TBHP/I2-mediated domino oxidative cyclization for one-pot synthesis of polysubstituted oxazoles

Article abstract of DOI:10.1021/ol1023085

A facile type of one-pot, transition-metal-free domino process was developed for the synthesis of oxazoles. Thus, a variety of polysubstituted oxazoles were easily synthesized via t-BuOOH/I₂-mediated domino oxidative cyclization from readily available starting materials under mild conditions.

Full text of DOI:10.1021/ol1023085

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5561-5563
TBHP/I2-Mediated Domino Oxidative
Cyclization for One-Pot Synthesis of
Polysubstituted Oxazoles
Huanfeng Jiang,* Huawen Huang, Hua Cao, and Chaorong Qi
School of Chemistry and Chemical Engineering, South China UniVersity of
Technology, Guangzhou 510640, P. R. China
jianghf@scut.edu.cn
Received September 25, 2010
ABSTRACT
A facile type of one-pot, transition-metal-free domino process was developed for the synthesis of oxazoles. Thus, a variety of polysubstituted oxazoles
were easily synthesized via t-BuOOH/I2-mediated domino oxidative cyclization from readily available starting materials under mild conditions.
Oxazole is a fundamental class of five-membered hetero-
cycles, which directly stimulated more and more interest in
both the industrial and academic fields over the past decades.1
The 1,3-oxazole substructure is generally considered as the
indispensable chemical block in organic synthesis2 and the
significant pharmacophore of many natural products,3 which
are very important antifungal medicines containing three
oxazole rings such as ulapualide A.4 Generally oxazole
derivatives are synthesized by three typical synthetic methods
including cyclization of acyclic precursors,5 oxidation of
oxazolines,6 and the coupling of the prefunctionalized
oxazoles with other organometallic reagents.7 Cyclization of
acyclic precursors to access prefunctionalized oxazoles from
readily available materials has attracted intensive attention.8
Despite primordial importance in synthetic chemistry, these
methods face the limitation of inaccessible starting materials
and the utilization of the toxic transition-metal catalysts.9
Hence, development of a more eco-friendly procedure for
acquisition of oxazole derivatives from easily available
starting materials still represents a continuing challenge.
Domino strategy has been extensively investigated and
widely examined for the synthesis of organic compounds in
modern synthetic chemistry due to its great usefulness.10
Recently, our group has reported a series of domino processes
(5) (a) Lee, J. C.; Kim, S.; Lee, Y. C. Synth. Commun. 2003, 33, 1611.
(b) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604. (c) Yeh, V.
Tetrahedron 2004, 60, 11995. (d) Nesi, R.; Turchi, S.; Giomi, D. J. Org.
Chem. 1996, 61, 7933. (e) Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier,
F.; Aulakh, V. S.; Ciufolini, M. A. Org. Lett. 2009, 11, 1539.
(6) (a) Meyers, A. I.; Tavares, F. Tetrahedron Lett. 1994, 35, 2481. (b)
Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett.
2000, 2, 1165. (c) Meyers, A. I.; Tavares, F. X. J. Org. Chem. 1996, 61,
8207.
(1) (a) Ignatius, J. T.; Michael, J. S. Chem. ReV. 1975, 75, 389. (b) Jin,
Z. Nat. Prod. Rep. 2009, 26, 382.
(2) (a) Vedejs, E.; Barda, D. A. Org. Lett. 2000, 2, 1033. (b) Atkins,
J. M.; Vedejs, E. Org. Lett. 2005, 7, 3351. (c) Zhang, J. M.; Ciufolini,
M. A. Org. Lett. 2009, 11, 2389.
(7) (a) Besselieivre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48, 9553.
(b) Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2006, 8, 2495.
(c) Lee, K.; Counceller, C. M.; Stambuli, J. P. Org. Lett. 2009, 11, 1457.
(d) Williams, D. R.; Fu, L. F. Org. Lett. 2010, 12, 808.
(3) (a) Wipf, P. Chem. ReV. 1995, 95, 2115. (b) Searle, P. A.; Molinski,
T. F. J. Am. Chem. Soc. 1995, 117, 8126. (c) Shin-ya, K.; Wierzba, K.;
Matsuo, K.; Ohtani, T.; Yamada, Y.; Furihata, K.; Hayakawa, Y.; Seto, H.
J. Am. Chem. Soc. 2001, 123, 1262. (d) Dalisay, D. S.; Rogers, E. W.;
Edison, A. S.; Molinski, T. F. J. Nat. Prod. 2009, 72, 732. (e) Hagelueken,
G.; Albrecht, S. C.; Steinmetz, H.; Jansen, R.; Heinz, D. W.; Kalesse, M.;
Schubert, W. D. Angew. Chem., Int. Ed. 2009, 48, 595. (f) Riego, E.;
Hernandez, D.; Albericio, F.; Alvarez, M. Synthesis 2005, 12, 1907. (g)
Jin, Z. Nat. Prod. Rep. 2006, 23, 464.
(8) (a) Wan, C. F.; Zhang, J. T.; Wang, S. J.; Fan, J. M.; Wang, Z. Y.
Org. Lett. 2010, 12, 2338. (b) Pan, Y. M.; Zheng, F. J.; Lin, H. X.; Zhan,
Z. P. J. Org. Chem. 2009, 74, 3148. (c) Wan, C. F.; Gao, L. F.; Wang, Q.;
Zhang, J. T.; Wang, Z. Y. Org. Lett. 2010, 12, 3902.
(9) (a) Verrier, C.; Martin, T.; Hoarau, C.; Marsais, F. J. Org. Chem.
2008, 73, 7383. (b) Besselieivre, F.; Piguel, S.; Betzer, F. M.; Grierson,
D. S. Org. Lett. 2008, 10, 4029.
(4) Rosener, J. A.; Scheuer, P. J. J. Am. Chem. Soc. 1986, 108, 846.
10.1021/ol1023085  2010 American Chemical Society
Published on Web 11/08/2010

