Catalyst-free intramolecular oxidative cyclization of N-allylbenzamides: A new route to 2,5-substituted oxazoles

Article abstract of DOI:10.1021/ol302031z

A catalyst-free intramolecular oxidative cyclization reaction of N-allylbenzamides has been developed to prepare 2,5-disubstituted oxazoles with good yields. This reaction gives an efficient synthetic strategy to form an oxazole nucleus directly from easi

Full text of DOI:10.1021/ol302031z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Catalyst-Free Intramolecular Oxidative
Cyclization of N‑Allylbenzamides: A New
Route to 2,5-Substituted Oxazoles
Wei Zhou, Chen Xie, Jianlin Han,* and Yi Pan*
School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination,
Nanjing University, Nanjing, 210093, China
hanjl@nju.edu.cn; yipan@nju.edu.cn
Received July 22, 2012
ABSTRACT
A catalyst-free intramolecular oxidative cyclization reaction of N-allylbenzamides has been developed to prepare 2,5-disubstituted oxazoles with
good yields. This reaction gives an efficient synthetic strategy to form an oxazole nucleus directly from easily accessible substrates under
temperate conditions.
The oxazole nucleus is an important structure in many
natural products and compounds with biological or phar-
maceutical activities.1À4 2,5-Substituted oxazoles also
serve as useful building blocks in organic synthesis,5 es-
pecially as intermediates for the formation of polysub-
stituted oxazoles.6 There are many synthetic strategies
available for the preparation of the oxazole nuclei,7 and
the use of N-propargylbenzamides as starting materials
with Au,8 Pd,9 Ag,10 Cu,11 and Mo12 catalysts is of great
importance. However, there are still shortcomings, such as
harsh reaction conditions and the use of expensive catalysts.
(7) For selected examples, see: (a) Kumar, D.; Sundaree, S.; Patel,
G.; Rao, V. S. Tetrahedron Lett. 2008, 49, 867. (b) Ueda, S.; Nagasawa,
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M.; Schymura, S.; Visus, J.; Frey, W. Eur. J. Org. Chem. 2006, 4905. (d)
Saito, A.; Matsumoto, A.; Hanzawa, Y. Tetrahedron Lett. 2010, 51,
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Schetter, S.; Littmann, A.; Rudolph, M.; Hamzic, M.; Visus, J.;
Rominger, F.; Frey, W.; Bats, J. W. Chem.;Eur. J. 2010, 16, 956.
(b) Doherty, S.; Knight, J. G.; Hashmi, A. S. K.; Smyth, C. H.; Ward,
N. A. B.; Robson, K. J.; Tweedley, S.; Harrington, R. W.; Clegg,
W. Organometallics 2010, 29, 4139. (c) Milton, M. D.; Inada, Y.
Nishibayashi, Y.; Uemura, S. Chem. Commun. 2004, 2712. (d) Hashmi,
A. S. K.; Yu, Y.; Rominger, F. Organometallics 2012, 31, 895. (e)
Egorova, O. A.; Seo, H.; Kim, Y.; Moon, D.; Rhee, Y. M.; Ahn, K. H.
Angew. Chem., Int. Ed. 2011, 50, 11446. (f) Paradise, C. L.; Sarkar,
P. R.; Razzak, M.; De Brabander, J. K. Org. Biomol. Chem. 2011, 9,
4017.
(1) For selected reviews, see: (a) Wipf, P. Chem. Rev. 1995, 95, 2125.
(b) Jin, Z. Nat. Prod. Rep. 2006, 23, 464. (c) Yeh, V. S. C. Tetrahedron
2004, 60, 11995. (d) Riego, E.; Hernandez, D.; Albericio, F.; Alvarez, M.
Synthesis 2005, 1907.
(2) (a) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J.
J. Am. Chem. Soc. 1991, 113, 2303. (b) Li, J.; Jeong, S.; Esser, L.; Harran,
P. G. Angew. Chem., Int. Ed. 2001, 40, 4765.
(3) Adamczeski, M.; Quinoa, E.; Crews, P. J. Am. Chem. Soc. 1988,
110, 1598.
(4) (a) Skepper, C. K.; Quach, T.; Molinski, T. F. J. Am. Chem. Soc.
2010, 132, 10286. (b) Wan, C.; Zhang, J.; Wang, S.; Fan, J.; Wang, Z.
Org. Lett. 2010, 12, 2338.
(5) (a) Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 389. (b)
Wasserman, H. H.; McCarthy, K. E.; Prowse, K. S. Chem. Rev. 1986, 86,
845. (c) Wipf, P. Chem. Rev. 1995, 95, 2115. (d) Jin, Z. Nat. Prod. Rep.
2003, 20, 584. (e) Jin, Z. Nat. Prod. Rep. 2009, 26, 382.
ꢀ
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Soc. 2011, 133, 191. (b) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011,
133, 8482. (c) Wipf, P.; Aoyama, Y.; Benedum, T. E. Org. Lett. 2004, 6,
3593. (d) Badillo, J. J.; Arevalo, G. E.; Fettinger, J. C.; Franz, A. K. Org.
Lett. 2011, 13, 418. (e) Wan, C. F.; Gao, L. F.; Wang, Q.; Zhang, J. T.;
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r
10.1021/ol302031z
XXXX American Chemical Society

