Electrophilic Vinylation of Thiols under Mild and Transition Metal-Free Conditions

Article abstract of DOI:10.1002/anie.202002936

The iodine(III) reagents vinylbenziodoxolones (VBX) were employed to vinylate a series of aliphatic and aromatic thiols, providing E-alkenyl sulfides with complete chemo- and regioselectivity, as well as excellent stereoselectivity. The methodology displays high functional group tolerance and proceeds under mild and transition metal-free conditions without the need for excess substrate or reagents. Mercaptothiazoles could be vinylated under modified conditions, resulting in opposite stereoselectivity compared to previous reactions with vinyliodonium salts. Novel VBX reagents with substituted benziodoxolone cores were prepared, and improved reactivity was discovered with a dimethyl-substituted core.

Full text of DOI:10.1002/anie.202002936

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Accepted Article
Title: Electrophilic Vinylation of Thiols under Mild and Transition Metal-
Free Conditions
Authors: Laura Castoldi, Ester Maria Di Tommaso, Marcus Reitti,
Barbara Gräfen, and Berit Olofsson
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10.1002/anie.202002936
Angewandte Chemie International Edition
COMMUNICATION
Electrophilic Vinylation of Thiols under Mild and Transition Metal-
Free Conditions
Laura Castoldi, Ester Maria Di Tommaso, Marcus Reitti, Barbara Gräfen and Berit Olofsson*[a]
In memory of Prof. Kilian Muñiz
Abstract: The iodine(III) reagents vinylbenziodoxolones (VBX) were
employed to vinylate a series of aliphatic and aromatic thiols,
providing E-alkenyl sulfides with complete chemo- and regio-
selectivity, as well as excellent stereoselectivity. The methodology
displays high functional group tolerance and proceeds under mild
and transition metal-free conditions without the need for excess
substrate or reagents. Mercaptothiazoles could be vinylated under
modified conditions, resulting in opposite stereoselectivity compared
to previous reactions with vinyliodonium salts. Novel VBX reagents
with substituted benziodoxolone cores were prepared, and improved
reactivity was discovered with a dimethyl-substituted core.
Most synthetic routes to vinyl sulfides involve the use of
transition metals, such as Ru-catalyzed hydrothiolation of
terminal alkynes,[16] and Cu-catalyzed cross coupling reactions
at elevated temperature.[17] Whereas metal-free additions to
alkynes proceed under mild conditions, other synthetic routes
require strong base, and often give diastereo- or regio-isomeric
mixtures.[18] Ochiai and co-workers reported a single vinylation of
PhSNa with a phenyl(4-tert-butylcyclohexenyl)iodonium under
mild conditions,[19] which has not been further explored.
a) First VBX synthesis from ArI
R2
I
OH
R
I
O
B(OH)2
0 °C to RT, 1 h
TfOH, m-CPBA
NaHCO3
RT, 1 h
O
O
CH2Cl2, 15 min
Hypervalent iodine compounds have emerged as
sustainable alternatives to metal-based oxidants and organo-
metallic catalysts. Most iodine(III) reagents are nontoxic, easily
synthesized, and reactive under mild conditions.[1] Iodonium
salts have a unique ability to form C-C and C-heteroatom bonds
through transfer of one carbon ligand to a variety of nucleo-
philes.[2] Although vinyl(aryl)iodonium salts can be employed to
vinylate nucleophiles,[3] their reactivity is difficult to control under
metal-free conditions, often leading to product mixtures.[4] Benz-
iodoxolones have enhanced stability and more controllable
reactivity compared to iodonium salts. This feature has been
demonstrated by the Togni trifluoromethylation reagents and
Waser’s alkynylations using alkynylbenziodoxolones (EBX).[5]
