Hypervalent iodine in synthesis; 60: A novel method for the synthesis of 2-mercaptothiazoles by cyclocondensation of alkynyl(phenyl)iodonium salts and ammonium dithiocarbamate

Article abstract of DOI:10.1055/s-2001-11422

A novel method for the synthesis of 2-mercaptothiazoles is achieved by cyclocondensation of alkynyl(phenyl)iodonium salts with ammonium dithiocarbamate. A reaction mechanism is proposed.

Full text of DOI:10.1055/s-2001-11422

358
SHORT PAPER
Hypervalent Iodine in Synthesis; 60: A Novel Method for the Synthesis of
2-Mercaptothiazoles by Cyclocondensation of Alkynyl(phenyl)iodonium Salts
and Ammonium Dithiocarbamate
Peng-Fei Zhang, Zhen-Chu Chen*
Department of Chemistry, Zhejiang University (XiXi Campus), Hangzhou, Zhejiang 310028, China
E-mail: zhenchuc@mail.hz.zj.cn
Received 21 June 2000; revised 22 August 2000
nyl)iodonium salts are highly reactive towards a variety of
Abstract: A novel method for the synthesis of 2-mercaptothiazoles
nucleophilic species of heteroatoms.4 These encouraging
results coupled with the ready availability and high reac-
is achieved by cyclocondensation of alkynyl(phenyl)iodonium salts
with ammonium dithiocarbamate. A reaction mechanism is pro-
tivity of alkynyl(phenyl)iodonium salts prompted us to
examine their reaction with nucleophilic ammonium
dithiocarbamate. Herein we report a new effective method
for the synthesis of 2-mercaptothiazoles by cycloconden-
sation of alkynyl(phenyl)iodonium salts with ammonium
dithiocarbamate.
posed.
Key words: cyclocondensation, 2-mercaptothiazoles, alkynyl(phe-
nyl)iodonium salts, ammonium dithiocarbamate, iodine, sulfur, het-
erocycles
Thiazoles, in particular, 2-mercaptothiazoles have be-
come increasingly important in pharmaceutical, biochem-
ical, and technical fields.1 Recently, Prakash and Saini2
reported a useful synthesis of 2-mercaptothiazoles. The
approach involves hypervalent iodine oxidation of ace-
tophenones with [hydroxy(tosyloxy)iodo]benzene, fol-
lowed by treatment with potassium thiocyanate to afford
the corresponding -thiocyanatoacetophenones and their
cyclization using NH2C(S)NH2/HCl. Although it offers a
superior and general alternative of existing synthesis,3
which involves the use of lachrymatory and toxic -halo-
genoketones, the overall yield is low. For example, the
yield of 2-mercapto-4-(p-chlorophenyl)thiazole is only
20%.
Simple stirring of the alkynyl(phenyl)iodonium salts 1
with the ammonium dithiocarbamate (2) in DMF and wa-
ter at room temperature gave after workup the 2-mercap-
tothiazoles 3 in good yield (Scheme 1). The results are
summarized in the Table.
Scheme 1
The products were characterized by mp, 1H NMR, IR and
mass spectral data. The mass spectra showed the correct
M+ peaks and peaks for the fragments. Compound 3b is
taken as an example to describe the general fragmentation
mechanism of the thiazole ring which is proposed in
Scheme 2.
In our earlier reports dealing with hypervalent iodine in
organic synthesis, it has been observed that alkynyl(phe-
Table Yields of 2-Mercaptothiazoles 3 Prepared from the Reaction
of Alkynyl(phenyl)iodonium Salts and Ammonium Dithiocarbam-
ates
Entry Alkynyl(phenyl)iodonium
Salts
Product
Yield
(%)
1
2
3
4
3a
3b
3c
3d
73
63
57
66
5
3e
61
Scheme 2
6
7
3f
45
51
The reaction was found to be general and applicable to
alkylethynyl(phenyl)iodonium salts or arylethynyl(phe-
nyl)iodonium salts. Several arylethynyl(phenyl)iodonium
3g
Synthesis 2001, No. 3, 358–360 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A Novel Method for the Synthesis of 2-Mercaptothiazoles by Cyclocondensation
359
Scheme 3
13C NMR (DMSO-d6, 500 MHz ): = 163.782, 163.097 (1JCF
=
salts containing various substituents, such as fluoro, chlo-
ro, bromo and methyl groups were successfully reacted.
253.8 Hz), 155.416, 130.504, 128.785 (3JCF = 7.8 Hz), 118.728,
116.445 (2JCF = 20.7 Hz).
A plausible mechanism for the formation of 2-mercap-
