Synthetic strategies to access silacycles

In comparison with all-carbon parent compounds, the incorporation of Si-element into carboskeletons generally endows the corresponding sila-analogues with unique biological activity and physical-chemical properties. Silacycles have recently shown promising application potential in biological chemistry, pharmaceuticals industry, and material chemistry. Therefore, the development of efficient methodology to assemble versatile silacycles has aroused increasing concerns in the past decades. In this review, recent advances in the synthesis of silacycle-system are briefly summarized, including transition metal-catalytic and photocatalytic strategies by employing arylsilanes, alkylsilane, vinylsilane, hydrosilanes, and alkynylsilanes, etc. as starting materials. Moreover, a clear presentation and understanding of the mechanistic aspects and features of these developed reaction methodologies have been high-lighted.


Introduction
Nonmetallic Si-element which constitutes almost 30% of the mass of earth´s crust in silica and silicates exists extensively in our planet. As is well-known that aza-, oxa-, or thiaorganic molecules are commonly encountered in many natural products and pharmaceuticals, but sila-organic molecules are not readily available in nature. Compared with all-carbon organic compounds, sila-analogues generally possess unique bioactive and photophysical properties (Förster et al., 2014;Pujals et al., 2006;Lippert et al., 2009) due to that silicon element has larger covalent radius (r Si vs. r C : 111 p.m. vs 67 p.m.) and less electronegativity (χ Si vs. χ C : 1.74 ev vs. 2.50 ev) different from carbon atom (Allred and Rochow, 1958). For instance, some representative examples of therapeutically potential silacycles are described in Figure 1. However, incorporating Si-element into all-carbon skeletons and heterocyclic systems has not been wellestablished. The main reason is that extra 3d orbitals of silicon element easily interact with heteroatoms and metal ions to form hypervalent fiveor six-coordinated intermediates (Breit et al., 2013;Shen et al., 2017), leading to decomposition of organosilicanes (Akiyama and Imazeki, 1997;Fleming and Winter 1998). Meanwhile, transmetalation between sila-compounds and metal catalysts can often occur to make the silane-based chemical reactions show poor chemoselectivity Pawley et al., 2022). Therefore, the development of versatile strategies to access various organosilanes has recently aroused increasing concerns. To date, the scope, mechanism, and applications for intermolecular silylations of alkanes, alkenes, arenes, diazo-compounds, and alkynes, etc., have been widely explored, and the corresponding studies involved transition metal-catalysis and photocatalysis have also been summarized OPEN ACCESS EDITED BY by different research groups (Cheng and Hartwig, 2015;Li et al., 2015;Xu et al., 2015;Van Hoveln et al., 2019;Keipour et al., 2017;Chatgilialoglu et al., 2018;Huang W S et al., 2022). However, no comprehensive review about synthetical strategies of silacycles through C-C bond and C-heteroatom bond formation reactions has been published. This review will focus on the assembly of unique structural silacyclical skeletons through intermolecular and intramolecular coupling-cyclization of alkylsilanes, arylsilanes, alkynylsilanes, vinylsilanes, and hydrosilanes, etc., with different coupling-reagents.
2 Synthetic strategy of silacycles via C-Si σ bond functionalization C-Si σ bond is commonly encountered in many organic silamolecules. Therefore, the development of C-Si bond cleavage-based transformation will provide a novel platform to assemble silacycles with high step-economy. Generally, C-Si bonds include strained C-Si σ bonds and unstrained C-Si σ bonds. The cleavage of C-Si bonds catalyzed by transition metal is still in its infancy because of the unmet challenges on reactivity, selectivity, and substrate scope.

