A General, Enantioselective Synthesis of Protected Morpholines and Piperazines

O’Reilly, Matthew C.; Lindsley, Craig W.

doi:10.1021/ol301203z

Cited by 31 publications

(15 citation statements)

References 12 publications

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“…So far, the most commonly used approaches to synthesize piperazines are the reduction of (di)ketopiperazines and stepwise N -alkylation of 1,2-diamines 10 – 13 . These methods generally use amino acids and 1,2-diamines as starting materials and require multiple steps.…”

Section: Introductionmentioning

confidence: 99%

Expedient syntheses of N-heterocycles via intermolecular amphoteric diamination of allenes

Adhikari

Xia

et al. 2018

Nat Commun

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Saturated 1,4-diazo heterocycles including piperazines, 1,4-diazepanes, and 1,4-diazocanes, are highly important for therapeutic development, but their syntheses are often tedious. We describe here an amphoteric diamination strategy to unite readily available 1,2-, 1,3- or 1,4-diamine derivatives with electron-deficient allenes via a formal [n + 2] (n = 4, 5, 6) cyclization mode to produce the corresponding 1,4-diazo heterocycles in just one step. This strategy features mild reaction conditions, high functional group tolerance, and scalability (gram scale). The reagents used are cheap and readily available and no transition metal catalysts are needed. More sophisticated products containing trifluoromethyl group or bicyclic ring systems can be accessed via a one-pot procedure as well. Our mechanistic studies support that formation of mono-iodinated or chlorinated diamine intermediates is important for the desired transformation and the commonly proposed chloride-iodide exchange process and a radical N−C bond formation is unlikely when the combination of NCS/KI is used.

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Section: Introductionmentioning

confidence: 99%

Expedient syntheses of N-heterocycles via intermolecular amphoteric diamination of allenes

Adhikari

Xia

et al. 2018

Nat Commun

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“…5 Enantioenriched 2-substituted morpholines with moderate ee values (up to 60%) can be realized through Pd-catalyzed allylic substitution reactions. 6 Examples of other catalytic strategies from prochiral starting materials include enantioselective α-chlorination of aldehydes followed by reductive amination and base-induced cyclization, 7 oxyamination, 8 Pd-catalyzed carboamination, 3c and hydroamination of functionalized aminoalkenes to arrive at disubstituted morpholines diastereoselectively. 9 The enantioselective preparation of N-heterocycles with substitutions α to N is of interest due to the biological relevance of α-chiral amines; 10 however, none of these aforementioned approaches can be used to synthesize such morpholine products in an enantioselective manner.…”

Section: ■ Introductionmentioning

confidence: 99%

Catalytic Asymmetric Synthesis of Morpholines. Using Mechanistic Insights To Realize the Enantioselective Synthesis of Piperazines

2016

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An efficient and practical catalytic approach for the enantioselective synthesis of 3-substituted morpholines through a tandem sequential one-pot reaction employing both hydroamination and asymmetric transfer hydrogenation reactions is described. Starting from ether-containing aminoalkyne substrates, a commercially available bis(amidate)bis(amido)Ti catalyst is utilized to yield a cyclic imine that is subsequently reduced using the Noyori-Ikariya catalyst, RuCl [(S,S)-Ts-DPEN] (η-p-cymene), to afford chiral 3-substituted morpholines in good yield and enantiomeric excesses of >95%. A wide range of functional groups is tolerated. Substrate scope investigations suggest that hydrogen-bonding interactions between the oxygen in the backbone of the ether-containing substrate and the [(S,S)-Ts-DPEN] ligand of the Ru catalyst are crucial for obtaining high ee's. This insight led to a mechanistic proposal that predicts the observed absolute stereochemistry. Most importantly, this mechanistic insight allowed for the extension of this strategy to include N as an alternative hydrogen bond acceptor that could be incorporated into the substrate. Thus, the catalytic, enantioselective synthesis of 3-substituted piperazines is also demonstrated.

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“…1). 9,10 ML398 was active in vivo; however, the SAR analysis was limited due to the synthetic feasibility of modification of the upper right-hand phenethyl group. Thus, we wanted to evaluate alternative linker groups in order to more fully explore the SAR around both the N -linked groups as well as moieties adjacent to the oxygen group of the morpholine.…”

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confidence: 99%

Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D4R) antagonists

Witt

McCollum

Hurtado

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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Herein, we report the synthesis and structure–activity relationship of a series of chiral alkoxymethyl morpholine analogs. Our efforts have culminated in the identification of (S)-2-(((6-chloropyridin-2-yl) oxy)methyl)-4-((6-fluoro-1H-indol-3-yl)methyl)morpholine as a novel potent and selective dopamine D4 receptor antagonist with selectivity against the other dopamine receptors tested (<10% inhibition at 1 µM against D1, D2L, D2S, D3, and D5).

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A General, Enantioselective Synthesis of Protected Morpholines and Piperazines

Abstract: A short, high yielding protocol has been developed for the enantioselective and general synthesis of C2-functionalized, benzyl protected morpholines and orthogonally N,N′-protected piperazines from a common intermediate.

Cited by 31 publications

References 12 publications

Expedient syntheses of N-heterocycles via intermolecular amphoteric diamination of allenes

Expedient syntheses of N-heterocycles via intermolecular amphoteric diamination of allenes

Catalytic Asymmetric Synthesis of Morpholines. Using Mechanistic Insights To Realize the Enantioselective Synthesis of Piperazines

Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D4R) antagonists

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