Oxidation of 4-carboxylate thiazolines to 4-carboxylate thiazoles by molecular oxygen

Article abstract of DOI:10.1016/j.tetlet.2010.01.091

A facile and environment-benign oxidation by molecular oxygen was applied for the conversion of 4-carboxylate thiazolines to 4-carboxylate thiazoles. The substituent effect on thiazoline ring was investigated. It was found that electron-poor group on the thiazoline ring could facilitate the oxidation.

Full text of DOI:10.1016/j.tetlet.2010.01.091

Tetrahedron Letters 51 (2010) 1751–1753
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidation of 4-carboxylate thiazolines to 4-carboxylate thiazoles
by molecular oxygen
*
*
Yue Huang, Haifeng Gan, Shang Li, Jinyi Xu, Xiaoming Wu , Hequan Yao
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing, Jiangsu 210009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and environment-benign oxidation by molecular oxygen was applied for the conversion of 4-car-
boxylate thiazolines to 4-carboxylate thiazoles. The substituent effect on thiazoline ring was investigated.
It was found that electron-poor group on the thiazoline ring could facilitate the oxidation.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 27 November 2009
Revised 20 January 2010
Accepted 26 January 2010
Available online 1 February 2010
S
Thiazoles are important building blocks for preparing various
pharmaceuticals. Recently, many natural products containing thia-
zole moiety were isolated and most of them exhibit considerable
cytotoxicities and anti-tumor potentials.1 It is presumed that, in
organism, thiazole could be synthesized through a condensation
between amino acid and cysteine, followed by an oxidation by oxi-
dase.2 A variety of protocols have been reported for the oxidation
of thiazoline to thiazole.3–6 For example, activated manganese
dioxide (MnO2),3 nickel oxide (NiO2)4 and CBrCl3/DBU5 can oxidize
thiazoline to thiazole in excellent yields (Scheme 1, Eqs. 1 and 2).
Although these reagents are quite effective for this conversion,
excessive amount of activated MnO2 or NiO2 are needed, and
CBrCl3 is harmful to the environment. Up to date, few
environment-benign methods and further investigations for this
conversion have been explored.7 Herein, we report an oxidation
of 4-carboxylate thiazolines to 4-carboxylate thiazoles using
molecular oxygen as an oxidant (Scheme 1, Eq. 3).
We screened the reaction conditions for this conversion using
3a as the substrate. Choosing potassium carbonate as the base
and anhydrous DMF as the solvent, very low conversion was ob-
served and low yield of the desired product 4a was obtained at
room temperature (Table 1, entry 1). It was found that the reaction
was stepwise and the intermediate alcohol 6, which was fully char-
acterized,8 could be isolated. The low yield was due to the incom-
plete consumption of 3a and the incomplete dehydration of 6.
When the reaction temperature was increased to 60 °C (entry 2),
4a was acquired in 52% yield. Although 3a was fully consumed at
this temperature, 6 was not fully dehydrated to furnish 4a. When
the reaction was performed at 80 °C or 100 °C, 6 disappeared after
2 h and the desired product 4a was obtained in 67% and 66% yields,
respectively (entries 3 and 4). At higher temperatures (entries 3
and 4), 4a was found to be partially hydrolyzed, which could be ac-
counted for by the fact that tiny amount of water was generated
during the reaction. In order to suppress the hydrolysis of the ester
MnO2 or NiO2
BrCCl3, DBU
S
N
R1
R
N
Eq. 1
Eq. 2
COOR2
COOR2
COOR2
COOR2
1
2
S
N
S
N
R1
R1
1
2
S
N
air or O2
this work
S
N
R1
R1
COOR2
Eq. 3
COOR2
1
2
R1=alkyl, aryl
R2=alkyl
Scheme 1. Synthesis of thiazole from thiazoline.
