I2-Catalyzed C-O Bond Formation and Dehydrogenation: Facile Synthesis of Oxazolines and Oxazoles Controlled by Bases

Article abstract of DOI:10.1021/acs.orglett.5b01933

A general method for the synthesis of oxazolines and oxazoles was developed through I₂-catalyzed C-O bond formation and dehydrogenation with the same oxidant, TBHP. By simply tuning reaction bases, either oxazolines or oxazoles were selectively

Full text of DOI:10.1021/acs.orglett.5b01933

Letter
pubs.acs.org/OrgLett
I2‑Catalyzed C−O Bond Formation and Dehydrogenation: Facile
Synthesis of Oxazolines and Oxazoles Controlled by Bases
Wen-Chao Gao,* Fei Hu, Yu-Ming Huo, Hong-Hong Chang,* Xing Li, and Wen-Long Wei
College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, P.R. China
S
* Supporting Information
ABSTRACT: A general method for the synthesis of oxazo-
lines and oxazoles was developed through I2-catalyzed C−O
bond formation and dehydrogenation with the same oxidant,
TBHP. By simply tuning reaction bases, either oxazolines or
oxazoles were selectively produced from β-acylamino ketones.
producing oxazoles and oxazolines via oxidative cyclization via
different methods (Scheme 1, (2)). Thus, direct synthesis of
oxazolines from N-allylbenzamides can be readily achieved using
hypervalent iodine reagents, tBuOI or 1,3-dichloro-5,5-diphe-
nylhydantoin.5 In 2012, the first example of oxazole synthesis
from N-allylbenzamides with NBS as the oxidant was reported.6
Although oxazoles and oxazolines can be separately prepared
from N-allylbenzamides using different methods, there has never
been a general route to access both oxazoles and oxazolines from
common substrates using the same oxidant. In addition, although
oxazolines can be converted to oxazoles with various oxidants,
such as activated MnO2,7 NiO2,8 CBrCl3,9 CuBr,10 DDQ,11
NBS,12 etc.,13 these methods often suffer from the use of metal or
hazardous halo reagents,7−10 excess amounts of oxidant,11,12 or
high reaction temperatures (>100 °C).13 Therefore, conversion
of oxazolines to oxazoles under mild and metal-free conditions is
still in high demand.
xazole and oxazoline derivatives are ubiquitous hetero-
Ocycles found in a wide range of natural products,
pharmaceuticals, and agrochemicals, and enantiomerically pure
oxazolines also serve as effective chiral sources or ligands for
asymmetric transformations.1 Their diverse biological activities
and synthetic applications have stimulated substantial interest in
the synthesis of these important heterocycles. Many synthetic
strategies have been developed for the preparation of oxazoles
and oxazolines,2 with one of the most straightforward strategies
being intramolecular cyclization of amide precursors.3 Partic-
ularly, cyclodehydration of α-acylamino ketones promoted by
Brønsted or Lewis acids, which is called the Robinson−Gabriel
synthesis, is a classic method for the preparation of oxazoles
(Scheme 1, (1)).4 N-Allylbenzamides are common substrates for
Scheme 1. Synthetic Methods for Oxazolines and Oxazoles
Molecular iodine or iodide (TBAI) has recently emerged as a
promising catalyst for C−O bond formation due to its “metal-
like” character without the toxicity, supply, or cost issues of
transition-metal salts.14 In 2010, Ishihara and co-workers
pioneered the intramolecular cycloetherification of ketones
using the quaternary ammonium iodide/H2O2 system,14a and
their asymmetric version was also applied to the enantioelective
synthesis of tocopherols.14b Furthermore, the intra- and
intermolecular α-oxyacylation of ketones involving iodide-
catalyzed C−O bond formation can also be realized with
TBHP or H2O2 as the co-oxidant.14c Inspired by these works, it
occurred to us that if acylamino groups were located at the β-
position of ketones, polysubstituted oxazolines might be
constructed via iodine-catalyzed C−O bond formation. As a
continuation of our work in iodine-mediated transformation,15
herein, we report an intramolecular cyclization of ketones for the
synthesis of oxazolines by I2-catalyzed C−O bond formation with
TBHP as the terminal oxidant in the presence of K2CO3.
Furthermore, by tuning K2CO3 to DBU, the construction of
oxazoles via I2-catalyzed C−O bond formation and dehydrogen-
Received: July 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01933
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ation could also be achieved efficiently (Scheme 1, (3)). To the
best of our knowledge, this is the first example of access to both
oxazoles and oxazolines from common substrates using the same
oxidant.
