Facile Diels−Alder Reactions with Pyridines Promoted by Tungsten

Abstract

The isoquinuclidine (2-azabicyclo[2.2.2]octane) core is found in numerous molecules of biological and medicinal importance, including the widely investigated Iboga alkaloids and their related bisindole Cantharanthus alkaloids (Sundberg, R. J.; Smith, S. Q. Alkaloids (San Diego, CA, United States) 2002, 59, 281-386). A diverse range of synthetic methods for the stereoselective construction of this architecture is required for the efficient development of related pharmaceuticals. Here, we report a fundamentally new methodology that constructs the isoquinuclidine core directly from pyridines, using a pi-basic tungsten complex to disrupt the aromatic stabilization of these otherwise inert heterocycles. By this approach, common pyridines are found to undergo stereoselective Diels-Alder reactions with electron-deficient alkenes under mild reaction conditions, thus providing access to a broad range of functionalized isoquinuclidines. Further, by using the common terpene alpha-pinene, a single enantiomer of the tungsten fragment can be isolated and used to provide access to enantio-enriched isoquinuclidines from pyridines.

Transition metals in organic synthesis: Highlights for the year 2005

“…Tungsten pyridine complexes underwent Diels-Alder reactions [1541]. Indium mediated alkyl radical additions to ( 6 -arene)-manganese complexes in aqueous media (Eq.…”

Acrylonitrile

“…105 When complexed to tris(pyrazolo)boratetungsten, 2,6-lutidine will function as a dieneophile in Diels-Alder reactions with acrylonitrile to yield highly functionalized cycloadducts after oxidative decomplexation. 106 When PhNCO is mixed with crotonaldehyde in conjunction with catalytic quantities of PTSA acid, the diene formed is trapped in situ by acrylonitrile furnishing aminocyanocylohexenes in reasonable yield and with excellent levels of diastereoselectivity. 107 The analogous reaction can be carried out with acetic anhydride in the place of PhNCO to provide alkoxy carbonyl cyano cyclohexenes which can be hydrolyzed enzymatically to form enantiopure cyclohex-2-en-1-ols (eq 24 Acrylonitrile will undergo a [2 + 2] cycloaddition with itself under thermal conditions.…”

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

“…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 3The 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.…”

“…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-3,8dienes 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 possessing both a 2azabicyclo [2.2.2]octane and a 7,8-benzomorphane substructure.…”

“…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 possessing both a 2azabicyclo [2.2.2]octane and a 7,8-benzomorphane substructure. In addition, Diels-Alder reactions were performed with 4-allyl-substituted 1,4-dihydropyridines, which proceeded intramolecularly leading to 1-substituted 4-azatricyclo[3.3.1.0 2,7 ]non-3-enes with a unique polycyclic skeleton.…”