One-pot synthesis of 2,4,5-trisubstituted oxazoles via a tandem passerini three-component coupling/staudinger/aza-wittig/isomerization reaction

Article abstract of DOI:10.1055/s-0033-1340596

2,4,5-Trisubstituted oxazoles were prepared via a tandem Passerini three-component coupling/Staudinger/aza-Wittig/isomerization reaction in one-pot fashion, starting from easily accessible α-azidocinnamaldehydes, acids, isocyanide and triphenylphosphine. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340596

LETTER
▌721
letter
One-Pot Synthesis of 2,4,5-Trisubstituted Oxazoles via a Tandem Passerini
Three-Component Coupling/Staudinger/Aza-Wittig/Isomerization Reaction
Synthesis of 2,4,5-Trisubstituted Oxazoles
Long Wang, Zhi-Lin Ren, Min Chen, Ming-Wu Ding*
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan 430079, P. R. of China
Fax +86(27)67862041; E-mail: mwding@mail.ccnu.edu.cn
Received: 31.10.2013; Accepted after revision: 10.12.2013
wish to report herein a facile synthesis of 2,4,5-trisubsti-
Abstract: 2,4,5-Trisubstituted oxazoles were prepared via a tan-
tuted oxazoles by a tandem Passerini three-component
dem Passerini three-component coupling/Staudinger/aza-Wittig/
coupling/Staudinger/aza-Wittig/isomerization reaction in
one-pot fashion.
isomerization reaction in one-pot fashion, starting from easily ac-
cessible α-azidocinnamaldehydes, acids, isocyanide and triphe-
nylphosphine.
A mixture of α-azidocinnamaldehyde18 (1 equiv), isocya-
nide (1 equiv), and various acids (1 equiv) was stirred in
methanol at room temperature for five to seven days. The
Passerini reaction occurred but the reaction rate was very
slow and the azide 2 was produced in low yield. We also
attempted to perform the subsequent reaction in a one-pot
fashion. However, these attempts failed probably due to
the long reaction time needed for the above Passerini re-
action as methanol was used as solvent.
Key words: oxazole, tandem reaction, aza-Wittig reaction,
Passerini reaction, isomerization
Oxazoles, especially fully substituted oxazoles, still hold
a center stage in organic synthesis over the past years due
to their interesting biological activities. For example,
some oxazoles were found to display good anti-inflamma-
tory,1 antifungal,2 and antiproliferative activity.3 They are
also a key structural skeleton in many natural products.4
The structural diversity and complexity of oxazoles have
generated much interest in development of new methods
for their synthesis.5 Oxazole derivatives can be generally
prepared by cyclization of acyclic precursors,6 or by the
catalytic cross-coupling reaction of the prefunctionalized
oxazoles with other organometallic reagents,7 or by oxida-
tion of oxazolines.8 Recently, Zhu reported an organocat-
alytic sp3 C–H activation reaction to prepare oxazole
derivatives.9 Later, Wu showed a convergent integration
of two self-labor domino sequences to synthesize the ox-
azole derivatives.10 Zhang, Davis, Jiang, and Jiao reported
the fragment-assembling strategy based on oxidative cou-
pling reactions for the synthesis of disubstituted or trisub-
stituted oxazoles.11 Meanwhile, our group developed
tandem reaction sequences to prepare oxazoles.12
Fortunately, we found that when the solvent was changed
from methanol to dichloromethane, the Passerini reaction
took place faster to give azides 2. The azides 2 could be
further used in Staudinger reaction and intramolecular
aza-Wittig reaction to produce 2,4,5-trisubstituted oxa-
zoles 5 (Scheme 1). The best result was obtained when the
reaction was carried out in one-pot fashion.19 After a mix-
ture of α-azidocinnamaldehyde, isocyanide, and various
acids was stirred in dichloromethane at room temperature
or at 40–50 °C, triphenylphosphine was added to the solu-
tion. The reaction mixture was stirred for two hours and
the solvent was removed under reduced pressure. Then
toluene was added, and the reaction mixture was refluxed
in the presence of catalytic amount of solid potassium car-
CHO
R3HNOC
Passerini and Ugi reactions are two isocyanide-based
multicomponent reactions, which have been used widely
to prepare various α-acyloxy or α-acylamino amide ad-
ducts from easily accessible starting materials.13 The se-
quences of Passerini reaction, followed by post-
condensation transformations, constitute powerful syn-
thetic methods for the preparation of structurally diverse
molecules, especially heterocyclic compounds.14 The aza-
Wittig reaction has been utilized extensively to form het-
erocyclic structures in mild neutral condition.15 The com-
bination of Passerini or Ugi reaction with aza-Wittig
reaction has been recently utilized in the synthesis of a se-
ries of heterocycles.16 Continuing our interest in the syn-
thesis of N-heterocycles via the aza-Wittig reaction,17 we
R1
N3
O
O
Ph3P
R2
1
CH2Cl2
R1
N3
2
R2COOH
R3NC
R1
R3HNOC
O
O
K2CO3 (s)
R2
N
H
R1
N
R2
CONHR3
O
4
PPh3
3
R1
R1
HO CO2K
CONHR3
N
N
-
R2
CONHR3
R2
O
5
O
SYNLETT 2014, 25, 0721–0723
Advanced online publication: 14.01.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340596; Art ID: ST-2013-W1022-L
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 One-pot synthesis of 2,4,5-trisubstituted oxazoles 5