Efficient, catalyst-free, synthetic methods for securing
oxazoles remain of importance.
we did not get the expected cyclization products (entries 12,
13, and 14). When Br2 or the combination of Br2/K2CO3
was used in this reaction, the brominated product 3a
was obtained in high yield and only a trace amount of 2a was
detected (entries 15 and 16). Overall, ClCH2CH2Cl was
found to be the most effective solvent for this oxidative
cyclization process using NBS as the oxidant at 100 °C.
There have been some reports about the formation of
oxazolines from N-allylbenzamides,13 which needed an
additional oxidant to form the oxazoles.14 However, the
direct synthesis of oxazoles from the readily available
N-allylbenzamides still remains unexplored until now.
So, we decided to explore an efficient tandem method-
ology for the preparation of 2,5-substituted oxazoles
with N-allylbenzamides as starting materials. Herein, we
wish to report a new route to 2,5-substituted oxazoles via
intramolecular oxidative cyclization of N-allylbenzamides
under temperate conditions without the use of any catalyst.
Our studies on this reaction began by choosing 1a as the
model substrate, to test the possibility of cycloaddition under
the oxidation of NBS (Scheme 1).
Table 1. Optimization of the Oxidative Cyclization of
N-Allylbenzamidea
temp
t
2a
(%)b
3a
(%)b
Scheme 1. NBS-Mediated Cyclization of N-Allylbenzamides
entry
oxidative
solvent
(°C)
(h)
1
NBS
DCE
80
24
24
24
24
12
24
24
24
24
24
24
24
24
24
24
24
72
NR
0
19
2
NBS
DCE
rt
3
NBS
DCE
50
43
0
4
NBS
DCE
100
100
100
100
100
100
100
100
100
100
100
100
100
88
52
NRc
0
5
NBS
DCE
30
6
NBS
DCE
7
NBS
CH3CN
toluene
dioxane
DMF
HOAc
DCE
45
80
87
8
NBS
NR
0
We were delightedtofind the yield ofthismodel reaction
was good when the starting material 1a was treated with
NBS (3.0 equiv) in ClCH2CH2Cl at 80 °C (Table 1, entry
1). This resulted in the 2,5-substituted oxazole 2a, along
with a 19% yield of the dibrominated product 3a. No
cyclization product was found when the reaction was
decreased to 50 °C, and only 3a was obtained in 43% yield
(entry 3). No reaction took place when the temperature
was further decreased to room temperature (entry 2). The
best result was obtained when the reaction was kept at
100 °C. The highest yield was 88% (entry 4). The reaction
time also had a great effect on the reaction, and a dramatic
lower yield was found when the reaction was stopped at
12 h (entry 5). After investigation of the solvents, we found
that the treatment of 1 in dioxane or CH3CN gave only
product 3a, which was just the bromine addition product
to the allyl group in 1 (entries 7 and 9). The use of other
solvents did not improve this reaction (entries 8, 10, and 11).
Furthermore, the addition of H2O also inhibited it (entry 6).
When NCS, NIS, or PhI(OAc)2 was used instead of NBS,
9
NBS
10
11
12
13
14
15
16
NBS
NR
0
NBS
NCS
NR
NR
NR
0
NIS
DCE
PhI(OAc)2
Br2
DCE
DCE
99
91
Br2/K2CO3
DCE
<5
a All reactions were performed at 0.1 M with 3.0 equiv of oxidant in a
sealed tube. b Isolated yields. c 2.0 equiv of water were added.
Under the optimized conditions, the scope of the N-
allylbenzamide substrates was examined (Table 2). Be-
cause increased reaction times decreased the yield of this
reaction, for each substrate this parameter was examined
carefully. As shown in Table 2, the intramolecular cycliza-
tion can proceed smoothly for a wide range of substrates,
resulting in moderate to excellent chemical yields. We
found that the reaction of substrates with strong electron-
withdrawing groups on the aromatic ring proceeded very
rapidly. The reaction could complete within 2 h (entries
2, 9, and 10). Contrastingly, the existence of a strong
electron-donating group on the aromatic ring inhibited
this reaction, even prolonging the reaction time to 48 h
(entry 16). It was also found that substrate 1o with a
1-naphthyl group worked well in the system with a mod-
erate yield (entry 15). Varying steric effects of the sub-
strates had no dramatic effect on the reaction; these sub-
strates still provided good yields (entries 2, 7, and 11À13).
Notably, in the case of 1h, the reaction gave the cycliza-
tion product, along with the methyl group on the para-
position of the phenyl ring brominated by NBS (entry 8).
(10) Harmata, M.; Huang, C. Synlett 2008, 1399.
(11) (a) Prior, A. M.; Robinson, R. S. Tetrahedron Lett. 2008, 49, 411.
(b) Jin, C.; Burgess, J. P.; Kepler, J. A.; Cook, C. E. Org. Lett. 2007, 9,
1887. (c) Jin, C.; Manikumar, G.; Kepler, J. A.; Cook, C. E.; Allan,
G. F.; Kiddoe, M.; Bhattacharjee, S.; Linton, O.; Lundeen, S. G.; Sui, Z.
Bioorg. Med. Chem. Lett. 2007, 5754.
(12) Meng, X. J.; Kim, S. Org. Biomol. Chem. 2011, 9, 4429.
(13) (a) Jaganathan, A.; Garzan, A.; Whitehead, D. C.; Staples, R. J.;
Borhan, B. Angew. Chem., Int. Ed. 2011, 50, 2593. (b) Minakata, S.;
Morino, Y.; Oderaotoshi, Y.; Komatsu, M. Org. Lett. 2006, 8, 3335. (c)
Morino, Y.; Hidaka, I.; Oderaotoshi, Y.; Komatsu, M.; Minakata, S.
Tetrahedron 2006, 62, 12247.
(14) (a) Jiang, H. F.; Huang, H.; Cao, H.; Qi, C. Org. Lett. 2010, 12,
5561. (b) Murai, K.; Takahara, Y.; Matsushita, T.; Komatsu, H.;
Fujioka, H. Org. Lett. 2010, 12, 3456.
B
Org. Lett., Vol. XX, No. XX, XXXX