Initially, 3-acetylamino-1,3-diphenylpropan-1-one (1a) was
chosen as a model substrate to explore the reaction conditions
needed for oxazoline formation. Oxidative cyclization took place,
and oxazoline 2a was isolated in 22% yield in the presence of I2
(10 mol %), KOH (2 equiv), and TBHP (3 equiv) in THF
(Table 1, entry 1). Control experiments indicated that no
With the optimal reaction conditions in hand (Table 1, entries
6 and 8), the generality of base-induced switchable access to
oxazolines and oxazoles was then investigated (Table 2). In all
cases, oxazoline 2 and oxazole 3 were selectively produced from
the corresponding β-acylamino ketones using different bases.
First, the substituents on the aroyl moiety of β-acylamino
ketones were examined, and products containing either electron-
donating or electron-withdrawing substituents could be
furnished in good to excellent yields (entries 1−5). Other
aromatic rings such as naphthyl, furyl, and thienyl groups were all
tolerated, and the desired products were obtained in good to high
yields (entries 6−8). For the substituents on the aryl rings, the
present transformations were also compatible for electron-
donating, electron-withdrawing, and naphthyl groups (entries
9−13). Notably, the substrate bearing a p-nitrophenyl group only
gave the desired products in moderate yields due to its strong
electron-withdrawing ability (entry 10). When R2 was replaced
by a methyl group, the reaction also proceeded well and gave the
desired products in moderate to good yield (46% for 2n and 77%
for 3n) (entry 14). However, replacement of R3 and R2 with a
methyl group failed to produce either oxazoles or oxazolines.16 In
addition, the present transformations also proceeded well when
the acetyl group in the substrates was changed to the bulky aroyl
groups, which made this methodology applicable to the synthesis
of 2-aryl oxazolines and oxazoles (entries 15−17).
To gain insight into the reaction mechanism, a few control
experiments were conducted.16 The addition of radical
scavengers such as TEMPO, BHT, and cyclohexadiene did not
retard the oxidative cyclization of 1a under standard conditions,
which indicated that the cyclization might not proceed through a
radical pathway. The oxidative cyclization also did not occur in
the presence of a stoichiometric amount of I2 under neutral
conditions, which suggested that I2 was not the actual oxidant
species for the C−O bond formation. To elucidate the
conversion of oxazolines to oxazoles, a one-pot reaction for the
synthesis of 3a was carried out (Scheme 2): after the reaction of
1a under conditions A for 1 h, the addition of 2 equiv of DBU led
to 3a in 78% yield. This experiment strongly confirmed the
formation of intermediate oxazoline for oxazole synthesis and
that DBU played important roles in the conversion of oxazolines
to oxazoles.
Table 1. Optimization of the Reaction Conditions for the
a
Synthesis of Oxazoline
b
entry
catalyst
base
solvent
yield (%)
1
2
3
4
5
6
7
I2
I2
KOH
THF
THF
THF
THF
THF
THF
THF
THF
MeOH
MeCN
EtOAc
THF
THF
THF
THF
THF
THF
22
0
KOH
0
I2
Cs2CO3
Na2CO3
K2CO3
DABCO
DBU
39
70
82
38
0
I2
I2
I2
c
8
I2
9
10
11
12
13
14
15
16
I2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
trace
62
71
10
66
74
81
80
80
I2
I2
TBAB
TBAI
KI
NaI
NIS
I2
d
17
a
Reaction conditions: 0.3 mmol of 1a, 0.03 mmol of catalyst, 0.6
mmol of base, 0.9 mmol of TBHP (70% in water), in 2 mL of solvent,
b
c
at 60 °C for 2−4 h. Isolated yield. 3a was isolated in 95% yield.
d
Reaction was run on a 5 mmol scale.
On the basis of the results of our control experiments and
related work, a tentative mechanism is proposed in Scheme 3.
According to Ishihara’s studies,14a−c the oxidation of I2 with
TBHP might produce an active species, [IO]−, which could be
further oxidized by TBHP to the potential actual oxidant species,
[IO2]−.17 β-Acetylamino ketone 2a could possibly react with
[IO2]− to give an intermediate A, which undergoes intra-
molecular cyclization to produce 2a and the reductive form
[IO]−. When DBU is used as the base, an active iodoimine
intermediate B could be generated via the disproportionation of
I2 in the presence of DBU,18 followed by the reaction with 2a to
form the α-iodo intermediate C. Subsequent elimination of HI
with DBU would provide the oxazole 3a and release HI for the
next cycle.
