Silicon‐Derived Singlet Nucleophilic Carbene Reagents in Organic

Author Manuscript

Title: Silicon-Derived Singlet Nucleophilic Carbene Reagents in Organic Synthesis

Authors: Daniel Priebbenow

This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofrea- ding process, which may lead to differences between this version and the Version of Record.

To be cited as: 10.1002/adsc.202000279

Link to VoR: https://doi.org/10.1002/adsc.202000279 REVIEW

DOI: 10.1002/adsc.202000279 Silicon-Derived Singlet Nucleophilic Carbene Reagents in Organic Synthesis

Daniel L. Priebbenowa* a School of Chemistry, The University of Melbourne, Parkville, Victoria, Australia, 3010 [email protected]

Dedicated to Prof. Dr. Carsten Bolm on the occasion of his 60th birthday.

Received:

Abstract. Over fifty years ago, the 1,2-rearrangement of This review aims to cover the historical literature and acyl silanes was first described by Adrian Brook and co- recent advances with regards to these valuable silicon- workers. This rearrangement (now termed the Brook based reagents and highlight additional aspects related to rearrangement) yields reactive silicon-based singlet the intriguing reactivity of both the carbene and nucleophilic carbene (SNC) intermediates that participate in oxocarbenium intermediates. a variety of chemical transformations including 1,2-carbonyl addition, 1,4-addition to electron-deficient unsaturated bonds Keywords: Organosilicon; Siloxy Carbene; Acyl and insertion into C-H and O-H bonds. Silane; Singlet Nucleophilic Carbene; Photochemistry

mediated synthetic transformations. 1.0 Introduction In addition to its important physical properties, silicon also plays a valuable role in organic Silicon containing molecules have unique and [3] important physical properties that have been synthesis. Silyl groups are employed as protecting exploited in organic, medicinal and materials groups to inhibit reaction at specific carbon or chemistry. In a medicinal chemistry setting, silicon oxygen atoms or can be used to trap the enol has been employed as a bioisostere of carbon, tautomer of ketones to generate silyl enol ethers which act as nucleophilic reagents in processes such affording access to analogues with enhanced [4] physicochemical properties and novel intellectual as the aldol reaction. property (IP) space.[1] Comparatively, the silicon- Organosilicon groups can also be transformed into carbon bond is almost 20% longer than a carbon- a variety of other functional groups. For example, the carbon bond and silicon analogues are generally more Hiyama-Denmark coupling makes use of a silyl functional group as a handle for cross-coupling lipophilic and have higher electropositivity than the [5] corresponding carbon analogues.[1a] In materials reactions. In the example shown in Scheme 1, a chemistry, silicon derivatives have been explored as silyl-alkyne reagent facilitates incorporation of a an alternative to carbon based graphite anodes in silicon motif into an isoxazole, with this silyl group batteries due to their extremely high theoretical then taking part in the palladium-mediated cross- [2] coupling process to afford 3,4,5-trisubstituted specific capacity. [6] isoxazole heterocycles. Dr Daniel Priebbenow completed his PhD in 2011 at Deakin University investigating palladium catalysed domino reactions. Daniel was then awarded an Alexander von Humboldt Fellowship with Prof. Dr. Carsten Bolm at RWTH Aachen University in Germany where his interest in carbene intermediates began. Daniel subsequently worked as a Senior Scientist within the Australian Translational Medicinal Chemistry Facility (ATMCF) at Monash University before joining the University of Melbourne where his current research focus is the discovery of new light-

This article is protected by copyright. All rights reserved Scheme 1. Silicon functional groups can be employed in utility of silicon-based nucleophilic carbene reagents cross-coupling reactions intermediates in chemical synthesis.

More recently, Mancheno and co-workers reported the use of silyl groups to access radical intermediates that underwent the Giese reaction with electron- deficient alkenes.[7] The key radical intermediate is generated following oxidation of the carbon-silicon bond via a singlet electron transfer process facilitated by an acridinium photocatalyst (Scheme 2). Scheme 4. Electrophilic and nucleophilic carbene intermediates have been employed in chemical synthesis

Since Dumas’ initial efforts to prepare methylidine in 1835,[10] the concept of a divalent carbon reactive intermediate has captured the imagination of many Scheme 2. Silicon reagents can be employed in photoredox chemists with decades of research culminating in the catalysed transformations pioneering isolation of the first stable carbene by Bertrand in 1988 (Figure 2).[11] Carbenes are neutral carbon species that contain To prepare silicon containing derivatives for six valence electrons. Four of the valence electrons application in organic or medicinal chemistry, occupy two low-energy sigma-bonding orbitals, and suitable methods must exist to enable the efficient the other two electrons occupy either one or both preparation of organosilicon compounds. To this end, non-bonding orbitals giving rise to four possible Oestreich and co-workers have recently disclosed the carbene electronic states (Figure 1).[12] Carbenes exist discovery of new reactions that facilitate installation in the singlet state (paired non-bonding electrons) or of silicon functionality into small molecules triple state (unpaired non-bonding electrons).[13] including cyclopropanes. (Scheme 3).[8]

Figure 1. The various possible electrons configurations at the carbenic carbon.

Scheme 3. Silicon-containing molecules can be accessed A large variety of carbene species are now known. As via a range of catalytic strategies. early as the 1960s, Hines stated that for a reactive species to be defined as a carbene, there must exist a stable dimer or a four-coordinate adduct produced via One strategy to incorporate silicon into target carbene insertion into a σ-bond (for example H- molecules is the use of silyl-derived carbene reagents. OR).[14] Traditional carbenes such as methylidene Silicon-based electrophilic singlet carbene cannot be isolated and display reactivity that is intermediates (see Scheme 4) accessed from -silyl- typically electrophilic including insertion into C–H -diazoesters or -silyl--diazoketones have been bonds and cyclopropanation reactions. On the other employed to prepare a range of silicon-containing hand, N-heterocyclic carbenes (NHCs), for example compounds. For example, Bolm and co-workers imidazolylidene or triazolylidene derivatives are reported the rhodium-catalysed synthesis of silyl highly nucleophilic and can be “bottled”. substituted -amino acids, dioxolanones and - For a divalent carbene of linear geometry, the two hydroxyacetic acids from -silyl -diazoacetates.[9] unbound valence electrons are typically distributed Silicon-based nucleophilic carbene intermediates across degenerate orbitals affording a triplet ground (Scheme 4) can be accessed from the corresponding state carbene. For the simplest possible carbene (i.e. acyl or amidoyl silane via Brook rearrangement and H2C:), the triplet ground state is favored over the react in a variety of transformations to form valuable singlet state by approximately 9 kcal/mol.[15] To note, silicon-containing molecules. To this end, it is the solvent interactions can also influence whether the focus of this review to highlight the broad synthetic carbene exists in its triplet or singlet ground state.[16] The reactivity of triplet carbenes often parallels that

This article is protected by copyright. All rights reserved of radicals (e.g. abstraction reactions).[12c, 17] Despite to form ylides which themselves are useful not being isolable, the application of triplet carbenes intermediates for subsequent transformations.[17, 21] in synthesis has advanced significantly in recent years Additional stabilisation of these carbenes is often due to the efforts of Tomioka, Hirai and others.[12c] achieved by generating the carbene intermediates For singlet carbenes the non-bonding electrons on from diazo compounds using an organometallic the carbene nucleus are paired. Singlet carbenes complex which affords a metal carbenoid species.[21d, should be ambiphilic as they possess the 22] Recently, the metal-free photochemical generation characteristics of both a carbocation and a of electrophilic carbene intermediates has gained carbanion—an empty p-orbital and a carbon-centred increasing interest in organic synthesis.[23] lone pair. As such, substituents that stabilise a With regards to singlet nucleophilic carbenes carbocation or carbanion relative to a radical can also (SNCs), the isolation of stable N-heterocyclic stabilise a singlet carbene.[18] carbenes (NHCs), first achieved by Arduengo and co- For stabilised singlet carbenes, at least one carbene workers in the early 1990s (Figure 2),[24] has enabled substituent is typically a heteroatom capable of π- significant advances to be realised with such carbenes donation. Singlet electrophilic carbenes now widely utilised as ligands in organometallic predominantly contain electron-withdrawing complexes that catalyse a range of transformations.[25] substituents such as an -ketone or -ester groups More recently, cyclic alkyl amino carbenes have which accept electron density through π-effects or demonstrated significant potential in catalysis (Figure inductive withdrawing effects which stabilise the 2).[26] carbene intermediate.[19] As the 2p-orbital remains N-heterocyclic carbenes have also been exploited vacant, these carbenes exhibit electrophilic reactivity. in organocatalysis, where chiral derivatives have been The most relevant stabilising interaction for a singlet developed to catalyse a range of new chemical nucleophilic carbene is electron donation to the reactions with exceptional chemo- and enantio- unoccupied, non-bonding p-orbital from this adjacent selectivity (see example in Figure 2).[27] The focus of heteroatom.[12b] this article is not however singlet nucleophilic Depending on the major form of stabilisation from carbene derivatives in their capacity as ligands or carbene substituents, the terms donor (or push) and catalysts, rather with regards to their application as acceptor (or pull) have been used in varying reagents and building blocks in organic synthesis combinations to classify carbenes (see Figure 2).[19] Donation of electron density is considered a “push” (from substituents including NR2 or OSiMe3) whereas 2.0 Discussion “pull” indicates the presence of a carbene substituent with π-electron accepting or inductive withdrawing A variety of singlet nucleophilic carbene (SNC) [19-20] properties (e.g. CF3 or CO2Et). reagents have been investigated and applied as reagents in chemical synthesis. Examples of such carbene derivatives include cyclic oxacarbenes, dimethoxycarbenes, aryl alkoxy carbenes, amino aryl carbenes and siloxy carbenes. Oxacarbenes can be generated photochemically from cyclic ketones such as cyclopentanone and cyclobutanone.[28] Ultraviolet irradiation of such ketones promotes homolysis to generate an alkyl acyl biradical that rearranges to form a cyclic oxcarbene that can undergo subsequent transformations such as O-H insertion in the presence of alcohols (Scheme 5).[28a]

Scheme 5. Photochemically generated oxacarbenes undergo O-H insertion processes Figure 2. Overview of the first stable carbenes to be isolated and common classifications of carbenes. Another class of singlet nucleophilic carbenes is aryl alkoxy carbenes, for example phenyl methoxy Extensive investigations have been conducted into carbene, generated photochemically from the the application of electrophilic singlet carbenes in corresponding diazirine. Moss and co-workers chemical synthesis (for example the acceptor and published a series of papers in the late 1980’s donor-acceptor carbenes shown in Figure 2). Such describing the unusual ambiphilic reactivity of these carbenes readily participate in C-H insertion and aryl alkoxy species when compared to the cyclopropanation processes or react with heteroatoms

Scheme 6. Aryl alkoxy carbenes, generated from diazirines, react with electron deficient alkenes

The synthetic utility of dimethoxycarbene has been investigated extensively by Warkentin and others who generated dimethoxycarbene thermally from the Scheme 9. Aryl amino carbenes undergo C-H insertion corresponding 2,5-dihydro-1,3,4-oxadiazoles and with proximal tert-butyl groups developed new chemical reactions utilising a range of substrates.[30] For example, Nair and co-workers developed the multicomponent reaction of 2.1 Siloxy Carbenes dimethoxycarbene and DMAD with carbonyl [31] substrates such as aldehydes (Scheme 7). Siloxy carbenes, first described by Brook and co- workers in the 1960s,[33] are accessed from the corresponding acyl silane via 1,2-Brook rearrangement of the silicon motif which can be initiated thermally or photochemically.[34] The siloxy carbene precursors, acyl silanes themselves possess unique properties due to the inductive release of electrons from the silicon atom to the carbonyl Scheme 7: Multicomponent reaction of dimethoxycarbene group.[35] intermediates. When acyl silanes are activated thermally or photochemically (using visible or near-UV irradiation), an n–* transition occurs involving In addition to their use as ligands and organocatalysts promotion of an electron from the non-bonding in chemical synthesis, aryl and alkyl substituted orbital of the oxygen atom to the anti-bonding orbital amino carbenes have also been explored as [32] of the carbonyl -system. This transition generates an reagents. For example, Bertrand and co-workers acyl silane excited singlet state, from which reported that aryl amino carbenes accessed via intersystem crossing (ISC) to the acyl silane triplet deprotonation of an iminium ion readily insert into C- state occurs. From the acyl silane excited triplet state, H and O-H bonds (Schemes 8 and 9). the 1,2-Brook rearrangement of the silicon atom to generate a carbene can take place or alternatively, homolysis of the carbon-silicon bond can occur (Scheme 10).[36]

Scheme 8. Generation of amino aryl carbenes from iminium ions Scheme 10. Overview of siloxy carbene formation

When homolysis occurs, Norrish-Yang and Paternò-Büchi reactivity has been observed analogous to that which takes place following the photochemical activation of ketones.[37] An example of chemistry arising from the homolysis process includes an intramolecular (2+2) cycloaddition of

This article is protected by copyright. All rights reserved acyl(allyl)silanes developed by Hammaecher and Portella.[38] More recently, Capaldo and co-workers reported the use of a decatungstate photoredox catalyst to exclusively facilitate homolyses of acyl silanes to generate acyl radical species.[39] When the 1,2-Brook rearrangement takes place, a singlet nucleophilic carbene intermediate is generated (with stabilising contributions from the ylide resonance form). Since the first report of siloxy carbenes, a range of studies have been reported Figure 4. Interaction of the oxygen’s lone pair of electrons exploring the formation and reactivity profiles of [35c, 40] with the carbene vacant 2p orbital stabilises the singlet these intriguing singlet carbene intermediates. carbene with contributions from the ylide resonance form In addition to hydride abstraction and insertion into (adapted from Reference 18) polar bonds, siloxy carbenes undergo electrocyclisations,[40a] 1,2-addition to carbonyl [40f] groups (benzoin-type reactivity) and 1,4-addition The silicon-derived carbene intermediates outlined to electron deficient double bonds (Stetter-type [40c] herein contain either one or two heteroatom reactivity). substituents (e.g. N or O) which affords nucleophilic (Lewis basic) carbene intermediates. Two approaches to provide insight into the nature of carbenes using DFT analysis have been developed involving determination of the EST (singlet-triplet gap) and carbene stabilisation enthalpy (CSE). A positive EST indicates a triplet carbene ground state whereas a negative EST value indicates a singlet state carbene. Nearly all heteroatom substituted carbenes have significant CSE (singlet) values and moderate to low CSE (triplet) values, the net effect being a strong shift towards the singlet state characterised by large singlet-triplet gaps with preferences for the singlet carbene as high as 60 kcal/mol in some cases. The outcomes of a study into the EST and CSE of siloxy carbenes were recently published by the Figure 3. The range of products accessible from acyl and Priebbenow group which included calculation of the amidoyl silanes via carbene intermediates. atomic orbital occupancy to determine the extent of the interaction of the oxygen lone pair with the vacant 2p carbene orbital.[41] From this study, it was As shown in Figure 3, a diverse array of structures determined that the EST for alkyl substituted siloxy can be accessed from siloxy carbene intermediates, carbenes ranged from -11 to -23 kcal/mol. the formation of which can often be attributed to the Interestingly, the singlet-triplet gap for cyclic alkyl properties of the corresponding oxocarbenium siloxy carbenes (EST = -11 to -18 kcal/mol) was intermediate (formed following carbene protonation lower than that for the corresponding acyclic [41] or nucleophilic addition to an electrophile) rather than carbenes (EST = -19 to -23 kcal/mol). the properties of the parent carbene itself. The calculated EST for aryl substituted siloxy Singlet nucleophilic carbenes are stabilised by carbenes ranged from -11 to -19 kcal/mol. In electron donation to the vacant 2p-orbital via addition, aryl siloxy carbenes were determined to be conjugation from the adjacent heteroatom. This is less hard and more electronegative overall than the illustrated for siloxy carbenes as shown in Figure 4. alkyl siloxy carbene derivatives. For the amino siloxy Interaction of oxygen’s non-bonding valence carbenes investigated in this study, the EST averaged electrons with the unoccupied 2p carbene orbital -50 kcal/mol, with the presence of the secondary stabilises the carbene nucleus through a reduction in heteroatom adjacent to the carbene centre providing energy of the no orbital energy. Due to this additional stabilisation compared to aryl and alkyl interaction, the energy of the unoccupied molecular siloxy carbene variants.[41] orbital is shifted to a higher energy causing a net Based on the additional understanding provided by increase in Enb which leads to a greater preference this study, the literature regarding silicon-based for the singlet state and renders such carbenes [18] nucleophilic carbenes is herein reviewed with the aim nucleophilic. In general, all SNCs contain at least to provide new insight that enables these unique one heteroatom capable of -donation into the silicon-derived carbene intermediates to be further carbene centre raising the energy of the LUMO and [18] exploited in synthetic organic chemistry. Of decreasing the electrophilicity of these substrates. significant advantage is that most transformations employing siloxy carbenes only require the use of

