An Overview the N-Heterocyclic Carbene-Catalyzed

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Apr 28, 2018 - The multifunctionality and high reactivity of α-amino ketones makes these structures attractive ... Catalytic cycle of aza-benzoin condensation. Scheme 2. .... Alkyl N-phosphinoyl imines are unsuitable for the reaction since they ...

catalysts Review

An Overview the N-Heterocyclic N-Heterocyclic Carbene-Catalyzed Aza-Benzoin Aza-Benzoin Condensation Condensation Reaction Reaction 2, * Domenico C. M. Albanese 11 ID and Nicoletta Gaggero Domenico C. M. Albanese and Nicoletta Gaggero 2,*

ID

1

Department of Chemistry, Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy; Department of Chemistry, Università degli Studi di Milano, via Golgi 19, 20133 Milano, Italy; [email protected] 2 [email protected] Department of Pharmaceutical Sciences, Sezione di Chimica Generale e Organica “A. Marchesini”, 2 Department of Pharmaceutical Sciences, Sezione di Chimica Generale e Organica “A. Marchesini”, Università degli Studi di Milano, via Venezian 21, 20133 Milano, Italy Università degli Studi di Milano, via Venezian 21, 20133 Milano, Italy * Correspondence: [email protected]; Tel.: +39-0250314470 * Correspondence: [email protected]; Tel.: +39-0250314470 1

Received: 23 March 2018; Accepted: 26 April 2018; Published: date 28 April 2018

 

Abstract: The N-heterocyclic carbene(NHCs)-catalyzed aza-benzoin condensation condensation reaction reaction is an carbene(NHCs)-catalyzed aza-benzoin efficient, which employs easily available substrates, such as aldehydes and imines, efficient, single singlestep stepstrategy strategy which employs easily available substrates, such as aldehydes and to provide α-aminoα-amino ketones.ketones. The multifunctionality and high reactivity of α-amino ketonesketones makes imines, to provide The multifunctionality and high reactivity of α-amino these attractive for medicinal chemistrychemistry and as precursors of a varietyofofaamine derivatives. makesstructures these structures attractive for medicinal and as precursors variety of amine The different electrophilic characteristics aldehydes and of imines ensure aand highimines regioselective derivatives. The different electrophilicofcharacteristics aldehydes ensurereaction. a high Enantiomerically-enriched α-amino ketones have been synthesized through stereoselective regioselective reaction. Enantiomerically-enriched α-amino ketones have been synthesizedcouplings through promoted by chiral N-heterocyclic dominocarbenes. procedures, including an aza-benzoin stereoselective couplings promotedcarbenes. by chiralOne-pot N-heterocyclic One-pot domino procedures, step, allowan valuable complex molecules to be accessed. including aza-benzoin step, allow valuable complex molecules to be accessed. Keywords: aza-benzoin aza-benzoin condensation; condensation; N-heterocyclic N-heterocyclic carbene carbene (NHC); (NHC); alpha-aminoketone; alpha-aminoketone; organocatalysis; imine; bis(amino)-cyclopropenylidene bis(amino)-cyclopropenylidene (BAC) (BAC)

1. Introduction α-Amino α-Amino ketones are widespread structural moieties, common to both natural and synthetic significant compounds in medicinal chemistry (Figure (Figure 1) 1) [1–4]. [1–4].

Figure 1. 1. Synthetic biologically-active α-amino α-amino ketones. ketones. Figure Synthetic and and natural natural biologically-active

They are largely employed as building blocks in the preparation of a large number of molecules, They are largely employed as building blocks in the preparation of a large number of molecules, in particular, 1,2-aminoalcohols, and vicinal diamines (Scheme 1). They are important motifs in in particular, 1,2-aminoalcohols, and vicinal diamines (Scheme 1). They are important motifs in many pharmaceutical compounds and are widely applied as chiral auxiliaries and ligands in the many pharmaceutical compounds and are widely applied as chiral auxiliaries and ligands in the field of asymmetric synthesis [5,6]. Moreover, they are precursors in the preparation of many field of asymmetric synthesis [5,6]. Moreover, they are precursors in the preparation of many x; doi: FOR PEER REVIEW Catalysts 2018, 8, 181; doi:10.3390/catal8050181

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heterocycles [7–11] andsmoothly smoothlyundergo undergo nucleophilic nucleophilic addition of of heterocycles [7–11] and addition reactions reactionstotogive givea avariety variety derivatives [12]. derivatives [12]. heterocycles [7–11] and smoothly undergo nucleophilic addition reactions to give a variety of derivatives [12].

Scheme1.1.Synthetic Synthetic potential potential of Scheme of α-amino α-aminoketones. ketones. Scheme 1. Synthetic potential of α-amino ketones.

Numerous synthetic routes to α-amino ketones have been reported in the literature. However, Numerous synthetic routes to α-amino ketones have been reported in the literature. However, theseNumerous methods involve from functionalized reactantsHowever, such as syntheticmultistep routes to transformations α-amino ketonesstarting have been reported in the literature. these methods involve multistep transformations starting from functionalized reactants such as α-azido α-azido ketones [13], α-nitro ketones [14] or α-amino acids [12,15]. these methods involve multistep transformations starting from functionalized reactants such as ketonesThe [13], aza-benzoin α-nitro ketones [14] or α-amino acids [12,15]. condensation strictly related to the well-known benzoin α-azido ketones [13], α-nitro ketones [14]reaction, or α-amino acids [12,15]. The aza-benzoin condensation reaction, strictly related to the well-known benzoin condensation reaction, represents the more straightforward to α-amino ketonescondensation andbenzoin occurs The aza-benzoin condensation reaction, strictly approach related to the well-known reaction, represents the more straightforward approach to α-amino ketones and occurs with an atom with an atom economy of 100%. the more straightforward approach to α-amino ketones condensation reaction, represents and occurs economy of 100%. most general of form, the aza-benzoin condensation reaction, first reported in 1988 [16], is a with In anits atom economy 100%. In In itsitsmost general form, theaza-benzoin aza-benzoin condensation in [16], 1988 N-heterocyclic carbene (NHC)-catalyzed coupling betweenreaction, anreaction, aldehyde andreported an in activated imine most general form, the condensation first first reported 1988 is[16], a is a(Scheme N-heterocyclic carbene (NHC)-catalyzed coupling between an aldehyde and an activated imine 2). The mechanism of this process, in analogy with the benzoin condensation, envisages the N-heterocyclic carbene (NHC)-catalyzed coupling between an aldehyde and an activated imine (Scheme 2).2). The this analogy with thebenzoin benzoin condensation, envisages formation ofThe amechanism nucleophilic NHC II from in azolium I, the under basiccondensation, conditions. Itsenvisages additionthe tothe (Scheme mechanismofof thisprocess, process, in analogysalt with aldehyde by proton generates an acyl anion equivalent III Itsknown as to a formation of afollowed NHC II transfer from azolium salt I,salt under basic conditions. Its addition to aldehyde formation ofnucleophilic a nucleophilic NHC II from azolium I, under basic conditions. addition Breslow-Intermediate, causing a reversal of equivalent the carbonyl reactivity, followed by proton transfer generates an acyl anion IIIelectrophilic known as a Breslow-Intermediate, aldehyde followed bythus proton transfer generates an original acyl anion equivalent III known as a universally (dipole inversion). acyl anion equivalent be stabilized by thus causing aknown reversalasofumpolung the original electrophilic carbonyl reactivity, universallycan known asreactivity, umpolung Breslow-Intermediate, thus causing a reversal of The the original electrophilic carbonyl π-back-donation of the carbanion onto the empty p z orbital of the carbene atom, giving rise to a universally known umpolung (dipole inversion). The acylbyanion equivalent can be stabilized (dipole inversion). Theasacyl anion equivalent can be stabilized π-back-donation of the carbanion by onto (Scheme π-back-donation carbanion onto giving the empty pz a2). orbital of the carbene atom, giving rise to a thehydroxy-enamine-type empty pz orbitalofofthe theBreslow carbeneIntermediate atom, rise to hydroxy-enamine-type Breslow Intermediate hydroxy-enamine-type Breslow Intermediate (Scheme 2). (Scheme 2).

Scheme 2. Catalytic cycle of aza-benzoin condensation. Scheme 2. Catalytic cycle of aza-benzoin condensation.