The structure of 2d was identified by single-crystal X-ray
diffraction analysis (Figure 1).
Scheme 2. Insights into the Mechanism
Table 2. Synthesis of 2,5-Disubstituted Oxazoles from
N-Allylbenzamide Substratesa
process. Initially, N-allylbenzamide 1a reacts with NBS to
form the dibrominated intermediate 3a, which also exists as
its imidic tautomer A. Intermediate A ungergoes intramo-
lecular nucleophilic attack by the oxygen atom to form the
cyclic intermediate B, along with loss of HBr. Intermediate
B is then quickly brominated by NBS at 100 °C resulting in
intermediate C, which proceeds through the elimination
reaction to afford the target product 2a.8a,14b
entry
Ar
product
t (h)
yield (%)b
1
C6H5
2a
2b
2c
2d
2e
2f
24
1
88
70
69
88
78
81
75
60c
60
77
62
72
91
76
53
NR
2
2-ClC6H4
3
3-ClC6H4
12
12
2
4
4-ClC6H4
5
4-FC6H4
6
4-BrC6H4
2
7
2-MeC6H4
4-MeC6H4
4-CF3C6H4
4-NO2C6H4
2,3-diCl-C6H3
2,4-diCl-C6H3
2,6-diCl-C6H3
3,4-diCl-C6H3
1-naphthyl
4-MeOC6H4
2g
2h
2i
12
8
8
9
1
10
11
12
13
14
15
16
2j
1
Scheme 3. Possible Mechanism
2k
2l
12
2
2m
2n
2o
-
2
2
12
48
a All the reactions were performed at 0.1 M with 3.0 equiv of NBS in
ClCH2CH2Cl at 100 °C in a sealed tube. b Isolated yields. c The para-methyl
group of the phenyl ring was also substituted by NBS to be BrCH2C6H4.
Scheme 4. Some Reactions of 2d
Figure 1. X-ray crystallography for 2d.
To gain insight into the reaction mechanism, we tried to
isolate the intermediate of this reaction. Decreasing the
reaction temperature or reducing the reaction time led to
the dibrominated product 3a. After careful isolation of
compound 3a, we used it as starting material to perform
the reaction under the same reaction conditions (Scheme 2).
To our delight, 3a could be converted into 2a in high chem-
ical yield under the same reaction conditions (89% yield).
Thus, compound 3a may be the intermediate or the captured
intermediate of this oxidative cyclization procedure.
On the basis of the above experimental results, a plau-
sible reaction mechanism for this intramolecular reaction
is proposed in Scheme 3. It includes an oxidation/cyclization
The presence of the CÀBr bond in the obtained 2,5-
substituted oxazoles provided an easy access to other
useful organic blocks (Scheme 4). When the product 2d
Org. Lett., Vol. XX, No. XX, XXXX
C

was treated with acetone/water at room temperature for
4 h, 4d15 with an exocyclic hydroxyl group was quantita-
tively obtained. Product 2d was also easily aminated by
treatment with BnNH2 in CH2Cl2 at room temperature to
afford 5d in 82% yield.
In conclusion, we have developed a facile catalyst-free
pathway for the synthesis of 2,5-substituted oxazoles
directly from N-allylbenzamides. This reaction involves
readily available starting materials and tolerates a wide
scope of substrates affording good yields. Subsequent
research will focus on application of this methodology to
access polysubstituted oxazoles.
Acknowledgment. We gratefully acknowledge the fi-
nancial support from the National Natural Science Foun-
dation of China (No. 21102071) and the Fundamental
Research Funds for the Central Universities (Nos.
1107020522 and 1082020502). The Jiangsu 333 program
(for Pan) and Changzhou Jin-Feng-Huang program (for
Han) are also acknowledged.
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data for new compounds, and
single-crystal X-ray diffraction analysis of 2d. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(15) Compound 4d could remain undecomposed at room tempera-
ture for at least 2 months.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX