An efficient synthesis of 2,4′-bi-1,3-oxa(thia)zoles as scaffolds for bioactive products

Article abstract of DOI:10.1007/s10593-011-0823-z

A rapid and efficient methodology to prepare 2,4′-bi-1,3-azoles as scaffolds for biologically active marine natural products is described. Hantzsch reaction and oxidative cyclodehydration of β-hydroxy amides or thioamides were used to construct the azole rings. The obtained biheterocycles displayed no cytotoxicity on HCT-15 cell line.

Full text of DOI:10.1007/s10593-011-0823-z

Chemistry of Heterocyclic Compounds, Vol. 47, No. 6, September 2011 (Russian original Vol. 47, No. 6, June, 2011)
AN EFFICIENT SYNTHESIS OF
2,4'-BI-1,3-OXA(THIA)ZOLES AS SCAFFOLDS
FOR BIOACTIVE PRODUCTS
S. Peña1, L. Scarone1, E. Manta1, and G. Serra1*
A rapid and efficient methodology to prepare 2,4'-bi-1,3-azoles as scaffolds for biologically active ma-
rine natural products is described. Hantzsch reaction and oxidative cyclodehydration of ꢀ-hydroxy ami-
des or thioamides were used to construct the azole rings. The obtained biheterocycles displayed no
cytotoxicity on HCT-15 cell line.
Keywords: bi-1,3-azoles, ꢀ-halo ketone, ꢁ-hydroxy amides, Hantzsch reaction, oxidative cyclodehydration.
It is well known that natural products play an important role in drug development, particularly that of
anticancer, antibiotic, and antiparasitic drugs [1]. The structural diversity of natural products has served as an
inspiration source for research of pharmacologically active molecules.
Bioxazoles, bithiazoles, and oxazole-thiazole scaffolds are present in numerous structurally novel and
biologically active marine products [2–4]. Representative examples include hennoxazoles, with a 2,4'-bioxazole
system, isolated from the sponge Polifibrospongia as potent anti-herpes virus agents [5], bengazoles, containing
an uncommon 2,5'-bioxazole, isolated from the sponge Jaspis sp. as anthelmintic, antifungal, and antitumor
agents [6–8], leucamide A, a cyclic heptapeptide with an oxazole-thiazole system, isolated from the sponge
Leucetta microraphis, as moderately cytotoxic towards several tumor cell lines [9], and largazole, a depsipeptide
containing a thiazoline-thiazole system, isolated from the cyanobacterium Symploca sp., a potent histone
deacetylase (HDAC) inhibitor [10].
The 2,4'-biazole fragment is a more common moiety in marine natural products than 2,5'-biazole system.
This is consistent with the biogenesis of those heterocycles that are derived from serine, threonine, or cysteine
residues in peptides by a cyclodehydration and oxidation process [3].
The interest in synthesis of these biheterocycles has stimulated the development of different methodolo-
gies. To construct the 2,4'-bioxazole moiety of (+)-hennoxazole A, Wipf and co-workers employed the
cyclodehydrating Burgess reagent and cupric bromide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) and hexamethylenetetramine (HMTA) to prepare one of the oxazole rings, and Dess-Martin oxidation
and 1,2-dibromotetrachloroethane to prepare the other ring [11]. Later, Williams' group synthetized (–)-hen-
noxazole A using diethylaminosulfur trifluoride (DAST) to prepare oxazoline rings from the appropriate ꢁ-hyd-
roxy amides and bromotrichloromethane in the presence of DBU to obtain the corresponding oxazoles [12].
_______________
*To whom correspondence should be addressed, e-mail: gserra@fq.edu.uy.
1Quimica Farmaceutica Facultad de Quimica, 2124 Montevideo, Uruguay.
______________________________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, 852–859, June, 2011. Original article
submitted September 30, 2010, with revisions April 1, 2011
0009-3122/11/4706-0703©2011 Springer Science+Business Media, Inc.
703
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In 2003, Nan and co-workers reported the synthesis of 2,4'-biheterocycles as intermediates toward the
total synthesis of leucamide A [13, 14]. The methodology used involves Holzapfel’s modified Hantzsch
procedure to obtain the thiazole component, followed by a coupling reaction, DAST-mediated cyclization, and
treatment with bromotrichloromethane with DBU to obtain the oxazole component [15]. A few years later, in
2009, Nan’s group reported the synthesis of C(7)-demethyl largazole analogs containing 2,4'-bithiazole using
two consecutive Hantzsch reactions [16].
