Ex Situ Formation of Methanethiol: Application in the Gold(I)-Promoted Anti-Markovnikov Hydrothiolation of Olefins

Article abstract of DOI:10.1002/anie.201809051

A protocol for the Au-promoted anti-Markovnikov hydrothiolation of olefins using ex situ generated methanethiol is reported. The use of S-methylisothiourea hemisulfate salt as a solid precursor for methanethiol generation ensures a safe and reliable deliverance of a stoichiometric amount of this thiol. The procedure was shown to work for a broad range of olefins providing the corresponding hydrothiolated adduct in good to excellent yields. Mechanistic evaluations suggest that thiyl radicals are generated and that gold acts as an efficient but stable radical initiator.

Full text of DOI:10.1002/anie.201809051

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Accepted Article
Title: Ex Situ Formation of Methanethiol: Application in the Gold(I)-
Promoted anti-Markovnikov Hydrothiolation of Olefins
Authors: Troels Skrydstrup, Steffan Kristensen, Simon Laursen, and
Esben Taarning
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809051
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10.1002/anie.201809051
Angewandte Chemie International Edition
COMMUNICATION
Ex Situ Formation of Methanethiol: Application in the
Gold(I)-Promoted anti-Markovnikov Hydrothiolation of Olefins
Steffan K. Kristensen,[a] Simon L. R. Laursen,[a] Esben Taarning[b] and Troels Skrydstrup*[a]
Abstract: A protocol for the Au-promoted anti-Markovnikov hy-
drothiolation of olefins using ex situ generated methanethiol is re-
ported. The use of S-methylisothiourea hemisulfate salt as a solid
precursor for MeSH generation ensures a safe and reliable deliver-
ance of a stoichiometric amount of methanethiol. The procedure was
shown to work for a broad range of olefins providing the correspond-
ing hydrothiolated adduct in good to excellent yields. Mechanistic
evaluations suggest that thiyl radicals are generated and that gold
acts as an efficient but stable radical initiator.
of carbon monoxide,[14] dihydrogen,[15] ethylene[16] and hydrogen
cyanide,[17] could be exploited for the ex situ delivery of MeSH.
Established methods: Transition metal-catalyzed hydrothiolation with
aryl and none volatile thiols
SR'
Catalyst
SR'
+
+
R'SH
R
R
R
R'SH = Aryl- or nonvolatile
alkylthiols
[Pd], [Ni], [Rh]
[Au], [Cu], [Rh]
This work: Au-promoted anti-Markovnikov hydrothiolation of olefins
with ex situ generated MeSH
Chamber A
Au-complex (1.0 mol%)
The transition metal-catalyzed hydrothiolation of C–C p-bonds
represents an atom-efficient route for the introduction of sulfur-
containing fragments,[1] being highly represented in numerous
pharmaceuticals.[2] Whereas several transition metals promote
this C–S bond forming event,[1e, 3–8] metal complexes based on
Pd and Ni predominately provide the Markovnikov adduct,[3–5]
while those on Au and Cu lead to anti-Markovnikov selectivity.
Nevertheless, most procedures for hydrothiolation are devel-
oped for alkynes and allenes (Scheme 1a).[6, 7] In 2016, Ogawa
and co-workers reported the Au(I)-mediated anti-Markovnikov
hydrothiolation of olefins, exploiting the alkenophilic nature of
this metal.[6g, 9, 10] Although transition metal-promoted hydrothio-
lations are a powerful synthetic tool, so far they are primarily
limited to easy-to-handle thiols, such as aryl and none-volatile
aliphatic thiols. No reports for utilizing methanethiol have been
made, which is undoubtedly connected to its adverse properties,
being volatile with a pungent odor, corrosive and flammable.11
gaseous
flammable
SMe
R
Methyl sulfides
+
MeSH
(Only 2.5 equiv)
Chamber B
R
NaOH (aq)
Safe & easy setup
Highly regioselective
High yields
SMe
crystalline
inexpensive
(<0.1 €/g)
1/2 H2SO4
H2N
NH
Broad scope
Scheme 1. Established and presented methods for the hydrothiolation of π-
systems with transition metal complexes.