Table 1
The screening of reaction conditionsa,
7
S
S
reaction conditions
N
N
COOEt
COOEt
3a
4a
Entry
Conditions
T (°C)
Time (h)
Yieldb
1
2
3
4
5
6
7
8
9
DMF, K2CO3
DMF, K2CO3
DMF, K2CO3
DMF, K2CO3
rt
24
6
2
2
2
2
2
6
24
8
12
52
67
66
77
76
79c
75
37
66
60
80
100
80
100
80
80
78
78
DMF, K2CO3, 4 Å MS
DMF, K2CO3, 4 Å MS
DMF, K2CO3, 4 Å MS
DMF, NaHCO3, 4 Å MS
EtOH, NaHCO3, 4 Å MS
EtOH, K2CO3, 4 Å MS
10
a
Reactions were performed on a 0.5 mmol scale with inorganic bases (3 equiv)
and open to air.
b
Isolated yields after flash column chromatography.
The reaction was performed with O2 (balloon).
* Corresponding author. Tel.: +86 25 83271042; fax: +86 25 83301606.
E-mail address: hyao@cpu.edu.cn (H. Yao).
c
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.091

1752
Y. Huang et al. / Tetrahedron Letters 51 (2010) 1751–1753
Table 2
Oxidation of 4-carboxylate thiazolines to 4-carboxylate thiazoles by molecualr oxygen
Entrya
Substrate (3a–p)
Time (h)
Methodb
A
Product (4a–p)
Yieldc (%)
77
S
S
1
N
2
N
COOEt
COOEt
4a
3a
O2N
O2N
S
S
2
3
2
2
A
A
82
83
N
N
4b
COOEt
COOEt
3b
NO2
S
NO2
S
N
N
COOEt
COOEt
4c
3c
S
S
F
F
4
5
2
2
A
A
80
83
N
N
COOEt
COOEt
COOEt
4d
3d
S
S
Cl
Br
Cl
N
N
COOEt
COOEt
COOEt
4e
3e
3f
S
N
S
N
Br
6
2
A
A
A
A
A
81
91
80
77
80
COOEt
COOEt
4f
S
S
F3C
F3C
7
2
N
N
3g
4g
S
S
N
EtOOC
EtOOC
O2N
8
2
N
COOEt
COOEt
4h
3h
S
S
O2N
9
2
N
N
COOEt
COOEt
3i
4i
S
N
S
N
10
2.5
COOEt
COOEt
4j
3j
S
S
MeO
MeO
11
12
2.5
A
56
N
N
COOEt
COOEt
4k
3k
S
S
Me
Me
Et
Et
24
7
A
B
23d
67
N
N
COOEt
COOEt
COOEt
COOEt
3l
3m
S
S
N
6
6
B
B
N
13
14
69
67
4l
4m
S
S
N
N
B
COOEt
COOEt
4n
3n
a
b
c
Reactions were performed in DMF on a 0.5 mmol scale with K2CO3(3 equiv) and molecular sieves (4 Å, 200 wt %).9
A: the reaction was open to air; B: the reaction was performed with O2 (balloon).
Isolated yields after flash column chromatography.
d
The starting material was not completely consumed after 24 h.

Y. Huang et al. / Tetrahedron Letters 51 (2010) 1751–1753
1753
Weinig, S.; Nordsiek, G.; Brandt, P.; Blocker, H.; Hofle, G.; Beyer, S.; Muller, R. J.
Biol. Chem. 1999, 274, 37391; (h) Abe, H.; Takaishi, T.; Okuda, T. Tetrahedron Lett.
1978, 19, 2791.
group in 4a, we added molecular sieves (4 Å, 200 wt %) to absorb
the water generated during the reaction. Gratifyingly, under the
new condition the yield of 4a was increased significantly (entries
5 and 6). When molecular oxygen, in lieu of air, was used as the
oxidant, 4a was obtained in 79% yield, which is close to that
obtained with air (entry 7). The reactions were rather slow when
NaHCO3 was used as the base or anhydrous EtOH was used as
the solvent (entries 8–10).
