Thiazole synthesis by cyclocondensation of 1-alkynyl(phenyl)- λ3-iodanes with thioureas and thioamides

Article abstract of DOI:10.1002/anie.200502438

(Chemical Equation Presented) The isolation and intramolecular cyclization of (S)-(1-alkynyl)isothiouronium and (S)-(1-alkynyl)thiobenzimidonium salts suggest the mechanism for the one-pot synthesis of 2,4-disubstituted thiazoles (see scheme; Ms = methanesulfonyl): Michael addition of sulfur nucleophiles to hypervalent iodanes followed by the 1,2-rearrangement of sulfenyl groups in the resulting alkylidene carbenes.

Full text of DOI:10.1002/anie.200502438

Communications
Hypervalent Iodine
The more common Michael addition pathway with the initial
formation of an isomeric vinyliodonium ylide 6 was discarded,
and it was proposed that this Michael addition pathway would
provide thiazoles 8 with an inverse C4,C5-substitution pattern
through successive reductive elimination of iodobenzene and
DOI: 10.1002/anie.200502438
Thiazole Synthesis by Cyclocondensation of
3
1
-Alkynyl(phenyl)-l -iodanes with Thioureas
intramolecular 1,5 NꢀH insertion of the alkylidene carbene 7
and Thioamides**
[1]
(pathway B).
It occurred to us that a third mechanism (pathway C) that
involved the Michael addition of thio nucleophiles followed
by a 1,2-rearrangement of the iminothio group in the
alkylidene carbene 7, instead of the intramolecular 1,5 NꢀH
Kazunori Miyamoto, Yoshio Nishi, and
Masahito Ochiai*
insertion, thus yielding the alkynyl sulfide 9, seems to be a
more attractive alternative. Further intramolecular cycliza-
tion of 9 probably provides 2 selectively. In fact, the 1,2-
rearrangement of sulfenyl groups in alkylidene carbenes is
known to be a facile and very rapid process because of the
In 1996, Wipf and Venkatraman reported an efficient method
for the synthesis of thiazoles, which involved the cyclo-
3
condensation of hypervalent 1-alkynyl(phenyl)-l -iodanes
[
1]
with thioureas or thioamides. For instance, the reaction of
3
[5]
phenylethynyl(phenyl)(mesylato)-l -iodane (1a) (X = OMs,
excellent migratory aptitude of sulfenyl groups. Further-
Ms = methanesulfonyl) with thiourea in methanol in the
presence of triethylamine at 08C directly afforded 2-amino-4-
more, it has been shown that soft sulfur nucleophiles, such as
[
6]
[7]
[8]
thiolates, thiosulfonates, phosphorodithioates, thiocya-
[
9]
[10]
phenylthiazole (2; R = Ph, R’ = NH ) in a good yield
nates, and sulfinates,
preferentially undergo Michael
2
3
3
(
Scheme 1). 1-Hexynyl-l -iodane 1b (X = OMs) also pro-
additions towards 1-alkynyl(phenyl)-l -iodanes. We report
herein some evidence that 9 is a reactive intermediate in the
cyclocondensation of hypervalent 1-alkynyl(phenyl)-l -
3
iodanes with thioureas or thioamides and that the thiazole
synthesis probably proceeds through pathway C.
3
The cyclocondensations of 1-alkyny l( phenyl)-l -iodanes
with thioureas or thioamides that yield 2 were carried out in
the presence of a base, such as potassium carbonate or
[
1]
triethylamine. The reaction course, however, dramatically
changed without a base being present. Thus, when the reaction
3
Scheme 1. Synthesis of thiazoles.
