Aza-annulation reaction

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. 

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... 

Regioselective aza-annulation reactions have been achieved through the use of aryl substituted keto enamine substrates. Aryl substitution at the a-position of the enamine provides for regioselective imine-enamine tautomerization at the non aryl (i carbon. Early studies in this area compared the utility of pyrrolidine enamine versus benzyl imine derivatives of a-tetralone.8 In the absence of solvent, aza-annulation of 75 with acrylamide led to the formation of 76, but use of imine derivative 77 resulted in significantly higher yield of 76 (eq. 19).8 Similar reactions were observed between an aryl ethyl ketone and acrylamide (72% yield, dioxane, 70 °C) or acrylonitrile when catalyzed by AICI3 at 25 °C.33... 

Methyl acrylate (37) was used as a reagent for annulation with the phenyl imine derivative of acetophenone. For example, phenyl imine 78 was converted to 79 by treatment with 37 in the presence of AICI3 (eq. 20).34 The enamine formed from acetophenone (80) and NH4OAC was converted to 82 by combination with 81 (eq. 21).17 In the case of 81, the aryl substituent provided a steric and electronic hindrance to the aza-annulation reaction, but the reactivity of the reagent was enhanced by the combined effects of the C02Et and CN functionality. Due to the nature of the substituents on the intermediate dihydropyridone, dehydrogenation occurred to form pyridone 82. 

P-Diketone substrates have been valuable in the aza-annulation reaction with a,(J-unsaturated carboxylic acid derivatives, and both acyclic and cyclic (i-diketone species have been investigated. The simplest acyclic P-diketone, 150, underwent condensation reaction with BnNH2 to generate the... 

The seven-membered ring analog, 327, showed different properties than those observed for 324 (eq. 64).85 Complete regioselective formation of 328 was observed for the acryloyl or crotyl derivatives. In these aza-annulation reactions, the use of acid chloride reagents resulted in higher yields than the corresponding ethyl esters. 

Hydrogenation of this annulation product resulted in stereoselective formation of 340. In each of these examples, formation of a stereogenic center occurred, and this methodology was used as the ground work for asymmetric induction in the aza-annulation reaction (see Section 8). 

There has been increased use of acrylate reagents with an a-nitrogen substituent, and the corresponding aza-annulation reaction products were a-amido 6-lactams, which represented an interesting class of conformationally restricted peptide analogs. Oxidation of the dihydropyridones that resulted from aza-annulation led to the corresponding pyridones. 

Vinylogous urea substrates have also been used in the aza-annulation reaction to form 6-lactam products. This process was illustrated by the condensation of fi-keto amide 366 followed by aza-annulation with acryloyl chloride to give 367 (eq. 75).57-59 Catalytic reduction of the tetrasubstituted double bond led to stereoselective formation of 368. The products formed in this reaction were fi-enamino peptide units, and this chemistry can be extended to the preparation of tri-and tetrapeptide analogs. 

J-Enamino nitriles also serve as suitable substrates for aza-annulation reactions with various acrylate derivatives, and both acyclic and cyclic enamino nitriles have been used in this process for the construction of alkaloid skeletons. As illustrated in equation 80, substituted pyridone 390 was prepared in good yield through aza-annulation of enamino nitrile 389 with acryloyl chloride (64).57,59... 

Isoquinoline derivative 406 was smoothly converted to the emetine-related species 408 through the aza-annulation reaction with acrylonitrile and sodium ethoxide followed by hydrolysis of the intermediate imine 407 (eq. 82).100... 

Phosphonate groups also provided regiochemical control in the aza-annulation reaction. Condensation of 409 with BnNH2, followed by reaction with acryloyl chloride gave 410 in good yield (eq. 83).57 59 Catalytic hydrogenation of 410 was less efficient than the corresponding ester and amide derivatives and resulted in the formation of a mixture of diastereomeric products 411. 

Substrates in this section contain a stereogenic center, which was utilized to selectively generate additional asymmetry. Several important features of the aza-annulation reaction are illustrated in this section. In some examples, asymmetric carbon-carbon bond formation resulted from the aza-annulation process, while other aza-annulation reactions led to a 8-lactam skeleton with an asymmetric substituent attached to the ring, as seen for the synthesis of (-)-pumiliotoxin (eq. 2).5 In this case, asymmetry was not generated through aza-annulation, but rather, peripheral asymmetry directed diastereoselective reduction of the aza-annulation product. 

Development in the area of asymmetric aza-annulation reactions paralleled achievements in the analogous area of asymmetric Michael addition reactions with chiral imines.111 Induction of asymmetry has been primarily controlled through substitution at the nitrogen of the imine or enamine that becomes incorporated into the heterocycle. Restricted rotation of this asymmetric substituent led to preferred conformational isomers, which provided stereofacial bias for carbon-carbon bond formation. 

Asymmetric induction in the aza-annulation reaction through the use of a chiral auxiliary was pioneered by d Angelo and coworkers in their work with 456. Even though annulation was not accomplished with the use of methyl crotonate, crotonyl cyanide produced an equimolar mixture of 458 and 459 in moderate yield (Scheme 36).112 Both 458 and 459 reflect regioselective Michael addition at the most substituted cx-carbon. The vicinal methyl substituents that resulted from aza-annulation were oriented in a cis relationship. 

Enders and coworkers reported studies in which the RAMP and SAMP chiral auxiliaries were employed in the aza-annulation process (Scheme 39).1,4 Condensation of 179 with RAMP provided a route to the optically active enamino hydrazone 473, which was then metalated with nBuLi to generate the corresponding anion. Aza-annulation of 473 with 474 produced intermediate 475, which could be cyclized slowly (2 d) at 60 °C to give 476. Alternatively, heterocycle formation could be facilitated by an increase in reaction temperature (toluene, heat). Removal of the chiral auxiliary gave 477 in 50-52% overall yield from 179 in >99 1 enantiomeric purity. Substituents on the aromatic ring did not have a measureable effect on the yield of the aza-annulation reaction. 

Amino acid derivatives have also been explored as potential chiral auxiliaries in the asymmetric aza-annulation reaction. As reported for the Michael addition to acrylate derivatives, the reaction outcome has also shown sensitivity to the special balance of complementary steric demands of the methyl and phenyl substituents. The degree of diastereoselectivity in carbon-carbon bond... 

Substituted acrylate derivatives have also been employed in the asymmetric aza-annulation reaction (Scheme 40). Aza-annulation of 479b with crotonyl chloride (490) demonstrated several important features of this reaction.115 First, concomitant formation of two stereogenic centers gave 491 with high internal asymmetric induction, while high relative asymmetric induction resulted from the amine substituent. However, the presence of a methyl substituent at the (3-position of the acrylate derivative slowed the reaction significantly, and resulted in a poor yield. 

Studies of aza-annulation reaction with tetrasubstituted (3-keto amide substrates have also been performed. Investigations centered around those substrates that were analogous to the ester species described in Section 8.3. In general, the amide substrates were found to react 20-25% slower than their ester counterparts, and as a result, greater diastereoselectivity was observed.116... 

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