With the optimized condition in hand, we then examined the oxi-
dation of a variety of 2-substituted thiazolines and the results are
summarized in Table 2. We found that various thiazole derivatives
with aryl groups could be obtained using this protocol (entries 1–
11). The substrates with aryl groups generally afforded the desired
products in moderate to good yields, although prolonged reaction
time was required for substrates bearing electron-rich aryl groups
(entries 10 and 11). However, for the substrates with alkyl substitu-
ent at 2-position, the reaction proceeded sluggish and most of the
substrates were not consumed even after 24 h (entry 12). Gratify-
ingly, higher yields could be achieved for substrates with alkyl group
when molecular oxygen was used instead of air (entries 12–14).
These results shown in Table 2 indicated that electron-deficient
group at 2-postion of the thiazoline ring could facilitate the
oxidation.
2. (a) Schneider, T. L.; Shen, B.; Walsh, C. T. Biochemistry 2003, 42, 9722; (b) Chen,
H. W.; O’Connor, S.; Cane, D. E.; Walsh, C. T. Chem. Biol. 2001, 8, 899.
3. For examples of direct oxidation by MnO2, see: (a) Deeley, J.; Bertram, A.;
Pattenden, G. Org. Biomol. Chem. 2008, 6, 1994; (b) Merinoa, P.; Tejeroa, T.;
Unzurrunzagaa, F. J.; Francoa, S.; Chiacchiob, U.; Saitab, M. G.; Iannazzoc, D.;
Pipernoc, A.; Romeoc, G. Tetrahedron Asymmetry. 2005, 16, 3865; (c) Pang, H.;
Xu, Z.; Chen, Z.; Ye, T. Lett. Org. Chem. 2005, 2, 699; (d) Serra, G.; Mahler, G.;
Manta, E. Heterocycles 1998, 48, 2035; (e) Bergeron, R. J.; Wiegand, J.; Weimar,
W. R.; Vinson, J. R.; Bussenius, J.; Yao, G. W.; McManis, J. S. J. Med. Chem. 1999,
42, 95.
4. For examples of direct oxidation by NiO2, see: (a) Nakagawa, K.; Konaka, R.;
Nakata, T. J. Org. Chem. 1962, 27, 1597; (b) Evans, D. L.; Minster, D. K.; Jordis, U.;
Hecht, S. M.; Mazzu, A. L.; Meyers, A. I. J. Org. Chem. 1979, 44, 497; (c) Bock, M.;
Dehn, R.; Kirschning, A. Angew. Chem., Int. Ed. 2008, 47, 9134.
5. For examples of oxidation by CBrCl3/DBU, see: (a) Phillips, A. J.; Uto, Y.; Wipf, P.;
Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2, 1165; (b) Burrell, G.; Evans, J. M.;
Jones, G. E.; Stemp, G. Tetrahedron Lett 1990, 31, 3649; (c) Lafargue, P.; Lellouche,
J. P. Heterocycles 1995, 41, 947.
6. For examples of oxidation by other reagents, see: (a) Meyers, A. I.; Tavares, F. X. J.
Org. Chem. 1996, 61, 8207; (b) Tavares, F.; Meyers, A. I. Tetrahedron Lett. 1994, 35,
6803; (c) Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2481.
