Recent Advances in the Synthesis of Piperidines: Functionalization of Preexisting Ring Systems

Liu, Gong‐Qing; Opatz, Till

doi:10.1016/bs.aihch.2017.10.001

Cited by 36 publications

(31 citation statements)

References 428 publications

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“…[7] It should be noted that piperidine is the top nitrogen heterocyclic ring in drug discovery; [8,9] it is found in a total of 76 unique small-molecule FDA-approved pharmaceuticals. [7] It should be noted that piperidine is the top nitrogen heterocyclic ring in drug discovery; [8,9] it is found in a total of 76 unique small-molecule FDA-approved pharmaceuticals.…”

Section: Introductionmentioning

confidence: 99%

“…Derivatives of other regioisomers can also be found among marketed pharmaceuticals, e.g. Although there are many methods which rely on the modification of a preexisting piperidine ring, [7] we have considered retrosynthetic approach shown in Scheme 1 as more promising synthetic strategy. 7-13).…”

Section: Introductionmentioning

confidence: 99%

“…ifenprodil (5) and melperone (6), as well as compounds that have reached various drug development phases (e.g. [7] Some of them relied on the use of homogeneous Rh- [13] or Ir-based, [14,15] and metalfree [16][17][18] cata-lytic systems; nevertheless, heterogeneous catalysts like Pd-C, PtO 2 , Pd(OH) 2 -C, Rh, or RuO 2 often remained more preferable. Despite their extensive use in drug discovery, synthetic accessibility of (cyclo)alkylpiperidines have remained far from being satisfactory.…”

Section: Introductionmentioning

confidence: 99%

“…tion of this idea is given by the case of piperidine derivatives, where the problem can be reduced to modification of the pyridine ring with its subsequent hydrogenation (Scheme 1). [7] It should be noted that piperidine is the top nitrogen heterocyclic ring in drug discovery; [8,9] it is found in a total of 76 unique small-molecule FDA-approved pharmaceuticals. Also, this core is one of prevalent structural motifs in nature compounds.…”

Section: Introductionmentioning

confidence: 99%

“…Despite their extensive use in drug discovery, synthetic accessibility of (cyclo)alkylpiperidines have remained far from being satisfactory. Although there are many methods which rely on the modification of a preexisting piperidine ring, [7] we have considered retrosynthetic approach shown in Scheme 1 as more promising synthetic strategy. Indeed, numerous efforts were put into the development of protocols for hydrogenation of the pyridine ring in the last decade.…”

Section: Introductionmentioning

confidence: 99%

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Scalable and Straightforward Synthesis of All Isomeric (Cyclo)alkylpiperidines

et al. 2019

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An efficient approach towards introducing (cyclo)alkyl substituents at C‐2, C‐3 or C‐4 positions of the piperidine ring was described. The method relied on the straightforward two‐step reaction sequence based on the formal sp3–sp3 retrosynthetic disconnection. The procedure commenced with selective directed ortho metalation of 2‐ and 3‐bromopyridine, followed by reaction with aldehydes or ketones. The optimized methods were developed for all three isomers of hydroxyalkyl‐substituted pyridines, which were synthesized in 28–84 % overall yield (20 examples). Catalytic hydrogenation of these adducts could be performed selectively with or without retention of the hydroxyl group in their molecules, so that either (cyclo)alkylpiperidines (14 examples) or the corresponding saturated amino alcohols (16 examples) were obtained (28–96 % and 82–96 % yield, respectively). After minor modifications, the developed method was also implemented in a flow reactor and a 5 L autoclave, which allowed for the preparation of up to 0.5 kg of the representative (cyclo)alkylpiperidines.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Scalable and Straightforward Synthesis of All Isomeric (Cyclo)alkylpiperidines

et al. 2019

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Stereoselective Palladium‐Catalyzed C(sp³)−H Mono‐Arylation of Piperidines and Tetrahydropyrans with a C(4) Directing Group

et al. 2022

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A selective Pd‐catalyzed C(3)−H cis‐functionalization of piperidine and tetrahydropyran carboxylic acids is achieved using a C(4) aminoquinoline amide auxiliary. High mono‐ and cis‐selectivity is attained by using mesityl carboxylic acid as an additive. Conditions are developed with significantly lower reaction temperatures (≤50 °C) than other reported heterocycle C(sp3)−H functionalization reactions, which is facilitated by a DoE optimization. A one‐pot C−H functionalization‐epimerization procedure provides the trans‐3,4‐disubstituted isomers directly. Divergent aminoquinoline removal is accomplished with the installation of carboxylic acid, alcohol, amide and nitrile functional groups. Overall, fragment compounds suitable for screening are generated in 3–4 steps from readily‐available heterocyclic carboxylic acids.

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Recent Updates on Azido‐reductive Cyclization Approaches: Syntheses of aza‐Heterocyclic Frameworks

2021

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The first organic azide (phenyl azide) was synthesized in 1864 and since then, its structure, syntheses, and applications have reaped extreme attention from chemists across the globe. Later, the unambiguous documentation of its linear structure and chemical reactivity led to allembracing research in the chemistry of azides. The unique electronic structure and chemical reactivity placed the organic azides at the interface between chemistry, biology, medicine, and material science. In this regard, the reaction of azides where a single-nitrogen atom is retained was well implemented for the synthesis of natural products and other vital organic frameworks embedding various aza-heterocyclic skeletons. This review emphasizes the recent applications (2015-2021) of organic azides in the synthesis of the aforementioned organic molecules employing an azidoreductive cyclization approach with the retention of a single nitrogen atom.

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Recent Advances in the Synthesis of Piperidines: Functionalization of Preexisting Ring Systems

Cited by 36 publications

References 428 publications

Scalable and Straightforward Synthesis of All Isomeric (Cyclo)alkylpiperidines

Scalable and Straightforward Synthesis of All Isomeric (Cyclo)alkylpiperidines

Stereoselective Palladium‐Catalyzed C(sp³)−H Mono‐Arylation of Piperidines and Tetrahydropyrans with a C(4) Directing Group

Recent Updates on Azido‐reductive Cyclization Approaches: Syntheses of aza‐Heterocyclic Frameworks

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Recent Advances in the Synthesis of Piperidines: Functionalization of Preexisting Ring Systems

Cited by 36 publications

References 428 publications

Scalable and Straightforward Synthesis of All Isomeric (Cyclo)alkylpiperidines

Scalable and Straightforward Synthesis of All Isomeric (Cyclo)alkylpiperidines

Stereoselective Palladium‐Catalyzed C(sp3)−H Mono‐Arylation of Piperidines and Tetrahydropyrans with a C(4) Directing Group

Recent Updates on Azido‐reductive Cyclization Approaches: Syntheses of aza‐Heterocyclic Frameworks

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Stereoselective Palladium‐Catalyzed C(sp³)−H Mono‐Arylation of Piperidines and Tetrahydropyrans with a C(4) Directing Group