We initially investigated the hydrothiolation of safrole (1a) in-
to sulfide 1 using a slight excess of MeSH (Table 1). Preliminary
screenings revealed that the dimeric Au-complex [Au2(NTf2)2(μ-
dppf)] was superior to other phosphine-based Au-complexes
(entries 1–5, and SI), and if the gold complex was omitted all
together, no conversion into 1 was observed (entry 6). Dioxane
proved to be the best solvent for the reaction with solvents such
as CPME, CH3CN or EtOAc resulting in reduced conversions
(entries 7–9). Lowering the amount of MeSH from 2.5 equiva-
lents to 1.5 equivalents gave a sluggish and irreproducible con-
version to 1, indicating that the MeSH partial pressure is crucial
for the reaction to proceed (entry 10). Lastly, the temperature
was lowered to 25 °C (entry 11), and the reaction was diluted
(entry 12), however, this only resulted in poor conversions into 1
(See SI for full optimization).
To circumvent the direct use of methanethiol, protocols have
been developed relying on DMSO or MeSSMe to introduce a
methyl sulfide unit.[12, 13] Unfortunately, these protocols operate
at elevated reaction temperatures, thereby hampering the gen-
erality of the methods. We set out to develop a system from
which methanethiol could be delivered in a safe and reliable way
for the gold-mediated anti-Markovnikov hydrothiolation of olefins.
Our search for a thiol precursor ultimately led us to the commer-
cially available and inexpensive S-methylisothiourea hemisulfate
salt (Scheme 1b), which upon treatment with equimolar amounts
of NaOH produces methanethiol. We envisioned that the
two-chamber system, previously used for the ex situ generation
With the optimized reaction conditions in hand, we explored
the scope of the Au-promoted hydrothiolation with ex situ gener-
ated methanethiol (see Scheme 2). Allyl benzenes were well-
tolerated, and the corresponding hydrothiolated product could be
isolated in yields ranging from 92% to quantitative (2–9). Other
allylic systems, like allyl phenyl carbonates, allyloxy benzene,
3-allyl rhodanine, allyl pyridine and allyl 4-methylbenzene-
sulfonate all afforded the desired hydrothiolated product in good
to excellent yields (10–14), with no trace of the Markovnikov
adduct or other side-products. Allyl methyl carbonate, allyl car-
bamates and allyl phosphonates were also tolerated yielding
compounds 15–17, in yields ranging from 93% to quantitative.
[a]
[b]
Dr. S. K. Kristensen, S. L. R. Laursen, Prof. Dr. T. Skrydstrup,
Carbon Dioxide Activation Center (CADIAC), Department of Chem-
istry and the Interdisciplinary Nanoscience Center (iNANO), Aarhus
University, Gustav Wieds vej 14, 8000 Aarhus C (Denmark)
E-mail: ts@chem.au.dk
Dr. E. Taarning, Haldor Topsøe A/S, New Business R&D,
Nymøllevej 55, 2800 Kgs. Lyngby, Denmark
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201809051
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COMMUNICATION
MeSH Consuming Chamber
Table 1: Optimization of the Au-promoted anti-Markovnikov hydrothiolation of
[Au2(NTf2)2(µ-dppf)] (1.0 mol%)
1,4-Dioxane (0.15 mL), 45 oC, 20 h
safrole.[a]
SMe
1–34
R
R
SMe
MeSH Producing Chamber
SMT (2.5 equiv)
1M NaOH (aq) (2.5 equiv, 1.25 mL)
(0.5 mmol)
1/2 H2SO4
1M NaOH (aq)
(2.5 equiv)
H2N
NH
(2.5 equiv)
MeO
MeO
MeSH
[Au2(NTf2)2(µ-dppf)]
O
O
SMe
SMe
SMe
O
SMe
O
S
O
O
O
(1.0 mol%)
SMe
O
MeO
F
1 - 99%
2 - 98%
1,4-Dioxane (0.15 mL)
3 - 100%
O
45 o
C
1a (0.5 mmol)
1
O
O
SMe
SMe
O
Entry
Deviations from standard cond.
