Stable and easily available sulfide surrogates allow a stereoselective activation of alcohols

Article abstract of DOI:10.1039/d1sc01602d

Isothiouronium salts are easily accessible and stable compounds. Herein, we report their use as versatile deoxasulfenylating agents enabling a stereoselective, thiol-free protocol for synthesis of thioethers from alcohols. The method is simple, scalable and tolerates a broad range of functional groups otherwise incompatible with other methods. Late-stage modification of several pharmaceuticals provides access to multiple analogues of biologically relevant molecules. Performed experiments give insight into the reaction mechanism.

Full text of DOI:10.1039/d1sc01602d

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Stable and easily available sulfide surrogates allow
a stereoselective activation of alcohols†
Cite this: Chem. Sci., 2021, 12, 7770
ab
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Jeremy Merad,
´ ´
‡
Jan Matyasovsky,‡a Tobias Stopka,‡a Bogdan R. Brutiu,§a
´ ˇ ´
Alexandre Pinto,§a Martina Dreschera and Nuno Maulide
a
*
Isothiouronium salts are easily accessible and stable compounds. Herein, we report their use as versatile
deoxasulfenylating agents enabling a stereoselective, thiol-free protocol for synthesis of thioethers from
alcohols. The method is simple, scalable and tolerates a broad range of functional groups otherwise
incompatible with other methods. Late-stage modification of several pharmaceuticals provides access to
multiple analogues of biologically relevant molecules. Performed experiments give insight into the
reaction mechanism.
Received 20th March 2021
Accepted 28th April 2021
DOI: 10.1039/d1sc01602d
rsc.li/chemical-science
thioethers via halides proceeds with retention of conguration
due to twofold inversion. Thio-Mitsunobu reaction efficiently
Introduction
converts alcohols into thioethers, while requiring a combina-
tion of two stoichiometric activating agents (Scheme 1A). Again
the reaction generally proceeds with stereochemical inversion
Sulfur is the 5th most abundant element (aer C, H, O and N) in
pharmaceuticals and agrochemicals. Indeed, more than 20% of
recently approved drugs contain at least one sulfur atom.1 This
widespread occurrence is likely due to this element's oxidation-
state versatility, from thioethers and sulfonium salts to sulfox-
ides, sulfones and their derivatives.
In addition to being constitutive of multiple bioactive
molecules,1 thioethers (or suldes) readily participate in
substitution and cross-coupling reactions.2 Thus, synthetic
approaches allowing the incorporation of divalent sulfur have
been vigorously investigated during past decades.3 A traditional
SN2-type approach is still the method of choice for most
synthetic applications. In fact, catalytic nucleophilic substitu-
tions have recently emerged as alternatives to traditional
approaches,4 relying on in situ activation of (secondary) alco-
hols, ultimately leading to amines, esters, azides or halides with
high selectivities.5 Classical strategies, however, require prior
functional group interconversion (FGI) when alcohols and
thiols are considered as the reaction substrates, effectively
employing two linear steps to achieve this transformation
(Scheme 1A). Reactions of chiral alcohols in such a way gener-
ally provide the desired thioethers with clean inversion of
conguration (unless SN1-type processes operate, such as with
benzylic, allylic or tertiary alcohols under acid catalysis).6
Alternatively, the stepwise conversion of alcohols into
a
¨
Department of Organic Chemistry, University of Vienna, Wahringer Straße 38, 1090
Vienna, Austria. E-mail: nuno.maulide@univie.ac.at; Web: http://maulide.univie.ac.at
b
´
Univ. Lyon, Universite Claude Bernard Lyon 1, CNRS CPE Lyon, INSA Lyon, ICBMS,
ˆ
UMR 5246 Bat. Lederer, 1 rue Victor Grignard, 69622 Villeurbanne, France
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1sc01602d
‡ These authors contributed equally to this manuscript.
§ These authors contributed equally to this manuscript.
Scheme 1 Synthetic strategies to access thioethers from alcohols.
