A facile access to 3,5-disubstituted oxazolones featuring a Cu-catalyzed cyclization of N-alkynyl tert-butyl carbamates

Article abstract of DOI:10.1246/cl.2012.636

Using cheap and readily accessible CuCl as the catalyst, an operationally simple and efficient method for the synthesis of 3,5-disubstituted oxazolones has been realized by the cyclization of N-alkynyl tert-butyl carbamates. The reaction proceeds under mild reaction conditions and shows good functional group compatibility.

Full text of DOI:10.1246/cl.2012.636

doi:10.1246/cl.2012.636
636
Published on the web June 2, 2012
A Facile Access to 3,5-Disubstituted Oxazolones Featuring a Cu-catalyzed Cyclization
of N-Alkynyl tert-Butyl Carbamates
Zenghui Lu,1 Zhaozhen Yang,1 Weijian Cui,1 and Gangguo Zhu*1,2
1Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, P. R. China
2Key Laboratory of the Ministry of Education for Advanced Catalysis Materials,
Zhejiang Normal University, Jinhua 321004, P. R. China
(Received April 1, 2012; CL-120279; E-mail: gangguo@zjnu.cn)
Table 1. Screening of the reaction conditionsa
Using cheap and readily accessible CuCl as the catalyst, an
operationally simple and efficient method for the synthesis of
3,5-disubstituted oxazolones has been realized by the cyclization
of N-alkynyl tert-butyl carbamates. The reaction proceeds under
mild reaction conditions and shows good functional group
compatibility.
O
Boc
Bn
catalyst
solvent
O
Ph
N
N
Ph
Bn
1a
2a
Entry
Catalyst
Solvent
Yieldb/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
CuCl2
®
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH3CN
DCE
DMF
DMSO
THF
dioxane
EtOAc
toluene
toluene
72
Oxazolones are a common structural motif that occurs in
numerous natural products and pharmacological active mole-
cules.1 They are also found to be one of the most important
building blocks in organic synthesis and have been widely
utilized in a variety of organic reactions, including radical
reactions,2 [4 + 2] cycloaddition,3 Pauson-Khand reaction,4 and
preparation of functionalized oxazolidinones and their deriva-
tives.5 Consequently, it is highly desirable to develop new
methods allowing the efficient construction of oxazolones from
readily available starting materials. Among these, oxazolones
are often prepared by the Lewis acid- or base-catalyzed
condensation of 1,2-aminoketones with carbonyl compounds.6
However, the harsh conditions, such as strong acidic or basic
additives, high temperature, or the utilization of toxic carbon-
ylation reagents, limit the application of these methods.
NRc
68
CuBr2
Cu(OAc)2
CuSO4
CuBr
CuCl
Cu2O
FeCl3
ZnCl2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
38
trace
90
91 (92)d
trace
messy
25
80
84
55
40
77
60
80
77e
88f,g
Hashmi7a and Gagosz7b independently reported an elegant
method for the synthesis of highly functionalized oxazolones
using a Au-catalyzed cycloisomerization of N-alkynyl tert-butyl
carbamates.7,8 More recently, Lautens and co-workers disclosed
a Pd-catalyzed efficient synthesis of 3,5-disubstituted oxazo-
lones from ¢,¢-dibromoenamides.9 Despite these significant
successes, the utilization of costly catalysts, such as gold or
palladium complexes, has greatly diminished the synthetic
utility of the aforementioned methods.
aThe reactions were carried out using 1a (0.5 mmol) and Cu
catalyst (0.05 mmol) in 2 mL of solvent at 50 °C for 5 h.
bIsolated yields. NR: no reaction. Isolated yield on 10 mmol
c
d
scale. eThe reaction was run at room temperature for 24 h.
f5 mol % of CuCl. 18 h.
g
On the other hand, copper-catalyzed reactions have been
dramatically increased over the past decade, and it proves to be
one of the most powerful synthetic tools for the assembly of
carbon-carbon and carbon-heteroatom bonds in organic chem-
istry.10 Moreover, copper catalysts are usually low cost, readily
accessible, and stable under a number of reaction conditions.
Pursuing our interest in the development of transition-metal-
catalyzed reactions from heteroatom-substituted acetylenes,11 we
wish to report here an efficient method for the synthesis of 3,5-
disubstituted oxazolones via a Cu-catalyzed cyclization of N-
alkynyl tert-butyl carbamates.
At the outset of this study, the reaction of N-alkynyl tert-
butyl carbamates 1a was chosen as a model reaction to evaluate
the reaction parameters. As a result, the 3,5-disubstituted
oxazolone 2a was obtained in 72% isolated yield by treating
1a with 10 mol % of CuCl2 in toluene at 50 °C for 5 h (Table 1,
Entry 1). The control experiment revealed that the metal catalyst
is essential for the occurrence of this cyclization reaction
(Entry 2). Encouraged by this promising result, we then
examined other catalysts for this transformation.
Among the catalysts we tested, CuBr and CuCl turned out to
be the best choices, giving rise to 3,5-disubstituted oxazolone 2a
in 90% and 91% yields, respectively (Entries 6 and 7). Other
metal complexes, such as FeCl3 and ZnCl2, proved to be much
less effective (Entries 9 and 10). Afterward, we decided to
perform further optimization using CuCl as the catalyst.
A brief survey of the solvent indicated that toluene was the
optimal solvent, although other solvents, such as CH3CN, THF,
and EtOAc, were also effective (Entries 11-17). Running the
reaction at room temperature led to a decrease of the yield to
77% (Entry 18). In contrast, the decrease of amounts of CuCl
from 10 to 5 mol % provided the desired product 2a in 88%
Chem. Lett. 2012, 41, 636-638
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

