A versatile synthesis of 2,4-substituted oxazoles

Article abstract of DOI:10.1039/b805430d

A variety of five-membered ring oxazoles have been synthesised with complete regiocontrol and without the requirement for ring oxidation via a reaction sequence based on a vinyl sulfonamide template. The Royal Society of Chemistry.

Full text of DOI:10.1039/b805430d

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A versatile synthesis of 2,4-substituted oxazolesw
Vijay Chudasama and Jonathan D. Wilden*
Received (in Cambridge, UK) 2nd April 2008, Accepted 8th May 2008
First published as an Advance Article on the web 16th June 2008
DOI: 10.1039/b805430d
A variety of five-membered ring oxazoles have been synthesised
with complete regiocontrol and without the requirement for ring
oxidation via a reaction sequence based on a vinyl sulfonamide
template.
Five-membered ring aromatic heterocycles are important
molecules that have found application throughout the chemical
sciences.1 In particular, oxazoles are important peptidomi-
metics,2,3 agrochemicals4 and are found in many natural pro-
ducts.5 Imidazoles have become important constituents of ionic
Scheme 1
DMF gave the corresponding oxazolines (6a–e) in excellent
yields (Scheme 2, Table 1).
liquids,6 N-heterocyclic carbene complexes7 and are important
organocatalytic moieties.8 Thiazoles have found recent applica-
tion as organic metals9 and magnets.10 In addition to this, these
compounds as well as the classic heterocyclic units (pyrrole, furan
and thiophene) have been and continue to be highly significant
medicinal compounds, with most new drugs containing at least
one heterocyclic ring.1,11 Occasionally, simple heterocyclic com-
pounds are commercially available and can be manipulated
directly to yield the target molecule. More usually, however, it
is necessary to prepare the heterocyclic compound de novo. Classic
routes to heterocyclic compounds involve condensation reactions
of 1,4-dicarbonyl compounds. Although these reactions are
usually reliable and high yielding, preparation of the intermediate
1,4-diketone or aldehyde can be difficult and achieving the desired
substitution pattern raises other synthetic and regiochemical
issues.12 New reliable routes to such heterocyclic systems are
continually being sought, particularly for the preparation of
compounds with more unusual substitution patterns.13 Following
the work in our laboratory on the chemistry of sulfonamides and
sulfonate esters,14 we here report a new synthesis of disubstituted
oxazoles with the potential to be expanded to the synthesis of
numerous other heterocyclic systems.
It was then found that treatment of the oxazolines with
aqueous sodium hydroxide in NMP or DMF resulted in the 2-
substituted oxazoles (7a–e) in excellent yields (Scheme 4,
Table 2). This approach therefore represents an efficient
synthesis of 2-substituted oxazoles. It is interesting to note
that aqueous basic conditions are required for the aromatisa-
tion of the oxazolines which implies a mechanism which relies
on ring opening followed by elimination of SO2 rather than an
E1 elimination of the sulfonamide (Scheme 3).
Having established the generality of our approach in the
synthesis of 2-substituted oxazoles, we proceeded to explore
how the approach might be modified to allow the preparation
of 2-, 4- and 2,4-substituted oxazoles.
It occurred to us that vinyl sulfonamide 1 might be a suitable
partner
coupling
for
palladium
catalysed
‘Heck’
arylations. Indeed, the literature contains numerous examples
of vinyl sulfonamides participating in such reactions (although
often yields are low).15 Arylation with iodobenzene proceeded
without incident and the vinyl bromide species was also readily
isolated. We were, however, disappointed to observe that ex-
posure of the vinyl bromide to ammonia resulted in no 1,4-
addition product being formed and only starting materials being
recovered. Various reaction conditions and solvents were exam-
ined, however the olefin remained intact in all cases (Scheme 5).
It was reasoned that the sulfonamide motif is not sufficiently
electron withdrawing for the addition of ammonia (and
concomitant loss of extended conjugation) to be thermodyna-
mically viable. If this rationale was correct then a more electron
withdrawing sulfonate moiety should alleviate this problem and
allow us to proceed further with the synthesis. The well defined
phenyl vinylsulfonate was therefore chosen as the new starting
The synthesis begins with the vinyl sulfonamide 1 which is
routinely transformed into vinyl bromide 3. 1,4-Addition of
ammonia to this species then proceeds smoothly to give the
highly functionalised species 4 (Scheme 1).
We were struck by the regioselectivity that was observed in
the formation of 4, no displacement of the bromine atom in
the alpha-position being observed (our previous experience
with these systems indicates that intermolecular SN2 reactions
of these species are difficult). Acylation of the free amine with
various acid chlorides then proceeds to yield an array of
amides which on treatment with sodium tert-butoxide in
The Christopher Ingold Laboratories, University College London, 20
Gordon Street, London, UK WC1H 0AJ. E-mail: j.wilden@ucl.ac.uk;
Fax: +44 (0)20 7679 7463; Tel: +44 (0)20 7679 3395
w Electronic supplementary information (ESI) available: Full charac-
terisation data for all compounds quoted. See DOI: 10.1039/b805430d
Scheme 2
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Table 1
Amide
yield
%
Isolated
yield %
Entry
1
R
Oxazoline
Scheme 4
93
5a
89
6a
2
83
5b
92
6b
3
4
CH3(CH2)8– 68
5c
62
6c
55
5d
57
6d
Scheme 5
Despite the relative lack of literature precedent, sulfonate
ester 14 was found to undergo palladium catalysed cross
coupling with various iodides under ligand-free conditions
(Scheme 6) to give the corresponding coupled products
15a–e, Table 3. Numerous attempts were made to maximise
the efficiency of these reactions (employing various catalysts,
ligands and solvents), however only the combination of dicy-
clohexylmethylamine as base and palladium(II) acetate in
DMF or NMP in the absence of classical ligands has so far
given significant yields.
5
80
5e
50
6e
material and it was expected that this species would be routinely
elaborated via Heck chemistry. However, only one comparable
reaction of this species was found in the literature (which
utilised a palladium catalyst derived from a tetraphosphine).16
At this juncture we wished to test the feasibility of employ-
ing a sulfonate ester such as 16 in the preparation of a
Scheme 6
Table 3
Table 2
Isolated
yield %
Entry
1
Halide
Product
Isolated
yield %
Entry
1
R
Oxazole
37
15a
68
7a
2
3
48
15b
2
70
7b
26
15c
3
4
CH3(CH2)8–
62
7c
92
7d
4
5
48
15d
5
83
7e
37
15e
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Chem. Commun., 2008, 3768–3770 | 3769
Scheme 3

