Alcohols as nucleophile

Seqnendal Michael addidons are versatile methods for the constnicdon of cyclic compounds. Although a variety of these reacdons have been developed, the use of alcohols as nucleophiles for the Michael addidon to nltroalkenes has been little studied. Recently, Dteda and coworkers have reported an elegant synthesis of octahydtobett2o[li furans via the seqnendal Michael addidon of 1-nltro-cyclohexenev/ith methyl4-hydroxy-2-bittynoatein the presence of r-BnOK followed by radical denitradon fEq. 7.74. ... 

Scheme 39 Racemization in the cyclization of a fi-nitroalkyl phosphate with an alcohol as nucleophile...

Introduction 877 Alcohols as Nucleophiles 881 Allenyl Ketones 889 Allenic Carboxylic Acids 895... 

ARO reaction with phenols and alcohols as nucleophiles is a logical extension of HKR of epoxides to synthesize libraries of stereochemically defined ring-opened products in high optical purity. To this effect Annis and Jacobsen [69] used their polymer-supported Co(salen) complex 36 as catalyst for kinetic resolution of epoxides with phenols to give l-aiyloxy-2-alcohols in high yield, purity and ee (Scheme 17). Conducting the same reaction in the presence of tris(trifluoromethyl)methanol, a volatile, nonnucleophilic protic acid additive accelerates KR reaction with no compromise with enantioselectivity and yield. Presumably the additive helped in maintaining the Co(III) oxidation state of the catalyst. 

Alkylations and other reactions using polynitroaliphatic alcohols as nucleophiles usually require Lewis acid catalysts. A comprehensive review of the chemistry of fluoronitro compounds. 

Although the initial report included amine nucleophiles, the scope was limited to activated amines such as indole (which actually undergoes C-alkylation at the 3-position), phthalimide, and 7/-methylaniline. Furthermore, enantioselectivities were inferior to those observed with alcohols as nucleophiles. Lautens and Fagnou subsequently discovered a profound halide effect in these reactions. The exchange of the chloride for an iodide on the rhodium catalyst resulted in an increased enantioselectivity that is now comparable to levels achieved with alcoholic nucleophiles ... 

J. Joubert, S. Roussel, C. Christophe, T. Billard, B.R. Langlois, T. Vidal, Trifluoroa-cetamides from amino alcohols as nucleophilic trifluoromethylating reagents, Angew. Chem. Int. Ed. 42 (2003) 3133-3136. 

As Schaffer has found 2.4.6-triphenyl-X -phosphorin 22 and other 2.4.6-tri-substituted X -phosphorins react smoothly with aryl diazonium salts in benzene. Nitrogen develops and the aryl residue bonds with the phosphorus. In presence of alcohols as nucleophiles, l-alkoxy-l-aryl-2.4.6-triphenyl-X -phosphorins 100 can be isolated. The aryl diazonium-tetrafluoroborate without any nucleophile in DMOE yields l-aiyl-l-fluoro-2.4.6-triphenyl-X -phosphorin 70i. As with other oxidants like halogen or mercury-Il-acetate, we suppose that in the first step triphenyl-X -phosphorin radical cation is formed. This could be shown by ESR spectroscopy. The next step may be a radical-radical addition to the X -phosphorin cation or a nucleophileradical addition respectively ... 

Resolution of branched alkanoic adds. Hydrolase-catalyzed esterification of 2-methylalkanoic acids can be fairly efficient, especially for acids with long chains, provided that the conditions are carefully adjusted by immobilization of the enzyme (in some cases), by control of the water activity, and by proper choice of the appropriate alcohol as nucleophile as well as the correct solvent [134]. The alcohol concentration does also influence the E-value [133]. It is important to note that the esterifications are reversible, thus preventing easy access to the remaining substrate in high ees. Some representative examples are given in Table 4.4. A procedure based on iterative resolutions can be used to provide both enantiomers of 2-methyloctanoic acid in high ees (>99%) and reasonable yields (25% for S- and 43% for R-acid based on the starting racemic acid) [137]. 

Fu and co-workers have also applied their planar chiral catalyst 9 to dynamic kinetic resolution of racemic azalactones [50], Azalactones 54 racemize under the reaction conditions, allowing all material to be funneled to optically pure product. Protected (S)-amino acids 55 are formed in excellent yields with moderate enantioselectivities (83-98% yield, 44-61% ee, see Scheme 11). Use of more sterically encumbered alcohols as nucleophiles increases enantioselectivities but reaction rates become slower. 

We showed in Figs. 3-2 and 3-3 that the tetrahedral intermediate which is initially formed from the reaction of a nucleophile with a carbonyl compound may further react in a number of different ways. In this section, we will consider some reactions which proceed along the pathway indicated in Fig. 3-3. The hydration of ketones is a reaction analogous to the hydrolysis of an ester, with the first step of the reaction involving nucleophilic attack of water on the carbonyl group. The tetrahedral intermediate is trapped by reaction with a proton to yield the hydrated form of the ketone, the geminal diol (Fig. 3-15). Similar reactions occur with alcohols as nucleophiles to yield, initially, hemiacetals. 

Table 5. Carboxylic acids and alcohols as nucleophiles in the Wacker oxidation ofsp -C-H bonds. 

H20 or alcohols as nucleophiles give low molecular weight compounds when they add to the C=0 double bond of carbonyl compounds. These addition products are called aldehyde or ketone hydrates (Section 9.1.1) and hemiacetals or hemiketals (Section 9.1.2), respectively, depending on whether they result from the addition to an aldehyde or a ketone. Today, one no longer distinguishes systematically between hemiacetals and hemiketals, but the expression hemiacetal is frequently used to cover both. 

Oxidation States of Alcohols and Related Functional Groups 467 11-2 Oxidation of Alcohols 469 11-3 Additional Methods for Oxidizing Alcohols 472 11-4 Biological Oxidation of Alcohols 474 11-5 Alcohols as Nucleophiles and Electrophiles Formation ofTosylates 476... 

Ether formation by dehydration is an example of nucleophilic substitution with the protonated alcohol as substrate and a second molecule of alcohol as nucleophile. 

The 1,4-oxidation has also been extended to the use of alcohols as nucleophiles. By performing the reaction in an alcohol as the solvent with Pd(OAc)2 as catalyst and p-benzoquinone as the oxidant, a 1,4-dialkoxylation was obtained (equation 17). It was essential to add a catalytic amount of acid to get a reaction. The reaction is highly regio-and stereoselective and 1,3-cyclohexadiene and 1,3-cycloheptadiene afforded exclusively 1,4-syn addition products (Table 1). 

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