Selective synthesis of 2-substituted 4-carboxy oxazoles, thiazoles and thiazolidines from serine or cysteine amino acids

Article abstract of DOI:10.1016/j.tet.2010.09.104

The synthesis of new 4-carboxy oxazoles, thiazoles and thiazolidines by condensation of serine or cysteine with aldehydes or acids is described. Due to the optimization of a mild and selective procedure, which takes advantage of the positive effect of mic

Full text of DOI:10.1016/j.tet.2010.09.104

Tetrahedron 67 (2011) 267e274
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Tetrahedron
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Selective synthesis of 2-substituted 4-carboxy oxazoles, thiazoles and
thiazolidines from serine or cysteine amino acids
*
Barbara Di Credico, Gianna Reginato , Luca Gonsalvi, Maurizio Peruzzini, Andrea Rossin
Consiglio Nazionale delle Ricerche, Istituto di Chimica dei Composti Organometallici (ICCOM-CNR), Via Madonna del Piano 10, 50019 Sesto Fiorentino (Firenze), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 July 2010
Received in revised form 3 September 2010
Accepted 28 September 2010
Available online 25 November 2010
The synthesis of new 4-carboxy oxazoles, thiazoles and thiazolidines by condensation of serine or cys-
teine with aldehydes or acids is described. Due to the optimization of a mild and selective procedure,
which takes advantage of the positive effect of microwave irradiation on the MnO2 mediated oxidation
step, the 2-substituted-4-carboxy derivatives can be obtained in multi-gram scale. Examples of co-
ordination chemistry to Ni(II) and Co(II) are described.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Carboxy thiazoles
Carboxy oxazoles
Microwave activation
Multidentate ligands
1. Introduction
Finally, they can be used as stabilizers for polymeric materials,22 as
photosensitizers23 and, once coordinated to technetium or rhe-
The development of macromolecular architectures having de-
fined structural motifs is a subject of intense research in different
fields: molecular and ion recognition,1e3 supramolecular chemis-
try,4 drug design5,6 and material science.7 In this regard nitrogen-
containing heterocycles have been widely used as ligands as they
may favour the assembly of polymeric, polydimensional architec-
tures also by establishing a variety of non-covalent interactions,
such as dipoleedipole and hydrogen-bonding via chelation or co-
ordination to different metal centres.
In particular, mixed N, S- or N, O-heterocycles, such as thiazo-
lidines, thiazoles and oxazoles have received large attention. These
heterocycles exhibit an interesting biological activity. Their struc-
tural motifs are present in thiopeptide antibiotics,8,9 and are re-
cognized as signature metal binding sites, common to many
clinically important macrocyclic peptides.10,11 Many oxazole and/or
thiazole-containing macrocycles are naturally occurring molecules,
i.e., Bistratamides,12 Didmolamides A and B,13 Lyngbyabellin A,14
Calyculins,14,15 and show cytotoxic, antimicrobial and multiple
drug resistance activities. Furthermore, these compounds have
shown wide practical applications in material science; they exhibit
favourable fluorescence,16,17 solvatochromic, electrochemical, NLO
and photochromic properties and have been used for organic light-
emitting diodes (OLEDs) and semiconductor materials, as well as in
optical data storage devices, and second-harmonic generators.18e21
nium, as radiopharmaceuticals for tumour imaging and/or
radiotherapy.24
Recently, thiazole-based nicotinate and isonicotinate derivatives
were chosen as promising organic connectors in crystal engineer-
ing, as the coexistence of thiazole-spaced pyridyl and carboxylate
moieties could afford a rich variety of coordination modes, result-
ing in interesting polymetallic architectures.25 These studies sug-
gest that such flexible ligands may be quite versatile to stabilise
metallorganic supramolecular systems.25 Obviously the screening
of a wider class of thiazole(oxazole)-based ligands would be very
important to obtain a better insight on the substituent effects on
the 3D self-assembly when coordinating transition metal moieties.
For this reason, a general, mild and selective procedure for pre-
paring 4-carboxy oxazole, thiazole and thiazolidine compounds in
large quantities would be very desirable.
Herein, we report on the preparation and full characterization of
some new carboxy thiazole(oxazole)-based ligands using a simple
synthetic approach, which starts from easily available building
blocks and has been optimized to allow for multi-gram scale
preparation of a variety of 2-substituted, 4-carboxy heterocycles,
and examples of the coordination chemistry towards Ni(II) and Co
(II) salts.
2. Results and discussion
Cyclisation of cysteine side-chains onto carbonyl groups yield-
ing thiazole five-membered heterocycles is a well established
* Corresponding author. Tel.: þ39 055 5225255; fax: þ39 055 5225203; e-mail
address: gianna.reginato@iccom.cnr.it (G. Reginato).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.104

268
B. Di Credico et al. / Tetrahedron 67 (2011) 267e274
procedure,26 which has found many applications.27e29 Following
this approach, -cysteine ethyl ester 1 was reacted with different
pyridyl- and carboxaldehydes 2aed to afford the corresponding
thiazolidine derivative 3aed as shown in Scheme 1.
Finally, ester saponification with Cs2CO3 in aqueous methanol
afforded the corresponding carboxythiazoles 5aed, which were
isolated after crystallization from acidic water and fully character-
ized in solution by conventional NMR and MS techniques. Suitable
crystals of 5a$0.5H2O were grown from diluted water solutions and
the corresponding X-ray crystal structure is presented in Fig. 1.
L
KHCO3
S
H2O/MeOH
RCHO
2a-d
SH
+
R
N
EtOOC
N
EtOOC
NH2.HCl
H
3a-d
1
N
87-91%
a
b
R =
R =
R =
COOEt
c
COOEt
d
R =
Scheme 1.
Condensation reactions were carried out in aqueous methanol
containing potassium bicarbonate and, as expected, mixtures of
two diastereoisomers were obtained, due to the presence of a new
stereogenic centre generated at the C-2 atom of the thiazolidine
ring.
The thiazolidines 3aed synthesised by this procedure were
converted into the corresponding thiazoles via oxidative de-
hydrogenation. Several methods are described to perform this
transformation albeit drawbacks, such as low yields, limited sta-
bility to reaction conditions, loss of optical purity in the case of
some chiral thiazoles and hazardous reaction conditions hamper
large scale synthesis. Our aim was to improve the existing pro-
cedures to obtain the targeted thiazoles in large scale and high
yields. First attempts using a mixture of CBrCl3/DBU10,30 yielded as
expected the thiazole derivatives 4aed, albeit in poor yields. DDQ31
and NiO2.27,32,33 were also effective, however the yields were very
poor and partially reduced thiazolines were found as by-products
in some cases. Oxidation was most conveniently performed with
manganese dioxide,12e14,26,34e41 which provided the desired thia-
zoles in very good yields, although under rather harsh conditions.
