Enamines compounds using

Quite recently, the same research group compared the electrophilicity of 6-nitro-tetrazolo[l,5- ]pyridine and 6,8-dini-trotetrazolo[l,5- ]pyridine 11 with a series of electron-deficient aromatic and heteroaromatic compounds <2005JOC6242>. As reference nucleophiles, fV-methylpyrrole, indole, fV-methylindole, and some morpholino enamines were used. The reactivity of the electrophiles studied followed the linear-free energy relationship defined by Mayr et al. <2003ACR66>. 

This resonance form can then act as a nucleophile, in much the same way as an enolate anion can. However, there is a marked difference, and this is what makes enamines such useful synthetic intermediates. Generation of an enolate anion requires the treatment of a carbonyl compound with a base, sometimes a very strong base (see Section 10.2). 

The term enamine is used mainly for classifications of the functional group as an ensemble, but individual compounds are termed with respect to the parent compound usually as amino substituted olefins, i.e. tertiary enamines as (N,iV-dialkylamino)alkenes. The correct IUPAC nomenclature for tertiary enamines is dialkylalkenylamines, i.e. the basic compound in this case is the amine not the alkene. The difference may be demonstrated for two examples 73 is in the first notation l-iV-methylanilino-2-methyl-propene and, in IUPAC notation, iV-methyl-jV-(2-methyl-l-propenyl)aniline. Correspondingly 74 is usually called 2-methyl- 1-pyrrolidinopropene but in IUPAC notation it is jV-(2-methyl-l-propenyl)pyrrolidine. 

In the following discussion the expression simple enamine is used to designate enamines where the only substituents Rx-R3 on the double bond are H or alkyl, irrespective of their molecular complexity. The spectra of such conjugated compounds as those where R2 and/or R3 are aryl groups, or those containing the N—C=C—C=C (dienamines), C=C(N)—C=C (2-amino-1,3-butadienes) and Aryl—C(N)=C (1-arylenamines) systems, will also be included in this section. The greatest simplicity occurs in tertiary enamines (1, R4 = R5 H) where tautomerism is excluded and the only isomerism possible is the E, Z isomerism around the carbon-carbon double bond. 

Enamine catalysis using proline or related catalysts has now been applied to both intermolecular and intramolecular nucleophilic addition reactions with a variety of electrophiles. In addition to carbonyl compounds (C = O), these include imines (C = N) in Mannich reactions (List 2000 List et al. 2002 Hayashi et al. 2003a Cordova et al. 2002c ... 

If you want to do a conjugate addition of a carbonyl compound without having a second anion-stabilizing group, you need some stable and relatively unreactive enol equivalent. In Chapters 27 and 28 you saw how enamines are useful in alkylation reactions. These neutral species are also perfect for conjugate addition as they are soft nucleophiles but are more reactive than ends and can be prepared quantitatively in advance. The reactivity of enamines is such that heating the reactants together, sometimes neat, is all that is required. Protic or Lewis acid catalysis can also be used to catalyse the reaction at lower temperature. 

Enamine-based organocatalytic a-aminoxylation of carbonyl compounds using proline in ionic liquids. 

In the recent literature numerous reactions in which enamines are used for synthesis of enantiomerically pure compounds (EPC) can be found . Optically active enamines from substituted pyrrolidine (e.g. 27, R = CH20Me, CH20SiMe3, or 28, R = Me, CH20Me), or from piperidine , such as 29, (S)-phenylethylamine (30) " and stanna-N,0-heterocyclic amine (31) , are used. The cyclohexanenamines seem to be the preferred test compounds for this kind of reaction, whereas enamines of open-chain ketones and aldehydes have been investigated only rarely . Enamines from carbonyl compounds and secondary amines are obtained with azeotropic removal of water or by die Weingarten method with TiC. A titanium chloride-catalysed variation in which perfluorinated alkyl groups can be introduced is also known " . 

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. 

In continuation of our efforts in the development of new synthetic routes for the synthesis of heterocyclic compounds using nanocatalysts, we have recently reported a novel synthesis of 3,4,5-trisubstituted furan-2(5H)-one derivatives by the one-pot three-component condensation of aldehydes, amines, and dimethyl acetylenedicar-boxylate (DMAD) by nsing nanoparticulate ZnO as a catalyst in Et0H H20 (1 1) at 90°C (Scheme 9.30) (Tekale et al. 2013). Almost all the employed aldehydes and amines reacted smoothly to afford excellent yields of the prodncts, irrespective of the natnre of the snbstitnent present on the aldehyde or amine. The plausible mechanism for the synthesis of furan-2(5 f)-ones using nano-ZnO is depicted in Figure 9.3. The catalyst promotes the formation of enamines (99) from amines (97) and DMAD (96). ZnO polarizes the carbonyl group of aldehydes to form a polarized adduct (100) which reacts with the enamines, followed by cyclization with the elimination of methanol molecules to afford the corresponding trisubstituted furanone derivatives (98). 

