Facile preparation of thiazoles from 1/H-(1′-alkynyl)-5-methyl-1,2,3- benziodoxathiole 3,3-dioxide with thioamides

Article abstract of DOI:10.1055/s-0028-1083439

Thiazoles were obtained in high yields by the reaction of 1H-1 -(1′-alkynyl)-5-methyl-1,2,3-benziodoxathiole 3,3-dioxides, which were easily prepared from the reaction of 1H-1-hydroxy-5-methyl-1,2,3- benziodoxathiole 3,3-dioxide and 1-alkynes, with thioam

Full text of DOI:10.1055/s-0028-1083439

LETTER
2637
Facile Preparation of Thiazoles from 1H-1-(1¢-Alkynyl)-5-methyl-1,2,3-
benziodoxathiole 3,3-Dioxide with Thioamides
P
reparationof Thi
o
a
zoles shihide Ishiwata, Hideo Togo*
Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
E-mail: togo@faculty.chiba-u.jp
Received 27 June 2008
Method 1:
S
Abstract: Thiazoles were obtained in high yields by the reaction of
OTs
R1
R2
R3
1H-1-(1¢-alkynyl)-5-methyl-1,2,3-benziodoxathiole 3,3-dioxides,
which were easily prepared from the reaction of 1H-1-hydroxy-5-
methyl-1,2,3-benziodoxathiole 3,3-dioxide and 1-alkynes, with
thioamides. Here, the co-product, potassium 2-iodo-5-methylben-
zenesulfonate, was recovered quantitatively by simple filtration of
the reaction mixture, and was regenerated to 1H-1-(1¢-alkynyl)-5-
methyl-1,2,3-benziodoxathiole 3,3-dioxides to be reused for the
same preparation of thiazoles, keeping good yields.
R2
R2
S
NH2
HTIB
R1
O
O
R3
R3
+
N
+
TsOH
PhI
S
Method 2:
R2
R1
S
NH2
HTIB
R2
I
Ph
R1
N
PhI
MsOH
R2
OMs
+
+
Key words: thiazole, 1H-1-(1¢-alkynyl)-5-methyl-1,2,3-benziod-
oxathiole 3,3-dioxide, 1-alkyne, thioamide
Method 3 (present work):
S
R1
n SO2
O
The thiazole unit is a very important moiety in medicinal
chemistry, because certain pharmaceuticals containing
the thiazole unit1 possess such biological activities as anti-
inflammatory,2a antihypertensive,2b antibacterial,2c and
anti-HIV.2d Examples are meloxicam (anti-inflammato-
ry), arotinolol (antihypertensive), nizatidine (gastric anti-
secretory). Many methods for the preparation of the
thiazole moiety are available,1 and among them, the
Hantzsch thiazole synthesis3 using a-haloketones with
thioamides is one of the most excellent methods. On the
other hand, thiazoles can also be prepared in two steps
without using a-haloketones. The reaction of ketones with
S
NH2
R2
R1
I
N
R2
reuse
A n = 0
B n = 1
+
R2
regeneration [O]
n SO2
O
SO3H
n
I
I
OH
A′ n = 0
B′ n = 1
Scheme 1 Synthetic approach to thiazoles with hypervalent iodines
As part of our study for the preparation of heterocyclic
compounds using hypervalent iodines,4g,h,6 we would like
to report herein the preparation of thiazoles using cyclic 1-
alkynyliodonium hypervalent iodine, as shown in method
3, that is, 1H-1-(1¢-alkynyl)-1,2,3-benziodoxathiole 3,3-
dioxides (A: n = 0, five-membered ring).
Koser’s
reagent
[(hydroxy)(tosyloxy)iodobenzene]
(HTIB) to form a-tosyloxyketones, and the subsequent
treatment of a-tosyloxyketones with thioamides provide
corresponding thiazoles in moderate yields (Scheme 1,
method 1).4 However, in method 1, iodobenzene and p-
toluenesulfonic acid are formed as co-products. Recently,
another preparation method of thiazoles using hyperval-
ent iodine, that is, cyclocondensation of thioamides and
alkynyl(aryl)iodoniums, was reported (method 2).5 This is
very interesting since 1-alkynes can be used as the starting
material, instead of ketones. However, the yields of thiaz-
oles were not so good. And iodobenzene and methane-
sulfonic acid, which are difficult to recover, are formed as
co-products. Moreover, in the preparation of alkynyl(ar-
yl)iodonium mesylates or tosylates, the addition products
of mesylate or tosylate anion to the triple bond of the alky-
nyl(aryl)iodoniums are formed partly, and it is not easy to
restrain the addition reaction.
