Synthesis of bicyclo[2.2.2]octane derivatives

A process comprising contacting a compound of the formula

• with (i) a transition metal catalyst comprising a palladium compound and (ii) an oxidizing agent;
• optionally in the presence of at least one of
• (I) a compound of the formula
• wherein R is chosen from hydrogen;
• and C1-C12 alkyl, optionally substituted by one or more of groups chosen from C1-C6 alkoxy, halo, nitro, and cyano;
• R* is chosen from hydrogen;
• C1-C12 alkyl, optionally substituted by one or more of groups chosen from C1-C6 alkoxy, halo, nitro, and cyano;
• and an alkali metal cation;
• or
• (II) a compound having at least one C1-C12 alkanoyloxy moiety of the formula
• to afford a compound of the formula
• wherein each R1 is independently hydrogen or a group of the formula
• further comprising a step chosen from (a), (b), or (c):
• (a) the step of reaction with carbon monoxide in the presence of a strong acid, followed by quenching with at least one of (i) water or (ii) an alcohol of the formula R—OH, to afford compounds of the formula
• optionally further comprising the step of:
• contacting with hydrogen in the presence of a heterogeneous copper catalyst or a homogeneous ruthenium catalyst to afford a compound of the formula
• optionally followed by reductive amination to afford a compound of the formula
• (b) the step of conversion to a compound of the formula:
• which comprises reaction of (I) with a nitrile in the presence of an acid followed by hydrolysis to the corresponding amine;
• optionally further comprising treatment with phosgene (COCl2) to afford a compound of the formula:
• or
• (c) the step of halogenation of (I) to afford a compound of the formula:
• wherein x is halo;
• optionally further comprising a step chosen from:
• a. reaction with carbon monoxide in the presence of a strong acid, followed by quenching with at least one of (i) water or (ii) an alcohol of the formula R—OH, to afford compounds of the formula
• b. amination via treatment with ammonia to afford a compound of the formula:
• or
• c. hydroformylation via treatment with carbon monoxide and hydrogen in the presence of at least one of a cobalt or ruthenium catalyst at a temperature of about 90 to 250° C. and a pressure of about 5 to 300 bar, to afford a compound of the formula:
• optionally further comprising:
• a. treatment with an oxidizing agent, optionally in the presence of a homogeneous and/or heterogeneous catalyst to afford a compound of the formula:
• or
• b. hydrogenation, optionally in the presence of a homogeneous and/or heterogeneous catalyst to afford a compound of the formula: