Halogenation with thionyl chloride

Reductive ring closure with thionyl chloride led to the introduction of a chloro group in the 5-position. When the 5-position was blocked by a substituent, halogen attack occurred in the 7-position. The mechanism is shown in Scheme 177 (67AHC(8)277>. 

Jsomerides of Morphine and Codeine. When morphine is treated with thionyl chloride, phosphorus trichloride or tribromide, the alcoholic hydroxyl group is replaced by the halogen, forming a-chloromorphide and bromomorphide respectively. The former on treatment with concentrated hydrochloric acid is converted into /3-chloromorphide. Schopf and Hirsch have provided evidence that the two are structural isomerides. With the same reagents codeine yields a parallel set of compounds, viz., a- and -chlorocodides, and bromocodide. The chief characteristics of these products may be summarised thus —... 

Treatment of pyridyl carbinol 51 with thionyl chloride leads to the corresponding chloride (52), Treatment of that intermediate with 5-methoxy-2-mercaptobenzimidazole (53), obtained from reaction of 4-methoxy-q-phenylenediamine with potassium ethylxanthate leads to displacement of halogen and formation of the sulfide (54). Finally, oxidation with 3-chloroperbenzoic acid produces the sulfoxide omeprazole (55) fl7]. 

Alcohols are commonly converted into the corresponding halogen on treatment with agents such as thionyl chloride in order to provide suitable sites for further variation in functionality. For example, treatment of primary alcohol 81 with thionyl chloride leads to chloro derivative 82 (Equation 16) <1997JME2196>. 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

The benzodiazepine (236) can be chlorinated at the 1-position using sodium hypochloride or t-butyl hypochlorite, or at the 3-position using NCS. The 3-chloro derivative can also be prepared by treatment of the 3-hydroxy compound with thionyl chloride. Halogens at the 3-position can be displaced to give 3-amino derivatives. 

The hydroxy groups of pyrrolizidine amino-alcohols are readily replaced by chlorine atoms upon treatment with thionyl chloride (see, e.g., refs. 101 and 103). In this reaction, the allylic hydroxyl group is more reactive and can be selectively replaced by chlorine.79 In some particular cases, methoxyl groups can also be substituted for halogen e.g., l/3-methoxymethyl-8a-pyrrolizidine, when treated with hydro-bromic acid, gives rise to the corresponding bromo derivative.104... 

The hydroxyl group of the side-chain alcohols is readily replaced by halogen by treatment with thionyl chloride 87,190,336,486,526-528,529 or by treatment with phosphorus tribromide in chloroform193 439 447-... 

Halogenoalkylquinuclidines were prepared by the reaction of the corresponding alcohols with thionyl chloride or halogen acids.24,49,121>... 

It is liable to explode on contact with thionyl chloride in absence of inert solvent. See other ENDOTHERMIC COMPOUNDS, HALOGEN OXIDES, OXIDANTS... 

The halogenation of benzothiazinotropones 361 and 362 as depicted in Scheme 97 affords 7- and/or 9-substituted derivatives like 363 and 364 (66BCJ1980). Chlorination of 362 additionally gives the 9-chloro compound or, on treating the tropone with thionyl chloride in excess (2.5 molar equivalents), a 7,9,Jc-trichloro derivative, presumably substituted at the benzene ring. 

Like carbonyl oxygen in azolinones, sulfur in azolinethiones can be displaced by a halogen atom. For example, benzimidazoline-2-thiones react with thionyl chloride producing 2-chlorobenzimidazoles. 

In addition to the traditional introduction of a halogen atom via a lactam group, maleic hydrazide was transformed into 3,6-dichloropyridazine with thionyl chloride or thionyl chloride and methyl sufonyl chloride [87CI(L)694]. Bromine in glacial acetic acid has been found to add at the 4,5-double bond of l,2-disubstituted-3,6-pyridazinediones (82M15). 

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