As a five-membered ring, we selected and prepared 1H-1-
(1¢-phenylethynyl)-5-methyl-1,2,3-benziodoxathiole 3,3-
dioxide (A-1) from 2-amino-5-methylbenzenesulfonic ac-
id. Thus, we employed the Griess reaction of 2-amino-5-
methylbenzenesulfonic acid to form sodium 2-iodo-5-
methylbenzenesulfonate, followed by oxidation with per-
oxyacetic acid to 1H-1-hydroxy-5-methyl-1,2,3-benziod-
oxazole (A¢) based on the literature,7 as shown in
Scheme 2.
Treatment of cyclic hypervalent iodine A¢ with 1-phenyl-
acetylene provided 1H-1-(1¢-phenylethynyl)-5-methyl-
1,2,3-benziodoxazole (A-1) in 50–60% yields. Using the
same method, 1H-1-(1¢-hexynyl)-5-methyl-1,2,3-benz-
iodoxathiole 3,3-dioxide (A-2) and 1H-1-(1¢-octynyl)-5-
methyl-1,2,3-benziodoxathiole 3,3-dioxide (A-3) were
prepared in almost the same yields. However, as a six-
SYNLETT 2008, No. 17, pp 2637–2641
x
x
.x
x
.2
0
0
8
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083439; Art ID: U06808ST
© Georg Thieme Verlag Stuttgart · New York

2638
Y. Ishiwata, H. Togo
LETTER
1) NaNO2, HCl
0 °C, 1 h
sponding thiazoles B again in good yields. The results are
shown in Table 2.8 After these reactions, potassium 2-
iodo-5-methylbenzenesulfonate (C) was recovered quan-
titatively by simple filtration of the reaction mixture. Ox-
idation of potassium salt C with peroxyacetic acid in the
presence of sulfuric acid gave 1H-1-hydroxy-5-methyl-
1,2,3-benziodoxathiole (A¢), and subsequent treatment
with 1-alkynes gave 1H-1-(1¢-alkynyl)-5-methyl-1,2,3-
benziodoxathiole 3,3-dioxides (A) in 50–60% yields.
Me
SO3H
SO3Na⋅H2O
Me
2) NaI, urea
NH2
I
0 °C, 2 h, r.t., 1 h
50 °C, overnight
50%
O2
S
Me
AcOOH, H2SO4
O
AcOH
I
10–15 °C, 1 h,
r.t., overnight
OH
A′ 75%
The reaction mechanism is proposed in Scheme 3. The
initial I–S bond formation between iodine atom of 1H-1-
(1¢-alkynyl)-5-methyl-1,2,3-benziodoxathiole 3,3-diox-
ide (A) and sulfur atom of thioamide occurs to form inter-
mediate a, followed by [3,3] sigmatropic rearrangement
to provide intermediates b and b¢. Then, a-cleavage of in-
termediate b¢ occurs to generate vinyl carbene c, and cy-
clization ensures to give thiazole B, as proposed in
method 2. In supporting of initial I–S bond formation, the
DIB-mediated N-acylation of 1,3-disubstituted thiourea
was reported recently to proceed through the initial I–S
bond formation.9
Scheme
2
Preparation of 1H-1-hydroxy-5-methyl-1,2,3-benz-
iodoxazole A¢
membered ring, 1H-1-(1¢-alkynyl)-1,2,3-benziodoxathio-
ine 3,3-dioxide (B) could not be obtained in pure state by
the reaction of 1-alkyne with 1H-1-hydroxy-1,2,3-benz-
iodoxathioine 3,3-dioxide (B¢), which was prepared from
the oxidation of o-iodophenylmethanesulfonic acid with
peroxyacetic acid. Therefore, we decided to use 1H-1-(1¢-
phenylethynyl)-5-methyl-1,2,3-benziodoxathiole 3,3-di-
oxide (A-1) with various thioamides, such as thiobenz-
amide, thioacetamide, 4-methylthiobenzamide, 4-meth-
oxythiobenzamide, 4-nitrothiobenzamide, and thiourea,
in the presence of potassium carbonate under THF warm-
ing conditions, and corresponding thiazoles B were ob-
tained in better yields than those with method 2, as shown
in Table 1.8 Among diethyl ether, THF, and dichlo-
romethane solvent, THF showed the best result.
