Radical hydrazones

Hydroperoxides have been obtained from the autoxidation of alkanes, aralkanes, alkenes, ketones, enols, hydrazones, aromatic amines, amides, ethers, acetals, alcohols, and organomineral compounds, eg, Grignard reagents (10,45). In autoxidations involving hydrazones, double-bond migration occurs with the formation of hydroperoxy—azo compounds via free-radical chain processes (10,59) (eq. 20). 

Unsaturated ketones react with phenyUiydrazines to form hydrazones, which under acidic conditions cyclize to pyrazolines (35). Oxidation, instead of acid treatment, of the hydrazone with thianthrene radical cation (TH " ) perchlorate yields pyrazoles this oxidative cyclization does not proceed via the pyrazoline (eq. 4). 

Hexafluoroacetone azine accepts nucleophiles (ROH, RSH, R NH) in positions 1 and 2 to yield hydrazones [27] Phosphites give open-chain products via a skeletal rearrangement [22] Radical addition reactions are also reported [22] Treatment of tnfluoropyruvates with tosylhydrazine and phosphorus oxychlo-ride-pyndme yields tnfluoromethyl-substituted diazo compounds [24] (equation 3)... 

Recent studies have been directed towards the synthesis of heterocyclic hydrazones which have lower toxicities than thiosemicarbazones [44], It has been proposed that the hydrazinic N-H group is essential for activity since it might be involved in a crucial radical formation step important in the mechanism of RDR. This is supported by the loss of antileprotic activity for this series of compounds when the hydrazinic hydrogen is replaced by a methyl group [44]. The heterocyclic hydrazones, like thiosemicarbazones, behave as tridentate ligands. 

Several functional groups containing carbon-nitrogen double bonds can participate in radical cyclizations. Among these are oxime ethers, imines, and hydrazones.337 Hydrazones and oximes are somewhat more reactive than imines, evidently because the adjacent substituents can stabilize the radical center at nitrogen.338 Cyclization at these functional groups leads to amino- substituted products. 

Entries 20 to 23 involve additions to C=N double bonds in oxime ethers and hydrazones. These reactions result in installation of a nitrogen substituent on the newly formed rings. Entry 20 involves the addition of the triphenylstannyl radical to the terminal alkyne followed by cyclization of the resulting vinyl radical. The product can be proto-destannylated in good yield. The ring closure generates an anti relationship for the amino substituent, which is consistent with the TS shown below. 

Entry 21 involves addition to a glyoxylic hydrazone and the cis ring junction is dictated by strain effects. The primary phenylselenyl group is reductively removed under the reaction conditions. Entry 22 involves generation of a stannyloxy radical by addition of the stannyl radical at the carbonyl oxygen. Cyclization then ensues, with the cis-trans ratio being determined by the conformation of the cyclization TS. 

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... 

Another example of the application of high pressure in the field of domino transformations has been revealed by Brinza and Fallis, representing a carbonylation/cy-clization procedure [4]. Thus, when hydrazones 10-12, bearing a bromine atom, are subjected to standard radical conditions under a high-pressure atmosphere of carbon dioxide, cyclopentanones 10-16 and 10-17 are smoothly produced in good yields (Scheme 10.3). 

It is assumed that the reaction is initiated by a radical bromine abstraction to give 10-13, which after carbon monoxide insertion undergoes a rapid 5 -exo cycliza-tion onto the hydrazone moiety. The two diastereomeric hydrazinyl cyclopentanones 10-16 and 10-17 are formed with good yields, though with low stereoselectivity. 

Photo-oxidation is the main photofading pathway for the majority of dyes.18 Oxygen, particularly singlet oxygen, and radicals such as hydroxyl and hydroperoxyl, are believed to be the major electrophilic species responsible for photodegradation. Attack normally occurs at or around the azo (or hydrazone) group and plausible mechanistic pathways for the photo-oxidation of hydro-xyazo dyes have been proposed.18,19... 

In earlier studies the in vitro transition metal-catalyzed oxidation of proteins and the interaction of proteins with free radicals have been studied. In 1983, Levine [1] showed that the oxidative inactivation of enzymes and the oxidative modification of proteins resulted in the formation of protein carbonyl derivatives. These derivatives easily react with dinitrophenyl-hydrazine (DNPH) to form protein hydrazones, which were used for the detection of protein carbonyl content. Using this method and spin-trapping with PBN, it has been demonstrated [2,3] that protein oxidation and inactivation of glutamine synthetase (a key enzyme in the regulation of amino acid metabolism and the brain L-glutamate and y-aminobutyric acid levels) were sharply enhanced during ischemia- and reperfusion-induced injury in gerbil brain. 

