Bis isoxazolines

This series of compounds was also discussed briefly by Quilico in 1962 and only a limited number of new representatives have been reported (62HC(l7)l,p. 3). The pressure reaction of ethylene and nitric acid in the presence of Ni, Zn or Cu produced 3,3 -bis(isoxazoline) (70FRP94493), and the isoxazoline TV-oxide (515) was prepared by the reaction of (3-dimethylaminoacrylaldehyde and methyl nitroacetate (74IZV845). 

Ethyl acetoacetate and hydroxylamine with a large excess of alkali produced (516) which on heating generated 4-methylene-2-isoxazoline (517), while limited base generated the dimer (518) (80JHC763). 

5 -Bis(isoxazoline) decomposes to a number of products depending on the substitution (77H(6)1599) on photolysis using NiS04, two major products were formed. ESR spin trapping demonstrated the intermediacy of imino and 2-isoxazolinyl radicals (77TL4619). 

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In a similar treatment of 3,4-bis(alkylsulfonyl)furoxans, both sulfonyl groups were eliminated (Scheme 191) (86H889). Bis(isoxazoline) 294 was isolated in 10-17% yield. 

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). 

Under oxidation conditions, a C—C double bond can be functionalized by either two alkoxycarbonyl groups or one alkoxycarbonyl group and one heteroatom. As shown in Scheme 4.14, two ester groups are successfully introduced to styrene in an enantioselective manner, producing a phenylsuccinic ester using a Pd/MeO-BIPHEP complex. mcw-Diols are converted into cyclic ethers in an asymmetric manner when catalyzed by Pd/chiral bisoxazoline. Intramolecular aminopallada-tion followed by carbomethoxylation gives an cyclic amino ester in moderate ee when catalyzed by a Pd/bis(isoxazoline) complex. " ... 

Several silver complexes have been investigated in C-H insertion reactions of carbenes. One of the earliest reports by Sulikowski and Burgess describes an intramolecular C-H insertion of a chiral aryl diazoacetate 80 as part of a study on the total synthesis of mitomycin family of natural products (Scheme 8.15).41 Among several catalysts that were screened was AgSbly, in the presence of bis(isoxazoline)-type ligands, which led to the formation of the desired insertion product 81 in moderate yield and modest diastereoselectivity. 

Isoxazoline rings include two heteroatoms which could serve as Lewis bases. Chiral spiro bis(isoxazoline) ligands, named SPRIXs, bearing a chiral spiro skeleton and two isoxazoline rings, have been reported <19990L1795>. 

Enantioselective radical conjugate addition of an alkyl group to 587 was promoted by alkyltin hydride in the presence of chiral bis-isoxazoline derivatives <2002JA984>. 

Sasai s group [13] developed a series of bisnitrogen ligands with fused hetero spiro cyclic backbones, including spiro bis(isoxazoline) 11 and 12, spiro isoxazole-isoxazoline 13, spiro bis(oxazoline) 14, spiro bis(pyrazole) 15, and spiro bis(isoxazole) 16 (Figure 3). Ligands 11 [14] and 13 [15] exhibited excellent reactivity and enantioselectivity in the Pd-catalyzed oxidative cyclization reactions. 

Arai et al. reported that asymmetric tandem cyclization of the dialkenyl alcohol 182 in the presence of Pd(II)— spiro bis(isoxazoline) catalyst gave the bicyclic heterocycle 183 in 89% yield with 82% ee (Scheme 61).132d The reaction proceeds through Wack-er-type oxypalladation, formation of the palladacycle 185 by carbopalladation of the resulting alkylpalla-dium intermediate 184, elimination of HX, and subsequent reductive elimination of Pd(0) to give the product 183. 

Butadienyl-4-isoxazolines, such as 68, underwent thermolysis to afford mainly a dihydroazepine derivative through the formation of an intermediate azomethine ylide <01T4349>. Spiro bis(isoxazoline) ligands 71 were used in the catalytic asymmetric Wacker-type cyclisation of alkenyl alcohols <01 JA2907>. 

In 2011, Sasai and co-workers developed an asymmetric oxidative cyeliza-tion of 4-alkenoic acids in good yields and moderate ees (Scheme 5.16). The utilization of the spiro bis(isoxazoline) ligand (M,5,5)- Pr-SPRIX was crucial for this asymmetric transformation. Preliminary mechanistic investigation showed that a [(n-allyl)Pd] intermediate was involved in the reaction. This represents the first example of enantioselective oxidation of allylic C—H bonds by using only a chiral palladium catalyst. 

Recently, Sasai s group published the enantioselective oxidative carbonylation of alkenylureas. By using the palladium-spiro bis(isoxazoline) system, the desired products were produced in good yields and with moderate to good ee (Scheme 8.12) [72]. 

An oxidative cyclization of 4-alkenoic acids (37) has been developed. The reaction occurs in the presence of p-benzoquinone as oxidant and is believed to proceed via the TT-allyl Pd intermediate (38), generated by an allylic C—H activation. Moderate to good enantioselectivity was observed when the spiro bis(isoxazoline) ligand (SPRIX) (39) was employed. ... 

The reactions were performed in the presence of a series of different substituted chiral spiro bis(isoxazoline) ligands (SPRIX), Pd(II), and benzoquinone. The best results (53% ee), obtained under catalytic conditions, employ 30% mol Pd (0C0CF3)2/(M,S,S)-H-SPRIX 72, 4 equiv. of benzoquinone at —20°C under CO (1 atm) in methanol. 

Shinohara, T., Arai, M.A., Wakita, K., Aral, T. and Sasai, H. (2003) The first enantioselective intramolecular aminocarbonylation of alkenes promoted by Pd(ll)-spiro bis(isoxazoline) catalyst. Tetrahedron Letters, 44, 711-714. 

An enantioselective oxidative cyclization of 4-alkenoic acids to give y-lactone derivatives via palladium-catalyzed allylic C-H activation was also disclosed by Sasai in 2011 (Scheme 3.42) [76]. In the presence of 10mol% Pd(OAc)2 and 15mol% spiro bis(isoxazoline) ligand, a variety of five-membered ring lactones could be constructed in moderate to excellent yields. However, the enantioselectivity is highly depended on the structures of substrates. 

In contrast with the impressive evolution of asymmetric reactions with paUadium(0) catalyst, palladium(II)-catalyzed asymmetric Wacker-type oxidations have received only scant attention. For instance, Alper and Hamel and Cao and Zhang described asymmetric Pd(II)-catalyzed car-bonylation of aUyUc alcohols. Chiral bis(oxazolines) based on binaphtyl (Boxaxs ) or biphenyl backbone were also successfiiUy applied in the asymmetric Wacker-type cycUzation of aUylphenoIs. Sasai and co-workers reported on the oxidative cychzation of alkenyl alcohols with spiro bis(isoxazolines) (SPRIXs). ... 

Aral MA, Kuraishi M, Aral T, Sasai H. A New asymmetric Wacker-type cyclization and tandem cyclization promoted by Pd(II)-spiro bis(isoxazoline) catalyst. J. Am. Chem. Soc. 2001 123 2907-2908. 

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