4-substituted Cyclohexanones Research Articles

Stable Axially Chiral Cyclohexylidenes from Catalytic Asymmetric Knoevenagel Condensation.

Axially chiral cycloalkylidenes are interesting but less developed axially chiral molecules. Here, a bispidine-based chiral amine catalytic system was developed to promote efficiently the asymmetric Knoevenagel condensation of N-protected oxindoles and benzofuranones with 4-substituted cyclohexanones. A variety of alkylidenecycloalkanes with stable axial chirality were obtained in good yields and fairly good er (enantiomeric ratio). Based on the absolute configuration determination of product and DFT calculations, a possible mechanism of stereoselective induction was proposed.

Enantioselective Potassium-Catalyzed Wittig Olefinations.

We report asymmetric potassium-isothiourea-boronate-catalyzed Wittig olefinations of 4-substituted cyclohexanones with non-stabilized phosphorus ylides to afford highly enantioenriched axially chiral alkenes. The optimal catalyst features an unusual macrocyclic amide-potassium-boronate chelate. Kinetic and spectroscopic analyses are consistent with a Lewis acid mechanism for the catalytic olefination that results in the formation of the oxaphosphetane adduct under cryogenic conditions. Thermal fragmentation of the oxaphosphetane to the alkene product occurs after the reaction is complete. Computational studies indicate that cycloaddition proceeds via a stepwise mechanism involving enantiodetermining polar 1,2-addition to afford an intermediate potassium betaine complex.

Diastereofacial selectivity of α-aminonitrile formation from substituted cyclohexanones

The formation of α-aminonitriles from substituted cyclohexanones exhibits diastereofacial selectivity resulting in unequal amounts of the two possible geometric isomers. The degree of selectivity increases with the nature of the substitution on the cyclohexyl ring indicating that this likely results from the degree to which the substitution can ‘lock’ the conformation of the cyclohexyl ring into the most stable conformation. The ratio of trans:cis isomers seen for the reaction of 4-substituted cyclohexanones with dimethylamine hydrochloride and potassium cyanide in water were 92:8 for 4-phenyl, 81:19 for 4-t-butyl, and 62:38 for 2-methyl. Varying the size of the amino group substituents did not have a dramatic effect on the selectivity that was observed.

Chiral-boron-Lewis-acid-catalysed desymmetric ring expansion of 4-substituted cyclohexanones with α-diazomethylphosphonates

A methodology to access chiral cyclic β-ketophosphonates with a stereogenic center at the α-position has been establishedviaan asymmetric desymmetrizing ring-expansion reaction of 4-substituted cyclohexanones with α-diazophosphonates catalysed by a chiral boron Lewis acid.

Total Synthesis of 2-Isocyanoallopupukeanane: Construction of Caged Skeleton by Intramolecular Alkylation of Bromonitriles.

A new method for constructing the bicyclo[3.2.1]octane skeleton was developed by the intramolecular alkylation of a nitrile-side-chain-containing cyclohexanone derivative. The cyclization precursors were prepared via the stereoselective bromination of the triisopropylsilyl enol ethers of 4-substituted cyclohexanones. Upon treatment with LiNEt2, the bromonitriles underwent a stereoselective intramolecular SN2 reaction to afford bicyclo[3.2.1]octane derivatives with a cyano group on the convex face. The total synthesis of 2-isocyanoallopupukeanane (6.5% yield) from methyl vinyl ketone was accomplished via a 17-step transformation.

Enantioselective Total Synthesis of (+)-Alstilobanine C, (+)-Undulifoline, and (-)-Alpneumine H.

We report herein the enantioselective total synthesis of three monoterpene indole alkaloids, namely, (+)-alstilobanine C, (+)-undulifoline, and (-)-alpneumine H. The key features of our synthesis include: a) introduction of chirality via enantioselective deprotonation of a prochiral 4-substituted cyclohexanone; b) use of methoxymethyl (MOM) ether as both a hydroxyl protective group and a latent oxonium species for the formation of bridged oxepane and c) domino double reductive cyclization to build both the indole and the piperidine ring at the end of the synthesis. The synthesis confirmed the absolute configuration of these natural products assigned based on the biogenetic hypothesis.

