Synthesis of sulfonimide-based dendrimers and dendrons possessing mixed 1?→?2 and 1?→?4 branching motifs

Article abstract of DOI:10.1016/j.tetlet.2018.12.052

The synthesis of dendrimers and a chlorosulfo-dendron possessing a unique combination of 1 → 2 and 1 → 4 branching types is described. The procedure consists of a two-step preparation of 3,5-dinitrobenzene-1-sulfonyl chloride, which was used for the persu

Full text of DOI:10.1016/j.tetlet.2018.12.052

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of sulfonimide-based dendrimers and dendrons possessing
mixed 1 ? 2 and 1 ? 4 branching motifs
a,
Mykola Kolotylo a, Volodymyr Holovatiuk b, Julia Bondareva c, Oleg Lukin c, , Vladimir Rozhkov
⇑
⇑
a Institute of Organic Chemistry, National Academy of Science, 5 Murmanskaya St., Kiev 02660, Ukraine
b Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences, 50 Kharkovskoye Shosse, Kiev 02660, Ukraine
c Skolkovo Institute of Science and Technology, 3 Nobel St., 143026 Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of dendrimers and a chlorosulfo-dendron possessing a unique combination of 1 ? 2 and
1 ? 4 branching types is described. The procedure consists of a two-step preparation of 3,5-dinitroben-
zene-1-sulfonyl chloride, which was used for the persulfonylation of p-toluidine and 4-(benzylthio)ani-
line. The obtained tetranitro compounds were reduced to the corresponding tetraamines. The latter were
decorated with eight 4-toluene sulfonyl groups each to furnish the corresponding dendrimers. Oxidation
of the dendrimer possessing a 4-(benzylthio)phenylene core with N-chlorosuccinimide resulted in the
formation of a dendron with a sulfonyl chloride functionality at the focal point.
Received 24 October 2018
Revised 18 December 2018
Accepted 21 December 2018
Available online xxxx
Keywords:
Dendrimers
Nitro compounds
1,3,5-Trinitrobenzene
Sulfonyl chlorides
Sulfonimides
Ó 2018 Elsevier Ltd. All rights reserved.
Introduction
[6]. Müllen and co-workers reported the four-fold Diels–Alder
reaction of functionalized tetraphenylcyclopentadienone (the so-
The first series of ‘‘cascade molecules” was synthesized by
Vögtle and co-workers in 1978 [1,2]. The term ‘‘cascade” was cho-
sen because it evokes analogies to the repetitive branching of the
arms and with some justification this type of molecule could have
been called dendritic. These molecules were synthesized diver-
gently utilizing two branching motifs. In 1985 Tomalia and co-
workers developed branched poly(amidoamines) (PAMAM),
coined, and propagated the name ‘‘dendrimer” [3,2]. PAMAM den-
drimers were obtained by a divergent method involving the 1 ? 2
branching motif, which means every branching point is capable of
attaching two branches or terminal groups. Fréchet and Hawker
described the first convergent synthesis of dendrimers. They con-
structed poly(arylether) architectures ‘‘from the outside inwards”
applying again the 1 ? 2 branching type [4]. Newkome and co-
workers, in turn, presented a divergent synthetic route to water-
soluble, highly branched ‘‘arborol systems” with terminal hydroxyl
groups. In this case, the 1 ? 3 branching motif was utilized [5].
Percec and co-workers described an original convergent synthesis
of four generations of dendrons with the 1 ? 3 branching motif
based on the AB3 building block methyl 3,4,5-trishydroxybenzoate
called A4B building block) with tetraethynylbiphenyl leading to
the first and thus far only type of dendrimer with a 1 ? 4 branch-
ing motif [7].
Herein, we describe an alternative approach to the branched
architectures involving combined 1 ? 2 and 1 ? 4 divergent
growth type.
Results and discussion
The key compound for the preparation of the highly branched
dendrons described in this work is 3,5-dinitrobenzene-1-sulfonyl
chloride 2 (Scheme 1). Examination of the literature revealed that
compound 2 could be obtained from 3,5-dinitroaniline via reaction
with NaNO2 with subsequent treatment of the diazonium salt with
SO2 [8]. However, this method has some drawbacks. Applying gas-
eous SO2 onto the diazonium salt solution complicates the synthe-
sis. Additionally, 3,5-dinitroaniline is a rather expensive reagent.
We developed a new two-step synthetic pathway to sulfonyl
chloride 2 starting from 1,3,5-trinitrobenzene (TNB) (CAUTION:
TNB is an explosive and should be handled with great care),
the product of the primary processing of 2,4,6-trinitrotoluene. As
shown in Scheme 1, in the first step the nucleophilic displacement
of one nitro group in 1,3,5-trinitrobenzene with benzyl thiol in the
presence of K2CO3 takes place [9]. The process of the substitution
⇑
Corresponding authors.
E-mail addresses: o.lukin@skoltech.ru (O. Lukin), vladimir_rozhkov@mail.ru (V.
Rozhkov).
https://doi.org/10.1016/j.tetlet.2018.12.052
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: M. Kolotylo, V. Holovatiuk, J. Bondareva et al., Synthesis of sulfonimide-based dendrimers and dendrons possessing mixed 1 ? 2
and 1 ? 4 branching motifs, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2018.12.052