In conclusion, 1H-1-(1¢-alkynyl)-5-methyl-1,2,3-benz-
iodoxathiole 3,3-dioxides (A), which can be smoothly
prepared from the reaction of 2-iodo-5-methylbenzene-
sulfonic acid and 1-alkynes, reacted smoothly with thio-
amides to give the corresponding thiazoles B in good
yields. Here, co-products, such as iodobenzene and p-tol-
uenesulfonic acid are not formed, and the formed potassi-
um 2-iodo-5-methylbenzenesulfonate (C) can be
recovered quantitatively, and regenerated to 1H-1-(1¢-
alkynyl)-5-methyl-1,2,3-benziodoxathiole 3,3-dioxides
(A) in moderate yields. Regenerated 1H-1-(1¢-alkynyl)-5-
methyl-1,2,3-benziodoxathiole 3,3-dioxides (A) could be
When 1H-1-(1¢-hexynyl)-5-methyl-1,2,3-benziodoxathi-
ole 3,3-dioxide (A-2) and 1H-1-(1¢-octynyl)-5-methyl-
1,2,3-benziodoxathiole 3,3-dioxide (A-3) were treated
with the same thioamides and thiourea, the reactions pro-
ceeded smoothly at room temperature to provide corre-
Table 2 Reaction of 1H-1-(1¢-Alkynyl)-5-methyl-1,2,3-benziod-
oxathiole 3,3-Dioxides A-2 and A-3 with Thioamides
Table 1 Reaction of 1H-1-(1¢-Phenylethynyl)-5-methyl-1,2,3-
benziodoxathiole 3,3-Dioxide (A-1) with Thioamides
S
S
S
S
R1
(1.2 equiv)
NH2
R1
(1.2 equiv)
NH2
O2
S
O2
S
R1
N
R1
R2
Me
N
Me
Ph
O
O
K2CO3 (2.3 equiv)
THF , r.t. , 5 h
K2CO3 (2.3 equiv)
B
+
B
I
I
THF , 45 °C , overnight
+
Me
Me
SO3
SO3K
A-2 R2 = n-Bu
A-1
A-3 R2 = n-C6H13
R2
Ph
I
I
C
C
Entry
R1
Yield of B (%)
Entry
R1
Yield of B (%)
A-2
67 (74)a
63
A-3
1
Ph
65 (78)a
61
1
2
3
4
5
6
Ph
76 (80)a
76
2
Me
Me
3
Tol
78
Tol
80 (76)a
70
84
4
PMP
4-O2NC6H4
NH2
82 (80)a
46
PMP
72
5b
6
4-O2NC6H4
NH2
56
69
66
66
73
a Regenerated A-1 from recovered C was used.
b Reaction temperature was 60 °C.
a Regenerated A-2 or A-3 from recovered C was used.
Synlett 2008, No. 17, 2637–2641 © Thieme Stuttgart · New York

LETTER
Preparation of Thiazoles
2639
Vrang, L.; West, S. J.; Zhang, H.; Zhou, X. X. J. Med. Chem.
1995, 38, 4929.
(3) (a) Hantzsch, A.; Weber, J. H. Ber. Dtsch. Chem. Ges. 1887,
20, 3118. (b) Wiley, R. H.; Behr, L. C. Org. Rec. 1951, 6,
367.
O2
S
O
Me
SO3K
Me
K2CO3
I
I
S
S
R1
NH2
HN
A
R1
(4) (a) Koser, G. F.; Wettach, R. H. J. Org. Chem. 1977, 42,
1476. (b) Moriarty, R. M.; Vaid, R. K.; Hopkins, T. E.; Vaid,
B. K.; Prakash, O. Tetrahedron Lett. 1990, 31, 201.
(c) Moriarty, R. M.; Vaid, R. K.; Duncan, M. P.; Levy, S. G.;
Prakash, O.; Goyal, S. Synthesis 1992, 845. (d) Prakash, O.;
Goyal, S. Synthesis 1992, 629. (e) Prakash, O.; Rani, N.;
Goyal, S. J. Chem. Soc., Perkin Trans. 1 1992, 707.
(f) Prakash, O.; Saini, N.; Sharma, P. K. Synlett 1994, 221.
(g) Ueno, M.; Nabana, T.; Togo, H. J. Org. Chem. 2003, 68,
6424. (h) Ueno, M.; Togo, H. Synthesis 2004, 2673.
(5) Wipf, P.; Venkatraman, S. J. Org. Chem. 1996, 61, 8004.
(6) (a) Togo, H.; Hoshina, Y.; Muraki, T.; Nakayama, H.;
Yokoyama, M. J. Org. Chem. 1998, 63, 5193. (b) Katohgi,
M.; Togo, H.; Yamaguchi, K.; Yokoyama, M. Tetrahedron
1999, 55, 14885. (c) Harada, Y.; Togo, H.; Yokoyama, M.
J. Org. Chem. 2000, 65, 926. (d) Misu, Y.; Togo, H. Org.
Biomol. Chem. 2003, 1, 1342. (e) Akiike, J.; Yamamoto, Y.;
Togo, H. Synlett 2007, 2168. (f) Kawano, Y.; Togo, H.
