Ruthenium-Catalyzed Brook Rearrangement Involved Domino Sequence Enabled by Acylsilane-Aldehyde Corporation

Article abstract of DOI:10.1021/acs.orglett.0c01983

A ruthenium-catalyzed [1,2]-Brook rearrangement involved domino sequence is presented to prepare highly functionalized silyloxy indenes with atomic- and step-economy. This domino reaction is triggered by acylsilane-directed C-H activation, and the aldehyde controlled the subsequent enol cyclization/Brook Rearrangement other than β-H elimination. The protocol tolerates a broad substitution pattern, and the further synthetic elaboration of silyloxy indenes allows access to a diverse range of interesting indene and indanone derivatives.

Full text of DOI:10.1021/acs.orglett.0c01983

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Letter
Ruthenium-Catalyzed Brook Rearrangement Involved Domino
Sequence Enabled by Acylsilane−Aldehyde Corporation
Xiunan Lu, Jian Zhang,* Liangyao Xu, Wenzhou Shen, Feifei Yu, Liyuan Ding, and Guofu Zhong*
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ABSTRACT: A ruthenium-catalyzed [1,2]-Brook rearrangement
involved domino sequence is presented to prepare highly
functionalized silyloxy indenes with atomic- and step-economy.
This domino reaction is triggered by acylsilane-directed C−H
activation, and the aldehyde controlled the subsequent enol
cyclization/Brook Rearrangement other than β−H elimination.
The protocol tolerates a broad substitution pattern, and the further
synthetic elaboration of silyloxy indenes allows access to a diverse
range of interesting indene and indanone derivatives.
cylsilane represents a fascinating class of organosilicon
compounds, exhibiting a wide variety of synthetic
transformations, so the synthesis of silyloxy indenes seems
particularly attractive. Recently, rhodium(III)-catalyzed ortho-
olefination of aroylsilanes followed by light-induced intra-
molecular cyclization via siloxycarbenes represents an efficient
two-step access to silyloxy indenes (Scheme 1g).3e
A
applications, including nucleophilic addition, cross-coupling,
radical cyclization, and aldol reaction.1 Notably, acylsilanes are
intriguing for potential [1,2]-anion transposition, defined as
the Brook rearrangement, and there are many reports on
nucleophilic addition/Brook rearrangement reactions using a
quantitative amount of organometallic reagents (Scheme
1a).1a,2 Acylsilane also undergoes a photochemical or thermal
[1,2]-Brook rearrangement to provide the siloxycarbene
intermediate for further insertion of C−H, B−H, C−B, and
unsaturated C−C bonds (Scheme 1b).3 Furthermore, there
have been several exciting organo-catalytic sequences,4
including thiazolium-catalyzed acylsilane addition to unsatu-
rated esters/ketone (Scheme 1c),4a cyanide-catalyzed silyl
benzoin reaction (Scheme 1d),4b phosphine-promoted se-
quential Brook/Wittig reactions (Scheme 1e),4c and enantio-
selective bisguanidinium-catalyzed anionotropic rearrangement
(Scheme 1f).4d To the best of our knowledge, transition-metal-
catalyzed Brook rearrangement of acylsilanes still remains
elusive,5 although there are several Cu- or Pd-catalyzed
examples using other different carbonyl or organosilicon
substrates.6
Indenes are widely utilized as building blocks for the
synthesis of natural products and pharmaceutical molecules as
well as ligands in various transition-metal-catalyzed reactions.7
Consequently, many efforts have been devoted to the
preparation of indene frameworks, but these conventional
approaches usually require multiple steps and/or suffer from
limited substrate scopes.8 In recent years, tremendous
advances have been made in transition-metal-catalyzed C−H
activations9 as well as the C−H activation/carbocyclization
sequence to construct indenes, indenones, and hetero-
cycles.10−12 Silyl enol ethers are recognized as versatile
functionalities that have been utilized in numerous synthetic
Domino-type reactions by careful design of a multistep
reaction in one-pot sequence provide efficient and step-
economical approaches using much simpler raw chemicals.