As a part of our search for anticancer or antiparasitic drugs candidates employing molecular simplifica-
tion [17–22], we focused on the synthesis of 2,4'-biheterocycles as scaffolds of bioactive products using
Hantzsch and cyclodehydration-oxidation reactions. In the present work, we report the synthesis of biheterocy-
cles of type 1 (Scheme 1) using commercially available starting materials: L-serine methyl ester hydrochloride,
ethyl bromopyruvate, and thioacetamide.
Scheme 1
Me
MeO2C
Me
O
N
N
A
N
N
MeO2C
HO
A
B
X
S
S
H
1
O
Br
EtO2C
MeO2C
HO
Me
S
.
O
NH2
N
A
HCl
+
+
HO
H2N
Me
S
X = O, S
In order to prepare the thiazole ring A, ethyl bromopyruvate and thioacetamide were refluxed in ethanol.
Thiazole 2 was obtained in 81% yield (Scheme 2). Conventional hydrolysis using lithium hydroxide in tetrahyd-
rofuran–water gave carboxylic acid 3 in low yield (44%). In contrast, hydrolysis using 10% aqueous potassium
hydroxide produced the acid 3 in very good yield (86%).
The next step to prepare the ꢁ-hydroxy amide 4 involved amide bond formation to obtain the precursor
of ring B (Scheme 1). The use of N,N'-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP)
as coupling agent allowed us to obtain amide 4 in 83% yield.
Scheme 2
O
KOH,
THF/H2O,
rt, 2 h
Br
EtOH,
reflux, 6 h
EtO2C
H2N
Me
O
N
+
S
EtO
Me
2
S
MeO2C
HO
NH2
Me
O
N
Me
O
N
MeO2C
HO
S
N
S
HO
DCC, Et3N,
DMAP, CH2Cl2,
0ºC to rt, 24 h
H
4
3
704
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Cyclodehydration reaction of ꢁ-hydroxy amide 4 to obtain the corresponding oxazoline 5 was performed
using DAST (Scheme 3). Subsequent oxidation employing bromotrichloromethane and DBU resulted in the
formation of 2-(thiazol-4-yl)oxazole 6 in 78% yield. Consequently, compound 6 was obtained from 4 in 67%
overall yield. The one-pot procedure gave oxazole 6 from ꢁ-hydroxy amide 4 in 53% yield. The isolation of
oxazoline 5 not only allows to improve the yield of oxazole 6, but also to use it as a precursor in the synthesis of
thiazolinylthiazole 8 (Scheme 4).
Scheme 3
1) DAST, CH2Cl2,
–78ºC, 1 h
MeO2C
Me
N
O
N
S
4
2) K2CO3,
–20ºC to rt
5
CBrCl3, DBU,
CH2Cl2,
rt, 12 h
1) DAST, CH2Cl2, –78ºC, 1 h
2) K2CO3, –20ºC to rt
3) BrCCl3, DBU, rt, 12 h
MeO2C
Me
N
N
O
S
6
Thiolysis of oxazoline 5 employing Wipf’s methodology [23], followed by cyclodehydration, permitted
the transformation of ꢁ-hydroxy thioamide 7 into 4-(thiazolin-2-yl)thiazole 8, as well as the unexpected
2,4'-bithiazole 9. Air oxidation of thiazolines to thiazoles during the purification of tantazole A has been
observed previously by Carmelli [24]. Recently, Yao reported the oxidation of thiazoline-4-carboxylates to
thiazole-4-carboxylates by molecular oxygen [25]. Consequently, the formation of bithiazole 9 could be
explained by air oxidation of thiazolinylthiazole 8.
Scheme 4
Me
S
1) DAST,
CH2Cl2,
N
H2S,
MeOH/Et3N
MeO2C
HO
MeO2C
Me
MeO2C
Me
N
S
N
N
S
N
S
–78ºC, 1 h
N
5
+
H
S
S
2) K2CO3,
–78ºC to rt
rt, 12 h
9
7
8
In order to introduce some structural modifications for biological evaluation, the ester group of compo-
und 6 was first hydrolyzed to acid 10, and N-methylamide 11 was obtained using 2-(1H-benzotriazol-1-yl)-
1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) as the coupling agent (Scheme 5).
Alcohol 12 was obtained from ester 6 in very good yield employing an excess of NaBH4 in methanol.
Then a bulky and electron-withdrawing group was introduced by esterification of compound 12 to obtain the
protected alcohol 13.
