Reaction compounds using enamine

Reaction of organometallic compounds with enamine salts have been successfully used for the synthesis of some natural products (256). Thus reaction of the immonium salt of 0-alkylated enamino ketone 122 with isobutyllithium affords the compound 169. 

Enamines can be used in place of an aldehyde or ketone in the Gewald reaction. Compound 19 reacted with ethylcyanoacetate and sulfur in the presence of morpholine to give aminothiophene 20 in good yield. ... 

Mannich bases (see 16-15) and p-halo carbonyl compounds can also be used as substrates these are converted to the C=C—Z compounds in situ by the base (16-15, 17-12). Substrates of this kind are especially useful in cases where the C=C—Z compound is unstable. The reaction of C=C—Z compounds with enamines (12-18) can also be considered a Michael reaction. Michael reactions are reversible. 

Another advantage of this method is that no catalyst is needed for the addition reaction this means that the base-catalyzed polymerization of the electrophilic olefin (i.e., a,j8-unsaturated ketones, esters, etc.) is not normally a factor to contend with, as it is in the usual base-catalyzed reactions of the Michael typCi It also means that the carbonyl compound is not subject to aldol condensation which often is the predominant reaction in base-catalyzed reactions. An unsaturated aldehyde can be used only in a Michael addition reaction when the enamine method is employed. 

The alkylation of caclohexanone has been studied as a model reaction in detail. Generally, enamino compounds (126) are allowed to react with alkyl halides or a, 3-unsaturated carbonyl compounds. The enamine (126a) is prepared directly from the ketone and a chiral secondary amine (route A). A metalloenamine (126b) can be synthesized from chiral azomethine, derived from the model ketone and a primary chiral amine (route B). The primary amine used for the formation of (126b) must possess an oxygen function. This oxygen function plays a key role in the coordination of the lithium ion in the complex (126b). 

White and Weingarten [44] recently reported a novel method for converting carbonyl compounds to enamines using titanium tetrachloride and the free amine (Eq. 9). In this reaction the titanium tetrachloride acts as an effective... 

In the thiazolium cation the proton in the 2-position is acidic and its removal gives rise to the ylide/carbene 227. This nucleophilic carbene 227 can add, e.g., to an aldehyde to produce the cationic primary addition product 228. The latter, again via C-deprotonation, affords the enamine-like structure 229. Nucleophilic addition of 229 to either an aldehyde or a Michael-acceptor affords compound(s) 230. The catalytic cycle is completed by deprotonation and elimination of the carbene 227. Strictly speaking, the thiazolium salts (and the 1,2,4-triazolium salts discussed below) are thus not the actual catalysts but pre-catalysts that provide the catalytically active nucleophilic carbenes under the reaction conditions used. This mechanism of action of thiamine was first formulated by Breslow [234] and applies to the benzoin and Stetter-reactions catalyzed by thiazolium salts [235-237] and to those... 

Alkyllithium compounds and alkali cyanides, mercaptides, and alkoxides,322,323 etc. have been used as nucleophilic reagents in reactions with the enamine salts. Nitrile groups can be removed by reduction or by treatment with acids. Treatment of cotarnine (100)... 

The overall process, from carbonyl compound to carbonyl compound, amounts to an enolate alkylation, but no strong base or enolates are involved so there is no danger of self-condensation. The example below shows two specific examples of cyclohexanone alkylation using enamines. Note the relatively high temperatures and long reaction times enamines are among the most reactive of neutral nucleophiles, but they are still a lot less nucleophilic than enolates. 

Some of the examples where a diazo or a diazonium compound reacts with activated double bonds, specifically with enamines and with 1,2-dimethoxy-ethene have been mentioned in sections 2.1.2 and 2.1.4, respectively (12, 29). A similar reaction is the azo coupling of arenediazonium salts with tropolones (34) The diazonio group reacts at the C-5 atom, so the reaction is used as a diagnostic tool for the presence of substituents at C-5, as well as for the synthesis of 5-amino tropolones by reduction of the azo compound. 

Amines and -keto carbonyl compounds form enamines in high yields. This reaction has been used to protect amino acids and amino acid esters (Scheme 17). Enamines (28) from acyclic P-dicarbonyl com-... 

Interesting intramolecular reactions were observed using enamines to give products 7 and 8. The combination of fluoride anion or l,4-diazabicyclo[2.2.2]octane as base and carbonyl compounds gave tetrahydropyran 10. ... 

There are numerous reactions in which enamines and enamine derivatives, such as metalloenamines, are used for the synthesis of enantiomerically pure compounds (EPC synthesis) In principle, such EPC synthesis could involve a chiral amine component of the enamine reacting with an achiral electrophile or an achiral enamine reacting with a chiral electrophile. The cyclohexenamines seem to be the preferred test objects for this kind of reaction enamines of open-chain ketones and aldehydes have been investigated only rarely. Examples are chiral enamines from substituted pyrrolidine 104i -i (R = CHjOMe,CHiOSiMe3,COOMeX = Me,CH20Me),... 

The amino substituent increases the nucleophilicity of the jff-carbon due to the electron-donating power of the nitrogen and makes it useful in alkylation reactions . Isotopically labelled enamines have been utilized to study the conjugation of the double bond with nitrogen in these and related compounds by investigating the deuterium isotope effects on C and N nuclear shielding in enamine derivatives. Mechanistic... 

The nucleophilic properties of enamines uncovered by Stork have found a wide application in Michael additions. Secondary enamines are usually in equilibrium with the corresponding imines. These imines are generally more stable, unless the tautomeric enamine is stabilized by conjugation (Figure 7.71). The primary product of the reaction of an enamine with an a,P-unsaturated carbonyl compound is a dipolar intermediate 7.108. This intermediate is converted to a 1,5-dicarbonyl compound on exposure to aqueous add. Proton transfers can take place before hydroysis to the ketone occurs, and the stereoselectivity of the process may be determined by such steps. Moreover, the enamine addition reaction can be reversible. These problems notwithstanding, the use of chiral amines to generate imines or enamines for use as Michael donors has been widely developed. The chiral imine/enamine can be preformed or, espedally in the case of intramolecular reactions, the amine can be added to the reaction medium in stoichiometric amounts. 

Peterson olefination reaction. The application to reaction of an /V-(tri methyl silylmethyl) formamidine with carbonyl compounds provides enamines that are use ful for transformation into homologous nitriles via the A/, -dimethylhydrazones. 

Endocyclic enamines, such as pyrrolines and tetrahydropyridines are useful for the synthesis of complex heterocyclic compounds, as found in many alkaloids. Thus, reaction of the enamine 27 with methyl vinyl ketone gave the alkaloid mesem-brine(1.41). 

Many other reactions in nature use enamines, mostly those formed from lysine. However, a more common enol equivalent is based on thiol esters derived from coenzyme A. Coenzyme A is an adenine nucleotide at one end, linked by a S -pyrophosphate to pantothenic acid, a compound that looks rather like a tripeptide, and then to an amino thiol. Here is the structure broken down into its parts. 

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