Coupling-cyclization by catalytic cleavage of the strained C-Si σ bond activation
The scope of strained C-Si bond cleavage is primarily restricted to the silacycles with a small ring size such as silacyclobutanes (SCBs), in which strain release can provide thermodynamic driving forces. In these regards, Oshima and Yorimitsu early reported a Pd-catalyzed intermolecular cycloaddition of SCBs with enones, in which couplingcyclization of SCBs with enones under Pd-catalysis conditions could smoothly proceed via formal cycloaddition to yield the corresponding eight-membered ring (Hirano et al., 2008). The reaction was first triggered by the initial oxidative addition (O. A.) of SCBs to Pd (0) catalysts, producing palladasilacyclopentane which was then trapped by a, βunsaturated ketones (Scheme 1A).
Intermediates A then undergo an intramolecular insertion of the alkyne to form 1-pallada-4-sila-2-cycloheptenes B, followed by the subsequent reductive elimination (R. E.) to produce compounds 5 along with regeneration of Pd (0)-catalysts. Meanwhile, β-H elimination from intermediate B gives alkenylpalladium hydride species C, and successive reductive elimination results in the formation of byproducts 6.
Subsequently, Hayashi and Shintani further developed a Pdcatalyzed intermolecular desymmetrization of SCBs with alkynes almost using the same reaction conditions (Shintani et al., 2012), assembling Si-stereogenic 1-sila-2-cyclohexenes. The reaction mechanism possibly proceeds through Path A, in which oxidative addition of a C-Si σ bond of SCBs 7 to Pd (0) gives 1-pallada-2-silacyclopentane A. A species then undergo insertion of alkynes 8 to produce 1-pallada-4-sila-2cycloheptenes B, the reductive elimination of B leads to the formation of products 9 along with regeneration of Pd (0)catalysts. Alternatively, coordination of 8 to Pd (0) could precede cleavage of the C-Si σ bond of 7 as shown in Path B. Subsequent transmetalation (or σ-bond metathesis) of 7 can provide the same intermediates B, which eventually give silacycles 9 and Pd (0)-catalysts by reductive elimination (Scheme 1C). Of course, the detailed experiments and DFT calculation about this transformation were further performed by Xu, confirming that Path B (Scheme 1C) is reasonable (Zhang Q W et al., 2016). In 2021, the similar transformation of Rh/Cucatalyzed coupling-cyclization of SCBs with arylpropiolate-type internal alkynes was also achieved by Xu (Wang X C et al., 2021). In 2022, Song developed a Rh (I)-catalyzed intermolecular asymmetric coupling-cyclization of siprosilacyclobutanes 10 with terminal alkynes 11 to produce spirosilabicyclohexenes 12 with up to 96% ee (Scheme 1D) (Chen et al., 2022). Meanwhile, Song still utilized allenoates 13 and 14 as coupling reagents to react with silacyclobutanes 7 to furnish 2-or 3-(E)enoate-substituted silacyclohexenes 15 and 16 (up to 80% ee) in the presence of chiral phosphoramidite L 3 (Scheme 1E) .
Frontiers in Chemistry frontiersin.org 03 Besides that a, β-unsaturated ketones and alkynes could be employed to couple with SCBs via C-Si σ bond cleavage, cycloketones, cyclopropenones, arenes, and trisylhydrazones were also demonstrated to be efficient coupling-partners. In this vein, Murakami successively developed Pd-catalyzed intramolecular and intermolecular coupling-strategies of cyclobutanones with SCBs to construct complex structural benzosilacycles through σ-bond exchange process. For the intramolecular coupling-cyclization of cyclobutanone-SCHEME 2 Transition metal-catalyzed coupling-cyclization of silacyclobutanes with cycloketones, cyclopropenes, and arylhalides.
Frontiers in Chemistry frontiersin.org 04 containing SCBs 17 (Ishida et al., 2014), the key step is involved the oxidative addition of Pd (0) onto Si-C σ bond of silacyclobutane moiety to generate silapalladacycles A (Scheme 2A). On the contrary, for the intermolecular coupling-cyclization of cyclobutanones 19 with SCBs 7 (Okumura et al., 2017), the control experiments confirmed that the oxidative addition of Pd (0) onto C-C bond of cycloketone moiety to generate palladacycle (II) intermediates (A) prefer to occur (Scheme 2B). Based on the similar reaction mechanism, Xu and co-workers developed a Pd (II)-catalyzed [4 + 2] annulation of cyclopropenes with benzosilacyclobutanes to rapidly assemble silabicyclo [4.1.0] heptanes 23 and 25 in which cyclopropenes include gem-difluorocyclopropenes 24 (Scheme 2C) (Wang W et al., 2021;Xu et al., 2022). Meanwhile, Zhao still found Pd (II)-or Ni (II)-catalytical system could rapidly enable the intermolecular coupling-cyclization of silacyclobutanes 26 with cyclopropenones 27 (Scheme 2D) and aryl halides 29, 31, and 33 (Schemes 2E-G), furnishing silacycles 28, 30, 32, and 34 (Zhao et al., 2018a;Qin et al., 2020;Qin et al., 2021;. Meanwhile, the more challenging Rh-catalyzed intramolecular coupling-cyclization of SCBs with Csp 2 -H bonds has recently been achieved to make π-conjugated siloles with good regioselectivities by He . As shown in Scheme 3A, this transformation undergoes sequential C-Si bond and aryl Csp 2 -H bond activation process, and the catalytic cycle involves a rarely endocyclic β-hydride elimination of fivemembered metallacycles A, which after reductive elimination gave rise to a Si-Rh I species B that is capable of C-H activation. Apart from the Rh-catalysts, Zhao further developed a Ni (0)catalyzed asymmetric intramolecular coupling-cyclization of alkene and SCBs to make enantioenriched silicon-stereogenic benzosiloles by utilizing ortho-vinylaryl silacyclobutanes 37 as substrates . Two distinct pathways of this transformation are proposed. Path A begins with the coordination of the nickel (0) catalyst with alkene moiety to generate η 2 -coordinated complex A or B, then followed by an SCHEME 3 Transition metal-catalyzed coupling-cyclization of silacyclobutanes with Csp 2 -H bonds.
Frontiers in Chemistry frontiersin.org 05 alkoxide-promoted transmetalation, β-hydride elimination, and reductive elimination to produce the desired benzosilacycles 38. In the contrast, Path B involves the oxidative addition of C-Si bond on SCB and sequential intramolecular insertion of an alkene moiety (Scheme 3B).
More recently, Wang reported a highly effcient Pd (II)-catalyzed carbene insertion into C-Si bonds of SCBs 7 to deliver silacyclopentanes 40 with excellent enantioselectivity by using trisylhydrazones 39 as carbenoid precursors (Huo et al., 2021). This reaction features with wide substrate scope and high tolerance of functional groups. Mechanistic studies including DFT calculations suggest a catalytic cycle involving oxidative addition of Pd to strained C-Si bonds, carbenoid migratory insertion, and reductive elimination (Scheme 4). Moreover, the roles of the chiral ligand L 5 in controlling the reaction enantioselectivity are also elucidated.