The present oxidative cyclization for the synthesis of
polysubstituted oxazolines provides an easy access to other
useful organic blocks (Scheme 4, eq 2). For example, the
hydrolysis of 2a with HCl (1.2 M) yielded the α-hydroxyl-β-
amino ketone 4, which has served as a versatile intermediate in
various organic syntheses.19 Furthermore, the present dehydro-
genation was also suitable for other kinds of oxazoline: the
treatment of oxazoline 5 with 10 mol % of I2, 1 equiv of DBU, and
cyclization occurred in the absence of iodine or any base (entries
2 and 3). A series of bases were then screened for this
transformation (entries 4−8). We found that the yield of this
model reaction could be increased to 82% when K2CO3 was used
as the base (entry 6). Organic bases were also tried for this
reaction, but 2a was only obtained in 38% yield with the use of
DABCO. However, when the base DBU was used, no oxazoline
was detected, while oxazole 3a was isolated as the sole product
(95% yield), which indicated that further dehydrogenation
catalyzed by iodine occurred in the present reaction system
(entry 8).16 Other commonly used solvents were also tested for
this reaction (entries 9−11), but none of them gave a better
result for C−O bond formation. Furthermore, an attempt to use
other salts such as TBAB, TBAI, KI, NaI, or NIS as a catalyst also
gave less effective results than iodine (entries 12−16). Notably,
the present reaction could be effectively scaled up to gram scale
with similar efficiency (1.06 g, with 80% yield for the model
reaction) (entry 17), suggesting that the present oxidative
cyclization could be employed as a practical method to access this
kind of polysubstituted oxazoline.
B
DOI: 10.1021/acs.orglett.5b01933
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Substrate Scope of Oxazoline and Oxazoline
Construction
Scheme 2. One-Pot Synthesis of Oxazole 3a
a
Scheme 3. Tentative Mechanism
Scheme 4. Hydrolysis of 2a and Oxidation of 5
2 equiv of TBHP gave rise to the corresponding oxazole 6 in 81%
yield (Scheme 4, eq 3), which demonstrated the potential of this
method for the conversion of oxazolines to oxazoles.
In summary, we have developed a general method for the
synthesis of oxazolines and oxazoles from β-acylamino ketones
by I2-catalyzed C−O bond formation and dehydrogenation. The
selectivity of products was controlled using either K2CO3 or
DBU as the base. This facile method has the advantage of broad
substrate scope, mild reaction conditions, and high efficiency.
Furthermore, the oxidative dehydrogenation catalyzed by I2 has
also provided a reliable alternative for oxazoline oxidation.
Further work exploring the utility of this method and elucidation
of the detailed mechanism is underway and will be reported in
due course.
a
Conditions A: 0.3 mmol of 1, 0.03 mmol of I2, 0.6 mmol of K2CO3,
0.9 mmol of TBHP (70% in water), in 2 mL of THF, stirred at 60 °C.
Conditions B: 0.3 mmol of 1, 0.03 mmol of I2, 0.6 mmol of DBU, 0.9
mmol of TBHP (70% in water), in 2 mL of THF, stirred at 60 °C.
b
c
Reaction time and isolated yields of products are shown. Reaction
d
was run with 1.2 mmol of TBHP and 0.9 mmol of DBU. Conversion:
57%.
C
DOI: 10.1021/acs.orglett.5b01933
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) Zhou, W.; Xie, C.; Han, J.; Pan, Y. Org. Lett. 2012, 14, 4766.
(7) (a) Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.; Anzai,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01933.
■
S
M.; Ando, A.; Shioiri, T. Synlett 1998, 1998, 35. (b) Glockner, S.; Tran,
̈
D. N.; Ingham, R. J.; Fenner, S.; Wilson, Z. E.; Battilocchio, C.; Ley, S. V.
Org. Biomol. Chem. 2015, 13, 207.
(8) Yokokawa, F.; Hamada, Y.; Shioiri, T. Synlett 1992, 1992, 153.
(9) Williams, D. R.; Lowder, P. D.; Gu, Y. G.; Brooks, D. A. Tetrahedron
Lett. 1997, 38, 331.
(10) Meyers, A. I.; Tavares, F. X. J. Org. Chem. 1996, 61, 8207.