Despite the wide application of acylsilanes in synthetic organic
chemistry, there is still no report on tandem bond formation
integrating directed C−H activation9 and Brook rearrange-
ment to produce valuable organosilicon compounds. With our
ongoing interest in directed C−H activation,9f−h,13j herein, we
report the first ruthenium-catalyzed C−H functionalization/
cyclization/[1,2[-Brook rearrangement sequence, and such a
one-pot/cascade transformation provides one atom/step-
economic access toward silyloxy indenes from readily available
aroylsilanes and acroleins. Cooperation of the acylsilane and
aldehyde controls the selectivity and sequence of the domino
reaction efficiently (Scheme 1h).
Control of chemoselectivity is highly sought after in organic
synthesis. In the realm of directed C−H functionalization,
chemoselectivity can be controlled by change of catalyst,
directing group, electron-withdrawing group, or additive.13 We
postulated that the C−H functionalization of aroylsilanes using
acroleins or vinyl ketones could facilitate the carbocyclization-
involved cascade sequence due to a key metallo−enol
Received: June 13, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01983
© XXXX American Chemical Society
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A

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a
Scheme 1. Brook Rearrangements of Acylsilanes in Organic
Synthesis
Table 1. Optimization of Catalytic Conditions
b
yield (%) of
entry catalyst EWG group additive
solvent
3, 4, 5
1
2
3
4
5
6
7
8
[Ru]-1 CHO
[Ru]-1 CHO
[Ru]-1 CHO
[Ru]-1 CHO
[Ru]-1 CHO
[Ru]-1 CHO
[Ru]-1 CHO
[Ru]-1 CHO
[Ru]-1 CHO
[Ru]-1 CHO
[Ru]-1 CHO
[Ru]-1 CHO
[Ru]-2 CHO
DCE
DCE
DCE
DCE
DCE
DCE
toluene
MeOH
THF
DMF
HCCl3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
AgSbF6
Ag2O
AgBF4
62, <5, 18
<5, <5, 5
AgOAc
Ag2CO3
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
9
<5, −, −
10
11
12
13
14
15
16
17
18
19
20
39, −, −
73, <5, 5
61, 6, 5
[Rh]
[Ir]
CHO
CHO
52, 0, 5
<5, <5, −
−, −, 19
−, −, 31
−, −, 69
−, −, 79
−, −, 53
[Ru]-1 COEt
[Ru]-1 COOMe
[Ru]-1 PO(OEt)2
[Ru]-1 SO2Ph
[Ru]-1 4-CF3C6H4
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (0.6 mmol, 3.0
equiv), catalyst (5 mol %), additive (20 mol %), Cu(OAc)2 (1.3
b
equiv), in solvent at 60 °C for 16 h. Isolated yields. [Ru]-1 = [Ru(p-
cymene)Cl2]2; [Ru]-2
= Ru(p-cymene)(OAc)2; [Rh] =
[RhCp*Cl2]2; [Ir] = [IrCp*Cl2]2.
We next examined the scope of acylsilane substrates 1 by
varying the substituents (Scheme 2). Although both of the p-
and m-methyl-substituted aroylsilanes were effective (3ba and
3ca), o-Methyl-substituted substrates were totally inert due to
great steric repulsion. A number of aroylsilane substrates
bearing p-Et, n-Bu, i-Pr, t-Bu, OMe, OCF3, F, Cl, Br, and Ph on
the aromatic ring were investigated, and all of them underwent
tandem C−H functionalization/cyclization/[1,2]-Brook rear-
rangement to provide the corresponding silyloxy indenes 3 in
good to excellent yields (3da−3na). Notably, meta-Cl
substituted aroylsilane led to mixed products generated from
o- and p-C−H activation (3la and 3la′), but m-Me-substituted
aroylsilane 1b led to the only product 3ba, presumably due to
the bulkier of methyl group retarding the o-C−H activation.
Interestingly, incorporation of a large aromatic ring such as
naphthalene also led to good yield as well as excellent
regioselectivity (3oa). The optimized reaction conditions were
also smoothly applied to various multisubstituted aroylsilanes,
providing moderate to good yields for the formation of a range
of silyloxy indenes 3 with excellent chemo- and site-selectivities
(3pa−3sa). A chiral substrate from 4-(trans-4-
propylcyclohexyl)benzoic acid still converted well to afford
good yield (3ta).
isomerization. Our study commenced with the model reaction
between acrolein 2a and acylsilane 1a obtained from aroyl
chloride (Table 1).1,2 Although robust complex [Ru(p-
cymene)Cl2]2 alone did not catalyze the reaction in DCE,
addition of AgSbF6 greatly promoted the cascade reaction,
leading to silyloxy indene 3 in 62% yield, albeit with the
formation of alkenylation product 5 in 18% yield (Table 1,
entries 1 and 2). However, other silver salts such as Ag2O,
AgBF4, AgOAc, and Ag2CO3 were inefficient (entries 3−6).