Best conditions required benzene as solvent in the presence of
pyridine for 24 h at 55 ꢀC, using a 25-fold excess of the commer-
cially available activated MnO2.26,40
Fig. 1. Double hydrogen bonding of water to neighbouring thiazole molecules in the
lattice of 5a$0.5H2O (a) and X-ray crystal structure of its asymmetric unit (b). Thermal
ellipsoids in (b) are drawn at 40% probability.
In order to find milder and more general reaction conditions for
our synthetic protocol, we decided to investigate the effect of mi-
crowave irradiation on the oxidation step, since the efficiency of
microwave flash heating in accelerating oxidation processes has
been successfully demonstrated42 and beneficial effects have been
reported in MnO2 mediated oxidations.43,44 In keeping with our
expectations, the microwave-assisted reaction shortened the re-
action time significantly and, although an excess of MnO2 was still
necessary (5 equiv), under optimised conditions, (30 s irradiation,
300 W microwave source, 100 ꢀC), using toluene instead of benzene
and without the need of pyridine, led to quantitative formation of
thiazoles 4aed (Scheme 2) irrespective of the substituent at the C-2
position. The absence of added base, made possible by the use of
microwave (MW) irradiation, results in turn in a wider scope of this
protocol, potentially applicable to the synthesis of optically active
thiazoles, where the presence of bases in the reaction mixture
should be avoided being responsible, in some cases, of product
racemization.27,45
The asymmetric unit consists of two thiazoles and a clathrated
water molecule hydrogen-bonded to one carboxylic group {d[O
ꢀ
(1)/O(5)]¼2.582(4) A} that reduces the overall symmetry (Fig. 1b).
Additional hydrogen bonding with the N atom of the thiazole ring
of the neighbouring molecule is present {d[O(5)/N(3)]¼3.032
ꢀ
(5) A, Fig. 1a}, thus creating a 3D network. The distance between
ꢀ
two adjacent thiazole rings is 3.73 A, thus confirming the existence
of a strong
p-stacking in the lattice. Surprisingly, the Cambridge
Crytallographic Database includes only one organic structure con-
taining the thiazole ring, i.e., the (oxythiamineH)(pic-
rolonate)2$2H2O.46 However, in such derivative, the N atom of the
five-membered heterocycle is alkylated, and the overall charge is
positive (thiazolium ion). This situation slightly modifies the bond
lengths with respect to the neutral ring, without strong deviations
from the ordinary C]C and C]N bonds. (see Supplementary data).
4-Carboxyoxazolidines analogues were also prepared. Many
methodologies have been developed in the past for oxazoles for-
MnO2 (5eq)
mation.47 We decided to prepare
b-hydroxyamides 8aed from
Cs2CO3
MeOH/H2O
toluene
serine ethyl or benzyl esters 6a,b by EDC-mediated coupling with
terephthalic acid monomethyl ester (7a) or isonicotinic acid (7b).
One-pot cyclization and oxidation with bis(2-methoxyethyl)ami-
nosulfur trifluoride solution (Deoxo-Fluor) and CBrCl3 and DBU led
to oxazole 9aed without the need to isolate the intermediate
oxazoline (Scheme 3).48,30
S
S
MW
3a-d
R
R
N
4a-d
N
5a-d
EtOOC
HOOC
98-99%
Scheme 2.

B. Di Credico et al. / Tetrahedron 67 (2011) 267e274
269
O
EDC, Et3N
DCM
OH
O
O
OH2
OH
.
R'OOC NH2.HCl+
6a,b
M(OAc)2 4H2O
RCOOH
H2O
H2O
R
N
H
COOR'
S
5c
N
O
M
7a,b
8a-d
H2O
O
95 °C 24h
H2O
6a
R' = Et
1) Deoxo-Fluor
2) DBU, CBrCl3
6b
R' = Bn
a
M = Ni,
12a,b
b Co
7a R =
COOMe
O
R
Scheme 6.
7b
R =
N
N COOR'
9a-d
9a
R' = Bn R = Py (52%)
9b
9c
9d
R' = Et R = PhCOOMe (50%)
R' = Et R = Py (72%)
R' = Bn R = PhCOOMe (51%)
Scheme 3.
In particular, serine benzyl ester was used to evaluate a different
protecting group, which might be especially useful in view of de-
manding orthogonally protected carboxy moieties, as in com-
pounds 9b or 9d. Saponification of 9c with Cs2CO3 gave the
corresponding carboxazole 10a, which was isolated after crystalli-
zation from acidic water and characterized by elemental analysis
and spectroscopic methods. Alternatively, 10a was obtained by
palladium(0)-catalyzed hydrogenation of 9a, albeit in significantly
lower yield (Scheme 4).
Fig. 2. 3D solid state packing and hydrogen bonding network in the lattice of 12a.
Hydrogen bonds drawn in yellow dotted lines.
Cs2CO3
MeOH/H2O
ligands, in a cis-disposition. One carboxylic group is linked to the
metal, while the other is ‘pendant’, engaging in extensive hydrogen
bonding with the neighbouring water molecules and with the
carboxylic groups of the adjacent molecules in the crystal lattice
(see Fig. 3 and Supplementary data for details).
H2/Pd
O
N
N
9c
9a
COOH 39%
69%
10a
Scheme 4.
The dicarboxylic acid 10b was prepared by saponification of 9b
with Cs2CO3 in aqueous methanol as above, while the mono-
protected oxazoles 11a and 11b could in turn be obtained by sa-
ponification or hydrogenolysis of 9d, respectively. These results
confirm that in such compounds the benzyl ester can be advanta-
geously used as orthogonal protective group for obtaining mono-
carboxy derivatives (Scheme 5).
Cs2CO3
MeOH/H2O
O
N
HOOC
HOOC
9b
Fig. 3. X-ray crystal structure of complex 12a. Thermal ellipsoids are drawn at 40%
probability. The same colour code of Fig. 1 has been used.
COOH
10b
Cs2CO3
MeOH/H2O
O
N
9d
Suitable crystals of 12a$H2O were grown from diluted water
solutions and the corresponding X-ray crystal structure is pre-
sented in Fig. 2. The resulting complex [Ni(5c)(H2O)4$H2O] shows
an (N,O)-chelating coordination mode of the (deprotonated) 5c to
the Ni(II) ion. The octahedral geometry is completed by four aquo
ligands, in a cis-disposition. One carboxylic group is linked to the
metal, while the other is ‘pendant’, engaging in extensive hydrogen
bonding with the neighbouring water molecules and with the
carboxylic groups of the adjacent molecules in the crystal lattice
(see Fig. 3 and Supplementary data for details).
COOBn
98%
89%
11a
H2/Pd
O
N
MeOOC
COOH
11b
Scheme 5.
As an example of the coordination ability of these new ligands,
thiazole-2,4-dicarboxylic acid 5c was reacted with several transi-
tion metals using solvotermic conditions.49 Interesting results have
been obtained in the case of nickel and cobalt acetate tetrahydrate,
which under hydrothermal conditions at 90 ꢀC gave the two new
complexes 12a,b (Scheme 6).
