Domino Heck/Hiyama cross-coupling: Trapping of the σ-alkylpalladium intermediate with arylsilanes

Article abstract of DOI:10.1039/d1ob00595b

A palladium-catalyzed domino Heck cyclization/Hiyama coupling reaction by the trapping of the σ-alkylpalladium intermediate with arylsilanes is described. A wide range of aryl-tethered alkenes and arylsilanes are all compatible with the reaction conditions. This approach shows good yields and excellent functional group tolerance, presenting a more practical and sustainable alternative to the conventional domino Heck cyclization/Suzuki coupling reaction.

Full text of DOI:10.1039/d1ob00595b

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Domino Heck/Hiyama cross-coupling: trapping of
the σ-alkylpalladium intermediate with arylsilanes†
Cite this: DOI: 10.1039/d1ob00595b
Xin-Xing Wu, * Hao Ye, Guomin Jiang* and Lanping Hu*
Received 29th March 2021,
Accepted 16th April 2021
DOI: 10.1039/d1ob00595b
rsc.li/obc
A palladium-catalyzed domino Heck cyclization/Hiyama coupling reported by the same group, who demonstrated a Ni-catalyzed
reaction by the trapping of the σ-alkylpalladium intermediate with reductive diarylation of activated alkenes with an external stoi-
arylsilanes is described. A wide range of aryl-tethered alkenes and chiometric amount of a reducing agent by domino cyclization/
1
1
arylsilanes are all compatible with the reaction conditions. This cross-coupling of aryl bromide. Despite significant achieve-
approach shows good yields and excellent functional group toler- ments made in capturing the σ-alkylmetal species by the cross-
ance, presenting a more practical and sustainable alternative to coupling processes, to the best of our knowledge, the coupling
the conventional domino Heck cyclization/Suzuki coupling of nucleophiles was limited to boronic acids and aryl bro-
reaction.
mides, and no report has appeared using arylsilanes as nucleo-
philes in Heck/coupling-capture sequences for the achieve-
ment of diarylation of tethered alkenes.
Over the past decades, the cascade reaction has emerged as a
powerful and atom-economical approach for the construction
of highly functionalized, diverse and complex molecules effec-
tively while reducing waste output as well as the time and
12
On the other hand, organosilicon compounds are usually
employed in cross-coupling processes due to their ease of
handling and/or low toxicity. The classic Hiyama cross-coup-
ling provides an indispensable synthetic method for the prepa-
ration of useful industrial and pharmaceutical materials by uti-
1
labor required for the overall transformation. Typically, the
intramolecular domino Heck cyclization has shown unique
efficacy and attracted considerable attention since it generates,
after the carbometallation of alkene, an in situ generated active
13
lizing arylsilanes as the coupling reagent. To date, nearly all
studies of the Hiyama reaction have focused on couplings of
aryl or vinyl-palladium species; the Hiyama coupling of alkyl-
palladium species remains scarce. In this context, we postu-
lated that utilization of the σ-alkylpalladium species generated
2
σ-alkylmetal species that can be further functionalized. The
3
4
5
6
7
groups of Zhu, Lautens, Li, Gu, and Jia have made great
contributions in this respect. Among the various transform-
ations of the σ-alkylmetal species in the domino Heck cycliza-
tion, the cross-coupling strategy provides an efficient avenue to
realize diarylation of tethered alkenes. For example, Grigg’s
group demonstrated the first Pd-catalyzed domino Heck cycli-
zation/Suzuki coupling reaction for the synthesis of 3,3-di-
substituted oxindoles bearing quaternary all-carbon centers in
the 1990s. Subsequently, a domino carbopalladation cross-
coupling reaction for the formation of valuable oxindole
scaffolds was developed by the group of Somfai. Recently,
Kong’s group demonstrated a nickel-catalyzed intramolecular
14
in situ instead of aryl or vinyl-palladium species to couple
with arylsilanes may be an effective way to realize the diaryla-
tion of tethered alkenes. Herein, we report our investigation of
a palladium-catalyzed cascade Heck cyclization/Hiyama cross-
coupling of aryl-tethered activated/unactivated alkenes with
3
arylsilanes involving two sequential C(sp2)–C(sp ) bond for-
8
mations in a single synthetic sequence (Scheme 1). Compared
with the previous reports of cascade Heck cyclization/Suzuki-
9
8,10
coupling route,
this described approach avoids the limit-
ations of difficult synthesis and purification of substrates.
