Rhodium carbene routes to oxazoles and thiazoles. Catalyst effects in the synthesis of oxazole and thiazole carboxylates, phosphonates, and sulfones

Article abstract of DOI:10.1021/jo902256r

(Chemical Equation Presented) Dirhodium tetraacetate catalyzed 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(heptafluorobutyramide) catalysis results in a dramatic change of regioselectivity to give oxazole-5-carboxylates and 5-phosphonates. α-Diazo-β-ketosulfones behave similarly and give 5-sulfonyloxazoles upon dirhodium tetrakis-(heptafluorobutyramide) catalyzed reaction with carboxamides. The analogous reactions of thiocarboxamides give the corresponding thiazole-5-carboxylates, -phosphonates, and -sulfones. 2009 American Chemical Society.

Full text of DOI:10.1021/jo902256r

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Rhodium Carbene Routes to Oxazoles and Thiazoles. Catalyst Effects in
the Synthesis of Oxazole and Thiazole Carboxylates, Phosphonates, and
Sulfones
Baolu Shi,† Alexander J. Blake,† William Lewis,† Ian B. Campbell,‡ Brian D. Judkins,‡ and
Christopher J. Moody*,†
†School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K. and
‡GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
c.j.moody@nottingham.ac.uk
Received October 20, 2009
Dirhodium tetraacetate catalyzed reaction of R-diazo-β-keto-carboxylates and -phosphonates with
arenecarboxamides gives 2-aryloxazole-4-carboxylates and 4-phosphonates by carbene N-H inser-
tion and cyclodehydration. In stark contrast, dirhodium tetrakis(heptafluorobutyramide) catalysis
results in a dramatic change of regioselectivity to give oxazole-5-carboxylates and 5-phosphonates.
R-Diazo-β-ketosulfones behave similarly and give 5-sulfonyloxazoles upon dirhodium tetrakis-
(heptafluorobutyramide) catalyzed reaction with carboxamides. The analogous reactions of thio-
carboxamides give the corresponding thiazole-5-carboxylates, -phosphonates, and -sulfones.
Introduction
biological activity of relatively simple synthetic oxazoles and
thiazoles as, for example, peptide mimetics4,5 and enzyme
inhibitors,6-8 and the structural diversity of complex natu-
rally occurring derivatives have combined to ensure that new
methods continue to be developed for their synthesis.9-11
Of the intermediates available for the synthesis of five-
membered heteroaromatic rings, 1,4-dicarbonyl compounds
are preeminent. In the field of 1,3-azole synthesis, the
cyclodehydration of such a 1,4-dicarbonyl compound (an
R-acylaminoketone) is the basis of the Robinson-Gabriel
oxazole synthesis.9 Although this reaction was discovered
some time ago, it continues to undergo modification,
for example, the preparation of the intermediate R-acylami-
noketone by acylation of R-amino-β-ketoesters4,12 or by
The 1,3-azoles-oxazoles, thiazoles, and imidazoles-abound
in nature and continue to capture the attention of organic
chemists. Thus, while oxazoles and thiazoles occur widely in
a range of bioactive natural products, particularly the non-
ribosomal peptides,1-3 the imidazole ring plays a key role in
the chemistry of the proteinogenic amino acid histidine. The
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Nat. Prod. Rep. 1999, 16, 249.
(2) Schwarzer, D.; Finking, R.; Marahiel, M. A. Nat. Prod. Rep. 2003, 20,
275.
(3) Hughes, R. A.; Moody, C. J. Angew. Chem., Int. Ed. 2007, 46, 7930.
(4) Gordon, T. D.; Singh, J.; Hansen, P. E.; Morgan, B. A. Tetrahedron
Lett. 1993, 34, 1901.
(5) Falorni, M.; Dettori, G.; Giacomelli, G. Tetrahedron-Asymmetry
1998, 9, 1419.
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L.; Vongsouthi, V.; Gerusz, V.; Denis, A.; Escaich, S. Bioorg. Med. Chem.
2009, 17, 1276.
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17, 3916.
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Kruchten, P.; Oster, A.; Frotscher, M.; Birk, B.; Hartmann, R. W. J. Med.
Chem. 2008, 51, 6725.
(9) Palmer, D. C.; Venkatraman, S. In Oxazoles: Synthesis, Reactivity and
Spectroscopy. Part A; Palmer, D. C., Ed.; John Wiley & Sons Inc.: Hoboken,
NJ, 2003; p 1.
(10) Yeh, V.; Iyengar, R. In Comprehensive Heterocyclic Chemistry III;
Joule, J. A., Ed.; Elsevier: New York, 2008; Vol. 4, p 487.
(11) Chen, B.; Heal, W. In Comprehensive Heterocyclic Chemistry III;
Joule, J. A., Ed.; Elsevier: New York, 2008; Vol. 4, p 635.
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152 J. Org. Chem. 2010, 75, 152–161
Published on Web 12/02/2009
DOI: 10.1021/jo902256r
r
2009 American Chemical Society

Shi et al.
JOCArticle
oxidation of β-hydroxyamides.13 Recently we reported a new
variation on the Robinson-Gabriel synthesis in which the
key 1,4-dicarbonyl intermediate was obtained by an inser-
tion reaction of a rhodium carbene derived from a diazo-
carbonyl compound into the N-H bond of a carboxamide,14
followed by conversion into oxazoles or thiazoles by dehy-
dration or thionation, respectively.14,15 We originally devel-
oped the reaction for the synthesis of the oxazole building
blocks of natural products such as nostocyclamide,16 marte-
fragin,17 diazonamide A,18-22 promothiocin A,23 amythia-
micin A,24 and siphonazole.25 Other researchers have also
used this rhodium carbene N-H insertion protocol in the
synthesis of natural products26 and of oxazole-containing
peptide mimetics.5
SCHEME 1. Synthesis of Oxazole-4- and -5-carboxylates
Although oxazoles can be also be obtained by the rho-
dium-catalyzed reaction of diazocarbonyl compounds with
nitriles,27 this reaction usually requires the use of nitrile as
solvent and therefore is only applicable to simple nitriles.
Hence the ready availability of carboxamides, combined
with the robustness of the rhodium carbene N-H insertion
chemistry, renders the methodology highly suitable for
the synthesis of a wide range of oxazoles. Indeed Janda
and co-workers have developed a solid-phase variant of the
reaction and applied it in the synthesis of oxazole arrays.28,29
In continuation of our own work, we sought to develop a
solution-phase, one-pot method that was applicable to a
diverse array of substituted 1,3-azoles and have reported
some preliminary results on the synthesis of 4- and 5-
functionalized oxazoles.30 We now describe the results of a
comprehensive study of the conversion of carboxamides into
4- and 5-substituted oxazole-carboxylates, -phosphonates,
and -sulfones, extended to include the corresponding con-
version of thiocarboxamides into thiazoles.
compounds 3 were readily isolated and subsequently dehy-
drated under the conditions developed by Wipf and Miller13
to give oxazole-4-carboxylates 4a-4c in reasonable yield
(45-54% over two steps).30 In an attempt to compress the
process into a one-pot operation using the reaction of
benzamide with the more functionalized diazocarbonyl
compound, methyl 4-chloro-2-diazo-3-oxobutanoate 5, as
an example, the first step was carried out using the same
catalyst/solvent combination but under microwave irradia-
tion at 80 °C for 5 min, followed by addition of phosphorus
oxychloride (2 equiv) and heating to 110 °C for 30 min, again
under microwave irradiation. This gave the expected oxa-
zole-4-carboxylate 6 in 56% yield, the structure of which was
confirmed by X-ray crystallography (see Supporting Infor-
mation). Surprisingly, the isomeric oxazole-5-carboxylate 7
was also isolated (23%), and this formation of mixtures of
oxazoles somewhat detracted from the one-pot method.
Nevertheless the formation of the unexpected oxazole-5-
carboxylate was intriguing and is discussed in detail below
(q.v.).
The failure of the above method to deliver a single oxazole
product prompted a search for alternative reaction condi-
tions, and we reasoned that the Lewis acidic nature of
dirhodium carboxylates and carboxamidates31 might be
sufficient to mediate the cyclization of the intermediate 1,4-
dicarbonyl. This would clearly streamline the procedure
further by obviating the need for addition of a second
reagent. Therefore we investigated other rhodium catalysts
and turned to dirhodium tetrakis(heptafluorobutyramide), a
catalyst with fluorinated carboxamide ligands that we had
found superior in other reactions of diazocarbonyl com-
pounds.32,33 The reactions of benzamides 1 with diazocarbonyl
Results and Discussion
Initially we investigated the reaction of substituted benzamides
1 with methyl 2-diazo-3-oxobutanaote 2 in dichloromethane
using dirhodium tetraacetate as catalyst (Scheme 1).
Under these conditions, the intermediate 1,4-dicarbonyl
(13) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604.
(14) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J. J. Chem. Soc.,
Perkin Trans. 1 1998, 591.
(15) Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60, 3967.
(16) Moody, C. J.; Bagley, M. C. J. Chem. Soc., Perkin Trans. 1 1998, 601.
(17) Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J. Org.
Chem. 2005, 70, 5840.
(18) Bagley, M. C.; Hind, S. L.; Moody, C. J. Tetrahedron Lett. 2000, 41,
6897.
(19) Bagley, M. C.; Moody, C. J.; Pepper, A. G. Tetrahedron Lett. 2000,
41, 6901.
(20) Davies, J. R.; Kane, P. D.; Moody, C. J. J. Org. Chem. 2005, 70, 7305.
(21) Palmer, F. N.; Lach, F.; Poriel, C.; Pepper, A. G.; Bagley, M. C.;
Slawin, A. M. Z.; Moody, C. J. Org. Biomol. Chem. 2005, 3, 3805.
(22) Lachia, M.; Moody, C. J. Nat. Prod. Rep. 2008, 25, 227.
(23) Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.; Moody, C. J. J. Am.
Chem. Soc. 2000, 122, 3301.
(24) Hughes, R. A.; Thompson, S. P.; Alcaraz, L.; Moody, C. J. J. Am.
Chem. Soc. 2005, 127, 15644.
(25) Linder, J.; Blake, A. J.; Moody, C. J. Org. Biomol. Chem. 2008, 6,
3908.
(26) Nicolaou, K. C.; Dethe, D. H.; Leung, G. Y. C.; Zou, B.; Chen,
D. Y. K. Chem. Asian J. 2008, 3, 413.
(27) Moody, C. J.; Doyle, K. J. Prog. Heterocycl. Chem. 1997, 9, 1.
(28) Clapham, B.; Spanka, C.; Janda, K. D. Org. Lett. 2001, 3, 2173.
(29) Clapham, B.; Lee, S. H.; Koch, G.; Zimmermann, J.; Janda, K. D.
Tetrahedron Lett. 2002, 43, 5407.
(31) Doyle, M. P. J. Org. Chem. 2006, 71, 9253.
(32) Cox, G. G.; Miller, D. J.; Moody, C. J.; Sie, E.-R. H. B.; Kulagowski,
J. J. Tetrahedron 1994, 50, 3195.
(30) Shi, B.; Blake, A. J.; Campbell, I. B.; Judkins, B. D.; Moody, C. J.
Chem. Commun. 2009, 3291.
(33) Brown, D. S.; Elliott, M. C.; Moody, C. J.; Mowlem, T. J.; Marino,
J. P.; Padwa, A. J. Org. Chem. 1994, 59, 2447.
J. Org. Chem. Vol. 75, No. 1, 2010 153

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TABLE 1. Complementary Routes to Oxazole-4- and -5-carboxylates 4
and 8 Using Dirhodium Catalysts, Rh2L4
TABLE 2. Synthesis of Oxazole-5-phosphonates 12
entry
Ar
R
R1 conditionsa 12 yield (%)
yield
(%)
yield
(%)
yield
(%)
1
2
3
4
5
6
7
8
Ph
Ph
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
A
B
B
12a
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
49
73
49
70
46
54
35
28
49
55
51
52
26
51
45
entry
Ar
L
3
4
8
1
2
3
4
5
6
Ph OAc
4-MeOC6H4 OAc
4-BrC6H4
Ph
4-MeOC6H4 NHCOC3F7
4-BrC6H4 NHCOC3F7
3a
3b
3c
60 4a
55 4b
77 4c
83
81
70
2-BrC6H4
2-BnOC6H4
4-BrC6H4
4-MeOC6H4
4-NO2C6H4
4-CbzNHC6H4
4-PhC6H4
B
OAc
NHCOC3F7
A
A
A
B
A
A
A
A
A
A
A
8a
8b
8c
18
24
38
9
10
11
12
13
14
15
3,5-F2C6H3
2-thienyl
SCHEME 2. Synthesis of Oxazole-4- and -5-phosphonates
2-benzothiophenyl Me Me
Me Me
PhCHdCH
Ph
2-thienyl
Et
Et
Ph
Ph
aConditions: (A) 2 mol % Rh2(NHCOC3F7)4, toluene, reflux,
ca. 16 h; (B) 2 mol % Rh2(NHCOC3F7)4, toluene, 135 °C, microwave,
30 min.
with benzamide in boiling dichloromethane gave the N-H
insertion product 10 in 62% yield.34-36 Cyclodehydration
gave the oxazole-4-phosphonate 11 in modest 44% yield
(Scheme 2). In stark contrast, use of the perfluorobutyra-
mide catalyst in boiling toluene gave directly the oxazole-5-
phosphonate 12a in 49% yield, increased to 73% under
microwave heating. Likewise heating substituted benza-
mides with diazophosphonates 9a or 9b in toluene (under
conventional reflux or microwave heating) gave the oxazoles
12b-12i and 12m (28-70%). Heterocyclic carboxamides
and cinnamamide also participate in the reaction to give
oxazole-5-phosphonates 12j-12l and 12n (Table 2), the
location of the phosphonate at C-5 being confirmed by
X-ray crystallography in the case of oxazole 12k.30 Phos-
phonic acid derivatives of 1,3-azoles are known, and we and
others have previously reported the dirhodium tetraacetate
catalyzed reaction of diazocarbonyl phosphonate deriva-
tives with nitriles to give oxazole-4-phosphonates.37,38
Hence, whereas the 4-phosphonates are accessible by these
or other methods,39 there appear to be no general routes to
the 5-phosphonates. The methodology described above now
renders a range of oxazole-5-phosphonates readily available.
Next, we investigated the reactions of the R-diazo-β-
ketosulfone 13 with carboxamides. Using dirhodium
tetrakis(heptafluorobutyramide) as catalyst in 1,2-dichlor-
oethane (reflux or microwave heating), oxazole-5-sulfones
14 were obtained directly from amides 1 (Scheme 3, Table 3).
Attempts to prepare oxazole-4-sulfones by the rhodium
carbene N-H insertion-cyclodehydration route were not
successful. However, oxazole-4-sulfones are accessible by
reaction of R-diazo-β-carbonylsulfones with nitriles.37,40
For example, dirhodium tetraacetate catalyzed reaction of
the R-diazo-β-ketosulfone 13 with benzonitrile gave the
oxazole-4-sulfone 15 (Scheme 3). The structures of the iso-
meric oxazole sulfones 14a30 and 15 (see Supporting
Information) were confirmed by X-ray crystallography.
Hence, again, rhodium carbene methodology provides com-
plementary routes to 4- or 5-substituted-oxazoles.
compound 2 were carried out with 2 mol % catalyst under
more forcing conditions (1,2-dichloroethane, 105 °C, micro-
wave irradiation, 30 min) and gave directly a single oxazole
product, albeit in modest yield. However, the products were not
the same oxazoles 4 obtained by the dirhodium tetraacetate
catalyzed N-H insertion-cyclodehydration route but rather
the isomeric oxazole-5-carboxylates 8 (Scheme 1). Although
oxazoles 4 and 8 had very similar 1H NMR spectra, their 13
C
NMR spectra were different, and for final confirmation X-ray
crystallography structures were obtained for the 4-methoxy-
phenyl derivatives 4b and 8b as previously described.30
The results of these complementary routes to oxazole-4- and
-5-carboxylates are summarized in Table 1.
The change in catalyst from dirhodium tetraacetate to
dirhodium tetrakis(heptafluorobutyramide) evidently causes
a dramatic change in reactivity that results in the formation
of the isomeric series of oxazoles. Although the yields of the
oxazole-5-carboxylates were modest at best, this remarkable
catalyst effect clearly merited further investigation using a
wider range of carboxamides and diazocarbonyl com-
pounds. The effect of catalyst is not limited to R-diazo-β-
keto carboxylate esters 2 since R-diazo-β-ketophosphonates
9 behave similarly. Thus, dirhodium tetraacetate catalyzed
reaction of dimethyl 1-diazo-2-oxopropylphosphonate 9a
(34) Aller, E.; Buck, R. T.; Drysdale, M. J.; Ferris, L.; Haigh, D.; Moody,
C. J.; Pearson, N. D.; Sanghera, J. B. J. Chem. Soc., Perkin Trans. 1 1996,
2879.
(35) Ferris, L.; Haigh, D.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1
1996, 2885.
(36) Buck, R. T.; Clarke, P. A.; Coe, D. M.; Drysdale, M. J.; Ferris, L.;
Haigh, D.; Moody, C. J.; Pearson, N. D.; Swann, E. Chem.;Eur. J. 2000, 6,
2160.
(37) Doyle, K. J.; Moody, C. J. Tetrahedron 1994, 50, 3761.
(38) Gong, D. H.; Zhang, L.; Yuan, C. Y. Synth. Commun. 2004, 34, 3259.
(39) Palacios, F.; Aparicio, D.; de Retana, A. M. O.; de los Santos, J. M.;
Gil, J. I.; Alonso, J. M. J. Org. Chem. 2002, 67, 7283.
(40) Kuo, Y.-C.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1982, 30,
526.
154 J. Org. Chem. Vol. 75, No. 1, 2010

Shi et al.
JOCArticle
SCHEME 3. Synthesis of Oxazole-4- and -5-sulfones
SCHEME 4. Synthesis of Thiazole-5-carboxylates, -phospho-
nates, and -sulfones
TABLE 4. Synthesis of 5-Functionalized Thiazoles 17
entry
Ar
diazo
Z
conditionsa 17 yield (%)
1
2
3
4
5
6
7
8
9
4-BrC6H4
Ph
2-BnOC6H4
4-BrC6H4
2
CO2Me
PO(OMe)2
PO(OMe)2
PO(OMe)2
PO(OMe)2
Ts
Ts
Ts
Ts
A
B
C
C
C
D
E
E
E
17a
17b
17c
17d
17e
17f
17g
17h
17i
47
75
59
35
55
85
87
88
83
9a
9a
9a
4-CbzNHC6H4 9a
Ph
2-BnOC6H4
4-BrC6H4
13
13
13
TABLE 3. Synthesis of Oxazole-5-sulfones 14
entry
Ar
conditionsa
14
yield (%)
4-CbzNHC6H4 13
1
2
3
4
5
6
7
8
9
10
Ph
Ph
A
B
B
B
A
A
B
A
A
A
14a
14a
14b
14c
14d
14e
14f
14g
14h
14i
77
81
40
79
73
22
47
64
77
62
aConditions: (A) 2 mol % Rh2(NHCOC3F7)4, CH2Cl2, 120 °C,
microwave, 10 min. (B) 2 mol % Rh2(NHCOC3F7)4, toluene, reflux,
ca. 16 h. (C) 2 mol % Rh2(NHCOC3F7)4, toluene, 135 °C, microwave, 30
min. (D) 2 mol % Rh2(NHCOC3F7)4, DCE, reflux, ca. 16 h. (E) 2 mol %
Rh2(NHCOC3F7)4, DCE, 105 °C, microwave, 30 min.
2-BrC6H4
2-BnOC6H4
4-BrC6H4
4-NO2C6H4
4-CbzNHC6H4
4-PhC6H4
of the intermediate rhodium carbene, Z(COMe)CdRh2L4,
upon changing ligands L, and provides a selective route to
4- or 5-functionalized oxazoles.
2-thienyl
PhCHdCH
aConditions: (A) 2 mol % Rh2(NHCOC3F7)4, DCE, reflux, ca. 16 h;
In contrast to the reaction of diazocarbonyl compounds
with carboxamides, the corresponding reactions with thio-
carboxamides are less well-known. The reaction of thioben-
zamides with diazoketones is reported to give thiazoles, often
in poor yield,47,48 while the boron trifluoride etherate pro-
moted reaction of diazopyruvate with thioamides gives
thiazole-4-carboxylates in good yield.49 In this instance the
diazopyruvate acts as an equivalent to bromopyruvate in
the classical Hantzsch route to thiazole-4-carboxylates.
More recently, the copper(I) bromide catalyzed reaction of
R-diazo-β-ketoesters with thiobenzamides to give thiazole-5-
carboxylates has been described.50 Interestingly, it was
reported that dirhodium tetraacetate was an unsatisfactory
catalyst for this transformation,50 and therefore we were
keen to see if our optimized conditions using dirhodium
tetrakis(heptafluorobutyramide) as catalyst fared any better.
In the event, this proved to be the case, and reaction of
4-bromothiobenzamide with methyl 2-diazo-3-oxobuta-
naote 2 gave the thiazole-5-carboxylate 17a in reasonable
yield (Scheme 4, Table 4), complementing the Hantzsch
synthesis of thiazole-4-carboxylates from halopyruvates.
The diazophosphonate 9a and diazosulfone 13 reacted simi-
larly, leading to a range of oxazole-5-phosphonates and
-sulfones 17b-17i in modest to excellent yield (Table 4).
The structures of the 2-(4-bromophenyl)oxazoles 17a, 17d,
and 17h were determined by X-ray crystallography, confirm-
ing the locus of the ester, phosphonyl, or sulfonyl substituent
(B) 2 mol % Rh2(NHCOC3F7)4, DCE, 135 °C, microwave, 30 min.
