Synthetic Applications of Enamines

The formation of enamines by the reaction of aldehydes and ketones with secondary amines was described in Section 17.11. As the following equation illustrates, the reaction is reversible. 

When preparing enamines, the reaction is normally carried out by heating in benzene as the solvent. No catalyst is necessary, but / -toluenesulfonic acid is sometimes added. The water formed is removed by distillation of its azeotropic mixture with benzene, which shifts the position of equilibrium to the right to give the enamine in high yield. Conversely, enamines can be hydrolyzed in aqueous acid to aldehydes and ketones. 

Enamines resemble enols in that electron-pair donation makes their double bond electron-rich and nucleophilic. 

Because nitrogen is a better electron-pair donor than oxygen, an enamine is more nucleophilic than an enol. Enamines, being neutral molecules are, however, less nucleophilic than enolates, which are anions. 

Reactions of enamines with electrophiles (E ) lead to carbon-carbon bond formation. Subsequent hydrolysis gives an a-substituted derivative of the original aldehyde or ketone. 

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Descriptive Passage and Interpretive Problems 21 Synthetic Applications of Enamines 910... 

The synthetic application of reactions based upon the intramolecular addition of a carbanion or its enamine equivalent to a carbonyl or nitrile group has been explored extensively. One class of such reactions, namely the Dieckman, has already been discussed in Section 3.03.2.2, since ring closure can often occur so as to form either the C(2)—C(3) or C(3)—C(4) bond of the heterocyclic ring. Some illustrative examples of the application of this type of ring closure are presented in Scheme 46. 

The bulk of enamine studies since Stork s original publication have focused on establishing the breadth and limitations of individual substitution reactions and on extending the list of useful electrophiles. In addition, auxiliary studies have enriched our knowledge about the ambident nature of the vinyl nitrogen system, stereoelectronic factors governing its reactivity, its stability and spectroscopic properties. An increasing number of synthetic applications of these fundamental studies can be expected in future years. 

It is hoped that this chapter will be stimulating and helpful to those interested in synthetic applications df enamines. Thus the amount of discussion has been held at a minimum so that a maximum of variety and information could be presented in the form of examples, which may be useful as analogues in the solution of synthetic problems. 

Other interesting synthetic applications of the ketone-derived enamine alkylation are found in the monomethylation of steroid enamines (249), extension of the benzylation reaction (250) to a ferrocene derivative (251), the use of a-bromoesters (252) and ketones (252) or their vinylogues (25J), in the syntheses of alantolactone (254-256), isoalantolactone (257), and with a bridged bis-enamine (258). The use of bifunctional alkylating agents is also seen in the introduction of an acetylenic substituent in the synthesis of the characteristic fragrant constituent of jasmine (259), the synthesis of macrocyclic ketolactones (260), the use of butyrolactone (261), and the intermolecular or intramolecular double alkylations of enamines with dihalides (262). 

The enamines derived from cyclohexanones are of particular interest. The pyrrolidine enamine is most frequently used for synthetic applications. The enamine mixture formed from pyrrolidine and 2-methylcyclohexanone is predominantly isomer 17.106 A steric effect is responsible for this preference. Conjugation between the nitrogen atom and the tt orbitals of the double bond favors coplanarity of the bonds that are darkened in the structures. In isomer 17 the methyl group adopts a quasi-axial conformation to avoid steric interaction with the amine substituents.107 A serious nonbonded repulsion (A1,3 strain) in 18 destabilizes this isomer. 

In this survey, selected synthetic applications of tandem hydroformylation sequences are described and complementing the more comprehensive reviews covering the literature up to 1998/99 [27], and up to 2003 [28,29]. The material is ordered according to the type of the additional transformation involving heterofunctionalization of the aldehyde group to form acetals, aminals, imines and enamines, as well as reduction of the latter in an overall hydroaminomethylation. Furthermore, numerous conversions of oxo aldehydes with additional C,C-bond formation at the carbonyl group or at the acidic... 

Hantzch synthesis is a well-known pathway to dihydro derivatives of azines. In some of the variations of this synthesis, the electrophilic reagents can be unsaturated ketones (Scheme 3.1, reactions a and b). Hantzch syntheses, including reaction b in Scheme 3.1 in which enamines are formed in situ from ammonia and the corresponding carbonyls, are not a topic of this book. However, synthetic applications of such condensations were described in detail in some reviews [1,2]. 

