Solution versus fluorous versus solid-phase synthesis of 2,5-disubstituted 1,3-azoles. Preliminary antibacterial activity studies

Article abstract of DOI:10.1021/jo9016265

(Chemical Equation Presented) A small library of compounds with an oxa(thia)zole scaffold and structural diversity in both positions 2 and 5 has been synthesized. Double acylation of a protected glycine affords intermediate α-amido-β-ketoesters, which in turn can be dehydrated to afford 1,3-oxazoles or reacted with Lawesson's reagent to furnish 1,3-thiazoles. This procedure was designed with its adaptation to fluorous techniques in mind. Thus, when a protected glycine with a fluorous tag in the ester moiety is used as a starting material, the synthesis can be easily completed without column chromatography purification of intermediate compounds with good to excellent yields, thus affording a suitable entry to the preparation of small libraries of these bioactive compounds. The prepared oxa(thia)zoles were assayed for their antibacterial activity, and several of them were active against Staphylococcus aureus.

Full text of DOI:10.1021/jo9016265

pubs.acs.org/joc
Solution versus Fluorous versus Solid-Phase Synthesis of 2,5-
Disubstituted 1,3-Azoles. Preliminary Antibacterial Activity Studies
‡
‡
§
‡
Juan F. Sanz-Cervera,*,†,‡ Raul Blasco, Julio Piera, Michael Cynamon, Ignacio Ibanez,
€
ꢀ~
Marcelo Murguı
a,† and Santos Fustero*,†,‡
´
†
‡
Departamento de Quımica Organica, Universidad de Valencia, 46100 Burjassot, Spain, Laboratorio de
´
Moleꢀculas Orgaꢀnicas, Centro de Investigacioꢀn Prıncipe Felipe, 46013 Valencia, Spain, and Department of
ꢀ
§
´
Medicine, VA Medical Center, SUNY Upstate Medical University, Syracuse, New York 13210
juan.f.sanz@uv.es; santos.fustero@uv.es
Received July 27, 2009
A small library of compounds with an oxa(thia)zole scaffold and structural diversity in both positions
2 and 5 has been synthesized. Double acylation of a protected glycine affords intermediate R-amido-
β-ketoesters, which in turn can be dehydrated to afford 1,3-oxazoles or reacted with Lawesson’s
reagent to furnish 1,3-thiazoles. This procedure was designed with its adaptation to fluorous
techniques in mind. Thus, when a protected glycine with a fluorous tag in the ester moiety is used
as a starting material, the synthesis can be easily completed without column chromatography
purification of intermediate compounds with good to excellent yields, thus affording a suitable entry
to the preparation of small libraries of these bioactive compounds. The prepared oxa(thia)zoles were
assayed for their antibacterial activity, and several of them were active against Staphylococcus aureus.
Introduction
enzyme inhibitors, and peripheral analgesics.2 The structural
diversity of complex naturally occurring 1,3-azoles and the
biological activity of synthetic analogues have ensured that
new methods continue to be developed for their synthesis. In
Nature, oxazoles are formed through enzyme-catalyzed
cyclodehydration-oxidation of derivates of acylserine,3
and most of the synthetic methods developed somehow
mimic this scheme. Typical procedures for the preparation
of oxazoles include cyclodehydration of R-acylamino-
ketones, esters, or amides (known as the Robinson-Gabriel
oxazole synthesis),4 treatment of tosylmethyl isonitrile with
The synthesis of 1,3-oxazoles and 1,3-thiazoles has at-
tracted the attention of many chemists due to their presence
in a large number of natural products, many of which have
been isolated from marine organisms.1 Most of these com-
pounds display significant biological activities as cytotoxic,
antifungal, antiviral, antibacterial, antileukemia agents,
(1) For some leading references, see: (a) Wipf, P. Chem. Rev. 1995, 95,
2115–2134. (b) Jin, Z. Nat. Prod. Rep. 2003, 20, 584–605. (c) Yeh, V. S. C.
Tetrahedron 2004, 60, 11995–12042. (d) Evans, D. A.; Cee, V. J.; Smith, T. E.;
Fitch, D. M.; Cho, P. S. Angew. Chem., Int. Ed. 2000, 39, 2533–2536. (e)
Evans, D. A.; Fitch, D. M. Angew. Chem., Int. Ed. 2000, 39, 2536–2540. (f)
Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.; Moody, C. J. J. Am. Chem.
Soc. 2000, 122, 3301–3313. (g) Kobayashi, J.; Tsuda, M.; Fuse, H.; Sasaki,
T.; Mikami, Y. J. Nat. Prod. 1997, 60, 150–154.
(3) (a) Li, Y.-M.; Milne, J. C.; Madison, L. L.; Kolter, R.; Walsh, C. T.
Science 1996, 274, 1188–1193. (b) Herrera, A.; Martınez-Alvarez, R.;
´
(2) (a) Palmer, D. C., Ed. Oxazoles: Synthesis, Reactions, and Spectroscopy,
Part A; John Wiley & Sons: Hoboken, NJ, 2003. (b) Palmer, D. C., Ed. Oxazoles:
Synthesis, Reactions, and Spectroscopy, Part B; John Wiley & Sons: Hoboken,
NJ, 2004.
Ramiro, P.; Molero, D.; Almy, J. J. Org. Chem. 2006, 71, 3026–3032.
(4) (a) Robinson, R. J. Chem. Soc. 1909, 95, 2167–2174. (b) Gabriel, S.
Chem. Ber. 1910, 43, 1283–1287. (c) Weeserman, H. H.; Vinick, F. J. J. Org.
Chem. 1973, 38, 2407–2408.
8988 J. Org. Chem. 2009, 74, 8988–8996
Published on Web 11/06/2009
DOI: 10.1021/jo9016265
r
2009 American Chemical Society

Sanz-Cervera et al.
JOCArticle
aldehydes under basic catalysis,5 reaction of R-metalated
isonitriles with acid chlorides,6 addition of R-diazocarbonyl
compounds to nitriles, and decomposition in the presence
of a Lewis acid or a transition metal catalyst and different
copper-,7 gold-,8 ruthenium-,9 and rhodium-catalyzed10
reactions.
SCHEME 1. Preparation of 1,3-Oxazoles 1 and 1,3-Thiazoles 2
by Means of Solution and Fluorous Syntheses
Similar methods employed for the synthesis of 1,3-oxa-
zoles can be used for the preparation of 1,3-thiazoles. The
most common method for the synthesis of the latter was
developed by Hantzsch and entails the condensation of a
suitably substituted R-haloketone with a thioamide.11 Other
methods include the reaction of R-aminonitriles with CS2,
COS, derivatives of dithiocarboxylic acids, and isothiocya-
nates,12 as well as the reaction of R-acylaminoketones with
phosphorus pentasulfide or the Lawesson’s reagent, which
affords 1,3-thiazoles.13
On the basis of the aforementioned biological activity of
1,3-oxa(thia)zoles, these compounds seem to be good candi-
dates for the preparation of a library of potentially bioactive
compounds. In this context, fluorous synthesis is now widely
accepted as a key methodology for the preparation of large
numbers of chemical libraries avoiding tedious and time-
consuming purification steps.14 Fluorous synthesis displays
the advantages of both solid-phase and solution syntheses.