tothiazoles 3 is analogous to the synthesis of thiazoles
from alkynyl(phenyl)iodoniuin salts and thioamides5 and
is shown in Scheme 3. lt involves the attack of the iodoni-
um ion of alkynyl(phenyl)iodonium salts 1 on the sulfur
of the ammonium dithiocarbamate (2) to form the primary
addition products 4 followed by a polyhetero-Claisen
rearrangement6 and 1,1-elimination of iodobenzene to
generate the carbene 8, and cycloaromatization of 8 to
give 2-mercaptothiazoles 3.
MS: m/z = 211 (M+, 100), 152 (60.20), 134 (13.23), 133 (10.89),
102 (2.77), 89 (20.66).
Anal. calcd for C9H6FNS2: C, 51.17; H, 2.86; N, 6.63; Found: C,
51.55; H, 2.48; N, 6.37.
2-Mercapto-4-phenylthiazole (3b)
Yield: 63%; mp 171 173 °C (Lit.3h mp 172 173 °C).
IR (KBr): = 3100 (m, sharp), 1490 (s), 1460 (s), 1060 (vs), 690
cm 1 (vs).
1H NMR (acetone-d6, 60 MHz): = 7.20 8.20 (1 H, br), 7.20 7.62
(5 H, m), 6.90 (1 H, s).
In conclusion , the present study provides a novel method
of synthesis of 2-mercaptothiazoles which has some ad-
vantages over the existing ones such as avoiding the use
of lachrymatory and toxic -halogenoketones, mild reac-
tion conditions, simplicity of the procedure and higher
yields. Furthermore, the range of useful applications of
alkynyl(phenyl)iodonium salts in organic chemistry has
been extended.
MS: m/z = 193 (M+, 100), 134 (55.80), 102 (7.16), 89 (16.42), 77
(7.75), 51 (7.03).
4-(p-Chlorophenyl)-2-mercaptothiazole (3c)
Yield: 57%; mp 208 210 °C (Lit.3h mp 210 212 °C).
IR (KBr): = 3105 (m, sharp), 1470 (s), 1355 (s), 1070 (vs), 880
cm 1 (vs).
1H NMR (acetone-d6 60 MHz): = 7.92 (1 H, br), 7.45 7.85 (4 H,
m), 6.85 (1 H, s).
MS: m/z = 229 (M+ + 2, 44.73), 227 (M+, 100), 170 (13.97), 168
(33.39), 134 (20.08), 133 (20.33), 102 (3.09), 89 (21.69).
Melting points were determined on a X4-Data microscopic melting
point apparatus and were uncorrected. Microanalyses were obtained
using Carlo-Erba 1106. 1HNMR spectra were obtained at 500 MHz
or 60 MHz (Avance DMX 500 or Jeol PMX 60SI) in DMSO-d6 or
acetone-d6 using TMS as an interal standard. IR spectra were re-
corded on a Perkin-Elmer 683 spectrometer at r.t. Mass spectra
were obtained by electron inipact at 70eV (HP5989B).
4-(p-Bromophenyl)-2-mercaptothiazole (3d)
Yield: 66%; mp 219 221 °C (Lit.3h mp 220 222 °C).
IR (KBr): n = 3100 (m, sharp). 1530 (s), 1375 (s), 1050 (vs), 820
cm 1 (vs).
1H NMR (acetone-d6, 60 MHz): = 8.00 (1 H, br), 7.47 7.95 (4 H,
m), 7.15 (1 H, s).
MS: m/z = 273 (M+ + 2, 36.45), 271 (M+, 34.11), 214 (4.71), 212
(4.73), 193 (100), 134 (54.40), 102 (5.50), 89 (20.56).
4-(p-Fluorophenyl)-2-mercaptothiazole (3a); Typical Proce-
dure
To solid ammonium dithiocarbamate (220 mg, 2 mmol) was added
a solution of p-fluorophenylethynyl(phenyl)iodonium salt (la;
493 mg, 1 mmol) in DMF (10 mL) and H2O (5 mL) and the resulting
mixture was stirred for 30 min at r.t. H2O (30 mL) was added and
the solution was extracted with Et2O (2 î 10 mL). The combined or-
ganic extracts were dried (Na2SO4), concentrated and chromato-
graphed on a silica gel plate using mixtures of petroleum ether (bp
60 90 °C)/Et2O (4:1) as eluent to afford 3a; yield: 0.15 g (73%);
mp 190 192 °C.
2-Mercapto-4-(p-methylphenyl)thiazole (3e)
Yield: 61%; mp 188 190 °C (Lit.3h mp 190 °C).
IR (KBr): = 3110 (m, sharp), 2980 (s), 2950 (s), 1545 (s), 1455 (s),
1060 (vs), 840 cm 1 (vs).
1HNMR (acetone-d6, 60 MHz): = 8.02 (1 H, br), 7.18 7,66 (4 H,
m), 7.03 (1 H s), 2.20 (3 H, s).
MS: m/z = 207 (M+, 100), 192 (11.88), 134 (31.67), 102 (3.20), 89
(25.12).
IR (KBr): = 3120 (m, sharp), 1510 (s), 1450 (s), 1060 (vs), 840
cm 1 (vs).
1H NMR (DMSO-d6, 500 MHz): = 8.29 (1 H, s), 8.00 8.03 (2 H,
2-Mercapto-4-methoxymethylthiazole (3f)
Yield: 45%; mp 108 110 °C.
IR (KBr): = 3108 (m, sharp), 1455 (s), 1370 cm 1 (s).
m), 7.32 7.34 (2 H, m), 7.30 (1 H, s).
Synthesis 2001, No. 3, 358–360 ISSN 0039-7881 © Thieme Stuttgart · New York