2
M. Kolotylo et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Synthesis of 3,5-dinitrobenzene-1-sulfonyl chloride. Reagents and
conditions: (i) K2CO3, DMF, rt; (ii) N-chlorosuccinimide, HCl, AcOH, CH2Cl2, 0 °C.
has been previously studied in detail and product 1 was obtained
in 87% isolated yield [9]. Compound 1 readily reacts with N-chloro-
succinimide in the presence of concentrated aqueous HCl giving
sulfonyl chloride 2 in nearly quantitative yield. Notably, since our
last report on this type of reaction [10] we optimized the condi-
tions which resulted in improved yields and shorter reaction times.
The reaction was carried out in a homogeneous solution of both
reagents in a 1:1 mixture of AcOH and CH2Cl2 (Scheme 1). The
overall isolated yield of 2 over the two steps was 83%.
The sulfonyl chloride was attached to p-toluidine to form per-
sulfonylated nitro compound 3. The reaction was carried out in
CH2Cl2 in the presence of Et3N (Scheme 2). Tetranitro compound
3 precipitated from the reaction mixture. The product was filtered
and washed with hot i-PrOH. Upon drying a colorless solid was
obtained in 75% isolated yield. The use of p-toluidine is justified
on account of its ready availability, higher reactivity in the persul-
fonylation reaction compared with aliphatic amines, and the ease
of 1H NMR interpretation of its derivatives. Four nitro groups of 3
were reduced to the amino groups with SnCl2Á2H2O to furnish
amine 4 which was obtained as a yellow solid in 23% isolated yield.
The obtained amine is a stable compound and can be stored at
ambient conditions for a long time without any detectable decom-
position. Most likely, the relatively low yield of tetraamine 4 is due
to its poor solubility in the extracting solvent (CH2Cl2) at the isola-
tion stage. Finally, tetraamine 4 was treated with p-toluenesulfonyl
chloride (12 eq.) to give dendrimer 5 in 41% isolated yield. The
reaction was heated at reflux in CH2Cl2 in the presence of Et3N
Scheme 3. Synthesis of superbranched sulfonyl chloride 10. Reagents and condi-
tions: (i) Et3N, CH2Cl2, reflux; (ii) SnCl2Á2H2O, CH2Cl2–MeOH (1:1), HCl, reflux; (iii)
TsCl, Et3N, CH2Cl2, reflux; (iv) N-chlorosuccinimide, HCl, AcOH, CH2Cl2, 0 °C.
from the reaction mixture after reaction completion. Consequently,
the solvent was evaporated and the residue was triturated with
water (to remove triethylamine hydrochloride) and then with i-
PrOH. The product was obtained as a white solid in 71% isolated
yield. Analogous to the preparation of 4, tetranitro compound 7
was reduced to tetraamine 8 in 32% isolated yield. As in the case
of tetraamine 4 the yield of 8 was moderate. This confirmed our
assumption regarding the low solubility of amines in CH2Cl2 at
the isolation stage. The use of other reducing reagents such as
Fe/NH4Cl, Zn/AcOH, and N2H4/FeCl3-C gave complex mixtures of
products. In contrast to tetraamine 4, compound 8 was unstable
and fully decomposes within 24 h. Therefore, compound 8 was