We have obtained 2,4'-biheterocycles from readily available precursors using a rapid and efficient syn-
thetic pathway. These compounds were modified to prepare new derivatives. Our preliminary evaluation of the
biological activities demonstrated no cytotoxicity on HCT-15 cell line [26]. All of the obtained biheterocycles
exhibited an activity about 1000 times lower than that of Mytomicin C (GI 50 (Mytomicin C) = 2.5 ꢂM). Insights
gained from these studies will serve for further preparations of new potential and selective antiparasitic com-
pounds. Our process could be used for construction of natural products and their analogs containing 2,4'-biazoles.
705
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Scheme 5
MeNH2 . HCl, Et3N,
O
KOH
Me
THF, CH2Cl2, HBTU,
Me
HO2C
Me
N
O
N
N
O
N
N
H
THF/H2O
0ºC to rt, 72 h
6
S
S
rt, 2 h
10
11
O
NaBH4,
MeOH,
rt, 4 h
Cl
O
Me
F3C
Me
N
N
N
O
N
HO
O
CH2Cl2, Py,
50ºC, 10 min
S
S
F3C
O
12
13
EXPERIMENTAL
Optical rotation was measured using a Kruss Optronic GmbH P8000 polarimeter with a 0.5 ml cell. IR
13
spectra were recorded on a Shimadzu FTIR 8101A spectrophotometer. 1H and C NMR spectra were recorded
on a Bruker Avance DPX-400 instrument (400 and 100 MHz, respectively) in CDCl3 (all compounds) or MeOD
(compound 10) using TMS as internal standard. High-resolution mass spectra (ESI) were obtained on a Bruker
Daltonics MicrOTOF-Q instrument. Flash column chromatography was carried out on Silica gel 60
(J.T. Baker, 40 μm average particle diameter). All reactions and chromatographic separations were monitored by
TLC (Macherey/Nagel, Polygram SIL G/UV 254). TLC plates were analyzed under 254 nm UV light, by iodine
vapor, p-hydroxybenzaldehyde spray, or ninhydrine spray.
Ethyl 2-Methyl-1,3-thiazole-4-carboxylate (2). A solution of ethyl bromopyruvate (3.9 g, 20 mmol)
and thioacetamide (1.5 g, 20 mmol) in dry EtOH (14.0 ml) was refluxed under N2 for 6 h. Then, the reaction
mixture was concentrated under reduced pressure and NaHCO3 (sat. sol.) was added until pH 8. The aqueous
layer was extracted with Et2O (4×20 ml), and the combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude residue was purified by flash chromatography (eluent n-hexane–
1
AcOEt, 2:1) to give 2.78 g (81%) of thiazole 2 as an orange oil. Rf = 0.65 (n-hexane–AcOEt, 2:1). H NMR
spectrum ꢃ, ppm (J, Hz): 1.41 (3H, t, J = 7.2, CH3CH2); 2.77 (3H, s, 2-CH3); 4.43 (2H, q, J = 7.1, CH3CH2); 8.04
(1H, s, H-5). 13C NMR spectrum ꢃ, ppm: 14.4; 19.4; 61.4; 127.3; 146.9; 161.4; 166.8.
2-Methyl-1,3-thiazole-4-carboxylic Acid (3). To a stirred solution of thiazole 2 (0.54 g, 3.15 mmol) in
THF (3.0 ml), 10% KOH solution (3.0 ml) was added at room temperature. Stirring was continued for 2 h. HCl
(5 M) was added until pH 3. The aqueous phase was extracted with ethyl acetate (4×15 ml). The combined
organic layers were dried (Na2SO4) and evaporated under reduced pressure. Thiazole 3 (0.39 g, 86%) was
1
obtained and used without further purification; Rf 0.37 (CHCl3–AcOEt, 3:1). H NMR spectrum ꢃ, ppm: 2.82
13
(3H, s, CH3); 8.19 (1H, s, H-5); 10.51 (1H, s, COOH). C NMR spectrum ꢃ, ppm: 19.2; 128.9; 145.9; 164.8;
167.5.
