Aza-annulation

The Stork s aza-annulation method with acrylamide180,181 has been used frequently for the synthesis of six-membered nitrogen-containing heterocycles. Recently, this reaction was applied to the synthesis of 315 and 316 from protected enamine 314 (equation 68)182. Compound 315 is a key intermediate in the synthesis of the alkaloid Huperzine A and its analogues. 

Scheme 41 Coupling- mmation-aza-annulation four-component synthesis of 5-acyl dihydro-pyrid-2-ones 72...

Mechanistically, the sequence commences by coupling of the (hetero)aroyl chloride 7 and the aUcyne 4 to give the alkynone 8 (Scheme 43). Upon addition of the tryptamine derivative 73 the enaminone 75 is obtained. Finally, the addition of the a, p-unsaturated acid chloride 71 triggers the aza-annulation reaction to furnish the acyliminium ion 76 which terminates the sequence by a Pictet-Spengler cyclization. 

Scheme 42 Coupling-amination-aza-annulation-Pictet-Spengler four-component synthesis of tetrahydro-P-carbolines 74...

In order to rationalize the exclusive diastereoselectivity of the sequence, two mechanistic pathways can be proposed for the stereogenic aza-annulation step... 

The overall yields for the stepwise reaction with intermediate isolation of the enaminone 75 after the coupUng-addition sequence and its subsequent aza-annulation-Pictet-Spengler transformation fie in the same range as for the coupling-amination-aza-annulation-Pictet-Spengler sequence. However, avoiding the isolation and purification of the intermediate p-enanfinone favors the application of the one-pot approach. 

Karpov AS, Oeser T, Miiller TJJ (2004) A novel one-pot four-component access to tetrahydro-P-carbolines by a coupling-amination-aza-annulation-Pictet-Spengler sequence (CAAPS). Chem Commun 1502-1503... 

Benovsky P, Stephenson GA, Stille JR (1998) Asymmetric formation of quaternary centers through aza-annulation of chiral P-enamino amides with acrylate derivatives. J Am Chem Soc 120 2493-2500... 

Paulvannan K, Chen T (2000) Solid-phase synthesis of l,2,3,4-tetrahydro-2-pyridones via aza-annulation of enamines. J Org Chem 65 6160-6166... 

Phosphonylated. V-bciizyI enamine, formed from benzylamine and diethyl 2-oxopropylphosphonate, undergoes aza-annulation with acryloyl chloride in refluxing THF to provide a phosphonylated unsaturated lactam in 72% yield. - Subsequent hydrogenation generates a 78 22 ratio of diastereomeric products in 67% yield (Scheme 7.114). These compounds represent an interesting class of rotationally constrained P-aminophosphonic acid analogues. 

Paulvannan, K., and Stille, J.R., Conformationally restricted P-amino acid isosteres prepared through regioselectivity controlled aza-annulation. Tetrahedron Lett., 34, 8197, 1993. 

Reactions of nitroalkenes and enamines take place not only in good chemical yields but also in excellent diastereomeric yields (>W%) . A topological rule has been formulated for carbon-carbon bond-forming processes between prochiral centres in enamines and nitroalkenes as well as other systems The reaction of enamines and imines with acrylamide results in aza-annulation ° . Other electrophilic alkenes which have been us to alkylate enamines and the products used in hetero- or carbocyclic synthesis include ethyl /5-nitroacrylate, where reaction occurs beta to the nitro not the ester group, 2- phenylseleno)prop-2-enenitrile [CH2 = C(SePh)CN] , phenyl a-phenylselenovinyl sulphone [CH2 = C(SePh)-S02Ph] and phenyl a-bromovinyl sulphone. An electrophilic allene, phenylsulpho-nylpropadiene, has also been used to alkylate enamines (Scheme 44). 

Racemic prosopinine (222) was synthesized using an aza-annulation to form the piperidine ring, and homologation of the lactam to prepare the alkyl side chain [499],... 

