Straightforward chemoselective access to unsymmetrical dithioacetals through a thiosulfonate homologation-nucleophilic substitution sequence

Article abstract of DOI:10.1039/d0cc04896h

A sequential C1-homologation-nucleophilic substitution tactic is presented for the preparation of rare unsymmetrical dithioacetals. The judicious selection of thiosulfonates as convenient sulfur electrophilic sources - upon the homologation event conducted on an intermediate a-halothioether - guarantees the release of the non-reactive sulfonate group, thus enabling the subsequent nucleophilic displacement with an external added thiol [(hetero)- aromatic and/or aliphatic]. Uniform high yields and excellent chemocontrol were deduced during the extensive scope study, thus documenting the versatility of the direct technique for the preparation of these unique and manipulable materials.

Full text of DOI:10.1039/d0cc04896h

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DOI: 10.1039/D0CC04896H
Journal Name
ARTICLE
Straightforward Chemoselective Access to Unsymmetrical
Dithioacetals through a Thiosulfonates Homologation-Nucleophilic
Substitution Sequence
Received 00th January 20xx,
Accepted 00th January 20xx
Laura Ielo,a Veronica Pillari,a Natalie Gajic,b Wolfgang Holzera and Vittorio Pacea,c*
DOI: 10.1039/x0xx00000x
A sequential C1-homologation – nucleophilic substitution tactic is presented for preparing rare unsymmetrical dithioacetals.
The judicious selection of thiosulfonates as convenient sulfur electrophilic sources – upon the homologation event
conducting to an intermediate α-halothioether - guarantees the release of the non reactive sulfonate group, thus enabling
the subsequent nucleophilic displacement with an external added thiol [(hetero)aromatic and/or aliphatic]. Uniformly high
yields and excellent chemocontrol were deducted during an extensive scope study, thus documenting the versatility of the
direct technique for preparing these unique and manipulable materials.
www.rsc.org/
through a single operation under full chemocontrol [Scheme 1
Dithioacetals (RS-CH2-SR) represent entities featuring
a
– path (i) - Pace].9 Notably, the transformation is also flexible for
plethora of versatile characteristics which make them preparing diselenoacetals from diselenides. On a conceptually
important motifs across the chemical sciences.1 By transforming analogous homologative logic is levered the prior reduction of
a carbonyl group into a dithioacetal, Corey and Seebach the disulfide linkage to thiol which, treated with a convenient
introduced the concept of umpolung, enabling the switching of dihalomethane (as C1 donor) in the presence of a base,
the reactivity of the prototypal electrophilic carbon (CO) to a furnishes the dithioacetal scaffold [Scheme 1 – path (ii) -
nucleophilic one.2 Besides this synthetic significance of Cramer].3a,10 The search for alternative C1 sources motivated
dithioacetals, in recent years they emerged as privileged the development of alternative strategies became available in
structures enabling to properly address elusive drawbacks of recent years: a) the use of CO2 which through a selective four-
disulfides. In fact, their well-known lability to reducing and/or electron reduction delivers the formal methylene group (CH2)
nucleophilic agents - posing severe difficulties for their to connect the two (identical) thiol moieties [Scheme 1 – path
application in biological systems
–
has been elegantly (ii) - Xi];11 b) the employment of acetone under basic conditions
circumvented by homologating the sensitive disulfide bridge to for a sequential enolization- sulfenylation-decarboxylation
a more robust dithioacetal.3 As illustrated by Cramer in the case process [Scheme 1 – path (iii) - Chen];12 c) the use of orthoesters
of challenging native peptides, this operation – enlarging the S- amenable of In-catalyzed reductive insertion into disulfides
S distance by 0.90 Å – not only imparts an enhanced stability [Scheme 1 – path (iii) - Sakai].13 As a common feature, all these
but, also preserves the pharmacodynamic profile of the approaches conduct uniformly to symmetrical dithioacetals,
resulting adducts (e.g. oxytocin, octreotide, bactenecin).3a The leaving practically undisclosed the synthesis of unsymmetrical
tactic of assembling dithioacetal via an homologative analogues (RS-CH2-SR1). Inspired by our previous findings that a
transformation of disulfides appeared particularly suited lithium carbenoid (LiCH2X)14 attacks a disulfide forming an
because of the simplicity of inserting the C1 unit between the (isolable) α-chlorothioether and
a
mercapto anion,9 we
two sulfur atoms.4 Though the methylene donor source can act reasoned that taming or eliminating the nucleophilicity of the
in both nucleophilic (e.g. diazomethane,5 sulfur ylides6) and released sulfur-nucleophile (leaving group) could strategically
electrophilic regime (e.g. zinc carbenoids),7 this logic remained impede its attack en route to the symmetrical dithioacetal.