Methyl (S)-3-Hydroxy-2-{[(2-methyl-1,3-thiazol-4-yl)carbonyl]amino}propanoate (4). To a stirred
solution of acid 3 (0.2 g, 1.4 mmol) in dry CH2Cl2 (10 ml) cooled at 0ºC under N2, Et3N (0.2 ml, 1.4 mmol),
L-serine methyl ester hydrochloride (0.22 g, 1.4 mmol), and DMAP (0.017 g, 0.14 mmol) were added. The
reaction mixture was stirred for 30 min. Then DCC (0.32 g, 1.54 mmol) was added, and the reaction mixture
was stirred at room temperature for 24 h. The precipitated dicyclohexylurea was filtered off, water (10 ml) was
added and the mixture was extracted with AcOEt (4×15 ml). The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography
(AcOEt) to obtain ꢀ-hydroxy amide 4 (0.28 g, 83%) as a white solid; Rf 0.44 (AcOEt). IR spectrum, ꢁꢂꢃcm–1:
706
ꢀ

3399, 2956, 1746, 1653, 1545, 1215, 1181, 756. 1H NMR spectrum, ꢃ, ppm: 2.73 (3H, s, CH3); 3.09–3.06 (1H,
m, OH); 3.83 (3H, s, OCH3); 4.14–4.03 (2H, m, CH2OH); 4.86 (1H, m, NCH); 7.98 (1H, s, H thiazole); 8.14
13
(1H, s, NH). C NMR spectrum, ꢃ, ppm: 19.1; 52.9; 54.8; 63.5; 123.9; 148.8; 161.3; 166.4; 170.7. Found: m/z
245.0592 [M+H]+. C9H13N2O4S. Calculated: 245.0596.
Methyl (S)-2-(2-Methyl-1,3-thiazol-4-yl)-4,5-dihydro-1,3-oxazole-4-carboxylate (5). To a solution of
ꢁ-hydroxy amide 4 (0.2 g, 0.82 mmol) in dry CH2Cl2 (8 ml) at –78°C under N2, DAST (0.13 ml, 0.92 mmol)
was added dropwise. After stirring for 1 h, the reaction mixture was quenched with K2CO3 solution (0.17 g,
1.23 mmol) at –20°C. After warming to room temperature, the mixture was further diluted with a saturated
aqueous solution of Na2CO3 and then extracted with CH2Cl2 (4×20 ml). The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromate-
graphy (AcOEt) to obtain oxazoline 5 (0.16 g, 86%) as a white solid; mp 123–124°C; ꢄꢅꢆ20 +127° (c 0.5,
D
MeOH); Rf 0.44 (AcOEt). IR spectrum, ꢁꢂꢃcm–1: 3407, 2956, 1740, 1651, 1210, 1179. 1H NMR spectrum, ꢃ, ppm
(J, Hz): 2.77 (3H, s, CH3); 3.82 (3H, s, OCH3); 4.63 (1H, dd, J1 = 8.7, J2 = 10.5, CH2); 4.74 (1H, dd, J1 = 8.7,
J3 = 8.0, CH2); 4.98 (1H, dd, J2 = 10.5, J3 = 8.0, CH); 7.91 (1H, s, H thiazole). 13C NMR spectrum, ꢃ, ppm: 19.3;
52.1; 68.6; 69.9; 124.1; 142.9; 161.5; 167.2; 171.4. Found: m/z 227.0484 [M+H]+. C9H11N2O3S. Calculated:
227.0490.
Methyl 2-(2-Methyl-1,3-thiazol-4-yl)-1,3-oxazole-4-carboxylate (6). Oxazoline
5
(0.159 g,
0.709 mmol) was dissolved in dry CH2Cl2 (14 ml). The reaction mixture was cooled to –20ºC, and CBrCl3
(0.25 ml, 2.54 mmol) was slowly added. Then it was allowed to reach 0ºC and DBU (0.38 ml, 2.54 mmol) was
added dropwise. The reaction mixture was quenched with a saturated solution of NaHCO3, and the aqueous
layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and
concentrated. The crude residue was purified by flash chromatography (AcOEt) to obtain oxazole 6 (0.12 g,
1
78%) as a white-yellow solid; Rf 0.44 (AcOEt). IR spectrum, ꢁꢂꢃcm–1: 3129, 2953, 1717, 1566, 1323, 1294. H
NMR spectrum, ꢃ, ppm: 2.82 (3H, s, CH3); 3.96 (3H, s, OCH3); 8.06 (1H, s, H thiazole); 8.31 (1H, s,
H oxazole). 13C NMR spectrum, ꢃ, ppm: 19.3; 52.3; 121.3; 134.3; 142.1; 143.6; 157.8; 161.6; 167.7. Found: m/z
225.0334 [M+H]+. C9H9N2O3S. Calculated: 225.0328.
