Opportunities and challenges for direct C-H functionalization of piperazines

Abstract

Piperazine ranks within the top three most utilized N-heterocyclic moieties in FDA-approved small-molecule pharmaceuticals. Herein we summarize the current synthetic methods available to perform C-H functionalization on piperazines in order to lend structural diversity to this privileged drug scaffold. Multiple approaches such as those involving α-lithiation trapping, transition-metal-catalyzed α-C-H functionalizations, and photoredox catalysis are discussed. We also highlight the difficulties experienced when successful methods for α-C-H functionalization of acyclic amines and saturated mono-nitrogen heterocyclic compounds (such as piperidines and pyrrolidines) were applied to piperazine substrates.

Keywords: C–H functionalization; heterocycle; photoredox catalysis; piperazine; α-lithiation.

Figure 1

Selected piperazine-containing small-molecule pharmaceuticals.

Figure 2

Strategies for the synthesis of carbon-substituted piperazines.

Figure 3

The first α-lithiation of N-Boc-protected piperazines by van Maarseveen et al. in 2005 [37].

Figure 4

α-Lithiation of N-Boc-N’-tert-butyl piperazines by Coldham et al. in 2010 [38].

Figure 5

Diamine-free α-lithiation of N-Boc-piperazines by O’Brien, Campos, et al. in 2010 [40].

Figure 6

The first enantioselective α-lithiation of N-Boc-piperazines by McDermott et al. in 2008 [41].

Figure 7

Dynamic thermodynamic resolution of lithiated of N-Boc-piperazines by Coldham et al. in 2010 [38].

Figure 8

Enantioselective α-lithiation of N-Boc-N’-alkylpiperazines by O’Brien et al. in 2013 and 2016 [–43].

Figure 9

Asymmetric α-functionalization of N-Boc-piperazines with Ph₂CO by O’Brien et al. in 2016 [43].

Figure 10

A “chiral auxiliary” strategy toward enantiopure α-functionalized piperazines by O’Brien et al. 2016 [43].

Figure 11

Installation of methyl group at the α-position of piperazines by O’Brien et al. 2016 [43].

Figure 12

α-Lithiation trapping of C-substituted N-Boc-piperazines by O’Brien et al. 2016 [43].

Figure 13

Rh-catalyzed reactions of N-(2-pyridinyl)piperazines by Murai et al. in 1997 [52].

Figure 14

Ta-catalyzed hydroaminoalkylation of piperazines by Schafer et al. in 2013 [55].

Figure 15

Photoredox catalysis for α-C–H functionalization of piperazines by MacMillan et al. in 2011 and 2014 [,–66].

Figure 16

Copper-catalyzed aerobic C–H oxidation of piperazines by Touré, Sames, et al. in 2013 [67].

Figure 17

Free radical approach by Undheim et al. in 1994 [68].

Figure 18

Anodic oxidation approach by Nyberg et al. in 1976 [70].