There are two advantages to the enamine-Michael reaction versns the enolate-ion-Michael reaction that make enamines so useful in biological pathways. First, an enamine is neutral, easily prepared, and easily handled, while an enolate ion is charged, is sometimes difficult to prepare, and must be handled with care. Second, an enamine from a monoketone can be used in the Michael addition, whereas enolate ions from only jS-dicarbonyl compounds can be used. 

Novel syntheses of aldehydic or allyl enol ethers and enamines make use of the reagent dimethylphosphonyl diazomethane (121), which reacts with ketones and alcohols or secondary amines to give compounds of general formula (122, X=OR, NR2). "° ... 

Enamines are used as intermediates to form carbon-carbon bonds in reactions that parallel those of carbonyl compounds. The carbon-carbon double bond is nucleophilic because the lone pair electrons of nitrogen can be released to the carbon atom that was the a carbon atom of the original carbonyl compound. 

Identify the compounds used to prepare each of the following enamines. 

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. 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

Typical nucleophiles known to react with coordinated alkenes are water, alcohols, carboxylic acids, ammonia, amines, enamines, and active methylene compounds 11.12]. The intramolecular version is particularly useful for syntheses of various heterocyclic compounds[l 3,14]. CO and aromatics also react with alkenes. The oxidation reactions of alkenes can be classified further based on these attacking species. Under certain conditions, especially in the presence of bases, the rr-alkene complex 4 is converted into the 7r-allylic complex 5. Various stoichiometric reactions of alkenes via 7r-allylic complex 5 are treated in Section 4. 

Diacetates of 1,4-butenediol derivatives are useful for double allylation to give cyclic compounds. l,4-Diacetoxy-2-butene (126) reacts with the cyclohexanone enamine 125 to give bicyclo[4.3.1]decenone (127) and vinylbicy-clo[3.2.1]octanone (128)[85,86]. The reaction of the 3-ketoglutarate 130 with cij-cyclopentene-3,5-diacetate (129) affords the furan derivative 131 [87]. The C- and 0-allylations of ambident lithium [(phenylsulfonyl)methylene]nitronate (132) with 129 give isoxazoline-2-oxide 133, which is converted into c -3-hydroxy-4-cyanocyclopentene (134)[S8]. Similarly, chiral m-3-amino-4-hyd-roxycyclopentene was prepared by the cyclization of yV-tosylcarbamate[89]. 

Thiirane is more bactericidal than oxirane, and derivatives of 2-mei captomethylthiirane inhibit tuberculosis. The following pharmacological uses have been reported for compounds derived from thiirane derivatives gold complexes of the adducts of diethylphosphine and thiirane (antiarthritic), adducts of thiiranes and malononitrile (antibacterial, blood vessel dilators, muscle relaxants, sedatives), thermolysis products of thiirane 1-oxides and adducts of thiirane 1-oxides with sulfenyl chlorides (antibacterial), adducts of 2,3-diarylthiirene 1,1-dioxides with ynamines (antibacterial, parasiticidal), adducts of 2,3-diarylthiirene 1,1-dioxides with enamines (antifertility), adducts of p-aminophenylacetic esters with thiirane (immunosuppressants), adducts of amines and thiiranes (radioprotective drugs). 

Cross-conjugated dienones are quite inert to nucleophilic reactions at C-3, and the susceptibility of these systems to dienone-phenol rearrangement precludes the use of strong acid conditions. In spite of previous statements, A " -3-ketones do not form ketals, thioketals or enamines, and therefore no convenient protecting groups are available for this chromophore. Enol ethers are not formed by the orthoformate procedure, but preparation of A -trienol ethers from A -3-ketones has been claimed. Another route to A -trien-3-ol ethers involves conjugate addition of alcohol, enol etherification and then alcohol removal from la-alkoxy compounds. 

Analogous compounds with a secondary amino group (a,j8-unsaturated secondary amines) can, in principle, exist in either the form of imines (6) or the tautomeric form of enamines (7). As they practically occur and react in the former structure, it is more convenient to use the group designation imines. ... 

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. 

In the arylations of enamines with very reactive aryl halides (352,370) such as 2,4-dinitrochlorobenzene, the closely related mechanistic pathway of addition of the enamine to the aromatic system, followed by elimination of halide ion, can be assumed. The use of n-nitroarylhalides furnishes compounds which can be converted to indolic products by reductive cycliza-tion. Less reactive aryl halides, such as p-nitrochlorobenzene, lead only to N-arylation or oxidation products of the enamines under more vigorous conditions. 

The acylation of enamines has been applied to the use of long-chain acid chlorides (388) and particularly to the elongation of fatty acids (389-391) and substituted aliphatic acids (392). The method has been used in the synthesis of the antineoplastic cycloheximide and related compounds (393-395) and in the acylation of steroids (396). Using an optically active chlorocarbonate, an asymmetric synthesis of lupinine could be achieved (397). 

The formation of adducts of enamines with acidic carbon compounds has been achieved with acetylenes (518) and hydrogen cyanide (509,519,520) (used as the acetone cyanohydrin). In these reactions an initial imonium salt formation can be assumed. The addition of malonic ester to an enamine furnishes the condensation product, also obtained from the parent ketone (350,521). 

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