A crystallization water molecule is included in the asymmetric
unit, interacting through additional hydrogen bonding to the co-
ordinated aquo ligands. The presence of an extended hydrogen
bonding network due to the presence of several polar groups in the
asymmetric unit confers a ‘pseudo-polymeric’ nature to these
solids, being insoluble in all solvents.
Suitable crystals of 12a$H2O were grown from diluted water
solutions and the corresponding X-ray crystal structure is pre-
sented in Fig. 2. The resulting complex [Ni(5c)(H2O)4$H2O] shows
an (N,O)-chelating coordination mode of the (deprotonated) 5c to
the Ni(II) ion. The octahedral geometry is completed by four aquo
3. Conclusions
We have reported a selective and general procedure for the
synthesis of 4-carboxythiazoles, showing that both reaction time

270
B. Di Credico et al. / Tetrahedron 67 (2011) 267e274
and the need of polluting reagents can be dramatically reduced
by MW activation during the oxidation step. The corresponding
4-carboxy oxazoles have also been prepared via a similar syn-
thetic protocol, while the use of a benzyl moiety as protective
group has been exploited to prepare orthogonally protected car-
boxy moieties. The coordination ability of 5c towards nickel(II)
and Co(II) in aqueous environment has been analysed, leading to
(N,O)-bidentate chelation in two new complexes in which an
extensive 3D network is created through hydrogen bonding.
Different transition metal ions and the possible assembly of thi-
azole/oxazole-based metal-organic frameworks are currently
under investigation.
a yellow oil containing a 1:1 mixture of diastereoisomers. The
mixture (100 mg) were purified by flash column chromatography
to get an analytically pure sample. Rf¼0.5 (petroleum ether/
AcOEt¼2/1); 1H NMR (300 MHz, CDCl3, 25 ꢀC):
d 8.64e8.61
(8.58e8.55) (m, 1H), 7.70e7.62 (m, 1H), 7.35e7.16 (m, 2H), 5.85
(5.65) [br s (d, J¼11.25 Hz), 1H], 4.51 (br s, 1H), 4.27 (4.26) (q,
J¼7.1 Hz, 2H), 3.48e3.29 (m, 2Hþ1H), 1.32 (1.31) (t, J¼7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3, 25 ꢀC):
d 171.6 (170.6), 158.7 (156.6), 149.8
(149.6), 136.7, 123.3 (122.9), 122.1 (121.4), 71.6 (71.0), 66.3 (65.6),
61.6 (61.5), 39.4 (38.7), 14.13; IR (KBr): n ;
3290 (NH), 1747 (CO) cmꢁ1
MS, m/z (%): 238(3) [Mþ], 166(100) [(MꢁCOOEt)þ]. C11H14N2O2S
(238.31): calcd C, 55.44; H, 5.92; N, 11.76, found C 55.73, H 5.93, N
11.78.
4. Experimental section
4.1. General
4.2.2. (R,S)-Ethyl-2-(4-(pyridin-4-yl)-phenyl)-thiazolidine-4-(R)-
carboxylate (3b). Reaction of 1 (2.00 g, 10.8 mmol,) with 4-(4-for-
mylphenyl)-pyridine (2.18 g, 11.9 mmol) and KHCO3 (10.8 g,
10.8 mmol) in MeOH (54.0 mL) and H2O (54.0 mL) gave 9.75 g (99%)
All manipulations were performed under a dry nitrogen atmo-
sphere using vacuum-lines and standard Schlenk techniques.
Dichloromethane, benzene and methanol were dried by standard
methods and distilled under nitrogen before use. All the other
solvents were dried and degassed by MB SPS solvent purification
system (http://solventpurifier.com). All reagents were obtained
from commercial suppliers and used without further purification.
Reactions were monitored by TLC on SiO2 plates; detection was
made using a KMnO4 basic solution. Flash column chromatography
was performed using glass columns (10e50 mm wide) and SiO2
(230e400 mesh).
of 3a as
a yellow solid containing a 1:1.5 mixture of di-
astereoisomers. The mixture (100 mg) were purified by flash col-
umn chromatography to get an analytically pure sample. Rf¼0.4
(petroleum ether/AcOEt¼1/3); 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
8.63e8.60 (m, 2H), 7.70e7.62 (m, 4H), 7.47e7.44 (m, 2H), 5.86
(5.58) (s, 1H), 4.24 (4.23) (q, J¼7.1 Hz, 2H), 3.99e3.94 (4.16e4.12)
(m, 1H), 3.48e3.44 (3.40e3.35) (m, 1H), 3.17e3.13 (3.14e3.08) (m,
1H), 2.74 (br s, 1H), 1.29 (1.28) (t, J¼7.1 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3, 25 ꢀC):
d 170.9 (171.4), 150.02, 147.3 (147.5),
138.2 (142.6), 139.1 (137.2), 128.0 (127.4), 127.0 (126.8), 121.3, 71.8
(70.0), 65.5 (64.2), 61.5 (61.4), 39.1 (38.1), 14.0; IR (KBr): 3255
Microwave irradiation experiments were performed using a sin-
gle-mode Discover System BenchMate 220VAC750 Hz from CEM
Corporation,50 using standard Pyrex vessels or flasks in open vessel
mode.
n
(NH), 1730 (CO) cmꢁ1
;
MS, m/z (%): 314(3) [Mþ], 241(52)
[(MꢁCOOEt)þ], 214(100). C17H18N2O2S (314.40): calcd C, 64.94; H,
5.77; N, 8.91, found C 65.09, H 5.75, N 8.92.
Deuterated solvents for routine NMR measurements were dried
over molecular sieves. 1H NMR spectra were recorded operating at
300.13 and 400.1 MHz; 13C NMR spectra were recorded operating at
75.48 and 100.61 MHz. Peak positions are relative to tetrame-
thylsilane (1H) and were calibrated against the residual solvent
resonance. Coupling constants (J) were reported in hertz. When
a mixture of diastereoisomers is present, signals of the minor di-
astereoisomer are reported in parentheses. FTIR spectra were
measured using KBr pellets or solution cells.
4.2.3. (S,R)-Diethyl thiazolidine-2,4-(R)-dicarboxylate (3c). Reaction
of 1 (8.00 g, 43.1 mmol) with ethyl glyoxalate (50% in toluene)
(9.00 mL, 90.5 mmol) and KHCO3 (4.31 g, 43.1 mmol) in MeOH
(215 mL) and H2O (215 mL) gave 9.23 g (92%) of 3c as a yellow oil
containing
a 1:3 mixture of diastereoisomers. The mixture
(100 mg) were purified by flash column chromatography to get an
analytically pure sample. Rf¼0.7 (hexane/AcOEt¼3/2); 1H NMR
(300 MHz, CDCl3, 25 ꢀC):
d 5.07 (4.88) (s, 1H), 4.26e4.17 (m,
Mass spectra were obtained at a 70 eV ionization potential and
are reported in the form m/z (intensity relative to base¼100).
