Calcium-catalyzed bis-hydrothiolation of unactivated alkynes providing dithioacetals

Article abstract of DOI:10.1021/om500442u

Bis-hydrothiolation of alkynes providing anti-Markovnikov dithioacetals is reported. Lewis-acidic Ca(OSO₂C₄F₉)₂ (Ca(ONf)₂) was synthesized for the first time and was shown to be an excellent catalyst

Full text of DOI:10.1021/om500442u

Communication
pubs.acs.org/Organometallics
Calcium-Catalyzed Bis-hydrothiolation of Unactivated Alkynes
Providing Dithioacetals
Martin Hut’ka, Tetsu Tsubogo, and Shu Kobayashi*
̅
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: Bis-hydrothiolation of alkynes providing anti-Markovnikov
dithioacetals is reported. Lewis-acidic Ca(OSO2C4F9)2 (Ca(ONf)2) was
synthesized for the first time and was shown to be an excellent catalyst for
the transformation. The reaction is highly selective and has a wide
substrate scope. It was revealed that vinyl sulfides were intermediates for
this transformation and that Ca(ONf)2 efficiently catalyzed the
unprecedented reactions of unactivated vinyl sulfides with thiols to afford the dithioacetals in good to high yields.
ydrothiolation of an alkyne provides Markovnikov adduct
radius. In spite of these interesting properties, the use of Ca in
organic synthesis has been limited.12 While additions of amines,
phosphines, and alcohols to alkynes catalyzed by calcium
complexes have been reported,13−16 Ca amides or basic Ca
complexes have been used for these reactions, in which Ca
complexes work as strong bases to deprotonate hydrogens of
the substrates, and successful examples have been mostly
limited to intramolecular additions. To our knowledge, there is
no example of addition of thiols (RSH) to alkynes catalyzed by
calcium catalysts.
H
3 and/or anti-Markovnikov adduct 4 (Scheme 1).1−5 In
Scheme 1. Hydrothiolations of Terminal Alkynes
We started investigating the reaction of phenylacetylene (1a)
with benzylthiol (2a). When the reaction was conducted in the
17
presence of 10 mol % of Ca(N(SiMe3)2)2 at 60 °C in THF,
anti-Markovnikov vinyl sulfide 4a was obtained in 70% yield
with an E/Z mixture (E/Z = 10/90) (Table 1, entry 1). We
then examined Lewis-acidic Ca complexes. Recently, it has been
reported that some Lewis-acidic Ca complexes such as
Ca(OTf)2, Ca(NTf2)2, and Ca(NTf2)2/Bu4NPF6 have interest-
ing catalytic activities in several reactions.18−20 We tested
Ca(OTf)2 and Ca(NTf2)2 under identical reaction conditions
and found that 4a was obtained in good yields as an E/Z
mixture (entries 2 and 3). We then focused on a more Lewis-
acidic Ca complex, calcium nonafluorobutanesulfonate (Ca-
(OSO2C4F9)2 = Ca(ONf)2).21 Ca(ONf)2 could be prepared
from CaCO3 and C4F9SO3H (Scheme 2).22 It was found that in
the presence of Ca(ONf)2 the reaction of 1a with 2a proceeded
smoothly to afford 4a and β-dithioacetal 7a in 45% and 43%
yields, respectively (entry 4). When the reaction was conducted
at 100 °C in 1,4-dioxane, 7a was obtained in 84% yield with a
small amount of 4a (entry 5). The reaction also proceeded
smoothly in 1,2-diethoxyethane (DEE) (entry 6). Relatively
longer reaction time led us to consider the use of a microwave
apparatus to accelerate the reaction. Under modified
general, 3 is formed by Brønsted acid- or transition metal-
catalyzed reactions, while 4 is produced by radical-mediated,
Brønsted base-catalyzed, or transition metal-catalyzed reactions.
For the formation of 4, while an E/Z mixture is obtained by
radical-mediated reactions, Brønsted base-catalyzed reactions
give 4Z and transition metal-catalyzed reactions afford 4E or 4Z
selectively. In most cases, the addition stops at the stage of vinyl
sulfides (the first addition); however, the successive second
addition occurs in some cases. While Markovnikov adduct 3
gives α-dithioacetal (5) and vicinal dithioether (6), anti-
Markovnikov adduct 4 provides 6 and another dithioacetal, β-
dithioacetal (7). Dithioacetals are useful and versatile
compounds6−9 and are generally synthesized from carbonyl
compounds.10 Compared with this standard method, direct bis-
hydrothiolation of alkynes represents a more atom-economical
route to dithioacetals. However, this route has not been well
explored; in particular, the route to 7 is very limited.11 In this
paper, we describe a highly selective and efficient route from 1
to 7 using a novel, very Lewis-acidic calcium catalyst.
