Key words
organotrisulfane - organotetrasulfane - sulfur-sulfur bond - trisulfide - tetrasulfide
1
Introduction
It has been some years since the last reviews on the topic of organopolysulfane synthesis,[1] despite the recent emergence of organopolysulfane motifs in a range of expressions
and applications. These include natural products,[2] designing substrates for, and understanding, H2S production as a gasotransmitter,[3] linkers in antibody-drug conjugates,[4] and high-capacity materials for cathodes in rechargeable lithium batteries,[5] to name but a few (Figure [1]). While reviews on disulfane synthesis have been plentiful in the last few years,[6] an update on the next most important members as organotri- and organotetrasulfanes,
is long overdue. Such targets are ideally suited to S–S bond formation via heterolytic
approaches, which are the focus of this review. Radical and concerted approaches are
virtually non-existent for synthesising these targets, and an overview of sulfur transfer
to double bonds is covered in previous reports,[1] which will not be covered here. The same applies to the reduction of organotri-
and organotetrasulfane oxides (S=O and SO2) as well as the extrusion of sulfur from a polysulfane using a phosphine.
Figure 1 Some examples of polysulfanes from modern literature
The mechanistic and historical-account format of this review distinguishes it from
other similar reports; there is also emphasis on updating new developments in the
last twenty years or so since the last reviews.[1] We have adopted usage of the term sulfane in line with IUPAC nomenclature rather
than the popular and much used (particularly in the older literature) ‘sulfide’, retaining
the word ‘sulfide’ for inorganic salts of sulfur only. The descriptions symmetrical/unsymmetrical
sulfane (tri- or tetra) and homo/heterosulfane will be used interchangeably. In the
main text, organotrisulfane and organotetrasulfane will be abbreviated to trisulfane
and tetrasulfane, respectively.
Mechanistic Considerations for Synthesis
2
Mechanistic Considerations for Synthesis
In the present era of retrosynthesis, it is useful to start this review by rationally
identifying the various heterolytic disconnection points on offer to the synthetic
chemist for tri- and tetrasulfane synthesis as shown in Figure [2]. Using symmetrical (homo) targets R(S)
n
R for analysis, with n = 3 (trisulfane) and 4 (tetrasulfane), Figure [2] identifies two and three disconnection points, (i)–(v), for an organotri- and organotetrasulfane,
respectively. These translate into a variety of heterolytic nucleophilic and electrophilic
sulfur synthons in each case.
An examination of known literature methodologies for accessing the two chemotypes
reveals that only two types of overall disconnection have representation. These involve the coupling of either two synthons,
which arises from a one-bond disconnection, involving any of the (i)–(v) disconnections
in Figure [2]. Alternatively, one observes three synthons from a two-bond disconnection sequence.
Each type assumes that a one-pot reaction can access the respective target. One-bond
disconnections can access unsymmetrical tri- and tetrasulfanes, while two-bond disconnections
are realistically only suitable for homosulfane synthesis (see Figure [2] for examples).
Figure 2 Disconnection points and examples for organotri- and organotetrasulfanes
The various methodological approaches known are illustrated in Table [1], in which the nucleophilic partner is always placed first in the combination description,
and the numbers in parentheses refer to the number of sulfurs in any synthon.
Table 1 Known Heterolytic Disconnections for Organotri- and Organotetrasulfane Synthesis
(M = Metal, H; Lg = Leaving group)
|
Type
|
Number of disconnections
|
Combination
|
Description
|
Product
|
|
A
|
Two
|
[3 + 0 + 0]
[4 + 0 + 0]
|
MS3M + RX + RX
MS4M + RX +RX
|
trisulfane
tetrasulfane
|
|
B
|
Two
|
[1 + 1 + 1]
[2 + 1 + 1]
|
MSM + RSLg + RSLg
MS2M + RSLg + RSLg
|
trisulfane
tetrasulfane
|
|
C
|
Two
|
[1 + 1 + 1]
[1 + 1 + 2]
|
RSM + RSM + LgSLg
RSM + RSM + LgS2Lg
|
trisulfane
tetrasulfane
|
|
D
|
One
|
[2 + 1]
[2 + 2]
[3 + 1]
|
RSSM + RSLg
RSSM + RSSLg
RSSSM + RSLg
|
trisulfane
tetrasulfane
tetrasulfane
|
|
E
|
One
|
[1 + 2]
[1 + 3]
[0 + 3]
|
RSM + RSSLg
RSM + RSSSLg
RM + RSSSLg
|
trisulfane
tetrasulfane
trisulfane
|
Methodology A: M(S)
n
M (n = 3, 4) + 2 × RX
2.1
Methodology A: M(S)
n
M (n = 3, 4) + 2 × RX
The earliest report of a dialkylation of trisulfide dianion was more than a hundred
years ago[7] when Strecker (that is Willem, not Adolph, the latter famous for the Strecker reaction)
demonstrated that dimethyl trisulfane could be prepared by reaction of Na2S3 (prepared from Na2S + 2S) with dimethyl sulfate in about 80% isolated yield. The trisulfane was purified
by vacuum distillation (bp14 mm, 60–62 °C) out of the mixture of polysulfane products. The trisulfane could also
be prepared from Na2S5 and dimethyl sulfate followed by heating the product to convert the pentasulfane
into its trisulfane. A few years later, in 1923, Richard William Riding and John
Smeath Thomas, working at the Universities of Cape Town and Liverpool, respectively,
reported that K2S5 reacted with alkyl iodides to give pentasulfanes.[8] On heating, these also rearranged to the disulfane and sulfur, which then combined
to give the trisulfane mixed in with the disulfane. These two reports set the scene
for this methodology for the next hundred years, highlighting its limitations due
to the interconversion of polysulfide anions, a relevant chemistry aspect that is
eminently supported by the inorganic literature.[9] Hence, one can start with the stable Na2S and add appropriate equivalents of sulfur to convert into the tri (Na2S3)[10a] or tetrasulfide (Na2S4) dianions,[10b] but these will always exist in an equilibrium of polysulfide anions. No-one has
found a solution to this problem as yet, and hence the best that one can conclude
for this methodological option is that although straightforward to carry out, it is
limited regarding only being able to access mixtures of homopolysulfanes (these are
difficult to separate even using C18 reverse-phase chromatography when R is non-polar),
in which the organic R groups are mainly limited to SN2-active groups in the halide RX (SNAr reaction on a chloro, nitroaromatic has been demonstrated).[11] Needless to say, this is not the method of choice for producing tetrasulfanes in
pure form, and definitely not unsymmetrical versions. The three reviews[1] cited in the introduction cover many examples of this approach cited during the
twentieth century, but all of them suffer from these limitations. Rather than start
with the inorganic sulfide, substituting with sulfur and an inorganic hydroxide together
with an alkyl halide is also known[12`]
[b]
[c] in which it is safe to assume that the reaction proceeds via a polysulfide anion
or dianion and hence suffers from the same limitations (hydrazine as a reductant may
also be added to reduce S8 to produce reactive polysulfide anions).[12b] Similarly, one may start from sulfur with either sodium metal in an aprotic solvent
like DME (Scheme [1], entry 1),[13] or a tin/copper promotor (Scheme [1], entry 2),[14] but, once again, reaction in each case with RX yields a range of polysulfanes. Interestingly,
reaction of sulfur with acrylonitrile in DMF and ammonia yields a moderate yield (49%)
of the trisulfane, which is claimed by the authors to proceed via conjugate addition
of a sulfur radical anion (Scheme [1], entry 3).[15] Nucleophilic substitution of alkyl halides by electrochemically generated polysulfide
anions in DMA is also known.[16] Cyclic tri- and tetrasulfanes are also known to be available using methodology A, and have been fully reviewed,[1] but once again, mixtures of polysulfanes are invariably produced as with the acyclic
variants (Scheme [1], entries 4 and 5).[17]
[18] Scheme [1] illustrates entries 1–5 based on examples from the last twenty years or so.
