Synthesis of endo‐ and exo‐N‐Protected 5‐Arylated 2‐Aminothiazoles through Direct Arylation: An Efficient Route to Cell Differentiation Accelerators

Abstract

An improved protocol for the direct arylation of N-phenyl-N-benzyl(thiazol-2-yl)amine by using aryl bromides as aryl donors is reported. The procedure was compared with a previously reported protocol in which aryl iodides were used as arylating agents. The improved direct arylation protocol was applied to structurally isomeric and nonaromatic 3-benzyl-N-phenylthiazol-2(3H)-imine. The two substrates for direct [a]

Direct (Hetero)arylation Reactions of (Hetero)arenes as Tools for the Step- and Atom-Economical Synthesis of Biologically Active Unnatural Compounds Including Pharmaceutical Targets

“…Interestingly, compounds 115 and 116 were found to exhibit low nanomolar σ 1 affinities (1.6 nM for 115 and 2.4 nM for 116). 69 Some years earlier, Pellet-Rostaing and co-workers had used palladium-catalyzed direct (hetero)arylation reactions of benzo [b]thiophene and thiophene derivatives 71 to carry out the synthesis of 3-formyl-2-phenylbenzo [b]thiophene (117), 3-formyl-2-(3-pyridyl)benzo [b]thiophene (118), and 3-methoxy-2-(3-pyridyl)-5-(3-trifluoromethylphenyl)thiophene (119), three new inhibitors of the NorA multidrug transporter of Staphylococcus aureus 72 which is one of the…”

“…In 2015, Schnürch and co-workers reported a new synthesis of compounds of general formula 202 by direct C5arylation of 201 with 1.5 equiv of electron-rich and electron-deficient aryl bromides in DMA at 140 °C in the presence of 1 mol% Pd(OAc) 2 and 1.5 equiv of KOAc (Scheme 45). 118 The arylation reactions, which were carried out under ligand-free conditions, produced compounds 202 in yields ranging from 44 to 88%. Compounds 202 included derivatives that had previously been synthesized through the protocol illustrated in Scheme 44.…”

“…It should be noted that 202b (Figure 25), which was one of the compounds synthesized by the new procedure, was found to exhibit moderate activity in the promotion of skeletal muscle cell differentiation. 118…”

“…Schnürch and co-workers also investigated the unprecedented direct arylation of N-[3-benzylthiazol-2(3H)ylidene]aniline (203) with aryl iodides and bromides and found that the ligand-free Pd(OAc) 2 -catalyzed reaction of this substrate in DMA in the presence of KOAc provided 5aryl-N-[3-benzylthiazol-2(3H)-ylidene]anilines 204 in moderate to good yields (Scheme 46). 118…”

“…Compound 203 was prepared in 55% yield by treatment of 1.0 equiv of N-phenylthiazol-2-amine (199) with 1.33 equiv of benzyl bromide (200) and 1.0 equiv of Et 3 N in dioxane at 120 °C for 24 hours and purification of the resulting crude reaction product by crystallization (Scheme 46). 118 The direct arylation reaction of 1.0 equiv of 203 with 2.0 equiv of an aryl iodide, 1 mol% Pd(OAc) 2 and 2.0 equiv of KOAc in DMA at 120 °C for 24 hours gave compounds 204 in considerably higher yields than those obtained using aryl bromides as arylating reagents. A preliminary biological evaluation showed that compounds 204 were cell-differentiation accelerators and possessed an activity similar to that of compounds 202.…”