ESI-MS spectra were done on an LCQ Orbitrap mass spectrom-
eter equipped with a conventional ESI source by direct injection of
the sample solution 80 scans were accumulated and averaged for
each spectrum.
2Hþ2H), 4.15e4.13 (4.40e4.36) (m, 1H), 3.84e3.78 (3.7e3.71) (dd,
JAB¼6.0, JBX¼10.2 Hz, 1H), 3.29e3.23 (3.23e3.17) (dd, JAx¼10.2,
JAB¼6.0 Hz, 1H), 2.75 (t, Japp¼10.2 Hz, 1H), 1.26 (1.25) (t, J¼7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3, 25 ꢀC):
d 170.8 (171.0), 169.8 (170.3),
66.4 (65.4), 64.6 (65.2), 61.6 (62.0), 37.7 (37.4), 14.0, 13.9; IR (KBr):
n
3293 (NH), 1740 (CO) cmꢁ1; MS, m/z (%): 233(2) [Mþ], 160(100)
[(MꢁCOOEt)þ]. C9H15NO4S (233.28): calcd C, 46.34; H, 6.48; N, 6.00,
found C 46.46, H 6.45, N 5.09.
4.2. General procedure to ethyl 2(R,S)-substituted-
thiazolidine-4(R)-carboxylate (3aed)
4.2.4. (R,S)-Ethyl-2-[4-(methoxycarbonyl)phenyl]-thiazolidine-4(R)-
carboxylate (3d). Reaction of 1 (8.00 g, 43.1 mmol) with methyl
4-formylbenzoate (7.78 g, 47.4 mmol) and KHCO3 (4.31 g,
43.1 mmol) in MeOH (215 mL) and H2O (215 mL) gave 12.4 g (98%)
of 3d as a yellow oil containing a 1:1 mixture of diastereoisomers.
The mixture (100 mg) were purified by flash column chroma-
tography to get an analytically pure sample. Rf¼0.4 (hexane/
Aldehydes 2aed (1.1 equiv) were suspended in MeOH, then
a solution of the commercially available L-cysteine ethyl ester
hydrochloride 1b (1.1 equiv) dissolved in H2O together with
KHCO3 (1.0 equiv) was added and the resulting mixture was stir-
red at room temperature overnight. After evaporation of MeOH
the aqueous layer was extracted with ethyl acetate. The combined
organic layers were washed with brine (100e200 mL depending
on the reaction scale) and dried over Na2SO4. Evaporation of the
solvent afforded compounds 3aed, which were used without
further purification.
AcOEt¼2/1); 1H NMR (300 MHz, CDCl3, 25 ꢀC):
d 7.91 (7.95)(d,
J¼8.3 Hz, 2H), 7.54(7.47) (d, J¼8.3 Hz, 2H), 5.80 (5.51) (s, 1H), 4.28
(4.30) (q, J¼7.1 Hz, 2H), 3.94e3.88 (4.08e4.05) (m, 1H), 3.84 (3.83)
(s, 3H), 3.43e3.37 (3.31e3.24) (dd, JAB¼10.3, JAX¼7.1 Hz, 1H),
3.11e3.04 (m, 1H), 2.91 (br s, 1H), 1.24 (1.23) (t, J¼7.1 Hz, 3H); 13C
4.2.1. (R,S)-Ethyl-2-(pyridin-2-yl-)thiazolidine-4-(R)-carboxylate
(3a)51. Reaction of 1 (7.70 g, 41.5 mmol) with 2-pyridinecarbox-
aldehyde (4.00 mL, 49.8 mmol) and KHCO3 (41.5 g, 41.5 mmol) in
MeOH (210 mL) and H2O (210 mL) gave 9.85 g of 3a (99%) as
NMR (75 MHz, CDCl3, 25 ꢀC):
d 171.3 (170.2), 166.4 (166.3), 146.8
(143.1), 129.4 (129.7), 129.2, 127.3 (126.5), 69.8 (71.7), 64.2 (65.4),
61.5 (61.4), 51.9 (51.8), 38.0 (39.0), 13.9; IR (KBr): n 3290 (NH), 1725
(CO) cmꢁ1; MS, m/z (%): 295 (8) [Mþ], 223(100) [(MꢁCOOEt)þ].

B. Di Credico et al. / Tetrahedron 67 (2011) 267e274
271
C14H17NO4S (295.35): calcd C, 56.93; H, 5.80; N, 4.74, found C
56.84, H 5.82, N 4.75.
overnight. The reaction mixture was then concentrated in vacuo to
remove MeOH. The aqueous phase was washed with ethyl acetate
then acidified with concentrated HCl (1ꢂpHꢂ4) to let carboxylic
acid gradually precipitate from the reaction medium. The solid was
collected by filtration on paper and washed several times with
EtOH, H2O and Et2O to afford the pure acids 5aed.
4.3. General MnO2 oxidation procedure (4aed)
To a solution of the (S,R)-2-substituted-4-(R)-carbethoxy-1,3-
thiazolidine 3aed (1.0 equiv) in toluene, activated MnO2 (5.0 equiv)
was added. The sealed flask was inserted into the cavity of a Dis-
covery Microwave System apparatus and heated for 30 s at 100 ꢀC
and 300 W irradiation (value preset on the Microwave oven). The
reaction mixture was then filtered through Celite and washed with
toluene. The filtrate and washings were put together and concen-
trated under vacuum to afford thiazoles 4aed, which were purified
by flash chromatography.
4.4.1. 2-(Pyridin-4-yl)-thiazole-4-carboxylic acid (5a). Reaction of
4a (6.88 g, 29.5 mmol) with Cs2CO3 (19.2 g, 59.0 mmol), in MeOH
(295 mL) and H2O (295 mL) gave 4.41 g (72%) of 5a as a white solid.
1H NMR (300 MHz, DMSO-d6, 25 ꢀC):
d
8.66 (dm, J¼4.8 Hz, 1H), 8.57
(s, 1H), 8.15 (dm, J¼7.9 Hz, 1H), 8.00 (dtapp, J¼7.8, 1.7 Hz, 1H), 7.54
(ddd, J¼7.8, 4.8, 1.1 Hz, 1H); 13C NMR (100.6 MHz, DMSO-d6, 25 ꢀC):
d
n
168.8, 162.1, 149.9, 149.8, 148.4, 138.0, 130.9, 125.7, 119.4; IR (KBr):
3114 (OH), 1709 (CO) cmꢁ1; ESI-MS, m/z (%): 206(100) [Mþ];
4.3.1. Ethyl-2-(pyridin-2-yl)-thiazole-4-carboxylate (4a)52. Reaction
of 3a (10.0 g, 42.1 mmol) with MnO2 (18.3 g, 210 mmol) in toluene
C9H6N2O2S$1/2H2O (215.23): calcd C, 50.02; H, 3.28; N,13.02, found
C 50.07, H 3.31, N 12.98.