Scheme CatalyticIntermediate cycle of aza-benzoin The nucleophilic attack of a2. Breslow on the condensation. electrophilic imine, a second proton transfer step and subsequent elimination furnish the condensation product, at athe sameproton time The nucleophilic attack of a Breslow Intermediate on the electrophilic imine, second The nucleophilic attack of a Breslow Intermediate on the electrophilic imine, a second proton regenerating The wide choice of chiral azolium salts reported in theatliterature transfer step the andcatalyst. subsequent elimination furnish the condensation product, the sameallows time transfer step subsequent furnish the condensation product, atketones the same time access to the and asymmetric version of the reaction, affording enantio-enriched α-amino [17]. In regenerating the catalyst. The elimination wide choice of chiral azolium salts reported in the literature allows regenerating the catalyst. The wide choice of chiral azolium salts reported in the literature allows addition to NHCs, bis(amino)-cyclopropenylidenes (BACs) have also been successfully applied as access to the asymmetric version of the reaction, affording enantio-enriched α-amino ketones [17]. In access to the version of the reaction, affording α-amino ketones [17]. umpolung-promoting species [18]. addition to asymmetric NHCs, bis(amino)-cyclopropenylidenes (BACs) enantio-enriched have also been successfully applied as

In addition to NHCs, bis(amino)-cyclopropenylidenes (BACs) have also been successfully applied as umpolung-promoting species [18]. umpolung-promoting species [18].

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Recently, increased attention has been given to the nature of nucleophilic partners, including Recently, increased acylsilanes as acyl donors.attention has been given to the nature of nucleophilic partners, including acylsilanes as acyl donors. The chemoselective The scope scope of of this review article is to provide an overview of the advances in chemoselective The scope of this review article is to provide an overview of the advances in chemoselective aza-benzoin condensation condensation reactions, covering involving racemic and reactions, covering methodsmethods involving both racemic both and enantiomericallyaza-benzoin condensation reactions, covering methods involving both racemic and enantiomerically-enriched ketones. synthesis more complex molecules via tandem enriched α-amino ketones.α-amino The synthesis of The more complexofmolecules via tandem reactions which enantiomerically-enriched α-amino ketones. The synthesis of more complex molecules via tandem reactions involve coupling an aza-benzoin step is[19]. also described [19]. involve anwhich aza-benzoin step is coupling also described reactions which involve an aza-benzoin coupling step is also describedwhich [19]. employs Finally, the synthesis of a selected pharmaceutical candidate aza-benzoin Finally, the synthesis of a selected pharmaceutical candidate which employs aza-benzoin condensation as the key reaction of the process is considered. condensation as the key reaction of the process is considered.

2. Chemoselective Chemoselective Aza-Benzoin Aza-Benzoin Condensation Reactions 2. Chemoselective Aza-Benzoin Condensation Reactions The major major issue issue regarding successful successful execution execution of the aza-benzoin aza-benzoin condensation condensation reaction reaction is is the the The The major issue regarding successful execution of the aza-benzoin condensation reaction is the should evolve evolve under under kinetical kinetical control, control, in which which imines imines are are more requirement that the whole process should requirement that the whole process should evolve under kinetical control, in which imines are more a second molecule of aldehyde, but less with reactive towards towards Breslow BreslowIntermediates Intermediatesthan thantoto a second molecule of aldehyde, but reactive less reactive reactive towards Breslow Intermediates than to a second molecule of aldehyde, but less reactive the NHC catalyst compared to aldehyde. with the NHC catalyst compared to aldehyde. withActivated the NHC catalyst compared to often aldehyde. Activated imines (Figure (Figure carbonyl imines 2) are employed in organic chemistry as equivalents of carbonyl Activated imines (Figure 2) are in organic chemistry reagents [20–22].as equivalents of carbonyl compounds in reactions with a wide often array employed of nucleophilic compounds in reactions with a wide array of nucleophilic reagents [20–22].

Figure Figure 2. 2. Activated Activated imines. imines. Figure 2. Activated imines.

Compared to the controlled cross-acyloin reaction between two different aldehydes [23], the Compared to the cross-acyloin reaction between two different aldehydes [23],[23], the use thecontrolled controlled cross-acyloin reaction between two different aldehydes the use of imines astoacyl anion acceptors is advantageous due to the difference in electrophilicity of imines as acyl anion acceptors is advantageous due to the difference in electrophilicity between use of imines as acyl is possibility advantageous due tofine theadjustment difference tointhe electrophilicity between aldehydes andanion iminesacceptors and to the of further reactivity of aldehydes and imines and to the possibility of further fine adjustment to the reactivity of imines between aldehydes and imines and to the possibility of further fine adjustment to the of imines because of the trivalency of nitrogen. The choice of the imine-protecting group isreactivity critical. In because of the trivalency of nitrogen. The choice ofchoice the imine-protecting group is group critical.isIn fact, the imines because of the trivalency of nitrogen. The of the imine-protecting critical. In fact, the addition of carbene to activated N-tosyl and N-phosphinoyl imines gives stable nitrogen addition carbeneoftocarbene activated andN-tosyl N-phosphinoyl imines givesimines stable nitrogen analogues of fact, the of addition toN-tosyl activated andcatalytic N-phosphinoyl gives stable analogues of Breslow Intermediate that can stop the cycle [24]. However, recentnitrogen studies Breslow Intermediate that can stop the catalytic cycle However, recent studies have shown that analogues Breslow Intermediate that the[24]. catalytic [24]. However, recent studies have shownofthat the carbene/iminium ioncan pairstop undergoes a fast cycle dissociation-recombination process the carbene/iminium ion pair undergoes a pair fast dissociation-recombination process in the presence of have shown that the carbene/iminium ion undergoes a fast dissociation-recombination process in the presence of an acid catalyst (Scheme 3) [25,26]. an acidpresence catalyst of (Scheme [25,26].(Scheme 3) [25,26]. in the an acid3)catalyst

Scheme 3. Fast dissociation-recombination of aza-Breslow Intermediate. Scheme 3. 3. Fast of aza-Breslow aza-Breslow Intermediate. Intermediate. Scheme Fast dissociation-recombination dissociation-recombination of

Arylsulfonylamides and tert-butyl- or benzyl aryl(tosyl) carbamates have been widely Arylsulfonylamides and thanks tert-butylor simple benzylpreparation, aryl(tosyl) high carbamates havethebeen widely employed as imine precursors toor their stability and to Arylsulfonylamides and tert-butylbenzyl aryl(tosyl) carbamates have been widelyaptitude employed employed as imine precursors thanks to their simple preparation, high stability and the aptitude to provide, in situ, thanks reactive imines under mild conditions. the to introduction of as imine precursors to their simple preparation, high stability Moreover, and the aptitude provide, in situ, provide, in situ, reactive imines under mild conditions. Moreover, the introduction of alkoxycarbonyl functionalities (e.g., tert-butoxycarbonyl (Boc) or carboxybenzyl (Cbz))functionalities as activating reactive imines under mild conditions. Moreover, the introduction of alkoxycarbonyl alkoxycarbonyl functionalities (e.g., tert-butoxycarbonyl (Boc)deprotected or carboxybenzyl (Cbz)) as activating groups allows the final amino which can be easily to be obtained. (e.g., tert-butoxycarbonyl (Boc)derivatives or carboxybenzyl (Cbz)) as activating groups allows the final amino groups allows the final amino derivatives which can be easily deprotected to be obtained. The substrate scope is presently limited to aldimines derived from aryl or heteroaryl aldehydes. derivatives which can be easily deprotected to be obtained. The substrate scope is presently limited to aldimines derived from aryl or heteroaryl aldehydes. Conversely, iminesscope obtained from aliphatic undergo decomposition tautomerization to The substrate is presently limitedaldehydes to aldimines derived from aryl or or heteroaryl aldehydes. Conversely, imines obtained from aliphatic aldehydes undergo decomposition or tautomerization to the more stable enamide derivatives, and their use has undergo not yet been realized (Scheme 4). Conversely, imines obtained from aliphatic aldehydes decomposition or tautomerization to the more stable enamide derivatives, and their use has not yet been realized (Scheme 4). the more stable enamide derivatives, and their use has not yet been realized (Scheme 4).

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Scheme4.4.Imine/enamide Imine/enamide equilibrium. Scheme equilibrium. Scheme 4. Imine/enamide equilibrium.

On the other hand, ketimines are of particular interest because they serve as precursors of On the other hand, ketimines are of particular interest because they serve as precursors of tetrasubstituted carbon However, utilization has proved be more due of to On the other hand,atoms. ketimines are oftheir particular interest becausetothey servechallenging as precursors tetrasubstituted carbon atoms. However, their utilization has proved to be more challenging due to their poor reactivity. tetrasubstituted carbon atoms. However, their utilization has proved to be more challenging due to

their poor reactivity.

their poor reactivity. 3. Methods to Produce Racemic α-Amino Ketones

3. Methods to Produce Racemic α-Amino Ketones 3. Methods to Produce Racemic α-Amino Ketones 3.1. Use of N-heterocyclic Carbenes

3.1. Use of N-heterocyclic Carbenes

3.1. Use of N-heterocyclic Carbenes Murry and co-workers envisioned the coupling of N-benzylidene cyclohexanecarboxamide, Murry and co-workers envisioned the coupling of N-benzylidene cyclohexanecarboxamide, slowly generated in situ by eliminationthe of coupling sulfinic acid from the parent α-amido sulfone, with Murry and co-workers envisioned of N-benzylidene cyclohexanecarboxamide, slowly generated in situ by elimination of sulfinic acid from the parent α-amidosalt sulfone, with 4-pyridinecarboxaldehyde in the presence of commercially available thiazolium I-1 with and slowly generated in situ by elimination of sulfinic acid from the parent α-amido sulfone, 4-pyridinecarboxaldehyde in the these presence of commercially available thiazolium salt I-1 and triethylamine (Scheme 5). Under conditions, the corresponding amino ketone was 4-pyridinecarboxaldehyde in the presence of commercially available thiazolium salt obtained I-1 and triethylamine (Scheme 5). Under these conditions, the corresponding amino ketone was obtained with with a yield of(Scheme 98% [27].5). Under these conditions, the corresponding amino ketone was obtained triethylamine

a yield 98% of [27]. with of a yield 98% [27].

