Palladium-Catalyzed Carbothiolation via Trapping of the σ-Alkyl Palladium Intermediate with RSTIPS

Article abstract of DOI:10.1021/acs.orglett.9b03046

A palladium-catalyzed carbothiolation via the reaction of a σ-alkyl palladium intermediate with a TIPS thioether is described. It was found that the use of Cs₂CO₃, (IPr)Pd(allyl)Cl, and a TIPS thioether was key to obtaining alkyl aryl and dialkyl sulfides in high yield through the reaction of a σ-alkyl palladium intermediate. The developed reaction is applicable to a wide range of substrates and thiols.

Full text of DOI:10.1021/acs.orglett.9b03046

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Carbothiolation via Trapping of the σ‑Alkyl
Palladium Intermediate with RSTIPS
Yosuke Hosoya, Ikumi Kobayashi, Kota Mizoguchi, and Masahisa Nakada*
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo,
Shinjuku-ku, Tokyo 169-8555, Japan
S
* Supporting Information
ABSTRACT: A palladium-catalyzed carbothiolation via the
reaction of a σ-alkyl palladium intermediate with a TIPS
thioether is described. It was found that the use of Cs2CO3,
(IPr)Pd(allyl)Cl, and a TIPS thioether was key to obtaining
alkyl aryl and dialkyl sulfides in high yield through the reaction
of a σ-alkyl palladium intermediate. The developed reaction is
applicable to a wide range of substrates and thiols.
ascade reactions, which are chemical processes that
consist of more than two consecutive reactions, are
Scheme 1. Palladium-Catalyzed Cascade Reactions
C
important in organic synthesis, in terms of efficiency, because
they enable the successive formation of new bonds, leading to
the construction of complex structures while reducing waste
output, as well as the time and labor required for the overall
transformation. Catalytic reactions are also vital in reducing the
use of energy and resources.
Palladium-catalyzed reactions are ideal reactions, because
they feature a catalytic cycle of successive basic reactions.
Moreover, the generated reactive species undergo sequential
reactions in a cascade manner. For example, the Heck reaction
has been a widely used palladium-catalyzed reaction, and the
reaction of substrate, in which β-elimination does not occur,
affords a σ-alkyl palladium intermediate that undergoes
subsequent reaction. Thus, an aryl-Pd(II) intermediate,
which is derived from the oxidative addition of Pd(0) to
compound A (Scheme 1), undergoes alkene insertion to afford
the σ-alkyl palladium intermediate B with an all-carbon
quaternary center at the adjacent position. Intermediate B
does not undergo β-elimination, because of the lack of a β-
hydrogen; however, B will react with a nucleophile to form a
new bond to afford C.
It has been reported that the reaction of σ-alkyl palladium
intermediate B with nucleophiles affords compound C with an
all-carbon quaternary center (see Scheme 1a).1 In addition to
this type of palladium-catalyzed reaction, the reactions of
intermediate B with bis(pinacolate) diboron (Scheme 1b),2
hexamethyldisilane, and hexamethyldistannane (Scheme 1c)3
affording the corresponding alkyl pinacol borane, silane, and
stannane, respectively, have recently been reported.4
Sulfide is stable under both acidic and basic reaction
conditions and can be converted to the corresponding
carbonyl group, a useful synthetic intermediate for organic
synthesis, via the Pummerer rearrangement of the correspond-
ing sulfoxide. Moreover, the carbon−sulfur bond can be
reductively cleaved,7 and when sulfide is oxidized to sulfone, its
anion can act as a nucleophile to form a new bond, after which
the new carbon−sulfur bond can be converted to a carbon−
hydrogen bond by reduction.
Over the course of our synthetic studies on bioactive natural
products, we have noticed that a benzylic all-carbon quaternary
center appended with a functional group is included in many
structures of bioactive natural products.5 Specifically, some
bioactive compounds include an allylic or a benzylic all-carbon
quaternary center with an arylthiomethyl group in their
structures.6
The efficiency and power of palladium-catalyzed processes,
as well as the reasoning described above, prompted us to
develop a method to prepare compound D possessing a
Received: August 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03046
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
benzylic all-carbon quaternary center with an adjacent alkyl or
arylthiomethyl group via σ-alkyl palladium intermediate B.