We commenced the study by using N-(2-iodophenyl)-N-
methylmethacrylamide (1a) and triethoxy(4-methoxyphenyl)
silane (2a) as the model substrates to evaluate the feasibility of
the proposed Heck cyclization/Hiyama coupling process
Heck cyclization/Suzuki coupling reaction of a range of electro-
philes and aryl boronic acids. Another related example was
1
0
College of Chemistry and Chemical Engineering, Nantong University, Nantong
(
Table 1). Gratifyingly, the desired product 3a was first realized
in 63% yield by using 5 mol% of Pd(OAc)2 as the catalyst,
0 mol% of PCy as the ligand, and Bu NF as the silane activa-
2
26019, People’s Republic of China. E-mail: wuxinxng@163.com, jgm@ntu.edu.cn,
hlp@ntu.edu.cn
Electronic supplementary information (ESI) available. See DOI: 10.1039/
1
3
4
†
d1ob00595b
tor in MeCN at 80 °C for 12 h (entry 1). Subsequently, extensive
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comparison with Bu
4
NF, while other fluorides such as CsF, KF,
CaF , NH F and Py·HF were ineffective in activating the inert
2
4
C–Si bond and facilitating the transmetalation from silicon to
the palladium catalyst (entries 8–14). In addition, TBAI or
TBAB were also ineffective for the transformation (entry 14).
Furthermore, a careful survey of palladium catalysts was then
2
performed, which showed that Pd(OAc) was still the best
choice. Finally, a control experiment revealed that none of the
product 3a was obtained without the addition of the fluoride
activator (entry 19).
With the optimized reaction conditions established, we
next investigated the scope of the Heck cyclization/Hiyama
coupling procedure by testing various methacrylamides 1 in
the reaction with 2a. As shown in Table 2, para- and meta-sub-
stituents of aryl iodides, such as methoxy, methyl, halide, tri-
fluoromethoxy, and ester groups, were well tolerated to give
the products 3b–3h in 62–88% yields. The substrates with an
n
n
N-Et, N- Pr, or N- Bu protecting group were efficient reaction
partners, giving access to the corresponding products 3i–3k in
satisfactory yields. Moreover, various N-benzyl groups (Bn,
Scheme 1 Design plan for the Heck cyclization/Hiyama coupling
process.
3
4-MeBn, and 4-OCH Bn) could also be readily converted to the
corresponding products 3l–3n in 74–81% yields.
a
Table 1 Optimization of reaction conditions
The substrate scope with respect to arylsilanes 2 was investi-
gated next (Table 3). Arylsilanes with electron-donating substi-
tuents (phenyl, methyl and methoxyl) or electron-withdrawing
substituents (trifluoromethoxyl and ester) were found to be
suitable substrates and underwent the cascade Heck cycliza-
b
Entry
Catalyst
Ligand
PCy
Additive
Yield (%) tion/Hiyama coupling reaction with acrylamide with good
yields (3o–3t). Additionally, organosilicon with a benzothio-
phenyl backbone was also a pertinent precursor (3u and 3v).
Notably, aryl-tethered unactivated alkenes also worked well in
1
2
3
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
3
Bu
Bu
Bu
Bu
Bu
Bu
Bu
4
4
4
4
4
4
4
NF
NF
NF
NF
NF
NF
NF
63
P(p-MeOC
P(2-furyl)
PPh
H
6 5
)
3
69
72
85
<5
<5
0
62
79
<10
<10
<10
<10
0
3
Pd(OAc)
2
3
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
2
2
2
DPPF
DPPB
DPEphos
a,b
Table 2 Scope of acrylamide
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
3
3
3
3
3
3
3
3
3
3
3
3
NEt
3
·3HF
TBAF·3H
CsF
KF
2
O
10
11
12
13
14
15
16
17
18
19
CaF
NH
Py·HF
2
4
F
c,d
Pd
Pd(TFA)
[Pd(C
PdCl
Pd(OAc)
2
(dba)
3
Bu
Bu
Bu
Bu
—
4
NF
4
NF
4
NF
4
NF
50
76
69
77
0
2
3
H
5
)Cl]
2
2
(PPh
)
3 2
2
a
Reaction conditions unless otherwise noted: 1a (0.2 mmol), 2a
(
0.3 mmol), catalyst (5 mol%), ligand (10 mol%), MeCN (2.0 ml, 0.1
M), additive (0.4 mmol), 80 °C, 12 h under argon atmosphere con-
ditions. Isolated yields. TBAI as the additive. TBAB as the additive.
