Simple and practical method for selective acylation of primary hydroxy group catalyzed by N-methyl-2-phenylimidazole (Ph-NMI) or 2-phenylimidazo[2,1-b]benzothiazoles (Ph-IBT)

Article abstract of DOI:10.1016/j.tetlet.2014.10.130

N-Methyl-2-phenylimidazole (Ph-NMI) and 2-phenylimidazo[2,1-b]benzothiazoles (Ph-IBT) catalyzed selective acylation of primary alcohols using acid anhydrides. The Ph-NMI- or Ph-IBT-catalyzed reaction using (PhCO)₂O as an acylating agent could particularly acylate the primary hydroxy group of 1,n-diols (n ≥ 3) with a high, synthetically useful selectivity.

Full text of DOI:10.1016/j.tetlet.2014.10.130

Accepted Manuscript
Simple and practical method for selective acylation of primary hydroxy group
catalyzed by N-methyl-2-phenylimidazole (Ph-NMI) or 2-phenylimidazo[2,1-
b]benzothiazoles (Ph-IBT)
Kouta Ibe, Yu-suke Hasegawa, Misuzu Shibuno, Tsukasa Shishido, Yuzo Sakai,
Yu Kosaki, Keisuke Susa, Sentaro Okamoto
PII:
S0040-4039(14)01837-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.10.130
TETL 45359
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 September 2014
17 October 2014
24 October 2014
Please cite this article as: Ibe, K., Hasegawa, Y-s., Shibuno, M., Shishido, T., Sakai, Y., Kosaki, Y., Susa, K.,
Okamoto, S., Simple and practical method for selective acylation of primary hydroxy group catalyzed by N-
methyl-2-phenylimidazole (Ph-NMI) or 2-phenylimidazo[2,1-b]benzothiazoles (Ph-IBT), Tetrahedron Letters
(2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.10.130
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Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Simple and practical method for selective acylation of primary hydroxy group
catalyzed by N-methyl-2-phenylimidazole (Ph-NMI) or
2-phenylimidazo[2,1-b]benzothiazoles (Ph-IBT)
Kouta Ibe,a Yu-suke Hasegawa,a Misuzu Shibuno,a Tsukasa Shishido,a Yuzo Sakai,a Yu Kosaki,a Keisuke
Susa,a and Sentaro Okamotoa,*
a Department of Material and Life Chemistry, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan. Phone:
+81-45-481-5661. Fax: +81-45-413-9770. E-mail: okamos10@kanagawa-u.ac.jp
ARTICLE INFO
ABSTRACT
Article history:
Received
N-Methyl-2-phenylimidazole (Ph-NMI) and 2-phenylimidazo[2,1-b]benzothiazoles (Ph-IBT)
catalyzed selective acylation of primary alcohols using acid anhydrides. The Ph-NMI- or
Ph-IBT-catalyzed reaction using (PhCO)2O as an acylating agent could particularly acylate the
primary hydroxy group of 1,n-diols (n ≥ 3) with a high, synthetically useful selectivity.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Acylation
Catalyst
Substututed Imidazole
Imidazobenzothiazole
Primary Alcohol

Selective acylation of a primary hydroxyl group in the
presence of secondary hydroxyl group(s) is often required as a
discriminatory protection in organic synthetic schemes.
Conventionally, processes which use a controlled amount of
bulky acylation agents, such as pivalic acid derivatives, under
mild reaction conditions have widely been accepted.1 In
Initially, we studied the selectivity for acetylation of a
primary alcohol in the presence of a secondary alcohol by the
catalytic reaction of a mixture of benzyl alcohol (1) and
2-phenylethanol (2) with acetic anhydride (Ac2O) using 5
mol%
N-methylimidazole
(Ph-NMI),17
2,3-dihydro-4H-pyrimido[2,3-b]benzothiazole
of
4-N,N-dimethylaminopyridine
(DMAP),
(NMI),
N-methyl-2-phenylimidazole
addition,
3-acetylthiazolidine-2-thiones-NaH2
and
AcCl-hindered amine3 have been employed for the selective
acylation system for primary alcohols. Recently, Wakita and
Hara developed N,N-diethyl-α,α-difluorobenzylamine as a
selective agent of primary hydroxy benzoylation.4 Besides
such reagent-control systems, catalyst-control of the reaction
has been realized by development of efficient catalyses with
Cu(OTf)2,5 lanthanide trichlorides6 such as YbCl3 and CeCl3,
(DHPB),15,18 IBT or its 2-phenyl derivative Ph-IBT
(Equation 1). The selectivity for acylation of the primary
alcohol was evaluated as a value of Ac-1/Ac-2 (Figure 1). We
found that Ph-NMI and Ph-IBT exhibited high Ac-1/Ac-2
values of more than 15, due to the bulkiness of the 2-Ph group.
Interestingly, IBT also exhibited a high selectivity (12.7),
however, the selectivity of DHPB, with a similar thioguanidine
structure, was low.
Y5(O-i-Pr)13O,7
InCl3,8
Sc(OTf)3,9
TMSOTf,9
[ClBu2SnOSnBu2Cl]2,10 NaHSO4/SiO2,11 KF-Al2O3,12 and
iminophosphoranes.13 Acylation catalyzed by enzymes such as
lipases is also versatile, although the method is not necessarily
general to substrate diversity.14 With the exception of catalysis
by TMSOTf, iminophosphoranes or enzymes, the methods
have been developed based on using metallic compounds as
catalysts and, somewhat surprisingly, catalysis based on
organic compounds (organic catalysts) has been less explored.
Here we report that N-methyl-2-phenylimidazole (Ph-NMI)
and 2-substituted imidazo[2,1-b]benzothiazoles (IBTs)
catalyzed the selective acylation of a primary hydroxy group in
diols.
Following these results, we studied the selectivity for
primary alcohol acylation catalyzed by Ph-NMI, IBT and its
derivatives.
imidazo[2,1-b]benzothiazoles (IBTs) were readily synthesized
in good yields from commercially available
In
this
study,
substituted
2-aminobenzothiazoles 3 and α-haloketones 4 according to
previously reported procedures19 (Scheme 1).
Table 1 shows results of the competitive reaction of a
mixture of 1 and 2 with Ac2O in the presence of various IBTs
as catalysts. Comparing the results of entries 5–7, the
substitution at the 2-position of IBT increased the selectivity;
however, the deference between Me-IBT and Ph-IBT was not
large in this acetylation reaction. As previously mentioned,
Ph-NMI was also assessed as a selective catalyst (entry 4).
The use of more sterically demanding acid anhydrides
enhanced the selectivity (entries 12–14). In toluene and
1,2-dichloroethane a somewhat enhanced selectivity was
observed (entries 8 and 9). Interestingly, reactions under higher
concentrations or with a larger loading of catalyst exhibited
higher selectivity (entries 10 and 11). Substitution at the
7-position of IBT affected the rate and selectivity of the
reaction (entries 15 and 16). The selectivity was improved by
the substitution, and an electron-withdrawing group at the
7-position decreased the reaction rate (entry 16).
In the course of our research for catalytic acyl transfer
reactions,15,16 we discovered that imidazo[2,1-b]benzothiazole
(IBT) catalyzed acylation of alcohols with acid anhydrides.
Figure 1. The results of the preliminary investigation of the
acetylation of a mixture of 1 and 2.
Scheme 1. Preparation of imidazobenzothiazoles.

Table 1. Reaction of a mixture of 1 and 2 with Ac2Oa
entry
1
catalyst (mol%)
DMAP (5)
acid anhydride
Ac2O
Ac-1/1/Ac-2/2b
84/16/15/85
78/32/18/82
60/40/9/91
93/7/6/94
selectivity, Ac-1/Ac-2b
total conversion, %b
5.6
99
96
96
99
82
97
98
85
76
82
82
83
73
99
91
58
2
NMI (5)
Ac2O
4.3
3
DHPB (5)
Ac2O
6.7
4
Ph-NMI (5)
Ac2O
15.5
12.7
15.2
15.3
16.0
18.0
19.5
26.0
26.7
35.5
32.0
17.2
18.3
5
IBT (5)
Ac2O
76/24/6/94
91/9/6/94
6
Me-IBT (5)
Ac2O
7
Ph-IBT (5)
Ac2O
92/8/6/94
8
Ph-IBT (5) [toluene]c
Ph-IBT (5) [Cl(CH2)2Cl]d
Ph-IBT (5) [2.0 M]e
Ph-IBT (20)
Ac2O
80/20/5/95
72/28/4/96
78/22/4/96
79/21/3/97
80/20/3/97
71/29/2/98
96/4/3/97
9
Ac2O
10
11
12
13
14
15
16
Ac2O
Ac2O
Ph-IBT (5)
(EtCO)2O
(i-PrCO)2O
(PhCO)2O
Ac2O
Ph-IBT (5)
Ph-IBT (5)
Ph,MeO-IBT (5)
Ph,NO2-IBT (5)
86/14/5/95
55/45/3/97
Ac2O
aThe reaction was performed at room temperature for 24 h. Unless other wise indicated, the concentration (1 or 2 in CH2Cl2) was 1.0 M.
bDetermined by 1H NMR analysis of the crude mixture.
cThe reaction was conducted in toluene instead of CH2Cl2.
dThe reaction was carried out in 1,2-dichloroethane instead of CH2Cl.
eThe concentration of 1 or 2 in CH2Cl2 was 2.0 M.
Having these results in hand, the Ph-NMI- and
Ph-IBT-catalyzed reactions of 1,n-diols 5 (n = 2, 3, 4 and 5)
with Ac2O, (i-PrCO)2O or (PhCO)2O were investigated and the
results are summarized in Table 2. The reaction yielded a
mixture of primary ester 6, secondary ester 7, and diester 8.
The selectivity for acylation of a primary hydroxy group was
evaluated by comparison of (6 + 8)/(7 + 8) values.
acylated with a high primary-selectivity (entries 7 and 11–22).
In the acetylation reaction of 1,3-diol 5b (1,3-butanediol),
Ph-NMI and Ph-IBT demonstrated better selectivity (entries
4–6, 8, and 9). The reactions with (PhCO)2O catalyzed by
Ph-NMI or Ph-IBT exhibited high selectivity in producing the
desired 6 with formation of a small amount of 8 (entries 7 and
12). Ph-IBT-catalyzed reactions of other 1,3-diols 5c and 5d
with (PhCO)2O afforded the primary ester 6 with a high,
synthetically useful selectivity (entries 14 and 16). Similarly,
1,4-diols 5e and 5f (entries 18 and 20) and 1,5-diol 5g (entry
22) could be converted by Ph-IBT-catalyzed reactions with
(PhCO)2O to the desired primary esters with a high selectivity.
The reaction of 1,2-diol (1,2-butanediol, 5a) proceeded
selectively at primary hydroxyl group; however, the selectivity
was unfortunately not high and thus inapplicable for practical
use, even when sterically demanding anhydrides were
employed (entries 1–3). Meanwhile, 1,n-diols (n ≥ 3) were
Table 2. Acylation of diolsa

entry
5b
catalyst
acid anhydride
6:7:8c
selectivity
(6+8)/(7+8)c
conversion, %c
1,2-diol
1
5a
5a
5a
5b
5b
5b
5b
5b
5b
5b
5b
5b
5c
5c
5d
5d
5e
5e
5f
Ph-NMI
Ph-IBT
Ph-IBT
DMAP
NMI
(PhCO)2O
(i-PrCO)2O
(PhCO)2O
Ac2O
83:13:4
72:25:3
75:20:5
64:34:2
78:17:5
92:4:4
97:0:3
77:5:18
90:3:7
85:2:13
96:1:3
96:0:4
96:2:2
97:0:3
96:1:3
97:2:1
94:2:4
96:1:3
97:2:1
98:1:1
97:1:2
98:1:1
5.1
92
93
91
93
91
98
95
80
85
86
91
92
86
95
96
96
90
95
91
91
91
95
2
2.7
3
3.2
1,3-diols
4
1.9
5
Ac2O
3.8
6
Ph-NMI
Ph-NMI
Me-IBT
Ph-IBT
Me-IBT
Ph-IBT
Ph-IBT
Ph-IBT
Ph-IBT
Ph-IBT
Ph-IBT
Ph-IBT
Ph-IBT
Ph-IBT
Ph-IBT
Ph-IBT
Ph-IBT
Ac2O
12
7
(PhCO)2O
Ac2O
33.3
4.1
8
9
Ac2O
9.7
10
11
12
13
14
15
16
17
18
19
20
21
22
(i-PrCO)2O
(i-PrCO)2O
(PhCO)2O
(i-PrCO)2O
(PhCO)2O
(i-PrCO)2O
(PhCO)2O
(i-PrCO)2O
(PhCO)2O
(i-PrCO)2O
(PhCO)2O
(i-PrCO)2O
(PhCO)2O
6.5
24.8
25.0
24.5
33.3
24.8
32.7
16.3
24.8
32.7
49.5
33.0
49.5
1,4-diols
5f
1,5-diol
5g
5g

aThe reaction was performed at room temperature for 12-24 h. The concentration of 5 in CH2Cl2 was 1.0 M.
bFor the structure of diols 5, see below.
cDetermined by 1H NMR analysis of the crude mixture.
As a result, the reaction with (PhCO)2O catalyzed by Ph-NMI
or Ph-IBT acylated the primary hydroxy group of 1,n-diols (n ≥
3) with a high synthetically useful selectivity. In an actual
synthesis, isolation of the desired 6 from diester 8 by column
chromatography will be easier than from 7 because of the
difference of their polarity. The minimum generation of 7 in
Ph-NMI- or Ph-IBT-catalyzed reactions was a characteristic of
the method, which might be attained by the reasonably fast
reaction rate of conversion of 7 to 8 (Scheme 2). For instance,
We thank the Ministry of Education, Culture, Sports, Science
and Technology (MEXT) for financial support.
References and notes
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Tetrahedron 2002, 58, 1369.
using
a slightly excess amount of (PhCO)2O in the
Ph-NMI-catalyzed reactions, 6b, 6g, and 6h were obtained in
good isolated yields from diols 5b, 5g, and 5h, respectively, by
column chromatography (Scheme 3). In the 20 mmol scale
reaction of 5b, the desired 6b was isolated in a good yield.
6. (a) Clarke, P. A. Tetrahedron Lett. 2002, 43, 4761. (b) Clarke, P.
A.; Holton, R. A.; Kayaleh, N. E. Tetrahedron Lett. 2000, 41,
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2420.
Scheme 2. Formation pathway of 6, 7 and 8.
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Scheme 3. Examples of actual synthesis.
22. General Procedure for Selective Primary Acylation of Diols.
To a mixture of diol 5 (1.0 mmol) and Ph-IBT (12.5 mg, 0.05
mmol, 5 mol%) in solvent (0.5 or 1.0 mL) was added
(i-PrCO)2O or (PhCO)2O (1.0 or 1.1 mmol) at room temperature.
The resulting mixture was stirred at ambient temperature. After
checking the reaction progress by TLC analysis, saturated
aqueous NH4Cl was added and the mixture was extracted with
ether, washed with brine, dried over MgSO4 and concentrated.
The crude residue was chromatographed on silica gel to separate
the corresponding mono-ester 6.
In
N-methyl-2-phenylimidazole
2-phenylimidazo[2,1-b]benzothiazoles
summary,
we
demonstrated
(Ph-NMI)
(Ph-IBT)
that
and
catalyzed
selective acylation of primary alcohols using acid anhydrides. In
particular, the Ph-NMI- or Ph-IBT-catalyzed reaction, using
(PhCO)2O as an acylating agent, acylated a primary hydroxy
group of 1,n-diols (n ≥ 3) with a high synthetically useful
selectivity.22
Acknowledgments

Graphical abstract