While the corresponding vinyl-benziodoxolones were reported
as products from the addition of azide to EBX already in 1996,[6]
they have remained unexplored as synthetic reagents. In 2016,
we reported a one-pot synthesis of vinylbenziodoxolones from 2-
iodobenzoic acid and abbreviated these novel reagents VBX
(Scheme 1a).[7] Their unique reactivity was demonstrated in the
vinylation of nitrocyclohexane, with opposite regioselectivity to
the corresponding vinyliodonium salt[8] (Scheme 1b).[7] In parallel,
Yoshikai and co-workers developed the synthesis of b-oxygen-
functionalized VBX reagents through Pd-catalyzed hydro-
carboxylation of EBX-type reagents (Scheme 1c).[9] The scope
of VBX has since increased further by addition of heteroatom
nucleophiles to various iodine(III) precursors,[10] and the reagent
class has been employed in metal-catalyzed cross couplings
and C-H vinylations, as well as in metal-free reactions.[9-11]
VBX
b) Opposite regioselectivity
Ph
Ph
NO2
Ph
O2N
O2N
I
FBF3
Ph
VBX
tBuOK, THF, RT
tBuOK, THF, RT
c) Synthesis from EBX derivatives
H
O
O
R1
I
O
I
O
CF3
CF3
CF3
CF3
PdII (cat)
R2 R1
R2CO2H
+
t-BuOMe, RT
R3
d) This work
R2
R3
✓ high E-selectivity
✓ no excess reagents
✓ transition metal-free
I
O
tBuOK
THF, RT, 2 h
R2
R1 SH
+
S
O
R4
R1
VBX
Scheme 1. Preparation of vinylbenziodoxol(on)es and vinylations with VBX.
Intrigued by the different regiochemical outcome with VBX and
vinyliodonium salts (Scheme 1b), and inspired by Waser’s EBX-
alkynylation of thiols,[20] we have investigated the reactivity of
VBX with thiols, and herein report our results. The reaction was
found to proceed under mild and transition metal-free conditions,
and contrary to the vinylation of nitrocyclohexane, regiospecific
formation of (E)-1,2-substituted vinyl sulfides was observed
(Scheme 1d). During the course of our investigation, three types
of metal-free S-vinylations with VBX were reported, although
only 1-2 examples were given in each case: vinylation of
sulfenate anions to (E)-alkenyl sulfoxides,[11e] thiophenol
vinylation with a sulfonamide-substituted VBX,[11a] and with a
regular VBX using a large excess of thiophenol.[11f]
Vinyl sulfides are important building blocks in organic
synthesis,[12] natural products and biologically active
compounds.[13] Their reactivity is interesting since they can be
considered as enolate equivalents[14] and Michael acceptors.[15]
The vinylation of thiophenol (1a) with VBX 2a was first
attempted in THF with TMG as base,[20] resulting in 64% of the
vinylated product 3a with disulfide 4a as byproduct (Table 1,
entry 1). For atom efficiency reasons, equimolar conditions were
maintained in the optimization to suppress the formation of 4a.[21]
Considerable amounts of 4a were obtained with various bases,
as well as in the absence of base (entries 2-5). Reactions in
THF with tBuOK with 2 h reaction time proved best. The E:Z
ratio of 3a increased to >20:1 when VBX was added before the
[a]
Dr. L. Castoldi, E. M. Di Tommaso, Dr. M. Reitti, B. Gräfen, Prof. B.
Olofsson
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University, SE-106 91 Stockholm, Sweden
E-mail: Berit.Olofsson@su.se
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202002936
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Influence of substituents on the benziodoxolone core.[a]
base (entry 6), and 4a was further suppressed in anhydrous and
degassed solvent, delivering 3a in 87% yield (entry 7). Vinylation
of the corresponding TMS-protected thiophenol 7 was feasible
by in situ-deprotection with TBAF prior to addition of 2a (entry
8).[21] This strategy could be beneficial with base-sensitive thiols.
