Catalyzed Aerobic Alcohol Oxidation

Many reports of aerobic alcohol oxidation involve homogeneous Pd- [7] and Ru-based [8] catalysts that are effective with benzylic, allylic, and ahphatic primary and secondary alcohols. These catalysts are often inhibited by coordinating functional groups such as heterocycles, amines, and oxygen- or sulfur-containing moieties and are capable of oxidizing alkenes. Efforts to develop scalable applications of Pd-based catalysts raised concerns about large-scale prospects for these 

Liquid Phase Aerobic Oxidation Catalysis Industrial Applications and Academic Perspectives, 

First Edition. Edited by Shannon S. Stahl and Paul L Alsters. 

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Schultz MJ, Sigman MS (2006) Recent advances in homogeneous transition metal-catalyzed aerobic alcohol oxidations. Tetrahedron 62(35) 8227-8241... 

Catalytic oxidation of alcohols with molecular oxygen has attracted much attention as an alternative to traditional oxidation methods such as Dess-Martin [195], Jones [196] or Swern [197] oxidations, which require the use of stoichiometric toxic reagents and/or low temperatures. Significant advances have been made in Pd-catalyzed aerobic alcohol oxidations in the last few years [198-200] Sigman and co-workers have shown the broad scope of two IPr-Pd(II) complexes with low catalyst loadings and mild temperatures [201,202]. Some representative examples are summarized in Table 7. 

Early reports of Cu-catalyzed aerobic alcohol oxidation focused on simple homogeneous complexes [11] with nitrogenous ligands, such as 2,2 -bipyridine and 1,10-phenanthroline. However, copper-catalyzed methods that include nitroxyl radical or azodicarboxylate cocatalysts exhibit significant synthetic advantages and have been widely investigated in the literature (Figure 6.1). 

Figure 6.1 Catalyst types developed for copper-catalyzed aerobic alcohol oxidation.

Figure 6.2 Scope of copper(l)/DBED-catalyzed aerobic alcohol oxidation.

Scheme 6.1 Simplified mechanism of Cu/TEMPO- and oxoammonium-catalyzed aerobic alcohol oxidation.

The selectivity, activity, and broad scope of recently reported Cu/nitroxyl-catalyzed aerobic alcohol oxidation protocols make these methods well suited for application on both laboratory and process scale in the pharmaceutical and fine chemicals industry. The early catalyst systems of Semmelhack et al. [14] and Sheldon [16] have attracted industrial interest, albeit not necessarily for commercial production. 

Scheme 6.4 BASF adaptation of Cu/TEMPO-catalyzed aerobic alcohol oxidation.

Figure 6.10 Zeneca application of Cu/DBAD-catalyzed aerobic alcohol oxidation.

Copper-catalyzed aerobic alcohol oxidation has proven to be a key step in the production of vanillin, but other commercial-scale applications have not yet been realized. Nevertheless, the industrial interest in some of the early cop-per/cocatalyst systems for aerobic oxidation bodes well for future apphcations. Recent academic studies have led to significantly improved catalyst systems... 

The stepwise reduction of NO2 to NO occurs at standard reduction potentials very close to the standard potential for the reduction of O2 to H2O (Table 15.1, Eqs. (15.1-15.3)). This relationship implies that NO cocatalysts are able to capture nearly the full thermodynamic driving force of O2 as a terminal oxidant [4]. This favorable feature, together with the kinetically facUe oxidation of NO to NO2 (Table 15.1, Eq. (15.4)), contributes to the effectiveness of NO -based cocatalysts in aerobic oxidation reactions. Depending on the reaction conditions, NO2 can equilibrate with other nitrogen oxide species, such as N2O4, and NO, which could also serve as catalytically relevant oxidants in NO -catalyzed aerobic alcohol oxidation reactions (Eq. (15.5)) [5]. 

Minisci reported the first nitroxyl-catalyzed aerobic alcohol oxidation in the presence of precursors in 2001 (Scheme 15.7a) [28]. The optimal reaction conditions included a combination of catalytic Mn(N03)2 and Co(N03)2 with TEMPO (10 mol%) under 1 atm of O2. The authors demonstrated that Mn(NOg)2, Co(N03)2, and Cu(N03)2 were independently effective catalysts, implicating the nitrate anion as an important contributor to the reaction. Primary and secondary benzylic alcohols, primary allylic alcohols, and primary and secondary aliphatic alcohols were oxidized to the corresponding aldehydes/ketones in excellent yields. 

Scheme 15.6 General proposed catalytic cycles for (a) NO - and nitroxyl-catalyzed aerobic alcohol oxidation and (b) NOj -, Xj-, and nitroxyl-catalyzed aerobic alcohol oxidation.

Scheme 15.7 Minisd s MntNOjIj/CotNOjjj/TEMPO-catalyzed aerobic alcohol oxidation and Hu s NaNOj/Brj/TEMPO-catalyzed aerobic alcohol oxidation.

Iwabuchi demonstrated that sterically less bulky nitroxyls enable increased catalytic activity in nitroxyl/NO -catalyzed aerobic alcohol oxidation reactions. A broad array of densely functionalized and/or sterically bulky alcohol... 

In conclusion, NO -catalyzed aerobic alcohol oxidation is a growing research area and offers the potential for metal-free aerobic oxidation reactions. Applications of nitroxyl/NO -catalyzed oxidation reactions that employ the sterically unhindered bicyclic nitroxyls (e.g., F-AZADO, ABNO, keto-ABNO) are especially effective with a broad range of substrates bearing diverse functional groups, and reactionengineering advances that allow using these reactions in continuous processes should help to enhance reaction efficiency and promote safety. 

Recent Advances In Homogeneous Transition Metal-Catalyzed Aerobic Alcohol Oxidations Schultz, M.J. Sigman, M.S. Tetrahedron 2006, 62, 8227. 

Ligand-Modulated Palladium-Catalyzed Aerobic Alcohol Oxidations Sigman, M.S. Jensen, D.R. Acc. Chem. Res. 2006, 39, 221. 

In 2015, Yao, Zhao, and co-workers reported a base-catalyzed IV-alkylation of anilines and heteroarylamines with benzylic, heterobenzylic, aliphatic alcohols using catalytic amounts of O2 as the initiator (Eq. 69) [208]. They found air or O2 play important roles in the reactions because the reactions under O2 or in open air led to formation of imines in high ratios. The authors further optimized the reaction conditions and found that adding 2-5 mol% O2 to the reaction vessel was the best, giving high yields and selectivies of the product amines. Therefore, they proposed a mechanism for the N-alkylation reaction that was initiated by base-catalyzed aerobic alcohol oxidation by O2 to the aldehydes (Scheme 48). 

Sigman MS, Jensen DR (2006) Ligand-modulated palladium-catalyzed aerobic alcohol oxidations. Acc Chem Res 39(3) 221-229... 

Grunwaldt, J., Caravati, M. and Baiker, A. (2006). Oxidic or Metalhc Palladium Which is the Active Phase in Pd-Catalyzed Aerobic Alcohol Oxidation J. Phys. Chem. B, 110, pp. 25586-25589. 

Sigman, M. and Jensen, D. (2006). Ligand-Modnlated PaUadium-Catalyzed Aerobic Alcohol Oxidations, Acc. Chem. Res, 39, pp. 221-229. 

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