Like in solid-phase techniques, the separation and purifica-
tion of the compounds are fast and easy. However, instead of
a solid support, a fluorous tag (perfluoroalkyl chain) is
attached to our compound.15 The presence of the fluorous
tag facilitates the purification of the products through
fluorous solid-phase extraction (F-SPE)16 and at the same
time makes it possible to follow the reactions by means of
techniques such as TLC, GC, or NMR. Naturally, the
perfluorinated chain must be compatible with the reaction
conditions and easy to remove at the end of the synthetic
strategy to furnish the desired product.17
TABLE 1. Synthesis of Double R-Amido-β-Ketoesters 3 from Protected
Glycine 5
entry
Product
R1
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
o-MeOC6H4
o-MeOC6H4
p-MeOC6H4
p-MeOC6H4
t-Bu
i-Pr
Me
p-MeC6H4
p-ClC6H4
p-NO2C6H4
R2
yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5
55
57
87
87
74
78
61
62
79
80
62
68
80
91
64
62
52
52
42
24
o-FC6H4
o-MeOC6H4
o-CF3OC6H4
m-MeOC6H4
m-CF3OC6H4
p-MeOC6H4
p-CF3OC6H4
3,4,5-(OMe)3C6H2
Piperonyl
p-NO2C6H4
p-CF3OC6H4
Me
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
t-Bu
C6H5
o-MeOC6H4
C6H5
o-MeOC6H4
C6H5
C6H5
C6H5
C6H5
65
53
54
p-ClC6H4
C6H5
aReactions carried out on a 1 mmol scale. Overall yields of purified
products after three steps (from compound 5).
Herein, we would like to report on a simple and efficient
synthesis of a small library of 1,3-oxazoles 1 and 1,3-thia-
zoles 2 in solution starting from glycine, employing inexpen-
sive and accessible compounds. The synthesis starts with a
double C,N-acylation, which affords R-amido-β-ketoester
intermediates 3, which in turn will be finally transformed into
the corresponding oxazoles 1 or thiazoles 2 with a variety of
SCHEME 2. Double Acylation of Protected Glycine
(5) Van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron
Lett. 1972, 13, 2369–2372.
€
€
(6) Schollkopf, U.; Schroder, R. Angew. Chem. 1971, 83, 358; Angew.
Chem., Int. Ed. Engl. 1971, 10, 333.
´
(7) Martın, R.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 5521–
5524.
(8) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett.
2004, 6, 4391–4394.
(9) Milton, M. D.; Inada, Y.; Nishibayashi, Y.; Uemura, S. Chem.
Commun. 2004, 2712–2713.
(10) (a) Clapham, B.; Spanka, C.; Janda, K. D. Org. Lett. 2001, 3, 2173–
2176. (b) Lee, Y. R.; Yeon, S. H.; Seo, Y.; Kim, B. S. Synthesis 2004, 2787–
2798.
(11) Hantzch Chem. Ber. 1888, 21, 942–946.
(12) Cook, A. H.; Heilbron, I.; MacDonald, S. F.; Mahadevan, A. P.
J. Chem. Soc. 1949, 1064–1068.
groups in positions 2 and 5. We will also describe the
adaptation of the synthetic strategy to fluorous syn-
thesis (Scheme 1). Finally, we will indicate the outcome of
some preliminary studies of the antibacterial activity of the
1,3-oxazoles 1 and 1,3-thiazoles 2 synthesized.
(13) Thomsen, I.; Pedersen, U.; Rasmussen, P. B.; Yde, B.; Andersen, T.
P.; Lawesson, S. O. Chem. Lett. 1983, 6, 809–810.
Results and Discussion
(14) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1174–1196.
(15) (a) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf,
P.; Curran, D. P. Science 1997, 275, 823–826. (b) Handbook of Fluorous
Solution Synthesis of 1,3-Oxazoles 1 and 1,3-Thiazoles 2:
The synthetic strategy starts with a double glycine protec-
tion. Thus, the first step consists of the double protection of
the carboxylic moiety of glycine by means of treatment with
benzyl alcohol in the presence of a catalytic amount of
ꢀ
Chemistry; Gladysz, J. A., Curran, D. P., Horvath I. T., Eds.; Wiley-VCH:
Weinheim, Germany, 2004. (c) Zhang, W. Chem. Rev. 2004, 104, 2531–2556.
(16) Curran, D. P. Synlett 2001, 1488–1496.
(17) Zhang, W. Curr. Opin. Drug Discovery Dev. 2004, 7, 784–797.
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SCHEME 3. Alternative Synthesis of R-Amido-β-Ketoesters 3u and 3y
SCHEME 4. Synthesis of R-Amido-β-Ketoesters 3z and 3aa
SCHEME 5. Cyclization and Deprotection of R-Amido-β-Ketoesters 3
p-toluenesulfonic acid in toluene and, then, in the second
step, benzophenone imine is added to a solution of the
benzyl-protected glycine to furnish the double-protected
glycine 5.18 Condensation of 5 with several different acyl
chlorides in the presence of NaHMDS as a base, followed by
imine hydrolysis and subsequent acylation of the free amino,
gave R-amido-β-ketoester intermediates 3 in good to excel-
lent yields for the three steps (52-91%) when R1 is aromatic
(Table 1, entries 1-18) and in low yield when R1 is aliphatic
(Table 1, entries 19 and 20) (Scheme 2).
It was not possible to obtain the desired product when
R1 = Me (Table 1, entry 21). This anomalous behavior
might be understood assuming that acetyl chloride under-
goes an elimination reaction in the basic reaction medium to
afford ketene, which might escape the reaction medium.
The unsuccessful synthesis of the R-amido-β-ketoester
3u prompted us to look for an alternative synthesis of
2-substituted 5-methyloxa(thia)zole-4-carboxylic acid deri-
vatives, so we altered the initial steps of the proposed
synthetic path shown in Scheme 2. Thus, commercially
available methyl acetoacetate was transesterified and con-
veniently nitrosated to achieve oxime 7a in good yields.19
Reduction of oxime 7a with Zn dust in glacial acetic acid and
subsequent reaction with benzyl anhydride gave the desired
R-amido-β-ketoester 3u although in low yield (23%). How-
ever, in a different example in which acetic anhydride was
employed as the acylating reagent, R-amido-β-ketoester 3y
was obtained in almost quantitative yield (Scheme 3).
In an attempt to improve the total yield of this alternative
strategy, two later modifications were performed; first, and
given that the last step of the strategy is the deprotection of
the ester moiety in position 4 of the oxazole ring, the
transesterification reaction was eliminated, and second,
due to a smaller number of available commercial acid
anhydrides in comparison with commercial acid chlorides,
oxime 7b (obtained directly from methyl acetoacetate
through nitrosation) was catalytically reduced with hydro-
gen and reacted with two different acid chlorides (R2 =
p-NO2C6H4, 3,4,5-(MeO)3C6H2) to afford methyl R-amido-
β-ketoesters 3z and 3aa in 42 and 33% yield, respectively
(Scheme 4). In this way, we achieved higher yields than, for
example, 3u and skipped one synthetic step.
