Organocatalytic chemoselective monoacylation of 1,n-linear disulfonamides

Article abstract of DOI:10.1016/j.tetlet.2017.01.039

Predominant monoacylation of 1,n-linear disulfonamides took place in the presence of pyrrolidinopyridine-type organocatalysts when the chain length of the linear disulfonamides was n?=?3, 4, or 5 (monoacylate/diacylate?=?up to 44). The chemoselectivity of

Full text of DOI:10.1016/j.tetlet.2017.01.039

Accepted Manuscript
Organocatalytic Chemoselective Monoacylation of 1,n-Linear Disulfonamides
Keisuke Yoshida, Atsushi Hirata, Hisashi Hashimoto, Ayumi Imayoshi,
Yoshihiro Ueda, Takumi Furuta, Takeo Kawabata
PII:
S0040-4039(17)30061-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.039
TETL 48542
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 November 2016
9 January 2017
12 January 2017
Please cite this article as: Yoshida, K., Hirata, A., Hashimoto, H., Imayoshi, A., Ueda, Y., Furuta, T., Kawabata,
T., Organocatalytic Chemoselective Monoacylation of 1,n-Linear Disulfonamides, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.01.039
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Monoacylation of 1,n-Linear Disulfonamides
Keisuke Yoshida, Atsushi Hirata, Hisashi Hashimoto, Ayumi Imayoshi, Yoshihiro Ueda, Takumi Furuta, Takeo
Kawabata

1
Tetrahedron Letters
Organocatalytic Chemoselective Monoacylation of 1,n-Linear Disulfonamides
Keisuke Yoshida, Atsushi Hirata, Hisashi Hashimoto, Ayumi Imayoshi, Yoshihiro Ueda, Takumi Furuta,
and Takeo Kawabata*
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Predominant monoacylation of 1,n-linear disulfonamides took place in the presence of
pyrrolidinopyridine-type organocatalysts when the chain length of the linear disulfonamides
was n=3, 4, or 5 (monoacylate/diacylate = up to 44). The chemoselectivity of the competitive
acylation between N,N’-ditosyl-1,5-pentanediamine (n=5) and N,N’-ditosyl-1,3-propanediamine
(n=3) was found to be 36, favoring the former substrate. Different chain length by only one
carbon atom was discriminated in the competitive acylation between N,N’-ditosyl-1,5-
pentanediamine (n=5) and of N,N’-ditosyl-1,4-butanediamine (n=4) with the relative acylation
rate of 16 in the presence of the organocatalyst.
Available online
Keywords:
Organocatalyst
Acylation
Chemoselectivity
Diamine
2009 Elsevier Ltd. All rights reserved.
Molecular Recognition
Introduction
pyrrolidinopyridine (PPY) catalyst 4 that enables the highly
chemoselective monoacylation of 1,n-linear diols (Scheme 2a).9
Monoacylated diamines are useful building blocks for the
construction of bioactive molecules and chemical probes.1 While
selective monoacylation of symmetrical diamines is seemingly
like a simple process, it has been known to be a difficult
molecular transformation because overacylation is often
unavoidable (Scheme 1).2 Similar reactivity of the amino groups
in diamines 1 and monoacylated diamines 2 (k1~k2) makes
selective monoacylation difficult, especially in the case of long
chain 1,n-linear diamines.3 Use of large excess of diamines
compared to the acyl donor is often adopted for the purpose of
selective monoacylation, by minimizing the unavoidable
overacylation.4 In order to achieve selective monoacylation with
only stoichiometric amount of diamine substrates, either strategy
that increase k1 (acceleration strategy) or decrease k2
(deceleration strategy) is assumed to be feasible. Wang reported
selective monobenzoylation of diamines based on the
acceleration strategy employing highly reactive dianions
generated with two equivalents of a strong base, n-BuLi.5 Several
methods based on in situ protection of a amino group by forming
metal complexes6 and ammonium salts7 have been developed as
the examples of the deceleration strategy. We report here
selective monoacylation of 1,n-linear diamine derivatives
(ditosylamides) through substrate recognition by organocatalysts
as an additional example of the acceleration strategy.
A
molecular recognition process including H-bonding
interactions between the hydroxy groups of the substrates and the
functional groups of the catalytic intermediate was proposed to
be the origin of the highly chemoselective and accelerative
monoacylation based on both experimental and computational
studies.9b The role of the unreacting hydroxy group as a H-bond
donor in the molecular recognition process was proposed to be
the key for the accelerative acylation. These backgrounds
prompted us to develop
a method for chemoselective
monoacylation of 1,n-linear diamine derivatives based on the
molecular recognition process by the catalyst (Scheme 2b).
Sulfonamide derivative 1a with acidic NH was chosen as the
substrate for monoacylation due to the expectation that the NH
group would serve as an effective H-bond donor for the
molecular recognition process with the catalytic intermediate.10
O
O
H
H
(a)
N
N
C8H17
HN
O
OC8H17
NH
N
N
O
O
H-bond
donor
reactive
site
catalyst 4 (5 mol%)
Ac2O (1.03 eq.)
2,4,6-collidine (1.5 eq.)
O
HO
OH
HO
O
CHCl3, 60 C, 24 h
5
6
In the course of our continuous efforts toward the
development of chemo- and regioselective transformation of
multi-functionalized molecules,8 we developed chiral
89% yield
(b)
H-bond
donor
reactive
site
catalytic chemoselective
monoacylation
O
Ts
N
Ts
N
Ts
Ts
O
O
N
N
k1
k2
H
H
H
NHR
n NHR
RHN CH2
R'
N
CH2
N
R'
R'
N
CH2
n
n R
1a
O
2a
R
R
1
2
3
Scheme 2. Organocatalytic chemoselective monoacylation of (a)
1,5-pentanediol (previous work) and (b) N,N’-ditosyl-1,5-
pentanediamine (this work).
Scheme 1. Acylation of 1,n-linear diamines.

2
Tetrahedron Letters
Table 1. Optimization of chemoselective monoacylation of N,N’-ditosyl-1,5-pentanediamine 1a
catalyst (10 mol%)
Ac2O (1.03 eq.)
base (1.7 eq.)
+
TsHN
monoacylate 2a
NTs
Ac
TsN
Ac
NTs
Ac
TsHN
NHTs
1a
0.05 M, 48 h
diacylate 3a
Entry
1
Catalyst
Base
Solvent
Temperature (°C)
Yield of 2a (%)
Yield of 3a (%)
S.M. recovery (%)
DMAP
2,4,6-collidine
2,4,6-collidine
2,4,6-collidine
PEMP
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DMF
20
46
34
0
12
2
42
60
2
4
20
3
4
–60
–60
–60
–60
–60
–60
–60
–60
–60
–60
0
100
30
4
DMAP
39
53
37
80
46
42
72
0
29
12
10
7
5
4
5
6
7
8
9
6
6
PEMP
32
6
PEMP
53
7
PEMP
10
8
PEMP
3
47
9
PEMP
5
45
10
11
12
PEMP
12
0
13
2,4,6-collidine
PEMP
100
90
8
2
O
O
O
O
O
O
O
O
H
H
H
H
H
H
H
H
H
H
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(S)
(S)
(R)
(R)
(S)
(S)
N
N
N
N
N
N
N
N
N
N
N
C8H17
HN
O
OC8H17 C8H17
NH
O
OC8H17 C8H17
O
OC8H17 C8H17
O
OC8H17
N
N
N
N
O
O
O
O
O
O
O
O
O
O
N
HO
OH
N
N
N
N
9
5
6
7
8
Results and discussion
4-Dimethylaminopyridine (DMAP)-catalyzed acylation of
N,N’-ditosyl-1,5-pentanediamine (1a) was first investigated as a
control experiment (Table 1). Treatment of 1a with 1.03 equiv. of
acetic anhydride in the presence of 10 mol% of DMAP in CHCl3
at 20 °C gave monoacylate 2a and diacylate 3a in 46% and 12%
yield, respectively, in addition to 42% recovery of 1a (entry 1).
The reaction with catalyst 4 gave 2a and 3a in 34% and 2% yield,
respectively, in addition to 60% recovery of 1a (entry 2). We
next run a reaction using catalyst 4 at –60 °C, expecting the
higher chemoselectivity due to the more effective H-bonding
interaction between the substrate and the catalyst. However, the
corresponding reaction at –60 °C resulted in the complete
recovery of 1a (entry 3). We then searched for the effective
auxiliary base that can promote acylation of 1a even at –60 °C,
and found that 1,2,2,6,6-pentamethylpyperidine (PEMP) is
suitable for this purpose. Catalysts 4-98 (10 mol%) with various
functional side chains were examined for the selective
monoacylation of 1a at –60 °C in the presence of 1.7 equiv. of
PEMP (entries 5-10). Each catalyst gave monoacylate 2a more
selectively (80/7~37/10) than DMAP
(entry 4, 39/29).
Chemoselectivity for the monoacylation was found to be
dependent on the catalyst structure. These results suggest that the
side chains of catalysts affected the chemoselectivity of the
acylation between 1a and 2a. The best result was obtained in the
acylation of 1a with catalyst 611. Treatment of 1a with 10 mol%
of 6 in the presence of 1.7 equiv. of PEMP gave monoacylate 2a
and diacylate 3a in 80% and 7% yield, respectively, in addition
to 10% recovery of 1a (entry 7). Use of 2,4,6-collidine as a base
or DMF as a solvent under the otherwise identical conditions
resulted in further poor conversion of the reaction (entries 11,
12).
The acylation of various 1,n-linear disulfonamides were
examined (Figure 1a) under optimized conditions for
monoacylation (Table 1, entry 7). For comparison, DMAP-
catalyzed acylation reactions (Figure 1b) were also run under the
otherwise identical reaction conditions. Highly chemoselective
monoacylation of 1 (n = 3–5) took place to give the
Figure 1. Ratios between the mono- and diacylate in the acylation
of various linear diamine derivatives. (a) Acylation catalyzed by 6.
(b) Acylation catalyzed by DMAP.

3
two disulfonamides) in the presence of 10 mol% of DMAP
gave monoacylate m-1 in 50% yield as a major product with
concomitant formation of diacylate m-2, monoacylate n-1, and
diacylate n-2 in 10%, 16%, and 3% yield, respectively, and
recovery of m (29%) and n (70%) (entry 1). According to the
equation shown in the footnote [a] in Table 2,9 the relative
reaction rate (km/kn) was determined to be 5.0, which was
assumed to correspond to the relative intrinsic reactivities
between N,N’-ditosyl-1,3-propanediamine (m=3) and N,N’-
ditosyl-1,4-butanediamine (n=4). On the other hand, the
corresponding competitive acylation reaction catalyzed by 6 gave
m-1 highly chemoselectively in 88% yield without the formation
of diacylate m-2 and n-2 (entry 2). The calculated relative
acylation rate (km/kn =16) was much larger than that (km/kn =5) by
DMAP. A further larger relative rate (km/kn =36) was observed in
the competitive acylation reaction of N,N’-ditosyl-1,3-
propanediamine (m=3) and N,N’-ditosyl-1,5-pentanediamine
(n=5) in the presence of catalyst 6, whereas the corresponding
relative rate catalyzed by DMAP (km/kn =4.5) was comparable
with that in competitive acylation reaction for m,n=3,4 (entries 1
vs. 3). On the other hand, much smaller relative rate (km/kn =4.7)
was observed in the competitive acylation between N,N’-ditosyl-
1,4-butanediamine (m=4) and N,N’-ditosyl-1,5-pentanediamine
(n=5) even in the presence of catalyst 6 (entry 5). These results
suggests that DMAP promotes acylation depending on the
intrinsic reactivity of the each of the sulfonamide substrates,
whereas catalyst 6 does based on the chain-length recognition of
the substrates.
corresponding monoacylate
2
in 80–94% yield with
chemoselectivity (2/3 = 11–44) in the presence of catalyst 6.
Moderately chemoselective monoacylation of 1 (n = 2, 6, 7) was
observed in the presence of 6 to give the corresponding
monoacylate 2 in 60–65% yield with chemoselectivity (2/3 = 4–
10). In contrast, random acylation of 1 took place in DMAP-
catalyzed acylation, independent of the chain length of
disulfonamides 1 (2/3 = 0.8–3.0). The ratios of 2/3 observed in
the DMAP-catalyzed acylation are assumed to be the result from
the relative intrinsic reactivities of the disulfonamides 1 and the
corresponding monoacylates 2 generated in the reaction medium.
The dependence of the chain length on chemoselectivity of the
monoacylation of 1 catalyzed by 6 suggests that the molecular
recognition process between the catalyst 6 and disulfonamide
substrates 1 may be responsible for the observed phenomena.
Table 2. Competitive acylation between different
disulfonamides catalyzed by either 6 or DMAP.
In order to further examine whether the chemoselective
monoacylation of the disulfonamides proceeds in an accelerative
manner by hydrogen bonding interaction between the catalyst
and the substrate, we chose N,N’-ditosyl-1,3-propanediamine
(10) and as a standard substrate and compare its rate of acylation
with those of the corresponding NMeTs derivative 11b and N-
tosyl-1,3-propanediamine (11a) lacking the second NHTs group
(Table 3). Acylation of the NHTs derivative 10 proceeded 63
times faster than that of the corresponding NMeTs derivative 11b
in the presence of catalyst 6 (entry 4). The relative intrinsic
reactivity between 10 and 11b was estimated to be 6.4 based on
the corresponding DMAP-catalyzed acylation (entry 3). The
observation suggests that acylation of 10 was ca. 10 times more
accelerated than its intrinsic reactivity in the presence of catalyst
6. Similar phenomena were also observed in the competitive
acylation between 10 and 11a. Acylation of 10 proceeded 142
times faster than that of 11a in the presence of catalyst 6 (entry
2). The corresponding DMAP-catalyzed competitive acylation
suggested that the intrinsic reactivity of 10 was estimated to be
19 times higher than that of 11a (entry 1). These results also
imply that acylation of 10 was ca. 7 times more accelerated than
its intrinsic reactivity in the presence of catalyst 6. All of these
results suggest that chemoselective monoacylation of 10
proceeds in an accelerative manner in the presence of catalyst 6.
The hydrogen-bonding interaction between the substrate NHTs
group and the catalyst is expected to be responsible for the
accelerative acylation.
a
Entry
1b
m, n
3, 4
3, 4
3, 5
3, 5
4, 5
4, 5
Catalyst
DMAP
6
m/m-1/m-2/n/n-1/n-2
29 : 50 : 10 : 70 : 16 : 3
11 : 88 : 0 : 85 : 10 : 0
18 : 55 : 18 : 72 : 18 : 3
7 : 93 : 0 : 90 : 5 : 0
35 : 42 : 10 : 63 : 25 : 5
25 : 73 : 0 : 71 : 23 : 0
km/kn
5.0
16
2b
3c
DMAP
6
4.5
36
4c
5b
DMAP
6
2.2
4.7
6b
a Determined by the following equation. Conversion was calculated from the
total amount of the recovery of the two disulfonamides.
b Run at the substrate concentration of 0.025 M based on the total amount of
the two sulfonamides.
c Run at the substrate concentration of 0.05 M based on the total amount of
the two sulfonamides..
In conclusion,
a
method for the organocatalytic
chemoselective monoacylation of 1,n-linear disulfonamides has
been developed. Catalyst 6 also promoted chain-length selective
monoacylation of N,N’-ditosyl-1,3-propanediamine preferentially
over that of N,N’-ditosyl-1,4-butanediamine and N,N’-ditosyl-
1,5-pentanediamine. Since acylsulfonamide moiety has been
widely found in bioactive compounds,12 selective modification of
sulfonamide groups would become an additional tool for the
development in the sulfonamide-related medicinal chemistry.
The results in Figure 1a suggest that the catalyst 6 might
recognize the chain lengths of the linear disulfonamides. In order
to examine this assumption, the competitive acylation reactions
between two disulfonamides with different chain lengths were
examined (Table 2). Treatment of a 1:1 mixture of N,N’-ditosyl-
1,3-propanediamine (m=3) and N,N’-ditosyl-1,4-butanediamine
(n=4) with acetic anhydride (0.51 equiv. of the total amount of

(10-1+10-2)–11-1
(10-1+10-2)+11-1
(10-1+10-2)–11-1
(10-1+10-2)+11-1
ln{(1–conversion) 1–
ln{(1–conversion) 1+
}
}
푘푚
푘푛
=
4
Tetrahedron Letters
Asada, S.; Kigoshi, H.; Uesugi, M. J. Am. Chem. Soc. 2004, 126,
3461–3471; (f) Sato, S.; Watanabe, M.; Katsuda, Y.; Murata, A.;
Wang, D. O., Uesugi, M. Angew. Chem. Int. Ed. 2015, 54, 1855–
1858.
Acknowledgments
This research was financially supported by Grants-in-Aids for
Scientific Research (S) (JP26221301), Young Scientists (B)
(JP15K18827, 16K17903), and Scientific Research on Innovative
Areas
Organocatalysts’ (JP23105008) and ‘Middle Molecular Strategy’
(JP16H01148).
2.
3.
4.
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F.; Wang, T. Org. Lett. 2003, 5, 3399–3402.
‘Advanced
Molecular
Transformations
by
5.
6.
Table 3. Competitive acylation between 10 and its analogues
catalyzed by either 6 or DMAP.a
7.
(a) Atwell, G. J.; Denny, W. A. Synthesis 1984, 1032–1033; (b)
Verma, S. K.; Acharya, B. N.; Kaushik, M. P. Org. Lett. 2010, 12,
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Yoshida, K.; Furuta, T.; Ueda, Y.; Kawabata, T. Adv. Synth.
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10. Acylation of free 1,5-diaminopentane was found to produce the
corresponding diacylate as the major product even in the presence
of the catalysts described in Table 1.
b
Entry
11
Catalyst
DMAP
6
10/10-1/10-2/11/11-1
25 : 55 : 13 : 82 : 12
1 : 96 : 1 : 97 : 1
k10/k11
11. (a) Yoshida, K.; Mishiro, K.; Ueda, Y.; Shigeta, T.; Furuta, T.;
Kawabata, T. Adv. Synth. Catal. 2012, 354, 3291–3298; (b)
Yamanaka, M.; Yoshida, U.; Sato, M.; Shigeta, T.; Yoshida, K.;
Furuta, T.; Kawabata, T. J. Org. Chem. 2015, 80, 3075–3082.
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A. K.; Karoli, T.; March, D. R.; Mensah, L.; Nairn, M. R.;
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1
2
3
4
11a (R=H)
19
11a (R=H)
142
11b (R=NMeTs)
DMAP
32 : 45 : 17 : 73 : 19
6.4
11b (R=NMeTs)
6
2 : 93 : 1 : 94 : 2
63
a Run at the substrate concentration of 0.05 M based on the total amount of
the two sulfonamides.
b Determined by the following equation. Conversion was calculated from the
total amount of the recovery of the two disulfonamides.
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
References and notes
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For examples, (a) Walsh, D. A.; Green, J. B.; Franzyshen, S. K.;
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(e) Shimogawa, H.; Kwon, Y.; Mao, Q.; Kawazoe, Y.; Choi, Y.;

5
Highlights
• An organocatalytic monoacylation of 1,n-
linear disulfonamides has been developed.
• Chain-length selective acylation was
observed.
• Accelerative acylation was proposed to be
the origin of the selective monoacylation.