This article is protected by copyright. All rights reserved light to drive the reaction, minimising the use of either the carbonyl carbon to form a silyl ether; or (ii) transition-metal or organocatalysts and additives. at the silicon atom which leads to cleavage of the Siloxy carbenes can react as either a Brønsted base oxygen-silicon bond and regeneration of the carbonyl or Lewis base, depending on the structure of the system (Scheme 11). Consideration of the parent acyl silane and the solvent and reagents oxocarbenium ion is thus central to the discussion present. Several decades ago, Arduengo determined that follows. the proton affinity of what are now known as the Arduengo-type carbenes to be approximately 250 kcal/mol.[42] Since that time, the Brønsted basicity of carbenes has emerged as an important topic of consideration in the design and development of catalysts and ligands.[43] To this end, several groups have recently reported the outcomes of studies into carbene basicity and its impact on NHC catalysed transformations.[44] To explore the basicity of siloxy carbenes, Hacid was calculated for alkyl, aryl and amino siloxy [41] Scheme 11. The oxocarbenium ion has two reactive carbenes. The Hacid value provides insight into the basicity of carbenes by determining the energy electrophilic sites required to remove the proton from the corresponding protonated carbene. Compared to methylidene (Hacid = 208 kcal/mol), the siloxy carbenes returned much The enhanced proton affinity of siloxy carbenes higher values ranging from 259-270 kcal/mol for the accounts for the product formed from the 1,2-Brook alkyl siloxy carbenes, 260-275 kcal/mol for the aryl rearrangement of isopropyl acyl silane whereby siloxy carbenes and an average of 265 kcal/mol for following siloxy carbene formation, a 1,2-hydride shift yields the corresponding silyl enol ether in high the amino siloxy carbenes. To note, experimental [47] measurements have shown that the protonated yield (Scheme 12). carbenium ion of carbenes containing at least one An analogous intramolecular 1,2-proton shift was heteroatom substituent possess a pKa in the range of observed following the thermal activation of acetyl [43, 45] (dimethylphenyl)silane to afford the corresponding 15-23. [47] The proton affinity of carbenes gives rise to the silyl enol ether in 98% yield (Scheme 13). common reactions observed for nucleophilic carbenes Isobutyryltrimethylsilane was also reported to undergo a similar rearrangement process involving being 1,2-hydride shift or insertion into the O-H bond [47] of weak proton donors such as water or an alcohol. insertion of the carbene into the  C-H bond. Independent of whether the siloxy carbene reacts as a base or nucleophile, the structure of the final product formed is influenced by the properties of the corresponding oxocarbenium intermediate which is generated following the initial reaction of the carbene with a proton or electrophile (Figure 5).

Scheme 12. 1,2-hydride shift of siloxy carbenes generates silyl enol ethers

Figure 5. Siloxy carbenes can react as Brønsted bases or as nucleophilic Lewis bases

For the cation formed following protonation or addition to an electrophile, the oxocarbenium resonance form is preferred over the carbonium ion as all atoms retain a full octet.[46] The structure of the Scheme 13. Thermally generated siloxy carbene products formed from reaction of siloxy carbenes can intermediates undergo 1,2-H shift to afford the be reconciled via analysis of the oxocarbenium ion corresponding silyl enol ether. intermediate which undergoes subsequent nucleophilic attack at one of two electrophilic sites (i)

This article is protected by copyright. All rights reserved A similar transformation was observed by Hassner Svarovsky and co-workers capitalised on the ability and Soderquist, who in 1980 reported that vapor of siloxy carbenes to undergo O-H insertion to phase pyrolysis of cyclic acylsilane at 550°C afforded prepare a series of silicon-derived glycosides the cyclic silyl enol ether product via a carbene designed as potential pH-sensitised prodrugs for intermediate (Scheme 14).[48] To note, during the treating cancer (two examples shown in scheme reaction some of the decarbonylated product was also 17).[50] From this study, one glucose derivative formed through the radical pathway. reportedly exhibited moderate anti-cancer activity.

Scheme 14. 1,2-H shift occurs within cyclic siloxy carbene intermediates.

The formal insertion of carbenes into X-H bonds (where X is a heteroatom including O, N, S or Si) to form the corresponding mixed acetal (or analogous species) is the most common transformation reported for siloxy carbenes and variations on this process have been disclosed by several groups.[33, 34f, 47-49] Scheme 17. Siloxy carbene intermediates undergo O-H Duff and Brook first reported on the Brønsted insertion to produce siloxy acetal glycoside derivatives basicity of siloxy carbene intermediates formed from 1,2-Brook rearrangement of acyl silanes in 1973.[34f] They observed that the reagents that most effectively The light-mediated formal insertion of siloxy- carbenes into Si-H bonds has also been described by trapped the proposed siloxy carbene intermediate [51] were, in general, quite acidic, generating a range of Watanabe and co-workers. This process afforded a silyl derivatives (e.g. ROH, HOAc, HCN, HCl, and variety of aryl substrates containing both silane and pyrrole – Schemes 15 and 16). Brook and co-workers siloxy functional groups (Scheme 18). also noted that acetonitrile (pKa ~25) failed to react with the basic carbene whereas malonitrile (pKa ~ 12) reacted, providing further evidence that it was the acidity of a substance rather than the availability of a site for electrophilic attack (i.e. CN group) that dictated the reaction outcome.

Scheme 18. Siloxy carbenes insert into Si-H bonds.

Recently, Glorius and co-workers reported the insertion of siloxy carbenes into the B-H bond of pinacolborane by irradiation of acyl silanes using 3W [52] Scheme 15. Insertion of siloxy carbene intermediates into blue LEDS (λmax = 420 nM). A range of both alkyl O-H bonds to form acetals. and aryl derived acyl silanes were applicable to this reaction process to afford a series of siloxy borane derivatives in quantitative yield (Scheme 19).

Scheme 16. Siloxy carbenes have been observed to insert into a variety of X-H bonds. Scheme 19. Insertion of siloxy carbene intermediates into B-H bonds

This article is protected by copyright. All rights reserved Glorius also showed that if light of a higher In 2009, Dong & co-workers reported the thermal wavelength was used (λmax = 455 nM) carbene 1,2-Brook rearrangement of ortho-benzyloxy formation did not efficiently occur, however at this substituted acyl silanes to generate a siloxy carbene wavelength inclusion of a catalytic amount of the that underwent C-H insertion to afford the [56] photosensitiser [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 corresponding dihydrofuran (Scheme 22). If heated (commonly utilised to facilitate triplet-triplet energy for an extended period, subsequent elimination of the transfer processes)[53] was promoted reaction between siloxy group occurred to yield the 2-aryl benzofuran. the siloxy carbene and pinacol borane.[52] Such an Interestingly, for the O-benzyl substrates, the cis- outcome infers that siloxy carbene intermediates are isomer was formed predominantly, whereas for the S- generated from the T1 acyl silane excited state. benzyl derivative, the trans-isomer was the major Whether the mechanistic pathway for the X-H diastereomer formed. insertion processes involving siloxy carbenes (Schemes 15–19) proceeds in a stepwise or concerted fashion has been an ongoing topic of discussion (Scheme 20). The stepwise ionic process involves a basic singlet carbene removing the acidic proton from a secondary substrate to generate the corresponding nucleophile (conjugate base) which then reacts with the oxocarbenium ion (equivalent to an activated aldehyde) to form the mixed acetal type products. In their recent report, Glorius and co-workers proposed that the insertion of siloxy carbenes into the B-H bond of pinacol boranes likely proceeds in a concerted fashion,[52] however a 1998 article from Steenken on the formation of carbenium ions from Scheme 22. Insertion of siloxy carbene into O-benzyl and carbenes via protonation reports that several carbenes S-benzyl C-H bonds undergo O-H insertion into alcohols via a stepwise ionic pathway.[54] Both processes are plausible and the actual pathway involved most likely depends on In 2012, Wang & co-workers conducted the solvent, basicity of the carbene and the acidity of computational studies into this reaction process and the X-H bond in the reagent.[55] proposed that this transformation proceeded through an excited singlet carbene state, with proton abstraction without spin multiplicity change leading to formation of a diradical species, which underwent subsequent diradical coupling to afford the final product.[57] Such abstraction-recombination pathways have been reported for other cyclisation reactions involving carbene intermediates.[20, 58] Of interest, an analogous C-H insertion process was observed during pyrolysis of 2-(2-methoxyphenyl)-2-oxoacetic acid which proposedly proceeds via the hydroxy carbene Scheme 20. Insertion of siloxy carbenes into X-H bonds [59] can occur in a stepwise or concerted fashion. generated following decarboxylation (Scheme 23).