Scheme 1 Some recent examples of methodology A for tri- and tetrasulfane synthesis
Methodology B: M(S)
n
M (n = 1, 2) + 2 × RSLg
2.2
Methodology B: M(S)
n
M (n = 1, 2) + 2 × RSLg
Seminal work by Brian Milligan and John Swan in the early 1960s[19]
[20] established the first examples of trisulfane synthesis using methodology B, in which a Bunte salt (an S-alkyl or S-arylthiosulfate salt as RSSO3
–M+) was used as the sulfenylating agent of sodium sulfide (Na2S), which is the most reliable of all the sulfide salts in regards to purity and constitution.
In cases involving a reactive RSLg, H2S can be used as the monosulfur nucleophilic source, and once again, earlier reviews
on polysulfanes[1] give an extensive coverage of this approach. Bunte salts first appeared in the literature
in 1874 when Hans Bunte reacted thiosulfate with ethyl bromide,[21] and Xuefeng Jiang has recently reviewed their usage in sulfur–carbon bond formation.[22] Milligan and Swan noted that the primary products of the first substitution, namely
sulphite ion (SO3
2–) and disulfanyl anion (RSS–), could undergo subsequent reactions with the trisulfane once formed to generate
di- and tetrasulfanes as by-products, respectively. This they found could be suppressed
using formaldehyde, and the reaction was optimised recently by Hemant Srivastava and
Krishna Bhabak in 2019 (entry 6, Scheme [2]).[23] Milligan and Swan also went on to use their method to prepare cyclic trisulfanes
from di-Bunte salts (Scheme [2], entry 7).[24] Indeed, cyclic polysulfanes can only be realistically accessed using two-bond disconnections
(three synthons) in which one of the substrates accommodates two of the synthons.
Several other monosulfur electrophiles have been used for both tri- and tetraorganosulfane
synthesis, including thiosulfonates (Scheme [2], entry 8),[25] sulfenyl halides[26`]
[b]
[c]
[d]
[e] (Scheme [2], entry 9),[26a,e] thiosulfonates and thiosulfinates (entry 10 for the latter, Scheme [2]),[27] and N-thiophthalimides (Scheme [2], entry 11).[28] The literature also reports the extension of sulfenyl chlorides (as in entry 9)
and bromides to reaction with M2S2 for producing symmetrical tetrasulfanes in which M can be H,[26`]
[b]
[c]
[d]
[e] and the metals[26`]
[c]
[d] Na, Ag, Hg, Tl and Pb, although the equilibrium issue mentioned earlier makes it
unlikely that the tetrasulfane products generally can be isolated free of other polysulfanes
as by-products. Varying the metal of the sulfide to silicon[27]
[28] and tin[29] has also been reported, as well as titanium in the form of a disulfanyl transfer
agent (Cp′4Ti2S4)[30] from the extensive work by Ralf Steudel’s group on titanium thiolato complexes as
sulfur transfer agents. Cp′4Ti2S4 reacts with a sulfenyl halide (e.g., CCl3SCl) to afford homotetrasulfanes in good yield (Scheme [2], entry 9).[30] In spite of these innovations, this methodological option B can only deliver on homosulfanes, with tetrasulfane target products often contaminated
with other polysulfanes. For homotrisulfane synthesis, Field’s thiosulfonate methodology
(Scheme [2], entry 8)[25] is arguably the most efficient option. Scheme [2] summarises some of these examples, with a mechanism in entry 10 presented for Giuseppe
Capozzi’s intriguing trisulfane synthesis methodology using the reaction of bis(trimethylsilyl)
sulphide with a thiosulfinate.
Scheme 2 Examples of methodology B for tri- and tetrasulfane synthesis
Methodology C: 2 × RSM + Lg(S)
n
Lg (n = 1, 2)
2.3
Methodology C: 2 × RSM + Lg(S)
n
Lg (n = 1, 2)
This is the final of the three-component methodologies and the one that is the most
efficient for producing both tri- and tetrasulfane homo-products in relatively high
yield and purity. The reagents of choice, sulfur dichloride (SCl2) and sulfur monochloride (S2Cl2), are both available in reasonable purity commercially, albeit that it is advisable
to use freshly distilled material for reactions. However, despite their foul-smelling
odour and tendency to disproportionate, these reagents continue to be the ones of
choice up to the present time, which highlights the need for researchers to explore
alternatives for bringing the field into line with modern-day, green standards.
