Oxazole synthesis from isocyanides

Article abstract of DOI:10.1055/s-0031-1290939

A new synthetic path toward oxazoles starting from isocyanides is presented. This two-step oxazole preparation involves a bromination-cyclization followed by a Suzuki cross-coupling. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290939

LETTER
▌1361
letter
Oxazole Synthesis from Isocyanides
Oxazole Synthesis from Isocyanides
Laurent El Kaïm,* Laurence Grimaud,* Pravin Patil
Laboratoire DCSO ENSTA-Polytechnique-CNRS, UMR 7652, Ecole Nationale Supérieure de Techniques Avancées, 32 Bd Victor, 75739 Paris,
Cedex 15, France
Fax +33(1)45528322; E-mail: laurent.elkaim@ensta.fr; E-mail: grimaud@dcso.polytechnique.fr
Received: 16.02.2012; Accepted after revision: 15.03.2012
To test the feasibility of the process, isocyano glycinate 1a
Abstract: A new synthetic path toward oxazoles starting from iso-
was treated with one equivalent of bromine. As previously
cyanides is presented. This two-step oxazole preparation involves a
observed, the bromination could be perfomed in various
solvents at room temperature, such as dichloromethane or
acetonitrile. Decoloration of the solution occurred within
a few minutes giving quantitative formation of the desired
bromination–cyclization followed by a Suzuki cross-coupling.
Key words: oxazoles, Suzuki, palladium, isocyanides, dihaloge-
noisocyanides
gem-dibromo isocyanoester intermediate, which is then
treated under basic conditions. Different bases have been
Due to their carbenic nature, isocyanides are versatile re-
tested in acetonitrile. Potassium phosphate, potassium
agents, which have been widely used in heterocyclic
carbonate, and triethylamine failed to give any product
chemistry. Their success is mainly associated with the Ugi
even at reflux, and in all the cases, the starting isocyanide
reaction,1 considered as the most powerful four-compo-
was recovered up to 60%. When treated with one equiva-
nent coupling. Aside these applications, they are excellent
lent of DBU at 0 °C, the desired bomooxazole was isolat-
ligands for transition metals, as attested by the impressive
ed in 11% yield, but it turned to be quite unstable.
bibliography available in inorganic chemistry. However,
Due to the instability of this intermediate, the sequence
was repeated with substituted isocyano glycinates derived
from valine 1b and phenylalanine 1c. Similar trials failed
to give any cyclized adducts. Surprisingly, when treated
with two equivalents of imidazole, the gem-dibromoiso-
cyano valinate gave 33% of the corresponding bromoam-
idine 2b, which can be cyclized under DBU treatment to
afford the imidazolo oxazole 3b in 50% yield (Scheme 2).
due to this high affinity, few metal-catalyzed processes
have been reported2 as they are often limited to the use of
bulky isocyanides.3 To circumvent such difficulties, the
isocyanides may be transformed into dihalogenoisocya-
nides, intermediates which have proven their interest in a
few palladium-catalyzed processes.4,5 More recently, we
used this strategy in a one-pot tetrazole and 1,2,4-triazole
synthesis starting from isocyanides (Scheme 1).6 We wish
to report herein a new oxazole synthesis involving gem-
dihalogenoisocyanoester derivatives (Scheme 1).7
Ethyl α-phenyl-α-isocyanoacetate 1d gave, after sequen-
tial treatment with bromine and DBU at 0 °C, the desired
R1NC
Br2
N
N
N
N
intermolecular
trapping (TMSN3...)
N
ArB(OH)2
Br
NR1
Br
N
or
Ph
Ar
N
Ar
Br
N
N
N
Suzuki
cross-coupling
R1
R1
R1
previous work
intramolecular
trapping
ArB(OH)2
EtO
R2
EtO
O
O
R1 = CHR2-CO2Et
Ar
Br
Suzuki
cross-coupling
N
R2
N
this work
Scheme 1 Cascades involving dibromoisocyanides
MeO
N
O
MeO2C
N
N
1. Br2, MeCN, r.t.
MeO2C
NC
N
N
DBU, CH2Cl2
2. imidazole, MeCN
Br
2b 33%
N
1b
3b 50%
Scheme 2 Attempted oxazole formation in the presence of imidazole
SYNLETT 2012, 23, 1361–1363
Advanced online publication: 14.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290939; Art ID: ST-2012-D0142-L
© Georg Thieme Verlag Stuttgart · New York