Special Issue: Catalytic and Organometallic Chemistry of Earth-
Abundant Metals
Calcium is abundant, less toxic, and inexpensive, so the use of
Ca in place of rare elements is desirable. Chemically, Ca has
lower electron negativity, its stable oxidation state is 2, and
there are various coordination sites because of its large ionic
Received: April 27, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/om500442u | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
Table 1. Optimization of the Reaction Conditions
Table 3. Bis-hydrothiolation of Alkynes with Dithiols
entry
1
R1
R2
n
time (h)
8
yield (%)
4a
4a (E/
7a
Ph
H
1
1
1
1
1
2
2
2
2
2
1
2
2
8
8a
8b
8c
8d
8e
8f
81
89
81
81
88
entry
catalyst
conditions
(%)
Z)
(%)
a
2
p-PhC6H4
p-MeOC6H4
p-nBuOOCC6H4
2,5-(MeO)2C6H3
Ph
H
12
12
10
15
1
2
3
4
5
Ca(N(SiMe3)2)2 THF, 24 h, 60 °C
70
75
55
45
<5
10/90
81/19
30/70
60/40
3
4
5
6
H
Ca(OTf)2
Ca(NTf2)2
Ca(ONf)2
Ca(ONf)2
THF, 24 h, 60 °C
THF, 24 h, 60 °C
THF, 24 h 60 °C
H
H
b
b
43
84
H
6 (8)
85 (77)
a
a
dioxane, 24 h,
7
a
p-PhC6H4
p-NO2C6H4
p-CNC6H4
Ph
H
12
10
15
20
20
20
8g
8h
8i
78
92
83
80
81
84
70
100 °C
8
H
6
Ca(ONf)2
Ca(ONf)2
Ca(ONf)2
DEE, 24 h, 100 °C
DEE, 6 h, 100 °C
DEE, 4 h, 100 °C
81
75
82
9
H
b
7
bc
,
a
10
Me
nPr
nPr
Ph
8j
8
11
Ph
8k
8l
a
b
c
Dioxane = 1,4-dioxane. Reaction under microwave conditions. 1 M
a
12
13
Ph
solution.
c
Ph
24
8m
a
b
c
2.0 equiv of 2 was used. 3.0 mmol scale. 2.5 equiv of 2 was used.
Scheme 2. Preparation of Ca(ONf)2
amounts of thiol 2 (entries 5−8). The scope of thiols was
also investigated. It is noted that even aromatic thiophenols
with lower nucleophilicity reacted smoothly under the
conditions to afford the corresponding thioacetals 7i−7k in
good to high yields (entries 9−11). The desired thioacetal (7l)
was also obtained in good yield using another simple alkyl thiol
(entry 12).
conditions, the desired product 7a was obtained in 82% yield in
shorter reaction time (4 h) (entries 7 and 8).
Having established optimized reaction conditions, we next
evaluated the substrate scope of this transformation (Tables 2
After the successful synthesis of acyclic thioacetals, we next
focused on bis-hydrothiolation of alkynes with dithiols leading
to 1,3-dithianes/1,3-dithiolanes (Table 3). Using ethane-1,2-
dithiol or propane-1,3-dithiol, substituted phenylacetylenes
were successfully transformed into substituted 2-benzyl-1,3-
dithiolane (8a−e) or 2-benzyl-1,3-dithiane (8f−i) in high
yields. It is noteworthy that phenyl, methoxy, ester, and nitro
groups were tolerated under the conditions and that the
corresponding dithiolanes 8a−h were obtained in high yields
(entries 1−8). The ortho-substitution of the aromatic ring in 2-
ethynyl-1,4-dimethoxybenzene did not retard the reaction at all
(entry 5). Bis-hydrothiolation of 4-ethynylbenzonitrile also
proceeded regioselectively to form dithiane 8i, and no
competitive addition to nitrile was observed (entry 9).
Moreover, internal alkynes also reacted smoothly to afford
the desired 1,3-dithianes and dithiolanes 8j−m in good to high
yields (entries 10−13).
We then investigated the mechanism of this unprecedented
Ca-catalyzed bis-hydrothiolation of alkynes. Because a mixture
of vinyl sulfide 4a and dithioacetal 7a was obtained in Table 1,
entry 4, we assumed that 4a might be an intermediate of this
transformation. Vinylsulfide 4aE was prepared independently,
and the reaction of 1a with 2a (eq 1) and the reaction of 4aE
with 2a (eq 2) were carefully examined.23 The reaction profiles
of eq 1 and eq 2 are shown in Figure 1. Interestingly, the
reaction of eq 2 was much faster than that of eq 1. It should be
noted that, while not only Ca(ONf)2 but also Ca(OTf)2,
Ca(NTf2)2, and even Ca(N(SiMe3)2)2 catalyzed the reaction of
first addition in eq 1 (Table 1, entries 1−3), only Ca(ONf)2
could catalyze the reaction of eq 2. To our knowledge, the
reaction of an unactivated vinyl sulfide with a thiol is
unprecedented, and this is the first example.24
Table 2. Substrate Scope of Bis-hydrothiolation of Terminal
Alkynes
entry
R1
R2
time (h)
7
yield (%)
1
2
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
4
10
10
8
7a
7b
7c
7d
7e
7f
83
84
83
88
66
76
79
51
81
72
78
78
p-MeC6H4
p-PhC6H4
p-BrC6H4
nBu
a
3
4
a
5
12
12
10
12
12
24
20
20
a
6
a
n-pentyl
n-hexyl
Ph(CH2)3
Ph
7
7g
7h
7i
8
9
a
10
Ph
p-MeOC6H4
p-ClC6H4
n-hexyl
7j
a
11
Ph
7k
7l
a
12
Ph
a
4.0 equiv of 2 was used.
