alkyl-substituted aldehydes

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Tetrahedron 70 (2014) 2207e2236

Contents lists avai

Tetrahedron

journal homepage: www.elsevier .com/locate/ tet

Tetrahedron report number 1032

Methods for direct generation of a-alkyl-substituted aldehydes

David M. Hodgson *, Andrew CharltonDepartment of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK

a r t i c l e i n f o

Article history:Received 12 September 2013Available online 25 November 2013

Keywords:AldehydeAlkylationEnamineEnantioselectiveOrganocatalysis

* Corresponding author. Tel.: þ44 (0)1865 275697e-mail address: [email protected] (D.M.

0040-4020/$ e see front matter � 2013 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2013.11.046

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22072. Methods to prepare racemic a-alkyl-substituted aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2208

2.1. Enolates and related oxo-intermediates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22082.2. Enamines, aza-enolates, and related nitrogen intermediates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2210

3. Chiral auxiliary-based methodology to access enantioenriched a-alkyl-substituted aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22114. Organocatalytic a-alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2214

4.1. SN2 alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22144.2. Cation alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2216

4.2.1. Brønsted acid co-catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22164.2.2. Lewis acid co-catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22194.2.3. Hydrogen-bond co-catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2221

4.3. Dehydrogenative a-alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22234.4. Transition metal co-catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2223

4.4.1. Allylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22234.4.2. Propargylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2226

4.5. Radical and electron transfer processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22264.5.1. SOMO activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22264.5.2. Photoredox organocatalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2231

5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2233References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2233Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2236

1. Introduction

This review focuses on Csp3eCsp3 bond-forming processes that,by overall formal nucleophilic substitution, result in an electrophile

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losing a leaving group and becoming attached at the a-carbon of analdehyde (Scheme 1). Direct Csp3eCsp3 bond formation at the a-carbon of an aldehyde by oxidative coupling, where the non-aldehydic partner typically loses a proton or proton equivalent(e.g., an organosilyl group), is also discussed. The emphasis is onrecent developments (up to mid 2013), particularly asymmetrictransformations; however, to put the newer work in context, anoverview of significant older and established strategies is also

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Scheme 1. Scope of review.

D.M. Hodgson, A. Charlton / Tetrahedron 70 (2014) 2207e22362208

included. Rather than just simply present relevant transformations,an attempt has also been made to provide likely principal un-derlying reaction pathways and, where relevant, catalytic cycles andorigins of asymmetric induction. a-Substituted aldehydes arisingfrom heteroatom incorporation, or CeC bond formation resulting inattachment to Csp2 centres (e.g., a-arylation/a-vinylation), or byaddition processes to C]O (e.g., aldol), to C]N (e.g., Mannich), toC]C (e.g., Michael), constitute large areas of important syntheticchemistry, but lie outside the scope of the present review.

Scheme 2. Competing reactions in aldehyde a-alkylations.

a-Alkyl-substituted aldehydes are used extensively in synthesis.Numerous transformations are possible for such compounds, in-cluding addition reactions with a wide range of nucleophiles (es-pecially involving CeC bond formation). As such, chiral, non-racemic, a-alkyl-substituted aldehydes constitute substrates in at-tractive strategies to reach more complex asymmetric molecularframeworks.1 Chiral a-alkylated aldehydes may also show usefulolfactory properties.2 Not surprisingly, there has been substantialinterest in the development of methodology to access these valu-able chiral building blocks.3 Several recent reviews cover aspects ofprogress in asymmetric ‘a-alkylation’ of aldehydes;4 in the presentmore broader overview, we place the significant achievements theysummarise in the context of the long-standing challenge of direct(i.e., single-step) installation of a simple alkyl group at the a-posi-tion of an aldehyde.

2. Methods to prepare racemic a-alkyl-substituted aldehydes

While this review principally concerns asymmetric alkylation,a-alkylation of aldehydes in a racemic manner is itself oftenproblematic, typically more so than with ketones,5 and the diffi-culties encountered cannot be ignored in the design of stereo-controlled approaches.

2.1. Enolates and related oxo-intermediates

For alkylation in a racemic manner, a variety of enolate-basedmethods have been examined; however, the techniques

developed are far from general. Successful formation of the enolateis highly dependent on conditions for deprotonation, which oftendo not prevent reaction of the enolate with the aldehyde precursorand this gives rise to mixtures of products (Scheme 2). In someinstances, the aldehyde is so electrophilic that the bases used mayalso competitively undergo 1,2-addition to the carbonyl group.Additionally, reactions may suffer from the base used (e.g., LDA)acting as a hydride transfer agent, reducing the aldehyde to thecorresponding alcohol (Scheme 2).6 Aside from the issue of clean

aldenolate generation, depending on the electrophile employed,reactions may also suffer from polyalkylation, competing C- and O-alkylation, and other side reactions, among which aldol addition/condensation, Cannizzaro and Tishchenko products are commonlyobserved (Scheme 2).5,7

Despite the above challenges, certain enolate approaches haveshown some success. C- vs O-Enolate alkylation can be biased bythe use of larger counter-cations (e.g., K vs Li) and less polar sol-vents.8 In the gas-phase O-alkylation of aldenolates is favoured.9

Non-polar solvents more closely mimic a gas-phase environmentand thus under such conditions the size of the counter-cationgreatly influences the extent of electrophilic attack at oxy-gendlarger ions provide greater steric encumberment at oxygen,and promote C-alkylation.5b Biphasic conditions have also provedeffective for generation of some aldenolates.10 In such systems,a phase transfer catalyst (e.g., Bu4NþX�) is used to solvate smallamounts of hydroxide into the organic phase, in turn generatingsmall amounts of the enolate, which reacts with the alkyl halidepresent. Such alkylations are limited to more reactive halides (e.g.,allylic/benzylic halides and MeI), as with less ‘active’ alkyl halides(e.g., i-PrI) self-condensation of the aldehyde dominates. Aldolcondensation is less problematic for potassium enolates since po-tassium is a poor chelator, therefore, the aldolate and precursorenolate are likely to be in equilibrium so allowing alkylation toreach completion.5 However, while O-alkylation may be sup-pressed using potassium enolates (vide supra), this is generally onlysuccessful for reactions involving more reactive halides. Reactionsbetween aldenolates and unactivated alkyl halides, regardless of

D.M. Hodgson, A. Charlton / Tetrahedron 70 (2014) 2207e2236 2209

the counter-cation, are prone to undesirable mixtures of O- and C-alkylation products.

Metal enolates of less electropositive elements, such as tin,where the metaleoxygen bond is more covalent in nature, givebetter yields of C-alkylation.5 Early studies by Odic and Pereyredemonstrated high C-alkylation regioselectivity could be achievedusing tri-n-butyltin aldenolates.11 Subsequent work by Jung andBlum demonstrated this to be an effective strategy for alkylation ofacetaldehyde, albeit less so for less reactive electrophiles such as EtI(40%, Scheme 3).12

Scheme 3. Tin enolate-mediated a-alkylation of acetaldehyde.

More recently, Baba et al. showed that manipulation of the co-ordination number at tin (from four to five) can give remarkablechanges in chemoselectivity of tin enolates, at least for those de-rived from cyclic and acyclic ketones (Scheme 4).13 Jacobsenet al. have exploited this type of reactivity for asymmetric alkyl-ation of ketones, including for the generation of all-carbon-substituted quaternary stereocentres;14 however, this chemistryhas not been extended to aldehydes, possibly due to accessibility ofthe tin enolates, which are typically prepared by transmetallationfrom other metal enolates or from enol acetates (e.g., using tri-n-butyltin methoxide, Scheme 3).

- -

Scheme 4. Reactivity of tetra- and pentavalent tin enolates.