Conversion [%][b]
R
OMe
9 - 95%
O
10 - 98%
4: R = H - 92%
5: R = OMe - 99%
6: R = F - 97%
7: R = CH3 - 97%
8: R = CF3 - 93%
1
2
3
4
5
none
100 [99][c]
SMe
SMe
PPh3AuNTf2 (2.0 mol%)
PCy3AuNTf2 (2.0 mol%)
XPhosAuNTf2 (2.0 mol%)
[Au2(NTf2)2(μ-dcypf)] (1.0 mol%)
63
83
41
71
N
NH
11 - 97%
O
tBu
O
O
O
S
12 - 90%
N
SMe
O
SMe
O
S
S
14 - 74%
O
O
SMe
13 - 69%
15 - 94%
O
6
7
8
No Au
0
O
P
Cl
O
O
SMe
H2N
O
SMe
CPME instead of 1.4-Dioxane
CH3CN instead of 1.4-Dioxane
89
90
O
16 - 98%
17 - 93%
N
Cl
9
EtOAc instead of 1.4-Dioxane
1.5 equiv of MeSH
78
77
64
73
N
O
SMe
MeS
O
O
SMe
10
11
12
19 - 97%
18 - 99%
SMe
25 °C instead of 45 °C
0.3 mL of 1.4-Dioxane
SMe
R
SMe
20: R = H - 95%
21: R = Cl - 96%
22: R = tBu - 92%
23 - 94%
[a] All reactions were performed in a 6 mL two-chamber system, in which
methyl mercaptan was generated from S-methylisothiourea hemisulfate (174.0
mg, 2.5 equiv) and 1M NaOH (1.25 mL, 2.5 equiv) in one chamber; See
supporting information for all details. [b] Conversion determined from 1H NMR
using mesitylene as an internal standard. [c] Yield of isolated product. Tf =
Trifluoromethylsulfonyl, dppf = 1,1’-Bis(diphenylphosphino)ferrocene, XPhos =
24 - 64%
O
O
S
Si
Si
O
O
SMe
MeS
O
SMe
Ph
Ph
S
SMe
27 - 99%
SMe
26 - 96%
S
SMe
SMe
7
O
O
2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl,
Bis(dicyclohexylphosphino)ferrocene, CPME = Cyclopentyl methyl ether.
dcypf
=
1,1’-
25 - 96%
28 - 100%
30 - 96%
29 - 92%
SMe
AcO
Gratifyingly, the Au-promoted hydrothiolation of di-O-allyl-
bisphenol A and imazalil, a widely used fungicide, led to the
corresponding hydrothiolated product 18 and 19 in a 99% and
97% isolated yield, respectively. A small selection of styrenes
were tested and afforded yields from 92% to 96% (20–22). For
1,2-disubstituted olefins, like indene and stilbene, yields of 94%
and 64% for the sulfides 23 and 24 could be obtained, respec-
tively. From here, vinylsulfones and divinyltetramethyldisiloxane
were tested. Much to our delight, these substrates were well
tolerated under the reaction conditons and the hydrothiolated
adducts 25–27 could be isolated in 96% to 99%. Next, the hy-
drothiolation of simple aliphatic olefins, provided methyl sulfides
28–32 in yields close to quantitative. Lastly, the Au-mediated
hydrothiolation of O-acetyl quinidine and the di-O-allylated es-
tradiol were tested with excellent results (33 and 34).
SMe
MeS
O
SMe
31 - 100%
O
32 - 100%
N
H
H
MeO
H
H
MeS
O
N
33 - 90%
34 - 99%
Scheme 2. Scope of the Au-mediated hydrothiolation using ex situ generated
MeSH. For compounds 18, 27 and 34, 5 equiv of MeSH were used. See SI for
full details. Yields are given as an average of two separate reactions. SMT =
S-methylisothiourea hemisulfate.
