Alkoxymethyl ketones

Silyl enol ethers serve as precursors to a variety of -(substituted methyl) ketones (Scheme 54). Trimethylsilyl trifluoromethanesulphonate catalyses the formation of a-alkoxymethyl ketones from dialkoxymethanes in the presence of a sterically hindered nitrogen base, and titanium tetrachloride catalyses the site-specific ureidoalkylation of silyl enol ethers of cycloalkanones by reaction with chloromethyl carbamates. Mannich dimethylaminomethylation can be... 

Catalyst for a-AUcoxymethylation of Ketones. Silyl enol ethers react with a-chloro ethers in the presence of TMS-I to afford a-alkoxymethyl ketones (eq 29). ... 

Functionalized 5-alkoxymethyl- and 5-phenoxymethyl-2(5//)-furanones 44-46 were obtained starting from 3-alkoxy- and 3-phenoxy-2-hydroxy ketones 40 (98T1801). Condensation of the hydroxy ketones 40 with a slight excess of diethyl malonate 41 (Z = COOMe R = Me), ethyl cyanoacetate 42 (Z = CN R = Me),... 

Thiophene is sufficiently acidic to be directly metallated upon treatment with n-BuLi (see Figure 4.1). This direct lithiation can also be realized with polystyrene-bound 3-(alkoxymethyl)thiophene [96]. The resulting organolithium compounds react as expected with several electrophiles, such as amides (to yield ketones), alkyl halides, aldehydes, and Me3SiCl [96]. 

There is a competition between alkoxymethylation and acylation in this reaction. Alkoxymethylation by cleavage of acetals is also applicable to alcoholates obtained by condensing Reformatsky reagents with aldehydes and ketones (98, 174a). 

Alkoxymethyl and Thiomethyl Dipeptidyl Ketone-Based Inhibitors... 

AlkoxYmethyl and Thiomethy] Dipeptidyl Ketone Based Inhibitors 1141... 

Berthelette and coworkers [144] developed the synthesis of vinyl ethers 328 (Scheme 111) from (z-alkoxymethyl BT sulfones 326 and various aldehydes or ketones 327. The olefination reaction was carried out using LHMDS in THF at 0 °C. In general, very good chemical yields and poor stereoselectivities were recorded. Selected examples are presented in Table 31. 

The reactions of 2-lithio- and 2-sodio-imidazoles and -benzimidazoles are not particularly novel. The compounds do, however, prove a means of introducing a variety of functional groups into the 2-position of the heterocyclic ring. Such metalation reactions at C-2 can only occur readily when there is no alternative site for the metal. Therefore, only N-substituted imidazoles are of synthetic utility, and it may be necessary to select an N-substituent which can be removed later. For this reason, benzyl (removed by reductive or oxidative methods), benzenesulfonyl (removed by ammoniacal ethanol), trityl (hydrolyzed by mild acid treatment) and alkoxymethyl (easily hydrolyzed in acid or basic medium) groups have proved useful in this context. A typical reaction sequence is shown in Scheme 136 <78JOC438l, 77JHC517). In addition, reactions with aldehydes and ketones (to form alcohols), with ethyl formate (to form the alcohol) and with carbon dioxide (to form carboxylic acids) have found application (B-76MI40701). 

Ar,Ar-Unsubstituted selenoureas reacted with a,/ -unsaturated ketones at both positions a to carbonyl carbon to give two isomeric 2-dialkylamino-l,3-selenazoles 71, 72 in alcohol in the presence of ferric chloride at room temperature (Equation 12). Reactions of a selenourea with methyl vinyl ketone in methanol, -propanol, r -propanol, and /-butanol also gave corresponding 5-(l-alkoxymethyl)-2-amino-l,3-selenazole derivatives 73 (Equation 13) <2006H(68)2145>. 

A very convenient hydroxymethylation process has been developed based on the Sml2-mediated Bar-bier-type reaction. Treatment of aldehydes or ketones with benzyl chloromethyl ether in the presence of Smh provides the alkoxymethylated products in good to excellent yields. Subsequent reductive cleavage of the benzyl ether provides hydroxymethylated products. Even ketones with a high propensity for enolization can be alkylated by this process in reasonable yields. The method was utilized by White and Soners as a key step in the synthesis of ( )-deoxystemodinone (equation 27). This particular ketone substrate resisted attack by many other nucleophilic reagents (such as methyllithium) owing to conpeti-tive enolate formation. 

A unique alkoxymethylation reaction can be acconplished by treatment of a-alkoxycarboxylic acid chlorides with ketones in the presence of Sml2 (equation 28). llie reaction is postulated to proceed by a reductive decarbonylation process, leading to a relatively stable a-alkoxy radical. Addition ctf this radical to the Sm -activated carbonyl and further reduction and hydrolysis provides the observed product. An... 

H)-Furanones are formed from alkoxyalkyl diazomethyl ketones. The insertion proceeds with retention of configuration at the carbinyl center of a -alkoxymethyl a-diazomethyl ketones. A surprising stereoselectivity is found during the formation of 2-deoxyxylolactone from a symmetrical diazoacetic ester. ... 

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