Metal-free oxidative amination reaction

As before, the exploration of the metal-free oxidative amination was a competitive process. Both Chang" and Antonchick" simultaneously discovered nearly identical I(III)-mediated aminations. They both proposed that the reactions operated by generating an electrophilic nitrogen source in situ. This new species then acted as an R2N equivalent and aminated the arene via an electrophilic aromatic substitution mechanism. This hypothesis seemed appealing, but their data could not be directly compared to ours, as neither Chang nor Antonchick performed reactions on arene substrates that could provide mixtures of regiomers (e.g., toluene). 

Ammonium-directed metal-free oxidation of cyclic allylic and homoallylic amines has been reviewed. Such reactions yield all four diastereoisomers of the corresponding 3-amino-1,2-diols, and have featured in recent syntheses of ( )-l-deoxynojirimycin and ( )-l-deoxyaltronojirimycin. ... 

PhI(OTf)2 is an effective oxidant for the direct formation of bicyclic diazenium salts from a variety of linear hydrazone precursors. This oxidative cyclization is postulated to occur by the iodine(III)-mediated formation of an l-aza-2-azoniaallene salt intermediate. A direct intermolecular allylic amination has been achieved with up to 99% yields using metal-free conditions. The reaction employs a hypervalent iodine(lll) reagent as an oxidant and bistosylimide as a nitrogen source. Mechanistic studies including isotope labelling and Hammett correlation indicated that depending... 

The fact that complex 38 does not react further - that is, it does not oxidatively add the N—H bond - is due to the comparatively low electron density present on the Ir center. However, in the presence of more electron-rich phosphines an adduct similar to 38 may be observed in situ by NMR (see Section 6.5.3 see also below), but then readily activates N—H or C—H bonds. Amine coordination to an electron-rich Ir(I) center further augments its electron density and thus its propensity to oxidative addition reactions. Not only accessible N—H bonds are therefore readily activated but also C—H bonds [32] (cf. cyclo-metallations in Equation 6.14 and Scheme 6.10 below). This latter activation is a possible side reaction and mode of catalyst deactivation in OHA reactions that follow the CMM mechanism. Phosphine-free cationic Ir(I)-amine complexes were also shown to be quite reactive towards C—H bonds [30aj. The stable Ir-ammonia complex 39, which was isolated and structurally characterized by Hartwig and coworkers (Figure 6.7) [33], is accessible either by thermally induced reductive elimination of the corresponding Ir(III)-amido-hydrido precursor or by an acid-base reaction between the 14-electron Ir(I) intermediate 53 and ammonia (see Scheme 6.9). 

An overview of some metal-free reactions, for example oxidation, amination, and halogenation, is given in Table 7. 

The large group of inhibitors of free radical chain reactions are frequently used in combination with metal salts or organometallic stabilizers. They are amines, sulfur- or phosphorus-containing compounds, phenols, alcohols, or chelates. Aromatic phosphites at about 1 p.p.r. chelate have undesirable metal impurities and inhibit oxidative free radical reactions. Some of the more popular are pentaerythritol, sorbitol, melamine, dicyan-diamide, and benzoguanamine. Their synergistic effect is utilized in vinyl floors where low cost is imperative. 

Unlike most of the other oxidative reactions developed in our group, the I(III)-mediated amination did not require the arene reagent to be used as a solvent. Near 1 1 ratios of the N-H and the C-H substrate could be used. Unfortunately, the metal-free amination provided intractable mixmres of products with monosubstituted and nonsymmetric arene substrates (Scheme 9). This problem was exemplified by the amination of toluene, which produced three regiomers in a 10 6 5 (ortho/meta/para) ratio. We demonstrated the application of the metal-free amination reaction with 18 substrates, but all nonsymmetric arenes produced complex mixtures of aminated products. " ... 

A metal-free direct oxidative preparation of amides 107 from aldehydes 105 and amines 106 using the ion-supported hypervalent iodine(III) reagent S>9 as a recyclable oxidant under mild conditions has been reported (Scheme 5.35) [100]. The oxidant and its reduced form 108 are completely insoluble in diethyl ether consequently, products 107 can be extracted directly from the reaction mixture and the reagent 99 can be easily recycled. 