360
P.-F. Zhang, Z.-C. Chen
SHORT PAPER
1H NMR (acetone-d6, 500 MHz): = 7.30 7.81 (1 H, br), 7.00 (1
H, s), 4.25 (2 H, s), 3.31 (3 H, s).
(b) Smerson, W.; Patrick, JR. T. M. J. Org. Chem. 1948, 13,
722.
(c) Stewart, F. D.; Mathes, R. A. J. Org. Chem. 1949, 14,
1111.
(d) Bunnett, J. F.; Tarbell, D. S. J. Am. Chem. Soc. 1945, 67,
1944.
MS: m/z = 161 (M+, 100), 102 (23.32), 70 (18.73).
Anal. calcd for C5H7NOS2: C, 37.24; H, 4.38; N, 8.69; Found: C,
37.62, H, 4.05; N, 8.31.
(e) Mathes, R. A.; Stewart, F. D.; Beber, A. J. J. Am. Chem.
Soc. 1948, 70, 1451.
4-Ethoxymethyl-2-mercaptothiazole (3g)
Yield: 51%; mp 116 118 °C.
(f) John, J. R.; Sokol, H. J. Am. Chem. Soc. 1948, 70, 3419.
(g) D'Amico, J. J. J. Am. Chem. Soc. 1953, 75, 102.
(h) Vernin, G.; Metzger, J. Bull. Soc. Chim. Fr.1963, 11, 2498.
(i) Klaus, R.; Anneliese, G.; Vlrich, S. J. Prakt. Chem. 1960,
11, 54.
IR (KBr): = 3105 (m, sharp), 1455 (s), 1375 cm 1 (s).
1H NMR (acetone-d6, 500 MHz): = 7.31 7.80 (1 H, br), 6.83 (1
H, s), 4.05 (1 H, s), 3.45 (2 H, q, J = 6.6 Hz), 1.18 (3 H, t, J = 6.6
Hz).
(j) Isomura, Y.; Sakamoto, S.; Ito, N.; Homma, H.; Abe, T.;
Kubo, K. Chem. Pharm. Bull. 1984, 32, 152.
(k) Ahluwalia, V. K.; Arora, K. K.; Kaur, G. Heterocycles
1985, 23, 2583.
MS: m/z = 175 (M+, 100), 116 (15.87), 84 (13.69).
Anal. calcd for C6H9NOS2: C, 41.12; H, 5.18; N, 7.99; Found: C,
41.51; H, 5.04; N, 7.61.
(l) Ahluwalia, V. K. Indian J. Chem. 1986, 25(B), 502.
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30, 881.
(n) D'Amico, J. J. US Patent 2 817 641 (1957); Chem. Abstr.
1958, 52, 5019.
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Article Identifier:
1437-210X,E;2001,0,03,0358,0360,ftx,en;F03700SS.pdf
Synthesis 2001, No. 3, 358–360 ISSN 0039-7881 © Thieme Stuttgart · New York