Synlett 2008, 217.
R2
R2
a
Me
SO3K
Me
SO3K
I+
[3,3]
I
S
S
•
•
–
R1
R1
R2
N
R2
N
H
H
b
b'
cyclization
H-shift
S
S
•
α-cleavage
•
R1
R1
N
R2
R2
N
H
B
c
Me
SO3K
I
C
(7) Koser, G. F.; Sun, G.; Porter, C. W.; Youngs, W. J. J. Org.
Scheme 3 Possible reaction pathway
Chem. 1993, 58, 7310.
(8) Typical Procedure for Preparation of 1H-1-(1¢-Hexynyl)-
5-methyl-1,2,3-benziodoxathiole 3,3-Dioxide
reused for the same preparation of thiazoles B (entries 1
A mixture of 1H-1-hydroxy-5-methyl-1,2,3-benziodoxa-
thiole 3,3-dioxide (5 mmol), PTSA·H2O (5 mmol), and 1-
hexyne (25 mmol) in MeCN (40 mL) was refluxed for 20 h.
After removal of the solvent to obtain an oil, a solution of the
oil in CHCl3 (200 mL) was washed with 5% NaHCO3 (80
mL) and H2O (3 × 50 mL), and was concentrated to a solid.
Recrystallization of the solid with a mixture of CH2Cl2 (30
mL), Et2O (100 mL), and hexane (60 mL) gave 1H-1-(1¢-
hexynyl)-5-methyl-1,2,3-benziodoxathiole 3,3-dioxide in
53% yield.
and 4 in Table 1, and entries 1 and 3 in Table 2).
Acknowledgment
Financial support in the form of a Grant-in-Aid for Scientific Re-
search on Priority Area (20031007) from the Ministry of Education,
Culture, Sports, Science, and Technology is gratefully acknow-
ledged.
1H-1-(1¢-Hexynyl)-5-methyl-1,2,3-benziodoxathiole 3,3-
Dioxide (R = n-Bu)
References and Notes
Mp 164–166 °C (dec.); lit.7 179–181 °C (dec.). IR (Nujol):
2166 cm–1. 1H NMR (400 MHz, CDCl3, TMS): d = 8.01(s, 1
H), 7.92 (d, J = 8.5 Hz, 1 H), 7.47 (d, J = 8.7 Hz, 1 H), 2.73
(t, J = 7.2 Hz, 2 H), 2.50 (s, 3 H), 1.61–1.74 (m, 2 H), 1.43–
1.55 (m, 2 H), 0.98 (t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz,
CDCl3, TMS): d = 143.7, 141.6, 135.1, 130.8, 126.8, 115.5,
105.8, 29.9, 28.5, 22.1, 20.8, 20.6, 13.5.
(1) (a) Metzger, J. V. Comprehensive Heterocyclic Chemistry,
Vol. 6; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon:
Oxford, 1984, 235–331. (b) Dondoni, A.; Merino, P.
Comprehensive Heterocyclic Chemistry II, Vol. 3;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier Science: Oxford, 1996, 373–474. (c) Boden, C. D.
J.; Pattenden, G.; Ye, T. Synlett 1995, 417. (d) Wipf, P.
Chem. Rev. 1995, 95, 2115. (e) Dondoni, A. Synthesis 1998,
1681. (f) Potewar, T. M.; Ingale, S. A.; Srinivasan, K. V.
Tetrahedron 2007, 63, 11066. (g) Yadav, J. S.; Reddy, B. V.
S.; Rao, Y. G.; Narsaiah, A. V. Tetrahedron Lett. 2008, 49,
2381. (h) Potewar, T. M.; Ingale, S. A.; Srinivasan, K. V.
Tetrahedron 2008, 64, 5019.
1H-1-(1¢-Octynyl)-5-methyl-1,2,3-benziodoxathiole 3,3-
Dioxide (R = n-C6H13)
Mp 150 °C (dec.); lit.7 152–154 °C (dec.). IR (Nujol): 2168
cm–1. 1H NMR (400 MHz, CDCl3, TMS): d = 8.04 (s, 1 H),
7.90 (d, J = 8.7 Hz, 1 H), 7.48 (dd, J = 1.6, 8.6 Hz, 1 H), 2.73
(t, J = 7.1 Hz, 2 H), 2.51 (s, 3 H), 1.64–1.74 (m, 2 H), 1.42–
1.52 (m, 2 H), 1.30–1.40 (m, 4 H), 0.92 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3, TMS): d = 143.8, 141.5, 135.0,
130.8, 126.6, 115.5, 105.8, 31.1, 28.5, 28.4, 27.8, 22.4, 20.9,
20.7, 14.0.