In the enolate strategies employed, the greatest success is ach-ieved using a,a-disubstituted aldehyde substrates, where dia-lkylation is not possible.5b By contrast, attempted alkylations of a-monosubstituted aldehydes via enolates commonly suffers fromdialkylation; since an excess of the alkylating agent should not beused when attempting monoalkylation of such aldehydes, self-condensation is more difficult to avoid. Nevertheless, isolated ex-amples of aldenolate monoalkylation do exist (Scheme 5).15 Despitethe above discussion regarding the problems associated with

Scheme 5. Diastereoselective al

alkylation of aldehyde enolates, when the aldehyde substrate inScheme 5 was treated sequentially with LiHMDS and MeI the cor-responding a-methylated aldehyde was generated in remarkablygood yield with complete diastereoselectivity. To the best of ourknowledge, the transformation illustrated in Scheme 5 representsthe only example of a stereocontrolled direct aldehyde enolate al-kylation with a simple alkyl halide. In this case, the b-branching/substituents may contribute to minimising self-aldolisation anddimethylation. The sense and magnitude of the stereoinduction areless easily rationalised.16

Monoalkylations with SN1-active electrophiles (2� and 3� alkylhalides) are routinely performed using silyl enol ethers in thepresence of a Lewis acid (LA, Scheme 6).17 The covalent SieO bondprevents unwanted side reactions but also lowers reactivity,therefore, silyl enol ethers react only with activated (typically ascarbocations) alkylating agents.5b Their lower reactivity is actuallyof benefit since aza-enolates and enamines, which are often usefulfor alkylations with SN2-mode electrophiles (Section 2.2), typicallyundergo elimination reactions with SN1-active electrophiles, thussilyl enol ethers offer a complementary reactivity mode.18

Scheme 6. Alkylation of silyl enol ethers with SN1-active alkylating agents.

In recent years, Brønsted acid catalysis has shown utility in al-kylations with SN1-active electrophiles (Scheme 7). Synergisticamino-/acid-catalysed systems are covered within the context ofchiral organocatalysis (Section 4). Regarding racemic SN1 alkyl-ations, in 2011 Chi et al. reported a monocatalytic system relying ona Brønsted acid to facilitate both formation of a carbocation (froma suitable alcohol precursor) and also tautomerisation to the re-active enol form of the aldehyde.19 A series of common acid cata-lysts in conjunction with a broad range of diaryl methanol-derivedcarbocation electrophiles (notably including ‘less stabilised’ car-bocation substrates) and aliphatic aldehydes were tested, whichgave the corresponding a-substituted aldehydes in high yields.Almost contemporaneously, Guo et al. reported similar findings.20

Both studies showed limited success for diastereocontrol in alkyl-ations involving unsymmetrical benzhydryl electrophiles (i.e.,Ar1sAr2, Scheme 7). However, the use of ‘less stabilised’

dehyde enolate alkylation.

Scheme 7. SN1-activation using Brønsted acid catalysis.


carbocations is advantageous to amine/acid co-catalysis, whichdoes not tolerate such substrates. The systems that were examinedshow strong solvent dependencies and the pKa of the acid alsoinfluences reaction yields. Improved yields were observed by Guoet al. at elevated reaction temperature. In contrast, the conditions ofChi et al. gave efficient conversion at ambient temperature for

Scheme 8. a-Alkylation of 2-butenoic acids with subsequent olefinic-oxidative cleavage.

many of the aldehydes examined, though higher temperatureswere required for some reactions involving ‘less stabilised’ elec-trophiles. In this work it was found that t-BuOH (1 equiv) additivewas required in some instances to suppress self-redox reactions ofether intermediate 1, which is formed during the reaction; the tert-butyl ether will form but the product is less susceptible to self-redox (Scheme 7). While both catalytic systems represent novelstrategies to alkylations with SN1-active electrophiles, a potentiallimitation of this chemistry is the reaction stoichiometry withvaluable aldehydes, as significant excesses of aldehydes are used[3 equiv (Chi) and 10 equiv (Guo)].

Less direct methods, which achieve the formation of a-alkylatedaldehydes, include reactions through amide or ester enolates, withpost-alkylationereduction required to obtain the aldehyde (see, forexample, Evans’, Myers’, and Oppolzer’s asymmetric alkylationstrategies in Section 3 below). An alternative ingenious route to a-

-

Scheme 9. C- and N-alky

alkylated aldehydes is illustrated in Scheme 8. a-Alkylation of thedianions (dienediolates) of 2-butenoic acids with n-alkyl bromidesprovide a-substituted b,g-butenoic acids. Subsequent ozonolysis ofthe terminal alkene gives, following spontaneous decarboxylationof the transient b-formyl carboxylic acid, the a-alkyl-substitutedaldehyde.21

2.2. Enamines, aza-enolates, and related nitrogenintermediates

Seminal work by Stork et al. established the use of enamines asnon-charged enolate equivalents.22,23 While this work provided anexemplary solution to previously problematic a-monoalkylation ofketones [via ketenamines (3/4 {R4¼alkyl/aryl}, Scheme 9)], al-kylation of aldenamines is more limited. Reactive (activated) elec-trophiles, such as benzylic, allylic and propargylic halides, aresuitable reaction partners for aldenamines since N-alkylation isreversible with benzylic halides,24 and in the case of allylic25 andpropargylic halides26 C-alkylation is achieved by reaction at N fol-lowed by [3,3] sigmatropic rearrangement (e.g., 3/5/6/4,Scheme 9). However, the less-hindered nature of aldenaminescompared with their ketenamine counterparts invariably results inirreversible N-alkylation (3/2 {R4¼H}, Scheme 9) with weaker

-

lation of enamines 3.


electrophiles, i.e., simple alkyl halides.25a,27 Furthermore, synthesisof aldenamines 3 (R4¼H) is intrinsically more difficult due to thehigh reactivity of the aldehyde and the basicity of the secondaryamines employed, which can lead to aldol side reactions. Alden-amines are also prone to hydrolysis, oxidation and polymerisa-tion.28 Enamines are typically prepared through condensationaccording to the method first reported byMannich and Davidsen in1936.29 The mechanistic sequence involves formation of an in-termediate aminal, which upon destructive distillation generatesthe enamine. Several alternative enamine syntheses have also beenreported,28e30 though substitution about nitrogen is often a limit-ing factordmore sterically hindered amines generally return loweryields of the corresponding aldenamines, which is unfortunatesince these enamines are more prone to C-alkylation (vide infra).

Curphey et al. were the first to demonstrate that stericallyhindered (about N) aldenamines can circumvent the problem ofN-alkylation.31 For example, ethylation of enamine 9, preparedby K2CO3-mediated condensation from amine 7 and valeraldehyde(8), gave the desired a-ethylated aldehyde 10 in good yield(Scheme 10). In contrast, a comparatively less reactive alkyl halide,BuI, provided the corresponding aldehyde 11 in significantly loweryield (24%, Scheme 10), although Hodgson et al. have since shownthe efficiency for this alkylation can be higher (54%).32b

Scheme 10. Synthesis and C-alkylation of a sterically hindered aldenamine.

Further work by Hodgson et al. expanded on this chemistry todemonstrate that severely hindered aldenamines provide an effi-cient solution to the non-trivial task of monoalkylation at the a-position of aldehydes, including secondary halide electrophiles(e.g., i-PrI), to give a-alkylated aldehydes 15 (Scheme 11).32

Aldenamine 14 was prepared by eliminative (eLi2O) insertion ofhindered lithium amide 13 into the a-lithiated derivative of ter-minal epoxide 12. Synthesis of the aldenamine is a potential

Scheme 11. Synthesis and C-alkylation of

Scheme 12. Generation and a

limitation of this chemistry, as classical condensation is not possi-ble owing to the hindered nature of the amine 13 (Li¼H), and thelithium amidedepoxide methodology used to generate the en-amine is in this case modest yielding and restricted to enamines oflow molecular weight (since the enamine is sensitive to hydrolysisand purification is by distillation).

Due to the issues of aldenamine N-alkylation with unhinderedenamines and the limited methodology available for preparation ofhindered aldenamines, a-monoalkylation of aldehydes is morecommonly achieved by way of the enamine salt 17 [also termedaza-enolate (Scheme 12)].33 Such metalloenamines 17, which areformed by deprotonation of aldimines 16 (readily prepared bycondensation of a primary amine and aldehyde34) with an appro-priate organometallic reagent (e.g., LDA or RMgX), are not suscep-tible to N-alkylation and are highly nucleophilic (at the b-carbon)towards less active SN2-mode alkylating agents, such as simplealkyl halides; the product aldimine 18 is then hydrolysed to give thea-alkylated aldehyde 19. One of the great benefits of this chemistryis that it can be adapted to an efficient asymmetric version (seediscussion of Enders’ SAMP/RAMP hydrazone process, Section 3).However, a drawback of this chemistry is the strongly basic con-ditions necessary to form the aza-enolate.