637
Table 2. Synthesis of 3,5-disubstituted oxazolones 2a
O
Boc
[Cu]+
O
O
R1
N
Boc
CuCl
O
N
R1
R2
H+
R2
R1
N
1
N
R2
R1
toluene, 50 °C
R2
2
1
2
Entry
1
R1
Ph
R2
Yieldb/%
O
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
91 (2a)
76 (2b)
84 (2c)
83 (2d)
86 (2e)
85 (2f)
81 (2g)
85 (2h)
82 (2i)
80 (2j)
72 (2k)
68 (2l)
83 (2m)
NRc
O
O
4-F-C6H4
4-Cl-C6H4
2-Cl-C6H4
4-Br-C6H4
3-Br-C6H4
4-Me-C6H4
4-t-Bu-C6H4
4-MeO-C6H4
3,4-(MeO)2-C6H3
2-Naphthyl
n-C8H17
TBSO(CH2)2
TES
Ph
Ph
Ph
N
N
R1
R1
R2
R2
C4H8 + H+
[Cu]
[Cu]
B
A
Scheme 1. Proposed mechanism.
catalyzed cyclization of N-alkynyl tert-butyl carbamates. Al-
though the Au-catalyzed version has been previously reported
by the groups of Hashmi7a and Gagosz,7b the utilization of
inexpensive and readily accessible copper catalyst represents a
practical alternative to access 3,5-disubstituted oxazolones.
In view of the previous results,7 a plausible mechanism is
proposed in Scheme 1 to account for this Cu-catalyzed trans-
formation of N-alkynyl tert-butyl carbamates. First, a cationic
copper intermediate A is believed to be generated by the
intramolecular attack of oxygen atom to the Cu-activated C-C
triple bond. Then, the release of isobutylene and proton from
species A leads to an oxazolone-copper intermediate B,
followed by protodemetallation to produce 3,5-disubstituted
oxazolones 2 with concurrent regeneration of the copper catalyst
(Scheme 1).
In conclusion, a simple and practical method for the
effective synthesis of 3,5-disubstituted oxazolones has been
developed by a Cu-catalyzed cyclization of N-alkynyl tert-butyl
carbamates. Using inexpensive and readily accessible CuCl
catalyst, the reaction proceeds smoothly at mild reaction
conditions, and it is operationally simple and practical for the
synthetic community. Further investigations on synthetic appli-
cations of this protocol will be described in due course.13
80 (2o)
75 (2p)
73 (2q)
n-Bu
Cy
aThe reactions were carried out using 1 (0.5 mmol) and CuCl
b
(0.05 mmol) in 2 mL of toluene at 50 °C for 5-8 h. Isolated
c
yields. The reaction was carried out at 80 °C for 8 h.
yield, albeit with a prolonged reaction time (18 h) (Entry 19).
Therefore, we chose 10 mol % of CuCl as the catalyst, 50 °C as
the reaction temperature, and toluene as the solvent for the
optimal reaction conditions to access 3,5-disubstituted oxazo-
lones.12 Indeed, the reaction could be scaled up to 10 mmol to
provide oxazolone 2a in 92% isolated yield (Entry 7).
Having secured a reliable preparative protocol for the
synthesis of 3,5-disubstituted oxazolones, we next focused on
investigation of the scope and limitations of this reaction. As
shown in Table 2, under the standard conditions, the cyclization
of either aryl or alkyl N-alkynyl tert-butyl carbamates proceeded
smoothly to furnish the desired 3,5-disubstituted oxazolones 2 in
good to excellent yields. For example, substrate 1b resulted in
the formation of 3,5-disubstituted oxazolone 2b in 76% yield
(Entry 2). The N-alkynyl tert-butyl carbamates 1c and 1d
afforded the corresponding 3,5-disubstituted oxazolones 2c
and 2d in respective yields of 84% and 83%, implying that
the steric hindrance on the benzene ring has little influence on
this transformation (Entries 3 and 4).
The reaction of aliphatic ynamides 1l and 1m occurred
uneventfully as well to give oxazolones 2l and 2m in good
yields, while the formation of desired product from the silylated
substrate 1n did not take place, even at an elevated temperature
(Entries 12-14). In addition, the effects of substituents on the
nitrogen atom of starting materials 1 were briefly examined.
Both N-phenyl substrate 1o and N-Cy substrate 1q successfully
gave rise to the expected 3,5-disubstituted oxazolones 2o and 2q
in good yields (Entries 15 and 17).
This work has been supported by the National Natural
Science Foundation of China (Nos. 20902084 and 21172199),
Qianjiang Talents Project of the Science and Technology Office
in Zhejiang Province (No. 2010R10016), and ZJNU GlycoDrug
Research Centre.
References and Notes
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As such, we have developed an efficient and convenient
method to assemble 3,5-disubstituted oxazolones via the Cu-
Chem. Lett. 2012, 41, 636-638
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

638
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12 Representative procedure for the Cu-catalyzed synthesis of
3,5-disubstituted oxazolones: To a solution of 1a (154 mg,
0.5 mmol) in 2 mL of toluene was added CuCl (5.0 mg,
0.05 mmol) at 50 °C. After stirring for 5 h, the reaction
mixture was concentrated and purified by column chroma-
tography on silica gel (hexane/EtOAc = 6/1) to give
114 mg (yield: 91%) of 2a as a white solid, mp: 148-
150 °C. 1H NMR (CDCl3, 400 MHz): ¤ 4.79 (s, 2H), 6.64 (s,
1H), 7.21-7.50 (m, 10H); 13C NMR (CDCl3, 100 MHz): ¤
47.9, 108.9, 122.9, 127.3, 128.0, 128.2, 128.5, 128.8, 129.1,
135.3, 139.3, 155.0; MS (EI, m/z): 251 (M+, 95), 207 (2),
160 (8), 132 (20), 105 (100).
7
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Ma, Q. Cai, Acc. Chem. Res. 2008, 41, 1450. c) G. Evano, N.
13 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2012, 41, 636-638
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/