α-Sulfanyl and α-selanyl propadienyl cations: regioselective generations and cycloadditions with thioamides and selemides controlled by MeNO2-H2O System

Article abstract of DOI:10.1021/ol9011844

α-Sulfanyl and α-selanyl propadlenyl cations were easily generated by the catalytic system, scandium triflate-nitromethane-H₂O In the presence of Bu₄NHSO₄, to regioselectively afford the multifunctionalized thiazoles and s

Full text of DOI:10.1021/ol9011844

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2952-2955
r-Sulfanyl and r-Selanyl Propadienyl
Cations: Regioselective Generations and
Cycloadditions with Thioamides and
Selemides Controlled by MeNO2-H2O
System
Mitsuhiro Yoshimatsu,*,† Teruhisa Yamamoto,† Arisa Sawa,† Tomohiro Kato,†
Genzoh Tanabe,‡ and Osamu Muraoka‡
Department of Chemistry, Faculty of Education, Gifu UniVersity, 1-1 Yanagido,
Gifu 501-1193, Japan, and School of Pharmacy, Kinki UniVersity, 3-4-1 Kowakae,
Higashi-osaka, Osaka 577-8502, Japan
yoshimae@gifu-u.ac.jp
Received May 27, 2009
ABSTRACT
r-Sulfanyl and r-selanyl propadienyl cations were easily generated by the catalytic system, scandium triflate-nitromethane-H2O in the presence
of Bu4NHSO4, to regioselectively afford the multifunctionalized thiazoles and selenazoles in high yields.
Thiazole and its derivatives are among the most useful hetaryl
functional groups and found in many natural products and
biologically active compounds.1 Numerous methods for the
preparation of thiazoles have been reported;2 however, the
most widely used method is the Hantzsch thiazole synthesis
that uses reactions between R-haloketones and their analogs
with thioamides.3 Despite the modified methods reported
recently for the syntheses of thiazoles, novel methods for
synthesizing thiazoles are required because of the importance
of synthetic thiazole in medicinal and agricultural chemistry.4
Recently, we reported scandium-catalyzed carbon-carbon
bond forming reactions using 3-sulfanyl and selanyl prop-
argyl alcohols with the soft nucleophiles.5
Scandium metals effectively catalyze the generation of
propargyl cations through the electron-donating ability of the
heteroatom on the terminal acetylene group. Usually, the
propargyl cations have been generated either as a complex
protected by dicobalt hexacarbonyl6 or as an allenylidene
complex.7 Our propargylation would be applied to the
cycloadditions with thioamide, which serve a convenient
† Gifu University.
‡ Kinki University.
(1) (a) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew. Chem.,
Int. Ed. 1998, 37, 2014. (b) Rivkin, A.; Cho, S. S.; Gabarda, A. E.;
Yoshimura, F.; Danishefsky, S. J. J. Nat. Prod. 2004, 67, 139. (c) Bach,
T.; Heuser, S. Angew. Chem., Int. Ed. 2001, 40, 3184. (d) Plazzi, P. V.;
Bordi, F.; Silva, C.; Morini, G.; Caretta, A.; Barocelli, E.; Vitali, T. Eur.
J. Med. Chem. 1995, 30, 881. (e) Ganesh, T.; Schilling, J. K.; Palakodety,
R. K.; Ravindra, R.; Shanker, N.; Bane, S.; Kingston, D. G. I. Tetrahedron
2003, 59, 9979. (f) Shao, J.; Panek, J. S. Org. Lett. 2004, 6, 3083.
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Eds.; Pergamon: New York, 1984; Vol. 6, p 235.
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Kuhn, C.; Roberts, R. S.; Smith, M. L.; Venier, O. Chem. Commun. 1998,
2019. (b) Potewar, T. M.; Ingale, S. A.; Srinnivasan, K. V. Tetrahedron
2007, 63, 11066. (c) Ueno, M.; Togo, H. Synthesis 2004, 2673. (d) Narender,
M.; Reddy, M. S.; Sridhar, R.; Nageswar, Y. V. D.; Rao, K. R. Tetrahedron
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10.1021/ol9011844 CCC: $40.75
Published on Web 06/08/2009
 2009 American Chemical Society