(2) (a) Haviv, F.; Ratajczyk, J. D.; DeNet, R. W.; Kerdesky,
F. A.; Walters, R. L.; Schmidt, S. P.; Holms, J. H.; Young,
P. R.; Carter, G. W. J. Med. Chem. 1988, 31, 1719. (b)Patt,
W. C.; Hamilton, H. W.; Taylor, M. D.; Ryan, M. J.; Taylor,
D. G. Jr.; Connolly, C. J. C.; Doherty, A. M.; Klutchko,
S. R.; Sircar, I.; Steinbaugh, B. A.; Batley, B. L.; Painchaud,
C. A.; Rapundalo, S. T.; Michniewicz, B. M.; Olson, S. C. J.
J. Med. Chem. 1992, 35, 2562. (c) Tsuji, K.; Ishikawa, H.
Bioorg. Med. Chem. Lett. 1994, 4, 1601. (d) Bell, F. W.;
Cantrell, A. S.; Hoegberg, M.; Jaskunas, S. R.; Johansson,
N. G.; Jordon, C. L.; Kinnick, M. D.; Lind, P.; Morin, J. M.
Jr.; Noreen, R.; Oberg, B.; Palkowitz, J. A.; Parrish, C. A.;
Pranc, P.; Sahlberg, C.; Ternansky, R. J.; Vasileff, R. T.;
1H-1-(1¢-Phenylethynyl)-5-methyl-1,2,3-benziodoxa-
thiole 3,3-Dioxide (R = Ph)
Mp 217–219 °C (dec.); lit.7 221–223 °C (dec.). IR (Nujol):
2160 cm–1. 1H NMR (400 MHz, DMSO-d6, TMS): d = 8.12
(d, J = 8.4, 1 H), 7.76–7.81(m, 3 H), 7.53–7.67 (m, 4 H),
2.45 (s, 3 H). 13C NMR (100 MHz, DMSO-d6, TMS): d =
142.6, 142.4, 135.0, 133.0, 131.6, 129.1, 129.1, 128.9,
119.4, 107.7, 107.2, 41.3, 20.2.
Typical Procedure for Preparation of Thiazoles
To a solution of thiobenzamide (0.48 mmol) in THF (2 mL)
Synlett 2008, No. 17, 2637–2641 © Thieme Stuttgart · New York

2640
Y. Ishiwata, H. Togo
LETTER
were added K2CO3 (0.92 mmol) and 1H-1-(1¢-phenyl-
ethynyl)-5-methyl-1,2,3-benziodoxathiole 3,3-dioxide (0.4
mmol). The obtained mixture was stirred at 45 °C overnight
under argon atmosphere. After the reaction, the mixture was
filtered to remove potassium 2-iodo-5-methyl-benzene-
sulfonate quantitatively. After evaporation of the filtrate, the
residue was chromatographed on SiO2 (eluent: hexane–
CHCl3, 1:1) to afford pure 1,4-diphenylthiazole in 65%
yield.
3 H). 13C NMR (100 MHz, CDCl3, TMS): d = 164.2, 160.1,
148.2, 139.4, 127.0, 124.2, 115.0, 31.3, 22.3, 13.9. HRMS–
FAB: m/z calcd for C13H15N2O2S [M + H]: 263.0854; found:
263.0838.
2-Amino-4-butylthiazole
Oil. IR (Nujol): 3436, 1607, 1521, 1113, 696 cm–1. 1H NMR
(400 MHz, CDCl3, TMS): d = 6.08 (s, 1 H), 4.91 (s, 2 H),
2.53 (t, J = 7.8 Hz, 2 H), 1.56–1.68 (m, 2 H), 1.30–1.43 (m,
2 H), 0.92 (t, J = 7.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3,
TMS): d = 167.3, 102.5, 102.5, 31.7, 31.2, 22.7, 14.2.
HRMS–FAB: m/z calcd for C7H13N2S [M + H]: 157.0799;
found: 157.0811.
2,4-Diphenylthiazole
Mp 91–92 °C; lit.10 91–92 °C. 1H NMR (400 MHz, CDCl3,
TMS): d = 7.98–8.09 (m, 4 H), 7.41–7.51 (m, 6 H), 7.35 (t,
J = 7.4 Hz, 1 H).
