Trithioorthoester Exchange and Metathesis: New Tools for Dynamic Covalent Chemistry

Article abstract of DOI:10.1055/s-0039-1690992

To expand the toolbox of dynamic covalent and systems chemistry, we investigated the acid-catalyzed exchange reaction of trithioorthoesters with thiols. We found that trithioorthoester exchange occurs readily in various solvents in the presence of stoichiometric amounts of strong Bronsted acids or catalytic amounts of certain Lewis acids. The scope of the exchange reaction was explored with various substrates, and conditions were identified that permit clean metathesis reactions between two different trithioorthoesters. One distinct advantage of S, S, S-orthoester exchange over O, O, O-orthoester exchange is that the exchange reaction can kinetically outcompete hydrolysis, thereby making the process less sensitive to residual moisture. We expect that the relatively high stability of the products might be beneficial in future supramolecular receptors or porous materials.

Full text of DOI:10.1055/s-0039-1690992

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–G
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M. Bothe et al.
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Trithioorthoester Exchange and Metathesis: New Tools for
Dynamic Covalent Chemistry
Michael Bothea
Trithioorthoester exchange
A. Gastón Orrillob
Ricardo L. E. Furlan*b
Max von Delius*a
SR1
SR1
SR1
SR1
SR1
SR2
SR1
SR2
SR2
SR2
SR2
SR2
acid
R1SH
R
R2SH
R
R
R
0
0
0
0-0
0
0
3-1
8
5
2-
2
9
6
9
tripodal geometry
a Institute of Organic Chemistry I, University of Ulm,
Albert-Einstein-Allee 11, 89081 Ulm, Germany
max.vondelius@uni-ulm.de
b Farmacognosia, Facultad de Ciencias Bioquímicas y
Farmacéuticas, Universidad Nacional de Rosario-CONICET,
S2002LRK Rosario, Argentina
Trithioorthoester metathesis
SR1 SR2
SR1 SR2
SR1 SR2
SR1
SR1
SR2
SR1
SR2
SR2
acid
R
R
R
R
rfurlan@fbioyf.unr.edu.ar
up to 8 compounds
Published as part of the Cluster Metathesis beyond Olefins
Received: 06.09.2019
Accepted: 11.09.2019
Published online: 18.09.2019
DOI: 10.1055/s-0039-1690992; Art ID: st-2019-b0470-c
(Scheme 1). Both reactions share similarities, such as a re-
quirement for acid catalysis in organic solvents12 and their
widespread use in protective-group chemistry.13 The tripo-
dal nature of orthoesters makes them uniquely suited for
the self-assembly of cage-type architectures.14,15 Also, or-
thoester exchange gives rise to a remarkable level of molec-
ular diversity, because by mixing one orthoester with one
alcohol, an equilibrium mixture consisting of four different
orthoesters is obtained (Scheme 1A). In contrast, dithioace-
tal exchange produces fewer products (Scheme 1B) and is
more suited to the preparation of cyclic hosts.16 This ex-
change can be connected to that of disulfides and thioesters
to generate multilevel dynamic systems.17 Compared with
orthoesters, dithioacetals are less susceptible to hydrolysis
and they demand more-acidic media for exchange.
Abstract To expand the toolbox of dynamic covalent and systems
chemistry, we investigated the acid-catalyzed exchange reaction of
trithioorthoesters with thiols. We found that trithioorthoester ex-
change occurs readily in various solvents in the presence of stoichio-
metric amounts of strong Brønsted acids or catalytic amounts of cer-
tain Lewis acids. The scope of the exchange reaction was explored with
various substrates, and conditions were identified that permit clean me-
tathesis reactions between two different trithioorthoesters. One dis-
tinct advantage of S,S,S-orthoester exchange over O,O,O-orthoester ex-
change is that the exchange reaction can kinetically outcompete
hydrolysis, thereby making the process less sensitive to residual mois-
ture. We expect that the relatively high stability of the products might
be beneficial in future supramolecular receptors or porous materials.
Key words transesterification, trithioorthoesters, thiols, exchange
reaction, metathesis, dynamic covalent chemistry
A
B
C
Orthoester exchange (von Delius, 2015)
OR1 OR1
OR1 OR1
OR1 OR2
OR1
OR2
OR2
OR2
OR2
OR2
R
R2OH
R
R
R
R1OH
Dynamic covalent chemistry (DCC)1 has emerged in the
last two decades as an area that combines the best attri-
butes of organic chemistry (synthesis of stable compounds)
with those of supramolecular chemistry (error correction).2
At the heart of DCC are robust and reliable chemical reac-
tions that, at least in the presence of suitable catalysts,3 lead
to the formation of equilibrium mixtures under relatively
mild conditions. Typical examples include the exchange of
disulfides with thiols,4 and the reversible condensation re-
actions of imines,5 hydrazones,6 and oximes.7 However, in
the light of new applications of DCC, especially in the syn-
thesis of porous materials8 and in the life sciences,9 there is
unabated interest in the development of new dynamic co-
valent reactions.
