Bromoacetaldehyde dimethyl acetal

Benzothiophenes have always been of interest for medicinal chemistry and can be found in a number of marketed drugs such as Sertaconazole (Gineder-mofix), Zileuton (Leutrol) and Raloxifene (Evista). The classical synthesis of benzo thiophenes starts from thiophenols, reacting with bromoacetaldehyde dimethyl acetal, followed by cycUzation using strong acid. An alternative and more convenient route was also described starting from benzaldehydes which... 

The ozonolysis reaction, followed by reductive workup with sulfur dioxide, as described in Part A of the present procedure, illustrates a general method which has been developed for the preparation of acetals.3 Application of the procedure is illustrated by conversion of the following olefins in alcoholic solution to the corresponding acetals 3 (1) l-chloro-4-(o-nitrophenyl)-2-butene to o-nitrophenylacetaldehyde dimethyl acetal in 84% yield (2) l,4-dibromo-2-butene to bromoacetaldehyde dimethyl acetal in 67% yield (3) 3-butenoic acid to malonaldehydie acid diethyl acetal ethyl ester in 61% yield (4) cyclopentadiene to malonaldehyde bis(diethyl acetal) in 48% yield and (5)... 

Hydroxybenzyl alcohols have been converted to dioxepins, as the major product, by forming methoxyethoxy-methyl (MEM) ethers either on the phenolic -OH or on the benzylic -OH and reacting the other -OH group with bromoacetaldehyde dimethyl acetal, followed by treatment with BF3-OEt2 (Scheme 9) <2004T11453>. 

Thieno[2,3-f>]thiophene is readily prepared from commercially available 2-thiophenethiol (Scheme 17.4) [79], Alkylation with bromoacetaldehyde dimethyl acetal proceeds in quantitative yield. Deprotection and ring closure occur in one pot in the presence of polyphosphoric acid (PPA) in refluxing chlorobenzene to afford the product as a colorless oil. Alkyl groups can readily be introduced into the 3-position by alkylation of 2-thiophenethiol with a chloro ketone, such as l-chlorodecan-2-one. Ring closure again occurs in the presence of polyphosphoric acid to afford the 3-alkylated monomers [80],... 

Mercaptothiophene (180) S-alkylated with 2-bromoacetaldehyde dimethyl acetal (181) gave 182, ring closed with PPA in refluxing chlorobenzene giving 3 (Scheme 43) [20, 68]. Similarly, 3-alkyl-TTs (184) are produced via S-alkylation of 180 with an a-chloroketone, then acid-catalyzed ring closure [69]. 

Robin and Huet have reported a general method for the synthesis of 8-lactones as weU as lactones with several ring sizes via oxidation of the corresponding lactol [87] (Scheme 43). Alkylation of sulfone 211 with bromoacetaldehyde dimethyl acetal, cleavage of the silyl ether, and treatment with acetic acid afforded lactol 212. Oxidation of lactol 212 with PCC furnished the corresponding saturated 8-lactone 213, which underwent elimination of sulfinic acid in the presence of DBU to provide lactone 214. 

The benzazepines, veri 1 opam (79) and anilopam (81), for example, represent significant departures from the above generalization. Construction of the former starts with the alkylation of veratrylamine (74) with the dimethyl acetal of bromoacetaldehyde to give the secondary amine 7, Cyclization under acidic conditions leads to the benzazepine... 

A reported procedure based on lithium diisopropylamide induced double elimination of ethanol from bromoacetaldehyde diethyl acetal also was not very effective for the large scale preparation of phenylthioacetylene.8 Another more recent synthesis of the title compound relies on the reaction of dimethyl(chloroethynyl)carbinol with an alkali metal phenylthiolate, followed by... 

The highly substituted indole, ecopladib (82), which shares many structural elements with the phospholipase inhibitor varespladib (37), shows similar biological activity. Alkylation of hydroxy benzoate (72) with the dimethyl acetal from bromoacetaldehyde (73) affords the ether (74). Acid-catalyzed reaction of this intermediate with 2-methyl-5-chloroindole (75) in the presence of triethylsilane leads in effect to condensation of the acetal with the activated 3 position on the indole ring to afford 76. The nature of the reduction of the aldehyde carbon is not immediately apparent. Alkylation of the anion on nitrogen from reaction of the indole with sodium hydride and bromodiphenylmethane then adds the third... 

Dann and Dimmling showed that (2,5-dimethyl-3-thienylthio)acetic acid (86) may by cyclized to 4,6-dimethyl-2,3-dihydrothieno[3,4-6]-thiophen-3-one (87) by anhydrous hydrogen fluoride, and then reduced to 4,6-dimethylthieno[3,4-b]thiophene (88). The latter was obtained by cyclization of acetal (89) synthesized from 3-mercapto-2,S-c ethylthiophene (90) and bromoacetaldehyde dimethylacetd using hydrogen fluoride at 70°-80°. The synthetic route is illustrated by Scheme 6. 

---