Coupling-cyclization by catalytic cleavage of the unstrained Si-C σ bond activation
In comparison with the strained C-Si bonds, unstrained C-Si σ bonds possess higher thermodynamic stability. Therefore, the inert C-Si bond cleavage generally requires the use of stoichiometric amounts of either organomagnesium (van Klink et al., 2002) or organolithium reagents (Yu et al., 2008) and harsh reaction conditions. Nevertheless, transition metal-catalyzed C-Si σ bond activation provides an alternative mild approach to enable C-Si σ bond cleavage. In these regards, Chatani first reported an Rh (I)-catalyzed benzosilole synthesis in 2009 through the coupling-cyclization of 2-silylphenylboronic acids with alkynes (Tobisu et al., 2009). The corresponding mechanism starts from the formation of arylrhodium intermediates A, generated by the transmetalation of arylboronic acids 41 to rhodium hydroxide Rh (I)OH, and adds across alkynes 8 to form the vinylrhodium intermediates B, which subsequently undergo oxidative addition at a trimethylsilyl group to afford intermediates C, producing benzosilole products 42 and methyl-rhodium D through reductive elimination. Meanwhile, protonolysis of D regenerates the catalytically active Rh (I)OH (Scheme 5A). By using the similar strategy, Xi, He, Ogoshi, and Zhao successively developed Pd-, Rh-, and Ni-catalyzed coupling-cyclization of unstrained C-Si σ bonds with alkynes (Schemes 5B, 5C), aldehydes (Scheme 5D), and alkenes (Scheme 5E), providing various synthetic methods to construct complex structural benzosiloles 45  and 47 (Zhang et al., 2014), benzoxasiloles 49 (Hoshimoto et al., 2014), and spirosilacycles 51 (Shi et al., 2022).