(420 mL) gave 6.87 g (70%) of 3a as white solid. Rf¼0.5 (petroleum
1
ether/AcOEt¼2/1); H NMR (300 MHz, CDCl3, 25 ꢀC):
d
8.56 (ddd,
4.4.2. 2-[4-(Pyridin-4-yl)phenyl]-thiazole-4-carboxylic acid (5b). Re-
action of 4b (1.76 g, 5.70 mmol) with Cs2CO3 (3.70 g, 11.3 mmol), in
MeOH (50.0 mL) and H2O (50.0 mL) gave 1.25 g (78%) of 5b as
J¼4.8, 1.7, 1.1 Hz, 1H), 8.28 (dtapp, J¼7.7, 1.1 Hz, 1H), 8.21 (s, 1H), 7.77
(tappd, J¼7.7, 1.7 Hz, 1H), 7.31 (ddd, J¼7.7, 4.8, 1.1 Hz, 1H), 4.40 (q,
J¼7.1 Hz, 2H), 1.38 (t, J¼7.1 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3,
a white solid. 1H NMR (400 MHz, DMSO-d6, 25 ꢀC):
d 13.25 (br s,
25 ꢀC):
d
161.3, 169.8, 150.3, 149.3, 148.1, 137.0, 129.4, 125.0, 120.1,
1H), 8.68 (d, J¼5.9 Hz, 2H), 8.55 (s, 1H), 8.12 (d, J¼8.3 Hz, 2H), 8.00
61.4, 14.2 ppm; IR (KBr):
n
1724 (CO) cmꢁ1; MS, m/z (%): 234(5)
(d, J¼8.3 Hz, 2H), 7.80 (d, J¼5.9 Hz, 2H); 13C NMR (100.6 MHz,
[Mþ], 161(100) [(MꢁCOOEt)þ]; C11H10N2O2S (234.27): calcd C,
DMSO-d6, 25 ꢀC):
d 167.0, 162.5, 150.8, 148.9, 146.2, 139.5, 133.5,
56.39; H, 4.30; N, 11.96, found C 56.22, H 4.61, N 12.01.
129.5, 128.2, 127.6, 121.6; IR (KBr): n ;
3122 (OH), 1690 (CO) cmꢁ1
ESI-MS, m/z (%): 283(100) [(MþH)þ]; C15H10N2O2S$1/2H2O
(282.32): calcd C, 61.84; H, 3.81; N, 9.62, found C 61.71, H 3.84, N
9.56.
4.3.2. Ethyl-2-[4-(pyridin-4-yl)phenyl]-thiazole-4-carboxylate
(4b). Reaction of 3b (2.90 g, 9.20 mmol) with MnO2 (4.00 g,
46.0 mmol) in toluene (92.0 mL) gave 1.86 g (65%) of 3a as yellow
solid. Rf¼0.3 (petroleum ether/AcOEt¼2/1); 1H NMR (400 MHz,
4.4.3. Thiazole-2,4-dicarboxylic acid (5c). Reaction of 4c (3.90 g,
17.0 mmol) with Cs2CO3 (22.2 g, 68.0 mmol) in MeOH (170 mL) and
H2O (170 mL) gave 2.46 g (83%) of 5c as a white solid. 1H NMR
CDCl3, 25 ꢀC):
d
8.67 (dd, J¼4.6, 1.6 Hz, 2H), 8.17 (s, 1H), 8.11 (dd,
J¼8.4, 1.1 Hz, 2H), 7.70 (dd, J¼6.6, 1.8 Hz, 2H), 7.52 (dd, J¼4.6, 1.6 Hz,
2H), 4.44 (q, J¼7.1 Hz, 2H), 1.42 (t, J¼7.1 Hz, 3H); 13C NMR
(300 MHz, DMSO-d6, 25 ꢀC): 8.73 (s, 1H); 13C NMR (75 MHz,
DMSO-d6, 25 ꢀC):
d 162.8, 161.6, 160.7, 149.7, 135.0; IR (KBr): n 3140
d
(100.6 MHz, CDCl3, 25 ꢀC):
d
167.8, 161.3, 150.3, 148.2, 147.0, 140.1,
133.2, 127.6, 127.5, 127.3, 121.4, 61.5, 14.3; IR (KBr):
n
1720
(OH), 1719 (CO) cmꢁ1; ESI-MS, m/z (%): 173(100) [Mþ], 128(30)
[(MꢁCO2H)þ]; C5H3NO4S$H2O (191.16): calcd C, 31.41; H, 2.64; N,
7.33, found C 31.68, H 2.66, N 7.35.
(CO) cmꢁ1; MS, m/z (%): 238(100) [(MꢁCOOEt)þ]; C17H14N2O2S
(310.37): calcd C, 65.79; H, 4.55; N, 9.03, found C 66.01, H 4.56, N
9.02.
4.4.4. 2-(4-Carboxyphenyl)thiazole-4-carboxylic acid (5d). Reaction
of 4d (8.25 g, 28.3 mmol) with Cs2CO3 (36.9 g, 113 mmol) in MeOH
(280 mL) and H2O (280 mL) gave 5.39 g (76%) of 5d as a white solid.
4.3.3. Diethyl thiazole-2,4-dicarboxylate (4c). Reaction of 3c (6.10 g,
26.1 mmol) with MnO2 (11.35 g, 130.5 mmol) in toluene (261.0 mL)
gave 4630 mg (77%) of 4c as white solid. Rf¼0.7 (hexane/AcOEt¼3/
1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
8.55 (s, 1H), 8.11e8.05 (m, 4H);
13C NMR (100.6 MHz, DMSO-d6, 25 ꢀC):
167.3, 166.5, 162.7, 136.4,
3134 (OH), 1695
2); 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
8.30 (s, 1H), 4.25 (q, J¼7.0 Hz,
d
2H), 4.19 (q, J¼7.0 Hz, 2H), 1.20 (t, J¼7.0 Hz, 3H), 1.16 (t, J¼7.0 Hz,
133.3, 130.7, 130.6, 129.5, 126.9; IR (KBr): n
3H); 13C NMR (100.6 MHz, CDCl3, 25 ꢀC):
d
180.0, 158.8, 158.4, 148.1,
(CO) cmꢁ1; ESI-MS, m/z (%): 249(15) [Mþ], 248(100) [(MꢁH)þ];
C11H7NO4S$H2O (267.26): calcd for C, 49.43; H, 3.39; N, 5.24, found
C 49.76, H 3.30, N 5.21.
132.0, 62.3, 61.0, 13.6, 13.5; IR (KBr): n
1731 (CO) cmꢁ1; MS, m/z (%):
229(5) [Mþ]; 157(100) [(MꢁCO2Et)þ]. C9H11NO4S (229.25): calcd C,
47.15; H, 4.84; N, 6.11, found C 47.25, H 5.02, N 6.02.