Siloxy carbenes also insert into C-H bonds in an intramolecular fashion. For example, the carbene generated thermally from pivaloylsilane inserted into a C-H bond of a proximal methyl group to afford a dimethyl siloxy cyclopropane (Scheme 21).[47] Scheme 23. Insertion of carbene into O-methyl C-H bond

In 2015, Becker and co-workers published a related study whereby silicon-derived N-heterocyclic indoline products were formed from the corresponding ortho-amino aroylsilanes (Scheme 24).[40c] Interestingly, it was observed that in the presence of the phenyl group (carbene generated thermally, Scheme 24, equation 1) the cis- diastereoisomer was the major isomer formed whereas for the ester derivative (carbene generated photochemically, Scheme 24, equation 2), the trans- Scheme 21. Intramolecular insertion of siloxy carbene into [40c] C-H bond. isomer was predominantly formed.

This article is protected by copyright. All rights reserved reactivity can be more simply explained by the nucleophilic addition of a singlet carbene to an electron deficient olefin, with properties of the resultant oxocarbenium ion influencing product formation (compare Pathways A, B and C in Scheme 26).

Scheme 24. Insertion of siloxy carbene into proximal C-H bonds

Shih and Swenton reported the thermal rearrangement of 2-methyl benzoyl silanes to generate silicon-derived benzaldehydes (Scheme 25).[60] A mechanism involving intramolecular C-H insertion followed by a ring opening process to generate an oxocarbenium ion was proposed to account for the 2-silylmethyl benzaldehyde product Scheme 26. Multiple pathways are possible following formed. addition of siloxy carbenes to unsaturated systems.

The predominant pathway observed from the reaction of siloxy carbenes with electron-deficient alkenes and alkynes is Pathway A, whereby the carbanion generated following conjugate addition reacts with the proximal silicon group on the oxocarbenium ion to form a new carbon-silicon bond and regenerate the carbonyl group (refer to Scheme 11). The reactivity of siloxy carbenes through Pathway A has been reported in a series of publications by the Bolm group who have described the inter- and intramolecular silyl acylation of internal alkynes and alkenes.[40b-d] For example, in 2013, Becker et al. described the Scheme 25. Thermal rearrangement of acyl silanes intermolecular silyl acylation of electron-deficient following C-H insertion into the proximal methyl group. alkynes to afford vinyl silanes (Scheme 27, equation 1).[40b] This process was initiated by the In addition to their ability to insert into X-H and C-H photochemical 1,2-Brook rearrangement to generate a bonds, heteroatom-stabilised singlet carbenes are also nucleophilic singlet carbene which adds to the excellent nucleophiles. This has been widely alkyne. The resultant carbanion then attacks the silyl exploited in the case of highly stabilised N- group (cleaving the O-Si bond) through a 1,4-retro- heterocyclic carbenes as nucleophilic organocatalysts Brook rearrangement to regenerate the carbonyl to catalyse a range of useful (asymmetric) synthetic system and afford a vinyl silane. The use of more transformations. The nucleophilicity of siloxy bulky silyl groups resulted in decreased yield, carbenes is discussed in the following section, and proposedly due to a less efficient Brook again it is the properties of the corresponding rearrangement. Of interest, for internal alkynes oxocarbenium ion which typically influences the containing neutral substituents (e.g. diethyl or structure of the final products formed. diphenyl acetylene), no reaction occurred. A range of reports have described the activation of In 2012, Zhang and co-workers reported the acyl silanes to yield siloxy carbene intermediates that intramolecular version of this reaction (Scheme 27. undergo 1,4-conjugate addition to electron deficient equation 2), whereby the carbene generated alkynes and alkenes (Stetter-type reactions). The photochemically added across the proximal alkyne to products formed from such processes include afford a series of silylated chroman-4-ones. Both alkyl and aryl substituents on the alkyne were cyclopropanes, hexanones and functionalised [40d] ketones. Despite an array of possible mechanisms tolerated for this process. Zhang et al. postulated throughout the literature including subsequently demonstrated that the silyl group could diradicals and cyclopropenes, the variation in be used as a handle for cross-coupling with aryl halides in a copper-mediated arylation process.

This article is protected by copyright. All rights reserved (Scheme 28).[34d] While both a stepwise and concerted mechanism can be envisaged, the concerted [2+2]-cycloaddition process is most feasible here due to the trans-isomer being formed exclusively.[62] In the case of acetyl trimethylsilane, the carbene intermediate reacts with electron-deficient alkenes to afford the cyclopropane adduct (Scheme 29).[63] For the reaction with fumarate, the trans-cyclopropane was formed exclusively, however, the corresponding reaction with dimethyl maleate was non- stereospecific, affording a 3:2 mixture of trans/cis cyclopropanes.

Scheme 28. Addition of cyclic siloxy carbenes to electron deficient alkenes generates cyclopropanes.

Scheme 27. Siloxy carbenes react in intra- and intermolecular silyl acylation processes with alkenes and alkynes

In 2015, the Bolm group extended this work to the Scheme 29. Nucleophilic addition of alkyl siloxy carbenes nitrogen analogues, prepared via the ortho-amidation to electron deficient alkenes generates cyclopropanes. of acyl silanes using iridium catalysis, exploiting the ability of the acyl silane group to act as a weakly coordinating directing group for C-H activation Nucleophilic siloxy carbenes also undergo 1,2- (Scheme 27, equation 3).[40c] For these particular carbonyl addition to aldehydes and ketones (benzoin- substrates, the photochemical method to generate the type processes). Again, multiple mechanistic siloxy carbene did not lead to a clean reaction pathways are possible and product formation appears (proposedly due to photo-mediated isomerisation of to be governed by steric factors associated with the the alkene in the product) and as such, thermal oxocarbenium ion intermediate (Scheme 30). activation (210°C in a microwave reactor) was instead employed to successfully furnish a series of silicon-derived dihydroquinolinones in high yield with 100% atom economy. To further explore the substrate scope, Becker and co-workers prepared a series of alkenyl substrates which reacted in a similar silyl acylation process to afford silyl indolinones via Michael addition of the carbene (generated photochemically) to the tethered alkene followed by a 1,4-retro Brook rearrangement to afford the final product (Scheme 27, equation [40c] 4). Scheme 30. Siloxy carbenes undergo 1,2-carbonyl addition While the stepwise process involving 1,4- to form a range of products. nucleophilic addition followed by 1,4-retro Brook rearrangement detailed in pathway A (Scheme 26) above appears most common, products arising from In 2018, Kusama and co-workers reported the Pathways B and C involving siloxy carbenes have intermolecular 1,2-carbonyl addition of siloxy been reported. Examples of Pathways B and C also carbenes to aldehydes (benzoin reaction). For this exist in the literature for the reaction of ylides with process, siloxy carbenes were generated [61] electron-deficient alkenes. photochemically from acyl silanes and a range of The reaction of a cyclic acyl silane with diethyl Lewis acids were trialled to increase the reactivity of fumarate afforded the trans-cyclopropane adduct

This article is protected by copyright. All rights reserved the aldehyde, with zinc(II) iodide (5 mol%) proving to form the oxirane in 43% yield (Scheme 33).[34d] to be most effective (Scheme 31).[40f] Such a process can be considered similar to the This reaction process follows Pathway A as Corey-Chaykovsky reaction utilised for the synthesis outlined in Scheme 30, with the oxyanion generated of oxiranes and cyclopropanes using sulfur ylides.[65] following 1,2-carbonyl addition of the nucleophilic For one case involving nucleophilic 1,2-carbonyl carbene, reacting with the proximal silyl group of the addition of a siloxy carbene to a ketone, steric factors oxocarbenium ion to generate a new oxygen-silicon gave rise to a third pathway whereby the resultant bond and regenerate the carbonyl system. The authors oxyanion intermediate deprotonates the beta-position demonstrated that this process can be applied to over of the silyl oxocarbenium ion to afford the cyclic silyl 25 examples including both aryl and alkyl acyl enol ether (Scheme 34).[34d] silanes and aldehydes in yields ranging from 32- 88%.[40f]

Scheme 33. Nucleophilic addition of cyclic siloxy carbenes to acetaldehyde afforded the oxirane product.