of phenylethynyl-l -iodane 1a (X=OMs) with thiourea
(
1 equiv) was carried out in dichloromethane at ꢀ78!108C
duced the thiazole 2 (R = nBu, R’ = NH or Ph) by reaction
under nitrogen in the absence of triethylamine, no formation of
2
with thiourea or thiobenzamide. This direct method for the
synthesis of thiazoles based on the cyclocondensation of 1-
2 (R =Ph, R’=NH ) was observed; instead, a hitherto
unknown S-(phenylethynyl)isothiouronium mesylate 9-MsOH
2
3
alkynyl-l -iodanes was applied to the synthesis of 2-mercap-
(R=Ph, R’=NH ) was isolated in 82% yield after repeated
2
[
2]
[11]
tothiazoles and selenazoles.
decantation with hexane. The IR spectrum of this salt showed
ꢀ1
The one-step thiazole synthesis developed by Wipf and
Venkatraman is a very useful reaction, as many biologically
the characteristic peak of the triple bond at 2180 cm , as well as
the strong absorption of the iminium group at 1683 and
[
3]
ꢀ1
13
active natural products contain thiazole moieties. They
proposed a reaction mechanism that involves a unique [3,3]-
sigmatropic rearrangement of an initially formed 1-alkyn-
1662 cm , whereas the C NMR spectra revealed two peaks of
acetylenic carbon atoms at d=65.8 and 106.6 ppm.
Single crystals of 9-MsOH for X-ray structural analysis
were grown from a mixture of methanol/dichloromethane/
3
yl(iminothio)-l -iodane 3 through ligand exchange on the
[
12]
hypervalent iodine. Reductive elimination of the resulting
vinyliodonium ylide 4 generates an a-thioamido alkylidene
carbene 5, which undergoes an intramolecular cyclization to
hexane.
Figure 1a illustrates a planar S-(1-alkynyl)iso-
thiouronium structure with the sum of the C(9)-centered
bond angles Æ8C(9) = 359.978. Interestingly, the phenyl and
the isothiouronium groups lie almost on the same plane, with
a dihedral angle of 8.19(3)8.
[
4]
yield 2,4-disubstituted thiazole 2 (Scheme 2, pathway A).
It should be noted that exposure of S-(phenylethynyl)-
isothiouronium mesylate (9-MsOH) to an aqueous saturated
solution of NaHCO3 at room temperature produced a
moderate yield (51%) of 2-amino-4-phenylthiazole (2)
through an intramolecular 5-endo digonal cyclization. The
same type of intramolecular cyclization in substituted S-
[
*] K. Miyamoto, Dr. Y. Nishi, Prof. M. Ochiai
Faculty of Pharmaceutical Sciences
University of Tokushima
1-78 Shomachi, Tokushima 770-8505 (Japan)
Fax: (+81)88-633-9504
E-mail: mochiai@ph.tokushima-u.ac.jp
[
11,13]
alkynylisothiouronium salts has been reported.
These
[
**] We gratefully acknowledge the Ministry of Education, Culture,
3
results suggest that methanesulfonic acid generated from l -
iodane 1a (X = OMs) during the reaction with thiourea
Sports, Science, and Technology of Japan for financial support in the
formof a grant.
(
Scheme 2) probably inhibits the intramolecular cyclization of
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
9 (R = Ph, R’ = NH ) under our conditions by formation of
2
6
896
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 6896 –6899

Angewandte
Chemie
Scheme 2. Possible reaction mechanisms.
product by decantation with hexane/
diethyl ether at room temperature
resulted in partial cyclization, and the
ratio of 9-HBF /2-HBF was reversed to
4
4
3
1:69 (91% yield). Treatment with a base
(
Na CO /H O) accelerates the cycliza-
2
3
2
tion and gave 4-octyl-2-phenylthiazole
[
15]
(
2) in 93% yield. Reaction of 1-hex-
3
ynyl-l -iodane 1b (X = BF ) with thio-
4
benzamide also afforded a 94:6 mixture
of labile S-(1-hexynyl)thiobenzimido-
nium tetrafluoroborate 9-HBF4 and 4-
butyl-2-phenylthiazolium tetrafluorobo-
rate 2-HBF4 (for each R = nBu, R’ =
Ph), which on treatment with a solution
Figure 1. ORTEP drawing of a) isothiouroniumsalt 9-MsOH (R=Ph, R’=NH ) and b) thio-
benzimidonium salt 10. Selected interatomic distances [Š] and angles [8]: 9-MsOH: C(7)-C(8)
2
1
1
.193(1), S(1)-C(8) 1.6888(8), S(1)-C(9) 1.7695(7), C(8)-S(1)-C(9) 102.19(4); 10: C(8)-C(9)
.187(2), S(1)-C(8) 1.691(2), S(1)-C(1) 1.752(1), C(8)-S(1)-C(1) 101.69(7).