4.5. General procedure to methyl 2(R)-amido-3-
hydroxypropanoate3-hydroxy amide (8aed)48
4.3.4. Ethyl-2-[4-(methoxycarbonyl)phenyl]-thiazole-4-carboxylate
(4d). Reaction of 3d (12.0 g, 40.8 mmol) with MnO2 (17.7 g,
204 mmol) in toluene (410 mL) gave 8.25 g (69%) of 4d as yellow
solid. Rf¼0.4 (hexane/AcOEt¼2/1); 1H NMR (300 MHz, CDCl3,
L-Serine methyl ester hydrochloride 6a,b (1.0 equiv) was dis-
solved in CH2Cl2 together with acids 7a,b (1.1 equiv), Et3N
(1.1 equiv) and EDC (1.1 equiv). After stirring overnight, the solution
was washed with H2O, NaHCO3 satd sol and brine, then dried over
Na2SO4. Evaporation of the solvent gave amide 8aed, which were
used without further purification.
25 ꢀC):
d
8.20 (s, 1H), 8.11e8.05 (m, 4H), 4.44 (q, J¼7.1 Hz, 2H), 3.93
(s, 3H), 1.42 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3, 25 ꢀC):
d
167.4, 166.2, 161.2, 148.4, 136.4, 131.8, 130.2, 127.8, 126.8, 61.6, 52.3,
14.3; IR (KBr):
n
1720 (CO) cmꢁ1; MS, m/z (%): 291(100) [Mþ], 218
(100) [(MꢁCO2Et)þ]; C14H13NO4S (291.32): calcd C, 57.72; H, 4.50;
N, 4.81, found C 58.01, H 4.48, N 5.00.
4.5.1. (S)-Benzyl 3-hydroxy-2-(isonicotinamido)-propanoate (8a). Re-
action of 6a (2.47 g, 10.6 mmol) with 7a (1.44 g, 11.7 mmol), Et3N
(1.60 mL, 11.7 mmol), EDC (2.24 g, 11.7 mmol) in CH2Cl2 (90.0 mL)
gave 2.28 g (72%) of 8a as a white solid. 100 mg of the amide were
purified by flash column chromatography to get an analytically
pure sample. Rf¼0.3 (hexane/AcOEt¼1/2); 1H NMR (300 MHz,
4.4. General procedure of saponification (5aed)
2-Substituted-4-carbethoxy-1,3-thiazole 4aed (1 equiv) was
dissolved in MeOH. A solution of cesium carbonate (2 equiv) in H2O
was added and the mixture was stirred at room temperature
CDCl3, 25 ꢀC):
d
8.73 (dd, J¼4.5, 1.6 Hz, 2H), 7.64 (dd, J¼4.5, 1.6 Hz,

272
B. Di Credico et al. / Tetrahedron 67 (2011) 267e274
2H), 7.37 (br s, 5H), 7.19 (br d, J¼3.2 Hz, 1H), 5.26 (s, 1H), 4.92e4.87
(m, 1H), 4.15 (dd, JAB¼11.3, JAX¼3.4 Hz, 1H), 4.06 (dd, JAB¼11.3,
dried over Na2SO4. Evaporation of the solvent and purification by
flash chromatography gave compounds 9aed.
JBX¼3.2 Hz, 1H); 13C NMR (75 MHz, CDCl3, 25 ꢀC):
d 170.1, 165.5,
150.7, 141.0, 135.1, 128.7, 128.3, 127.6, 121.0, 67.9, 63.1, 55.2; IR (KBr):
4.6.1. Benzyl 2-(pyridin-4-yl)oxazole-4-carboxylate (9a). Reaction
of 8a (2.27 g, 7.60 mmol) with Deoxo-Fluor (3.50 mL, 16.1 mmol),
BrCCl3 (2.70 mL, 27.4 mmol) and DBU (4.10 mL, 27.4 mmol) in
CH2Cl2 (76.0 mL) gave 1.10 g (52%) of 9a as a white solid (hexane/
AcOEt¼grad). Rf¼0.25 (hexane/AcOEt¼1/1); 1H NMR (400 MHz,
n
3289 (NH), 3250 (OH),1748 (CO),1644 (CO) cmꢁ1; ESI-MS, m/z (%):
301(100) [(MþH)þ]. C16H16N2O4 (300.31): calcd C, 63.99; H, 5.37; N,
9.33, found C 64.07, H 5.34, N 9.29.
4.5.2. (R)-Methyl 4-(1-ethoxy-3-hydroxy-1-oxopropan-2-ylcarba-
moyl)benzoate (8b). Reaction of 6b (2.14 g, 12.6 mmol) with 7a
(2.50 g, 13.9 mmol), 0.70 mL of Et3N (13.9 mmol) and EDC (2.66 g,
13.9 mmol) in CH2Cl2 (90.0 mL) gave 3.56 g (95%) of 8b as a white
solid. 100 mg of the amide were purified by flash column chro-
matography to get an analytically pure sample. Rf¼0.6 (hexane/
CDCl3, 25 ꢀC):
d
8.77 (d, J¼6.0 Hz, 2H), 8.35 (s, 1H), 7.96 (dd,
J¼6.0 Hz, 2H), 7.35e7.44 (m, 5H), 5.41 (s, 2H); 13C NMR (100.6 MHz,
CDCl3, 25 ꢀC):
d 160.3, 159.9, 150.4, 144.6, 135.0, 134.6, 132.9, 128.4,
128.3, 120.0, 67.0; IR (KBr):
n
1734 (CO) cmꢁ1; MS, m/z (%): 280(5)
[Mþ],146(100) [(MꢁCO2Bn)þ]; C16H12N2O3 (280.28): calcd C, 68.56;
H, 4.32; N, 9.99, found C 68.38, H 4.31, N 10.09.
AcOEt¼1/2); 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
8.05 (d, J¼8.3 Hz,
2H), 7.88 (d, J¼8.3 Hz, 2H), 7.38 (br d, J¼3.2 Hz, 1H), 4.85e4.79 (m,
1H), 4.68 (br s, 1H), 4.28 (q, J¼7.1 Hz, 2H), 4.10 (dd, JAB¼11.3,
JAX¼3.6 Hz, 1H), 4.05 (dd, JAB¼11.3, JBX¼3.2 Hz, 1H), 3.9 (s, 3H), 1.31
4.6.2. Ethyl 2-(4-(methoxycarbonyl)phenyl)-oxazole-4-carboxylate
(9b). Reaction of 8b (3.72 g, 12.6 mmol) with Deoxo-Fluor
(5.70 mL, 26.5 mmol), BrCCl3 (4.50 mL, 45.4 mmol) and DBU
(6.80 mL, 45.4 mmol) in CH2Cl2 (125 mL) gave 1.72 g (50%) of 9b as
a white solid. Rf¼0.35 (hexane/AcOEt¼1/2); 1H NMR (400 MHz,
(t, J¼7.1 Hz, 3H); 13C NMR (100.6 MHz, CDCl3, 25 ꢀC):
¼170.4,166.8,
d
166.2,137.4, 132.9, 129.7, 127.2, 63.1, 62.0, 55.3, 52.4, 14.1; IR (film):
n
3547 (NH), 3277 (OH), 1723 (CO), 1640 (CO) cmꢁ1; ESI-MS, m/z (%):
296(100) [(MþH)þ]. C14H17NO6 (295.29): calcd C, 56.94; H, 5.80; N,
4.74, found C 56.87, H 5.84, N 4.76.
