Chloromethyl methyl ether synthesis

The chloromethylated polystyrene resin used for Merrifteld solid-phase peptide synthesis is prepared by treatment of polystyrene with chloromethyl methyl ether and a Lewis acid catalyst. Propose a mechanism for the reaction. 

The potential utility of cyclopentadienylthallium(I) in organic synthesis, and its advantages over the much more commonly employed sodium salt, have been illustrated recently 22). Treatment of (I) (Scheme 2) with chloromethyl methyl ether in dry ether resulted in smooth monoalkylation... 

Recently, Moody et al. reported a biomimetic synthesis of calothrixin B (378) by oxidation of Hibino s 6-formylindole[2,3-fl]carbazole 1555 (870). The key intermediate 6-formyl-indole[2,3-fl]carbazole was readily obtained in six steps from indigo (1458). Using Somei s procedure, indigo (1458) was transformed to the cis-chlorohydrin 1461 in three steps and 50% overall yield (see Scheme 5.247). The reduction of the chlorohydiin 1461 gave 5-hydroxy-indolo[2,3-fl]carbazole 1564, and subsequent Vilsmeier formylation delivered the desired 6-formyl-indole[2,3-fl]carba-zole 1565 in 45% yield. Reaction of hydroxy-indolocarbazole 1565 with an excess of chloromethyl methyl ether (MOMCI) afforded the tiis-MOM-protected compound 1555. Following Hibino s approach, the tris-MOM-protected indolocarbazole 1555... 

Chloromethyl methyl ether is an alkylating agent and very poisonous.Therefore this synthesis must be carried out with rubber gloves under a hood, preferentially in a glove box. 

An additional indication of the mildness of the cyclization is provided by the synthesis of the chiral tetrahydroisoquinoline-3-carboxylic acid (294) (72HCA15) in the presence of hydrogen and palladium-on-charcoal the jV-methyl derivative was obtained. Acetaldehyde gave a mixture of diastereoisomers in which the cis isomer (295) predominated (95 5). Unstable aldehydes can sometimes be generated in situ, as when the phenylglycidate (296) replaces the much less stable phenylacetaldehyde (66T(S8)129) acetals, enol ethers and chloromethyl methyl ethers have also been used. The mild conditions also allow the isolation of 4-hydroxytetrahydroisoquinolines (297) (75H(3)311). A review is available listing syntheses of 4-oxytetrahydroisoquinolines (73AHC(15)99). 

The support originally used for solid-phase synthesis was partially chloromethy-lated cross-linked polystyrene, which was prepared by chloromethylation of cross-linked polystyrene with chloromethyl methyl ether and tin(IV) chloride [1-3] or zinc chloride [4] (Figure 6.1). Haloalkylations of this type are usually only used for the functionalization of supports, and not for selective transformation of support-bound intermediates. Because of the mutagenicity of a-haloethers, other methods have been developed for the preparation of chloromethyl polystyrene. These include the chlorination of methoxymethyl polystyrene (Figure 6.1 [5]), the use of a mixture of dimethoxymethane, sulfuryl chloride, and chlorosulfonic acid instead of chloromethyl methyl ether [6], the chlorination of hydroxymethyl polystyrene [7], and the chlorination of cross-linked 4-methylstyrene-styrene copolymer with sodium hypochlorite [8], sulfuryl chloride [8], or cobalt(III) acetate/lithium chloride [9] (Figure 6.1, Table 6.1). 

A starting material for the synthesis of 9 is the 7-methoxymethyl ether of fraxetin (41), which was prepared by different workers using alternative methods. Tanaka et al. found it convenient to prepare it from fraxetin (35) by dropwise addition of a solution of chloromethyl methyl ether to a solution of 35 in a suspension of sodium hydride in THF. The reaction of this fraxetin derivative 41 with ethyl 2-bromo-3-(4-benzyloxy-3-methoxyphenyl)-3-oxopropionate (40) yielded an ether (42), which on lithium borohydride reduction yielded a mixture of diastereomers with threo- and erythro-Aio %, 43. Cyclization of this compound with sulphuric acid (5%) afforded cleomiscosin A monoacetate (44), which gave cleomiscosin A (9) on mild alkaline... 

Examples of benzylic alkylation, aromatic ring deprotonation, and nucleophilic addition to a -position were used in a synthesis of (+)-20-methoxy-serrulat-14-en-7,8-diol. Deprotonation of the optically active complex (54) followed by reaction with chloromethyl methyl ether affords (55)... 

Chloromethyl methyl ether, 1, 132-135 5, 120 7, 61-62. The conventional synthesis produces the potent carcinogen bis(chloromethyl) ether as a by-product. A new preparation (equations I and II) is free from this drawback. Methanol is required only in a catalytic amount, since it is regenerated as the ether is formed. The by-product is methyl acetate. 

The first synthesis of phosphonoacrolein (209) was achieved by acid decomposition of p-ethoxy-a-(methoxymethyl)vinylphosphonate (210) derived from lithiated phosphonate (211) and chloromethyl methyl ether (MOMCL) (Scheme 58). The phosphonoacrolein (209) appeared to be a particularly active heterodiene in the Diels-Alder additions with electron rich alkenes and alkynes. 

Chloromethyl methyl ether. A new synthesis from methoxyacetic add involves chlorination with thionyl chloride followed by decarbonylation of the methoxyacetyl chloride catalyzed by aluminum chloride ... 

Solid-phase peptide synthesis (1,516-517 2,227). Originally, Merrifield used stannic chloride and chloromethyl methyl ether for chloromethylation of... 

Chloromethyl methyl ether (CMME) is used as a methylating agent in the synthesis of chloromethylated compounds. 

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