Efficient Synthesis of Piperidine Derivatives. Development of Metal Triflate-Catalyzed Diastereoselective Nucleophilic Substitution Reactions of 2-Methoxy- and 2-Acyloxypiperidines

Okitsu, Osamu; Suzuki, Ritsu; Kobayashi, Shū

doi:10.1021/jo001297m

Cited by 112 publications

(53 citation statements)

References 45 publications

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“…IR spectra were recorded with a Nicolet 6700 spectrophotometer and are reported as wavenumbers (cm À1 ). Enamides and enecarbamates 1 a-i, [21] 1 m, [21] 1 n, [21] 1 j, [22] 1 k, [23] 1 l, [24] a-bromine b-keto esters, and 1,3-diketones 2 c-g [25] were prepared according to published literature procedures.…”

Section: Methodsmentioning

confidence: 99%

Direct CH Functionalization of Enamides and Enecarbamates by Using Visible‐Light Photoredox Catalysis

Jiang

Huang

Guo

et al. 2012

Chemistry A European J

179

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Direct C-H functionalization of various enamides and enecarbamates was realized through visible-light photoredox catalyzed reactions. Under the optimized conditions using [Ir(ppy)(2)(dtbbpy)PF(6)] as photocatalyst in combination with Na(2)HPO(4), enamides such as N-vinylpyrrolidinone could be easily functionalized by irradiation of the reaction mixture overnight in acetonitrile with visible light. The scope of the reaction with respect to enamide and enecarbamate substrates by using diethyl 2-bromomalonate for the alkylation reaction was explored, followed by an investigation of the scope of alkylating reagents used to react with the enamides and enecarbamates. The results indicated that reaction takes place with quite broad substrate scope, however, tertiary enamides with an internal C=C double bond in the E configuration could not be alkylated. Alkylation of N-vinyl tertiary enamides and enecarbamates gave monoalkylated products exclusively in the E configuration. Alkylation of N-vinyl secondary enamides gave doubly alkylated products. Double bond migration was observed in the reaction of electron-deficient bromides such as 3-bromoacetyl acetate with N-vinylpyrrolidinone. A mechanism is proposed for the reaction that is different from reported reactions of SOMOphiles with a nonfunctionalized C=C double bond. Further tests on the trifluoromethylation and arylation of enamides and enecarbamates under similar conditions showed that the reactions could serve as a mild, practical, and environmentally friendly approach to various functionalized enamides and enecarbamates.

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Section: Methodsmentioning

confidence: 99%

Direct CH Functionalization of Enamides and Enecarbamates by Using Visible‐Light Photoredox Catalysis

Jiang

Huang

Guo

et al. 2012

Chemistry A European J

179

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“…11,42 Recently, a highly cis-selective synthesis of α,β-disubstituted piperidines has been accomplished through nucleophilic additions to N-acyliminium ions with aryl-and alkenyl boronic acids (Eq. 8).…”

Section: -2 Diastereoselective Nucleophilic Substitutionmentioning

confidence: 99%

Anodic Selective Functionalization of Cyclic Amine Derivatives

Onomura¹

2012

HETEROCYCLES

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“…[1][2][3][4] It is well known that d-1 and d-2 are related to each other's isomerization via waminoenone 5,6) (3) (Chart 1). Among reported methods [7][8][9][10][11][12][13][14][15][16][17][18][19][20] of d-1, we had believed that our method 10,13) was widely applicable to the synthesis of the derivatives needed to study the structure-activity relationship of d-1. However, we could not successfully prepare some derivatives because our method involved uncontrollable trans-cis isomerization in the final step.…”

mentioning

confidence: 99%

Concise Synthesis of dl-Febrifugine

Takeuchi

Oshige

Azuma

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Racemic compound (1) of the antimalarial agents febrifugine (d-1) was synthesized using an stereoselective Michael reaction of an w w-amidoenone (5) which was prepared by the Wittig reaction of piperidinediol (7).Key words total synthesis; stereoselective Michael reaction; Wittig reaction; febrifugine; antimalarial activity Febrifugine (d-1) is an antimalarial agent that has been isolated from Dichroa febrifuga and Hydrangea umbellate along with isofebrifugine (d-2).1-4) It is well known that d-1 and d-2 are related to each other's isomerization via waminoenone 5,6) (3) (Chart 1). Among reported methods [7][8][9][10][11][12][13][14][15][16][17][18][19][20] of d-1, we had believed that our method 10,13) was widely applicable to the synthesis of the derivatives needed to study the structure-activity relationship of d-1. However, we could not successfully prepare some derivatives because our method involved uncontrollable trans-cis isomerization in the final step. In recent our study, we found that cis form of N-protected febrifugine derivatives (cis-4) also afforded a mixture of trans-4 and cis-4 form under the presence of acid by the isomerization (Chart 2). 21)From those findings, we planed a synthetic strategy via an w-amidoenone (5) as a key intermediate, which would afford trans piperidine derivative (trans-6) by the intramolecular Michael reaction with the stereoselectivity (Chart 3). In this paper, we describe a novel synthesis of dl-febrifugine (dl-1).The synthesis of the key intermediate, w-amidoenone (5), was achieved to utilize the Wittig reaction of 2-hydroxypiperidine derivative which we have developed in our synthetic study of deoxyfebrifugine.22) The Wittig reaction of 2,3-piperidinediol (7), which was easily prepared in 84% yield from tetrahydropyridine (8) by Oxone ® -acetone oxidation, 23) afforded (E)-w-amidoenone (E-5) in which the double bond had E configuration based on the coupling constant (Jϭ16 Hz) of olefinic protons in 1 H-NMR. The Michael reaction of trans-5 (E-5) with BF 3 · OEt 2 afforded the Michael adduct (trans-6). N-Cbz febrifugine (10) was afforded by successive reactions, silylation of the hydroxy and ketone group, bromination, and coupling with 4(3H)-quinazolinone. Hydrogenolysis of 10 gave dl-1 which was identical with the reported one by mp or 1 H-NMR data (Chart 4). In the Michael reaction of E-5 with BF 3 · OEt 2 , we could obtain the furan derivative (9) and 1,4-diketone derivative (11) along with trans-6. It is known that 9 and 11 can be transformed from cis-6 by acid.24) Decreasing yield of trans-6 with the prolongation of the reaction time or heat of reaction mixture suggests that there is an equilibrium relationship via E-5 between trans-6 and cis-6 in the presence of Lewis acid (Table 1).Herein, we could develop the the synthetic method for dlfebrifugine derivatives in high total yield and short steps without using the very expensive, toxic, or dangerous reagents used in other reports. [25][26][27][28][29][30] We are now progress the asymmetric synthesis using this me...

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Efficient Synthesis of Piperidine Derivatives. Development of Metal Triflate-Catalyzed Diastereoselective Nucleophilic Substitution Reactions of 2-Methoxy- and 2-Acyloxypiperidines

Cited by 112 publications

References 45 publications

Direct CH Functionalization of Enamides and Enecarbamates by Using Visible‐Light Photoredox Catalysis

Direct CH Functionalization of Enamides and Enecarbamates by Using Visible‐Light Photoredox Catalysis

Anodic Selective Functionalization of Cyclic Amine Derivatives

Concise Synthesis of dl-Febrifugine

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