Chloromethyl with carbon nucleophiles

Trifluoromethyl iodide is a poor substrate for SN2 reactions [28], The increased donativity of the methylene carbon as rendered by the fluorine atoms is reflected in its reluctance to enter a bonding relationship with a nucleophile. Similar reactivity patterns are known for chloromethyl phenyl sulfone [28] and chloromethyltrimethyl-silane. In these latter compounds the reactive center is directly linked to an acceptor group. 

In the search for a reactive functional group which could be substituted on the acetylacetonate ring, chloromethylation of these chelates was attempted. The initially formed products were too reactive to be characterized directly. Treatment of rhodium acetylacetonate with chloromethyl methyl ether in the presence of boron trifluoride etherate afforded a solution of a very reactive species, apparently the chloromethyl chelate (XXX) (26). Hydrolytic workup of this intermediate yielded a polymeric mixture of rhodium chelates, but these did not contain chlorine On the basis of evidence discussed later on electrophilic cleavage of carbon from metal chelate rings and on the basis of their NMR spectra, these polymers may be of the type shown below. Reaction of the intermediate with dry ethanol afforded an impure chelate which is apparently the trisethyl ether (XXXI). Treatment of the reactive intermediate with other nucleophiles gave intractable mixtures. 

The use of chloromethyl phenyl sulfone as a carbon nucleophile in the VNS reaction of 17 and 18 allowed one to obtain substitution products 27 and 28. In this case, the undesirable para-substituted regioisomer of 27 was formed in only 4% yield. Reduction of the nitro group in sulfones 27, 28 provided corresponding anilines 29 and 30, which gave good yields of imines 31, 32 with both electron-acceptor and electron-donor benzalde-hydes. Further cychzation under basic conditions provided access to 2-aryl substituted 5(6)-SF5-indoles 33 and 34 (Scheme 7). 

When butadiene is treated with PdCU the l-chloromethyl-7r-allylpalladium complex 336 (X = Cl) is formed by the chloropalladation. In the presence of nucleophiles, the substituted 7r-methallylpalladium complex 336 (X = nucleophile) is formed(296-299]. In this way, the nucleophile can be introduced at the terminal carbon of conjugated diene systems. For example, a methoxy group is introduced at the terminal carbon of 3,7-dimethyl-I,3,6-octatriene to give 337 as expected, whereas myrcene (338) is converted into the tr-allyl complex 339 after the cyclization[288]. 

All reactions of benzotriazole derivatives of the type Bt-CR RbS discussed above are based on electrophilic or nucleophilic substitutions at the ot-carbon, but radical reactions are also possible. Thus, the first report on unsubstituted carbon-centered (benzotriazol-l-yl)methyl radical 841 involves derivatives of (benzotriazol-l-yl)methyl mercaptan. 3 -(Benzotriazol-l-yl)methyl-0-ethyl xanthate 840 is readily prepared in a reaction of l-(chloromethyl)-benzotriazole with commercially available potassium 0-ethyl xanthate. Upon treatment with radical initiators (lauroyl peroxide), the C-S bond is cleaved to generate radical 841 that can be trapped by alkenes to generate new radicals 842. By taking the xanthate moiety from the starting material, radicals 842 are converted to final products 843 with regeneration of radicals 841 allowing repetition of the process (Scheme 134). Maleinimides are also satisfactorily used as radical traps in these reactions <2001H(54)301>. 

Reaction of several purines with l-benzyl-4-(chloromethyl)piperidine has been studied. It proceeds through the initial formation of l-benzyl-l-azoniabicyclo[2.2.1]heptane system which undergoes nucleophilic attack at two different carbons yielding JV-benzylpiperidine and Af-benzylpyrrolidine substituted purines <02S911>. 

Neutral a-alkyliron complexes are obtained upon reaction of Na[Cp(CO)2pe] (5) with alkyl halides (9) (Scheme 6), and as with Collman s reagent this occurs in an Sn2 fashion with inversion of coirfiguration at the carbon atom. Epoxides also participate in this reaction, but tertiary alkyl halides are poor substrates. Alternatively, complexes (9) may be prepared by reaction of an appropriate metal alkyl with Cp(CO)2PeX (6). Typically complexes of this type are prepared in order to gain access to the synthetically nseful cationic rf--alkene iron complexes (Section 4.1.2). Also, nucleophilic addition of (5) to heteroatom-snbstituted alkyl halides (snch as methoxymethylchloride or chloromethyl methyl snllide) affords complexes of type (9) that can be converted to cationic... 

When a side chain also contains a halogen atom, such as in l,l-dichloro-2-(chloromethyl)cy-clopropane (22) or 2-(bromomethyl)-l,l-dichlorocyclopropane, elimination can occur to give a methylenecyclopropane followed by two elimination-addition cycles. The elimination-addition products are accompanied by variable amounts of substitution products in which the two chlorine atoms on the ring remain intact. Thus, for example, reaction of 22 with phenolate under phase-transfer conditions gives 10% of the substitution product 24 along with 73.5% of the double-addition product, 2-methylene-l,l-bis(phenoxy)cyclopropane (23). Bulkier nucleophiles, such as those derived from 2-phenylpropanenitrile and diphenylacetonitrile, do not add twice to the same carbon atom and give 88 and 46% yield of the 2,3-bisadducts 25, respectively. 

Bonds to Carbon.—Arsenic(ja) Compounds. Organoarsenic chemistry for 1971 has been reviewed. Methyldichloroarsine reacts with diazomethane to give the chloromethyl derivatives MeAs(CH2Cl)Cl and MeAs(CH2Cl)2, and the action of nucleophiles on these compounds is described. Ketoxime esters of benzenearsonous acid, PhAs(ON CR R )2, can be obtained by the reaction of PhAsO with ketoximes, while an alternative route from PhAsCl2 is also described. 

Dobutamine is a development compoimd from Eli Lilly in the 1970s. [121 ] Ho-moveratrylamine is obtained by chloromethylation of 1,2-dimethoxybenzene, nucleophilic substitution with cyanide, and hydrogenation. The carbon skeleton is extended by reductive amination, and the methyl groups are cleaved oif with HBr. 

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