Enamines synthetic applications

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. 

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. 

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. 

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. 

As evidenced by diverse chapters in the current volume and other reviews, interest in enamines has been dominated by the convenience and versatility of their numerous synthetic applications As such, numerous enamines have been prepared and their reaction chemistry studied and enjoyed. Regrettably, by contrast, enamines have not particularly attracted the attention of the thermochemical community few enthalpies (heats) of formation (AJ/f) have been reported for enamines, and essentially no other thermochemical properties such as entropies (either S° or ASf), heat capacities (Cp) and phase change enthalpies have been reported. In this chapter we will concern ourselves primarily with enthalpies of formation, and thus the derived concepts of resonance and strain energies. Only occasionally will we employ the long known Gibbs free energy (AG), two accompanying identities (equations 1 and 2) and a commonly employed approximation (equation 3) for its use. 

Asymmetric hydrogenation was boosted towards synthetic applications with the preparation of binap 15 by Noyori et al. [55] (Scheme 10). This diphosphine is a good ligand of rhodium, but it was some ruthenium/binap complexes which have found spectacular applications (from 1986 up to now) in asymmetric hydrogenation of many types of unsaturated substrates (C=C or C=0 double bonds). Some examples are listed in Scheme 10. Another important development generated by binap was the isomerization of allylamines into enamines catalyzed by cationic rhodium/binap complexes [57]. This reaction has been applied since 1985 in Japan at the Takasago Company for the synthesis of (-)-menthol (Scheme 10). 

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... 

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

The enamines derived from cyclohexanones have been of particular interest. The enamine mixture formed from pyrrolidine and 2-methylcyclohexanone consists predominantly of structure 6. " The pyrrolidine enamine is most frequently used for synthetic applications. The tendency to provide the less substituted enamine is... 

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 ... 

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