Structure-activity relationship of dihydroimidazo-, dihydropyrimido, tetrahydrodiazepino-[2,1-b]-thiazoles, and -benzothiazoles as an acylation catalyst

Article abstract of DOI:10.1016/j.tetlet.2014.01.135

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 analogues 7, 8, and 9 were synthesized by a condensation reaction of cyclic thioureas 15 and α-bromoacetophenones 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. Remarkable 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.

Full text of DOI:10.1016/j.tetlet.2014.01.135

Tetrahedron Letters 55 (2014) 1909–1912
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Structure–activity relationship of dihydroimidazo-, dihydropyrimido,
tetrahydrodiazepino-[2,1-b]-thiazoles, and -benzothiazoles as an
acylation catalyst
⇑
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
⇑
Corresponding author. Tel.: +81 45 481 5661; fax: +81 45 413 9770.
E-mail address: okamos10@kanagawa-u.ac.jp (S. Okamoto).
Figure 1. Various cyclic isothioureas.
http://dx.doi.org/10.1016/j.tetlet.2014.01.135
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

1910
S. Okamoto et al. / Tetrahedron Letters 55 (2014) 1909–1912
Various isothioureas 2 were synthesized according to the proce-
dure involving Pd- or Cu-catalyzed cyclization of thiourea-alcohols
12 derived from ortho-bromoanilines 10 as key reaction
chlorobenzo-oxazole and chlorobenzothiazole by treatment with
the corresponding amine followed by cyclization or methylation
on the ring nitrogen (Scheme 1).
a
(Scheme 1). After converting bromoanilines 10 to the correspond-
ing isothiacyanates 11, the reaction with 3-aminopropanol gave
thioureas 12, which were cyclized to benzothiazoles 13 in the pres-
ence of Pd(PPh3)4 or CuI/1,10-phenanthroline as a catalyst and
Cs2CO3.18 Finally, the resulting benzothiazoles 13 were cyclized
by treatment with MsCl and Et3N and isothioureas 2 was obtained
in moderate to good yields through four steps.
Nonbenzo derivatives 7a–d, 8, and 9 were readily synthesized
by the corresponding
a-bromoacetophenone derivatives 14 and
cyclic thioureas 15 by heating in EtOH, followed by neutralization
(Scheme 2).20 Similarly, chiral 2-phenyl substituted 7e–h were ob-
tained from 14 and (R)-4-phenylimidazolidine-2-thione; produc-
tion of a possible regioisomer 16 was not observed presumably
because of the steric repulsion in an intermediate A.
Similarly, BTM (3a) and its derivatives 3b and 3g were readily
synthesized from the corresponding ortho-bromoanilines and (R)-
2-phenyl-2-aminoethanol (Scheme 1). Oxa analogue 5 of HBTM
and noncyclic benzothiazole-amine 619 were synthesized from
With cyclic isothioureas 2, 5, 6, 7, 8, and 9 in hand, we evaluated
their catalytic activity in the acylation reaction of 1-phenylethanol
with acid anhydride (Scheme 3).
First, we performed the reactions using DHPB (2a) and its
substituted analogues 2b–e as a catalyst (0.5 mol %), isobutyric
anhydride (1.0 equiv), and Et3N (1.5 equiv) in CH2Cl2 (0.25 M) at
20 °C. The time course of the reaction was traced by TLC analysis.
Digitized stained TLC images were analyzed using image process-
ing and analysis software (NIH-image).21 The amounts of alcohol
and ester were quantified to determine the conversion. The calcu-
lated rate constant k for each catalyst22,23 and the relative activity
(100 for DHPB) are summarized in Table 1. It was found that sub-
stitution on the benzene ring electronically affected the catalytic
ability. Thus, the introduction of an electron-donating substitu-
ent(s) increased the reaction rate (2b, 2e, 2c); in contrast, an elec-
tron-withdrawing substituent (Br) decreased the activity (2d).
In a similar way, activities of 1a, 2a, oxa analogue 5, open struc-
ture 6, and nonbenzo derivatives 7a, 8, and 9 were compared by
measuring conversions at each reaction time and calculating rate
constants in the reactions of 1-phenylethanol with a catalyst
(1 mol %), acetic anhydride (1.5 equiv), and Et3N (2 equiv) in CH2-
Cl2 (0.2 M) at 20 °C.22,23 The calculated relative activities (100 for
DHPB) are shown in Table 2. Among nonbenzo derivatives 7a, 8,
Scheme 1. Synthesis of 2, 3, 5, and 6.
Scheme 2. Synthesis of 7, 8, and 9.

