Cyclic enamines, formation

The most general method for synthesis of cyclic enamines is the oxidation of tertiary amines with mercuric acetate, which has been investigated primarily by Leonard 111-116) and applied in numerous examples of structural investigation and in syntheses of alkaloids 102,117-121). The requirement of a tram-coplanar arrangement of an a proton and mercury complexed on nitrogen, in the optimum transition state, confers valuable selectivity to the reaction. It may thus be used as a kinetic probe for stereochemistry as well as for the formation of specific enamine isomers. 

The formation of an enamine from an a,a-disubstituted cyclopentanone and its reaction with methyl acrylate was used in a synthesis of clovene (JOS). In a synthetic route to aspidospermine, a cyclic enamine reacted with methyl acrylate to form an imonium salt, which regenerated a new cyclic enamine and allowed a subsequent internal enamine acylation reaction (309,310). The required cyclic enamine could not be obtained in this instance by base isomerization of the allylic amine precursor, but was obtained by mercuric acetate oxidation of its reduction product. Condensation of a dihydronaphthalene carboxylic ester with an enamine has also been reported (311). 

Rearrangements of vinylogous urethanes to vinylogous carbonic acids and decarboxylation are other interesting enamine rearrangements which may be synthetically useful in the formation of cyclic enamines (623,624). 

Extension of this work by reacting 5-nitropyrimidine with 0,0-ketene acetals and with other cyclic and non-cyclic enamines showed that also with these electron-rich dienophiles the addition is regioselective and gives rise to the formation of 2-mono- or 2,3-disubstituted 5-nitropyridines (Scheme 30). Thus, reaction of 5-nitropyrimidine with the cyclic N,S-ketene acetals 4,5-dihydro-1 -methyl-2-methylthiopyrrole and 4,5,6,7-tetrahydro-1 -methyl-2-methylthioazepine gives in low yields 2,3-dihydro-1-methyl-5-nitropyr-olo[2,3-h]pyridine and the 5,6,7,8-tetrahydro-9-methyl-3-nitropyrido [2,3-Z)]azepine, respectively (89T2693) (Scheme 30). 

Scheme 38 Formation of five-, six-, and seven-membered cycloalkane-annelated ethoxy-cyclopentadienes 175 from the phenylethynylcarbene complex 173 and cyclic enamines 174 [119,120]...

Dicyano-substituted triafulvenes react with enamines to produce exclusively the cross-conjugated dicyanomethylene compounds 519, whose formation can be rationalized by a methylene bicyclo(2,l,0)pentane intermediate 51879 296 Since cyclanone enamines 520 and other cyclic enamines 522 react analogously, this C-C-insertion 237) of the triafulvene ring skeleton into the enamine C=C bond represents a versatile ring expansion mode (C + C3), which makes accessible a series of unsaturated medium-ring compounds (521/523) that are otherwise difficult to synthesize. 

General Procedure for the Enantioselective Hydrogenation/Hydroformylation/Enamine Formation. Synthesis of Cyclic Enamine Amino Acids. Prochiral dieneamide (1 eq) and... 

In this subsection, two types of cyclodehydrations will be discussed, namely the formation of cyclic Schiff bases, and the formation of cyclic enol ethers and cyclic enamines. 

In addition to several general reviews on enamine chemistry, all of which include heterocyclic syntheses, there is an extensive survey by Hickmott which is entirely concerned with the formation of heterocycles. More specialized reviews deal with heterocyclic enamines, enaminones, the photochemistry of enamides , heterocyclic jS-enamino esters , enamino thiones , the synthesis of indole alkaloids via enamines , formation of pyrimidines, pyridopyrimidines, pyridines and pyrrolizines from enamines , synthesis of lactams , formation of heterocycles from cyclic enamino ketones and 2-acetylcyclohexen-l-ones, the synthesis of 3-cyano-2(l -pyrimidine-thiones and -selenones from jS-enamino ketones and the chemistry of cyclic en-aminonitriles. ... 

Trichloroacetic acid [1, 1194, before references]. Trichloroacetic acid reacts with the cyclic enamine 1-morpholino-l -cyclohexene in ethylene dichloride with elimination of carbon dioxide and formation of N-[l-(trichloromethyl)cyclohexyl]morpholine,... 

