Furan nitrone compounds

Kelleher etal, US Patent 6,376,540 (April 23, 2002) Assignee Centaur Pharmaceuticals, Inc. 

N-Isopropylhydroxylamine and 5-formylfuran-2-sulfonic acid, sodium salt hydrate (5.94 g), were refluxed in 200ml methyl alcohol 24 hours. Thereafter, another portion of N-isopropylhydroxylamine was added and the mixture refluxed 24 hours, then solvent was removed and a yellow solid isolated. The solid was re-crystallized in EtOAc and the product isolated in 15% yield, mp = 230 °C (dec). and C-NMR and IR data supplied. 

The preparation of the reagent of Step 1 and other alkylhydroxylamine analogues is provided by the author. 

2-[(Sulfamoyl-N-morpholino)furan-5-yl]nitrone derivatives were also prepared by the author as illustrated in Eq. 1. Other derivatives are provided below. 

Cyclic nitrones have been prepared by the oxidation of 3,4-dihydroisoquinolines using sodium tungstate (2) as illustrated in Eq. 2. Spiro nitrones, (II), have also been prepared using this method. 

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Kelleher JA, Maples KR, Waterbury LD, Wilcox AL, Xu H, Zhang Y-K. Furan nitrone compounds, US Patent No. 5942507, August 24, 1999. 

Diacetates of 1,4-butenediol derivatives are useful for double allylation to give cyclic compounds. l,4-Diacetoxy-2-butene (126) reacts with the cyclohexanone enamine 125 to give bicyclo[4.3.1]decenone (127) and vinylbicy-clo[3.2.1]octanone (128)[85,86]. The reaction of the 3-ketoglutarate 130 with cij-cyclopentene-3,5-diacetate (129) affords the furan derivative 131 [87]. The C- and 0-allylations of ambident lithium [(phenylsulfonyl)methylene]nitronate (132) with 129 give isoxazoline-2-oxide 133, which is converted into c -3-hydroxy-4-cyanocyclopentene (134)[S8]. Similarly, chiral m-3-amino-4-hyd-roxycyclopentene was prepared by the cyclization of yV-tosylcarbamate[89]. 

One possible solution of this problem is to differentiate a radical first as electrophilic or nucleophilic with respect to its partner, depending upon its tendency to gain or lose electron. Then the relevant atomic Fukui function (/+ or / ) or softness f.v+ or s ) should be used. Using this approach, regiochemistry of radical addition to heteratom C=X double bond (aldehydes, nitrones, imines, etc.) and heteronuclear ring compounds (such as uracil, thymine, furan, pyridine, etc.) could be explained [34], A more rigorous approach will be to define the Fukui function for radical attack in such a way that it takes care of the inherent nature of a radical and thus differentiates one radical from the other. 

Trimethylsilyl perrhenate forms colorless crystals, which are very sensitive to hydrolysis and which must be handled in a dry atmosphere. Under anhydrous conditions, the compound is stable to light and oxidation. Contaminated products undergo slow decomposition at room temperature, blue reduction products of Re(VII) being formed. In an excess of water trimethylsilyl perrhenate is hydrolyzed quickly and quantitatively. The perrhenic acid formed in this reaction together with trimethylsilanol can be determined by acidimetric titration or precipitation as nitron perrhenate. Trimethylsilyl perrhenate is soluble without decomposition in all common anhydrous and aprotic solvents (benzene, cyclohexane, ethyl ether, tetrahydro-furan, chloroform, etc.). 

Benzyne can be trapped in 1,3-dipolar cycloaddition reactions provided that the 1,3-dipolar species is sufficiently stable under the conditions necessary for benzyne generation. As an illustration of this, benzyne reacts with the nitrile oxide group in preference to the furan ring of compound 19, whereby adduct 20 is obtained.27 Benzyne and the nitrone 21 give adduct 22,28 and... 

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