Efficient direct generation of a-alkylated aldehydes is also pos-sible from nitrile precursors by way of a three-step one-pot syn-thesis (Scheme 13).35 Reaction of a primary or secondary nitrilewith DIBAL-H forms the corresponding aluminium imide 20 readilyat 0 �C. Addition of an appropriate base [LDAeHMPA (or n-BuLi,which is limited to benzylic substrates (R1 or R2¼aryl) and requires1:1 Et2O/hexane solvent mixture to give useful yields)] gives rise toa lithiumealuminium complex that can be C-alkylatedwith a broadrange of alkylating agents (notably including i-PrI).

3. Chiral auxiliary-based methodology to access enantioen-riched a-alkyl-substituted aldehydes

Currently, one of the more popular methods to access enan-tioenriched a-alkyl-substituted aldehydes is Enders’ SAMP/RAMPhydrazone chemistry (Scheme 14).36 Hydrazone derivatives22, which are readily formed by condensation of aldehydes anda chiral, non-racemic hydrazine auxiliary, such as commerciallyavailable (S)-1-amino-2-methoxymethylpyrrolidine (21, SAMP),undergo facile deprotonation and alkylation with simple alkyl ha-lides. This strategy routinely provides high levels of asymmetricinduction, and a host of other related auxiliaries are now availableoffering potential to optimise stereoselectivity, if required.37

However, while this chemistry is capable of attaining very highlevels of diastereoinduction, it is not without limitations. One

a severely hindered aldenamine 14.

lkylation of aza-enolates.

Scheme 13. a-Alkylation via metallated aluminium imide.

Scheme 14. Enders’ hydrazone asymmetric alkylation.


constraint is the requirement for very low reaction temperatures(typically between �80 �C and �120 �C). Furthermore, an addi-tional step (e.g., ozonolysis or hydrolytic cleavage mediated by MeIand acid; Scheme 14) is required to retrieve the aldehyde fromalkylated hydrazone 23; and the byproduct of this cleavage (a toxicnitrosamine when ozone is used) also requires further manipula-tion (reduction) to regenerate the auxiliary 21, which can often onlypartially be recovered.38

Alternative (enolate) approaches, such as those developedby Evans (Scheme 15),39 Myers (Scheme 16),40 and Oppolzer(Scheme 17)41 perform alkylations at a higher oxidation level, andalso constitute well-established routes to enantioenriched a-alkyl-substituted aldehydes. These methods consistently produce highlevels of chirality transfer, and oxazolidinone 24 (R¼H, Evans),pseudoephedrine 27 (Myers) and camphorsultam 30 (Oppolzer)chiral auxiliaries are all commercially available. Precursors 25/28/31 to the enolates are routinely prepared in high yield by simplesubstitution of the appropriate acyl chloride (or {mixed}anhy-dride). An additional advantage of Myers’ methodology is that N-

Scheme 15. Evans’ strategy fo

acyl products 28/29 are often crystalline, providing a means to in-crease (chiral) purity through re-crystallisation. However, the in-direct nature of thesemethodologies is a disadvantage, requiring anadditional reduction step in each case to access the aldehyde, whichin certain cases can be problematic (e.g., endo vs exo N-acyl oxa-zolidinone cleavage); this latter problem can be minimised byuse of a modified auxiliary (e.g., Davies’ ‘SuperQuat’,42 R¼Me;Scheme 15). Additionally, while Evans’ oxazolidinone is a powerfulauxiliary for alkylations involving activated electrophiles [e.g., re-action of imide 25 (R1¼Me) with BnBr gave imide 26 (R1¼Me,R2¼Bn) in excellent yield (92%) and dr (>99%)] alkylation withsimple alkyl halides is less successful [e.g., ethylation of imide 25(R1¼Me)with EtI gave imide 26 (R1¼Me, R2¼Et) in only 36% yield].3

Although more efficient for alkylation with unactivated alkyl ha-lides, Myers’ asymmetric alkylations require the addition of a largeexcess of LiCl to increase reaction rate and inhibit O-alkylation ofthe free hydroxyl group on the auxiliary.

Given the efficiency of alkylations between hindered alden-amines and simple alkyl halides (Section 2.2), Hodgson considered

r asymmetric alkylation.

Scheme 16. Myers’ strategy for asymmetric alkylation.

Scheme 17. Oppolzer’s strategy for asymmetric alkylation.


the possibility of using chiral, non-racemic, hindered aldenaminesfor asymmetric intermolecular SN2 alkylation. In 2008, Hodgsonand Kaka reported the first ‘direct’ synthesis of enantioenrichedmono-a-alkyl-substituted aldehydes 34a,b involving in-termolecular nucleophilic substitution, by way of C-alkylation ofchiral piperidine-derived enamines 33a,b (Scheme 18).43

Scheme 18. Direct, asymmetric SN2 intermolecular a-alkylation.

Fig. 1. Axial (ax) and equatorial (eq) conformers of trialkylpiperidine-derived en-amines 33.

In this work, diastereocontrol was achieved using chiral tri-alkylpiperidine auxiliaries 32a,b (Li¼H), where the derived alden-amines 33a,b were found to alkylate in moderate to high yield.While stereoselectivity could be improved by installation of a ste-rically more demanding substituent a- to N on the piperidine(Me/i-Pr, 33b/34b, Scheme 18), this resulted in diminishedyields of alkylation. Computational analysis44 indicated that the C-6Me substituent resides axial in the ground state conformation ofenamine 33a (i.e., 33 (ax) {R¼Me}, Fig. 1) in order to minimise A1,3

strain, which is present in the ring-flipped conformer (33 (eq),Fig. 1). Conversely, the C-6 i-Pr substituent in enamine 33b liesequatorial in the ground state (33 (eq) {R¼i-Pr}, Fig. 1). This mini-mises more significant 1,3-diaxial interactions imposed by the iso-propyl substituent but reduces the reactivity of the enamine (in theground state), since the olefinic component twists orthogonal to thenitrogen lone pair rendering the enamine inactive to C-

alkylation.22a,23,45 While the reactive axial conformation(where N lone pairep* overlap becomes possible) is attainable atelevated temperatures for enamine 33b increasing the size of thesubstituent at this position (e.g., exchanging i-Pr for t-Bu) is pre-dicted to lower enamine reactivity and in turn reduce yields ofalkylation.

In the exploration of more reactive enamines, the present au-thors considered tropane 35a (Scheme 19).46 It was believed en-amines derived from the conformationally locked tropane 35awould give improved reactivity compared with enamine 33b and,given the structural similarity between these auxiliaries, a similardegree of stereocontrol might be attained. Ethylation of tropane-derived enamine 37a with EtI proceeded in high yield but

Scheme 19. Tropane- and homotropane-derived enamines for asymmetric a-alkylation.


showed a substantial reduction in er, interestingly with opposingdiastereofacial selectivity. The observed facial preferencewas foundto be consistent with DFT studies. Subsequent DFT calculationspredicted formal expansion of the embedded pyrrolidine wouldgive significantly improved er (85:15), with the originally envisagedsense of asymmetric induction. Indeed, ethylation of the corre-sponding homotropane-derived enamine 37b proceeded with an-ticipated enantioinduction and a higher degree of stereoselectivity,although lower than for alkylations with enamine 33b. The en-amines themselves were prepared according to a modified pro-cedure based on Hansson and Wickberg’s earlier work;47 thisinvolves an unusual Grignard additioneelimination with the cor-responding formamides 36a,b, and represents one of few availablemethods to access such hindered enamines (see Section 2.2).

