Intramolecular enamine cyclizations

There are several ways to synthesize these alkaloids. The way developed in the author s laboratory, an intramolecular enamine cyclization, not only allows the synthesis of the naturally occurring stereoisomers but also the others by variation of the starting materials and/or reaction conditions, and, by the same procedure, the alkaloids of the gephyrotoxin class may also be obtained (refs. 17, 18, 19). Results on the antimicrobial activity of the gephyrotoxins are,however, not yet available. 

The formation of five- (362) and six- (581) membered vinylogous lactams and pyrroles by intramolecular enamine acylations has been accomplished in some examples by formation of the cyclization precursor through an initial enamine exchange (362). 

An iminium ion-alkene cyclization has been employed to assemble the phenylmorphan ring system (Scheme 26). The conversion of enamine (64) to (66) was suggested to arise by 1,5-hydride migration of an initially formed bicyclic cation (65). Direct intramolecular ene cyclization of the iminium ion (67) produced by protonation of (64) provides an alternative rationale for the net cis addition to the terminal alkene that occurs in this transformation, and avoids postulating the intervention of a relatively unstable fully formed secondary carbocation. 

Intramolecular enamine formation between an aldehyde or ketone and the nitrogen atom of a piperidine ring can serve as the key step in the preparation of quinolizidine derivatives. For example, the ketal (184), prepared by double addition of the lithio derivative (183) to 6-methoxy-2,3,4,5-tetrahydropyridine, can be easily cyclized to the quinolizidine derivative (185) by double acid-catalyzed deprotection, cyclization, and dehydration (Scheme 31). These reactions constitute the first steps of a stereocontrolled total synthesis of the alkaloid ( )-porantherine <87JA4940>. 

The ease with which cyclopent-2-enones are prepared by intramolecular aldol cyclizations of 1,4-diones has been much exploited in synthesis. A particularly attractive route to y-keto-aldehydes has been described by Martin etal, which has as a key stage the reaction between 2,3-dibromopropene (functioning as a 2-oxopropyl synthon) with an enamine (Scheme 11). In a similar type of approach to... 

An intramolecular application of this type of catalysis was included in his first publication on this process, whereby the SOMO activated enamine cyclized onto an unactivated alkene using catalyst 103 (Scheme 1.26). 

The mechanism proposed by the authors is depicted in this scheme. A first equivalent of a,fS-unsaturated aldehyde was activated as its corresponding iminium ion by chiral diphenylprolinol trimethylsilyl ether and then underwent the first nitromethane Michael addition to afford a nitroalkane enamine intermediate. Subsequent hydrolysis generated a nitroaldehyde intermediate and the catalyst, which could promote a second Michael addition with a second equivalent of iminium, furnishing an enamine intermediate. This enamine reacted via an intramolecular aldol cyclization to give a novel iminium intermediate. After hydrolysis, the catalyst was regenerated, and the intermediate alcohol could be dehydrated to afford the final products. 

This facile and efficient thiophene formation can be rationahzed by primary S-alkylation of 33 to give the iminium cation 35 followed by deprotonation (HBr ehmination) to the ketene-S,N-acetal 36, which cyclizes by intramolecular enamine addition to the carbonyl group (36->-37) intermediate 37 aromatizes to the products 34 by H2O elimination. Thiomorpholides (33) are easily obtained by Willgerodt-Kindler reaction of acetophenones with sulfur/morphoHne [81]. 

In a tentative mechanistic proposal, formation of a carbocation intermediate 91 from the benzylalcohol is assumed, which reacts with the FeCls-acivated p-ketoesterenolate to give the benzylated acetoacetate 92. ZnCl2-promoted cyclization by intramolecular enamine formation (92 -> 93) and dehydrogenation of 93 by air oxygen provide the quinoline 90. 

Michael addition via iminium catalysis and subsequent intramolecular Mannich cyclization via enamine catalysis allows the formation of carbocycles with high efficiencies (Scheme 7.27) [44]. 

Subsequent oxidation might lead to the formation of the bisimine 68, which tautomerizes to its corresponding enamine 69. Next, intramolecular tandem cyclization may lead to the formation of the tetracyclic lycodane skeleton... 

Stereochemical positioning of a functional group, relative to a separate enamine moiety in the same molecule, can be done in such a manner that a simple intramolecular alkylation or acylation will cause cyclization. Such intramolecular cycloalkylations with alkyl halides have been reported 107,108). Inftamolecular cycloacylations of enamines with esters 109, 110,110a) and with nitriles 110a,l 11,111a) have also been observed. 

While esters do not usually react with enamines and can, in fact, be substituents in the azeotropic preparation of enamines, they can be used in acylation reactions when these involve intramolecular cyclizations. Such reactions have been observed even at room temperature when they lead to the formation of five- and six-membered vinylogous lactams (362). Applications to precursors for azasteroids (40S) and alkaloids (309,406) are key steps in synthetic sequences. 

The intramolecular cyclization of enolate of l-tryptophyl-3-((3-ketobutyl) pyridinium bromide (160) afforded enamine 161, which undergoes stereoselective acid cyclization with cone. HCl to give the pentacyclic ketone 162 (Catalytic hydrogenation of 162 led to (d,l)-pseudoyohimbone (163) (76JA3645). Again, H3-H15 were found to have the tmns configuration in 162. 

It is believed (54IZV47 72JPR353) that in the first stage the intermediate 282 is formed due to the addition of the CH acid to the enamine moiety with subsequent elimination of amine. The enol form of the intermediate 282 undergoes cyclization in two fashions, depending on the nature of substituent X. In the case of the ester (X = OMe) the attack is directed to the cyano group to form substituted 3-methoxycarbonyl-I//-pyridin-2-one (283) or its tautomer (2-hydroxy-3-methoxycarbonylpyridine). With the amide (X = NH2) intramolecular condensation leads to 3-cyano-l//-pyridin-2-one and its hydroxy tautomer (284). 

