Radical addition to imines

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

Other examples of ZnR2-initiated radical additions to C=N bond-containing compounds can be found in a recent review by Miyabe et al 7 Overall, radical additions to imines and related derivatives may be considered as a valuable alternative to nucleophilic additions, particularly for the introduction of secondary and tertiary alkyl groups. In general, organozinc-mediated radical reactions are a new and significant direction with great potential.382,385... 

Scheme 14.7 General mechanism for the nucleophilic radical addition to imines mediated by Ti (IV).

Furthermore, we also performed kinetic studies for alkyl radical additions onto different types of C=N bonds such as imines and oxime ethers. The kinetic data are summarized in Figure S. Kinetic analysis of the intramolecular addition of alkyl radicals to C=N bonds provides several experimentally important results. First, alkyl radical additions to C=N bonds are much faster than the corresponding additions to C=C bonds, indicating that C=N bonds are much better radical acceptors than C=C bonds. Furthermore, 5-exo cyclization is faster than 6-exo cyclization. Second, the intramolecular additions of alkyl radicals to C=N bonds are essentially irreversible. Third, alkyl radical additions to oxime ethers and hydrazones are faster than alkyl radical additions to imines, suggesting the possibility of a dependence of the cyclization rate on the electron density at the carbon atom of the radical acceptor. 

Intermolecular alkyl radical addition to imine derivatives was studied in aqueous media using indium as a single electron transfer radical initiator. The one-pot reaction based on radical addition to glyoxylic hydrazone provided a convenient method for preparing the a-amino acids. Indium-mediated radical addition to an electron-deficient C=C bond also proceeded effectively to provide a new carbon-carbon bond-forming method in aqueous media (Scheme 7.11).15... 

Radicals are also produced by manipulation of the a-carboxy and amino groups. The former usually results in decarboxylation, with the products no longer being a-amino acids [61]. Aminyl radicals have been generated from sulfenamide precursors and exploited in cyclization reactions, as illustrated in Scheme 11 [62]. Radical additions to imines [63], oximes [64], isothiocyanates [65] and isocyanides [66] of a-... 

MeON=CH(CH2)3CHO with BusSnH and AIBN, for example led to trans-2-(methoxyamino)cyclopentanol in good yield.Addition of radical to the C=N unit of R—C=N—SPh or R—C=N—OBz led to cyclic imines. Radical addition to... 

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. 

Intramolecular addition of trialkylboranes to imines and related compounds have been reported and the main results are part of review articles [94, 95]. Addition of ethyl radicals generated from Et3B to aldimines affords the desired addition product in fair to good yield but low diaster control (Scheme 40, Eq. 40a) [96]. Similar reactions with aldoxime ethers [97], aldehyde hydrazones [97], and N-sulfonylaldimines [98] are reported. Radical addition to ketimines has been recently reported (Eq. 40b) [99]. Addition of triethylborane to 2H-azirine-3-carboxylate derivatives is reported [100]. Very recently, Somfai has extended this reaction to the addition of different alkyl radicals generated from trialkylboranes to a chiral ester of 2ff-azirine-3-carboxylate under Lewis acid activation with CuCl (Eq. 40c) [101]. 

In the presence of an alkyl iodide, selective alkyl radical addition to the C-atom of the imine generated in situ occurs, overcoming the competitive phenylation reaction (Equation 14.20) [30]. The Ph- radical, generated by decomposition of the diazonium salt, as described before, generates the alkyl radical by selective iodine atom transfer (Equation 14.21). 

Even imines formed by in situ condensation of aromatic amines with either acetaldehyde or formaldehyde afforded the desired products. The successful radical addition to these rather unstable and polymerizable imines in aqueous medium may be ascribed to the lack of steric hindrance at the C-atom. 

The C=N bond of simple imines possesses modest reactivity toward intermolecular radical additions, so such acceptors have rarely been exploited. To enhance their reactivity toward nucleophilic radicals, electron-withdrawing groups at the imine carbon have been effective, as demonstrated by Bertrand in radical additions to a-iminoesters prepared from chiral amines [25]. Also, more reactive oxime ethers have been exploited extensively for radical addition, mainly through the longstanding efforts of Naito [26]. In most cases, stereocontrol has been imparted through the substituents on the imino carbon chiral O-substituents on oximes for stereocontrol were ineffective, presumably due to poor rotamer control [27, 28]. 

The quinoline formation from 2,4-dinitrophenyl oximes suggested to us the possibility of generating radical intermediates and prompted us to study the synthesis of cyclic imines by iminyl radical addition to an internal olefinic moiety as shown in Scheme 44. 

Radical cyclization is not limited to reaction with a C=C unit (see 15-29 and 15-30), and reactions with both C=N and C=0 moieties are known. Reaction of MeON=CH(CH2)3CHO with Bu3SnH and AIBN, for example, led to trans-2-(methoxyamino)cyclopentanol in good yield.Conjugated ketones add to aldehyde via the p-carbon under radical conditions (2 equivalents of Bu3SnH and 0.1 equivalent of CuCl) to give a p-hydroxy ketone.Addition of radical to the C=N unit of R C=N SPh ° or R—C=N—led to cyclic imines. Radical addition to simple imines leads to aminocycloalkenes. Radical also add to the carbonyl unit of phenylthio esters to give cyclic ketones. 

Boron trifluoride catalyses the 1,3-phosphotropic rearrangement of the a-phosphorylated imine (65) to give (66).35 This reaction takes place at room temperature, whereas the uncatalysed reaction requires heating to 150-2000C. High yields of the addition products (67) have been obtained from the reaction of carbon-centred radicals with diphenylvinylphosphine oxide.36 Radical addition to the chiral phosphine oxides (68) using Barton s method provides diastereomeric ratios of up to 9 1 in the case of (69). 

Although a few examples of radical additions to carbonyl compounds are known (23, 24), none are known to the authors for imines (25) ... 

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 ... 

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