Scheme 31. Lewis acid mediated benzoin reaction of photochemically generated siloxy carbenes with aldehydes

It has been observed that for alkyl acyl silanes, when exposed to light-irradiation to generate siloxy carbenes, Norrish type II fragmentations can occur leading to unwanted side reactions. To circumvent this during the benzoin reaction outlined above, Kusama and co-workers have demonstrated that the desired carbene intermediates can be accessed via triplet-energy transfer using the photosensitiser Scheme 34. Nucleophilic addition of siloxy carbenes to [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (which is commonly utilised to facilitate triplet-triplet energy transfer cyclohexanone afforded the silyl enol ether product. processes).[64] This strategy enables irradiation at a higher wavelength to be employed which suppressed Norrish-type fragmentations of alkanoyl silanes and The nucleophilicity of siloxy carbenes has also been afforded the desired product in higher yield (Scheme exploited in reaction with boronic esters (boronates). 32). This process involves initial addition of the nucleophilic siloxy carbene to the boron atom to form the oxocarbenium ion, followed by migration of the phenyl group to afford intermediate I, from which either trans-acetalisation occurs to afford new heterocycle II, or acid-mediated hydrolysis takes place to generate the ketone product (Scheme 35).[66] Again, Kusama and co-workers noted that Norrish- type fragmentations of alkanoyl silanes under direct excitation led to reduced efficiency in carbene Scheme 32. Side reactions could be minimised in the formation during this reaction process and thus lower benzoin reaction when the siloxy carbenes were generated yields of the desired product. To overcome this, the via triplet-triplet energy transfer catalysis. use of the photosensitiser and higher wavelengths to form the carbene via a triplet-triplet energy transfer process was successfully able to suppress the In the case of cyclic acyl silanes, following initial unwanted side reactions (Scheme 36).[64] 1,2-addition of the carbene to the aldehyde due to ring strain the oxyanion intermediate cannot “reach” the silyl motif of the oxocarbenium ion, and as such, reacts at the central carbon of the oxocarbenium ion

This article is protected by copyright. All rights reserved acryloyl silanes. Exposure of these substrates to light facilitated formation of a siloxy carbene intermediate that underwent 6-electrocyclisation to afford a new 5-membered carbocyclic ring (Scheme 38).[67] Initial isomerisation of the double bond under photochemical conditions was required to enable this electrocyclisation to take place. Subsequent 1,3-retro Brook rearrangement followed by a 1,3-H shift proposedly occurred to afford a series of silicon containing 2,3-dihydrocyclopenta[b]indol-1(4H)-ones in moderate yields. Scheme 35. Nucleophilic addition of siloxy carbenes to boronates

Scheme 36. Addition of siloxy carbenes to boronates can be accomplished using a triplet-energy transfer catalyst to mitigate the formation of unwanted by-products

The ability of siloxy carbenes (generated via 1,2- Brook rearrangement of acyl silanes) to undergo Scheme 38. Light-mediated electrocyclisation of indole- electrocyclisation processes has also been derived siloxy carbenes observed.[40a] Becker and co-workers reported a 6- electrocyclisation of ortho-olefinated acyl silanes, prepared via rhodium(III)-mediated alkenylation of 2.2 Amino Siloxy Carbenes aromatic acyl silanes, employing acyl silanes as a weakly coordinating directing group for C-H The 1,2-Brook rearrangement of amidoyl or activation. Following electrocyclisation, a 1,5- carbamoyl silanes generates the corresponding amino sigmatropic shift proposedly occurs to reform the siloxy carbenes. Carbamoyl silanes are typically aromatic system, affording a series of silyl enol ether prepared via deprotonation of a formamide followed indenes which could be readily hydrolysed to afford by reaction with a silyl chloride.[68] Due to additional the corresponding indanones (Scheme 37). resonance contributions provided by the second heteroatom substituent (i.e. NR2), these carbenes are more stable than the alkyl or aryl siloxy carbenes previously discussed. Computational analysis of amino siloxy carbenes revealed a EST (i.e. singlet-triplet gap) of approximately -50 kcal/ mol and CSE of 88 kcal/mol for the singlet and 23 kcal/mol for the triplet.[41] The enhanced stability of these intermediates is readily apparent by the ease at which these carbenes are generated thermally (typically 60-100°C compared to 210-250°C required for alkyl or aryl substituted acyl silanes). The reactivity of carbamoylsilanes and the corresponding amino siloxy carbenes is discussed in Scheme 37. Light-mediated electrocyclisation of ortho- the following section. olefinated benzoyl silanes. In comparison to the alkyl and aryl silanes discussed previously, for a number of processes involving amino siloxy carbenes, the silicon The electrocyclisation of siloxy carbene derivatives functionality is not incorporated into the final was also reported by Loh and co-workers, who product, however the silyl group is critical for prepared a series of 2-alkenyl indoles via C-H generation of the carbene intermediate and a range of activation, coupling the indole-C2-position with

This article is protected by copyright. All rights reserved interesting products can be generated using these deficient alkynes (e.g. DMAD), followed by retro- silicon reagents. Brook rearrangement to afford the vinyl silane Chen and co-workers observed that the carbene (Scheme 40, equation 2).[70] generated from the 1,2-Brook rearrangement of carbamoyl silanes could insert into the C-H bond of Table 1. Products resulting from 1,4-Michael addition highly electron deficient aromatic systems (Scheme (Stetter type reaction) of amino siloxy carbenes with 39).[69] A series of hemi-aminal or amidoyl electron-deficient alkenes. functionalised aryl and heteroaryl substrates were prepared using this method. Interestingly, in the presence of reactive carbonyl and isocyanate groups, C-H insertion proceeds exclusively over nucleophilic addition to these electrophilic motifs. Entry Sia Product Yield (%) Cunico also discovered that the insertion of a 1 TMS 74 carbene derived from carbamoyl silane into the C-H bond of the terminal alkyne methyl propiolate. The carbene readily inserts into the acidic alkynyl C-H 2 TBS 65 bond to afford the siloxy hemi-aminal (Scheme 40, equation 1).[70] 3 TMS 80

4 TBS 86

5 TMS 65

6 TMS 77

7 TBS 87

8 TMS 84

a TMS = trimethylsilyl; TBS = tert-butyldimethylsilyl

Scheme 39. Insertion of amino siloxy carbenes into aryl C- Pathway C as outlined in Scheme 26 has been H bonds. observed for amino siloxy carbenes where following 1,4-conjugate addition to an electron deficient alkene, the resultant negative charge is further stabilised through resonance forms involving the electron- withdrawing group on the alkene. In these cases, the carboxylate or nitrate intermediates react with the silyl group of the oxocarbenium ion, cleaving the silicon-oxygen bond and regenerating the carbonyl motif (Scheme 41).[71b] Exploiting this unique mechanistic pathway, a range of silicon containing amide derivatives were prepared (Scheme 42).

Scheme 40. C-H insertion and Stetter-type reaction of amino siloxy carbenes with electron-deficient alkynes

In addition to C-H insertion processes, the carbene intermediates generated from the 1,2-Brook rearrangement of carbamoyl silanes also display enhanced Lewis basicity. Amino siloxy carbenes undergo 1,4-addition to electron deficient alkenes followed by a 1,4-retro Brook rearrangement to form Scheme 41. Silyl abstraction generates unique silyl amides beta-silyl amides (refer to Pathway A, Scheme 26).[71] following 1,4-addition of amino siloxy carbenes. Some of the products generated from this silicon transfer Stetter-type process are highlighted in Table 1. In a similar fashion to that outlined in Table 1, amino siloxy carbenes also undergo Stetter-type reactions involving conjugate addition to electron-

Scheme 45. Benzoin reaction of amino siloxy carbene with functionalised isatins

Chen and Cunico also developed a protocol involving addition of nucleophilic carbenes derived from carbamoyl silanes to iminium salts to form the corresponding -(dimethylamino)amides (Scheme 46, equation 1).[75] In 2015, Chen and co-workers disclosed two reports describing the addition of carbenes derived thermochemically from either N,N-dimethyl or N- Scheme 42. 1,4-addition of amino siloxy carbenes to methyl-N-methyl methoxy carbamoyl silane to N- electron-deficient alkenes followed by silyl abstraction. sulfonylimines (Scheme 46, equation 2).[76] Of utility, TBS = tert-butyldimethylsilyl the methoxymethyl protecting group could be subsequently hydrolysed under acidic conditions to afford the corresponding methyl amide. The carbenes generated from carbamoyl silanes have also been reported to undergo 1,2-addition to ketones, keto-esters, isatins, acid chlorides, imines and iminium ions. For example, Cunico observed the formation of -siloxyamides following the reaction of amino siloxy carbenes with alkyl or aryl substituted aldehydes and ketones (Scheme 43).[72]

