Oxindoles are an important class of compounds with significant biological activities. Spirocyclic derivatives are present in a variety of natural products. We describe here the formation of spirooxindoles using an intermolecular nitrone cycloaddition reaction. The nitrone dipole was prepared in situ by cyclisation of an oxime, itself prepared in situ from an aldehyde. The stereochemistry of one of the spirooxindoles was determined by single crystal X-ray diffraction studies via crystallisation using encapsulated nanodroplet crystallisation (ENaCt) protocols. The chemistry involves cascade or tandem condensation, cyclisation, and cycloaddition as an efficient strategy for the rapid formation of complex spirocyclic products that could have value for the formation of novel, bioactive oxindoles.

Piperidines and their 2-substituted derivatives are fundamental intermediates for the development of new active pharmaceutical ingredients with improved pharmacokinetic profiles and unique three-dimensional properties. Consequently, the design of synthetic methodologies for their selective transformations into highly valuable scaffolds, aimed at increasing the molecular diversity, is of high importance. We disclose herein a general and efficient organolithium-mediated protocol to promote chemo- and regioselective anionic Fries rearrangement or kinetic resolution processes starting from O-aryl carbamates of 2-substituted piperidines. The use of t-BuLi allows a regioselective ortho-metalation of the O-aryl carbamate followed by an intramolecular carbamoyl migration, thereby delivering a series of functionalized N-piperidinyl salicylamides in yields of 33 to 95%. The protocol has been successfully extended to 5- and 7-membered saturated N-heterocyclic scaffolds with comparable yields and selectivity. Mechanistic aspects and studies on the use of bench-type aerobic conditions are also detailed. In addition, the chiral n-BuLi/(+)-sparteine complex promotes the kinetic resolution of the O-aryl carbamate by regioselective lithiation at the 2-position of the piperidine ring. Upon electrophilic quench, the enantioenriched starting material is recovered with a good level of stereoselectivity (up to 85 : 15 er).

Kinetic resolution of N-Boc-spirocyclic 2-arylpiperidines with spiro substitution at C-4 was achieved with high enantiomeric ratios using the chiral base n-BuLi/sparteine. Cyclopropanation or metallaphotoredox catalysis were used to access the piperidines, which could be further functionalised without loss of enantiopurity, highlighting their use as potential 3D fragments for drug discovery.

Piperazines are important heterocycles in drug compounds. We report the asymmetric synthesis of arylpiperazines by photocatalytic decarboxylative arylation (metallaphotoredox catalysis) then kinetic resolution using n-BuLi/(+)-sparteine. This gave a range of piperazines with very high enantioselectivities. Further functionalizations gave enantioenriched 2,2-disubstituted piperazines, and either N-substituent can be removed selectively. Late-stage functionalizations of enantioenriched piperazine derivatives were demonstrated, including synthesis of a drug compound with glycogen synthase kinase (GSK)-3β inhibitor activity with potential for treating Alzheimer's disease.

A new series of benzotriazole-derived α-substituted hemiaminal ethers have been synthesized as human cholinesterase (hChE) inhibitors with enhanced activity. The synthesized compounds were extensively characterized by 1H NMR and 13C NMR spectroscopy, mass spectrometry, and SC-XRD studies. All the compounds demonstrated dual inhibition potential against acetyl and butylcholinesterases (AChE and BChE) in the in-vitro studies. Results revealed that compounds carrying the optically active (R)-menthol group demonstrated more activity than the bicyclic (R)-fenchol moiety. For instance, α-butyl-(R)-menthyl-benzotriazole derivative (5a-iii) exhibited the best AChE inhibition with an IC50 value of 44.03 nM, while its α-methyl analog (5a-i) showed promising results against BChE inhibition (IC50 = 80.74 nM). The molecular modeling study was carried out to assess the binding interactions with the target proteins to rationalize the structural–activity relationship. Subsequently, the stability of the protein–ligand complex was verified through molecular dynamics (MD) simulations. Pharmacokinetic and bioavailability parameters further supported the suitability of the new inhibitors as lead compounds for neurological disorders.

