Microwave-assisted regioselective direct C-H arylation of thiazole derivatives leading to increased σ₁ receptor affinity

New thiazole analogues 2 of spirocyclic thiophenes 1, which are known to show high σ₁ receptor affinities, have been developed as potentially better σ₁ receptor ligands. To introduce an aryl group onto the thiazole core of 2 (C4 or C5 positions), we used Pd-catalyzed regioselective C-H arylation reactions. The Pd-catalyzed C5 arylation of 2a could be considerably improved by using microwave irradiation technique. The Pd-catalyzed C4 arylation of thiazole 2a with arylboronic acid 6 could be achieved in the presence of Pd(OAc)₂, 1,10-phenanthroline, TEMPO, and LiBF₄. Under these conditions, the tertiary amine and the tertiary alcohol were well-tolerated. The regioselective arylation of 2a led to new compounds 2b and 2c, with a 4-tolyl moiety in the C5- and C4-positions, displaying five to nine-fold increased σ₁ affinity. The same σ₁ affinity of the regioisomeric thiazoles 2b and 2c can be explained by fast rotation around the piperidine-thiazole bond. Compared to spirocyclic thiophenes 1, thiazoles 2 are considerably more polar.