Alkyl -mandelates

Thus, reduction of the Mannich reaction product (65) from acetophenone leads to alcohol 66. Replacement of the hydroxyl group by chlorine (67) followed by displacement of halogen with the anion from o-cresol affords the ether 68. Removal of one of the methyl groups on nitrogen by means of the von Braun reaction or its modem equivalent (reaction with alkyl chloroformate followed by saponification) leads to racemic 69 which is then resolved with L-(+)-mandelic acid to give the levorotary antidepressant tomoxetine (69) [16]. 

The (17 )-menthyl ester of mandelic acid 8 has been deprotonated to form the enediolate 9 which was preferentially alkylated to give the (7 )-product 10 in 32% yield and with 50% diastereoselectivity116. 

Further examples of alkylation of (l/ )-menthyl mandelate are shown in the following table ... 

Premaratne, S., Mandel, M. Mower, H.F. (1995) Detection of mutagen specific adduct formation in DNA using sequencing methodology. Int. J. Biochem. Cell Biol., 27, 789-794 Quintero-Ruiz, A., Paz-Neri, L.L. Villa-Trevino, S. (1981) Indirect alkylation of CBA mouse... 

This general method has been applied to the synthesis of a variety of alkyl-substituted mandelic acids.2... 

A number of substituted mandelic acids have been prepared in fair yields by the following series of reactions (Ando synthesis), where 7. may be alkyl, aryl, acyl, or halogen. ... 

Many other groups may be present in the alcohol or phenol during alkylation. Dimethyl sulfate and chlorohydrins give chloro ethers. Halo ethers are also prepared by the action of this reagent on halogenated phenols, e.g., w-bromoanisole (91%)- Phenolic aldehydes are converted in excellent yields to alkoxy aldehydes with dimethyl sulfate or alkyl p-toluenesulfonates. The conversion of a phenolic ketone to an alkoxy ketone is illustrated by the preparation of p-methoxypropiophenone (88%). Phenolic acids, esters, and cyanides, and nitrophenols respond favorably to this method for methylation. The sodium salt of mandelic acid, C H, CHOHCOOH, is methylated with dimethyl sulfate to furnish, after acidification, a-methoxyphenylacetic acid (42%). ... 

Microwave irradiation of a mixture of an acid anhydride, an amine adsorbed on silica gel, and TaCl5/Si02 is a solvent-free method for the synthesis of A-alkyl and A-aryl-imides [47]. Ni(II) promotes the conversion of an acrylamide to ethyl acrylate via a Diels-Alder adduct with (2-pyridyl)anthracene [48], Aromatic carboxylic acids [49] and mandelic acid [50] are efficiently esterified with Fc2(S04)3 XH2O as catalyst. Co(II) perchlorate in MeOH catalyzes the methanolysis of acetyl imidazole and acetyl pyrazole [51]. Hiyama et al. used FeCb as a catalyst for the acylation of a silylated cyanohydrin. The resulting ester was then cyclized to 4-amino-2(5H)-furanones (Sch. 5) [52]. 

Alkylation of alcohols with haloalkanes is promoted by cesium hydroxide [42]. This Williamson ether synfhesis proceeds with efficiency that can be explained by dissociation of the cesium compound into ions. The alkoxide is highly nucleophilic. Treatment of a chiral mandelate with Mel and cesium carbonate is accompanied by partial racemization (Scheme 2.26). 

The free base 3a was further converted to the mandelate salt, a white crystalline product. The cyclobutyl analog 3b was similarly prepared from 8 and converted to the crystalline mandelate salt. The (S ) A-tetrahydrofurfuryl derivative 3c was prepared from (S) tetrahydrofurfuryl (1/f) camphor-10-sulfonate (10) as previously reported (Mertz et al., 1997). The 10-keto morphinans were prepared by the oxidation (Michne and Albertson, 1972) of the morphi-nan 7 with Cr03/H2S04 followed by alkylation with cyclopropyl methyl bromide and 0-demethylation to yield 4b (Scheme 1). O-Demethylation of 11 to form 13 followed by alkylation with (S) tetrahydrofurfuryl (I R) camphor-10 sulfonate (10), led to 4a. The assignment of the stereochemistry of 4a was based on the work of Merz and Stockhaus (1979). 

The first highly enantioselective construction of a-methyl-p-hydroxycarbonyl units, described by Masamune et al., used alkenyloxyboranes (29) prepared by enolization of ethyl ketone (30) derived in three steps from enantiomerically pure mandelic acid. Various dialkylboryl triflates are used with diiso-propylethylamine for enolization. The alkenyloxyboranes (29) exhibit striking stereoselectivity as chiral reagents in reactions with representative aldehydes. With judicious choice of the alkyl ligands on the... 

Alcohols are appreciably harder than phenols to alkylate with dialkyl sulfates. Here an essential point for success is complete exclusion of water.691 Alkylation of alcohols is relatively smooth only if they contain activated hydroxyl groups, as in allyl alcohol, benzyl alcohol,692 acetylenic alcohols,693 cyanohydrins, trifluoroethanol,694 mandelic acid,695 2-chloro-ethanol,696 or 2-alkoxyethanols.697... 

Thehydroxybenzofuranderivative,5-hydroxy-2-oxo-3-phenyl-2,3-dihydrobenzo-furan underwent 2-alkylation and ring closure with 4-(2-n-butoxyethoxy)mandelic acid in acetic acid at 110°C containing sulphuric acid during 9 hours, followed by oxidation by the addition of ammonium persulphate with further reaction at 110°Cfor 1 hour (ref.72). 

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