Nitrones radical addition

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

Radical additions to imines, nitrones, and related compounds 401... 

The use of Et3B as a radical initiator makes it possible to carry out the addition of other alkyl radicals to nitrone (286) using alkyl iodides. Good yields have been obtained of products (288b-d) when an excess of the appropriate alkyl iodide was used (Scheme 2.110). It has been established that the yield of alkyl by-products (288a) tends to decrease with the increase of the reaction temperature. The stereochemical features of this reaction are explained by the alkyl radical addition taking place predominantly from the less hindered re-face of (286) to avoid steric interaction with the phenyl group (525). 

Excellent diastereoselectivity of alkyl radical addition was also observed in a number of other nitrones (291-293) (Scheme 2.111) (526). 

This reaction is very important for the synthesis of natural products and for the design of diversely substituted ligands. The use of Sml2 in radical additions of nitrones to 0.,j3-unsaturated amides and esters, constitutes a convenient synthesis of various functionalized y-amino acids with high enantiomeric excess (Schemes 2.114 and 2.115) (531-533). 

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. 

Naito reported a radical addition to nitrones that occurs with high stereocontrol (Scheme 41) [102],... 

Atom abstraction from the cr-carbon atom in spin adducts, which leads to nitrones, and thence in some instances to spin adducts of these nitrones (e.g. Scheme 9), is undoubtedly a general phenomenon. For this sequence to be observed it is necessary that some, or all, of the following conditions are fulfilled. (0 The nitrone is more reactive towards radical addition than is the original spin trap and/or the latter is substantially consumed in the reaction. (h) The initial spin adduct is particularly susceptible to hydrogen-atom loss (and probably reacts this way by disproportionation). ( 7) The secondary spin adduct is particularly persistent. 

B. Free Radical Additions to Oximes, Oxime Ethers and Nitrones. 142... 

Cyclization of nitro-stabilized radicals provides another method for the generation of cyclic nitronates (221). Oxidation of the aci-foim of nitroalkanes with ceric ammonium nitrate generates the ot-carbon centered radical, which in the presence of an alkene, leads to the homologation of the a-radical. In the case of a tethered alkene of appropriate length, radical addition leads to a cyclic nitronate (Scheme 2.20). 

Nitrone 82 may be used to distinguish carbon radicals and oxygen radicals. With alkyl- and aryl radicals addition to the nitrone group with formation of aminyloxides... 

An appropriate modified reaction Scheme 16 is shown and involves the regeneration of nitrone radicals. Unsaturation is believed to be important here although it could not be identified but this is believed to be due to the rapid addition of nitrones with unsaturation by a 1,3- addition on processing. 

There is one important exception to the statement that radical termination steps produce products with an even number of electrons. A radical addition step may produce a radical product that is much less reactive than the reacting precursor, such that further addition may be precluded. This process, known as spin trapping, is primarily useful as a means of studying radicals that cannot be studied directly by EPR. Adding a nitroso compound or a nitrone to a reaction mixture involving short-lived radicals can produce a spin adduct, a longer-lived species that can be studied directly by EPR spectrometry. The spectrum of the product is often diagnostic of its radical precursor. 

When molecules with a double bond are quite polar such as nitrone, the addition reaction rates of non-polar arythiyl radical are also reduced in polar solvents. The large dipole moment of nitrone in the reactant is reduced on the addition of ArS producing a less polar nitroxide radical, as shown Scheme 19 [55],... 

The radical addition to a nitrone is actually more analogous to the addition of a radical to butadiene because in both cases the unpaired electron in the addition product is stabilized by delocalization in a ir-orbital over two or three atoms. The 9-12 fold increase in rate constant of addition produced by attaching the vinyl substituent to ethylene (butadiene) is much greater when an oxygen atom is attached to the nitrogen of an imine to make a nitrone ... 

The absolute rate constants of radical addition to butadiene are 1.25x10 sec l for methyl (26) and 4.0x10 sec for trifluoromethyl (19) both in aqueous solution. These values are of the same order of magnitude as estimated for additions to nitrones in benzene. 

It is convenient to refer here to the addition of free radicals, in this case generated from azo-bis-isobutyronitrile, to nitrones and nitroso-compounds. 1 2-Adducts are formed, as shown in equations (43) and... 

Although these reactions are formulated as ionic reactions via 947 and 949, because of the apparent partial formation of polymers and inhibition of the fluoride-catalyzed reaction of pyridine N-oxide 860 with aUyl 82 or benzyltrimethylsilane 83 by sulfur or galvinoxyl yet not by Tempo, a radical mechanism caimot be excluded [61, 62]. The closely related additions of allyltrimethylsilane 82 (cf. Section 7.3) to nitrones 976 are catalyzed by TMSOTf 20 to give, via 977, either o-unsatu-rated hydroxylamines 978 or isoxazoHdines 979 (cf also the additions of 965 to 962a and 969 in schemes 7.20 and 7.21). 

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