Cyclic enamines, synthesis

The reduction of enamides (62-73) has been applied primarily to the synthesis of cyclic enamines (74-76), but also to acyclic enamines (77). 

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 synthesis of cyclic enamines through intramolecular reactions offers further structural flexibihty (129-135). 

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

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). 

The benzoylation reaction was applied to cyclic enamines (384) and the synthesis of a heptazulene (385). 

Scheme 39 Synthesis of tetracyclic skeletons 179 from the dihydronaphthalene-annelated pyranylidene complex 178 and cyclic enamines 174 [29]...

The DA reaction of 5-acetyl-3-methylthio-1,2,4-triazine with cyclic enamines has been used in the total synthesis of new indazolo[2,3-a]quinolizine alkaloids <06T5736>. 

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

MUller reports a four component, one-pot synthesis of pyridines <02TL6907>. For example, aryl halide 15 and propargylic alcohol 16 were combined in the presence of copper and palladium to afford enone 17. The addition of cyclic enamine 18 led to Michael addition and the subsequent cyclocondensation was achieved by adding ammonium chloride and acetic acid (19—>20). Other multicomponent approaches to substituted pyridines have been reports by Litvinov <02RCBIE362>, Elkholy <02SC3493> and Veronese <02T9709>. 

Lithiated cyclic enamines 691 " 5 996 and amidines 692989,997 have been prepared by deprotonation of the corresponding heterocycles with f-BuLi in THF at — 78 °C, being allowed to react with several electrophiles. This methodology has been applied to the synthesis of pyrrolidine and piperidine derived compounds, intermediates 691 and 692 acting in these cases not as acyllithium equivalents. 

Evans and Domeier189,438 have described a general method for the synthesis of a variety of cyclic enamines from imine anions. An imine was added to a cooled ( — 30 °C) solution of lithium diisopropylamide in THF and, after 15 min, l-chloro-2-iodoethane (or l-chloro-3-iodopropane) was added in one portion (equation 28). This method was used by Bruno and coworkers439. 

Cyclic enamines, ynamines and ureas, preparative methods 86MI12. Design of free radical reactions for the synthesis of heterocycles 88S417, 88S489. 

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. ... 

The answer is to use a protected form of the unsaturated ketoaldehyde 75 instead and build the pyridine afterwards.13 The synthesis of the cyclic enamine 73 appears as a problem in the workbook. Conjugate addition of the enamine 73 gives one enolate 77 that equilibrates with the other 78 cyclisation now gives 79. Deprotection reveals the aldehyde 80 that exists as a mixture with the hemiacetal of its enol 81. The 6/5 ring junction is formed preferentially syn while the third chiral centre is lost in equilibration with 81. 

A synthesis " (Scheme 16) of (+)-quebrachamine (102) employs the cyclic enamine (103) which, after introduction of an acetic ester side chain by enamine... 

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... 

A variety of secondary cyclic and acyclic amines may also couple with vinyl bromides catalyzed by Pd/BINAP or L13.117 This serves as a useful alternative for enamine synthesis. The vinylation of primary amines gives enamines which immediately tataumerize to the corresponding imine. Competition experiments reveal that vinyl bromides react in preference to aryl bromides. Vinyl chlorides are also aminated to give enamines or amino dienes118 as well. These may then serve as useful nucleophiles or dienes for Diels-Alder reactions. 

Some other preparative methods have also been reported in the literature <76RTC220,90TL131>. A more general synthetic method is the condensation reaction between 2-arylaminonicotinic acid chloride and cyclic enamines, one example being the synthesis of compound (104) (Scheme 7) <86MI... 

SCHEME 13 Synthesis of (-)-deoxocassine (2) using cyclic enamine. 

As is shown in Scheme 13.5, the authors found that treatment of enol ether 32 with TEA resulted in both the removal of the Boc group and hydration of the enol ether to give lactol 33. After removal of the DNs (2-(2,4-dinitrophenyl)ethoxycarbonyl) group with pyrrolidine, the hemiacetal moiety reacted with the prereleased secondary amine to produce the cyclic enamine 34. Subsequently, the Michael addition of the enamine to the unsaturated ester and Mannich reaction of the indole to the resultant iminium ion furnished the desired 35 as the sole isomer. Finally, a regioselective dehydration and stereoselective epoxidation, followed by a deprotection step, gave the desired lower segment (-)-taberhanine, which was used for the total synthesis of conophylline. 

Cyclic compounds continue to find use as chain extenders. 5-Methylcyclo-hexane-l,3-dione has been used for the synthesis of 3-methyl- and 3,6-di-methyl-tridecanoic ester, and the enamine synthesis, usually utilizing cyclopentanone or cyclohexanone, has been extended to the use of cyclo-decanone and cyclododecanone. Reaction occurs through a cyclobutanone... 

Uleine belongs to a relatively small group of indole alkaloids lacking the usual two-carbon chain biogenetically derived from tryptophanJ The synthesis of uleine outlined below illustrates one approach to this class of compounds involving isomerization of the key indol-2-yl-A -piperideine ketone (A) to a A -piperideine, followed by protonation of the cyclic enamine to an immonium species (D) and Mannich-type closure on the indole /3-position for formation of ring C. 

Synthesis of enamines from carboxylic acid amides via 1-alkoxyazomethinium salts and amide acetals Cyclic enamines via lactam acetals... 

Thermal and photochemical electrocyclic reactions are particularly useful in the synthesis of alkaloids (W. Oppolzer, 1973,1978 B K. Wiesner, 1968). A high degree of regio- and stereoselectivity can be reached, if cyclic olefin or enamine components are used in ene reactions or photochemical [2 + 2]cycloadditions. 

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