Dithioacetal exchange (Furlan, 2016)
SR1
SR1
SR2
SR2
SR2
R2SH
Ar
R1SH
Ar
Ar
SR1
Trithioorthoester exchange (this work)
SR1
SR1
SR1
SR1
SR1
SR2
SR1
SR2
SR2
SR2
SR2
SR2
R
R2SH
R
R1SH
R
R
Scheme 1 Exchange reactions of (A) orthoesters, (B) dithioacetals, and
(C) trithioorthoesters
In this study, we focus on trithioorthoester exchange, an
area of chemical space that, from the perspective of topolo-
gy and reactivity, lies between orthoester exchange and
dithioacetal exchange (Scheme 1C). Trithioorthoesters18
can be obtained from, inter alia, O,O,O-orthoesters,19 chlo-
roform,20 orthothioformates,21 or dithioacetals,22,23 and
To this end, the groups of von Delius and of Furlan re-
cently reported investigations of O,O,O-orthoester ex-
change10 and dithioacetal exchange reactions,11 respectively
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Bothe et al.
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trithioorthoester groups have been used primarily as pro-
tective groups, especially when the product is required to
be more stable toward acid hydrolysis than its oxygen
counterpart.13 Here, we present a comprehensive investiga-
tion of the conditions required for trithioorthoester ex-
change and for trithioorthoester metathesis, in the hope
that these transformations will prove useful in areas where
the advantages of thermodynamic control can be har-
nessed.8e,24
ful for promoting trithioorthoester exchange. These condi-
tions were used in exchange experiments initiated from
various starting materials,1c,27 which confirmed the revers-
ibility of the reaction (Figures S1–S3, SI).
In the hope of identifying milder and truly catalytic
(substoichiometric) conditions, we proceeded to investigate
some representative Lewis acids.28 For reasons of solubility,
we chose CD3CN as a solvent to investigate FeCl3, AlCl3, and
BF3·OEt2, whereas CDCl3 was used in combination with
SnCl4, TiCl4, and FeCl3. We found that one equivalent of each
of the Lewis acids FeCl3, AlCl3, SnCl4, and BF3·OEt2 led to
equilibration after roughly one hour; experiments with 0.1
equivalent of these Lewis acids showed that they can in-
deed be regarded as catalysts for this reaction (Table 1, en-
We started by testing the feasibility of trithioorthoester
exchange under conditions similar to those used for the ac-
tivation of O,O,O-orthoesters10 or dithioacetals.11 To this
end, trifluoroacetic acid (TFA; 1 or 10 equiv) was added to a
chloroform-d solution containing tris(phenylthio)methane
(A13; 50 mM, 1 equiv) and phenylmethanethiol (2; 3 equiv)
at room temperature (Table 1). All solvents were dried over
molecular sieves before use to minimize the irreversible hy-
drolysis of trithioorthoesters to thioesters. The composi-
Table 1 Scope of Trithioorthoester Exchangea
SPh
SPh BnSH
SPh
SBn
SPh
SPh
SBn
SBn
SPh
SBn
SBn
SBn
acid
1
PhSH
H
H
H
H
tions of the reaction mixtures were analyzed by H NMR
org. solv.
spectroscopy after one hour and 24 hours. The use of ten
equivalents of TFA led to equilibration of the mixture with-
in one hour of reaction time. The apparent bias toward
trithioorthoesters rich in building block 2 (Table 1, entry 1)
can be rationalized in terms of differences in steric demand.
The undesired hydrolysis reaction led to ≤2% of thioesters
A1 and A2 with respect to the initial trithioorthoesters. A
tenfold decrease in the amount of TFA was possible, but led
to slower exchange, as indicated by the dominance of start-
ing material A13 after 24 hours of reaction time (Table 1,
entry 2). The harsh Brønsted acidic conditions, which are
required to equilibrate trithioorthoesters within a reason-
able timespan, are similar to those giving rise to dithioace-
tal exchange, whereas O,O,O-orthoester exchange proceeds
under much milder conditions.
A range of parameters was next investigated to better
understand the reaction. First, various solvents were tested
by using TFA in a standard amount of ten equivalents. In
benzene-d6, equilibrium was reached after one hour of re-
action (Table 1, entry 3), whereas in acetonitrile-d3 the ex-
change was slow and the composition after 24 hours was
still far from equilibrium (Table 1, entry 4). No exchange
products were observed in DMSO-d6 or THF-d8. When
stronger Brønsted acids were compared in acetonitrile-d3
(for solubility reasons), a correlation between the pKa val-
ue25 and the reaction kinetics was observed. Slow exchange
was observed with TFA (pKa = 12.7) or methanesulfonic acid
(pKa = 10.0) (entries 4 and 5), whereas the mixtures with p-
toluenesulfonic acid (pKa = 8.0) or sulfuric acid (pKa = 7.2)
equilibrated after 24 hours (entries 6 and 7). Only the mix-
ture with trifluoromethanesulfonic acid (pKa = 2.6) equili-
brated after one hour of reaction (entry 8). Trifluorometh-
anesulfonic acid turned out to be a less effective catalyst in
DMSO-d6, whereas THF-d826 was unstable in the presence of
this acid [see the Supplementary Information (SI)]. Stoi-
chiometric or excess Brønsted acids were shown to be use-
A13
(50mM)
2
A122
A122
A23
1
(150 mM)
O
O
hydrolysis
products
H
SPh
H
SBn
A1
A2
Entry
Acid (Equiv)
Solvent
Reaction time A13/A122/A122/
(h)
A23/(A1 + A2)b
1
2
TFA (10)
TFA (1)
CDCl3
1
24
3:17:38:42:–
2:16:38:43:1
CDCl3
1
24
97:3:–:–:–
46:30:16:8:–
3
TFA (10)
TFA (10)
MsOH (1)
PTSA (1)
H2SO4 (1 )
TfOH (1)
FeCl3 (0.1)
AlCl3 (0.1)
C6D6
1
24
8:17:33:42:–
3:17:39:41:–
4
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
CD3CN
1
24
98:2:–:–:–
66:22:8:4:–
5
1
24
97:3:–:–:–
56:26:13:5:–
6
1
24
60:24:1:5:–
2:11:37:50:–
7
1
24
73:18:6:3:–
4:14:39:43:–
8
1
24
1:18:42:39:–
2:19:43:36:–
9
1
24
35:26:23:16:–
3:15:39:43:–
10
1
24
48
92:8:–:–:–
24:21:26:29:–
14:15:29:42:–
11
12
BF3·OEt2 (0.1)
FeCl3 (0.1)
CD3CN
CDCl3
1
24
48
78:18:4:–:–
9:14:33:44:–
4:15:38:43:–
1
3:17:40:40:–
a Reaction conditions: A13 (37.5 mol), 2 (112.5 mol), TFA (375 mol),
CDCl3 (Vtotal: 750 L), r.t.