Meanwhile, Nikolay had started his new research on the preparation, reactions, and synthetic applications of p-chloro vinyl ketones and related compounds (p-aminovinyl ketones, p-kctoacetals). Efficient synthetic methods were developed and improved, including C-ketovinylation (introduction of the RCOCH = CH group), and a number of useful heterocyclic compounds (pyrazoles, triazoles, pyridines, and so on) were synthesized. The discovery of enamine-imine tautomerism in p-aminovinyl ketones was another remarkable achievement by Nikolay at that time. For these studies he received in 1953 the degree of Doctor of Science in chemistry. He continued as a lecturer and supervisor of postgraduates at the University, becoming docent (associate professor) in 1951 and full professor in 1955. 

Nine years after his first publication6 Stork quoted in his own review article8 90 publications devoted to enamines. Our computer search21 in the chemical abstract service (CAS) resulted in 4389 hits for enamines from 1967 to 1992 (up to Volume 117 of Chemical Abstracts) which indicate the importance, use and applications of enamines. A CAS search for reviews on enamines for the same period yielded 92 hits. However, many of these referred to difficultly accessible sources and have therefore been neglected. Only the 22 most important reviews on preparations, properties and synthetic uses of enamines are listed here22-42, and their titles and lengths are given in the list of references. 

Although A-acyl enamines and their cationoid derivatives are not the intermediates in all the above-mentioned syntheses of pyrimidines, these reactions are listed here for demonstration of the synthetic applicability of the reaction between nitriles and carbonyl compounds and their derivatives. During the course of investigation of these processes interesting theoretical results were obtained which allow one to evaluate from a new viewpoint some concepts regarding this field. 

Stimulated by the recent introduction of photochemical means to synthetic organic chemistry, the reaction and application of enamines and their derivatives have been studied (3). Although enamines have been regarded as one of the most useful synthetic weapons developed in modern organic chemistry (3), these particular groups are usually too unstable and decompose rather readily under photochemical conditions. Therefore, A-acylen-amines, which are readily prepared from imines by simple acylation, were the compounds of choice to study for photochemical reaction. 

Scheme 9 demonstrates the further synthetic application of the thus obtained N,0-acetals. Substitution of the alkoxy or acyloxy group by nucleophiles like enol ethers, enol esters, enamines, other electron-rich olefins, CH-acidic compounds, electron-rich aromatics, isocyanides, trimethylsilyl cyanide, organometallics, vinyl and allyl silanes, hydroxy functions, or trialkylphosphites either catalyzed by Lewis acids or proton acids leads to the product of the amidoalkylation reaction (path a). In the presence of stereocenters as control elements, diasteroselective amidoalkylation reactions can be performed as shown in a large number of examples. On the other side, as Nyberg showed for the first time [196], elimination with formation of enecarbamates [208] and enamides [196,208,209] followed by reaction with electrophiles or nucleophiles (path b) also is possible. 

One of the most thoroughly investigated synthetic applications of phosphonylated aldehydes involves the fonnation of heterocyclic compounds containing a phosphoryl group in the side chain and, historically, the first attempt to prepare dietliyl 1-fonnylmethylphosphonate was undertaken with the aim of synthesizing phosphonylated heterocycles. - This section is concerned essentially with the reactions of formylphosphonates, 1-fonnylmethyIphosphonates and 2-formylethylphosphonates. In most cases they are employed in their masked forms, as phosphonylated acetals or enamines, rather than in the free form. 

Both symmetrical and unsymmetrical ketones have been utilized in synthetic applications of the aza-annulation reaction of enamine derivatives with acrylamides. The most efficient use of this methodology involved generation of the enamine from the symmetrical ketone 21 (eq. 5).11 Aza-annulation with this enamine led to the formation of 22 as an 85 15 mixture of the regioisomeric tetra- and trisubstituted alkenes (b and a), respectively, which were then oxidized to the corresponding pyridone 23. Formation of intermediate 23 was a key to the synthesis of the... 