Ph
COOH
R
I
O
tBuOK (1.0 equiv)
S
S
+
Ph
1a
o
R
+
Ph
Ph
O
THF, RT, 2 h
m
3a
5
2 (1.1 equiv)
p
Table 1. Optimization on thiophenol.[a]
Entry
2, R
Yield of 3a (%)
E:Z ratio
Yield of 5 (%)
Ph
I
O
base (1.0 equiv)
solvent, RT, t
1
2
3
4
5
6
7
8
2a, H
87
11
67
75
90
9
>20:1
>20:1
11:1
0
40
0
S
S
Ph
Ph SH
+
+
Ph
Ph
Ph
S
O
2b, p-NO2
2c, p-Br
1a
3a
4a
2a (1.1 equiv)
Entry
Solvent
Base
Time
(h)
Yield of
3a (%)[b]
E:Z
ratio
Yield of
4a (%)[b]
2d, p-OMe
2e, m,p-Me2
2f, o-NO2
2g, o-Me
>20:1
>20:1
>20:1
>20:1
1:1
0
0
1
THF
TMG
TMG
-
15
15
15
15
15
2
68
53
15:1
>20:1
20:1
18
34
30
30
18
13
7
18
0
2
Toluene
THF
68
20
3
54
Ph
0
4
THF
NaHCO3
tBuOK
tBuOK
tBuOK
-
36
9:1
I
FBF3
Ph
6
5
THF
78
10:1
[a] Reaction conditions: see Table 1 entry 7; NMR yields given.
6
THF
76[c]
87[c, d]
77[d]
>20:1
>20:1
>20:1
Halide substituents were well tolerated, also in the ortho position
(3h-3k). Both linear and cyclic aliphatic thiols could be vinylated
at rt to provide (E)-thioethers 3l-3q with complete E-selectivity,
even with sterically demanding substituents (3o).
7
THF
2
8[e]
THF
2
12
[a] Reaction conditions: 1a (0.3 mmol) and base were stirred in solvent for 5
min before addition of 2a. [b] 1H-NMR yield using trimethoxybenzene as
internal standard. [c] Addition of VBX, then base. [d] Anhydrous and degassed
solvent. [e] PhS-TMS (7) and TBAF (1.0 equiv) used instead of 1a and base.
TMG = 1,1,3,3-tetramethylguanidine.
More challenging substrates were subsequently examined to
evaluate the functional group tolerance (Scheme 2B). Allyl,
furanyl and pyridyl substituents were well tolerated, providing 3r-
3t, and double vinylation to products 3u,3v could be achieved.
The S-vinylation proceeded with complete chemoselectivity in
the presence of unprotected hydroxy- and amino groups, as
demonstrated by the vinylation of 2-mercaptoethan-1-ol and
cysteine ethyl ester to give products 3w and 3x with complete E-
selectivity. Under slightly modified conditions, also the S-
vinylation of amino thiophenols to provide products 3y and 3z
was achieved. The high functional group tolerance was further
demonstrated by late stage functionalization of the ACE inhibitor
Captopril,[24] which could be vinylated without protection of the
carboxylic acid moiety to provide 3aa. Moreover, the carbo-
hydrate thio-b-D-glucose tetraacetate was vinylated in good
yield (3ab).[25] Vinylations of cysteine and thio-b-D-glucose to
provide the unprotected derivatives of 3x and 3ab were low-
yielding, likely due to solubility problems.[21]
The reactivity of iodine(III) compounds can be influenced by
ortho-substituents,[22] and EBX reagents with substituted
benziodoxolone cores have been investigated.[23] Hence, a
series of novel, substituted VBX derivatives were synthesized
using Nachtsheim’s procedure.[11b,
investigated through 2b-2e with p-substituted benziodoxolone
cores, and steric effects were screened with o-substituted VBX
2f, 2g (Table 2). The chemoselectivity was poor in reactions with
nitro-substituted reagents 2b and 2f, with preferential transfer of
the aryl group to yield diaryl sulfide 5 (entries 2,6). The other
reagents all delivered product 3a with complete chemoselectivity
and E:Z ratios ranging from 11:1 (2c) to >20:1. Me2-VBX reagent
2e provided 3a in 90% yield (entry 7), indicating that moderately
electron-donating substituents can be favorable in benziodo-
xolone chemistry. A control reaction with vinyliodonium salt 6
delivered 3a in poor yield with 1:1 E/Z-ratio (entry 8).