Synthetic strategy of silacycles via Si-H σ bond functionalization
Hydrosilanes belong to readily accessible organosilanes which possess versatile reactivity. So, the cross-coupling of hydrosilanes with alkanes, arenes, alkenes, and alkynes could provide an alternative strategy to form C-Si bonds. Among them, transition metal-catalyzed C-H/Si-H coupling and hydrosilylation of unsaturated hydrocarbons represent two main chemical transformations to assemble silacycles. SCHEME 4 Pd (II)-catalyzed carbene insertion into C-Si bonds of silacyclobutanes.
Frontiers in Chemistry frontiersin.org Meanwhile, hydrosilanes including dihydrosilanes and monohydrosilanes are also the most common precursors of chiral tetraorganosilicons, and the development of synthetic methodology for chiral silacycles which are derived from hydrosilanes, has become more challenging.

Intramolecular coupling-cyclization of Si-H bonds with alkanes
As is well-known, Csp 3 -H bond functionalization is one of the most useful and versatile strategies for constructing organic molecules. In comparison with Csp-H bond and Csp 2 -H bond, the reactivity of alkyl Csp 3 -H bond is inerter. Therefore, examples of Csp 3 -H/Si-H coupling reactions are very rare.
The pioneer studies on transition metal-catalyzed Csp 3 -H/Si-H bond coupling reaction were mainly performed by Hartwig, but most of these transformations suffered from high reaction temperatures (135°C~200 C) (Tsukada and Hartwig, 2005). In 2010, Takai and co-workers reported Rh (I)-catalyzed Csp 2 -H/ Si-H coupling reaction to produce the mixture of silafluorene 53 and dibenzo [b, d]saline 54 by using ortho-arylphenylsilanes including 33 as starting materials (Scheme 6A) (Ureshino et al., 2010). Subsequently, they further found that increasing the reaction temperature could chemoselectively enable Csp 3 -H/ Si-H coupling under the same catalytical system, giving dibenzo [b, d]silane 56 as a sole intermolecular coupling-cyclization product by using ortho-alkylphenylsilanes as starting materials (Kuninobu et al., 2013a). The proposed mechanism was involved in the oxidative addition of the Si-H bond to Rh (I)-catalysts, SCHEME 5 Transition metal-catalyzed unstrained C-Si bond activation.
Frontiers in Chemistry frontiersin.org then undergoing Si-H bond activation and σ-bond metathesis to form cyclorhodiumates B and C, respectively. Subsequently, reductive elimination of intermediate B or C produces benzosilacycle 56 and regenerates the Rh (I)-catalyst (Scheme 6B). To our satisfaction, Takai continued to optimize these reaction parameters by utilizing phosphorus ligand and 3,3dimethyl-1-butene as additional additives, significantly lowering the reaction temperatures from 180°C to 50 C (Murai et al., 2015).
Although chiral Si-atoms are not naturally occurring, these organosilanes show great application potential, especially in the SCHEME 6 Transition metal-catalyzed Csp 3 -H/Si-H bond coupling reaction.