The reaction of a thiol with S2Cl2 to produce a tetrasulfane, perhaps surprisingly, dates to as far back as 1923 (Scheme
[3], entry 12) by Gopal Chandra Chakravarti.[31] This was extended to include SCl2 for trisulfanes in 1947 by James Clayton.[32] Later, in 1964, Takeshiga Nakabayashi demonstrated that triphenylmethanethiol (TrSH)
could be used for both bis(triphenylmethyl)tri- and tetrasulfane synthesis using SCl2 and S2Cl2, respectively.[33] Also, in the 1920s, a variety of thiocarbonates were used as non-thiol, sulfur nucleophiles
such as potassium thiobenzoate,[34] Bender’s salt (EtOCO(SK) = potassium O-ethylthiocarbonate),[35] potassium O-ethyldithiocarbonate (EtOCS(SK)), and potassium ethyl trithiocarbonate (EtSCS(SK)),
which gave rise to end-substituted trisulfides.[35] The trend in using non-thiol nucleophiles continued with Franz Fehér’s contributions
in 1958[36] using mercuric thiocyanate for accessing NC-(S)
n
-CN polysulfanes, covering both tri (n = 3, from SCl2) and tetra (n = 4, from S2Cl2) cases. Then, in the 1960s and early 1970s, the range of metal thiolates was extended
to silyl[37] and stannyl[38] sulfides for accessing homo tri- and tetrasulfanes bearing an organic R group, respectively.
In the 1990s, Ralf Steudel’s group[1]
[39] extended the metal to titanium (see methodology B
[30] for a variant on this theme) using an intriguing insertion reaction of titanocene
dicarbonyl into a disulfide bond to form bis-thiolato complexes of titanocene of the
form (CO)2Ti(SR)2. The latter reacted with SCl2 or S2Cl2 to homologate to trisulfanes and tetrasulfane entities, respectively.[39] The method is aptly suited to the synthesis of cyclic sulfanes, although the yields
are very low. Finally, Munavalli extended the synthesis of bis(trifluoromethyl)trisulfane
(see entry 9 in methodology B, Scheme [2]) using trifluoromethylthiocopper with SCl2.[26e]
Turning away from metal thiolates to neutral sulfur sources, in the 1980s, George
Barany and Andrew Mott published extensively[40] on using dimethyl dithiocarbonate and similar reagents (as neutral nucleophiles
and not as salts) with both sulfur dichloride and sulfur monochloride. The prototype
to afford tri- and tetrasulfanes is illustrated in Scheme [3], entry 13. Following sulfenylation of the thiocarbonate thiocarbonyl sulfur by the
electrophilic chloride, dealkylation of the OMe substituent occurred to afford the
final products. Once again, these products contained the end sulfur atoms functionalized
as thiocarbonates, similar to work carried out in the 1920s with Bender’s salt and
others.[34]
[35]
Scheme 3 Reactions of sulfur chlorides to afford tri- and tetrasulfanes
Hence, by the 1990s, both sulfur dichloride and sulfur monochloride had been extensively
used for both symmetrical tri- and tetrasulfane synthesis. In 1994, Professor David
Harpp of McGill University in Canada, a prolific researcher in the field, published
a landmark paper in Tetrahedron Letters that reported on the first use of SCl2 and S2Cl2 for preparing unsymmetrical tri- and tetrasulfanes.[41] Although carried out in a one-pot reaction using sequential addition of the thiols,
the use of freshly distilled sulfur chloride and a low reaction temperature (–78 °C),
with pyridine as base and likely transfer agent in diethyl ether, ensured good to
excellent yields of the unsymmetrical products. Until very recently, the method has
stood as the method of choice for synthesizing tetrasulfanes using sulfur monochloride,
although yields can be extremely low (compare with Jiang’s methodology in methodology
E). Recently, Harpp’s method has been used to access heterotetrasulfanes showing nematocidal
activity against parasitic worms (Scheme [3], entry 14)[42] as well as cytotoxicity against HCT116 cancer cells (Scheme [3], entry 15).[43] Harpp went on in 2003 to report on the use of his method for optimising the production
of homotri- and tetrasulfanes with aromatic R groups.[44] Scheme [3] (entries 12–15) depicts reactions involving sulfur halides.
Turning to surrogates of SCl2 and S2Cl2 – an advisable development given their nasty nature – the first example (1960), appears
to be due to an intriguing N-arylamidothiosulfite (formed from reaction of N-thionylaniline with a thiol) by Günter Kresze (Scheme [4], entry 16),[45] which reacted with a thiol to produce trisulfane and disulfane mixtures. While mechanistically
intriguing, inevitably a mixture of di- and trisulfanes is produced that needs to
be separated. At the beginning of the 1970s, two papers emerged dealing with more
reliable-looking surrogates. The first of these, by Alfred Sullivan and Kamel Boustany,[46] involved synthesizing PhthNSSR from: (a) sequential substitution of SCl2 with phthalimide (to afford PhthNSCl as a surrogate of SCl2) and then a thiol, RSH, using triethylamine as base at low temperature, or (b) via
RSSCl plus phthalimide. PhthNSSR was then shown by the authors[46] to afford unsymmetrical organotrisulfanes in high yield (ca. 90%) by reaction with
a thiol in benzene at room temperature (no base needed). Further application of this
reagent as a RSSLg synthon will be discussed under methodology E. The second, by David Ash and David Harpp,[47a] describes synthesis of the same disulfanyl transfer agent, PhthNSSR, but via mono-substitution
of N,N′-thiobisphthalimide, (PhthN)2S, with a thiol, RSH (1 equiv), in refluxing benzene.[47a] The Harpp group went on to use this disulfanyl reagent to prepare unsymmetrical
trisulfanes[47b]
[c] in the same way as Sullivan and Boustany.[46] Of note here is that the original work on the reaction of SCl2 or S2Cl2 with phthalimide dates back to Kuverji Naik in 1921.[48] However, his assignment of structure was questioned by Malda Kalnins[49] in the 1960s, who established that the outcome for producing (PhthN)2S versus (PhthN)2S2 with S2Cl2 is solvent dependent.
