Protonation of reduction intermediates

Protonation of reduction intermediates, 17 Pyridine bases, 287 Pyridineborane, 74... 

III. The Birch Reduction of Aromatic Steroids /II Mechanism of the reduction of aromatic compounds / 12 Factors influencing the rate of reduction / 14 Protonation of reduction intermediates / 17... 

Reduction in liquid NH3 and NaCl at Pt electrodes gives a 90% yield of a mixture consisting of 85% (A) (Fig. 60) and 14% (C) [329]. The hydrogenations in methy-lamine or ammonia are cathodic Birch reductions in which the final protonation of the intermediate anion leads to the thermodynamically more favorable trans product. 

C=X bonds The stereochemistry of the reduction of carbonyl compounds has been intensely studied with regard to synthetic and mechanistic aspects. The reduction of 1,2-diphenyl-l-propanone at a Hg cathode in aqueous EtOH and pH 8 affords the erythro alcohol as the major diastereomer (erythro threo = 5 to 1.4 1) [332]. This selectivity is in accord with a protonation of the intermediate anion, formed in an ECE sequence, from the least hindered side (Fig. 61). 

The HOPG (highly oriented pyrolytic graphite) carbon electrode chemically modified with (5[-phenylalanine at the basal surface led to 2% ee in the reduction of 4-acetylpyridine [377]. A cathode modified with a chiral poly(pyrrole) reduced 4-methylbenzophenone or acetophenone in DMF/LiBr and phenol as proton donor to 1-phenylethanol with up to 17% ee [382]. Alkyl aryl ketones have been reduced to the corresponding alcohols at a Hg cathode in DMF/water in the presence of (1R,2S)-A,A-dimethylephedrinium tetrafluorobo-rate (DET), producing (5 )-l-phenylethanol with 55% ee from acetophenone. Cyclovoltammetry supports an enantioselective protonation of the intermediate (PhCOH(CH3)) [383]. 

A less common reactive species is the Fe peroxo anion expected from two-electron reduction of O2 at a hemoprotein iron atom (Fig. 14, structure A). Protonation of this intermediate would yield the Fe —OOH precursor (Fig. 14, structure B) of the ferryl species. However, it is now clear that the Fe peroxo anion can directly react as a nucleophile with highly electrophilic substrates such as aldehydes. Addition of the peroxo anion to the aldehyde, followed by homolytic scission of the dioxygen bond, is now accepted as the mechanism for the carbon-carbon bond cleavage reactions catalyzed by several cytochrome P450 enzymes, including aromatase, lanosterol 14-demethylase, and sterol 17-lyase (133). A similar nucleophilic addition of the Fe peroxo anion to a carbon-nitrogen double bond has been invoked in the mechanism of the nitric oxide synthases (133). 

In the presence of excess monoalkylamine, carbonyl compounds in aqueous solution are in equilibrium with the corresponding imine. In most cases these imines cannot be isolated but they are reduced at a less negative potential than the carbonyl compound. Selective reduction of such equilibrium mixtures is a useful route to alkylamines from ketones in yields of 70-90%. The process fails with hindered ketones such as camphor and with bulky amines such as fert.-butyl amine. Overall the reaction has advantages of lower costs and simpler work-up compared to the use of cyanoborohydride reducing agents. In the electrochemical reaction, protonation of carbanion intermediates occurs from the more hindered side and where two isomeric products are fomied, the least hindered amine predominates [193]. 

A third enzyme is required to reduce the epoxide to vitamin K (Eq. 15-57). The biological reductant is uncertain but dithiols such as dithiothreitol serve in the laboratory.518 See also Eq. 18-47. Protonation of an intermediate enolate anion would give 3-hydroxy-2, 3-dihydrovitamin K, an observed side reaction product. 

Stereoselective l.4-reduction oi the 1.3-butadiene system to olefin 57 lakes place tinder the conditions of the Birch reduction. Intramolecular protonation of the intermediate carbanion at the 18-position to give 57 occurs with high selectivity syn to the hydroxymethy-iene group Conversion into phosphoric acid derivative 58 and cleavage of the phosphoric acid amide group under (he conditions of the Bcnkeser reduction provides compound 5921 Fluonde ion causes the release of free p-amyrin (1) in a final step I Li, NH3(iyTllF (1/1.75), -78 C 93%. 

Asymmetric induction during the reduction of 4-(48) was observed when a surface-modified carbon cathode was used.70 Optical yields were low but the effect of the chiral amino acid bound to the carbon surface was proved to be a true surface phenomenon. Induction of chirality by homogeneous rather than surface-bound agents has also been studied.71 All the isomeric acetylpyridines (48) were reduced in the presence of three different chiral alkaloids. Both carbinol products 2- and 4-(49) were shown to possess induced chirality, but the 3-carbinol (49) had none under any of the conditions tried. More rapid protonation of the intermediate was proposed to account for the lack of induced chirality. Optimization of optical yields was done.72 The pinacols (50) formed along with 49 were found to have no induced chirality. Optical yields have been as high as 50%.73 The role of electroabsorption was found to be important in the reduction of 2-(48).74 Product distributions were noted as a function of surfactant present in the electrolyte, carbinol 49 being favored... 

