Oximes fragmentation

The key stage of the synthesis to prepare 100 g amounts of a novel anthelmintic drug 500 from the metabolite VM-44866 (499) was a Beckmann-type oxime fragmentation (equation 217). A two-step reassembly of the spiroketal moiety efficiently produced the target molecule (30% yield of complete sequence in a 0.5 kg scale). 

The nmR chemical shifts of the methyl groups in boron-capped iron(II) diacetylmonooxime hydrazonates (14.0 and 17.7 ppm) are lower than that in the [Fe(thz)](BF4)2 complex (18.6 ppm). A second signal was assigned to the methyl substituent in a hydrazonate fragment. A signal from the azomethine carbon atoms at 168 ppm is also attributed to this fragment, whereas a line at 154 ppm corresponds to an oxime fragment. The NMR... 

Apparently, higher electron saturation and lower steric hindrance of the acetyl oxime group enable its easier (as compared to the benzoyl oxime fragment) nucleophilic addition to acetylene. 

Substituted pyrazoles fragment following pathways that are strongly dependent on the nature of the substituent. Thus iV- and C-phenylpyrazoles lead to iV-phenylaziridinium, -cyclopropenium and benzodiazepinium ions (68ZOR689, 78CHE1123), C-diphenylpyrazoles to the fluorenium ion (m/e 165) (690MS(2)739), and 1-phenylpyrazol-4-yl oximes to the 1-phenylpyrazolium ion (m/e 144) (69JCS(C)2497). 

BECKMANN Rearrangement or fragmentation Acid catalyzed rearrangement of oximes to amides or cleavage of oximes to nitnies... 

Base-catalyzed fragmentation also occurs on treatment of 5,6j9-epoxy-19-aldehyde (hemiacetal, hemiacetal-acetate or 3)5,6/ -acetal) accessible from nitrous acid-acetic acid treatment of 5a-bromo-6jS-hydroxy-19-oximes followed by mild base hydrolysis (yield not reported)... 

Treatment of 210 under traditional Eschenmoser fragmentation conditions gave only low yields of the desired alkynyl ketone 211, but this result was improved significantly by use of p-nitrobenzenesulfonylhydrazine in place of the commonly used p- lolueriesul fonylhydrazine. Compound 211 was transformed into the bis-oxime 212, reductive cyclization of which by treatment with ZrCU and NaBH4 and subsequent acylation afforded the polycyclic compound 213 with the desired all-cis... 

Certain ketoximes can be converted to nitriles by the action of proton or Lewis acids. Among these are oximes of a-diketones (illustrated above), a-keto acids, a-dialkylamino ketones, a-hydroxy ketones, p-keto ethers, and similar compounds. These are fragmentation reactions, analogous to 17-25 and 17-26. For example, ot-dialkylamino ketoximes also give amines and aldehydes or ketones besides nitriles. 

The oxime 299 is silylated in the presence of catalytic amounts of TMSOTf 20 to 300, which affords, via the Beckmann fragmentation intermediate 301 and alkylation with allyltrimethylsilane 82, 66% of the seco nitrile 302 [101, 102] (Scheme 4.39). Tris(trimethylsilyl) ketenimine 303 reacts with aldehydes such as benzaldehyde in the presence of Bp3-OEt2, via the aldol adduct 304, to give the unsaturated nitriles 305, in 99% yield, and HMDSO 7 [103]. 

A fragmentation reaction occurs if one of the oxime substituents can give rise to a relatively stable carbocation. Fragmentation is very likely to occur if a nitrogen, oxygen, or sulfur atom is present a to the oximino group. 

This rule is equally applicable to all types of true nitronates and is the most characteristic parameter of the C=N—>-0 fragment. This is particularly typical of the 13C NMR signals of the a-C atoms, which are shifted to higher field by more than 30 ppm compared to the analogous signals of the corresponding oximes. 

Except for slight differences in the bond lengths and bond angles, the structure of the nitronate fragment weakly depends on the nature of the substituents at the carbon and oxygen atoms. The lengths of analogous bonds for related types of compounds, such as nitrone (86) and ()- methyl ester oxime (87), are included for comparison (281) (Chart 3.8). 

For example, the reaction of lithium diisopropylamine (82) with N-oxide (134) leads to a rather selective deprotonation at the C-4 atom (Scheme 3.111, Eq. 1). An analogous transfer of double bond was observed for six-membered cyclic nitronates 135 (Eq. 2) (143). However, intermediates (136) that formed in the latter case undergo fast fragmentation and give conjugated ene-oximes (137) as the final products. 

These enoximes can be prepared through available annelated six-membered cyclic nitronates (391) by their silylation giving rise to the iminium cations A, whose deprotonation affords annelated 2H-5,6-dihydrooxazines (392). After the known retro-fragmentation (490), the latter compounds are transformed into the target conjugated en oximes (395). 

N,C Elimination The reactions of standard BENAs with bases were considered in the previous section. As a rule, these reactions proceed at the silicon atom of the nitroso acetal fragment. However, if a EWG-group is adjacent to the y-C atom of BENA, the ally lie proton (Hy) at this carbon atom becomes so labile that it can be eliminated already in the presence of bases at room temperature (504), thus initiating the transformation of such BENA into conjugated en oximes (Scheme 3.227). 

As can be seen in Scheme 3.249, a-azido oximes (465) can be involved with advantage in the selective reduction of the azido group in the presence of the oximino fragment and also in the selective or nonselective reduction of the oximino fragment (525). 

In some cases, silylation of AN and their derivatives produces nitroso acetals containing the N -siloxy fragment or cyclic ethers of oximes (predominantly substituted 5.6-dihydro-4f/-oxazines). To use these products in strategies for synthesis, it is worthwhile to develop convenient procedures for selective reductions of the above derivatives to the corresponding amines. 

The natural antipode of corynantheine (35, 155, 20/ ) has elegantly been prepared by Autrey and Scullard (168), starting from yohimbone (305), synthesized and resolved previously by Swan (169). Yohimbone (305) was converted to 18-formylyohimbone (306) and then through 307 to oxime 308. On reaction with thionyl chloride, 308 underwent a Beckmann fragmentation to the trans-substituted indolo[2,3-a]quinolizine 310, which after desulfurization and esterification resulted in the levorotatory methyl corynantheate (304). This product... 

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