Palladium-Catalyzed Thiocarbonylation of Benzyl Chlorides with Sulfonyl Chlorides for the Synthesis of Arylacetyl Thioesters

Article abstract of DOI:10.1002/adsc.202100112

A convenient procedure for the synthesis of thioesters has been developed via a palladium-catalyzed thiocarbonylation of benzyl chlorides with sulfonyl chlorides. Various arylacetyl thioesters were produced in good yields by using sulfonyl chlorides as an odorless sulfur source. Furthermore, W(CO)₆ exhibited dual roles as both a solid CO surrogate and reductant here. (Figure presented.).

Full text of DOI:10.1002/adsc.202100112

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DOI: 10.1002/adsc.202100112
Palladium-Catalyzed Thiocarbonylation of Benzyl Chlorides with
Sulfonyl Chlorides for the Synthesis of Arylacetyl Thioesters
Wei Wang,a Xinxin Qi,a,* and Xiao-Feng Wub,*
a
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, People’s Republic of China
E-mail: xinxinqi@zstu.edu.cn
b
Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 116023,
Dalian, Liaoning, People’s Republic of China
and
Leibniz-Institut für Katalyse e.V. an der, Institution Universität Rostock, Albert-Einstein-Straße 29a, Rostock 18059, Germany
E-mail: xiao-feng.wu@catalysis.de
Manuscript received: January 26, 2021; Revised manuscript received: March 2, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100112
since its discovery.[10,11] This catalytic system has been
regarded as one of the most atom-economic approach
for its broad applications in the synthesis of carbonyl-
Abstract: A convenient procedure for the synthesis
of thioesters has been developed via a palladium-
catalyzed thiocarbonylation of benzyl chlorides with
containing compounds. Hence, various carbonylation
sulfonyl chlorides. Various arylacetyl thioesters
reactions has been achieved for the preparation of
were produced in good yields by using sulfonyl
thioesters from aryl halides[12] and unsaturated
chlorides as an odorless sulfur source. Furthermore,
compounds.[13] However, these reactions usually em-
W(CO)6 exhibited dual roles as both a solid CO
ployed thiols as sulfur source, which suffered from
surrogate and reductant here.
some disadvantages such as bad odor and poisonous
catalyst properties.[14] As a result, several carbonylation
reactions with alternative sulfur sources have been
Keywords: palladium
catalyst;
Carbonylation;
reported. For examples, in 2016, thiosulfates were used
as sulfurating reagent in a palladium-catalyzed thio-
carbonylation in Jiang’s group (Scheme 1, eq a).[15]
Benzyl chloride; Sulfonyl Chloride; Thioester
Thioesters represent a type of useful building scaffolds,
which are widely investigated in organic synthesis as
air-stable and easy-handling acyl donors for construct-
ing diverse aldehydes,[1] ketones,[2] esters,[3] and so
on.[4] They play an important role in biological process,
for example, acetyl CoA involved citric acid cycle,[5]
or in the case of native chemical ligation, an valuable
protein preparation from
a
C-terminal peptide
thioester.[6] Therefore, the synthesis of thioesters has
drawn much attentions from chemists and much efforts
has been put on it. Traditionally, methods for the
synthesis of thioesters are mainly based on the acyl
substitution, which used thiol as the sulfur source.[7]
Alternatively, many other protocols, including oxida-
tive coupling reactions of aldehydes,[8] and substitution
of haloalkanes have been explored as well.[9] Although
much efforts have been put on this area, the develop-
ment of novel alternative catalytic system remains an
interesting field to study.
In recent decades, transition-metal-catalyzed car-
bonylation reactions has been intensively investigated
Scheme 1. Thiocarbonylation Reactions with Sulfur Sources.
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Table 1. Screening of Reaction Conditions.[a]
Very recently, Lee and co-workers disclosed the
palladium-catalyzed carbonylative synthesis of thioest-
ers in the presence of thioacetates, and sulfonyl
hydrazides, respectively (Scheme 1, eq b–c).[16] Addi-
tionally, our group also explored the thiocarbonylation
reactions with sulfonyl chlorides as an inexpensive and
attractive sulfur precursor (Scheme 1, eq d).[17]
On the other hand, compare to aryl halides, the
utilization of benzyl halides (a class of special Csp3À X
electrophile) has not been reported in thiocarbonylation
reactions. In our continuous study on sulfonyl chlor-
ides involved thiocarbonylation reactions, we wish to
disclose here a palladium-catalyzed thiocarbonylation
reaction of benzyl chlorides with sulfonyl chlorides
(Scheme 1, eq e). With sulfonyl chlorides as an odor-
less sulfur source, various desired arylacetyl thioesters
were produced in good yields by using W(CO)6 as
both a solid CO surrogate and reductant.