Palladium-catalyzed carbothiolations starting from organo-
sulfur compounds8 and thiolation of the π-allyl palladium
intermediates9 have been reported. However, to the best of our
knowledge, the thiolation of σ-alkyl palladium intermediate B
has never been reported.10 We have investigated the thiolation
of σ-alkyl palladium intermediate B and found that the
carbon−sulfur bond was successfully formed, affording alkyl
aryl and dialkyl sulfides for the first time; this palladium-
catalyzed cascade reaction was applicable to a wide range of
substrates. Herein, we report the observed findings and results.
We selected compound 1a as a model compound for the
optimization of reaction conditions for the carbothiolation
reaction. Compound 1a was readily prepared by the
Mitsunobu reaction of 2-iodophenol with 3-methylbut-3-ene-
1-ol.11 The preliminary reaction of 1a was performed using
thiophenol and Cs2CO3 in the presence of a catalytic amount
of Pd(PPh3)4 in toluene (see Table 1, entry 1), but no reaction
was noted. The reactions using thiophenol under several
reaction conditions also failed to afford the desired product.
Table 1 indicated that the use of Cs2CO3 accelerated the
reaction rate to afford the desired product, 2a.
We next screened various palladium catalysts to further
optimize the conditions determined from Table 1. Cs2CO3 was
used to investigate the conditions, because 2a was not formed
in the reaction of 1a using Cs2CO3. The reaction using
Pd2dba3 and PPh3 at 100 °C resulted in a decreased yield
(15%) of 2a and the formation of 2b (19%) was observed
(Table 2, entry 1). The use of PdCl2dppf2-CH2Cl2 increased
Table 2. Palladium-Catalyzed Carbothiolation of 1a
a
Yield (%)
entry
catalyst
time (h)
2a
2b
1
2
3
Pd2dba3, PPh3 (20 mol %)
PdCl2(dppf)2-CH2Cl2
21
21
22
8
24
24
24
23
36
36
15
54
74
0
19
0
0
82
54
65
0
0
0
0
0
b
Pd2dba3, dppf (10 mol %)
Pd2dba3, Xantphos (10 mol %)
Pd2dba3, QPhos (20 mol %)
Pd2dba3, AmPhos (20 mol %)
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(allyl)Cl
(IPr)Pd(allyl)Cl
(IPr)Pd(allyl)Cl
4
5
6
Table 1. Palladium-Catalyzed Carbothiolation of 1a
0
12
76
85
91 (90)
14
b
7
8
9
b c
,
c
d
e
10
11
b
Yield (%)
cf
,
36
79
a
a
b
c
entry
base
solvent
temperature (°C) time (h) 2a
2b
Isolated yields. 1b (trace) was formed. Cs2CO3 (3.0 equiv) was
c
d
d
d
1
Cs2CO3
Cs2CO3
Cs2CO3
Et3N
Cs2CO3
K2CO3
Na2CO3
K3PO4
Ag2CO3
CsF
toluene
toluene
DMF
100
80
80
12
10
10
10
10
10
10
10
10
10
24
0
0
used. The yield using the corresponding bromide is given in
parentheses. The reaction in the absence of Cs2CO3. PhSTBS was
e
f
e
2
43
d
0
d
used.
3
4
5
6
0
0
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
80
13
65
48
7
81
14
50
77
9
0
25
21
6
0
16
0
100
100
100
100
100
100
100
the yield to 54% (Table 2, entry 2), while the reaction with
Pd2dba3 and dppf afforded 2a in a yield of 74%, with the
formation of a trace amount of 1b (Table 2, entry 3).
Interestingly, when Pd2dba3 and Xantphos (Table 2, entry
4) or Pd2dba3 and QPhos (Table 2, entry 5) were used, 2a was
not formed; instead, 2b was formed in yields of 82% and 54%,
respectively.14 The reaction with Pd2dba3 and AmPhos also
preferentially afforded 2b (see Table 2, entry 6).
The reactions employing catalysts with NHC ligands
showed different results, compared to those with phosphine
ligands; the reaction using (IPr)Pd(cinnamyl)Cl15 (Table 2,
entry 7) proceeded faster than that with dppf (Table 2, entry
3) to afford 2a in a comparable yield (76%) without forming
2b, giving a trace amount of 1b as a side product. When the
reaction with (IPr)Pd(cinnamyl)Cl was performed with 3.0
equiv of Cs2CO3 (Table 2, entry 8), the yield was increased to
85%, but a trace amount of 1b was still obtained.
