Sequential molecular conjugation using thiophene S,S-dioxides bearing a clickable functional group

Article abstract of DOI:10.1246/cl.170426

Electron-deficient thiophene dioxides have been found to react rapidly with a bicyclo[6.1.0]non-4-yne derivative to afford benzocyclooctenes in excellent yields. Thiophene dioxides bearing a clickable functional group served as efficient bisreactive platf

Full text of DOI:10.1246/cl.170426

Advance Publication Cover Page
Sequential Molecular Conjugation
using Thiophene S,S-Dioxides Bearing a Clickable Functional Group
Tomohiro Meguro, Suguru Yoshida,* and Takamitsu Hosoya*
Advance Publication on the web May 19 , 2017
doi:10.1246/cl.170426
© 2017 The Chemical Society of Japan
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Publication manuscripts.

Sequential Molecular Conjugation
using Thiophene S,S-Dioxides Bearing a Clickable Functional Group
Tomohiro Meguro, Suguru Yoshida,* and Takamitsu Hosoya*
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062
(E-mail: s-yoshida.cb@tmd.ac.jp, thosoya.cb@tmd.ac.jp)
Electron-deficient thiophene dioxides have been found
to react rapidly with a bicyclo[6.1.0]non-4-yne derivative to
afford benzocyclooctenes in excellent yields. Thiophene
dioxides bearing a clickable functional group served as
efficient bisreactive platform molecules that enabled
sequential molecular conjugation in a simple operation.
feasible under milder conditions that would suit our purpose.
Based on this idea, we screened for the highly reactive
dienophile in the reaction with commercially available 3,4-
dichlorothiophene S,S-dioxide (7a) in methanol and found
that bicyclo[6.1.0]non-4-yne (BCN) derivative 24c reacted
smoothly with 7a even at room temperature to afford the
desired benzocyclooctene 8a in high yield (Figure 1C).
Keywords: Thiophene S,S-dioxide | Cyclooctyne | Diels–
Alder reaction
A
R1
R1
H
H
H
OH
OH
Inverse electron demand Diels–Alder (IEDDA) reactions
between electron-deficient dienes and electron-rich
dienophiles have been used widely to conjugate molecules
covalently across a broad range of research fields such as
materials, pharmaceuticals, and life sciences.1 In particular,
reactions of 1,2,4,5-tetrazines with t-cyclooctenes or
cyclooctynes have been applied extensively to bioconjugation
as these reactions proceed rapidly in a bioorthogonal manner
(Figure 1A).2 However, despite rapid advances in click
chemistry in recent years,3,4 including the IEDDA reactions,5
the synthesis of multifunctional molecules via sequential
conjugation of functional modules to a platform molecule
bearing several connectable groups is not easy.6,7 This is due
to the lack of user-friendly conjugation reactions that are
orthogonal to each other.
N
N