CDCl3, 25 ꢀC):
d
8.35 (s, 1H), 8.17 (d, J¼8.4 Hz, 2H), 8.12 (d, J¼8.4 Hz,
2H), 4.42 (q, J¼7.0 Hz, 2H), 3.93 (s, 3H), 1.40 (t, J¼7.0 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3, 25 ꢀC):
d 160.2, 161.4, 161.1, 144.1, 132.2,
130.5, 130.1, 130.0, 126.8, 61.4, 52.3, 14.3; IR (KBr):
n 1721
4.5.3. (R)-Ethyl 3-hydroxy-2-(isonicotinamido)-propanoate (8c). Re-
action of 6b (5.00 g, 29.5 mmol) with 7b (3.99 g, 32.4 mmol), Et3N
(4.50 mL, 32.4 mmol) and EDC (6.21 g, 32.4 mmol) in CH2Cl2
(250 mL) gave 6.55 g (93%) of 8c as a white solid. 100 mg of the
amide were purified by flash column chromatography to get an
analytically pure sample. Rf¼0.6 (hexane/AcOEt¼1/2); 1H NMR
(CO) cmꢁ1; MS, m/z (%): 275(30) [Mþ], 163(100); C14H13NO5
(275.26): calcd C, 61.09; H, 4.76; N, 5.09, found: C 61.05, H 4.73, N
5.06.
4.6.3. Ethyl 2-(pyridin-4-yl)oxazole-4-carboxylate (9c). Reaction of
8c (1.70 g, 7.10 mmol) with Deoxo-Fluor (3.40 mL, 15.7 mmol),
BrCCl3 (2.50 mL, 25.7 mmol) and DBU (3.80 mL, 25.7 mmol) in
(300 MHz, CDCl3, 25 ꢀC):
d
8.75 (dd, J¼4.4, 1.7 Hz, 2H), 7.66 (dd,
J¼4.4, 1.7 Hz, 2H), 7.12 (br d, J¼3.0 Hz, 1H), 4.85e4.81 (m, 1H), 4.29
(q, J¼7.1 Hz, 2H), 4.13 (dd, JAB¼11.3, JAX¼3.5 Hz, 1H), 4.07 (dd,
JAB¼11.3, JBX¼3.2 Hz, 1H), 1.33 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz,
CH2Cl2 (75.0 mL) gave 1.02 g (72%) of 9c as a white solid. Rf¼0.6
1
(hexane/AcOEt¼1/2); H NMR (400 MHz, CDCl3, 25 ꢀC):
d 8.77 (d,
J¼6.0 Hz, 2H), 8.35 (s, 1H), 7.96 (d, J¼6.0 Hz, 2H), 4.43 (q, J¼7.2 Hz,
CDCl3, 25 ꢀC):
14.14; IR (KBr):
d 170.2, 165.5, 150.6, 140.7, 121.0, 63.2, 62.3, 55.2,
2H), 1.40 (t, J¼7.2 Hz, 3H); 13C NMR (100.6 MHz, CDCl3, 25 ꢀC):
n
3328 (NH), 3260 (OH), 1749 (CO), 1644
d 160.8, 160.1, 150.7, 144.5, 135.3, 133.3, 120.3, 61.5, 14.3; IR (KBr): n
(CO) cmꢁ1; ESI-MS, m/z (%): 239(100) [(MþH)þ]. C11H14N2O4
(238.24): calcd C, 55.46; H, 5.92; N, 11.76, found C 55.52, H 5.91, N
11.73.
1734 (CO) cmꢁ1; MS, m/z (%): 218(22) [Mþ], 106(100); C11H10N2O3
(218.21): calcd C, 60.55; H, 4.62; N, 12.84, found C 60.68, H 4.65, N
12.91.
4.5.4. (R)-Methyl 4-(1-(benzyloxy)-3-hydroxy-1-oxopropan-2-ylcar-
bamoyl)benzoate (8d). Reaction of 6a (2.42 g, 10.4 mmol) with
2.06 g of monomethyl terephthalate 7b (11.4 mmol), 1.60 mL of
Et3N (11.4 mmol) and EDC (2.18 g, 11.4 mmol) in CH2Cl2 (110 mL)
gave 2.75 g (74%) of 8d as a white solid. 100 mg of the amide were
purified by flash column chromatography to get an analytically
pure sample. Rf¼0.6 (hexane/AcOEt¼1/2); 1H NMR (400 MHz,
4.6.4. Benzyl 2-(4-(methoxycarbonyl)phenyl)-oxazole-4-carboxylate
(9d). Reaction of 8d (2.70 g, 7.60 mmol) with Deoxo-Fluor (3.50 mL,
16.1 mmol), BrCCl3 (2.70 mL, 27.4 mmol) and DBU (4.10 mL,
27.4 mmol) in CH2Cl2 (75.0 mL) gave 1.30 g (51%) of 9d as a white
solid. Rf¼0.6 (hexane/AcOEt¼1/1); 1H NMR (400 MHz, CDCl3,
25 ꢀC):
d 8.32 (s, 1H), 8.21e8.12 (m, 4H), 7.48e7.34 (m, 5H), 5.41 (s,
2H), 3.95 (s, 3H); 13C NMR (100.6 MHz, CD2Cl2, 25 ꢀC):
160.8, 144.7, 135.6, 134.7, 132.4, 130.2, 130.0, 129.9, 128.6, 128.5,
d 166.1, 161.4,
CDCl3, 25 ꢀC):
d
8.08 (d, J¼8.7 Hz, 2H), 7.86 (d, J¼8.7 Hz, 2H), 7.35
(br s, 5H), 7.22 (bd, J¼7.2 Hz, 1H), 5.24 (s, 2H); 4.93e4.88 (m, 1H),
126.7, 66.8, 52.3; IR (KBr): n
1722 (CO) cmꢁ1; MS, m/z (%): 246 (2)
4.12 (dd, JAB¼11.3, JAX¼3.6 Hz, 1H), 4.05 (dd, JAB¼11.3, JBX¼3.3 Hz,
[(MꢁCO2Bn)þ], 163(100); C19H15NO5 (337.33): calcd C, 67.65; H,
1H), 3.9 (s, 3H); 13C NMR (100.6 MHz, CDCl3, 25 ꢀC):
d
170.3, 166.7,
4.48; N, 4.15, found: C 67.86, H 4.49, N 4.13.
166.2, 137.3, 135.0, 133.1, 129.8, 128.7, 128.6, 128.2, 127.2, 67.7, 63.3,
55.3, 52.4; IR (KBr):
n
3495 (NH), 3285 (OH), 1724 (CO), 1628
4.7. General procedure for debenzylation
(CO) cmꢁ1; ESI-MS, m/z (%): 358(100) [(MþH)þ]. C19H19NO6
(357.36): calcd C, 63.86; H, 5.36; N, 3.92, found C 63.78, H 5.37, N
3.91.
