Iron catalysis of grignard reductions. Mechanism of 1, 3-reductive eliminations from γ-propyl halides

The iron-catalyzed reduction of various 3-substituted propyl bromides by Grignard reagents affords propylene and cyclopropane. The reduction to propylene is particularly noteworthy since it formally represents a 1, 2-hydrogen shift. Two key intermediates have been identified in propylene formation, in which 3-methoxypropyl bromide is first catalytically reduced to the magnesium derivative by Grignard reagent. The iron-catalyzed β-elimination of the 3-methoxypropylmagnesium intermediate affords allyl methyl ether, which is then reduction cleaved to propylene. Extensive studies of deuterium labeling in the reactants, as well as in both intermediates, allow the course of the hydrogen shift to be followed unequivocally. The mechanism of iron catalysis is proposed in Scheme 2 and 3, representing the first and second stages of the reduction to propylene.     

Computing quasi-steady state reductions

There is a systematic approach to the computation of quasi-steady state reductions, employing the classical theory of Tikhonov and Fenichel, rather than the commonly used ad-hoc method. In the present paper we discuss the relevant case that the local slow manifold (in the asymptotic limit) is a vector subspace, give closed-form expressions for the reduction and compare these to the ones obtained by the customary method. As it turns out, investment of more theory pays off in the form of simpler reduced systems. Applications include a number of standard models for reactions in biochemistry, for which the reductions are extended to the fully reversible setting. In a short final section we illustrate by example that a QSS assumption may be erroneous if the hypotheses for Tikhonov’s theorem are not satisfied.     

Forty years of hydride reductions

Forty years ago, it was observed that diborane, a hydride, reduces aldehydes and ketones with exceptional ease even at 0°. Since then various hydride reagents have evolved for the convenient reduction of typical organic functional groups. Electrophilic reducing agents such as borane and alane possess markedly different reducing characteristics than those of nucleophilic reducing agents such as sodium borohydride and lithium aluminum hydride. Explorations have revealed means of both enhancing and diminishing the electrophilic character of borane and alane on the one hand and both enhancing and diminishing the nucleophilic character of borohydrides and aluminohydrides on the other. Such derivatives reveal unique characteristics making possible valuable selective reductions, not practical previously. These developments have completely altered the procedures normally used in organic chemistry for the reduction of functional groups.     

Regioselective reductions of 2,3-epoxy alcohols

Regioselective reduction of 3-substituted-2,3-epoxy alcohols to 1,3-diols with sodium bis(2-methoxyethoxy)aluminum hydride (Red-al) is shown to be a general reaction for these substitutes.     

Orientation in metal ammonia reductions

The unique orientation effects observed in the alkali metal-ammonia reactions of aromatic compounds are considered from a molecular orbital viewpoint. The Birch rule governing the reduction of substituted aromatics, the peculiar effect of substituents on the ease of hydrogenolysis of benzyl alcohols, the similar effect in the dealkylation and dearylation of alkyl aryl ethers and aryl ethers, the course of dealkoxylation of alkyl aryl ethers, are all found to be reasonably accommodated by molecular orbital theory.     

Highly diastereoselective catalytic Meerwein-Ponndorf-Verley reductions

[reaction: see text] Very practical synthesis of ephedrine analogues in high yields and enantiopurity was realized by a highly diastereoselective Meerwein-Ponndorf-Verley (MPV) reduction of protected alpha-amino aromatic ketones using catalytic aluminum isopropoxide. The high anti selectivity resulted from the chelation of the nitrogen anion to the aluminum. In contrast, high syn selectivity was obtained with alpha-alkoxy ketones and other compounds via Felkin-Ahn control.     

Stereoselective reductions of chiral iminium ions

Chiral iminium ions derived from α-phenethylamine have been reduced stereoselectivey with NaBH₄. Diastereoselection of the reduction ranged from 88:12 to 94:6. The sense of asymmetric induction has been unambiguously assigned by correlation of reduction products with S-(−)-salsolidine and S-(−)-nor-laudanosine.     

Enzyme-catalyzed enantioselective diaryl ketone reductions

The synthesis of diarylmethanols via the reduction of a range of substituted benzophenone and benzoylpyridine derivatives with ketoreductase enzymes (KREDs) has afforded chiral products with high yield (>90%) and ee (up to >99%). Ortho, meta, and para substitutions with a variety of electron-donating, electron-withdrawing, and halogen groups were examined. Substitution at the ortho position and/or highly electronically dissymmetric molecules were not required for good selectivity, as is the case with conventional chemical catalyst reductions. [reaction: see text].     

Microbiological reductions of chromen-4-one derivatives

From the microbiological reductions of 2-acetyl or 2-benzoylchromen-4-one both enantiomers of the corresponding alcohols were obtained with high enantiomeric excess. The absolute configurations were determined directly by an X-ray structural determination. The results obtained showed that for most of the microorganisms tested, an inversion of the configuration of the alcohol occurred with the change of the substituent (methyl to phenyl group) in position 2, but also with the presence of a bromine atom in position 6 of the aromatic ring, positioned quite far from the prochiral centre.     

Regio- and stereoselective reductions of gem-difluorinated vinyloxiranes

[reaction: see text] gem-Difluorinated vinyloxiranes are versatile building blocks for the synthesis of fluorinated compounds. Investigations of their reactions with nucleophiles resulted in highly regio- and stereoselective reductions. In their reactions with LiAlH4, hydride reacted at the allylic epoxide carbon to produce homoallylic alcohols exclusively. Moreover, regio- and stereoselective S(N)2' reactions were observed with DIBAL-H and BH3 x THF; the former afforded E allylic alcohols, whereas the latter furnished the corresponding Z isomers with excellent selectivities.     