Intramolecular coupling-cyclization of Si-H bonds with arenes
Silicon-containing π-conjugated molecules can be utilized in the areas of electro-and photo-luminescence, the intramolecular coupling-cyclization of aryl Csp 2 -H bonds with Si-H bonds has therefore been widely explored to furnish silaarenes. Usually, the present synthetic methods to access benzosilacycles are mainly focused on the set-up of different reaction systems, including arylsilanes and catalysts. The reaction mechanism was generally involved in the oxidative addition of low-valent metal ions including Rh (I) and Ir (I) to Si-H bond of hydrosilanes 66, followed by the sequential aryl Csp 2 -H bond activation and reductive elimination process to afford diverse silaarenes 67 (Scheme 8A). The earlier study about transition metal-catalyzed aryl Csp 2 -H/Si-H couplingreaction was reported by Takai in 2010 (Ureshino et al., 2010). Takai and co-workers utilized RhCl(PPh 3 ) 3 as catalysts, and employed biarylmonohydrosilanes as substrates to rapidly assemble silafluorenes through Rh (I)-catalyzed double activation of Si-H and C-H bonds with dehydrogenation. Since then, Hartwig (Li et al., 2014), Shi (Su et al., 2017), Zhao (Zhao et al., 2018b), and Xu (Lin et al., 2017) also realized Ir (I)-catalyzed intramolecular dehydrogenation-coupling of aryl Csp 2 -H bonds with monohydrosilanes 68, 70, and 72, producing azo-silacycles 69 (Scheme 8B), oxa-silacycles 71 (Scheme 8C) and cyclic disiloxanes 73 (Scheme 8D), respectively.
Besides that transition metal Rh (I)-and Ir (I)-catalysts could efficiently enhance the cross-coupling of aryl Csp 3 -H bonds with hydrosilanes, Studer and Li also found that oxidants-promoted aryl Csp 2 -H bond/Si-H coupling could easily occur to deliver benzosilacycles 80 in good reaction conversions (Scheme 10). This transformation is generally involved in the homolysis of oxidants such as DTBP and TBHP to produce alkoxyl radicals, which then abstracted the H atom from monohydrosilanes to form Si-centered radicals. Finally, the radical-cyclization between Si-centered radicals and arenes gave 9-silafluorene skeletons (Leifert and Studer, 2015;Xu et al., 2015).

