Ir(III)-Catalyzed and Ag2O-Promoted C?H/C?H Cross-Coupling/Intramolecular Cyclization of Ketene Dithioacetals with Benzothiophene

Article abstract of DOI:10.1002/adsc.202100682

A tandem Ir(III)-catalyzed and Ag₂O-promoted cross-dehydrogenative coupling (CDC)/ intramolecular cyclization of ketene dithioacetals with benzothiophene derivatives was developed, affording a series of sulfur-containing cyclization compounds. Mechanistic investigation demonstrated a radical process may be involving intramolecular cyclization. This tandem reaction described herein could be carried out with a broad range of substrates and wide functional group tolerance. (Figure presented.).

Full text of DOI:10.1002/adsc.202100682

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doi.org/10.1002/adsc.202100682
Ir(III)-Catalyzed and Ag2O-Promoted CÀ H/CÀ H Cross-
Coupling/Intramolecular Cyclization of Ketene Dithioacetals with
Benzothiophene
Jinkang Chen,a Chuanliu Yin,b Jian Zhou,b and Chuanming Yua, b,*
a
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology,
310014 Hangzhou, People’s Republic of China
Fax: (+86)571-88320867)
E-mail: ycm@zjut.edu.cn
b
College of Pharmaceutical Sciences, Zhejiang University of Technology, 310014 Hangzhou, People’s Republic of China
Manuscript received: June 4, 2021; Revised manuscript received: July 7, 2021; Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100682
and high efficiency. Although these methods are
efficient, the tandem Ir(III)-catalyzed cross-dehydro-
Abstract: A tandem Ir(III)-catalyzed and Ag2O-
promoted cross-dehydrogenative coupling (CDC)/
genative coupling and the intramolecular cyclization to
intramolecular cyclization of ketene dithioacetals
construct of various polycycle scaffolds still needs
with benzothiophene derivatives was developed,
further exploration.
affording a series of sulfur-containing cyclization
compounds. Mechanistic investigation demonstrated
On the other hand, sulfur-containing motifs were
frequently found as core structures in agrochemical,
a radical process may be involving intramolecular
pharmaceutical and material science.[8] In particular,
cyclization. This tandem reaction described herein
ketene dithioacetals, as an important class of sulfur-
could be carried out with a broad range of substrates
containing compounds, have been widely used in the
and wide functional group tolerance.
synthesis of heterocycles, tetrasubstituted alkenes, and
aromatic compounds.[9] In this area, a number of
directed C(olefin)-H functionalization of ketene di-
Keywords: Ir(III)-catalyzed; Ag2O-promoted; cross-
dehydrogenative coupling; ketene dithioacetals; ben-
zothiophene derivatives
thioacetals has been reported successfully by Yu’s,
Lei’s, Wang’s and other groups, such as
alkenylation,[10]
alkoxylation,[13]
alkylation,[11]
allylation,[12]
phosphorylation,[14]
and
other
functionalizations.[15] In 2011, Yu’s group reported a
Recently, transition-metal catalyzed CÀ H functionali- Pd-catalyzed Liebeskind-Srogl cross-coupling reaction
zation has emerged as a straightforward, atom/step- of α-oxo ketene dithioacetals with boronic acids to
economic and powerful approach in modern organic afford multisubstituted olefins (Scheme 1a).[16] Re-
synthesis.[1] In particular, the cross-dehydrogenative cently, they reported photoredox-catalyzed C(olefin)-H
coupling (CDC) of arenes and heteroarenes provides a arylation of ketene dithioacetals with aryldiazonium
straightforward and reliable strategy for the construc- salts to afford tetrasubstituted alkenes (Scheme 1b).[17]
tion of various bi(hetero)aryls.[2] Moreover, the chela-
Despite these great success achieved, the transition-
tion assisted CDC reaction, which can not only metal catalyzed C(aryl)-H functionalization of ketene
improve the regioselectivity and chemoselectivity, but dithioacetals, especially arylation and heteroarylation,
also construct more complex and interesting com- still remains unsolved. Inspired by studies on CÀ H
pounds through further synthesis.[3] In this field, functionalization of ketene dithioacetals as well as our
various functional groups has been achieved as recent research on CÀ H functionalization,[18] herein, we
directing groups on cross-dehydrogenative coupling present a highly efficient and simple one-pot synthetic
reaction to construct bi(hetero)-aryls using various protocol to sulfur-containing cyclization compounds
transition metal catalysts, such as Ru(II),[4] Rh(III),[5] via tandem Ir(III)-catalyzed CÀ H/CÀ H cross-coupling
Ir(III),[6] Pd(II),[7] etc. Specifically, Ir(III)-catalyzed of ketene dithioacetals with benzothiophene derivatives
oxidative cross-dehydrogenative coupling of functional and Ag2O-promoted intramolecular cyclization (Sche-
arenes with heteroarenes has gained increasing atten- me 1c).