b Product ratios were determined by integration of 1H NMR signals. Equilib-
rium mixtures are highlighted in bold face; ‘–’ indicates not detected. For
full spectra, see Figures S4–S25 in the Supplementary Information.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–G

C
M. Bothe et al.
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tries 9–12) with the following reactivity trend: FeCl3
>
SR1
SR1
SR1
XR2
SR1
SR1
XR2
XR2
SR1
TFA
BF3·OEt2 > AlCl3. In addition, the use of Lewis acids in CDCl3
was found to be promising. When 0.1 equivalent of FeCl3 in
CDCl3 was tested, equilibrium was attained after one hour
(entry 12). Although the equilibrium position seems to be
unaffected by the presence of the iron cation, signal broad-
ening was observed, which increased with reaction time,
preventing accurate integration after 24 hours of reaction.
These results show that Lewis acids require a lower catalyst
loading than do Brønsted acids. Future work might focus on
Lewis acid catalysis in CDCl3 to achieve shorter reaction
times when using substoichiometric amounts of catalyst. To
this end, alternative analytical tools such as HPLC might be
helpful in avoiding interference by the paramagnetic effects
induced by metal cations.
H
R2XH
H
H
H
CDCl3
A13 (R1: Ph) or
A83 (R1: Me)
2–7
XR2
XR2
XR2
R1SH
trithioorthoester
R2XH:
nucleophile
SH
SH
SH
3
4
2
A13:A122:A122:A23
A13:A123:A132:A33
A13:A124:A142:A43
15:40:35:10a
3:17:38:42a
7:30:43:20a
SH
SeH
SH
5
6
7
A13:A125:A152:A53
A13:A126
55:45a
A13:A127:A172:A73
To explore the scope of the reaction, we studied the ef-
fects of the nucleophile on the kinetics and thermodynam-
ics of exchange. To this end, trithioorthoester A13 was com-
bined with thiols 2–6 in the presence of TFA (10 equiv)
(Scheme 2). Primary thiols such as phenylmethanethiol (2)
or hexane-1-thiol (3) gave compositions shifted toward
trithioorthoester products containing more-exchanged
units. Secondary and aromatic thiols, such as propane-2-
thiol (4) and 4-methylbenzenethiol 5, respectively, led to
nearly symmetrical statistical distributions of trithio-
orthoesters. The use of bulky adamantane-1-thiol (6) led to
the formation of only a single exchange product containing
one building block 6. The exchange kinetics were not no-
ticeably affected by thiol structures, because all the mix-
tures were equilibrated after one hour of reaction time.
Comparable equilibrium distributions were obtained after
24 hours when A13 was exposed to the nucleophiles in
CD3CN in the presence of FeCl3 (0.1 equiv) as catalyst (see
SI). These results are in agreement with those observed in
O,O,O-orthoester exchange, in which the equilibrium posi-
tion, but not the equilibration kinetics, depends on the size
of the nucleophile.10 Finally, inspired by recent studies on
(crossed) dichalcogenide exchange reactions,29 we investi-
gated the reaction of trimethyl trithioorthoformate A83
with benzeneselenol 7. After one hour, four signals in the
diagnostic trithioorthoester range were observed; these ap-
peared in a statistical proportion, showing the feasibility
and the reversibility of the reaction (after 24 hours, selenol
oxidation dominates the reaction outcome). To our knowl-
edge, this is the first example of selenol/trithioorthoester
exchange.
9:34:41:16a
9:38:44:9b
Scheme 2 Effect of the structure of the nucleophile on the distribution
of trithioorthoesters at equilibrium. Reaction conditions: A13 or A83
(37.5 mol), nucleophile (112.5 mol), TFA (375 mol), CDCl3 (Vtotal
:
750 L), r.t. Product ratios were determined by integration of 1H NMR
signals after 1 h. Hydrolysis was negligible (<2%) in all cases except for
thiol 6 (7%). a Exchange performed with A13 (CDCl3 or CD3CN). b Ex-
change performance with A83 (CDCl3). For full spectra, see Figures
S26–S36 (SI).
ous decrease in the concentration of TFA to 10 equivalents
(50 mM) slowed the exchange reaction considerably (96% of
A13 was present after 1 h).