The protonation leads specifically to the trans-decalin system, though reduction could apparently give rise to two stereoisomeric products. The guiding principle appears to be that protonation of the intermediate allylic anion 12 takes place axially, orthogonal to the plane of the double bond, and to the most stable conformation of the carbanion which allows the best sp3-orbital overlap on the /Tcarbon with the -orbital system of the double bond. 

In contrast, C-substituted benzenes like biphenyl 7.96 are reduced to 3-substituted cyclohexa-1,4-dienes 7.99, and this too fits the analysis. The Hiickel coefficients for the SOMO of the radical anion 7.97 also reflect the total 7r-electron distribution, since the other three filled orbitals lead to a more or less even distribution of 7i-electron population. So, regardless of whether it is the Coulombic or the frontier orbital term that is more important, both contributions lead to protonation at C-4 to give the radical 7.98. Reduction and protonation of this intermediate (or possibly a mixture with the 1-protonated isomer) leads to the observed product 7.99. Further reduction of this molecule then takes place, but now the benzene ring is an X-substituted one. The major final product, accordingly, is the hydrocarbon 7.100, which has been reduced 1,4 in one ring and 2,5 in the other. 

A saturated ketone is obtained when an a, unsaturated ketone is treated with lithium in liquid ammonia, followed by water or a similar protonating species. Most steroidal A -3-ketones and similar compounds give products with the trnns-fused all-chair structure of minimum energy, which led Barton [32] to the generalisation that the more stable product is produced by protonation of an intermediate carbanion (14) in its thermodynamically preferred conformation (15) (see p. 54). Further studies, including the reduction of substituted... 

Generally, the conditions employed in the work-up of metal-ammonia reductions leads to products having the more stable configuration at the a-carbon atom, but products having the less stable configuration at this center have been obtained by kinetic protonation of enolate intermediates.A more detailed discussion of stereochemistry in metal-ammonia reduction of a, -unsaturated carbonyl compounds is given in ref 10. 

Asymmetric reduction of activated olefins has been performed using prochiral cumarin derivatives [414—416]. A maximum asymmetric yield reported was 17%, as in Eq. (62) [415], and an asymmetry induction mechanism has also been discussed [416]. Later, Schafer and coworkers carried out similar enantioselective electroreduction of various 4-substituted cumarins by systematic variation of the electrolysis conditions, and they obtained optical yields as high as 67% [Eq. (62)] [417-419]. Computational chemistry using semiempirical AMI demonstrates that ri-protonation of the intermediate anion by protonated yohimbine to form the (i )-isomer is energetically favored [418,419]. 

Rabideau, P. W., Huser, D. L. Protonation of anion intermediates in metal-ammonia reduction 1,2- vs. 1,4-dihydro aromatic products. J. Org. Chem. 1983,48,4266-4271. 

Reductive cleavage of allylic alcohols, ethers, or acetates (4, 574—575). An example of this reaction has been published in detail in Org. Syn. and a number of other examples are tabulated. Formation of the less stable olefin is a result of protonation of an intermediate allylic zinc chloride at the more substituted end of the system. 

Reduction of cyclic a,p-unsaturated ketones in which there are substituents on the (3- and y -carbon atoms could give rise to two stereoisomeric products. In many cases one isomer is formed predominantly, generally the more stable of the two. The guiding principle appears to be that protonation of the intermediate anion takes place orthogonal to the enol double bond (axially in six-membered rings). Thus,... 

The structure of the products is determined by the site of protonation of the intermediate radical anion. In general, electron-releasing substituents favor protonation at the ortho and meta positions, leading to 2,5-dihydro products, whereas electron-attracting groups favor the ipso and para position.The reduction of... 

The next stage of the synthesis required reduction of the Cj-Cs double bond with control over stereochemistry at Cs- The tactics ultimately used to accomplish this transformation involved conjugate addition of thiophenoxide to the enone to provide 58 with Cj stereochemistry that was never established. The critical stereochemistry (Cs), however, was clean and presmnably controlled by kinetic protonation of the intermediate enolate. Reduction of the C9 ketone was followed by esterification to provide acetate 59 as a single stereoisomer (C7 stereochemistry still not defined). Reduction of the C7 thiol was followed by excision of the extra carbon in the usual manner to provide aldehyde 60. The final carbons of the seco- dA were introduced via crossed condensation of the enolate derived from a thioester of propionic acid, with aldehyde 60. This reaction provided the proper stereochemistry at C3, but the undesired stereoisomer at C2. The C2 stereochemistry was corrected by kinetic protonation of the enolate derived from 61 with acetic acid. The structure of the resulting seco-zcid derivative (62) was established by X-ray crystallography. 

An alternative interpretation to the mechanism proposed in Scheme 7.7, could be the protonation of allenyl intermediate 13 before the addition of a new hydride, to form free allene 15. The subsequent reduction of this compound would also lead to allyl ethers 3 in a pathway fully compatible with the observed deuteration pattern. To exclude this possibility, the authors of the original work prepared allene 15 from 1-ethoxy-3-phenyl-2-propyne and BuLi, (formulate the reaction ) and treated it with NaBH4 in EtOH under the same conditions employed for compound 9. The allene 15 was recovered unchanged after several hours of reaction (Scheme 7.8). 

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