tion owing to their broad functional group tolerance
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Table 1. Optimization of Reaction Conditions.[a]
Entry Variation from the standard conditions
Yield[b]
1
None
70
(65[c])
34
2
3
4
5
[Cp*RhCl2]2 instead of [Cp*IrCl2]2
Other catalysts instead of [Cp*IrCl2]2
DCE, TFE instead of HFIP
Other solvents instead of HFIP
Ag2CO3 instead of Ag2O
0[d]
30, 36
0[e]
36
6
7
8
9
10
11
12
13
14
15
Cu(OAc)2 instead of Ag2O
0
0
49
52
39
36
60
0
Scheme 1. CÀ H Arylation and Heteroarylation of Ketene
PhI(OAc)2 instead of Ag2O
HOPiv instead of Cu(OPiv)2
Zn(OAc)2 instead of Cu(OPiv)2
NaOPiv instead of Cu(OPiv)2
(BnO)2PO2H instead of Cu(OPiv)2
Cu(OAc)2 instead of Cu(OPiv)2
without [Cp*IrCl2]2
[Cp*IrCl2]2 (5 mol%)/AgSbF6 (20 mol%) was 54
used
3.0 equiv. 1a and 1.0 equiv. 2a were used
Dithioacetals.
Initially, ketene dithioacetal 1a and 1-benzothio-
phene 2a had been chosen as the model to optimize
reaction conditions (Table 1). The desired product 3aa
could be obtained in 65% isolated yield in the presence
of [Cp*IrCl2]2 (7.5 mol%), AgSbF6 (30 mol%), Ag2O
(4.0 equiv.), Cu(OPiv)2 (50 mol%) and HFIP (1 mL) at
16
56
[a] Reaction condition: 1a (0.1 mmol), 2a (0.3 mmol),
[Cp*IrCl2]2 (7.5 mol%), AgSbF6 (30 mol%), Ag2O
(0.4 mmol), Cu(OPiv)2 (0.05 mmol), HFIP (1 mL), Ar,
°
135 C for 24 h under an argon atmosphere (entry 1),
and its precise structure was unambiguously verified
by X-ray crystallography (CCDC 2085472). Further
screening catalysts showed that [Cp*IrCl2]2 was found
to be the optimal choice (entries 2–3). Various sol-
vents, such as DCE, TFE, MeCN, EtOH, DMF, toluene
and 1,4-dioxane were tested for their efficacies, all of
these solvents were less effective than HFIP (entries 4–
5). In this reaction, the efficacy of HFIP might be
attributed to its ability to stabilize cationic
intermediates.[19] Then screening of oxidants showed
that 4.0 equiv. of Ag2O was superior to other oxidants
°
135 C, 24 h.
[b] Determined by 1H NMR with 1,3,5-trimethoxybenzene
standard.
[c] Isolated yields.
[d] [(p-cym)RuCl2]2,
Cp*Co(CO)I2,
IrCl3 ·3H2O were used as catalyst.