To take advantage of the low boiling point of methane-
thiol (6 °C), A83 was treated with 4-methylbenzenethiol (5)
in the presence of excess TFA (10 equiv) under a smooth ni-
trogen stream while the temperature was increased from
r.t. to 40 °C and then to 60 °C to shift the equilibrium com-
pletely towards trithioorthoesters containing exchanged
side chains.30 The composition could indeed be shifted al-
most completely toward the formation of exchange product
A53 (Figure S38). This straightforward method might be
useful whenever a complete shift in the equilibrium toward
the product side is desired.
In a comparative study, we examined the hydrolytic sta-
bility of trimethyl trithioorthoformate [(S,S,S)-A83], its oxy-
gen-containing counterpart trimethyl orthoformate
[(O,O,O)-A93], and the dithioacetal bis(methylthio)methane
(AH82).31 Increasing amounts of TFA were added to solu-
tions containing each compound with one equivalent of
water, and the samples were analyzed by 1H NMR spectros-
copy after one hour of reaction (Figure 1; note the logarith-
mic scale of the x-axis).
While keeping the ratio of trithioorthoester A13 to thiol
2 at 1:3, and with a constant total amount of TFA, we next
investigated the effect of the trithioorthoester concentra-
tion (Figure S37). We found that a tenfold decrease in the
concentration of A13 from 50 mM to 5 mM did not affect
the equilibrium position. This indicates that trithioortho-
ester exchange might well be suited to experiments requir-
ing low concentrations of reactants. However, a simultane-
As expected, the trithioorthoester compound was con-
siderably more stable to hydrolysis than was the orthoester,
but was less stable than the dithioacetal. We found that the
addition of ten equivalents of TFA led to complete hydroly-
sis of (O,O,O)-A93, whereas (S,S,S)-A83 and AH82 were most-
ly stable. The addition of 100 equivalents of TFA was neces-
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–G

D
M. Bothe et al.
Cluster
Synlett
To answer this question, a set of trithioorthoesters suit-
able for crossover experiments were synthesized.38–41
Treatment of compounds A13 and B83 with TFA (10 equiv)
led to a Type I metathesis, as indicated by the appearance in
1
the H NMR spectrum of a set of signals corresponding to
the eight expected trithioorthoesters (Figure 2 and Table 2,
entry 1). As in the case of related orthoester metathesis,10
we believe that the generation of small quantities of free
thiol42 is responsible for the observed reactivity.
SPh
SPh
SPh
A13
SMe
SMe
SMe
B83
TFA
A128
B821
A182
B812
A83
B13
H
Me
CDCl3
A128
A182
B821
B812
A13
A83
B83
B13
0.08
Figure 1 Effects of increasing amounts of TFA on the hydrolysis of
orthoester (O,O,O)-A93, trithioorthoester (S,S,S)-A83, and dithioacetal
AH82. Reaction conditions: A93 or A83 or AH82 (37.5 mol), increasing
amounts of TFA [from 37.5 nmol (50 M) to 3.75 mmol (5.0 M)], CDCl3
(Vtotal: 750 L), r.t., 1 h; internal standard: toluene. For full spectra, see
Figures S39–S56 in the SI.
0.17
0.43
0.33
0.07
0.13
0.42
0.37
sary to hydrolyze(S,S,S)-A83 completely, whereas AH82 re-
mained stable under these conditions. These findings
indicate that in terms of hydrolytic stability, the trithio-
orthoester compound is located at an intermediate position
between the orthoester and dithioacetal compounds. Most
importantly, the results point towards faster exchange ver-
sus slower hydrolysis kinetics of trithioorthoesters: over a
one hour period, treatment of (S,S,S)-A83 with ten equiva-
lents of TFA led to complete equilibration (Figure S57), but
only to 30% hydrolysis. This observation explains why the
rigorous exclusion of water is not as essential for (S,S,S)-or-
thoester exchange as it is for the (O,O,O)-orthoester variant.
When trimethyl trithioorthoacetate (C83) was hydrolyzed
with ten equivalents of TFA, the hydrolysis ratio after one
hour was 93%, indicating that the same electronic effects as
previously reported account for differences in hydrolytic
stability (Figure S58).15e The observed differential suscepti-
bility to hydrolysis of orthoesters, trithioorthoesters, and
dithioacetals is relevant for the selective removal of protec-
tive groups.
8
7
6
5
4
3
2
1
0
chemical shift [ppm]
Figure 2 Trithioorthoester metathesis between A13 and B83 (top) and
1H NMR spectrum measured after one hour (bottom). The two dashed
boxes show the corresponding formate and acetoxy hydrogen atoms of
trithioorthoesters formed from A13 and B83. Reaction conditions: A13
(37.5 mol), B83 (37.5 mol), TFA (375 mol), CDCl3 (Vtotal: 750 L),
r.t., 1 h. Product distributions are given by normalized integral values
below the corresponding peaks for both sets. See also Table 2, entry 1
and the full spectra in Figure S59 in the SI.
