The rhodium carbene route to oxazoles: A remarkable catalyst effect

Article abstract of DOI:10.1039/b903878g

Dirhodium tetraacetate catalysed reaction of α-diazo-β-keto- carboxylates and -phosphonates with arenecarboxamides gives 2-aryloxazole-4- carboxylates and 4-phosphonates by carbene N-H insertion and cyclodehydration; in stark contrast, dirhodium tetrakis(

Full text of DOI:10.1039/b903878g

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The rhodium carbene route to oxazoles: a remarkable catalyst effectw
Baolu Shi,a Alexander J. Blake,a Ian B. Campbell,b Brian D. Judkinsb
and Christopher J. Moody*a
Received (in Cambridge, UK) 24th February 2009, Accepted 3rd April 2009
First published as an Advance Article on the web 24th April 2009
DOI: 10.1039/b903878g
Dirhodium tetraacetate catalysed reaction of a-diazo-b-
keto-carboxylates and -phosphonates with arenecarboxamides
gives 2-aryloxazole-4-carboxylates and 4-phosphonates by
carbene N–H insertion and cyclodehydration; in stark contrast,
dirhodium tetrakis(heptafluorobutyramide) catalysis results in a
dramatic change of regioselectivity to give oxazole-5-carboxylates
and 5-phosphonates.
Owing to their important role in nature, the 1,3-azoles—
oxazoles, thiazoles, imidazoles—have attracted the attention
of chemists for many years. Thus, the imidazole ring
plays a key role in the chemistry of the proteinogenic amino
acid histidine, and oxazoles and thiazoles occur widely
in a range of bioactive natural products, particularly the
non-ribosomal peptides.1–3 The structural diversity of
complex naturally occurring oxazoles, and the biological
activity of synthetic analogues as, for example, peptide
mimetics4 and kinase inhibitors,5 has ensured that new
Scheme 1 a, Ar = C6H5; b, Ar = 4-MeOC6H4; c, Ar = 4-BrC6H4; d,
Ar = 4-PhC6H4.
methods continue to be developed for their synthesis.6 We
now report a new one-pot route to oxazoles based on the
oxazole-containing peptide mimetics,4 whilst Janda and
dirhodium(II) catalysed reaction of a-diazo-b-keto-esters
co-workers have developed a solid-phase variant of this
reaction, and applied it to the synthesis of an array of
oxazoles.20,21 In continuation of our own work, we sought
to develop a solution-phase, one-pot route to arrays of azoles,
and therefore investigated the reaction of benzamides 1
with methyl diazoacetoacetate 2 (Scheme 1). Under the
‘‘conventional’’ two step method using dirhodium tetraacetate
as catalyst, the intermediate 1,4-dicarbonyl compounds 3 were
readily isolated (30–77%) and subsequently dehydrated in
good yield (70–91%) under the conditions developed by Wipf
and Miller22 to give oxazole-4-carboxylates 4a–d in modest
overall yield (27–54% over two steps). In a new one-pot route
to oxazoles 4, the first step was carried out using the same
catalyst–solvent combination but under microwave irradiation
at 80 1C for 5 minutes, followed by addition of phosphorus
oxychloride (2 equiv.) and heating to 110 1C for 30 minutes
again under microwave irradiation. In an attempt to streamline
the procedure further and obviate the need for addition of a
second reagent, we investigated other rhodium catalysts. On
switching to dirhodium tetrakis(heptafluorobutyramide),
a catalyst with fluorinated carboxamide ligands that we
had found superior in other reactions of diazocarbonyl
compounds,23,24 we discovered a dramatic change in reactivity
that resulted in the formation of isomeric oxazole-5-carboxylates
5a–c in modest yields (18–38%). Although oxazoles 4 and
5 had very similar 1H NMR spectra, their 13C NMR
spectra were different, and for final confirmation, X-ray crystal
structures were obtained for the 4-methoxyphenyl derivatives
(carboxylic or phosphonic) with carboxamides that shows a
remarkable catalyst effect to enable selective access to 4- or
5-functionalised oxazoles.
The most versatile intermediates available for the synthesis
of 5-membered heteroaromatic rings are 1,4-dicarbonyl
compounds, readily exemplified in the field of 1,3-azole synthesis
by the Robinson–Gabriel oxazole synthesis. Although this
reaction was discovered some time ago, a number of more
modern versions have been developed.6 Our own contributions
have centred on a variation in which the key 1,4-dicarbonyl
intermediate was obtained by a rhodium carbene N–H insertion
reaction, and then subsequently converted into oxazoles
or thiazoles by dehydration or thionation, respectively.7,8
We developed the reaction specifically for the synthesis
of the oxazole building blocks of natural products such
as nostocyclamide,9 martefragin,10 diazonamide A,11–15
promothiocin A,16 amythiamicin A,17 and siphonazole.18
Others have since used our rhodium carbene N–H insertion
protocol in the synthesis of natural products,19 to access
a School of Chemistry, University of Nottingham, University Park,
Nottingham, UK NG7 2RD. E-mail: c.j.moody@nottingham.ac.uk;
Fax: +44 (0)115 951 3564
b GlaxoSmithKline, Gunnels Wood Road, Stevenage, UK SG1 2NY
w Electronic supplementary information: Spectroscopic data for
compounds 3–5, 7–9, and 11. CCDC 721492, 721493, 721494,
721495 and 721496 for 4b, 5b, 7, 9f and 11a, respectively. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b903878g
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Scheme 2 a, Ar = C6H5; b, Ar = 4-MeOC6H4; c, Ar = 4-BrC6H4; d,