Thus, simple ketones or aliphatic aldehydes may be successfully used as starting materials in the CSIC (Carbanion mediated Sulfonate Intramolecular Cyclization) reaction. Ai-alkylsulfonamides could be also cyclized under CSIC conditions (99T(55)7625) affording the spiroisothiazoline 79. By treatment with TMSCl, Nal in acetonitrile at r.t., hydrolysis of the enamine and formation of the corresponding keto derivative 80 was obtained. 

The intramolecular Heck reaction presented in Scheme 8 is also interesting and worthy of comment. Rawal s potentially general strategy for the stereocontrolled synthesis of the Strychnos alkaloids is predicated on the palladium-mediated intramolecular Heck reaction. In a concise synthesis of ( )-dehydrotubifoline [( )-40],22 Rawal et al. accomplished the conversion of compound 36 to the natural product under the conditions of Jeffery.23 In this ring-forming reaction, the a-alkenylpalladium(n) complex formed in the initial oxidative addition step engages the proximate cyclohexene double bond in a Heck cyclization, affording enamine 39 after syn /2-hydride elimination. The latter substance is a participant in a tautomeric equilibrium with imine ( )-40, which happens to be shifted substantially in favor of ( )-40. 

Alternatively, the enamine portion may be located in the Aralkyl chain. For instance, piperidines bearing a 7-chloro substituent yielded quinolizidines 263 through a conjugate addition of the nitrogen atom to acetylenic sulfones followed by an intramolecular alkylation (Scheme 55) <2000JOC4543>. Other cyclizations that are summarized below used as starting materials piperidine derivatives obtained by similar conjugate additions to vinyl sulfones (see Section 12.01.9.3.6). 

The reaction of 2-polyfluoroalkylchromones (e.g., 323) with l,3,3-dimethyl-3,4-dihydroisoquinolines (e.g., 324) gave zwitterionic 6,7-dihydrobenzo[ ]quinolizinium compounds such as 326 (Scheme 70). The mechanism proposed for this transformation involves an addition-elimination displacement of the chromane heterocyclic oxygen by the enamine tautomer of the dihydroisoquinoline, followed by intramolecular cyclization of the intermediate 325 <20030L3123>. 

Most of the work on the C-N bond-forming crosscoupling reactions has concentrated on the formation of aromatic C-N bonds. Recent studies show that the application of cross-coupling reactions to alkenyl halides or triflates furnished enamines (Scheme 19) (for palladium-catalyzed reaction, see 28,28a-28d, and for copper-catalyzed reaction, see 28e-28g). Brookhart et al. studied the palladium-catalyzed amination of 2-triflatotropone 109 for the synthesis of 2-anilinotropone 110.28 It was found that the reaction of 109 proceeded effectively in the presence of racemic BINAP and a base. As a simple method for the synthesis of enamines, the palladium-catalyzed reactions of alkenyl bromide 111 with secondary amine were achieved under similar conditions.2841 The water-sensitive enamine 112 was isolated as pure compound after dilution with hexane and filtration through Celite. The intramolecular cyclization of /3-lactam 113, having a vinyl bromide moiety, was investigated by Mori s... 

The existence of diazonium ion 95b is confirmed by controlled potential oxidation of 95 in CH3CN-O.I mol/1 Bu4NPF6 solution in an undivided cell [134]. The diazonium ion 95b reacts with the cathodically formed 3-aminoc-rotononitrile in a paired-type electrolysis to form enamine 96 which undergoes either hydrolysis to give 98 or oxidative intramolecular cyclization to give triazole 97 (Scheme 53). 

Activated enamines are expected to be useful precursors for 1,2,3-dithiazoles. In fact, the reaction of /i-ketoenamines with sulfur monochloride gave 5H-l,2,3-dithiazoles 125 via intramolecular cyclization of an intermediate N-thiosulfinylamine with the possibility of its isolation (1981H803,1981BCJ3541 Scheme 62). 

Enamine 106 (derived from Meldrum s acid), in a process of mono-decarboxylating transesterification and subsequent intramolecular alkylation, is cyclized to form enamino ester 107 (90H(31)1251). The direct route by flash vacuum thermolysis does not work in the case of 6/7 bicyclic 107. Methylene compound 109 originates (analogously to bicyclic 40b) from... 

A Piperidine acts both as a nucleophile and as a base. First it combines with the pyrylium cation at C-2, forming an adduct which then ring opens, deprolonates and tautomerizes to an enamino ketone (Schema 4.3), This product cyclizes through an intramolecular reaction between the enamine unit and the carbonyl group, followed by dehydration to form the phenylpiperidine. 

A recent report on trifluoromethylsulfenylation of (3-keto acids and derivatives describes isolation of 29 in good yield from reaction of 27 with trifluoromethyl-sulfenyl chloride (Scheme 6.10). Mechanistically, this was rationalized via electrophilic attack of trifluoromethylsulfenyl chloride on the enamine tautomer 27a to generate 28 followed by intramolecular cyclization through the imide oxygen with concomitant loss of CF3SH to produce 29. The product was characterized spectroscopically. 

This type of interesting phenomenon has also been observed in non-organometallic reactions. The Hajos-Wiechert intramolecular aldol reaction of the triketone to the bicyclic aldol exhibits a nonlinear relation between the enantiomeric purity of the (S)-proline catalyst and the en-antioselectivity (Scheme 44) (75). With the partially resolved amino acid, the cyclization affords the product in an ee lower than anticipated. The reaction occurring via an enamine intermediate again may be interpreted in terms of participation of two proline molecules in the productdetermining transition state. 

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