Enamines, alkylation Michael additions

Enamine addition to an unsaturated ester, followed by an intramolecular alkylation, provided a facile synthesis of an adamantane bis-/3-ketoester 674). Michael addition of pyrrolidinocycloheptene to other acrylic esters 668) and of other enamines to acrylic acids 675), a chloroacrylonitrile 676), and an unsaturated cyanocarboxamide (577) were reported. 

The jS-position of enamines is highly nucleophilic and may react with alkyl halides, acyl chlorides or anhydrides, or with Michael addition substrates to give carbon-carbon bonds as shown in the examples (1). 

The utilization of the Robinson annellation method for the synthesis of cory-nanthe-type alkaloids has been thoroughly investigated by Kametani and coworkers (149-152). The tetracyclic ring system was efficiently formed via the Michael addition of dimethyl 3-methoxyallylidenemalonate (247) to the enamine derived from 3,4-dihydro-1 -methyl-(3-carboline (150). Alkylation of 248, followed by hydrolysis and decarboxylation, resulted in a mixture of stereosiomeric enamides 250 and 251. Hydrogenation of 250 afforded two lactams in a ratio of 2 1 in favor of the pseudo stereoisomer 253 over the normal isomer 252. On the other hand, catalytic reduction of 251 gave 254 as the sole product in nearly quantitative yield. Deprotection of 254, followed by lithium aluminum hydride reduction, yielded ( )-corynantheidol (255) with alio relative configuration of stereo centers at C-3, C-15 and C-20. Similar transformations of 252 and 253 lead to ( )-dihydrocorynantheol and ( )-hirsutinol (238), respectively, from which the latter is identical with ( )-3-epidihydrocorynantheol (149-151.). 

The nucleophilicity of the carbon of enamines makes them particularly useful reagents in organic synthesis because they can be acylated, alkylated, and used in Michael addition. 

In related asymmetric Michael-additions of enamine (206) and 2-aryl- 1-nitro-ethylenes, only one of the four possible enantiomerically pure diastereomers was formed 204). Hydrolysis of the crude primary products furnished a-alkylated cyclohexanones of > 90 % enantiomeric excess 204). 

Bicyclic keto esters can easily be prepared by a process called a,a -annulation.29 Thus, treatment of the enamine of cyclopentanone (64) with ethyl a-(bromomethyl)acrylate (98) affords, after work-up, the bicyclic keto ester (99) in 80% yield (equation IS).2911 The mechanism probably involves an initial Michael addition and elimination (or a simple Sn2 or Sn2 alkylation) followed by an intramolecular Michael addition of the less-substituted enamine on the acrylate unit. The use of the enamine of 4,4-bis(ethoxycarbonyl)cyclohexanone (100 equation 26) with (98) gives a 45% yield of the adaman-tanedione diester (101) (yield based on 100 70% when based on 98) via a,a -annulation followed by Dieckmann condensation.29 Enamines of heterocyclic ketones can also serve as the initial nucleophiles, e.g. (102) and (103) give (105) via (104), formed in situ, in 70% yield (Scheme 11 ).29>... 

A pyrrolidine-thiourea organocatalyst (69) facilitates Michael addition of cyclohexanone to both aryl and alkyl nitroalkenes with up to 98% de and ee 202 The bifunctional catalyst (69) can doubly hydrogen bond to the nitro group, leaving the chiral heterocycles positioned for cyclohexyl enamine formation over one face of the alkene. 

Asymmetric Alkylations and Michael Additions. Asym-metne alkylation of the cyclohexanone enamine derived from (+)-tran.s-2,5-dimethylpyrrolidine has been studied (eq 4). Alkylation with lodomethane, n-propyl bromide, and Allyl Bromide afforded the corresponding 2-n-alkylcyclohexanones in yields of 50-80% and with enantiomeric purities of 66, 86, and 64%, respectively. 

One specific enol equivalent that works very well for aldehydes is an enamine. Secondary amines such as Me2NH, Et2NH, pyrrolidine, piperidine, or morpholine 34 add cleanly to aldehydes to give enamines 36. These relatively stable nitrogen analogues of enols react well with reactive alkyl halides, such as a-carbonyl halides, and in Michael additions. They were considered in chapter 2 and only a few extra examples will be given here. 

Reactions of enamine derivatives of auxiliary 1.64 [162, 252, 262] are often disappointing, except when R = CH20SiMe3 [162], However, the alkylation of enamines derived from 1.65 (R = Me) gives satisfactory results [253, 275], as do the Michael additions of enamines of bicyclic pyrrolidine 1.68 [294],... 

R,2S)-Ephedrine has found most application, e.g., as a catalyst in photochemical proton transfer reactions (Section D.2.1.). and as its lithium salt in enantioselective deprotonations (Section D.2.1.). The amino function readily forms chiral amides with carboxylic acids and enamines with carbonyl compounds these reagents perform stereoselective carbanionic reactions, such as Michael additions (Sections D.1.5.2.1. and D. 1.5.2.4.), and alkylations (Section D.1.1.1.3.1.). They have also been used to obtain chiral alkenes for [1 +2] cycloadditions (Section D. 1.6.1.5.). 

Bicyclic rings can also be constructed from enamines using bifunctional reagents. The bromoester 7, for example, reacts by both an Sn2 alkylation and a Michael addition, giving the bicyclic ring system 8 ° ... 

The nucieophiiicity of the carbon of enamines makes them particularly useful reagents in organic synthesis because they can be acylated, alkylated, and used in Michael additions (see Section 19.7A). Enamines can be used as synthetic equivalents of aldehyde or ketone enolates because the alkene carbon of an enamine reacts the same way as does the a carbon of an aldehyde or ketone enolate and, after hydrolysis, the products are the same. Development of these techniques originated with the work of Gilbert Stork of Columbia University, and in his honor they have come to be known as Stoik enamine teactions. 

Early work by Tomioka and coworkers [39] described a two-component Michael/ aldol process to cyclopentenes. Furthermore, rhodium-assisted Michael/aldol processes to cyclopentanes and cyclohexanes have also been reported [40]. Later, a Michael addition reaction in combination with an adehyde a-alkylation reaction was reported for the highly stereoselective formation of y-nitroaldehydes 50 [41]. In this publication, a series of aliphatic aldehydes 49 (at Rj) and ( )-5-iodo-l-nitropent-1-ene 48 were reacted in the presence of the organocatalyst 1 and benzoic acid in dimethyl sulfoxide (DMSO) to afford the resulting cyclopentene ring system 50 (Scheme 7.9). The diastereo- and enantioselective process follows the proposed mechanism beginning with enamine activation of the aldehyde to 51 by the catalyst 1 (blocking the re face), and Michael addition of 48 occurs at its more accessible si face. The full enamine-enamine mechanism, illustrated in Scheme 7.9, provided... 

Recently, the same group successfully extended this methodology to 3-substituted 2-(bromomethyl)-acrylates proceeding with concomitant generation of two contiguous stereocenters with high diastereo- and also enantioselectivity [115]. Based on the proposed reaction mechanism (Scheme 8.25), Palomo s a-aUcylation S/ 2 pathway suggests the addition of an activated aldehyde as enamine to an sp carbon of ammonium salt 77 followed by DMAP elimination, and thus this process is Michael addition rather than an a-alkylation [116]. 

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