S. Okamoto et al. / Tetrahedron Letters 55 (2014) 1909–1912
1911
Table 3
Relative acylation activity of catalysts 7a–d
7a
7b
7c
7d
8.2
Scheme 3. Acylation reactions for evaluating catalytic activity.
Relative activity
1.0
2.5
4.4
Table 1
Relative acylation activity of catalysts 2a–e
2b
2e
2c
2a
2d
DMAP
k (minꢀ1Mꢀ2
Relative activity
)
536
197
500
184
400
147
272
100
172
63
124
46
Figure 2. Structure for electronic effects and ring strains.
such as pyrrolidine, piperidine, and azepane. However, in the acyl-
ated intermediates, a compound comprised with a smaller ring has
higher strain enegy, which could destabilize iii or iv. Considering a
balance of these factors, it would be reasonable to conclude that
six-membered derivatives such as 2 and 8 would exhibit the high-
est activity.
Table 2
Relative acylation activity of catalysts 1a, 2a, and 5–9
Table 4 summarizes the results of kinetic resolution of 1-phen-
ylethanol with isobutyric anhydride in the presence of a chiral cat-
alyst 3a (BTM) or 7e–h. It is evident that lack of benzo structure
decreased the S value. Interestingly, introducing an electron-
donating group on the phenyl substituent improved the selectivity.
The effect of the substituent(s) on the benzene ring of BTM (3a)
was studied (Table 5). Compared to 3a, selectivity factor S25 for 3b,
which has a trimethoxybenzo structure, decreased; however, it
remained similar to that of 3a. The introduction of an electron-
withdrawing CF3 greatly decreased both the reaction rate and S.
2a
8
1a
9
7a
6
5
Relative activity
100
89
20
15
3.3
3.0
2.3
and 9, which have a different annulating ring, six-membered
compound 8 was more active than five-membered 7a and seven-
membered 9. Compound 6, which has an open structure, was much
less reactive than 1a and 2a. Accordingly, in both series of benzo
and nonbenzo analogues, the compounds comprised with a six-
membered ring were the most active catalysts. Oxa analogue 5
showed very low activity because of a higher electronegativity of
O (3.5) than S (2.4).24
Table 4
Kinetic resolution of 1-phenylethanol with 3a or 7e–h catalystsa
The catalytic activities of 7a–d which have a differently substi-
tuted phenyl group were compared in the reactions of 1-phenyl-
ethanol with
a
catalyst (4 mol %), isobutyric anhydride
(1.5 equiv), and Et3N (2 equiv) in CHCl3 (0.25 M) at 20 °C. The
calculated relative activities (1.0 for 7a) are shown in Table 3.
Introduction of an electron-rich substituent(s) increased the reac-
tivity. In particular, introducing a NMe2 group at the p-position
greatly enhanced the reaction rate.
Introducing an electron-donating group(s) R to i and ii can
increase the electron density of the sp2 N by a positive inductive
effect, which enhances the nucleophilicity (Fig. 2). In addition,
the electron-donating R may stabilize the iminium cation in the
acylated intermediates iii and iv and increase their existence ratio.
The size of the annulating ring of i and ii is smaller, nucleophilicity
of sp.2 N may become higher, similar to saturated N-heterocycles
b
Catalyst
Time (h)
CHPLC (%)
S
3a
7e
7f
7g
7h
44
26
3
5
3
21.3
26.7
30.0
38.9
46.3
13.9
3.5
6.6
5.8
8.4
a
Evaluated by the reaction of 1-phenylethanol with isobutyric anhydride
(0.75 equiv), i-Pr2NEt (0.75 equiv), and a catalyst (4 mol %) in CHCl3 (0.25 M) at
room temperature.
b
Conversion.

1912
S. Okamoto et al. / Tetrahedron Letters 55 (2014) 1909–1912
9. Birman, V. B.; Jiang, H.; Li, X. Org. Lett. 2007, 9, 3237–3240.
Table 5
Kinetic resolution of 1-phenylethanol with 3a, 3b, and 3g catalystsa
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S
3a
3b
3g
1.5
1
18
60.2
54.1
45.4
16.5
11.3
5.6
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a-bromoace-
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isothiourea catalysts revealed their structure–activity relation-
ships. Remarkable electronic effects resulting from substituent(s)
on a benzo or phenyl moiety and the influence of the size of the
annulating ring were observed. A few substitution effects on chiral
catalysts of type 3 and 7 were also studied.
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21. Version 1.63 for Macintosh was used. This is available via the internet at http://
rsb.info.nih.gov/nih-image/download.html. See Ref. 3.
22. For
determination
of
rate
constant
When
in.
Table
1:
ꢀd[ROH]/
dt = k[cat.][ROH][anhydride].
[ROH] = [anhydride]
and
k0 = k[cat.] = constant, ꢀd[ROH]/dt = k0[ROH]2. Then 1/[ROH] ꢀ1/[ROH]0 = k0t.
From the time versus 1/[ROH] plot, k0 was calculated. The value of k was
obtained by k = k0/[cat.]. In other experiments (Tables
2 and 3), the rate
constants were determined from time (t) versus log(1-c) plots [c: conversion, c
<0.4], treating the reaction as a pseudo-first order one in the substrate alcohol
because concentration of anhydride was not change so much in
a low-
conversion (c <0.4).
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catalyst, alcohol, and anhydride.
24. Kinetic resolution of secondary alcohols by a chiral N-methylbenzoguanidine
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25. Selectivity factor is defined as s = k(fast-reacting enantiomer)/k(slow-reacting
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