E-enamine

The thermal [1] or photochemical [5] isomerization of N-silylated allylamine in the presence of Fe(CO)5 provides the corresponding N-silylated enamines 7a and 7b. Z-enamine 7b does not react in any of the examined cycloadditions. The cyclopropanation of E-enamine 7a with methyl diazoacetate under copper(I) catalysis provides the donor-acceptor-substituted cyclopropane 9 [1], which can be converted in good yield into the interesting dipeptide 10 [6]. 

Figure 6.32 Proposed intermediates in the 100-catalyzed Michael addition of ketones to nitroalkenes favored Z-enamine (A) and disfavored E-enamine (B).

This topological rule readily explained the reaction product 211 (>90% stereoselectivity) of open-chain nitroolefins 209 with open-chain enamines 210. Seebach and Golinski have further pointed out that several condensation reactions can also be rationalized by using this approach (a) cyclopropane formation from olefin and carbene, (b) Wittig reaction with aldehydes yielding cis olefins, (c) trans-dialkyl oxirane from alkylidene triphenylarsane and aldehydes, (d) ketenes and cyclopentadiene 2+2-addition, le) (E)-silyl-nitronate and aldehydes, (f) syn and anti-Li and B-enolates of ketones, esters, amides and aldehydes, (g) Z-allylboranes and aldehydes, (h) E-alkyl-borane or E-allylchromium derivatives and aldehydes, (i) enamine from cyclohexanone and cinnamic aldehyde, (j) E-enamines and E-nitroolefins and finally, (k) enamines from cycloalkanones and styryl sulfone. 

The highly enantioselective direct conjugate addition of ketones to nitroalkenes has been promoted by a chiral primary amine-thiourea catalyst (7).31 The observed anti diastereoselectivity has suggested participation of a (Z)-enamine intermediate, given (g) the complementary diastereoselectivity obtained in analogous reactions involving (E)-enamines generated from secondary amine catalysts. 

Zhong rationalized the enantioselectivity by proposing an enamine mechanism which proceeds via the chair transition state shown in Figure 7.1 [11]. In this transition state, the Si face of an E enamine formed from the aldehyde and the catalyst L-proline approaches the less-hindered oxygen atom of nitrosobenzene leading to the chiral product with (R) configuration. This mechanism is in accordance with the proposed reaction mechanism for the aldol reaction (see chapter 6.2). 

The s-trans conformation of the (E)-enamine reacts in the C-C bond-forming transition state. The s-cis conformation results in steric interaction between the enamine and the substituent at the 2-position of the pyrrolidine ring. 

Enamines - alkenes.1 Hydroboration of (E)-enamines of aldehydes or ke- ones with 9-BBN followed by methanolysis (retention) affords alkenes in 60-80%... 

Sauer and Prahl258 showed that the main product from the base-catalysed transformation of allyldimethylamine and several other allylamines, including 1-allylpiperidine and 1-allylpyrrolidine, is the Z-enamino isomer. Seebach and coworkers145 isomerized 4-allylmorpholine with r-BuOK in DMSO to a mixture of Z- and E-4-(l-prope-nyl)morpholine in a 87 13 ratio. The E-enamine which presumably arose by a subsequent isomerization of the (Z) isomers was shown to be the thermodynamically stable isomer. 

Mixtures of Z and E stereoisomers have been obtained in most syntheses. This undoubtedly holds in the presence of an acid catalyst. The tendency of the E-enamine to isomerize to the Z-enamine was readily observed on numerous occasions under unexpectedly mild conditions. Munk and Kim357 summarized the requirements for the stereospecific synthesis of enamines. First, if the introduction of the double bond is to be the final step of the synthesis, it must be stereospecific in character. Second, once the enamine is formed it must retain its stereochemical integrity under the conditions employed in the double-bond-forming step. The base-induced bimolecular -elimination reaction fulfills both these requirements. Indeed, treatment of the mesitoate esters of ( )-threo- (99) and ( )-erythro- (100) l-(4-morpholino)-l,2-diphenylethanol with... 

Clarke and Parker54 have reported a thermodynamic study of the tautomerization of 2-(J/V-cyclohexylimino)-l,3-diphenylpropane (47) to its Z- and E-enamine tautomers 48a and 48b in DMSO-d6 solution (Scheme 4). The equilibrium constants and the values of the thermodynamic parameters AH, AG and AS have been determined by variable-temperature NMR measurements. Polar solvents are found to favor enaminization, but have little effect on the E Z isomerization of the enamine tautomers. 

Details are also available for isomerization of prochiral N,N-dialkylamines to the optically pure corresponding (E)-enamine (11, 53- 54) using BINAP as the chiral catalyst. This novel chemistry permits a short synthesis of optically pure (R)-( + )-citronellal (4) from isoprene utilizing the isomerization of N,N-diethylneiylamine (2) to R( — )-3. ... 