The next step for the synthesis of the oxazoles is the
cyclization of compounds 3. This reaction was performed
by treating the R-amido-β-ketoesters 3 with triphenylpho-
sphine in the presence of iodine and triethylamine in dichlor-
omethane at room temperature to give 2,5-disubstituted
oxazoles 8 in good to excellent yields (62-98%) (Scheme 5
and Table 2).20 Finally, the deprotection of the ester in
position 4 of the oxazole ring through palladium-catalyzed
hydrogenation (benzyl ester in the case of 8a-8y) or hydro-
lysis with LiOH in THF/H2O (methyl ester in the case of 8z
and 8aa) gave the final oxazole compounds 1 in excellent
yields (96-99%) (Scheme 5 and Table 2).
Moreover, it is possible to obtain thiazoles from the same
R-amido-β-ketoesters 3 by reaction of such intermediates
with Lawesson’s reagent. Thus, thiazoles 9 were obtained in
high to excellent yields (60-97%) except in the case of 9d,
which was obtained in only 30% yield. This drop in yield
might be caused by steric hindrance between Lawesson’s
phosphine and the trifluoromethyl group in the ortho posi-
tion of the R2 group. Finally, the ester deprotection was
(18) Pinter, A.; Haberhauer, G.; Hyla-Kryspin, I.; Grimme, S. Chem.
Commun. 2007, 36, 3711–3713.
(19) Ribeiro, R. S.; de Souza, R. O. M. A.; Vasconcellos, M. L. A. A.;
Oliveira, B. L.; Ferreira, L. C.; Aguiar, L. C. S. Synthesis 2007, 1, 61–64.
(20) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604–3606.
8990 J. Org. Chem. Vol. 74, No. 23, 2009

Sanz-Cervera et al.
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TABLE 2. Synthesis of 2,5-Disubstituted Oxazoles 8 and 1
complete, and some starting fluorous alcohol 10 remained
in the reaction mixture. This fact meant that the mixture had
to be purified by means of flash chromatography on silica
gel, which allowed us to recover the fluorous alcohol. A
nitrosation reaction on 14 gave oxime 15 in good yield.
Catalytic reduction of 15 with hydrogen in the presence of
Pd (C) followed by reaction with benzoyl chloride
(procedure A, Scheme 8) gave a complex mixture of fluorous
products, and thus intermediate 13h had to be purified by
flash chromatography with a yield of the purified compound
of only 23%. In contrast, reduction of 14 with Zn dust in
acetic medium and subsequent reaction with acetic anhy-
dride (procedure B, Scheme 8) exclusively gave fluorous R-
amido-β-ketoester 13i in 84% yield.
The cyclization of fluorous R-amido-β-ketoesters 13 was
achieved by means of treatment with triphenylphosphine in
the presence of iodine and triethylamine in good to excellent
yields (71-98%) except for compounds 13d and 13e (in these
two compounds, R2 = alkyl group), in which the reaction
stopped with still a large amount of starting material un-
reacted (the reaction progress was followed by TLC in both
cases). A temperature increase or a bigger excess of reagents
did not improve the yield. Finally, we determined that when
concentrated H2SO4 was used as a dehydrating agent to
perform this reaction R-amido-β-ketoesters 13d and 13e were
obtained in good yields (63 and 73%, respectively). The last
step was, as in the synthesis in solution, the deprotection of
the carboxylic moiety, which was achieved by means of basic
hydrolysis with LiOH in THF/H2O (4:1) to give 2,5-disub-
stituted 1,3-oxazoles in high yields (95-99%) (Scheme 9 and
Table 5).
The cyclization of fluorous R-amido-β-ketoesters 13 with
Lawesson’s reagent gave fluorous 1,3-thiazoles 17 in high
yields (54-82%), which are only slightly lower than those
obtained for the analogous nonfluorous 1,3-thiazoles 9
(67-97%).21 Again, the last step was the basic hydrolysis
with LiOH in THF/H2O (4:1) to deprotect the carboxylic
moiety, which gave 2,5-disubstituted 1,3-thiazoles 2 in high
yields (95-99%) (Scheme 10 and Table 6).
Although the yields are somewhat lower in the fluorous
synthesis when compared to the solution synthesis, the
former has several advantages, which are mostly related to
the ease and speed of purification for the intermediate
compounds. These processes are both faster and less expen-
sive in the fluorous synthesis because the cartridges for the
fluorous solid-phase extraction (F-SPE) can be recycled and
reused many times.
entry
3
8a
yield (%)b
1
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
73
83
96
85
91
92
91
89
91
97
98
96
81
83
86
91
94
74
91
93
75
70
99
62
82
80
80
1ac
1bc
1cc
1dc
1ec
1fc
99
99
97
99
99
99
97
99
98
96
99
98
99
99
99
98
98
99
99
99
99
99
98
98
99
99
96
1gc
1hc
1ic
1jc
1kd
1lc
1mc
1nc
1oc
1pc
1qc
1rc
1sc
1tc
3s
3t
8s
8t
3u
3v
3w
3x
3y
3z
3aa
8u
8v
8w
8x
8y
8z
8aa
1uc
1vc
1wc
1xd
1yc
1ze
1aae
aReactions carried out on a 0.2 mmol scale. A solution of R-amido-β-
ketoesters 3 in CH2Cl2 (2 mL) is added to a solution of triphenylpho-
sphine (2 equiv) and iodine (2 equiv) in CH2Cl2 (4 mL) and stirred at rt
until the reaction is complete (TLC). bYields of purified products.
cHydrogenolysis carried out through treatment of oxazole 8 with Pd(C)
(10%) in AcOEt (5 mL) under 1 atm of H2. dPd(OH)2 was used as
catalyst to reduce the nitro group to amino simultaneously. eHydrolysis
performed by means of treatment of oxazole 8 with LiOH (3 equiv) in
THF/H2O (4:1) (5 mL).
achieved in the same way as for oxazoles 1, which is
palladium-catalyzed hydrogenolysis for 9a-y and hydroly-
sis by LiOH in THF/H2O in the case of 9z and 9aa (Scheme 6
and Table 3).
Fluorous Synthesis of 1,3-Oxazoles 1 and 1,3-Thiazoles 2:
The synthetic strategy is analogous to that described pre-
viously for compounds 1 and 2, although now it is necessary
to attach a fluorous tag to a suitably protected glycine. Thus,
in the first step, commercially available alcohol 10 is attached
to N-Boc-protected glycine by means of esterification to give
compound 11 with excellent yield (97%). The Boc protecting
group was then replaced by phenonimine in good yield to
give an intermediate 12 analogous to double-protected gly-
cine 5. In the same way as for the synthesis of R-amido-β-
ketoesters 3, substrate 12 was subjected to double C,N-
acylation to afford fluorous R-amido-β-ketoesters 13
(Scheme 7). This reaction displayed good yields (49-60%
for three steps) when R1 is aromatic (Table 4, entries 1-5),
although the yields are somewhat lower than in the corre-
sponding solution synthesis (42-91%). When R1 is aliphatic
(Table 4, entries 6 and 7), the yields are moderate and in this
case similar to those obtained in solution (53 and 22% vs
42 and 24%).