Pleasingly, the reaction in the presence of a catalytic amount
of (IPr)Pd(allyl)Cl16 in toluene at 100 °C afforded 2a in a 91%
yield (Table 2, entry 9). Under these conditions, the reaction
required 36 h to reach completion; however, 1b and 2b were
not formed. The reaction of the analogous bromide of 1a also
proceeded under the same reaction conditions to afford 2a in
90% yield, while the reaction of the corresponding chloride did
not proceed under the same conditions. The reaction using
(IPr)Pd(allyl)Cl in the absence of Cs2CO3 afforded 2a in a
yield of only 14% (see Table 2, entry 10), indicating that the
reaction was accelerated by the presence of Cs2CO3. The
e
7
8
9
f
10
11
Cs2CO3
a
b
c
d
e
1.5 equiv. Isolated yields. PhSH was used. No reaction. 1a
f
remained. 1b (56%) was formed.
It has been reported that sulfur compounds can poison
palladium catalysts, because of their strong affinity.12 There-
fore, we next examined the reaction using a thiophenol
derivative bearing a bulky group, which would not coordinate
with a palladium catalyst. Triisopropylsilyl ether of thiophenol
(PhSTIPS)13 was selected for the reaction, because of the
bulkiness of the TIPS group and its stability. To our delight,
the reaction of 1a with PhSTIPS and Cs2CO3 in the presence
of a catalytic amount of Pd(PPh3)4 in toluene at 80 °C
afforded 2a in a 43% yield (Table 1, entry 2). Toluene was
found to be a suitable solvent for this reaction, whereas the use
of other solvents resulted in low yields or no reaction (e.g.,
DMF; see Table 1, entry 3). The use of other bases, except
K3PO4, resulted in lower yields (Table 1, entries 4, 6, 7, 9, and
10) and, in the case of K3PO4 (Table 1, entry 8), the formation
of iodide 2b was noted, while the yield was 81%.14 The
reaction at 100 °C (Table 1, entry 5) and a prolonged reaction
time increased the yield (Table 1, entry 11). The results in
B
DOI: 10.1021/acs.orglett.9b03046
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Letter
reaction with PhSTBS resulted in an inferior yield (79%)
(Table 2, entry 11).
Scheme 3. Palladium-Catalyzed Carbothiolation of 1a with
PhSTIPS in the Presence of PhSH
Under the optimized reaction conditions, reactions of 1a
with a variety of TIPS thioethers were examined (see Scheme
2). The reaction of TIPS thioethers of p-substituted
Scheme 2. Palladium-Catalyzed Carbothiolation of 1a with
Various TIPS Thioethers
Scheme 4. Palladium-Catalyzed Carbothiolation of 3 with
Various TIPS Thioethers
thiophenols afforded 2c−2f with yields of 74%−96%. The
reaction of p-fluorothiophenol was sluggish and required 82 h
to come to completion, likely because of the electronic effect of
the fluorine substituent.17 The reaction of TIPS thioethers of
m- and o-substituted thiophenols proceeded without problem
(affording 2g and 2h−2k, respectively). The reaction of o-
dimethyl thiophenol slowly afforded 2l in a yield of 25%, while
the yield was increased to 48% after 82 h. However, the
reaction of o-dichloro thiophenol did not afford 2m. The
results of 2l and 2m indicate that the yield of this reaction
could be dependent on the steric and electronic effect of the
substituents.17 The reaction of TIPS thioethers of alkanethiols
also afforded the desired products 2n−2p, while these
reactions were sluggish, except the reaction with TIPS
thioether of benzylthiol.
Note that the yield is strongly dependent on the purity of
TIPS thioether, because the crude TIPS thioether contains
thiol, which could coordinate with a catalyst to retard the
reaction. Indeed, the reaction of 1a in the presence of
benzenethiol was found to be sluggish (see Scheme 3).
We next explored the reaction of compound 3 using a
variety of TIPS thioethers under the optimized reaction
conditions (see Scheme 4). The yields of products 4a−4j were
67%−99%, and most yields were better than the corresponding
reactions of 1a (Scheme 2), which forms the six-membered
ring, indicating that this palladium-catalyzed reaction would be
more effective for the formation of five-membered rings. The
reactions with TIPS thioethers of benzylthiol, dodecanethiol,
and propane-2-thiol resulted in low yields.