Scheme 5. Selected examples of aza-benzoin condensation between acylimines and aldehydes from Ref. [27].5. Selected examples of aza-benzoin condensation between acylimines and aldehydes from Scheme Scheme 5. Selected examples of aza-benzoin condensation between acylimines and aldehydes from Ref. [27]. Ref. [27].reaction displays a wide scope with respect to the aldehyde. It is noteworthy that The

α,β-unsaturated does notItundergo 1,4-addition The reactioncinnamaldehyde, displays a wideunder scopethese withreaction respectconditions, to the aldehyde. is noteworthy that The displays a wide scope withwith respect to the aldehyde. It is noteworthy that and alsoreaction aliphaticcinnamaldehyde, acetaldehyde reacts although moderate yield (Scheme α,β-unsaturated under these reaction conditions, does not 5). undergo 1,4-addition The aliphatic process is also tolerant in although regard towith the moderate amide portion of not the undergo tosylamide. However, α,β-unsaturated cinnamaldehyde, under these reaction conditions, does 1,4-addition and and also acetaldehyde reacts yield (Scheme 5). tosylamides derived from aliphatic aldehydes bearing an α-proton fail to generate the also aliphatic acetaldehyde reacts although with moderate yield (Scheme 5). The process is also tolerant in regard to the amide portion of the tosylamide. However, corresponding acylimines, likely due to to the aptitude these of compounds to isomerize enamides. The processderived is also tolerant in regard the amide of portion theα-proton tosylamide. tosylamides tosylamides from aliphatic aldehydes bearing an failHowever, to to generate the Crossover experiments havebearing highlighted that this reaction is underthe kinetic controltoand that the corresponding acylimines, likely due to the of fail these tocorresponding isomerize enamides. derived from aliphatic aldehydes anaptitude α-proton tocompounds generate acylimines, corresponding benzoins arethese not observed and to doisomerize not serve as Crossover experiments have highlighted that this reaction is under kinetic control and that the likely due to the aptitude of compounds to substrates. enamides. corresponding benzoins arehave not observed and do serve as substrates. Crossover experiments highlighted thatnot this reaction is under kinetic control and that the

corresponding benzoins are not observed and do not serve as substrates.

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Subsequently, methodology to to a novel one-pot synthesis of Subsequently,Murry Murrydisclosed disclosedthe theapplication applicationofofhis his methodology a novel one-pot synthesis highly-functionalized imidazoles, an important class of heterocycles widespread in natural products of highly-functionalized imidazoles, an important class of heterocycles widespread in natural and in medicinal chemistrychemistry (Scheme 6). products and in medicinal (Scheme 6).

Scheme 6. Selected one-pot synthesis imidazoles from Ref. [28]. Scheme examples 6. Selectedofexamples of one-potofsynthesis of imidazoles from Ref. [28].

The addition of an appropriate amine and acetic acid to the reaction mixture of the α-amino The addition of an appropriate amine and acetic acid to the reaction mixture of the α-amino ketone ketone intermediate followed by heating to reflux allowed the ring to close, forming imidazole. intermediate followed by heating to reflux allowed the ring to close, forming imidazole. Moreover, Moreover, chiral imidazoles can be prepared starting from chiral amines or amino acids. It is chiral imidazoles can be prepared starting from chiral amines or amino acids. It is noteworthy that noteworthy that tetra-substituted imidazoles, difficult to obtain by other routes, can be synthesized tetra-substituted imidazoles, difficult to obtain by other routes, can be synthesized with moderate with moderate to good yields using this methodology. This approach also allows the production of to good yields using this methodology. This approach also allows the production of substituted substituted oxazoles and thiazoles with good yields by replacing the amine with oxazoles and thiazoles with good yields by replacing the amine with triphenylphosphine/iodine or triphenylphosphine/iodine or the Lawesson’s reagent, respectively [28]. the Lawesson’s reagent, respectively [28]. Pseudo-homo-couplings (defined as an aldehyde reacting with an imine derived from the same Pseudo-homo-couplings (defined as an aldehyde reacting with an imine derived from the same aldehyde, Ar = Ar22) and cross-couplings (Ar ≠ Ar22) under thermodynamic control were developed aldehyde, Ar = Ar ) and cross-couplings (Ar 6= Ar ) under thermodynamic control were developed some years later using unactivated aryl imines, aryl aldehydes, thiazolium salt I-1 as the precatalyst some years later using unactivated aryl imines, aryl aldehydes, thiazolium salt I-1 as the precatalyst and triethylamine as the base, during the reflux of ethanol for 48 h (Scheme 7). and triethylamine as the base, during the reflux of ethanol for 48 h (Scheme 7). Under these conditions, competing benzoins can reversibly form and behave as substrates for Under these conditions, competing benzoins can reversibly form and behave as substrates for α-aminoketone formation. α-aminoketone formation. Cross experiments have highlighted that α-aminoketone formation is reversible. This protocol Cross experiments have highlighted that α-aminoketone formation is reversible. This protocol allows aza-benzoin coupling using less reactive aryl imines [29]. allows aza-benzoin coupling using less reactive aryl imines [29].

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Scheme 7. Selected examples of intermolecular coupling between unactivated imines with aldehydes Scheme 7. Selected examples of intermolecular coupling between unactivated imines with aldehydes from Ref. [29]. [29]. from Ref. [29].

Acylsilanes, discovered by Brook in 1957, are considered to be sterically-hindered aldehydes by Acylsilanes, discovered by Brook inin1957, are toto bebe sterically-hindered aldehydes by discovered Brookand 1957, areconsidered considered sterically-hindered aldehydes virtueAcylsilanes, of the removable silylby group, undergo smoothly nucleophilic addition reactions [30]. virtue of thethe removable silyl group, smoothly nucleophilic reactions [30]. by virtue removable group,and andundergo undergo smoothly nucleophilicaddition addition reactions [30]. They haveofbeen employed assilyl unconventional donor partners in regioselective intermolecular acyloin They have been employed as unconventional donor partners in regioselective intermolecular acyloin They have been employed as unconventional donor partners in regioselective intermolecular acyloin condensation in a number of procedures catalyzed by cyanides [23]. condensation in in aa number number of of procedures procedures catalyzed catalyzed by by cyanides cyanides [23]. [23]. condensation In the benzoin-type condensation reaction, after the nucleophilic attack of the cyanide catalyst In the benzoin-type condensation reaction, after the nucleophilic attack cyanide catalyst In the benzoin-type reaction, aafter theshift nucleophilic of of thethe cyanide catalyst on on the acylsilane, the condensation mechanism involves [1,2] of the attack migrating SiR 3 group (Brook on the acylsilane, the mechanism involves a [1,2] shift of the migrating SiR 3 group (Brook the acylsilane, thegenerating mechanismthe involves a [1,2] shift of anion the migrating SiR3 in group (Brook rearrangement), rearrangement), key stabilized acyl equivalent, analogy with the Breslow rearrangement), generating stabilized acyl in anion equivalent, analogy with the Breslow generating the key stabilizedthe acylkey anion equivalent, analogy with thein Breslow catalytic cycle. catalytic cycle. catalytic cycle. The subsequent addition of this species to a competent electrophile, followed by catalyst release, The subsequent addition of this species to a competent electrophile, followed by catalyst release, leads to the desired condensation product (Scheme 8). leads to the desired condensation product (Scheme 8).

Scheme 8. Acylsilanes donors in cross benzoin condensation. Scheme Acylsilanes as as acyl acyl Scheme 8. 8. Acylsilanes as acyl donors donors in in cross cross benzoin benzoin condensation. condensation.

Scheidt disclosed the reaction of alkyl and aryl acylsilanes with aromatic Scheidt disclosed disclosed the reaction of aryl alkyl and with arylaromatic acylsilanes with aromatic Scheidt the reaction of alkyl and acylsilanes N-diphenylphosphinoyl N-diphenylphosphinoyl imines upon exposure to catalytic N-methyl 4,5-dimethyl thiazolium salt N-diphenylphosphinoyl imines upon exposure to catalytic N-methyl 4,5-dimethyl salt imines upon exposure to catalytic N-methyl 4,5-dimethyl thiazolium salt (I-2) (30 thiazolium mol %), using (I-2) (30 mol %), using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base and a stoichiometric (I-2) (30 mol %), using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base andofaisopropanol stoichiometric 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base and a stoichiometric amount for amount of isopropanol for 48 h. Under these new conditions, the Brook rearrangement occurs amount of isopropanol for 48 h. Under these new conditions, thesmoothly Brook rearrangement occurs 48 h. Under these new conditions, the Brook rearrangement occurs without the need for smoothly without the need for charged and potentially toxic cyanide, fluoride or phosphite anions smoothlyand without the need charged and potentially toxicanions cyanide, charged potentially toxicfor cyanide, fluoride or phosphite [31].fluoride or phosphite anions [31]. [31]. N-phosphinylated amino ketones, completely devoid of any homo-coupling product N-phosphinylated amino ketones, completely devoid of any homo-coupling product N-phosphinylated amino ketones, completely devoid of any homo-coupling product contamination have afforded yields of 51–94% (Scheme 9). contamination have afforded yields of 51–94% (Scheme 9). contamination have afforded yields of 51–94% (Scheme 9).

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Scheme 9. Selected examples of aza-benzoin coupling between acylsilanes and Scheme 9. Selected examples of aza-benzoin coupling between acylsilanes and N-diphenylphosphinoyl N-diphenylphosphinoyl imines from Ref. [31]. imines from Ref. Scheme 9. [31]. Selected examples of aza-benzoin coupling between acylsilanes and N-diphenylphosphinoyl imines from Ref. [31].

The phosphinoyl group on the nitrogen atom can be removed at the end of the reaction under The phosphinoyl group on the nitrogen atom can be removed the end of the under mild conditions to give α-aminoketones. Alkyl N-phosphinoyl iminesatare unsuitable forreaction the reaction The phosphinoyl group on the nitrogen atom can be removed at the end of the reaction under mild conditions to give α-aminoketones. Alkyl N-phosphinoyl imines are unsuitable for the reaction since they undergo isomerization to more stable enamides due to the presence of an enolizable mildthey conditions to give α-aminoketones. Alkyl N-phosphinoyl imines are for the reaction since undergo isomerization to more stable enamides due theunsuitable presence an enolizable proton. On the other hand, the N-phosphinoyl protecting group istoessential for theof success of the since they undergo isomerization to more stable enamides due to the presence of an enolizable proton. OnIn thefact, other hand, the N-phosphinoyl protecting is essential for the success of the reaction. more reactive N-benzoyl, N-sulfinyl and group N-sulfonyl imines interact irreversibly proton. On the other hand, the N-phosphinoyl protecting group is essential for the success of the reaction. In fact, more reactive N-benzoyl, N-sulfinyl and N-sulfonyl imines interact irreversibly with with the catalyst, thus stopping the catalytic cycle. NHCs derived from imidazolium or triazolium reaction. In fact, more reactive N-benzoyl, N-sulfinyl and N-sulfonyl imines interact irreversibly thesalts catalyst, stopping thereaction. catalyticThe cycle. NHCsmechanism, derived from imidazolium or triazolium salts do notthus allow the desired proposed illustrated in Scheme 10, envisages with the catalyst, thus stopping the catalytic cycle. NHCs derived from imidazolium or triazolium of carbene to acylsilane followedmechanism, by the formation of intermediate viaenvisages Brook dothe notaddition allow the desired II-2 reaction. The proposed illustrated in SchemeIV10, salts do not allow the desired reaction. The proposed mechanism, illustrated in Scheme 10, envisages rearrangement. The reaction ofacylsilane this intermediate withbythe imine is reversible and thus, unproductive. thethe addition of carbene II-2 to followed the formation of intermediate IV via Brook addition of carbene II-2 to acylsilane followed by the formation of intermediate IV via Brook The subsequent transfer of Si(CH 3 ) 3 to isopropanol provides the less congested intermediate III-2 rearrangement. The reaction of this intermediate with the imine is reversible and thus, unproductive. rearrangement. The reaction of this intermediate with the imine is reversible and thus, unproductive. (Breslow Intermediate) which, after imine addition, allows the production of the protected α-amino The subsequent provides theless lesscongested congested intermediate III-2 The subsequenttransfer transferofofSi(CH Si(CH33))33 to to isopropanol isopropanol provides the intermediate III-2 ketone and regenerates the catalyst. (Breslow Intermediate) allowsthe theproduction productionofofthe theprotected protected α-amino (Breslow Intermediate)which, which,after afterimine imine addition, addition, allows α-amino ketone and regenerates the catalyst. ketone and regenerates the catalyst.

Scheme 10. Catalytic cycle of acyloin-type coupling between acylsilanes and N-aryldiphenylphosphinoyl imines. Scheme 10. Catalytic cycle of acyloin-type coupling between acylsilanes and Scheme 10. Catalytic cycle of acyloin-type coupling between acylsilanes and N-aryldiphenylphosphinoyl imines. N-aryldiphenylphosphinoyl imines.

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AnAnindependent V and and its its reaction reactionwith withN-(diphenylphosphinyl) N-(diphenylphosphinyl) independentsynthesis synthesis of of intermediate intermediate V An independent synthesis of intermediate V and its reaction with N-(diphenylphosphinyl) benzaldimine in the presence of DBU and isopropanol to give the desired product providedprovided substantial benzaldimine in the presence of DBU and isopropanol to give the desired product benzaldimine in the presence of DBU and isopropanol to give the desired product provided evidence for the proposed catalytic cyclecatalytic (Schemecycle 11) [31]. This 11) strategy opened a newopened route of access, substantial evidence for the proposed (Scheme [31]. This strategy a new substantial evidence for by theneutral proposed catalytic (Scheme 11) [31]. This strategy opened a new induced byaccess, neutral carbenes, for thecarbenes, Brook rearrangement. route of induced for cycle the Brook rearrangement. route of access, induced by neutral carbenes, for the Brook rearrangement.

Scheme11. 11.Synthesis Synthesis and and reactivity Scheme reactivityof ofintermediate intermediateV.V. Scheme 11. Synthesis and reactivity of intermediate V.

Non-enolizable N-protected aryl trifluoromethyl ketimines have been used as acceptor partners Non-enolizable N-protected aryl ketimineshave havebeen beenused usedasasacceptor acceptor partners Non-enolizable N-protected aryltrifluoromethyl trifluoromethyl ketimines partners in coupling with a series of highly-reactive furan-2-carbaldehydes to produce the corresponding in in coupling with a series of highly-reactive furan-2-carbaldehydes to produce the corresponding coupling with a series of highly-reactive to produceinthe corresponding α-amino-α-trifluoromethyl ketones, bearing a furan-2-carbaldehydes valuable quaternary stereocenter, moderate to good α-amino-α-trifluoromethyl ketones, bearing aa valuable quaternarystereocenter, stereocenter,ininmoderate moderate good α-amino-α-trifluoromethyl ketones, bearing valuable quaternary to to good yields (32–87%) in the presence of triazolium salt I-3 (Scheme 12) [32]. yields (32–87%) inin the 12) [32]. [32]. yields (32–87%) thepresence presenceofoftriazolium triazoliumsalt salt I-3 I-3 (Scheme 12)

Scheme 12. Selected examples of trifluoromethyl ketimine and aldehyde coupling from Ref. [32]. Scheme 12. Selected examples of trifluoromethyl ketimine and aldehyde coupling from Ref. [32]. Scheme 12. Selected examples of trifluoromethyl ketimine and aldehyde coupling from Ref. [32].

3.2. Use of Bis(Amino)-Cyclopropenylidenes (BACs) 3.2. Use of Bis(Amino)-Cyclopropenylidenes (BACs) 3.2. UseN-heterocyclic of Bis(Amino)-Cyclopropenylidenes (BACs) carbenes have emerged as powerful, efficient and versatile organocatalysts, N-heterocyclic carbenes haveand emerged as powerful, efficient and versatile organocatalysts, which still allow access to new unexpected organic trasformations. Efforts to develop non N-heterocyclic carbenes have emerged as powerful, efficient and versatile organocatalysts, which which still allow access to new and unexpected organic trasformations. Efforts non five-membered nitrogen-containing heterocyclic carbenes have been rather limited astoa develop consequence still allow access to new and unexpected organic trasformations. Efforts to develop non five-membered five-membered carbenes have been rather limited as a consequence of the success ofnitrogen-containing NHCs. However, heterocyclic bis(amino)-cyclopropenylidenes (BACs), the smallest aromatic nitrogen-containing heterocyclic carbenes have been rather limited as(BACs), a consequence of thearomatic success of of the success of NHCs. However, bis(amino)-cyclopropenylidenes the smallest rings containing a carbene center, have recently been employed in some intriguing applications NHCs. However, bis(amino)-cyclopropenylidenes (BACs), the smallest aromatic rings containing a rings containing a carbene recently been employed incatalytically some intriguing [33,34]. Easily prepared in a center, one-pothave reaction, BACs, likewise NHCs, induceapplications acyl anion carbene center, have recently employed some likewise intriguing applications [33,34]. Easily prepared [33,34]. Easily prepared in abeen one-pot reaction,inBACs, NHCs, catalytically induce acyl anion reactivity in aldehydes. Moreover, a significant amount of aldehyde self-condensation side product in reactivity a one-potin reaction, BACs, likewise NHCs, catalytically induce acyl anion reactivity in aldehydes. aldehydes. Moreover, a significant amount of aldehyde self-condensation side product is often formed during NHC chemistry whereas it is normally absent in umpolung reactions Moreover, significant amount aldehydewhereas self-condensation sideabsent product often formed during is often aformed during NHC of chemistry it is normally in isumpolung reactions catalyzed by BACs. NHC chemistry whereas it is normally absent in umpolung reactions catalyzed by BACs. catalyzed by BACs. The limited ability of BACs to mediate aldehyde couplings, even under ideal conditions, The limited ability of BACs to mediate aldehyde couplings, even under ideal conditions, prompted The limited ability ofofBACs to mediate aldehyde couplings, even under ideal conditions, prompted the exploration their potential in aza-benzoin reactions. After fruitless attempts with prompted theof exploration of their potential in aza-benzoin reactions. After fruitless attempts with theBoc exploration their potential in aza-benzoin reactions. After fruitless attempts Bocpractical and tosyl and tosyl imines, P,P-diphenyl N-[(aryl)(tosyl)methyl] phosphinic amides, thewith more Boc and tosyl imines, P,P-diphenyl N-[(aryl)(tosyl)methyl] phosphinic amides, the more practical imines, P,P-diphenyl N-[(aryl)(tosyl)methyl] phosphinic amides, the more practical surrogates of surrogates of the corresponding protected imines, gave productive results in the reaction withthe surrogates ofprotected the corresponding protected imines, gaveinproductive results the reaction with in corresponding imines, gave results the reaction with aromatic aldehydes aromatic aldehydes in the presence of productive bis(diethylamino)cyclopropenium salt VIin (Scheme 13) [18]. aromatic aldehydes in the presence of bis(diethylamino)cyclopropenium salt VI (Scheme 13) [18]. the presence of bis(diethylamino)cyclopropenium salt VI (Scheme 13) [18].

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Scheme 13. 13. Selected Selected examples examples of enantioselective aza-benzoin condensation catalyzed catalyzed by by BACs BACs from from Scheme of enantioselective enantioselective aza-benzoin aza-benzoin condensation condensation Scheme 13. Selected examples of catalyzed by BACs from Ref. [18]. Ref. [18]. [18]. Ref.

The reaction is effective with heteroaromatic, para or meta-substituted benzaldehydes. In some The reaction is effective with heteroaromatic, para or meta-substituted meta-substituted benzaldehydes. In some cases, an excess of aldehyde has been necessary to drive the reaction towards the product. cases, an excess of aldehyde has been necessary to drive the reaction towards the product. product. Both electron-poor and electron-rich groups on the para position of the aromatic ring of the Both electron-poor electron-poor and and electron-rich electron-rich groups groups on on the the para position of the aromatic ring of the acceptor are compatible with the reaction. Although the acidic deprotection of phosphinic amides acceptor are are compatible compatiblewith withthe thereaction. reaction.Although Although acidic deprotection of phosphinic amides thethe acidic deprotection of phosphinic amides can can be performed under mild conditions, the product has shown in stability as a free base, therefore, can be performed under mild conditions, the product has shown in stability as a free base, therefore, be performed under mild conditions, the product has shown in stability as a free base, therefore, it is it is necessary to reinsert the nitrogen-protecting group. it is necessary to reinsert the nitrogen-protecting group. necessary to reinsert the nitrogen-protecting group. Until now, attempts to develop an asymmetric version of the reaction using a chiral BAC have Until now, attempts to develop an asymmetric version of the reaction using a chiral BAC have not succeeded. not succeeded. 4. Methods to Produce Enantiomerically-Enriched α-Amino Ketones 4. Methods to Produce Enantiomerically-Enriched α-Amino Ketones The first first example example of of asymmetric asymmetric aza-benzoin aza-benzoin reaction reaction was was given given by by Miller Miller and and co-workers, co-workers, who who The used an unconventional unconventional chiral chiral thiazolium thiazolium salt. Ideally, it is derived from histidine histidine by replacing the salt. Ideally, Ideally, it used an unconventional chiral thiazolium salt. is derived from by replacing the imidazole ring with the thiazole one one (Figure (Figure 3). 3). imidazole ring with the thiazole

Figure 3. Thiazolium derivative and its precursors. Figure 3. Thiazolium derivative and its precursors.

In order to ensure the presence of a chiral binding pocket for the reaction partners, In orderto to ensure presence the presence of binding a chiralpocket binding pocket forpartners, the reaction partners, In order ensure chiral for the thiazolylalanine thiazolylalanine has the been used of as athe middle amino acid inreaction a tripeptide sequence and is thiazolylalanine has been used as the middle amino acid in a tripeptide sequence and is has been used converted as the middle amino acid in a tripeptide sequence subsequently to the corresponding thiazolium salt. and is subsequently converted to the subsequently converted to salt. the corresponding thiazolium salt. corresponding thiazolium Enantiomerically-enriched α-amino ketones have been obtained by the coupling of aromatic Enantiomerically-enriched α-amino ketones have been by coupling aromatic Enantiomerically-enriched α-amino ketones have been obtained obtained by the thethiazolylalanine coupling of of aromatic aldehydes with in situ-generated acylimines in the presence of the chiral (Taz) aldehydes with in situ-generated acylimines in the presence of the chiral thiazolylalanine (Taz) aldehydes with in situ-generated acylimines in the presence of the chiral thiazolylalanine (Taz) containing peptide salt I-4 (Scheme 14) [35]. containing I-4 (Scheme (Scheme 14) 14) [35]. [35]. containing peptide peptide salt salt I-4

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Scheme 14. Selected examples of enantioselective intermolecular aza-benzoin condensation Scheme 14. Selected examples of enantioselective intermolecular aza-benzoin condensation catalyzed catalyzed byRef. salt [35]. I-4 from Ref. [35]. by salt I-4 from Scheme 14. Selected examples of enantioselective intermolecular aza-benzoin condensation

catalyzed by salt I-4 from Ref. [35].

The reaction product undergoes racemization under basic reaction conditions due to

The reactionInproduct racemization under is basic reaction toand enolization. enolization. order to undergoes ensure an excess of enantiomeric produced, theconditions amount of due amine the The reaction product undergoes racemization under basic reaction conditions due to In order to ensure an excess of enantiomeric reaction time need to be carefully evaluated.is produced, the amount of amine and the reaction time enolization. In order to ensure an excess of enantiomeric is produced, the amount of amine and the assumption that a less activated imine would lead to increased stability of the need to beThe carefully evaluated. reaction time need to be carefully evaluated. newly-formed stereocenter employ N-Boc-protected imines inofthe of The assumption that a lessprompted activatedRovis iminetowould lead to increased stability thepresence newly-formed The assumption that a less activated imine would lead to increased stability of the chiral I-5 and aliphatic aldehydes (Scheme 15) [25]. stereocenter prompted Rovis prompted to employRovis N-Boc-protected imines in theimines presence of presence chiral I-5 newly-formed stereocenter to employ N-Boc-protected in the of and aliphatic aldehydes (Scheme 15) [25]. chiral I-5 and aliphatic aldehydes (Scheme 15) [25].

Scheme 15. Selected examples of enantioselective intermolecular aza-benzoin condensation from Ref. [25].

Scheme 15. Selected examples of enantioselective intermolecular aza-benzoin condensation from Ref.

Scheme 15. Selected examples of enantioselective intermolecular aza-benzoin condensation from Cesium acetate has been used as a base in order to generate, in situ, the catalytic amount of the [25]. Ref. [25]. acid required for catalyst regeneration. The reactions have been carried out at −20 °C to suppress racemization, and molecular have been prevent the of imines due toofthe Cesium acetate has been sieves used as a base inadded order to generate, in hydrolysis situ, the catalytic amount the Cesium acetate been used as a base in order tohave generate, in situ,out theat catalytic amount of the igroscopic nature of the salt. Following the of the conditions, the scope reaction acid required for has catalyst regeneration. Theoptimization reactions been carried −20 of °Cthe to suppress ◦ C tochain has been explored. Excellent ees andhave high yields have to been obtained with a variety of20 straight acidracemization, required forand catalyst regeneration. The reactions have been out of at imines − suppress molecular sieves been added prevent thecarried hydrolysis due to the aldehydes.nature Onmolecular the other hand, lower yields have to been observed when igroscopic of the salt.sieves Following optimization of the conditions, theβ-branched scope of thealiphatic reaction racemization, and havethe been added prevent the hydrolysis of imines due to the aldehydes such as iso-butyraldehyde have been employed, whereas α-branched aldehydes dochain not has been explored. Excellent ees and high have beenofobtained with a variety of straight igroscopic nature of the salt. Following theyields optimization the conditions, the scope of the reaction react. Electron-rich and electron-poor Boc-arylimines have been used; however, ortho-fluoro aryl On theExcellent other hand, lower yields havehave beenbeen observed when β-branched has aldehydes. been explored. ees and high yields obtained with a varietyaliphatic of straight derivativessuch do not participate in the reaction. aldehydes as iso-butyraldehyde have been employed, whereas α-branched aldehydes not chain aldehydes. On the other hand, lower yields have been observed when β-brancheddoaliphatic react. Electron-rich and electron-poor Boc-arylimines have been used; however, ortho-fluoro aryl aldehydes such as iso-butyraldehyde have been employed, whereas α-branched aldehydes do not react. derivatives do not participate in the reaction.

Electron-rich and electron-poor Boc-arylimines have been used; however, ortho-fluoro aryl derivatives do not participate in the reaction.

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One of the challenges for organic chemists is the ability to highlight different substrate reactivities One of the challenges for organic chemists is the ability to highlight different substrate in a selective manner. reactivities in a selective manner. couplings is an arduous task since homoenolate, enolate and The use of enals in cross-acyloin The use of enals in cross-acyloin couplings is an arduous task since homoenolate, enolate and acyl anion equivalent can all be generated by reacting with NHCs through different reaction pathways acyl anion equivalent can all be generated by reacting with NHCs through different reaction (Scheme 16). pathways (Scheme 16).

Scheme 16. Use of enals in N-heterocyclic carbene (NHC) chemistry.

Scheme 16. Use of enals in N-heterocyclic carbene (NHC) chemistry. The choice of the catalyst is the key factor that controls the chemoselectivity of these three species. The choice of the catalyst is the key factor that controls the chemoselectivity of these three species. Ye studied the influence of and steric and electronic of aofseries of L-pyroglutamic Ye studied the influence of steric electronic factorsfactors of a series L-pyroglutamic acid-derived acid-derived triazolium salts on the reactivity of cynnamaldehyde with N-Boc-protected triazolium salts on the reactivity of cynnamaldehyde with N-Boc-protected trifluoromethyl phenyl trifluoromethyl phenyl ketimine (Scheme 17) [36]. ketimine (Scheme [36]. group on the catalyst plays a key role not only in the reduction of steric The free17) hydroxy The free hydroxy group the catalyst plays key role not onlythanks in thetoreduction of steric hindrance compared to itsonsilylated analogue, but,a more importantly, the possible hindrance compared its silylated but, more importantly, thanks to obtained the possible hydrogen hydrogen bond to formation with analogue, the ketimine. The desired products have been in high yields andwith enantioselectivities catalyst products I-6 (Scheme Electron-withdrawing and bond formation the ketimine. using The desired have17). been obtained in high yields and electron-donating substituents on the aromatic ring of enals do not change yields and enantioselectivities using catalyst I-6 (Scheme 17). Electron-withdrawing and electron-donating enantioselectivities. β-alkyl enals have been shown to work well in the reaction; however, the use of substituents on the aromatic ring of enals do not change yields and enantioselectivities. β-alkyl enals β-alkyl and β-aryl ynals has resulted in decreased yields, although high ees have still been obtained. have been shown to work well in the reaction; however, the use of β-alkyl and β-aryl ynals has resulted in decreased high ees have still been obtained. Catalystsyields, 2018, 8, x although FOR PEER REVIEW 12 of 21

Scheme 17. Selected examples of enantioselective intermolecular aza-benzoin condensation using enals from Ref [36]. Scheme 17. Selected examples of enantioselective intermolecular aza-benzoin condensation using enals from Ref [36].

In order to further explore the scope of the reaction, (Z)-methyl 2-((tert-butoxycarbonyl) imino)-2-phenylacetates and (Z)-tert-butyl(cyano(phenyl))methylene)carbamate were used as acceptors. The aza-benzoin products were obtained with good yields and high enantiomeric excesses (Scheme 18).

Scheme 17. Selected examples of enantioselective intermolecular aza-benzoin condensation using 12 of 20 enals from Ref [36].

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further explore the the scope scope of of the the reaction, reaction, (Z)-methyl (Z)-methyl 2-((tert-butoxycarbonyl) 2-((tert-butoxycarbonyl) In order to further imino)-2-phenylacetates and (Z)-tert-butyl(cyano(phenyl))methylene)carbamate (Z)-tert-butyl(cyano(phenyl))methylene)carbamate were imino)-2-phenylacetates were used as acceptors. The Theaza-benzoin aza-benzoinproducts products were obtained with good yields and high enantiomeric were obtained with good yields and high enantiomeric excesses excesses 18). (Scheme 18). (Scheme

Scheme reactions from from Ref Ref [36]. [36]. Scheme 18. 18. Selected Selected examples examples of of aza-benzoin aza-benzoin reactions

Cyclic N-protected ketimines have attracted significant interest, especially within asymmetric Cyclic N-protected ketimines have attracted significant interest, especially within asymmetric synthesis, due to their easy preparation and handling and their stable E/Z configuration which synthesis, due to8,their and handling and their stable E/Z configuration which Catalysts 2018, x FOReasy PEER preparation REVIEW 13 ofensures 21 high enantiofacial differentiation. In particular, the oxindole scaffold is a privileged structural motif ensures high enantiofacial differentiation. In particular, oxindole scaffold is a privileged common in natural products and in pharmacological active the compounds. structural motif common in natural products and in pharmacological active compounds.(isatin)-derived The chemoselectivity of the reaction between 2,3-dioxo-2,3-dihydroindole The chemoselectivity of the reaction between 2,3-dioxo-2,3-dihydroindole ketimines and enals has been studied by Chi [37]. When precatalyst I-7 was used, the(isatin)-derived reaction produced ketimines and enals has been studied by Chi [37]. When precatalyst I-7 was used, the reaction homoenolate-derived adducts (pathway A). The replacement of the encumbered and electron-rich produced homoenolate-derived adducts (pathway A). The replacement of the encumbered and N-mesityl substituent with the less hindered and electron-deficient pentafluorophenyl moiety (I-8) electron-rich N-mesityl substituent with the less hindered and electron-deficient pentafluorophenyl switched the(I-8) outcome of the the aza-coupling with product high chemoselectivity moiety switched the reaction outcome towards of the reaction towards theproduct aza-coupling with high (pathway B) (Scheme 19). chemoselectivity (pathway B) (Scheme 19).

Scheme 19. Reaction pathways between enals and isatin-derived ketimines catalysed by NHCs. (A) Scheme 19. Reaction pathways between enals and isatin-derived ketimines catalysed by NHCs. β-carbon reaction. (B) Carbonyl carbon reaction. (A) β-carbon reaction. (B) Carbonyl carbon reaction.

3-Aminooxindoles bearing a quaternary stereocenter with high ees and good yields have been

3-Aminooxindoles prepared (Scheme 20).bearing a quaternary stereocenter with high ees and good yields have been prepared (Scheme 20).

Scheme 19. Reaction pathways between enals and isatin-derived ketimines catalysed by NHCs. (A) β-carbon reaction. (B) Carbonyl carbon reaction.

3-Aminooxindoles bearing a quaternary stereocenter with high ees and good yields have been Catalysts 2018, 8, 181 13 of 20 prepared (Scheme 20).

Scheme 20. Selected examples of enantioselective intermolecular aza-benzoin reactions between

Scheme 20. Selected examples of enantioselective intermolecular aza-benzoin reactions between enals enals and isatin-derived ketimines from Ref [37]. and isatin-derived ketimines from Ref [37]. An unprecedented enantioselective aza-benzoin coupling, starting from ring-strained

An unprecedented enantioselective coupling, starting fromsynthons ring-strained 2H-azirines 2H-azirines and aromatic aldehydes toaza-benzoin give chiral aziridines, useful building and valuable pharmaceutical structural motifs has been recently reported [38].synthons Functionalized benzaldehydes and and aromatic aldehydes to give chiral aziridines, useful building and valuable pharmaceutical heteroaromatic aldehydes are wellreported tolerated[38]. (Scheme 21). Aliphaticbenzaldehydes aldehydes failed and to participate in structural motifs has been recently Functionalized heteroaromatic the reaction (data not shown). aldehydes are well tolerated (Scheme 21). Aliphatic aldehydes failed to participate in the reaction (data not shown). Catalysts 2018, 8, x FOR PEER REVIEW 14 of 21

Scheme 21. Selected examples of enantioselective intermolecular aza-benzoin reactions between Scheme 21. Selected examples of enantioselective intermolecular aza-benzoin reactions between aldehydes and 2H-azirines from Ref [38]. aldehydes and 2H-azirines from Ref [38].

The scope of the reaction has been also tested with respect to the 2H-azirines by systematically

The scope of the reaction also tested with the 2H-azirines by have systematically varying substituent patternshas onbeen the aromatic ring. In respect all cases,tohigh ees and yields been varying substituent patterns on the aromatic ring. In all cases, high ees and yields have been obtained obtained When alkyl or alkenyl groupsreplaced replacedthe the aromatic aromatic ring, enantiomeric excesses were were When alkyl or alkenyl groups ring,excellent excellent enantiomeric excesses still achieved, although with lower yields. still achieved, although with lower yields. 5. Tandem Reactions In 2011, almost simultaneously, two papers dealing with the preparation of functionalized dihydroindenones with divergent diastereoselectivity were published. Ye and coworkers developed a tandem aza-benzoin/aldol reaction starting from benzene

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5. Tandem Reactions In 2011, almost simultaneously, two papers dealing with the preparation of functionalized dihydroindenones with divergent diastereoselectivity were published. Ye and coworkers developed a tandem aza-benzoin/aldol reaction starting from benzene 1,2-dicarboxaldehyde and N-Boc imines using I-1 as precatalyst which exclusively produced cis-2-amino-3-hydroxyindenones with yields of up to 93% (Scheme 22) [39]. Catalysts 2018, 8, x FOR PEER REVIEW 15 of 21 Catalysts 2018, 8, x FOR PEER REVIEW

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Scheme 22. Selected examples of tandem aza-benzoin/aldol reactions from Ref [39]. Scheme 22. Selected examples of tandem aza-benzoin/aldol reactions from Ref [39].

Scheme 22. Selected examples of tandem aza-benzoin/aldol reactions from Ref [39]. The achievement of optimized conditions required the use of cesium carbonate to generate the Theand achievement of optimizedconditions conditions required the the use cesium carbonate to generate the the The achievement of optimized required theformation useofof cesium carbonate to generate carbene diisopropylethylamine in order to promote of the imine. carbene and diisopropylethylamine in order to promote the formation of the imine. Phenyl imines with electron-withdrawing groups gave the corresponding indenones with carbene and diisopropylethylamine in order to promote the formation of the imine. Phenyl imines electron-withdrawing groups gave the corresponding indenones with higher yields compared to imines with electron-donating substituents. Imines bearing with both a Phenyl imines withwith electron-withdrawing groups gave the corresponding indenones higher higher yields compared to imines group with electron-donating substituents. Imines bearing both a m-chlorophenyl or a p-chlorophenyl showed a similar reactivity. Also, heteroarylimines gave yields compared to imines with electron-donating substituents. Imines bearing both a m-chlorophenyl m-chlorophenyl or a p-chlorophenyl group showed a similar reactivity. Also, heteroarylimines gave high yields. or a p-chlorophenyl group showed a similar reactivity. Also, heteroarylimines gave high yields. high The yields. resulting cis-1-hydroxy-3-oxo-2-(p-tolyl)-2,3-dihydro-1H-inden-2-yl)benzamide was shown The resulting cis-1-hydroxy-3-oxo-2-(p-tolyl)-2,3-dihydro-1H-inden-2-yl)benzamide was shown to The convert resultingtocis-1-hydroxy-3-oxo-2-(p-tolyl)-2,3-dihydro-1H-inden-2-yl)benzamide was23) shown to easily the corresponding isoquinolinone under Mitsunobu conditions (Scheme [39]. easilytoconvert to the corresponding isoquinolinone under Mitsunobu conditions (Scheme 23) [39]. easily convert to the corresponding isoquinolinone under Mitsunobu conditions (Scheme 23) [39].

Scheme 23. Indenone to isoquinolinone conversion. Scheme 23.Indenone Indenone to to isoquinolinone Scheme 23. isoquinolinoneconversion. conversion.

You and coworkers developed a process to substitute trans dihydroindenones through an You and coworkers a process toreaction, substitutestarting trans dihydroindenones an NHC-catalyzed tandem developed aza-benzoin/Michael from tert-butyl through aryl(tosyl) You and coworkers developed a process reaction, to substitute trans through NHC-catalyzed tandem aza-benzoin/Michael starting from tert-butyl methylcarbamates and (E)-ethyl 3-(2-formylphenyl)acrylates (Scheme 24)dihydroindenones [40]. In orderaryl(tosyl) to obtain an NHC-catalyzed aza-benzoin/Michael starting from aryl(tosyl) methylcarbamates and (E)-ethyl 3-(2-formylphenyl)acrylates (Scheme 24) [40]. Intert-butyl order to obtain high yields of the tandem desired product, 2.2 equivalents of reaction, cesium carbonate were used. A reduced base high yields the desired product, 2.2 equivalents of cesium were AInreduced base methylcarbamates and (E)-ethyl 3-(2-formylphenyl)acrylates (Scheme 24)used. [40]. order to obtain loading (1.5of equiv.) hampered the complete conversion of thecarbonate initially formed aza-benzoin product (1.5 equiv.) hampered the2.2 complete conversion of the initially formed aza-benzoin product to dihydroindenone. Onproduct, the other hand, lower yields obtained with awere higher excess equiv.) base high loading yields of the desired equivalents of were cesium carbonate used. A (4 reduced to Onthe thethe other hand, lower yields were obtained with a higher excess (4 equiv.) of dihydroindenone. Cs2CO 3. Under optimized conditions, tandem reaction tolerated both loading (1.5 equiv.) hampered complete conversion ofthe the initially formed aza-benzoin product to of Cs2CO3. Under and theelectron-donating optimized conditions, the tandem reaction tolerated both electron-withdrawing substituents on the phenyl group of the imine and also, dihydroindenone. On the other hand, lower yields were obtained with a higher excess (4 equiv.) of electron-withdrawing electron-donating substituents oncarbamate the phenyldid group the imine and also, heteroarylimines gave and good results. Cyclohexyl-substituted not of react. Cs2 CO3 . Under the optimized conditions, the tandem reaction tolerated both electron-withdrawing heteroarylimines gaveshown good results. Cyclohexyl-substituted carbamate did not react. Also, it has been that functionalized acrylates are suitable substrates. The catalytic cycle and electron-donating substituents on the phenyl group of the imine and also, heteroarylimines gave Also, itinhas been shown that functionalized acrylates are suitable substrates. The catalytic cycle is depicted Scheme 25. goodisresults. Cyclohexyl-substituted carbamate did not react. depicted in Scheme 25.

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Also, it has been shown that functionalized acrylates are suitable substrates. The catalytic cycle is depicted in Scheme 25. Catalysts 2018, 8, x FOR PEER REVIEW 16 of 21 Catalysts 2018, 8, x FOR PEER REVIEW

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Scheme 24. Selected examples of the tandem aza-benzoin/Michael reaction from Ref [40]. Scheme 24. Selected examples of the tandem aza-benzoin/Michael reaction from Ref [40].

Scheme 24. Selected examples of the tandem aza-benzoin/Michael reaction from Ref [40]. The Breslow Intermediate, generated from the reaction of the carbene catalyst with acrylate, The Breslow Intermediate, generated from the ofof thethe carbene catalyst withwith acrylate, The Breslow Intermediate, generated from the reaction carbene catalyst acrylate, produces intermediate VII after the addition of reaction imine. A subsequent proton transfer gives produces intermediate VII after the addition of imine. A subsequent proton transfer gives intermediate VIII, which releases the catalyst and the α-amino ketone. It istransfer worth noting that the produces intermediate VII after the addition of imine. A subsequent proton gives intermediate VIII, which releases the α-amino ketone. Ititisreacts worth noting that the acts imine actsthe as an electrophile incatalyst the firstand step of the when with the Breslow VIII,intermediate whichcarbon releases catalyst and the the α-amino ketone. It process is worth noting that the imine carbon imine carbon acts as an electrophile in the first step of the process when it reacts with the Breslow as afirst nucleophile in the following Michael addition step.Breslow In fact, the enolizable but as anIntermediate, electrophilebut in the step of the process when it reacts with the Intermediate, Intermediate, nucleophile product in the following addition step. Insite fact, the enolizable α-carbon atombut in as theaaza-benzoin results inMichael a stronger nucleophilic compared to the as a nucleophile in the following Michael addition step. In fact, the enolizable α-carbon atom in the α-carbon atom in the aza-benzoin productinresults in a stronger nucleophilic site compared to the contiguous nitrogen atom and reacts the Michael addition, furnishing exclusively the aza-benzoin product results in a stronger nucleophilic site compared to the contiguous nitrogen contiguous nitrogen atom and reacts in the Michael addition, furnishing exclusively the atom dihydroindenone derivative. and reacts in the Michael addition, furnishing exclusively the dihydroindenone derivative. dihydroindenone derivative.

Scheme 25. Proposed catalytic cycle of the tandem aza-benzoin/Michael reaction. Scheme 25. Proposed catalytic cycle of the tandem aza-benzoin/Michael reaction.

Scheme 25. Proposed catalytic cycle of the tandem aza-benzoin/Michael reaction. Bode developed a cascade sequence involving an aza-benzoin/oxy-Cope strategy for Bode developed cascade sequence an aza-benzoin/oxy-Cope for synthesis of bicyclic a α-lactams with a involving diastereoisomeric ratio higher thanstrategy 10:1 and synthesis of bicyclic α-lactams with a diastereoisomeric ratio higher than 10:1 and

the the an an

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Bode developed a cascade Catalysts 2018, 8, x FOR PEER REVIEWsequence involving an aza-benzoin/oxy-Cope strategy for the synthesis 17 of 21 Catalysts 2018, 8, x FOR PEER 21 of bicyclic α-lactams withREVIEW a diastereoisomeric ratio higher than 10:1 and an enantioselectivity of17upof to 98%. The starting reactants 3-alkyl or 3-arylenals and both chalcone-derived sulfonyl imine enantioselectivity of up to included 98%. Theboth starting reactants included 3-alkyl or 3-arylenals and enantioselectivity of up to 98%. The starting reactants included both 3-alkyl or 3-arylenals and (Scheme 26) [41]. chalcone-derived sulfonyl imine (Scheme 26) [41]. chalcone-derived sulfonyl imine (Scheme 26) [41].

Scheme 26. Selected examples of synthesis of bicycle-lactams from Ref. [41]. [41]. Scheme Scheme 26. 26. Selected Selected examples examples of of synthesis synthesis of of bicycle-lactams bicycle-lactams from from Ref. Ref. [41].

Strictly related to the one-pot processes reviewed in this section is a paper dealing with the Strictly related to the one-pot one-pot processes reviewed in this section is aa paper paper dealing dealing with with the the addition of homoenolate equivalents to appropriate imines, followed by cyclization steps generating addition addition of homoenolate equivalents to appropriate imines, followed by cyclization steps generating γ-lactams (Scheme 27) [42]. γ-lactams (Scheme 27) [42]. [42].

Scheme 27. Selected examples of catalytic synthesis of lactams from Ref. [42]. Scheme 27. 27. Selected Selected examples examples of of catalytic catalytic synthesis synthesis of of lactams lactams from from Ref. Ref. [42]. [42]. Scheme

Disubstituted γ-lactams with high diastereoselectivity have been obtained from the reaction of Disubstituted γ-lactams with high diastereoselectivity have been obtained from the reaction of a series of cinnamaldehydes N-sulfonyl imines in the presence of precatalyst Disubstituted γ-lactamswith with electron-rich high diastereoselectivity have been obtained from the reactionI-11. of a a series of cinnamaldehydes with electron-rich N-sulfonyl imines in the presence of precatalyst I-11. Novel acyl anion acceptors, namely benzylidene thio-ureas, have been used in a domino series of cinnamaldehydes with electron-rich N-sulfonyl imines in the presence of precatalyst I-11. Novel acyl anion acceptors, namely benzylidene thio-ureas, have been used in a domino aza-benzoin/intermolecular aza-acetalization process thio-ureas, for the Novel acyl anion acceptors, namely benzylidene have synthesis been used of in aza-benzoin/intermolecular aza-acetalization process for the synthesis of 5-hydroxy-imidazolidene-2-thiones, a class ofaza-acetalization heterocycles displaying biological activities a domino aza-benzoin/intermolecular processrelevant for the synthesis of 5-hydroxy-imidazolidene-2-thiones, a class of heterocycles displaying relevant biological activities (Scheme 28) [42]. 5-hydroxy-imidazolidene-2-thiones, a class of heterocycles displaying relevant biological activities (Scheme 28) [42]. (Scheme 28) [42].

Scheme 28. Strategy for the synthesis of 5-hydroxy-imidazolidene-2-thiones. Scheme 28. Strategy for the synthesis of 5-hydroxy-imidazolidene-2-thiones.

The generality of the strategy toward imidazolidine-2-thiones was investigated by considering The generality of the strategy toward imidazolidine-2-thiones was investigated by considering variations in the structures of both aromatic aldehydes and α-sulfonyl amines (Scheme 29). variations in the structures of both aromatic aldehydes and α-sulfonyl amines (Scheme 29).

Disubstituted γ-lactams with high diastereoselectivity have been obtained from the reaction of a series of cinnamaldehydes with electron-rich N-sulfonyl imines in the presence of precatalyst I-11. Novel acyl anion acceptors, namely benzylidene thio-ureas, have been used in a domino aza-benzoin/intermolecular aza-acetalization process for the synthesis of 5-hydroxy-imidazolidene-2-thiones, a class of heterocycles displaying relevant biological activities Catalysts 2018, 8, 181 17 of 20 (Scheme 28) [42].

Scheme Scheme 28. 28. Strategy Strategy for for the the synthesis synthesis of of 5-hydroxy-imidazolidene-2-thiones. 5-hydroxy-imidazolidene-2-thiones.

The generality of the strategy toward imidazolidine-2-thiones was investigated by considering

The generality of the strategy toward imidazolidine-2-thiones was investigated by considering Catalysts 2018, x FOR PEER REVIEW variations in8,the structures of both aromatic aldehydes and α-sulfonyl amines (Scheme 29). 18 of 21

variations in the structures of both aromatic aldehydes and α-sulfonyl amines (Scheme 29). Further studies demonstrated that the novel cyclization reaction could be run under optimized conditions on a large scale without without losing losing reactivity reactivity or or diastereoselectivity. diastereoselectivity.

Scheme 29. 29. Selected Selected examples examples of of the the one-pot one-pot synthesis synthesis of of 5-hydroxy-imidazolidene-2-thiones 5-hydroxy-imidazolidene-2-thiones from from Scheme Ref. [42]. Ref. [42].

6. A A Successful Successful Application Application of of Aza-Benzoin Aza-Benzoin Condensation Condensation to to the the Synthesis Synthesis of of aa Pharmaceutical Pharmaceutical 6. Candidate Candidate Metabotropicglutamate glutamatereceptor receptor 5 (mGluR5) is broadly expressed throughout thenervous central Metabotropic 5 (mGluR5) is broadly expressed throughout the central nervous system and is implicated in different cognitive and behavioural processes. The molecule system and is implicated in different cognitive and behavioural processes. The molecule depicted depicted Figure has been identified as a potential for the pre-clinical development of in Figure in 4 has been4 identified as a potential candidatecandidate for the pre-clinical development of mGluR5 mGluR5 modulators [43]. modulators [43].

6. A Successful Application of Aza-Benzoin Condensation to the Synthesis of a Pharmaceutical Candidate Metabotropic glutamate receptor 5 (mGluR5) is broadly expressed throughout the central nervous system and is implicated in different cognitive and behavioural processes. The molecule depicted in 8, Figure Catalysts 2018, 181 4 has been identified as a potential candidate for the pre-clinical development 18 ofof 20 mGluR5 modulators [43].

Figure approach, through the aza-benzoin reaction, for the for preparation of mGluR5 Figure 4.4. Synthetic Synthetic approach, through the aza-benzoin reaction, the preparation of modulator. mGluR5 modulator.

tert-Butyl and benzyl-((1R,2S)-1-(5-bromo pyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethyl) carbamate have been selected as key intermediates in the synthesis of the target mGluR5 modulator. Unfortunately, their preparation via aminohydroxylation occurs with low regioselectivity. The resolutive approach to this issue has been suggested as the asymmetric reduction of a protected α-aminoketone assembled by a regioselective aza-benzoin condensation catalysed by I-1. The same approach could be applied for the synthesis of other 1,2-amino alcohols, where the traditional methods based on functionalization of alkenes may suffer from selectivity issues. 7. Conclusions The aza-benzoin condensation reaction represents the useful enrichment of organic chemistry tools complementary to the traditional cross benzoin reaction. The different levels of electrophilicity of imines with respect to aldehydes and the possibility of further tuning their reactivity by careful choice of the protecting group on the nitrogen atom, offers the possibility of solving the problem of chemoselectivity which represents the weak point of the cross benzoin coupling between two different aldehydes. For this reason, the aza-benzoin condensation allows easy access, in a regioselective manner, to valuable α-amino ketones. The possibility to take advantage of a great number of structurally-different chiral N-heterocyclic carbenes has successful improved stereoselective protocols, which have produced α-amino ketones with high enantiomeric excesses. Moreover, the experimental requirements include aza-benzoin condensation in domino processes for the straightforward synthesis of complex cyclic derivatives. In conclusion, the aza-benzoin reaction is a general, practical and broad scope methodology which forebodes new interesting developments. Author Contributions: Domenico C. M. Albanese and Nicoletta Gaggero wrote the paper. Conflicts of Interest: The authors declare no conflict of interest.

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