Although ligand effects in dirhodium(II) catalyzed reactions
of diazocarbonyl compounds have been studied, notably by
Doyle and co-workers,41 the changes in regioselectivity
described herein are quite dramatic. The role of the
dirhodium(II) catalyst, Rh2L4 (L = ligand), is thought to
be in the generation of a reactive rhodium carbene,
Z(COMe)CdRh2L4, by reaction with the diazo compound,
Z(COMe)CdN2 (Z = CO2Me, PO(OMe)2, Ts), and hence
the nature of the ligands L will affect the reactivity of this
intermediate.42 Presumably the 5-substituted oxazoles 5, 9,
and 11 arise from O-H insertion of the rhodium carbene
intermediate into the carboxamide imino tautomer, followed
by cyclization, notwithstanding the fact that carboxamide
N-H insertion, with formation of a C-N bond, is usually
the dominant pathway and a process widely used in synth-
esis. 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,43-46 all of these involve lactam 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
(41) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; John Wiley: New York, 1998.
(42) Snyder, J. P.; Padwa, A.; Stengel, T.; Arduengo, A. J.; Jockisch, A.;
Kim, H. J. J. Am. Chem. Soc. 2001, 123, 11318.
(43) Galt, R. H. B.; Hitchcock, P. B.; McCarthy, S. J.; Young, D. W.
Tetrahedron Lett. 1996, 37, 8035.
(47) King, L. C.; Miller, F. M. J. Am. Chem. Soc. 1949, 71, 367.
(48) Capuano, L.; Bolz, G.; Burger, R.; Burkhardt, V.; Huch, V. Liebigs
(44) Busch-Petersen, J.; Corey, E. J. Org. Lett. 2000, 2, 1641.
(45) Nikolaev, V.; Hennig, L.; Sieler, J.; Rodina, L.; Schulze, B. Org.
Biomol. Chem. 2005, 3, 4108.
(46) Nikolaev, V. V.; Heimgartner, H.; Linden, A.; Krylov, I. S.; Nikolaev,
V. A. Eur. J. Org. Chem. 2006, 4737.
Ann. 1990, 239.
(49) Kim, H. S.; Kwon, I. C.; Kim, O. H. J. Heterocycl. Chem. 1995, 32,
937.
(50) Fontrodona, X.; Diaz, S.; Linden, A.; Villalgordo, J. M. Synthesis
2001, 2021.
J. Org. Chem. Vol. 75, No. 1, 2010 155

Shi et al.
JOCArticle
at the 5-position (see Supporting Information). The mechan-
ism of thiazole formation presumably involves initial S-H
insertion of the rhodium carbene into the thiocarboxamide
imino tautomer or, more likely, the formation of a thiocar-
bonyl ylide intermediate by attack of the nucleophilic sulfur
on the electrophilic metal carbene. Irrespective of mechan-
ism, the process is a useful route to 5-functionalized thia-
zoles, not readily accessible by other means.
C12H11NO3 þ Naþ requires 240.0637); νmax (CHCl3)/cm-1
1715, 1615, 1440, 1351; δH (400 MHz; CDCl3) 8.06-8.03 (2H,
m), 7.45-7.41 (3H, m), 3.92 (3H, s), 2.69 (3H, s); δC (100 MHz;
CDCl3) 162.8, 159.6, 156.3, 130.7, 128.7 (CH), 128.5, 126.5
(CH), 51.9 (Me), 12.0 (Me); one carbon unobserved.
Methyl 2-(4-Methoxyphenyl)-5-methyloxazole-4-carboxylate
4b. To a dry flask were added triphenylphosphine (157 mg,
0.6 mmol), iodine (152 mg, 0.6 mmol), and anhydrous dichlor-
omethane (15 mL). Once the solids had dissolved completely,
triethylamine (173 μL, 1.24 mmol) and a solution of methyl 2-(4-
methoxybenzoylamino)-3-oxobutanoate 3b (80 mg, 0.3 mmol)
in dichloromethane (5 mL) were added. The mixture was
allowed to stir under argon overnight and then concentrated
in vacuo. The product was purified by chromatography (silica,
50% ethyl acetate in light petroleum; Rf = 0.45) to give a
colorless solid (60 mg, 81%); mp 108-109 °C (lit.,52 mp
105-106 °C); (found C, 62.89; H, 5.21; N, 5.44. C13H13NO4
requires C, 63.15; H, 5.30; N, 5.67); (found M þ Hþ, 248.0915.
C13H13NO4 þ Hþ requires 248.0923); νmax (solid)/cm-1 1709,
1614, 1501, 1433, 1345, 1254; δH (300 MHz; CDCl3) 7.97 (2H, d,
J = 9.0), 6.93 (2H, d, J = 9.0), 3.92 (3H, s), 3.83 (3H, s), 2.67
(3H, s); δC (75 MHz; CDCl3) 162.9, 161.6, 159.7, 155.8, 128.2
(CH), 119.2, 114.1 (CH), 55.3 (Me), 51.9 (Me), 12.2 (Me); one
carbon unobserved.
Methyl 2-(4-Bromophenyl)-5-methyloxazole-4-carboxylate 4c.
To a dry flask were added triphenylphosphine (167 mg, 0.64 mmol),
iodine (162 mg, 0.64 mmol), and anhydrous dichloromethane
(30 mL). Once the solids had dissolved completely, triethyl-
amine (182 μL, 1.3 mmol) and a solution of methyl 2-(4-bromo-
benzoylamino)-3-oxobutanoate 3c (100 mg, 0.32 mmol) in
dichloromethane (10 mL) were added. The mixture was allowed
to stir under argon overnight and then concentrated in vacuo.
The product was purified by chromatography (silica, 50%
ethyl acetate in light petroleum; Rf = 0.61) to give a yellow solid
(66 mg, 70%); mp 125-127 °C; (found M þ Naþ, 317.9722.
C12H1079BrNO3 þ Naþ requires 317.9712); νmax (CHCl3)/cm-1
1715, 1614, 1482, 1350, 1240; δH (400 MHz; CDCl3) 7.89 (2H,
d, J = 8.8), 7.55 (2H, d, J = 8.8), 3.92 (3H, s), 2.67 (3H, s); δC
(100 MHz; CDCl3) 162.7, 158.9, 156.7, 132.1 (CH), 128.8, 128.1
(CH), 125.5, 125.4, 52.2 (Me), 12.2 (Me).
Experimental Section
General Method for N-H Insertion Reactions. A mixture of
the carboxamide (0.64 mmol) and rhodium(II) acetate dimer
(7 mg, 16 μmol) in anhydrous 1,2-dichloroethane (5 mL) was
stirred under argon and heated under reflux. A solution of
methyl 2-diazo-3-oxobutanoate (100 mg, 0.70 mmol) in 1,2-
dichloroethane (5 mL) was added dropwise by syringe pump
overnight. The solvent was removed in vacuo, and the residue
was purified by chromatography.
Methyl 2-Benzoylamino-3-oxobutanoate 3a. Following the
general method, benzamide (78 mg, 0.64 mmol) gave, after
chromatography (silica, 50% ethyl acetate in light petroleum;
Rf = 0.40), a colorless oil (90 mg, 60%); (lit.,51 mp 93-94 °C);
(found M þ Naþ, 258.0742. C12H13NO4 þ Naþ requires
258.0742); νmax (CHCl3)/cm-1 1727, 1606, 1256; δH (300
MHz; CDCl3) 7.84-7.80 (2H, m), 7.51-7.40 (4H, m), 5.44
(1H, d, J = 6.3), 3.82 (3H, s), 2.32 (3H, s); δC (75 MHz; CDCl3)
198.6, 166.9, 166.8, 133.0, 132.2 (CH), 128.7 (CH), 127.4 (CH),
63.5 (CH), 53.5 (Me), 28.1 (Me).
Methyl 2-(4-Methoxybenzoylamino)-3-oxobutanoate 3b. Fol-
lowing the general method, 4-methoxybenzamide (97 mg,
0.64 mmol) gave, after chromatography (silica, 50% ethyl
acetate in petroleum ether; Rf = 0.28), a colorless oil (93 mg,
55%); (found M þ Naþ, 288.0833. C13H15NO5 þ Naþ requires
288.0848); νmax (CHCl3)/cm-1 1732, 1606, 1492, 1256; δH
(300 MHz; CDCl3) 7.81-7.76 (2H, m), 7.25 (1H, d, J = 6.3),
6.93-6.89 (2H, m), 5.41 (1H, d, J = 6.3), 3.83 (3H, s), 3.81 (3H, s),
2.41 (3H, s); δC (75 MHz; CDCl3) 198.9, 166.9, 166.3, 162.8,
129.3 (CH), 125.2, 113.9 (CH), 63.4 (CH), 55.5 (Me), 53.4 (Me),
28.1 (Me).
Methyl 5-Chloromethyl-2-phenyloxazole-4-carboxylate 6. To
a microwave tube were added benzamide (500 mg, 4.13 mmol),
rhodium acetate dimer (36.5 mg, 0.083 mmol), and methyl
4-chloro-2-diazo-3-oxobutanoate (784 mg, 4.44 mmol) in di-
chloromethane (5 mL). The mixture was subjected to micro-
wave irradiation at 80 °C for 5 min. Phosphorus oxychloride
(770 μL, 11.9 mmol) was added, and the mixture was subjected
to microwave irradiation at 110 °C for 30 min. After cooling,
the crude product was purified by chromatography (silica, 0 to
50% EtOAc in cyclohexane over 40 min; Rf = 0.58) to give a
colorless solid (586 mg, 56%), mp 74-75 °C; (found C, 57.44; H,
3.95; N, 5.44. C12H10ClNO3 requires C, 57.27; H, 4.00; N, 5.57);
(found M þ Hþ, 252.0426. C12H1035ClNO3 þ Hþ requires
252.0427); νmax (solid)/cm-1 1713, 1446, 1358, 1330, 1244,
1214, 1154; δH (400 MHz; CDCl3) 8.10-8.08 (2H, m),
7.49-7.43 (3H, m), 5.00 (2H, s), 3.97 (3H, s); δC (100 MHz;
CDCl3) 161.7, 161.4, 152.6, 131.4, 130.4, 128.8, 126.9, 125.8,
52.4 (Me), 33.8 (CH2).
Methyl 2-(4-Bromobenzoylamino)-3-oxobutanoate 3c. Fol-
lowing the general method, 4-bromobenzamide (128 mg,
0.64 mmol) gave, after chromatography (silica, 50% ethyl
acetate in light petroleum; Rf = 0.29), a colorless solid (154 mg,
79
77%); mp 87-89 °C; (found M þ Naþ, 335.9836. C12H12
-
BrNO4 þ Naþ requires 335.9847); νmax (CHCl3)/cm-1 1754,
1728, 1661, 1477, 1216; δH (400 MHz; CDCl3) 7.68 (2H, d, J =
8.4), 7.54 (2H, d, J = 8.4), 7.35 (1H, d, J = 6.0), 5.41 (1H, d, J =
6.4), 3.81 (3H, s), 2.41 (3H, s); δC (100 MHz; CDCl3) 198.2,
166.4, 165.8, 131.8 (CH), 131.6, 128.8 (CH), 126.8, 63.2 (CH),
53.4 (Me), 28.0 (Me).
Dehydration of NH-Insertion Products To Form Oxazoles.