Scheme 5 shows products 5−13, which were prepared by
the optimized palladium-catalyzed reaction. Compounds 5 and
6 were formed in yields of 89% and 87%, respectively, by the
reaction of aryl-substituted derivatives of 1a. Compound 7,
which is a derivative of compound 3, was also formed in a yield
of 89%. Derivatives of indoline and indolin-2-one, 8−10, which
possess an important scaffold seen in bioactive compounds,5
were also prepared in yields of 74%−99%. The developed
reaction was applicable to the formation of 11, which contains
a six-membered carbocyclic ring, and 12, which is a 2,3,4,5-
tetrahydrobenzo[b]oxepine derivative. This reaction also
produced 13 bearing an electron-withdrawing ester group in
a yield of 79%.
The data shown in Schemes 2, 4, and 5 indicate that the
optimized reaction is applicable to a wide range of substrates
when a TIPS ether of the necessary thiol is used.
It has been reported that the oxidative addition of Pd(0) to
alkyl iodide affords σ-alkyl palladium.18 Hence, alkyl iodide 2b,
which was formed as a side product during the development of
our optimized reaction conditions, could be converted to the
corresponding σ-alkyl palladium intermediate and thus under-
go reaction with PhSTIPS to afford 2a. Indeed, when alkyl
iodide 2b was subjected to the optimized reaction conditions
shown in Scheme 6, 2a was formed in a yield of 64%. Since
compound 2a was formed in 91% yield by the reaction of 1a
under the same reaction conditions (Table 2, entry 9) and the
C
DOI: 10.1021/acs.orglett.9b03046
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Organic Letters
Letter
Scheme 5. Palladium-Catalyzed Carbothiolation with
PhSTIPS
Scheme 7. Plausible Mechanism for the Pd-Catalyzed
Carbothiolation
(allyl)Cl, and a TIPS ether derivative of thiol in toluene was
key to obtain the desired product in high yield. This is the first
example of the formation of alkyl aryl and dialkyl sulfides
through the trapping of the σ-alkyl palladium intermediate with
a TIPS thioether. The developed reaction is applicable to a
wide range of substrates and thiols. Further studies on the
reaction using a variety of substrates and TIPS thioethers are
currently underway.
Scheme 6. Reactions of 2b with PhSTIPS
ASSOCIATED CONTENT
* Supporting Information
■
S
formation of 2b was not observed via TLC during the course
of the reaction, the transformation from 2b to 2a is not
indicated as a major pathway in the reaction of 1a, although it
could not be ruled out. We also tested the reaction of 2b in the
absence of palladium catalyst; no reaction occurred, indicating
that the reaction of 2b with PhSTIPS and Cs2CO3 does not
afford 2a.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03046.
Experiment procedure and the characterizations of the
substrates and products (PDF)
Based on the results of this study and earlier reports, the
proposed catalytic cycle of the developed reaction is given in
Scheme 7. It was rationalized that the palladium-catalyzed
reaction involves the formation of σ-alkyl palladium
intermediates 15−17. The oxidative addition of Pd(0) to 1a
affords σ-aryl palladium intermediate 14, followed by insertion
to the alkene to afford 15. The use of a monodentate ligand,
such as (IPr)Pd(cinnamyl)Cl or (IPr)Pd(allyl)Cl, facilitates
the reaction of 15 with Cs2CO3 to give 16, which undergoes
transmetalation with R2STIPS (R2 = alkyl or aryl) to afford 17,
because of the high affinity of the O and Si atoms. Finally,
reductive elimination of 17 delivers product 2a and also
regenerates Pd(0). σ-Aryl palladium intermediate 14 could also
undergo transmetalation with R2STIPS (where R2 = alkyl or
aryl), but this pathway is dependent on the ligand used. When
a bulky phosphine ligand is employed,14 it could prevent the
reaction of 15 with Cs2CO3; thus, the reductive elimination
affording alkyl iodide 2b preferentially occurs. The iodide 2b
was confirmed to be reconverted to 15 via reaction with Pd(0).
In summary, we have developed a palladium-catalyzed
carbothiolation reaction via the interaction of a σ-alkyl
palladium intermediate with a TIPS ether derivative of alkane
or arylthiol. It was found that the use of Cs2CO3, (IPr)Pd-
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mnakada@waseda.jp.
ORCID
Masahisa Nakada: 0000-0001-6081-5269
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge supports of the Materials Characterization
Central Laboratory, Waseda University, for characterization of
new compounds. This work was financially supported in part
by JSPS KAKENHI (Grant No. JP15H05841 in Middle
Molecular Strategy) and a Waseda University Grant for Special
Research Projects.
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