hydrothiolation of 35 with MeSH, provided a 66% conversion the
ring-opened product 36. Contrary, conversion to the hydrothio-
We then turned to investigating the mechanism of this hy-
drothiolation event. Ogawa et al.[6g] concluded that the Au-
promoted transformation using thiophenol did not proceed by a
radical pathway as no ring opening was observed from the hy-
drothiolation of α-cyclopropylstyrene (35).[18] Based on this ob-
servation, we repeated this experiment using either MeSH or
PhSH (Scheme 3). As depicted in Scheme 3a, the Au-mediated
lated adduct 37 was obtained with PhSH in accordance to Oga-
19]
wa’s observations.[6g,
Although, one could conclude that a
fundamental switch in the mechanism had occurred, it is well
established that aryl thiols are better chain transfer reagents
than alkyl thiols due to a lower bond dissociation energy of the
S–H bond.[20, 21] However, to further verify that a radical pathway
is operating, we subjected N,N-diallyl-4-methylbenzenesulfon-
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COMMUNICATION
Condition a
SMe
a)
MeSH (2.5 equiv)
Complex 40 (1.0 mol%)
RSH (2.5 equiv)
Ph
36 - 66%
[Au2(NTf2)2(µ-dppf)]
1,4-Dioxane, 45 o
C
(1.0 mol%)
Ph
1,4-Dioxane (0.15 mL)
45 oC, 20 h
SPh
Condition b
35
O
O
O
Complex 40 (0.5 equiv)
1,4-Dioxane, 45 o
SR
1
(R = Me)
PhSH (2.5 equiv)
Ph
37 - 78%
C
O
1a
42 (R = nOct)
Conditions R Conv.
a
a
b
c
c
Me 83%
nOct 67%
[Au2(NTf2)2(µ-dppf)]
(1.0 mol%)
MeSH (2.5 equiv)
b)
Condition c
SMe
Complex 41 (1.0 mol%)
Me
0%
RSH (2.5 equiv)
Me 95%
nOct 82%
N
1,4-Dioxane, 45 o
C
N
1,4-Dioxane (0.15 mL)
45 oC, 20 h
Ts
Ts
38
39 - 99%
diastereomeric mixture
Lauroyl peroxide (10 mol%)
RSH (1.5 equiv)
O
O
O
O
SR
Scheme 3. Radical probe experiments. See SI for full details.
1,4-Dioxane, 45 o
C
1a
1 (R = Me)
42 (R = nOct)
51%
81%
amide (38) to the Au-mediated hydrothiolation using MeSH. As
expected, clean conversion to the pyrrolidine 39 was observed
further underlining a radical pathway.[22]
Scheme 5. Hydrothiolation studies of Au-complex 40 and 41 compared to the
use of lauroyl peroxide as a radical initiator. See SI for full details.
Next, the reaction between [Au2(NTf2)2(μ-dppf)] and MeSH
was examined to get insight into the possible reaction intermedi-
ates. From 31P NMR spectroscopy, we observed complete con-
sumption of [Au2(NTf2)2(μ-dppf)] after 20 h with the formation of
a new Au-complex displaying a phosphine signal at d 29.6 ppm
(Scheme 4a). Single crystal X-ray structure analysis revealed
the structure to be a linear tetra-nuclear Au-complex 40 pos-
sessing structural similarities to previously described Au(I)-
thiolates, albeit the dppf-ligands potentially prevent the formation
of a square-like Au-complex normally stabilized by aurophilic
into two identical dinuclear Au compounds 40a (Scheme 4a). If
methanethiol is replaced by n-octylthiol, a similar Au2-complex is
formed, tentatively assigned to the structure 41 based on the
observation of a single phosphine signal at d 29.7 ppm. Unfortu-
nately, all attempts to crystallize complex 41 were futile.[25]
With complexes 40 and 41 in hand, we set out to test their
reactivity (Scheme 5). Using 40 instead of [Au2(NTf2)2(μ-dppf)] in
the hydrothiolation of safrole (Condition a), provided an 83%
conversion to 1 with methanethiol, and a 67% conversion to 42
for n-octylthiol, the latter using a single reactor system. We also
checked the reactivity of 40 in a stoichiometric reaction without
adding additional MeSH (Condition b). Surprisingly no conver-
23, 24]
bonds.[6g,
However, in principle, two signals should be
observed for the Au4-complex 40 in the 31P NMR spectrum. But
as only one is observed, suggests that complex 40 dissociates
1
a)
sion to sulfide 1 was observed, and from the H NMR spectrum,
MeSH (2.0 equiv)
only starting material 1a could be detected (Condition b), sug-
gesting that complex 40 is only active in combination with the
thiol present. Lastly, a similar set of experiments as for Condition
a was applied to complex 41. Not surprisingly, this complex was
able to promote the hydrothiolation of both methanethiol and n-
octylthiol in excellent yields (Condition c).[26]
[Au2(NTf2)2(µ-dppf)]
31P NMR: δ 25.5 ppm)
1/2 [(Au2(µ-SMe))(µ-dppf)]2(NTf2)2
(40) (crystal structure)
1,4-Dioxane, 45 oC, 20 h
(
nOctSH (1.0 equiv)
1,4-Dioxane, 45 oC, 20 h
CDCl3
[(Au2(µ-SnOct))(µ-dppf)](NTf2)
(41)
[(Au2(µ-SMe))(µ-dppf)](NTf2)
(
31P NMR: δ 29.6 ppm)
(40a)
(
31P NMR: δ 29.7 ppm)
b)
To further highlight the importance of using Au for the hy-
drothiolation of olefins, we tested if lauroyl peroxide could induce
the same reactivity as observed for [Au2(NTf2)2(μ-dppf)]
(Scheme 5).[27] Here, it was observed that with 10 mol% of the
peroxide resulted in incomplete conversion of 1a to 1 (51%).