To explore the generality of this finding, additional me-
tathesis reactions were carried out with other pairs of
trithioorthoesters. Combinations of trithioorthoesters con-
taining different aromatic substituents on sulfur (Table 2,
entry 2) or aromatic and primary alkyl substituents (en-
tries 3–5) led to statistical distributions, whereas trithio-
orthoesters containing aromatic and secondary thiol side
chains (entry 6) led to a slightly biased composition favor-
ing the starting aromatic trithioorthoester. These experi-
ments can also be regarded as competitive hydrolysis ex-
periments: throughout our investigations, we found that
hydrolysis of trithioorthoesters with alkyl residues on sul-
fur is faster than that for aromatic ones (compare Figure
S60 with Figures S61–S64; SI). Next, we investigated the in-
fluence of electron-withdrawing and electron-donating
substituents on trithioorthoester metathesis by conducting
metathesis reactions between tris(ethylthio)methane
[A(11)3] and trithioorthoesters C13 and D13, containing
electron-withdrawing and electron-donating groups, re-
spectively (Figures S65 and S66). After one hour, similar
In light of the shuttle catalysis concept,32 there has re-
cently been an increase in interest in exchange reactions
between molecules having the same kind of functional
group, i.e. Type 1 metathesis.33 Among the Type 1 metathe-
sis reactions that have been studied from the perspective of
dynamic covalent/combinatorial chemistry are disulfide,4,34
trithiocarbonate,35 thiazolidine,36 acetal,37 orthoester,10 and
dithioacetal exchange.17a We therefore wondered whether a
direct metathesis reaction between two trithioorthoesters
might be possible.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–G

E
M. Bothe et al.
Cluster
Synlett
equilibrium distributions for the formate species and a
comparable degree of hydrolysis were observed in both cas-
es (entries 7 and 8). However, in the case of D13, degrada-
tion of the starting material, presumably by ether cleavage43
occurred, representing a notable limitation of this method.
Finally, several attempts were made to carry out crossed
metathesis reactions between (S,S,S)-A13 and (O,O,O)-A93;
these were unsuccessful due to instantaneous hydrolysis of
O,O,O-orthoester, further confirming the previously ob-
served differences in stability (Figure S67).
ate these exchange reactions might be advantageous for ap-
plications in materials science, such as the (solvothermal)
synthesis of porous materials.
Funding Information
This work was supported by the Deutsche Forschungsgemeinschaft
(Emmy-Noether grant DE1830/2-1), Fondo para la Investigación
Científica y Tecnológica (FONCYT) (PICT2015-3574) and a CONICET –
BAYLAT Bilateral Cooperation Programme, Level I, Res. 733/15.
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In summary, we have described a methodological inves-
tigation of the exchange reaction between trithioortho-
esters and thiols, as well as the direct trithioorthoester me-
tathesis reaction. These reactions have two appealing prop-
erties in the context of other reversible covalent reactions.
First, the tripodal structure of S,S,S-orthoesters provides an
elegant entry to sulfur-rich three-dimensional architec-
tures with possible applications in the removal of heavy-
metal ions. Second, the harsh conditions necessary to initi-
Acknowledgment
We acknowledge the assistance of Margit Lang with elemental analy-
sis.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690992.
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Table 2 Metathesis between Different Trithioorthoesters
References and Notes
SR1
SR1
SR1
HR1
SR2
SR2
SR2
XR2
HR12R2
XR22R1
HR1R2
HR2
XR1
2
2
3
acid
H
X
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Chem. Soc. 2001, 123, 8876.
XR2R1
3
3
3
substrate 1
substrate 2
substrates 1 and 2:
SPh
S(CH2)2Ph
SMe
SMe H
SMe
B83
SPhMe
SMe
H
S(CH2)2Ph
S(CH2)2Ph
A(10)3
H
SPh Me
SPh
A13
SPhMe
H
SMe
SMe
A83
SPhMe
A53
SEt
SEt H
SiPr
SiPr F
SiPr
A43
SPh
SPh
SPh
SPh
H
SPh MeO
SPh
SEt
C13
D13
A(11)3
Entry
Substrate 1
Substrate 2
Reaction outcome
HR1
XR2
HR13/HR12R2/HR1R22/HR2
thioesters (hydrolysis)a
/
3
3
3
1b
2c
3c
4d
5b
6c
7b
8b
17:43:33:7:–
A13
B83
(7) Ulrich, S.; Boturyn, D.; Marra, A.; Renaudet, O.; Dumy, P. Chem.
Eur. J. 2014, 20, 34.
A13
A53
13:36:36:13:2
13:35:36:13:3
10:36:37:11:6
12:34:33:10:12
18:28:30:12:12
3:21:42:28:6
(8) (a) Mastalerz, M. Acc. Chem. Res. 2018, 51, 2411. (b) Ong, W. J.;
Swager, T. M. Nat. Chem. 2018, 10, 1023. (c) Guan, X.; Li, H.; Ma,
Y.; Xue, M.; Fang, Q.; Yan, Y.; Valtchev, V.; Qiu, S. Nat. Chem.
2019, 11, 587. (d) Ono, K.; Iwasawa, N. Chem. Eur. J. 2018, 24,
17856. (e) Ding, H.; Chen, R.; Wang, C. In Dynamic Covalent
Chemistry: Principles, Reactions, and Applications; Zhang, W.;
Jin, Y., Ed.; Wiley: New York, 2018, 165. (f) Feng, X.; Ding, X.;
Jiang, D. Chem. Soc. Rev. 2012, 41, 6010.
