Dipolar nitrile oxide-based

Extensions of 1,3-dipolar additions of aromatic azides (720,721) to other enamines (636), and particularly to the enamine tautomer of SchilTs bases, were explored (722,723). Further nitrone additions were reported (724,725) and a double nitrile oxide added to an endiamine (647). Cyanogen azide and enamines gave cyanoamidines through rearrangement (726). 

These routes are dimerization to furoxans 2 proceeding at ambient and lower temperatures for all nitrile oxides excluding those, in which the fulmido group is sterically shielded, isomerization to isocyanates 3, which proceeds at elevated temperature, is practically the only reaction of sterically stabilized nitrile oxides. Dimerizations to 1,2,4-oxadiazole 4-oxides 4 in the presence of trimethylamine (4) or BF3 (1 BF3 = 2 1) (24) and to 1,4,2,5-dioxadiazines 5 in excess BF3 (1, 24) or in the presence of pyridine (4) are of lesser importance. Strong reactivity of nitrile oxides is based mainly on their ability to add nucleophiles and particularly enter 1,3-dipolar cycloaddition reactions with various dipolarophiles (see Sections 1.3 and 1.4). 

However, most asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides with alkenes are carried out without Lewis acids as catalysts using either chiral alkenes or chiral auxiliary compounds (with achiral alkenes). Diverse chiral alkenes are in use, such as camphor-derived chiral N-acryloylhydrazide (195), C2-symmetric l,3-diacryloyl-2,2-dimethyl-4,5-diphenylimidazolidine, chiral 3-acryloyl-2,2-dimethyl-4-phenyloxazolidine (196, 197), sugar-based ethenyl ethers (198), acrylic esters (199, 200), C-bonded vinyl-substituted sugar (201), chirally modified vinylboronic ester derived from D-( + )-mannitol (202), (l/ )-menthyl vinyl ether (203), chiral derivatives of vinylacetic acid (204), ( )-l-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1 -enes (205), enantiopure Y-oxygenated-a,P-unsaturated phenyl sulfones (206), chiral (a-oxyallyl)silanes (207), and (S )-but-3-ene-1,2-diol derivatives (208). As a chiral auxiliary, diisopropyl (i ,i )-tartrate (209, 210) has been very popular. 

A strategy based on the diastereoselective dipolar cycloaddition reaction of nitrile oxides and allylic alcoholates, has been applied to the synthesis of bis-(isoxazolines) that are precursors to polyketide fragments. These intermediates can be elaborated into protected polyols, for example, 439, by sequential chemos-elective reductive opening of each isoxazoline or, alternatively, by simultaneously, providing access to all stereoisomers of this carbon skeleton (479). 

The synthesis of C60-based dyads in which the Ccm core is covalently attached to a strong electron acceptor moiety, has been carried out by 1,3-dipolar cycloaddition of in situ generated nitrile oxides with C(,o- As expected, the obtained adducts show reduction waves of the fullerene core that are anodically shifted in comparison with the parent Cr>o. This indicates that they are remarkably stronger acceptors than Ceo-The electron acceptor organic addend also undergoes an anodic shift due to the electronic interaction with the C(,o moiety (545). 

Fluoride ion catalyzed 1,3-dipolar cycloaddition of bromo nitrile oxide, obtained in situ from dibromoformaldehyde oxime 184, to nonactivated alkynes provides a new approach to the synthesis of neuroactive isoxazoles. However, the regioselectivity of cycloaddition in this case is not high—products 185 and 186 are obtained in a 1 1 to 1 1.4 ratio (equation 80). Cycloaddition reaction of hydroximoyl chlorides and acetylene was snc-cessfully carried out also in the presence of NaHCOs as a base. For instance, a-keto oximes 187 were reacted with acetylene and NaHCOs to give isoxazoles 188 in good yields (equation 81). 

