Catalytic Generation of Carbanions through Carbonyl Umpolung

Abstract Carbonyl Umpolung is a powerful strategy in organic chemistry to construct complex molecules. Over the last few years, versatile catalytic approaches for the generation of acyl anion equivalents from carbonyl compounds have been developed, but methods to obtain alkyl carbanions from carbonyl compounds in a catalytic fashion are still at an early stage. This Minireview summarizes recent progress in the generation of alkyl carbanions through catalytic carbonyl Umpolung. Two different catalytic approaches can be utilized to enable the generation of alkyl carbanions from carbonyl compounds: the catalytic Wolff–Kishner reaction and the catalytic single‐electron reduction of carbonyl compounds and imines. We discuss the reaction scope, mechanistic insights, and synthetic applications of the methods as well as potential future developments.


Introduction
Thec oncept of Umpolung,f irst introduced by Wittig [1] and then popularized by Seebach, describes the polarity inversion of ap articular functional group in organic chemistry. [2] Umpolung reactions create new reactivity by inverting the natural polarity of common organic functionalities and consequently enable the development of unconventional bond-forming strategies in organic synthesis.With Umpolung tactics,retrosynthetic disconnections can be performed in an inverted manner, permitting the assembly of at arget molecule from synthons with both normal and reversed polarities. Over the past few decades,t he successful development of numerous CÀCbond-forming Umpolung reactions has greatly expanded the repertoire of methods for organic synthesis.
In the case of the carbonyl (C = O) functionality,t he electronegativity of the oxygen atom renders the carbon atom of the carbonyl group partially positively charged, which can be attacked by nucleophilic species.I natypical carbonyl Umpolung,the electronic nature of the carbonyl carbon atom is inverted from electrophilic to nucleophilic.T his allows chemists to construct new chemical bonds by reacting the newly obtained carbon nucleophiles with various electrophiles.T wo types of synthetically valuable anionic synthons are obtained through carbonyl Umpolung:acylanion equivalents and alkyl carbanionic intermediates (Scheme 1).
Research interest in the generation of acyl anion synthons by carbonyl Umpolung dates back to the cyanide-catalyzed benzoin reaction reported in 1832. [3] However,systematic and more vigorous Umpolung research started with Corey and Seebach, who described the use of dithianes to access acyl anion synthetic equivalents from aldehydes in the 1960s. [4] Thedevelopment of N-heterocyclic carbene (NHC) catalysis provides another valuable and important addition to the chemistry of acyl anion equivalents,with great efforts devoted to the design and synthesis of novel NHC catalysts that catalyze the carbonyl Umpolung reactions. [5] Thethree abovementioned Umpolung strategies constitute the most widely used approaches to access acyl anion species from carbonyl compounds.T hese seminal discoveries mark true breakthroughs in synthetic method development in the past decades and they have stimulated significant activity in designing efficient catalysts for carbonyl Umpolung.
On the other hand, Umpolung strategies can be applied for the generation of alkyl carbanionic species from aC =Om oiety.I nc omparison to its well-explored acyl anion counterpart, the generation of alkyl carbanions by carbonyl Umpolung has received considerably less attention. This type of carbonyl Umpolung holds great synthetic potential considering that the generated alkyl carbanion is av ersatile intermediate for the construction of C À Cb onds on reacting with electrophiles.T he earliest example of this Umpolung dates back to the Wolff-Kishner (WK) reduction, in which carbonyl functionalities are converted into methylene groups. [6] After more than one century since its discovery,the WK reaction and related modified reactions remain an important carbonyl deoxygenation method in modern synthesis. [6a, 7] Recent developments have provided new routes for the catalytic generation of carbanionic intermediates through the merger of the WK process and other catalytic reaction systems,s uch as transition-metal catalysis and photoredox Carbonyl Umpolung is apowerful strategy in organic chemistry to construct complex molecules.Over the last few years,versatile catalytic approaches for the generation of acyl anion equivalents from carbonyl compounds have been developed, but methods to obtain alkyl carbanions from carbonyl compounds in acatalytic fashion are still at an early stage.T his Minireview summarizes recent progress in the generation of alkyl carbanions through catalytic carbonyl Umpolung. Tw od ifferent catalytic approaches can be utilized to enable the generation of alkyl carbanions from carbonyl compounds:t he catalytic Wolff-Kishner reaction and the catalytic single-electron reduction of carbonyl compounds and imines.W ediscuss the reaction scope, mechanistic insights,and synthetic applications of the methods as well as potential future developments.
catalysis.T hese advances have greatly expanded the application of this century-old reaction and, therefore,have received increasing research interest.
Furthermore,i nr ecent years,n ew techniques for the catalytic generation of carbanionic species through the singleelectron reduction of imines and carbonyl compounds have emerged. Classically,t he reduction of imines or carbonyl compounds requires the use of stoichiometric reactants (e.g. low-valent metals) [8] or electrochemical methods [9] fort he reduction. Recent advances have demonstrated that photocatalysis can not only serve as an ideal replacement for the classic reaction system for the C=O/N moiety reduction, but also generate new carbanionic reactivity from carbonyl Umpolung. [10,11] We summarize and discuss in the following sections the catalytic generation of alkyl carbanionic species from carbonyl Umpolung,p articularly emphasizing emerging new technologies and trends.W es tructure our discussion along the two major reaction pathways for the generation of alkyl carbanions from carbonyl compounds:t he catalytic WK process (Scheme 1, pathway A) and the catalytic singleelectron reduction of imines and carbonyl compounds (Scheme 1, pathways Ba nd C).