Scheme 4 Examples of methodology C for tri- and tetrasulfane synthesis involving sulfur halide surrogates
These reagents, for example, (PhthN)2S, only exchanged sluggishly with thiols, but in a seminal 1978 JACS paper,[50] Harpp extended the range of options to include other N-based leaving groups (1,2,3-benzotriazole, benzimidazole, imidazole and 1,2,4-triazole)
and demonstrated that thiols reacted smoothly (at room temperature) in the case of
the benzimidazole reagent to afford the desired sulfanes (dibenzyl tri- and tetrasulfanes)
in effectively quantitative yield. Cyclic trisulfanes could also be accessed in high
yield using the benzimidazole reagent (Scheme [4], entry 17).[51] A few years later, Asoke Banerji[52] demonstrated the use of the bis(imidazole)sulfide variant for homotrisulfane synthesis,
which was used many years later by Haoyun An[53] for preparing homotrisulfanes in cancer-cell cytotoxicity evaluation (Scheme [4], entry 18).[53] Such transfer agents benefit from precipitation of the nitrogen ligand (imidazole
in Banerji’s case)[51] since the exchange can be run in hexane.
In 1984, Mott and Barany,[54] extending their work on thiocarbonates as nucleophiles with sulfur halides,[40] introduced a further variant on electrophilic SCl2 surrogates by introducing the reagent methoxycarbonyldisulfanyl chloride (MeO2CS2Cl) for trisulfane synthesis, containing Cl and monothiocarbonate as the two leaving
groups with different leaving abilities. Strictly speaking, this sequence is a two-component
category since the intermediate methoxycarbonyltrisulfane, MeO2CSSSR, can be isolated (making it an RSSLg + R′SH type in a two-component sense under
methodology E), and will be revisited there. The same concept applies for the SCl2 surrogate, PhthSSR, which is isolable in a stable form from reaction of a thiol with
PhthSCl (stable in the freezer). Finally, Xuefeng Jiang’s innovative recent work on
bilateral, disulfanyl scaffolds as electrophilic sulfur-transfer agents also falls
under this heading. These will all be covered under methodology E as two-component reaction options involving RSSLg.
The final word on electrophilic surrogates in methodology C belongs to intriguing work by Billy Vineyard[55] of the Monsanto company in the 1960s, who showed that sulfur reacted with a thiol
and an amine base as catalyst to afford homotrisulfanes or tetrasulfanes in decent
yields and purity depending on the nature of the thiol R group and thiol to sulfur
stoichiometry. Mechanistically, Vineyard rationalised this fascinating conversion
as involving attack of the thiolate (as RSM) on the S8 chain (as LgSLg) to generate a polysulfane anion that would undergo further S–S bond
substitution by a second equivalent of thiolate. Further S–S exchanges would then
disproportionate to the eventual dominant product according to the RSH/S stoichiometry.
Given the nature of the starting electrophilic reactant as S8, the chemoselectivity is remarkable (Scheme [4], entry 19). Billy Vineyard later went on to be part of the Monsanto Knowles’ team
(with Jerry Sabacky) who were co-recipients of the 2001 Nobel Prize in Chemistry for
their work on asymmetric hydrogenation (together with Ryoji Nyori). Barry Sharpless
was the other recipient of the prize for his work on chirally catalysed oxidation
reactions. Scheme [4] depicts relevant examples of methodology C, involving sulfur halide surrogates.
Methodology D: RSSM + R(S)
n
Lg, n = 1,2
2.4
Methodology D: RSSM + R(S)
n
Lg, n = 1,2
In this methodology D, for trisulfanes, coupling occurs via a [2nuc + 1elec] mode in which the disulfanyl component is a perthiol RSSH (also known in the literature
as a hydrodisulfane, hydrodisulfide, or a persulfide) or its thiolate form. Naturally,
this methodology is aptly set up for the synthesis of unsymmetrical trisulfanes, which
automatically covers symmetrical trisulfane synthesis too. For tetrasulfane synthesis,
two manifolds can be considered as RSSM + RSSLg and RSSSM + RSLg as [2nuc + 2elec] and [3nuc + 1elec], respectively. While there does not seem to be any literature examples of the latter,
the former has been demonstrated in the synthesis of CF3SSSSCF3
[56] for spectroscopic studies (Scheme [5], entry 20) via the reaction of CF3SSH (from the reaction of excess H2S with CF3SCl)[57] with CF3SSCl (most conveniently from the reaction of CF3SH with SCl2).[58] In principle, this approach should be applicable to heterotetrasulfane synthesis,
although the lengthy and old-fashioned syntheses of the reactants precludes it from
modern mainstream usage.
Scheme 5 Early examples of RSSH in methodology D
Perthiols are well known in the biological literature in conjunction with sulfur redox
biochemistry[59] and were first recognized synthetically in the 1950s in seminal work by Horst Böhme.[60] He demonstrated that a perthiol was reasonably stable in acidic medium (less so
in a basic one) and prepared it via acid deprotection of a disulfanyl acetate, RSSAc,
using ethanolic HCl (the RSSAc formed by coupling of acetylsulfenyl chloride with
a thiol; the AcSCl formed from chlorination of acetic thioanhydride, Ac2S, with chlorine gas). Very recently, Ming Xian’s group generated a perthiol from
a cyclic acyl disulfide using an amine as the unmasking agent.[61]
In the early 1960s, a Japanese group headed by Takeshiga Nakabayashi[62] extended Böhme’s method to the synthesis of unsymmetrical organotrisulfanes using
reaction of a perthiol with a sulfenyl chloride (Scheme [5], entry 21) or thiocyanate as electrophile. The synthesis of the two reagents had
been reviewed previously by Norman Kharasch,[63] and generally involved oxidising either a disulfide or a thiol with chlorine or
bromine to afford the sulfenyl halide, which could be substituted with thiocyanate
ion for producing the sulfenyl thiocyanate. More recently, sulfenyl chlorides, RSCl
(R = akyl, aryl), have been reliably prepared by reaction of a thioacetate, RSAc,
with sulfuryl chloride.[64] As an extension of this concept, Böhme was the first to show that a hydrodisulfide
could be oxidised in virtually quantitative yield to its homotetrasulfane with iodine
in methanol at room temperature (Scheme [5], entry 22).[60] The reaction presumably proceeds via a RSSH + RSSLg path, with Lg = I. This version
by Böhme was an improvement on his formation of tetrasulfanes via the reaction of
a chlorodisulfane (BzSSCl) with iodide ion, in which the intermediate iododisulfane
disproportionates to the tetrasulfane (BzS4Bz) and iodine (the latter can promote by-product formation).[77] Jitsuo Tsurugi later reported that the RSSH oxidative dimerization reaction could
also be achieved in high yield in aqueous dioxane using ferric chloride as oxidant
(Scheme [5], entry 22).[65]
Disulfanyl acetates have remained as popular sources for accessing perthiols to the
present time, as they are readily accessible via substitution of thiotosylates (RSTs)
with thioacetate ion.[66] In turn, RSTs, when R = alkyl, can be easily synthesised via substitution of RX
with thiotosylate ion,[67] while for R = aromatic, RSTs can be accessed via reaction of a disulfide with iodine
and sulfinate ion.[68] Into the 1970s, Harpp made use of this accessibility of perthiols by reacting one
(BnSSH) with PhthNSBn (a Harpp transfer reagent) to form dibenzyl trisulfane (Scheme
[5], entry 23) in excellent yield (98%).[69] Scheme [5] (entries 20–23) depicts these early examples of using a perthiol in the context
of methodology D.
