Letter

Cite This: Org. Lett. 2019, 21, 279−282 pubs.acs.org/OrgLett

Sulfur-Promoted Decarboxylative Sulfurative Hexamerization of

Phenylacetic Acids: Direct Approach to Hexabenzylidyne
Tetrasulfides
Thanh Binh Nguyen* and Pascal Retailleau
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1 avenue de la
Terrasse, 91198 Gif-sur-Yvette, France
*
S Supporting Information
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ABSTRACT: During our experiments aimed at understanding the reaction pathways by which arylacetic acids were oxidatively
decarboxylated and condensed with different nucleophiles in the presence of elemental sulfur, these acids have been treated with
sulfur powder in dimethyl sulfoxide (DMSO) and N-methylpiperidine in the absence of nucleophiles, producing a remarkable
symmetrical sulfurated hexamer consisting of six benzylidyne moieties and four sulfur atoms.

T he transformation of simple molecules to yield more

elaborate organic scaffolds in a single operation under
simple reaction conditions is one of the important features of
resulted from the reduction of o-nitroaniline in this case), we
wondered whether such an intermediate could be trapped as
sulfur-containing compounds by the formation of oligomer
organic chemistry in the pursuit of the ideal synthesis. In line molecules. Accordingly, we have reacted phenylacetic acid with
with this, we are focusing on the formation of several new sulfa 2 equiv of sulfur in dimethyl sulfoxide (DMSO) using N-
heterocycles by direct incorporation of elemental sulfur to the methylpiperidine3(NMP) as a sulfur activator in the absence of
organic scaffold with simultaneous formation of many C−C o-nitroaniline and iron salt. To our surprise, this reaction
bonds.1 As part of an exploration of the reactivity of produced, along with various amounts of dithiobenzoate salt as
phenylacetic acids with various organic substrates, we have orange crystals, a pale yellow solid, which is readily isolated by
investigated their redox condensation with o-nitroanilines in simply washing the reaction mixture with methanol and
the presence of catalytic amounts of sulfur and iron salts, removing the remaining traces of sulfur in vacuo at 100−120
leading to 2-arylbenzimidazoles.2 The formation of the °C.
benzimidazole products from oxidative decarboxylation of In its pure state, this compound as well as its derivatives
phenylacetic acids might be considered involving a sulfurated (vide infra) were found to be insoluble in most polar solvents
intermediate of the benzyl group from a mechanistic viewpoint such as methanol, DMSO, or DMF.
(Scheme 1). Sparingly soluble in CDCl3, the molecules displayed an
In this transformation, the intermediate issued from extremely simple 1H spectra with two sets of phenyl signals in a
phenylacetic acid was subsequently oxidized by the nitro 2:1 ratio. Fortunately, we were able obtain its single crystals
group. In the absence of nucleophiles (o-phenylenediamine and consequently its molecular structure was readily
determined by X-ray diffraction as depicted in Figure 1.
Scheme 1. Decarboxylative of Phenylacetic Acid Compound 2a crystallized in the monoclinic space group P21/
c, with a crystallographically imposed inversion center located
at the midpoint of the C1C1 #1 bond (Csp3 ···Csp3 ,
1.594(3)Å). This single bond links two 1,3-dithiole rings in
an axially similar manner that the bi-1,3-dithiacyclopentyl4 and
this dimer succeeded in fusing six phenyl groups into a
hexamer (Figure 1). The phenyl at the equatorial position 2
covers the other thiol partner with a centroid−centroid
distance of 3.625 Å, making a dihedral angle of 63.4°.