Catalytic Wolff-Kishner Reaction-Pathway A
Before discussing the catalytic WK process,i ti sw orthwhile to first give an overview of the WK reaction mechanism. In ar egular WK process,t he reaction proceeds through the formation of hydrazones from ac arbonyl compound and hydrazine.Asubsequent deprotonation-tautomerization sequence occurs to give the diazene intermediate from the hydrazone.A fter as econd deprotonation, this intermediate rapidly loses molecular nitrogen to give the carbanion, which is then protonated to yield the alkane product (Scheme 2A). [6a] Thef ormation of the two key intermediatesah ydrazone and the diazene anion-can considerably influence the course of aW Kp rocess.M any elegant modifications,i ncluding the well-known Huang-Minlong, [12] Barton, [13] Cram, [14] and Henbest [15] procedures,have focused on amore efficient formation of the hydrazone by removal of water from the reaction medium, whereas Caglioti [16] and Meyers [17] have utilized substituted hydrazones as alternatives to the classical WK reaction, thereby allowing the facile generation of the diazene intermediate.Inparticular,the use of sulfonyl hydrazone in the Caglioti modification not only allows the WK reduction to occur under mild conditions but also inspired the generation of substituted carbanions by reacting sulfonyl hydrazone with organometallic reagents (e.g. RLi, RMgBr;S cheme 2B). [18] This reaction pathway represents one of the earliest pathways for the utilization of the WK process for construction of aC À Cb ond.
Despite being av ery effective way of producing carbanions,s ynthetic applications of the WK reaction have been mainly limited to carbonyl deoxygenation. [6a] Only af ew attempts have been made over the past few years to develop new catalytic systems,n amely catalytic variants of the WK reaction for the generation and/or trapping of the generated alkyl carbanions,t hus forging C À Cb onds.H owever,t he transformation bears the potential for ap lethora of carbanion-based transformations by merging the WK process with other catalytic systems (e.g.transition-metal catalysis,photo-

Angewandte
Chemie redox catalysis;S cheme 2C,D) that wait to be further discovered.

