Copper-Catalyzed Oxyalkynylation of C-S Bonds in Thiiranes and Thiethanes with Hypervalent Iodine Reagents

Article abstract of DOI:10.1021/acs.orglett.9b04157

We report the oxyalkynylation of thiiranes and thietanes using ethynylbenziodoxolone reagents (EBXs) to readily access functionalized building blocks bearing an alkynyl, a benzoate, and an iodide group. The reaction proceeds with high atom efficiency most

Full text of DOI:10.1021/acs.orglett.9b04157

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Oxyalkynylation of C−S Bonds in Thiiranes and
Thiethanes with Hypervalent Iodine Reagents
Julien Borrel,† Guillaume Pisella,† and Jerome Waser*
́
́
Laboratory of Catalysis and Organic Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de
Lausanne, EPFL SB ISIC LCSO, BCH 1402, 1015 Lausanne, Switzerland
S
* Supporting Information
ABSTRACT: We report the oxyalkynylation of thiiranes and thietanes using ethynylbenziodoxolone reagents (EBXs) to
readily access functionalized building blocks bearing an alkynyl, a benzoate, and an iodide group. The reaction proceeds with
high atom efficiency most likely through an alkynyl−episulfonium intermediate. The transformation is copper-catalyzed and
compatible with a large array of thiiranes and thietanes.
train-promoted ring opening of small saturated heterocycles
they could be used for the generation of an alkynylated
S(three- and four-membered rings) is an attractive way to episulfonium intermediate from the corresponding thiirane
(Scheme 1c).
access 1,2- or 1,3-functionalized building blocks. This approach
has been thoroughly investigated for oxygen and nitrogen
heterocycles including epoxides,1 aziridines,2 and oxetanes.3 In
comparison, this strategy has been less explored for the sulfur
analogues, thiiranes1,4 and thietanes,5 despite the importance of
sulfur-containing molecules.6 The more reactive thiiranium ion
is a well-described intermediate and has been recently involved
in the development of highly enantioselective transformations.7
Its formation often relies on the reaction of alkenes with an
electrophilic sulfur source or the nucleophilic substitution of a
leaving group next to a thioether (Scheme 1a). Their generation
by reaction of an electrophile with the sulfur atom is unusual.7a,b
A few recent reports explored this method of activation either by
alkylation for a subsequent ring expansion8 or by arylation to
induce a ring opening.9
In contrast, the generation of a noncyclic sulfonium ion by
alkylation of thioethers is a well-known method.7b,10 To the best
of our knowledge, only one report published by Ochiai and co-
workers presented their formation by alkynylation (Scheme
1b).11 Ethynyliodonium salts were used to synthesize alkynyl-
(diphenyl)sulfonium salts. When thioanisole (1) was alkyny-
lated with iodonium 2, sulfonium intermediate A reacted with an
excess of 1 to give thioalkyne 4. Later, a mild and selective
protocol for the formation of thioalkynes was proposed by our
group using thiols and ethynylbenziodoxolones (EBX).12
Iodonium salts were not suitable for this transformation, as
they led to the formation of disulfides. Considering the high
sulfur affinity of hypervalent iodine reagents, we anticipated that
EBX reagents were expected to be superior in this reaction, as
their activation using metal catalysis is well-established13 and the
released benzoate 5 can act directly as a nucleophile for the
formed episulfonium, resulting in a highly atom-economical
process.14 The obtained β-hydroxy sulfide motif is found in a
large array of bioactive molecules15 and is mostly accessed by
epoxide ring opening. The reverse approach exploiting thiirane
chemistry has been less developed,16 except for the acetolysis of
carbohydrate bearing a thiirane at the C5−C6 position.17
Herein, we report the successful copper-catalyzed oxy-
alkynylation of thiiranes using EBX reagents. The reaction
probably proceeds through the formation of an episulfonium
intermediate and furnishes the desired β-hydroxy sulfides in
moderate to good yields using operationally simple conditions.
The methodology was also applied to the ring opening of
thietanes to access 1,3-difunctionalized products.