Moving on to more recent examples involving RSSH, although Harpp reported in 1976
that a sulfenylthiocarbonate (MeO2CSSR) – easily prepared via reaction of a thiol with methoxycarbonylsulfenyl chloride
– deprotects to form a perthiolate anion with tert-butoxide,[70] it took almost another forty years before base-mediated, disulfanyl acetate deprotection
methodology appeared in the context of methodology D. Although perthiolates have the advantage of being considerably more nucleophilic
than their perthiol conjugate acids, they suffer from the grave disadvantage of desulfurising
to the thiolate,[71] explaining why so many procedures generated using perthiols result in a mixture
of di- and trisulfane. Dariusz Witt was the first to make the breakthrough in this
context in 2013[72] when he showed that deprotection of a disulfanyl acetate using sodium methoxide
in dry methanol at 0 °C under N2 generated the corresponding perthiolate (RSS–) without loss of sulfur (by virtue of isolating heterotrisulfanes free of disulfane
by-products). This was due to him matching the anion with an appropriate electrophile,
leading to a fast coupling. The RSLg in question was in the form of a novel, cyclic
sulfanyl phosphorodithioate (the two oxygens diesterified in the form of a ring),
which had the added advantage that it could also be used to source the disulfanyl
acetate via its reaction with KSAc. Witt prepared a library of heterotrisulfanes with
different aliphatic groups (no aromatic R groups) in high yield and purity, although
the outcome was sensitive to the choice of each of the R groups (Scheme [6], entry 24).
Scheme 6 Recent examples of methodology D via a perthiol, RSSH
A few years later, in 2018, Ming Xian’s group reported[73] on a novel methodology for accessing the perthiol source via base deprotection of
a 9-fluorenylmethyl disulfide (RSSFm), in which the focus was on R as a cysteinyl
group. The deprotection to the perthiol RSSH (or perthiolate, RSS–) was achieved using DBU (2 equiv), taking advantage of the relatively acidic nature
of the benzylic hydrogen of the Fm group (similar to the principle governing FMoc
deprotection). The perthiolate coupled to SuccNSR, or 2-benzothiazole disulfide (Scheme
[6], entry 25) in low to excellent yield (32–95%). The targeted nature of these two
recent methods ensures that homotrisulfanes do not overly interfere as by-products.
Similarly, we have utilised[74] Witt’s conditions for disulfanyl acetate deprotection, but at –78 °C, demonstrating
that a very fast reaction (within 30–60 s) occurs between a disulfanyl acetate and
a thiotosylate (RSTs; R = alkyl or aryl) in the presence of sodium methoxide in a
mixture of THF/methanol to afford unsymmetrical trisulfanes in high yield and purity
(Scheme [6], entry 26).[74]
Finally, two groups have cleverly exploited certain disulfanyl reagents of the type
RSSX that can generate in situ both the electrophilic (RSLg) and nucleophilic reagent
(RSS–) for methodology D. The reaction constitutes a homo-coupling with two prerequisites. Firstly, the X
group of RSSX should be removable via an SNAc mechanism to liberate the perthiolate anion RSS–. Secondly, the SX group should also act as a leaving group in another molecule. Clearly,
such a variant of methodology D is only applicable for synthesizing homotrisulfanes, and the prototype reaction,
as already mentioned, was discovered by Harpp[70] in 1976. It involved reacting a sulfenyl thiocarbonate (MeO2CSSR) with methoxide in methanol as solvent at 0 °C, which gave a mixture of the homodisulfane
and homotrisulfane. Gratifyingly, as the steric bulk of the promotor increased, the
percentage of trisulfane improved dramatically, making tert-butoxide the promoter of choice. Logically, the nucleophilic promotor stoichiometry
must be less than half of the RSSX concentration. Recently, Pluth used Harpp’s method
to prepare dibenzyl trisulfide (BnSSSBn), which was reacted with a thiol to generate
H2S for studying as a biotransmitter. In their work, benzylsulfenyl thiocarbonate was
treated with t-BuOK in methanol to afford an inseparable mixture of di- and trisulfanes. The chemoselectivity
problem was solved by switching to a mixture of tetrahydrofuran and water, which generated
hydroxide ion as promoter, resulting in the formation of product BnSSSBn cleanly,
albeit in a low yield of 36% (Scheme [6], entry 27).[75]
The only other example of this intriguing methodology for homotrisulfane synthesis
is due to Witt,[76] using his sulfanyl phosphorodithioate. In his case, TBAF acted as a hard, nucleophilic
promotor, reacting at the harder phosphorus centre over the softer sulfur (Scheme
[6], entry 28).
In summary, although elegant in principle, the method can only be used to access homotrisulfanes.
It also runs the risk of the disulfanyl anion intermediate losing sulfur to form a
competing thiolate nucleophile, leading to a disulfane by-product. Scheme [6] depicts recent reactions for methodology D via a perthiol, RSSH.