Scheme 43. Benzoin reaction of amino siloxy carbenes with ketones and aldehydes

Chen and co-workers described the 1,2-addition of amino siloxy carbenes generated thermally from carbamoyl silanes to -ketoesters (Scheme 44).[73] Scheme 46. Aza-benzoin reaction of amino siloxy This research group then extended the scope of this carbenes with iminium ions and imines methodology to include reaction with isatins (Scheme 45).[74] The Chen research group have also reported the addition of nucleophilic carbenes generated thermally from carbamoyl silanes with alkyl or aryl substituted N-Boc imines to afford a series of -aminoamides (Scheme 46, equation 3).[77] Interestingly, the electronic properties of the imine appear to have little effect on the success of the transformation with similar yields obtained regardless of whether an electron donating or withdrawing substituent was present. The reaction of nucleophilic amino siloxy carbenes with acyl chloride electrophiles was also developed to afford a series of secondary -ketoamides (Scheme Scheme 44. Benzoin reaction of amino siloxy carbenes 47, equation 1).[78] More recently this work was with ketoesters extended to include reaction with -oxo acid

Scheme 49. Proposed intermediates involved in the palladium-catalysed coupling of amino siloxy carbenes

The palladium-catalysed reaction of the carbenes obtained thermochemically from carbamoyl silanes with imidoyl chlorides to afford -iminoamides has also been described (Scheme 50, equation 1).[82] Of interest, the reaction requires no additive or base and proceeds readily in THF at 60°C. Cunico and Pandey also reported the palladium-mediated reaction of Scheme 47. Reaction of amino siloxy carbenes with acyl carbamoyl silanes with alkenyl and benzyl halides to chlorides afford a series of amide derivatives (Scheme 50, equation 2).[83] Of interest, the authors also described attempts to form analogous benzylamides using In 2005, Chen, Pandey and Cunico described their pseudo halides such as benzyl trifluoroacetates (in investigations into the diastereoselective formation of place of benzyl halides) in the presence of a -aminoamides from carbamoyl silanes possessing a [80] palladium catalyst however the only product formed chiral auxiliary (Scheme 48). Moderate yields were was a result of nucleophilic 1,2-carbonyl addition of typical for this process, however for some substrates the carbene to the carbonyl of the trifluoroacetate a diastereomeric ratio (d.r.) as high as 1:16 was [83] [80] group (Scheme 51). obtained. Further investigations revealed that the diastereoselectivity of this process was enhanced when chiral substituents were present in both the carbamoyl silane and imino substrates, with the best d.r. values obtained when complementary sets of (S)- imines and (R)-carbamoyl silanes were utilized. Overall, with regards to selectivity, the N-[1-(1- naphthyl)ethyl] derived imines performed better than the N-(1-phenylethyl) derivatives.[80]

Scheme 50. Palladium-mediated coupling of amino siloxy carbenes

Scheme 48. Diastereoselective addition of amino siloxy carbenes to imines.

The enhanced stability of the amino siloxy carbenes Scheme 51. Attempted cross-coupling of amino siloxy generated from the 1,2-Brook rearrangement of carbenes with pseudohalides resulted in 1,2-carbonyl carbamoyl silanes has also been exploited in addition of carbene to the ester. palladium- and nickel-catalysed coupling reactions with aryl halides, alkyl halides, alkenyl halides and imino chlorides. This type of reactivity correlates Chen and co-workers discovered a nickel-catalysed with the known ability of N-heterocyclic carbenes to aminocarbonylation of aryl halides using carbamoyl stabilise metal complexes. The intermediates silanes as an amide source (Scheme 52).[84] Using proposed by Cunico for the palladium-mediated tetrakistriphenylphosphine nickel (0) in toluene at processes are outlined in Scheme 49.[81]

This article is protected by copyright. All rights reserved elevated temperatures, a large series of benzamide nucleophilic carbenes. Furthermore, reaction derivatives were accessed. processes involving siloxy carbene intermediates typically only require the use of light to activate the substrates, eliminating the need for additional catalysts or additives. It is hoped that this review draws attention to the synthetic utility and potential of silicon-derived carbene reagents in organic synthesis and inspires other research groups to explore these intriguing reactive intermediates.

Acknowledgements Scheme 52. Nickel-mediated coupling of amino siloxy carbenes with aryl halides Daniel Priebbenow acknowledges the generous support of the Australian Research Council (DE200100949).

A related reaction with aryl bromides and aryl chlorides was also developed by Chen employing a References palladium (0) catalyst in toluene at 100°C (Scheme 53, equation 1). Under these conditions, for some [1] a) R. Ramesh, D. S. Reddy, J. Med. Chem. 2018, 61, substrates hydrolysis of the methoxymethyl ether 3779-3798; b) A. K. Franz, S. O. Wilson, J. Med. group took place to afford the methylamide adduct.[85] Chem. 2013, 56, 388-405. Cunico and Maity also demonstrated that alkenyl and [2] X. Shan, Z. Cao, G. Zhu, Y. Wang, Q. Qu, G. Liu, H. alkynyl halides were suitable coupling partners for Zheng, J. Mater. Chem. A 2019, 7, 26029-26038. the palladium-mediated amidation process with [3] L. Li, Y.-L. Wei, L.-W. Xu, Synlett 2020, 31, 21-34. carbamoyl silanes, with selected examples outlined in [4] a) M. Bols, C. M. Pedersen, Beilstein J. Org. Chem. Scheme 53, equations 2 and 3.[81] 2017, 13, 93-105; b) M. Lalonde, T. H. Chan, Synthesis 1985, 1985, 817-845; c) J. Muzart, Synthesis 1993, 1993, 11-27; d) D. Cahard, P. Duhamel, Eur. J. Org. Chem. 2001, 2001, 1023-1031. [5] a) S. E. Denmark, R. C. Smith, W.-T. T. Chang, J. M. Muhuhi, J. Am. Chem. Soc. 2009, 131, 3104-3118; b) S. E. Denmark, A. Ambrosi, Org. Process Res. Dev. 2015, 19, 982-994. [6] S. E. Denmark, J. M. Kallemeyn, J. Org. Chem. 2005, 70, 2839-2842. [7] M. Uygur, T. Danelzik, O. García Mancheño, Chem. Commun. 2019, 55, 2980-2983. [8] a) A. Roy, V. Bonetti, G. Wang, Q. Wu, H. F. T. Klare, M. Oestreich, Org. Lett. 2020; b) L. Zhang, M. Oestreich, Chem. – Eur. J. 2019, 25, 14304-14307. [9] a) D. L. Priebbenow, C. Bolm, RSC Adv. 2013, 3, Scheme 53. Palladium-mediated coupling of amino siloxy 10318-10322; b) C. Bolm, S. Saladin, A. Kasyan, carbenes with aryl, alkenyl and alkynyl halides Org. Lett. 2002, 4, 4631-4633; c) C. Bolm, S. Saladin, A. Claßen, A. Kasyan, E. Veri, G. Raabe, Synlett 2005, 2005, 461-464; d) C. Bolm, A. Kasyan, 3.0 Conclusion K. Drauz, K. Günther, G. Raabe, Angew. Chem. Int. Ed. 2000, 39, 2288-2290. Acyl and amidoyl silanes undergo photochemical or [10] J. B. Dumas, E. Peligot, Ann. Chim. Phys. 1835, 58, thermally initiated 1,2-Brook rearrangement to 5-74. generate basic and nucleophilic siloxy carbene [11] A. Igau, H. Grutzmacher, A. Baceiredo, G. Bertrand, intermediates. Siloxy carbenes display unique J. Am. Chem. Soc. 1988, 110, 6463-6466. reactivity including the ability to insert into C-H [12] a) H. Tomioka, in Reactive Intermediate Chemistry bonds, undergo 1,2-carbonyl and 1,4-conjugate (Eds.: R. A. Moss, M. S. Platz, M. Jones Jr), John addition and participate in transition-metal mediated Wiley & Sons, Inc., Hoboken, NJ, 2004; b) D. cross-coupling reactions. Bourissou, O. Guerret, F. P. Gabbaï, G. Bertrand, Siloxy carbene intermediates offer significant Chem. Rev. 2000, 100, 39-92; c) K. Hirai, T. Itoh, H. value by enabling access a wide variety of substrates Tomioka, Chem. Rev. 2009, 109, 3275-3332. that contain useful silyl functionality. These carbene [13] M. Jones Jr, R. A. Moss, in Reactive Intermediate reagents also represent useful model substrates to Chemistry (Eds.: R. A. Moss, M. S. Platz, M. Jones explore the reactivity and properties of singlet Jr), John Wiley & Sons, Inc., Hoboken, NJ, 2004.