21]
Electronic factors were
A set of substituted VBX reagents was synthesized to
demonstrate the feasibility to transfer other vinyl groups
(Scheme 3). Indeed, reactions with E-VBX reagents 2g-2k,
having different electronic properties, resulted in thioethers 3ac-
3ag in good yields. High E-selectivities were obtained in all
cases except 3ae. Vinylations with cyclohexyl-substituted VBX
2m proved less reactive and gave a modest yield.[21] Attempts to
synthesize the Z-stereoisomer of 2a were in vain due to
isomerization to E-2a under the reaction conditions.[10f, 26]
The scope of the reaction was examined with VBX reagent
2a, due to its considerably less expensive precursor than 2e.
Thiophenols containing both electron-donating and electron-
withdrawing substituents could be employed to provide products
3a-k in good yields, with excellent E-stereoselectivity (Scheme
2A). While sterically hindered thiophenols reacted sluggishly at
RT, efficient vinylation to 3g was possible at 50 °C for 2 h.
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10.1002/anie.202002936
Angewandte Chemie International Edition
COMMUNICATION
Ph
are more convenient as column chromatography is not needed.
We are currently investigating the Me2-VBX backbone in other
transformations, and will report the results in due time. The
formed iodobenzoic acid can be recovered and reused in
formation of VBX, thus increasing the sustainability and
economy of the process.[21]
I
O
tBuOK (1.0 equiv)
S
R1
SH
+
R1
Ph
E:Z >20:1
O
THF, 2 h, RT
2a (1.1 equiv)
1
3
A: Aryl & Alkyl Thiols
S
S
S
Ph
Ph
Ph
S
Ph
Ph
tBu
MeO
R2
3c 73%
3a 81%
3b 72%
3d 77%
R1
F
R2
I
S
S
S
S
O
Ph
Ph
Ph
Ph
tBuOK (1.0 equiv)
S
Ph SH
+
R1
O
THF, 2 h, RT
Ph
R3
S
3e 71%[a]
3f 66%[a]
3g 68%[b]
Cl
3h 52%
2
1a
3
S
S
S
Ph
Ph
Ph
R2
S
S
Ph
Ph
Ph
Ph
Ph
R1
Br
Cl
S
3i 75%
3j 70%
3k 87%
I
O
OMe
Me
3ae 51%
E:Z 4:1
with 2j: R2=H
3ac 75%
E:Z 16:1
3ad 62%
E:Z >20:1
S
S
O
Ph
S
Ph
Ph
(C6H13
)
Ph
Ph
with 2h: R2=H
with 2i: R2=H
2h-2o
OMe
3l 77%
3m 71%
3n 67%
3o 52%
S
S
Ph
Ts
N
S
3p 85%
S
O
Ph
Ph
CF3
Cl
S
S
Ph
Ph
3ai 97%
E:Z >1:6
Ph
Ph
3q 69%
3af 93%
3ag 72%
E:Z >20:1
with 2l: R2=H
3ah 90%
E:Z >1:20
with 2n (trisubst)
E:Z >20:1
B: More challenging thiols
with 2k: R2=H
with 2o (trisubst)
S
O
Ph
S
S
N
Ph
Ph
R2
OMe
3t 60%[c]
3s 79%
3r 64%
R1
Ts
N
S
Ph
S
S
Ph
I
O
Ph
Ph
S
Ph
S
Ph
S
S
HO
Ph
Ph
Br
O
Ph
S
3aj 59%
E:Z >1:20
with 2p: R1=H
3l 97%
3i 77%
E:Z >20:1
3u 78%[d]
3v 54%[d]
3w 65%
2e, 2p
Me2-VBX
E:Z >20:1
with 2e: R2=H
with 2e: R2=H
NH2
NH2
S
H2N
S
S
EtO
Ph
Ph
Ph
Scheme 3. Scope with substituted VBX reagents.
