Synthesis and kinetic resolution of substituted tetrahydroquinolines by lithiation then electrophilic quench

Carter, Nicholas; Li, Xiabing; Reavey, Lewis; Meijer, Anthony J. H. M.; Coldham, Iain

doi:10.1039/c7sc04435f

Cited by 24 publications

(22 citation statements)

References 63 publications

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“…Both η 1 ‐ and η 3 ‐coordination of benzyllithiums is known . Density functional theory calculations with the related tetrahydroquinoline system suggest that coordination of a cyanoformate to the lithium atom alters the structure of the organolithium towards the η 3 ‐coordination mode . This is presumably also the case here with the 1‐benzazepine not only with cyanoformates but also with certain other electrophiles (MeOCOCl and PhSSO 2 Ph).…”

Section: Resultsmentioning

confidence: 66%

“…The barrier to rotation of the Boc group is about 63 kJ/mol at –50 °C and this is lower than that for the related azepane (approximate ΔG ‡ 71 kJ/mol at –50 °C) . The faster rate of rotation is likely due to at least partial conjugation of the nitrogen lone pair with the aromatic ring, thereby reducing the interaction with the carbonyl group.…”

Section: Resultsmentioning

confidence: 82%

“…In previous work with N ‐Boc‐2‐phenylazepane and N ‐Boc‐2‐phenyltetrahydroquinoline, we had found that lithiation followed by addition of alkyl cyanoformate electrophiles provided the unusual ortho ‐substituted products , . We therefore tested this with methyl cyanoformate and found the same type of switch to the ortho ‐substituted product 8a (Scheme ).…”

Section: Resultsmentioning

confidence: 91%

“…The faster rate of rotation is likely due to at least partial conjugation of the nitrogen lone pair with the aromatic ring, thereby reducing the interaction with the carbonyl group. However this conjugation will be tempered by the lack of planarity and the value of 63 kJ/mol is significantly higher than that for the corresponding tetrahydroquinoline (approximate ΔG ‡ 47 kJ/mol at –50 °C) where the torsion angle is lower …”

Section: Resultsmentioning

confidence: 94%

“…Many routes have been developed for the synthesis of tetrahydro‐1‐benzazepines, although the formation of 2,2‐disubstituted derivatives is relatively rare . Our research group has reported chemistry to prepare 2,2‐disubstituted tetrahydroquinolines, azepanes, and other alpha‐amino substituted compounds by using a lithiation‐trapping protocol. We were therefore interested to extend this chemistry to 1‐benzazepines.…”

Section: Introductionmentioning

confidence: 99%

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Preparation of Substituted Tetrahydro‐1‐benzazepines by Lithiation‐Trapping

2018

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The tetrahydro‐1‐benzazepine or benzo[b]azepine ring system is found in a number of drug molecules although methods to access 2,2‐disubstituted derivatives are rare. Here we report the preparation of N‐tert‐butoxycarbonyl‐2‐phenyltetrahydro‐1‐benzazepine followed by lithiation and trapping with electrophiles. The metallation reaction was optimized by using React‐IR spectroscopy, and VT‐NMR spectroscopy allowed the determination of the rate of rotation of the Boc group (approximate ΔG‡ 63 kJ/mol at –50 °C). The resulting organolithium was quenched to give either 2,2‐disubstituted products or, with certain electrophiles, the ortho‐substituted products, presumably through an η3‐coordinated benzyllithium intermediate. The chemistry was shown to be amenable to extension to the 7‐methoxy analog. Removal of the Boc group from the nitrogen atom led to amine products.

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Section: Resultsmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Preparation of Substituted Tetrahydro‐1‐benzazepines by Lithiation‐Trapping

2018

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Enantioselective Lithiation–Substitution of Nitrogen‐Containing Heterocycles

2019

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This review covers the enantioselective lithiation–substitution at the α‐position of nitrogen‐containing heterocycles mediated by strong organolithium bases and chiral ligands. The reactions occur by two main mechanistic pathways: asymmetric deprotonation and asymmetric substitution. For N ‐Boc heterocycles, asymmetric deprotonation is the predominant pathway, and s ‐BuLi, in combination with chiral diamines, such as (–)‐sparteine and the (+)‐sparteine surrogate, are used. This approach is highly successful with N ‐Boc pyrrolidines, piperidines, and piperazines. Substrates for asymmetric‐substitution‐mediated reactions include some N ‐Boc heterocycles, but other N ‐substituents, such as N ‐alkyl groups, N ‐alkyl‐BY 3 salts (Y = H, F) and N ‐thioamide groups are also used. With both mechanistic pathways, the lithiated heterocycle can be transmetalated to form an organocopper or organozinc species to widen the scope of the electrophile. The full scope and limitations of this approach to synthesize enantioenriched α‐substituted aziridines, azetidines, pyrrolidines, piperidines, piperazines, azepanes and other five‐/six‐membered‐ring heterocyles are summarized.

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Rhodium(III‐Catalyzed C8‐Selective C−H Alkenylation and Alkylation of 1, 2, 3, 4‐Tetrahydroquinolines with Styrenes and Allylic Alcohols

et al. 2023

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Rh(III)-catalyzed chelation-assisted C8-selective CÀ H alkenylation and alkylation of 1,2,3,4tretrahydroquinolines with styrenes and allylic alcohols have been realized. The cationic Rh(III) catalytic system in combination with a catalytic amount of copper acetate uses oxygen as the terminal oxidant and catalyzes the stereoselective C8-alkenylation of 1,2,3,4-tetrahydroquinolines with styrenes to give the corresponding products in 56-93% yields with wide substrate scope and broad functional group compatibility. The reaction can be scaled up. Moreover, this protocol can be extended to the C8-alkylation of 1,2,3,4tetrahydroquinolines with allylic alcohols, providing access to various 8-(3-oxoalkyl)-1,2,3,4-tetrahydroquinolines in 77-90% yields. The selection of N-directing group is essential for catalysis, and the readily installable and removable N-(2-pyrimidyl) group proves to be optimal choice. Preliminary mechanistic studies are performed to gain insights into the reaction mechanism.

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Synthesis and kinetic resolution of substituted tetrahydroquinolines by lithiation then electrophilic quench

Abstract: Treatment of N-Boc-2-aryl-1,2,3,4-tetrahydroquinolines with n-butyllithium in THF at –78 °C resulted in efficient lithiation at the 2-position and the organolithiums were trapped with a variety of electrophiles to give substituted products.

Cited by 24 publications

References 63 publications

Preparation of Substituted Tetrahydro‐1‐benzazepines by Lithiation‐Trapping

Preparation of Substituted Tetrahydro‐1‐benzazepines by Lithiation‐Trapping

Enantioselective Lithiation–Substitution of Nitrogen‐Containing Heterocycles

Rhodium(III‐Catalyzed C8‐Selective C−H Alkenylation and Alkylation of 1, 2, 3, 4‐Tetrahydroquinolines with Styrenes and Allylic Alcohols

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