of 5% aqueous Na CO3 produced 4-
2
[1]
butyl-2-phenylthiazole (2) in a high
yield (87%).
the 9-MsOH. Treatment with a base regenerates the free
sulfide 9 which undergoes spontaneous cyclization at room
temperature. The isolation and cyclization of 9-MsOH clearly
indicate that this alkynyl sulfide 9 is probably a reactive
intermediate in the one-step 2-aminothiazole synthesis in the
presence of a base, which is compatible with the alkylidene
carbene pathway C.
Isolation and full characterization of the labile S-(1-
alkynyl)thiobenzimidonium salts were achieved by reaction
3
of the more-sterically demanding 3,3-dimethyl-1-butynyl-l -
iodane 1c (X = BF ) with thiobenzamide, followed by acid-
4
ification of the reaction mixture with HBF ·Me O (1 equiv).
4
2
This procedure makes the quantitative isolation of S-(3,3-
dimethyl-1-butynyl)thiobenzimidonium tetrafluoroborate (9-
Comparable results were obtained from the reaction with
HBF ) as pale-yellow needles possible. Treatment with a base
4
3
[16]
thioamides. Reaction of 1-decynyl(tetrafluoroborato)-l -
(Na CO /H O) afforded 4-tert-butyl-2-phenylthiazole (2) in
2
3
2
[
14]
iodane (1d)
(X = BF ) with thiobenzamide in dichloro-
96% yield.
4
methane at ꢀ788C!room temperature afforded a 69:31
mixture of S-(1-decynyl)thiobenzimidonium tetrafluorobo-
rate (9-HBF ; R = n-C H , R’ = Ph) and 4-octyl-2-phenyl-
N,N-Dimethylthiobenzamide seems to be an attractive
nucleophile in the reaction, because the resulting N,N-
dimethylthiobenzimidonium salts cannot undergo the intra-
molecular 5-endo digonal cyclization. In fact, S-(3,3-dimethyl-
1-butynyl)thiobenzimidonium salt 10 was isolated as stable
colorless plates by the reaction of N,N-dimethyl-
4
8
17
thiazolium tetrafluoroborate (2-HBF ; R = n-C H , R’ = Ph)
4
8
17
1
quantitatively (as shown by H NMR spectroscopic analysis
of a crude reaction mixture). The thioimidonium salt 9-HBF4
is highly labile and tends to undergo intramolecular cycliza-
tion; thus, even the attempted purification of the crude
3
thiobenzamide with 3,3-dimethyl-1-butynyl-l -iodane 1c
(X = BF ) in 98% yield (Scheme 3). The structure of the
4
Angew. Chem. Int. Ed. 2005, 44, 6896 –6899
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6897

Communications
3
alkynyl(phenyl)-l -iodanes with thioureas or thioamides
yielding thiazoles.
Received: July 13, 2005
Published online: October 5, 2005
Scheme 3. Synthesis of (S)-(3,3-dimethyl-1-butynyl)thiobenzimidonium
salt 10.
Keywords: azoles · carbenes · iodanes · Michael addition · sulfur
.
[
1] P. Wipf, S. Venkatraman, J. Org. Chem. 1996, 61, 8004.
salt 10 was firmly established by solid-state structure analysis
[
2] a) Z.-C. Chen, P.-F. Zhang, Synthesis 2001, 358; b) Z.-C. Chen,
P.-F. Zhang, J. Heterocycl. Chem. 2001, 38, 503.