eclipsed for decades because of the inherent difficulties in Ideally, upon realizing the initial C1-homologation on a proper
achieving good chemical yields (Scheme 1 – path i).8 In this disulfide surrogate releasing a non-nucleophilic leaving group,
context, our group individuated the nucleophilicity of the C1 the subsequent substitution carried out with an externally
carbenoid source as a critical parameter for ensuring the added thiol would establish a modular access to unsymmetrical
success: we demonstrated that the highly nucleophilic dithioacetals.
bromomethyllithium (LiCH2Br) acts as
a
competent
homologating agent furnishing the (symmetrical) dithioacetals
a University of Vienna - Department of Pharmaceutical Chemistry. Althanstrasse, 14,
1090, Vienna, Austria. E-mail: vittorio.pace@univie.ac.at; vittorio.pace@unito.it
b
Web: http://drugsynthesis.univie.ac.at/; University of Vienna – X-Ray Structure
Analysis Center - Waehringerstrasse 42, 1090, Vienna, Austria; c University of Turin
– Department of Chemistry. Via P. Giuria 7, 10125, Turin, Italy.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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alternative sulfenylating agents were screened. The reactions
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i) C1-homologation tactics of disulfides to symmetrical dithioacetals
run on chlorophenylsulfide (PhS-Cl,DOeI:n10tr.1y0397/D)0CaCn0d4896NH-
phenylthiophthalimide (entry 8) – two common electrophilic
sulfur agents - produced the desired dithioacetal in promising
37% and 44% yield respectively, with no detectable formation
of the compounds resulting from the attack of the expulsed
leaving groups (Cl- and PhthN-). Finally, we were pleased to
identify the thiosulfonate ester16 (PhS-SO2Ph, entry 9) as the
optimal electrophilic sulfur source delivering – upon the
CH N S-ylides
Nucleophilic (
(Schill - Field, 1970s)
)
2
2,
S
R
RS
SR
R
S
ICH ZnI
Electrophilic (
)
2
(Field, 1975)
low yielding processes
fast
SN
Li
X
RS
Br
+
RSLi
(Pace, 2016)
ii) Thiol to symmetrical dithioacetal homologation
reactive
coupled nucleophilic substitution
– the unsymmetrical
dithioacetal in an excellent 86% isolated yield. The process
benefited from the addition of catalytic (0.1 equiv) NaI, whose
use maximized the yield up to 93% (entry 10). Some additional
points merit mention: a) a weaker nucleophile as a Mg
carbenoid did not trigger the homologation event, thus
resulting in full recovery of the thiosulfonate (entry 11);17 2)
removing the cooling bath and executing the displacement from
0 °C to rt was pivotal for activating the benzenethiolate attack,
since keeping the mixture at 0 °C resulted in no reactivity (entry
12); 3) the acidic quenching just after the homologation allows
to obtain the α-chlorothioether as the sole product in
comparable yield (entry 13); 4) the use of the reactive and easily
accessible18 thiosulfonate does not entail practical
shortcomings normally affecting sulfenylating agents (odor,
toxicity, low stability), thus guaranteeing a good manipulability.
X
X
SH
SH
(Cramer, 2016)
SR
RS
+
R
R
base
CO2, NaBH4 / I2
Xi (2018)
iii) Different C1-donors for disulfide to symmetrical dithioacetal homologation
O
OMe
OMe
Me
Me
MeO
S
R
R
S
Cs2CO3, 18-c-6
InBr3 (cat.), Si-H
(Chen, 2018)
(Sakai, 2020)
RS
SR
Synthetic plan for Unsymmetrical Dithioacetals
Li
R1-SH
X
R
Nu displacement
C1-Homologation
S
X
S
S
S
R1
R
LG
R
Which LG?