Metal-Assisted Trapping of Carbanions
TheL ig roup made significant progress in the catalytic trapping of the carbanion in aWKprocess.In2017, they first described ar uthenium-catalyzed strategy for the facile capture of the carbanionic species generated in aWKprocess from carbonyl compounds (ketone and aldehydes) to give the desired Grignard-type products. [19] Thereaction demonstrates broad functional-group tolerance for both the hydrazone and carbonyl compounds with different substitution patterns. Notably,t he reaction system is compatible with functional groups (including ester,a mide,a sw ell as tertiary alcohols), which are normally incompatible with classical Grignard reactions.Intheir mechanistic proposal, ruthenium complex I was initially generated from the association of hydrazone with the ruthenium catalyst. Ther esulting Ru complex I interacts with carbonyl compounds via aZ immerman-Traxler transition state II followed by its rearrangement to give intermediate III.T he Grignard-type addition product was released from III,c oncomitant with regeneration of the Ru catalyst. Thec oordination of the ruthenium complex with the substrate is believed to promote the decomposition of hydrazine, [20] thereby allowing N 2 extrusion from hydrazone under mild conditions.T his new catalysis opens new possibilities to harness the carbanions generated from readily available carbonyl compounds in the WK reaction for catalytic C À C bond-forming reactions.T he Ru catalytic system was later extended and the carbanionic species reacted with ab road range of electrophiles,i ncluding imines, [21] alkenes, [22,23] CO 2 , [24] dienes, [25] multi-fluoro arenes, [26] carbonyl compounds (for C = Cb ond construction), [27] and in situ generated carbonyl compounds (Scheme 3). [28] In addition, the Li group and others have demonstrated that other transition-metal catalysts,i ncluding Ni, Pd, and Fe, [29] could efficiently be merged with the WK processes to realize different mechanistic pathways (Scheme 4). This results in av astly expanded set of accessible coupling partners,such as alkyl halides, [30] dienes, [31] styrenes, [32] phenol derivatives, [33] and aryl halides [34] in Ni catalysis and methylenecyclopropanes, [35] alkynes, [36] allylic acetates, [37] and gemdifluorocyclopropanes [38] in Pd catalysis.S everal plausible reaction pathways for the different catalytic systems were postulated, as shown in Scheme 4. When styrenes and alkynes were employed as coupling partners,t he authors proposed six-membered intermediates,a nalogous to the Zimmerman-Tr axler transition state proposed for the Ru-catalyzed Grignard-type reaction, as the key species for the construction of new bonds.L igand exchange between the deprotonated hydrazone (C-nucleophile or N-nucleophile) and the metal complex (Ni or Pd) was proposed as the key step in the catalytic cycle in the case when (pseudo)halides were used as electrophiles.C ombining transition-metal catalysis with the WK reaction creates unprecedented reactivity for widespread use in organic synthesis.

Carbanion Generation by Radical Addition to Sulfonyl Hydrazones
Nucleophilic addition of organometallic reagents to C = N bonds of sulfonyl hydrazones leads to the generation of substituted carbanions (Scheme 2B). [18,39] However,t his approach has al imited functional-group compatibility,a nd competing side reactions may occur. Moreover,the number of nucleophiles that can be engaged in such am odified WK process is limited. Aiming to overcome these limitations, strategies for the addition of radical species to sulfonyl hydrazone derivatives were developed.
Thee arliest example which invokes such ar adical-initiated WK reaction pathway was reported by Kim and Cho as