Although not involving CeC bond formation, studies in2003 by Evans et al. demonstrated a novel and highly efficientderacemisation of unfunctionalised a-alkyl aldehydes usingcrystallisation-induced dynamic resolution (CIDR) of diastereomeric imines.48 For example, (�)-2-ethylhexanal was condensedwith enantiopure (R,R)-aminoindanol, which gave a 50:50 mixtureof diastereomeric imines that was subsequently enriched byCIDR in MeOH to provide essentially enantiopure (R,R,Ra)-imine(Scheme 20). Following mild hydrolysis, this gave (R)-2-ethylhexanal in excellent er (99:1 or 95:5, depending on the hy-drolysis method used). While this represents a highly efficientstrategy to chiral non-racemic a-alkyl aldehydes, it is substratedependent, as the approach relies on selective crystallisation of onealdimine diastereomer.

Scheme 20. CIDR of racemic a-alkyl-substituted aldehydes.

4. Organocatalytic a-alkylation

Over the last dozen years or so, groundbreaking studies oniminium49 and enamine50 catalysis have resulted in dramaticprogress in asymmetric a-functionalisation of aldehydes.51 Notablebreakthroughs include organocatalysed aldol, Mannich, tandemand cascade reactions.4e For organocatalytic asymmetric a-alkyl-ation of aldehydes, several ingeniousmethods have been developed

for specific classes of partner substrates.52 However, a general so-lutionwhich includes simple alkyl based-electrophiles has yet to befound, and has been termed a ‘Holy Grail’ of organocatalysis.4c

4.1. SN2 alkylation

Asymmetric aldenamine catalysis has found utility in a widerange of transformations.53 In 2004, List and Vignola reported thefirst aminocatalytic intramolecular a-alkylation of aldehydes asa powerful method for asymmetric ring formation (Scheme 21).54

Aldehydes containing a leaving group at the u-position un-derwent cyclisation in the presence of catalytic (S)-a-methyl pro-line in moderate to high yields, with excellent stereoselectivity.Computational studies provided support for the significant rise inasymmetric inductionwhen using a-methyl proline comparedwithproline, which was seen to provide a stronger bias for reactionproceeding through an anti-enamine in the transition state(Scheme 21).55 This slow (24e48 h), below ambient temperature,enamine alkylation process is facilitated by cyclisations leading tofive- and three-membered rings, but in this case also in the tran-sition state (necessarily containing a three-atom linear arrange-ment of ]C/CeX) by activation of the leaving group throughelectrostatic stabilisation of the developing negative charge on thehalide by trialkylammonium carboxylate.

Significantly, the above work shows that a secondary aminecatalyst (and a tertiary amine) under aldenamine-forming condi-tions is compatible with the presence of an unactivated simple sp3-hybridised organo halide (I or Br)/tosylate. Furthermore, the in-

termediate enamine underwent preferential intramolecular C-al-kylation (intramolecular N-alkylation of the E-enamine is notgeometrically feasible), rather than intermolecular aldolisation.However, attempts to develop this reactivity intermolecularlyproved unsuccessful, with self-aldolisation dominating.56 Attemp-ted reaction of propionaldehyde with BnBr, catalysed by proline inthe presence of Et3N resulted in benzylation of the catalyst, givingN-benzylproline and N-benzylproline benzyl ester.54 These studies

Scheme 21. a-Methylproline-catalysed intramolecular asymmetric a-alkylation.


indicate that amine-catalysed intermolecular alkylation of alde-hydes through enamine SN2-like reaction with simple alkylatingagents is less preferred than self-aldolisation and catalystalkylation.

Although organocatalysed intermolecular a-alkylation of alde-hydes with simple alkyl halides has yet to be achieved, Palomoet al. have developed an asymmetric intermolecular a-allylation(Scheme 22).57 In this work, a base additive (e.g., DABCO, carefullychosen to avoid racemisation of the product aldehyde) is used toactivate a 2-(bromomethyl)acrylate towards attack by a proline-

Scheme 22. Asymmetric a-allylation

Scheme 23. Asymmetric a-allylation with 3

derived enamine generated in situ. While the overall reactionconstitutes a simple substitution, DFT studies indicate the reactionis assisted by the electron-accepting ester group present on theallylating agent and support an initial Michael-type conjugate ad-dition, followed by elimination.

Building on this work, Palomo et al. have recently reporteda procedure for the a-allylation of aldehydes with 3-substituted-2-(bromomethyl)acrylates that generates two contiguous stereo-centres with excellent diastereo- and enantioselectivity(Scheme 23).58 However, a large excess of aldehyde is required.

with 2-(halomethyl)acrylates.

-substituted-2-(bromomethyl)acrylates.


Despite the difficulties mentioned above of using purely SN2-active electrophiles in alkylations, a variety of intramolecular SN2processes (including domino alkylations) have been reported sinceList and Vignola’s seminal paper; generally, these procedures utiliseproline-derived catalysts.4 A sub-category of reactions within thisclass are based on conjugate addition to chiral a,b-unsaturatediminium ions (formed by condensation of the aminocatalyst and anenal) where the nucleophile contains a (halide) leaving group,which is subsequently displaced by cyclisation of the enamine in-termediate. For example, C�ordova59 and Wang60 have demon-strated asymmetric cyclopropanation in excellent yields and ersusing this concept (Scheme 24). A potential reaction pathway is alsoindicated in Scheme 24. Under the reaction conditions, iminiumions are generated in situ from condensation of theJørgenseneHayashi proline-derived aminocatalyst61 with enals.Concurrent enolisation of the bromomalonate substrate providesthe Michael donor for 1,4-addition. Following conjugate addition,the transient enamine intermediate 38 undergoes SN2 intra-molecular alkylation, followed by in situ hydrolysis to provide thecyclopropane adduct 39. By changing the base used [from Et3N or2,6-lutidine (1.1 equiv) to NaOAc (4 equiv)], Wang establisheda concise route to (E)-a-substituted malonate a,b-unsaturated al-dehydes 40 (Scheme 24).

4 4 4 4

Scheme 24. Enantioselective cyclopropanation of a,b-unsaturated aldehydes.

In a more recent example, Reme�s and Vesel�y effected a tandemconjugate addition/a-alkylation sequence between u-halo-substituted 1,3-dicarbonyl systems and a,b-unsaturated aldehydesusing the same O-silylated prolinol catalyst, which generated1,1,2,3-tetrasubstituted cyclopentanes in good yields and with ex-cellent levels of stereocontrol (Scheme 25).62 Reactions between u-halo malonates (R2¼Oalkyl) and cinnamic-type aldehydes(R1¼aryl) proved the most effective.

Scheme 25. Cyclopentanes by tandem

In 2008, Enders et al. reported a remarkable alternative strategyto create an enamine intermediate, which undergoes intra-molecular alkylation with the creation of an all-carbon quaternarystereocentre (Scheme 26).63 In this work, an in situ generatedaldehyde-derived enamine undergoes preferential intermolecularMichael addition with an u-iodo-substituted nitroalkene. Protontransfer neutralises zwitterion 41 (evidently outcompeting poten-tial intramolecular alkylation a- to the nitro group) to give thecyclisation precursor.

4.2. Cation alkylation

4.2.1. Brønsted acid co-catalysis. In addition to the enamine-catalysed SN2 aldehyde a-alkylations described in Section 4.1,SN1-based processes have been a focus of considerable inter-est.4cee,64 Initial findings in the laboratories of Petrini and Mel-chiorre, concerning alkylation of an L-proline enamine bya carbocation formed in situ from a bisaryl sulfonate (Scheme 27),65

inspired new avenues of research in this area. For example, Cozziet al. have utilised this reactivity mode to a-alkylate aldehydes withbenzhydrol substrates (Scheme 27).66

Since this area was last reviewed4e,64 a number of papers havebeen published reporting similar modes of alkylation. Several of

these newmethods merge transition metal Lewis acid- and amino-catalysis, and are discussed in the next section (Section 4.2.2).Under Brønsted acid catalysis, Ji et al. have very recently docu-mented a strategy for enantioselective generation of 3-indolyloxindoles by way of asymmetric alkylation of aldehydes with 3-hydroxy-3-indolyloxindoles facilitated by an imidazolidinone(Scheme 28).67 While a variation of this method of a-alkylation hasfound application in the total synthesis of (þ)-gliocladin C,68

conjugate addition/a-alkylation.

Scheme 27. Melchiorre and Cozzi’s asymmetric SN1 a-alkylations.