N
N
N
+
N
rt
H
R2
2
3
R2
1
B
t-Bu
t-Bu
t-Bu
O
O
+
S
o-C6H4Cl2
reflux
7.5 h
t-Bu
4
5
6
92%
C
H
H
H
Cl
Cl
Cl
OH
OH
O
+
S
O
MeOH
rt, 2 h
Cl
H
7a
2
8a
93%
(1.5 equiv)
Figure 1. (A) Reported reaction of tetrazines 1 with BCN derivative 2.
(B) Reported reaction between thiophene dioxide 4 and cyclooctyne (5).
(C) Reaction of thiophene dioxide 7a with BCN derivative 2.
During the course of our studies on strained alkyne
chemistry,8 we found that cyclooctyne derivatives bearing a
terminal alkyne moiety serve as efficient bisreactive platforms
for conjugation of two ynophiles such as azides; treatment of
the platform diyne with an excess amount of a copper salt
enabled selective click reaction at the terminal alkyne moiety
via the transient protection of the higher azidophilic strained
alkyne moiety by complexation with copper.8c We assumed
that finding a novel combination of a reaction that is capable
of connecting two molecules efficiently would be of benefit in
achieving the convergent synthesis of multifunctional
molecules via sequential conjugation. Herein, we report that a
thiophene S,S-dioxide9 reacts smoothly with a cyclooctyne
and that thiophene S,S-dioxides bearing a clickable functional
group serve as efficient bisreactive platforms for sequential
conjugation.
Table 1. Reactions of various thiophene S,S-dioxides with 2
R1
R1
H
H
R2
R2
OH
R2
R2
OH
O
O
+
S
MeOH
rt
H
H
R1
R1
2
8
7
LUMO
(eV)a
Entry
R1
R2
7
8
Yield/%b k (M–1s–1)a,c krel
1
2
3
4
H
H
Br
I
Cl 7a –2.91 8a
Br 7b –2.93 8b
96
9.9 × 10–2
1
quant.
quant.
quant.
0.26
2.6
H
H
7c –2.79 8c
7d –2.73 8d
9.1 × 10–2 0.82
7.7 × 10–3 0.07
7
5
6
7
8
9
Cl
Br
Cl 7e –3.09 8e
Br 7f –3.09 8f
93
1.7
0.98
–
17
9.9
–
quant.
From a literature search, we found a pioneering study on
the Diels–Alder reaction between 3,4-di(tert-butyl)thiophene
S,S-dioxide (4) and cyclooctyne (5) reported by Nakayama
and coworkers in 1988; the reaction was performed in
SiMe3
C6H4-p-OMe H 7h –2.18 8h no reaction
C6H4-p-CF3 7i –3.09 8i 53
H 7g –2.15 8g no reaction
–
–
H
–
–
aSee Supporting Information for details. Isolated yields of the reactions
of 7 (1.0 equiv) with 2 (1.5 equiv) in methanol at room temperature. cThe
second-order rate constants of the reactions at 25 °C.
b
refluxing
o-dichlorobenzene
(180
°C)
to
afford
benzocyclooctene 6, which was formed with the release of
sulfur dioxide through cheletropic reaction of the initial
cycloadduct (Figure 1B).9d We assumed that using a thiophene
dioxide bearing electron-withdrawing groups in combination
with a more strained dienophile would render the reaction
Electronic and steric effects of substituents on thiophene
dioxides greatly affected the reactivity with BCN derivative 2
(Table 1). For example, in addition to 7a (entry 1), various

