Hydrogenation of pinacolone

PICA) show excellent activity and enantioselectivity for reaction of such bulky ketones.Selection of alcoholic solvent is important to achieve high catalytic performance. Thus, hydrogenation of pinacolone with the (5)-TolBINAP/PICA-Ru catalyst (S/C = 100,000) in C2H5OH quantitatively gives (5)-3,3-dimethyl-2-buta-nol in 98% ee (Figure 1.21). The reaction in conventional 2-propanol with the same catalyst results in the S alcohol in only 36% ee. 

Excellent enantioselectivity was achieved for the transfer hydrogenation of pinacolone by using (S)-25a as a catalyst with 2-propanol in the presence of (CH3)2CHONa to give the S alcohol in >99% ee (Scheme 28) [90], 2,2-Dimethyl-cyclohexanone was reduced with the same catalyst with 98% optical yield. Reduction of cyclohexyl methyl ketone with (S)-25b gave the S alcohol in 66% ee. 

The proposed mechanism (Scheme 17) involves the initial sp C-H bond oxidative addition to ruthenium(O) followed by aryl transmetallation and reductive elimination. It was suggested by Sames [11] that the role of the ketone was to insert into the Ru-H bond to favour traiw-arylation with the phenylboronate ester. Later on it was shown by Maes that pinacolyl alcohol was formed via Ru-catalysed hydrogenation of pinacolone rather than through a Ru-alkoxide intermediate [12]. 

A -Heterocyclic carbene complexes of Ir(I) and Ir(III) have also demonstrated high reactivity in transfer hydrogenation reactions of ketones (Scheme 2) [4]. Complex 4 catalyzed the reduction of a range of ketones into the corresponding alcohols, including the reduction of pinacolone 7 into alcohol 8 with a low catalyst loading and short reaction time [5]. The chelating bis(Af-heterocyclic carbene) complex 5 was shown to catalyze the reduction of ketones, and in the case of the reduction of benzophenone 9 to alcohol 10, the reaction was complete within 4 min [6]. 

In 1994, it was found that several reactions thought to proceed via the vinylic SflArl mechanism were contaminated by a nonradical, a, /t-ehrninalion/addition pathway (equation 40)178. However, this elimination/addition pathway becomes inaccessible when substrates without ft (or ft1) hydrogens are utilized. Thus, the reaction of pinacolone enolate (f-Bu(CO)CH2) with l-bromo-l,2,2-triphenylethylene was touted to be the first unequivocal example of vinylic substitution exclusively by the S l pathway. 

The synthesis route for (a) starts with the reaction between bromo pinacolone and triazole, followed by addition of a benzyl chloride derivate and hydrogenation of the carbonyl... 

The number of publications describing new ligands that allow the transfer hydrogenation of aromatic ketones with over 90 % ee has grown in leaps and bounds since 1996 [15]. In these reactions the use of ruthenium [15a-f] and iridium [15g] as the catalytically active metals has recently been augmented by the use of phosphorus-free ligands such as chiral diamines, amino alcohols, and bisthioureas such as 7 [15a,e-g]. A ruthenium-catalyzed transfer hydrogenation with 92 % ee has even been reported for the aliphatic ketone pinacolone (tert-butyl methyl ketone) [16]. 

The bromine may be added in a stream of nitrogen which also serves to remove the liberated hydrogen halide. In the bromination of pinacolone, aluminum amalgam or aluminum chloride is used as a catalyst, " Phosphorus pentabromide, N-btomosuccinimide, " and pyridine hydrobromide perbromide have been used as brominating agents. 

An analogous bond fission on hydrogenation was recently reported. Delco-sine diacetate was converted into the pinacolone (35). Hydrogenation of this over platinum gave the seco-compound (37), presumably by way of an immonium ion (36). 

In order to discover new modifiers in the hydrogenation of both C=0 and C=C bonds we have tested fS7-Qr,a-diphenil-2-pyrrolidinmethanol (DPPM) (Scheme 1), which was used as a ligand in the transition metal complex catalyzed enantioselective reduction of prochiral ketons, like acetophenone and pinacolone [8, 9, 10]. 

Figure 3.11 Molecular structure of bis(diisopropylamino)boron enolate of pinacolone (14). Hydrogen atoms are omitted for clarity. Copied from Ref. [42].

Heating of a mixture of pinaeol 41 and 33% sulfuric acid under reflux for 2 h gave two pinacolones 42 and 43 in 80 and 20 % yields, respectively. However, when hydrogen chloride gas was passed at room temperature over finely powdered 41 for 3 h, 42 was obtained selectively in 90% yield. The treatment of 44 with sulfuric acid as above gave a complex mixture of reaction products, 45, 46, and 47 in 48,29, and 5 % yields, respectively 27). The oily pinaeol 44 formed a 1 2 complex (48) with the host compound 4 as colorless crystals. The treatment of finely powdered 48 with hydrogen chloride gas under the same conditions as above gave 45 selectively in 44% yield 27>. 

The pinacolone enolate residue crystallizes as a dimer with solvation by N,lV,lV -trimethylethylene-diamine (TriMEDA) as indicated in formula (141). In this structure the NH hydrogen on the secondary amine is relatively close to the terminal carbon of the enolate residue, i.e. NH—C=C is 2.60 A. This... 

Overall, we have established a convenient and cost-effective three-step reductive amination process for the manufacture of multifarious a-1-arylalkylamines. Importantly, the new procedure outlined here also allows the preparation of previously unavailable enamides. including a-alkyl-substituted derivatives. For instance, this method has been used to convert pinacolone into enamide 22, which upon hydrogenation with the (S,S)-Me-DuPHOS-Rh catalyst affords the corresponding A-acetyl amine 23 with very high enantiomeric excess (99% ee) (Scheme 11) [27]. 

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