Entry [Pd]
Ligand
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2 DPEphos K3PO4 CH3CN
Pd(OAc)2 DPEphos Na2CO3 CH3CN
0
trace
19
11
6
Pd(OAc)2 DPEphos Et3N
CH3CN
Pd(OAc)2 DPEphos DIPEA CH3CN
Pd(OAc)2 DPEphos DBU
Pd(OAc)2 Xantphos Et3N
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
23
Pd(OAc)2 DPPP
Pd(OAc)2 Xphos
Pd(OAc)2 Sphos
Et3N
Et3N
Et3N
trace
trace
trace
36
20
trace
10[b] Pd(OAc)2 Xantphos Et3N
11
12
13
14
15
16
17
Pd(OAc)2 Xantphos Et3N
Pd(OAc)2 Xantphos Et3N
Pd(OAc)2 Xantphos Et3N
Pd(OAc)2 Xantphos Et3N
Pd(TFA)2 Xantphos Et3N
Pd(acac)2 Xantphos Et3N
DMSO
1,4-Dioxane trace
Initially, benzyl chloride and p-toluenesulfonyl
chloride were chosen as the model substrates for this
thiocarbonylation reaction. Conducting the reaction in
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
trace
25
18
20
62
°
CH3CN at 110 C for 24 h with Pd(OAc)2 as the
PdCl2
Xantphos Et3N
catalyst, DPEphos as the ligand, K3PO4 as the base,
Mo(CO)6 as the CO source in the presence of H2O,
unfortunately, no desired thioester 3ab was detected
(Table 1, entry 1). Then various bases, such as
Na2CO3, Et3N, DIPEA, and DBU were studied to
promote this reaction (Table 1, entries 2–5), to our
delight, 19% yield was observed with Et3N as the base
(Table 1, entry 3). We subsequently examined the
ligands effect, and a slightly higher yield was obtained
with Xantphos (Table 1, entry 6). When the temper-
18[c] Pd(OAc)2 Xantphos Et3N
19[c,d] Pd(OAc)2 Xantphos Et3N
20[c,d,e] Pd(OAc)2 Xantphos Et3N
63
72
[a] Reaction conditions: benzyl chloride (0.5 mmol), p-toluene-
sulfonyl chloride (0.6 mmol), catalyst (5 mol%), ligand
(10 mol% for monodentate ligands, 5 mol% for bidentate
ligands), Mo(CO)6 (1.5 equiv.), base (1.5 equiv.), H2O
°
(1 equiv.), CH3CN (2 mL), 110 C, 24 h. GC yield, with
dodecane as the internal standard.
[b]
°
100 C.
°
ature was decreased to 100 C, 36% yield of 3ab was
[c] W(CO)6 (1.5 equiv.).
formed (Table 1, entry 10). Solvent screening showed
that CH3CN tended to be the optimal solvent for this
transformation (Table 1, entries 11–14). Subsequently,
various palladium catalysts were used, including Pd-
(TFA)2, Pd(acac)2, and PdCl2, the yields were all
dropped (Table 1, entries 15–17). In addition, by using
[d] Pd(OAc)2 (3 mol%), Xantphos (3 mol%).
[e] Benzyl chloride (0.2 mmol), p-toluenesulfonyl chloride
(0.24 mmol), CH3CN (1 mL).
W(CO)6 as the CO source, the yield of 3ab increased target product could be detected by using CO gas
to 62% (Table 1, entry 18). This improvement is (1 bar) instead of W(CO)6.