2-Phenyl-4-hexylthiazole
Regeneration of Potassium 2-Iodo-5-methylbenzene-
sulfonate to 1H-1-Hydroxy-5-methyl-1,2,3-benziod-
oxathiole 3,3-Dioxide
Oil. IR(neat): 2926, 2856, 1517, 1458, 1239, 1003, 763, 689
cm–1. 1H NMR (400 MHz, CDCl3, TMS): d = 7.94 (dd,
J = 1.7, 7.8 Hz, 2 H), 7.36–7.47 (m, 3 H), 6.87 (s, 1 H), 1.70–
1.82 (m, 2 H), 1.27–1.47 (m, 6 H), 0.89 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3, TMS): d = 167.4, 158.9, 133.9,
129.7, 128.8, 126.5, 112.6, 31.7, 31.7, 29.2, 29.0, 22.6, 14.1.
HRMS–FAB: m/z calcd for C15H20NS [M + H]: 246.1316;
found: 246.1315.
Hydrogen peroxide (33%, 1.3 mL) was added dropwise to a
solution of acetic anhydride (1.2 mL) at 0 °C. The obtained
mixture was stirred overnight. After the reaction, the mixture
was added dropwise to a stirred mixture of potassium
2-iodo-5-methylbenzenesulfonate (2.4 mmol) in AcOH (4
mL) and concd H2SO4 (1.2 mL) while keeping the
temperature at 10–15 °C. The mixture was stirred at this
temperature for 1 h and overnight at r.t. After the reaction,
the precipitate was filtered to give 1H-1-hydroxy-5-methyl-
1,2,3-benziodoxathiole 3,3-dioxide in 50–60% yield.
2-Phenyl-4-butylthiazole
Oil. IR(neat): 2956, 2929, 2859, 1516, 1498, 1460, 1436,
1244, 1004, 763, 689 cm–1. 1H NMR (400 MHz, CDCl3,
TMS): d = 7.93 (dd, J = 1.4, 8.0 Hz, 2 H), 7.38–7.45 (m, 3
H), 6.86 (s, 1 H), 2.83 (t, J = 7.8 Hz, 2 H), 1.70–1.80 (m, 2
H), 1.37–1.49 (m, 2 H), 0.96 (t, J = 7.4 Hz, 3 H). 13C NMR
(100 MHz, CDCl3, TMS): d = 167.4, 158.9, 133.9, 129.7,
128.8, 126.5, 112.6, 31.4, 31.3, 22.4, 13.9. HRMS–FAB:
m/z calcd for C13H16NS [M + H]: 218.1003; found:
218.1006.
2-Methyl-4-hexylthiazole
Oil. IR(neat): 2955, 2926, 2856, 1523, 1457, 1183, 728
cm–1. 1H NMR (400 MHz, CDCl3, TMS): d = 6.69 (s, 1 H),
2.67–2.75 (m, 5 H), 1.62–1.75 (m, 2 H), 1.23–1.45 (m, 6 H),
0.88 (t, J = 7.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3, TMS):
d = 165.2, 157.4, 111.9, 31.6, 31.6, 29.2, 29.0, 22.6, 19.1,
14.1. HRMS–FAB: m/z calcd for C10H18NS [M + H]:
184.1160; found: 184.1167.
2-(4-Methylphenyl)-4-hexylthiazole
Oil. IR(neat): 2926, 2856, 1509, 1457, 1247, 1005, 817, 711
cm–1. 1H NMR (400 MHz, CDCl3, TMS): d = 7.82 (d,
J = 8.3 Hz, 2 H), 7.22 (d, J = 7.8 Hz, 2 H), 6.82 (s, 1 H), 2.80
(t, J = 7.6 Hz, 2 H), 2.38 (s, 3 H), 1.70–1.81 (m, 2 H), 1.27–
1.46 (m, 6 H), 0.89 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz,
CDCl3, TMS): d = 167.6, 158.7, 139.9, 131.3, 129.5, 126.4,
112.1, 31.7, 31.7, 29.2, 29.0, 22.6, 21.4, 14.1. HRMS–FAB:
m/z calcd for C16H22NS [M + H]: 260.1473; found:
260.1493.
2-Methyl-4-butylthiazole
Oil. IR(neat): 3427, 2956, 2929, 2859, 1637, 1523, 1457,
1183, 1133, 730, 560, 526 cm–1. 1H NMR (400 MHz, CDCl3,
TMS): d = 6.69 (s, 1 H), 2.67–2.76 (m, 5 H), 1.62–1.73 (m,
2 H), 1.32–1.44 (m, 2 H), 0.93 (t, J = 7.4 Hz, 3 H).13C NMR
(100 MHz, CDCl3, TMS): d = 165.2, 157.3, 111.9, 31.4,
31.2, 22.4, 19.1, 13.9. HRMS–FAB: m/z calcd for C8H14NS
[M + H]: 156.0847; found: 156.0837.