A53
A(10)3
A83
A13
A13
A(11)3
A43
A53
A(11)3
A(11)3
C13
D13
ether cleavage
(9) (a) Frei, P.; Hevey, R.; Ernst, B. Chem. Eur. J. 2019, 25, 60. (b) Liu,
Y.; Lehn, J.-M.; Hirsch, A. K. H. Acc. Chem. Res. 2017, 50, 376.
(c) Mondal, M.; Hirsch, A. K. H. Chem. Soc. Rev. 2015, 44, 2455.
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(11) Orrillo, A. G.; Escalante, A. M.; Furlan, R. L. E. Chem. Eur. J. 2016,
22, 6746.
a Product ratios were determined by integration of 1H NMR signals after 1 h
of reaction; ‘–’ indicates not detected. For full spectra, see Figures S60–S67
in the SI.
b Reaction conditions: HR13 (37.5 mol), XR23 (37.5 mol), TFA (375 mol),
CDCl3 (Vtotal: 750 L), r.t.
c Reaction conditions: HR13 (15 mol), XR23 (15 mol,), H2SO4-saturated
CDCl3, (Vtotal: 500 L), r.t.
d Reaction conditions: HR13 (37.5 mol), XR23 (37.5 mol), FeCl3
(3.75 mol), CD3CN (Vtotal: 750 L), r.t.
(12) Brachvogel, R.-C.; von Delius, M. Eur. J. Org. Chem. 2016, 3662.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–G

F
M. Bothe et al.
Cluster
Synlett
(13) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed; Wiley: New York, 1991. (b) Kocienski, P. J. Pro-
tecting Groups, 3rd ed; Thieme: Stuttgart, 1994.
(30) (a) DeWolfe, R. H. Synthesis 1974, 153. (b) Mochel, W. E.; Agre,
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M.; Ramström, O. Chem. Commun. 2010, 46, 8469.
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Matyjaszewski, K. Angew. Chem. Int. Ed. 2011, 50, 1660.
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Johnson, D. W. Chem. Eur. J. 2019, DOI: 10.1002/chem.201903854.
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2015, 6, 7129. (b) Brachvogel, R.-C.; Maid, H.; von Delius, M. Int.
J. Mol. Sci. 2015, 16, 20641. (c) Shyshov, O.; Brachvogel, R.-C.;
Bachmann, T.; Srikantharajah, R.; Segets, D.; Hampel, F.; Puchta,
R.; von Delius, M. Angew. Chem. Int. Ed. 2017, 56, 776. (d) Wang,
X.; Shyshov, O.; Hanževački, M.; Jäger, C. M.; von Delius, M.
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von Delius, M. Chem. Sci. 2018, 9, 4785.
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A. G.; Furlan, R. L. E. Chem. Sci. 2019, DOI: 10.1039/C9SC02166C.
(18) Lebel, H.; Grenon, M. In Science of Synthesis, Vol. 22; Charette, A.
B., Ed.; Thieme: Stuttgart, 2005, 749.
(38) Tris[(4-methylbenzene)thio]methane
(A53),
tris(isoprop-
(19) (a) Seebach, D.; Geiß, K.-H.; Beck, A. K.; Graf, B.; Daum, H. Chem.
Ber. 1972, 105, 3280. (b) Barsamian, A. L.; Blakemore, P. R.
Organometallics 2012, 31, 19.
ylthio)methane (A43), and tris[(2-phenylethyl)thio]methane
[A(10)3] were synthesized by a modified version of the reported
procedure; see Ref. 20.
(20) Cao, Y.-J.; Lai, Y.-Y.; Cao, H.; Xing, X.-N.; Wang, X.; Xiao, W.-J.
Can. J. Chem. 2006, 84, 1529.
Tris[(4-methylbenzene)thio]methane (A53); Typical Proce-
dure
(21) Seebach, D. Angew. Chem. 1967, 79, 468.
CHCl3 (1.48 g, 12.4 mmol, 1.0 equiv), DBU (9.79 g, 64.3 mmol,
5.2 equiv), and 4-methylbenzenethiol (6.14 g, 49.4 mmol,
4.0 equiv) were dissolved in anhyd THF (10 mL), and the
mixture was heated to 100 °C for 24 h under N2 in a pressure
tube. The mixture was cooled, H2O (30 mL) was added, and the
resulting mixture was extracted with Et2O (2 × 50 mL). The
combined organic phases were washed with brine (50 mL),
dried (Na2SO4), filtered, and concentrated on a rotary evapora-
tor. The residue was purified by column chromatography [silica
gel, PE–CH2Cl2 (100:0 to 80:20)]. Subsequent crystallization
(22) (a) Tlach, B. C.; Tomlinson, A. L.; Ryno, A. G.; Knoble, D. D.;
Drochner, D. L.; Krager, K. J.; Jeffries-EL, M. J. Org. Chem. 2013,
78, 6570. (b) Corey, E. J.; Seebach, D. Angew. Chem. 1965, 77,
1134. (c) Gröbel, B.-T.; Seebach, D. Synthesis 1977, 357.
