One-pot synthesis of oxazoles using isocyanide surrogates

Article abstract of DOI:10.1016/j.tetlet.2009.07.001

We wish to present herein a simple one-pot synthesis of 2,5-disubstituted oxazoles, starting from benzyl halides and acyl chlorides. The in situ formation of isocyanides, followed by the addition of an acyl chloride in the presence of a base leads to the

Full text of DOI:10.1016/j.tetlet.2009.07.001

Tetrahedron Letters 50 (2009) 5235–5237
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One-pot synthesis of oxazoles using isocyanide surrogates
*
*
Laurent El Kaim , Laurence Grimaud , Aurélie Schiltz
Laboratoire Chimie et Procédés, DCSO, UMR 7652, Ecole Nationale Supérieure de Techniques Avancées, 32 Bd Victor, Paris 75015, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We wish to present herein a simple one-pot synthesis of 2,5-disubstituted oxazoles, starting from benzyl
halides and acyl chlorides. The in situ formation of isocyanides, followed by the addition of an acyl chlo-
ride in the presence of a base leads to the desired oxazoles in good yields.
Ó 2009 Published by Elsevier Ltd.
Received 15 May 2009
Revised 29 June 2009
Accepted 1 July 2009
Available online 4 July 2009
Keywords:
Isocyanide
Oxazole
Alkylation
Silver cyanide
Multicomponent reaction
Green chemistry, with its principles of step and atom economy,
has grown into being a major theme in organic research in the 21st
century. It often involves the association of several transformations
in a single reaction vessel, without requiring work-up and isolation
of intermediates.1 In our search for operationally simple, resource-
and cost-effective processes, we have been investigating isonitrile-
based multicomponent reactions (IMCRs) using in situ-generated
isocyanides. Their classical syntheses (dehydration of N-forma-
mides2 and carbylamine reaction3), combined with their foul odor,
are indeed strong deterrents for a wider use of isocyanide-based
reactions.
In order to further extend the scope of this process, we are cur-
rently exploring other reactions involving isocyanides. Having re-
cently reported a new synthesis of 2,5-disubstituted oxazoles
starting from an acyl chloride and a benzylic isocyanide (Scheme
2),7 we now wish to disclose a one-pot two-step sequence that pro-
vides such oxazoles thanks to in situ-made isocyanides.
In the first step, isocyanides are readily obtained by heating
overnight at 80 °C stoichiometric amounts of bromide derivative,
silver cyanide, and potassium cyanide in acetonitrile with a cata-
lytic amount of triethyl benzyl ammonium chloride (TEBAC).
The Nef-isocyanide coupling between the acyl chloride and the
isocyanide affords a nitrilium ylide intermediate which cyclizes
upon a proton exchange with a weak base to give the correspond-
ing 2,5-disubstituted oxazole.7
Inspired by the previous works of Lieke4 and Songstad,5 we re-
cently published an efficient and time-saving method that allowed
two different subsequent Ugi-type four-component couplings,
using an activated benzyl or allyl bromide in the presence of silver
and potassium cyanide6 (Scheme 1).
Obviously, the ‘free’ remaining equivalent of cyanide ions in the
medium might trigger a potential acyl cyanide formation upon acyl
H
AllNH2
i-BuCHO
AgCN, KCN
TEBAC cat.
N
N
R
O
NC
Br
MeCN, 80°C
p-NO2PhOH
R =
p
-NO2Ph 80%
R = COMe
84%
or AcOH
Scheme 1. One-pot Ugi and Ugi-Smiles processes.
* Corresponding authors. Tel.: +33 145525537; fax: +33 145528322 (L.E.K.), tel.:
+33 145526565; fax: +33 145528322 (L.G.).
E-mail addresses: laurent.elkaim@ensta.fr (L.E. Kaim), laurence.grimaud@ensta.
fr (L. Grimaud).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.07.001