We have previously described the synthesis of various
fluorinated compounds in solid phase as, for example,
fluorinated partially modified retropeptides,22 fluorinated
uracils and thiouracils,23 and β,β-difluorinated cyclic qua-
ternary R-amino acid derivatives.24 We were also interested
in the synthesis of the 2,5-disubstituted 1,3-oxazoles 1 and
2,5-disubstituted 1,3-thiazoles 2 in solid phase, and we
(21) Compare 3a with 13a, 3g with 13b, 3h with 13c, 3m with 13d, 3n with
13e, 3s with 13f, 3t with 13g, and 3u with 13h.
ꢀ
(22) Volonterio, A.; Chiva, G.; Fustero, S.; Piera, J.; Sanchez-Rosello,
M.; Sani, M.; Zanda, M. Tetrahedron Lett. 2003, 44, 7019–7022.
ꢀ
´
(23) Fustero, S.; Piera, J.; Sanz-Cervera, J. F.; Catalan, S.; Ramırez de
Arellano, C. Org. Lett. 2004, 6, 1417–1420.
Once again, it was not possible to obtain the desired
product 13h when R1 = Me (Table 4, entry 8) possibly
because of ketene formation. Like in the corresponding
solution synthesis, we made use of an alternative strategy.
Thus, we started with a transesterification reaction to obtain
fluorous ketoester 14;19 the reaction, however, was not
ꢀ
(24) Fustero, S.; Sanchez-Rosello, M.; Rodrigo, V.; Sanz-Cervera, J. F.;
Piera, J.; Simon-Fuentes, A.; del Pozo, C. Chem.;Eur. J. 2008, 14, 7019–
ꢀ
ꢀ
7029.
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SCHEME 6. Synthesis of Thiazoles 2 from R-Amido-β-Ketoesters 3
while we also cleaved in every case the material from the
beads and analyzed it by means of 1H NMR, we could only
observe very complex mixtures that would have been useless
in the final synthetic steps. The fluorous synthesis displays
the advantages of both solid-phase (which are mainly the
purification steps) and solution syntheses; therefore, in view
of the difficulties associated with the solid-phase synthesis,
we decided to abandon it.
There are some examples of 1,3-azoles that are considered
dipeptide mimetics in the literature.25 For this reason, we
thought that an interesting extension of this work would be
the addition of an amino acid to the carboxylic moiety in
position 4 of the 1,3-oxazoles 1 and 1,3-thiazoles 2 and in this
way extend the “peptidic chain”. With this purpose in
mind, benzyl-protected valine and leucine were condensed
to 1,3-azoles 1a and 1y and to 1,3-thiazoles 2a and 2y
by means of standard methods in good yields (64-87%).
Palladium-catalyzed deprotection of the benzyl ester gave
the desired products 22 in quantitative yield (Scheme 12 and
Table 7).
Finally, we tested the antibacterial activity of the 1,3-oxazoles
1 and 1,3-thiazoles 2. The above-mentioned compounds were
evaluated for their antimicrobial activity using a disk diffusion
method with 50 μg/disk against Staphylococcus aureus ATCC
29213, Escherichia coli ATTC 25922, Micrococcus luteus ATCC
49732, Mycobacterium smegmatis (clinical isolate), and
Candida albicans ATCC 14053. The initial screening demon-
strated promising activities against S. aureus (see Table 8) with
1a (11 mm zone), 1c (11 mm zone), 1g (12 mm zone), 1r (15 mm
zone), 2b (12 mm zone), 2c (20 mm zone), 2f (10 mm), 2h
(10 mm zone), 2o (15 mm), and 2p (14 mm).
Interestingly, compound 2h was also active against M.
luteus (13 mm zone) and methicillin-resistant S. aureus
(MRSA) ATCC 33591 (13 mm zone). The rest of the assayed
compounds were not active against the other studied organ-
isms. For 1s and 2s, there was some decreased growth around
the disk but not a clear zone of inhibition. These results
suggest that further modification of these scaffolds might
lead to compounds with enhanced antimicrobial activities. It
is unclear why 2a and 1h were inactive based on their
similarity to the active compounds.
TABLE 3. Synthesis of 2,5-Disubstituted Thiazoles 9 and 2
entry
3
9a
yield (%)b
2
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
9r
97
95
68
30
98
95
67
92
83
60
89
61
81
89
80
68
73
84
67
70
87
90
67
60
86
86
80
2ac
2bc
2cc
2dc
2ec
2fc
99
99
96
97
97
96
99
99
96
96
97
97
99
97
99
99
97
96
97
97
98
98
99
97
99
99
98
2gc
2hc
2ic
2jc
2kd
2lc
2mc
2nc
2oc
2pc
2qc
2rc
2sc
2tc
3s
3t
9s
9t
3u
3v
3w
3x
3y
3z
3aa
9u
9v
9w
9x
9y
9z
9aa
2uc
2vc
2wc
2xd
2yc
2ze
2aae
aReactions carried out on a 0.2 mmol scale. Lawesson’s reagent
(2 equiv) is added to a solution of R-amido-β-ketoesters 3 in anhydrous
THF (5 mL) and the mixture refluxed until no starting material is
detected by TLC. bYields of purified products. cHydrogenolysis carried
out by treatment of thiazole 9 with Pd (C) (10%) in AcOEt (5 mL) under
atmospheric pressure of hydrogen. dPd(OH)2 was used as catalyst to
reduce the nitro group to an amino group simultaneously to the benzyl
ester deprotection. eHydrolysis performed by means of treatment of
thiazole 9 with LiOH (3 equiv) in THF/H2O (4:1) (5 mL).
started the synthesis by attaching the Fmoc-glycine to Wang
resin and deprotection of the Fmoc group by standard
methods (Scheme 11). Next, we again protected the amino
group with benzophenonimine to obtain the protected gly-
cine 19. These three steps were easy, and the corresponding
IR spectra showed the expected bands (see Supporting
Information). However, it was very difficult to control the
first acylation step for the preparation of 20, and thus a very
complex mixture was obtained (as deduced from the IR
spectrum). Several different conditions were tested, for ex-
ample, changing the base used to generate the enolate, the
amount of base, the number of equivalents of acid chloride,
the addition of other acid derivatives (anhydrides and esters),
the temperature of formation of enolate, the temperature of
addition of acid chloride, and the reaction time (from 1 h to 2
days). In spite of our efforts, in every case, many new, low
intensity bands were observed in the IR spectrum. Moreover,
Conclusion
In this paper, we have established a new straightforward
and easy methodology to synthesize 2,5-disubstituted
(25) (a) Gordon, T. D.; Singh, J.; Hansen, P. E.; Morgan, B. A. Tetra-
hedron Lett. 1993, 34, 1901–1904. (b) Falorni, M.; Dettori, G.; Giacomelli, G.