RhCl3 ·3H2O
and
[e] MeCN, EtOH, DMF, toluene and 1,4-dioxane were used as
solvent.
(entries 6–8). Then various additives were also exam- had an effect on the reactivity. Unfortunately, the
ined, these includes HOPiv, Zn(OAc)2, NaOPiv, cyclization product 3ja could not be obtained due to 2-
(BnO)2PO2H and Cu(OAc)2 which provided the 3aa in bromo-substituted ketene dithioacetals was decom-
a lower yield (entries 9–13). Moreover, control experi- posed in the reaction. Moreover, 3-methyl-substituted
ments confirmed the necessity of [Cp*IrCl2]2 (en- ketene dithioacetal 1k also reacted smoothly in the
tries 14–15). When 3.0 equiv 1a and 1.0 equiv 2a reaction system, affording the corresponding 3ka in
were used, the yield dropped to 56% (entry 16).
63% yields. Disubstituted and 2-naphthyl-substituted
Having established optimized reaction conditions, benzene ring also underwent the reaction, providing
we subsequently examined the scope of ketene the corresponding products 3la and 3na in 71% and
dithioacetals 1 (Table 2). A series of electron- donating 45% yields, respectively. Particularly, for 3,4-dimeth-
and -withdrawing substituents at the para positions of oxy-substituted ketene dithioacetal 1m was also
the benzene ring could occur efficiently to provide the suitable for this reaction, generating the two isomers
corresponding coupling and cyclization products (3aa- 3ma and 3ma’ in 52% yields (3ma:3ma’=1.86:1).
3ab and 3da-3ga) in 44–68% yields. The product 3ca
Next, we examined the scope of thiophene deriva-
could not be obtained because of dithioacetals 1c was tives 2 as the coupling partners (Table 3). To our
decomposed in the reaction system. In addition, ortho- delight, it was found that 2 with halogen (À Cl and
substituted ketene dithioacetals could proceed À Br), electron-donating groups (À Me and À Ph) at the
smoothly, affording the corresponding 3ha and 3ia in 5- position of the benzothiophene proceeded smoothly
slightly lower yields, indicating that steric hindrance to give 3ab–3ac and 3lb–3lc in 40–46% yield. 4-
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Table 2. Scope of ketene dithioacetals.[a]
Table 3. Scope of benzothiophene derivatives.[a]
[a] Reaction condition:
1
(0.1 mmol), 2a (0.3 mmol),
[Cp*IrCl2]2 (7.5 mol%), AgSbF6 (30 mol%), Ag2O
(0.4 mmol), Cu(OPiv)2 (0.05 mmol), HFIP (1 mL), Ar,
°
135 C, 24 h, isolated yield.
[a] Reaction condition:
1
(0.1 mmol), 2a (0.3 mmol),
[Cp*IrCl2]2 (7.5 mol%), AgSbF6 (30 mol%), Ag2O
(0.4 mmol), Cu(OPiv)2 (0.05 mmol), HFIP (1 mL), Ar,
To further understand the reaction mechanism, a
series of control experiments were performed
(Scheme 2). Firstly, no desired product 3aa was
obtained from 1a under the standard conditions with
2,2,6,6- tetramethylpiperidinooxy or 2,6-di-tert-butyl-
°
135 C, 24 h, isolated yield.
Chlorobenzothiophene, and 7-bromobenzothiophene 4- methylphenol (Scheme 2a). These results suggested
were converted to the corresponding regioisomers 3ld that a radical pathway may be involved in this reaction.
