteroaryl-
amine units are ubiquitous in biological, pharmaceutical
and material sciences.1 Many traditional methods have
been developed to synthesize this skeleton, including palla-
dium-catalyzed Buchwald–Hartwig coupling, copper-cata-
lyzed Ullmann and Goldberg couplings, and cross-coupling
reactions of boronic acids, stannanes, and siloxanes with
corresponding amines.2 Although rapid and straightforward
access to heteroaryamines are provided by the methods
mentioned above, there remain some disadvantages, such
as high reaction temperature, high loading of noble metals,
and special ligands.1b,3 To find greener and more efficient
methods, direct C–H amination has been investigated be-
cause of its high atom efficiency compared with the report-
ed cross-coupling reactions, and because of its wide range
of applications in the synthesis of biologically active com-
pounds and organic intermediates.4
Seminal works on the direct C–H amination of het-
eroarenes have been reported; for example, Mori and Sch-
reiber successfully developed a copper-catalyzed amination
of azoles by using secondary amines as nitrogen sources.5
Miura developed a copper-catalyzed reaction that allowed
access to heteroarylamines with chloroamines instead of
the parent amines.6 Chang reported silver-catalyzed direct
amination of benzoxazoles.7 Hong achieved a copper-cata-
lyzed C–H amination of polyfluorobenzenes with an array
of primary aromatic amines for the first time.8 However,
these reported protocols have some drawbacks such as the
R1
O
N
O
N
CuCl, AcOH,16 h
R2
R1NH2
R2
NH
+
TBP, toluene, 80 °C
2
1
3
Scheme 1 Copper-catalyzed direct amination of benzoxazoles with
primary amines
The copper-catalyzed oxidative C–H amination of ben-
zoxazole (1a) with benzylamine (2a) was chosen as a model
reaction to optimize the reaction conditions. Copper cata-
lysts such as CuBr2, Cu(OAc)2, CuCl, and CuI were screened
for the C–H amination reaction (Table 1, entries 2–5). CuCl
showed good catalytic activity among the above catalysts
screened, furnishing 3a in 69% yield (entry 5). Subsequent
experiments revealed that the reaction requires 20 mol%
CuCl. However, increasing the amount of CuCl further did
not bring significant change in the yield of the reaction
(entries 5 and 6). The use of acid as an additive was essen-
tial; the addition of 0.8 equivalent acetic acid (AcOH) great-
ly improved the reaction yield, and 3a was obtained in 94%
yield (entry 9). Other acids such as HCOOH and PhCOOH,
were less effective than AcOH (entries 7 and 8). Ag2CO3,
TBHP and TBP were tested and when TBP was employed as
oxidant, the yield was enhanced to 94% (entries 9–11). Am-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 639–642

640
J. Gu, C. Cai
Letter
Synlett
Table 1 Optimizing the Reaction Conditionsa
O
O
NH2
cat, acid
oxidant, toluene, 80 °C
NH
+
N
N
1a
Catalyst
2a
3a
Entry
Acid (equiv)
Oxidant (equiv)
Yield (%)b
1
2
–
–
–
n.r.
39
n.r.
9
CuBr2
Cu(OAc)2
CuI
HCOOH (0.4)
HCOOH (0.4)
HCOOH (0.4)
HCOOH (0.4)
HCOOH (0.4)
HCOOH (0.8)
PhCOOH (0.8)
AcOH (0.8)
AcOH (0.8)
AcOH (0.8)
–
TBP (2)
TBP (2)
TBP (2)
TBP (2)
TBP (2)
TBP (2)
TBP (2)
TBP (2)
TBHP (2)
Ag2CO3 (2)
–
3
4
5
CuCl
CuClc
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
69
68
80
30
94
34
13
7
6
7
8
9
10
11
12
13
14
HCOOH (0.8)
–
–
25
13
TBP (2)
a Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), CuCl (20 mol%), toluene (2.0 mL), 16 h, 80 °C.
b Determined by GC analysis.
c CuCl (30 mol%).
ination of benzoxazole was not observed in the absence of
copper source, indicating that copper was crucial for the re-
action (entry 1).
the desired product 3h was obtained in 94% yield. Alkyl ter-
tiary amines 2i, 2j, and 2k provided the desired products 3i,
3j, 3j′, 3k, and 3k′ in moderate yields (Table 3, entries 2–4).
In conclusion, a facile, efficient protocol for direct oxida-
tive C–H amination of benzoxazoles with primary amines
through copper-catalyzed C–H bond activation has been
developed in good to excellent yields. This catalytic system
was also suitable when the nitrogen sources were second-
ary and tertiary amines, and the desired products were syn-
thesized in moderate yield. The ambient reaction tempera-
ture, inexpensive copper catalyst, and easily handled TBP
oxidant make this C–H amination protocol useful for future
applications, and provides a powerful tool for the synthesis
of substituted aminobenzoxazole derivatives.