Morpholino enamines, The lithium anion 2 of the reagent reacts with aldehydes to form the adducts 3 in high yield. These are converted into (E)-enamines (4) by treatment with potassium hydride. The method is applicable to ketones, but yields are lower because of formation of the enolate. 

Olefin isomerization can be promoted by a variety of metal complexes [288 — 294]. One of the best known examples is [Rh(P-P)][C104] (produced in situ by hydrogenation of [Rh(P-P)(cod)][C104.]), which converts an (Z)-allylamine 105 to a racemic (E)-enamine 106 with high chemical selectivity and conversion rate the best phosphine ligand for this purpose is BINAP, followed by dppe and dppf [295, 296]. 

Cordova et al. demonstrated in 2005 that the aldol condensation between 4-nitrobenzaldehyde (5 R=p-N02) and cyclic ketones or butanone in the presence of acyclic primary amino acids led to the antz-isomer 6 (Scheme 12.3). One year later, this author described the structure-activity relationship between acyclic amino acids and the aldol derivatives, the synthetic scope of catalysis by acyclic amino acids in aqueous media and water, and studies concerning the reaction mechanism. Excellent enan-tioselectivities (ee up to >99%) were achieved in several cases. As an example of the anh -induction, the (E)-enamine arising from cyclohexanone and the acyclic amino acid could display a proton transfer from the carboxylic acid function to the alkoxide, giving a six-membered chair-like conformation. The favoured approach of the aldehyde would then lead to an anfi-isomer. 

Depending of the catalyst structure, a dual catalyst activation mode may be involved in the process. For instance, in catalyst 42 (Fig. 2.4) [62] the presence of the trans-OH group in the 4-position of the pyrroUdine ring helps to activate the electrophile and also directs its approach from the less hindered face of the -enamine (B, Fig. 2.5). The bifunctional catalyst activation behavior is also suggested for other catalysts such as Jacobsen s thiourea 41 (Fig. 2.4) [61], where binding of the nitroalkene by the thioureamoiety allows the thermodynamically favorable E enamine to attain in close proximity for a highly diastereo- and enantioselective C-C bond-formation (C, Fig. 2.5). 

Chiral rhodium phosphine complex (E)-Enamines from 2-ethyleneamines Asym. induction... 

Tu et al. reported a Macmillan s catalyst 172-catalyzed asymmetric a-alkylation of tetrahydrofuran 170 containing an a,p-unsaturated aldehyde, via which chiral spiroether 171 could be prepared (Scheme 64) [129]. The sequential [l,5]-hydride transfer/cyclization was facilitated via cascade iminium/enamine activation. The presence of strong acid was indispensable to ensure sufficient electrophilicity of the iminium intermediate. Theoretically, substrate 170 reacts with 172 to give iminium intermediate I. Owing to the steric interaction of the bulky ferf-butyl group, the E enamine II is formed preferentially upon [1,5]-HT, which exists in two possible conformers III and IV. Because of dipole repulsion between the cyclic-oxocarbe-nium and enamine moieties in conformer III, IV is the more favored conformer, which undergoes intramolecular C-C bond formation to afford the final product 171. 

The Claisen rearrangement has been used to prepare j8,y-unsaturated amides, largely as the E-isomers, from 3-(trimethylsilyl)allyl alcohols and amide acetals (Scheme 48). Overall yields and stereoselectivities are excellent. Conditions have been found under which the stereochemical outcome of the related ynamine-Claisen rearrangement can be controlled. Thus, the kinetically favoured intermediate is the E-enamine (140) which leads to the "trans product (142), whereas the Z-isomer (141) is thermodynamically favoured and gives the cw ... 

There are few examples of asymmetric catalytic processes which are of practical use. A new study on the catalytic olefin isomerization of, A-diethylneryl-amine (32) or A,JV-diethylgeranylamine (33) has now shown that optically active iV,A-diethylcitronellal-(E)-enamine (34) can be obtained with excellent enantioselectivity (> ca. 95 % e.e.) and chemoselectivity (> ca. 98 %) (Scheme 51). 

When (S)-proline (13) is used as a catalyst, the (E)-enamine intermediate 26 predominates due to steric interactions in (Z)-enamine 25 (Figure 28.2). The antistereochemistry of the aldol product can be explained by transition state 27, because the Si face of the ( )-enamine 26 reacts with Re face of the aldehyde. In contrast, with primary amine-containing amino acid 21, the (Z)-enamine 29 of hydroxyketone predominates over ( )-enamine 28 due to intramolecular hydrogen bonding and, thus, syn-diastereoselectivity has been observed through the bondforming transition state 30 [16],... 

First, we showed that similar conclusions regarding the relative stability of intermediates and energy barriers could be drawn either from ReaxFF MD simulations or from DFT calculations at the M06-2X/6-31 -I- G(d,p) level. Regarding the particular studied step of the reaction, one showed that the iminium-enamine conversion is more likely to yield an E enamine and that the energy barrier for the reaction is also smaller starting from the s-cis isomer of iminium relatively to the s-trans one. 

---