Efficient synthesis of oxazoles by dirhodium(ii)-catalyzed reactions of styryl diazoacetate with oximes

Article abstract of DOI:10.1039/c2cc36537e

An efficient one-step synthesis of multi-functionalized oxazole derivatives is achieved in high yield by dirhodium(ii)-catalyzed reactions of styryl diazoacetate with aryl oximes. This journal is

Full text of DOI:10.1039/c2cc36537e

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Efficient synthesis of oxazoles by dirhodium(II)-catalyzed reactions of
styryl diazoacetate with oximesw
Xinfang Xu,ab Peter Y. Zavalij,a Wenhao Hub and Michael P. Doyle*a
Received 7th September 2012, Accepted 11th October 2012
DOI: 10.1039/c2cc36537e
An efficient one-step synthesis of multi-functionalized oxazole
derivatives is achieved in high yield by dirhodium(II)-catalyzed
reactions of styryl diazoacetate with aryl oximes.
isolated yield when 4 A molecular sieves was used as an
additive (eqn (2)). The structure of the generated oxazole
was confirmed by single-crystal X-ray diffraction analysis of
its bromo-derivative.11 This process represents a significant
improvement for the synthesis of 5-methoxyoxazoles from
diazoacetates compared to previously reported reactions with
nitriles (eqn (1))10 and for the synthesis of 4-vinyl-5-methoxyox-
azoles via a recently reported coupling strategy.7i In catalytic
reactions with styryldiazoacetates the easily accessible oximes are
more reactive than are nitriles and give the corresponding oxazoles
in high yield. The reaction of styryl diazoacetate 1 with benzonitrile
gives the corresponding oxazole in only 27% isolated yield under
the same reaction conditions.12
Oxazoles are widely distributed in nature, and many of them have
shown biological activities.1 Because oxazoles are used as building
blocks in organic synthesis2 for a,a-disubstituted amino acids,3 in
cycloaddition reactions,4 and in the total synthesis of natural
products,5 efficient methods for their syntheses continue to be of
intense interest.6 Significant achievements in the synthesis of their
core structures that are amenable to further substitutions have been
reported,7 and several transition metal catalyzed methodologies for
the functionalization of oxazoles have been developed.7c–j Because
these approaches require multistep syntheses, general synthetic
processes for functionalized oxazoles having structural diversity
and complexity continue to be needed.
Diazo compounds have been extensively studied during the last
few decades,8 and several synthetic methodologies for oxazole
formation have been reported,9 including oxazole syntheses from
diazocarbonyl compounds with nitriles catalyzed by transition
metal catalysts, Lewis acids or thermal conditions (eqn (1)).10
However, this transformation has been limited to diazoaceto-
acetates and diazoketones, and with ethyl diazoacetate the yield
of the corresponding 5-alkoxyoxazoles (R1 = OR) is only
26–31%.10a Here we report our recent discovery of a surprisingly
efficient dirhodium(II)-catalyzed reaction of styryl diazoacetate
with aryl oximes to give 4-styryl-5-methoxyoxazoles directly in
high yield under mild conditions (eqn (2)).
ð2Þ
Originally we thought that enoldiazoacetates 4 would undergo
stepwise [3,3]-cycloaddition with oximes analogous to their
asymmetric vinylogous reactions with hydrazones 5 catalyzed by
Rh2(R-PTL)4 followed by diastereoselective Sc(OTf)3-catalyzed
Mannich addition to form the corresponding tetrahydropyridazine
derivatives (6, Scheme 1).13 However, instead of the expected
six-membered outcome with enoldiazoacetates, rhodium acetate-
catalyzed reactions of oximes occurred by a completely different
processes.
(1)
The reaction between styryl diazoacetate 1 and the oxime of
4-chlorobenzaldehyde catalyzed by rhodium acetate yielded
the multi-functionalized 4-styryl-5-methoxyoxazole 3a in 82%
a Department of Chemistry and Biochemistry, University of Maryland,
College Park, Maryland, 20742, USA. E-mail: mdoyle3@umd.edu
b Shanghai Engineering Research Center for Molecular Therapeutics
and Institute of Drug Discovery and Development, East China
Normal University, 3663 Zhongshan Bei Road, Shanghai 200062,
China
w Electronic supplementary information (ESI) available. CCDC
895782 (3b) and 895783 (7a). For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2cc36537e
Scheme 1 Stepwise formal [3+3]-cycloaddition of hydrazones with
enoldiazoacetates.
c
11522 Chem. Commun., 2012, 48, 11522–11524
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Table 1 Dirhodium(II)-catalyzed oxazole synthesis reaction of styryl
diazoacetate 1 with aryl oximesa
Entry
Ar (2)
3
Yieldb (%)
1
2
3
4
5
6
7
8
4-ClC6H4 (2a)
4-BrC6H4 (2b)
4-FC6H4 (2c)
Ph (2d)
4-NO2C6H4 (2e)
4-MeOC6H4 (2f)
4-MeC6H4 (2g)
3-MeC6H4 (2h)
2-MeC6H4 (2i)
2-Furyl (2j)
3a
3b
3c
3d
3e
3f
3g
3h
3i
82
89
71
83
91
67
77
71
72
62
87
Scheme 2 Pathway to products with enoldiazoacetates.
The reaction of enoldiazoacetate 4a with 4-chlorobenzaldehyde
oxime 2a catalyzed by dirhodium(II) acetate gave succinate
derivative 7a14 and TBS-substituted oxime 8a as major products
(eqn (3)) without any evidence of an OH insertion product at the
vinylogous position. This outcome is consistent with initial rhodium
acetate catalyzed intramolecular conversion of enoldiazoacetate 4a
to 2-TBSO-cyclopropenecarboxylate15 followed by oxime
addition, ring opening, and TBS transfer (Scheme 2). The
outcome described in eqn (3), in contrast with that of
Scheme 1, suggests that hydrazones 5 are able to intercept
the intermediate metal carbene prior to its intramolecular
conversion to 2-TBSO-cyclopropenecarboxylate.
9
10
11
3j
3k
2-Naphthyl (2k)
a
Reactions were carried out over 2 h on a 1.0 mmol scale: 1b
(1.5 mmol), 2 (1.0 mmol), 4 A MS (100 mg), in 3.0 mL DCM with
b
Rh2(OAc)4 (2.0 mol%) at room temperature. Isolated yield of 3
(based on limiting reagent 2).
ð3Þ
The substrate scope for reactions of oximes with styryl
diazoacetate 1 under optimized dirhodium(II)-catalyzed conditions
has been determined, and the results are summarized in Table 1.
All of the oxazole products were obtained in good to high yields,
and 5-methoxyoxazoles 3 were the sole isolated reaction products.
Both electron-deficient and electron-rich oximes give good to high
yields of oxazoles. The position of the methyl substituent on the
hydroxylamine’s aryl group has little influence on product yields
(entries 7–9). The reaction of styryl diazoacetate 1 with 2-furyl and
2-naphthyl substrates also produced the corresponding oxazoles in
62% and 87% yield, respectively (entries 10 and 11).
Scheme 3
and furan derivative 10 was isolated as the major product
accompanied by a small amount of hydrolyzed furan. Another
demonstration of the utility of these 4-styryl-5-methoxyoxazole
derivatives, reported by Antilla and coworkers,7i is the synthesis
of functionalized amino alcohol 12 and amino acid 13 derivatives
in high yield.
With these results in hand we investigated transformations
of functionalized oxazole products to other synthetically
interesting motifs (Scheme 3). A Suga–Ibata reaction of
oxazole 3a with an aldehyde for the synthesis of oxazolines
was performed.16 When the reaction was promoted by SnCl4,
the desired addition product 9 was obtained in 66% isolated
yield with 2 : 1 diastereoselectivity; this compound is a useful
precursor of a-amino-b-hydroxyl carboxylic acids having a
quaternary carbon center.17 We also employed oxazole 3a for
1,3-diplar cycloaddition reactions with dimethyl 2-butynedioate
under thermal conditions.18 These reactions showed 100%
conversion when dimethyl 2-butynedioate was the solvent,
In summary, we have discovered an efficient dirhodium(II)-
catalyzed synthesis of 4-styryl-5-methoxyoxazoles starting
from styryl diazoacetate and oximes in high yield under mild
conditions. A possible mechanism for formation of 4-styryl-5-
methoxy-2-aryloxazoles (3) from catalytic reactions between 1 and
2 is described in Scheme 4. Dirhodium(II)-catalyzed dinitrogen
extrusion from styryldiazoacetate (1) forms metal carbene which
reacts with oximes and generates the azomethine yilde (II). Rapid
equilibration of this intermediate to the corresponding enol anion
(II0) followed by oxo-Mannich addition to produce the ring-closed
structure (III), that with final aromatization by dehydration gives
c
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styryldiazoacetate with oximes.
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MPD is grateful to the National Institutes of Health
(GM 465030) for their support of this research. WH thanks
the National Science Foundation of China (20932003), and the
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