2-(4-Methoxyphenyl)-4-hexylthiazole
Oil. IR(neat): 2855 cm–1. 1H NMR (400 MHz, CDCl3,
TMS): d = 7.87 (d, J = 9.0 Hz, 2 H), 6.94 (d, J = 8.8 Hz, 2
H), 6.79 (s, 1 H), 3.85 (s, 3 H), 2.80 (t, J = 7.8 Hz, 2 H),
1.69–1.80 (m, 2 H), 1.25–1.45 (m, 6 H), 0.89 (t, J = 6.9 Hz,
3 H). 13C NMR (100 MHz, CDCl3, TMS): d = 160.8, 158.6,
134.0, 127.9, 126.9, 114.1, 111.7, 55.4, 31.7, 31.7, 29.2,
29.0, 22.6, 14.1. HRMS–FAB: m/z calcd for C16H22NOS
[M + H]: 276.1422; found: 276.1401.
2-(4-Methylphenyl)-4-butylthiazole
Oil. IR(neat): 2955, 2928, 2859, 1509, 1457, 1246, 1007,
818, 735, 711 cm–1. 1H NMR (400 MHz, CDCl3, TMS):
d = 7.82 (d, J = 8.2 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 6.82
(s, 1 H), 2.81 (t, J = 7.7 Hz, 2 H), 2.38 (s, 3 H), 1.69–1.79 (m,
2 H), 1.36–1.48 (m, 2 H), 0.96 (t, J = 7.4 Hz, 3 H). 13C NMR
(100 MHz, CDCl3, TMS): d = 167.6, 158.7, 139.8, 131.3,
129.5, 126.4, 112.1, 31.4, 31.3, 22.4, 21.4, 13.9. HRMS–
FAB: m/z calcd for C14H18NS [M + H]: 232.1160; found:
232.1161.
2-(4-Nitrophenyl)-4-hexylthiazole
Mp 45–46 °C. IR (Nujol): 1523, 1339, 852 cm–1. 1H NMR
(400 MHz, CDCl3, TMS): d = 8.28 (d, J = 8.8 Hz, 2 H), 8.10
(d, J = 9.1 Hz, 2 H), 7.03 (s, 1 H), 2.84 (t, J = 7.8 Hz, 2 H),
1.72–1.81 (m, 2 H), 1.30–1.45 (m, 6 H), 0.90 (t, J = 7.8 Hz,
3 H). 13C NMR (100 MHz, CDCl3, TMS): d = 164.2, 160.1,
148.2, 139.4, 127.0, 124.2, 115.0, 31.6, 31.6, 29.1, 28.9,
22.6, 14.1. HRMS–FAB: m/z calcd for C15H19N2O2S
[M + H]: 291.1167; found: 291.1169.
2-(4-Methoxyphenyl)-4-butylthiazole
Oil. IR(neat): 2859 cm–1. 1H NMR (400 MHz, CDCl3,
TMS): d = 7.87 (d, J = 8.9 Hz, 2 H), 6.94 (d, J = 9.0 Hz, 2
H), 6.79 (s, 1 H), 3.85 (s, 3 H), 2.81 (t, J = 7.7 Hz, 2 H),
1.68–1.80 (m, 2 H), 1.36–1.48 (m, 2 H), 0.96 (t, J = 7.3 Hz,
3 H). 13C NMR (100 MHz, CDCl3, TMS): d = 167.5, 161.0,
158.7, 128.1, 127.1, 114.3, 111.8, 55.5, 31.6, 31.5, 22.6,
14.1. HRMS–FAB: m/z calcd for C14H18NOS [M + H]:
248.1109; found: 248.1119.
2-Amino-4-hexylthiazole
Mp 45–46 °C. IR (Nujol): 3432, 3235, 1606, 1508, 1103,
706 cm–1. 1H NMR (400 MHz, CDCl3, TMS): d = 6.08 (s, 1
H), 4.92 (s, 2 H), 2.52 (t, J = 6.9 Hz, 2 H), 1.56–1.68 (m, 2
H), 1.24–1.39 (m, 6 H), 0.88 (t, J = 6.9 Hz, 3 H). 13C NMR
(100 MHz, CDCl3, TMS): d = 167.0, 153.7, 102.2, 31.7,
31.6, 29.0, 28.7, 22.6, 14.1. HRMS–FAB: m/z calcd for
C9H17N2S [M + H]: 185.1112; found: 185.1106.