Tetrahedron: Asymmetry 1998, 9, 1419–1426. (c) Christensen, C.; Schiodt,
C. B.; Foged, N. T.; Meldal, M. QSAR Comb. Sci. 2003, 22, 754–766.
8992 J. Org. Chem. Vol. 74, No. 23, 2009

Sanz-Cervera et al.
JOCArticle
SCHEME 7. Fluorous Synthesis of R-Amido-β-Ketoesters 13
then purified by flash chromatography on silica gel for com-
pounds 3 and fluorous chromatography for compounds 13.
Benzyl 2-(2-methoxybenzamido)-3-oxo-3-phenylpropanoate
TABLE 4. Fluorous Synthesis of R-Amido-β-Ketoesters 13 from
Protected Glycine 12
entry
product
R1
R2
C6H5
p-MeOC6H4
p-CF3C6H4
Me
t-Bu
C6H5
C6H5
C6H5
yield (%)a
1
(3c): Yield 87%; colorless oil; H NMR (300 MHz, CDCl3) δ
1
2
3
4
5
6
7
8
13a
13b
13c
13d
13e
13f
13g
13h
C6H5
C6H5
C6H5
C6H5
C6H5
t-Bu
i-Pr
60
49
56
56
54
53
22
ppm 9.28 (d, J = 7.4 Hz, 1H), 8.09 (dd, J1 = 1.8 Hz, J2 = 7.8 Hz,
1H), 8.03 (d, J = 7.2 Hz, 2H), 7.48 (tt, J1 = 1.1 Hz, J2 = 1.8 Hz,
J3 = 7.5 Hz, 1H), 7.34 (t, J = 7.7 Hz, 3H), 7.09-7.16 (m, 3H),
6.98-7.05 (m, 2H), 6.94 (dt, J1 = 0.9 Hz, J2 = 7.7 Hz, 1H), 6.86
(d, J = 8.1 Hz, 1H), 6.36 (d, J = 6.9 Hz, 1H), 5.08 (d, J = 12.3
Hz, 1H), 5.01 (d, J = 12.3 Hz, 1H), 3.86 (s, 3H); 13C NMR (75
MHz, CDCl3) δ ppm 191.5 (C), 166.5 (C), 164.7 (C), 157.9 (C),
134.6 (C), 134.3 (C), 134.1 (CH), 133.3 (CH), 132.1 (CH), 129.4
(CH), 128.6 (CH), 128.3 (CH), 128.1 (CH), 127.8 (CH), 121.0
(CH), 120.1 (C), 111.4 (CH), 67.7 (CH2), 59.1 (CH), 55.9 (CH3);
HRMS (EI) m/z calcd for C24H21NO5 403.1420, found
403.1425.
Me
aReactions carried out on a 1 mmol scale. Yields of purified products
after three steps (from compound 12).
1,3-azoles 1 and 1,3-thiazoles 2, which starts with inexpen-
sive, commercially available reagents. In this way, a library
of more than 50 azoles and thiazoles has been synthesized.
We have successfully adapted the strategy to fluorous synth-
esis. Although the total yields of the fluorous synthesis are
slightly lower than in the synthesis in solution, the easy
purification by simple fluorous solid-phase extraction
(F-SPE) results in substantial time economy. The prepared
compounds have shown promising antibacterial activity in
preliminary in vitro testing.
3-(Perfluorooctyl)propyl 2-(benzamido)-3-oxo-3-phenylpro-
1
panoate (13a): Yield 60%; yellowish solid; mp 91-93 °C; H
NMR (300 MHz, CDCl3) δ ppm 7.94 (d, J = 8.1 Hz, 2H), 7.65
(d, J = 8.1 Hz, 2H), 7.41 (d, J = 6.9 Hz, 2H), 7.17-7.36 (m, 4H),
6.21 (dd, J1 = 1.2 Hz, J2 = 7.2 Hz, 1H), 3.89-4.11 (m, 2H),
1.55-1.83 (m, 4H); 19F NMR (282 MHz, CDCl3) δ ppm -81.31
(t, J = 9.6 Hz, 3F), -114.96 (t, J = 13.8 Hz, 2F), -122.34 (br s,
6F), -123.19 (s, 2F), -123.79 (s, 2F), -126.60 (s, 2F); 13C NMR
(75 MHz, CDCl3) δ ppm 191.4 (C), 167.0 (C), 166.5 (C), 134.7
(CH), 134.0 (C), 132.9 (C), 132.1 (CH), 129.5 (CH), 128.8 (CH),
128.6 (CH), 127.3 (CH), 64.8 (CH2), 58.6 (CH), 27.5 (t, J = 22.4
Hz), 19.7 (CH2); HRMS (FAB) m/z calcd for C27H18F17NO4
(M þ 1) 744.1043, found 744.1038.
Experimental Section
General Procedure for the Synthesis of r-Amido-β-Ketoesters
3 and 13: A solution of 5 or 12 (1 equiv) in anhydrous THF
(5 mL) was cooled to -78 °C under argon atmosphere, and a 1
M solution of sodium bis(trimethylsilyl)amide in THF (1 equiv)
was slowly added while maintaining the reaction temperature at
-78 °C. After 30 min, the red solution of the Schiff base anion
was added via cannula to a stirred solution of the acyl chloride
(1 equiv) in anhydrous THF (3 mL) at -78 °C, and the mixture
was stirred for 2 h. The reaction mixture was quenched with 1 M
HCl solution (3 mL) and concentrated to dryness under reduced
pressure. The residue was suspended in ether (5 mL) and filtered
to remove benzophenone. The intermediate β-ketoester hydro-
chloride salt was obtained as a white solid and used in the next
reaction without any additional purification. N-Methyl mor-
pholine (1.5 equiv) was added to a cooled solution (-20 °C) of
β-ketoester hydrochloride salt (1 equiv) in anhydrous THF (5 mL)
under argon atmosphere. Acyl chloride (1 equiv) was slowly
added while maintaining the reaction mixture at -20 °C, and the
bath was removed after stirring for 15 min. The reaction mixture
was stirred for an additional 2 h, and the solvent was removed
under reduced pressure. The residue was partitioned between
ethyl acetate (3 mL) and water (3 mL). The aqueous layer was
extracted with AcOEt (3 ꢀ 5 mL), and the organic layers were
dried over anhydrous sodium sulfate and the solvents removed
under reduced pressure to yield the crude product, which was
Reduction/Acylation of Oximes 7 and 15. Procedure A:
Reduction with Pd/AcOH. Pd/C (25% w/w, 0.1 equiv) was
added to a solution of oxime 7 or 15 (1 equiv) in a 1 M solution of
HCl in MeOH (3 mL) and stirred at rt under atmospheric
pressure of hydrogen for 24 h. The reaction mixture was filtered
through Celite, and the solid residue was washed with MeOH
(3 ꢀ 2 mL). The combined filtrates were concentrated under
reduced pressure to yield a yellowish solid, which was dissolved
in THF (5 mL). N-Methyl morpholine (1.5 equiv) and acyl
chloride (1 equiv) were slowly added to the previous solution,
and the reaction mixture was stirred for an additional 5 h. The
solvent was removed under reduced pressure, and the residue
was partitioned between ethyl acetate (3 mL) and water (3 mL).