[
12]
(
Figure 1b).
All of these results indicate that the one-step thiazole
[
3] a) P. Brookes, A. T. Fuller, J. Walker, J. Chem. Soc. 1957, 689;
b) K. Shin-ya, K. Wierzba, K. Matsuo, T. Ohtani, Y. Yamada, K.
Furihata, Y. Hayakawa, H. Seto, J. Am. Chem. Soc. 2001, 123,
3
synthesis using 1-alkynyl(phenyl)-l -iodanes 1 developed by
Wipf and Venkatraman involves the intermediate formation
of the alkynyl sulfides 9 (and/or their salts), probably
produced through the Michael addition of thioureas or
thioamides and 1,2-shift in the alkylidene carbenes 7. This
Michael addition has been well established as the most
1
262; c) L. J. Perez, D. J. Faulkner, J. Nat. Prod. 2003, 66, 247;
d) P. Wipf, Chem. Rev. 1995, 95, 2115; e) Z. Jin, Nat. Prod. Rep.
005, 22, 196.
2
[
4] This [3,3]-sigmatropic rearrangement mechanism was also
reported along with the synthesis of 2-mercaptothiazoles and
3
[
2]
common reaction pathway for 1-alkynyl-l -iodanes with soft
selenazoles.
[
17,18]
nucleophiles.
[5] M. Ochiai, Y. Takaoka, Y. Nagao, J. Am. Chem. Soc. 1988, 110,
An alternative mechanism that leads to the formation of 9
involves a tandem ligand exchange and ligand-coupling
process at the iodine(iii) center (Scheme 4). This tandem
6565.
[
[
6] P. J. Stang, V. V. Zhdankin, J. Am. Chem. Soc. 1991, 113, 4571.
7] B. L. Williamson, P. Murch, D. R. Fischer, P. J. Stang, Synlett
1993, 858.
[
[
8] Z.-D. Liu, Z.-C. Chen, J. Org. Chem. 1993, 58, 1924.
9] a) T. Kitamura, R. Furuki, L. Zheng, T. Fujimoto, H. Taniguchi,
Chem. Lett. 1992, 2241; b) D. R. Fischer, B. L. Williamson, P. J.
Stang, Synlett 1992, 535.
[
10] a) M. Ochiai, M. Kunishima, S. Tani, Y. Nagao, J. Am. Chem.
Soc. 1991, 113, 3135; b) R. R. Tykwinski, J. A. Whiteford, P. J.
Stang, J. Chem. Soc. Chem. Commun. 1993, 1800; c) B. L.
Williamson, R. R. Tykwinski, P. J. Stang, J. Am. Chem. Soc. 1994,
1
1
2
1
16, 93; d) T. Kosaka, T. Bando, K. Shishido, Chem. Commun.
997, 1167; e) K. S. Feldman, M. L. Wrobleski, Org. Lett. 2000, 2,
603; f) K. S. Feldman, J. C. Saunders, J. Am. Chem. Soc. 2002,
24, 9060.
[
11] (S)-(Ethylthioethynyl)isothiouronium chloride was prepared
from ethylthiochloroacetylene by reaction with thiourea in
44% yield; see: S. G. Dyachkova, N. K. Gusarova, E. A.
Nikitina, L. I. Larina, L. M. Sinegovskaya, A. V. Abramov,
B. A. Trofimov, Russ. J. Gen. Chem. 2001, 71, 1721.
[
12] Crystal data for 9-MsOH (R = Ph, R’ = NH ): C H N O S ,
2
10 12
2
3 2
3
colorless block, dimensions 0.50 ” 0.50 ” 0.30 mm , orthorhom-
bic, P2 2 2 (No. 19), a = 6.271(1), b = 12.077(2), c = 16.638(3) Š,
1
1 1
3
ꢀ3
Scheme 4. A mechanism that involves tandem ligand exchange and
ligand-coupling reactions.
