Nitrones reactions with Grignard

The furoxan ring is more susceptible to nucleophilic attack and reduction than it is to reaction with electrophiles or oxidation. Grignard reagents react with disubstituted furoxans primarily at C-3 and, in most cases, the resulting adduct fragments to a nitrile and a nitronate salt which affords a ketone on workup. 

The reaction of nitrones with various nucleophiles provides a powerful strategy for the introduction of a substituent at the a-position of secondary amines.9 The reaction of nitrones with Grignard reagents or organolithium compounds affords various a-substituted hydroxylamines, which can be converted into a-substituted secondary amines by catalytic hydrogenation. The nucleophilic reaction with potassium cyanide gives a-cyanohydroxylamines which are useful precursors for amino acids and N-hydroxyamino acids.10... 

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

O - P h e n y 1 - /V - e r y t h r o s y 1 nitrone (336), as a Ci,C i-bis-electrophile, when subjected to the double addition of Grignard reagents (in a domino style), leads to acyclic hydroxylamine (338) via the formation of open-chain nitrone (337 ). The reaction proceeds at 0°C with variable diastereoselectivity ranging from medium to good, depending on the organometalic reagent used (Scheme 2.140) (564). 

Recently, semiempirical PM3 computational analysis (568) and first ab initio study (569) of the nucleophilic addition to chiral nitrones of Grignard reagents have been carried out. The data revealed that all reactions are exothermic and proceed through /w-complexation of nitrones with the organometalic reagent. 

Reactions of allylic and benzylic Grignard reagents with alkyl nitro compounds can, under the right conditions, provide an acceptable route to nitrones [11]. Lack of regio- and stereoselectivity may be a problem, though the former can be controlled to some extent by varying the acid used for protonation, e.g. 

Ketoximes from R CH NOj and R MgBr. Reaction of the Vilsmeier reagent with the lithium nitronate of a nitroalkane activates the -position to attack by Grignard reagents to form ketoximes (equation I). 

Carbodiitnides (332 Scheme 55) form amidines on treatment with NaBH4 in alcohols, Grignard reagents, sodium phenylacetylide, carbon monoxide in the presence of s-butyl- or t-butyl-lithium and nitrones catalyzed by HBF4. In the reaction of stannylated or silylated ynamines with carbodiimides... 

Another method to introduce a substituent into the 1,2,4-triazine system is vicarious nucleophilic substitution. Here, a carbanion with a leaving group at the carbanionic center reacts with a 1,2,4-triazine replacing protons in the 5-, 3- and 6-position with the carbanionic moiety. The reactivity of the various positions decreases in the order 5 > 3 > 6. This reactivity differs from that toward Grignard reagents. Thus, substitution of the 5-position occurs in the 1,2,4-triazine to afford 15 which undergoes elimination to 16 followed by protonation to yield 17 275,276 Carbanions of the following compounds were used in this reaction nitrones, chloromethyl phenyl sulfones, chloromethanesulfonamides and acetonitriles.274-378... 

A general method for accessing allylamines from nitrones is by a Grignard reaction followed by reduction of the resulting hydroxylamines with Zn. 

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