Ar = 4-PhC6H4; e, Ar = 2-thienyl; f, Ar = benzothiophen-2-yl.
boiling toluene gave directly the oxazole-5-phosphonate 9a
in 49% yield. Likewise substituted benzamides 1b–1d gave the
oxazoles 9b–9d (46–54%), and thiophene- and benzothiophene-
carboxamides 1e and 1f gave the corresponding oxazoles 9e
(51%) and 9f (52%) (Scheme 2), the structure of the latter
compound being confirmed by crystallography (Fig. 2,
bottom).
Fig. 1 X-Ray crystal structures of (top) methyl 2-(4-methoxyphenyl)-
5-methyloxazole-4-carboxylate 4b and (bottom) methyl 2-(4-methoxy-
phenyl)-4-methyloxazole-5-carboxylate 5b showing crystallographic
numbering.w
4b and 5b (Fig. 1). Oxazoles 4 and 5 do not interconvert under
the reaction conditions.
Finally, we investigated the a-diazo-b-ketosulfone 10.
Using dirhodium tetrakis(heptafluorobutyramide) as catalyst,
oxazole-5-sulfones 11 were obtained directly from amides 1 in
good yield (64–77%) (Scheme 3); again the position of
the substituents was confirmed by X-ray crystallography
(of oxazole 11a) (Fig. 3).
This remarkable catalyst effect is not limited to diazo
carboxylate esters; a-diazo-b-ketophosphonates behave
similarly. Thus, dirhodium tetraacetate catalysed reaction of
dimethyl 1-diazo-2-oxopropylphosphonate 6 with benzamide
1a in boiling dichloromethane gave the N–H insertion product
7,25–27 the structure of which was confirmed by X-ray crystallo-
graphy (Fig. 2, top), in 62% yield. Cyclodehydration gave the
oxazole-4-phosphonate 8 in modest 44% yield (Scheme 2). In
stark contrast, use of the perfluorobutyramide catalyst in
Although ligand effects in dirhodium(II) catalysed reactions
of diazocarbonyl compounds are known,24,28 the dramatic
changes in regioselectivity described herein are unusual. The
role of the dirhodium(II) catalyst, Rh2L4 (L = ligand), is
thought to be in the generation of a reactive rhodium carbene,
Z(COMe)CQRh2L4, by reaction with the diazo compound,
Z(COMe)CQN2 (Z = CO2Me, PO(OMe)2, Ts), and hence the
nature of the ligands L will affect the reactivity of this
Scheme 3 a, Ar = C6H5; b, Ar = 4-BrC6H4; c, Ar = 4-PhC6H4; d,
Ar = 2-thienyl.
Fig. 2 X-Ray crystal structures of (top) dimethyl 1-benzoylamino-
2-oxopropylphosphonate 7 and (bottom) dimethyl 2-(benzothiophen-2-yl)-
4-methyloxazole-5-phosphonate 9f showing crystallographic numbering.w
Fig. 3 X-Ray crystal structures of 2-methyl-5-(4-methylphenylsulfonyl)-
2-phenyloxazole 11a showing crystallographic numbering.w
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intermediate.29 Presumably the 5-functionalised oxazoles 5, 9
and 11 arise from O–H insertion of the rhodium carbene
intermediate into the carboxamide imino tautomer, followed
by cyclisation, notwithstanding the fact that carboxamide
N–H insertion, with formation of a C–N bond, is usually the
dominant pathway, and a reaction widely used in synthesis.
Although there are a few other examples involving formation
of a C–O bond in the reaction of a rhodium carbene with
a carboxamide when an N–H bond is also available for
insertion,30–33 all of these involve lactams or imide systems,
rather than simple primary carboxamides. In the present case,
the change in selectivity is presumably electronic in nature
reflecting the changes in electrophilicity of the intermediate
rhodium carbene, Z(COMe)CQRh2L4, upon changing
ligands L, and provides a selective route to 4- or 5-functionalised
oxazoles.
11 M. C. Bagley, S. L. Hind and C. J. Moody, Tetrahedron Lett.,
2000, 41, 6897.
12 M. C. Bagley, C. J. Moody and A. G. Pepper, Tetrahedron Lett.,
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13 J. R. Davies, P. D. Kane and C. J. Moody, J. Org. Chem., 2005, 70,
7305.
14 F. N. Palmer, F. Lach, C. Poriel, A. G. Pepper, M. C. Bagley,
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3805.
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18 J. Linder, A. J. Blake and C. J. Moody, Org. Biomol. Chem., 2008,
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19 K. C. Nicolaou, D. H. Dethe, G. Y. C. Leung, B. Zou and
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20 B. Clapham, C. Spanka and K. D. Janda, Org. Lett., 2001, 3,
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22 P. Wipf and C. P. Miller, J. Org. Chem., 1993, 58, 3604.
23 G. G. Cox, D. J. Miller, C. J. Moody, E.-R. H. B. Sie and
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24 D. S. Brown, M. C. Elliott, C. J. Moody, T. J. Mowlem,
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25 For other N–H insertion reactions of diazophosphonates, see
ref. 25–27: E. Aller, R. T. Buck, M. J. Drysdale, L. Ferris,
D. Haigh, C. J. Moody, N. D. Pearson and J. B. Sanghera,
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D. Haigh, C. J. Moody, N. D. Pearson and E. Swann, Chem.–Eur. J.,
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28 M. P. Doyle, M. A. McKervey and T. Ye, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds, John Wiley,
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30 R. H. B. Galt, P. B. Hitchcock, S. J. McCarthy and D. W. Young,
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31 J. Busch-Petersen and E. J. Corey, Org. Lett., 2000, 2, 1641.
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We thank the EPSRC and GlaxoSmithKline for support of
this work under the Array Chemistry Programme.
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