2
halogenated thiophene dioxides 7b–7f also reacted smoothly
with 2 to afford the corresponding benzocyclooctenes 8b–8f
in excellent yields (entries 2–6). In particular, time-dependent
absorption analyses, which we conducted to determine the
second-order rate constants (k) of the reactions, indicated
significantly high reactivity of tetrachloro- and tetrabromo-
substituted thiophene dioxides, 7e and 7f, which reacted more
than tenfold faster than 3,4-dichlorothiophene dioxide 7a
(entries 5 and 6). While 3,4-dibromothiophene dioxide 7b
showed slightly higher reactivity than 7a (entry 2), almost the
same or decrease in reaction rates were observed for 2,5-
dibromo- and 2,5-diiodothiophene dioxide, 7c and 7d,
respectively (entries 3 and 4). The reactivities of thiophene
dioxides 7a–7f showed good correlations with their LUMO
energies obtained by DFT calculations (B3LYP/6-31G(d));
the reaction rate increased as the energy of LUMO decreased,
indicating that electron-withdrawing groups on the thiophene
dioxide contributed to the acceleration of the reaction as with
the general IEDDA reaction. In stark contrast, 2,5-
bis(trimethylsilyl)- and 2,5-di(4-methoxyphenyl)-substituted
thiophene dioxide, 7g and 7h, with high LUMO levels did not
react with BCN derivative 2 at room temperature (entries 7
and 8). Even 2,5-di(4-trifluoromethylphenyl)thiophene
dioxide 7i with a LUMO level as low as 7e and 7f reacted
Dienophiles other than BCN derivative 2 also reacted
with tetrachlorothiophene dioxide 7e, although the reaction
rate differed depending on the substrate (Table 2). Dibenzo-
fused cyclooctyne 94b and 4,8-diazacyclononyne 11,4d which
react rapidly with azides like BCN derivative 2, showed
significantly lower reactivity with 7e than 2 at room
temperature (entries 1 and 2). These reactions slowly
proceeded with heating at 50 °C to afford the corresponding
products in good yields. Similar to the previous reports,9c 4-
methoxystyrene (13) and 2-vinylpyridine (15) also reacted
with 7e to afford dihydrobenzenes 14 and 16, respectively,
although the reactions were not as fast as that with 2 (entries 3
and 4). The rates of these reactions were comparable to those
between azides and cyclooctynes, which have been frequently
used as reliable click reactions.
Boc
N
Boc
Boc
N
N
Cl
N
17a
Et3N
Cl
H
H
H
N
N
OH
2
O
O
7e
S
CH2Cl2
rt
MeOH
rt, 24 h
Cl
Cl
Cl
Cl
8j
quant.
[k = 0.021 M–1s–1 a
]
7j
67%
Scheme 1. Synthesis of N-Boc-piperazino-substituted trichlorothiophene
dioxide 7j and its reaction with BCN derivative 2. aSee Supporting
Information for details.
with
2
slowly and afforded the corresponding
benzocyclooctene 8i only in moderate yield (entry 9). These
results clearly show that substituents at 2,5-positions
considerably decreased the reactivity of thiophene dioxides
due to steric hindrance.
O
O
N
O
NH
17b
Et3N
O
N
Cl
N
O
O
CH2Cl2, rt
O
S
Table 2. Reactions of tetrachlorothiophene S,S-dioxide (7e) with various
Cl
dienophiles
7k
77%
Cl
Cl
Cl
7e
N
Cl
Cl
Cl
Cl
O
O
NH
N3
O
+
dienophile
(1.5 equiv)
S
17c
Et3N
MeOH
rt, 24 h
N
Cl
Cl
7e
Cl
N
N3
O
O
CH2Cl2, rt
S
Yield/%a k (M–1s–1)b
Cl
7l
63%
Entry Dienophile
Product
Cl
Scheme 2. Synthesis of piperazino-substituted trichlorothiophene
dioxides 7k and 7l bearing a terminal alkyne or azido moiety.
Cl
Cl
Cl
6c
1
9
10
–
(84)d
We then embarked on a study to develop a thiophene
dioxide bearing a connectable group such as a clickable
terminal alkyne or azido moiety. To elaborate such a
bisreactive molecule, we focused on tetrachlorothiophene
dioxide 7e. Considering the nuclephilic displacement
observed in the related compound, we assumed that 7e would
show electrophilic reactivity similar to that of halogenated
Cl
Ts
N
Ts
N
Cl
Cl
15c
(63)e
2
11
12
–
Cl
N
N
Cl
Ts
Ts
Cl
Cl
electron-deficient
olefins.10
Indeed,
treatment
of
Cl
3
13
15
14
16
91
5.5 × 10–3
7.8 × 10–4
tetrachlorothiophene dioxide 7e with N-Boc-piperazine (17a)
in the presence of triethylamine at room temperature
Cl
OMe
OMe
selectively
afforded
N-Boc-piperazino-substituted
Cl
Cl
trichlorothiophene dioxide 7j with a small amount of the
isomer (1%) (Scheme 1).11 The reaction of 7j with BCN
derivative 2 smoothly proceeded at a sufficient rate to afford
the corresponding product 8j quantitatively. This result
suggested that one chloro group of 7e is replaceable by the
other group without significantly affecting the ynophilicity.
Based on these results, we prepared two bisreactive thiophene
dioxides 7k and 7l bearing a clickable terminal alkyne or
azido group via the reaction with 7e and the corresponding
piperazine derivative 17b or 17c, respectively (Scheme 2).
Cl
Cl
N
4
72
N
aIsolated yields, unless otherwise noted. See Supporting Information for
details. cYields based on 1H NMR analysis by using 1,1,2,2-
tetrachloroethane as an internal standard. dYield when the reaction was
performed at 50 °C for 72 h is shown in parentheses. Yield when the
reaction was performed at 50 °C for 24 h is shown in parentheses.
b
e