and 3ld’, 3ad, 3lg and 3lg’, in 54% (3ld:3ld’= In addition, several control experiments were carried
5.9:1), 51% (3ad) and 54% (3lg:3lg’=4.9:1) yields, out to further understand the cascade process. Control
respectively. 6-Bromobenzothiophene was successfully experiments (Scheme 2b) substantiated the importance
coupling with 1l to deliver the corresponding product of Ag2O for this intramolecular cyclization. Moreover,
3le in 69% yield. Moreover, 2-methylthiophene and 2- no desired product 3aa was obtained from 4 under the
phenylthiophene were also viable, and afforded the conditions with Ag2O and 2,2,6,6-tetrameth-
corresponding products 3lf and 3ae in 50% and 36% ylpiperidinooxy. These results further suggested that
yield, respectively. Unfortunately, only trace amounts the cyclization process maybe was a Ag2O-promoted
of product was observed when benzofuran and radical cyclization. Further studies showed the HFIP
thiophene were used as the substrate under the standard has a vital effect on this cyclization process. Secondly,
conditions (See the supporting information).
no 3oa could be obtained from 1o. This result
excludes the possibility of the coupling reaction of α-
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On the basis of the above experiments and other
related literature reports,[21] a plausible mechanism for
this coupling system is proposed in Scheme 3. Initially,
the ligand exchange between [Cp*IrCl2]2, AgSbF6 and
Cu(OPiv)2 forms the active [Cp*IrIII(OPiv)2] complex.
Then the cyclometalation of ketene dithioacetal 1a
affords a five-membered intermediate I under assis-
tance of weakly coordinating carbonyl groups. Sub-
sequently, intermediate I reacts with 1-benzothiophene
2a to form the intermediate II. Then, a reductive
elimination reaction occurs to release the biaryl
product 4 and Cp*IrII species. Cp*IrII species is
oxidized to [Cp*IrIII(OPiv)2] complex by the silver salt
and PivOH. Then, the radical cyclization reaction of
the biaryl product 4 by Ag2O to form the desired
product 3aa. we proposed that this radical cyclization
process might undergo cationic radical intermediates,
indicates the importance of HFIP.
In summary, we have realized a simple one-pot
synthetic strategy to form a series of sulfur-containing
cyclization compounds via tandem Ir(III)-catalyzed
cross-dehydrogenative coupling (CDC) of ketene
dithioacetals with benzothiophene derivatives and
Ag2O-promoted intramolecular cyclization. Mechanis-
tic investigation demonstrated a radical process may be
involving intramolecular cyclization. This process
features broad substrate scope and functional group
tolerance. Further applications of this method to more
complex compounds are underway in our laboratory.
Experimental Section
General Procedure for the synthesis of products 3.To a
10 mL oven-dried sealed tube, ketene dithioacetal 1 (0.1 mmol),
thiophene derivatives
2 (0.3 mmol), [Cp*IrCl2]2 (6.0 mg,
7.5 mol%), AgSbF6 (10.3 mg, 30 mol%), Ag2O (92.7 mg,
0.4 mmol), Cu(OPiv)2 (13.3 mg, 50 mol%), and HFIP (1 mL)
were added sequentially under Ar atmosphere. The tube was
°
sealed and placed in a preheated oil bath at 135 C for 24 h.
After the reaction was completed as monitored by thin layer
chromatography (TLC), the reaction mixture was cooled to
Scheme 2. Control experiments.
position of ketene dithioacetals ketones with benzo-
thiophene (Scheme 2c). Third, the kinetic isotope
effect (KIE) value of competitive experiment (kH/kD =
3.0) and parallel experiment (kH/kD =3.2) indicated
that the CÀ H cleavage was likely involved in the rate-
determining step.[20]
Scheme 3. Proposed mechanism.
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room temperature and concentrated under vacuo. The resulting
mixture was purified by chromatography on silica gel with ethyl
acetate/petroleum ether (1:10 to 1:4) to give the corresponding
product 3. CCDC 2085472 (compound 3a) contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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This work was supported by the National Natural Science
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Ir(III)-Catalyzed and Ag2O-Promoted CÀ H/CÀ H Cross-
Coupling/Intramolecular Cyclization of Ketene Dithioacetals
with Benzothiophene
Adv. Synth. Catal. 2021, 363, 1–6
J. Chen, C. Yin, J. Zhou, C. Yu*