Inter- and Intramolecular [4+2]-Cycloaddition Reactions with 4,4-Disubstituted N-Silyl-1,4-dihydropyridines as Precursors for N-Protonated 2-Azabutadiene Intermediates

Abstract

An efficient and straightforward method for the synthesis of polycyclic ring systems with a central 2-azabicyclo[2.2.2]octane unit is developed. The process is based on [4+2]-cycloaddition reactions that are performed with N-protonated 2-azabutadiene intermediates as heterodienes, generated from 4,4-disubstituted N-silyl 1,4-dihydropyridines. As dienophiles, cyclopentadiene for the intermolecular cycloaddition and an allyl moiety already attached to the 4,4-disubstituted 1,4-dihydropyridines for the intramolecular variant, are used.The 2-azabicyclo[2.2.2]octane ring system (1) is found in various biologically active compounds. Well-known examples include ibogaine (2), a psychoactive indole alkaloid, and dioscorine (3), which is a modulator of the nicotinic acetylcholine receptor and leads to disorders in the central nervous system (Figure 1). 1 Figure 1 Structures of 2-azabicyclo[2.2.2]octane (1), ibogaine (2) and dioscorine (3) The synthesis of 2-azabicyclo[2.2.2]octane derivatives is often carried out via Diels-Alder reactions using pyridines, 2 pyridones, 3 1,2-dihydropyridines, 4 3,4-dihydropyridines, 5 or activated 1,4-dihydropyridines, 6,7 as dienes for the cyclizations. In the case of 1,4-dihydropyridines, Craig et al. published, for example, the [4+2] cyclization of N-phenyl-3,5-diethyl-2-propyl-1,4-dihydropyridine with maleic anhydride. 6 Further examples of inter-and intramolecular Diels-Alder reactions of 1,4-dihydropyridines, more precisely 4-aryl-substituted dimethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylates, with dienophiles have been reported by Hartman et al. 7 The reactions were performed in the presence of an acid as the catalyst to generate N-protonated 2-azabutadienes as intermediates, which underwent intermolecular [4+2] cyclizations with different alkenes (styrene, allyltrimethylsilane, cyclopentadiene, furan, thiophene). Similarly, intramolecular [4+2]-cyclization reactions were also carried out with 4-phenyl-substituted 1,4-dihydropyridines in which the dienophile, an alkene moiety, required for the cyclization with the generated intermediate N-protonated 2-azabutadiene, was already present in the molecule as an ortho-substituent attached to a phenyl residue at the 4-position. 7 We previously demonstrated the high synthetic utility of 4,4-disubstituted N-silyl-1,4-dihydropyridines, 8 that are easily accessible by trapping reactions of N-silylpyridinium ions, for the synthesis of 5-substituted 7,8-benzomorphans, as well as for 4,4-disubstituted 2-cyanopiperidines and 2,6-dicyanopiperidines. 9 Herein, we report on the highly efficient synthesis of 10,10-disubstituted 8-azatricyclo[5.2.2.0 2,6 ]undeca-3,8-dienes by acid-catalyzed cycloaddition reactions employing 4,4-disubstituted 1,4-dihydropyridines and cyclopentadiene as starting materials. The Diels-Alder addition products derived from 4,4-disubstituted 1,4-dihydropyridines could be successfully used in subsequent intramolecular Friedel-Crafts-type cyclization reactions resulting in polycyclic nitrogen heterocycles posses...

Synthesis and utility of N-boryl and N-silyl enamines derived from the hydroboration and hydrosilylation of N-heteroarenes and N-conjugated compounds

“…Cyclic N -silyl enamines have been utilized to synthesize polycyclic structures via Diels–Alder reactions ( Figure 15 ). Wanner et al pioneered the [4 + 2] cycloaddition of N -silyl-1,4-dihydropyridine with cyclopentadiene 12a to synthesize 2-azabicyclo [2.2.2]octane ( Schmaunz et al, 2014 ). The N -silyl-1,4-dihydropyridine precursor was prepared by the reaction of pyridines with triisopropylsilyl triflate, yielding the corresponding pyridinium salts, which were subsequently trapped in diorganomagnesium compounds.…”

Computational Study of Electronic Influence of Guanidine Substitution on Diels-Alder Reactions of Heterocyclic Dienes

“…These theoretical findings are conforming to literature calculations for protonated N-methylpyrrole which predicted lowering of the activation barrier [28] and computational and experimental results for [π4s + + π2s] cycloaddition reactions of methylated 2-butenone with ethyl vinyl ether [29] and reaction of N-protonated 2-azabutadiene with cyclopentadiene. [30]…”