O
3z 54%[e]
3x 60%
3y 37%[e]
AcO
O
N
OH
O
OAc
S
Ph
O
Ochiai and co-workers have demonstrated that metal-free
vinylation of various nucleophiles with E-alkylvinyl(phenyl)-
iodonium salts result in Z-vinylated products through a vinylic
SN2 mechanism.[3a] In this fashion, vinylation of mercaptobenzo-
thiazole in the absence of base resulted in selective formation of
the corresponding Z-vinylsulfide.[3a] To compare the reactivity of
VBX with vinyliodonium salts, the vinylation of a small series of
mercaptothiazoles 8 (X=S) was investigated. This substrate
class could indeed be vinylated in moderate yields and high
stereoselectivity (E:Z 10:1 to 20:1) under modified reaction
conditions (Scheme 4).[21] Interestingly, we observed opposite
stereochemistry compared to previous results with the vinyl-
iodonium salt. The methodology was also applied to
mercaptooxazole (X=O) to give 9d.
Ph
S
AcO
OAc
3ab 71%
3aa 63%[f]
Scheme 2. Scope of thiol vinylation with VBX, products were obtained
with E:Z >20:1 unless specified. [a] E:Z 16:1 [b] At 50 °C. [c] E:Z 5:1 [d]
With 2a (2.1 equiv) and base (2.0 equiv). [e] With 2a (1.5 equiv) at 50 °C.
[f] With 2.0 equiv base.
Waser and coworkers recently reported a vinylation of thio-
phenol with a Z-configured sulfonamide-substituted VBX to
provide
a
thioenamide with moderate Z-selectivity.[11a]
Considering the excellent stereoselectivity of our methodology,
we were intrigued to investigate the reactivity of such reagents
under our conditions. Indeed, trisubstituted thioenamide 3ah and
thioenol ether 3ai were obtained in excellent yields with good to
complete Z-selectivity.[27] However, the corresponding disubsti-
tuted thioenamide 3aj only formed in modest yield with 1,2-bis-
(phenylthio)ethene[11f] as the main byproduct, and attempts to
optimize the reaction conditions were in vain. Pleasingly, the
corresponding Me2-substitued VBX reagent 2p (cf 2e in Table 2)
proved more efficient, delivering thioenamide 3aj in 59% yield
with complete Z-selectivity and suppressed byproduct formation.
VBX 2a (1.1 equiv)
tBuOK (1.0 equiv)
N
S
N
R
SH
toluene, 2 h, 80 °C
X
X
R
8, X = S, O
9
S
S
S
S
N
S
N
N
Ph
Ph
Ph
Ph
S
N
S
O
Ph
9a 45%
E:Z 10:1
9b 44%
E:Z >20:1
9c 47%
E:Z 10:1
9d 21%
E:Z 8:1
Scheme 4. S-Vinylation of heterocycles with VBX.
Me2-VBX reagent 2e was thus investigated in selected E-
selective vinylations as alternative to 2a, and indeed provided
product 3l in increased yield (97 vs 77%). While vinyl sulfide 3i
formed in similar yields with 2a and 2e, reactions with Me2-VBX
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10.1002/anie.202002936
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COMMUNICATION
The observed regioselectivity of the S-vinylation is intriguing, as
the C-vinylation of nitrocyclohexane with VBX 2a gave a terminal
alkene as the main product (see Scheme 1b).[7] Furthermore, the
high E-stereoselectivity is opposite to reactions with
vinyliodonium salts and shows that VBX does not react through
a vinylic SN2 mechanism.[3a] While preliminary radical trap
experiments were inconclusive,[21] isomerization of 3e was
observed upon purification on column chromatography (from E:Z
>20:1 to 16:1), and we hence propose that the main reaction
pathway gives the E-product, while the Z-product is formed by
isomerization. We are currently investigating the mechanisms of
VBX vinylations with various nucleophiles by DFT calculations
and 13C-labelling studies to detect any carbene pathways, and
will report the results in due time.