We started our investigation by optimizing the reaction
conditions using TIPS-EBX (6a) and the commercially available
cyclohexene sulfide (7a) as a model substrate (Table 1; see
Supporting Information for a full list of tested reaction
conditions, Table S1). No product was observed in the absence
of catalyst or in the presence of TMSCl as Lewis acid (entries 1
and 2). However, we were pleased to see that addition of a
catalytic amount of Cu(CH3CN)4BF4 afforded the desired
Received: November 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With the optimized conditions in hand (entry 5), we first
investigated a range of structurally diverse thiiranes (Scheme 2).
Using cyclopentene sulfide allowed the synthesis of 8b in a
slightly improved yield. Incorporation of an oxygen or a
protected nitrogen atom in the ring afforded 8c and 8d in
good and moderate yield, respectively. Simple ethylene sulfide
6e provided a lower yield of 8e (46%). However, this result has
to be put in perspective with the known tendency of 7e to
polymerize, as well as its low boiling point (55 °C).19 When the
reaction was performed with unsymmetrical propylene sulfide,
8f was obtained as a mixture of regioisomers (2.1:1 rr), the major
one resulting from the attack of the carboxylate at the most
substituted position. A similar outcome was observed with a
longer alkyl chain (product 8g). Using the disubstituted
analogue 7h led to a significant improvement of the
regioselectivity (15.5:1 rr), although with a diminished yield
of 8h. When the reaction was run with the enantioenriched
substrate 7i, it afforded 8i with full conservation of the ee for
both regioisomers. In this case, we were surprised to observe an
inversion of regioselectivity. We hypothesize that it could be due
to the inductive effect of the nearby oxygen. The synthesis of 8j
incorporating two protected alcohols was achieved in a lower
yield.
Scheme 1. Strategies Exploiting Thiiranium and Sulfonium
Ions for C−S Bond Activation
Next, we examined different hypervalent iodine reagents.
Substitution of the TIPS group by aryl substituents was well-
tolerated and showed little impact on the reaction (8k−m).
Alkyl-EBX gave also good results (8n−o). A lower yield was
observed for 8p, and decreasing the temperature furnished a
slightly better result. Modification of the iodobenzoic acid core
with a methoxy, a nitro, or a fused benzene ring allowed the
synthesis of products 8q−s in good yields. Importantly,
vinylbenziodoxolone reagents (VBX) could be used successfully
in the transformation, providing the oxyvinylated products 8t−u
in promising yields without further optimization.
a
Table 1. Optimization of the Oxyalkynylation
We next examined the transformation of the less strained
thietane heterocycles (Scheme 3). We were pleased to see that
simple thiacyclobutane (9a) reacted under similar reaction
conditions to deliver 1,3-functionalized thioalcohol 10a in
moderate yield. Introduction of a phenyl group at the 3-position
of the thiacyclobutane did not affect the transformation
(product 10b). Spirocyclic substrates 9c and 9d gave improved
yields of products 10c and 10d and demonstrated the selectivity
of the reaction for sulfur heterocycles. Considering the good
results obtained with four-membered rings, the reaction of
tetrahydrothiophene (9e) was examined next. At higher
temperature (100 °C), we could obtain the 1,4-functionalized
thioalcohol 10e in moderate yield.
To highlight the synthetic utility of our method, further
functionalizations of 8a were performed (Scheme 4a). We first
focused on the reactivity of the iodobenzoate ester: Sonogashira
cross-coupling with the iodine afforded 11 in good yield, and the
saponification of the iodobenzoic ester allowed the synthesis of
the free alcohol 12. Next, we turned our attention toward the
thioalkyne function. A sequence of TIPS deprotection followed
by copper-catalyzed alkyne−azide cycloaddition afforded
triazole 14 in excellent yield. A scale-up reaction (2 mmol)
was then carried out using Ph-EBX (6k) and cyclohexene sulfide
(7a) (Scheme 4b). The reaction gave a similar yield at this scale.