722
L. Wang et al.
LETTER
bonate. The 2,4,5-trisubstituted oxazoles 5 were finally
Acknowledgment
obtained in 43–70% overall yields (Table 1).
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (No. 21172085,
21032001).
Table 1 One-Pot Preparation of Compounds 5a–j
Product
R1
R2
R3
Yield (%)a
Supporting Information for this article is available online at
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Ph
t-Bu
70
66
57
51
61
67
56
53
69
65
47
43
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
4-MeC6H4
2-MeC6H4
2-ClC6H4
H
t-Bu
References and Notes
t-Bu
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t-Bu
t-Bu
Ph
c-C6H11
c-C6H11
c-C6H11
t-Bu
5g
5h
5i
4-MeC6H4
2-ClC6H4
Me
5j
Ph
n-Bu
t-Bu
5k
5l
Ph
4-MeC6H4
t-Bu
a Yields based on azides 1.
The tandem formation of 2,4,5-trisubstituted oxazoles 5
can be viewed as an initial Staudinger reaction between
the vinyl azide 2 and triphenylphosphine to create the im-
inophosphorane intermediate 3. Further intramolecular
aza-Wittig reaction of 3 produces dihydrooxazoles 4, in
which a 1,3-H shift takes place in the presence of solid po-
tassium carbonate to give the oxazoles 5. In the absence of
the catalytic amount of solid potassium carbonate, a mix-
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1
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to the hydrogen of CONH. The signal of CH2 was found
at δ = 4.34 ppm as a singlet. The tert-butyl signal appeared
at δ = 1.50 ppm as singlet. The signals attributable to the
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= 334 with 87% abundance.
In conclusion, we have developed a facile one-pot synthe-
sis of 2,4,5-trisubstituted oxazoles by a tandem Passerini
three-component coupling/Staudinger/aza-Wittig/isomer-
ization reaction. The mild reaction conditions and the easy
availability of starting materials make this method a valu-
able tool for generating 2,4,5-trisubstituted oxazoles,
which are of considerable interest as potential biologically
active compounds or pharmaceuticals.
Synlett 2014, 25, 721–723
© Georg Thieme Verlag Stuttgart · New York

LETTER
Huang, L.; Chen, H.; Wu, W.; Huang, H.; Jiang, H. Chem.
Synthesis of 2,4,5-Trisubstituted Oxazoles
723
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(19) General Procedure for the Preparation of Oxazoles 5: A
mixture of α-azidocinnamaldehyde 1 (0.17 g, 1 mmol),
isocyanide (1 mmol), and acid (1 mmol) was stirred in
CH2Cl2 (5 mL) at r.t. or at 40–50 °C for 24–48 h. Then Ph3P
(0.26 g, 1 mmol) in CH2Cl2 (5 mL) was added dropwise to
the reaction system and the reaction mixture was stirred at
r.t. for 2 h. The solvent was evaporated under reduced
pressure, and toluene (10 mL) was added. After the resulting
solution was refluxed for 8–10 h, solid K2CO3 (0.014 g, 0.1
mmol) was added to the reaction system and the solution was
refluxed for further 1–2 h. The solvent was removed under
reduced pressure and the residue was purified by flash
chromatography on silica gel (Et2O–petroleum ether, 1:6) to
give oxazoles 5. 5a: white solid; mp 145–146 °C. 1H NMR
(600 MHz, CDCl3): δ = 8.03 (d, J = 7.2 Hz, 2 H, ArH), 7.18–
7.45 (m, 7 H, ArH), 6.08 (s, 1 H, NH), 4.34 (s, 2 H, CH2),
1.50 (s, 9 H, 3 × Me). 13C NMR (150 MHz, CDCl3): δ =
159.8, 157.6, 145.4, 139.4, 138.6, 131.1, 129.0, 128.7,
128.3, 126.8, 126.5, 126.3, 51.7, 32.8, 29.0. MS (EI, 70 eV):
m/z (%) = 334 (87) [M+], 278 (86), 261 (33), 131 (100), 103
(39). Anal. Calcd for C21H22N2O2: C, 75.42; H, 6.63; N, 8.38.
Found: C, 75.56; H, 6.73; N, 8.59.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 721–723

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