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of conguration for secondary alcohols.7 However, aliphatic
thiols are mostly considered unsuitable for the Mitsunobu
reaction, as the thiol group itself is not acidic enough for the
reaction to take place.7b Additionally, there are noteworthy
functional group tolerance issues in Mitsunobu-type protocols
(e.g. azides or peroxides are incompatible with the phosphine
reactants typical of Mitsunobu procedures). Finally, both of
these methods employ practically unsuitable thiols as the
nucleophilic components. Indeed, more than being notoriously
malodorant compounds and susceptible to oxidation, very few
thiols are commercially available, severely limiting the diversity
of readily accessible thioether derivatives.
Isothiouronium salts are odorless, stable, easily accessible
compounds, which represent potentially interesting activators
for the hydroxyl group. Indeed, Kajigaeshi published a general
one-pot two-step convergent strategy for preparation of thio-
ethers from primary alcohols utilizing isothiouronium salts
(Scheme 1B).8 This work showcases 12 examples with moderate
yields, but establishes precedence for using thiouronium salts.
Proline-derived cyclic iminium salts were used in a similar work
in an attempt to kinetically resolve secondary benzylic alcohols
with mediocre results (Scheme 1C).9 Related iminium salts were
used for preparation of alkyl(tetrazolyl)suldes using an exog-
enous aryl thiol or for deoxygenative iodination of alcohols,
with notorious erosion of stereochemical purity of enantiopure
starting material.10 Analogous reagents have also found limited
applications in the syntheses of 2-pyridinethioesters,11a Barton's
esters,11b N-thioalkenyl and N-(o-thio)aryl-benzimidazol-2-
ones.11c Thioimidazolinium salts have been used extensively for
the preparation of suldes or as cyanation agents.12 Hopkinson
recently demonstrated that benzothiazolium reagents can be
used in triuoromethyl(alkyl) sulde synthesis or uorinated
thioester synthesis.13 However, to the best of our knowledge,
a successful chiral thioether synthesis using isothiouronium
Scheme 2 Thioetherification of optically active secondary alcohols:
impact of the counteranion. aReactions were performed at rt for 2 h
with alcohol (0.30 mmol, 1.0 equiv.), isothiouronium salt (0.30 mmol,
1.0 equiv.) and BTMG (0.33 mmol, 1.1 equiv.) in CHCl3 (0.14 M
concentration). bReaction conditions: AgSbF6, H2O (0.35 M), rt, 30 min,
84% yield. Yields refer to isolated products. BTMG ¼ 2-tert-butyl-
1,1,3,3-tetramethylguanidine.
While it was tempting to interpret this result as a consequence
of simultaneous operation of SN2 and SN1-type pathways, we
also wondered if the counterion Xꢀ of the isothiouronium
reactant 1a might play a non-innocent role.9 Indeed, bromide is
a competent nucleophile while also serving as a good leaving
group, an ability best expressed in Finkelstein and related
reactions.15 Therefore, exchanging the bromide counteranion of
isothiouronium 1a for the less nucleophilic hexa-
uoroantimonate using AgSbF6 in water gave the salt 1aa in
84% yield. Repeating the deoxysulfenylation reaction with 1aa
resulted in excellent inversion of conguration (96% ee), while
the yield of the reaction remained unchanged. Additionally, the
stereochemical outcome of the reaction was the same utilizing
either tetrauoroborate (1ab, 96% ee) or hexauorophosphate
thiouronium salts (1ac, 97% ee), while the overall reaction
yields dropped slightly.14 Similarly excellent results were
observed when related isothiouronium antimonate 1bb was
employed (product 2b, 73% yield, 97% ee). Other chiral
secondary alcohols were then investigated. A slight drop in ee
was observed for naphtyl-bearing substrate 2c (82% ee), while
the presence of electron-withdrawing groups led to a product
with >99% ee (2d). Excellent results were also obtained with
propargylic substrates (2e and 2f, >97% ee). A successful dia-
stereoselective thioetherication of an allylic substrate 2g
provided the desired thioether as a single diastereomer when
isothiouronium 1bb was used (compared to increased amounts
of a second diastereomer, when salt 1b was used). Finally, to
unambiguously verify SN2-type inversion of conguration, thi-
oether 2h was prepared in 67% yield and >98% ee. The optical
rotation was in good agreement with the value reported in the
literature ([a]2D0 ¼ ꢀ57.4 (c ¼ 1, CHCl3); lit. [a]2D0 ¼ ꢀ54.7 (c ¼ 1,
CHCl3)).16,17
salts involving
a conguration inversion of enantiopure
secondary alcohols has not been reported. Additionally, we
believe that the straightforward reactivity of uronium salts
could prove advantageous in a range of synthetic contexts
ranging from late-stage modication to enabling preparation of
thioethers carrying sensitive functional groups. Herein, we
report our ndings in all of the above-mentioned endeavours
(Scheme 1D).