Dienamine is a recent extension of the enamine concept to extended donors by using the principle of vinylogy. By extension of the enamine to conjugated dienamine starting from alkyl substituted enals or enones, it allows for the functionalization of a,p-unsaturated carbonyls in a- or 7-position using various electrophiles (Scheme 11.26). This potential of amine catalysts to promote extended functionalization is highly interesting, but because of its relative infancy, few synthetic applications of such activation have been reported to date. 

The first section of this chapter describes the preparation and several synthetic applications of a-fluoroalkyl P-sulfmyl enamines and imines the second deals with the chemistry of di- and trifluoropyruvaldehyde A, 5-ketals, stereochemically stable synthetic equivalents of P-di and P-trifluoro a-amino aldehydes, which can be prepared from the corresponding p-sulfinyl enamines the third overviews the preparation of chiral sulfinimines of trifluoropyruvate and their use to prepare a library of a-trifluoromethyl (Tfm) a-amino acids the fourth section is mainly dedicated to the asymmetric synthesis of monofluorinated amino compounds, using a miscellany of methods such as MifstmobuAike azidation of P-hydroxy sulfoxides, ring opening of fluoroalkyl epoxides with nitrogen-centered nucleophiles and 1,3-dipolar cycloadditions with chiral fluorinated dipolarophiles. 

Two synthetic bridged nitrogen heterocycles are also prepared on a commercial scale. The pentazocine synthesis consists of a reductive alkylation of a pyridinium ring, a remarkable and puzzling addition to the most hindered position, hydrogenation of an enamine, and acid-catalyzed substitution of a phenol derivative. The synthesis is an application of the reactivity rules discussed in the alkaloid section. The same applies for clidinium bromide. 

While esters do not usually react with enamines and can, in fact, be substituents in the azeotropic preparation of enamines, they can be used in acylation reactions when these involve intramolecular cyclizations. Such reactions have been observed even at room temperature when they lead to the formation of five- and six-membered vinylogous lactams (362). Applications to precursors for azasteroids (40S) and alkaloids (309,406) are key steps in synthetic sequences. 

The reaction of enamines with iminium salts provides an alternative route to Mannich bases which are an attractive class of compounds, since they have found many applications (synthesis of drugs, pesticides, synthetic building blocks, etc.). This methodology has several basic advantages compared to the classic aminomethylation procedure15-18-24 ... 

During the past decade, metal-catalyzed asymmetric reactions have become one of the indispensable synthetic methodologies in academic and industrial fields. The asymmetric isomerization of allylamine to an optically active enamine is a typical example of the successful application of basic research to an industrial process. We believe that Takasago s successful development of large-scale asymmetric catalysis will have a great impact on both synthetic chemistry and the fine chemical industries. The Rh-BINAP catalysts, though very expensive, have become one of the cheapest catalysts in the chemical industry through extensive process development. 

Asymmetric hydroboration of enamines with chiral diboranes, followed by oxidation with hydrogen peroxide, in aqueous sodium hydroxide, gives /1-amino alcohols in good yields and high ee (equation 29)153. The products of this reaction are useful in medicinal applications and as synthons for further synthetic elaboration. 

Some special enamines, such as ethyl / -aminocrotonate and its alkylation and acetylation products, have already been known since the last century4. The general preparation of enamines was first reported by Mannich and Davidsen5 in 1936. However, this class of compounds found widespread synthetic applications only in the fifties due to the pioneering work of Stork and his coworkers6-8 and for a long period of time enamines have been studied mainly as synthetic intermediates and as tools for specific mono-substitution of ketones or aldehydes. 

Despite the large utility of enamines in organic synthesis, the study of the electrochemistry of enamines and especially the application to synthetic organic reactions has been a rather minor area in electroorganic chemistry, and only a few studies have been reported. In this review these works are summarized and electrochemical synthesis and some reactions of a,/ -unsaturated urethanes (enecarbamates) are also described, since their chemical reactivity is considerably similar to that of the enamines. 

The photochemical behavior of enamines and their derivatives has been the subject of extensive mechanistic and synthetic investigations. The goal of this chapter is to summarize the photochemistry of enamines as well as enamides, enaminones, en-amidones and enaminonitriles, with particular emphasis on the application of the photochemistry of these chromophores in the synthesis of natural products. 

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