Nitriles, oxidative cleavage

The conversion of the polystyrene-supported selenyl bromide 289 into the corresponding acid 290 allowed dicyclohexylcarbodiimide (DCC)-mediated coupling with an amidoxime to give the 1,2,4-oxadiazolyl-substituted selenium resin 291 (Scheme 48). Reaction with lithium diisopropylamide (LDA) and allylation gave the a-sub-stituted selenium resin 292, which was then used as an alkene substrate for 1,3-dipolar cycloaddition with nitrile oxides. Cleavage of heterocycles 293 from the resin was executed in an elegant manner via selenoxide syn-elimination from the resin <2005JC0726>. 

A rapid access to carbocyclic nucleosides, containing a fused isoxazoline ring has been proposed, starting from cyclopentadiene. The route involves a het-ero Diels-Alder cycloaddition reaction of nitrosocarbonylbenzene followed by a 1,3-dipolar cycloaddition of nitrile oxides, cleavage of the N-0 tether and transformation of the heterocyclic aminols into nucleosides via construction of purine and pyrimidine heterocycles (457). 

Methods of synthesis for carboxylic acids include (1) oxidation of alkyl-benzenes, (2) oxidative cleavage of alkenes, (3) oxidation of primary alcohols or aldehydes, (4) hydrolysis of nitriles, and (5) reaction of Grignard reagents with CO2 (carboxylation). General reactions of carboxylic acids include (1) loss of the acidic proton, (2) nucleophilic acyl substitution at the carbonyl group, (3) substitution on the a carbon, and (4) reduction. 

Transformation of the amino nitriles to the corresponding amino acids, with removal of the dioxane ring, is carried out in two steps. Treatment with concentrated hydrochloric acid results in the hydrolysis of both the nitrile and the acetal group, and in cyclization to the corresponding 3-substituted 5-hydroxyniethyl-3-methyl-2-oxo-6-phenylmorpholinc hydrochlorides. Oxidative cleavage with 2 N sodium hydroxide solution, air and Raney nickel at 120 CC (ca. 30 h) delivers the hydrochlorides of the free a-methylamino acids in high yield. 

A nitrile oxide generated from a sugar derived aldoxime 30 underwent INOC reaction to the chiral pyranoisoxazoline 31 (Eq. 4) [20]. Reductive cleavage of isoxazoline 31 followed by acetylation provided the tetrasubstituted pyran 32. 

Intramolecular nitrone cycloadditions often require higher temperatures as nitrones react more sluggishly with alkenes than do nitrile oxides and the products contain a substituent on nitrogen which may not be desirable. Conspicuously absent among various nitrones employed earlier have been NH nitrones, which are tautomers of the more stable oximes. However, Grigg et al. [58 a] and Padwa and Norman [58b] have demonstrated that under certain conditions oximes can undergo addition to electron deficient olefins as Michael acceptors, followed by cycloadditions to multiple bonds. We found that intramolecular oxime-olefin cycloaddition (lOOC) can occur thermally via an H-nitrone and lead to stereospecific introduction of two or more stereocenters. This is an excellent procedure for the stereoselective introduction of amino alcohol functionality via N-0 bond cleavage. 

Stable furoxans are convenient starting compounds for generating short-lived nitrile oxides XCNO (X = ONC, NC, Cl, Br, and Me) by thermolysis (10, 11, 80, 81). The thermolysis of benzotrifuroxan (200°, in excess PhCN) proceeds (Scheme 1.6) with the cleavage of the C-C and 0-N(0) bonds in only one furoxan ring to give bifuroxan bis(nitrile oxide). The latter undergoes further reactions such as cycloaddition with PhCN or conversion to bisisocyanate (82). 

Certain specific steric effects are operative on intramolecular nitrile oxide— olefin cycloadditions. These effects are governed by both ring size and character of substituents. Thus, cycloadditions to the exomethylene group are successful with substituted methylenecyclohexanones 334 (m = 1, 2 n = 2) and gave tricyclic 335 (m = 1, 2), but do not occur with methylenecyclopentanones 334 (m = 1, 2, 3 n = 1). Activation energies calculated by molecular mechanics are consistent with these results. Cleavage of 335 (m = 2) by Raney Ni gives cA-decalone 336 (403). 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