Received: November 21, 2018

Published: December 14, 2018

© 2018 American Chemical Society 279 DOI: 10.1021/acs.orglett.8b03728

Org. Lett. 2019, 21, 279−282
Organic Letters Letter

Table 1. Decarboxylative Sulfurative Hexamerization of

Arylacetic Acid 2

entrya arylacetic acid 1 R 2, yield (%)b

1 1b 4-Me 2b, 56
Figure 1. Molecular structure of 2a (displacement ellipsoids drawn at
the 30% probability level); H atoms are not shown for clarity; selected 2 1c 4-t-Bu 2c, 47
interatomic distances (Å) and angles (deg): C1S1, 1.835(2); C1 3 1d 4-MeO 2d, 50
S2, 1.832(1); C1C1#1, 1.594(3); S1C2, 1.762(2); S2C3, 4 1e 3-MeO 2e, 46
1.757(2); C2C3, 1.339(2); S1C1S2, 105.9(7); S1C1 5 1f 3-F 2f, 66
C1 # 1, 110.2(1); S2C1C1 # 1, 108.7(1); C4C1C1 # 1; 6 1g 3-Cl 2g, 65
113.3(2); S1C1C4, 108.9(1); S2C1C4, 109.6(1); C1 7 1h 3-CF3 2h, 54
S1C2, 97.9(7); C1S2C3, 97.3(7). Symmetry transformations 8 1i 3-CO2Me 2i, 62
used to generate equivalent atoms: #1 −x + 1, −y + 1, −z + 1. 9 1j 3,4-(CH)4 2j, 58
10 1k 2-Me 2k, 0c
Structurally, although only four sulfur atoms are required to 11 1l 2-Cl 2l, 0c
form the hexamer 2a, the reaction is best performed with 2 12 1m 2-MeO 2m 0c
equiv of atomic sulfur (Scheme 2). Indeed, lowering the sulfur a
Reaction conditions: arylacetic acid (1 mmol), sulfur (2 mmol, 64
mg), NMP (1 mmol), DMSO (3 mmol, 0.2 mL), 80 °C, 16 h.
Scheme 2. Decarboxylative Sulfurative Hexamerization of b
Isolated yield by filtration. cNo trace of hexamer was detected in the
Phenylacetic Acid reaction mixture.

2b−2d were also determined unambiguously by X-ray

crystallography (see the Supporting Information).
We emphasized that the solubility of this kind of compound
is in general very low when the phenyl ring bears other para
substituents. The reactions with p-fluoro-, p-chloro-, or p-
content to 1 equiv led to a significantly lower yield of the bromo-phenylacetic acid led to the expected hexamers (present
expected hexamer and resulted in unchanged phenylacetic acid. in the crude mixtures by 1H NMR analysis). These hexamers
On the other hand, increasing the sulfur content to more than could be isolated, but due their low solubilities, we could not
2 equiv did not improve appreciably the yield of the hexamer. record any 1H NMR.
Other organic bases that were used in the related reactions At this stage, we have little information about the reaction
involving elemental sulfur such as N-methylmorpholine, pathway of this sulfurative self-condensation described above.
pyridine, and 3-methylpicoline5 failed to promote the reaction. However, we supposed that the primary product of this
In these cases, phenylacetic acid remained unchanged at 80 transformation would have a sulfurated benzyl group. To
°C while increasing the reaction temperature to 130 °C led to confirm this hypothesis, the chemical behavior of dibenzyl
its oxidation to a benzoate anion. The unique oxidative role of disulfide 3, a stable derivative bearing both a benzyl group and
DMSO was confirmed by the fact that phenylacetic acid sulfur atom, was considered under similar conditions.
remained unchanged when DMSO was replaced by DMF or In the absence of elemental sulfur, this compound was
another polar aprotic solvent such as N,N-dimethylacetamide essentially recovered unchanged, but comparable conversion
and N-methylpiperidone. into 2a was observed in the presence of 1 atomic equiv of
The scope and limitation of this unusual sulfurative sulfur (Scheme 3, eq 1). This observation suggested that
hexamerization reaction was next investigated with a range of elemental sulfur involved in the reaction was necessary for the
substituted phenylacetic acid derivatives (Table 1). In general, formation of sulfurated benzyl derivatives and also for further
the reaction was found to proceed in the same manner with oxidative hexamerization of these species. When benzyl
phenylacetic acids substituted in the para or meta position by mercaptan 4 was used as a possible sulfurated benzyl
an alkyl, a halogen, an electron-donating group (methoxy), or derivative, 0.5 equiv of elemental sulfur was used for oxidative
an electron-withdrawing group (CO2Me, CF3). coupling into dibenzyl disulfide even by simple mixing of the
The reaction conditions were also applicable to 2-naphthyl- thiol compound with sulfur and NMP in DMSO at rt (Scheme
acetic acid. On the other hand, the reaction failed with o- 3, eq 2).
substituted phenylacetic acids (o-methyl, o-chloro, o-methoxy) Nevertheless, dibenzyl monosulfide 5 has proven to be
and resulted in the recovery of the starting materials and totally inert, probably due to its highly stable C−S bonds
heating at higher temperature led only to their oxidation into (Scheme 3, eq 3).
the corresponding benzoates. This failure can be explained by On the basis of the aforementioned results and our
the steric hindrance of these substituents. The structures of previously reported work,2a a plausible mechanism was
280 DOI: 10.1021/acs.orglett.8b03728
Org. Lett. 2019, 21, 279−282
Organic Letters Letter