Methyl 5-Methyl-2-phenyloxazole-4-carboxylate 4a. To a dry
flask were added triphenylphosphine (178 mg, 0.68 mmol),
iodine (173 mg, 0.68 mmol), and anhydrous dichloromethane
(17 mL). Once the solids had dissolved completely, triethylamine
(194 μL, 1.4 mmol) and a solution of methyl 2-benzoylamino-3-
oxobutanoate 3a (80 mg, 0.34 mmol) in dichloromethane (5 mL)
were added. The mixture was allowed to stir under argon
overnight and then concentrated in vacuo. The product was
purified by chromatography (silica, 50% ethyl acetate in light
petroleum; Rf = 0.62) to give a pale yellow solid (61 mg, 83%);
mp 89-91 °C (lit.,52 mp 88-89 °C); (found M þ Naþ, 240.0624.
Also formed was methyl 4-chloromethyl-2-phenyl-oxazole-5-
carboxylate 7, isolated by chromatography (Rf = 0.62) as a
colorless solid (236 mg, 23%), mp 97-98 °C (lit.,53 no data
given); (found C, 57.31; H, 3.98; N, 5.38. C12H10ClNO3 requires
C, 57.27; H, 4.00; N, 5.57); (found M þ Hþ, 252.0430.
C12H1035ClNO3 þ Hþ requires 252.0427); νmax (solid)/cm-1
(51) Nemoto, T.; Harada, T.; Matsumoto, T.; Hamada, Y. Tetrahedron
Lett. 2007, 48, 6304.
€ €
(53) Nell, P.; Hubsch, W.; Albrecht-Kupper, B.; Keldenich, J.; Vakalo-
€
poulos, A.; Sussmeier, F.; Zimmermann, K.; Lang, D.; Meibom, D. WO
2009/015776, 2009.
(52) Ferreira, P. M. T.; Monteiro, L. S.; Pereira, G. Eur. J. Org. Chem.
2008, 4676.
156 J. Org. Chem. Vol. 75, No. 1, 2010

Shi et al.
JOCArticle
1729, 1604, 1545, 1480, 1442, 1373, 1202, 1158; δH (400 MHz;
CDCl3) 8.14-8.12 (2H, m), 7.52-7.45 (3H, m), 4.85 (2H, s), 3.97
(3H, s); δC (100 MHz; CDCl3) 163.0, 158.1, 145.4, 137.7, 131.9,
128.8, 127.3, 125.8, 52.4 (Me), 36.2 (CH2).
Dimethyl 5-Methyl-2-phenyloxazole-4-phosphonate 11. To a
suspension of solid-phase bound triphenylphosphine (182 mg,
0.58 mmol) in anhydrous dichloromethane (5 mL) were added
iodine (148 mg, 0.58 mmol) and triethylamine (166 μL, 1.19 mmol)
in dichloromethane (5 mL). The mixture was stirred for 5 min
under argon before a solution of 10 (83 mg, 0.29 mmol) in
dichloromethane (5 mL) was added. The mixture was allowed to
stir under argon at room temperature for 18 h. The product was
purified by chromatography (silica, 20% light petroleum in
ethyl acetate; Rf = 0.34) to give a pale yellow solid (34 mg,
44%); mp 39-40 °C; (found M þ Naþ, 290.0549. C12H14NO4P þ
Naþ requires 290.0558); νmax (CHCl3)/cm-1 1246, 1036; δH
(500 MHz; CDCl3) 8.03 (2H, m), 7.44 (3H, m), 3.84 (6H, d,
J = 11.5), 2.66 (3H, d, J = 2.0); δC (125 MHz; CDCl3) 161.4
(d, J = 21.0), 159.2 (d, J = 38.0), 130.9 (CH), 128.9 (CH), 126.7
(CH), 124.3 (d, J = 242.0), 53.2 (Me, d, J = 5.0), 11.7 (Me); one
carbon unobserved.
General Method for One-Pot Synthesis of Oxazole-5-phos-
phonates (Table 2, Conditions A). To an anhydrous toluene
solution (8 mL) of diazophosphonate 9 (100 mg, 0.52 mmol)
were added the carboxamide (0.47 mmol) and rhodium(II)
heptafluorobutyramide dimer (12.5 mg, 11.8 μmol). The mix-
ture was allowed to stir under argon and heated to reflux
overnight. The solvent was evaporated, and the residue was
purified by chromatography.
General Method for Microwave-Assisted Synthesis of Methyl
Oxazole-5-carboxylates. To a dry microwave tube flushed with
argon were added aryl carboxamide (0.32 mmol), rhodium(II)
heptafluorobutyramide dimer (8.4 mg, 8 μmol) ,and methyl 2-
diazo-3-oxobutanoate (50 mg, 0.35 mmol) in anhydrous 1,2-
dichloroethane (6 mL). The mixture was then subjected to
microwave irradiation at 105 °C for 30 min. The solvent was
removed in vacuo, and the residue was purified by column
chromatography on silica gel with the eluants specified.
Methyl 4-Methyl-2-phenyloxazole-5-carboxylate 8a. Follow-
ing the general method, benzamide (39 mg, 0.32 mmol) gave,
after chromatography (silica, 50% ethyl acetate in light petro-
leum; Rf = 0.62), a colorless solid (40 mg, 18%); mp 54-55 °C
(lit.,54 mp 45-47 °C); (found M þ Hþ, 218.0894. C12H11NO3 þ
Hþ requires 218.0817); νmax (CHCl3)/cm-1 1713, 1542; δH
(400 MHz; CDCl3) 8.13-8.11 (2H, m), 7.50-7.47 (3H, m),
3.94 (3H, s), 2.55 (3H, s); δC (100 MHz; CDCl3) 162.5, 159.4,
147.5, 137.4, 131.7 (CH), 129.0 (CH), 127.4 (CH), 126.5, 52.1
(Me), 13.6 (Me).
Methyl 2-(4-Methoxyphenyl)-4-methyloxazole-5-carboxylate
8b. Following the general method, 4-methoxybenzamide (48 mg,
0.32 mmol) gave, after chromatography (silica, 50% ethyl
acetate in light petroleum; Rf = 0.57), a colorless solid (19 mg,
24%); mp 68-70 °C (lit.,55 white solid, mp not given); (found
M þ Hþ, 248.0913. C13H13NO4 þ Hþ requires 248.0923); νmax
(solid)/cm-1 1707, 1608, 1254, 1108; δH (400 MHz; CDCl3) 8.05
(2H, d, J = 8.0), 6.97 (2H, d, J = 8.0), 3.93 (3H, s), 3.86 (3H, s),
2.52 (3H, s); δC (100 MHz; CDCl3) 162.7, 162.5, 159.6, 147.5,
136.9, 129.2 (CH), 119.1, 114.5 (CH), 55.6 (Me), 52.0 (Me),
13.6 (Me).
Dimethyl 4-Methyl-2-phenyloxazole-5-phosphonate 12a. Fol-
lowing the general method, benzamide (57 mg, 0.47 mmol) gave,
after chromatography (silica, ethyl acetate; Rf = 0.33), a color-
less solid (61 mg, 49%); mp 29-30 °C; (found C, 53.99; H, 5.30;
N, 5.05. C12H14NO4P requires C, 53.94; H, 5.28; N, 5.24);
(found M þ Hþ, 268.0716. C12H14NO4P þ Hþ requires
268.0739); νmax (CHCl3)/cm-1 1260, 1034; δH (500 MHz;
CDCl3) 8.07 (2H, m), 7.51-7.45 (3H, m), 3.83 (6H, d, J =
11.5), 2.49 (3H, d, J = 2.0); δC (125 MHz; CDCl3) 164.6 (d, J =
14.0), 151.3 (d, J = 28.0), 134.3 (d, J = 240.0), 131.5 (CH), 129.0
(CH), 127.2 (CH), 126.5, 53.3 (Me, d, J = 5.0), 12.9 (Me).
Dimethyl 2-(4-Bromophenyl)-4-methyloxazole-5-phosphonate
12d. Following the general method, 4-bromobenzamide (95 mg,
0.47 mmol) gave, after chromatography (silica, ethyl acetate,
Rf = 0.44, followed by a second column using 4% methanol in
dichloromethane), a colorless solid (75 mg, 46%); mp 74-75 °C;
Methyl 2-(4-Bromophenyl)-4-methyloxazole-5-carboxylate
8c. Following the general method, 4-bromobenzamide (64 mg,
0.32 mmol) gave, after chromatography (silica, 50% ethyl
acetate in light petroleum; Rf = 0.66), a pink solid (36 mg,
79
38%); mp 109-111 °C; (found M þ Hþ, 295.9919. C12H10
-
BrNO3 þ Hþ requires 295.9922); νmax (solid)/cm-1 1714, 1610,
1599, 1436, 1100; δH (400 MHz; CDCl3) 7.97 (2H, d, J = 8.4),
7.61 (2H, d, J = 8.4), 3.94 (3H, s), 2.53 (3H, s); δC (100 MHz;
CDCl3) 161.6, 159.3, 147.5, 137.6, 132.2, 128.8, 126.5 (CH),
125.4 (CH), 52.2 (Me), 13.5 (Me).
(found C, 41.34; H, 3.72; N, 3.74. C12H13BrNO4P requires C,
41.64; H, 3.79; N, 4.05); (found M þ Naþ, 369.9634. C12H13
-
79
BrNO4P þ Naþ requires 369.9663); νmax (CHCl3)/cm-1 1261,
1035; δH (500 MHz; CDCl3) 7.94 (2H, d, J = 8.5), 7.61 (2H, d,
J = 8.5), 3.85 (6H, d, J = 11.5), 2.48 (3H, d, J = 2.0); δC
(125 MHz; CDCl3) 163.7 (d, J = 14.0), 151.4 (d, J = 28.0), 134.8
(d, J = 240.0), 132.3, 128.7, 126.3 (CH), 125.5 (CH), 53.3 (Me, d,
J = 6.0), 12.9 (Me).
Dimethyl (1-Benzoylamino-2-oxopropyl)phosphonate 10. Dia-
zophosphonate 9a (100 mg, 0.52 mmol), benzamide (57 mg,
0.47 mmol), and rhodium(II) acetate dimer (5.6 mg, 11.8 μmol)
were heated under reflux in dichloromethane (8 mL) overnight.
The solvent was evaporated, and the residue was purified by
chromatography (silica, ethyl acetate; Rf = 0.34) to give the title
compound as a colorless solid (83 mg, 62%); mp 64-66 °C;
(found C, 50.18; H, 5.54; N, 4.73. C12H16NO5P requires C,
50.53; H, 5.65; N, 4.91); (found M þ Naþ, 308.0657.