Chemoselectivity?
+
LG
36 cases
(up to 93%)
Table 1. Reaction optimization.
low-reactive
Ph
R1-SH
Li
X
S
X
S
S
S
S
S
Ph
LG
Ph
+
Ph
Ph
(1a)
(R1 = 4-BrC6H4)
Scheme 1. General context of the presented work.
Br
+
LG
LG = SPh (1)
2
2a
( )
(
)
We targeted the formation of the unsymmetrical dithioacetal 2
presenting an aromatic bromine potentially sensitive to the
lithiating environment and, thus constituting a diagnostic
element for the chemoselective profile of the reaction (Table 1).
Conducting the homologation with LiCH2Br on diphenyl
disulfide 1, followed by the addition of p-bromothiophenol,
resulted in the formation of the symmetrical adduct 2a with
only traces of the desired motif 2 (entry 1). Realizing the
homologation with LiCH2I (entry 2) substantially confirmed the
previous outcome, while homologating with LiCH2Cl resulted in
noticeable formation of 2 (13%, entry 3). Further improvement
was achieved by dissolving the external thiol in DMF (entry 4) –
a medium known to facilitate nucleophilic displacements on
alkyl halide systems15 (as the intermediate α-chlorothioether,
1a) - prior to the addition to the homologating reaction crude.
Increasing the loading of p-bromothiophenol (2.6 equiv., entry
5) or, the temperature for the displacement (entry 6) did not
result in a significant improvement, furnishing in both instances
variable mixtures of symmetrical and unsymmetrical adducts.
Collectively, these experiments confirmed the feasibility of the
two distinct part of the process and, in particular, the
effectiveness of the nucleophilic substitution constituting the
conditio sine qua non for preparing the unsymmetrical
dithioacetal. In agreement with the initial hypothesis of
rendering innocent the leaving group expulsed from the
electrophilic sulfur during the homologation step, a series of
LG Substrate
LiCH2X
Solv.,Temp [° C]
Ratio
2/2aa
Yield
of
2 (%)b
Homologation
(X, equiv)
Nu Substitution
Entry
1
2
PhS
PhS
(Br, 1.8)
(I, 1.8)
THF, -78 to rt
THF, -78 to rt
THF, -78 to rt
DMF, -78 to rt
DMF, -78 to rt
DMF, -78 to 60
DMF, -78 to rt
DMF, -78 to rt
DMF, -78 to rt
DMF, -78 to rt
DMF, -78 to rt
DMF, 0
>1:99
>1:99
18:82
25:75
33:67
28:72
>99:1
>99:1
>99:1
>99:1
-
-
-
3
PhS
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
(Cl, 1.8)
13
21
27
23
37
44
86
93
-
4
PhS
5c
6
PhS
PhS
7
Cl
8
PhN-Phth
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
9
10d
11e
12d
13f
-
-
DMF, -78 to rt
-
-
2 | J. Name., 2012, 00, 1-3
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Otherless stated the corresponding carbenoid was generated under Barbier-type
conditions starting from the corresponding dihalomethane (2.0 equiv): ICH2Br (LiCH2Br),
ICH2I (LiCH2I), ICH2Cl (LiCH2Cl) – respectively - and MeLi-LiBr (Et2O solution 1.5 M, 1.8
equiv) in THF at -78 °C. 4-BrC6H4SH (1.3 equiv) were used. For entries 7-12 the ratio 2/2a
is referred to the possible adduct generated through SN conducted with the leaving group
1) ICH2Cl (2.0 equiv)
MeLi-LiBr (1.8 equiv)
THF, -78 °C, 1 h
View Article Online
DOI: 10.1039/D0CC04896H
O
S
S
S
R
S
R
R1
R
O
2) R1SH (1.3 equiv)
NaI (0.1 equiv)
DMF, 0 °C to rt, 6 h
-
expulsed during the homologation (Cl-, PhthN-, PhSO2 ).