Intramolecular coupling-cyclization of Si-H bonds with alkenes and alkynes
Despite the rich history of the synthesis of silacycles, the method of intramolecular coupling-cyclization of hydrosilanes with alkenes or alkynes has been significantly lacking. To date, only Nakamura in 2008 reported a Me 3 SnLi-promoted intramolecular coupling-cyclization of hydrosilanes with alkynes to produce benzosiloles (Ilies et al., 2008), in which nucleophilic addition of Et 3 SnLi to alkynes was involved (Scheme 11A). Subsequently, Nakamura further found that strong base KH could also promote the same transformation by using (2-alkynylphenyl)monohydrosilanes as substrates (Scheme 11A) (Ilies et al., 2009). By utilizing the similar substrates, Xu realized a Rh-catalyzed dynamic kinetic SCHEME 8 Transition metal-catalyzed intramolecular aryl Csp 2 -H/Si-H bond coupling reactions.
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Synthetic strategy of silacycles via coupling-cyclization of vinylsilanes
Although vinylsilanes have been widely used in the Hiyama cross-coupling reaction to make C-C bonds with the release of the silyl group, transition metal-catalyzed Mizoroki-Heck reaction of vinylsilanes with aryl halides can form new C-C bonds at the β-position of vinylsilane and keep silyl moiety untouched. Therefore, the development of intramolecular Mizoroki-Heck coupling-cyclization of vinylsilanes may provide an efficient approach to access silacycles. Unfortunately, the examples involving vinylsilane which participated in the Mizoroki-Heck reaction are rarely reported. To date, only Xi and Teen successively reported Pdcatalyzed intramolecular coupling-cyclization of vinylsilanes with aryl Csp 2 -X bonds (X = Br and I) to assemble benzosilacycles (Scheme 12A) (Teng and Keese, 1999;Ouyang et al., 2012).
Aryl migration via Smiles rearrangement is a powerful tool for the synthesis of polycyclic arenes. However, the modes of radical Smiles rearrangement are very limited. More recently, Zeng reported a novel photo-catalyzed cycloaromatization of orthoalkynylaryl vinylsilanes 99 with arylsulfonyl azides 100 for delivering naphthyl-fused benzosiloles 101, various orthoalkynylaryl vinylsilanes including ortho-alkynylaryl allylsilanes and arylsulfonyl azides are well-allowed for this SCHEME 11 Intramolecular coupling-cyclization of Si-H bonds with alkenes and alkynes.
Frontiers in Chemistry frontiersin.org reaction system . The corresponding reaction mechanism features a unique combination of cascade S-N/C-S bond cleavages and α-silyl radical Smiles rearrangement, in which silyl hyperconjugation effect (the so-called β-effect) plays a key role in controlling the regioselective couplingcyclization (Scheme 12B). Post-synthetic applications indicate that these silaarenes show promising potential in luminescent materials.
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Synthetic strategies of silacycles via Si-Si σ bond activation of disilanes
The relatively weak Si-Si σ bond (ca. 54 kcal/mol) (Sanderson, 1983) suggests that disilanes could be converted into Si-M n + 2 -Si species via low-valent metal-based oxidative addition. Thus, the addition of intermetallic Si-M n + 2 -Si σ-bonds to alkynes can provide an efficient route for the preparation of silacycles. In these regards, the first example was evidenced by Sakurai et al., 1975, that a strained cyclic disilane 112 can react with activated alkynes 8 in the presence of Pd(II)-catalysts to provide disilyla-cycloheptenes 113 (Scheme 14A). Encouraged by this pioneering work, different disilanes were successively designed and synthesized to react with alkynyl moieties via intramolecular couplingcyclization. For examples, Ito and Matsuda reported Pd-catalyzed intramolecular syn bis-silylation of alkyl/alkyl internal alkynes (Ito et al., 1991;Ahmad et al., 2017), providing straightforward access to a large set of syn-disilylated olefins 115 and 117 (Scheme 14B). In 2012, Matsuda and co-workers (Matsuda and Ichioka, 2012) utilized Rh (I)catalysts to enable an intramolecular bis-silylation of aryl/aryl internal alkynes 118 into silylbenzosilanes 119 (Scheme 14C). Of course, apart from the coupling-cyclization of disilanes with alkynes, Pd-catalyzed intramolecular σ-bond metathesis between disilanes with cyclobutanones was also investigated by Murakami (Ishida et al., 2012) to furnish an acylsilane-tethered silaindane skeletons 121 (Scheme 14D).

Conclusion and perspectives
In summary, the methods for rapid assembly of silacycles are valuable to the fields of synthetic chemistry, material science, and biological chemistry. Therefore, the discovery of new reagents and new synthetic methodologies plays an important role in the development of organosilane chemistry. To date, the coupling-reaction between hydrosilanes with unsaturated hydrocarbons, alkanes, and arenes has been well-established; meanwhile, the studies on C-Si σ bond activation-and Si-Si σ bond activation-based couplingcyclization have also obtained significant progress. By contrast, silylenoid-involved coupling-cyclization is very rarely reported. Although several silylenoid precursors such as di-tertbutyldiazidosilanes (Welsh et al., 1988), diamidodichlorosilanes (Denk et al., 1994), and cyclohexene-derived silacyclopropanes (Driver et al., 2002) have been reported, their applications in the construction of silacycles are very limited. Thus, a major goal for the future focus of this field is the development of silylenoid-based new organic reactions, which will be believed to provide a versatile strategy to access more complex structural silacycles.

Author contributions
FC: investigation and editing; LL: investigation; WZ: supervision, writing-review. All authors contributed to the article and approved the submitted version.

Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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