Enantioselective reductions of [m] ferrocenophanones

Enantioselective reductions of prochiral ferrocenophane ketones were investigated. Oxazaborolidine mediated reduction led to corresponding chiral alcohols generally in good yields and enantioselectivities up to 97% ee. Ruthenium-catalyzed transfer hydrogenation was rather unsuccessful in reducing cyclic ferrocene ketones. Proline-derived activator together with trichlorosilane also proved to be an effective method for some substrates (up to 99% ee). Pronounced tendency of α-ferrocenyl ketones toward reductive deoxygenation was studied by DFT computational methods.     

Selective reductions. 59. Effective intramolecular asymmetric reductions of alpha-, beta-, and gamma-keto acids with diisopinocampheylborane and intermolecular asymmetric reductions of the corresponding esters with B-chlorodiisopinocampheylborane

A comparison of the stereochemistry of the products obtained from the intramolecular asymmetric reduction of a series of keto acids with (-)-diisopinocampheylborane and intermolecular asymmetric reduction of the corresponding series of keto esters with (-)-B-chlorodiisopinocampheylborane ((-)-DIP-Chloride) has been made. The stereochemistry of the hydroxy acids from the reduction of keto acids is dependent only on the enantiomer of the reagent used. The stereochemistry of the products from the reduction of keto esters is also consistent, except those of aliphatic alpha-keto esters. alpha-, beta-, and gamma-keto acids provide the corresponding hydroxy acids in 77-98% ee, and the alpha- and gamma- keto esters afford the hydroxy esters in 82->or=99% ee. beta-Keto esters do not undergo reduction. Although the reduction of delta-keto acids does not proceed under the same reaction conditions, the reduction of delta-keto esters is facile. All of the products from the reduction of gamma-keto acids and esters and delta-keto esters were converted to the corresponding lactones. This study revealed that DIP-Chloride is an efficient reagent for the reduction of alpha-keto esters at low temperatures.     

Biphenylthioureas as organocatalysts for electrochemical reductions

Thioureas are able to act as organocatalysts in the electrochemical reduction of aromatic carboxylates.     

Towards preparative-scale, biocatalytic alkene reductions

Simple strategies for using alkene reductase enzymes to produce gram-scale quantities of both (R)- and (S)-citronellal have been developed. The methodology is easily accessible to non-specialist laboratories, allowing alkene reductases to be added to the toolbox of routine synthetic transformations.     

Stereoselective reductions with macrocyclic NADH models

Macrocyclic NADH models with two (C₂ symmetry) or four (D₂ symmetry) nicotinamide units comprised in a ring have been prepared and found to reduce activated carbonyl compounds in good yields and high enantiomeric excess. The roles of magnesium ions as a cocatalyst and the temperature have also been investigated. The smaller, C₂-symmetric macrocycle gave 96% ee upon reduction of ethyl benzoylformate whereas the best result with the larger D₂-symmetric model was 81% ee for the reduction of methyl benzoylformate.     

Stereoselective, biocatalytic reductions of alpha-chloro-beta-keto esters

Eighteen known and putative reductases from baker's yeast (Saccharomyces cerevisiae) were tested for the ability to reduce a series of alpha-chloro-beta-keto esters. In nearly all cases, it was possible to produce at least two of the four possible alpha-chloro-beta-hydroxy ester diastereomers with high optical purities. The utility of this approach was demonstrated by reducing ethyl 2-chloroacetoacetate to the corresponding syn-(2R,3S)-alcohol on a multigram scale using whole cells of an Escherichia coli strain overexpressing a single yeast reductase identified from the screening studies.     

Through-shell alkyllithium additions and borane reductions

The through-shell borane reduction and methyllithium addition to benzaldehyde (1), benzocyclobutenone (2), and benzocyclobutenedione (3) incarcerated inside a hemicarcerand (4) with four tetramethylenedioxy bridges are reported. All guests could be reduced and methylated. Selective monoreduction and monomethylation were observed for 3. In the methyllithium addition to 4[symbol: see text]3, the initially formed lithium alcoholate underwent a Moore rearrangement. The reactivity of the incarcerated guests toward methyllithium increased in the order 1 < 2 < 3 and toward borane in the order 1 < 2 approximately equal 3. Guest reactivity was correlated with the inner-phase location of the reacting carbonyl group in the preferred guest inner-phase orientation. The latter was determined from the X-ray structures of 4[symbol: see text]1, 4[symbol: see text]2, and 4[symbol: see text]3, from molecular mechanical calculations, and from the hemicarcerand-induced upfield shift of the guest proton resonances. In the methyllithium and n-butyllithium addition to 4[symbol: see text]1 and 4[symbol: see text]3 at elevated temperatures, selective cleavage of a host's spanner or tetramethylenedioxy bridge, respectively, was observed. The cleavage of one spanner also took place in the methyllithium addition to the 1-methyl-2-pyrrolidinone hemicarceplex. These scission reactions are initiated by the initially formed lithium alcoholates, which show enhanced basicity and nucleophilicity in the inner phase as compared to the bulk phase. Mechanisms for the host scission reactions are discussed.