Enamines, bicyclic

Another interesting fact to be noted is that the bicyclic enamine (87) and its pyrrolidine analogue failed to undergo reduction with 98% formic acid, whereas the pyrrolidine enamine of 2-bicyclo[2.2.1]hepten-5-carboxalde-hyde (94), which exists largely in the transoid form (49), was readily reduced to (95). However, the saturated amine-substituted norbornane can be obtained directly from norbornanone under the more vigorous conditions of the Leuckart reaction (49a). 

The cycloaddition of sulfene to bicyclo[2.2.1]heptyl enamines is stereospecific, addition coming from the exo side (156). However, the steric preference of cis and trans isomers relative to the four-membered ring generated does not seem as strong, at least in the case of the addition of chlorosulfene (CICH = SOj) to bicyclic enamines, where a mixture of stereoisomers is obtained (157). 

When the 1-monoximes or dioximes of 4-acetyl-l-tetralones are hydrogenated in the presence of palladium, mixtures of diastereoisomeric 1-aminotetralones are formed. The m-aminoketone isomers readily form dehydrobenzoisoquinuclideines (3,4-disubstituted-1,4-dihydro-1,4-ethano-isoquinolines). Quaternary immonium salts prepared from these bicyclic imines are then converted by bases to bicyclic enamines [2,4-disubstituted-3-alkylidene-1,4-ethano-1,2,3,4-tetrahydroisoquinolines (25)]. 

The bicyclic enamine 383 deviates from the above reaction scheme when interacting with diphenyl cyclopropenone the betaine 384 formed initially does not iso-merize to the amide 385, but to the a-amino cyclopentenone 386, possibly favored by steric reasons248. ... 

Heterocyclic azides react with enamines31 1,8-naphthyridine azides give isolable triazolines.220 The bicyclic enamine 2-N-morpholinonorbornene with aryl and benzoyl azides furnishes stable, crystalline aminotri-azolines.39,213 Likewise, alkyl azidoformates yield stable triazolines.30,221... 

With the procedure for constructing the quaternary carbon stereocenter in hand, the conversion of the ris-form to the trans form was explored in accordance with the synthetic plan shown in Scheme 9. The ketone moiety of the 1,4-conjugated adduct 61 was protected by an acetal group, followed by decarboxylation of compound 65 using sodium ethylthiolate to yield lactam trans-62 and cis-62 as an 8 1 diastereomixture [31]. The reason why the lactam trans-62 was obtained as a major product is that the subsequent protonation after decarboxylation proceeded kinetically. This assertion is supported by experimental results in which the trans- and cis-lactam diastereomixture (8 1) in ethanol was refluxed in the presence of potassium hydroxide to afford a 1 5 mixture [15,32,33]. The mixture of the lactam trans-62 and cis-62 was reduced with DIBALH, followed by treatment with sodium hydroxide to give bicyclic enamine 63. The kinetic iminium salt prepared from bicyclic enamine 63 with hydrochloric acid was reduced with sodium cyanoborohydride, leading to the frans-decahydroisoquinoline structure [22], The acetal moiety of the resultant 67 was removed to provide the objective ketones 68a and 2c. This method enabled the construction of the tra s-decahydroisoquinoline structure without an intermediate resembling the neurotoxic MPTP, and in fewer steps. 

A simple efficient synthesis of the bicyclic enamine 31 (95%) by distillation of the ro-carboxyalkyllactam 145 from soda lime seems to be a variant of the classical Ruzicka cyclization of dicarboxylic acids (83CJC2016). 

Bicyclic enamines were prepared using the bicyclic ketone, tris(dimethylamino)borane, dimethylamine and potassium carbonate in an autoclave heated to 95-105 °C494. 

Albeit no examples of a stable bicyclo[3.2.0]hept-5-ene obtained by a metal-catalyzed reaction from a 1,6-enyne have been observed, interestingly, following earlier work done with PtCl2 as catalyst,it was found that the gold-catalyzed reaction of 1,6-ene-ynamides gives cyclobutanones (equation 42), in a process that probably proceeds through unstable bicyclic enamines. 

Synthetically versatile [3.1.0] and [4.1.0] bicyclic enamines have been prepared by intramolecular oxidative cycloamination of N-unsubstituted aziridine-containing tethered alkenes <2006JOC6067, 2006ACR194, 2003JA14242>. This process is initiated by iV-bromosuccinimide (NBS) followed by base-mediated elimination of HBr to afford highly strained exo-bicyclic enamines (Scheme 57). 

Allyl amines 611 and pyrazoles 612 could be obtained by hydrazinolysis of 2-ketoaziridines 610 (Equation 127) <2006TL255>. A variety of aziridines, including N-unprotected, N-substituted, as well as bicyclic enamine and aminal types, were transformed into diversely substituted linear or cyclic products. The hydrazinolysis of homochiral aziridines proceeded without racemization and usually allylamines are obtained in greater yields than the pyrazoles in each case. Addition of hydrazines to /3-hydroxy acylsilanes 613 afforded 3-trimethylsilyl pyrazoles 614 (Equation 128) (TMS = trimethylsilyl group) <2000TL9791>. 

