Palladium-Catalyzed Alkene Thioacylation: A C?S Bond Activation Approach for Accessing Indanone Derivatives

Article abstract of DOI:10.1002/adsc.202100293

A palladium-catalyzed intramolecular alkene thioacylation reaction initiated by the activation of thioester C(acyl)?S bonds is reported. This approach successfully suppressed decarbonylation and β-hydrogen elimination with related acyl and alkyl metal thiolate intermediates, providing an efficient and atom-economical method to access indanone scaffolds. Mechanistic studies provide support for C(acyl)?Pd bond insertion of olefins. The synthetic utility of this protocol is demonstrated by the further conversion of the newly formed methylene sulfide substituent. (Figure presented.).

Full text of DOI:10.1002/adsc.202100293

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DOI: 10.1002/adsc.202100293
Palladium-Catalyzed Alkene Thioacylation: A CÀ S Bond
Activation Approach for Accessing Indanone Derivatives
Jianing Wu,a Wen-Hua Xu,a,* Hong Lu,a,* and Peng-Fei Xub,*
a
Key Laboratory of Synthetic and
Natural Functional Molecule Chemistry of the Ministry of Education,
College of Chemistry & Materials Science,
Northwest University, Xi’an 710069
E-mail: xuwenhua.qf@gmail.com; luh@nwu.edu.cn
State Key Laboratory of Applied Organic Chemistry,
b
College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000
E-mail: xupf@lzu.edu.cn
Manuscript received: March 6, 2021; Revised manuscript received: April 11, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100293
can be synthesized using various methods based on
acylation chemistry or metal-catalyzed transforma-
tions. The decarbonylative addition of thioesters to
unsaturated bonds represents an attractive approach for
Abstract: A palladium-catalyzed intramolecular al-
kene thioacylation reaction initiated by the activa-
tion of thioester C(acyl)À S bonds is reported. This
approach successfully suppressed decarbonylation
the simultaneous introduction of carbon and sulfur
and β-hydrogen elimination with related acyl and
functional groups,[7] demonstrated in the pioneering
alkyl metal thiolate intermediates, providing an
works of Pt-catalyzed carbothiolation of alkynes,[8a] as
efficient and atom-economical method to access
well as the recent work of Matsubara et al. on Ni-
indanone scaffolds. Mechanistic studies provide
catalyzed reactions.[8b–d] In contrast, transition-metal-
support for C(acyl)À Pd bond insertion of olefins.
catalyzed thioacylation of unsaturated systems, espe-
The synthetic utility of this protocol is demonstrated
cially for alkene, is relatively underdeveloped
by the further conversion of the newly formed
(Scheme 1A).[9–11] The hitherto known successful ex-
methylene sulfide substituent.
amples are limited to the use of activated olefins such
as allenes[9c] and norbornenes.[9e]
Motivated by the pivotal role of CÀ S bond
formation in organic synthesis and the pharmaceutical
importance of sulfur-containing compounds,[12] we
wanted to explore the feasibility of using a “cut and
sew” approach by investigating thioesters. The intra-
Keywords: Thioacylation; Thioester; CÀ S Bond
activation; Palladium catalysis; Indanone
The transition-metal-catalyzed “cut and sew” trans- molecular insertion of olefins into the C(acyl)À S bonds
formation has recently emerged as a useful strategy for of thioesters, which proceed much faster than inter-
preparing complex molecular structures.[1] This strat- molecular reactions and are easier to control in
egy provides efficient access to substituted molecules transition-metal-catalyzed reaction, leads to an inda-
from readily available alkenes by installing functional none framework, which is a key motif in a number of
groups across their carbonÀ carbon double bonds. biologically important natural products (Figure 1).[13]
Molecular complexity can be built by coupling olefins However, achieving the desired CÀ S bond formation is
with a range of simple, readily available starting not trivial (Scheme 1B, Path A) because decarbon-
materials, such as aldehydes,[2] ketones,[3] esters,[4] and ylative products are generally dominant when olefin
amides.[5]
insertion is slow (Scheme 1B, Path B),[14] and alkyl
Thioesters are more reactive than alcohol-derived metal thiolate intermediates tend to undergo β-hydride
esters because of the poorer orbital overlap between elimination rather than the desired CÀ S bond formation
the sulfur atom and the carbonyl group. They have (Scheme 1B, Path C).[15] Herein, we describe the
similar reactivity to acyl chloride, but they are bench development of a palladium-catalyzed olefin thioacyla-
stable and can be stored for a long time.[6] Thioesters tion reaction of thioesters for rapid access to indanone.