alternative to the syntheses of thiazoles, because the orga-
nosulfanyl and organoselanyl acetylenes can easily react with
both nucleophiles and electrophiles.8 As a preliminary step,
we carried out the scandium-catalyzed reactions of the
3-selanylpropargyl alcohol and thiobenzamide give the
cycloadducts; the regioselectivity and the positioning of
between the nitrogen and sulfur atoms were determined by
the X-ray analysis. The crystal data confirmed 4-(p-bro-
mobenzyl)-2-phenyl-5-(phenylselanyl)thiazole (Figure 1).
Table 1. Discovering Reaction Conditions for
Scandium-Catalyzed Preparations of
4-(4-Methoxybenzyl)thiazole 2a
entry
conditiona
yield (%)
1
2
3
4
5
6
7
8
MeNO2, rt, 1 h
19
52
14
62
34
47
46
94
MeNO2, reflux, 10 min
Bu4NHSO4 (0.2 equiv), MeNO2, reflux, 10 min
Bu4NHSO4 (0.2 equiv), MeNO2, reflux, 10 min
Bu4NHSO4 (0.5 equiv), MeNO2, reflux, 10 min
Bu4NCl (0.2 equiv), MeNO2, reflux, 10 min
Bu4NBr (0.2 equiv), MeNO2, reflux, 10 min
Bu4NHSO4 (0.2 equiv), MeNO2-H2O (10:1),
reflux, 10 min
9
DBU (0.1 equiv), MeNO2-H2O (10:1),
-
reflux, 10 min
10
11
Bu4NBF4 (0.2 equiv), MeNO2-H2O (10:1),
reflux, 10 min
48
93
Bu4NHSO4 (0.2 equiv), MeNO2-H2O (5:1),
reflux, 10 min
a Five mol % of scandium triflate was used except in entry 3.
reaction temperature increased the yields (entries 1-2); the
additives, such as ammonium salts, gave the desired product
in good yields (entries 3-8, 10-11); the addition of water
as a cosolvent increased the yield considerably (entries
8-11). The use of DBU as an additive decreased the yield
of the product (entry 9). The use of scandium triflate (5 mol
%), MeNO2-H2O (10:1), Bu4NHSO4 (10 mol %) under
reflux conditions provided the best yield of this product 2a
(entry 8).
Next, we examined the reaction on the various intermedi-
ates bearing the phenylsulfanyl group under the reaction
conditions of both method A and B. Most of the reactions
carried out using method B (MeNO2/H2O ) 10:1) resulted
in the formation of 2-phenyl and 2-methyltriazoles 2 and 3.
Note that the reaction of 2-thienyl derivative 1g with
thioacetamide gave a mixture of both 2-methyl-5-(phenyl-
sulfanyl)-4-(2-thienylmethyl)thiazole and 2-methyl-4-(phe-
nylsulfanyl)-5-(2-thienylmethyl)thiazole; however, the prod-
uct by method B gave 2-methyl-5-(phenylsulfanyl)-4-(2-
thienylmethyl)thiazole 3g (Table 2, entry 9).
Figure 1. ORTEP drawing of 4-p-bromobenzyl-2-phenyl-5-phe-
nylselanylthiazole.
This is a surprising result in that the thiazole was formed
from the cycloaddition of the R-phenylselanylpropadienyl
cation, not the 3-selanylpropargyl cation. The thiazoles from
3-bromoalk-1-ynes and thioamides are usually obtained
