Syntheses using alcohols

Plan multistep syntheses using alcohols as starting materials and intermediates. 

Raphael has deyised a commercial synthesis using intermediates 365A and B to provide the two halves of the molecule. B is converted in aqueous add to an isomeric alcohol. Draw this. 

Synthesis of alcohols using organolithi um reagents (Section 14 7) Organolithi um reagents react with aldehydes and ketones in a manner similar to that of Grignard reagents to produce alcohols... 

A reaction useful only with sub strates that do not undergo E2 elimi nation readily It is rarely used for the synthesis of alcohols since alkyl halides are normally prepared from alcohols... 

Although the chemical reactions of epoxides will not be covered m detail until the fol lowing chapter we shall introduce their use m the synthesis of alcohols here... 

The reaction of esters with Gngnard reagents and with lithium aluminum hydride both useful m the synthesis of alcohols were described earlier They are reviewed m Table 20 4 on page 848... 

Pyrrohdinone (2-pyrrohdone, butyrolactam or 2-Pyrol) (27) was first reported in 1889 as a product of the dehydration of 4-aminobutanoic acid (49). The synthesis used for commercial manufacture, ie, condensation of butyrolactone with ammonia at high temperatures, was first described in 1936 (50). Other synthetic routes include carbon monoxide insertion into allylamine (51,52), hydrolytic hydrogenation of succinonitnle (53,54), and hydrogenation of ammoniacal solutions of maleic or succinic acids (55—57). Properties of 2-pyrrohdinone are Hsted in Table 2. 2-Pyrrohdinone is completely miscible with water, lower alcohols, lower ketones, ether, ethyl acetate, chloroform, and benzene. It is soluble to ca 1 wt % in aUphatic hydrocarbons. 

Hydroboration - regloseiective and stereoselective (syn) addition of BH3 (RBH2, R2BH) to olefins. Synthesis of alcohol including optically active alcohols from olefins. Also useful In synthesis of ketones by stitching ot olefins and CO... 

All that has been said in this section applies with equal force to the use of organo-lithium reagents in the synthesis of alcohols. Grignard reagents are one source of nucleophilic carbon organolithium reagents are another. Both have substantial carbanionic char acter in their- car bon-metal bonds and undergo the same kind of reaction with aldehydes and ketones. 

The reaction of esters with Gr-ignard reagents and with lithium aluminum hydride, both useful in the synthesis of alcohols, were described earlier. They are reviewed in Table... 

For the classical Williamson synthesis an alcohol is initially reacted with sodium or potassium to give an alkoxide, e.g. 1. Alternatively an alkali hydroxide or amide may be used to deprotonate the alcohol. Phenols are more acidic, and can be converted to phenoxides by treatment with an alkali hydroxide or with potassium carbonate in acetone. ... 

A variant of the Williamson ether synthesis uses thallium alkoxides. The higher reactivity of these can be of advantage in the synthesis of ethers from diols, triols and hydroxy carboxylic acids, as well as from secondary and tertiary alcohols on the other hand however thallium compounds are highly toxic. 

Akaji K, Kiso Y, Carpino LA. Fmoc-based solid-phase peptide synthesis using a new t-alcohol type 4-(l, l -dimethyl-l -hydroxypropyl)phenoxyace-tyl handle (DHPP)-resin (Fmoc = 9-fluorenyloxycarbonyl). J Chem Soc Chem Comm 1990 584-586. 

Another synthesis using in situ-prepared o-benzoquinones has been reported by Liao and coworkers [45]. These authors observed that oxidation of 2-methoxy-phenols 7-92 with DAIB in the presence of unsaturated alcohols 7-93 furnish transient o-benzoquinone monoacetal intermediates, which easily undergo an intramolecular Diels-Alder reaction to provide bicyclo[2.2.2]octenones 7-94 with high regio- and stereoselectivity, as well as in acceptable yields (Scheme 7.25). 

Primary nitro compounds are good precursors for preparing nitriles and nitrile oxides (Eq. 6.31). The conversion of nitro compounds into nitrile oxides affords an important tool for the synthesis of complex natural products. Nitrile oxides are reactive 1,3-dipoles that form isoxazolines or isoxazoles by the reaction with alkenes or alky nes, respectively. The products are also important precursors for various substrates such as P-amino alcohols, P-hydroxy ketones, P-hydroxy nitriles, and P-hydroxy acids (Scheme 6.3). Many good reviews concerning nitrile oxides in organic synthesis exist some of them are listed here.50-56 Applications of organic synthesis using nitrile oxides are discussed in Section 8.2.2. 

Nucleophilic additions to carbonyl groups lead to alcohols which on dehydration, furnish alkenes70,71. This two-step protocol has been extremely useful for diene and polyene synthesis with wide variation in the carbonyl substrate and the nucleophilic addendum. Diene synthesis using aldol-type condensation as well as phenyl sulphonyl carbanion (the Julia reaction) are also discussed in this section. 

In summary, the research effort aimed towards active, chemoselective hydrogenations of certain C=0 and C=N bonds have delivered several catalysts that approach the level of activity required for use in the synthesis of alcohols and amines. However, other classes of substrate require considerable additional investigations to be conducted before homogeneous catalysts may be considered for this purpose. 

Synthesis using TiF4 (as the source of Ti), TEOS, TPAOH, and distilled water. Gel composition Si02 xTi02 0.4TPA 30H20, 0 < x < 0.05 Prehydrolysis method. Crystallization without evaporating the alcohol in the conventional synthesis (7,8)... 

Enantioselective organic synthesis using modified skeletal catalysts has wide application in areas such as pharmaceutical production for example, synthesis of chiral alcohols from ketones [90], which is described in detail elsewhere in this book. 

Attempts by Fish and Johnson to effect a steroid synthesis using a standard epoxide-initiated pentacyclization of a polyene afforded complex mixtures [69]. Alternatively, the allyl alcohol 326 was synthesized and treated with TFA (Scheme 19.60). Protonation affords a symmetrical tetramethylallyl cation that undergoes cyclization to give pentacycle 327 in 31% yield. Simultaneous cleavage of the isopropylidene and vinylidene groups was carried out to furnish the diketone 328 in 88% yield, which was then converted to sophoradiol (329). 

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