2-Phenyl-4-butylthiazole
2-(4-Nitrophenyl)-4-butylthiazole
Mp 47–48 °C. IR (Nujol): 1522, 1345, 851 cm–1. 1H NMR
(400 MHz, CDCl3, TMS): d = 8.29 (d, J = 8.9 Hz, 2 H), 8.11
(d, J = 9.2 Hz, 2 H), 7.03 (s, 1 H), 2.85 (t, J = 7.7 Hz, 2 H),
1.71–1.81 (m, 2 H), 1.38–1.49 (m, 2 H), 0.97 (t, J = 7.4 Hz,
Oil. IR(neat): 2956, 2929, 2859, 1516, 1498, 1460, 1436,
1244, 1004, 763, 689 cm–1. 1H NMR (400 MHz, CDCl3,
Synlett 2008, No. 17, 2637–2641 © Thieme Stuttgart · New York

LETTER
Preparation of Thiazoles
2641
TMS): d = 7.93 (dd, J = 1.4, 8.0 Hz, 2 H), 7.38–7.45 (m, 3
H), 6.86 (s, 1 H).
C16H14NOS [M + H]: 268.0796; found: 268.0802.
2-(4-Nitrophenyl)-4-phenylthiazole
2-Methyl-4-phenylthiazole
Mp 164–165 °C. IR (Nujol): 1514, 1339, 849 cm–1. 1H NMR
(400 MHz, CDCl3, TMS): d = 8.33 (d, J = 8.9 Hz, 2 H), 8.22
(d, J = 8.9 Hz, 2 H), 8.00 (d, J = 8.2 Hz, 2 H), 7.63 (s, 1 H),
7.48 (t, J = 7.4 Hz, 2 H), 7.40 (t, J = 7.4 Hz, 1 H). 13C NMR
(100 MHz, CDCl3, TMS): d = 164.8, 157.3, 148.4, 139.1,
133.9, 128.9, 128.7, 127.1, 126.5, 124.3, 114.6. HRMS–
FAB: m/z calcd for C15H11N2O2S [M + H]: 283.0541; found:
283.0547.
Mp 60 °C; lit.4h 64 °C. 1H NMR (400 MHz, CDCl3, TMS):
d = 7.87 (d, J = 8.3 Hz, 2 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.32
(t, J = 7.5 Hz, 1 H), 7.31 (s, 1 H), 2.78 (s, 3 H).
2-(4-Methylphenyl)-4-phenylthiazole
Mp 126 °C. IR (Nujol): 974, 815, 741, 690, 676 cm–1. 1H
NMR (400 MHz, CDCl3, TMS): d = 8.00 (d, J = 8.2 Hz, 2
H), 7.94 (d, J = 8.2 Hz, 2 H), 7.41–7.48 (m, 3 H), 7.35 (t,
J = 7.3 Hz, 1 H), 7.26 (d, J = 6.5 Hz, 2 H), 2.41 (s, 3 H). 13
NMR (100 MHz, CDCl3, TMS): d = 168.0, 156.1, 140.3,
C
2-Amino-4-phenylthiazole
Mp 145–147 °C. IR (Nujol): 3433, 1595, 1518, 1038, 714
cm–1. 1H NMR (400 MHz, CDCl3, TMS): d = 7.78 (d,
J = 8.0 Hz, 2 H), 7.38 (t, J = 7.6 Hz, 2 H), 7.29 (t, J = 7.4 Hz,
1 H), 6.73 (s, 1 H), 5.03 (s, 2 H). 13C NMR (100 MHz,
CDCl3, TMS): d = 167.0, 151.3, 134.6, 128.6, 127.7, 126.0,
102.9. HRMS–FAB: m/z calcd for C9H9N2S [M + H]:
177.0486; found: 177.0485.
134.6, 131.1, 129.6, 128.7, 128.1, 126.5, 126.4, 112.1, 21.4.
HRMS–FAB: m/z calcd for C16H14NS [M + H]: 252.0847;
found: 252.0851.
2-(4-Methoxyphenyl)-4-phenylthiazole
Mp 97–98 °C. IR (Nujol): 1256, 1173, 979, 833, 738 cm–1.
1H NMR (400 MHz, CDCl3, TMS): d = 7.96–8.02 (m, 4 H),
7.40–7.48 (m, 3 H), 7.34 (t, J = 7.4 Hz, 1 H), 6.98 (d, J = 8.9
Hz, 2 H), 3.88 (s, 3 H). 13C NMR (100 MHz, CDCl3, TMS):
d = 177.6, 161.4, 134.9, 133.6, 128.9, 128.3, 127.0, 126.6,
115.0, 114.5, 111.9, 55.7. HRMS–FAB: m/z calcd for
(9) Singh, C. B.; Ghosh, H.; Murru, S.; Patel, B. K. J. Org.
Chem. 2008, 73, 2924.
(10) Ishida, M.; Nakanishi, H.; Kato, S. Chem. Lett. 1984, 1691.
Synlett 2008, No. 17, 2637–2641 © Thieme Stuttgart · New York

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