A-Bromo acetals

HydroxyMTX (614), which is an inactive metabolite of MTX, has been prepared by condensation of 2,4-diamino-7-hydroxypteridine-6-(a-bromo)-acetic acid (613) with p-methylaminobenzoylglutamic acid hydrobromide decarboxylation takes place during the reaction to give (614) directly... 

In a parallel study, it was found that chelating chiral diamines 208 or 209 are well suited as ligands to promote Kumada-type couplings of primary and secondary alkyl halides 202 with aryl Grignard reagents 203 (entry 4) [281]. This reaction was applicable to alkyl bromides and alkyl iodides, while alkyl chlorides gave only low yields. Acetal and ester functions are tolerated. A notable feature is the stereoretentive arylation of fra s-a-bromo acetals with excellent diastereo-selectivity. The involvement of radicals is supported by the stereoconvergent formation of cxo-phenvI norbornane from both endo- or exo-bromonorbomane (cf. Part 1, Fig. 9) and radical 5-exo cyclizations (see below). 

Bromination of acetals affords satisfactory yields of the a-bromo acetals. The reaction is carried out in cold chloroform solution in the presence of calcium carbonate, which reacts with the liberated hydrogen bromide. ... 

In presence of a base, a-bromo acetals can be converted into ketene acetals, products difficult to obtain by the classical processes. The reaction was studied in the presence of KOH in solvent-free conditions. The effects of a phase transfer agent as well as that of ultrasound, a non-classical method of activation especially efficient in heterogeneous solid-liquid systems due to cavitation phenomenon, were studied (Table 6) [87]. 

We have already seen how cyclic sulfates such as 123 can be converted into amino alcohols that might have been made by amino hydroxylation. The conversion of 1,2-diols, made by the AD reaction, into epoxides has been very widely used. A combination of acetyl bromide and an orthoester gives a bromo-acetate via an oxonium ion 182. The ion is formed with retention, bromide opens it with inversion at the benzylic centre, and epoxidation in base inverts it again. The net result is retention.39... 

Owing to the simplicity, selectivity and economy of this new procedure, the a-bromo alkyl aryl acetals have been proposed as starting materials for the industrial production of some 2-aryl propionic acids such as the important pharmaceutical drugs, Ibuprofen and Naproxen. For instance, the preparation of enantiomerically pure Naproxen has been carried out, in one step, by means of the highly stereoselective Lewis acid catalyzed rearrangement of a starting a-bromo acetal, involving a 1,2-aryl shift (ref. 3) (Fig. 3) ... 

The reductive coupling of a-bromo acetate to succinic acid diesters mediated by Sml2 in the presence of HMPA has been reported [76] (Scheme 32). 

In the absence of sodium methoxide only traces of the a-bromo acetal are obtained. Hamaoka and Brown suggest that the reaction involves methyl hypobromite. 

Furanes. In a furane synthesis described recently the a-bromo acetal (1) and silyl enol ethers (2) react, in the presence of TiCU, to form alkoxy-7-bromoketones (3). The products undergo dehydrohalogenation and loss of CH3OH when heated in toluene for 5-8 hr. to form furanes (4). The furanes (4) are sometimes accompanied by (5), formed by elimination of only CH3OH. 

Rieke and Uhm have published more details concerning the preparation of a highly reactive zinc by reduction of anhydrous zinc chloride with potassium metal in refluxing THF (5, 753). The Reformatsky reaction of ethyl a-bromo-acetate with various aldehydes and ketones can be conducted in ether at 20° when this reactive form of zinc is used. Yields of hydroxy esters are usually greater than 95%. 

Bromination, 17, 71, 97 Bromine, 70-73, 75 a-Bromo acetals, 72 co-Bromoacetates, 352 Bromoacetyl fluoride, 103 Bromacetylium hexafluoroantimonatc,... 

Thallous ethoxide added in one portion at room temp, to a stirred soln. of 3-azido-4-phenyl-2-azetidinone in dimethylformamide, then tert-hutyl a-bromo-acetate in dimethylformamide added during 5 min., and stirred 1 hr. at room temp. l-( err-butoxycarbonylmethyl)-3-azido-4-phenyl-2-azetidinone. Y 50%, -Other methods failed. F. e. s. J. N. Wells and O. R. Tarwater, J. Med. Chem. 14, 242 (1971). 

Scheme 24.1 (a) Synthesis of asymmetric cyanine dyes (A) bromo acetic acid, EtOAc (B) Mei, K2CO3, DMF (C) TosOMe,... 

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