Piperidines decorated by small (cyclo)alkyl substituents (microreview)

The microreview describes recently developed methods for the synthesis of piperidines bearing small (cyclo)alkyl substituent via functionalization of preexisting unsaturated ring system.

Introduction

Piperidine is the top nitrogen heterocycle in drug discovery, which appears in 73 FDA-approved pharmaceuticals.^1,2 Therefore piperidine-based building blocks attract significant interest of medicinal chemists. Taking into account recent trends in piperidine derivative design,³ (cyclo)alkyl-substituted piperidines are among the most valuble objects. The sets of such decorated compounds are actively used in hit to lead and lead optimization projects. For example, the minilibraries based on 2-, 3-, and 4-(cyclo)alkylpiperidines are tested as CXCR3 receptor agonists (Cellgene), Abeta protein inhibitors (Bristol-Myers Squibb), and MGAT-2 inhibitors (Eli Lilly).^4,5,6 In spite of the visual simplicity of the above-mentioned building blocks, convenient methods for their synthesis allowing wide variety of the (cyclo)alkyl substituents still remain challenging task. The microreview is directed on the recent approaches to the C(sp³)–C(sp³) coupling strategies applicable for the synthesis of (cyclo)alkyl piperidines.

C( sp ³ )–C( sp ³ ) coupling

Starting from seminal Fu paper in 2003,⁷ where first C(sp³)–C(sp³) Ni-catalyzed Negishi coupling was disclosed (Table 1, entry 1), a set of other examples was published by Fu group using N-protected 4-halopiperidines 1 and reagents 2. In the case of α-metalated Boc-piperidine using chiral diamine 4, Ni-catalyzed Negishi coupling led to stereoselective formation of piperidine 3 with 94% ee (entry 2).⁸ In 2007,⁹ Fu group performed more challenging alkyl–alkyl Suzuki coupling using NiCl₂ and chiral diamine 6 (entry 3), which was then optimized in 2010 with diamine 5 (entry 4).¹⁰ In 2012, Nakamura group proposed Fe-catalyzed coupling using in situ generated magnesium tetraalkylborates (entry 5).¹¹ In the case of Kumada coupling, two different conditions based on Ni and Cu catalysis were proposed by Hu and Lui group, respectively (entries 6, 7).^12,13

Table 1. Synthesis of 4-(cyclo)alkyl piperidines via C(sp³)–C(sp³) couplings

Andrii I. Subota was born in 1979 in Kyiv, Ukraine. He graduated from the National Technical University of Ukraine "Igor Sikorsky Kyiv Polytechnic Institute", obtaining his Specialist of Science degree in 2003. Currently he is PhD student at the Institute of Organic Chemistry of the National Academy of Sciences of Ukraine and works as the head of the laboratory of Enamine Ltd. His scientific interests include organometallic chemistry, chemistry of heterocycles, catalysis.

Dmitriy M. Volochnyuk at present shares his time as head of Biologically Active Compounds Department at the Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Professor of Institute of High Technology of Taras Shevchenko National University of Kyiv, and Senior Scientific Adviser of Enamine Ltd. He received his PhD in organic chemistry in 2005 as well as Dr. Sci in organic and organomettalic chemistry in 2011. He has over 10 year experience in managing chemical outsourcing projects previously working in CRO's industry. Dr. D. M. Volochnyuk is an expert in fluoroorganic, organophosphorus, heterocyclic, combinatorial, and medicinal chemistry. He is an author of over 130 scientific papers.

C(sp³)–C(sp³) coupling (continued)

Besides traditional redox neutral cross coupling, reductive variants were proposed. In 2011, Gong group described Ni-catalyzed reductive coupling using Zn as reductant under conditions close to the seminal ones described by Fu (entry 8).¹⁴ In 2013, Deng group developed alternative Ni-based procedure using ligand 7 and B₂Pin₂ as reductive component (entry 9).¹⁵ Finally, MacMillan group developed dual Ir/Ni metallaphotoredox method using supersilanol ((TMS)₃SiOH) as a radical source in catalytic cycle (entry 10).¹⁶ Method allowed to introduce a wide set of alkyl substituents into the C-4 position of piperidine. It should be noted, that only MacMillan metallaphotoredox methodology was applied to 3-substituted piperidines, while another variants are still not known. In 2018, decarboxylative Ni-catalyzed Negishi cross coupling of organozinc compounds (formed in flow reactor in situ) with HATU-activated Cbz-protected isonipecotic acid in the presence of ligand 8 was proposed (entry 11).¹⁷

Catalytic alkene addition

In 2018, two independent groups from China proposed elegant NiH-catalyzed reductive relay cross coupling of internal 2- and 4-octene with protected 4-piperidinyl iodides in the presence of ligands 10, 11 affording 4-n-octyl derivatives 9 in good preparative yields.^18,19

In 2009, Schafer group developed innovative Ta-catalyzed strategy for the hydroaminoalkylation of secondary amines in the presence of precatalyst 12,²⁰ which was further successfully applied for diastereoselective modification of unprotected in the C-2 position piperidine.²¹ In 2017, this group showed that analogous Nb-amidate complexes also could catalyze the hydroaminoalkylation.²²