An efficient synthetic route to (10Z)- and (10 )-19-lluoro-la,25-dihydroxy vitamin D3 has been developed (488). The key feature of this pathway is the introduction of a 19-fluoromethylene group to a (5 )-19-nor-10-oxo-vitamin D derivative. The 10-oxo compound 445 has been obtained via a 1,3-dipolar cycloaddition reaction of (5 )-la,25-dihydroxyvitamin D with in situ generated nitrile oxide, followed by ring cleavage of the formed isoxazoline moiety with molybdenum hexacarbonyl. Conversion of the keto group of (5 )-19-nor-10-oxo-vitamin D to the E and Z fluoromethylene group has been achieved via a two-step sequence, involving a reaction of lithiofluoromethyl phenyl sulfone, followed by the reductive de-sulfonylation of the u-lluoro-j3-hydroxysulfone. The dye-sensitized photoisomerization of the (5 )-19-fluorovitamin D affords the desired (5Z)-19-fluorovitamin D derivatives, (10Z)- and (10 )-19-fluoro-la,25-dihydroxy-vitamin D3. 

Sealants obtained by curing polysulfide liquid polymers with aryl bis(nitrile oxides) possess stmctural feature of thiohydroximic acid ester. These materials exhibit poor thermal stability when heated at 60°C they soften within days and liquefy in 3 weeks. Products obtained with excess nitrile oxide degrade faster than those produced with equimolar amounts of reagents. Spectroscopic studies demonstrate that, after an initial rapid addition between nitrile oxide and thiol, a second slower reaction occurs which consumes additional nitrile oxide. Thiohydroximic acid derivatives have been shown to react with nitrile oxides at ambient temperature to form 1,2,4-oxadiazole 4-oxides and alkyl thiol. In the case of a polysulfide sealant, the rupture of a C-S bond to form the thiol involves cleavage of the polymer backbone. Continuation of the process leads to degradation of the sealant. These observations have been supported by thermal analysis studies on the poly sulfide sealants and model polymers (511). 

Autoxidation of secondary acetonitriles under phase-transfer catalytic conditions [2] avoids the use of hazardous and/or expensive materials required for the classical conversion of the nitriles into ketones. In the course of C-alkylation of secondary acetonitriles (see Chapter 6), it had been noted that oxidative cleavage of the nitrile group frequently occurred (Scheme 10.7) [3]. In both cases, oxidation of the anionic intermediate presumably proceeds via the peroxy derivative with the extrusion of the cyanate ion [2], Advantage of the direct oxidation reaction has been made in the synthesis of aryl ketones [3], particularly of benzoylheteroarenes. The cyanomethylheteroarenes, obtained by a photochemically induced reaction of halo-heteroarenes with phenylacetonitrile, are oxidized by air under the basic conditions. Oxidative coupling of bromoacetonitriles under basic catalytic conditions has been also observed (see Chapter 6). 

The formation of unsaturated cyanohydrins (from a, -unsaturated aldehydes) is of further advantage as these products possess an additional synthetic potential. As in the saturated cyanohydrins (above in Scheme 6) they possess the same opportunities for elaboration of the hydroxyl or nitrile moiety, although the presence of the carbon-carbon double bond offers the possibility for additional transformations to be performed such as additions [108], oxidative cleavage [117,118] and epoxidation [119] (Scheme 7). Thus, these highly functionalised chiral units can be of greater importance to an organic chemist. 

Substituted 1,2,4-oxadiazoles were prepared by addition of nitrile oxides to imines or hydrazones. It has been reported that interaction of hydroximoyl chlorides 262 with chiral hydrazones 263 in the presence of EtsN leads to intermediates 264 with diastereoselectivity up to 97%. A subsequent N-N bond cleavage to remove chiral auxiliary by formic acid leads to 1,2,4-oxadiazolines 265 with ee up to 91% (equation 113). ... 

While arylnitrile oxides dimerize in protic solvents and in pure pyridine (cf. 4.04.8.1.3.), they form bis(adducts) (191) and (192) via zwitterions (189) with pyridine in apolar solvents (Scheme 83) <89JHC757,90Gi>. Significantly, the cycloaddition of the nitrile oxide to pyridine to give (190) is not a concerted process. Heterocycles (191) undergo base catalyzed ring cleavage (Scheme 84). 

Aminoalcohol Ring Cleavage of Nitrile Oxide Cycloadducts Synthesis of... 

Ring cleavage with concomitant fragmentation, giving nitrile oxides. 

Aminoalcohol Ring Cleavage of Nitrile Oxide Cycloadducts Synthesis of Amino Polyols, Amino Sugars, and Amino Acids... 

In the great major tiy of applications that use the intramolecular nitrile oxide-alkene cycloaddition, the intention is to prepare intermediates for the synthesis of natural products or related compounds. The most popular transformations of these isoxazolines are the following ring cleavage modes ... 

Synthesis of Macrocycles Employing Intramolecular Nitrile Oxide Cycloaddition and Aldol Cleavage... 

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