1362
L. El Kaïm et al.
LETTER
bromooxazole 2d in 83% yield. The same behavior was lino derivatives). Unfortunately, the corresponding dibro-
observed with other aromatic derivatives as bromooxa- mo isocyanide decomposed spontaneously, and no trace
zole were isolated in good yields with a methyl or a chloro of product could even be detected.
as substituent (Scheme 3).
Table 1 Synthesis of Aryl Oxazoles 3
EtO2C
NC
RO2C
NC
EtO
RO
O
N
O
N
1. Br2, CH2Cl2, r.t.
1. Br2, CH2Cl2, r.t.
Br
Br
2. DBU, CH2Cl2,
–5 to 0 °C
2. DBU, CH2Cl2,
–5 to 0 °C
83%
RO
1d
2d
X
2
X
O
N
1
Ar
ArB(OH)2
K2CO3
MeO
MeO
O
MeO
O
N
O
Pd(PPh3)4
MeCN, 60 °C
Br
Br
Br
N
X
N
3
Entry
R
X
Ar
Yield (%)
Cl
Me
66%
92%
68%
1
2
Et
H
4-MeC6H4
4-t-BuC6H4
59
33
49
30
23
33
53
–
Scheme 3 2-Bromooxazole synthesis from isocyanides
Et
H
3
Et
H
4-MeOC6H4
2-MeOC6H4
Ph
To circumvent the instability of the bromooxazole, which
rapidly decomposed after 24 hours at room temperature,
we decided to test if its formation could be combined with
the subsequent Suzuki–Miyaura cross-coupling. For this
purpose, acetonitrile was chosen as solvent, and the tolyl
boronic acid, potassium carbonate, and a catalytic amount
of Pd(0) were added to the reaction mixture containing
both bromooxazole and DBU hydrobromide salt. Unfor-
tunately, no traces of cross-coupling could be detected un-
der these conditions. However, after rapid filtration of the
mixture to eliminate the amine salt, the bromooxazole 2d
was successfully transformed into the corresponding aryl
oxazole 3d. Due to the necessity of this intermediate fil-
tration, the more volatile dichloromethane was selected
instead of acetonitrile for the first step. The Suzuki cou-
pling was performed using two equivalents of tolyl boron-
ic acid, 10 mol% of tetrakistriphenyl phosphine
palladium, and a slight excess of potassium carbonate in
acetonitrile, under stirring for 16 hours at 60 °C. The re-
sulting aryl-substituted oxazole was isolated in 59% (Ta-
ble 1, entry 1). All attempts to improve the yields varying
the solvent (toluene instead of acetonitrile) and the tem-
perature (60 °C to reflux) failed to improve the reaction
outcome. Under these conditions, different arylated oxa-
zoles have been synthesized using various boronic acids
(Table 1). The reactions proceed smoothly with electron-
donating groups and halogens on the boronic acid. How-
ever, electron-withdrawing groups such as acetyl (Table
1, entry 14) or cyano (Table 1, entry 8) inhibit the reac-
tion. For low efficient couplings, the reduced oxazole was
isolated as a side product: for instance, the 4-(4-chloro-
phenyl)-5-methoxyoxazole (Table 1, entry 14; Figure 1)
was isolated as the major compound instead of the corre-
sponding coupled product.
4
Et
H
5
Et
H
6
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
4-EtC6H4
7
H
4-t-BuC6H4
4-NCC6H4
2-MeC6H4
4-ClC6H4
8
H
9
H
19
18
18
54
29
10
11
12
13
14
15
16
17
H
Me
Me
Me
Cl
Cl
Cl
Cl
4-MeOC6H4
2-MeOC6H4
4-MeC6H4
4-MeCOC6H4
4-MeOC6H4
4-MeC6H4
4-t-BuC6H4
a
–
45
58
49
a The reduced oxazole (Figure 1) was isolated in 62% yield.
MeO
O
N
4-ClH4C6
Figure 1
To conclude, a new synthetic path to trisubstituted oxa-
zoles was developed based on isocyanide chemistry. Ox-
azoles are found in a large number of natural compounds
isolated from various marine sources as well as numerous
bacteria.9 Beside the interest for the synthesis of natural
products, the preparation of oxazoles has been the object
Considering the three-component aminooxazole forma-
tion reported by Zhu et al.,8 we thought that a similar se-
quence could be performed starting with the
corresponding isocyano amides (pyrrolidino and morpho-
Synlett 2012, 23, 1361–1363
© Georg Thieme Verlag Stuttgart · New York