b
c
d
screening of ligands revealed that monophosphine ligands
(
(
entries 2–4) performed better than bis(phosphine) ligands
entries 5–7) in this reaction. More gratifyingly, the inexpensive
PPh was the most effective ligand to generate the product 3a
3
a
Reaction conditions unless otherwise noted: 1 (0.2 mmol), 2a
in 85% yield (entry 4). Several fluoride additives were evaluated
and had a pronounced influence on the transformation:
NEt ·3HF and Bu NF·3H O showed inferior performance in
(
2 3 4
0.3 mmol), Pd(OAc) (5 mol%), PPh (10 mol%), Bu NF (0.4 mmol),
MeCN (2.0 ml, 0.1 M), 80 °C, 12 h under argon atmosphere conditions.
b
Isolated yields.
3
4
2
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Table 3 Substrate scope of the Heck cyclization/Hiyama coupling
a,b
process
Scheme 3 The cascade Heck cyclization/Hiyama coupling of the ezeti-
mibe derivative.
a
Reaction conditions unless otherwise noted: (0.2 mmol),
1
2
(
0.3 mmol), Pd(OAc)
2
(5 mol%), P(PPh) (10 mol%), Bu NF (0.4 mmol),
3
4
MeCN (2.0 ml, 0.1 M), 80 °C, 12 h under argon atmosphere conditions.
b
Isolated yields.
Scheme 4 Proposed reaction mechanism.
this transformation, leading to 3v, 3w, 3x, 3y, and 3z, respect-
ively, all in acceptable yields under the standard reaction con- the reaction of 1a with arylsilane 5 derived from ezetimibe, a
ditions. Most remarkably, the substrate N-(3-methylbut-3-en-1- drug known to inhibit cholesterol absorption, was performed,
yl)aniline was also applicable to the reaction and yielded the which proceeded through Heck cyclization/Hiyama coupling to
corresponding product 3aa in 55% yield.
yield oxindole functionalized ezetimibe 6 in 74 yield with a
A gram-scale experiment of 1a with 2a was carried out to 1.2 : 1 dr value. This transformation shows great promise for
examine the scalability, and 79% yield of 3a was isolated on a drug discovery and development as a powerful tool for the syn-
3
.0 mmol scale under the standard conditions. As a compari- thesis of ezetimibe analogues.
son, a lower yield was obtained for the reaction of aryl
A mechanistic pathway is proposed in Scheme 4. Oxidative
bromide and almost no product was observed when using aryl addition of Pd(0) to the carbon–halogen bond takes place fol-
chloride as the substrate, which showed that the disconnection lowed by intramolecular carbopalladation to generate the
3
of C–X bonds of different substrates had a great effect on this primary C(sp )–Pd(II) species B. Subsequent transmetalation
cascade Heck cyclization/Hiyama coupling reaction. In with the pentavalent silicate C generated in situ by the fluoride
addition, the reaction of 1t bearing N-allyl and N-methylacryl ion results in the formation of intermediate D, which under-
moieties forming 2-indolinone 4 predominantly in a good goes reductive elimination to produce product 3a, meanwhile
yield showed good regioselectivity (Scheme 2).
regenerating the Pd(0) species for the catalytic cycle.
To demonstrate both the application prospect and the func-
tional group tolerance of this method, as shown in Scheme 3,
Conclusions
In conclusion, an efficient strategy for the palladium-catalyzed
domino Heck cyclization/Hiyama coupling reaction of aryl-
tethered activated/unactivated alkenes with arylsilanes has
been presented. Outstanding functional group tolerance and
broad substrate scope were demonstrated. This protocol pre-
sents a more practical and sustainable alternative to the pre-
vious domino Heck cyclization/Suzuki coupling reaction.
Further investigations toward exploring this type of domino
reaction and the application of this novel technique in the
late-stage modification of complex molecules are ongoing in
our laboratory.
Scheme 2 Gram-scale reaction and synthetic regioselectivity.
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The authors declare no competing financial interest.
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