Under the optimized conditions, the scope of this oxida-
tive C–H amination reaction was investigated with a range
of amines (Table 2).12 Benzylamines substituted with either
electron-withdrawing or electron-donating groups reacted
with benzoxazole to give the desired products 3a–d in good
yield. Other primary amines, such as n-butylamine, tert-bu-
tylamine, and cyclohexylamine were tested for the oxida-
tive C–H amination reaction to give the corresponding
products 3e–g in 88–91% yield.
The scope of this reaction was then investigated with
respect to azole under the optimized conditions (Table 2).
Alkyl- and halogen-substituted benzoxazoles were aminat-
ed effectively in good yield (3l–n). Unfortunately, no desired
product was obtained when benzoxazole containing elec-
tron-withdrawing groups such as nitro was employed. In
contrast to benzoxazoles, benzothiazole and benzimidazole
did not afford the corresponding products 3p and 3q under
the reaction conditions. The lower reactivity of the latter
two substrates may be caused by their lower acidity.
To expand the substrate scope, cyclic secondary amine
piperidine and tertiary amines 2i–k were tested with ben-
zoxazole under the optimized conditions (Table 3). When
piperidine was used for this oxidative amination procedure,
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379886.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
References and Notes
(1) (a) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284. (b) Seregin,
I. V.; Gevorgan, V. Chem. Soc. Rev. 2007, 36, 1173.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 639–642

641
J. Gu, C. Cai
Letter
Synlett
Table 2 Substrate Scope of the Reaction with Amines and Azolesa,b
Table 3 Substrate Scope of Secondary and Tertiary Aminesa
R1
NH
R1
N
R2
O
R1
R3
O
N
O
O
N
CuCl, AcOH, 16 h
CuCl, AcOH, TBP
toulene, 80 °C
N
R2
H
R1NH2
R2
+
R2
+
N
TBP, toluene, 80 °C
N
1a
2
2
3
1
3
Entry
1
Amine 2
Product 3
Yield (%)b
94
O
O
N
NH
NH
NH
NH
O
N
F
N
N
N
3a, 91%
3b, 85%
N
H
N
3h
2h
F
O
N
O
N
O
N
2
3
67
33
3c, 92%
3e, 91%
3d, 90%
N
3i
2i
O
N
O
N
H
N
H
N
O
3f, 88%
N
N
Ph
O
O
N
H
N
3j
NH
2j
N
Cl
3l, 80%
3g, 91%
O
N
Ph
O
44
Ph
O
N
NH
NH
N
3j′
N
3m, 95%
3n, 72%
3p, 0%
Me
O
Me
Ph
N
N
N
Ph
O
N
4
24
47
Ph
S
N
Me
2k
N
NH
Me
Me
NH
3k
O2N
3o, 0%
O
H
N
Ph
N
Ph
3k′
NH
a Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), CuCl (20 mol%), AcOH
(0.8 equiv), TBP (2 equiv), toluene (2.0 mL), 80 °C, 16 h.
b Isolated yield.
N
3q, 0%
a Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), CuCl (20 mol%), AcOH
(0.8 equiv), TBP (2 equiv), toluene (2.0 mL), 16 h, 80 °C.
b Isolated yield.
(4) (a) Yasuo, S.; Megumi, Y.; Satoshi, Y.; Tomoko, S.; Midori, I.;
Tetsutaro, N.; Kokichi, S.; Fukio, K. J. Med. Chem. 1998, 41, 3015.
(b) Yoshida, S.; Shiokawa, S.; Kawano, K. I.; Ito, T.; Murakami, H.;
Suzuki, H.; Yasuo, S. J. Med. Chem. 2005, 48, 7075. (c) Gao, M.;
Wang, M.; Hutchins, G. D.; Zheng, Q.-H. Eur. J. Med. Chem. 2008,
43, 1570. (d) Sato, Y.; Imai, M.; Amano, K.; Iwamatsu, K.;
Konno, F.; Kurata, Y.; Sakakibara, S.; Hachisu, M.; Izumi, M.;
Matsuki, N.; Saito, H. Biol. Pharm. Bull. 1997, 20, 752.
(e) Verderame, M. J. Med. Chem. 1972, 15, 693. (f) Liu, K. G.; Lo,
J. R.; Comery, T. A. Bioorg. Med. Chem. Lett. 2009, 19, 1115.
(g) Armstrong, A.; Collins, J. C. Angew. Chem. Int. Ed. 2010, 49,
2282. (h) Cho, S.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068.
(i) Thirunavukkarasu, V.; Ackermann, L. Chem. Commun. 2014,
50, 29. (j) Louillat, M. L.; Patureau, F. W. Chem. Soc. Rev. 2014, 43,
901.