The synthesized phenyl thioalkyne 8k was hydrated to afford
thioester 15 in good yield.
b
entry
1
2
catalyst
solvent T (°C) time (h)
yield (%)
none
THF
THF
THF
DCE
DCE
DCE
DCE
70
30
rt
24
4
traces
c
TMSCl
not observed
3
4
5
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(OTf)2
24
24
1.5
0.5
1.5
53
66
65
67
66
rt
50
100
50
d
6
7
a
Reaction conditions: TIPS-EBX (6a) (0.1 mmol), cyclohexene
sulfide (7a) (0.15 mmol), catalyst (10 mol %), solvent (0.07 M),
b
c
reactions were carried out under N2 atmosphere. Isolated yield. 1
d
equiv of TMSCl was used. Reaction was performed under microwave
irradiation.
product 8a in 53% yield as a single diastereoisomer (entry 3).
The relative trans configuration was confirmed by X-ray
crystallography. Different solvents were screened: replacing
THF with DCE increased the yield to 66% (entry 4). Working at
higher temperatures resulted in a significant lower reaction time
with no influence on the yield (entries 4−6). Next, we examined
a range of copper catalysts (see Supporting Information). A
similar yield was obtained only when Cu(OTf)2 was used (entry
7). Oligomers containing multiple cyclohexyl sulfide motifs were
identified as byproducts of the reaction. To reduce this side
reactivity different concentrations, stoichiometries of 6a/7a and
copper loadings were examined (see Table S2 for details), but
the reaction yield was constantly between 45 and 65%.18
A series of experiments were carried out to gain more insight
into the reaction mechanism (Scheme 5). We first attempted the
ring opening of cyclohexene sulfide (7a) in the presence of a
B
DOI: 10.1021/acs.orglett.9b04157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of the Oxyakynylation with Thiiranes and HIRs*
*
a
b
The major regioisomer is drawn; rr = regioselectivity ratio. Reaction was carried out on 0.2 mmol scale. Reaction was heated to 70 °C. Reaction
was stirred at rt.
Scheme 3. Scope Extension to Thietanes and
Scheme 4. Product Modifications
Tetrahydrothiophene*
a
Conditions: (a) 8a (1.0 equiv), 2-ethynylnaphthalene (2.0 equiv),
*
a
Pd(PPh3)2Cl2 (10 mol %), CuI (20 mol %), Et3N (30 mM), 40 °C,
2.5 h; (b) 8a (1.0 equiv), K2CO3 (2.5 equiv), EtOH (0.1 M), 45 °C,
30 h; (c) 8a (1.0 equiv), TBAF (1.2 equiv), THF (80 mM), 0 °C, 1 h;
(d) 13 (1.0 equiv), BnN3 (1.2 equiv), Cu(H2O)5SO4 (10 mol %),
sodium ascorbate (20 mol %), CHCl3/H2O 15:1 (60 mM), rt, 24 h;
(e) 8k (1.0 equiv), PTSA (1.0 equiv), SiO2 (15.0 equiv), CH2Cl2 (0.2
M), 40 °C, 24 h.
Reactions were carried out on 0.2 mmol scale. The reaction mixture
was heated to 100 °C under microwave irradiation.
copper catalyst and sodium benzoate or benzoic acid (Scheme 5,
eq 1). No product formation was observed after 3 days,
highlighting the importance of the hypervalent iodine reagents
for thiirane activation. We applied our standard conditions to
cyclohexene oxide (17) (eq 2). Even if epoxides are more prone
to a ring-opening reaction due to their higher ring strain,4b no
trace of product 18 was observed. This result confirmed the
selectivity of the transformation for sulfur heterocycles. The
reaction was attempted using iodonium salt 6v instead of EBX
(eq 3). When cesium benzoate or benzoic acid was added to
replace the missing nucleophile, the desired product was formed
only in trace amounts. The addition of a radical scavenger led to
the formation of the desired product 8a with a decreased yield
(eq 4). No TEMPO adducts were detected. Nevertheless, a
radical pathway cannot be excluded at this stage, as such
intermediates may be too unstable to be isolated.
C
DOI: 10.1021/acs.orglett.9b04157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Additional Experiments for Mechanism
Elucidation
Scheme 6. Proposed Speculative Mechanism
nucleophilic attack of the copper carboxylate, affording the
desired product 8 and regenerating the initial copper catalyst I.
The product formed has a relative trans configuration resulting
from a SN2 attack of the carboxylate.