2 2

22

2 2

2

Scheme 26. Enamine Michael additioneproton transfereenamine alkylation.

(

Scheme 28. Asymmetric a-alkylation of aldehydes with 3-hydroxy-3-indolyloxindoles.

Scheme 29. ‘Acid-free’ asymmetric intermolecular SN1 a-alkylation.


a limitation of these methodologies is the requirement for func-tionality in the electrophile that is capable of promoting generationof the transient carbocation.

Loh et al. have reported an ‘acid-free’ method of SN1-activationusing trifluoroethanol (Scheme 29).69 While this chemistry hasobvious benefits for acid-sensitive substrates, high temperaturesare required and although the chemistry expands the utility offluorinated solvents, expense and toxicity are potential drawbacks.

With organocatalytic a-alkylation using secondary (benz-hydryl-type) alcohols now well-established, the pursuit of moreelaborate tandem reactions is underway. For example, Behr,


Christmann et al. have reported a one-pot hydroformylation/SN1alkylation (Scheme 30).70 A range of terminal alkenes were ex-amined, which gave moderate to excellent yields with goodstereocontrol. Conjugated alkenes did not undergo reaction.

Scheme 30. Tandem hydroformylation/a-alkylation.

An alternative approach to methods employing alcohols for SN1a-alkylations has been developed by Tian et al., which recognisesthe potential of N-doubly benzylic sulfonamides as SN1-substrates(Scheme 31).71 Under the acidic reaction conditions, a sulfon-amide undergoes CeN cleavage generating a stabilised carbocationthat subsequently reacts with an in situ generated chiral alden-amine. The acid and amine catalyst are regenerated on hydrolysis ofthe resulting iminium ion 42.

Scheme 31. Asymmetric a-alkylation of aldehydes with N-benzylic sulfonamides.

While not an SN1 process (and an addition rather than a sub-stitution), Xiao, Li et al. have recently developed an a-aldehydealkylation route to molecular scaffolds, which are structurally re-lated to those accessed through the above discussed Brønsted-acid/

amino-catalysis (Scheme 32).72 Highly enantioselective ‘conjugate’addition to a series of acridinium iodides by a range of aliphaticaldehydes and phenylacetaldehyde was facilitated with an aminocatalyst.

In the same study, tropylium hexafluorophosphate was exam-ined as a cationic electrophile, and a-alkylations proceeded incomparably high yields and excellent enantioselectivities(Scheme 33).

Of particular merit in the area of cationic organocatalytictransformations is a strategy conceived by Cozzi et al. that achievesformal asymmetric a-methylation of aldehydes (Scheme 34).73 Inthis work, enamines derived from an imidazolidinone undergo

highly stereoselective addition to 1,3-benzodithiolylium tetra-fluoroborate in good yield. The resulting aldehydes are reduced totheir corresponding alcohols in order to avoid post-reaction epi-merisation. Subsequent reduction with Raney Ni of the 1,3-

Scheme 32. Asymmetric 1,4-addition of aldehydes to acridiniums.

Scheme 33. Asymmetric aldehyde a-alkylation by tropylium cation.

Scheme 34. Asymmetric a-alkylation with a 1,3-benzodithio cation.


benzodithiol group provides access to the enantioenriched 2-methylated alcohol. Furthermore, the 1,3-benzodithiol group inthe product following alkylationereduction can be easily metal-lated and then alkylated (with alkyl halides) to provide longer chainalkyl groups in the a-position, without degrading the enantiopurityof the aldehyde. While this is a significant advance towards the‘Holy Grail’,4c it is still an indirect approach (as the a-alkylated al-dehyde is not directly obtained from the alkylation step).

Cozzi et al. have subsequently extended this methodology toaccess all-carbon quaternary stereocentres from a-substitutedpropanal (Scheme 35).74 In this work, a range of readily accessibleamino acids, primary amines and an imidazolidinone were exam-ined as potential organocatalysts; however, all proved unsuitable.Subsequent examination of a series of cinchona alkaloid-derivedprimary amines established a good organocatalyst candidate. Fur-ther enhancement of asymmetric induction was achieved by

introducing a chiral acidic additive [(�)-CSA]. Interestingly, enan-tiofacial selectivity could be reversed by changing the solvent (fromMeCN to CH2Cl2); an experimental result in congruencewith findings by Melchiorre et al. in asymmetric sulfa-Michaeladditions to a-branched enones.75 a-Alkyl-substituted propanalsgave the corresponding quaternary alkylation adducts in highyield (76e79%) but enantioselectivity in these cases was lower(66:34 to 73:27 er) than with a-aryl systems.

4.2.2. Lewis acid co-catalysis. Cozzi et al. have exploited indiumsalts as co-catalyst for a-allylation of aldehydes with allylic alcohols(Scheme 36).76 Recognising the compatibility of indium salts withwater (an uncommon property of a Lewis acid) and their ability toundergo dynamic exchange with basic nucleophiles, such asamines, the authors conceived such salts to be suitable species forthe generation of allylic cations under aminocatalytic conditions.

Scheme 35. Quaternary stereocentres by asymmetric a-alkylation of a-substituted propanal.

Scheme 36. InBr3-catalysed stereoselective a-triarylallylation.


Examination of a variety of indium salts established InBr3 as thepreferred catalyst. Screening of solvents showed significant solventdependency, with CH2Cl2 proving to be the only effective solventfor such transformations. The choice of organocatalyst also provedcritical; whereas proline or the JørgenseneHayashi prolinol silylether gave no trace of product, MacMillan’s imidazolidinone gaveefficient conversion and high stereocontrol. A limitation of thischemistry is the substrate scope, where large vinylic substituentsare required to promote diastereoselectivity in the reaction and the

Scheme 37. Lewis acid-catal

aromatic substituents are necessary for stabilisation of the in-termediate carbocation. The observed syn-selectivity likely arisesfrom different steric demands of the 1,1-diphenyl tether and the Argroup in postulated syn- and anti-transition states, with greatersteric interaction envisaged between the 1,1-diphenylethenylgroup and imidazolidinone tert-butyl group.

In 2012, Xiao reported a similar cooperative catalysis system toachieve stereoselective a-benzhydrylation with symmetrical (andunsymmetrical) diarylmethanols (Scheme 37).77

ysed a-benzhydrylation.


In the same year, Cozzi et al. published similar findings, usinga combination of In(OTf)3 with a MacMillan imidazolidinone(Scheme 38).78 This method allows the use of substrates that can-not form stable carbocations through Brønsted acid catalysis (c.f.,Section 4.2.1).79 It demonstrates the coupling of alcohols possessingan alkyl tether (R2¼alkyl), although an electron-rich benzylic 4-(Me2N)C6H4 group is required for successful reaction and modestdrs are observed.

Scheme 38. Lewis acid-catalysed a-benzylations.

Rueping et al. have applied similar dual catalysis to the synthesisof chromenes in modest drs (Scheme 39).80 Following reduction,the absolute configuration of the major alcohol diastereomer wasdetermined to be S,R through CD- and NMR-spectroscopy. Sug-gested competing transitions states are illustrated in Scheme 39,which depict reaction of the enamine at the Si- and Re-faces of theoxonium intermediate; favourable p-stacking interactions may biasSi-face addition.

Scheme 39. Asymmetric substitution through oxocarbenium ions.

In 2010, MacMillan and Allen merged organocatalysis and Lewisacid catalysis to achieve a-trifluoromethylation (Scheme 40).81 Inthis work, 3,3-dimethyl-1-trifluoromethyl-1,2-benziodoxole (Tog-ni’s reagent) is used as the a-trifluoromethylation agent. It is pro-posed that aldenamine 43 reacts with iodonium salt 44 (formed bycopper-assisted IeO cleavage of Togni’s reagent) through an

addition/reductive elimination sequence (the latter occurring withretention of configuration) that furnishes iminium 45 and liberatesthe Lewis acid catalyst. Hydrolysis regenerates the organocatalystand provides the a-trifluoromethylated aldehyde.