The authors declare no conflict of interest.
Keywords: alkenyl sulfides • benziodoxolones • hypervalent
compounds • synthetic methods • VBX
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2014; b) T. Wirth, in Top. Curr. Chem., Vol. 373, Springer International
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To conclude, we have reported a high-yielding method for
vinylation of aromatic and aliphatic thiols with the recently
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metal-free methodology uses equimolar amounts of reagents
and proceeds under mild conditions with complete chemo- and
regioselectivity, as well as high stereoselectivity. Mercapto-
heterocycles could be vinylated under modified conditions.
Moreover, the synthesis and reactivity of several novel,
substituted VBX reagents was described to illustrate the
influences of steric and electronic factors on the vinylation. The
Me2-VBX backbone proved superior to the parent VBX, a
discovery that could have impact on reactions with other
benziodoxolone reagents too, such as alkynylations and
trifluoromethylations. Results from our ongoing mechanistic
studies of metal-free vinylations with VBX and various
nucleophiles will be reported in due time.
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General Procedure for Vinylation of Thiols
Thiol 1 (1.0 equiv, 0.3 mmol) was placed in an oven-dried
microwave vial with magnetic stirring bar under argon, followed
by the addition of anhydrous and degassed THF (2.0 mL).
Subsequently, VBX 2 (1.1 equiv) and tBuOK (1.0 equiv) were
sequentially added and the vial was rinsed with THF (1.0 mL).
The mixture rapidly turns yellow and it was stirred at RT for 2 h.
The reaction was quenched with water (2.0 mL) and the
aqueous phase was extracted with CH2Cl2 (2 x 10 mL) and the
combined organic phases were dried over Na2SO4, filtered and
concentrated under reduce pressure. The crude reaction was
purified via column chromatography to provide product 3.
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Acknowledgements
Per-Ola Norrby is kindly acknowledged for mechanistic
discussions. Carl Trygger Foundation (CTS 17:341) and the
Swedish Research Council (2015-04404) are acknowledged for
financial support.
Conflict of interest
This article is protected by copyright. All rights reserved.

10.1002/anie.202002936
Angewandte Chemie International Edition
COMMUNICATION
[18] a) R. Sridhar, K. Surendra, N. S. Krishnaveni, B. Srinivas, K. R. Rao,
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This article is protected by copyright. All rights reserved.

10.1002/anie.202002936
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Laura Castoldi, Ester Maria Di
Tommaso, Marcus Reitti, Barbara
Gräfen and Berit Olofsson*
N
R2
R1
R4 R1
HS
R2
√ transition metal-free
√ chemoselective
R4 SH
tBuOK
S
X
X
I
O
R1
tBuOK
N
S
O
√ stereoselective
R3
R4
toluene
80 °C, 2 h
THF
RT, 2 h
√ no excess reagents
R4
VBX
Page No. – Page No.
Electrophilic Vinylation of Thiols
under Mild and Transition Metal-Free
Conditions
Novel vinylation reagent - The iodine(III) reagents vinylbenziodoxolones (VBX)
have been employed to vinylate aliphatic and aromatic thiols, as well as mercapto-
thiazoles. The methodology proceeds under mild and transition metal-free
conditions to provide alkenyl sulfides with excellent stereoselectivity. A novel VBX
reagent with a substituted benziodoxolone core had superior efficiency.
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