Acceptors, hydride

Zinc-containing alcohol dehydrogenases take up two electrons and a proton from alcohols in the form of a hydride. The hydride acceptor is usually NAD(P) (the oxidized form of nicotinamide adenine dinucleotide (NADH) or its phosphorylated derivative, NADPH). Several liver alcohol dehydrogenases have been structurally characterized, and Pig. 17.8 shows the environment around the catalytic Zn center and the bound NADH cofactor. 

Certain lanthanide alkoxides, such as r-BuOSmL, have also been found to catalyze hydride exchange between alcohols and ketones.194 Isopropanol can serve as the reducing agent for aldehydes and ketones that are thermodynamically better hydride acceptors than acetone. 

The hydride acceptor is the iminium ion that results from condensation of the amine with formaldehyde. 

Nature uses enantioselective transfer hydrogenation to reduce metabolites, for example pyruvate to give (S)-lactic acid and 2-ketoglutarate to give (S)-2-hydroxy -glutarate. The reaction is reversible and the equilibrium position depends on the concentration of the species. The enzyme catalysts are named dehydrogenases, and they employ a soluble cofactor or hydride acceptor called NAD(P) in its oxi-... 

However, for an unsubstituted pyridine, the leaving group to finish off this reaction is hydride, which is a strong base and thus a poor leaving group (see Section 6.1.4). It may be necessary to use an oxidizing agent to function as hydride acceptor to... 

Clearly, this is a different system in detail, and the only feature that I want to carry over is the possibility of hydride transfer to the copper, which we know to be a strong hydride acceptor. One could, of course, accommodate this feature of the mechanism by a variety of detailed schemes, including one involving chelation. 

The two functional groups of the catalyst contribute, to some degree independently, to determining its activity. Thus, the Cu++ ion, a good electron and hydride acceptor, activates hydrogen even when coupled with a relatively weak base such as water. At the other extreme, a very strong... 

This dehydrogenation with Pd(II) can become catalytic in the presence of maleic anhydride or dimethyl fumarate as hydride acceptor. 

Cyclohexane can be acylated with acetyl chloride and AICI3 to yield l-acetyl-2-methylcyclopentene in 37% yield.127 Alkanes, such as 2-methylbutane, cyclohexane, methylcyclopentane, and methylcyclohexane, are easily acylated with a,p-unsaturated acyl chlorides in the presence of A1C13 and a hydride acceptor to afford mono- or bicyclic products after secondary transformations.128 Isoalkanes (isopentane, 2-methylpentane, 3-methylpentane, 2,3-dimethylbutane) undergo diacylation and eventually form pyrilium salts under Friedel-Crafts acylation conditions with acetyl chloride or acetic anhydride.129... 

Pyrans and thiins are also easily aromatized, e.g. (483) + S2Cl2 — 1-benzothiinium ion. 2H-Thiins are aromatized by hydride acceptors such as triphenylmethyl cations to give thiinium salts, and similar conversions produce pyrylium salts from pyrans. 

Although the value of this route has been improved by developments in the synthesis of 1,5-diketones, it is often easier to generate the diketone in situ. Provided that the reaction is carried out in the presence of a hydride acceptor, a direct synthesis of pyrylium salts is available from simple precursors. 

The use of ethyl acetoacetate in this route allows the formation of a 3-ethoxycarbonyl-pyrylium salt (68JOC1102). Some care is appropriate in this type of reaction in the absence of an added hydride acceptor, however, since the chalcone may undergo a Michael condensation with the intermediate 1,5-dione, leading to side products. 

The dehydrogenation of penta-2,4-dien-l-ones is a convenient route to pyrylium salts unsubstituted at C-4 (17CB1008) the usual variations in hydride acceptors are allowed. A minor variation probably involves ionization of the chlorodienone (670) to a carbocation and hence to the pyrylium salt (Scheme 266) (66AG448). 

Oxidation of the ring system in thiins has also been achieved with hydride acceptors such as triphenylmethyl cations, and results in high yields of thiopyrylium salts. This is far more efficient than the disproportionation reactions discussed above, as the only byproduct is triphenylmethane. The reaction will be discussed in the section on synthesis. 