4.2.3. Hydrogen-bond co-catalysis. Following a rather differentcationic (SN1-type) pathway to those described previously, isJacobsen et al. enantioselective a-benzhydrylation of a-aryl

propanals catalysed by primary aminothiourea derivatives(Scheme 41).82 In this work, the anion-binding properties of ami-nothioureas are exploited to generate a carbocation from a neutralbenzhydryl bromide substrate by anion abstraction, which thenundergoes attack by in situ generated enamine. Where non-primary amines were employed as potential H-bond catalysts noreaction was observed. Additionally, the urea moiety was found tobe crucialdif amino-carbamate catalysts were employed no re-

action was observed. The suggested reaction pathway is illustratedin Scheme 41. The possibility of an SN2-type pathway was ruled outbased on Hammet and kinetic isotope studies, and through com-petition experiments. This chemistry is an elegant approach tothe construction of aldehydes with a-quaternary stereocentres.However, as with the SN1-processes discussed earlier, this

Scheme 40. Enantioselective a-trifluoromethylation.

Scheme 41. Hydrogen-bond catalysed a-benzhydrylation.



methodology is restricted to electrophiles that can generate stabi-lised carbocations.

4.3. Dehydrogenative a-alkylation

The xanthyl group has also been introduced at the a-position ofaldehydes in an asymmetric manner by way of dehydrogenativeelectro-organocatalysis, albeit with modest enantioselectivity(Scheme 42).83 Electrochemical investigations and control experi-ments favour an enamine radical cationexanthene radical couplingpathway (c.f., Scheme 61), though a xanthene cationic intermediatecannot be entirely dismissed since no homocoupled products couldbe isolated.

Scheme 42. Asymmetric dehydrogenative a-xanthylation by electro-organocatalysis.

Following preliminary benzylic CeH activation studies for a-alkylation of aldehydes performed by Cozzi et al. (which weremediated by DDQ at�25 �C acting as oxidant),84 Cui, Jiao et al. havedeveloped an asymmetric intermolecular dehydrogenative alde-hyde a-xanthylation procedure facilitated by molecular oxygen asoxidant (Scheme 43).85 Under the acidic conditions either of thetwo peroxides shown in Scheme 43 could be formed, which sub-sequently liberate hydrogen peroxide and the corresponding ben-zylic (xanthyl) carbocation.

In related work, Xiao et al.86 have modified Cozzi’s original DDQprocedure; by replacing MacMillan’s imidazolidinone with theJørgenseneHayashi catalyst they were able to slightly reduce

catalyst loading (from 20 to 10 mol %) and perform reactions in-volving xanthyl and tropylium cations at rt.

4.4. Transition metal co-catalysis

4.4.1. Allylation. Recent research has demonstrated the power ofmerging transition metal and organo-catalysis.87 In 2006, C�ordovaand Ibrahem reported that palladium and enamine catalysis canwork in synergy to achieve intermolecular a-allylation of aldehydesin high yield and chemoselectivity (Scheme 44),88 the latter re-ferring to the avoidance of catalyst N-allylationda persistingproblem in the attempts to achieve transition metal-free organo-catalytic a-alkylation (see also Section 4.1).

In this chemistry, an enamine is allylated by an allylic acetateafter the latter is activated through p-allyl palladium formation.Preliminary investigation of chiral, non-racemic pyrrolidine andproline derivatives with the aim of developing an asymmetricprocess led to good levels of asymmetric induction (up to 87:13 er),but yields were poor (5e45%).88 Subsequent optimisationstudies showed solvent to be important for both reactivity andstereocontrol, with DMSO giving the highest levels of conversionand DMF the best er; using a 1:1 mixture of these solvents at re-duced temperature gave significantly improved yields and excel-lent levels of asymmetric induction (Scheme 45).89 The aldehydesformed were directly reduced to the corresponding alcohols to

Scheme 43. Asymmetric dehydrogenative a-xanthylation of aldehydes using O2.

Scheme 44. The concept of combined transition metal and enamine organo-catalysis for a-allylation.


minimise epimerisation. Breit et al. also successfully examined al-lylic alcohols as partners for aldehyde (and ketone) a-allylationsunder proline/Pd co-catalysis but did not achieve ‘efficientenantioinduction’.90

Ibrahem, C�ordova et al. have very recently extended amine andPd(0) co-catalysis to enantioselective intramolecular aldehyde a-allylation, where the precursor enamine intermediate is obtained insitu by reversible Michael addition of a substituted malonate orcyanoacetate to an enal activated as the corresponding iminium; up

to four stereocentres, including one quaternary carbon, are createdin this process.91

In 2007, Mukherjee and List published an alternative enamine-based route to a-allylated aldehydes employing a chiral phosphoricacid catalyst [(R)-TRIP] in combination with palladium, which to-gether mediate high enantioselectivity through a TsujieTrost-typemechanism (Scheme 46).92 Here an allylic secondary amine acts asboth a source of the allylic palladium and the aldehyde-derivedenamine. The phosphoric acid co-catalyst functions both as

Scheme 45. C�ordova’s asymmetric a-allylation.

Scheme 46. Mukherjee and List’s asymmetric a-allylation using benzhydryl allyl amine.


a Brønsted acid and a counteranion/ligand for the p-allyl in-termediate, imparting facial selectivity on the attacking nucleo-phile. This chemistry is also applicable to a,a-disubstitutedaldehydes (R1 and R2sH, see e.g., in Scheme 46), providing a novelroute to all-carbon quaternary stereocentres.

Jiang and List subsequently extended the above methodology,replacing the original benzhydryl amino-allylating reagent bybenzhydrylamine and simple allylic alcohols (Scheme 47).93

Scheme 47. Jiang and List’s asymmetric a-allylation with allylic alcohols.

While promising ers have been achieved by both C�ordova andby List, since these reactions proceed via palladium p-allyl com-plexes they are restricted to allylations giving g,d-unsaturatedaldehydes.

In addition to palladium sources, gold complexes have recentlybeen shown to be effective co-catalysts for asymmetric intra-molecular a-allylation.94 Bandini et al. utilised a cationic goldcomplex in combination with MacMillan’s imidazolidinone to ef-fect a-allylation through an anti/anti SN20 reaction sequence(Scheme 48). The putative reaction cycle involves initial conden-sation of aldehyde and MacMillan’s imidazolidinone catalyst, ac-celerated by benzoic acid. Electrophilic activation of the Z-allylic

alcohol present in the resulting enamine by cationic gold (which isless effective for thermodynamically more stable E-allylic alcohols)promotes anti-carboauration, the product of which undergoes anti-b-hydroxy elimination to give iminium ion. Subsequent hydrolysis

Scheme 48. Bandini’s synergistic gold(I) and amino-catalysis for stereoselective intramolecular a-allylation.


furnishes the a-allylated aldehyde and regenerates the organo-catalyst. With secondary alcohols (i.e., RsH, Scheme 48), a varietyof prolinol and imidazolidinone organocatalysts were employedwith varying degrees of success. An interesting aspect of the resultsobtained with secondary alcohols is the observed discriminationbetween (R)- and (S)-enantiomers by the dual catalytic system:with the S-imidazolidinone shown, S-configured secondary alcohol(R¼CH2CH2Ph, X¼NTs, Scheme 48) provided the correspondingproduct [42%, 49:1 dr, 99:1 E/Z ratio, 99:1 (88:12) er], while R-al-cohol failed to react.

4.4.2. Propargylation.95 Expanding on their earlier work con-cerning enantioselective propargylic substitution reactions,Nishibayashi et al. have developed a ruthenium-assisted alkyl-ation of in situ generated enamines 46 with propargylic alcoholsto give a-propargylated aldehydes (Scheme 49).96 The proposedreaction pathway proceeds by initial formation of an allenylideneruthenium complex 47 by reaction of propargyl alcohol with thetransition metal catalyst (a thiolate-bridged diruthenium com-plex). Lack of an analogous reaction for internal alkynes providessupport for an allenylidene intermediate. Subsequent attack ofaldenamine 46 [formed in situ as the anti-(E)-enamine (energet-ically favoured)] at the g-position of the allenylidene complexes47 generates a diastereomeric mixture of alkynyl imminumcomplex 48 (as a consequence of Re-/Si-facial attack of allenyli-dene 47, by contrast, only the Si-face of enamine 46 is attackeddue to steric shielding of the Re-face by the prolinol substituents).Hydrolysis of the alkynyl iminium ion complex 48 and subsequentligand exchange with propargylic alcohol continues the catalyticcycle and liberates the product diastereomeric propargylic alde-hydes, which were directly reduced to the correspondingalcohols.