(23) For syntheses of dithioacetals see: (a) Firouzabadi, H.; Iranpoor,
N.; Hazarkhani, H. J. Org. Chem. 2001, 66, 7527. (b) Tazaki, M.;
Takagi, M. Chem. Lett. 1979, 8, 767.
(24) (a) Moulin, E.; Cormos, G.; Giuseppone, N. Chem. Soc. Rev. 2012,
41, 1031. (b) Li, J.; Nowak, P.; Otto, S. J. Am. Chem. Soc. 2013, 135,
9222. (c) Jin, Y.; Yu, C.; Denman, R. J.; Zhang, W. Chem. Soc. Rev.
2013, 42, 6634.
(25) (a) Eckert, F.; Leito, I.; Kaljurand, I.; Kütt, A.; Klamt, A.;
Diedenhofen, M. J. Comput. Chem. 2009, 30, 799. (b) Kütt, A.;
Selberg, S.; Kaljurand, I.; Tshepelevitsh, S.; Heering, A.; Darnell,
A.; Kaupmees, K.; Piirsalu, M.; Leito, I. Tetrahedron Lett. 2018,
59, 3738. (c) Paenurk, E.; Kaupmees, K.; Himmel, D.; Kütt, A.;
Kaljurand, I.; Koppel, I. A.; Krossing, I.; Leito, I. Chem. Sci. 2017,
8, 6964.
(26) Pruckmayr, G.; Wu, T. K. Macromolecules 1978, 11, 662.
(27) (a) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. J. Am. Chem. Soc.
2000, 122, 12063. (b) Delius, M.; Geertsema, E. M.; Leigh, D. A.;
Slawin, A. M. Org. Biomol. Chem. 2010, 8, 4617.
(28) (a) Schmittel, M.; Levis, M. Synlett 1996, 315. (b) Kamal, A.;
Laxman, E.; Reddy, P. S. M. M. Synlett 2000, 1476. (c) Gauthier, J.
Y.; Martins, E. O.; Young, R. N.; Zamboni, R. J. Synlett 2002, 984.
(d) Kumar, V.; Dev, S. Tetrahedron Lett. 1983, 24, 1289.
(e) Patney, H. K. Tetrahedron Lett. 1991, 32, 2259. (f) Tamami, B.;
Borujeny, K. P. Synth. Commun. 2003, 33, 4253.
(29) (a) Rasmussen, B.; Sørensen, A.; Gotfredsen, H.; Pittelkow, M.
Chem. Commun. 2014, 50, 3716. (b) Ji, S.; Cao, W.; Yu, Y.; Xu, H.
Angew. Chem. Int. Ed. 2014, 53, 6781. (c) Chuard, N.; Poblador-
Bahamonde, A. I.; Zong, L.; Bartolami, E.; Hildebrandt, J.;
Weigand, W.; Sakai, N.; Matile, S. Chem. Sci. 2018, 9, 1860.
(d) Bartolami, E.; Basagiannis, D.; Zong, L.; Martinent, R.;
Okamoto, Y.; Laurent, Q.; Ward, T. R.; Gonzalez-Gaitan, M.;
Sakai, N.; Matile, S. Chem. Eur. J. 2019, 25, 4047. (e) Steinmann,
D.; Nauser, T.; Koppenol, W. H. J. Org. Chem. 2010, 75, 6696.
(CH2Cl2) gave A53 as
a white solid; yield: 2.10 g (44%,
5.48 mmol); Rf = 0.3 (silica gel, PE–CH2Cl2, 80:20, UV254).
1H NMR (400 MHz, 298 K, CDCl3):  = 7.43–7.41 (m, 6 H), 7.17–
7.15 (m, 6 H). 5.32 (s, 1 H), 2.37 (s, 9 H). 13C NMR (100 MHz,
298 K, CDCl3):  = 138.5, 133.4, 130.4, 129.6, 65.9, 21.2. Anal.
calcd for C22H22S3: C, 69.07; H, 5.80; S, 25.14. Found: C, 69.00; H,
5.93; S, 25.22.
(39) Synthesis of 1,1,1-Tris(methylthio)ethane (B83)
This was synthesized by a modified version of the reported pro-
cedure.21 Trimethyl trithioorthoformate (A83; 5.28 g,
34.2 mmol, 1.0 equiv) was dissolved in anhyd THF (50 mL) and
cooled to –78 °C under N2. A 2.5 M solution of BuLi in hexane
(20.5 mL, 51.3 mmol, 1.5 equiv) was added dropwise and the
mixture was stirred for 80 min. MeI (12.13 g, 85.5 mmol,
2.5 equiv) was added dropwise, and the mixture was allowed to
slowly warm to r.t. overnight. Et2O (100 mL) was added and the
mixture washed with aq Na2S2O3 (50 mL). The combined
extracted organic phases were washed with brine (50 mL), sep-
arated, dried (Na2SO4), filtered, and concentrated on a rotary
evaporator. Distillation through a short Vigreux column (oil-
bath temperature: 120 °C; pressure: 7 mbar; bp 70 °C) gave a
colorless oil; yield: 4.55 g (79%, 27.0 mmol); Rf = 0.7 (silica gel,
PE–EtOAc, 95:5, UV254).
1H NMR (400 MHz, 298 K, CDCl3):  = 2.16 (s, 9 H), 1.87 (s, 3 H).