In summary, we have described an atom-efficient copper-
catalyzed ring opening of thiiranes and thietanes through the use
of hypervalent iodine reagents. The transformation works with
different cheap copper sources at a broad range of concen-
trations and temperatures. In the case of unsymmetrical
episulfides, the product resulting from the addition on the
carbon-bearing substituents stabilizing better a partial positive
charge was observed. Based on the relevant literature and our
control experiments, we propose a speculative reaction
mechanism involving formation of an episulfonium intermediate
for C−S bond activation.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04157.
Considering the successful ring opening of nonstrained
tetrahydrothiophene (Scheme 3, 10e), we wondered if non-
cyclic thioethers could be cleaved using our method. We were
pleased to see that dibenzyl sulfide 20 reacted to afford the
corresponding thioalkyne 21a and benzyl ester 21b in moderate
yields at 100 °C (eq 5). A competitive experiment was carried
out with 6k and 6q possessing different alkynes and iodobenzoic
cores (eq 6). In total, four different products were isolated: the
expected products 8k and 8q and the crossover products 8a and
8v bearing one functional group from each reagent. This showed
that external addition can occur but is less favored (∼1:2 ratio).
Indeed, when the reaction was performed in the presence of an
excess of methanol, ether product 8w could be obtained in 16%
yield together with 46% of 8a (eq 7).20
■
S
Experimental procedures and analytical data for all new
compounds (PDF)
Accession Codes
CCDC 1962904 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
Based on these results, we propose a possible reaction
mechanism in Scheme 6. First, the copper(I) catalyst activates
EBX reagent 6. Two different modes of activation could be
envisaged: formation of the iodonium salt II or oxidative transfer
to generate the copper(III) complex III.21 In the former case,
activated iodonium salt II would react directly with cyclohexene
sulfide (7a) to give sulfonium IV. Both a concerted α-addition−
elimination or a β-addition/α-elimination/1,2-shift pathway
could be considered.22 In the latter case, coordination of the
copper(III) center followed by reductive elimination would lead
to sulfonium IV.23 At this stage, exchange of carboxylates could
happen. Sulfonium IV then undergoes a ring opening by
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jerome.waser@epfl.ch.
ORCID
Jerome Waser: 0000-0002-4570-914X
Author Contributions
†J.B. and G.P. contributed equality to this work.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b04157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ACKNOWLEDGMENTS
■
We thank the Swiss National Science Foundation (Grant No.
200020_182798) and the Institute of Chemistry and Chemical
Engineering at EPFL (Master grant for J.B.) for financial
support. Dr. Rosario Scopelliti and Dr. Farzaneh Fadaei Tirani
(ISIC, EPFL) are acknowledged for the X-ray study.
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(18) We also attempted the use of in situ-generated unstable
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Epoxides with Phosphine Selenides and Trifluoroacetic Acid. Evidence
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2094. However, no product was obtained.
̌
(19) Zelcans, G.; Gervay-Hague, J.; Maulie, I. Ethylene Sulfide. In
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(20) The use of an EBX reagent bearing a less nucleophilic 2-iodo-5-
nitrobenzoate did not increase the product ratio in favor of ether 8w.
No reaction was observed when using an ethynylbenziodoxole reagent
derived from hexafluoro-2-(2-iodophenyl)propan-2-ol.
(21) (a) Holt, D.; Gaunt, M. J. Copper-Catalyzed Oxy-Alkenylation of
Homoallylic Alcohols to Generate Functional Syn-1,3-Diol Derivatives.
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stituted Alkenes. J. Am. Chem. Soc. 2013, 135, 5332−5335. (c) Hick-
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(23) Another plausible mechanism not depicted here would involve
non-oxidative alkyne transfer from iodine to copper, resulting in an
iodine(III)-activated Cu(I) acetylide, similarly to the computed
mechanism for the gold-catalyzed alkynylation of indoles: Ariafard, A.
A Density Functional Theory (DFT) Mechanistic Study of Gold(I)-
Catalyzed Alkynylation of the Indole and Pyrrole Substrates, Using a
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DOI: 10.1021/acs.orglett.9b04157
Org. Lett. XXXX, XXX, XXX−XXX