The first Pd-catalyzed Buchwald–Hartwig aminations at C-2 or C-4 in the estrone series

Abstract

A facile Pd-catalyzed C(sp2)–N coupling to provide a range of 2- or 4-[(subst.)phenyl]amino-13α-estrone derivatives has been achieved under microwave irradiation. The reactions were mediated with the use of Pd(OAc)2 as a catalyst and KOt-Bu as a base in the presence of X-Phos as a ligand. The desired products have been obtained in good to excellent yields. The nature and the position of the aniline substituent at the aromatic ring influenced the outcome of the couplings. 2-Amino-13α-estrone was also synthesized in a two-step protocol including an amination of 2-bromo-13α-estrone 3-benzyl ether with benzophenone imine and subsequent hydrogenolysis.

Sustainable ppm level palladium-catalyzed aminations in nanoreactors under mild, aqueous conditions

“…Another recent example providing further testimony to the potential savings of precious metal is shown in Scheme 5B. 18 Amination at C-2 in a 3-substituted estrone derivative afforded product 42 using 40 times less palladium and ligand (10 mol% ¼ 100 000 ppm), run at a lower temperature (45 vs. 110 C), and in less time (16 vs. 24 h). The level of residual Pd in the product from both approaches led to the expected outcomes: from amination in toluene: 165 ppm Pd, while from this ppm level amination in water: 3 ppm Pd.…”

Pd-Catalyzed microwave-assisted synthesis of phosphonated 13α-estrones as potential OATP2B1, 17β-HSD1 and/or STS inhibitors

“…This might be attributed to the decreased polarity of the 3-benzyloxy compounds 3 and 6 . We have recently disclosed our finding that toluene is an appropriate solvent for C(sp 2 )–N coupling reactions of 2- or 4-bromo-13α-estrone 3-benzyl ethers [ 30 ]. The structures of the newly-synthesized derivatives 8 – 13 were established through 1 H, 13 C, 31 P, COSY, HSQC and/or HMBC measurements.…”

Transition metal-catalysed A-ring C–H activations and C(sp2)–C(sp2) couplings in the 13α-oestrone series and in vitro evaluation of antiproliferative properties

“…Reactions of the steroidal substrates with N,N-dimethylcarbamoyl chloride using sodium hydride as a base afforded the desired carbamate esters (13,14) in high yields. Pivalate and sulfamate derivatives (15)(16)(17)(18)(19)(20) were synthesised in a microwave reactor. Esterifications of the substrates (11 or 12) using pivaloyl chloride as a reagent and triethylamine and (4dimethylamino)pyridine as bases furnished the required pivalates (17,18) in excellent yields.…”

“…Esterifications of the substrates (11 or 12) using pivaloyl chloride as a reagent and triethylamine and (4dimethylamino)pyridine as bases furnished the required pivalates (17,18) in excellent yields. Microwave irradiation of the starting compounds (11 or 12) with sodium hydride and sulfamoyl or N,Ndimethylsulfamoyl chloride yielded the corresponding sulfamates (15,16,19,20) in moderate to high yields.…”

“…We have recently described Pd-catalysed cross couplings at the C-2 or C-4 position of the 13a-estrane core (Scheme 2) [17][18][19][20] . Starting from steroidal aryl halides (5-7), microwave-assisted C-C, C-N, or C-P couplings were performed.…”