Because the reactions of related in -cyclohexadienyl complexes are synthetically valuable, the reactions of this ligand have been studied extensively. An outline of how this chemistry can be conducted on the Fe(CO)j fragment is shown in Equation 11.51. A variety of cyclohexadienes are readily available from Birch reduction of substituted aromatics. Coordination and abstraction of a hydride, typically by trityl cation, leads to cationic cyclohexadienyl complexes. These cyclohexadienyl complexes are reactive toward organolithium, -copper, -cadmium, and -zinc reagents, ketone enolates, nitroal-kyl anions, amines, phthalimide, and even nucleophilic aromatic compounds such as indole and trimethoxybenzene. Attack occurs exclusively from the face opposite the metal, and exclusively at a terminal position of the dienyl system. This combination of hydride abstraction and nucleophilic addition has been repeated to generate cyclohexa-diene complexes containing two cis vicinal substituents. The free cyclohexadiene is ttien released from the metal by oxidation with amine oxides. ... 

The one-pot synthesis of 2-substituted-3-carboxychromones is readily attained by the reaction of 3-oxo-3-(2,6-di luorophenyl)propanoates and acyl chlorides (13CC5313) and of 3-[2-(methoxymethoxy)phenyl]propio-lates and aldehydes followed by DDQ oxidation of the formed chroma-nones (13T647), via transition metal-free approaches. Palladium(II) -catalyzed cascade carbonylative cyclization of 2-bromophenols and terminal alkenes gives chromones 44 in moderate to good yields. Variation on the amine used in the catalytic system led to aurones 45 as major products (Scheme 74) (13TL1802). 

Previous reviews have dealt with metal-catalyzed [93] and stoichiometric [94] oxidation of amines in a broad sense. This section will be limited to the selective oxidation of tertiary amines to N-oxides. Amine N-oxides are synthetically useful compounds [95, 96] and are frequently used as stoichiometric oxidants in osmium-[97-99] manganese- [100] and ruthenium-catalyzed [101,102] oxidations, as well as in other organic transformations [103-105]. Aliphatic tert-amine N-oxides are usefid surfactants [96] and are essential components in hair conditioners, shampoos, toothpaste, cosmetics, and so on [106]. Chiral N-oxides have been used in asymmetric catalysis involving metal-free catalytic transformations [107] as well as metal-catalyzed reactions where the N-oxide serves as a ligand [107, 108]. Chiral tertiary amine N-oxides were recently used as reagents in asymmetric epoxidation of a,(3-unsaturated ketones [109]. 

Chlorodimethylsulfonium chloride (Swem reagent) represents another metal-free alternative for hydrazone oxidation [54]. The strategy was discovered by chance during research on a new conversion of free hydrazones to alkyl chlorides [159]. When benzophenone hydrazone was exposed to Swern reagent in the absence of an amine base, Brewer and laved observed localized yet transient red coloration of the reaction mixture. Diligent experimentation then led to the... 

With Fe2(CO)9 as catalyst, the CDC reaction of saturated heterocycles with 1,3-diketones was accomplished using TBP as an eflhcient oxidant (Scheme 2.12) [48]. This protocol shows good compatibility to cyclic and acyclic ethers, thioe-thers, and tertiary amines. Gratifyingly, besides C(sp )-C(sp ) coupling, the oxidative C-N coupling of ethers with azoles also works well (Scheme 2.12) [49]. As a update, with 2-chloranil (tetrachloro-l,2-benzoquinone) as oxidant, benzyl thioethers can be employed as substrates under metal-free conditions [50]. Notably, 2,2,6,6-tetramethylpiperidine-l-oxoammonium tetrafluoro borate is also an effective oxidant for metal-free CDC reaction of isochromanes and carbonyl compounds [51, 52]. 

The conversion of boronic acids into phenols has been achieved using visible light catalysis (Scheme 2.32) [42]. hi addition to light, the catalyst components consisted of a ruthenium bipyridine species, an amine, and DMF. All the components were needed for a successful reaction since low conversions were observed if any of the components were absent. The ability to use air as the oxidant was one of the practical aspects of this chemistry. While a wide range of arylboronic acids were successfully transformed into phenols, a pinacol-derived arylboronate also served as a substrate in these reactions (up to 94% conversion). In addition to the ruthenium-catalyzed reaction, a metal-free version of die chemistry was also developed using an organic dye. 

Yoshida and coworkers developed a method for C-H nitrogenation of aromatics based on electrochemical oxidation of aromatic compounds in the presence of pyridine followed by the reaction of the resulting A -arylpyridinium ions with piperidine to selectively give aromatic primary amines as products [108]. This transformation provides a metal-free protocol for one-pot synthesis aromatic amines with broad functional groups compatibility (Scheme 2.10). 

---