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Table 1. Optimization of reaction conditions.[a]
entry catalyst
ligand
additive yield (%)[b]
1
2
3
4
5
6
7
Ni(cod)2
Ni(acac)2
Ni(PPh3)2Cl2
Pd(PPh3)4
Pd(OAc)2
PdCl2
dppb
dppb
dppb
dppb
dppb
dppb
–
–
–
–
–
–
–
54
52
22
49
55
57
8
[Rh(OH)(cod)]2 dppb
8
9
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
dppp
PPh3
IMes·HCl
2,2’-bipyridine
dppb
dppb
dppb
dppb
–
–
–
–
<5
48
n.r.
n.r.
67
79
10
11
12
13
14
NaF
KF
K2CO3 63
KF 51
Scheme 1. Transition-metal-catalyzed C(O)–S bond cleavage
and transfer reactions.
15[c] PdCl2
[a] Reaction conditions: 1a (0.1 mmol), catalyst (10 mol%),
°
ligand (20 mol%), additive (10 mol%) in MeCN at 120 C
for 18 h.
1
[b] The yield was determined by H NMR using CH2Br2 as an
internal standard.
[c] PdCl2 (5 mol%) and dppb (10 mol%) were used.
improving the yield to 79%. Finally, reducing the
catalyst loading resulted in diminished yields, with the
formation of 2a with 51% yield.
With the optimized reaction conditions determined,
the substrate scope with regard to the thioester was
examined. As shown in Table 2, a range of thioesters
smoothly underwent the olefin thioacylation reaction
to deliver an indanone in moderate to high yields
(Table 2, 2a–2k). Indanone 2a was isolated in 75%
Figure 1. Representative biologically active molecules derived
from indanone derivatives.
For optimization of the reaction conditions, we yield, and other thioesters with electron-withdrawing
utilized thioester 1a, which incorporates a terminal (2b–2d) and electron-donating (2e–2g) substituents,
olefin, as a standard substrate. Initially, various types at either the para or meta position, were similarly
of Pd, Ni, and Rh catalysts, which have previously efficient. Disubstituted phenyl (2i) and 2-naphthyl (2j)
been successfully used in the activation of C(acyl)À S substituents could also be readily incorporated. Fur-
bonds,[12] were tested (Table 1, entries 1–7). As thermore, heterocyclic thioesters (2k) can readily
anticipated, these catalysts afforded the desired product participate in this reaction. It is notable that the
2a, as confirmed by X-ray crystallography,[16] and a sterically hindered thioester provided indanone 2h in a
promising result was achieved using PdCl2 as the moderate yield of 51%, accompanied by the recovery
catalyst (Table 1, entry 6). Although the reactions with of 1h in 38% yield. Alkyl thioesters with benzyl and
Ni(cod)2, Ni(acac)2 and Pd(OAc)2 gave the products in ethyl substituents were also investigated, but no
comparable yields, a complex mixture with decom- product was observed.[18]
position of the starting material was observed (Table 1,
After examining the influence of the thioester on
entries 1, 2 and 5). Next, other ligands were tested to the reactivity, the effect of substitution on the arene
improve the reaction efficiency, and dppb was deter- moiety was evaluated. A broad range of functional
mined to be the best (Table 1, entries 8–11). Attempts groups can readily generate indanone products (2l–
with additives succeeded in improving the reaction 2v). Methyl and electron-rich methoxy groups at the
performance, and KF displayed the best result,[17] 3-, 4-, or 5-positions of arene all gave the thioacylation
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Table 2. Substrate scope of Pd-catalyzed olefin thioacylation
reaction of thioesters.[a,b]
Scheme 2. Proposed mechanism.
C(acyl)À S bond to form aroyl palladium(II) intermedi-
ate I. At this stage, two pathways are possible: one is
the migration insertion of the C(acyl)À Pd bond into the
olefin (Scheme 2, Path A), which undergoes reductive
elimination to form the product. An alternative path is
the olefin insertion into the PdÀ S bond (Scheme 2,
Path B), and the subsequent reductive elimination via
intermediate III to form the product.
To gain mechanistic insights, a preliminary DFT
study was conducted. Two possible mechanistic path-
ways are shown in Figure 2. The catalytic cycle starts
with coordination between the Pd(0) complex and
substrate 1a, giving catalyst-substrate complex INT0.