Azolium/Hydroquinone Organo-Radical Co-Catalysis: Aerobic C-C-Bond Cleavage in Ketones.

Organo-radical catalysts have recently attracted great interest, and the development of this field can be expected to broaden the applications of organocatalysis. Herein, the first example of a radical-generating system is reported that does not require any photoirradiation, radical initiators, or preactivated substrates. The oxidative C-C-bond cleavage of 2-substituted cyclohexanones was achieved using an azolium salt and a hydroquinone as co-catalysts. A catalytic mechanism was proposed based on the results of diffusion-ordered spectroscopy and cyclic voltammetry measurements, as well as computational studies.

Norcoclaurine Synthase-Mediated Stereoselective Synthesis of 1,1’-Disubstituted, Spiro- and Bis-Tetrahydroisoquinoline Alkaloids

The Pictet–Spenglerase norcoclaurine synthase (NCS) catalyzes the formation of (S)-norcoclaurine, an important intermediate in the biosynthetic pathway of benzylisoquinoline alkaloids. NCS has been used as a biocatalyst with meta-hydroxy phenethylamines and aldehydes for the preparation of single-isomer tetrahydroisoquinoline alkaloids (THIAs). Recently, it was also reported that some ketones can be accepted as substrates, including 4-substituted cyclohexanones and phenyl acetones. Here, we report the use of wild-type NCS and selected variants with aliphatic, cyclic, α-substituted cyclic, heterocyclic, and bicyclic ketones to access challenging non-natural THIAs. Remarkably, fused bicyclic ketones as well as diketones could also be accepted by some of the NCS variants, and in silico modeling was used to provide insights into the rationale for this.

Cerium(III) Chloride-Mediated Stereoselective Reduction of a 4-Substituted Cyclohexanone Using NaBH4

Several additives were screened for the stereoselective reduction of a 4-substituted cyclohexanone en route to linrodostat mesylate. It was found that the addition of sub-stoichiometric cerium(III)...

Microwave Assisted Vilsmeier-Haack Reaction on Substituted Cyclohexanone Hydrazones: Synthesis of Novel 4,5,6,7-Tetrahydroindazole Derivatives

Vilsmeier-Haack reaction is one of the most important chemical reactions used for formylation of electron-rich arens. Even though Vilsmeier-Haack reaction was studied on a wide variety of hydrazones of enolizable ketones, literature lacks the examples of the use of 4-substituted cyclohexanones as a substrate. The cyclization potential of hydrazones of cyclic keto compounds is still interested topic of investigation. In the present study, the reaction of various hydrazines with 4-substituted cyclohexanones was proceeded and the resulted hydrazones in crude form were treated with Vilsmeier- Haack reagent using both conventional as well as microwave methods. The reaction of phenyl hydrazine with 4-phenylcyclohexanone yielded the corresponding tetrahydro-1H-carbazole instead of hydrazone during solvent evaporation at 40ºC. By keeping the temperature of water bath to 0ºC, the corresponding hydrazone was isolated in crude form which was immediate treated with POCl3/DMF for 10 min at 90ºC using microwave irradiation method afforded novel 4,5,6,7-tetrahydroindazole derivative. Using this optimized condition, the substrate scope for the synthesis of tetrahydroindazole derivatives was explored and synthesized total 6 final compounds. The microwave assisted synthesis of tetrahydroindazoles from 4-substituted cyclohexanones has been reported for the first time under mild conditions in good yield. Easy work up procedure, high yielding, shortened reaction times, clean and ecofriendly are the main advantages of this protocol.