C12H16NO5P þ Naþ requires 308.0664); νmax (CHCl3)/cm-1
3606, 3425, 1723, 1665, 1509, 1482, 1264, 1037; δH (400 MHz;
CDCl3) 7.82 (2H, d, J = 8.2), 7.51 (1H, t, J = 8.2), 7.43 (2H, t,
J = 8.2), 7.21 (1H, br d, J = 7.6), 5.54 (1H, dd, J = 24.0, 7.6),
3.85 (3H, d, J = 11.0), 3.76 (3H, d, J = 11.0), 2.47 (3H, d,
J = 0.8); δC (100 MHz; CDCl3) 199.8 (d, J = 2.0), 166.8 (d, J =
4.0), 133.2, 132.2 (CH), 128.8 (CH), 127.3 (CH), 57.9 (CH, d,
J = 141.0), 54.3 (Me, d, J = 5.0), 53.9 (Me, d, J = 7.0),
29.1 (Me).
Dimethyl 2-(4-Methoxyphenyl)-4-methyloxazole-5-phospho-
nate 12e. Following the general method, 4-methoxybenzamide
(72 mg, 0.47 mmol) gave, after chromatography (silica, ethyl
acetate, Rf = 0.38, followed by a second column using 10%
methanol in dichloromethane), a pale yellow solid (75 mg, 54%);
mp 70-72 °C; (found M þ Naþ, 320.0650. C13H16NO5P þ Naþ
requires 320.0664); νmax (CHCl3)/cm-1 1258, 1032; δH (400 MHz;
CDCl3) 7.99 (2H, d, J = 8.8), 6.94 (2H, d, J = 8.8), 3.84 (3H, s),
3.80 (6H, d, J = 11.6), 2.45 (3H, d, J = 2.4); δC (100 MHz;
CDCl3) 164.7 (d, J = 15.0), 162.3, 151.4 (d, J = 27.0), 133.6
(d, J = 242.0), 129.0 (CH), 119.2, 114.4 (CH), 55.5 (Me), 53.2
(Me, d, J = 6.0), 12.9 (Me).
Dimethyl 4-Methyl-2-(4-nitrophenyl)oxazole-5-phosphonate
12f. Following the general method, 4-nitrobenzamide (78 mg,
0.47 mmol) gave, after chromatography (silica, ethyl acetate,
Rf = 0.44, followed by a second column using methanol in
dichloromethane), a yellow solid (52 mg, 35%); mp 119-120 °C;
(found C, 45.82; H, 4.03; N, 8.47. C12H13N2O6P requires C,
46.16; H, 4.20; N, 8.97); (found M þ Naþ, 335.0392.
(54) Vernin, G.; Treppendahl, S.; Metzger, J. Helv. Chim. Acta 1977, 60,
284.
(55) Ammenn, J.; Gillig, J. R.; Heinz, L. J.; Hipskind, P. A.; Kinnick,
M. D.; Lai, Y.; Morin, J. M.; Nixon, J. A.; Ott, C.; Savin, K. A.; Schotten, T.;
Slieker, L. J.; Snyder, N. J.; Robertson, M. A. WO2003097047-A1, 2003.
J. Org. Chem. Vol. 75, No. 1, 2010 157

Shi et al.
JOCArticle
C12H13N2O6P þ Naþ requires 335.0409); νmax (CHCl3)/cm-1
1602, 1526, 1354, 1261, 1036; δH (500 MHz; CDCl3) 8.32 (2H,
d, J = 9.5), 8.24 (2H, d, J = 9.5), 3.85 (6H, d, J = 11.5), 2.49
(3H, d, J = 2.0); δC (125 MHz; CDCl3) 162.2 (d, J = 14.0), 151.5
(d, J = 26.0), 149.4, 136.3 (d, J = 239.0), 131.9, 128.1 (CH),
124.3 (CH), 53.4 (Me, d, J = 6.0), 12.9 (Me).
J = 16.5), 7.53-7.51 (2H, m), 7.40-7.35 (3H, m), 6.91 (1H, dd,
J = 16.5, 0.5), 3.82 (6H, d, J = 11.5), 2.44 (3H, d, J = 2.0); δC
(125 MHz; CDCl3) 164.4 (d, J = 14.0), 151.2 (d, J = 26.0), 139.2
(CH), 135.0, 133.9 (d, J = 240.0), 129.9 (CH), 129.1 (CH), 127.6
(CH), 112.9 (CH), 53.3 (Me, d, J = 5,0), 12.8 (Me).
Diethyl 2,4-Diphenyloxazole-5-phosphonate 12m. To a solu-
tion of diazophosphonate 9b (100 mg, 0.35 mmol) in anhydrous
toluene (6 mL) were added benzamide (39 mg, 0.32 mmol) and
rhodium(II) heptafluorobutyramide dimer (8.5 mg, 8 μmol).
The mixture was allowed to stir under argon and heated to reflux
overnight. The solvent was evaporated, and the residue was
purified by chromatography (silica, 20% ethyl acetate in light
petroleum; Rf = 0.56) to give a yellow oil (58 mg, 51%); (found
M þ Hþ, 358.1209. C19H20NO4P þ Hþ requires 358.1208); νmax
(CHCl3)/cm-1 1558, 1257, 1017; δH (400 MHz; CDCl3) 8.18
(2H, d, J = 7.4), 8.06 (2H, d, J = 6.4), 7.52-7.26 (6H, m),
4.26-4.11 (4H, m), 1.29 (6H, t, J = 7.2); δC (100 MHz; CDCl3)
164.1 (d, J = 13.0), 150.9 (d, J = 22.0), 135.5 (d, J = 240.0),
131.5 (CH), 130.3, 129.5 (CH), 129.0 (CH), 128.9 (CH), 128.4
(CH), 127.4 (CH), 126.6, 63.3 (CH2, d, J = 5.0), 16.2 (Me, d, J =
7.0).
Diethyl 4-Phenyl-2-(2-thienyl)oxazole-5-phosphonate 12n. To
a solution of diazophosphonate 9b (100 mg, 0.35 mmol) in
anhydrous toluene (6 mL) were added thiophene-2-carboxa-
mide (41 mg, 0.32 mmol) and rhodium(II) heptafluorobutyra-
mide dimer (8.5 mg, 8 μmol). The mixture was allowed to stir
under argon and heated to reflux overnight. The solvent was
evaporated and the residue was purified by chromatography
(silica, 20% ethyl acetate in light petroleum; Rf = 0.53) to give a
yellow oil (52 mg, 45%); (found M þ Hþ, 364.0788.
C17H18NO4PS þ Hþ requires 364.0772); νmax (CHCl3)/cm-1
1587, 1255, 1017; δH (500 MHz; CDCl3) 8.02 (2H, m), 7.83 (2H,
dd, J = 4.0, 1.5), 7.51 (2H, dd, J = 5.0, 1.5), 7.46-7.38 (3H, m),
7.14 (2H, dd, J = 5.0, 4.0), 4.24-4.08 (4H, m), 1.28 (6H, td, J =
7.0, 0.5); δC (125 MHz; CDCl3) 160.1 (d, J = 15.0), 150.9 (d, J =
24.0), 134.9 (d, J = 238.0), 130.1, 130.0, 129.8 (CH), 129.6 (CH),
128.9 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 63.4 (CH2, d,
J = 5.0), 16.2 (Me, d, J = 6.0).
General Method for Microwave-Aided Synthesis of Oxazole-5-
phosphonates (Table 2, Conditions B). To a dry microwave tube
flushed with argon were added carboxamide (0.24 mmol),
rhodium(II) heptafluorobutyramide dimer (6 mg, 5.9 μmol),
and diazophosphonate 9a (50 mg, 0.26 mmol) in anhydrous
toluene (4 mL). The mixture was then subjected to microwave
irradiation at 135 °C for 30 min. The solvent was removed in
vacuo, and the residue was purified by chromatography.
Dimethyl 4-Methyl-2-phenyloxazole-5-phosphonate 12a. Fol-
lowing the general method, benzamide (29 mg, 0.24 mmol) gave
a colorless solid (46 mg, 73%); data as above.
Dimethyl 2-(2-Bromophenyl)-4-methyloxazole-5-phosphonate
12b. Following the general method, 2-bromobenzamide (47 mg,
0.24 mmol) gave, after chromatography (silica, ethyl acetate,
Rf = 0.35), a colorless oil (40 mg, 49%); (found M þ Naþ,
367.9658. C12H1379BrNO4P þ Naþ requires 367.9663); νmax
(CHCl3)/cm-1 1583, 1260, 1026; δH (500 MHz; CDCl3) 7.93
(1H, m), 7.70 (1H, m), 7.40 (1H, m), 7.32 (1H, m), 3.85 (6H, d,
J = 11.5), 2.51 (3H, d, J = 2.0); δC (125 MHz; CDCl3) 163.1
(d, J = 14.0), 150.9 (d, J = 26.0), 135.1 (d, J = 239.0), 134.7
(CH), 132.2 (CH), 131.9 (CH), 127.7, 127.6 (CH), 121.5, 53.5
(Me, d, J = 5.0), 12.9 (Me).
Dimethyl 2-(4-Biphenyl)-4-methyloxazole-5-phosphonate 12h.
Following the general method, 4-biphenylcarboxamide (93 mg,
0.47 mmol) gave, after chromatography (silica, ethyl acetate,
Rf = 0.41, followed by a second column using 4% methanol in
dichloromethane), a colorless solid (79 mg, 49%); mp 78-80 °C;
(found C, 62.67; H, 5.37; N, 3.85. C18H18NO4P requires C,
62.97; H, 5.28; N, 4.08); (found M þ Naþ, 366.0881.
C18H18NO4P þ Naþ requires 366.0871); νmax (CHCl3)/cm-1
1602, 1261, 1035; δH (500 MHz; CDCl3) 8.15 (2H, m), 7.70 (2H,
m), 7.63 (2H, d, J = 7.5), 7.47 (2H, d, J = 7.5), 7.39 (1H, m),
3.85 (6H, d, J = 11.5), 2.51 (3H, d, J = 2.0); δC (125 MHz;
CDCl3) 164.5 (d, J = 14.0), 151.5 (d, J = 26.0), 144.3, 140.0,
134.4 (d, J = 241.0), 129.1 (CH), 128.2 (CH), 127.8 (CH), 127.6
(CH), 127.3 (CH), 125.3, 53.3 (Me, d, J = 5.0), 12.9 (Me).
Dimethyl 2-(3,5-Difluorophenyl)-4-methyloxazole-5-phospho-
nate 12i. Following the general method, 3,5-difluorobenzamide
(74 mg, 0.47 mmol) gave, after chromatography (silica, ethyl
acetate, Rf = 0.48, followed by a second column using 3%
methanol in dichloromethane), a colorless solid (70 mg, 55%),
further purified by LCMS (reverse phase C18, 10% to 95%
acetonitrile in water); mp 46-47 °C; (found C, 47.39; H, 3.95; N,
4.75. C12H12F2NO4P requires C, 47.54; H, 3.99; N, 4.62); (found
M þ Hþ, 304.0546. C12H12F2NO4P þ Hþ requires 304.0550);
ν
max (solid)/cm-1 1580, 1264, 1021; δH (400 MHz; CDCl3) 7.59
(2H, m), 6.94 (1H, m), 3.84 (6H, d, J = 11.5), 2.47 (3H, d, J =
2.0); δC (100 MHz; CDCl3) 163.2 (dd, J = 250.0, 13.0), 151.2
(d, J = 28.0), 135.4 (d, J = 241.0), 131.6, 129.1 (CH, d, J =
11.0), 110.2 (dd, J = 20.0, 8.0), 106.8 (CH, t, J = 25.0), 53.3
(Me, d, J = 5.0), 12.7 (Me).