benefited by the fact that W(CO)6 can release CO at
With the optimal reaction conditions in hand, the
lower temperature. This decreased reaction temper- substrate scope of benzyl chlorides was investigated
ature then favor the target reaction due to the high and shown in Scheme 2. Benzyl chlorides with
reactivity of benzyl chloride and low stability of electron-rich group, including methyl, tert-butyl, and
benzylpalladium intermediate. When employing methoxy groups, the target products were produced in
3 mol% of Pd(OAc)2 along with 3 mol% of Xantphos moderate to good yields (3ab–3fb). Substrate with
could also provide comparable yield as with 5 mol% of disubstituted group could also work well to provide the
Pd(OAc)2 (Table 1, entry 19). It was noteworthy that desired thioester product in good yield (3gb). Benzyl
the concentration of the reaction mixture affected the chlorides bearing electron-deficient group such as
product yield dramatically, 72% yield of the expected trifluoromethyl and ester groups, the targeted products
thioester was obtained with 0.2 molar-scale in 1 mL were obtained in moderate yields (3hb–3ib). Addi-
CH3CN (Table 1, entry 20). Decreased concentration tionally, halogen groups, involving fluoro and chloro
improves the reaction selectivity significantly, because substituents were tested, the corresponding thioesters
less thioether were formed at lower concentration. It is were formed in 48–75% yields (3jb–3mb). Substrates
also important to mention that no reaction occurred in with 1-naphthalene moiety also worked well in this
the absence of palladium catalyst. Additionally, no thiocarbonylation reaction, resulting the final product
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Scheme 3. Substrate Scope of Arylsulfonyl Chlorides. Reaction
conditions: benzyl chloride (0.2 mmol), arylsulfonyl chlorides
(0.24 mmol), Pd(OAc)2 (3 mol%), Xantphos (3 mol%), W(CO)6
(1.5 equiv.), Et3N (1.5 equiv.), H2O (1 equiv.), CH3CN (1 mL),
Scheme 2. Substrate Scope of Benzyl Chlorides. Reaction
conditions: benzyl chlorides (0.2 mmol), p-toluenesulfonyl
chloride (0.24 mmol), Pd(OAc)2 (3 mol%), Xantphos (3 mol%),
W(CO)6 (1.5 equiv.), Et3N (1.5 equiv.), H2O (1 equiv.), CH3CN
°
100 C, 24 h, isolated yield.
°
(1 mL), 100 C, 24 h, isolated yield.
in 56% yield (3nb). Moreover, 3-(chloromethyl)
thiophene could smoothly reacted with p-toluenesul-
fonyl chloride to afford the expected product in 58%
yield (3oa) as well.
We then continue our studies with the variation of
arylsulfonyl chlorides under our standard reaction
conditions, and the results are summarized in
Scheme 3. Arylsulfonyl chlorides with electron-donat-
ing group, including methyl, tert-butyl, methoxy, and
trifluoromethoxy groups worked very well to provide
the desired products in moderate to good yields (3aa–
3af). Substrate with poly-substituents was also toler-
ated well to afford the corresponding thioester in 51%
Scheme 4. Proposed Reaction Mechanism.
yield (3ag). Furthermore, Halogen groups, such as chloride promoted by W(CO)6 in the presence of water.
fluoro, chloro, and bromo groups were examined, the Nucleophilic attack of the sulfide to acylpalladium
target thioesters were obtained in 66%, 59%, and 56% complex II affords intermediate III,[17b] which under-
yields, respectively (3ah–3aj). 1-Biphenyl and 1- goes reductive elimination to furnish the desired
naphthalene substituents were also found to be compat- thioester products and regenerates the active palladium
ible; the desired products were obtained in 66% and complex for the next catalytic cycle.
54% yields (3ak–3al), respectively.
In summary, we have disclosed a general and
Based on the previous study, a plausible reaction straightforward palladium-catalyzed thiocarbonylation
mechanism is proposed (Scheme 4). Firstly, the oxida- reaction of benzyl chlorides with sulfonyl chlorides. A
tive addition of benzyl chlorides to Pd0Ln leads to variety of arylacetyl thioesters were obtained in
benzylpalladium complex I, which is then transformed moderate to good yields with good functional group
into acylpalladium complex II via insertion of CO tolerance. Notably, benzyl chlorides were first utilized
(released from W(CO)6). Meanwhile, a reduced sulfide as carbon electrophiles in thiocarbonylation reaction,
intermediate was obtained by reduction of sulfonyl and sulfonyl chlorides served as odorless sulfur source.
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Pd(OAc)2 (3 mol%, 1.4 mg), Xantphos (3 mol%, 3.5 mg), W-
(CO)6 (0.3 mmol, 105.6 mg) were added to an oven-dried tube
(15 mL), which was then placed under vacuum and refilled with
nitrogen for three times. Benzyl chlorides (0.2 mmol), sulfonyl
chlorides (0.24 mmol), H2O (0.2 mmol, 3.6 mg), Et3N
(0.3 mmol, 30.4 mg), and CH3CN (1 mL) were added into the
tube via syringe. The tube was sealed, and the mixture was
°
stirred at 100 C for 24 h. After the reaction was completed, the
crude mixture was filtered and concentrated under vacuum. The
crude product was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate=50/1, volume ratio) to afford
the desired thioester products.
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We thank the financial supports from the Natural Science
Foundation of Zhejiang Province (LY21B020010) and the
Fundamental Research Funds of Zhejiang Sci-Tech University
(2020Q038).
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Palladium-Catalyzed Thiocarbonylation of Benzyl Chlorides
with Sulfonyl Chlorides for the Synthesis of Arylacetyl Thio-
esters
Adv. Synth. Catal. 2021, 363, 1–6
W. Wang, X. Qi*, X.-F. Wu*