Highly enantiomerically enriched dihydrohydroquinolines were prepared in two steps from quinoline. Addition of aryllithiums to quinoline with tert-butoxycarbonyl (Boc) protection gave N-Boc-2-aryl-1,2-dihydroquinolines. These were treated with n-butyllithium and electrophilic trapping occurred exclusively at C-4 of the dihydroquinoline, a result supported by DFT studies. Variable temperature NMR spectroscopy gave kinetic data for the barrier to rotation of the carbonyl group (ΔG≠ ≈49 kJ mol-1 , 195 K). Lithiation using the diamine sparteine allowed kinetic resolutions with high enantioselectivities (enantiomer ratio up to 99 : 1). The enantioenriched 1,2-dihydroquinolines could be converted to 1,4-dihydroquinolines with retention of stereochemistry. Further functionalisation led to trisubstituted products. Reduction provided enantioenriched tetrahydroquinolines, whereas acid-promoted removal of Boc led to quinolines, and this was applied to a synthesis of the antimalarial compound M5717.

AbstractKinetic resolution provided a highly enantioselective method to access a range of 3-aryl-3,4-dihydro-2H-1,4-benzoxazines using n-butyllithium and the chiral ligand sparteine. The enantioenrichment remained high on removing the tert-butoxycarbonyl (Boc) protecting group. The intermediate organolithium undergoes ring opening to an enamine. The kinetic resolution was extended to give enantiomerically enriched substituted 1,2,3,4-tetrahydroquinoxalines and was applied to the synthesis of an analogue of the antibiotic levofloxacin that was screened for its activity against the human pathogen Streptococcus pneumoniae.

The base n-BuLi with sparteine allows a kinetic resolution of N-Boc-2-aryl-4-methylenepiperidines. The 2,2-disubstituted products and recovered starting materials were isolated with high enantiomeric ratios. From VT-NMR spectroscopy and DFT studies, the rate of rotation of the N-Boc group is fast. Lithiation and trapping of the enantioenriched starting materials gave 2,2-disubstituted piperidines with retention of stereochemistry. Functionalization of the 4-methylene group led to a variety of 2,4-disubstituted piperidines without loss of enantiopurity that could be useful building blocks for drug discovery.

Abstract Kinetic resolution of 2‐arylindolines (2,3‐dihydroindoles) was achieved by treatment of their N‐tert‐butoxycarbonyl (Boc) derivatives with n‐butyllithium and sparteine in toluene at −78 °C followed by electrophilic quench. The unreacted starting materials together with the 2,2‐disubstituted products could be isolated with high enantiomer ratios. Variable temperature NMR spectroscopy showed that the rate of Boc rotation was fast (ΔG ≠≈57 kJ/mol at 195 K). This was corroborated by DFT studies and by in situ ReactIR spectroscopy. The enantioenriched N‐Boc‐2‐arylindolines were converted to 2,2‐disubstituted products without significant loss in enantiopurity. Hence, either enantiomer of the 2,2‐disubstituted products could be obtained with high selectivity from the same enantiomer of the chiral ligand sparteine (one from the kinetic resolution and the other from subsequent lithiation‐trapping of the recovered starting material). Secondary amine products were prepared by removing the Boc group with acid to provide a way to access highly enantioenriched 2‐aryl and 2,2‐disubstituted indolines.

Simple ketone starting materials with a halide leaving group and an alkene were prepared in one step and heated with glycine or glycine esters to promote a tandem imine formation, cyclization, and dipolar cycloaddition cascade. The chemistry was also feasible with acetylhydrazide. In each case a single stereoisomer of the tricyclic amine or pyrazolidine product was formed and the stereochemistry was verified by single crystal X-ray diffraction. When the reaction with glycine, which occurs with loss of CO2, was unsuccessful, the cascade process could be promoted by cross metathesis to give the vinyl sulfone starting material that provides a more reactive dipolarophile. Reductive cleavage of the pyrazolidine gave a spirocyclic diamine product.

Celebrating the life of Stuart Warren.

1-Methyl-3,4-dihydroquinoxalin-2(1H)-one was heated with a range of aldehydes to generate intermediate azomethine ylides which underwent [3 + 2] cycloaddition reactions with N-methyl or N-phenylmaleimide to give substituted tetrahydropyrroloquinoxalinones. Only one (racemic) stereoisomer was formed in each case and the stereochemical outcome was verified by single crystal X-ray analysis. The products from this multicomponent reaction could be oxidised with DDQ to the pyrroloquinoxalinones. Crown Copyright (C) 2019 Published by Elsevier Ltd. All rights reserved.

