Halides acid-sensitive

When carbon tetrabromide is used, the alkyl bromide is formed. Providing moisture is excluded from the reaction mixture (HX is formed otherwise), the reaction conditions are completely neutral, affording a convenient preparation of the halides of acid-sensitive substrates (for example, sugars). 

Another general method for converting alcohols to halides involves reactions with halides of certain nonmetallic elements. Thionyl chloride, phosphorus trichloride, and phosphorus tribromide are the most common examples of this group of reagents. These reagents are suitable for alcohols that are neither acid sensitive nor prone to structural rearrangement. The reaction of alcohols with thionyl chloride initially results in the formation of a chlorosulfite ester. There are two mechanisms by which the chlorosulfite can be converted to a chloride. In aprotic nucleophilic solvents, such as dioxane, solvent participation can lead to overall retention of configuration.7... 

The reaction of acceptor-substituted carbene complexes with alcohols to yield ethers is a valuable alternative to other etherification reactions [1152,1209-1211], This reaction generally proceeds faster than cyclopropanation [1176], As in other transformations with electrophilic carbene complexes, the reaction conditions are mild and well-suited to base- or acid-sensitive substrates [1212], As an illustrative example, Experimental Procedure 4.2.4 describes the carbene-mediated etherification of a serine derivative. This type of substrate is very difficult to etherify under basic conditions (e.g. NaH, alkyl halide [1213]), because of an intramolecular hydrogen-bond between the nitrogen-bound hydrogen and the hydroxy group. Further, upon treatment with bases serine ethers readily eliminate alkoxide to give acrylates. With the aid of electrophilic carbene complexes, however, acceptable yields of 0-alkylated serine derivatives can be obtained. 

The reactions involving bromine or chlorine generate hydrogen halide and are autocata-lytic. Reactions with /V-bromosuccinimide or tetrabromocyclohexadienone form no hydrogen bromide, and these reagents may therefore be preferable in the case of acid-sensitive compounds. 

As illustrated by the examples in Table 3.9, resin-bound 4-alkoxybenzylamides often require higher concentrations of TFA and longer reaction times than carboxylic acids esterified to Wang resin. For this reason, the more acid-sensitive di- or (trialkoxy-benzyl)amines [208] are generally preferred as backbone amide linkers. The required resin-bound, secondary benzylamines can readily be prepared by reductive amination of resin-bound benzaldehydes (Section 10.1.4 and Figure 3.17 [209]) or by A-alkyla-tion of primary amines with resin-bound benzyl halides or sulfonates (Section 10.1.1.1). Sufficiently acidic amides can also be A-alkylated by resin-bound benzyl alcohols under Mitsunobu conditions (see, e.g., [210] attachment to Sasrin of Fmoc cycloserine, an O-alkyl hydroxamic acid). 

In effect, this reaction converts a dialkyl ether into two alkyl halides. The conditions are very strong, however, and the molecule must not contain any acid-sensitive functional groups. 

Improved selectivity may be obtained with acid-sensitive substrates due to avoidance of accumulation of hydrogen halide, and in the case of iodination the reverse reaction can be suppressed. 

Although technically ether formations, the displacement of halides by hydroxyl groups differs from the examples presented above in that these reactions are base mediated. As such, under these conditions, C-glycosidations complement the previously described cyclization strategies given that they allow reactions with acid sensitive substrates. As shown in Scheme 7.100, Schmid and Whitesides [244] used this approach in the preparation of C-furanosides. Specifically, the illustrated... 

The reactions of thionyl chloride and phosphorus halides, also in their polymer-modifled form, involve the formation of hydrogen halide and cannot, therefore, be applied without complications to acid sensitive compounds. The combination of triphenylphosphine and tetrachloromethane as reagent provides conditions under which, for instance, pelargonic acid can be converted to the acid chloride in good yield according to equation (5). ° This method has been recently applied to polymer-bound triphenylphos-phine. Table 2 lists some examples of acids treated in this manner. 

Sometimes the addition of a small amount of ZnCh as a catalyst is recommended, e.g. succinic acid is transformed to the dichloride only in the presence of this catalyst. It has to be noticed, however, that under these conditions hydrogen chloride is evolved and, therefore, acid sensitive compounds cannot be taken. Af-acylamino acid chlorides and chlorides of fully acetylated sugar acids are also obtainable in yields of 70% or more. Whereas most reagents seem to be unsuited to the preparation of acid halides of a-keto acids, dichloromethyl methyl ether is successful in this reaction (equation 10). Pyruvyl chloride can now be made in ca. 50% yield. In some examples the corresponding a,a-dibromomethyl methyl ether has also been tested. ... 

This alternative to the Friedel-Crafts reaction, extensively developed by Stille and coworkers, is particularly important, since the reaction conditions are essentially neutral, and so provides a method for acylation of compounds containing an acid-sensitive functionality which would preclude the use of the Friedel-Crafts reaction. Reaction temperatures are often below 100 C, and high (1000-fold) turnovers of the catalyst have been achieved. Solvents employed include chloroform, toluene, and, on occasions, HMPA. Some reactions have been carried out under an atmosphere of carbon monoxide to prevent excessive decarbonylation of the acyl palladium intermediate. Indeed, carbonylative coupling of alkenylstannanes with allyl halides in the presence of carbon monoxide ca. 3 atm or greater 1 atm =101 kPa) offers an alternative to the Friedel-Crafts acylation, ketones being formed by the reaction of the stannane with the acyl species formed by carbon monoxide insertion into the allyl palladium intermediate. ... 

Alternatively, starting from the benzaldehyde 101 (66), the naphthalene could also be built up nonbiomimetically (67) (see Scheme 24) directly in a side-chain functionalized form 103, with or without halogen in the aromatic ring. The required conversion of the alcohol 102 into the acid-sensitive halide 103 could... 

Dn the other hand, anhydrides tend to be less volatile than acyl halides and are therefore more likely to interfere with the more volatile derivatives in analysis by gas chromatography. Also, the reaction medium is acidic, and so this approach cannot be used with acid-sensitive compounds. For such compounds an acylation reagent which has a basic leaving group on reaction, such as an acylimidazole, may be preferable (equation (10)). 

Like thionyl chloride, acyl halides are sensitive to moisture and quickly hydrolyze into the corresponding carboxylic acid and HCl. This is an example of the nucleophilic substitution at the unsaturated carbon with H2O as the nucleophile. 

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