A practical synthesis of a key pharmaceutical intermediate, 2-[(1H-pyrrolo[2,3-b]pyridine-4-yl)methylamino]-5-fluoronicotinic acid (1), is described. To introduce the aminomethyl moiety of 2 via a palladium-catalyzed cyanation/reduction sequence, a regioselective chlorination of 7-azaindole via the N-oxide was developed. A highly selective monodechlorination of 2,6-dichloro-5-fluoronicotinic acid was discovered to afford the nicotinic acid 3. The two building blocks 2 and 3 were then coupled to complete the preparation of 1.
Calculations up to the MP2/6-31G*//HF/3-21G level have been carried out to study the thermal cycloreversion of 2,2,6-trimethyl-4H-l,3-dioxin-4-one (1) and 2,2,4-trimethyl-6iT-l,3-oxazin-6-one (3). At this level of calculation, the enthalpy of activation for the thermal cycloreversion of dioxinone 1 was found to be 31.3 kcal/mol with zero-point vibrational energy correction. The experimental value for the reaction in solution is 30.4 kcal/mol. The enthalpy of activation for the as of yet unsynthesized oxazinone 3 was found to be 44.2 kcal/mol with zero-point correction. Contrasting with the standard view that the thermal cycloreversion of dioxinone 1 is a retro-Diels-Alder reaction is the structural information from the HF/3-21G-optimized transition state 5 which shows the plane of the acetone dienophile tilted roughly 90°to the plane of the acylketene diene.
An unprecedented high barrier to ring inversion [Eq. (1)] prevents 1 from engaging in bifacial complexation with lithium ions. The X-ray crystal structure analysis of this hexaspiro compound corroborates the adoption of a cyclohexane chair with all six C-O bonds projected equatorially (1-eq).
The four tetraspiro carbinols 28, 30, 41, and 43 and the three trispiro cyclohexenones 25, 38, and 53 have been synthesized and individually subjected to intramolecular oxymercuration. The three-dimensional structures of all 10 products have been unequivocally established by X-ray crystallographic analysis. In seven of these structures, the preferred solid-state conformation features an axially disposed C-Hg bond where the mercury atom is internally chelated in a 1,3-diaxial relationship to at least one or, more often, two oxygen centers. An unusually strong preference has been observed for equatorial occupancy on the part of the C-O bonds. This bias can be attributed to the relief of torsional strain effects that arise when gauche CH 2 ---CH 2 interactions are skirted. An important mechanistic distinction separates the kinetically preferred trans mercuricyclization of the tetraspiro alcohols from the contrasting cis stereochemical ring closure exhibited predominantly by the unsaturated ketones. In the first instance, the approach of Hg 2+ to the double bond is governed to a large extent by coordination to a proximal axially oriented ether oxygen. Where the ketones are concerned, precoordination to the Lewis basic carbonyl oxygen presumably initiates spirocyclization in a fashion controlled by the conformational preference of the resident tetrahydrofuranyl subunits.
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