(11) McGarvey, G. J.; Wilson, K. J.; Shanholtz, C. E. Tetrahedron Lett.
1992, 33, 2641.
Experimental procedures, optimization of reaction con-
ditions, characterization data, copies of 1H NMR and 13
NMR of products (PDF)
C
AUTHOR INFORMATION
■
(12) (a) Meyers, A. I.; Tavares, F. Tetrahedron Lett. 1994, 35, 2481.
(b) Murai, K.; Takahara, Y.; Matsushita, T.; Komatsu, H.; Fujioka, H.
Org. Lett. 2010, 12, 3456.
(13) Huang, Y.; Ni, L.; Gan, H.; He, Y.; Xu, J.; Wu, X.; Yao, H.
Tetrahedron 2011, 67, 2066.
Corresponding Authors
*E-mail: gaowenchao@tyut.edu.cn.
*E-mail: changhonghong@tyut.edu.cn.
Notes
(14) For iodide-catalyzed C−O bond formation, see: (a) Uyanik, M.;
Okamoto, H.; Yasui, T.; Ishihara, K. Science 2010, 328, 1376. (b) Uyanik,
M.; Hayashi, H.; Ishihara, K. Science 2014, 345, 291. (c) Uyanik, M.;
Suzuki, D.; Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2011, 50, 5331.
(d) Wei, W.; Zhang, C.; Xu, Y.; Wan, X. Chem. Commun. 2011, 47,
10827. (e) Shi, E.; Shao, Y.; Chen, S.; Hu, H.; Liu, Z.; Zhang, J.; Wan, X.
Org. Lett. 2012, 14, 3384. (f) Xue, Q.; Xie, J.; Xu, P.; Hu, K.; Cheng, Y.;
Zhu, C. ACS Catal. 2013, 3, 1365. (g) Tan, B.; Toda, N.; Barbas, C. F.,
III Angew. Chem., Int. Ed. 2012, 51, 12538. (h) Yu, H.; Shen, J. Org. Lett.
2014, 16, 3204. (h) Xu, W.; Nachtsheim, B. J. Org. Lett. 2015, 17, 1585.
(i) Boominathan, S. S. K.; Hu, W.-P.; Senadi, G. C.; Vandavasi, J. K.;
Wang, J.-J. Chem. Commun. 2014, 50, 6726.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of Shanxi Province (Grant No. 2015021037) and
the project supported by Special/Youth Foundation of Taiyuan
University of Technology (2014QN011).
REFERENCES
■
(1) For selected reviews on oxazole derivatives, see: (a) Wipf, P. Chem.
Rev. 1995, 95, 2115. (b) Jin, Z. Nat. Prod. Rep. 2006, 23, 464. (c) Riego,
E.; Hernandez, D.; Albericio, F.; Alvarez, M. Synthesis 2005, 2005, 1907.
For selected reviews on oxazoline derivatives, see: (d) Bergeron, R. J.
Chem. Rev. 1984, 84, 587. (e) Davidson, B. S. Chem. Rev. 1993, 93, 1771.
(f) Frump, J. A. Chem. Rev. 1971, 71, 483. (g) Johnson, J. S.; Evans, D. A.
Acc. Chem. Res. 2000, 33, 325. (h) Meyers, A. I. J. Org. Chem. 2005, 70,
6137.
(15) (a) Gao, W.-C.; Zhao, J.-J.; Chang, H.-H.; Li, X.; Liu, Q.; Wei, W.-
L. RSC Adv. 2014, 4, 49329. (b) Gao, W.-C.; Zhao, J.-J.; Hu, F.; Chang,
H.-H.; Li, X.; Wei, W.-L. RSC Adv. 2015, 5, 25222.
(16) For details, see Supporting Information.
(17) (a) Siddaraju, Y.; Prabhu, K. R. Org. Biomol. Chem. 2015, 13, 6749.
(b) Ma, L.; Wang, X.; Yu, W.; Han, B. Chem. Commun. 2011, 47, 11333.
(18) For the halogen−DBU complexes, see: (a) Wei, Y.; Lin, S.; Liang,
(2) For selected examples on oxazole syntheses, see: (a) Jiang, H.;
Huang, H.; Cao, H.; Qi, C. Org. Lett. 2010, 12, 5561. (b) Wan, C.; Gao,
L.; Wang, Q.; Zhang, J.; Wang, Z. Org. Lett. 2010, 12, 3902. (c) Wan, C.;
Zhang, J.; Wang, S.; Fan, J.; Wang, Z. Org. Lett. 2010, 12, 2338. (d) Xie,
J.; Jiang, H.; Cheng, Y.; Zhu, C. Chem. Commun. 2012, 48, 979. (e) Xu,
Z.; Zhang, C.; Jiao, N. Angew. Chem., Int. Ed. 2012, 51, 11367. For
selected examples on oxazolines syntheses, see: (f) Minakata, S.;
Morino, Y.; Ide, T.; Oderaotoshi, Y.; Komatsu, M. Chem. Commun.