The intermediate (45a) previously employed1" in a synthesis of aspidospermine has been neatly prepared52 by a potentially general method which has already been applied to the syntheses of several other alkaloid systems. The key step is the reaction of a cyclic enamine, in this case (46a), with methyl vinyl ketone and the formation of a homocyclic ring and the required carbonyl function. Scheme 16... 

Diacetoxylation (probably a radical process) of the cyclic enamine (122) with lead tetraacetate in glacial acetic acid gave (123), which was readily hydrolyzed to the diol (124) <92CPB235>. Treatment of (125) with Raney nickel led to desulfurization and the formation of (126) <94JHC409>. 

Various cyclic compounds can be prepared by the reaction of ketones with bifunctional aryl halides. The jS-naphthol derivative 52 was obtained by a-arylation of dibenzyl ketone (14) with o-bromobenzaldehyde derivative 51, followed by aldol condensation [38], Also the indole derivative 54 was synthesized by the reaction of cyclohexanone with 2-iodoaniline (53). Formation of 54 may be explained by enamine formation at first, followed by intramolecular Mizoroki-Heck reaction, rather than via a-arylation [39],... 

Hexachloroacetone acts as a source of positive chlorine on reaction with enamines, furnishing, after acid hydrolysis, good yields of a-chloro-ketones. Thus the regioselectivity of enamine formation dictates the regioselectivity of chlorination.Similarly, cyclic enamines react with N2F2 to give the a-fluorocyclo-alkanone after hydrolysis. ... 

Since enamine formation requires the loss of a molecule of water, enamine preparations are usually carried out in a way that allows water to be removed as an azeotrope or by a drying agent. This removal of water drives the reversible reaction to completion. Enamine formation is also catalyzed by the presence of a trace of an add. The secondary amines most commonly used to prepare enamines are cyclic amines such as pyrrolidine, piperidine, and morpholine ... 

Secondary amines react with aldehydes and ketones to form enamines. The name enamine is derived from -en- to indicate the presence of a carbon-carbon double bond and -amine to indicate the presence of an amino group. An example is enamine formation between cyclohexanone and piperidine, a cyclic secondary amine. Water is removed by a Dean-Stark trap (Figure 16.1), which forces fhe equilibrium to the right. 

The same conditions applied to cyclic ketones fused with an aromatic core affords unexpected results. Silyl enol ethers are the primary products observed, and steric hindrance of the peri-H has been presumed to obstruct the enamine formation between the nitrogen and the carbonyl carbon, allowing for reversal of silylamine reactivity. Under these conditions, silicon attacks the oxygen electrophilically to give enol ether in good yield. 

Intramolecular nucleophilic substitution of fluorine led to the formation of the pyrrole ring in the above mentioned transformations. However, the C-arylation can precede the heterocyclization. For example, condensation of cyclic enamines 143 with perfluorobenzenes 142 gave fluorinated indoles 144 via formation of C-N and C-C bonds. The authors reported that initial C-arylation was in competition with an initial iV-arylation producing A-dialkylaminopoly-fluoroarenes. The C versus N arylation ratio was found to be dependent upon the nature of the enamine [55]. 

Conceptually, the acetone component could be replaced with any carbonyl conqmund containing an adjacent methylene groi which will undergo enamine formation. Carbonyl variations, iriiich we found to readily undergo this reaction widi 4-chloroaniline and BTF in dry acetonitrile, are aliphatic linear, branched and cyclic ketones, pyruvates, P-ketoesters, P-ketosulfones and 1,3-diones. Biacetyl did not provide product under these conditions. Aldehydes and acetophenones required pre-formation of the enamine intermediate prior to BTF addition and tended to proceed in lower yields. Eighty exanqiles were chosen to test steric, electronic and lipophilic properties. In cases where the carbonyl conqionent was unsymmetrical and could produce two isomeric enamines, multiple dihydropyridine products were formed. 

Imines (like carbonyl compounds that form enols) are in equilibrium with their tautomeric forms, enamines (Section 17-9). If we write this form for our oxime, we arrive at an aminocarbonyl compound that is poised to undergo fast intramolecular formation of another hemiaminal. Dehydration produces a new cyclic enamine, which, upon inspection, is nothing but a hydrated pyridine. Finally, the driving force of aromaticity facilitates the rapid loss of water and generation of the pyridine product. 

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