Next, a series of representative solvents, including toluene,
MeOH, THF, and DMF, were examined, but none of them led
to the desired products, exhibiting a significant solvent effect
(entries 7−10). Although chloroform only produced indene in
moderate yield, DCM further improved the reaction, and the
desired product was obtained in 73% yield (entries 11 and 12).
Notably, silyl indene product was not observed in all of the
conditions, although there have been catalytic nucleophilic
additions without Brook rearrangement.1b,c Another complex
[Ru(p-cymene)(OAc)2] was also tested, albeit with slightly
decreased efficacy (entry 13). Notably, while [RhCp*Cl2]2 was
also effective in such cascade reactions, [IrCp*Cl2]2 exhibited
no catalytic activity (entries 14 and 15). Finally, a wide variety
of alkenes were investigated, but all of them only produced
styrene derivatives due to the preference of β-H elimination
over cyclization, exhibiting the key role of the aldehyde in such
cascade transformation (entries 16−20).
The scope of other representative α,β-unsaturated aldehydes
as substrates was investigated (Scheme 3). The reaction of
benzoylsilane 1a with methacrolein 2b converted well, giving
decarbonyl indene product 4ab in 71% yield, albeit using 10
B
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a
a
Scheme 2. Reaction Scope of Acylsilanes
Scheme 3. Reaction Scope of Aldehydes and Acylsilanes
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (2.0 mmol, 10
equiv), [Ru(p-cymene)Cl2]2 (10 mol %), AgSbF6 (40 mol %),
b
Cu(OAc)2 (1.3 equiv) in DCM (1 mL) at 40 °C for 36−48 h.
7
c
d
equiv of 2 used, 48 h. 15 equiv of 2 used, 24 h. Acrolein 2 (0.6
mmol, 3 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), AgSbF6 (20 mol %),
at 60 °C for 16 h.
Scheme 4. Controlled Experiments
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a (0.6 mmol, 3.0
equiv), [Ru(p-cymene)Cl2]2 (5 mol %), AgSbF6 (20 mol %),
Cu(OAc)2 (1.3 equiv) in DCM (0.6 mL) at 60 °C for 16 h. Isolated
b
yields are shown. These compounds were not cleanly isolated;
however, they are believed to be the coproducts 4 or 5 as drawn.
equiv of aldehyde to promote the conversion. Notably, acrolein
bearing ethyl or even longer aliphatic chains still converted,
producing the corresponding products in moderate yields (4ac
and 4ad). Moreover, the reaction of a β-substituted acrolein
such as crotonaldehyde 2e proceeded well to give indene
aldehyde 3ae in 68% yield, showing the robustness of this
protocol. Finally, we turned to examine some other
representative silyl groups such as −SiMe2Ph, −SiMePh2,
and −SiEt3, and good yields were achieved in all cases (3ua,
3va, and 3wa; 55%, 68%. and 66% yields respectively).
In order to elucidate the working mode of the protocol, we
conducted experimental mechanistic studies. The cascade
reaction still proceeded in the dark, excluding the possible
light-induced 6-π electrocyclizations and 1,5-hydride shift
mechanism by siloxycarbene intermediate (Scheme 4a).3e If
alkenylation product 5aa was exposed to the optimal
conditions, no cyclization was observed with 43% recovery,
exhibiting that 5aa is not an intermediate in the cascade
reaction (Scheme 4b). Compounds 6 and 7 were synthesized
and subjected to the optimal conditions, respectively, but no
product 4ab was obtained, excluding the formation of both 6
and 7 (Scheme 4c). Moreover, crossover experiments using 1n
and 1u led to only products 3na and 3ua in 31% and 20%
yields, respectively, not only exhibiting the comparable
reactivity of 1n and 1u, but also supporting an intramolecular
[1,2]-silyl group migration event (Scheme 4d). To this end, we
performed intermolecular competition experiments using
aroylsilanes 1k and 1h, showing the electron-rich substrate
to be converted preferentially (Scheme 4e).
