Direct synthesis of 1,3-dithiane substituted nitroarenes via vicarious nucleophilic substitution with 2-phenylthio- 1,3-dithiane

Article abstract of DOI:10.1016/S0040-4039(00)00784-X

2-Phenylthio-l,3-dithiane underwent VNS with various nitroarenes to provide para-dithianyl nitroarenes regiospecifically in good to excellent yields. The resulting nitroaryl dithianes were readily unmasked to the corresponding aldehydes. (C) 2000 Elsevier

Full text of DOI:10.1016/S0040-4039(00)00784-X

Tetrahedron Letters 41 (2000) 5111±5114
Direct synthesis of 1,3-dithiane substituted nitroarenes
via vicarious nucleophilic substitution with
2-phenylthio-1,3-dithiane
Won-Kyum Kim, Seung-Chul Paik, Haiwon Lee and Cheon-Gyu Cho*
Department of Chemistry, Hanyang University, Seoul 131-791, South Korea
Received 14 April 2000; revised 9 May 2000; accepted 12 May 2000
Abstract
2-Phenylthio-1,3-dithiane underwent VNS with various nitroarenes to provide para-dithianyl nitroarenes
regiospeci®cally in good to excellent yields. The resulting nitroaryl dithianes were readily unmasked to the
corresponding aldehydes. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: vicarious nucleophilic substitution; nitroarenes; formylation; SNAr, 1,3-dithiane.
Vicarious nucleophilic substitution (VNS) of hydrogen in nitroarenes is a valuable synthetic
tool in introducing various substituents into the ring.1 6 It is particularly so since ordinary
electrophilic substitutions are not applicable to such electron-de®cient aromatic compounds.
Formylations of nitroarenes have been successfully executed with VNS of the formyl equivalents,
followed by hydrolysis. Those formyl equivalents are trisphenylthiomethane3 and haloforms,4
both developed by Makosza et al. and more recently tris(benzotriazol-1-yl)methane5 by Katritzky
et al.
For our ongoing study directed towards synthesis of complex biaryls, we needed nitroaryl
aldehydes masked with 1,3-dithiane. They could be synthesized in three steps, through a VNS of
nitroarenes with one of the above formyl equivalents, followed by hydrolysis, and subsequent
masking with 1,3-propanedithiol. Direct addition of 1,3-dithiane anion with some nitroarenes
was reported in which the initial addition products were subsequently treated with DDQ to give
the dithianylated nitroarenes as mixtures of regioisomers in low yields.7 Realizing there is no
regiospeci®c single step synthesis available, we ®gured that we could elaborate 1,3-dithiane in a
way to be suited for VNS reaction with nitroarenes. A brief literature survey revealed several 1,3-
dithiane candidates with a leaving group at 2 position. We ®rst studied 2-chloro-1,3-dithiane,8
which, we found, underwent VNS reaction with nitrobenzene, in the presence of base, to p-(1,3-
dithian-2-yl)-nitrobenzene in a reasonable yield. The reaction was extremely capricious, though,
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00784-X

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presumably due to the intrinsic instability of the reagent, 2-chloro-1,3-dithiane. The chlorine
would certainly be too reactive leaving group, thus it needed to be replaced with less reactive
ones. Thiophenol substituted 1,3-dithiane9 was thought to be a good candidate, which indeed was
found to be e€ective in introducing 1,3-dithiane group into the nitroarenes,10 exclusively at the
position para.
The 2-phenylthio-1,3-dithiane (2), readily prepared in one-pot from 1,3-dithiane according to
the literature protocol,9 can be stored on a shelf without decomposition. The VNS reactions with
nitroarenes were e€ectuated by adding a mixture of the isolated 2 and nitroarene into the DMSO
solution of KOtBu or KHMDS at rt, which furnished the p-(1,3-dithiane-2-yl)-nitroarenes 4 in
good to excellent isolated yields (Table 1).10 Use of potassium counter ion seemed to be critical,
which might be in part due to its coordination to the aromatic rings, developing negative
Table 1
Preparation of 1,3-dithiane substituted nitroarenes

5113
1
charge.11 All the new p-(1,3-dithiane-2-yl)-nitroarenes were fully characterized with H, 13C
NMR, IR and HR-MS.
Overall, 2-phenylthio-1,3-dithiane is somewhat analogous to trisphenylthiomethane, developed
by Makosza et al.3 In their work, triphenylthiomethane underwent VNS with four distinct types
of nitroarenes to give bisphenylthiomethyl nitroarenes in the yields of 15 to 65%. Our reagent is
apparently more general in the reaction scope and gives higher yields (11 examples with 48 to
95% yields), although they cannot be directly compared since each reagent produces di€erent
products.
Similar to Katritzky's case,5 the exclusive substitution of 1,3-dithiane at the position para to
the nitro group would be due to the steric bulkiness of the anion of the reagent 2, as further
evidenced by the slower rates in the VNS with meta-substituted nitroarenes than with ortho- or
unsubstituted ones. In case of 1f, 1g and 1j, the liberated phenylthiolate anion came back and
displaced halides, to give the doubly substituted 2-phenylthio-4-(1,3-dithianyl)-1-nitrobenzene
(4f, 4g, 4j). The entries 1h through 1k did not provide the desired VNS products with KOtBu, but
did so with more basic KHMDS. In contrast, very little reaction was observed with 2-nitro-
1
toluene (1l). Crude H NMR of the reaction mixture showed no -CH3 peak, thus we presumed
that the deprotonation of the methyl group interfered the VNS. Use of less basic KOH also
produced the same results. Such trend appeared to be consistent throughout the nitroarenes
containing acidic protons, except the entry 1e where the removal of the methine proton is thought
to be kinetically slow. The entry 1e is interesting in that two formyl groups were masked in two
di€erent ways, dioxolane and dithiane (4e). VNS with 1-nitro-naphthalene could be potentially
complicated, but yet cleanly provided 4-dithianylated nitronaphthalene 4h, regiospeci®cally in
high yield. Entry 1j experienced an unusual decarbonylation to give deformylated dithianyl
nitrobenzene 4j (same as 4a). The mechanism of the deformylation is not understood, o€ hand,
and needs further study. The dithianylated nitroarenes 4 were conveniently hydrolyzed to the
aldehydes in the range of 70 to 90% yields with AgNO3/NCS system.12
In conclusion, we were able to prepare p-(1,3-dithiane-2-yl)-nitroarenes, regiospeci®cally, in
one step from nitroarenes via VNS of 2-phenylthio-1,3-dithiane. The dithianylated products can
be directly hydrolyzed to the corresponding nitroaryl aldehydes without isolation, if necessary.
These 1,3-dithiane substituted nitroarenes may ®nd further uses as valuable building blocks in the
synthesis of other interesting aromatic compounds.
Acknowledgements
We would like to thank the ®nancial support of the Ministry of Science and Technology
(National Research Laboratory), Korea, made in the program year of 1999.
References
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was added a mixture of 2 (1.2 equiv.) and nitrobenzene (50 mg) in 1 mL of DMSO at rt. Quenching with AcOH
(0.5 mL), followed by usual work-up and chromatography, 95 mg of pure 4a was obtained as white crystals in
95% yield.
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