Slightly higher diastereoselectivity [w4:1 (syn/anti)] was sub-sequently observed using propargylic pentafluorobenzoates un-der CuOTf/enamine co-catalysis (Scheme 50).97 Excess BINAP isused to prevent dissociation of diphosphine from copper. The roleof BINAP is not specified, but it is not to impart stereocontrol(racemic BINAP gives similarly high dr); however, diphosphineadditive is essentialdwithout BINAP complex reaction mixtureswere formed.

In 2011, Nishibayashi et al. reported a strategy for enantiose-lective propargylation with internal alkynes employingInBr3 (acting as Lewis acid) in conjunction with a MacMillanimidazolidinone organocatalyst, which gave the corresponding a-propargylated aldehydes in excellent yields as diastereomericmixtures with high enantiopurity.98 Contemporaneously, Cozziet al. utilised indium triflate with a marginally different MacMillanimidazolidinone catalyst to facilitate propargylation (with internalalkynes, FG¼organosilyl, aryl, alkyl) under synthetically mildconditions on water (c.f., CH2Cl2 used by Nishibayashi), whichgave significantly improved diastereoselectivity (Scheme 51).99 Incomparison to Nishibayashi’s Ru/Cu work, this catalyst combina-tion gives opposite diastereoselectivity. Furthermore, if FG¼TMSfacile desilylation of the product aldehydes with K2CO3/MeOHprovides an efficient route to the anti-terminal alkyne, thus of-fering a stereo-complementary method to the above ruthenium-catalysed work.

4.5. Radical and electron transfer processes

4.5.1. SOMO activation. In early 2007, MacMillan et al. reporteda novel mode of activation for organocatalytic reactions of alde-hydes, termed SOMO activation.100,101 Typically, organocatalyticreactions are catalysed by either LUMO lowering iminium catal-ysis and/or HOMO raising enamine catalysis. MacMillan’s chem-istry intersects these two reaction modes utilising SOMOactivation.102 In MacMillan’s work involving CeC bond formation,selective one-electron oxidation [using ceric ammonium nitrate(CAN)] of a transient enamine, formed by condensation of an al-dehyde and imidazolidinone catalyst, provides a SOMO-activatedradical cation that is reactive to electron neutral but p-rich SOMOnucleophiles (SOMOphiles), such as allylic silanes, with highlevels of facial discrimination (Scheme 52). Further one-electronoxidation of the resulting dative-stabilised b-silyl radical gener-ates a b-silyl stabilised cation, which undergoes alkene-generating desilylation. This chemistry provides an attractiveapproach to enantioenriched a-allylated aldehydes, which isconceptually different to those methods developed by C�ordovaand List (Section 4.4.1). The process tolerates a range of solvents(DME identified as optimal) and, importantly, aldehyde

Scheme 50. Cu-BINAP catalysed enantioselective a-propargylation of aldehydes.

Scheme 49. Ru-complex catalysed enantioselective a-propargylation of aldehydes.


Scheme 51. a-Propargylation using indium- and amino-co-catalysis.


epimerisation or polyallylation was not observed with extendedreaction times.

MacMillan et al. have since utilised this same mechanistic par-adigm in intramolecular a-allylation, which enabled the construc-tion of five-, six- and seven-membered carbocycles, as well astetrahydropyrans and piperidines in high yield and with promisinglevels of stereocontrol (Scheme 53).103 Addition of water(2 equiv)dwhich assists solubilisation of CAN,104 and for somesubstrates exchanging the solvent (DME by acetone) and base[NaHCO3 by 2,6-di-tert-butylpyridine (2,6-DTBP)], gave improvedreaction efficiency and asymmetric induction.

Scheme 52. CAN-mediated SOMO cat

Utilising a similar SOMO activation platform, MacMillan et al.reported an asymmetric method for a-enolation of aldehydes(Scheme 54).105 In this chemistry, a SOMO-activated radical cationis accessed in a similar manner to that discussed above, which thencouples with a silyl enol ether. Further one-electron oxidation ofthe resulting a-silyloxy radical 49 by CAN generates an oxonium ionthat on desilylation and iminium hydrolysis gives an enantioen-riched g-ketoaldehyde.

The scope of organo-SOMO chemistry was usefullyexpanded, by exchanging the electron-rich olefinic couplingpartners (allyl/enol silanes) for simple, non-activated, styrenes

alysis in asymmetric a-allylation.

Scheme 53. Intramolecular a-allylation through organo-SOMO catalysis.

Scheme 54. Enantioselective a-enolation.


(Scheme 55).106 With styrenes, the carbocation 50, resulting fromoxidation of benzylic radical 51, does not undergo ready E1 elim-ination (due to the absence of a suitable b-activation/leavinggroup, unlike with allyl/enol silanes) and is preferentially trapped

by nitrate anion [released through reduction of the Ce(IV) oxidant]to form the corresponding nitrate ester (3:1 dr). The latter proveda useful handle for further transformations, such as hydro-genolysis (thus achieving overall aldehyde-a-homobenzylation in

Scheme 55. Enantioselective a-carbooxidation.


an enantioselective manner) and heterocycle formation throughborohydride reductionecyclisation (Scheme 55). While outsidethe scope of this review, it is noteworthy that this organo-SOMOcatalysis can also be utilised in a-vinylation with vinyltrifluoroborates.107

In 2013, the SOMO activation mode was extended to intra-molecular a-allylation of unactivated aldehydeeolefin substrates(Scheme 56).108 In this chemistry, ferric oxidation of an in situgenerated aldenamine forms the enamine radical cation, whichundergoes radical cyclisation and subsequent one electron

Scheme 56. Enantioselective intramolecular aldehyd

oxidation to give tertiary carbocation 52. Subsequent deprotona-tion/hydrolysis regenerates the organocatalyst and liberates the‘homo-ene’ product. Chair-E geometry in the transition state ra-tionalises the observed trans diastereoselectivity, whereas regio-selective formation of the less substituted alkene may reflectminimisation of allylic strain. Overall, this process can be viewedas a dehydrogenative coupling. Aside from being intramolecular,it also differs from those intermolecular examples comprisingSection 4.3, since in the present case the hydrogen atom removedfrom the aldehyde partner is not lost from the carbon becoming

e a-allylation with trialkyl-substituted alkenes.


attached at the aldehyde a-position (but rather from an allylicsite).

4.5.2. Photoredox organocatalysis. In 2008, Nicewicz and MacMil-lan facilitated aldehyde a-alkylations by way of single electrontransfer (SET) using a dual catalytic system of an imidazolidinonesalt and photoredox catalyst,109,110 which is widely recognised asa landmark achievement in the field of organocatalysis(Scheme 57).4a,b

Scheme 57. Dual organo- and photoredox catalysis for asymmetric a-alkylation.

The reaction pathway is rationalised by two intertwined cata-lytic cycles (Scheme 58) and follows an antipodal reactivity com-pared with the above methodology using allylic silanes (Scheme52). Initiation of the reaction occurs through application of a suit-able light source (e.g., a household 15 W fluorescent light bulb),which excites the photoredox catalyst [RuðbpyÞ2þ3 (bpy¼2,20-bipyridine)] to a higher energy state (*Ru(bpy)32þ). This excitedspecies oxidises a sacrificial quantity of (in situ generated) en-amine, creating a reduced ruthenium complex ðRuðbpyÞ2þ3 Þ. Thelatter enters into a productive catalytic cycle by single electrontransfer to the electron-deficient organohalide substrate, regen-erating RuðbpyÞ2þ3 and forming, by loss of halide anion, a radical53, which reacts with the enamine. This last step leads to an a-amino radical 54, which through SET to excited �RuðbpyÞ2þ3

Scheme 58. Dual organo- and p

provides iminium 55, closing the photoredox catalytic cycle. Theorganocatalytic cycle is closed by subsequent hydrolysis of imi-nium ion 55. A base additive, 2,6-lutidine, neutralises the HBrbyproduct. This chemistry offers an elegant and efficient strategyfor a-alkylation of aldehydes (high yields and ers, synthetic sim-plicity, and compatibility with a wide range of substrates); how-ever, it does require electrophilic organohalide partners thatcontain a capto radical-stabilising functional group (FG) or groups,such as benzoyl. In contrast to the previous section (4.5.1) where

a SOMO-activated enamine radical cation reacts with p-rich sys-tems, here the neutral but electron-rich enamine reacts withelectron-deficient radicals.

