Tetrahedron Letters
Structure–activity relationship of dihydroimidazo-, dihydropyrimido,
tetrahydrodiazepino-[2,1-b]-thiazoles, and -benzothiazoles as an
acylation catalyst
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Sentaro Okamoto , Yuzo Sakai, Saki Watanabe, Shohei Nishi, Aya Yoneyama, Hitomi Katsumata,
Yu Kosaki, Rumi Sato, Megumi Shiratori, Misuzu Shibuno, Tsukasa Shishido
Department of Material and Life Chemistry, Kanagawa-University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclic isothioureas 1, 2, 3, and 4 were synthesized through a four-step procedure from the corresponding
ortho-bromoanilines 10 via Pd- or Cu-catalyzed cyclization–benzothiazole formation. Nonbenzo ana-
logues 7, 8, and 9 were synthesized by a condensation reaction of cyclic thioureas 15 and a-bromoace-
tophenones 14. Investigations of the acylation reactions of 1-phenylethanol with acid anhydrides in
the presence of these cyclic isothiourea catalysts revealed their structure–activity relationships. Remark-
able electronic effects resulting from substituent(s) on a benzo or phenyl moiety and the influence of the
size of the annulating ring were observed. Introduction of an electron-donating substituent(s) enhanced
the reaction rate. A few substitution effects on chiral catalysts of type 3 and 7 were also studied.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 26 December 2013
Revised 23 January 2014
Accepted 28 January 2014
Available online 5 February 2014
Keywords:
Cyclic isothiourea
Acylation
Catalyst
Substitution effect
Kinetic resolution
Recently, cyclic isothioureas such as 1–4 (Fig. 1) have received
considerable attention in research studies on organic catalysts and
asymmetric synthesis.1 In 2006, Birman et al. developed 3a (BTM)
as a very efficient asymmetric catalyst for acylative kinetic resolu-
tion of racemic secondary alcohols.2 In the same year, we indepen-
dently found that 2,3-dihydroimidazo[2,1-b]benzothiazole (1a,
DHIB) and 3,4-dihydro-2H-pyrimido[2,1-b]benzothiazole (2a,
DHPB) work well as a good catalyst for acyl transfer reactions. It is
noteworthy that 2a can catalyze the reactions quite efficiently.3
For instance, 2a catalyzed the acylation of alcohols with an anhy-
dride at a high rate, which was more than that of 4-dimethylamino-
pyridine (DMAP). Smith and co-workers pointed out that 2a
efficiently catalyzed Steglich rearrangement reactions and that the
analogous 1a was not effective.4 From 2006 to 2013, chiral deriva-
tives of 1a and 2a involving 3a and 4a attracted increasing interests,
and have been widely used to develop efficient asymmetric reac-
tions such as kinetic resolution of alcohols,2,5 acids,6 lactams7 and
2-oxazolidinones,8 desymmetrization of meso diols,9 dynamic ki-
and nucleophilicity) of cyclic isothioureas has been investigated pri-
marily for the corresponding nonbenzo saturated compounds,
2,3,5,6-tetrahydroimidazo[2,1-b]thiazole and 3,5,6,7-tetrahydro-
2H-thiazolo[3,2-a]pyrimidine, and their derivatives.16,17
Herein we report the development of a new method for synthe-
sizing 1, 2, 3, and 4 derivatives bearing a substituent(s) on the ben-
zene ring, 6, and nonbenzo analogues 7, 8, and 9. The experimental
results of the acylation reactions using these analogues as catalysts
are discussed to elucidate their structure–activity relationship.
netic resolution of
a
-thioalkanoic acids and azlactons,10 Steglich
rearrangement and related reactions,11 aldol-lactonization reac-
tion,12 Michael addition-cyclization reaction,13 and
a-amination of
carboxylic acids.14,15 During this period, the reactivity (basicity
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Corresponding author. Tel.: +81 45 481 5661; fax: +81 45 413 9770.
Figure 1. Various cyclic isothioureas.
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.