Methyl (S)-3-Hydroxy-2-{[(2-methyl-1,3-thiazol-4-yl)carbonothioyl]amino}propanoate (7). A solu-
tion of oxazoline 5 (0.2 g, 0.88 mmol) in MeOH–Et3N (8 ml, 2:1) was saturated with H2S, prepared from Na2S
and H2SO4, under continuous stirring at room temperature. The production of H2S was maintained for 10 min;
the reaction mixture was left at room temperature, while progress of the reaction was controlled by TLC. Excess
H2S, MeOH, and Et3N were removed by evaporation in vacuo through a solution of bleach. The residue was
purified by flash chromatography (n-hexane–AcOEt, 1:3) to obtain ꢁ-hydroxy thioamide 7 (0.18 g, 77%) as a
1
yellow oil; Rf 0.56 (AcOEt–n-hexane, 3:1). IR spectrum, ꢁꢂꢃcm–1: 3129, 1717, 1566, 1323, 1294. H NMR
spectrum ꢃ, ppm: 2.77 (3H, s, CH3); 3.99 (3H, s, OCH3); 4.25–4.21 (2H, m, CH2); 5.52–5.48 (1H, m, CH); 8.25
13
(1H, s, H thiazole); 9.92 (1H, s, NH). C NMR spectrum ꢃ, ppm: 19.3; 52.9; 59.2; 62.5; 126.0; 153.3; 165.9;
170.1; 187.4. Found: m/z 283.0182 [M+Na]+. C9H12N2NaO3S2. Calculated: 283.0187.
Methyl (R)-2'-Methyl-4,5-dihydro-2,4'-bi-1,3-thiazole-4-carboxylate (8) and Methyl 2'-Methyl-2,4'-
bi-1,3-thiazole-4-carboxylate (9). To a solution of ꢁ-hydroxy thioamide 7 (0.15 g, 0.58 mmol) in dry CH2Cl2
(6 ml) at –78°C under N2, DAST (0.09 ml, 0.65 mmol) was added dropwise. After stirring for 1 h, the reaction
mixture was quenched with K2CO3 solution (0.12 g, 0.27 mmol) at –20ºC. After warming to room temperature,
the mixture was further diluted with a saturated aqueous solution of Na2CO3 and then extracted with CH2Cl2
(4×20 ml). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude
residue was purified by flash chromatography (n-hexane–AcOEt, 1:4) to obtain thiazoline 8 (0.060 g, 43%) as a
yellow oil that subsequently solidified and thiazole 9 (0.020 g, 14%) as a yellow solid. Compound 8: mp 59–
60°C; ꢄꢅꢆ20 +18° (c 2.2, CH2Cl2); Rf 0.44 (n-hexane–AcOEt, 1:4). IR spectrum, ꢁꢂꢃcm–1: 3114, 29525, 1742,
D
1
1605, 1435, 1202, 1161. H NMR spectrum, ꢃ, ppm (J, Hz): 2.73 (3H, s, CH3); 3.70–3.58 (2H, m, CH2); 3.81
(3H, s, OCH3); 5.27 (1H, t, J = 9.3, CH); 7.86 (1H, s, H thiazole). 13C NMR spectrum, ꢃ, ppm: 19.2; 35.1; 52.8;
78.3; 121.1; 148.2; 165.5; 166.4; 171.2. Found: m/z 243.0250 [M+H]+. C9H11N2O2S2. Calculated: 243.0262.
707
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Compound 9: mp 157–158°C; Rf 0.60 (n-hexane–AcOEt, 1:4). IR spectrum, ꢁꢂꢃcm–1: 3129, 2994, 1713,
1
1495, 1238, 1165. H NMR spectrum, ꢃ, ppm (J, Hz): 2.78 (3H, s, CH3); 3.99 (3H, s, OCH3); 8.01 (1H, s,
H thiazole); 8.25 (1H, s, H thiazole). 13C NMR spectrum, ꢃ, ppm: 19.2; 52.6; 117.1; 127.9; 147.5; 147.9; 161.9;
166.9; 163.5. Found: m/z 241.0097 [M+H]+. C9H9N2O2S2. Calculated: 241.0105.
2-(2-Methyl-1,3-thiazol-4-yl)-1,3-oxazole-4-carboxylic Acid (10). Following the procedure for the
conversion of ester 2 into acid 3, ester 6 (0.042 g, 0.19 mmol) was transformed into acid 10. The crude product
was purified by flash chromatography (AcOEt–MeOH, 1:1) to obtain acid 10 (0.036 g, 91%) as a colorless
solid; Rf 0.47 (AcOEt–MeOH, 1:1). 1H NMR spectrum, ꢃ, ppm: 2.79 (3H, s, CH3); 8.18 (1H, s, H thiazole); 8.23
(1H, s, H oxazole).