A solution of carbobenzyloxy-oxazole 9a,d (1 equiv) in MeOH
was purged with N2 and Pd (10 wt %) on carbon was added. H2
(1 atm) was bubbled through the solution for 10 min, then the
mixture was stirred under H2 for 3 h. Filtration through Celite and
evaporation of the solvent gave 10a or 11b.
4.6. General procedure to 2-substituted oxazole-4-
carboxylate (9aed)
A solution of 8aed (1.0 equiv) in CH2Cl2 was cooled to ꢁ20 ꢀC.
Deoxo-Fluor (50% in THF) (2.2 equiv) was added dropwise, and the
mixture was stirred at ꢁ20 ꢀC for 50 min. After addition of BrCCl3
(3.6 equiv) and DBU (3.6 equiv) the reaction was left at 0 ꢀC for 5 h
and then quenched with NaHCO3 satd sol and extracted with ethyl
acetate. The combined organic layers were washed with brine,
4.7.1. 2-(2-Pyridyl)-1,3-oxazole-4-carboxylic acid (10a). Reaction of
9a (1.93 g, 6.90 mmol) and Pd/C (193 mg) in MeOH (140 mL) gave,
after filtration, 513 mg (39%) of 10a as white solid. 1H NMR
(400 MHz, DMSO-d6, 25 ꢀC):
d
8.93 (s, 1H), 8.79 (d, J¼3.5 Hz, 2H),
7.93 (d, J¼3.5 Hz, 2H); 13C NMR (100.6 MHz, DMSO-d6, 25 ꢀC):
d
162.2, 159.4, 151.3, 146.7, 146.6, 133.5, 120.4; IR (film): n 3378 (OH),

B. Di Credico et al. / Tetrahedron 67 (2011) 267e274
273
1726 (CO) cmꢁ1; ESI-MS, m/z (%): 191(100) [(MþH)þ]; C9H6N2O3
(190.16): calcd C, 56.85; H, 3.18; N, 14.73, found: C 56.82, H 3.20, N
14.74.
C5H11NNiO9S$H2O (337.92): calcd C, 17.77; H, 3.88; N, 4.15, found: C
17.70, H 3.62, N 4.43.
4.9.2. [Co(5c)(H2O)4$H2O] (12b). Reaction of Co(OAc)2$4H2O
(0.72 g, 2.89 mmol) and 5c (0.25 g, 1.44 mmol) in 5 mL of H2O gave
0.254 g of 12b as pink solid (29% calculated with respect to the li-
gand). IR (KBr): 3394 (H20), 3214 (OH), 1617 (CO);
C5H11NCoO9S$H2O (338.16): calcd C, 17.76; H, 3.87; N, 4.14, found: C
17.94, H 3.93, N 4.09.
4.7.2. 2-(4-(Methoxycarbonyl)phenyl)oxazole-4-carboxylic acid
(11b). Reaction of 9d (900 mg, 2.70 mmol) and Pd/C (9.03 mg) in
MeOH (55.0 mL) gave, after filtration, 600 mg (89%) of 11b as white
solid. 1H NMR (400 MHz, DMSO-d6, 25 ꢀC):
d
8.92 (s, 1H), 8.16e8.10
(m, 4H), 3.89 (s, 3H); 13C NMR (100.6 MHz, DMSO-d6, 25 ꢀC):
d
165.9, 162.3, 160.6, 132.3, 132.0, 130.5, 129.5, 128.2, 127.0, 52.8; IR
(film):
n
¼2958 (OH), 1718 (CO), 1687(CO) cmꢁ1; ESI-MS, m/z (%):
Acknowledgements
246(100) [(MꢁH)þ]; C12H9NO5 (247.20): calcd C, 58.30; H, 3.67; N,
5.67, found: C 58.31, H 3.60, N 5.77.
Dr. Massimo Calamante at the University of Florence is ac-
knowledged for recording ESI-MS spectra. The authors also thank
ECRF through the motu proprio FIRENZE HYDROLAB project
(www.iccom.cnr.it/hydrolab/) for supporting this research activity
and for sponsoring a doctoral grant to BDC and a post-doctoral
4.8. General procedure to 2-substituted oxazole-4-carboxylic
acids
ꢁ
grant to AR. Ms. Adeline Leliepault from the University of Rouen
Compound 9bed (1 equiv) was dissolved in MeOH and reacted
with a solution of cesium carbonate (2.0 equiv) in H2O. The mixture
was stirred at room temperature overnight, then MeOH was re-
moved. The aqueous phase was washed with ethyl acetate, then
acidified with concentrated HCl (1ꢂpHꢂ4) to let carboxylic acid
gradually precipitate from the reaction medium. The solid was
collected by filtration and washed several times with EtOH, H2O
and Et2O to afford products 10b,c or 11a.
(France) is kindly acknowledged for help in the synthesis of the
complexes 12a,b.
Supplementary data
1H and 13C NMR spectra of new compounds 3aed, 4aed, 5aed,
8aed, 9aed, 10a,b, 11a,b. Crystallographic tables and details for 5a
and 12a. The crystallographic data file (.cif) for 5a (CCDC number
748497) and 12a (CCDC number 783690) have been deposited.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2010.09.104. These data include
MOL files and InChiKeys of the most important compounds de-
scribed in this article.
4.8.1. 2-(4-Carboxyphenyl)oxazole-4-carboxylic acid (10b). Reaction
of 9b (1.72 g, 6.20 mmol) and Cs2CO3 (8.15 g, 25.0 mmol) in MeOH
(50.0 mL) and H2O (50.0 mL) gave 1.45 g (98%) of 10b as a yellow
solid. 1H NMR (400 MHz, DMSO-d6, 25 ꢀC):
d
8.88 (s, 1H), 8.09 (m,
2H), 8.02 (br s, 2H); 13C NMR (100.6 MHz, DMSO-d6, 25 ꢀC):
¼167.2, 167.1, 162.4, 146.4, 134.9, 133.3, 130.6, 129.9, 126.9; IR
d
(film):
n
3000 (OH), 1696 (CO) cmꢁ1; ESI-MS, m/z (%): 248(100)
References and notes
[(MꢁH)þ], 249(15) [Mþ]; C11H7NO5$H2O (251.19): calcd C, 52.60; H,
3.61; N, 5.58, found C 52.43, H 3.58, N 5.62.
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a white solid. 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
8.97 (s, 1H),
8.40e7.98 (m, 9H), 5.12 (s, 2H); 13C NMR (100.6 MHz, CDCl3, 25 ꢀC):
167.0, 162.3, 160.8, 146.5, 135.2, 133.3, 130.6, 130.1, 129.9, 128.1,
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274
B. Di Credico et al. / Tetrahedron 67 (2011) 267e274
~
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