The aqueous layer was extracted with AcOEt (3 ꢀ 5 mL), and
the organic layers were dried over anhydrous sodium sulfate and
the solvents removed under reduced pressure to yield the crude
product, which was then purified, when necessary, by means of
flash chromatography on silica gel.
Methyl 2-(4-nitrobenzamido)-3-oxobutanoate (3z): Yield
1
42%; yellowish solid; mp 103-105 °C; H NMR (300 MHz,
CDCl3) δ ppm 8.31 (d, J = 9.0 Hz, 2H), 8.01 (d, J = 9.0 Hz, 2H),
7.40 (d, J = 5.4 Hz, 1H), 5.44 (d, J = 6.3 Hz, 1H), 3.87 (s, 3H),
2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ ppm 197.8 (C), 166.1
J. Org. Chem. Vol. 74, No. 23, 2009 8993

Sanz-Cervera et al.
JOCArticle
SCHEME 8. Alternative Fluorous Synthesis of R-Amido-β-Ketoesters 13h and 13i
SCHEME 9. Fluorous Cyclization and Deprotection of R-Amido-β-Ketoesters 13
Reduction/Acylation of Oximes 7 and 15. Procedure B:
Reduction with Zn/AcOH. Zn powder was slowly added
(addition for 1 h) to a solution of oxime 7 or 15 (1 equiv) and
anhydride (2.5 equiv) in glacial AcOH (4 mL), and the mixture
was stirred for 18 h at rt. The reaction mixture was quenched
with 4 mL of H2O, filtrated over Celite, and the solid residue
washed with dichloromethane (3 ꢀ 5 mL). The layers were
separated, and the aqueous mixture was extracted with dichlor-
omethane (3 ꢀ 5 mL). The organic layers together were washed
with aqueous saturated NHCO3 solution and dried over anhy-
drous sodium sulfate, and the solvents were removed under
reduced pressure. The crude product was purified, when neces-
sary, by means of flash chromatography on silica gel for
compounds 7 and fluorous chromatography for compounds 15.
Benzyl 2-acetamido-3-oxobutanoate (3y): Yield 99%; white
TABLE 5. Fluorous Synthesis of 2,5-Disubstituted Oxazoles 16 and 1
entry
13
16a
yield (%)b
1d
yield (%)b
1
2
3
4
5
6
7
8
9
13a
13b
13c
13d
13e
13f
13g
13h
13i
16a
16b
16c
16dc
16ec
16f
16g
16h
16i
98
95
98
63
73
71
76
72
82
1a
1b
1c
1d
1e
1f
1g
1h
1i
99
95
97
99
99
99
99
98
97
aReactions carried out on a 0.2 mmol scale. A solution of R-amido-β-
ketoesters 13 in CH2Cl2 (2 mL) is added to a solution of triphenylpho-
sphine (2 equiv) and iodine (2 equiv) in CH2Cl2 (4 mL) and stirred at rt
until the reaction is finished (TLC). bYields of purified products.
cCyclization carried out by addition of concentrated H2SO4. dHydrolysis
performed by treatment of 1,3-oxazoles 16 with LiOH (3 equiv) in THF/
H2O (4:1) (5 mL).
1
solid; mp 100-102 °C; H NMR (300 MHz, CDCl3) δ ppm
7.29-7.40 (m, 5H), 6.78 (d, J = 5.4 Hz, 1H), 5.29 (d, J = 6.6 Hz,
1H), 5.24 (d, J = 12.3 Hz, 1H), 5.18 (d, J = 12.0 Hz, 1H), 2.29 (s,
3H), 2.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δ ppm 198.3 (C),
169.8 (C), 166.0 (C), 134.5 (C), 128.6 (CH), 128.3 (CH), 68.1
(CH2), 63.1 (CH), 28.0 (CH3), 22.5 (CH3); HRMS (EI) m/z calcd
for C13H15NO4 249.1001, found 249.1004.
TABLE 6. Fluorous Synthesis of 2,5-Disubstituted Thiazoles 17 and 2
entry
13
17a
yield (%)b
2c
yield (%)b
1
2
3
4
5
6
7
8
9
13a
13b
13c
13d
13e
13f
13g
13h
13i
17a
17b
17c
17d
17e
17f
17g
17h
17i
54
79
74
79
73
82
78
86
80
2a
2b
2c
2d
2e
2f
2g
2h
2i
99
95
97
99
99
99
99
99
98
General Procedure for the Synthesis of 1,3-Oxazoles 8 and 16:
Triethylamine (4 equiv) was added to a solution of triphenyl-
phosphine (2 equiv) and iodine (2 equiv) in dry dichloromethane
(6 mL) and stirred for 5 min. Then a solution of the R-amido-β-
ketoester (1 equiv) in dry dichloromethane (4 mL) was added
and the reaction mixture stirred until completion of reaction
(followed by TLC). The solvent was removed under reduced
pressure, and the residue was purified by flash chromatography
on silica gel for compounds 8 and fluorous chromatography for
compound 16.
Benzyl 2-(3-(trifluoromethyl)phenyl)-5-phenyloxazole-4-car-
boxylate (8f): Yield 92%; white solid; mp 130-132 °C; 1H
NMR (300 MHz, CDCl3) δ ppm 8.30 (s, 1H), 8.22 (d, J = 7.8
Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.93 (s, 1H), 7.63 (d, J = 7.8
Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.30-7.40 (m, 5H), 7.18-7.30
(m, 3H), 5.33 (s, 2H); 19F NMR (282 MHz, CDCl3) δ ppm
-63.29 (s, 3F); 13C NMR (75 MHz, CDCl3) δ ppm 161.8 (C),
aReactions carried out on a 0.2 mmol scale. Lawesson’s reagent
(2 equiv) is added to a solution of R-amido-β-ketoesters 13 in anhydrous
THF (5 mL) and the mixture refluxed until no starting material is
b
c
detected by TLC. Yields of purified products. Hydrolysis performed
by treatment of thiazole 17 with LiOH (3 equiv) in THF/H2O (4:1)
(5 mL).
(C), 164.8 (C), 150.0 (C), 138.4 (C), 128.5 (CH), 123.9 (CH), 63.5
(CH), 53.6 (CH3), 28.1 (CH3); HRMS (EI) m/z calcd for
C12H12N2O6 280.0695, found 280.0697.
8994 J. Org. Chem. Vol. 74, No. 23, 2009

Sanz-Cervera et al.