N-Methyl-2-(2-methyl-1,3-thiazol-4-yl)-1,3-oxazole-4-carboxamide (11). A stirred solution of acid 10
(0.027 g, 0.13 mmol) in DMF (2 ml) and CH2Cl2 (5 ml) was cooled to 0ºC; then MeNH2ꢄHCl (0.060 g,
0.89 mmol) and Et3N (0.61 mmol) were added. After 15 min, the reaction mixture was left to reach room
temperature, and HBTU (0.088 g, 0.23 mmol) was added. It was stirred during three days at room temperature.
A 5% HCl solution was added until pH 5. The aqueous layer was extracted with Et2O (4×10 ml), and the
combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash
chromatography (AcOEt) to obtain the desired amide 11 (0.012 g, 40%) as a colorless solid; Rf 0.44 (AcOEt).
1H NMR, spectrum, ppm (J, Hz): 2.84 (3H, s, CH3); 3.00 (3H, d, J = 4.9, NCH3); 7.87 (1H, s, H thiazole); 8.25
(1H, s, H oxazole). 13C NMR spectrum, ꢃ, ppm: 19.4; 25.1; 120.7; 137.5; 140.6; 142.2; 156.8; 160.8; 168.2.
Found: m/z 224.0488 [M+H]+. C9H10N3O2S. Calculated: 224.0494.
[2-(2-Methyl-1,3-thiazol-4-yl)-1,3-oxazol-4-yl]methanol (12). To a solution of ester 6 (0.050 g,
0.22 mmol) in MeOH (6 ml), NaBH4 (0.37 g, 9.74 mmol) was slowly added at room temperature with conti-
nuous stirring. After no more starting material was observed by TLC, MeOH was distilled under reduced
pressure, and 20 ml of H2O was added. The aqueous layer was extracted with AcOEt (5×25 ml), and the
combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash
chromatography with MeOH–AcOEt (1:5) to obtain alcohol 12 (0.039 g, 86%) as a white solid; Rf = 0.64
(MeOH–AcOEt, 1:5). 1H NMR spectrum, ꢃ, ppm: 2.83 (3H, s, CH3); 4.70 (2H, s, CH2); 7.66 (1H, s, H thiazole);
7.84 (1H, s, H oxazole). Found: m/z 197.0381 [M+H]+. C8H9N2O2S. Calculated: 197.0385.
[2-(2-Methyl-1,3-thiazol-4-yl)-1,3-oxazol-4-yl]methyl 4-Trifluoromethylbenzoate (13). 4-Trifluoro-
methylbenzoyl chloride (0.03 ml, 0.19 mmol) was added to a stirred solution of alcohol 12 (0.03 g, 0.15 mmol)
and pyridine (0.01 ml, 0.15 mmol) in CH2Cl2 (6 ml), and then the mixture was heated at 50ºC. After 90 min, the
reaction was quenched with ice water. A solution of HCl 5% was added until pH 2. The aqueous layer was
extracted with AcOEt (3×15 ml) and washed with a 5% solution of NaHCO3. The combined organic layers were
dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (n-hexane–
AcOEt, 2:1) to obtain the desired ester 13 (0.047 g, 84%) as a white solid; mp 145–146°C; Rf 0.76 (AcOEt–
n-hexane, 3:1). IR spectrum, ꢁꢂꢃcm–1: 3137, 3092, 2923, 1719, 1595, 1325, 1287. 1H NMR spectrum, ꢃ, ppm (J,
Hz): 2.82 (3H, s, CH3); 5.40 (2H, s, CH2); 7.72 (2H, d, J = 8.3, H Ar); 7.83 (1H, s, H oxazole); 7.87 (1H, s,
13
H thiazole); 8.20 (2H, d, J = 8.3, H Ar). C NMR spectrum, ꢃ, ppm: 19.3; 58.9; 119.8; 119.9; 125.4; 130.1;
130.3; 133.0; 136.7; 137.5; 137.6; 142.8; 157.8; 165.2; 167.7. Found: m/z 391.0331 [M+Na]+.
C16H11F3N2NaO3S. Calculated: 391.0340.
This work was supported by PEDECIBA (Programa de Desarrollo de Ciencias Básicas). The authors
acknowledge Prof. Sylvia Dematteis for performing the preliminary cytotoxic assays.
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