Addition of Enolates to Imines

The development of a catalytic asymmetric addition of enolates to imines (Mannich reaction) has only recently received attention and it was not until 1998 that there were reports of this process giving products in over 90% enantiomeric excess. Since then a large number of both metal-based catalysts and organocatalysts for the asymmetric Mannich reaction have been investigated. 

This reversal in selectivity is thought to arise from the reaction of an (E)-configured enamine aligned so as to minimise steric interactions of the nitrogen substituent with the pyrrolidine ring of the enamine. 

As the intermediate enamine reacts faster with imines than aldehydes, a one-pot three component coupling of the donor ketone, aldehyde and amine is possible. List and coworkers have achieved high ees in this reaction utilising L-proline (7.66) and some aliphatic aldehydes and aromatic aldehydes such as (7.136) in combination with p-anisidene (7.137). This catalyst system is also effective for the coupling of a-hydroxyketones. Use of the tetrazole-substituted proline (7.80) allows the reaction to be performed in dichloromethane rather than DMSO and high ees in the Mannich reaction between aliphatic ketones and imines derived from ethyl glyoxalate have been obtained imder these reaction conditions. 

The enamine catalysis detailed above proceeds via activation of the Mannich donor. An alternate strategy to the catalysis of the Mannich reaction is by the use of Brensted acids that activate the acceptor imine by protonation on nitrogen. Some of the most successful asymmetric variants of this process use BINOL-based phosphoric acids as catalysts. For instance Terada and coworkers used (7.144) to effect highly enantioselective addition of acetylacetone to a range of aryl aldimines  

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In spite of the steric and electronic differences, the nucleophilic addition of enolates to imines (aza aldoi reaction) proceeds probably through similar pericyclic transition states as the carbonyl compounds do. 

Since /1-lactams can be prepared via reactions of ester enolates with imines, these reactions are of great interest for synthetic and medicinal chemists. The synthesis of naturally occurring antibiotics and other physiologically active //-lactams is an objective of much current work. Though the stereocenters in those reactions are often established by addition of enolates to imines, they are discussed in Section D.1.6.1.3. In this section, only some basic results concerning //-lactams are presented. 

Until now, the regioselective addition of enolates to imines in the presence of an aldehyde functionality could not be realized with stoichiometric amounts of traditional Lewis acids such as SnCl4, TiCl4 or BF3 OEt2. Recently, Kobayashi and coworkers reported that, in the presence of... 

Although the diastereoselective addition of nucleophiles to imines offers an attractive route to chiral amine derivatives, most chiral nonracemic imines suffer from low reactivity (electrophilicity), resulting in no reaction or competitive reduction with organometallic reagents. Other problems include enolization of aliphatic imines, poor... 

The nucleophilic addition reactions of enolates to imines and related compounds (the so-called Mannich-type reactions, equation 39) are important tools in organic synthesis and a variety of electrophiles have been used to obtain the resulting nitrogen-containing... 

Kobayashi et al. found that lanthanide triflates were excellent catalysts for activation of C-N double bonds —activation by other Lewis acids required more than stoichiometric amounts of the acids. Examples were aza Diels-Alder reactions, the Man-nich-type reaction of A-(a-aminoalkyl)benzotriazoles with silyl enol ethers, the 1,3-dipolar cycloaddition of nitrones to alkenes, the 1,2-cycloaddition of diazoesters to imines, and the nucleophilic addition reactions to imines [24], These reactions are efficiently catalyzed by Yb(OTf)3. The arylimines reacted with Danishefsky s diene to give the dihydropyridones (Eq. 14) [25,26], The arylimines acted as the azadienes when reacted with cyclopentadiene, vinyl ethers or vinyl thioethers, providing the tet-rahydroquinolines (Eq. 15). Silyl enol ethers derived from esters, ketones, and thio-esters reacted with N-(a-aminoalkyl)benzotriazoles to give the /5-amino carbonyl compounds (Eq. 16) [27]. The diastereoselectivity was independent of the geometry of the silyl enol ethers, and favored the anti products. Nitrones, prepared in situ from aldehydes and N-substituted hydroxylamines, added to alkenes to afford isoxazoli-dines (Eq. 17) [28]. Addition of diazoesters to imines afforded CK-aziridines as the major products (Eq. 18) [29]. In all the reactions the imines could be generated in situ and the three-component coupling reactions proceeded smoothly in one pot. 

