Chloromethyl oxidation

Thiols may be converted into alkenes with one extra carbon atom by successive chloromethylation, oxidation at sulfur, and Ramberg-BScklund rearrangement. If the original thiol is prepared by free radical addition of H2S to an alkene, the sequence constitutes a one-carbon homologation of alkenes. Although these transformations were at one time important applications of the Ramberg-Backlund reaction, they have hardly been used in recent years. 

The hydroxyl groups can be alkylated in the usual manner. Hydroxyalkyl ethers may be prepared with alkylene oxides and chloromethyl ethers by reaction with formaldehyde and hydrogen chloride (86). The terminal chlorides can be easily converted to additional ether groups. 

Epichlorohydrin. Commercial polyester elastomers include both the homopolymer and the copolymer of epichl orohydrin with ethylene oxide. The very polar chloromethyl groups create basic resistance to oil for these polymers, and they have been extensively used in fuel lines however, the desire for lower fuel permeation is causing a search to be made for other polymers (10) (see Elastomers, synthetic-polyethers). 

Chromone, 3-hydroxymethyl-8-methoxy-antiallergic activity, 3, 707 Chromone, 7-methoxy-chlorosulfonation, 3, 708 Chromone, 7-methoxy-2-methyl-chloromethylation, 3, 708 Chromone, 2-methyl-chloromethylation, 3, 697 halogenation, 3, 709 IR spectra, 3, 596 mass spectra, 3, 613 oxidation, 3, 709 reactions... 

Selenazole, 2-aryl-4-chloromethyl-hydrolysis, 6, 344 Selenazole, 2-diethylamino-nitration, 6, 341 Selenazole, 2,4-dimethyl-oxidation, 6, 341 Selenazole, 2-hydrazino-oxidation, 6, 342 Selenazoles, 6, 339-347 electrophilic substitution, 6, 340 hetero fused synthesis, 6, 344 mass spectra, 6, 340 mesoionic... 

The six-position may be functionalized by electrophilic aromatic substitution. Either bromination (Br2/CH2Cl2/-5°) acetylation (acetyl chloride, aluminum chloride, nitrobenzene) " or chloromethylation (chloromethyl methyl ether, stannic chloride, -60°) " affords the 6,6 -disubstituted product. It should also be noted that treatment of the acetyl derivative with KOBr in THF affords the carboxylic acid in 84% yield. The brominated crown may then be metallated (n-BuLi) and treated with an electrophile to form a chain-extender. To this end, Cram has utilized both ethylene oxide " and dichlorodimethyl-silane in the conversion of bis-binaphthyl crowns into polymer-bound resolving agents. The acetylation/oxidation sequence is illustrated in Eq. (3.54). 

The reaction of 3-methoxy-1,2,4-triazine 1-oxide 20 with the carbanion generated from chloromethyl phenyl sulfone proceeds as the vicarious nucleophilic substitution (VNS) of hydrogen (Scheme 1, path B) via addition of the carbanion at position 5 of the heterocycle. Following base-induced elimination of HCl and protonation, 3-methoxy-5-phenylsulfonyl-1,2,4-triazine 4-oxides 65 result (88LA627). 

At the same time, the reaction of 1,2,4-triazine 4-oxides 55 with the anion of chloromethyl phenyl sulfone affords 5-(l-chloro-l-phenylmethyl)-l,2,4-triazines 66. In this case, autoaromatization of the a -adducts proceeds by the deoxygenative... 

It is only recently that the chloromethylation reaction, well known in the benzene series, has been extended to isoxazoles. It has been thereby found that this reaction results in 4-chloromethyl derivatives (69), their yield decreasing as follows 5-phenyl > 3,5-dimethyl > 5-methyl > 3-methyl isoxazoles > isoxazole. To prove the position of the chloromethyl group these compounds were oxidized to the known isoxazole-4-carboxylic acids (70). It is especially noteworthy that pyridine and its homologs do not undergo chloromethylation. 

Nucleophilic substitution of the halogen atom of halogenomethylisoxazoles proceeds readily this reaction does not differ essentially from that of benzyl halides. One should note the successful hydrolysis of 4-chloromethyl- and 4-(chlorobenzyl)-isoxazoles by freshly precipitated lead oxide, a reagent seldom used in organic chemistry. Other halides, ethers, and esters of the isoxazole series have been obtained from 3- and 4-halogenomethylisoxazoles, and 3-chloro-methylisoxazole has been reported in the Arbuzov rearrangement. Panizzi has used dichloromethylisoxazole derivatives to synthesize isoxazole-3- and isoxazole-5-aldehydes/ ... 

To a warm solution (50°C) of 172.5 g (0.7 mol) of 2-amino-5-chlorobenzophenone-o -oxime in one liter glacial acetic acid were added 110 cc (1.47 mols) chloroacetyl chloride. The mixture was heated for 10 minutes at 50°C and then stirred at room temeprature for 15 hours. The precipitated yellow prisms, 2-chloromethyl-4-phenyl-6-chloroquinazoline 3-oxide hydrochloride, were filtered off, melting range 128° to 150°C with dec. 