7. White, E. H.; McCapra, F.; Field, G. F. J. Am Chem. Soc. 1962, 85, 337.
8. The intermediates
characterized by IR, 1H NMR, 13C NMR and ESI-HRMS. Mp 105–107 °C; IR(KBr):
3415, 3137, 3002, 2834, 1754, 1590, 1189, 1112, 766, 690 cmÀ1 1H NMR
5 and 6 could be observed on TLC. Compound 6 was
;
(300 MHz, CDCl3) d 1.31 (t, 3H, J = 7.2 Hz), 3.54 (d, 1H, J = 12.0 Hz), 4.01 (d, 1H,
J = 12.0 Hz), 4.32 (m, 3H), 7.40–7.45 (m, 2H), 7.49–7.54 (m, 1H), 7.89 (d, 2H,
J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) d 173.6, 170.9, 132.4, 132.1, 128.7, 105.4,
62.9, 40.6, 14.01; MS(ESI) m/z 252.0 (M+H)+; HRMS(ESI) m/z calcd for
[C12H14NO3S]+ 252.0689, found 252.0694; 6 could be smoothly dehydrated to
4a in 91% yield using K2CO3 in DMF at 80 °C for 1 h.
In conclusion, we have developed a clean and facile oxidation of
4-carboxylate thiazolines to 4-carboxylate thiazoles by molecular
oxygen in moderate to good yields. This process is mild and envi-
ronment-benign. Moreover, this work could provide a useful meth-
od for the preparation of thiazole-containing building blocks.
Further investigations of this methodology for synthesis of thia-
zole-containing natural products are in progress and will be re-
ported in due course.
S
S
oxidation
OOH
N
COOEt
N
air
COOEt
3a
5
Acknowledgments
Financial support from the National Natural Science Foundation
(Grant No. 20902111), Program for New Century Excellent Talents
in University (NCET 2008) by the Ministry of Education of China
and the State Key Laboratory of Drug Research (Shanghai Institute
of Materia Medica, Chinese Academy of Sciences) are appreciated.
S
N
K2CO3/DMF
S
N
OH
COOEt
COOEt Molecular sieves
80oC, 91%
6
4a
Supplementary data
9. Typical experimental procedure for oxidation of thiazolines: Ethyl 2-(4-
nitrophenyl)thiazoline-4-carboxylate 3i (140 mg, 0.5 mmol) was dissolved in
anhydrous DMF (5 mL). Then molecular sieves (4 Å, 280 mg, 200 wt %) and
K2CO3 (207 mg, 1.5 mmol) were added and the reaction mixture was stirred at
80 °C for 2 h. The resulting solution was diluted with ethyl acetate and the
solution was washed with water and brine, dried over sodium sulfate, filtered
and concentrated under reduced pressure. The result residue was purified by
flash chromatography on silica gel to afford 107 mg (77%) of ethyl 2-(4-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.091.
References and notes
1. (a) Taori, K.; Paul, V. J.; Luesch, H. J. Am. Chem. Soc. 2008, 130, 1806; (b) Fuller, A.
T. Nature 1955, 175, 722; (c) Sasse, F.; Steinmetz, H.; Hôfle, G.; Reichenbach, H. J.
Antibiot. 2003, 56, 520; (d) Kehraus, S.; Konig, G. M.; Wright, A. D. J. Org. Chem.
2002, 67, 4989; (e) Gerth, K.; Bedorf, N.; Hofle, G.; Irschik, H.; Reichenbach, H. J.
Antibiot. 1996, 49, 560; (f) Umezawa, H.; Maeda, K.; Takeuchi, T.; Okami, Y. J.
Antibiot. 1966, 19, 200; (g) Silakowski, B.; Schairer, H. U.; Ehret, H.; Kunze, B.;
nitrophenyl)thiazole-4-carboxylate 4i as
a
yellow solid. Mp 158–159 °C;
IR(KBr): 3443, 1721, 1516, 1336, 1205, 851, 794 cmÀ1
;
1H NMR (300 MHz,
CDCl3) d 1.45 (t, 3H, J = 7.2 Hz), 4.47 (q, 2H, J = 7.2 Hz), 8.20 (d, 2H, J = 8.7 Hz),
8.28 (s, 1H), 8.33 (d, 2H, J = 8.7 Hz); 13C NMR (75 MHz, CDCl3) d 165.7, 161.0,
148.9, 148.8, 138.1, 128.5, 127.6, 124.3, 61.7, 14.3; MS(ESI) m/z 279.0 (M+H)+.