Transition Metal-Catalyzed Directed C(sp3)–H Functionalization of Saturated Heterocycles

Abstract

Synthetic methods that can readily access saturated heterocycles with different substitution patterns and with control of stereo- and regiochemistry are of huge potential value in the development of new medicinal compounds. Directed C–H functionalization of simple and commercially available precursors offers the potential to prepare diverse collections of such valuable compounds that can probe the different available exit vectors from a ring system. Nonetheless, the presence of the Lewis basic heteroatoms makes this a significant challenge. This review covers recent advances in the catalytic C–H functionalization of saturated heterocycles, with a view to different heterocycles (N, O, S), substitution patterns and transformations.1 Introduction2 α-C–H Functionalization with Directing Group on Nitrogen3 C–H Functionalization at Unactivated C(3), C(4), and C(5) Positions3.1 C–H Functionalization at C(3) with Directing Groups at C(2)3.2 C–H Functionalization at C(3), C(4), and C(5): Directing Groups at C(4) and C(3)4 Transannular C–H Functionalization5 Conclusion

Chemical and structural investigation of the paroxetine-human serotonin transporter complex

“…Transition metal-catalyzed C-H functionalization can promote the reaction of unactivated C(sp 3 )-H bonds with the aid of a directing group [21][22][23][24][25][26] . Here, C-H functionalization enabled installation of the appropriate aryl group on the pre-existing piperidine ring 27 , providing an attractive and short route to vary this functionality with inherent control of enantiomeric excess.…”

“…Purification by flash column chromatography (5% acetone/pentane) afforded piperidine (-)-9a as a white solid (225 mg, 60% over 2 steps). [ ]23 -36.0 (c 1.0, CHCl 3 ). R f 0.20 (5% acetone/pentane); mp = 53-58 °C;  max (film)/cm -1 2915, 1685 (C=O), 1483, 1424, 1230, 1163, 1129, 1036, 928, 816, 769; 1 H NMR (400 MHz, CDCl 3 , 298 K)  7.45-7.38 (m, 2 H, HC Ar ), 7.10-7.03 (m, 2 H, HC Ar ), 6.64 (d, J = 8.5 Hz, H, HC Ar ), 6.36 (d, J = 2.5 Hz, 1 H, HC Ar ), 6.14 (dd, J = 8.5, 2.5 Hz, 1 H, HC Ar ), 5.89 (s, 2 H, OCH 2 O), 4.44 (br s, 1 H, NCHHCHCH 2 OAr), 4.25 (br s, 1 H, NCHHCH 2 ), 3.61 (dd, J = 9.4, 2.8 Hz, 1 H, CHHOAr), 3.45 (dd, J = 9.4, 6.4 Hz, 1 H, CHHOAr), 2.92-2.73 (br m, 2 H, NCHHCHCH 2 OAr, NCHHCH 2 ), 2.67 (td, J = 11.7, 3.9 Hz, 1 H, CHAr), 2.08-1.97 (br m, 1 H, CHCH 2 OAr), 1.85-1.77 (br m, 1 H, NCH 2 CHH), 1.72 (td, J = 12.6, 4.3 Hz, 1 H, NCH 2 CHH), 1.50 (s, 9 H, C(CH 3 ) 3 ); 13 C NMR (101 MHz, CDCl 3 , 298 K)  154.7 (C=O), 154.2 (OC Ar quat), 148.1 (OC Ar quat), 142.4 (C Ar quat), 141.7 (OC Ar quat), 131.8 (2 × C Ar ), 129.1 (2 × C Ar ), 120.4 (BrC Ar quat), 107.8 (C Ar ), 105.5 (C Ar ), 101.1 (OCH 2 O), 98.0 (C Ar ), 79.7 (C(CH 3 ) 3 ), 68.7 (CH 2 OAr), 47.3 (br m, NCH 2 CHCH 2 OAr), 44.2 (NCH 2 CH 2 , CHAr), 41.7 (CHCH 2 OAr), 33.7 (NCH 2 CH 2 ), 28.4 (C(CH 3 ) 3 ); HRMS (ESI + ) m/z Calculated for C 24 H 29 NO 5 79 Br [M+H] 490.1229; Found 490.1240.…”

“…15% deiodinated derivative). [ ]23 -8.0 (c 1.0, CHCl 3 ). Characterization data identical to that reported for enantiomeric alcohol (+)-S4b (see S27).HPLC Conditions: Chiralpak ID 3-column, 90:10 n-hexane:i-PrOH, flow rate: 1 mL•min -1 , 35 ºC, UV detection wavelength: 230.1 nm.…”

Chemical and structural investigation of the paroxetine-human serotonin transporter complex

“…Transition metal-catalyzed C-H functionalization can promote the reaction of unactivated C(sp 3 )-H bonds with the aid of a directing group [21][22][23][24][25][26] . Here, C-H functionalization enabled installation of the appropriate aryl group on the pre-existing piperidine ring 27 , providing an attractive and short route to vary this functionality with inherent control of enantiomeric excess.…”

Conformationally Driven Ru(II)-Catalyzed Multiple ortho-C–H Bond Activation in Diphenylpyrazine Derivatives in Water: Where Is the Limit?

“…Catalytic C-H bond activation and subsequent formation of new C-C bonds, or C-heteroatom bonds, have remarkably contributed to the development of chemical transformations which enable the construction of complex molecular architectures from readily available precursors by shortening synthetic pathways and reducing waste production [1][2][3][4][5][6][7]. Heteroarylation via C-H bond activation has been largely applied to material science, for example, the synthesis of conjugated dyes [8] and polymers [9].…”