2007, 3279. (g) Rajaram, S.; Sigman, M. S. Org. Lett. 2002, 4, 3399.
(h) Ohshima, T.; Iwasaki, T.; Mashima, K. Chem. Commun. 2006, 2711.
(i) Hansel, J.-G.; O’Hogan, S.; Lensky, S.; Ritter, A. R.; Miller, M. J.
Tetrahedron Lett. 1995, 36, 2913.
F. Org. Lett. 2012, 14, 4202. (b) Castellote, I.; Moron
́
, M.; Burgos, C.;
ez-Sal, P.; Vaquero, J. J. Chem.
Alvarez-Builla, J.; Martin, A.; Gom
́
Commun. 2007, 1281. For the oxidation of iodide with TBHP, see:
(c) Cai, Z.-J.; Lu, X.-M.; Zi, Y.; Yang, C.; Shen, L.-J.; Li, J.; Wang, S.-Y.; Ji,
S.-J. Org. Lett. 2014, 16, 5108. (d) Zhu, T.-H.; Wang, S.-Y.; Tao, Y.-Q.; Ji,
S.-J. Org. Lett. 2015, 17, 1974. (e) Senadi, G. C.; Hu, W.-P.; Lu, T.-Y.;
Garkhedkar, A. M.; Vandavasi, J. K.; Wang, J.-J. Org. Lett. 2015, 17, 1521.
(19) (a) Das, B.; Reddy, K. R.; Ramu, R.; Thirupathi, P.; Ravikanth, B.
Synlett 2006, 2006, 1756. (b) Wang, Q.; Huang, W.; Yuan, H.; Cai, Q.;
Chen, L.; Lv, H.; Zhang, X. J. Am. Chem. Soc. 2014, 136, 16120. (c) Wan,
J.; Yan, X.; Ma, C.; Bi, S.; Zhu, H.-L. Med. Chem. Res. 2010, 19, 970.
(3) For the preparation of oxazoles from amide precursors, see: (a) Liu,
B.; Zhang, Y.; Huang, G.; Zhang, X.; Niu, P.; Wu, J.; Yu, W.; Chang, J.
Org. Biomol. Chem. 2014, 12, 3912. (b) Martín, R.; Cuenca, A.;
Buchwald, S. L. Org. Lett. 2007, 9, 5521. (c) Cheung, C. W.; Buchwald,
S. L. J. Org. Chem. 2012, 77, 7526. (d) Zheng, Y.; Li, X.; Ren, C.; Zhang-
Negrerie, D.; Du, Y.; Zhao, K. J. Org. Chem. 2012, 77, 10353.
(e) Wendlandt, A. E.; Stahl, S. S. Org. Biomol. Chem. 2012, 10, 3866.
(f) Paradise, C. L.; Sarkar, P. R.; Razzak, M.; De Brabander, J. K. Org.
Biomol. Chem. 2011, 9, 4017. (g) Yu, X.; Xin, X.; Wan, B.; Li, X. J. Org.
Chem. 2013, 78, 4895. For the preparation of oxazolines from amide
precursors, see: (h) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.;
Williams, D. R. Org. Lett. 2000, 2, 1165. (i) Brandstatter, M.; Roth, F.;
Luedtke, N. W. J. Org. Chem. 2015, 80, 40 and references therein.
(4) (a) Robinson, R. J. Chem. Soc., Trans. 1909, 95, 2167. (b) Gabriel, S.
Ber. Dtsch. Chem. Ges. 1910, 43, 1283. (c) Turchi, I. J.; Dewar, M. J. S.
Chem. Rev. 1975, 75, 389.
(5) (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. (d) Moon, N. G.; Harned, A. M.
Tetrahedron Lett. 2013, 54, 2960. (e) Alhalib, A.; Kamouka, S.; Moran,
W. J. Org. Lett. 2015, 17, 1453.
D
DOI: 10.1021/acs.orglett.5b01933
Org. Lett. XXXX, XXX, XXX−XXX