Methodology E: RSM + R(S)
n
Lg (n = 2, 3)
2.5
Methodology E: RSM + R(S)
n
Lg (n = 2, 3)
The second (and final) of the two-component methodologies, methodology E, is more prolific than methodology D. For trisulfane synthesis, it involves an electrophilic disulfanyl component and
a nucleophilic mono-sulfur component. As with methodology D, this methodology is also eminently suited for heterosulfane synthesis. However,
unlike methodology D, E has been extended to cover tetrasulfanes via recent work by Jiang using coupling
of an RSSSLg synthon with RSH. RSSLg + RSSM is also known for tetrasulfanes, but is
rare, and was covered under methodology D for the synthesis of CF3SSSSCF3.[56] To our knowledge, the variant RM + LgSSSSR for tetrasulfanes has not been reported.
For trisulfanes, the discussion using methodology E will centre on the scope of the RSSLg component since RSM is used as its thiol or
thiolate.
In the context of trisulfanes, the earliest examples of an electrophilic disulfanyl
species RSSLg in this context were with Lg as chloride, which was first studied extensively
by Böhme in the 1950s[60]
[77]
[78] In addition to his work on perthiols already discussed under methodology D,[60] he reacted[77] chlorine with diacetyl disulfide (Ac2S2) to give a separable mixture (by vacuum distillation) of acetyldisulfanyl chloride
(AcSSCl) and acetyl chloride.[77] Böhme then showed that AcSSCl reacted with thiols to give protected unsymmetrical
trisulfanes, AcSSSR.[77] Hence, AcSSCl was the first synthon of this type to be accessed. While the acetyl
group acted as a kind of protecting group for other conversions, for example, for
perthiol production, in the present context, it still left the question of how to
introduce the R group on the acetyl side. Hence, Böhme went on to show that sulfuryl
chloride (SO2Cl2) could also be used as the chlorinating agent for RSSCl production, here, starting
with either a disulfanyl acetate RSSAc (formed from AcSCl + RSH), or a trisulfane.[78] RSSCl was then reacted with thiols to access unsymmetrical trisulfanes, RSSSR′.[78]
A few years later, in 1964, Nakabayashi[33] followed up on his synthesis of unsymmetrical trisulfanes from perthiols[62] by demonstrating that AcSSCl (from Bohme’s[77]
[78] methods) reacted with TrSH (tritylthiol) to form TrSSSAc in 85% yield, in which
TrSSSAc is a precursor of TrSSSH via acid hydrolysis.[33] Another method for accessing RSSCl developed around this time (1958) that is still
used today is due to Fehér,[79] in which the original work involved adding a thiol dissolved in carbon disulfide
slowly to a large excess of sulfur dichloride (later examples used triethylamine as
base) at –78 °C. The RSSCl was isolated by vacuum distillation. No-one can say that
chemists were not brave back in the day!
Disulfanyl chlorides (or chlorodisulfanes), RSSCl, with R as alkyl or aryl groups,
even more than their sulfenyl chloride counterparts, RSCl, are highly reactive, hydrolytically
sensitive compounds prone to decomposition and thus difficult to isolate in a pure
form. Harpp’s synthesis and application[80] of Tr(S)
n
Cl (n = 1–3) take advantage of various aspects of the trityl group that include imparting
crystallinity and stability as well as interesting chemical properties to the S–Tr
bond. Importantly, such Tr(S)
n
Cl reagents have been used for various expressions in this E category. For instance, Harpp reacted n-BuSH with Tr(S)
n
Cl (n = 2, 3) to prepare the unsymmetrical tri- and tetrasulfanes, TrSSSBu[80] and TrSSSSBu[80] in 72% and 62% yield, respectively. Similarly, as a little-known RSSSLg + RM variant
equivalent to a [0 + 3] coupling, Harpp reacted TrSSSCl with n-BuLi (THF, –78 °C) or BuMgBr (ether, 0 °C) to prepare the trisulfane, TrSSSBu, in
yields of around 50% after purification by chromatography. Finally, some intriguing
heterolytic insertion reactions of Tr(S)
n
Cl into polysulfanes have been reported in a panoply of papers[81] to complement the titanium examples[30]
[39] cited under methodologies B and C. For instance, Tr(S)
n
Cl (n = 1, 2 as the electrophilic partner) reacts with a disulfane (as the nucleophilic
partner) to generate a sulfonium salt, which undergoes a secondary fragmentation/recombination
with expulsion of TrCl to afford the tri- or tetrasulfane, depending on the specific
Tr(S)
n
Cl used (Scheme [7], entry 29).[81c] Similarly, other creative expressions take advantage of the trityl group’s ability
to activate its adjacent S towards electrophilic activation, which can be used to
convert a suitably engineered substrate into a cyclic tetrasulfane (Scheme [7], entry 30).[81e]
Scheme 7 Examples of R(S)
n
Lg in insertion reactions and natural product synthesis for methodology E
This chemistry has recently been put to good use in natural product total synthesis
by Mohammad Movassaghi’s group for constructing the trisulfane and tetrasulfane bridges
of the epipolythioketopiperazine alkaloids, chaetocin C and dideoxychetracin A.[2] Here, the trityl group plays an important role in bridge closure, which involves
addition of the sulfur of the STr tether end onto an iminium ion to form an intermediate
cyclic sulfonium ion. The trityl group provides a synchronised stabilisation of the
incipient positive charge in addition to being lost as its cation to ultimately furnish
the final neutral bridge moiety (Scheme [7], entry 31).
Although not necessarily used in a direct substitution, RSSCl synthons have inspired
the development of other, more stable, derivatives of the form RSSLg, in which Lg
covers phthalimide,[46]
[47]
S-based leaving groups that include thiocarbonate,[54] phosphorodithioate,[82] and p-tolylsulfinate,[83] as well as O-based in the form of alkoxy.[84] Each of these important types will be discussed separately.
