Imides, alkylation with alcohols

The use of trichloroimidates for the preparation of ethers is an effective method for O-alkylation of alcohols [27]. This method has found widespread use in the protection of alcohols as benzyl ethers since the corresponding trichlorobenzylimi-date is inexpensive and commercially available. The mechanism involves activation of the imidate with a catalytic amount of a strong acid (typically TfOH) which leads to ionization of the electrophile and the formation of carbocation which is rapidly trapped by an alcohol. For the preparation of sec-sec ethers, this protocol has been limited to glycosidation reactions, due to the SN1 nature of the reaction which often leads to diastereomeric mixtures of products [26],... 

In 1975, van der Baan and Bickelhaupt reported the synthesis of imide 37 from pyridone 34 as an approach to the hetisine alkaloids, using an intramolecular alkylation as the key step (Scheme 1.3) [23]. Beginning with pyridone 34, alkylation with sodium hydride/allyl bromide followed by a thermal [3,3] Claisen rearrangement gave alkene 35. Next, formation of the bromohydrin with A -bi omosuccinimide and subsequent protection of the resulting alcohol as the tetrahydropyranyl (THP) ether produced bromide 36, which was then cyclized in an intramolecular fashion to give tricylic 37. 

Phthalimide. C<,H4 (CO), NH, is an imide of commercial and industrial importance, forming a number of interesting derivatives. With alcoholic potash, phthalimide forms a potassium derivative. C(,H4 (COb -NK. which, when reacted with ethyl iodide (or other alkyl halides), yields eihylphthalimidc. C(,H4 (COi N - C2Hj Ihe latter product, when hydrolyzed wilh an acid or alkali, further yields ethylamine. Such reaction chains are useful in ihe preparation of certain primary amines and their derivatives. 

PINNER REACTION. Formation of imino esters (alkyl imidates) by addition of dry hydrogen chloride to a mixture of a nitrile and an alcohol. Treatment of alkyl imidates with ammonia or primary or secondary amines affords amidines. while treatment with alcohols yields ortho-esters. 

Nitrile oxides react with the methyl enol ethers of (Rs)-l -fluoro-alkyl-2-(p-tolylsulfinyl)ethanones to produce (45,5/f,/fs)-4,5-dihydroisoxazoles with high regio-and diastereo-selectivity.87 In the 1,3-dipolar cycloaddition of benzonitrile oxide with adamantane-2-thiones and 2-methyleneadamantanes, the favoured approach is syn, as predicted by the Cieplak s transition-state hyperconjugation model.88 The 1,3-dipolar cycloaddition reaction of acetonitrile oxide with bicyclo[2.2.l]hepta-2,5-diene yields two 1 1 adducts and four of six possible 2 1 adducts.89 Moderate catalytic efficiency, ligand acceleration effect, and concentration effect have been observed in the magnesium ion-mediated 1,3-dipolar cycloadditions of stable mesitonitrile oxide to allylic alcohols.90 The cycloaddition reactions of acryloyl derivatives of the Rebek imide benzoxazole with nitrile oxides are very stereoselective but show reaction rates and regioselectivities comparable to simple achiral models.91. 

Asymmetric aikyiation of imide etiolates.1 The sodium enolates of 3 and 7 are alkylated with marked but opposite diastereoselectivity by alkyl halides. The selectivity is improved by an increase in the size of the electrophile, with methylation being the least stereoselective process. The asymmetric induction results from formation of (Z)-enolates (chelation) with the diastereoselectivity determined by the chirality of the C4-substituent on the oxazolidone ring (equations I and II). The products can be hydrolyzed to the free carboxylic acids or reduced by LiAlH4 to the corresponding primary alcohols and the unreduced oxazolidone (1 or 2). 

In the synthesis of ionomycin published in 1990, the Evans group provided a convincing acid test of their auxiharies in several alkylation and aldol addition steps. Just one of those, the preparation of the alcohol 72, that was required as C-13 to C-16 fragment of ionomycin, may serve as an Ulustrative example, shown in Scheme 4.13. The hthium enolate of imide 48 was alkylated with cinnamyl bromide in a highly diastereoselective manner. The a-branched imide 71 thus obtained was reduced to the alcohol 72 that, after conversion into the primary iodide 15 (Scheme 4.3), served as electrophile in Evans prolinol procedure for chain elongation en route to ionomycin [12b]. 

N-Alkyl amides or imides can also be prepared starting from alcohols by treatment of the latter with equimolar amounts of the amide or imide, Ph3P, and diethyl azodicarboxylate (EtOOCN=NCOOEt) at room temperature (the Mitsunobu reaction, see p. 396).925... 

The dyes may be prepared by treatment of l,4-diamino-2,3-dicyanoanthraquinone with sulfuric acid followed by alkylation of the imide by primary alkyl amine exchange. Alternatively, the sulfuric acid treatment may be carried out in the presence of a secondary alcohol (Scheme 11). 

Alcohols can also be prepared from support-bound carbon nucleophiles and carbonyl compounds (Table 7.4). Few examples have been reported of the a-alkylation of resin-bound esters with aldehydes or ketones. This reaction is complicated by the thermal instability of some ester enolates, which can undergo elimination of alkoxide to yield ketenes. Traces of water or alcohols can, furthermore, lead to saponification or transesterification and release of the substrate into solution. Less prone to base-induced cleavage are support-bound imides (Entry 2, Table 7.4 see also Entry 3, Table 13.8 [42]). Alternatively, support-bound thiol esters can be converted into stable silyl ketene acetals, which react with aldehydes under Lewis-acid catalysis (Entries 3 and 4, Table 7.4). 

The yield of amino alcohols has been shown to improve by addition of tertiary alkyl bulkhead amines, and catalytic cycles using chloramine-T (364, 366, 367) or IV-chloro-lV-argentocarbamates (368) have been devised. By the use of asymmetric inductants such as (-)-10,11-dihydro-quinine with the imide, optically active amino alcohols have been produced (369). 

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