Process for the preparation of heteroaryl-substituted sulfur(vi) compounds

A process for the preparation of a compound of Formula I

• comprising reacting a compound of Formula II
• with a compound of Formula III
• in the presence of a base;
• wherein:
• X is independently selected at each occurrence from O or NR4;
• R1 is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)(C0-C3alkyl), (C3-C7heterocycle)(C0-C3alkyl), (6- to 10-membered monocyclic or bicyclic aryl)(C0-C3alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)(C0-C3alkyl), or NR6R7, each of which may be optionally substituted as allowed by valence with one or more Y or Z groups;
• R2 and R3 are independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)(C0-C3alkyl), (C3-C7heterocycle)(C0-C3alkyl), (6- to 10-membered monocyclic or bicyclic aryl)(C0-C3alkyl), or (5- to 10-membered monocyclic or bicyclic heteroaryl)(C0-C3alkyl), each of which may be optionally substituted as allowed by valence with one or more Y or Z groups;
• R4 is selected at each occurrence from hydrogen, C1-C6alkyl, (C3-C7cycloalkyl)(C0-C3alkyl), (C3-C7heterocycle)(C0-C3alkyl), (6- to 10-membered monocyclic or bicyclic aryl)(C0-C3alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)(C0-C3alkyl), C(═O)R8, or Si(R9)(R10)(R11), each of which may be optionally substituted as allowed by valence with one or more Y or Z groups;
• or R4 is a nitrogen protecting group;
• or R1 and R2 may be brought together with the atoms to which they are attached to form a cycloalkyl or heterocycle ring, each of which may be optionally substituted as allowed by valence with one or more Y or Z groups;
• or R2 and R3 may be brought together with the carbon to which they are attached to form a cycloalkyl or heterocycle ring, each of which may be optionally substituted as allowed by valence with one or more Y or Z groups;
• or R1 and R4 may be brought together with the atoms to which they are attached to form a monocyclic or bicyclic heterocycle or heteroaryl ring, each of which may be optionally substituted as allowed by valence with one or more Y or Z groups;
• R5 is a leaving group, for example a halo, a sulfonate, or a sulfone group;
• hetAr is a monocyclic or bicyclic 6- to 10-membered heteroaryl group having one or more ring heteroatoms selected from N, O, and S, wherein at least one of the ring heteroatoms is N, and wherein hetAr may be optionally substituted as allowed by valence with one or more Y groups;
• R6 and R7 are each selected from hydrogen, C1-C6alkyl, (C3-C7cycloalkyl)(C0-C3alkyl), (C3-C7heterocycle)(C0-C3alkyl), (6- to 10-membered monocyclic or bicyclic aryl)(C0-C3alkyl), and (5- to 10-membered monocyclic or bicyclic heteroaryl)(C0-C3alkyl), each of which may be optionally substituted with one or more Y or Z groups;
• R8 is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)(C0-C3alkyl), (C3-C7heterocycle)(C0-C3alkyl), (6- to 10-membered monocyclic or bicyclic aryl)(C0-C3alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)(C0-C3alkyl), —ORa, or —NRaRb, each of which may be optionally substituted as allowed by valence with one or more Y or Z groups;
• R9, R10, and R11 are independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)(C0-C3alkyl), (C3-C7heterocycle)(C0-C3alkyl), (6- to 10-membered monocyclic or bicyclic aryl)(C0-C3alkyl), and (5- to 10-membered monocyclic or bicyclic heteroaryl)(C0-C3alkyl), each of which may be optionally substituted as allowed by valence with one or more Y or Z groups;
• Y is selected at each occurrence from halo, nitro, cyano, azido, oxo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)(C0-C3alkyl), (C3-C7heterocycle)(C0-C3alkyl), (6- to 10-membered monocyclic or bicyclic aryl)(C0-C3alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)(C0-C3alkyl), —ORa, —SRa, —NRaRb, —S(O)Rc, and —S(O)2Rc, each of which may be optionally substituted with one or more Z groups as allowed by valence;
• Ra and Rb are independently selected at each occurrence from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)(C0-C3alkyl), (C3-C7heterocycle)(C0-C3alkyl), (6- to 10-membered monocyclic or bicyclic aryl)(C0-C3alkyl), and (5- to 10-membered monocyclic or bicyclic heteroaryl)(C0-C3alkyl), each of which may be optionally substituted as allowed by valence with one or more Z groups;
• Rc is independently selected at each occurrence from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)(C0-C3alkyl), (C3-C7heterocycle)(C0-C3alkyl), (6- to 10-membered monocyclic or bicyclic aryl)(C0-C3alkyl), (5- to 10-membered monocyclic or bicyclic heteroaryl)(C0-C3alkyl), —ORa, —SRa, and —NRaRb, each of which may be optionally substituted as allowed by valency with one or more Z groups;
• and
• Z is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic ester, ether, halo, hydroxyl, ketone, cyano, silyl, sulfo-oxo, sulfonyl, sulfoxide, sulfonamide, thiol, or combinations thereof.