a
The ratio has been calculated by 1H-NMR analysis using 1,3,5-trimethylbenzene as an
From aromatic thiosulfonates
b
c
d
internal standard. Isolated yield. 4-BrC6H4SH (2.6 equiv) were used. NaI (0.1 equiv)
was added. e ClCH2MgCl-LiCl [generated – coeteris paribus - from ICH2Cl (2.0 equiv) and
i-PrMgCl-LiCl (1.8 equiv) under non-Barbier conditions at -78 °C in THF]. f 1a was obtained
in 89% isolated yield.
Cl
S
S
S
S
S
S
Br
Cl
Cl
2
3
4
(89%)
(93%)
(93%)
CF3
S
S
S
S
S
6
S
With the optimized condition in hand, we then studied the
scope of the method documenting a wide tolerance of
functional groups potentially sensitive to the lithiating
conditions (Scheme 2). Differently substituted halogenated
thiophenols [4-bromo (2), 4-chloro (3), the sterically hindered
2,6-dichloro analogue (4), 4-fluoro (5), 2-trifluoromethyl (6)] act
as competent partners in the nucleophilic substitution. Taming
the nucleophilicity of the thiophenol by installing a strong
electron-withdraming group as a nitro, only marginally affects
the chemical yield (7). With much of our delight, a genuine
selectivity for the S-alkylation (8) was deducted when
employing the bis-nucleophilic species 4-aminothiophenol, thus
leaving not affected the per se nucleophilic amino group.
Unsubstituted thiophenols smoothly reacted as noticed in the
case of the canonical one (9) or the naphthyl-analogue (10).
Switching to aliphatic thiols do not alter the efficiency of the
method [cyclopentyl (11), cyclohexyl (12)]; of particular
relevance is the outcome of the reaction with a sterically
encumbered tertiary mercaptane (13). Additional evidence of
the generality of the technique was deducted when using
benzyl- (14) and the heteroaromatic benzoxazolyl- (15) thiols.
The flexibility of the method to alkyl-type thiosulfonates
enabled to prepare different unsymmetrical alkyl-aryl and alkyl-
alkyl dithioacetals. Comparable yields with the above discussed
aryl thiosulfonates were ensured when using halogenated-type
thiophenols (16-19), or nitrogen-containing motifs [4-nitro (20)]
and 4-aminothiophenol whose precise S-alkylation confirmed
the excellent chemoselectivity profile mentioned with the
aromatic analogue. Again, simple thiophenols (22-23) were
amenable materials for the reaction, as well as, benzyl- (24-25)
and cycloalkyl (26-27) ones. Steric factors do not affect the
success of the transformation, as indicated by the trityl- (28)
and 1-adamantyl- (29) derivatives. A series of heteroaromatic
dithioacetals of potential biological interest [benzoxazolyl- (30),
pyridinyl- (31) and the elaborated 1,3,4-thiadiazolyl- (32)]
complement the plethora of structures accessible with the
method. Benzyl-type thiosulfonates analogously undergo the
homologation – nucleophilic displacement strategy yielding a
benzyl-aryl mixed dithioacetal (33) or, a simple bis-benzylic
(symmetrical) one (34). As showcased by this latter example,
the homologation realized on the thiosulfonate, provides
compound 34 in sensitively higher yield (ca. 10%) respect to the
transformation carried out on the less reactive disulfide.9
Further insights into the chemoselectivity is gathered in the
case of the ester-containing thiol (35) which did not suffer any
concomitant nucleophilic attack despite the organolithium
environment and, the allyl-system (36) in principle constituting
a cyclopropanation manifold.19
NO2
F
5
7
(85%)
(91%)
(95%)
S
S
S
S
S
S
NH2
8
9
10
(95%)
(88%)
(93%)
S
S
N
S
S
Ph
Ph
S
S
Ph
S
S
O
n
11
12
(n =1, 87%)
(n =2, 85%)
13
S
14
15
S
(96%)
(91%)
(86%)
From aliphatic thiosulfonates
Cl
S
S
S
S
F
Me
Me
S
S
Me
Me
Br
Cl
Cl
16
20
17
18
19
S
(95%)
(93%)
(91%)
(94%)
S
S
S
S
S
S
S
Me
Me
Me
Me
NO2
NH2
Cl
Me
21
22
23
(94%)
(85%)
(87%)
(96%)
t-Bu
Ph
Ph
S
S
S
S
Ph
Me
Me
S
S
S
S
Me
Me
Me
n
24
S
25
26
27
28
N
(89%)
(87%)
(n =1, 83%)
(n =2, 88%)
(91%)
S
S
S
S
N
Me
Me
S
S
S
N
Me
N
Me
S
N
O
S
Me
(91%)
CF3
29
30
31
32
(95%)
(87%)
(85%)
From benzyl thiosulfonates
O
OMe
S
S
Me
MeO
S
S
S
S
35
(95%)
S
S
33
34
(92%)
(89%)
36
(87%)
Carbenoid-sensitive moieties
Scheme 2. Scope of the homologation – nucleophilic substitution strategy for
converting thiosulfonates into unsymmetrical dithioacetals.