JOCArticle
SCHEME 10. Fluorous Synthesis of Thiazoles 2 from R-Amido-β-Ketoesters 13
SCHEME 11. Solid-Phase Synthesis of 1,3-Oxazoles 1 and 1,3-Thiazoles 2
SCHEME 12. Addition of Benzyl-Protected Amino Acid to 1,3-Oxazoles 1a and 1y and to 1,3-Thiazoles 2a and 2y
TABLE 7. Addition of Benzyl-Protected Amino Acid to 1,3-Oxazoles
1a and 1y and 1,3-Thiazoles 2a and 2y and Deprotection
TABLE 8. Antimicrobial Activity of 1,3-Oxazoles 1 and 1,3-Thiazoles 2
against S. aureus ATCC 29213
entry
R1
C6H5 C6H5 i-Pr
Me Me i-Bu
C6H5 C6H5 i-Pr
Me Me i-Bu
R2
R3
X
21a yield (%)b 22c yield (%)b
entry
compounda
activity (mm)b
1
2
3
4
O
O
S
21a
21b
21c
21d
76
87
64
85
22a
22b
22c
22d
99
99
98
99
1
2
3
4
5
6
7
8
9
1a
1c
1g
1r
2b
2c
2f
2h
2o
2p
11
11
12
15
12
20
10
10
15
14
20
0
S
aReactions carried out on a 0.5 mmol scale. 1 or 2, O-Bn-amino acid
(1.5 equiv), HBTU (3 equiv), and N-ethylisopropylamine (3 equiv) in
anhydrous DMF (5 mL) are stirred at 60 °C under microwave irradia-
tion for 45 min. Yields of purified products. Hydrogenolysis carried
out by treatment of 21 with Pd(C) (10%) in AcOEt (5 mL) under 1 atm
of H2.
b
c
10
11
12
oxacillind
blank experimentc
2
158.3 (C), 155.8 (C), 135.4 (C), 131.4 (q, J = 32.7 Hz), 130.5
aFifty micrograms of compound per disk spotted from a 5 mg/mL
DMSO solution. bBacterial growth inhibition halo against S. aureus
ATCC 29213. cOnly DMSO was added. dFifty micrograms of com-
pound per disk spotted from a 5 mg/mL DMSO solution for the tested
compounds, while only 1 microgram was used for the oxacillin used as
reference.
(CH), 129.8 (CH), 129.4 (CH), 128.6 (CH), 128.5 (CH), 128.5
(CH), 128.4 (CH), 128.3 (CH), 128.2 (C), 127.4 (q, 3J = 3.7 Hz),
127.1 (C), 126.6 (C), 123.6 (q, 3J = 3.8 Hz), 123.6 (q, 1J = 270.8
Hz), 67.0 (CH2); HRMS (EI) m/z calcd for C24H16F3NO3
423.1082, found 423.1076.
3-(Perfluorooctyl)propyl 2-(4-(trifluoromethyl)phenyl)-5-phe-
nyloxazole-4-carboxylate (16c): Yield 98%; yellowish solid;
mp 53-55 °C; H NMR (300 MHz, CDCl3) δ ppm 8.27 (d,
General Procedure for the Hydrogenation of 8a-y: Pd/C
(25% w/w, 0.1 equiv) was added to a solution of 1,3-oxazole 8
(1 equiv) in dry ethyl acetate (5 mL) and stirred at rt under
atmospheric pressure of hydrogen overnight. The catalyst was
filtered off and washed with methanol (2 mL). The combined
filtrates were concentrated under reduced pressure to yield the
pure product.
2-(2-Fluorophenyl)-5-phenyloxazole-4-carboxylic acid (1b):
Yield 99%; white solid; mp 176-178 °C; 1H NMR (300 MHz,
DMSO-d6) δ ppm 8.03-8.17 (m, 3H), 7.37-7.69 (m, 6H); 19F
NMR (282 MHz, DMSO-d6) δ ppm -111.76 (s, 1F); 13C NMR
(75 MHz, DMSO-d6) δ ppm 162.9 (C), 159.3 (d, 1J = 254.0 Hz),
155.1 (d, 3J = 3.8 Hz), 153.8 (C), 133.3 (d, 3J = 8.3 Hz), 130.2
1
J = 8.1 Hz, 2H), 7.98-8.16 (m, 2H), 7.75 (d, J = 8.1 Hz, 2H),
7.66-7.87 (m, 3H), 4.46 (t, J = 5.9 Hz, 2H), 3.87 (s, 3H),
1.99-2.37 (m, 4H); 19F NMR (282 MHz, CDCl3) δ ppm -63.51
(s, 3F), -81.30 (t, J = 9.6 Hz, 3F), -114.78 (t, J = 13.8 Hz, 2F),
-122.17 (s, 2F), -122.36 (s, 4F), -123.18 (s, 2F), -123.83 (s,
2F), -126.60 (s, 2F); 13C NMR (75 MHz, CDCl3) δ ppm 161.8
(C), 158.5 (C), 156.1 (C), 132.7 (q, 2J = 32.3 Hz), 130.7 (CH),
129.5 (C), 128.7 (CH), 128.5 (CH), 128.2 (C), 127.1 (CH), 126.7
(C), 125.9 (q, 3J = 3.2 Hz), 123.7 (q, 1J = 270.8 Hz), 63.9 (CH2),
27.9 (t, J = 22.1 Hz), 20.0 (CH2); HRMS (FAB) m/z calcd for
C28H15F20NO3 793.0733, found 793.0727.
J. Org. Chem. Vol. 74, No. 23, 2009 8995

Sanz-Cervera et al.
JOCArticle
(CH), 129.6 (CH), 128.7 (C), 128.4 (CH), 128.2 (CH), 126.7
(C), 125.1 (d, 3J = 2.9 Hz), 117.0 (d, 2J = 20.8 Hz), 114.1
(d, 2J = 10.9 Hz); HRMS (EI) m/z calcd for C16H10FNO3
283.0645, found 283.0649.
CDCl3) δ ppm 7.88 (d, J = 8.7 Hz, 2H), 7.61-7.69 (m, 2H),
7.40-7.48 (m, 3H), 6.98 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ ppm 165.3 (C), 161.9 (C), 161.7 (C),
146.5 (C), 138.8 (C), 130.0 (CH), 129.6 (CH), 129.3 (C), 128.3
(CH), 128.1 (CH), 124.8 (C), 114.5 (CH), 55.5 (CH3); HRMS (EI)
m/z calcd for C17H13NO3S 311.0616, found 311.0608.
General Procedure for the Synthesis of Compounds 21:
A solution of 1 or 2 (1 equiv), OBn-protected amino acid
(1.5 equiv), HBTU (3 equiv), and N-ethyldiisopropylamine
(1 equiv) in anhydrous DMF (5 mL) was irradiated with micro-
waves at 60 °C for 45 min. The reaction mixture was then
evaporated under reduced pressure, and the residue was dissolved
in AcOEt, washed with 10% citric acid solution and saturated
solution of NaHCO3, dried with Na2SO4, and concentrated under
reduced pressure to yield the crude product. Purification was
performed by flash chromatography on silica gel.
General Procedure for the Hydrolysis of 8z-aa and 16: A stirred
solution of ester 8 or 16 (1 equiv) in THF/H2O 4:1 (5 mL) was
chilled in an ice bath. Then lithium hydroxide monohydrate (3
equiv) was added, the ice bath was allowed to reach rt, and the
mixture stirred until completion of the reaction (followed by
TLC). The reaction mixture was then evaporated under reduced
pressure, and the residue suspended in 1 M HCl solution (1 mL)
and extracted with ethyl acetate to yield the pure product.