The rarity and associated toxicity issues of ruthenium-basedcatalysts have prompted investigation of replacement photoredoxcatalysts in the above chemistry. For example, Zeitleret al. examined Eosin Y, an organic xanthene dye sensitizer, whichproved a good substitute showing comparable photoredox prop-erties to the transition metal complex.111 Performing reactionswith Eosin Y under microflow conditions was found to be addi-tionally advantageousdreducing reaction times from 18 h to45 min.112 Another ‘green’ method has been reported by Ferroudet al. where the ruthenium-based catalyst was exchanged for RoseBengal, an alternative organic dye sensitizer.113 K€onig et al. have

hotoredox catalytic system.


also recently demonstrated the utility of heterogeneous catalysis,using inorganic semiconductors [e.g., PbBiO2Br, blue light(l¼440 nm)] in place of ruthenium or dye photo-sensistizers.114

Another notable extension of MacMillan’s work is the de-velopment, by He and Duan, of chiral metaleorganic frameworks(MOFs) that house the organocatalyst (in this case, L- or D-pyrroli-dine-2-ylimidazole) and photoactive unit (4,40,400-nitrilo-tribenzoate).115 These heterogeneous reaction systems simplifyrecovery and re-use of the catalysts (since they are embeddedwithin a Zn-based solid support), and help to reduce heavy metalcontamination of the product. Additional benefits of MOFs are thereduced hazards and costs, not only in the reactions themselves,but also in terms of disposal. While these latter modifications areencouraging, with the exception of Konig et al. (who also testedbromoacetophenone and 2,4-dinitrobenzyl bromide), an a-bromomalonate was the only electrophilic partner examined.

MacMillan has extended his photoredox/organocatalysis strat-egy to a-benzylation of aldehydes (Scheme 59).116 In this work, aniridium photoredox catalyst [fac-Ir(ppy)3 (ppy¼2-phenylpyridine)]was used to facilitate s-bond cleavage of the benzylic bromide togive the key electrophilic benzyl radical. Following a similarmechanism to that illustrated in Scheme 58 for a-alkylation, a-benzylationwas achieved using organocatalyst 57 in high yield ander; however, this chemistry is limited to reactions with benzylbromides that have electron-withdrawing aryl motifs; attemptedreaction with simple benzyl bromide (56, Ar¼Ph) provedunsuccessful.

Scheme 59. Asymmetric a-benzylation through organo-photoredox catalysis.

The MacMillan laboratory has also shown photoredox organo-catalysis to be an efficient method for preparation of a-per-fluoroalkylated aldehydes (Scheme 60).117 Preliminary investigation of a range of aldehyde substrates showed broad functional

Scheme 60. Enantioselectiv

group compatibility, achieving trifluoromethylation (R2¼R3¼F) inexcellent yields and high ers (analysed as the alcohol, followingreduction with NaBH4) with an iridium photoredox catalyst [Ir(p-py)2(dtb-bpy) (dtb-bpy¼4,40-di-tert-butyl-2,20-bipyridine)] andimidazolidinone organocatalyst 59; carrying out the reaction at�20 �C avoids racemisation. Subsequent examination of a series offluoroalkyl halides 58 (R2 and/or R3sF) showed similar propensityfor formation of the corresponding a-perfluoroalkylated aldehydes,with comparable stereoselectivity.

Most recently, Melchiorre et al. have shown that visible lightonly (household 23 W compact fluorescent light (CFL) bulb orsunlight) will facilitate enamine-catalysed enantioselective a-ben-zylation and a-phenacylation of aldehydes (Scheme 61),118 in-cluding generation of a quaternary stereocentre through benzylation of 2-phenylpropanal. Mechanistic studies support a processinvolving formation of an electron donor/acceptor (EDA) complexbetween enamine and electron-poor benzylic (or phenylacyl) ha-lide, followed by (sun)light-assisted electron transfer, then bromideloss from the radical anion. In-cage combination of the resultingelectron-deficient benzylic (or 2-keto) radical with the enamineradical cation followed by the usual iminium hydrolysis providesthe a-substituted aldehyde and regenerates the organocatalyst.This work is notable for photochemical asymmetric catalysis in theabsence of a photosensitizer. It provides access to similar adductsobtained through MacMillan photoredox catalysis (see Scheme 57),albeit with slightly lower enantioselectivity for phenylacylation.The latter may be partly due to the different organocatalysts fav-

oured to generate the EDA complex, and/or to the nature of theradicaleradical cation CeC bond-forming event (c.f., Scheme 42),which is slightly different to the radical addition to the neutralenamine proposed in the photoredox chemistry (Scheme 58).

e a-perfluoroalkylation.

Suggested Reaction Pathway (R2 = H):

Scheme 61. Photosensitiser-free enantioselective a-alkylation via chiral electron donor/acceptor complexes.


5. Summary

Alkyl-bearing stereogenic centres are ubiquitous both in naturaland synthetic compounds of interest. Enantioenriched a-alkyl-substituted aldehydes provide a convenient way of introducingsuch groups into molecules, since aldehydes are highly reactive anddemonstrate predictable chemoselectivity. However, typical eno-late approaches to prepare these building blocks are thwarted by anarray of possible side reactions. As a consequence, powerfulauxiliary-based strategies to generate enantioenriched a-alkyl al-dehydes have been developed through enamine salts, or the ‘sta-bility’ of higher oxidation level enolates. Although thesemethodologies are well-established, they are not without limi-tationsda requirement for stoichiometric quantities of the auxil-iary, the use of strong bases to generate enolate intermediates andan additional step to cleave the auxiliary/reveal the aldehyde arecommon drawbacks to these strategies. Efforts to improve overallefficiency have seen the development of chiral hindered alden-amines, which are able to alkylate in high yield (overcomingproblematic N-alkylation), confer moderate to high ers, and obtainthe aldehyde in a one-pot reaction from the enamine. Especiallysignificant organocatalysis-based advances to a-alkyl-substitutedaldehydes have been made, which involve a variety of reactionmodes (intramolecular SN2, SN1, SOMO). While methods discussedin this review are capable of achieving asymmetric a-alkylation,either directly or indirectly, the challenge still remains for

development of straightforward strategies to enantioenricheda-alkylated aldehydes that can exploit the synthetic/commercialavailability of simple alkyl electrophiles (halides or halideequivalents).

References and notes

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etrahedron 70 (2014) 2207e2236
D.M. Hodgson, A. Charlton / T2236
Biographical sketch

David M. Hodgson obtained his first degree in Chemistry at Bath University. Aftera Ph.D. at Southampton University in the field of natural product synthesis (with P.J.Parsons) and a research position at Schering, he was appointed in 1990 to a lectureshipat Reading University. In 1995 he moved to the Chemistry Department at Oxford Uni-versity, where he is now a Professor of Chemistry. In recognition of achievements byhis research group, he has received a GSK Award for Innovative Organic Chemistry,a Pfizer Academic Award and an AstraZeneca Research Award in Organic Chemistry,and the Royal Society of Chemistry Bader Award. His research interests are broadlyin the development and application of synthetic methods, particularly asymmetricgeneration and transformations of carbenoids.

Andrew Charlton studied Chemistry [MChem (Hons)] at The University of Edinburgh,which included a year in industry with GlaxoSmithKline and a research project on ar-yne chemistry with Mike Greaney. He then moved to the University of Oxford (TrinityCollege) for Ph.D. research under the supervision of David M. Hodgson, obtaining hisdoctorate in 2013. His work was sponsored by an EPSRC Pharma studentship, and in-volved the asymmetric synthesis of tropanes and homotropanes and their evaluationin enamines for the generation of a-alkyl-substituted aldehydes.

alkyl-substituted aldehydes

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