through the cycloaddition of propargylic sulfinamide.9 This
unprecedented result would offer a new strategy for the
preparations of thiazoles. Herein, we report the scandium-
catalyzed generation and cycloaddition of the R-sulfanyl and
R-selanyl propadienyl cations with thioamides under opti-
mized phase transfer conditions.
In our initial study, 1-p-methoxyphenyl-3-(phenylsulfa-
nyl)prop-2-yn-1-ol (1a) was reacted with thiobenzamide
under a variety of conditions (Table 1). This led to the fol-
lowing conclusions: scandium triflate in nitomethane
(MeNO2) afforded the product 2a and an increase in the
The phenylselanylpropargyl alcohols 4 with thioamides
were also investigated under the same conditions (Method
B). We successively carried out the deselanylation of the
cycloadducts using MeLi and obtained the thiazoles 5, 6 and
the selenazoles 7 in good to excellent yields (Table 3).
Scheme 1 depicts a catalytic cycle for the thiazole
cycloaddition, which involves in situ generation of the
R-selanyl propadienyl cation as a reactive species. The
propargyl cation 10 is generated from scandium-catalyzed
activation and dehydroxylation of the alcohol 8. Because of
the high number of nucleophilicities, the carbon nucleophiles
attack the propargyl cation to form the propargylated
products.5 However, nucleophilicity of thioamides is weaker,
and therefore, the propargyl cation would isomerize to the
(6) (a) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207, and references
therein. (b) Caffyn, A. J. M.; Nicholas, K. M. In ComprehensiVe Organo-
metallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon: New York, 1995; Vol. 12, Chapter 7.1. (c) Caffyn, A. J. M.;
Nicholas, K. M. J. Am. Chem. Soc. 1993, 115, 6438.
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S. J. Am. Chem. Soc. 2002, 124, 11846. (b) Nishibayashi, Y.; Inada, Y.;
Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2002, 124, 7900. (c) Inada, Y.;
Nishibayashi, Y.; Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2002, 124,
15172. (d) Nishibayashi, Y.; Shinida, A.; Miyake, Y.; Matsuzawa, H.; Sato,
M. Angew. Chem., Int. Ed. 2006, 45, 4835.
(8) (a) Godoi, B.; Speranca, A.; Back, D. F.; Brandao, R.; Nogueira,
C. W.; Zeni, G. J. Org. Chem. 2009, 74, 3469, and references therein. (b)
Yoshimatsu, M.; Naito, M.; Shimizu, H.; Muraoka, O.; Tanabe, G.; Kataoka,
T. J. Org. Chem. 1996, 61, 8200. (c) Yoshimatsu, M.; Machida, K.; Fuseya,
T.; Shimizu, H.; Kataoka, T. J. Chem. Soc., Perkin Trans. 1 1996, 1839.
(9) Beyerstedt, F.; Mcelvain, S. M. J. Am. Chem. Soc. 1937, 59, 2266.
Org. Lett., Vol. 11, No. 13, 2009
2953