Results and discussion
Taking Kajigaeshi's work8 into consideration, it is reasonable to
assume that the thioetherication of most primary alcohols
involves an SN2-type mechanism. However, it remained unclear
how such a reaction manifold would hold for more hindered
substrates. In particular, the possibility of SN1/SN2 mechanistic
competition and its impact on stereocontrol appeared to be
potential pitfalls, especially for secondary benzylic/allylic alco-
hols. Aer a survey of reaction conditions,14 deoxasulfenylation
using the thiouronium bromide 1a was performed on enantio-
pure (>99% ee) (R)-1-phenylethan-1-ol (Scheme 2) in order to
discriminate between these two possible mechanisms. Thio-
ether 2a was obtained in 71% yield and a moderate 73% ee.
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Scheme 3 Late-stage modification of various drugs. aReactions were
performed at rt for 2 h with the corresponding drug (0.30 mmol, 1.0
equiv.), isothiouronium salt (0.30 mmol, 1.0 equiv.) and BTMG
(0.33 mmol, 1.1 equiv.) in CHCl3 (0.14 M concentration). Yields refer to
isolated products. bThio-Mitsunobu conditions: dihydroartemisinin
(0.2 mmol, 1.0 equiv.), thiol (0.2 mmol, 1.0 equiv.), PPh3 (0.3 mmol, 1.5
equiv.), diethyl azodicarboxylate (0.3 mmol, 1.5 equiv.) in THF (at 0.1 M
concentration). Yield 0%.
The synthetic potential of isothiouronium salts in deox-
asulfenylation reactions was then investigated in late-stage
derivatisation (Scheme 3). Indeed, several clinically used
drugs carry free hydroxyl groups and we were eager to probe
these salts in such challenging, functional-group-rich contexts.
As shown, several nitrogen-containing bioactive compounds
such as metronidazole (antibiotic), quetiapine (antipsychotic),
atropine (antispasmodic) and trityl-losartan (antihypertensive) were
smoothly converted to their corresponding thioethers (3a–e). The
modication of prednisone (3f) and corticosterone (3g) proved to be
perfectly chemoselective despite the presence of reactive Michael
acceptors (enones) and multiple hydroxyl groups: the result with
corticosterone (3g) additionally suggests useful chemoselectivity
between primary and secondary alcohols. The derivatization of
dihydroartemisinin (3h) is particularly relevant, since standard thio-
Mitsunobu conditions led only to decomposition of this redox-
sensitive substrate possessing cyclic peroxide. Notably, it has been
shown that C-10 thioethers derived from artemisinine display
signicant anticancer activity.18
Scheme 4 Thioetherification scope. aReactions were performed at rt
for 2 h with alcohol (0.30 mmol, 1.0 equiv.), isothiouronium salt
(0.30 mmol, 1.0 equiv.) and BTMG (0.33 mmol, 1.1 equiv.) in CHCl3
(0.14 M concentration). Yields refer to isolated products. bOpen-flask
conditions. cGram scale. dBTMG
¼
2.2 equiv. eThio-Mitsunobu
conditions: azidoalcohol (0.2 mmol, 1.0 equiv.), thiol (0.2 mmol, 1.0
equiv.), PPh3 (0.3 mmol, 1.5 equiv.), diethyl azodicarboxylate
(0.3 mmol, 1.5 equiv.) in THF (at 0.1 M concentration). Yield 0%.