Dimethyl 4-Methyl-2-(2-thienyl)oxazol-5-phosphonate 12j.
Following the general method, thiophene-2-carboxamide (60 mg,
0.47 mmol) gave, after chromatography (silica, ethyl acetate;
Rf = 0.32), a colorless solid (66 mg, 51%); mp 67-68 °C; (found
C, 43.95; H, 4.43; N, 4.86. C10H12NO4PS requires C, 43.96; H,
4.43; N, 5.13%); (found M þ Hþ, 274.0312. C10H12NO4PS þ
Hþ requires 274.0303); νmax (CHCl3)/cm-1 1591, 1259, 1033; δH
(400 MHz; CDCl3) 7.74 (1H, dd, J = 4.5, 1.5), 7.48 (1H, dd, J =
6.5, 1.5), 7.11 (1H, dd, J = 6.5, 4.5), 3.81 (6H, d, J = 14.0), 2.44
(3H, d, J = 3.0); δC (100 MHz; CDCl3) 160.6 (d, J = 15.0), 151.4
(d, J = 27.0), 133.8 (d, J = 241.0), 130.1 (CH), 129.7 (CH),
128.8, 128.3 (CH), 53.3 (Me, d, J = 5.0), 12.8 (Me).
Dimethyl 2-(Benzo[b]thiophen-2-yl)-4-methyloxazole-5-phos-
phonate 12k. Following the general method, benzothiophene-
2-carboxamide (83 mg, 0.47 mmol) gave, after chromatography
(silica, ethyl acetate, Rf = 0.44, followed by a second column
using 4% MeOH in dichloromethane), a colorless solid (77 mg,
52%); mp 144-145 °C; (found C, 51.73; H, 4.31; N, 4.04.
C14H14NO4PS requires C, 52.01; H, 4.36; N, 4.33); (found M þ
Naþ, 346.0276. C14H14NO4PS þ Naþ requires 346.0279); νmax
(CHCl3)/cm-1 1596, 1261, 1036; δH (500 MHz; CDCl3) 8.01
(1H, s), 7.86 (2H, m), 7.42 (2H, m), 3.85 (6H, d, J = 11.5), 2.50
(3H, d, J = 2.5); δC (125 MHz; CDCl3) 160.6 (d, J = 15.0), 151.6
(d, J = 26.0), 141.1, 139.4, 134.7 (d, J = 240.0), 128.4, 126.6
(CH), 126.5 (CH), 125.3 (CH), 125.0 (CH), 122.7 (CH), 53.5
(Me, d, J = 5.0), 12.9 (Me).
Dimethyl 2-(2-Benzyloxyphenyl)-4-methyloxazole-5-phospho-
nate 12c. Following the general method, 2-benzyloxybenzamide
(54 mg, 0.24 mmol) gave, after chromatography (silica, ethyl
acetate, Rf = 0.50), a colorless solid (62 mg, 70%); mp 103-105 °C;
(found M þ Naþ, 396.0966. C19H20NO5P þ Naþ requires
396.0977); νmax (CHCl3)/cm-1 1589, 1262, 1023; δH (500
MHz; CDCl3) 8.04 (1H, m), 7.55 (2H, m), 7.46 (1H, m), 7.39
(2H, m), 7.33 (1H, m), 5.19 (2H, s), 3.70 (6H, d, J = 11.5), 2.52
Dimethyl 4-Methyl-2-styryloxazole-5-phosphonate 12l. Fol-
lowing the general method, cinnamamide (70 mg, 0.47 mmol)
gave, after chromatography (silica, ethyl acetate, Rf = 0.44, fol-
lowed by a second column using 4% methanol in dichlo-
romethane), a yellow oil (36 mg, 26%); (found M þ Hþ,
294.0883. C14H16NO4P
þ
Hþ requires 294.0895); νmax
(CHCl3)/cm-1 1260, 1027; δH (500 MHz; CDCl3) 7.64 (1H, d,
158 J. Org. Chem. Vol. 75, No. 1, 2010

Shi et al.
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(3H, d, J = 1.5); δC (125 MHz; CDCl3) 163.8 (d, J = 14.0),
157.2, 151.1 (d, J = 28.0), 136.6, 134.2 (d, J = 239.0), 132.9
(CH), 131.4 (CH), 128.6 (CH), 128.0 (CH), 127.4 (CH), 121.2
(CH), 116.3, 113.4 (CH), 70.7 (CH2), 53.2 (Me, d, J = 5.0), 12.9
(Me).
0.38 mmol) gave, after chromatography (silica, 20% ethyl
acetate in light petroleum; Rf = 0.24), a colorless solid (95 mg,
64%); mp 174-176 °C; (found C, 70.33; H, 4.85; N, 3.55.
C23H19NO3S requires C, 70.93; H, 4.92; N, 3.60); (found M þ
Hþ, 390.1156. C23H19NO3S þ Hþ requires 390.1164); νmax
(CHCl3)/cm-1 1336, 1178; δH (500 MHz; CDCl3) 8.07 (2H, d,
J = 8.5), 7.94 (2H, d, J = 7.5), 7.67 (2H, d, J = 8.5), 7.61 (2H, d,
J = 7.5), 7.46 (2H, m), 7.38 (3H, m), 2.60 (3H, s), 2.43 (3H, s); δC
(125 MHz; CDCl3) 162.6, 145.1, 144.9, 144.5, 142.1, 139.6,
137.6, 130.1 (CH), 128.9 (CH), 128.2 (CH), 127.6 (2 ꢀ CH),
127.5 (CH), 127.1 (CH), 124.5, 21.6 (Me), 12.8 (Me).
4-Methyl-2-(2-thienyl)-5-(toluene-4-sulfonyl)oxazole 14h.
Following the general method, thiophene-2-carboxamide (49 mg,
0.38 mmol) gave, after chromatography (silica, 40% ethyl
acetate in light petroleum; Rf = 0.49), a colorless solid (94 mg,
77%); mp 158-159 °C; (found C, 56.45; H, 4.07; N, 4.22.
C15H13NO3S2 requires C, 56.41; H, 4.10; N, 4.39); (found
M þ Naþ, 342.0214. C15H13NO3S2 þ Naþ requires 342.0234);
νmax (CHCl3)/cm-1 1587, 1337, 1145; δH (500 MHz; CDCl3)
7.89 (2H, d, J = 8.0), 7.71 (1H, dd, J = 4.0, 1.5), 7.49 (1H, dd,
J = 5.0, 1.5), 7.35 (2H, d, J = 8.0), 7.10 (1H, dd, J = 5.0, 4.0),
2.54 (3H, s), 2.42 (3H, s); δC (125 MHz; CDCl3) 158.9, 145.3,
145.1, 141.6, 137.6, 130.8 (CH), 130.3 (CH), 130.2 (CH), 128.4
(CH), 128.2, 127.7 (CH), 21.8 (Me), 12.9 (Me).
4-Methyl-2-styryl-5-(toluene-4-sulfonyl)oxazole 14i. Follow-
ing the general method, cinnamamide (56 mg, 0.38 mmol) gave,
after chromatography (silica, 20% ethyl acetate in light petro-
leum; Rf = 0.26), a colorless solid (80 mg, 62%); mp 119-120 °C;
(found C, 67.08; H, 5.03; N, 4.02. C19H17NO3S requires C,
67.24; H, 5.05; N, 4.13); (found M þ Naþ, 362.0811.
C19H17NO3S þ Naþ requires 362.0827); νmax (CHCl3)/cm-1
1337, 1145; δH (500 MHz; CDCl3) 7.91 (2H, d, J = 8.5), 7.61
(1H, d, J = 16.5), 7.52-7.50 (2H, m), 7.40-7.36 (5H, m), 6.81
(1H, d, J = 16.5), 2.54 (3H, s), 2.44 (3H, s); δC (125 MHz;
CDCl3) 162.7, 145.3, 145.0, 141.7, 140.2 (CH), 137.7, 134.8,
130.2 (CH), 129.1 (CH), 127.7 (2 ꢀ CH), 112.4 (CH), 21.8 (Me),
12.9 (Me); one carbon unobserved.
General Method for Microwave-Assisted Synthesis of Oxa-
zole-5-sulfones (Table 3, Conditions B). To a dry microwave tube
flushed with argon were added diazosulfone 13 (50 mg, 0.21 mmol),
carboxamide (0.19 mmol), rhodium(II) heptafluorobutyramide
dimer (5.0 mg, 4.77 μmol), and dry 1,2-dichloroethane (3.5 mL).
The mixture was subject to microwave irradiation at 105 °C for
30 min. The solvent was then removed in vacuo, and the residue was
purified by chromatography.
Dimethyl 2-(4-Benzyloxycarbonylaminophenyl)-4-methyloxa-
zole-5-phosphonate 12g. Following the general method,
4-(benzyloxycarbonylamino)benzamide (64 mg, 0.24 mmol) in
1,2-dichloroethane gave, after chromatography (silica, ethyl
acetate, Rf = 0.39, followed by a second column using 10%
methanol in dichloromethane, Rf = 0.50), a colorless solid
(28 mg, 28%); mp 38-39 °C; (found M þ Hþ, 417.1217.
C20H21N2O6P þ Hþ requires 417.1216); νmax (CHCl3)/cm-1
1735, 1528, 1216; δH (400 MHz; CDCl3) 8.01 (2H, d, J = 8.8),
7.54 (2H, d, J = 8.8), 7.41-7.32 (5H, m), 7.22 (1H, br s), 5.21
(2H, s), 3.82 (6H, d, J = 11.6), 2.47 (3H, d, J = 2.0); δC (100
MHz; CDCl3) 164.4 (d, J = 14.0), 153.1, 151.4 (d, J = 27.0),
141.1, 135.9, 133.9 (d, J = 241.0), 128.8 (CH), 128.6 (CH), 128.5
(CH), 128.4 (CH), 121.4, 118.4 (CH), 67.4 (CH2), 53.3 (Me, d,
J = 5.0), 12.9 (Me).
General Method for One-Pot Synthesis of Oxazole-5-sulfones
(Table 3, Conditions A). To a dry flask were added diazosulfone
13 (100 mg, 0.42 mmol), the carboxamide (0.38 mmol),
rhodium(II) heptafluorobutyramide dimer (10 mg, 9.5 μmol),
and anhydrous 1,2-dichloroethane (7 mL). The mixture was
allowed to stir under argon and heated to reflux overnight. The
solvent was evaporated, and the residue was purified by chro-
matography.
