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Silicon‐Derived Singlet Nucleophilic Carbene Reagents in Organic

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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- 1 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 2 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
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