While the abstraction of protons adjacent to the carbon-nitrogen double bond of imines/imine derivatives has been utilized for tiie regioselective generation of azaallyl anions (which are useful in asymmetric ketone synthesis), it competes with and often prevents the addition of nucleophiles to imines. For this reason, imine additions often involve azomethines (e.g. benzylidineanilines) which are not capable of enolization. Many potentially useful additions, however, involve substrates capable of proton abstraction. By avoiding in certain instances some of the structural features of imines/imine derivatives and the reaction conditions responsible for proton abstraction, products resulting from this serious side reaction can be minimized. 

Addition to C=N. Imine derivatives which contain a chirality center adjacent to, or one atom away from the nitrogen atom are attacked by nucleophiles enantioselectively. Examples include p-toluenesulfinimines " and 42, 43, and 447 Reaction of lithium ester enolates with imines in the presence of the Cj-symmetric dimethoxybibenzyl leads to P-lactams in good ee, and a bis(aziridine) ligand is useful for enantioselective addition of RLi to imines. ... 

In other reactions that proceed via an acyliminium ion, O-vinyl iV,0-acetals rearrange smoothly to /3-(A-acylainino)aldehydes at 0 °C in CH2CI2 in the presence of TMSOTf with moderate to high diastereoselectivities (eq 78). However, TMSOTf failed to promote aprotic alk)fne-iminium cyclizations, which are readily enhanced by TMSCl, TMSBr, or SiCU. On the other hand, TMSOTf assists in the addition of enols to heteroaromatic imines or hydroxyaminal intermediates. ... 

The area of reactions of phosphate derivatives has been dominated by highly stereoselective reactions in which the latter were used as chiral catalysts or achiral reagents. Among this group of reactions, it is worthy to note several asymmetric reactions ring opening of w 50-aziridinium and episulfonium ions, addition of alcohols to imines, 1,3-dipolar addition of aldehydes, amino esters and dipolarophiles, protonation of silyl enol ethers, epoxidation of a,p-unsaturated aldehydes, aza-ene-type reactions as well as asymmetric versions of named reactions Mannich, Friedel-Crafts, Kabachnik-Fields, aza-Darzens and aza-Henry. 

A report from the Kobayashi lab has illustrated a unique alternative approach to Mannich-type additions. Instead of employing standard enolate equivalents such as silyl enol ethers, a Cu(II)-catalyzed enantioselective addition of enamides to imines has been developed [39]. Utilizing the now well-known complex Cu(OTf)2/diamine (121) as the chiral Lewis acid, addition of a variety of enamides to N-amide- or... 

Addition of Sulfonylimidates to Imines. Alkaline earth metal alkoxides are attractive catalysts in organic chemistry as they display both Lewis acidic and basic properties. They are perfectly suited for the addition of enolates to electrophiles due to their chelating properties. In particular, catalytic Mg(OtBu)2 can be used in the addition of sulfonylimidate nucleophiles 1 to Boc-protected imines 2 (eq 1). Both yields and anti/syn ratios are... 

However, diastereoselective transformations like this are not to be discussed within this monograph, as they do not fulfill the criteria of asymmetric synthesis, according to Marckwald s definition (in today s language) this would mean [...] those reactions, or sequences of reactions, which produce chiral nonracemic substances from achiral compounds with the intermediate use of chiral nonracemic materials, but excluding a separation operation [35]. Thus, diastereoselective conversions not included for that reason in this book are, for example, aldol additions, Mannich reactions, and Michael additions of enolates to ketones, imines, and cx,P-unsaturated carbonyl compounds, respectively, with any chiral skeleton. For such stereoselective enolate reactions that are not asymmetric syntheses, the reader is referred to the literature, which treated this topic in a comprehensive manner [36]. 

The first step in either direction consists of addition of NaHS03 to one of the double bonds of the ring, which gives an enol (or enamine) that tautomerizes to the keto (or imine) form. The conversion of 12 to 13 (or vice versa) is an example of 16-12 (or... 

Scheme 18 Reagent-induced enantioselective catalytic synthesis of 2,3-diamino esters by addition of a-amino and a-iminoester enolates to imines...

