Enamines special

Knowledge of the mechanism enables one to obtain more insight into the various factors which determine the extent of reaction along both pathways. In this chapter special attention will be given to the kinetics and mechanism of the hydrolysis of simple enamines.f... 

Some enamines with special structural features are those derived from ammonia (19 ) and the quinuclidine enamines (19J). Aminocyclobutenes... 

The illumination of enamines as general activa ting derivatives of ketones in alkylation reactions also threw light on their special usefulness for controlling alkylations (3), particularly in the formation of monosubstituted cyclohexanones. Thus 2-methylcyclohexanone could be obtained in 80% yield from the pyrrolidine enamine of cyclohexanone, and further alkylation, which required more drastic conditions, gave only 2,6-dimethylcyclo-hexanone (1,237). 

Angles where the central atom is di- or trivalent (ethers, alcohols, sulfides, amines and enamines) represent a special problem. In these cases an angle of 180° corresponds to an... 

It is occasionally necessary to carry out special operations in connection with a synthetic procedure. An example frequently encountered is the removal of water from a reaction mixture in order to alter equilibrium concentrations (for example, in the preparations of enamines). For this purpose, a Dean-Stark trap is employed as shown (Fig. A3.6). The reaction is carried out in a solvent that forms an azeotrope with water... 

Although catalytic hydrogenation is the method most often used, double bonds can be reduced by other reagents, as well. Among these are sodium in ethanol, sodium and rerr-butyl alcohol in HMPA, lithium and aliphatic amines (see also 15-14), " zinc and acids, sodium hypophosphate and Pd-C, (EtO)3SiH—Pd(OAc)2, trifluoroacetic acid and triethylsilane (EtsSiH), and hydroxylamine and ethyl acetate.However, metallic hydrides, such as lithium aluminum hydride and sodium borohydride, do not in general reduce carbon-carbon double bonds, although this can be done in special cases where the double bond is polar, as in 1,1-diarylethenes and in enamines. " °... 

One of the most widely applied cycloaddition techniques for the preparation of thietanes is the reaction of sulfenes with enamines. The stereochemistry of these reactions has been extensively investigated by Truce and Rach. Whether the mechanism is a two-step or a concerted process, both in accordance with the stereoselective formation of the cis form in Scheme 1, is still unresolved. The special orientation of the 1,4-dipolar intermediate 64, in which the charged phenyl and dimethylamino moieties are in proximity, enforces the cis geometry of the resulting thietane dioxide. In the concerted mode of reaction, formation of the orthogonal oriented unsaturated system, 65 should also yield the cis cycloadduct. 

Among the facts supporting this mechanism (which is an A-Se2 mechanism because the substrate is protonated in the rate-determining step) are (1) lsO labeling shows that in ROCH=CH2 it is the vinyl-oxygen bond and not the RO bond that cleaves 497 (2) the reaction is subject to general acid catalysis 498 (3) there is a solvent isotope effect when D2O is used.498 Enamines are also hydrolyzed by acids (see 6-2) the mechanism is similar. Ketene dithioacetals R2C=C(SR )2 also hydrolyze by a similar mechanism, except that the initial protonation step is partially reversible.499 Furans represent a special case of enol ethers that are cleaved by acid to give 1,4 diones. Thus... 

Most known thiamin diphosphate-dependent reactions (Table 14-2) can be derived from the five halfreactions, a through e, shown in Fig. 14-3. Each halfreaction is an a cleavage which leads to a thiamin- bound enamine (center, Fig. 14-3) The decarboxylation of an a-oxo acid to an aldehyde is represented by step b followed by a in reverse. The most studied enzyme catalyzing a reaction of this type is yeast pyruvate decarboxylase, an enzyme essential to alcoholic fermentation (Fig. 10-3). There are two 250-kDa isoenzyme forms, one an a4 tetramer and one with an ( P)2 quaternary structure. The isolation of ohydroxyethylthiamin diphosphate from reaction mixtures of this enzyme with pyruvate52 provided important verification of the mechanisms of Eqs. 14-14,14-15. Other decarboxylases produce aldehydes in specialized metabolic pathways indolepyruvate decarboxylase126 in the biosynthesis of the plant hormone indoIe-3-acetate and ben-zoylformate decarboxylase in the mandelate pathway of bacterial metabolism (Chapter 25).1243/127... 

A series of special linkers and cleavage strategies has been developed for the release of amines from insoluble supports (Table 3.23). These include the attachment of amines as triazenes, enamines, aminals, amidines, sulfonamides, sulfinamides, hydrazines, or amides. 

A special subject of comprehensive investigation is electrophilic attack (see Section V,C). This reaction can be considered to be an electrophilic aromatic substitution and also to be an electrophilic reaction with enamines,234 enol... 