Scheme 3. Control Experiments nucleophilicity and oxidizing ability compared to elemental

sulfur.
Consequently, polysulfide A was capable of oxidatively
decarboxylating phenylacetate B to provide benzyl polysulfide
C, existing in equilibrium with dibenzyl disulfide D via sulfur
exchange with A. The oxidative fragmentation of D promoted
by A would provide two molecules of thiobenzaldehyde E,
which could be considered as a principal monomer for the
subsequent hexamerization process.
The dimerization of thiobenzaldehyde E into dithiobenzoin
J could proceed in a similar manner to classical benzoin
condensation reaction. Indeed, intermediate F or G, which
derived from addition of one or two polysulfide chains to
thiobenzaldehyde E, could be deprotonated to give carbanion
H stabilized by gem-disulfur atoms and subsequently added to
another thiobenzaldehyde molecule E to provide dithioben-
zoin J. Its vic-dimercaptostilbene tautomer K could condense
with thiobenzaldehyde E to generate trimer L. Subsequent
transformation of trimer L into hexamer 2a could occur via
depicted in Scheme 4. First, cyclooctasulfur was activated by a radical oxidative dimerization. Alternatively, we proposed also
ring opening reaction with NMP to provide piperidinium a stepwise pathway starting with a base-catalyzed benzoin
polysulfide A with various chain lengths and enhanced condensation type reaction with thiobenzaldehyde E, followed
by an oxidation of the resulting thiol M into thioketone N.
Scheme 4. Proposed Mechanism Final condensation of tetramer N with dimer J would give
hexamer 2a.
In summary, we have shown that elemental sulfur in the
presence of N-methylpiperidine in DMSO effects the
decarboxylative sulfurative self-condensation of phenylacetic
acids to produce a range of unusual sulfa heterocycles. These
cascade transformations are reminiscent of, but go beyond, the
sulfur-mediated oxidative oligomerization reactions of small
molecules.6 We strongly believe that the practical and chemical
value of this stable and symmetrical skeleton will be extremely
interesting, for example as an excellent scaffold for catalyst
design and development of new functional materials. One can
readily conceive of different modes of desymmetrization of
these molecules which could lead to a huge number of
possibilities. We also have evidence that this unusual structure
could be obtained from other kinds of readily available
functional groups.

■
*
ASSOCIATED CONTENT
S Supporting Information

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03728.
Experimental procedures, characterizations of new
compounds, and copies of their NMR spectra (PDF)
Accession Codes
CCDC 1874679 and 1875507−1875509 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing [email protected], or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■ AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected].
ORCID
Thanh Binh Nguyen: 0000-0001-8779-9641
281 DOI: 10.1021/acs.orglett.8b03728
Org. Lett. 2019, 21, 279−282
Organic Letters Letter

Notes
The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS
We thank ICSN-CNRS for financial support and Dr. A.
Marinetti (ICSN-CNRS) for her helpful support.

■ REFERENCES
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reviews on recent advances in organic chemistry using elemental
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(c) Nguyen, T. B. Asian J. Org. Chem. 2017, 6, 477.
(2) (a) Nguyen, T. B.; Ermolenko, L.; Corbin, M.; Almourabit, A.
Org. Chem. Front. 2014, 1, 1157. For a similar reaction of
decarboxylative coupling of phenylacetic acids with sulfur and amines
leading to thiobenzamides, see: (b) Guntreddi, T.; Vanjari, R.; Singh,
K. N. Org. Lett. 2014, 16, 3624.
(3) Nguyen, T. B.; Retailleau, P. Org. Lett. 2017, 19, 3887.
(4) Brahde, L. B. Acta Chem. Scand. 1954, 8, 1145.
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282 DOI: 10.1021/acs.orglett.8b03728

Org. Lett. 2019, 21, 279−282