Lhommet and co-workers synthesized (- )-436 by the route shown in Scheme 66 [422). Wittig-Homer reaction between the 2,5-rrans -disubstituted pyrrolidine aldehyde 509, made from (S)-pyroglutamic acid [423), and the protected keto-phosphonate 510 introduced all the skeletal carbon atoms of the target. Simultaneous hydrogenation and //-deprotection of enone 511 gave the aminoketone 512, which spontaneously formed the bicyclic enamine 513 in 98% yield when exposed to trifluoroacetic acid—apparently the first time that such an intermediate has actually been isolated en route to indolizidines. Reduction with sodium cyanoborohydride in acidic medium acid produced a diastereomeric mixture (92 8) of (- )-436 and (+ )-437. The former was isolated in 84% yield after chromatography on silica gel. The overall yield of this 15-step sequence was 8% based on (S)-pyroglutamic acid. 

This method may be used in the case of aliphatic methyl ketones which give, under acidic conditions, the products of aldol condensation, while higher homologues require a very long tirne . N-Methylation of dihydroisoquinolines [32, R = H, Ph, R = R = Me R = H,R = Me,R = Et R R = (CH2)s] with methyl iodide gave enamines JJ186 bicyclic enamine 34 has been prepared by alkylation of the imine 35 followed by treatment of the iminium salt with base . ... 

Dehydrogenation of amino alcohols of type 88 affords cyclic compounds 89, the formation of which can be explained by an intramolecular nucleophilic attack of the hydroxyl group on the formed enamine salt . Several cyclic " and bicyclic enamines were prepared by mercuric acetate oxidation. 

When treated with acrylic acid, bicyclic enamine 195 was converted to the tricyclic vinylogous imide 196, which was then incorporated into the synthesis of the Lycopodium alkaloid annotinine (197) as well as an annotinine degradation product (eq. 42).67... 

Paquette72 has described experiments designed to assess the stereoselectivity of the sulfene-enamine reaction. He found that sulfenes reacted stereoselectively with bicyclic enamines giving a single product, where the sulfene attacks the bicyclic enamine from exo side in most of the cases. Stephen and Marcus190 further supported this result when they... 

As with reductive aminations and imine reductions that employ sodium cyanoborohydride, a significant number of enamine reductions now are reported to afford products stereoselectively. Two representative examples include a reduction and subsequent transformation of a bicyclic enamine (eq 47) and the reduction of a highly functionalized enamine (eq 48) In both instances the... 

Use of carbocations to initiate the Schmidt reaction has been the subject of several investigations during the last two decades. The cationic intermediate can be generated from secondary or tertiary alcohols or from olefins. The first example was described by the Pearson group for the synthesis of a bicyclic enamine. However, various drawbacks still remain when carbocations are involved limited stability of the intermediates, low selectivity, and the need... 

Monocyclic amino-ketone salts can be converted via their bicyclic iminium salts to give bicyclic enamines (Scheme 2). The reaction proceeds well to give... 

A. Carbocyclic - A few new methods are available to prepare the steroidal skeleton. For tne most part, these involve variations of the previously reported methods for the total synthesis of steroids. Racemic equilenin is prepared stereo-specifically starting with 2-bromo-6-methoxynaphthalene and the i "butyl enol ether of 2-methyl-l,3-cyclopentanedione. Estrone was prepared from the cheap natural product eugenol the key intermediate m-methoxyallylbenzene. Progress toward the total synthesis of terpenes, specifically the pentacyclic triterpene alnusenone, is reported. The synthesis of B-nor, B-nor-D-homo, or normal steroids by the use ot an electrophilic reagent on a bicyclic enamine is recorded. In addition, a bicyclic intermediate can be converted into a D-homo-8g-methyl-B-norestrane. ... 

B. Heterocyclic - A number of ring-aza steroids are conveniently prepared by total synthesis. The 6,7-diaza steroid was prepared from a bicyclic enamine intermediate with m-methoxydiazonium fluoroborate which was used to introduc the adjacent nitrogens prior to completion of the rest of the steroidal skeleton. The enamines of g-tetrolone and 6-methoxy -tetralone were treated with a-bromoacetate and then treated with hydrazine hydrate followed by either malonyl dichloride or propiolactone to give 13,14-diozo steroids. By this sequence the D-homo-diaza steroidal system could also be prepared.The 8,13-diazaestranes were prepared by... 

The route employed to prepare indanone 51 involved the cycloaddition-hydrolysis-aldol sequence shown in Scheme 3.9. Accordingly, condensation of cyclopentenone 52 with ynamine 53 (84) afforded the bicyclic enamine 54 which was converted to indanones 51 and 55 by hydrolytic cyclobutane ring opening followed by intramolecular aldol condensation. Interestingly, treatment of 54 with aqueous formic acid yielded indanone 51 which has stereochemistry complementary to that at C(15) and C(20) in reserpine. In contrast, hydrolysis of this substance with aqueous hydrochloric acid afforded the trans-fused indanone 55. Subsequent to this work, the Ficini group found that esterification of 51 followed by photochemically induced addition of methanol afforded adduct 56 which has four of the reserpine stereocenters in place (23). While no further work on this problem has been reported, these preliminary investigations demonstrate a novel use of [2 -h 2] photocycloaddition chemistry in potential approaches to yohimbane alkaloid synthesis. 

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