Tetrahydroisoquinolines are found in many natural products and drug compounds and a convenient method to access 1‐substituted derivatives is to carry out the lithiation at C‐1 followed by trapping with an electrophile. Here we explore the feasibility of lithiation at C‐3 by using a substrate with a benzylic proton on both sides of the nitrogen atom such that lithiation with nBuLi could occur at either C‐1 or C‐3 of the tetrahydroisoquinoline. The regioselectivity in the lithiation was determined using the substrate N‐tert‐butoxycarbonyl (Boc)‐3‐phenyltetrahydroisoquinoline. The lithiation could be followed by in situ ReactIR spectroscopy and the rate of rotation of the carbamate group was determined (barrier to rotation was approximately ΔG‡ 58 kJ/mol at –50 °C). Subsequent trapping of the organolithium species with an electrophile gave a mixture of two regioisomeric products with a preference for reaction at C‐1. This led to the isolation of 1,3‐disubstituted tetrahydroisoquinolines with trans relative stereochemistry. Removal of the Boc group from the nitrogen atom gave secondary and tertiary amine products.

Quinolinium salts, Q(+)-CH2-CO2Me Br- and Q(+)-CH2-CONMe2 Br- (where Q = quinoline), were prepared from quinolines. Deprotonation of these salts with triethylamine promoted the reaction of the resulting quinolinium ylides (formally azomethine ylides) with electron-poor alkenes by conjugate addition followed by cyclization or by [3 + 2] dipolar cycloaddition. The pyrroloquinoline products were formed as single regio- and stereoisomers. These could be converted to other derivatives by Suzuki-Miyaura coupling, reduction or oxidation reactions.

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.

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. Variable temperature NMR spectroscopy gave kinetic data that showed that the rate of tert-butoxycarbonyl (Boc) rotation was fast (ΔG‡ ≈ 45 kJ mol-1 at -78 °C) and in situ ReactIR spectroscopy showed fast lithiation at -78 °C. By carrying out the lithiation in the presence of the chiral ligand sparteine, kinetic resolutions with very high levels of enantioselectivity were achieved. The resulting enantioenriched N-Boc-2-aryltetrahydroquinolines were converted to 2,2-disubstituted products without significant loss in enantiopurity. Most electrophiles add at the 2-position and the chemistry provides a way to access tetrahydroquinolines that are fully substituted alpha to the nitrogen atom. Notably, either enantiomer of the 2,2-disubstituted tetrahydroquinolines can be obtained with high selectivity from the same enantiomer of the chiral ligand. Unusually, when methyl cyanoformate was used as the electrophile, substitution occurred in the ortho position of the aryl ring attached at C-2. This change in regioselectivity on changing the electrophile was probed by deuterium isotope studies and by DFT calculations which suggested that the binding of the cyanoformate altered the structure of the intermediate organolithium. Secondary amine products can be prepared by removing the Boc group with acid or by inducing the Boc group to rearrange to the 2-position in the presence of triethylborane and this carbonyl N-to-C rearrangement occurs with retention of configuration from the intermediate enantiomerically enriched organolithium species.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

A cascade or domino sequence of condensation of hydroxylamine and an aldehyde to give an oxime, cyclization to a nitrone, and intramolecular 1,3-dipolar cycloaddition has been successfully employed where there is branching at C-4 as a route to the iboga alkaloids. Cyclization occurs with displacement of chloride as a leaving group and intramolecular cycloaddition occurs with an alkene as a dipolarophile. The reaction gives an azabicyclo[2.2.2]octane product containing a fused isoxazolidine as a single stereoisomer and this was converted to an isoquinuclidine that completed a formal synthesis of the alkaloid (±)-19-hydroxyibogamine.

Preparation of 2,2-disubstituted azepanes was accomplished from N-tert-butoxy(N-Boc)-2-phenylazepane by treatment with butyllithium then electrophilic quench. The lithiation was followed by in situ ReactIR spectroscopy and the rate of rotation of the carbamate was determined by variable temperature (VT)-NMR spectroscopy and by DFT studies. Most electrophiles add α to the nitrogen atom but cyanoformates and chloroformates gave ortho-substituted products. Cyclic carbamates were formed from an aldehyde or ketone electrophile. Kinetic resolution with sparteine was only poorly selective. Removal of the Boc group promoted cyclization to a homoindolizidine or an isoindolinone.