for synthesis of heterocycle compounds.11 In this com-
munication, we present a novel synthetic method for prepara-
tion of polysubstituted oxazoles from olefins and benzylic
amines with a transition-metal-free reaction. The method
includes three principal procedures: the consecutive halo-
genation and oxidation of olefins and then functionalization
of the sp3 C-H bond adjacent to the nitrogen atom.
To initiate our study, we have optimized the reaction
conditions for the formation of oxazole with styrene (1a) and
benzylamine (2a) as substrates (Table 1). Various oxidants were
(Table 1, entries 6-8) and found that 1,5-diphenyl oxazole was
obtained in moderate yield with NIS as the additive. Among
various solvents (entries 9-12 of Table 1), DMSO was the most
effective media for this oxidative cyclization process, while 80
°C was found as the optimal temperature (Table 1, entries
13-15). Owing to the fact that the benzylamine tended to be
oxidized to phenylaldehyde in this reaction system,12 the
addition of excess benzylamine (2.5 equiv) in two portions was
necessary, which increased the yield of the desired product up
to 91% (Table 1, entry 16).
Under the optimized reaction conditions, i.e., aryl alkenes
(0.5 mmol), benzylamine derivatives (2.5 equiv in two
portions), TBHP (1.5 equiv) as the suitable oxidant, I2 (1.2
equiv) as the additive, and DMSO (3 mL) as the solvent,
the scope of a one-pot synthesis of polysubstituted oxazoles
was explored by using a series of terminal aryl alkenes and
benzylamine as the substrates (Scheme 1, 3aa-3na). Pleas-
Table 1. Optimization of Reaction Conditionsa b
,
entry
oxidant
DDQ
TBHP
IBX
O2 (1 atm)
PhI(OAc)2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
additive
solvent
DMSO
temp (°C) yield (%)c
Scheme 1
.
Scope of Aryl Alkenesa b
,
1
2
3
4
5
6
7
8
I2
I2
I2
I2
60
60
60
60
60
60
60
60
60
60
60
60
rt
21
72
75
44
8
15
32
69
55
32
28
<5
23
85
84
91
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
I2
ICl
NBS
NIS
I2
I2
I2
I2
I2
I2
I2
9
10
11
12
13
14
toluene
THF
1,4-dioxane
DMSO
DMSO
DMSO
DMSO
80
100
80
15d TBHP
16e TBHP
I2
a Reaction was carried out with 0.5 mmol of 1a, 2.0 equiv of 2a, 1.2
equiv of additive, 1.5 equiv of oxidant, 3 mL of solvent, 12 h. b IBX )
2-iodoxybenzoic acid. DDQ ) 2,3-dichloro-5,6-dicyanobenzoquinone.
TBHP ) tert-butyl hydroperoxide. c Determined by GC. d 2.5 equiv of 2a
was used. e 2.5 equiv of 2a was added in two portions.
first examined. In a typical procedure, a mixture of 1a (0.5
mmol, 1 equiv), 2a (2 equiv), oxidant (1.5 equiv), and I2 (1.2
equiv) in 3 mL of DMSO was stirred for 12 h at 60 °C. After
completion of the reaction (monitored by TLC), 3aa was
detected in 21%, 72%, 75%, 44%, and 8% yields by GC
when 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), t-BuOOH
(TBHP), 2-iodoxybenzoic acid (IBX), O2 (1 atm), and PhI-
(OAc)2 were used as the oxidant, respectively (Table 1, entries
1-5). Obviously, IBX was the relatively efficient oxidant.
Considering the economical and environmental impact, we
chose TBHP as the suitable oxidant. We used several different
additives such as ICl, NBS, and NIS in this reaction system
a Reaction conditions: aryl alkenes (0.5 mmol, 1 equiv), benzylamine
(2.5 equiv, being added in two portions), TBHP (1.5 equiv), I2 (1.2 equiv),
DMSO(3mL).b Isolatedyieldwasgiveninparentheses.c (E)-Prop-1-enylbenzene
was used as the substrate.
(10) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Ikeda, S. Acc. Chem.
Res. 2000, 33, 511. (c) Enders, D. C.; Wang, J. W. Angew. Chem. 2008,
120, 7649.
ingly, all of the olefins, regardless of their electronic or steric
properties, proceeded smoothly in good yields to afford the
expected 1,5-diaryl oxazoles (66-88%). Generally, higher
(11) (a) Cao, H.; Jiang, H. F.; Yao, W. J.; Liu, X. H. Org. Lett. 2009,
11, 1931. (b) Liu, W. B.; Jiang, H. F.; Zhang, M.; Qi, C. R. J. Org. Chem.
2010, 75, 966. (c) Cao, H.; Jiang, H. F.; Mai, R. H.; Zhu, S. F.; Qi, C. R.
AdV. Synth. Catal. 2010, 352, 143. (d) Wang, A. Z.; Jiang, H. F. J. Org.
Chem. 2010, 75, 2321.
(12) Around half of benzylamine was oxidized to benzaldehyde detected
by GC-MS.
5562
Org. Lett., Vol. 12, No. 23, 2010

