(4+3) Cycloaddition Reactions of N‐Alkyl Oxidopyridinium Ions

Abstract

N-Methylation of methyl 5-hydroxynicotinate followed by reaction with adiene in the presence of triethylamine afforded (4+ +3) cycloadducts in good to excellent yields.H igh regioselectivity was observed with 1-substituted and 1,2disubstituted butadienes.D ensity functional theory calculations indicate that the cycloaddition involves concerted addition of the diene onto the oxidopyridinium ion. The process provides rapid access to bicyclic nitrogenous structures resembling natural alkaloids.

Pathway Bifurcation in the (4 + 3)/(5 + 2)-Cycloaddition of Butadiene and Oxidopyrylium Ylides: The Significance of Molecular Orbital Isosymmetry

“…A point that remains to be addressed is why a mixture of products is not observed in the related (4 + 3)-cycloaddition of Krenske and Harmata. 38 The improved product specificity is likely due to the estersubstituent of the oxidopyridinium reactant, Harm-OP (Scheme 4). 56 In contrast to the cycloaddition of OP, the exo transition state, Harm-TS-3, is preferred, leading exclusively to the (4 + 3)-product.…”

“…These data are consistent with the product distribution observed experimentally by Sammes and Street. 37 The results also provide an insight into the work of Krenske and Harmata, 38 suggesting the presence of the ester-substituent suppresses any bifurcating behavior in the related oxidopyridinium system. The coincidence of secondary orbital interactions and PTSBs, and the elaboration of known bifurcating reactions to new orbital isosymmetric systems, will greatly assist in the location of latent pathway bifurcations.…”

“…The insights discussed above led to the search for reaction pathway bifurcations in oxidopyrylium cycloadditions. While the reaction has been used extensively in synthesis, 30−36 two reports by Sammes and Street, 37 and Krenske and Harmata (deploying the related oxidopyridinium ylides), 38 attracted our attention for their use of a butadiene reactant (Scheme 2). In some of the earliest work on oxidopyrylium cycloadditions, Sammes and Street noted that dienes, when reacted with OP (generated in situ from the deprotonation/elimination of acetate Pro-OP), yielded both the (5 + 2)-and (4 + 3)products Prod-2 and Prod-1, with a preference for the (4 + 3)products.…”

“…More recently, Krenske and Harmata have documented the exclusive (4 + 3)cycloaddition of ester-substituted oxidopyridinium Harm-OP with a variety of dienes. 38 Extensive computational investigation at the M06-2X/6-311+G(d,p)//M06-2X/6-31G(d) level of theory confirmed the preference for the (4 + 3)product through the lowest energy exo transition state (see below), though experimentally both the endo and exo products were observed (for instance, reaction of penta-1,3-diene "methylbutadiene" MBD yields a 1:1 mixture of Prod-1D and Prod-1E).…”

“…■ RESULTS AND DISCUSSION Reaction Profile. We initially elected to model the cycloaddition of oxidopyrylium and butadiene at the M06-2X/6-311+G(d,p) level of theory (as used by Krenske and Harmata), 38,39 with DCM solvation modeled implicitly using Truhlar's SMD method. 40 The free energy profile for the reaction is shown in Scheme 3.…”