Angewandte
Chemie early as 1992. [40] In their report, the intramolecular addition of alkyl or vinyl radicals,generated from alkyl or vinyl bromides under AIBN/ n BuSnH conditions,t oaC = Nb ond affords ac yclized diazene intermediate.T he alkyl diazene forms ac yclized alkane as product, likely via ac arbanion intermediate,w hereas its allylic diazene counterpart undergoes ap ericyclic rearrangement to give an endocyclica lkene product after N 2 extrusion (Scheme 5).
Although this reaction could be deemed as ar epresentative radical-initiated WK process for the versatile formation of diazene species,this chemistry has been little explored over the past few decades,w ith only af ew scattered examples reported. [41] However,t his reaction sequence needs to be revisited in view of reports of radical addition to other hydrazone acceptors (e.g. N,N-dialkyl hydrazones) under transition-metal or photoredox catalysis (Scheme 6A). [42,43] In ac atalytic radical functionalization approach, aminyl radical intermediate V is first generated from radical addition to the C=Nmoiety of an N-sulfonyl hydrazone (Scheme 6B). Ther esulting N-centered radical undergoes b-fragmentation to release as ulfonyl radical, thereby affording the diazene intermediate VI. [40] This diazene then enters aW Kr eaction sequence to afford the desired carbanion VII after N 2 extrusion. There are several distinct advantages in introducing new catalysis to this reaction sequence:m ilder reaction conditions to access carbanion equivalents and the facile generation of functionalized carbanions using different radicals.
In this context, Baran and co-workers described that carbon radicals formed in the reaction of an intermediate [Fe-H] species with an alkene partner can couple efficiently with formaldehyde-derived n-octylsulfonylhydrazone to give ah ydromethylation product (Scheme 7). [44] This reaction sequence could be initiated by using as toichiometric or catalytic amount of Fe(acac) 3 ,with excess B(OMe) 3 being an essential additive.Alkyl hydrazide X was observed as the key intermediate,w hich decomposes upon heating to 60 8 8Ci n MeOH to eliminate sulfinate and nitrogen to yield the hydromethylated product, presumably by an ionic pathway.
In contrast to the organometallic-functionalization method shown in Scheme 2B,this radical-based reaction tolerates base-and nucleophile-sensitive functional groups,such as free alcohols,halides,azides,and esters.T he iron catalytic system was further extended by Bradshaw and co-workers to the alkylation of non-activated alkenes by using N-tosylhydrazones as radical acceptors. [45] Over the last few decades,photocatalysis has emerged as apowerful tool to access radicals for use in abroad range of chemical transformations through single-electron transfer between the excited state of ap hotocatalyst and the substrates. [46] In the context of our ongoing research on developing photoredox catalytic approaches for carbanion generation, we questioned if ap hoto-Wolff-Kishner process could be realized by adding photogenerated radicals to sulfonyl hydrazones. [47] Thee nvisioned reaction process was initiated by single-electron-transfero xidation of as uitable substrate by the excited photocatalyst to afford the radical and the reduced photocatalyst. Subsequent radical addition to Scheme 5. Intramolecular radical functionalizationo fsulfonylhydrazones.

Angewandte
Chemie the N-sulfonylhydrazone produces an aminyl radical species XI,w hich undergoes b-sulfonyl radical fragmentation to generate af unctionalized diazene intermediate XII.T he resulting diazene enters the WK process to give the key carbanion species XIII,w hich is capable of reacting with various electrophiles in ap olar fashion. Finally,e lectron transfer between the reduced photocatalyst and the sulfonyl radical regenerates the catalyst, thus rendering the overall transformation redox-neutral. When thiols were used as the radical precursors with an Ir-based catalyst, the a-substituted carbanions were efficiently produced, then trapped by CO 2 or aldehydes.I nt he case of aC F 3 radical, gem-difluoroalkenes were produced as the final product after E1cB elimination of af luoride anion from the resulting a-CF 3 carbanions (Scheme 8). This procedure shows that the merger of photocatalysis and ac lassical WK process leads to the efficient generation of acarbanion and broadens the available scope of electrophiles for carbanion trapping.

Generation of Carbanions by Catalytic Single-Electron Reduction of Imines-Pathway B
Theg eneration of imine radical anions through singleelectron reduction is well-documented and has been employed for many transformations utilizing stoichiometric reductants. [48] In recent years,n ew photocatalytic strategies have been developed as desirable alternatives for the singleelectron reduction of imine derivatives. [10] Imine radical anions can show C-centered and N-centered radical reactivity depending on the precursor and the reaction conditions.T he C-centered radical species have been shown to engage in various radical coupling reactions, [10,11a,c] while the N-centered radical can abstract hydrogen atoms from the reaction medium to give an a-amino carbanion. This intermediate is capable of reacting with various electrophiles in an ionic fashion, as pioneered by Fanand Walsh (Scheme 9).
In 2018, Fan, Walsh et al. reported aphotoredox catalytic procedure for the hydrocarboxylation of N-alkyl and N-aryl imines with CO 2 by using Ir(ppy) 2 (dtbbpy)PF 6 as ap hotocatalyst and Cy 2 NMe as the terminal reductant. [49] Their mechanistic proposal commences with the reductive quenching of the photoexcited Ir 3+ species by Cy 2 NMe to generate the reducing Ir 2+ species and the amine radical cation. Subsequent single-electron transfer between the imine and the Ir 2+ species gives an amine radical cation and regenerates Ir 3+ .T he generated N-centered radical anion reacts with the amine radical cation in aH AT process to provide the key carbanion intermediate,w hich was then trapped by CO 2 to afford ac arboxylic acid as the product after protonation. Furthermore,they found that the carbanions generated in the reaction are efficiently trapped by protons, [50] aldehydes, [51] or isocyanate [52] (Scheme 10).
As imilar photoredox catalytic procedure for the hydrocarboxylation of enamides and aromatic imines with CO 2 (1 atm) was independently discovered by Yu and co-workers (Scheme 11). [53] Ther eaction relies on the photochemical

Angewandte
Chemie reduction of the imine using at ertiary amine (DIPEA) as asacrificial reductant to generate the a-amino carbanion XIV as the key intermediate for CO 2 trapping.T he authors conducted as eries of control experiments and deuteriumlabeling studies to prove the existence of the carbanion intermediate in the reaction. However,aspecific pathway for the generation of a-amino carbanion XIV has not been provided. From amechanistic point of view,this species could be produced through aS ET/HATm echanism as shown in Scheme 9oraphotocatalytic aza-Bouveault-Blanc reduction process,which will be discussed in Section 2.3.

Generation of Carbanions by Catalytic Sequential Single-Electron Reduction of aC arbonyl Compound-Pathway C
Single-electron reduction of carbonyl groups results in the formation of ak etyl radical, areactive intermediate that can participate in aw ide range of chemical transformations. Although the resonance structure of ak etyl radical has carbon radical and carbon anion character,the most explored reactions,s uch as radical-radical coupling and radical addition to double bonds,arise from its carbon radical nature. [48c] In contrast to imine radical anions,t he generation of ac arbanion from ac arbonyl group requires as econd singleelectron reduction process of the ketyl radical. This pathway dates back to the well-known Bouveault-Blanc reduction, wherein an a-hydroxy carbanion is produced as ak ey intermediate through two sequential single-electron reduction steps of esters by sodium metal (Scheme 12 A). [54] Classic methods to induce the carbonyl reduction rely on strong reductants such as alkali metals, [8i, 55] vanadium, [8h] titanium, [56] tin, [57] zinc, [58] and samarium diiodide (SmI 2 ). [48c, 59] In this context, visible-light-induced photocatalysis has been developed as an ideal alternative to access ketyl radicals from carbonyl compounds by leveraging the reduction power of photocatalysis.Asaconsequence,awide range of CÀCbondcoupling reactions have been discovered by reacting ketyl radicals with C-centered radicals or unsaturated bonds (Scheme 12 B). Thea dvances in exploiting the reactivity of ketyl radicals for CÀCbond construction have been summarized in several recent reviews. [11] We will, therefore,f ocus on the catalytic generation of carbanions by the sequential reduction of carbonyl compounds (Scheme 12 C).
In 1983, Pac and co-workers reported the first example of ap hotoredox catalytic reduction of carbonyl compounds in the presence of Ru(bpy) 3 Cl 2 as the photocatalyst and Nbenzyl-1,4-dihydronicotinamide( BNAH) as the reductant (Scheme 13 A). [60] In the proposed mechanism, the excited state of *Ru(bpy) 3 2+ was quenched by BNAH to produce Ru(bpy) 3 + and BNAC (XVI)a fter deprotonation. Singleelectron transfer occurred between Ru(bpy) 3 + and the carbonyl group to yield ak etyl radical and regenerate the photocatalyst. Ther esulting ketyl radical can undergo either as ingle-electron transfer process with BNAC to give an Scheme 11. Photoredox catalytic hydrocarboxylation of imines developed by Yu and co-workers.
Scheme 12. Generation of carbanions by the sequential reduction of carbonyl compounds.
Scheme 13. Photoinduced Ru-catalyticg eneration of carbanions by the sequential reduction of carbonyl compounds.

Angewandte
Chemie alcohol or radical-radical coupling with BNAC to form compound XVII.T he interaction between the ketyl radical and XVI was dependent on the electronic properties and structure of the carbonyl compounds,a nd it was found that the existence of electron-withdrawing substituents and steric hindrance favors electron transfer between the two species. Later, asimilar photoredox catalytic system for the reduction of activated ketones,i ncluding benzil and ethyl benzoylformate,w as reported by Willner et al. with Ru(bpy) 3 Cl 2 as the photocatalyst and Et 3 Na st he reductant. [61] Ther eaction involves two successive photoinduced SET processes to generate the a-hydroxy carbanion XVIII,w hich was protonated to afford the hydrogenated product (Scheme 13 B).
Recently,J iang and co-workers demonstrated au nique dual photo/asymmetric Brønsted acid catalysis system for the enantioselective hydrogenation of 1,2-diketones (Scheme 14). [62] Thec atalytic system consists of an organic photocatalyst (DPZ), ac hiral guanidinium salt catalyst 1, ab orate additive NaBArF,a nd an electron donor N-2naphthyl tetrahydroisoquinoline (THIQ). Noncovalent bonding between the Brønsted acid and the ketyl intermediate was found to be crucial for the reaction process.T he second reduction of intermediate XIX was accomplished by THIQ to afford carbanion XX,w hich was poised for the subsequent enantioselective protonation process.T he authors noted that the reaction occurs in the absence of DPZ through an electron-donor-acceptor mechanism, reaching comparable yields and enantioselectivities to those obtained in the catalytic photoredox system. Thep hotocatalytic system was further applied for the asymmetric hydrogenation of a-keto ketimines to produce a-amino ketones by exchanging the chiral catalyst derived from guanidinium salt 1 with ac hiral 1,2-cyclohexanediamine-based catalyst 2 containing urea and tertiary amine units.
Later, the same group extended this dual catalysis strategy to the asymmetric reduction of azaarene-based ketones (Scheme 15). [63] Similarly,k etones underwent two single-electron reduction processes to give carbanions that participate in enantioselective protonation or deuteration when using SPINOL-CPA 3 as ac hiral catalyst. Aw ide range of chiral azaarene-based secondary (deuterated) alcohols with diverse substitution patterns could be prepared in high yields with moderate to excellent enantioselectivity using this procedure.
Theaforementioned methods relied on the photocatalytic successive single-electron reduction of an activated carbonyl functionality to access a-hydroxy carbanions,t hus enabling the facile hydrogenation of these ketones.W especulated that the ketyl radical from ap hotoinduced single-electron reduction process could be further deoxygenated by an external reductant to afford other types of functionalized carbanions. In 2019, we demonstrated that aketyl radical generated from an aromatic aldehyde by the photoredox catalytic system could be deoxygenated with B 2 pin 2 to yield an a-boryl carbanion (Scheme 16). [64] Thek ey to obtaining the desired reactivity was the use of at hiol as ac o-catalyst for shuttling electrons from B 2 pin 2 to the photocatalytic system. The resulting a-boryl carbanion reacted with another molecule of benzaldehyde to afford the alkene as the final product, thus providing am ild and efficient photocatalytic McMurry reaction. Thereaction system was applicable to the synthesis of both symmetrical and unsymmetrical alkenes with broad substrate scope and ahigh level of functional-group tolerance. Based on the in situ NMR studies and experimental results, we propose the following reaction mechanism:r eductive quenching of the excited Ir III complex by thiolate affords at hiyl radical and the reduced photocatalyst Ir II .T he singleelectron transfer between the Ir II species and benzaldehyde regenerates the photocatalyst and yields aketyl radical XXI, which participates in ar adical borylation-"bora-Brook" rearrangement sequence to give a-oxyboryl carbanion XXIV and abase-bound boryl radical anion XXII.Reduction of the thiyl radical by XXII regenerates the thiolate.The a-oxyboryl

Angewandte
Chemie carbanion XXIV reacted with another molecule of B 2 pin 2 to yield the 1,1-benzyldiboronate ester XXV,w hich underwent base-assisted deborylation to give an a-boryl carbanion XXVI. Subsequent B-O elimination after nucleophilic addition to another aldehyde and an energy-transfer process yielded amixture of the E-and Z-alkenes.

Conclusion and Outlook
We have summarized recent advances in the generation of carbanionic intermediates by catalytic carbonyl Umpolung strategies.T hree reaction pathways yield carbanions starting from carbonyl compounds.F irst, the merger of the Wolff-Kishner reaction with catalysis provides efficient methods for the generation and/or trapping of carbanionic species,w hich impressively revitalizes this century-old chemistry.Second, aamino carbanions are obtained by exploiting the carbanionic property of an imine radical anion arising from ac atalytic single-electron reduction process.B esides this,c atalytic strategies have been applied for the production of carbanionic species by the successive reduction of carbonyl functionalities. In comparison to catalytic carbonyl Umpolung reactions involving an acyl anion, research addressing the analogous catalytic chemistry of alkyl carbanion equivalents from carbonyl compounds has received considerably less attention. One reason was the absence of suitable catalytic methods. This has changed and the combination of the classic reaction modes with recent transition-metal or photocatalysis has demonstrated ag reat potential for the generation of alkyl carbanions that are capable of participating in various CÀC bond-forging reactions in amild and controllable manner. However,d espite the advances in this field, further development is still required to address the limitations and challenges.T he catalytic radical-initiated WK reaction using as ulfonyl hydrazone as ar adical acceptor has appeared in only al imited number of literature reports (Scheme 1, pathway A). We anticipate that synthetic applications of this chemistry can be further explored towards addressing the following aspects:1 )Expanding the scope of radical precursors for the production of carbanions,2 )exploiting the reactivity of the generated diazene intermediates for more transformations (e.g.p ericyclic arrangements to construct unsaturated bonds), and 3) exploring the possibility of combining other types of catalysis (for radical generation) with the WK process to produce anionic species.Inthe case of strategies involving the catalytic single-electron reduction of imines and carbonyl compounds (Scheme 1, pathways Ba nd C), related transformations remain in their infancyand suffer from al imited substrate scope as well as al ow diversity of trapping electrophiles.E fforts are,t herefore,e xpected to be devoted to the development of more efficient catalytic systems to address these challenges and limitations.
In our opinion, numerous exciting opportunities in catalytic carbonyl Umpolung for carbanion generation still wait to be discovered, thereby expanding the arsenal of valuable transformations in organic synthesis.W eh ope this Minireview will stimulate more chemists to exploit new catalytic methods and strategies to address the abovedescribed challenges in the future.