Noyori s BINAP catalysts deserve special attention because their chirality is based on the bulkiness of the naphthalene groups, rather than on carbon or phosphorus asymmetric centers (Figure 3.28, inset) [77]. One of the many examples of asymmetric catalysis using BINAP is the synthesis of (—)-menthol, an important additive for flavors, fragrances, and pharmaceuticals. Starting from myrcene, the process is carried out by Takasago International on a multi-ton scale. The key step is the isomerization of geranyldiethylamine to (R)-citronellal enamine [78], which is then hydrolyzed to (R)-citronellal with nearly 99% ee. 

The most important of the heterocycles fused to benzene rings are the indoles 75. The obvious enamine disconnection gives 76 which would certainly cyclise to the indole, but how are we to make 76 As a result of this difficulty, many special reactions have been invented to make indoles and the most important is the Fischer indole synthesis.12 A phenylhydrazone 77 of a ketone or aldehyde is treated with acid or Lewis acid and the product is an indole. 

The study of the enamine structure may be associated, to a certain degree, with the problem of the so-called pseudobases an instructive, but somewhat specialized, review of these compounds was contributed by the late Professor Beke 47 to the first volume of this series. The name pseudobases was given by Hantzsch,48 towards the end of the last century, to those a-aminocarbinols which undergo a structural change during salt formation and yield salts with the loss of one molecule of water. The liberation of pseudobases from their salts is accompanied by rehydration. This behavior has been observed with a,/3-unsaturated heterocyclic compounds and, to a certain degree, with aromatic heterocyclic pyridine derivatives. As formulated by Gadamer,49 the pseudobases represent a potential tautomeric system of three components, the quaternary hydroxide A, the carbinolamine B, and the open-chain amino-carbonyl derivative C, in which all three components exist in a mobile equilibrium ... 

Imines are formed by condensation of aldehydes or ketones with primary amines, but they form with more difficulty than enamines.84,85 A special case of enamine preparation was described with 20-oxo-steroids.86 Treatment of these ketones with a primary amine gives a 20-ketimine, which is acetylated with acetic anhydride, with migration of the double bond and formation of 20-(A-acetylalkylamino)-J17(20)-pregnene (14) reduction of 14 with lithium aluminum hydride affords the enamine. 

C. Aldolization reactions of enamines (a special case combining classes A and B). 

The enamine-mediated aldol addition of Figure 12.19 has several special features ... 

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. 

Among these reviews, that of Szmuszkovicz23 in 1963 and those of Hickmott37 in 1982 are very extensive and of special value. Our list contains three monographs28,33,41. Of these, the second edition of the book of Cook41 published in 1988 is the latest and most extensive available review on enamines. A set of Russian special reviews on enamines was edited in 1990 by Aleksandrov43 under the title Enaminy Org. Sint, to which, however, we did not have access. 

Although it is a generally accepted classification of enamines as (i) primary, (ii) secondary and (iii) tertiary, it was not necessary to form separate sets comprising these types of enamines for two reasons. The first was that (i) contained only 7 and (ii) 18 entries, which are insufficient for statistical analysis in comparison with the tertiary enamines (iii 449 entries). The second reason was a lack of special structural features which would justify such a separate treatment, as it was found that primary and secondary enamines contribute to all the four classes (a)-(d). The structures of the compounds in set S together with their reference codes (REFCOD s) ascribed to crystal structures in CSDS and the appropriate reference are given in the Appendix at the end of this chapter. It should be noted that the number of published crystal structures is less than the number of entries (enamine fragments), because more than one fragment may occur in a particular molecule. 

The NMR spectra of enamines with special reference to the proton spectra have been the subject of reviews containing references up to 19861. This chapter will therefore mainly deal with progress made since then, with emphasis on the resonances of 13C and 15N. Being the core of the enamine framework, the spectral parameters of these nuclei reflect structural changes in the molecule better than the parameters of the attached... 

The term enaminone is given and defined by Greenhill1 as a monoenamine of a 1,3-diketone or 3-ketoester. Because of their special chemical properties enaminones represent a class of organic compounds in its own right . In our opinion enamines from 3-ketonitriles exhibiting a similar reactivity may also be included in this definition. 

Enamines are classical reagents, most properties of which originate from their acidity or high basicity and their strong amphiprotic character. Their special molecular behaviour is a result of their being resonance hybrids of the two resonance structures 1 and 2. 

Since this is the first time the radical reactions of enamines are being reviewed, an attempt has been made to cover all the relevant literature. In Section II of this chapter, a brief discussion of the general principles of radical additions to. alkenes with special emphasis on the modifying effect due to the presence of amino group (as is the case in enamines) is included. Section III deals with the reactions of enamines in which the radical addition takes place on the C=C bond of enamines while Section IV describes the reactions with one-electron oxidants such as metal ions and oxygen. 

A special class of dienamines is the pyrroles. Since pyrroles are somewhat aromatic (and their conjugate acids are not), they are not as basic as ordinary enamines. However, the effects of substitution on the pyrrole nucleus should offer clues toward understanding and predicting substituent effects on the basicities of nonaromatic dienamines. Whipple, Chiang and Hinman have made a systematic study of the effects of methyl substitution on the pA H+ of pyrroles (equation ll)32,33. Their results are listed in Table 7. 

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