V= 1260.0(4) Š , Z = 4, 1
calcd
= 1.436 gcm . Data collected on a
RigakuRAXIS-RAPID imaging plate diffractometer with Mo Ka
radiation (l = 0.71075 Š) at T= 93 K, 2qmax = 54.98, 12160
reflections measured, of which 12112 unique (R = 0.017), m =
int
process does not, however, seem to take place, as the
attempted reaction of diphenyl-l -iodane 11 with thiobenza-
ꢀ1
4
.20 cm . R = 0.026, R = 0.025. For 10: C H BF NS, colorless
w
15 20
4
3
3
block, dimensions 0.30 ” 0.30 ” 0.20 mm , monoclinic, P2 /c
1
mide did not show any evidence of the formation of the
ligand-coupling product 12 and 11 was recovered (95%).
Further evidence against the ligand-coupling mechanism was
(No. 14), a = 11.756(5), b = 23.188(8), c = 12.865(5) Š, b =
3
ꢀ3
105.24(3)8, V= 3383(2) Š , Z = 8, 1
= 1.308 gcm . MoKa
calcd
radiation (l = 0.71075 Š) at T= 93 K, 2qmax = 54.88, 31313
reflections measured, of which 30889 unique (Rint = 0.076), m =
[
19]
reported recently: that is, the reaction of (E)-1-decenyl-
ꢀ
1
2
.24 cm . R = 0.122, R = 0.145. CCDC-269174 (9-MsOH) and
3
w
(
phenyl)-l -iodane 13 with thiourea resulted in unusual
-
269175 (10) contain the supplementary crystallographic data for
vinylic S 2 displacement that yields the inverted (Z)-(S)-
N
this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
vinylisothiouronium salt 14 stereoselectively in a good yield
(
Scheme 4). In this reaction, no formation of the ligand-
[
13] T. N. Komarova, A. S. Nakhmanovich, T. E. Glotova, V. N.
Elokhina, A. L. Albanov, V. A. Lopyrev, Russ. Chem. Bull.
coupling product, the (E)-(S)-vinylisothiouronium salt, was
detected.
In conclusion, the isolation and the intramolecular
cyclization of (S)-(1-alkynyl)isothiouronium and (S)-(1-alky-
nyl)thiobenzimidonium salts indicate that these species are
probably involved in the cyclocondensation of hypervalent 1-
1997, 46, 195.
[
[
14] M. Ochiai, M. Kunishima, K. Sumi, Y. Nagao, E. Fujita, M.
Arimoto, H. Yamaguchi, Tetrahedron Lett. 1985, 26, 4501.
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Org. Chem. 2003, 68, 7887.
6
898 www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2005, 44, 6896 –6899

Angewandte
Chemie
[
16] G. Vernin, S. Treppendahl, J. Metzger, Helv. Chim. Acta 1977, 60,
84.
17] Reviews: a) M. Ochiai in Topics in Current Chemistry, Vol. 224
Ed.: T. Wirth), Springer, Berlin, 2003, p. 5; b) P. J. Stang, J. Org.
Chem. 2003, 68, 2997; c) V. V. Zhdankin, P. J. Stang, Tetrahedron
998, 54, 10927; d) G. F. Koser in The Chemistry of Halides,
2
[
(
1
Pseudo-halides, and Azides, Supplement D2 (Eds.: S. Patai, Z.
Rappoport), Wiley, New York, 1995, p. 1173; e) A. Varvoglis,
The Organic Chemistry of Polycoordinated Iodine, VCH,
Weinheim, 1992.
[
[
18] However, hard nucleophiles, such as 2-lithiofuran and 2-
lithiothiophene, attack the positively charged iodine of 1-
alkynyl-l -iodanes; see: A. J. Margida, G. F. Koser, J. Org.
Chem. 1984, 49, 4703.
19] M. Ochiai, S. Yamamoto, T. Suefuji, D.-W. Chen, Org. Lett. 2001,
3
3, 2753.
Angew. Chem. Int. Ed. 2005, 44, 6896 –6899
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6899