Ninety-eight grams of 6-chloro-2-chloromethyl-4-phenylquinazoline 3-oxide hydrochloride were introduced into 600 cc of ice cold 25% methanolic methylamine. The mixture was initially cooled to about 30°C and then stirred at room temperature. After 15 hours the reaction product which precipitated was filtered off. The mother liquor was concentrated in vacuo to dryness. The residue was dissolved in methylene chloride, washed with water and dried with sodium sulfate. The methylene chloride solution was concentrated in vacuo and the crystalline residue was boiled with a small amount of acetone to dissolve the more soluble impurities. The mixture was then cooled at 5°C for 10 hours and filtered. The crystalline product, 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide, was recrystallized from ethanol forming light yellow plates, MP 236° to 236.5°C. 

The above methods occurred in 3 steps, therefore, these methods are not preferred. For instance, in the first step, o-, m-, and p-bromostyrene and its copolymer are synthesized. In the second step, Li-PS is synthesized from the reaction of copolymers with an organic compound containing LI. The abovementioned reactions are made with different compounds of Li-PS in the third step. These methods were also investigated by Ayres and Mann [34], who used the synthesis of PS containing chloro groups with chloromethylated PS as the first step. In the second step, formil resin was obtained by oxidation of chlorometylated PS. In the third step, carboxyl-ated PS was obtained by the oxidation of formol resin with acetic acid at 20°C for 48 h. There are some disad-... 

Chloromethyl)quinazoline 3-oxides, c.g. 8, react with ammonia and primary amines to yield 3//-1,4-benzodiazepine 4-oxides 10, sometimes accompanied by the simple substitution products 9.219 Dimethylamine220 and pyrrolidine221 react analogously, but other secondary amines afford only products of type 9. 

A suspension of 6-chloro-2-(chloromethyl)-4-phcnylquinazoline 3-oxide (8 40 g, 0.13 mol) in 15% NH3/ EtOH (400 mL, large excess) was stirred at 20 C for 5h. The precipitated product was filtered off and washed with H20, followed by Et20 yield 24 g (60%) pale-yellow prisms mp 255-256 C (McOH). 

It has been proposed that the ring-expansion reaction is initiated by attack of the base at position 2 of the quinazoline oxide, which is rendered electron deficient by the inductive effect of the (V-oxide group. In fact, 2-(Chloromethyl)quinazolines, compounds that lack this feature, react with amines to give only simple substitution products.1133... 

Benzodiazcpine 4-oxides are also produced from 2-(chloromethyl)-l,2-dihydroquin-azoline 3-oxides 11. Thus, the action of potassium /< )7-butoxide on compound 11a gives the fused aziridine 12a, which readily isomerizes to the 5H-], 4-benzodiazepine 4-oxidc 13a on heating. The homolog lib similarly affords the 5//-benzodiazepine oxide 13b on treatment with potassium rerr-butoxide via the aziridine 12b, which, however, could not be isolated. Under different conditions, i.e. with aqueous ethanolic sodium hydroxide, compound 11b is transformed into the tautomeric 3//-1,4-benzodiazepine 4-oxide 14.222... 

BuOK. (15.4 g, 0.139 mol) was added in portions to 6-chloro-2-(chloromethyl)-4-phenyl-l,2-dihydro-quinazoline 3-oxide (11a 42.2 g, 0.137 mol) in THF (700 mL), cooled in acetone/solid carbon dioxide, and the mixture was stirred for 4.5 h as it warmed to 20 C. It was filtered through Celite, the filtrate was evaporated under reduced pressure and the residue was recrystallized (benzene/hexane) to give the crude aziridinoquinazoline oxide 12a yield 22.Og (57%) mp 135-136.5 C. 

Another dihydro derivative has been described in connection with medicinal chemical studies. Thus, reaction of 2-(chloromethyl)quinazoline-3-oxide (3) with hydrazine gives hydr-oxytriazocinamine 4 (and not a diazepine derivative as originally assigned), vigorous acetylation of which results in a rearrangement to give oxazolotriazocine 5.10... 

The above explains the key roles of (a) the nucleophilicity of the nucleophile (b) the substituent(s) (c) the polarity of the reaction medium and (d) the the bulkiness of the nucleophile, in determining the regio- and stereo-specificity of the reaction. The reaction of alkyl chloromethyl ethers with thiirane oxides to give sulfenic esters128 appears to be mechanistically analogous. 

As has been mentioned in an earlier section, aqueous chlorination of sulphoxides leads to sulphones. If excess reagents are used, sulphonyl chlorides may be formed directly from sulphoxides in good yields (equation 75)89,90,193. In order for this reaction to be synthetically useful, the sulphoxide used should be symmetrical. The product is presumably formed in a stepwise manner via the sulphinyl chloride [RS(0)C1] and the sulphinic acid [RS(0)0H]. In the case of chloromethyl dichloromethyl sulphoxide, the only sulphonyl chloride formed is chloromethanesulphonyl chloride (equation 76) and this may be readily separated from the other products by distillation90,193. Similarly, oxidation of dichloromethyl methyl sulphoxide and methyl trichloromethyl sulphoxide with chlorine in aqueous acetic acid leads to the formation of methanesulphonyl chloride in 75% and 86% yields respectively. Other species are also produced but these are much more volatile and thus easily removed (equations 77 and 78). In the absence of acetic acid the yields are somewhat reduced. 

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