fReaction time 14 h (at 1 M concentration).
well as on a gram scale without any erosion of the yield. b-
Citronellol led to the desired thioether 4c in 75% yield. Deox-
asulfenylation of several allylic (4d–f), propargylic (4g) and a-
(heteroaryl) alcohols (4h–j) occurred smoothly with perfect
regioselectivity (no products resulting from SN20-type reaction
were observed). Pleasingly, the transformation remains efficient
in the presence of phenols (4k) and azides (4l). Such substrates
are indeed challenging in classical Mitsunobu reactions, due to
the nucleophilicity of phenoxide anion and the fast reaction
between azides and phosphines. Preparation of 4l was never-
theless attempted under thio-Mitsunobu conditions, showing
no product being formed. Moreover, a silylether is also tolerated
(4m). The methodology was successfully extended to secondary
alcohols to afford the corresponding thioethers 4n and 4o in
Finally, we wanted to extend the portfolio of substrates to
other primary and secondary alcohols (Scheme 4).8 Thioether-
ication of diversely substituted alcohols with salt 1b efficiently
delivered products 4a and 4b. In order to probe robustness and
reproducibility, the synthesis of thioether 4a was also per-
formed with technical solvents, under open-ask conditions as
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alcohols. Stereoinversion of chiral secondary alcohols was
shown to be counteranion dependent, leading to clean inver-
sion of conguration. Late-stage modication of several bio-
logically relevant substances is enabled by this procedure. This
method offers straightforward access to thioethers and consti-
tutes a valuable alternative to the established methods. This is
particularly visible on substrates otherwise incompatible with
thio-Mitsunobu reaction protocols. Finally, our ndings
provided mechanistic insight into the reaction. We believe that
these reactions of isothiouronium salts might be of interest as
rapid and mild methods for conjugation.
Author contributions
The work was conceptualized by J. Merad and N. M. The rst
dra of the manuscript was written by J. Merad and J.
Scheme 5 Mechanistic insight into thioetherification of alcohols using
isothiouronium salts.
ˇ
Matyasovsk´y, all of the authors contributed to the nal version
of the manuscript. The experiments were performed by J.
satisfying yields. Aliphatic secondary alcohols did not react as
efficiently, providing the desired sulde in 33% yield using
slightly modied reaction conditions (4p). We next turned our
attention to the structure of the transferable S-containing resi-
dues (Scheme 4). This switch led us to prepare thioethers 4a, 4b
and 4d by forging the opposite C–S bond. This demonstrates the
versatility of this approach, enabling access to the same product
by either of two disconnections depending on the accessibility
of the starting materials. Thioethers incorporating methyl (4q),
isopropyl (4r), and propargyl (4s) groups were prepared in good
yields. Also, several allylic thiols were transferred to access
polyunsaturated compounds 4t–v. However, no conversion was
observed with tertiary alcohols (5a), likely due to high steric
hindrance. Additionally, the reaction did not result in desired
products when either hydroxyalkyl halide (5b) or crotonate
derived alcohol (5c) were employed as substrates.19
ˇ
Merad, J. Matyasovsk´y, T. S., B. R. B., A. P. and M. D. N. M. was
involved in securing funding, manuscript editing and nalizing
and overall supervision of the project.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
Generous support of this research by the EU (VINCAT CoG
682002 to N. M.), the Austrian Science Fund (P32607) and
Covestro AG is acknowledged. We are grateful to the University
of Vienna for its continued and generous support of our
research programs.
The result of the reaction of alcohol 5b, namely the formation
of thioether 6 and dibromide 7 (cf. Scheme 5) resulting from two
consecutive substitutions, prompted us to reevaluate the reaction
Notes and references
ꢀ
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