5-Methyl-2-(3,4,5-trimethoxyphenyl)oxazol-4-carboxylic acid
(1aa): Yield 99%; white solid; mp 224-226 °C; 1H NMR
(300 MHz, 0.6 mL CDCl3 þ 0.1 mL MeOD) δ ppm 7.27 (s,
2H), 3.91 (s, 6H), 3.87 (s, 3H), 2.69 (s, 3H); 13C NMR (75 MHz,
0.6 mL CDCl3 þ 0.1 mL MeOD) δ ppm 164.3 (C), 159.5 (C),
156.5 (C), 153.4 (C), 140.3 (C), 128.5 (C), 121.7 (C), 103.8 (CH),
60.9 (CH3), 56.3 (CH3), 12.1 (CH3); HRMS (EI) m/z calcd for
C14H15NO6 293.0899, found 293.0908.
General Procedure for the Synthesis of 1,3-Thiazoles 9 and 17:
A solution of the R-amido-β-ketoester 3 or 13 (1 equiv) and
Lawesson’s reagent (2 equiv) in dry THF (5 mL) was heated to
reflux until completion of reaction (followed by TLC). The
reaction mixture was then evaporated under reduced pressure
and purified by flash chromatography on silica gel for com-
pounds 9 and fluorous chromatography for compound 17 to
yield the product.
Benzyl 2-(3-methoxyphenyl)-5-phenylthiazole-4-carboxylate
(9e): Purification by means of flash chromatography on silica
gel (hexane/AcOEt 4:1): yield 98%; white solid; mp 106-108 °C;
1H NMR (300 MHz, CDCl3) δ ppm 7.35-7.50 (m, 4H),
7.23-7.33 (m, 4H), 7.06-7.23 (m, 5H), 6.92 (dd, J1 = 2.6 Hz,
J2 = 8.3 Hz, 1H), 5.20 (s, 2H), 3.80 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ ppm 166.0 (C), 162.1 (C), 160.0 (C), 146.0 (C), 141.2
(C), 135.3 (C), 134.0 (C), 130.4 (C), 130.0 (CH), 129.8 (CH),
129.1 (CH), 128.3 (CH), 128.2 (CH), 128.2 (CH), 128.0 (CH),
119.4 (CH), 116.9 (CH), 111.4 (CH), 66.8 (CH2), 55.5 (CH3);
HRMS (EI) m/z calcd for C24H19NO3S 401.1086, found
401.1076.
3-(Perfluorooctyl)propyl 2-(4-methoxyphenyl)-5-phenylthia-
zole-4-carboxylate (17b): Yield 79%; yellowish solid; mp
129-131 °C; 1H NMR (300 MHz, CDCl3) δ ppm 7.93 (d, J =
9.0 Hz, 2H), 7.38-7.54 (m, 5H), 6.96 (d, J = 9.0 Hz, 2H), 4.28 (t,
J = 5.3 Hz, 2H), 3.86 (s, 3H), 1.79-1.94 (m, 4H); 19F NMR (282
MHz, CDCl3) δ ppm -81.26 (t, J = 9.9 Hz, 3F), -114.85 (t, J =
11.5 Hz, 2F), -122.37 (br s, 6F), -123.19 (s, 2F), -123.73 (s,
2F), -126.58 (s, 2F); 13C NMR (75 MHz, CDCl3) δ ppm 166.3
(C), 162.1 (C), 161.7 (C), 145.1 (C), 140.9 (C), 130.7 (C), 129.7
(CH), 129.2 (CH), 128.3 (CH), 128.2 (CH), 125.5 (C), 114.3
(CH), 63.6 (CH2), 55.4 (CH3), 27.8 (t, J = 22.3 Hz), 19.7 (CH2);
HRMS (FAB) m/z calcd for C28H18F17NO3S 771.0736, found
771.0761.
(S)-Benzyl 2-(2,5-dimethylthiazole-4-carboxamido)-4-methyl-
pentanoate (21d): Yield 85%; yellowish oil; [R]25 = þ2.11 (c
D
1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ ppm 7.75 (d, J =
8.7 Hz, 1H), 4.74-4.86 (m, 5H), 5.21 (d, J = 12.3 Hz, 1H), 5.15
(d, J = 12.6 Hz, 1H), 4.74-4.85 (m, 1H), 2.75 (s, 3H), 2.58 (s,
3H), 1.61-1.80 (m, 3H), 0.96 (d, J = 1.8 Hz, 3H), 0.94 (d, J =
3.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm 172.7 (C), 162.3
(C), 160.9 (C), 141.7 (C), 140.9 (C), 135.5 (C), 128.4 (CH), 128.1
(CH), 128.0 (CH), 66.8 (CH2), 50.4 (CH), 41.5 (CH2), 24.8 (CH),
22.7 (CH3), 21.8 (CH3), 18.7 (CH3), 12.4 (CH3); HRMS (EI) m/z
calcd for C19H24N2O3S 360.1508, found 360.1521.
Hydrogenolysis of Compounds 21: The procedure is the same
as that for compounds 8a-y.
In Vitro Evaluation of Various Compounds: A disk diffusion
method was utilized to evaluate the in vitro antibacterial activity
of various 2,5-disubstituted 1,3-azoles against S. aureus ATCC
29213. Culture plates were prepared using polystyrene 100 mm
tissue culture dishes (Corning Glass Works, Corning, NY) with
BBL Mueller Hinton II agar (Becton, Dickinson and Company,
Sparks, MD). The compounds were diluted with DMSO to yield
a final concentration of 5 mg/mL. The solutions were spotted on
6 mm blank paper disks (Becton, Dickinson and Company,
Sparks, MD) to deliver 50 μg per disk. The disks were placed on
lawns of S. aureus spread with cotton swabs from 0.5 McFar-
land unit turbidometric standard cell suspensions (Scientific
Device Lab. Inc., Des Plaines, IL). The culture plates were
incubated at 37 °C for 18-24 h prior to reading.
Acknowledgment. The authors acknowledge to Ministerio
ꢀ
of Educacion y Ciencia (CTQ2007-61462 and CTQ2006-
01317) and Centro de Investigacion Prıncipe Felipe (CIPF)
´
ꢀ
ꢀ
for financial support. R.B. thanks the Ministerio de Educacion
y Ciencia of Spain (FPU 2004-0303) for a predoctoral fellow-
ship; J.P. thanks the Instituto de Salud Carlos III del Ministerio
de Sanidad of Spain for a Miguel Servet research contract
(CP07/00314).
Hydrogenolysis or Hydrolysis of Compounds 9 and 17 To
Furnish Thiazoles 2: The procedures are the same as those for
compounds 8 and 16.
Supporting Information Available: Characterization data
1
and H and 13C NMR spectra for all of the new compounds.
2-(4-Methoxyphenyl)-5-phenylthiazole-4-carboxylic acid (2g):
Yield 99%; white solid; mp 160-162 °C; H NMR (300 MHz,
This material is available free of charge via the Internet at http://
pubs.acs.org.
1
8996 J. Org. Chem. Vol. 74, No. 23, 2009