Triethoxymethane, reaction with

Grignard reagents can also act as sources of negative carbon in displacement reactions, e.g. in the synthetically useful reaction with triethoxymethane (ethyl orthoformate, 58) to yield acetals (59) and, subsequently, their parent aldehydes (60) ... 

Alternative routes to pyrimidines, that avoid the later hydrogenation steps, were developed at Hoffmann-La Roche [46]. This alternative synthetic strategy is shown in Fig. 36. An amino-imine can be prepared in the same way, but this time it is not reacted with a substituted phenylmalonate. Instead an alkoxybenzaldehyde is subjected to a Wittig reaction with the phosphorus ylide of chloromethoxymethane to yield l-(4-al-koxyphenyl)-2-methoxyethane. Treatment with triethoxymethane in the presence of a Lewis acid such as boron trifluoride ether-ate gives the tetraethoxy derivative. Hydrolysis produces 2-(4-alkoxyphenyl)-3-me-thoxypropenal, reaction of this material with the imine results in the pyrimidine being formed directly. 

The fact that reaction can be made to go with (25), but not with the simple R OH, is due to the ASe (c/ p. 36) value for the former being more favourable than that for the latter, which involves a decrease in the number of molecules on going from starting material to product. Both aldehydes and ketones that are otherwise difficult to convert into acetals may often be transformed by use of orthoesters, e.g. HC(OEt)3, triethoxymethane ( ethyl orthoformate ), with NH Cl as catalyst. 

After reaction of 21 with triethoxymethane to give 22, the latter is transformed stereospeciReally into 23 only the trans-isomer could be isolated. Further reactions of 23, which are not outlined in detail here, finally lead to the amino benzindolone 24. 

Q A convenietu synthesis of aldehydes involves the reaction of a Grignard reagent with triethyl orthoformate [triethoxymethane, HC(OEt),]. Suggest a mechanism for this reaction and hence explain why the reaction stops at the aldehyde stage. 

When the aminomethylene 270 (R1 = R2 = H or Me), obtained from reaction of 1 with triethoxymethane in the presence of amine, was reacted with malononitrile, it gave the quinolines 271-273 (74M1283 03JHC689) and with cyanoacetamide 274 gave quinolines 272 (R = Ar) (04T8633) (Scheme 50). 

Reaction of 1 with triethoxymethane and various ureas afforded 2-ureidomethylenes 457, which were reacted with activated acetonitriles in the presence of a strong base to give 5-oxo-5,6,7,8-tetrahyd robenzo[t>]-pyrans 458 (81S225). 

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