Alkenes intramolecular reactions, nitrile oxides

The intramolecular cycloaddition of a nitrile oxide (a 1,3-dipole) to an alkene is ideally suited for the regio- and stereocontrolled synthesis of fused polycyclic isoxazolines.16 The simultaneous creation of two new rings and the synthetic versatility of the isoxa-zoline substructure contribute significantly to the popularity of this cycloaddition process in organic synthesis. In spite of its high degree of functionalization, aldoxime 32 was regarded as a viable substrate for an intramolecular 1,3-dipolar cycloaddition reaction. Indeed, treatment of 32 (see Scheme 17) with sodium hypochlorite... 

Intermolecular Cycloaddition at the C=C Double Bond Addition at the C=C double bond is the main type of 1,3-cycloaddition reactions of nitrile oxides. The topic was treated in detail in Reference 157. Several reviews appeared, which are devoted to problems of regio- and stereoselectivity of cycloaddition reactions of nitrile oxides with alkenes. Two of them deal with both inter- and intramolecular reactions (158, 159). Important information on regio-and stereochemistry of intermolecular 1,3-dipolar cycloaddition of nitrile oxides to alkenes was summarized in Reference 160. 

DFT studies of the intramolecular ene-like (or the so-called 1,3-dipolar ene) reaction between nitrile oxides and alkenes show that this reaction is a three-step process involving a stepwise carbenoid addition of nitrile oxide to form a bicyclic nitroso compound, followed by a retro-ene reaction of the nitrosocyclopropane intermediate. The competitive reactions, either the intramolecular [3 + 2] cycloaddition between nitrile oxides and alkenes or the intermolecular dimerization of nitrile oxides to form furoxans, can overwhelm the intramolecular 1,3-dipolar ene reaction if the tether joining the nitrile oxide and alkene is elongated, or if substituents such as trimethylsilyl are absent (425). 

A previous review has highlighted the following methods of ring synthesis intramolecular cyclization of oximes, nitro alkenes, and nitrones, and [4+2] cycloaddition reactions <1996CHEC-II(6)279>. In addition to that, this review includes the intramolecular cyclization of hydroxylamines, hydroxamates, hetero-Diels-Alder [4+2], 1,3-dipolar cycloaddition of nitrile oxides to alkenes, and [3+3] cycloaddition reactions. This review does not cover cycloaddition reactions of the [4+2] [3+2] and [4+2] [3+2] [3+2] types which primarily led to heterocycle-fused oxazine ring systems. 

Recently, the intramolecular nitrile oxide-alkene cycloaddition sequence was used to prepare spiro- w(isoxazolines), which are considered useful as chiral ligands for asymmetric synthesis (321). Reaction of the dibutenyl-dioxime (164) (derived from the diester 163) with sodium hypochlorite afforded a mixture of diastereomeric isoxazolines 165-167 in 74% combined yield (Scheme 6.80) (321). It was discovered that a catalytic amount of the Cu(II) complex 165-Cu(acac)2, where acac = acetylacetonate, significantly accelerated the reaction of diisopropylzinc... 

The most widely used, and often most convenient reagents for such one-pot reactions are sodium hypochlorite (45) or hypobromite (16). These reactions are performed in the presence of an organic base (generally triethylamine) that normally enhances the yield of cycloaddition products (45). This method was employed for many intermolecular reactions (71) and also seems especially suited for intramolecular ones (72-77) as well as for the solid-phase synthesis (78) of 2-isoxazolines. Hypohalite can also be replaced by sodium bromite in combination with a catalytic amount of tri-n-butyltin chloride (79). In a related method, O-tributylstannyl oximes were treated with fert-butyl hypochlorite to produce nitrile oxides that were trapped with alkenes or alkynes to afford the corresponding isoxazolines or isoxazoles in moderate to good yield (80). 

Cyclization of nitrile oxides with a four-atom intervening chain to the alkene always leads to 5,6-fused bicylic isoxazolines possessing a bridgehead C—N double bond. This is in contrast to nitrone cycliza-tions where competition to form bridged bicyclic isoxazolidines is observed. The alkenyl oximes (73) and (74) cyclize in typical fashion via nitrile oxide intermediates (Scheme 21).33a>36 The stereochemistry of cyclization here was studied both experimentally and by calculation. The higher stereoselectivity observed with the (Z)-alkene is typical. (Z)-Alkenes cycloadd much slower than ( >alkenes in intermole-cular reactions this is attributed to greater crowding in the transition state. Thus, intramolecular cycloaddition of (Z)-alkenes depends on a transition state that is heavily controlled by steric factors. 

The intramolecular nitrile oxide-alkene cycloaddition reaction of propargylic ethers offers a route to dihydrofuroisoxazoles (Equation (98)) <94JOC3783>. 

The use of diphenylmethylenecyclopropanes, as opposed to methylenecyclo-propanes, greatly enhances the Pd°-induced [3 + 2] cycloaddition with alkenes to produce five-membered rings. A one-carbon ring-contraction route to cyclopentanes involves a high-pressure version of the known 1,3-dipolar addition of azides to O-silylated enolates, which removes some of the previously observed steric limitations of the reaction, so that the adduct (47) fragments, as shown, to produce the ring-contracted product (48). The intramolecular nitrile oxide... 

Another [3+2]-cycloaddition process that has proven value in the construction of macrocyclic natural products, but has been underexplored to date for medicinal chemistry purposes, is the intramolecular addition of nitrile oxides (typically generated in situ from the corresponding oxime) with alkenes (Scheme 11.23). For example, this reaction has been employed for the conversion of oxime-acrylate 172 into 173, an intermediate for the synthesis of the macrosphelide skeleton, and for the construction of macrocycles useful in studies directed towards an asymmetric synthesis of brefeldin... 

Similarly, ethyl nitroacetate afforded, with 1,4-naphto-quinones, fair yields of condensed isoxazoline derivatives as a result of dehydration followed by elimination or dehydrogenation [80]. Later, more examples of condensations of ethyl nitroacetate and alkenes in the same reaction conditions have been reported to compete with oxidation [81]. The intramolecular version, using allyl nitroacetate 16 in the presence of Cu(II) and Mn(III), gives mainly the bicyclic isoxazoline 17 as the condensation product, predominant over monoelectronic oxidation 18 (Scheme 8.6). Noticeably, the intramolecular cyclization occurs with Cu (II) or Co(II) instead of Mn(III) acetate. As expected, secondary nitro compounds undergo only radical reactions. Condensations are reported to occur via intermediate nitrile... 

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