The first of the aforementioned variants to be discussed is the Harpp-type reagent
PhthNSSR, which, for R = Me, has achieved notoriety through the enediyne antibiotics
such as the calicheamicins and shishijimicins. These architecturally impressive natural
products contain a methyltrithio (SSSMe) warhead trigger and are potent antitumour
agents (shishijimicin A has an IC50 = 0.48 pM against P388 leukaemia cells and is thus ideal for incorporation as the
payload into an antibody-drug conjugate (ADC)). Harpp used reaction of SCl2 with phthalimide (2 equiv) to furnish the isolable and stable mono-sulfur transfer
agent, N,N′-thiobisphthalimide (PhthN)2S, which subsequently reacted with a thiol to furnish PhthNSSR[47a] as an isolable disulfanyl transfer reagent for unsymmetrical trisulfane formation.[47b]
[c] However, in the original procedure, Harpp did not use MeSH as the thiol for PhthNSSMe
generation. Hence, in his calicheamicinone (the aglycone of the caliceamicins) synthesis,[85] Danishefsky used the Sullivan and Boustany procedure[46] using sequential double substitution of SCl2 by first, phthalimide, followed by MeSH similar to methodology C, the reaction was carried out at 0 °C in DCM using 1 equivalent of each reactant.
Unfortunately, this produced the required PhthNSSMe transfer reagent in only 19% yield.
Recently, Nicolaou improved on synthesis of this reagent in his shishijimicin A synthesis[86] using first reaction of sulfur monochloride (S2Cl2) with phthalimide to furnish bis(1-phthalimidyl)disulfane, (PhthN)2S2, which could be efficiently converted into phthalimidosulfenyl chloride, (PhthNSCl),
with SO2Cl2 in 98% overall yield for the two steps. The sulfenyl chloride was found to be stable
in a desiccator at room temperature for several months, making it a very useful reagent
for hetero tri- and tetrasulfane synthesis for the future. Thereafter, inspired by
previous work by Harpp,[87] reaction of PhthNSCl with (TMS)SMe led to the required transfer reagent, PhthNSSMe,
in essentially quantitative yield after removal of the relatively volatile TMSCl.
PhthSSMe reacted rapidly with a thiol group of the natural product at room temperature
with loss of phthalimide, installing the required methyltrithio fragment (Scheme [7], entry 32). These innovations have greatly expanded the use of PhthNSSR as an important
disulfanyl transfer agent. While it has been used for unsymmetrical trisulfane synthesis,[46]
[47] the same cannot be said for tetrasulfane synthesis using a perthiol (as a RSSLg
+ R′SSH variant), probably because of the large number of steps needed to arrive at
the two reactants. Scheme [6] depicts some of Harpp’s insertion reactions[81] as well as the two natural product cases from Movassaghi[2] and Nicolaou[86] cited in the text.
The second variant on RSSLg is due to Mott and Barany from 1984 in the form of the
functionalised trisulfane, RSSSCO2Me,[54] in which Lg is a thiocarbonate (SCO2Me). The RSSSCO2Me is prepared by reacting methoxycarbonyldisulfanyl chloride (MeO2CSSCl) with a thiol and can be isolated as a stable intermediate in moderate yields.
This then reacts with a second thiol, using N-methylmorpholine (NMM) as base and promotor, with displacement of thiocarbonate,
furnishing the unsymmetrical trisulfane in 50–80% yield, albeit with contamination
by the disulfide in the more reactive cases. This method has certainly stood until
the present time[88] as a popular way of preparing heterotrisulfanes (see Scheme [8], entry 33). However, the long synthesis of the methoxycarbonyldisulfanyl chloride[54] using ungreen reagents is likely to result in the recent and improved methods for
trisulfane synthesis depicted in Scheme [6] and Scheme [8] finding greater usage in the future.
The third variant of Lg in RSSLg to be discussed uses Dariusz Witt’s cyclic phosphorodithioate,[82] which was mentioned[72] in the context of methodology D as the RSLg partner in RSSH + R′SLg. His application of this leaving group in the
RSSLg partner predates by a couple of years that of methodology D using an RSSH + RSLg approach.[72] For accessing the pivotal RSSLg partner, Witt uses an intriguing synthesis in the
style of methodology C, involving a one-pot reaction of an equimolar mixture of the cyclic, diesterified
phosphorodithioic acid and dodecane-1-thiol (as R1SH) with one equivalent of sulfur dichloride at –30 °C in DCM, using triethylamine
as base. Despite the homo-coupling possibilities, the mixed substitution product as
R1SSLg (Lg = cyclic phosphorodithioate; R1 = n-dodecyl) was isolated in 68% yield after column chromatography. Substitution of the
phosphorodithioate of R1SSLg with R2SH proceeded cleanly and rapidly in DCM at room temperature, again using triethylamine
as base, to afford unsymmetrical trisulfanes containing a range of both aliphatic
and aromatic R groups in >75% isolated yield (Scheme [8], entry 34). However, to avoid producing a complex mixture of symmetrical and unsymmetrical
di- and trisulfane products from the final substitution, it was important to have
the R1SSLg component in slight excess so as to consume the thiolate of R2SH. Once again, in principle, this attractive methodology could be used for unsymmetrical
tetrasulfane synthesis using a perthiol, R2SSH, in the final substitution step, but no examples of this have appeared to date.
Witt does note, however, that the scope of substitution in the R1 group of R1SH in the production of R1SSLg (and hence of R1 overall in R1SSSR2) is limited owing to the high reactivity of SCl2 in that step. For this reason, he developed the more versatile complementary methodology
already described under methodology D based on an R1SSH + R2SLg approach.[72]
The penultimate example[83] of RSSLg to be covered is due to the group of Zhenghu Xu, who demonstrated that
Lg can be p-tolysulfonyl in R1SSTs (Scheme [8], entry 35). The one limitation is that the only R1 group covered was tert-butyl, which was probably due to it being known from previous work that sulfenyl
thiotosylates (RSSTs), particularly with aromatic R groups, tend to extrude sulfur
in polar solvents to afford RSTs.[89] In Xu’s case, the t-BuSSTs was readily accessed from reaction of the sulfenyl chloride, t-BuSCl, with TsSK. Reaction with a small library of aromatic and aliphatic thiols
as R2SH with t-BuSSTs (1.5 equiv) in DCM at room temperature gave the desired unsymmetrical trisulfane
in moderate to excellent yields (50–91%). Not having to use a base for the final step
is a clear advantage, but the method is limited by restrictions in the R1 group (t-Bu only). As part of the work, Xu showed[83] that t-BuSSTs can be cross-coupled with a boronic acid, R2B(OH)2, using CuSO4/ NaHCO3 as promoter, to afford unsymmetrical disulfanes, R1SSR2.
