Process for the preparation of morphine analogs via metal catalyzed N-demethylation/functionalization and intramolecular group transfer

A process for the preparation of a compound of Formula VI:

• wherein
• X is selected from C(O)R2, S(O)R2, SO2R2, P(O)R2R2′, P(O)(OR2)R2′ and P(O)(OR2)(OR2′);
• R2 and R2′ are independently selected from C3-10cycloalkyl, C3-10heterocycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl and C5-10heteroaryl, each of the latter groups being unsubstituted or substituted with one or more substituents independently selected from C1-4alkyl, OC1-4alkyl, halo, CN, NO2, C6-10aryl and OC6-10aryl;
• represents a single or double bond, provided that two double bonds are not adjacent to each other;
• and
• R3 and R4 are independently selected from X, C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when represents═O, then R4 is not present;
• the process comprising:
• (a) reacting a compound of Formula VII with a compound of Formula VIII(a) or VIII(b) under conditions to provide a compound of Formula IX:
• wherein LG1 is a leaving group;
• X is selected from C(O)R2, S(O)R2, SO2R2, P(O)R2R2′, P(O)(OR2)R2′ and P(O)(OR2)(OR2′);
• R2 and R2′ are independently selected from C3-10cycloalkyl, C3-10heterocycloalkyl, C3-10cycloalkenyl, C1-10alkyl, C2-10alkenyl, C6-10aryl and C5-10heteroaryl, each of the latter groups being unsubstituted or substituted with one or more substituents independently selected from C1-4alkyl, OC1-4alkyl, halo, CN, NO2, C6-10aryl and OC6-10aryl;
• represents a single or double bond, provided that two double bonds are not adjacent to each other;
• and
• R3 and R4 are independently selected from H, C1-10alkyl, C6-10aryl, C3-10cycloalkyl, C1-10alkyleneC6-10aryl, C1-10alkyleneC3-10cycloalkyl and PG, except when represents ═O, then R4 is not present;
• and
• (b) reacting the compound of Formula IX with a metal catalyst in the presence of an oxidant under conditions to provide the compound of Formula VI,
• wherein in the compounds of Formulae VI, VII, VIII and IX, one or more available hydrogens in R2, R2′, R3 and R4 is/are optionally replaced with F and/or one or more of available atoms in R2,
• R2′, R3 and R4 is/are optionally replaced with an isotopic label.