used in the persulfonylation reaction immediately after its isola-
tion. The tetraamine 8 was characterized only by 1H NMR. In spite
of eight reaction centers, amine 8 was persulfonylated in one step
with tosyl chloride in the presence of triethylamine giving super-
branched sulfonimide 9 which was successfully converted into sul-
fonyl chloride 10 using N-chlorosuccinimide as a chlorinating
reagent (Scheme 3). The symmetrical structure of compound 10
is reflected in its simple 1H NMR spectrum that can be unambigu-
ously assigned (see ESI).
for 72 h and the product was obtained as
(Scheme 2).
a creamy solid
Similarly, as depicted in Scheme 3, a convenient synthesis of
‘‘superbranched” sulfonyl chloride 10 was carried out. In this syn-
thesis 4-(benzylthio)aniline 6 was first persulfonylated with sul-
fonyl chloride 2 in the presence of Et3N in CH2Cl2 to give
tetranitro compound 7. Notably, intermediate 7 did not precipitate
Dibutylamine was reacted with sulfonyl chloride 10 in MeCN in
the presence of NaHCO3 as a scavenger to give compound 11
(Scheme 4) proving that the reactivity of dendron 10 is comparable
to that of regular arylsulfonyl chlorides.
Scheme 2. Synthesis of dendrimer 5 utilizing the 1 ? 4 branching motif. Reagents
and conditions: (i) Et3N, CH2Cl2, reflux; (ii) SnCl2Á2H2O, CH2Cl2–MeOH (1:1), HCl,
reflux; (iii) TsCl, Et3N, CH2Cl2, reflux.
Scheme 4. Synthesis of superbranched sulfonamide 11. Reagents and conditions:
Bu2NH, NaHCO3, MeCN, rt.
Please cite this article as: M. Kolotylo, V. Holovatiuk, J. Bondareva et al., Synthesis of sulfonimide-based dendrimers and dendrons possessing mixed 1 ? 2
and 1 ? 4 branching motifs, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2018.12.052

M. Kolotylo et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Conclusion
A divergent method for the synthesis of dendrimers and den-
drons with a sulfonyl chloride functionality at the focal point pos-
sessing mixed 1 ? 2 and 1 ? 4 branching motifs was achieved. The
key compound involved in the synthesis of these dendritic archi-
tectures is symmetrical trinitrobenzene (TNB) in which one nitro
group can selectively be displaced by nucleophiles. It also was
shown that the prepared dendritic sulfonyl chloride reacts as a typ-
ical aromatic sulfonyl chloride despite its considerable steric size.
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Acknowledgments
The O.L. group is grateful to Professor I. S. Akhatov (Skoltech,
Russia) for his advice and continuous support.
Appendix A. Supplementary data
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Supplementary data (experimental procedures and spectral
data) to this article can be found online at https://doi.org/10.
1016/j.tetlet.2018.12.052.
Please cite this article as: M. Kolotylo, V. Holovatiuk, J. Bondareva et al., Synthesis of sulfonimide-based dendrimers and dendrons possessing mixed 1 ? 2
and 1 ? 4 branching motifs, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2018.12.052