Table 2. Scandium-Catalyzed Cycloadditions of
3-Sulfanyl-propargyl Alcohols 1 with Thioamides
Scheme 1
.
Tentative Mechanism for Scandium-Catalyzed
Cycloaddition
entry
alcohol 1 R1
yield (%/method)a
1
2
3
4
5
6
7
8
9
Ph
2b (50/A; 86/B)
2c (50/A; 84/B)
2d (quant/B)
2e (90/B)
2f (48/A; 93/B)
2g (quant/B)
3a (84/A; 86/B)
3d (quant/B)
3g (50/Ab; 84/B)
p-ClC6H4
p-FC6H4
p-BrC6H4
1-naphthyl
2-thienyl
p-MeOC6H4
p-FC6H4
2-thienyl
a Method A: Sc(OTf)3(5 mol %), MeNO2, reflux; Method B: Sc(OTf)3(5
mol %), MeNO2-H2O (10:1), reflux. b 2-Methyl-5-(phenylsulfanyl)-4-
(2-thienylmethyl)thiazole/2-methyl-4-(phenylsulfanyl)-5-(2-thienyl-meth-
yl)thiazole ) 60:40.
propadienyl cation stabilized by either the sulfur or the
selenium atom. The reaction of the propadienyl cation 10′
with thioamides probably gives the propadienylimine inter-
mediate 11, which easily cyclizes in the 5-exo mode, leading
to the product 12. Tetrabutylammonium hydrogensulfate
would effectively act as a scavenger of the eliminated
hydroxyl group. In fact, the slow disappearance of the
alcohols gave rise to the formations of the Meyer-Schuster
rearrangement products resulting from attack of the hydroxyl
group on the propadienyl cation 10′ even under the conditions
of Method B.
We extended the functional transformations of the thiazoles
by transmetalations or transition metal-catalyzed arylations
(typical results are shown in Scheme 2). The 5-phenylsela-
Scheme 2. Transformations of the Thiazoles
Table 3. Conversion of 3-Selanylpropargyl Alcohols 4 to
4-Arylmethylthiazoles and Selenazoles
entry
alcohol 4 R1
p-MeOC6H4
Ph
p-ClC6H4
p-BrC6H4
1-naphthyl
2-thienyl
3,4-(MeO)2C6H3
3,4-(methylenedioxy)-C6H3
2,4,6-Me3C6H3
p-MeOC6H4
2-thienyl
Y
yield (R2) (%)a
1
2
3
4
5
6
7
8
S
S
S
S
S
S
S
S
S
S
S
Se
Se
Se
Se
5a (R2 ) Ph) (63)
5b (R2 ) Ph) (58)
5c (R2 ) Ph) (84)
5d (R2 ) Ph) (67)
5e (R2 ) Ph) (86)
5f (R2 ) Ph) (86)
5g (R2 ) Ph) (65)
5h (R2 ) Ph) (84)
5i (R2 ) Ph) (94)
6a (R2 ) Me) (99)
6f (R2 ) Me) (99)
7a (R2 ) Ph) (99)
7f (R2 ) Ph) (54)
7i (R2 ) Ph) (70)
7j (R2 ) Ph) (78)
9
10
11
12
13
14
15
p-MeOC6H4
2-thienyl
2,4,6-Me3C6H3
p-FC6H4
nylthiazoles easily underwent transmetalation with Bu3SnH/
AIBN to form the 5-tributylstannylated thiazole intermediate.
The alkylations with benzyl bromide provided 13a-b in high
yields. The lithiations and alkylations of 5-sulfanyl thiazoles
gave 14a-c resulting from alkylations at the benzylic carbon.
5-Sulfanyl group of thiazoles underwent cleavage using Bu3SnH/
a 4-Arylmethyllthiazoles and selenazoles were obtained by treatment
with MeLi or Bu3SnH/AIBN then MeLi.
2954
Org. Lett., Vol. 11, No. 13, 2009

AIBN followed by treatment with MeLi to form 15a-b.
Palladium-catalyzed Stille couplings of thiazoles proceeded via
tributylstannylthiazole.
In summary, we have developed a new cycloaddition
reaction of the 3-sulphanyl and 3-selanylpropargyl alcohols
having thioamides and selenamide with complete regiose-
lectivities, presumably by the effective niromethane-H2O-
Bu4NHSO4 system. Further work in progress is aimed at
exploring the synthetic organic reactions using R-sulphanyl
and selanyl propadienyl cations as intermediates.
Supporting Information Available: Typical experimental
procedures, spectral data for all of the new compounds, the
copies for 1H and 13C NMR spectral data of 3c, 5g, 6b, 7b,
7d, 14c, 15b and X-ray crystallographic data (X-ray data
for 4-p-bromobenzyl-2-phenyl-5-phenylselanylthiazole). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL9011844
Org. Lett., Vol. 11, No. 13, 2009
2955