5236
L. E. Kaim et al. / Tetrahedron Letters 50 (2009) 5235–5237
Cl
Table 1
Two-step sequence yielding 2,5-disubstituted oxazoles
O
2,6-lutidine
O
Cl
+
O
Toluene, 80°C
Cl
NC
N
AgCN, KCN
R2
R1
Cl
O
TEBAC cat.
R1
73%
R1
2
R2
NC
N
Br
2,6-lutidine
MeCN, 80°C
Scheme 2. Synthesis of 2,5-disubstituted oxazoles.
1
Entry Bromide
derivative
R2
Product
Yield
(%)
chloride addition. Furthermore, as the oxazole synthesis was first
developed in toluene, there was no guarantee that the coupling
would take place in acetonitrile.
However, we were delighted to observe the sole formation of
oxazoles (Table 1) when introducing equivalent amounts of acyl
chloride and base in the isocyanide mixture heated at 80 °C over-
night. This procedure gave satisfying results: various benzyl bro-
mides behaved similarly as potential isocyanides to provide these
heterocycles.8 The reaction proceeded smoothly in fair yields, rang-
ing from 32% to 70%. However, the functionalized acyl chloride 2f
that had previously afforded the oxazole in good yields in the pre-
vious study did not react under these modified conditions.
Although allyl isocyanide was formed, it failed to perform such
a coupling. However, cinnamyl bromide turned out to be a moder-
ate reactant: upon reaction with isobutyryl chloride, it provided
the corresponding oxazole 3i with a 33% yield. Considering the ear-
lier recorded 48% yield obtained in the one-step reaction from iso-
lated cinnamyl isocyanide, this two-step procedure favorably
competes with the classical isocyanide syntheses.
O
O
1
2
p-tBuBnBr 1a
iBu 2a
70
40
N
3a
1a
1a
Bu 2b
Ph 2c
N
3b
O
3
41
N
3c
As a conclusion, we have settled a straightforward oxazole syn-
thesis, which usefully complements the Schöllkopf oxazole forma-
tion,9 affording 2,5-disubstituted oxazoles instead of the classical
3,4-disubstituted isomers.10 This reaction involves commercially
available reactants: the reasonably priced silver cyanide, and
bromide derivatives. The latter can de facto be seen as isocyanide
surrogates, later reacting with an acyl chloride in the presence of
a base to afford the awaited oxazoles. No handling of isocyanide
is required, therefore enhancing the interest in isocyanide chemis-
try while removing its less enticing aspects.
O
4
5
1a
1a
p-FPh 2d
34
35
F
N
3d
tBu 2e
O
N
3e
6
7
1a
—
—
OAllyl
Acknowledgments
2f
A.S. thanks the Délégation Générale de l’Armement for a fellow-
ship. Financial support was provided by the ENSTA.
O
O
BnBr 1b
2a
2a
50
N
References and notes
3f
1. Anastas, P.; Warner, J. Green Chemistry: Theory and Practice; Oxford University
Press: New York, 1998; Clarke, P. A.; Santos, S.; Martin, W. H. C. Green Chem.
2007, 9, 438–440.
2. Ugi, I.; Meyr, R. Chem. Ber. 1960, 93, 239–248; Ugi, I.; Fetzer, U.; Eholzer, U.;
Knupper, H.; Offermann, K. Angew. Chem. 1965, 77, 492–504; Angew. Chem.,
Int. Ed. Engl. 1965, 4, 472–484; Ugi, I.; Meyr, R.; Lipinski, M.; Bodensheim, F.;
Rosendahl, F. Org. Synth. 1973, coll vol V, 300–302.
3. Hoffmann, A. W. Ann. Chem. Pharm. 1867, 144, 114–120; Weber, W. P.; Gokel, G.
W.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1972, 11, 530–531; Gokel, G. W.; Widera,
R. P.; Weber, W. P. Org. Synth. 1988, coll vol VI, 232–235.
8
9
o-BrBnBr 1c
40
32
Br
N
3g
O
4. Lieke, W. Justus Liebigs Ann. Chem. 1859, 112, 316.
5. Songstad, J.; Stangeland, L. J.; Austad, T. Acta Chem. Scand. 1970, 24, 355–356;
Engemyr, L. B.; Martinsen, A.; Songstad, J. Acta Chem. Scand. Ser. A 1974, 28,
255–266.
O
p-OMeBnBr 1d
2a
N
6. El Kaim, L.; Grimaud, L.; Schiltz, A. Synlett 2009, 1401–1404; El Kaim, L.;
Grimaud, L.; Schiltz, A. Org. Biomol. Chem., 2009, doi:10.1039/b908541f.
7. Dos Santos, A.; El Kaim, L.; Grimaud, L.; Ronsseray, C. Chem. Commun. 2009,
3907–3909.
3h
Br
8. Typical procedure for 3f: To a solution of 120
lL of benzyl bromide (1.0 mmol,
O
10
11
2a
2a
33
—
1.0 equiv) in 0.5 mL of acetonitrile were added 134 mg of silver cyanide
(1.0 mmol, 1.0 equiv), 65 mg of potassium cyanide (1.0 mmol, 1.0 equiv), and
46 mg of TEBAC (0.2 mmol, 20 mol %). The mixture was then stirred at 80 °C
overnight. The formation of the isocyanide could be checked via 1H NMR
N
1e
3i
analysis of an aliquot. 140
lL of isobutyryl chloride (1.3 mmol, 1.3 equiv), and
AllBr 1f
—
116 L of 2,6-lutidine (1.0 mmol, 1.0 equiv) were then added to the mixture,
l

L. E. Kaim et al. / Tetrahedron Letters 50 (2009) 5235–5237
5237
which was stirred at 80 °C overnight. After checking the completion of the
reaction via TLC, the reaction is quenched with the addition of water and
diluted with dichloromethane. The organic phase is then washed several times
with water acidified with citric acid, dried over MgSO4 and concentrated in
vacuo. A flash column chromatography on silica gel (diethyl ether/petroleum
ether 90/10) affords the desired product 3f as a colorless oil (94 mg, 50%). 1H
NMR (400 MHz, CDCl3) d 8.03 (dd, J = 8.1, 1.8 Hz, 2H), 7.49–7.43 (m, 3H), 6.83
(d, J = 1.0 Hz, 1H), 3.07 (sept d, J = 6.8, 1.0 Hz, 1H), 1.35 (d, J = 6.8 Hz, 6H). 13C
NMR (100.6 MHz, CDCl3) d 160.9, 158.8, 130.3, 129.1, 128.3, 126.4, 122.2, 26.5,
21.2. IR (thin film) 2970, 1699, 1594, 1551, 1487, 1148 cmÀ1. HRMS calcd for
C12H13NO 187.0997, found 187.0998.
9. Schröder, R.; Schöllkopf, U.; Blume, E.; Hoppe, I. Liebigs Ann. Chem. 1975, 533–546.
10. For some recent oxazole synthesis from isocyanides: Wang, Q.; Xia, Q.; Ganem,
B. Tetrahedron Lett. 2003, 44, 6825–6827; Bonne, D.; Dekhane, M.; Zhu, J.
Angew. Chem., Int. Ed. 2007, 46, 2485–2488; Elders, N.; Ruijter, E.; Kanter, F.;
Groen, M.; Orru, R. Chem. Eur. J. 2008, 14, 4961–4973; Janvier, P.; Bienaymé, H.;
Zhu, J. Angew. Chem., Int. Ed. 2002, 41, 4291–4294.