Kevin C. Cannon

Selectfluor as a nucleofuge in the reactions of azabicyclo[n.2.1]alkane beta-halocarbamic acid esters (n = 2,3).

The ability of Selectfluor to act as a nucleofuge for hydrolysis of beta-anti-halides was investigated with N-alkoxycarbonyl derivatives of 6-anti-Y-7-anti-X-2-azabicyclo[2.2.1]heptanes and 4-anti-Y-8-anti-X-6-azabicyclo[3.2.1]octanes. The azabicycles contained X = I or Br groups in the methano bridge and Y = F, Br, Cl, or OH substituents in the larger bridge. The relative reactivities of the halides were a function of the azabicycle, the halide, and its bridge and the addition of Selectfluor or HgF(2) as a nucleofuge. All halide displacements occurred with retention of stereochemistry. Selectfluor with sodium bromide or sodium chloride, but not sodium iodide, competitively oxidized some haloalcohols to haloketones. A significant 15.6 Hz F...HO NMR coupling was observed with 4-anti-fluoro-8-anti-hydroxy-6-azabicyclo[3.2.1]octane.

SYNTHESIS OF 3-AZABICYCLO[3.1.0]HEXANES. A REVIEW

INTRODUCTION .............................................................................................................................. i05 I . SYNTHESIS OF 3-AZABICYCL0[3.1.O]HEXANES FROM SUBSTITUTED CYCLOPROPANES .............................................................................................................. 105 A . Synthesis by Ring Annulation of Cyclopropane-cis.1, 2.dicarboxylic Acids . Maleinides ........................................................................................................................... 106 a . Reduction of Cyclopropnnemaleimides to Amines ...................................................... 106 b . Partial Conversions of Cyclopropmmaleimide to Lactams ..................................... 106 c . Conversion of 3-AzabicVcio[R 1.01he~xan-2-ones (Lactams) to Amines and Aminols ................................................................................................. 107 d . Introduction and Modijkation of Substituents at C-2 of3-AzabicycIo[3.I.Olhexanes .................................................................................... 109

A stereoselective 3-endo-alkyl-5,6-dehydroisoquinuclidine synthesis.

Abstract Cycloaddition of N-carbethoxy-2-alkyl-1,2-dihydropyridines 4 with phenylvinylsulfone 5 provides adducts 6 , which upon desulfonylation afford stereoselectively N-carbethoxy-3- endo - alkyl-5,6-dehydroisoquinuclidines 1 .

Synthesis of Conformationally Constrained 5-Fluoro- and 5-Hydroxymethanopyrrolidines. Ring-Puckered Mimics of Gauche- and Anti-3-Fluoro- and 3-Hydroxypyrrolidines

N-acetylmethanopyrrolidine methyl ester and its four 5-syn/anti-fluoro and hydroxy derivatives have been synthesized from 2-azabicyclo[2.2.0]hex-5-ene, a 1,2-dihydropyridine photoproduct. These conformationally constrained mimics of idealized C(β)-gauche and C(β)-anti conformers of pyrrolidines were prepared in order to determine the inherent bridge bias and subsequent heteroatom substituent effects upon trans/cis amide preferences. The bridgehead position and also the presence of gauche(syn)/anti-5-fluoro or 5-hydroxy substituents have minimal influence upon the K(T/C) values of N-acetylamide conformers in both CDCl(3) (43-54% trans) and D(2)O (53-58% trans). O-Benzoylation enhances the trans amide preferences in CDCl(3) (65% for a syn-OBz, 61% for an anti-OBz) but has minimal effect in D(2)O. The synthetic methods developed for N-BOC-methanopyrrolidines should prove useful in the synthesis of more complex derivatives containing α-ester substituents. The K(T/C) results obtained in this study establish baseline amide preferences that will enable determination of contributions of α-ester substituents to trans-amide preferences in methanoprolines.

An Alternative Synthesis of 2-Chloro-5-Hydroxypyridine: A Key Component of the Non-Opioid Analgesic Agent ABT-594

Abstract The synthesis of the biologically useful synthon 2-chloro-5-hydroxypyridine from 3-iodo-6-chloropyridine is described.

2-Azabicyclo[2.2.0]hex-5-enes and 2-Azabicyclo[2.2.0]hexanes. A Review

The synthesis and reactions of 2-azabicyclo[2.2.0]hex-5-enes and 2-azabicyclo[2.2.0]hexanes are reviewed.

5(6)-anti-Substituted-2-azabicyclo[2.1.1]hexanes. A Nucleophilic Displacement Route

Nucleophilic displacements of 5(6)-anti-bromo substituents in 2-azabicyclo[2.1.1]hexanes (methanopyrrolidines) have been accomplished. These displacements have produced 5-anti-X-6-anti-Y-difunctionalized-2-azabicyclo[2.1.1]hexanes containing bromo, fluoro, acetoxy, hydroxy, azido, imidazole, thiophenyl, and iodo substituents. Such displacements of anti-bromide ions require an amine nitrogen and are a function of the solvent and the choice of metal salt. Reaction rates were faster and product yields were higher in DMSO when compared to DMF and with CsOAc compared to NaOAc. Sodium or lithium salts gave products, except with NaF, where silver fluoride in nitromethane was best for substitution by fluoride. The presence of electron-withdrawing F, OAc, N(3), Br, or SPh substituents in the 6-anti-position slows bromide displacements at the 5-anti-position.

Neighboring group participation in the additions of iodonium and bromonium ions to N-alkoxycarbonyl-2-azabicyclo[2.2.n]alk-5-enes (n = 1,2).

Additions of iodonium-X reagents to N-alkoxycarbonyl-2-azabicyclo[2.2.1]hept-5-enes and the homologous 2-azabicyclo[2.2.2]oct-5-enes have been found to mirror the outcomes of additions of bromonium-X reagents. Only rearranged products were observed for reactions of either of these halonium ion reagents with the azabicylo[2.2.1]hept-5-enes. For the azabicyclo[2.2.2]oct-5-enes, nitrogen participation in addition of IOH or BrOH was dependent on the N-alkoxycarbonyl group. With larger N-Boc, N-Cbz, or N-Troc protecting groups, unrearranged 5-anti-hydroxy-6-syn-I(or Br)-2-azabicyclo[2.2.2]octanes were formed by nucleophilic attack at C(5) on syn-halonium ions. The structure of N-methyl-8-anti-bromo-4-anti-hydroxy-2-azabicyclo[3.2.1]octane has been reassigned by X-ray analysis.

Regioselective Synthesis of 4-, 5-, and 6-Alkyl and Dialkyl 5,6-Dehydroisoquinuclidines from Phenylvinylsulfone Cycloadducts of N-Ethoxycarbonyl-1,2-Dihydropyridines

Abstract A regioselective route to 4-, 5-, and 6-alkyl or 4,5-, 4,6-, and 5,6-dialkyl-5,6-dehydroisoquinuclidines 1a-f is described.