4-Methyl-2-phenyl-5-(toluene-4-sulfonyl)oxazole 14a. Fol-
lowing the general method, benzamide (46 mg, 0.38 mmol) gave,
after chromatography (silica, 20% ethyl acetate in light petro-
leum; Rf = 0.53), a colorless solid (91 mg, 77%); mp 146-148 °C;
(found C, 65.05; H, 4.75; N, 4.42. C17H15NO3S requires C,
65.16; H, 4.82; N, 4.47); (found M þ Hþ, 314.0849. C17H15NO3Sþ
Hþ requires 314.0851); νmax (CHCl3)/cm-1 1580, 1338, 1147;
δH (400 MHz; CDCl3) 8.00 (2H, m), 7.92 (2H, d, J = 8.4),
7.51-7.42 (3H, m), 7.36 (2H, d, J = 8.4), 2.58 (3H, s), 2.43 (3H, s);
δC (100 MHz; CDCl3) 162.8, 145.3, 144.9, 142.2, 137.7, 132.0
(CH), 130.2 (CH), 129.0 (CH), 127.7 (CH), 127.3 (CH), 125.9,
21.8 (Me), 13.0 (Me).
2-(4-Bromophenyl)-4-methyl-5-(toluene-4-sulfonyl)oxazole 14d.
Following the general method, 4-bromobenzamide (76 mg,
0.38 mmol) gave, after chromatography (silica, 20% ethyl
acetate in light petroleum; Rf = 0.35), a colorless solid (109 mg,
73%); mp 175-176 °C; (found C, 51.91; H, 3.47; N, 3.44.
C17H14BrNO3S requires C, 52.05; H, 3.60; N, 3.57); (found
M þ Hþ, 391.9947. C17H1479BrNO3S þ Hþ requires 391.9956);
νmax (CHCl3)/cm-1 1601, 1336, 1148; δH (500 MHz; CDCl3)
7.91 (2H, d, J = 9.0), 7.85 (2H, d, J = 8.0), 7.57 (2H, dt, J =
9.0), 7.36 (2H, d, J = 8.0), 2.56 (3H, s), 2.42 (3H, s); δC
(125 MHz; CDCl3) 161.9, 145.4, 145.0, 142.5, 137.6, 132.4
(CH), 130.3 (CH), 128.7 (CH), 127.8 (CH), 126.8, 124.8, 21.8
(Me), 13.0 (Me).
4-Methyl-2-phenyl-5-(toluene-4-sulfonyl)oxazole 14a. Following
the general method, benzamide (23 mg, 0.19 mmol) gave a colorless
solid (48 mg, 81%); data as above.
2-(2-Bromophenyl)-4-methyl-5-(toluene-4-sulfonyl)oxazole 14b.
Following the general method, 2-bromobenzamide (38 mg,
0.19 mmol) gave, after chromatography (silica, 20% ethyl
acetate in light petroleum, Rf = 0.38, followed by a second
column using dichloromethane), a colorless solid (30 mg, 40%);
mp 88-90 °C; (found C, 52.02; H, 3.64; N, 3.41. C17H14BrNO3S
requires C, 52.05; H, 3.60; N, 3.57); (found M þ Naþ, 413.9773.
C17H1479BrNO3S þ Naþ requires 413.9775); νmax (CHCl3)/
cm-1 1583, 1333, 1149; δH (500 MHz; CDCl3) 7.94 (2H, m),
7.90 (1H, d, J = 8.0), 7.68 (1H, dd, J = 8.0, 1.0), 7.41-7.30
(4H, m), 2.60 (3H, s), 2.43 (3H, s); δC (125 MHz; CDCl3) 161.3,
145.4, 144.2, 142.9, 137.5, 134.8 (CH), 132.5 (CH), 132.0 (CH),
130.2 (CH), 128.0 (CH), 127.6 (CH), 127.0, 121.5, 21.8 (Me),
13.0 (Me).
2-(2-Benzyloxyphenyl)-4-methyl-5-(toluene-4-sulfonyl)oxazole 14c.
Following the general method, 2-benzyloxybenzamide (43 mg,
0.19 mmol) gave, after chromatography (silica, 20% ethyl
acetate in light petroleum; Rf = 0.24), a colorless solid (63 mg,
79%); mp 104-106 °C; (found C, 68.58; H, 4.94; N,
3.21. C24H21NO4S requires C, 68.72; H, 5.05; N, 3.34); (found
4-Methyl-2-(4-nitrophenyl)-5-(toluene-4-sulfonyl)oxazole 14e.
Following the general method, 4-nitrobenzamide (64 mg,
0.38 mmol) gave, after chromatography (silica, 20% ethyl
acetate in light petroleum; Rf = 0.25), a colorless solid (30 mg,
22%); mp 184-185 °C; (found C, 56.97; H, 3.85; N, 7.61.
C17H14N2O5S requires C, 56.98; H, 3.94; N, 7.82); (found
M þ Naþ, 381.0513. C17H14N2O5S þ Naþ requires 381.0521);
νmax (CHCl3)/cm-1 1548, 1340, 1148; δH (500 MHz; CDCl3)
8.31 (2H, d, J = 9.0), 8.18 (2H, d, J = 9.0), 7.93 (2H, d, J = 8.5),
7.39 (2H, d, J = 8.5), 2.60 (3H, s), 2.45 (3H, s); δC (125 MHz;
CDCl3) 160.4, 149.7, 145.8, 145.2, 143.8, 137.3, 131.4,
130.4 (CH), 128.2 (CH), 127.9 (CH), 124.4 (CH), 21.9 (Me),
13.0 (Me).
2-(4-Biphenyl)-4-methyl-5-(toluene-4-sulfonyl)oxazole 14g.
Following the general method, 4-biphenylcarboxamide (75 mg,
J. Org. Chem. Vol. 75, No. 1, 2010 159

Shi et al.
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M þ Naþ, 442.1078. C24H21NO4S þ Naþ requires 442.1089);
4-Methyl-2-phenyl-5-(toluene-4-sulfonyl)thiazole 17f. To a so-
lution of diazosulfone 13 (100 mg, 0.42 mmol) in anhydrous 1,2-
dichloroethane (7 mL) were added thiobenzamide (52 mg,
0.38 mmol) and rhodium(II) heptafluorobutyramide dimer
(10.0 mg, 9.5 μmol). The mixture was allowed to stir under
argon and heated to reflux overnight. The solvent was evapo-
rated, and the residue was purified by chromatography (silica,
20% ethyl acetate in light petroleum; Rf = 0.26) to give a
colorless solid (106 mg, 85%); mp 109-110 °C; (found C,
61.97; H, 4.50; N, 4.12. C17H15NO2S2 requires C, 61.98; H,
4.59; N, 4.25); (found M þ Hþ, 330.0609. C17H15NO2S2 þ Hþ
requires 330.0622); νmax (CHCl3)/cm-1 1326, 1154; δH
(500 MHz; CDCl3) 7.89-7.86 (4H, m), 7.45-7.40 (3H, m),
7.33 (2H, d, J = 8.0), 2.66 (3H, s), 2.41 (3H, s); δC (125 MHz;
CDCl3) 171.1, 157.8, 144.8, 138.9, 132.3, 132.1, 131.5 (CH),
130.1 (CH), 129.2 (CH), 127.4 (CH), 126.8 (CH), 21.7 (Me),
16.5 (Me).
ν
max (solid)/cm-1 1590, 1336, 1144; δH (500 MHz; CDCl3) 8.01
(1H, m), 7.75 (2H, m), 7.59 (2H, d, J = 8.0), 7.48-7.42 (3H, m),
7.36 (1H, t, J = 7.5), 7.21 (2H, d, J = 8.0), 7.07 (1H, d, J = 8.5),
7.03 (1H, t, J = 7.5), 5.20 (2H, s), 2.58 (3H, s), 2.37 (3H, s); δC
(125 MHz; CDCl3) 162.0, 157.2, 144.9, 144.3, 142.0, 137.8,
136.5, 133.3 (CH), 131.2 (CH), 130.0 (CH), 128.8 (CH), 128.1
(CH), 127.7 (CH), 127.3 (CH), 121.1 (CH), 115.5, 113.6 (CH),
70.6 (CH2), 21.7 (Me), 12.9 (Me).
2-[4-(Benzyloxycarbonylamino)phenyl]-4-methyl-5-(toluene-
4-sulfonyl)oxazole 14f. Following the general method,
4-(benzyloxycarbonylamino)benzamide (52 mg, 0.19 mmol)
gave, after chromatography (silica, 20% ethyl acetate in light
petroleum; Rf = 0.14), a colorless solid (41 mg, 47%); mp
174-175 °C; (found M þ Naþ, 485.1136. C25H22N2O5S þ Naþ
requires 485.1147); νmax (CHCl3)/cm-1 1738, 1518, 1336, 1147;
δ
H (500 MHz; CDCl3) 7.94 (2H, d, J = 8.5), 7.91 (2H, m), 7.48
(2H, d, J = 8.5), 7.41-7.36 (7H, m), 6.89 (1H, s), 5.21 (2H, s),
2.56 (3H, s), 2.43 (3H, s); δC (125 MHz; CDCl3) 162.6, 152.9,
145.2, 145.1, 141.8, 141.3, 137.8, 135.8, 130.2, 128.8 (CH), 128.7
(CH), 128.6 (CH), 128.5 (CH), 127.7 (CH), 120.8 (CH), 118.4
(CH), 67.6 (CH2), 21.8 (Me), 13.0 (Me).
General Method for Microwave-Aided Synthesis of Thiazole-
5-phosphonates (Table 4, Conditions C). To a dry microwave
tube flushed with argon were added thiocarboxamide (0.24 mmol),
rhodium(II) heptafluorobutyramide dimer (6 mg, 5.9 μmol),
and diazophosphonate 9a (50 mg, 0.26 mmol) in anhydrous
toluene (4 mL). The mixture was then subjected to microwave
irradiation at 135 °C for 30 min. The solvent was removed in
vacuo, and the residue was purified by chromatography.
Dimethyl 2-(2-Benzyloxyphenyl)-4-methylthiazole-5-phospho-
nate 17c. Following the general method, 2-benzyloxythiobenza-
mide (57 mg, 0.24 mmol) gave, after chromatography (silica,
ethyl acetate, Rf = 0.44), a yellow oil (54 mg, 59%); (found M þ
Naþ, 412.0732. C19H20NO4PS þ Naþ requires 412.0748); νmax
(CHCl3)/cm-1 1598, 1247, 1020; δH (400 MHz; CDCl3) 8.43
(1H, m), 7.46 (2H, m), 7.40-7.33 (4H, m), 7.07 (1H, m), 7.03
(1H, m), 5.35 (2H, s), 3.76 (6H, d, J = 11.6), 2.70 (3H, d, J =
2.0); δC (100 MHz; CDCl3) 166.7 (d, J = 13.0), 160.6 (d, J =
14.0), 155.9, 136.1, 131.7 (CH), 129.0 (CH), 128.7 (CH), 128.4
(CH), 127.7 (CH), 121.9, 121.4 (CH), 114.9 (d, J = 205.0), 112.8
(CH), 70.9 (CH2), 53.0 (Me, d, J = 6.0), 17.3 (Me).