Dipolar cycloaddition is one of the most important methods in assembling five-membered ring heterocycles. For the 1,4-(oxa/thia)-2-azole system, nitrile oxides, and nitrile sulfides have the correct sequence of atoms for the 47t 1,3-dipolar component and the 2n component can be a either a C=0 or a C=S heterodipolarophile (Scheme 41). Nitrile oxides, usually generated in situ from the corresponding hydroximoyl chlorides and a base, add to various types of (3=0 bond affording 1,4,2-dioxazole derivatives. 

The cycloaddition of a nitrile oxide with a chiral allylic ether affords an isoxazoline with selectivity for the pre/-isomer. This selectivity increases with the size of the alkyl substituent and is insensitive to the size of the allyl oxygen substituent. However, allyl alcohols tend to form the / ar/ isomcr preferentially, although the selectivity is often low.427"434 The product of dipolar cycloadditions based on nitrile oxides, the isoxazoline moiety, can be converted into a large variety of functional groups under relatively mild conditions.3 Among other products, the addition can be used to prepare P-hydroxy ketones (Scheme 26.17).435 The isoxazoline moiety can be used to control the relative stereochemistry through chelation control.436,437... 

Dipolar cycloadditions have been used successfully in assembling a number of these ring systems. Nitrile oxides, generated from a-chloro oximes and base, add to a wide range of aliphatic and aromatic aldehydes and ketones, but not to esters (Scheme 42), yielding... 

A simple synthesis of pyrazolo[4, 5 ][60]fullerenes from pyrazolyl hydrazones with [60]fullerene was achieved with microwave irradiation evidence of intramolecular charge-transfer interaction was shown <1999TL1587>. Novel C6o-fused isoxazolines have been synthesized from 1,3-dipolar cycloadditions of pyrazole nitrile oxides to Ceo under thermal or microwave irradiation <1999T4889>. A new triad based on pyrazolino[60]fullerene and a conjugated... 

Sequential [3+2] cycloaddition/silicon-based cross-coupling reactions allowed for the synthesis of 3,4,5-trisubsti-tuted isoxazoles. Regioselective 1,3-dipolar cycloaddition reactions between alkynyldimethylsilyl ethers 400 and ethyl or phenyl nitrile oxides, generated in situ from 1-nitropropane and A -hydroxybenzene carboximidoyl chloride, respectively, gave as predominant products after hydrolysis isoxazol-4-ylsilanols 401, converted into 4-arylisoxazoles 402 by cross-coupling with a variety of aryl iodides (Scheme 97) <2005JOC2839>. 

In a search for new isoxazole-based liquid crystalline compounds, a 22-member library of 3,5-diaryl isoxazoles 628 was prepared by parallel synthesis on solid phase (Rink resin) through 1,3-dipolar cycloaddition of supported phenylacetylene units with suitable aryl nitrile oxides generated in situ from hydroxyiminoyl chlorides. Cleavage from the resin under acidic conditions allowed the generation of the cyano moiety <2004TL2277>. 

The phosphonate derivatives of the dihydroisoxazole nucleosides 30 have been obtained in good yield via 1,3-dipolar cycloaddition reactions of the nitrile oxide 31 with corresponding vinyl nucleoside bases such as 32. ... 

Other reports on the [3+2] cycloadditions of indoles and nitrile oxides focus on intermolecular reactions. For example, Gribble [80] has investigated the reaction of (phenylsulfonyl)-2-(tri-n alkylstannyl)indoles 169 with tetranitromethane to give the novel isoxazolo[5,4-b]indole derivative 173 (Scheme 49). The mechanism cascade is thought to proceed through the degradation of the dinitromethyl anion to a nitrile oxide 171, followed by a 1,3-dipolar cycloaddition to form a nitroindole intermediate 172 and subsequent loss of nitrous acid or SnR3N02. Treatment of the isoxazole 173 with base then leads to the formation of the oxindole tautomer 175 as the major product. 

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