13C NMR (100 MHz, 298 K, CDCl3):  = 64.3, 28.3, 13.6. Anal.
calcd for C5H12S3: C, 35.68; H, 7.19; S, 57.14. Found: C, 37.04; H,
7.26; S, 57.81.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–G

G
M. Bothe et al.
Cluster
Synlett
(40) 1-[Bis(phenylthio)methyl]-4-fluorobenzene (CH12) and 1-[bis-
(phenylthio)methyl]-4-methoxybenzene (DH12) were synthe-
sized by a modified version of the reported procedure; see Ref
23a.
(2.49 g. 21.4 mmol, 2.8 equiv) were dissolved in anhyd THF
(15 mL) under N2. The solution was cooled to –78 °C and a 2.5 M
solution of BuLi in hexane (4.29 mL, 10.7 mmol, 1.4 equiv) was
added dropwise. The mixture was stirred for 80 min at –78 °C, a
solution of diphenyl disulfide (5.02 g, 23.0 mmol, 3.0 equiv) in
anhyd THF (10 mL) was added slowly, and the mixture was
allowed to warm to r.t overnight. The mixture was then cooled
to 0 °C and the reaction was carefully quenched with several
drops of H2O. The resulting mixture was extracted with Et2O
(2 × 70 mL), washed with H2O (100 mL) and brine (100 mL), and
the organic layer was separated, dried (Na2SO4), filtered, and
concentrated on a rotary evaporator. Purification by flash
column chromatography [silica gel, PE–CH2Cl2 (100:0 to 80:20)]
and subsequent crystallization from PE–CH2Cl2 gave C13 as a
white solid; yield: 2.30 g (69%, 5.30 mmol); Rf = 0.32 (silica gel,
PE–CH2Cl2, 80:20, UV254).
1-[Bis(phenylthio)methyl]-4-fluorobenzene (CH12); Typical
Procedure
Iodine (1.29 g, 5.10 mmol, 0.1 equiv) was added to a solution of
4-fluorobenzaldehyde (6.30 g, 50.8 mmol, 1.0 equiv) and ben-
zenethiol (11.7 g, 107 mmol, 2.1 equiv) in CHCl3 (75 mL), and
the resulting solution was stirred overnight at r.t. When the
reaction was complete, excess I2 was quenched with 0.1 M aq
Na2S2O3 (100 mL). The organic phase was separated, washed
with H2O (100 mL), dried (Na2SO4), filtered, and concentrated
on a rotary evaporator. Purification by flash column chromatog-
raphy [silica gel, PE–CH2Cl2 (95:5 to 80:20)] and subsequent
crystallization from petroleum ether gave CH12 as a white solid;
yield: 12.8 g (77%, 39.2 mmol). Rf = 0.30 (silica gel, PE–CH2Cl2,
80:20, UV254).
1H NMR (500 MHz, 298 K, CD2Cl2):  = 7.68–7.60 (m, 2 H), 7.34–
7.18 (m, 15 H), 6.90–6.82 (m, 2 H). 13C NMR (125 MHz, 298 K,
1H NMR (500 MHz, 298 K, CD2Cl2):  = 7.42–7.36 (m, 6 H), 7.34–
7.28 (m, 6 H), 7.03–6.99 (m, 2 H), 5.53 (s, 1 H). 13C NMR
(125 MHz, 298 K, CD2Cl2):  = 162.7 (d, 1JCF = 246.5 Hz), 135.9 (d,
CD2Cl2):  = 162.6 (d, JCF = 248.0 Hz), 135.7 (d, JCF = 3.1 Hz),
1
4
3
135.0, 133.1, 131.2 (d, JCF = 8.3 Hz), 129.0, 128.7, 114.9 (d,
2JCF = 21.6 Hz), 76.7. Anal. calcd for C25H19FS3: C, 69.09; H, 4.41;
S, 22.13. Found: C, 68.96; H, 4.61; S, 22.11.
3
4JCF = 3.2 Hz), 134.5, 132.9, 131.0 (d, JCF = 8.3 Hz), 129.3, 128.3,
114.6 (d, 2JCF = 21.8 Hz), 59.6. Anal. calcd for C19H15FS2: C, 69.91;
H, 4.63; S, 19.64. Found: C, 70.05; H, 4.84; S, 20.05.
(41) 1-Fluoro-4-[tris(phenylthio)methyl]benzene (C13) and 1-
methoxy-4-[tris(phenylthio)methyl]benzene (D13) were syn-
thesized by a modified version of the reported procedure; see
Ref 22a.
(42) In the case of O,O,O-orthoesters, hydrolysis is presumably the
source of the free nucleophile, whereas with S,S,S-orthoesters,
our observation of a bright-pink color might indicate that a
thiol/thionium pair is formed, even without participation of
water.
(43) (a) Fan, Y.; An, Z.; Pan, X.; Liu, X.; Bao, X. Chem. Commun. 2009,
7488. (b) Node, M.; Nishide, K.; Fuji, K.; Fujita, E. J. Org. Chem.
1980, 45, 4275.
1-Fluoro-4-[tris(phenylthio)methyl]benzene (C13); Typical
Procedure
Dithioacetal DH12 (2.49 g, 7.66 mmol, 1.0 equiv) and TMEDA
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–G