Ponka et al. [372] showed that pyridoxal isonicotinoyl hydrazone (PIH, Figure 19.23) is an iron chelating agent. Numerous studies showed the possibility of using this chelator for the treatment of iron overload disease [373], In subsequent studies the antioxidant activity of PIN has been confirmed. For example, Hermes-Lima et al. [374,375] showed that PIN protected plasmid pUC-18 DNA and 2-deoxyribose against hydroxyl radical damage. 

In a combination of photochemical cyclization and a radical reaction Yoshimatsu et al synthesized 2-azabicyclo[33.0locta-3,7-diene 169 from the trienal hydrazone 166.1891 The domino process was initiated by irradiation of 166 at 400-500 nm in benzene. The transformation may include an intermolecular [2+2]-cyclization, followed by ring opening to give... 

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]. 

Enantioselective radical addition to AT-acyl hydrazone using triethylborane as chain transfer reagent has been reported by Friestad. Enantiomeric excesses up to 95% were obtained in the presence of copper(II)-bisoxazolines Lewis acid (Scheme 51) [115]. 

Scheme 31 Enantioselective radical additions onto hydrazones...

Friestad and co-workers recently demonstrated that N-acyl hydrazones were excellent radical acceptors in the presence of a chiral Lewis acid [84], Valerolactam-derived hydrazone 117 proved to be the optimal substrate for enantioselective radical additions. Upon further optimization it was found that Cu(OTf )i and f-bulyl bisoxazoline ligand 96 gave the best yields and ee s (Scheme 31). Interestingly, a mixed solvent system (benzene dichloromethane in a 2 1 ratio, respectively) in the presence of molecular sieves (4 A) were necessary to achieve high yields and selectivities. 

Equation 13.58 describes the radical cyclization of SAMP hydrazone 173 [67]. In the presence of tributyltin hydride and a radical initiator, cyclization to 174 takes place in 78% yield. It is not clear what the full scope of this reaction is or what its utility in synthesis might be. 

Oxidation of ketone phenylhydrazones generates a radical-cation centre on the nitrogen atom adjacent to the benzene ring. The radical-cation is delocalised by both the hydrazone group and the phenyl ring. Reactions of 1,3,5-triphenyl-A -pyazolines illustrate the properties of these radical-cations. Two one-electron waves are seen at a rotating disc electrode in acetonitrile and for 1,3.5-triphenyl-pyrazoline, Ey. = 0.82 and 1.68 V vs. see [33]. The delocalised radical-cation is... 

The radical cations (47) produced by T oxidation of aryl aldehyde hydrazones acted as 1,3-dipoles in reaction with nitriles to form, after a second T oxidation, 1,2,4-triazoles (Scheme 4) (85TL5655). 

A Although it would be possible to convert 3-bromo-4-melhylani-line (7.2) into the corresponding hydrazine, by diazotization and reduction, react it with cyclohexanone, and then subject the product hydrazone to a Fischer indolization, the bromine substituent would still remain in the indole (note two isomers would form). Of course, this substituent could be displaced reductively using tributyltin hydride and a radical initiator [AIBN, azobis(isobuty-ronitrile)], but the overall synthesis is clumsy and non-selective and there should be a simpler route. 

The oxidation of hydrazine derivatives with diethyl azodicarboxylate is of particular interest because it involves direct hydrogen abstraction. The oxidation of keto hydrazones with lead tetraacetate leads to azoacetates, presumably by a free radical mechanism. 

It must be reiterated that, whereas aromatic azo compounds are relatively stable thermally and can be subjected to typical reactions of aromatic compounds [67, 68a, 88], the aliphatic azo compounds may be substantially less stable thermally. Aliphatic azo compounds, such as oc,a -azobis(isobutyro-nitrile), do decompose on heating and are used as free radical sources. Hence adequate safety precautions must be taken in handling them. This, by the way, does not mean that aliphatic azo compounds have not been subjected to distillation and to vapor phase chromatography. Many have been distilled and, as will be pointed out in a subsequent section, their preparation by isomerization of hydrazone depends on a distillation technique. 

The reaction of diphenykoethy) radical with benzophenone azine or benzophenone hydrazone gives 2,2,3,3-tetrapbenylaziridme384 (Eq, 23a). 

The base-catalyzed, / -elimination reaction of D-mannose phenyl-hydrazone is consistent with the acyclic structure for the phenylhydra-zone in solution. However, the small proportion of a nitroxide radical observed on treatment of the phenylhydrazone with a strong base may indicate the existence also of a fractional proportion in a cyclic structure in equilibrium with the open-ring structure, as was suggested by Blair and Roberts (43). The hydrazino moiety required for nitroxide-radical formation could be derived from the cyclic form of D-mannose phenylhydrazone in solution. 

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