Regioselective aza-annulation

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). 

Equation 7 illustrates the regioselective aza-annulation of an unsymmetrical ketone with a 0-substituted acrylate derivative.1 Although the P-phenyl substituent served to retard the aza-annulation process, reaction of 28 with 29 proceeded due to double activation of the acrylate reagent by both the amide and cyano substituents. Regioselective formation of 30 was the result of steric... 

Prior to the above investigation, Hickmott had reported a study on regioselective aza-annulation with an unsymmetrical ketone.30 Treatment of 63 with 64 resulted in selective formation of 66 in preference to 67 (eq. 16). Formation of 66 was the result of conjugate addition of the thermodynamically favored enamine isomer, which led to formation of a quaternary carbon in this process. Treatment of 63 with crotonyl or cinnamyl chloride resulted in (V-acylation of the enamine to give the corresponding analogs of 65 without significant heterocycle formation. 

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... 

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

Aza-annulation with unsymmetrical p-diketone 156 resulted in regioselective generation of 157, which gave 158 upon reaction with acryloyl chloride in benzene (47%) or THF (96%) (eq. 33) 56.57,59 xhe reaction of cinnamoyl chloride with 157 in benzene gave 158 in 30% yield.56... 

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. 

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. 

A tandem aza-Wittig/heterocumulene-mediated annulation route was developed for the efficient production of 6,7,8,9-tetrahydro-benzothieno[2,3-r/]-l,2,4-triazolo[l,5-a]pyrimidin-10(3F/)-ones <05S1601>, and an amine oxide rearrangement was key to the regioselective preparation of pyrrolo[2,3-J]pyrimidines <0581164>. Hexahydro-2-phenacylidene-pyrimidines gave -lactam fused 8-aroyl-2,3,4,5-tetrahydro-7-hydroxy-6//-pyrrolo[l,2-a]py-rimidine-6-ones when treated with (COCl), in the presence of NaH <05IJH87>, and methyl... 

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