Azolium enolates such as 65 can be generated directly through addition of NHCs to symmetrical or unsymmetrical ketenes. For example, Smith and co-workers have shown that NHC promoted p-lactam formation from isobutylphenylketene 61 and AT-tosyl imines 63 proceeds with good yields and moderate levels of diastereoselec-tivity via enolate 65 (Scheme 12.12) [17]. 

Addition of enols, enolates, or enolate equivalents to imines or iminium ions provides an important route to (3-amino ketones. 

Hagiwara et al.107 reported the chiral Pd(II) complex-catalyzed asymmetric addition of enol silyl ethers to imines, based on the belief that Pd(II) enolate was involved in the reaction. They found that with compound 171a as the catalyst, very low enantioselectivity was obtained in the asymmetric reactions between silyl enol ether and imine compounds (Scheme 3-58). However, in the... 

Although four-membered rings are highly strained and not very stable heterocycles, there are some examples (Fig. 3.5) for the preparation of heterocycles of this type on solid supports. Different /9-lactams (229-230) have been synthesized employing different synthetic pathways [133, 275, 306-309] such as the addition of ketenes (Scheme 3.34) [306], or ester enolates to imines [133]. Also the synthesis of four-membered rings with two heteroatoms has been reported [310]. 

In the course of examining the CAI effect of conformational restriction of the C3-side-chain, intermediate 24 was prepared. Shankar and co-workers (Shankar et al., 1996) demonstrated that 10, a key intermediate in the research synthesis could be accessed by Wacker oxidation of olefin 24 (Scheme 13.7). Additionally, an alternative chiral variant of the well-precedented addition of zinc enolates to imines was demonstrated. Treatment of the bromoacetate 25, derived from 8-phenylmenthol with zinc and sonication followed by imine addition afforded 26 in 55% yield with greater than 99% de. Ethyl magnesium promoted ring-closure followed by C3 alkylation with 28, intercepts the previously demonstrated route through formation of olefin 24 (Shankar et al., 1996). 

The first step in either direction consists of addition of NaHSO-, to one of the double bonds of the ring, which gives an enol (or enamine) that tautomerizes to the keto (or imine) form. The conversion of 10 to 11 (or vice versa) is an example of 6-14 (or 6-2). Evidence for this mechanism was the isolation of 10 " and the demonstration that for p-naphthol treated with ammonia and HSOj. the rate of the reaction depends only on the substrate and on HSOi. indicating that ammonia is not involved in the rate-determining step.112 If the starting compound is a (i-naphthol, the intermediate is a 2-keto-4-suIfonic acid compound, so the sulfur of the bisulfite in either case attacks meta to the OH or NH2-m... 

Ab initio MO methods have been used to predict the stereochemistry of aldol-type addition of boron enolates to imines, with due allowance for the degree and type of substitution, and the geometry (E or Z) of both the enolate and imine reactants.39 Only two important transition states were identified—both cyclic—one chair-like and the other boat-like. The results are compared with the stereo selections reported in various experimental methodologies. 

Coverage in this chapter is restricted to the use of alkenes or alkynes as enophiles (equation 1 X = Y = C) and to the use of ene components in which a hydrogen is transferred. Coverage in Sections 1.2 and 1.3 is restricted to ene components in which all three heavy atoms are carbon (equation 1 Z = C). Thermal intramolecular ene reactions of enols (equation 1 Z = O) with unactivated alkenes are presented in Section 1.4. Metallo-ene reactions are covered in the following chapter. Use of carbonyl compounds as enophiles, which can be considered as a subset of the Prins reaction, is covered in depth in Volume 2, Chtqiter 2.1. Addition of enophiles to vinylsilanes and allylsilanes is covered in Volume 2, Chapter 2.2, while addition of enophiles to enol ethers is covered in Volume 2, Chapters 2.3-2.S. Addition of imines and iminium compounds to alkenes is presented in Volume 2, Part 4. Use of alkenes, aldehydes and acetals as initiators for polyene cyclizations is covered in Volume 3, Chapter 1.9. Coverage of singlet oxygen, azo, nitroso, S=N, S=0, Se=N or Se=0 enophiles are excluded since these reactions do not result in the formation of a carbon-carbon bond. 

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