Scheme 8 Recent examples of methodology E
The final word on methodology E is left for describing Xuefeng Jiang’s recent innovative work on disulfanyl transfer
agents. In this, he has significantly extended the usefulness of synthons of the type
RSSLg and LgSSLg for preparing polysulfanes using a variety of stepwise substitutions
by S, N and, importantly, C-based nucleophiles. In the context of this section, we
will focus on his approach for furnishing both unsymmetrical trisulfanes using RSSLg
+ RSH, and to the much-needed tetrasulfanes, using a RSSSLg + RSH approach. First,
the unsymmetrical trisulfanes.
Building on earlier work that demonstrated that a disulfanyl acetate (RSSAc) could
be deprotected to its perthiol in situ and oxidatively coupled with a boronic acid,
RB(OH)2, to afford unsymmetrical disulfanes,[66] in later work,[84] Jiang used this protocol for converting RSSAc into the useful electrophilic synthon
RSSOMe. The conditions for the cross-coupling involved using Li2CO3 for thioacetate deprotection in methanol, PhI(OPiv)2 as S-H oxidant (to S-I) and a ligated Cu(II) catalyst for the cross-coupling with
methanol. The RSSOMe products could be purified by chromatography without decomposition
or rearrangement, and then coupled with thiols in DCM at room temperature to afford
a range of unsymmetrical trisulfanes R1SSSR2 with excellent scope for the R groups, in 40–99% yield. However, Jiang clearly had
his eye on a bilateral disulfanyl transfer reagent that would have greater versatility
in producing a range of polysulfanes through the sequential substitution by S, N,
or C-based nucleophiles. In 2020, he published[90] his first paper (Scheme [8], entry 36) on the design and development of such a construct, building on work from
Shinichi Motoki from 1977[91] who had demonstrated that homodialkoxy disulfanes, ROSSOR (R = Me, Et), underwent
stepwise substitution (the intermediate R1SSSOMe could be isolated via distillation) with two different thiols to afford unsymmetrical
tetrasulfanes in low yields (ca. 30%) for the two steps (Scheme [8], entry 37). Jiang’s design[90] rested on incorporating the dialkoxydisulfanyl moiety into a cyclic scaffold in
which the chemoselectivity of substitution could take advantage of ring-strain release
in the first step, making substitution much faster for the first substitution. After
considerable trial and error, he established that a ten-membered scaffold built onto
a 1,1-binaphthyl template satisfied the objective. Using this template, substitution
with an arylboronic acid using Cu(MeCN)4PF6 and 2,2′-bpy as ligand in DCM at room temperature smoothly generated a mono-disulfanyl
ether that could be purified. However, for trisulfane production, it was more convenient
to carry out the second substitution in a one-pot fashion using a thiol with B(C6F5)3 as promoter in DCM at room temperature, generating unsymmetrical trisulfanes bearing
an aryl group for R1 and either an aryl or alkyl (including hindered R groups) group for R2, in yields of 34–80%.[90] The concept could easily be extended to tetrasulfanes but changing the scaffold
to an eight-membered dialkoxydisulfane built onto a phenyl ring. Substitution by R1SH proceeded at low temperature in methanol (–78 °C), which could be followed by R2SH with a catalytic amount (1 mol%) of their hard oxophilic B(C6F5)3 catalyst. The substitution chemoselectivity (mono versus di-) was ensured by virtue
of a (calculated) 9.53 kcal/mol energy difference between the two S–O bond dissociation
energies (Scheme [8], entry 36).
In a very recent publication,[92] Jiang improved his design concept further using a six-membered scaffold fused onto
an aromatic ring, incorporating a disulfonamidodisulfanyl motif (TsNSSNTs) for disulfanyl
transfer. In this case, reaction conditions for each of the types (tri- and tetrasulfane)
could be simplified. Hence, for the challenging tetrasulfane, selective R1SH mono-substitution could be brought about at 0 °C in DCM. Substitution with R2SH only required Li2CO3 as promoter in DCM at room temperature to furnish the tetrasulfane, for which 20
examples were reported, varying the R group significantly, in a 72–93% yield range.
In terms of yield and quality (in this case, free from other polysufanes), compared
to Derbesy and Harpp’s famous 1994 protocol,[41] things have come some distance. Similarly, using the same six-membered, bilateral
disulfenamide scaffold, unsymmetrical trisulfanes could be accessed using first substitution
with R1SH at 0 °C in DCM followed by an acidic carbon nucleophile (e.g., a β-dicarbonyl type)
using DMAP as promoter in DCM at room temperature. Fourteen diverse examples covering
a yield range of 68–90% were reported (Scheme [8], entry 38).[92] These innovations serve to demonstrate that some considerable progress has been
made in unsymmetrical tri- and tetrasulfane synthesis. However, it should be noted
that all of Jiang’s bilateral creations stem from using S2Cl2 to synthesise the scaffolds. Scheme [8] depicts examples for methodology E.
3
Conclusions
This review serves to present a historical and mechanistic appraisal of heterolytic
methodologies available for triorgano- and tetrasulfane synthesis. The importance
of such polysulfane motifs in both biology and materials science has been on the rise
for some time and is likely to continue into the future. While there have been some
new innovations introduced in the last ten years or so, there still pervades a dependency
on using SCl2 and S2Cl2 as starting materials. As the demand for these polysulfane functional materials grows
in the future, it is likely that researchers will have to turn their attention towards
greener, catalytic methods, avoiding the production of large amounts of waste. These
might mirror recent trends in disulfane synthesis via photoactive catalysts,[93] aerobic oxidative coupling with metal catalysts,[94] photocatalysis with quantum dots,[95] electro-oxidative cross-coupling,[96] and radical reactions.[97] However, given the greater challenges in tri- and tetrasulfane construction compared
to disulfanes, it remains to be seen how these innovative technologies might be brought
to bear for tri- and tetrasulfane synthesis, particularly for unsymmetrical targets.
Using sulfur as an original source, as well as carrying out assemblies in aqueous
systems, are other green frontiers in this context that also need to be surmounted.