The X-ray analysis of selected representatives (compounds 10,
15 and 28) revealed interesting structural features of the
constitutive S-CH2-S moiety of unsymmetrical dithioacetals
(Figure 1). In all cases, a small - but evident - bond length
difference between C1-S1 and C1-S2 was noticed, presumably
due to the stereoelectronic alteration imparted by the two
different sulfur atoms.
This journal is © The Royal Society of Chemistry 20xx
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Pillari thanks the University of Vienna for a Uni:docs fellowship.
View Article Online
DOI: 10.1039/D0CC04896H
M. M. acknowledges OEAD for a Blau grant.
Notes and references
10
15
28
1. a) L. Pan, X. Bi and Q. Liu, Chem. Soc. Rev., 2013, 42, 1251; b) T.-Y.
Luh and M.-k. Leung, in Science of Synthesis, Thieme, 2018, vol. 30,
pp. 369; c) T. Y. Luh, Acc. Chem. Res., 1991, 24, 257; d) T.-Y. Luh and
C.-F. Lee, Eur. J. Org. Chem., 2005, 2005, 3875; e) T.-Y. Luh, J.
Organomet. Chem., 2002, 653, 209.
2. a) E. J. Corey and D. Seebach, Angew. Chem. Int. Ed., 1965, 4, 1075;
b) D. Seebach, Angew. Chem. Int. Ed., 1979, 18, 239; c) B.-T. Groebel
and D. Seebach, Synthesis, 1977, 357.
Compound
CCDC
C1-S1 (Å)
C1-S2 (Å)
S1-S2
(Å)
10
15
28
2016505
2016506
2016507
1.795
1.801
1.804
1.814
1.819
1.816
2.943
2.932
2.945
3. a) C. M. B. K. Kourra and N. Cramer, Chem. Sci., 2016, 7, 7007; b)
H. I. Mosberg and J. R. Omnaas, J. Am. Chem. Soc., 1985, 107, 2986.
4. H. Li, T. Yang, A. Riisager, S. Saravanamurugan and S. Yang,
ChemCatChem, 2017, 9, 1097.
5. a) N. Petragnani and G. Schill, Chem. Ber., 1970, 103, 2271; b) T.
Ghosh and V. P. Rao, Sulfur Reports, 1992, 12, 339.
6. L. Field and H.-K. Chu, J. Org. Chem., 1977, 42, 1768.
7. L. Field and C. H. Banks, J. Org. Chem., 1975, 40, 2774.
8. W. W. Wood, in Organosulfur Chemistry, ed. P. Page, Academic
Press, 1995, vol. 1, pp. 133.
9. V. Pace, A. Pelosi, D. Antermite, O. Rosati, M. Curini and W. Holzer,
Chem. Commun., 2016, 52, 2639.
10. a) U. Masaaki, I. Takayoshi, H. Kumiko, N. Keiko, S. Akihiko and K.
Hiroshi, Bull. Chem. Soc. Jpn., 1999, 72, 829; b) J. Xia, R. Yao and M.