Regioselective Synthesis of Potent 4,5,6,7-Tetrahydroindazole Derivatives via Microwave-assisted Vilsmeier-Haack Reaction and their Antioxidant Activity Evaluation

Background: Tetrahydroindazole, a member of the fused-pyrazole system, is a least studied class of heterocyclic compounds owing to its scarcity in nature. However, a large number of synthetically prepared tetrahydroindazoles are known to show a variety of biological activities such as interleukin- 2 inducible T-Cell kinase inhibitors, AMPA receptor positive allosteric modulators, antitumor, antituberculosis, anti-inflammatory and antimicrobial activities. Vilsmeier-Haack reaction is one of the most important chemical reactions used for formylation of electron rich arenes. Even though Vilsmeier- Haack reaction was studied on a wide variety of hydrazones derived from active methylene compounds, literature lacks the examples of the use of 4-substituted cyclohexanones as a substrate for the synthesis of 4,5,6,7-tetrahydroindazoles. The study of the reaction of Vilsmeier-Haack reagent with hydrazones derived from cyclic keto compounds having active methylene has been considered the interested topic of investigation. In the present study, ethyl cyclohexanone-4-carboxylate was treated with one equivalent of various hydrazines for two hours and the resulted hydrazones were further treated with an OPC-VH reagent (Vilsmeier-Haack reagent isolated from phthaloyl dichloride and N,Ndimethylformamide) afforded 4,5,6,7-tetrahydroindazoles in excellent yields. The synthesized compounds 4a-f and 5a-f were screened for their antioxidant activities using the DPPH radical scavenging assay. The target compounds were synthesized regioselectively using 4+1 approach in excellent yields. A number of experiments using both conventional heating as well as microwave irradiation methods were tried and on comparison, microwave irradiation method was found excellent in terms of easy work up, high chemical yields, shortened reaction times, clean and, no by-products formation. Some of the synthesized compounds showed significant antioxidant activity. The microwave assisted synthesis of 4,5,6,7-tetrahydroindazoles from ethyl cyclohexanone-4-carboxylate has been reported under mild conditions in excellent yield. Easy work up, high chemical yield, shortened reaction times, clean and no by-products formation are the major advantages of this protocol. These advantages may make this method useful for chemists who are interested in developing novel 4,5,6,7-tetrahydroindazole based drugs.

Asymmetric Baeyer-Villiger oxidation: classical and parallel kinetic resolution of 3-substituted cyclohexanones and desymmetrization of meso-disubstituted cycloketones.

Regioselectivity is a crucial issue in Baeyer-Villiger (BV) oxidation. To date, few reports have addressed asymmetric BV oxidation of 3-substituted cycloketones due to the high difficulty of controlling regio- and stereoselectivity. Herein, we report the asymmetric BV oxidation of 3-substituted and meso-disubstituted cycloketones with chiral N,N'-dioxide/Sc(iii) catalysts performed in three ways: classical kinetic resolution, parallel kinetic resolution and desymmetrization. The methodology was applied in the total and formal synthesis of bioactive compounds and natural products. Control experiments and calculations demonstrated that flexible and adjustable catalysts played a significant role in the chiral recognition of substrates.

Kinetics and enantioselectivity of the Baeyer-Villiger oxidation of cyclohexanones by chiral tetrapyridyl oxoiron(IV) complex

The previously reported oxoiron(IV) complex, [FeIV(asN4Py)(O)]2+ with chiral pentadentate ligand, asN4Py (asN4Py = N,N‑bis(2‑pyridylmethyl)‑1,2‑di(2‑pyridyl)ethylamine), is effective for the Baeyer-Villiger oxidation of cyclohexanone derivatives. The reaction is shown to be first order in both cyclohexanone and the oxoiron(IV) species. The second order rate constant is smaller by one order of magnitude than that obtained for the related achiral [FeIV(N4Py)(O)]2+ complex. Oxidation of 4-substituted cyclohexanone derivatives by the chiral oxoiron(IV) complex attains moderate enantioselectivities up to 45% enantiomeric excess (ee).

Corrigendum: Catalytic Desymmetrizing Dehydrogenation of 4-Substituted Cyclohexanones through Enamine Oxidation.

In Scheme 2 b of this Communication, derivatization product 5 d was reported to be a five-membered ring product. During recent investigations, the authors found that the structure of 5 d was incorrectly assigned. This error was caused by incorrect analysis of the NMR spectra. In a structural revision this compound was determined to be a four-membered ring product. A detailed analysis employing 2D NMR spectroscopy is provided in the Supporting Information accompanying this Corrigendum. This correction does not affect the results and conclusions in other parts of the Communication. The authors thank Prof. Josep Bonjoch for drawing their attention to this issue and they sincerely apologize for this mistake. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Catalytic Desymmetrizing Dehydrogenation of 4-Substituted Cyclohexanones through Enamine Oxidation.