and 3). With 4-alkyl- and 4-aryl-substituted phenylacetylenes,
prolongation of the reaction time and a slight increase in the
amount of 2 led to the corresponding thioacetals 7b and 7c in
high yields (Table 2, entries 2 and 3). An alkyne bearing a
bromo functional group worked well (entry 4). With aliphatic
alkynes, such as hex-1-yne, hept-1-yne, oct-1-yne, and pent-4-
yn-1-ylbenzene, moderate to good yields of the corresponding
thioacetals 7e−h were obtained by using slightly excess
B
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Organometallics
Communication
Scheme 3. Plausible Catalytic Cycle of Ca(ONf)2-Catalyzed
Bis-hydrothiolation of Alkynes
Figure 1. Reaction profiles of eqs 1 and 2.
cat. Ca(ONf)2
1a + 2a ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ [4a] → 7a
(2 equiv)
active species in, for example, hydroamination or hydro-
phosphination.13−16
(1)
(2)
cat. Ca(ONf)2
4aE + 2a ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ 7a
In summary, we have shown that novel and readily available
Ca(ONf)2 is an efficient catalyst for bis-hydrothiolation of
alkynes to afford anti-Markovnikov dithioacetals. This direct
approach toward the dithioacetals from unactivated alkynes has
been very limited. The reaction is highly selective and has a
wide substrate scope of aromatic and aliphatic alkynes bearing
various functional groups, providing dithioacetals, 1,3-dithianes,
and 1,3-dithiolanes directly from alkynes in good to high yields.
The kinetic studies revealed that vinyl sulfides were
intermediates for this transformation and that Ca(ONf)2
efficiently catalyzed the reactions of vinyl sulfides with thiols
to afford the products in good to high yields. To our
knowledge, this is the first example of the reactions of
unactivated vinyl sulfides with thiols. On the basis of 1H
NMR experiments, we hypothesized the formation of [Ca-
(RS)(ONf)2]−H+ as a key species. The enlargement of the
utilization of calcium catalysts in organic synthesis is also noted.
Further studies to clarify the detailed reaction mechanism and
to use Ca(ONf)2 and other Ca catalysts in other organic
syntheses are under way.
To gain further insight into the mechanism and the transition
states, NMR experiments were conducted. These investigations
revealed the temperature dependence of the interaction
between Ca(ONf)2 and a thiol.25 The coordination chemistry
of Ca is dominated by hard O-donor ligands, such as alkoxides,
crown-ethers, β-diketonates, and water (in hydrated salts), and
N-donor ligands, such as amides, diamines, and diimines.12,26 It
is also possible to form Ca complexes with neutral soft S-σ-
donor ligands, such as thioethers.27 According to our
observations from the 1H NMR experiments, we assumed
that Lewis-acidic Ca(ONf)2 interacted with the sulfur atoms
rather than the multiple bonds at 100 °C.28
On the basis of these results, we assumed two possible
transition states in the reaction of a vinyl sulfide with a thiol
catalyzed by Ca(ONf)2 (Figure 2). Model A considers the
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, kinetic experiments, NMR experi-
ments, and spectral data of the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
Figure 2. Possible transition states for Ca(ONf)2-catalyzed hydro-
thiolation of 4.
AUTHOR INFORMATION
Corresponding Author
*E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp.
Notes
interaction of Ca(ONf)2 with the double bond and the sulfur,
resulting in activation of the β-position of the vinyl sulfide,
followed by a sequential nucleophilic attack by the thiol from
the other side of Ca(ONf)2 (Figure 2, A). In model B,
Ca(ONf)2 interacts with the sulfur atoms of the thiol and the
vinyl sulfide. Coordination of the thiol to Ca might increase its
nucleophilicity as well as the acidity of the SH proton, and the
nucleophilic addition of the thiol occurs from the same side of
the coordinated Ca. In both models, the nucleophilic attack of
the thiol prefers the β-position of the vinyl sulfide.
We proposed a catalytic cycle (Scheme 3) involving a
complex, [Ca(RS)(ONf)2]−H+, that might be formed at high
temperature (Scheme 3, C).29 While the nonaflate anion in
Ca(ONf)2 may coordinate to a thiol to form [Ca(RS)-
(ONf)2]−H+, it seems likely that other counteranions such as
−OTf and −NTf2 cannot form [Ca(RS)X2]−H+. This result
indicates that Ca(ONf)2 does not deprotonate a thiol to form a
nucleophilic calcium species, although this is believed to be the
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Japan Society for the Promotion of
Science (JSPS) and Japan Science and Technology Agency
(JST).
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dx.doi.org/10.1021/om500442u | Organometallics XXXX, XXX, XXX−XXX