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disubstituted oxazole. Using sulfonate ester 16, a slightly
modified radical bromination protocol was employed which
furnished the desired product in near quantitative yield.
Elimination to yield the vinyl bromide 17 similarly proceeded
without incident. Treatment of 17 with ammonium carbonate
in NMP then gave the amine 18 as a 1 : 1 mixture of
diastereoisomers which were separable by column chromato-
graphy (Scheme 7).
vinyl sulfonates and sulfonamides. In doing so, we have also
developed a ligand free palladium catalysed coupling protocol
that has allowed the elaboration of phenyl vinylsulfonate.
We recognise that this approach may have wider potential
in the preparation of other heterocyclic systems such as
imidazoles, thiazoles, isoxazoles and pyrazoles and work is
currently underway in our laboratory to develop this metho-
dology.
We thank the EPSRC and UCL for generous financial
support of this work. We also gratefully acknowledge the
contributions of Dr A. Aliev and Dr L. Harris.
Scheme 7
Notes and references
1 J. Joule and K. Mills, Heterocyclic Chemistry, Blackwell
Publishing, Oxford, 4th edn, 2000.
2 For example see: E. Mann and H. Kessler, Org. Lett., 2003, 5,
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3 S. C. Annedi, K. Majumder, L. Wei, C. E. Oyiliagu, S. Samson and
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4 M. Izumi, Pestic. Sci., 2006, 31, 1–5.
Exposure of 18 to 4-nitrobenzoyl chloride led as expected to
the amide 19 in good yield. It was then found that treatment of
either diastereoisomer of 19 with sodium tert-butoxide gave
the oxazole directly without isolation of the oxazoline inter-
mediate (Scheme 8).
5 For
a review see: V. S. C. Yeh, Tetrahedron, 2004, 60,
11995–12042.
6 H. Zhao and S. V. Malhotra, Aldrichimica Acta, 2002, 35
75–83.
7 N-Heterocyclic Carbenes in Synthesis, ed. S. P. Nolan, Wiley-VCH,
Weinheim, 2006.
8 For a recent example see: L. Hojabri, A. Hartikka, F. M.
Moghaddam and P. I. Arvidsson, Adv. Synth. Catal., 2007, 349,
740–748.
9 S. Ando, J. Nishida, E. Fujiwara, H. Tada, Y. Inoue and Y.
Yamashita, Synth. Met., 2006, 156, 327–331.
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11 A. W. Czarnik, Acc. Chem. Res., 1996, 29, 112.
12 For recent work see: J. D. Kreisberg, P. Magnus and S. Shinde,
Tetrahedron Lett., 2002, 43, 7393–7396.
Scheme 8
13 Y. Ito, T. Konoike and T. Saegura, J. Am. Chem. Soc., 1977, 99,
1487–1493, and references therein.
We were intrigued by the discovery that cyclisation and
elimination of the sulfonate ester were simultaneous in this
case. It was reasoned that the aryl group at the 4-position of
the putative oxazoline serves to lower the pKa of the adjacent
proton sufficiently to allow an E1cb elimination of the sulfo-
nate ester (Scheme 9).
14 S. Caddick, J. D. Wilden and D. B. Judd, Chem. Commun., 2005,
2727–2728; S. Caddick, J. D. Wilden, H. D. Bush and D. B. Judd,
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D. Bush, S. N. Wadman and D. B. Judd, Org. Lett., 2002, 4,
2549–2551.
15 S. Hirooka, Y. Tanbo, K. Takemura, H. Nakahasha, T. Matsuoka
and S. Kuroda, Bull. Chem. Soc. Jpn., 1991, 64, 1431–1433;
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Harris, S. S. Labadie, J. La Fargue, J. M. Lapierre, S.
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Scheme 9
In conclusion, we have described a short, regioselective
synthesis of a variety of 2-substituted oxazoles and have
demonstrated the potential of the synthesis in the preparation
of 2,4-substituted oxazoles exploiting the unique reactivity of
16 A. Battace, T. Zair, H. Doucet and M. Santelli, Synthesis, 2006,
3495–3505.
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