yields were obtained with electron-withdrawing substituents
on the aromatic ring. The corresponding products were also
obtained in good yields with terminal heterocyclic alkenes
as the substrates (Scheme 1, 3ma and 3na). When (E)-1,2-
diphenylethene was employed as the substrate, the corre-
sponding 2,4,5-trisubstitution product was isolated in good
yield (Scheme 1, 3oa), which indicated that 2,5-diaryl
oxazoles or 2,4,5-triaryl oxazoles could be conveniently and
electively synthesized by using different olefin substrates.
However, (E)-prop-1-enylbenzene almost failed to yield the
desired product (Scheme 1, 3pa),13 due to the discrepancy
of reactivity of the relevant positions.
Scheme 3. Plausible Reaction Mechanism
Furthermore, various benzylamine derivatives were em-
ployed to probe the scope of the reaction substrates. As
shown in Scheme 2, the electron-rich group on the aromatic
Subsequently, C or its enolizational isomer D was formed
after the addition of benzylamine, then E was obtained
undergoing intramolecular nucleophilic addition of D. Con-
sequently, E collapsed into the final product (3aa) by
deprotonation and oxidation.16
Scope of Benzylamine Derivativesa b
,
Scheme 2
.
In conclusion, a new type of one-pot, transition-metal-
free domino process through a TBHP/I2-mediated oxidative
cyclization from easily available aryl alkenes and benzylic
amines was developed for the synthesis of polysubstituted
oxazoles. It is worthwhile for synthetic chemistry and
medical chemistry because oxazoles are useful synthetic
intermediates for bioactive compounds. Further studies for
the scope and the mechanism of this reaction are in progress.
Acknowledgment. We thank the National Natural Science
Foundation of China (Nos. 20625205, 20772034, and 20932002),
National Basic Research Program of China (973 Program) (No.
2011CB808600), the Doctoral Fund of the Ministry of Educa-
tion of China (No. 20090172110014), and Guangdong Natural
Science Foundation (No. 10351064101000000) for the financial
support. We also thank Professor Derong Cao for his helpful
discussion.
a Reaction condition: 1a (0.5 mmol), 2 (2.5 equiv, added in two portions),
TBHP (1.5 equiv), I2 (1.2 equiv), DMSO (3 mL). b Isolated yield. c n-BuNH2
was used as the substrate.
ring was unfavorable for the formation of oxazoles, while
the electron-deficient substituents increased the reaction
yields (Scheme 2, 3ab-3ai). It is worthy to note that there
is a slight influence when substituents are presented on the
para, meta, and ortho positions of the benzylamine such as
2d, 2e, or 2f. However, the desired product was not detected
with n-BuNH2 as the substrate (Scheme 2, 3aj).
Supporting Information Available: Experimental pro-
cedure and characterization of compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL1023085
(14) When the mixture of styrene 1a (1 equiv), TBHP (1 equiv), and
iodine (1 equiv) in dichloromethane was stirred at room temperature for
4 h, compound A was obtained in 92% yield.
A plausible mechanism of the present reaction could be
described as follows (Scheme 3): TBHP/I2-mediated oxida-
tion of 1a formed A,14 and A was conveniently converted
to B in the media of DMSO via Kornblum oxidation.15
(15) (a) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.;
Larson, H. O.; Levand, O.; Weaver, W. M. J. Am. Chem. Soc. 1957, 79,
6562. (b) Yin, G. D.; Zhou, B. H.; Meng, X. G.; Wu, A. X.; Pan, Y. J.
Org. Lett. 2006, 8, 2245.
(13) Aliphatic alkenes, such as 1-octene and methyl acrylate, could not
give the corresponding products as well.
(16) Reaction of B and 2a under the reaction conditions as 1a and 2a
afforded the desired product (3aa) in high yield (94%).
Org. Lett., Vol. 12, No. 23, 2010
5563