3
Bisreactive thiophene dioxides 7k and 7l were
This work was supported by Platform for Drug
Discovery, Informatics, and Structural Life Science of MEXT
and AMED, Japan; JSPS KAKENHI Grant Numbers
15H03118 (B; T.H.), 16H01133 (Middle Molecular Strategy;
T.H.), 26350971 (C; S.Y.); Suntory Foundation for Life
Sciences (S.Y.); Naito Foundation (S.Y.).
successfully applied to sequential conjugation (Schemes 3 and
4). For example, copper-catalyzed azide–alkyne cycloaddition
of 7k with benzyl azide (18) resulted in the formation of
triazole 7m, leaving the chloro groups and the thiophene
dioxide moiety untouched (Scheme 3). Subsequent reaction
between thiophene dioxide 7m and BCN derivative 2
furnished the cycloadduct 19 in high yield. Furthermore, a
simple one-pot operation involving the Staudinger–Bertozzi
ligation of azide-functionalized thiophene dioxide 7l with
phosphine 20, followed by cycloaddition between the
resulting amide 7n and 2 afforded the conjugate 21 in high
yield (Scheme 4). These results clearly indicate that thiophene
dioxides 7k and 7l would serve as efficient platforms for
preparing a variety of compounds, including multifunctional
molecules, from simple modules.
Supporting Information is available on http://dx.doi.org/
10.1246/cl.xxxxxx.
References and Notes
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BnN3 18
(1.8 equiv)
3
4
(MeCN)4CuBF4
(5 mol %)
TBTA
O
O
N
N
O
N
O
N
(5 mol %)
Cl
Cl
N
N
N
O
O
O
O
CH2Cl2
rt, 17 h
S
S
Bn
7m
94%
Cl
Cl
7k
Cl
Cl
2 (1.1 equiv)
MeOH
rt, 17 h
O
N
N
N
N
O
N
Cl
N
Bn
N
H
N
N
OH
3
Bn
TBTA
5
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Cl
H
Cl
19
92%
Scheme 3. Sequential conjugation using 7k via copper-catalyzed Huisgen
reaction with 18 followed by the Diels–Alder reaction with 2.
CO2Me
PPh2
O
O
20
(1.5 equiv)
N
N
Cl
H
N
Cl
N
O
N
N3
O
O
O
O
S
THF, H2O
(10/1)
rt, 24 h
S
7n
6
7
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P(O)Ph2
Cl
7l
Cl
Cl
Cl
2 (1.5 equiv)
rt, 24 h
O
N
Cl
Cl
H
N
H
H
N
O
OH
P(O)Ph2
Cl
21
90%
(2 steps, one-pot)
8
9
a) I. Kii, A. Shiraishi, T. Hiramatsu, T. Matsushita, H. Uekusa, S.
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Scheme 4. Sequential conjugation using 7l via the Staudinger–Bertozzi
ligation with 20 followed by the Diels–Alder reaction with 2.
In summary, we have demonstrated that thiophene
dioxides bearing multiple small halogeno groups react rapidly
with a bicyclononyne derivative.12,13 We have also shown that
electron-deficient thiophene dioxides bearing a connectable
group, which were easily prepared from tetrachlorothiophene
dioxide, served as good bisreactive platform molecules,
enabling efficient sequential conjugation in a simple manner.
Further applications for the facile synthesis of multifunctional
molecules based on the use of thiophene dioxides are
currently under way in our laboratory.
10

4
Visnevska, S. Belyakov, I. Shestakova, A. Gulbe, E. Jaschenko, E.
Abele, Heterocycl. Lett. 2012, 2, 245.
See Supporting Information for details.
A part of this work was presented in 2014, see: T. Meguro, Y.
Yoshida, T. Hosoya, 25th Symposium on Physical Organic
Chemistry, Sendai, Japan, Sep. 7, 2014, Abstr., No. 1P004.
13
During prepartion of this manuscript, a rapid generation of sulfur
dioxide via the reaction of tetrachlorothiphene dioxide with a BCN
derivative was reported. See: W. Wang, X. Ji, Z. Du, B. Wang,
Chem. Commun. 2017, 53, 1370.
11
12