Gregory W. Simpson

Cycloaddition Reactions of Nitrile Oxides with Alkenes

Publisher Summary This chapter reviews the cycloaddition reactions of nitrile oxides with alkenes. It covers the literature published between 1985 and 1992. The chapter emphasizes on the dramatic improvements in the degree of stereocontrol that has been attained in intermolecular reactions and to the developments in the use of intramolecular nitrile oxide cycloaddition (INOC) reactions, where the predisposition of the reacting groups within a molecule greatly enhances the regio and stereo-selectivity. The synthesis of benzonitrile oxide by chlorination of benzaldoxime, in order to give benzhydroximinoyl chloride followed by dehydrohalogenation with sodium carbonate forms the basis of the most common approach for the synthesis of nitrile oxides. The reactions of nitrile oxides with alkenes are essentially 1,3-dipolar cycloadditions and their mechanism have been subject of numerous investigations. The chapter also describes reactivity, regioselectivity, stereoselectivity, and the uses of isoxazolines. In specific, cycloaddition rates range over several orders of magnitude and to predict the likely success of a reaction, when alternative reaction pathways, such as nitrile oxide dimerization are possible, it becomes necessary to understand the reactivity of the system.

Reversal of regiochemistry in the synthesis of isoxazoles by nitrile oxide cycloadditions

Abstract The isoxazolines 2a , 2b and 8 obtained from nitrile oxide cycloadditions to cyclohex-2-enone 1a and its analogues 1b and 7 reacted with nickel peroxide to give the isoxazoles 3a , 3b and 9 . In contrast, the corresponding 2-bromocyclohex-2-enones 4a , 4b and 10 , prepared by bromination of the corresponding alkenes 1a , 1b and 7 , underwent nitrile oxide cycloadditions to afford the regioisomeric isoxazoles 6a , 6b and 12 , respectively.

Dipolar Cycloaddition Reactions of Nitrilimines

A series of γ-substituted α-methylidene-γ-butyrolactone derivatives underwent regiospecific 1,3-dipolar cycloaddition with N-methyl-C-phenylnitrilimine. These reactions proceeded regiospecifically and with high diastereoselectivity, generally favouring the anti diastereomer as determined by n.m.r. spectroscopy and semiempirical molecular orbital calculations. The assignment for one product was confirmed by X-ray crystallography. N-Methyl-C-phenylnitrilimine underwent regiospecific cycloaddition with a range of C=S-containing dipolarophiles. Substituted thioureas were generally unreactive as dipolarophiles, while 5-thio-substituted 1,3,4-thiadiazole-2(3H)-thiones underwent ready reaction to produce, rather than the expected cycloadducts, complex rearrangement products. The structure of one of these unusual products has been confirmed by X-ray crystallography. A series of disubstituted nitrilimines underwent regiospecific cycloaddition with thiobenzophenone; the structures of the products were confirmed by X-ray crystallography.

3-[(3′-Hydroxymethyl)-4′-hydroxybutyl]imidazo[4,5-b]pyridines—novel antiviral agents

Abstract Derivatives of 3- and 1-(4′-hydroxy-3′-(hydroxymethyl)butyl)-imidazo[4,5- b ]pyridine were prepared in several steps from 2-amino-5-chloropyridine. Selected compounds were evaluated against human cytomeglovirus (HCMV), herpes simplex virusus (HSV1/HSV2) and varicella zoster virus (VZV). Details of their synthesis and biological activities are presented.

Exploiting the 1,3-dithiane of 2-oxopropanenitrile oxide to limit competing dimerization in 1,3-dipolar cycloaddition reactions

Abstract The 1,3-dithiane of 2-oxopropanenitrile oxide is less prone to dimerization than the parent compound and, as a consequence, it undergoes more efficient cycloaddition reactions with a range of mono- and 1,1- and 1,2-di-substituted alkenes.

Total synthesis of herboxidiene, a complex polyketide from Streptomyces species A7847*

A formal total synthesis of the polyketide herboxidiene (1) has been achieved by Horner-Wittig coupling of the side-chain fragment 12-epi-(2) with the tetrahydropyran-2-acetic acid derivative (3) followed by desilylation of the resulting triene (19) and hydroxyl-directed mono-epoxidation of the ensuing bis-homoallylic alcohol (20).

Synthesis of unsymmetrically 4-substituted 2,2′-bipyridines

Abstract Pyridin-2-nitrile oxide was generated in situ and reacted with 2-substituted but-1-ene-4-ols to give 5-substituted 5-(2-hydroxyethyl)-3-(pyrid-2-yl)-Δ 2 -isoxazolines. The isoxazolines were reductively ring-opened with LiAlH 4 to give 2-(3-substituted-1-amino-3,5-dihydroxypentyl)-pyridines, which were subjected to Dess-Martin oxidation with concomitant dehydration to give 4-substituted 2,2′-bipyridines.

Perfluorohexane As a Novel Reaction Medium For Bromination Reactions

Abstract Perfluorohexane is shown to be a good alternative to carbon tetrachloride as a non-toxic, non-ozone-depleting, inert reaction medium for bromination reactions. Yields of brominated products were nearly quantitative and the reaction work-up was easier.

Asymmetric Synthesis of a Homochiral D2-Isoxazoline Amino Acid Derivative

(2R)-4-Methylene-2-phenyl-3-propionyloxazolidin-5-one underwent 1,3-dipolar cycloaddition with 2,6-dichlorobenzonitrile oxide to give (5S,7R)-3-(2,6-diphenyl)-7-phenyl-6-propionyl-2,6-diaza-1,8-dioxaspiro [4.4] non-2-en-9-one, a protected isoxazoline amino acid. The reaction proceeded regiospecifically and with high stereoselectivity. The anti addition product predominated. The regiochemistry of addition was determined by nmr and the stereochemistry of addition was determined by X-ray analysis. The transition state energies for syn and anti addition were calculated using the semi-empirical AM1 method in the MOPAC package

Aryl nitrile oxide cycloaddition reactions in the presence of baker's yeast and β-cyclodextrin

Abstract Contrary to recent reports, bakers yeast is not required for reactions of nitrile oxides with either ethyl cinnamate or 4-vinylpyridine to give isoxazolines. β-Cyclodextrin may alter the ratio of isomers isolated from the reactions of the cinnamate but only at concentrations of reactants much lower than those reported, and this effect is most likely due to selective product complexation rather than selective product formation.