(2) (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.
(b) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47,
6338. (c) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. (d) Antilla,
J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077. (e) Kwong, F. Y.;
Buchwald, S. L. Org. Lett. 2003, 5, 793. (f) Ley, S. V.; Thomas, A.
W. Angew. Chem. Int. Ed. 2003, 42, 5400. (g) Ma, D.; Cai, Q.;
Zhang, H. Org. Lett. 2003, 5, 2453. (h) Evano, G.; Blanchard, N.;
Toumi, M. Chem. Rev. 2008, 108, 3054. (i) Rao, H.; Fu, H.; Jiang,
Y.; Zhao, Y. Angew. Chem. Int. Ed. 2009, 48, 1114.
(3) (a) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (b) Dyker, G.
Angew. Chem. Int. Ed. 1999, 38, 1698. (c) Alberico, D.; Scott, M.
E.; Lautens, M. Chem. Rev. 2007, 107, 174. (d) Mori, A.; Sugie, A.
Bull. Chem. Soc. Jpn. 2008, 81, 548. (e) Zificsak, C. A.; Hlasta, D. J.
Tetrahedron 2004, 60, 8991. (f) Satoh, T.; Miura, M. Chem. Lett.
2007, 36, 200.
(5) (a) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett.
2009, 11, 1607. (b) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11,
5178.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 639–642

642
J. Gu, C. Cai
Letter
Synlett
(6) Kawano, T.; Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M.
J. Am. Chem. Soc. 2010, 132, 6900.
(7) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem. Int. Ed.
2009, 48, 9127.
volatiles were removed under vacuum to afford the crude prod-
uct, which was analyzed by GC. The crude product was purified
by column chromatography on silica gel (EtOAc–hexanes,
10:90) to afford the desired pure product 3.
(8) Zhao, H.; Wang, M.; Sun, W.; Hong, M. Adv. Synth. Catal. 2010,
352, 1301.
(9) (a) Li, Y. M.; Xie, Y. S.; Zhang, R.; Duan, C. Y. J. Org. Chem. 2011,
76, 5444. (b) Wang, J.; Ho, J. T.; Zhang, J.; Yu, X. Q. Chem.
Commun. 2011, 47, 3652.
(10) Guo, S. M.; Qian, B.; Xie, Y. J.; Huang, H. M. Org. Lett. 2011, 13,
522.
(11) Xie, Y. J.; Qian, B.; Huang, H. M. Adv. Synth. Catal. 2013, 355,
1315.
(12) (a) Synthesis of Aminobenzoxazoles from Benzoxazoles and
Amines; General Procedure: A mixture of benzoxazole (1.0
mmol), amine (1.0 mmol), CuCl (0.2 mmol), TBP (2.0 mmol),
and AcOH (0.8 mmol) in toluene (2.0 mL) was stirred at 80 °C
for 16 h. Upon completion, the reaction mixture was diluted
with EtOAc (4.0 mL) and filtered through a bed of silica gel. The
N-(2-Fluorobenzyl)benzo[d]oxazol-2-amine (3b): Colorless
solid; 1H NMR (500 MHz, CDCl3): δ = 7.36 (t, J = 7.0 Hz, 1 H),
7.23–7.14 (m, 3 H), 7.05 (t, J = 7.3 Hz, 1 H), 6.99 (dd, J = 17.3,
8.8 Hz, 2 H), 6.93 (t, J = 8.6 Hz, 1 H), 6.35 (s, 1 H), 4.63 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 161.0 (s), 159.0 (s), 142.1 (s),
128.7 (d, J = 37.4 Hz), 128.2–127.8 (m), 123.9 (s), 123.2 (d,
J = 52.9 Hz), 122.9–122.4 (m), 119.9 (s), 115.4 (s), 114.6 (s),
114.4 (s), 107.9 (s), 40.0 (s).
N-Benzyl-5-methylbenzo[d]oxazol-2-amine (3m): Brown
solid; 1H NMR (500 MHz, CDCl3): δ = 7.42 (t, J = 10.9 Hz, 3 H),
7.37 (d, J = 7.4 Hz, 2 H), 7.36–7.32 (m, 1 H), 7.14 (d, J = 8.0 Hz,
1 H), 6.92 (s, 1 H), 6.85 (d, J = 8.1 Hz, 1 H), 4.68 (s, 2 H), 2.40 (s,
3 H). 13C NMR (125 MHz, CDCl3): δ = 161.7 (s), 145.9 (s), 141.9
(s), 137.0 (s), 132.6 (s), 127.8 (s), 126.7 (s), 120.4 (s), 115.5 (s),
107.2 (s), 45.9 (s), 20.5 (s)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 639–642