Deuterium-labeling experiments were performed to gain
mechanistic insights. Treatment of 1a-d5 with acrolein under
C
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the optimal conditions led to an extensive H/D exchange on
both indene and recovered aroylsilane within 15 min,
indicating a rapid and reversible ortho-C−H bond activation
(Scheme 5a). While a KIE value of 3.0 was obtained from the
Scheme 6. Synthetic Applications
Scheme 5. Deuterium-Labeled Experiments
Scheme 7. Proposed Mechanism
intermolecular competition of 1a-d5 versus 1a, intramolecular
competition in 1a-d1 led to a KIE value of 1.2 (Scheme 5b,c).
These results indicated the C−H bond cleavage was not the
rate-determining step.14 Olefinic deuterium acrolein 2d-d2 was
also prepared and reacted with aroylsilane 1a, leading to the
complete deuterium incorporation to the benzylic position of
product 4ad-d2, exhibiting a directed hydroarylation of olefin
(Scheme 5d). However, deuterium aldehyde 2d−d produced
4ad with complete loss of deuterium (Scheme 5e).
To establish scalability, the conversion of 1a was also run at
a gram scale to give 3aa in 56% yield, exhibiting the robustness
of the protocol (Scheme 6a). Several synthetic elaborations
were attempted to reveal the synthetic potential of thus
obtained indene derivatives. As outlined in Scheme 6b, while
3aa was treated with phenyl hydrazine, phenyl hydrazones 8
and 9, with or without a silyloxy group, can be smoothly
obtained. Moreover, 3aa reacted well with a Grignard reagent
such as phenylmagnesium bromide to provide alcohol 10 in
83% yield, with the silyloxy group intact. Interestingly, if 3ab
was treated with 3-chloroperbenzoic acid (m-CPBA), 2-
silyloxy-1-indanone derivative 11 was obtained in 83% yield.
On the basis of previous reports,3,10−13 a possible
mechanism is proposed (Scheme 7). The reaction starts with
the removal of the chloride ligands from the [RuCl2(p-
cymene)]2 complex with the aid of the AgSbF6 salt. Next,
coordination of the carbonyl oxygen of 1 to the active
ruthenium cationic species followed by ortho-C−H metalation
provides intermediate I. Coordinative insertion of acrolein 2
into the Ru−C bond of I affords enolate intermediate II.
Notably, the sterically less bulk and enolate tautomerism of the
aldehyde group drives the following nucleophilic cyclization of
enolate II,13 and a disfavored acyl intermediate III led to
alkenylation product 5 by β-hydride elimination. For other
electron-withdrawing groups such as ester, phosphonate and
sulfone, the formation of ruthenium enolate species is
impossible, thus driving the reaction toward the C−H
olefination via β-H elimination (Table 1, entries 17−20).15
After the five-membered intermediate IV was generated by
cyclization, the following [1,2]-Brook rearrangement occurred
to afford V in which the [Ru] and H-atom adopt the syn-
configuration due to favored steric effects and the subsequent
β-hydride elimination produces 3.16 If α-substituted acrolein
was employed (R = alkyl), intermediate V′ was afforded
presumably due to decreased steric repulsion and the Ru−O
chelation between metal and aldehyde group. As both
compounds 6 and 7 led to no product 4ab under optimal
conditions (Scheme 4c), an intramolecular oxidative addition
of aldehyde likely to occur and generate the Ru(IV) complex
VI,17 and the subsequent decarbonylation by β-carbon
elimination could produce 4.18
In summary, we have reported a novel ruthenium-catalyzed
alkylation/carbocyclization/Brook rearrangement sequence
D
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example of the intriguing multiple roles of acylsilane in domino
reactions.
́
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01983.
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Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Jian Zhang − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou 311121,
China; orcid.org/0000-0001-8734-3003;
Email: zhangjian@hznu.edu.cn
Guofu Zhong − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou 311121,
China; orcid.org/0000-0001-9497-9069; Email: zgf@
hznu.edu.cn
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Authors
Xiunan Lu − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
Liangyao Xu − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
Wenzhou Shen − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
Feifei Yu − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
Liyuan Ding − College of Materials, Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01983
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge National Natural Science Founda-
tion of China (NSFC) (21502037 and 21672048), Natural
Science Foundation of Zhejiang Province (ZJNSF)
(LY19B020006), and the Hangzhou Normal University for
financial support. G.Z. acknowledges a Qianjiang Scholar
award from Zhejiang Province, China.
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