Cai, Appl. Organomet. Chem., 2015, 29, 221; c) Y. B. Kim, Y. H. Kim, J.
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12. Q. Chen, G. Yu, X. Wang, Y. Huang, Y. Yan and Y. Huo, Org. Biomol.
Chem., 2018, 16, 4086.
Figure 1. X-ray structural analysis of selected unsymmetrical
dithioacetals (for additional details see the ESI).
In order to take full advantage of the procedure and setting a
modular synthesis of dithioacetals manifesting tyrosinase
inhibition,20 selected modifications on the ester-decorated
analogue 35 were realized (Scheme 3). The treatment with a
Grignard reagent resulted in the double addition product (37),
whereas forming a transient (non isolated) Weinreb amide21
enabled the selective mono-addition giving the ketone-
containing structure 38, direct precursor – through trivial
carbonyl reduction - of carbinol 39.
i-Pr
i-Pr
O
OMe
HO
MeNHOMe-HCl
(2.0 equiv)
S
S
S
S
i
-PrMgCl (2.0 equiv)
Me
Me
i-PrMgCl (1.8 equiv)
CPME, 0 °C to rt, 2 h
2-MeTHF, 0 °C, 1 h
NH4Cl (aq.)
37
35
(87%)
13. N. Sakai, S. Adachi, S. Ogawa, K. Takahashi and Y. Ogiwara, Asian
J. Org. Chem., 2020, 9, 600.
Me
N
HO
S
i-Pr
O
i-Pr
i-PrMgCl
(1.3 equiv)
O
OMe
NaBH4, (2.0 equiv)
14. a) L. Castoldi, S. Monticelli, R. Senatore, L. Ielo and V. Pace, Chem.
Commun., 2018, 54, 6692; b) V. Pace, L. Castoldi, S. Monticelli, M. Rui
and S. Collina, Synlett, 2017, 28, 879; c) V. Pace, W. Holzer and N. De
Kimpe, Chem. Rec., 2016, 16, 2061; d) L. Ielo, S. Touqeer, A. Roller, T.
Langer, W. Holzer and V. Pace, Angew. Chem. Int. Ed., 2019, 58, 2479;
e) V. Pace, L. Castoldi, E. Mazzeo, M. Rui, T. Langer and W. Holzer,
Angew. Chem. Int. Ed., 2017, 56, 12677.
S
S
S
Me
Me
S
S
Me
AcOEt, 0 °C, 2 h
39
38
(85%)
(93%)
Not isolated
Scheme 3. Synthetic manipulation of an unsymmetrical dithioacetal.
In summary, we have developed a straightforward preparation
of rare unsymmetrical dithioacetals via a synthetic sequence
constituted by chloromethyllithium-mediated homologation –
nucleophilic substitution with a proper thiol. The opportune
selection of thiosulfonate as the sulfenylating agent is pivotal
for ensuring the chemical inertness – as nucleophile - of the
released sulfonate leaving group. Accordingly, upon completing
the homologation event, the (eventually isolable) α-
chlorothioether undergoes the nucleophilic displacement,
furnishing the requested dithioacetals. The uniformly high-yield
and the high chemocontrol – deducted by selectively preparing
variously decorated motifs – further document the potential of
this operationally simple and intuitive methodology.
15. S. Ding and N. Jiao, Angew. Chem. Int. Ed., 2012, 51, 9226.
16. a) P. Mampuys, C. R. McElroy, J. H. Clark, R. V. A. Orru and B. U.
W. Maes, Adv. Synth. Catal., 2020, 362, 3; b) N. S. Zefirov, N. V. Zyk,
E. K. Beloglazkina and A. G. Kutateladze, Sulfur Reports, 1993, 14,
223.
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Acknowledgements
We thank the University of Vienna, the University of Turin and
Fondazione RiMed (Palermo, Italy) for generous support. V.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC04896H
R1-SH
Nu displacement
Li
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R
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C1-Homologation
S
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R1
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36 cases
(up to 93%)
A two-steps electrophilic sulfur homologation strategy for building up unsymmetrical dithioacetals