LETTER
Oxazole Synthesis from Isocyanides
1363
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2-Bromo-5-ethoxy-4-phenyloxazole (2d)
To a solution of ethyl 2-isocyano-2-phenylacetate (1d, 500 mg, 2.65
mmol) in CH2Cl2 (5 mL) was added bromine (0.127 mL, 2.65
mmol), and the mixture was stirred for 2 min at r.t. The resulting
mixture was then cooled at 0 °C before dropwise addition of DBU
(1.0 mL, 6.62 mmol) and stirred at –5 °C to 0 °C for an additional
10 min. After completion of the reaction (checked by TLC analy-
sis), CH2Cl2 was evaporated. The crude residue was purified by
flash chromatography on silica gel using a 1:9 mixture of Et2O–PE
as eluant. Evaporation of the solvent under reduced pressure at 25–
30 °C gave 2d (590 mg, 83%) as a pale yellow liquid.
IR (thin film): 1739, 1683, 1595, 1456, 1270, 1207, 1176 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 7.78 (dd, 2 H, J = 1.2, 7.4 Hz), 7.39
(t, 2 H, J = 7.4 Hz), 7.28–7.22 (m, 1 H), 4.36 (q, 2 H, J = 7.1 Hz),
1.47 (t, 3 H, J = 7.1 Hz). 13C NMR (100.6 MHz, CDCl3): δ = 155.7,
130.2, 128.5, 127.0, 124.9, 122.8, 119.1, 70.7, 15.1. HRMS: m/z
calcd for C11H10BrNO2: 266.9895; found: 266.9885.
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5-Ethoxy-4-phenyl-2-(p-tolyl)oxazole (3d)
To a well-stirred solution of 2-bromo-5-ethoxy-4-phenyloxazole
(220 mg, 0.82 mmol) in MeCN (0.2 M) under argon atmosphere
were successively added K2CO3 (340 mg, 2.46 mmol), p-tolyl bo-
ronic acid (223 mg, 1.64 mmol), and Pd(PPh3)4 (47.5 mg, 5 mol%).
The resulting mixture was stirred under argon atmosphere at 55–
60 °C for 16 h. It was then cooled to r.t., filtered off, and the vola-
tiles were evaporated. The crude residue was purified by flash chro-
matography on silica gel (Et2O–PE) to afford 3d (135 mg, 59%) as
a pale yellow solid.
(7) The conversion of isocyano esters and amide into imidoyl
chlorides followed by cyclization into oxazoles has already
been observed during the Nef reaction between isocyanides
and acyl chlorides: (a) Mossetti, R.; Pirali, T.; Tron, G. C.;
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IR (thin film): 1738, 1686, 1499, 174, 1384, 1277, 1200, 1179, 1016
cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.85–7.77 (m, 4 H), 7.30 (t,
2 H, J = 7.8 Hz), 7.17–7.12 (m, 3 H), 4.32 (q, 2 H, J = 7.1 Hz), 2.30
(s, 3 H), 1.40 (t, 3 H, J = 7.1 Hz). 13C NMR (100.6 MHz, CDCl3):
δ = 153.6, 152.2, 139.8, 131.5, 129.4, 128.4, 126.3, 125.5, 125.0,
124.9, 116.7, 69.8, 21.5, 15.2. HRMS: m/z calcd for C18H17NO2:
279.1259; found: 279.1252.
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W.; Franci, X.; Pizzonero, M.; Donald, C.; Taylor, R. J. K.
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Acknowledgment
We thank the ENSTA, CNRS and ANR (CP2D Muse) for financial
support.
References
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