A desymmetrizing dehydrogenation process catalyzed by a chiral primary amine is described herein. The reaction proceeds through the oxidation of a ketone enamine by IBX and enables the highly enantioselective desymmetrization of 4-substituted cyclohexanones with the generation of chiral 4-substituted cyclohexenones containing a remote γ-stereocenter.

Enantioselective Synthesis of Chiral Oxime Ethers: Desymmetrization and Dynamic Kinetic Resolution of Substituted Cyclohexanones.

Axially chiral cyclohexylidene oxime ethers exhibit unique chirality because of the restricted rotation of C=N. The first catalytic enantioselective synthesis of novel axially chiral cyclohexylidene oximes has been developed by catalytic desymmetrization of 4-substituted cyclohexanones with O-arylhydroxylamines and is catalyzed by a chiral BINOL-derived strontium phosphate with excellent yields and good enantioselectivities. In addition, chiral BINOL-derived phosphoric acid catalyzed dynamic kinetic resolution of α-substituted cyclohexanones has been performed and yields versatile intermediates in high yields and enantioselectivities.

Stereoselective Csp(3) -Csp(2) Bond-Forming Reactions by Transition-Metal-Free Reductive Coupling of Cyclic Tosylhydrazones with Boronic Acids.

The reactions between alkenylboronic acids and tosylhydrazones derived from substituted cyclohexanones lead to the construction of disubstituted cyclohexanes with total regio- and stereoselectivity. In these transition-metal-free processes, a Csp(3) -Csp(2) and Csp(3) -H bond are formed on the same carbon atom. The stereoselective reaction is general for 2-, 3-, and 4-substituted cyclohexanone tosylhydrazones, as well as for 2-substituted cyclopentanones. However, no stereoselectivity is observed for acyclic derivatives. DFT computational modeling suggests that the stereoselectivity of the reaction is determined by the approach of the boronic acid to the diazocyclohexane on its most stable chair conformation through an equatorial trajectory.

Enantioselective Synthesis of Functionalized Polycarbocycles via a Three-Component Organocascade Quadruple Reaction.

An efficient organocascade quadruple reaction was conducted to synthesize a functionalized spiropolycyclic scaffold in high chemical yields (43-80%) and excellent levels of stereoselectivity (up to >19:1 dr and 99% ee). The quadruple reaction proceeded smoothly between 1,3-indanedione and aromatic aldehydes with concomitant desymmetrization of prochiral 4-substituted cyclohexanones through the Knoevenagel/Michael/aldol/aldol reaction sequence catalyzed by a bifunctional thiourea catalyst. Two of the formed products were transformed into spirocyclic epoxides containing four contiguous quaternary centers.

Enantioselective aldol reactions with aqueous 2,2-dimethoxyacetaldehyde organocatalyzed by binam-prolinamides under solvent-free conditions

Aqueous 2,2-dimethoxyacetaldehyde (60%wt solution) is used as an acceptor in aldol reactions, with cyclic and acyclic ketones and aldehydes as donors, organocatalyzed by 10mol% of N-tosyl-(Sa)-binam-l-prolinamide [(Sa)-binam-sulfo-l-Pro] at rt under solvent-free conditions. The corresponding monoprotected 2-hydroxy-1,4-dicarbonyl compounds are obtained in good yields and with high levels of diastereo- and enantioselectivity mainly as anti-aldols. In the case of 4-substituted cyclohexanones a desymmetrization process takes place to mainly afford the anti,anti-aldols. 2,2-Dimethyl-1,3-dioxan-5-one allows the synthesis of a useful intermediate for the preparation of carbohydrates in higher yield, de and ee than with l-Pro as the organocatalyst.

Enantioselective desymmetrization of prochiral ketones via an organocatalytic deprotonation process

The first desymmetrization of 4-substituted cyclohexanones by organocatalytic asymmetric deprotonation at low catalyst loading is reported. The combination of N,O-bis(trimethylsilyl)acetamide (BSA) and chiral quaternary ammonium aryloxide salts has been used as an efficient organocatalytic system to provide silyl enolates in high yields and with modest ee.