This article is protected by copyright. All rights reserved [14] J. S. Hine, Divalent Carbon, Ronald Press, New York Lee-Ruff, Molecules 2010, 15, 3816-3828; e) G. 1964. Mladenova, E. Lee-Ruff, Tetrahedron Lett. 2007, 48, [15] G. Bertrand, in Reactive Intermediate Chemistry 2787-2789; f) D. R. Morton, E. Lee-Ruff, R. M. (Eds.: R. A. Moss, M. S. Platz, M. Jones Jr), John Southam, N. J. Turro, J. Am. Chem. Soc. 1970, 92, Wiley & Sons, Inc., Hoboken, NJ, 2004. 4349-4357. [16] a) J. M. Standard, J. Phys. Chem. A 2017, 121, 381- [29] a) R. A. Moss, S. Shen, L. M. Hadel, G. Kmiecik- 393; b) Y. Wang, C. M. Hadad, J. P. Toscano, J. Am. Lawrynowicz, J. Wlostowska, K. Krogh-Jespersen, J. Chem. Soc. 2002, 124, 1761-1767. Am. Chem. Soc. 1987, 109, 4341-4349; b) J. [17] A. Nemirowski, P. R. Schreiner, J. Org. Chem. 2007, Włostowska, R. A. Moss, W. Guo, M. J. Chang, J. 72, 9533-9540. Chem. Soc., Chem. Commun. 1982, 432-433; c) J. P. [18] S. Gronert, J. R. Keeffe, R. A. More O'Ferrall, in Pezacki, P. D. Wood, T. A. Gadosy, J. Lusztyk, J. Contemporary Carbene Chemistry, Vol. 7 (Eds.: R. Warkentin, J. Am. Chem. Soc. 1998, 120, 8681-8691; A. Moss, M. P. Doyle), Wiley, Hoboken, New Jersey, d) R. A. Moss, J. Wlostowska, Tetrahedron Lett. 2013. 1988, 29, 2559-2561. [19] J. P. Moerdyk, C. W. Bielawski, in Contemporary [30] a) J. Warkentin, Acc. Chem. Res. 2009, 42, 205-212; Carbene Chemistry, Vol. 7 (Eds.: R. A. Moss, M. P. b) H. Zhou, G. Mloston, J. Warkentin, Org. Lett. Doyle), Wiley, Hoboken, New Jersey, 2013. 2005, 7, 487-489. [20] D. Zhu, L. Chen, H. Fan, Q. Yao, S. Zhu, Chem. Soc. [31] a) V. Nair, S. Bindu, L. Balagopal, Tetrahedron Lett. Rev. 2020, 49, 908-950. 2001, 42, 2043-2044; b) V. Nair, A. Deepthi, M. [21] a) H. Lebel, J.-F. Marcoux, C. Molinaro, A. B. Poonoth, B. Santhamma, S. Vellalath, B. P. Babu, R. Charette, Chem. Rev. 2003, 103, 977-1050; b) A. Mohan, E. Suresh, J. Org. Chem. 2006, 71, 2313- Padwa, S. F. Hornbuckle, Chem. Rev. 1991, 91, 263- 2319; cV. Nair, R. S. Menon, Chem. Rec. 2019, 19, 309; c) M. P. Doyle, R. Duffy, M. Ratnikov, L. Zhou, 347-361. Chem. Rev. 2010, 110, 704-724; d) H. M. L. Davies, [32] a) S. Solé, H. Gornitzka, W. W. Schoeller, D. B. T. Parr, in Contemporary Carbene Chemistry, Vol. Bourissou, G. Bertrand, Science 2001, 292, 1901; b) 7 (Eds.: R. A. Moss, M. P. Doyle), Wiley, Hoboken, X. Cattoën, H. Gornitzka, D. Bourissou, G. Bertrand, New Jersey, 2013. J. Am. Chem. Soc. 2004, 126, 1342-1343; c) B. Rao, [22] H. M. L. Davies, R. E. J. Beckwith, Chem. Rev. 2003, H. Tang, X. Zeng, L. Liu, M. Melaimi, G. Bertrand, 103, 2861-2904. Angew. Chem. Int. Ed. 2015, 54, 14915-14919; d) J. [23] a) F. He, R. M. Koenigs, Chem. Commun. 2019, 55, Vignolle, M. Asay, K. Miqueu, D. Bourissou, G. 4881-4884; b) R. Hommelsheim, Y. Guo, Z. Yang, C. Bertrand, Org. Lett. 2008, 10, 4299-4302. Empel, R. M. Koenigs, Angew. Chem. Int. Ed. 2019, [33] A. G. Brook, J. M. Duff, J. Am. Chem. Soc. 1967, 89, 58, 1203-1207; c) C. Empel, F. W. Patureau, R. M. 454-455. Koenigs, J. Org. Chem. 2019, 84, 11316-11322; d) C. [34] a) A. G. Brook, J. M. Duff, Can. J. Chem. 1972, 51, Empel, R. M. Koenigs, J. Flow Chem. 2020, 10, 157- 352-360; b) A. G. Brook, J. W. Harris, A. R. 160. Bassindale, J. Organomet. Chem. 1975, 99, 379-383; [24] a) A. J. Arduengo, R. L. Harlow, M. Kline, J. Am. c) A. G. Brook, H. W. Kucera, R. Pearce, Can. J. Chem. Soc. 1991, 113, 361-363; b) A. J. Arduengo, J. Chem. 1971, 49, 1618-1621; d) A. G. Brook, R. R. Goerlich, W. J. Marshall, J. Am. Chem.Soc. 1995, Pearce, J. B. Pierce, Can. J. Chem. 1971, 49, 1622- 117, 11027-11028; c) A. J. Arduengo, H. V. R. Dias, 1628; e) A. G. Brook, J. B. Pierce, J. M. Duff, Can. J. R. L. Harlow, M. Kline, J. Am. Chem. Soc. 1992, Chem. 1975, 53, 2874-2879; f) J. M. Duff, A. G. 114, 5530-5534; d) A. J. Arduengo, Acc. Chem. Res. Brook, Can. J. Chem. 1973, 51, 2869-2883; g) A. G. 1999, 32, 913-921. Brook, J. Organomet. Chem. 1986, 300, 21-37. [25] a) E. Peris, Chem. Rev. 2018, 118, 9988-10031; b) S. [35] a) P. C. B. Page, S. S. Klair, S. Rosenthal, Chem. Soc. Hameury, P. de Frémont, P. Braunstein, Chem. Soc. Rev. 1990, 19, 147-195; b) A. F. Patrocínio, P. J. S. Rev. 2017, 46, 632-733; c) D. Janssen-Müller, C. Moran, J. Braz. Chem. Soc. 2001, 12, 07-31; c) H.-J. Schlepphorst, F. Glorius, Chem. Soc. Rev. 2017, 46, Zhang, D. L. Priebbenow, C. Bolm, Chem. Soc. Rev. 4845-4854. 2013, 42, 8540-8571. [26] M. Melaimi, R. Jazzar, M. Soleilhavoup, G. Bertrand, [36] M. Trommer, W. Sander, Organometallics 1996, 15, Angew. Chem. Int. Ed. 2017, 56, 10046-10068. 189-193. [27] a) S. J. Ryan, L. Candish, D. W. Lupton, Chem. Soc. [37] G. Dormán, H. Nakamura, A. Pulsipher, G. D. Rev. 2013, 42, 4906-4917; b) D. Enders, O. Niemeier, Prestwich, Chem. Rev. 2016, 116, 15284-15398. A. Henseler, Chem. Rev. 2007, 107, 5606-5655; c) [38] C. Hammaecher, C. Portella, Chem. Commun. 2008, X.-Y. Chen, Q. Liu, P. Chauhan, D. Enders, Angew. 5833-5835. Chem. Int. Ed. 2018, 57, 3862-3873; d) X.-Y. Chen, [39] L. Capaldo, R. Riccardi, D. Ravelli, M. Fagnoni, ACS S. Li, F. Vetica, M. Kumar, D. Enders, iScience 2018, Catalysis 2018, 8, 304-309. 2, 1-26. [40] a) P. Becker, D. L. Priebbenow, R. Pirwerdjan, C. [28] a) R. S. Grewal, D. J. Burnell, P. Yates, J. Chem. Bolm, Angew. Chem., Int. Ed. 2014, 53, 269-271; b) Soc., Chem. Commun. 1984, 759-760; b) P. Yates, L. P. Becker, D. L. Priebbenow, H.-J. Zhang, R. Kilmurry, J. Am. Chem. Soc. 1966, 88, 1563-1564; c) Pirwerdjan, C. Bolm, J. Org. Chem. 2014, 79, 814- P. Yates, J. C. L. Tam, J. Chem. Soc., Chem. 817; c) P. Becker, R. Pirwerdjan, C. Bolm, Angew. Commun. 1975, 737-738; d) M. Jaffer, A. Ebead, E. Chem., Int. Ed. 2015, 54, 15493-15496; d) H.-J.