There are several methods reported in the literature for transforming vicinal diols into ct-diketones while avoiding the risk of C-C bond cleavage.26 Examples include the standard Swem conditions (dimethyl sulfoxide and oxalyl chloride followed by triethylamine), or the use of DMSO activated by acetic anhydride, pyridine-sulfur trioxide complex, or dicyclohexylcarbodiimide (Mq/J-att oxidation). Diones are also obtained by treatment with benzalacetone as a hydride acceptor in the presence of catalytic amounts of tris(triphenylphosphine)ruthenium dichlonde [(PPh RuCFl.27 Recent developments include the use of w-iodoxyben/.oic acid28 or the oxoammonium salt of 4-acctamidoletramethylpipcridine-1-oxyl and y -toluencNulfonic acid.29... 

Posner et al. found that commercial aluminium oxide is able to promote the oxidation of alcohols employing chloral as hydride acceptor.30 The reaction operates at room temperature in inert solvents like CCI4 and surprisingly no base-induced condensations are reported. Basically, the same experimental conditions were later applied for the oxidation of cyclobutanol,31 a compound with a great propensity to fragmentation under the action of other oxidants. 

It must be mentioned that about 1 equivalent of aluminium isoprop-oxide is needed in Oppeanuer oxidations using the classical protocol. Supposedly, compound 67 reacts with the alcohol, resulting in an aluminium alkoxide able to form a complex in which both free electron pairs of the oxygen atom in pivalaldehyde are coordinated with aluminium atoms, resulting in a very efficient activation of pivalaldehyde as hydride acceptor via a mechanism represented in Figure 6.1 ... 

In this very elegant transformation induced by aluminium compound 67 present in a 5 mol% proportion, an aldehyde operates as a hydride acceptor in the oxidation of a secondary alcohol present in the same molecule. 

Although the Mukaiyama oxidation is not in the top list of the most frequently used alcohol oxidants, the authors of this book have decided to pay full attention to this procedure because it succeeds in very sensitive organometallic compounds, where most other oxidants fail. The Mukaiyama oxidation operates via a somehow unique mechanism involving a hydride transfer from a metal alkoxide to a very good hydride acceptor, which resembles the Oppenauer oxidation. In variance with the Oppenauer oxidation, the Mukaiyama protocol involves much milder conditions and it does not promote as easily base-induced side reactions. 

Non-enolizable ketones with a relatively low reduction potential, such as benzophenone, can serve as the carbonyl component used as the hydride acceptor in this oxidation. 

In subsequent work, it was found that the reaction conditions could be modified to give a single product. Thus, carrying out the acid-catalyzed cyclization in the presence of an external source of hydride, such as triethylsilane, led to compound 75 in 92% yield, while the presence of an hydride acceptor such as DDQ resulted in the formation of 76 as the sole product, albeit in 45% yield. Compound 77 was finally transformed into the oxindole derivative 79 by oxidation with W-bromosuccinimide in the presence of ferf-butyl alcohol (Scheme 17). 

In the Oppenauer oxidation, an activated carbonyl compound acts as a hydride acceptor in the selective oxidation of an alcohol to give a ketone. Krohn et al. (208) used SiCL-anchored Zr(OnPr)4 in combination with chloral ... 

There is a second effect. In the transition state in which the stronger Lewis acid complexes the carbonyl oxygen, the carbonyl group is a better electrophile. Therefore, it becomes a better hydride acceptor for Brown s chloroborane than in the hydride transfer from Alpine-Borane. Reductions with Alpine-Borane can actually be so slow that decomposition of this reagent into a-pincnc and 9-BBN takes place as a competing side reaction. The presence of this 9-BBN is problematic because it reduces the carbonyl compound competitively and of course without enantiocontrol. 

Pathways C and D are less well documented, mainly because oxazoles lacking a 5-alkoxy substituent show reduced reactivity towards the usual dienophiles. An example of reaction C is the formation of 3-hydroxy-2-methylpyridine from 4-methyloxazole and acrylonitrile (equation 13). Dehydrogenation (path D) is rare but proceeds in the presence of a hydride acceptor. Thus 4-methyloxazole reacts with ethyl acrylate in the presence of hydrogen peroxide to give ethyl 3-hydroxy-2-methylpyridine-5-carboxylate in 27% yield (equation 14). 

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