INT0 undergoes oxidative addition via TS1, requiring
an activation free energy of 6.3 kcalmolÀ 1. This step is
exoergic by 0.2 kcalmolÀ 1 and generates INT1. In Path
A, olefin migration insertion into the C(acyl)À Pd bond
converts INT1 to INT2-A (via TS2-A), followed by
CÀ S reductive elimination (via TS3-A) to give the
product. An alternative path is olefin insertion into the
PdÀ S bond (Scheme 2, Path B), which generates
INT2-B (via TS2-B) for the C(acyl)À C reductive
elimination (via TS3-B) to form the product. The
reductive elimination processes (TS3-A and TS3-B)
have the highest energy barriers in these two pathways.
[a] Reaction conditions: 1 (0.1 mmol), PdCl2 (10 mol%), dppb
°
(20 mol%), KF (10 mol%) in MeCN at 120 C for 18 h.
[b] Isolated yield.
products in moderate to good yields (2u, 2l and 2p, TS3-A is more stable than TS3-B by 8.3 kcal/mol,
2q). Halide-functionalized substrates, such as chloro- which indicates that the CÀ S reductive elimination
(2m) and bromo- (2n) thioesters, which are generally (Path A) is preferred.
reactive moieties in transition metal catalysis, are well
To demonstrate the significance of the developed
tolerated. The use of substrates containing a fluoride protocol further, we performed a gram-scale reaction,
(2r) or trifluoromethyl group (2s), both of which are and the reaction proceeded smoothly to afford the
critical in medicinal chemistry, gave rise to products corresponding product 2f in comparable yield
smoothly. As demonstrated by the synthesis of 2o, (Scheme 3). In addition, considering the potential of
substrates bearing free phenol could also be utilized. It this methodology for the construction of indanone for
is important that full selectivity for C(acyl)À S activa- diverse applications, a reduction of 2f followed by a
tion was observed in the reaction of ester- and Friedel-Crafts-type cyclization was performed, produc-
thioester-containing substrates (1t), attesting to the ing polycycle product 3a (Scheme 3, eq A).[19]
high chemoselectivity of this protocol. Finally, arene Selective oxidation of 2f and further functionalization
containing a substituted allyl unit was also evaluated, can be achieved by transferring the CÀ S bond to a
forming the desired product in moderate yield (2v).
CÀ C bond (Scheme 3, eq B).[20] The thioether group
Two different pathways to achieve the desired can also be removed under mild conditions, and further
products are proposed in Scheme 2. Initially, the active cyclization giving polycycle product 3c with the
Pd(0) catalyst can oxidatively add to the thioester presence of P(p-tolyl)3 and PBu3 (Scheme 3, eq C).[21]
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Figure 2. DFT-calculated reaction energy profile of Pd-catalyzed alkene thioacylation.
scope of thioester-based coupling are ongoing in our
group and will be reported in due course.
Experimental Section
General experimental procedures of intramolecular cou-
pling. In a nitrogen filled glove box, a 2.0 mL vial was charged
with the thioester substrates (1, 0.1 mmol), PdCl2 (1.8 mg,
0.01 mmol), dppb (8.5 mg, 0.02 mmol) and potassium fluoride
(0.6 mg, 0.01 mmol). After adding 0.5 mL CH3CN, the vial was
°
capped and the solution was maintained at 120 C for 18 h.
Upon completion, it was cooled to room temperature and the
solvent was removed by rotary evaporator under reduced
pressure. The crude product was directly purified by silica gel
flash chromatography to yield 2.
Scheme 3. Derivatization of products.
In conclusion, we developed a Pd-catalyzed intra-
molecular alkene thioacylation reaction initiated by the
activation of thioester C(acyl)À S bonds. This process
tolerated variation on both the alkene and aryl
moieties, providing an efficient and atom-economical
method to access indanone scaffolds. Most impor-
tantly, this approach successfully suppressed decarbon-
ylation and β-hydrogen elimination with the related
acyl and alkyl metal thiolate intermediates, furthering
the utility of thioesters as powerful building blocks in
organic synthesis. DFT studies demonstrated that the
likely mechanism involves C(acyl)À Pd bond insertion
of olefins. Further studies aimed at expanding the
Acknowledgements
We are grateful to financial support from the Shaanxi Province
Science Foundation for Youths (No. 2020JQ-574), Scientific
Research Program Funded by Shaanxi Provincial Education
Department (No. 20JK0937) and the National Natural Science
Foundation of China (No. 21632003).
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Palladium-Catalyzed Alkene Thioacylation: A CÀ S Bond Ac-
tivation Approach for Accessing Indanone Derivatives
Adv. Synth. Catal. 2021, 363, 1–6
J. Wu, W.-H. Xu*, H. Lu*, P.-F. Xu*