This article is protected by copyright. All rights reserved Zhang, P. Becker, H. Huang, R. Pirwerdjan, F.-F. [60] C. Shih, J. S. Swenton, J. Org. Chem. 1982, 47, 2668- Pan, C. Bolm, Adv. Synth. Catal. 2012, 354, 2157- 2670. 2161; e) A. G. Brook, Acc. Chem. Res. 1974, 7, 77- [61] a) J.-C. Zheng, C.-Y. Zhu, X.-L. Sun, Y. Tang, L.-X. 84; f) K. Ishida, F. Tobita, H. Kusama, Chem. - Eur. Dai, J. Org. Chem. 2008, 73, 6909-6912; b) A. O. J. 2018, 24, 543-546. Chagarovsky, E. M. Budynina, O. A. Ivanova, E. V. [41] D. L. Priebbenow, J. Org. Chem. 2019, 84, 11813- Villemson, V. B. Rybakov, I. V. Trushkov, M. Y. 11822. Melnikov, Org. Lett. 2014, 16, 2830-2833. [42] D. A. Dixon, A. J. Arduengo, J. Phys. Chem. 1991, [62] A. G. Brook, H. W. Kucera, J. Organomet. Chem. 95, 4180-4182. 1975, 87, 263-267. [43] A. C. O'Donoghue, R. S. Massey, in Contemporary [63] J. C. Dalton, R. A. Bourque, J. Am. Chem. Soc. 1981, Carbene Chemistry, Vol. 7 (Eds.: R. A. Moss, M. P. 103, 699-700. Doyle), Wiley, Hoboken, New Jersey, 2013. [64] K. Ishida, H. Yamazaki, C. Hagiwara, M. Abe, H. [44] a) N. Wang, J. Xu, J. K. Lee, Org. Biomol. Chem. Kusama, Chem. –Eur. J. 2020, 26, 1249-1253. 2018, 16, 8230-8244; b) M. Chen, J. P. Moerdyk, G. [65] V. K. Aggarwal, J. Richardson, Chem. Commun. A. Blake, C. W. Bielawski, J. K. Lee, J. Org. Chem. 2003, 2644-2651. 2013, 78, 10452-10458; c) C. E. I. Knappke, I. I. I. A. [66] K. Ito, H. Tamashima, N. Iwasawa, H. Kusama, J. J. Arduengo, H. Jiao, J.-M. Neudörfl, A. Am. Chem. Soc. 2011, 133, 3716-3719. Jacobi von Wangelin, Synthesis 2011, 3784-3795; d) [67] P. Lu, C. Feng, T.-P. Loh, Org. Lett. 2015, 17, 3210- R. S. Massey, C. J. Collett, A. G. Lindsay, A. D. 3213. Smith, A. C. O’Donoghue, J. Am. Chem. Soc. 2012, [68] R. F. Cunico, J. Chen, Synth. Commun. 2003, 33, 134, 20421-20432; e) Y. Niu, N. Wang, A. Muñoz, J. 1963-1968. Xu, H. Zeng, T. Rovis, J. K. Lee, J. Am. Chem. Soc. [69] Y. Liu, P. Cao, J. Chen, Tetrahedron Lett. 2016, 57, 2017, 139, 14917-14930; f) N. Konstandaras, M. H. 937-941. Dunn, E. T. Luis, M. L. Cole, J. B. Harper, Org. [70] R. F. Cunico, Tetrahedron Lett. 2001, 42, 2931-2932. Biomol. Chem. 2020. [71] a) R. F. Cunico, A. R. Motta, J. Organomet. Chem. [45] a) J. R. Keeffe, R. A. More O’Ferrall, ARKIVOC 2006, 691, 3109-3112; b) R. F. Cunico, A. R. Motta, 2008, 183-204; b) J. P. Guthrie, R. A. More O'Ferrall, Org. Lett. 2005, 7, 771-774. A. C. O'Donoghue, W. E. Waghorne, I. Zrinski, J. [72] R. F. Cunico, Tetrahedron Lett. 2002, 43, 355-358. Phys. Org. Chem. 2003, 16, 582-587. [73] W. Li, Y. Han, J. Chen, Tetrahedron 2017, 73, 5813- [46] H. Grützmacher, C. M. Marchand, Coord. Chem. 5819. Rev. 1997, 163, 287-344. [74] J.-Y. Liang, H. Wang, Y.-L. Yang, S.-J. Shen, J.-X. [47] A. R. Bassindale, A. G. Brook, J. Harris, J. Chen, Tetrahedron Lett. 2017, 58, 2636-2639. Organomet. Chem. 1975, 90, C6-C8. [75] J. Chen, R. F. Cunico, Tetrahedron Lett. 2002, 43, [48] A. Hassner, J. A. Soderquist, Tetrahedron Lett. 1980, 8595-8597. 21, 429-432. [76] a) H. Liu, Q. Guo, J. Chen, Tetrahedron Lett. 2015, [49] R. A. Bourque, P. D. Davis, J. C. Dalton, J. Am. 56, 5747-5751; b) W. Tong, H. Liu, J. Chen, Chem. Soc. 1981, 103, 697-699. Tetrahedron Lett. 2015, 56, 1335-1337. [50] S. A. Svarovsky, M. B. Taraban, J. J. J. Barchi, Org. [77] Q. Guo, X. Wen, J. Chen, Tetrahedron 2016, 72, Biomol. Chem. 2004, 2, 3155-3161. 8117-8122. [51] a) H. Watanabe, T. Kogure, Y. Nagai, J. Organomet. [78] F. Ma, H. Liu, J. Chen, Tetrahedron Lett. 2016, 57, Chem. 1972, 43, 285-291; b) H. Watanabe, N. 5246-5250. Ohsawa, M. Sawai, Y. Fukasawa, H. Matsumoto, Y. [79] Y. Han, Y. Li, S. Han, P. Zhang, J. Chen, Synthesis Nagai, J. Organomet. Chem. 1975, 93, 173-179. 2019, 51, 2977-2983. [52] J.-H. Ye, L. Quach, T. Paulisch, F. Glorius, J. Am. [80] J. Chen, R. K. Pandey, R. F. Cunico, Tetrahedron: Chem. Soc. 2019, 141, 16227-16231. Asymmetry 2005, 16, 941-947. [53] F. Strieth-Kalthoff, M. J. James, M. Teders, L. Pitzer, [81] R. F. Cunico, B. C. Maity, Org. Lett. 2003, 5, 4947- F. Glorius, Chem. Soc. Rev. 2018, 47, 7190-7202. 4949. [54] S. Steenken, Pure Appl. Chem. 1998, 70, 2031-2038. [82] R. F. Cunico, R. K. Pandey, J. Org. Chem. 2005, 70, [55] a) W. Kirmse, M. Guth, S. Steenken, J. Am. Chem. 5344-5346. Soc. 1996, 118, 10838-10849; b) W. Kirmse, J. [83] R. F. Cunico, R. K. Pandey, J. Org. Chem. 2005, 70, Kilian, S. Steenken, J. Am. Chem. Soc. 1990, 112, 9048-9050. 6399-6400. [84] a) X.-P. Wen, Y.-L. Han, J.-X. Chen, RSC Adv. 2017, [56] Z. Shen, V. M. Dong, Angew. Chem. Int. Ed. 2009, 7, 45107-45112; b) X. Wen, W. Chen, J. Chen, Appl. 48, 784-786. Organomet. Chem. 2019, 33, e5174. [57] D. Cai, M. Wang, J. Wang, W. Duan, J. Phys. Org. [85] W. Tong, P. Cao, Y. Liu, J. Chen, J. Org. Chem. Chem. 2012, 25, 400-408. 2017, 82, 11603-11608. [58] W. Kirmse, I. S. Ozkir, J. Am. Chem. Soc. 1992, 114, 7590-7591. [59] D. Gerbig, D. Ley, H. P. Reisenauer, P. R. Schreiner, Beilstein J. Org. Chem. 2010, 6, 1061-1069.

Silicon-Derived Singlet Nucleophilic Carbene Reagents in Organic Synthesis

Adv. Synth. Catal. 2020, Volume, Page – Page

Daniel L. Priebbenow*

Minerva Access is the Institutional Repository of The University of Melbourne

Author/s: Priebbenow, DL

Title: Silicon-Derived Singlet Nucleophilic Carbene Reagents in Organic Synthesis

Date: 2020-04-22

Citation: Priebbenow, D. L. (2020). Silicon-Derived Singlet Nucleophilic Carbene Reagents in Organic Synthesis. ADVANCED SYNTHESIS & CATALYSIS, 362 (10), pp.1927-1946. https://doi.org/10.1002/adsc.202000279.

Persistent Link: http://hdl.handle.net/11343/275675

File Description: Accepted version