Several recent syntheses of 251 have been reported. Deoxymannonojirimycin was synthesized using the reaction of 5-keto-D-mannose with diphenylmethylamine and sodium cyanoborohydride as a key step [565]. Another synthesis of 251 used D-mannitoI as a starting material [571], while yet another began with D-glucono-6-1 actone [572]. Finally, racemic 251 was synthesized using an aza-annulation to form the piperidine ring [573]. 

Aza-Annulation of Enamine Related Substrates with a,b-Unsaturated Carboxylate Derivatives as a Route to the Selective Synthesis of d-Lactams and Pyridones... 

Six-membered nitrogen heterocycles are found in a wide variety of naturally occurring alkaloids, and are often incorporated into the design of biologically active pharmaceutical products. Of the many ways to construct these heterocycles, the aza-annulation of enamine substrates with a,(J-unsaturated carboxylic acid derivatives has been a versatile and efficient method for the formation of dihydropyridone and pyridone products. The synthetic utility of this approach has led to incorporation of aza-annulation methodology as a key step in the synthesis of a number of interesting heterocyclic molecules. 

The two approaches used most often for aza-annulation are shown in Scheme 1. In each case, the initial reaction in the aza-annulation process involves incorporation the nitrogen atom. 

An alternative approach to aza-annulation again utilizes condensation to form an enamine, which is subsequently. V-acylated (Scheme 2). The resultant acrylenamide is a stable, isolable intermediate which can be efficiently converted to the corresponding dihydropyridone through photochemical processes. However, application of this photochemical methodology has been the subject of previous reviews, and will not be discussed here.1 Alternative routes for conversion of the acrylenamide to the dihydropyridone, through the use of Lewis acids, protic acids, and heat,... 

The electronic and steric effects observed for the various carbonyl substrates and acrylate reagents used in this reaction clearly illustrate the pivotal role of the conjugate addition step in the aza-annulation process (Scheme 3). The nature of the carbonyl derivative is highly dependent upon the... 

Regioselective aza-annulation with acrylonitrile met with somewhat limited success. Aza-annulation of 10 with acrylonitrile resulted in the formation of a 75 25 mixture of 11 (eq. I).4 The mixture of 11 was taken on to 12, which was used in the synthesis of optically active 2,2 -bipyridines and 1,10-phenanthrolines. A more selective route to 11a was reported, and this approach started from optically pure (/ )-(+)-pu egone (13, eq. 2).5 In this case, regioselective Michael addition to give 14 was accomplished due to the presence of the isopropylidene moiety of the (/ )-(+)-pulegone. Subsequent rhodium catalyzed deisopropylidenation, nitrile hydration, and cyclization gave lib, which was taken on to (-)-pumiliotoxin C (15). 

Aza-annulation of enamine substrates with acrylamide (20) occurred under milder reaction conditions. Treatment of 19 with 20 in dioxane at reflux (100 °C) resulted in the efficient formation of 4b with reported yields of 70%7 and 83%8 (eq. 4). Subsequent study of this reaction led to the quantitative formation of 4b and 5b reported as a 50 50 mixture of the regioisomeric alkenes.9 This methodology was also extended to aza-annulation of the cyclopentanone enamine with 20 (72%).9 The analogous reactions have been performed by the combination of 20 with the benzyl imine (77%)8 or the propyl imine (18%)10 of cyclohexanone (lb). Limitations arose when the acrylamide was / -substituted or had a substituent at the [3-position (crotylanilide).9 When reagents with these features were used, the reaction did not proceed. 

Both symmetrical and unsymmetrical ketones have been utilized in synthetic applications of the aza-annulation reaction of enamine derivatives with acrylamides. The most efficient use of this methodology involved generation of the enamine from the symmetrical ketone 21 (eq. 5).11 Aza-annulation with this enamine led to the formation of 22 as an 85 15 mixture of the regioisomeric tetra- and trisubstituted alkenes (b and a), respectively, which were then oxidized to the corresponding pyridone 23. Formation of intermediate 23 was a key to the synthesis of the... 

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