5-Methyl-2-phenyl-4-(toluene-4-sulfonyl)oxazole 15. To a dry
two-neck flask were added diazosulfone 13 (100 mg, 0.42 mmol),
rhodium(II) acetate dimer (4 mg, 9.5 μmol), and a dichloro-
methane solution (7 mL) of benzonitrile (39 mg, 0.38 mmol)
under argon. The mixture was heated under reflux and stirred
under argon for 1 h. After cooling, the solvent was removed in
vacuo, and the residue was purified by chromatography (silica,
20% ethyl acetate in light petroleum; Rf = 0.25) to give a
colorless solid (50 mg, 42%); mp 137-139 °C; (found M þ
Hþ, 314.0843. C17H15NO3S þ Hþ requires 314.0851); νmax
(solid)/cm-1 1593, 1316, 1152; δH (400 MHz; CDCl3)
7.98-7.95 (4H, m), 7.45-7.39 (3H, m), 7.34 (2H, d, J = 8.0),
2.75 (3H, s), 2.42 (3H, s); δC (100 MHz; CDCl3) 160.3, 153.2,
144.7, 137.8, 136.9, 131.2 (CH), 129.9 (CH), 128.9 (CH), 128.1
(CH), 126.8 (CH), 126.2, 21.8 (Me), 11.8 (Me).
Methyl 2-(4-Bromophenyl)-4-methylthiazole-5-carboxylate 17a.
To a microwave tube were added 4-bromothiobenzamide (65 mg,
0.301 mmol), rhodium heptafluorobutyrate dimer (6.3 mg,
6.02 μmol), and methyl 2-diazo-3-oxobutanoate 2 (50 mg,
0.352 mmol) in dichloromethane (1 mL). The mixture was
immediately subjected to microwave at 120 °C for 10 min. After
cooling, the solvent was evaporated, and the residue was
purified by chromatography (silica, 0 to 50% EtOAc in cyclo-
hexane over 20 min; Rf = 0.71) to give a colorless solid (44 mg,
Dimethyl 2-(4-Bromophenyl)-4-methylthiazole-5-phosphonate
17d. Following the general method, 4-bromothiobenzamide
(51 mg, 0.24 mmol) gave, after chromatography (silica, ethyl
acetate, Rf = 0.32), a colorless solid (30 mg, 35%); mp 85-86 °C;
(found C, 39.70; H, 3.42; N, 3.63. C12H13BrNO3PS requires C,
39.80; H, 3.62; N, 3.87); (found
M
þ
Hþ, 361.9600.
C12H1379BrNO3PS þ Hþ requires 361.9615); νmax (CHCl3)/
cm-1 1252, 1028; δH (400 MHz; CDCl3) 7.81 (2H, d, J = 8.8),
7.58 (2H, d, J = 8.8), 3.81 (6H, d, J = 11.6), 2.68 (3H, d, J =
2.0); δC (100 MHz; CDCl3) 171.3 (d, J = 11.0), 162.7 (d, J =
14.0), 132.5, 131.7, 128.4 (CH), 125.6 (CH), 115.3 (d, J = 207.0),
53.1 (Me, d, J = 6.0), 17.4 (Me).
47%), mp 139-140 °C; (found
M
þ
Hþ, 311.9686.
C12H1079BrNO2S þ Hþ requires 311.9694); (found C, 46.16;
H, 3.09; N, 4.23. C12H10BrNO2S requires C, 46.17; H, 3.23; N,
4.49); νmax (solid)/cm-1 1715, 1520, 1428, 1369, 1319, 1260,
1194; δH (400 MHz; CDCl3) 7.82 (2 H, d, J = 8.5), 7.57 (2 H, d,
J = 8.5), 3.89 (3 H, s), 2.77 (3 H, s); δC (100 MHz; CDCl3) 168.5,
162.5, 161.4, 132.2 (CH), 131.8, 128.1 (CH), 125.4, 121.7, 52.2
(Me), 17.5 (Me).
Dimethyl 2-(4-Benzyloxycarbonylaminophenyl)-4-methylthia-
zole-5-phosphonate 17e. Following the general method,
4-(benzyloxycarbonylamino)thiobenzamide (68 mg, 0.24 mmol)
gave, after chromatography (silica, ethyl acetate, Rf = 0.35), a
yellow solid (56 mg, 55%); mp 39-40 °C; (found M þ Naþ,
455.0796. C20H21N2O5PS þ Naþ requires 455.0806); νmax
(CHCl3)/cm-1 1715, 1536, 1216, 1028; δH (400 MHz; CDCl3)
7.87 (2H, d, J = 8.4), 7.52 (2H, d, J = 8.4), 7.42 (1H, br s),
7.39-7.33 (5H, m), 5.20 (2H, s), 3.78 (6H, d, J = 11.6), 2.66 (3H,
d, J = 2.0); δC (100 MHz; CDCl3) 172.3 (d, J = 12.0), 162.6 (d,
J = 14.0), 153.2, 140.9, 135.9, 128.7 (CH), 128.6 (CH), 128.5
(CH), 127.9 (CH), 127.7, 118.7 (CH), 113.7 (d, J = 208.0), 67.3
(CH2), 53.1 (d, J = 5.0), 17.4 (Me).
General Method for Microwave-Assisted Synthesis of Thia-
zole-5-sulfones (Table 4, Conditions E). To a dry microwave tube
flushed with argon were added diazosulfone 13 (50 mg, 0.21
mmol), thiocarboxamide (0.19 mmol), rhodium(II) heptafluor-
obutyramide dimer (5.0 mg, 4.77 μmol), and dry 1,2-dichlor-
oethane (3.5 mL). The mixture was subjected to microwave
Dimethyl 4-Methyl-2-phenylthiazole-5-phosphonate 17b.
To a solution of diazophosphonate 9a (50 mg, 0.26 mmol)
in anhydrous toluene (4 mL) were added thiobenzamide (33 mg,
0.24 mmol) and rhodium(II) heptafluorobutyramide dimer
(6.2 mg, 5.9 μmol). The mixture was allowed to stir under argon
and heated to reflux overnight. The solvent was evaporated,
and the residue was purified by chromatography (silica, ethyl
acetate; Rf = 0.34) to give a yellow oil (50 mg, 75%); (found
M þ Hþ, 284.0506. C12H14NO3PS þ Hþ requires 284.0510);
νmax (CHCl3)/cm-1 1253, 1034; δH (400 MHz; CDCl3)
7.94-7.92 (2H, m), 7.46-7.42 (3H, m), 3.81 (6H, d, J = 11.6),
2.68 (3H, d, J = 2.0); δC (100 MHz; CDCl3) 172.7 (d, J = 12.0),
162.6 (d, J = 14.0), 132.7, 131.1 (CH), 129.2 (CH), 127.0
(CH), 114.6 (d, J = 207.0), 53.1 (Me, d, J = 5.0), 17.4 (Me).
160 J. Org. Chem. Vol. 75, No. 1, 2010

Shi et al.
JOCArticle
irradiation at 105 °C for 30 min. The solvent was then removed
in vacuo, and the residue was purified by chromatography.
2-(2-Benzyloxyphenyl)-4-methyl-5-(toluene-4-sulfonyl)thiazole
17g. Following the general method, 2-benzyloxythiobenzamide
(46 mg, 0.19 mmol) gave, after chromatography (silica, 20%
ethyl acetate in light petroleum; Rf = 0.20), a colorless solid
(72 mg, 87%); mp 138-139 °C; (found C, 66.14; H, 4.75; N, 3.05.
C24H21NO3S2 requires C, 66.18; H, 4.86; N, 3.22); (found M þ
Hþ, 436.1038. C24H21NO3S2 þ Hþ requires 436.1041); νmax
(solid)/cm-1 1597, 1320, 1150; δH (400 MHz; CDCl3) 8.36 (1H,
dd, J = 8.0, 1.6), 7.82 (2H, d, J = 8.4), 7.48-7.34 (6H, m), 7.30
(2H, d, J = 8.4), 7.07-7.02 (2H, m), 5.36 (2H, s), 2.67 (3H, s),
2.41 (3H, s); δC (100 MHz; CDCl3) 165.2, 156.0, 144.4, 139.5,
138.2, 135.8, 132.2, 132.1 (CH), 130.0 (CH), 128.8 (CH), 128.7
(CH), 128.6 (CH), 127.8 (CH), 127.3 (CH), 121.6, 121.4 (CH),
112.8 (CH), 71.1 (CH2), 21.7 (Me), 16.5 (Me).
2-(4-Bromophenyl)-4-methyl-5-(toluene-4-sulfonyl)thiazole 17h.
Following the general method, 4-bromothiobenzamide (41 mg,
0.19 mmol) gave, after chromatography (silica, 20% ethyl
acetate in light petroleum; Rf = 0.34), a colorless solid (68
mg, 88%); mp 171-173 °C; (found M þ Hþ, 407.9732.
C17H1479BrNO2S2 þ Hþ requires 407.9728); νmax (CHCl3)/
cm-1 1589, 1326, 1154; δH (400 MHz; CDCl3) 7.87 (2H, d,
J = 8.4), 7.75 (2H, d, J = 8.4), 7.57 (2H, d, J = 8.8), 7.35 (2H, d,
J = 8.8), 2.65 (3H, s), 2.43 (3H, s); δC (100 MHz; CDCl3) 169.8,
158.0, 145.0, 138.8, 132.6, 132.5 (CH), 131.3, 130.2 (CH), 128.3
(CH), 127.5 (CH), 126.1, 21.8 (Me), 16.6 (Me).
2-[4-(Benzyloxycarbonylamino)phenyl]-4-methyl-5-(toluene-
4-sulfonyl)thiazole 17i. Following the general method, 4-(ben-
zyloxycarbonylamino)thiobenzamide (54 mg, 0.19 mmol) gave,
after chromatography (silica, 20% ethyl acetate in light petroleum;
Rf = 0.10), a colorless solid (75 mg, 83%); mp 169-171 °C;
(found C, 62.59; H, 4.52; N, 5.48. C25H22N2O4S2 requires C,
62.74; H, 4.63; N, 5.85); (found M þ Naþ, 501.0900.
C25H22N2O4S2 þ Naþ requires 501.0919); νmax (solid)/cm-1
1728, 1526, 1517, 1315, 1148; δH (400 MHz; CDCl3) 7.87 (2H,
d, J = 8.4), 7.81 (2H, d, J = 8.8), 7.47 (2H, d, J = 8.4),
7.40-7.32 (7H, m), 7.03 (1H, s), 5.20 (2H, s), 2.63 (3H, s), 2.42
(3H, s); δC (100 MHz; CDCl3) 170.6, 157.7, 152.9, 144.6, 140.9,
138.8, 135.6, 131.2, 130.0 (CH), 128.6 (CH), 128.4 (CH), 128.3
(CH), 127.8 (CH), 127.2 (CH þ C), 118.5 (CH), 67.3 (CH2), 21.6
(Me), 16.4 (Me).
Acknowledgment. We thank the EPSRC and Glaxo-
SmithKline for support of this work under the Array Chem-
istry Programme and Daniel Bailey for collecting X-ray
diffraction data for compound 15.
Supporting Information Available: General experimental
details, experimental procedures for preparation of diazo com-
pounds 2, 5, 9, and 13, X-ray crystal structures of compounds 6,
15, 17a, 17d, and 17h, copies of 1H and 13C NMR spectra, and
CIF files for compounds 6, 15, 17a, 17d, and 17h. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 1, 2010 161