This was explained by a slow mass transport of MeSH from the
release chamber into the reaction chamber as a constant pres-
ence of MeSH is necessary for radical chain propagation. As
such, higher loadings of lauroyl peroxide were tested, but this
led only to considerable formation of side products. Support for
the slow mass transport of MeSH was confirmed by performing
a similar experiment applying n-octylthiol in a single chamber
reactor, providing an 81% of the sulfide 42.
In summary, a protocol for the delivery and use of a stoichi-
ometric amount of gaseous methanethiol in the Au-promoted
hydrothiolation of olefins has been developed. This procedure
omits the use of lecture bottles simplifying substantially the use
Scheme 4. a) Formation of Au-complexes 40 and 41. b) ORTEP representa-
tion of the crystal structure of 40. Hydrogens and one triflimide counterion are
omitted for clarity.
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COMMUNICATION
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Kalek, F. Himo, J. S. M. Samec, Chem. Eur. J. 2013, 19, 17939–17950;
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of MeSH. A broad range of olefins could be transformed into the
hydrothiolated adduct applying this protocol. Mechanistic evalua-
tion suggests that a radical pathway is operating, and that the
use of a dimeric Au-complex as a stable radical initiator was
crucial for optimal performance. The role of gold as a radical
initiator is currently being evaluated in our laboratory.
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This study was funded by the BioValue SPIR, Strategic Platform
for Innovation and Research on value added products from
biomass, co-funded by The Innovation Fund Denmark, case no:
0603-00522B. We are deeply appreciative of the generous
financial support from Haldor Topsøe A/S, the Danish National
Research Foundation (Grant No. DNRF118 and DNRF93) and
Aarhus University. Finally, we thank Jens Christian Kondrup for
the development of the small two-chamber reactors, and Drs.
Jacob Overgaard, Peter Nørby and Vibeke H. Lauridsen for the
X-ray crystallographic analysis.
Keywords: Hydrothiolation ∙ gold ∙ thioethers ∙ reaction mecha-
nism ∙ radical pathway
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Entry for the Table of Contents (Please choose one layout)
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Steffan K. Kristensen, Simon L. R. Laur-
sen, Esben Taarning, Troels Skrydstrup*
SMe
1/2 H2SO4
Cl
H2N
NH
crystalline
SMe
N
Two-chamber
system
Page No. – Page No.
N
NH
tBu
Cl
MeSH (2.5 equiv)
SMe
> 35 examples
Ex Situ Formation of Methanethiol:
Application in Gold(I)-Promoted an-
ti-Markovnikov Hydrothiolation of
Olefins
R
O
N
R
N
O
O
[Au2(NTf2)2(µ-dppf)]
(1 mol%)
R = alkyl,aryl,
heteroatom
MeS
SMe
S
S
We can control it: Finally, hydrothiolation of alkenes with gaseous methanethiol in
near stoichiometric amounts can be achieved promoted by a Au(I)-complex. Key to the
success is the use of a crystalline precursor and a two-chamber reactor, ensuring safe
delivery of the low molecular weight thiol.
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