Carbolithiation of ene-carbamates. Application to the synthesis of 2,3-disubstituted ene-carbamates

Lepifre, Franck; Cottineau, Bertrand; Mousset, Deborah; Bouyssou, Pascal; Coudert, G.

doi:10.1016/j.tetlet.2003.11.012

Cited by 10 publications

(10 citation statements)

References 6 publications

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“…For example, enecarbamates 7e and 7f (see Figure 2), bearing electron-rich arenes, as well as sterically encumbered 1-naphthyl bearing 7g mainly undergo addition of the alkyllithium into the Boc group, whereas 7h , which possesses a fluorine group on the aryl substituent, yields a complex mixture (presumably arising from competing aryl ortho-lithiation/benzyne formation or dehalogenation). 20 In addition, contrary to the observations made in the carbolithiation of a single azepene enecarbamate example, 16 our studies on piperidine enecarbamates have revealed that in the latter substrates, aryl lithium nucleophiles do not add easily to C3. This observation highlights the significant reactivity differences in the lithiation chemistry of azacycles of different ring sizes.…”

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confidence: 64%

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Stereocontrolled synthesis of vicinally functionalized piperidines by nucleophilic β-addition of alkyllithiums to α-aryl substituted piperidine enecarbamates

et al. 2015

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confidence: 64%

“…This latter goal is especially important given that only poor diastereoselectivity is observed in analogous processes attempted with the azepene homologue. 16 …”

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confidence: 99%

Stereocontrolled synthesis of vicinally functionalized piperidines by nucleophilic β-addition of alkyllithiums to α-aryl substituted piperidine enecarbamates

et al. 2015

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“…6,7 Taking advantage of our previous results, a synthesis of the original acyclic amide-derived vinylphosphates 3 was envisaged. Starting from aromatic primary amines 1, after protection of the nitrogen, the amide 2 was treated with LDA (1.2 equiv) at -78°C in THF providing the desired lithium enolate that was quenched with diphenylchlorophosphate (1.2 equiv, cf.…”

Section: Scheme 1 Access To A-amino Acidsmentioning

confidence: 99%

“…5 In a previous work, we reported a successful carbolithiation approach on seven-membered ring enecarbamates. 6 In this paper, we want to explore the scope of our method and to this purpose, study carbolithiation on acyclic ene-carbamates in order to develop a process that would give easy access to a-amino acids bearing a quaternary carbon next to the nitrogen (cf. Scheme 1).…”

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confidence: 99%

Synthesis of α-Amino Acids via a Carbolithiation Reaction on Acyclic Ene-Carbamates and an Internal N→C Alkyloxycarbonyl Migration

Cottineau¹,

Gillaizeau²,

Farard³

et al. 2007

Synlett

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A novel and efficient synthesis of precursors of a-amino acids is described. The key step involves a carbolithiation reaction on acyclic ene-carbamates generated from the corresponding vinylphosphates via a palladium cross-coupling reaction followed by a spontaneous internal N→C alkyloxycarbonyl migration.The development of new synthetic approaches to nonnatural amino acids is a blossoming field of research since such compounds find applications in the synthesis of pharmacologically useful molecules, analogues of bioactive peptides mimetics. 1 Our goal was to devise a new route to a-amino acids based on a vinyl carbolithiation performed on acyclic ene-carbamates as the original key synthetic step. Carbolithiation has seen increasing use as a powerful method for complex ring synthesis. 2 However, very few teams have reported the intermolecular nucleophilic addition of organolithium reagents to an alkene, an addition generally difficult to control since it may lead to polymerization of the olefin. 3 To obtain synthetically useful carbolithiation reactions, the final organometallic adduct must be stabilized 4 or must differ markedly from the starting one. 5 In a previous work, we reported a successful carbolithiation approach on seven-membered ring enecarbamates. 6 In this paper, we want to explore the scope of our method and to this purpose, study carbolithiation on acyclic ene-carbamates in order to develop a process that would give easy access to a-amino acids bearing a quaternary carbon next to the nitrogen (cf. Scheme 1). The first part of this work concerns the preparation of acyclic enecarbamates from the corresponding vinylphosphates via a palladium cross-coupling reaction. Carbolithiation on the latter will be investigated in a second stage. Scheme 1 Access to a-amino acidsIn connection with our efforts to develop synthetic routes to nitrogen-containing derivatives, we have undertaken a research program directed towards expanding the range of lactam-derived vinyl phosphates available to the organist chemist. 6,7 Taking advantage of our previous results, a synthesis of the original acyclic amide-derived vinylphosphates 3 was envisaged. Starting from aromatic primary amines 1, after protection of the nitrogen, the amide 2 was treated with LDA (1.2 equiv) at -78°C in THF providing the desired lithium enolate that was quenched with diphenylchlorophosphate (1.2 equiv, cf. Table 1). After workup and purification by silica gel chromatography, the required acyclic amide-derived vinylphosphates 3a-c were isolated in good yields. A Pd-catalyzed Suzuki-Miyaura coupling reaction was then investigated. By using classical conditions, a range of acyclic ene-carbamates 4a-f, substituted a to nitrogen by different aryl or heteroaryl groups, was isolated in fair to good yields (cf. Table 2). 8Carbolithiation was then considered, and acyclic ene-carbamates 4a-f were submitted to reaction with a small range of commercially available organolithium reagents. Treatment of 4a-f in THF at -78°C with an excess of RLi followed by war...

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“…The resulting intermediate iminium or N -acyliminium ions are electrophilic, and may themselves trap a nucleophile at the position α to the nitrogen substituent. However, we [3–4] and others [5–7] have shown that this typical reactive polarity may be reversed when N -acylenamines (especially N -vinyl ureas [8]) meet organolithium nucleophiles. N -Carbamoyl enamines bearing α-aryl substituents (in other words, α-acylaminostyrenes), may undergo reaction as electrophiles, with the carbon atom β to nitrogen succumbing to attack by organolithium nucleophiles in an enamine carbolithiation reaction [9].…”

Section: Introductionmentioning

confidence: 99%

Carbolithiation of N-alkenyl ureas and N-alkenyl carbamates

Lefranc¹,

Minassi²,

Clayden³

2013

Beilstein J. Org. Chem.

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Summary N-Alkenyl ureas and N-alkenyl carbamates, like other N-acyl enamines, are typically nucleophilic at their β-carbon. However, by incorporating an α-aryl substituent, we show that they will also undergo attack at the β-carbon by organolithium nucleophiles, leading to the products of carbolithiation. The carbolithiation of E and Z N-alkenyl ureas is diastereospecific, and N-tert-butoxycarbonyl N-alkenyl carbamates give carbolithiation products that may be deprotected in situ to provide a new connective route to hindered amines.

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Carbolithiation of ene-carbamates. Application to the synthesis of 2,3-disubstituted ene-carbamates

Cited by 10 publications

References 6 publications

Stereocontrolled synthesis of vicinally functionalized piperidines by nucleophilic β-addition of alkyllithiums to α-aryl substituted piperidine enecarbamates

Stereocontrolled synthesis of vicinally functionalized piperidines by nucleophilic β-addition of alkyllithiums to α-aryl substituted piperidine enecarbamates

Synthesis of α-Amino Acids via a Carbolithiation Reaction on Acyclic Ene-Carbamates and an Internal N→C Alkyloxycarbonyl Migration

Carbolithiation of N-alkenyl ureas and N-alkenyl carbamates

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