Addition Of Grignard Reagents Research Articles

Asymmetric Tandem Conjugate Addition and Reaction with Carbocations on Unsaturated Heterocycles

AbstractHeterocycles possessing multiple substituents and stereogenic centers are important structural motifs in many compounds of interest. We present here stereoselective tandem transformation based on Cu‐catalyzed conjugate addition of Grignard reagents to heterocyclic Michael acceptors, which is followed by one‐pot trapping of in situ formed enolates with stabilized carbocations or their equivalents. The transformations are highly enantio‐ and diastereoselective with Josiphos‐type ferrocene ligand. The reaction of chiral metal enolates with onium compounds allows the installation of structurally attractive substituents on chromenone or piperidinone core. Moreover, cycloheptatrienyl and benzodithiolyl substituents can be further modified, thus expanding synthetic possibilities of this methodology.magnified image

Direct Addition of Grignard Reagents to Aliphatic Carboxylic Acids Enabled by Bulky turbo-Organomagnesium Anilides.

Invited for the cover of this issue is the group of Abraham Mendoza at Stockholm University. The image depicts a Grignard reagent "turbo-charged" with a magnesium anilide additive. Read the full text of the article at 10.1002/chem.202104053.

Front Cover: Direct Addition of Grignard Reagents to Aliphatic Carboxylic Acids Enabled by Bulky turbo‐Organomagnesium Anilides (Chem. Eur. J. 9/2022)

Grignard reagents (R-Mg-X) are commercial carbon nucleophiles commonly used in organic synthesis, but their stability becomes a limitation for the least-reactive electrophiles. A bulky magnesium anilide additive (in purple) generates a new organometallic reagent (R−Mg-NHAr) in situ that boosts the nucleophilicity and selectivity of the organometallic ligand (in green). In the Research Article by A. Mendoza and co-workers (DOI: 10.1002/chem.202104053), these reagents prove to be instrumental in the direct synthesis of ketones from carboxylic acids, a transformation that was only possible with some organolithium reagents before.

First Total Syntheses of (±)-Callyspongidic Acids and 2-epi-(±)-Callyspongidic Acids

AbstractThe first total syntheses of (±)-callyspongidic acids and 2-epi-(±)-callyspongidic acids were achieved in high overall yield from epoxy ester derived from commercially available l-(+)-tartaric acid. The key features of these syntheses are the stereoselective opening of epoxide with organocuprates and the chemoselective addition of Grignard reagent to ketone in the presence of ester. The synthetic route reported here is operationally simple, very short and amenable for the synthesis of several analogues of this class.

Direct Addition of Grignard Reagents to Aliphatic Carboxylic Acids Enabled by Bulky turbo-Organomagnesium Anilides.

The synthesis of ketones through addition of organometallic reagents to aliphatic carboxylic acids is a straightforward strategy that is limited to organolithium reagents. More desirable Grignard reagents can be activated and controlled with a bulky aniline‐derived turbo‐Hauser base. This operationally simple procedure allows the straightforward preparation of a variety of aliphatic and perfluoroalkyl ketones alike from functionalized alkyl, aryl and heteroaryl Grignard reagents.

Asymmetric addition of Grignard reagents to ketones: culmination of the ligand-mediated methodology allows modular construction of chiral tertiary alcohols.

A new class of biaryl chiral ligands derived from 1,2-diaminocyclohexane (1,2-DACH) has been designed to enable the asymmetric addition of aliphatic and, for the first time, aromatic Grignard reagents to ketones for the preparation of highly enantioenriched tertiary alcohols (up to 95% ee). The newly developed ligands L12 and L12′ together with the previously reported L0 and L0′ define a set of complementary chiral promoters, which provides access to the modular construction of a broad range of structurally diverse non-racemic tertiary alcohols, bearing challenging quaternary stereocenters. The present advancements bring to completion our asymmetric Grignard methodology by expanding the scope to aromatic organomagnesium reagents, while facilitating its implementation in organic synthesis thanks to improved synthetic routes for the straightforward access to the chiral ligands. The synthetic utility of the method has been demonstrated by the development of a novel and highly enantioselective formal synthesis of the antihistamine API clemastine via intermediate (R)-3a. Exploiting the power of the 3-disconnection approach offered by the Grignard synthesis, (R)-3a is obtained in 94% ee with ligand (R,R)-L12. The work described herein marks the finalization of our ongoing effort towards the establishment of an effective and broadly applicable methodology for the asymmetric Grignard synthesis of chiral tertiary alcohols.

Development of a Scalable Lanthanide Halide/Quaternary Ammonium Salt System for the Nucleophilic Addition of Grignard Reagents to Carbonyl Groups and Application to the Synthesis of a Remdesivir Intermediate

Development of a Scalable Lanthanide Halide/Quaternary Ammonium Salt System for the Nucleophilic Addition of Grignard Reagents to Carbonyl Groups and Application to the Synthesis of a Remdesivir Intermediate

Stereodivergent Total Syntheses of (+)‐Monomorine I and (+)‐Indolizidine 195B

AbstractA simple and efficient stereoselective total syntheses of two natural products (+)‐monomorine I and (+)‐indolizidine 195B in high yields starting from a readily available alcohol is described. The key step in this synthetic route exploits the judicious use of solvent to enable a closed or open transition state in a nucleophilic addition of Grignard reagent to sulfinimine, giving selective access to two distinct diastereomers required for the formation of the two target natural products.

Enantioselective Catalytic Dearomative Addition of Grignard Reagents to 4-Methoxypyridinium Ions

We describe a general catalytic methodology for the enantioselective dearomative alkylation of pyridine derivatives with Grignard reagents, allowing direct access to nearly enantiopure chiral dihydro-4-pyridones with yields up to 98%. The methodology involves dearomatization of in situ-formed N-acylpyridinium salts, employing alkyl organomagnesium reagents as nucleophiles and a chiral copper (I) complex as the catalyst. Computational and mechanistic studies provide insights into the origin of the reactivity and enantioselectivity of the catalytic process.

Synthesis of β-Methyl Alcohols: Influence of Alkyl Chain Length on Diastereoselectivity and New Attractants of Rhynchophorus ferrugineus.

The diastereoselectivity of adducts in the addition reaction via the Felkin-Anh model is affected significantly by the steric effect of bulky groups. However, the influence of steric alkyl chain length has not been studied for the diastereoselectivity. In this work, we present a new strategy for the racemic synthesis of β-methyl alcohols to obtain various diastereomer ratios using the Felkin-Anh model. The addition of alkyl Grignard reagents to α-methyl aldehydes afforded diastereomer ratios of threo/erythro ≈ 2:1, while the reduction in structurally related ketones using LiAlH4 afforded ratios of threo/erythro ≈ 1:1. The experimental data showed no effect of alkyl chain length on either side on the stereoselectivity of adducts. All synthesized analogues were evaluated for attractiveness to Rhynchophorus ferrugineus weevils in the field. Five novel derivatives, including two alcohols and three ketones, were found to attract weevils in the field trials. Among them, 3-methyldecan-4-one (5b) and 4-methyldecan-5-ol (11a) were found to be the most attractive to the insects.

Alkoxyl-radical-mediated synthesis of functionalized allyl tert-(hetero)cyclobutanols and their ring-opening and ring-expansion functionalizations

tert -(Hetero)cyclobutanols are important synthetic building blocks. However, previous synthesis of these compounds has mainly focused on the nucleophilic addition of organometallic reagents to (hetero)cyclobutanones. Herein, we disclose a single-electron process for preparing allyl tert -(hetero)cyclobutanols with readily available organosilicon reagents. The success of the reaction is attributed to the favored radical 1,2-silyl transfer over β-carbon elimination of the alkoxyl radicals. The mechanism of the generation of carbon radicals from alkoxyl radicals is distinct from previous photoredox-mediated oxidation of hypervalent silicates. Our reaction shows broad substrate scope and wide functional-group tolerance. With the highly functionalized allyl tert -(hetero)cyclobutanols, we have achieved ring-opening reactions to synthesize thiolated 1,4-diketones and ring-expansion reactions to prepare seven-membered ring compounds. • Radical 1,2-silyl transfer over β-carbon elimination of alkoxy radicals • Ring-opening and ring-expansion reactions have been achieved • Broad substrate scope and wide functional-group tolerance The selectivity of a transformations is usually controlled by the reactivity of the reactive intermediate. (Hetero)cyclobutoxyl radicals are well known to be prone to undergo β-carbon elimination to generate carbon radicals. Our work disclosed here shows that radical 1,2-silyl transfer of (hetero)cyclobutoxy radicals is favored over β-carbon elimination. This radical C–Si bond-activation strategy is applied in the synthesis of functionalized allyl tert -(hetero)cyclobutanols. These compounds are challenging to prepare via previous two-electron processes, such as the addition of Grignard reagents to (hetero)cyclobutanones. Moreover, with the highly functionalized allyl tert -(hetero)cyclobutanols, we have achieved ring-opening reactions to synthesize thiolated ketones and ring-expansion reactions to prepare seven-membered ring compounds. Shen and coworkers present a photoredox process for synthesizing allyl tert -(hetero)cyclobutanols with readily available organosilicon reagents. The favored radical 1,2-silyl transfer over β-carbon elimination of the alkoxyl radicals is key to the success of the reaction. The reaction shows broad substrate scope and wide functional-group tolerance. With the highly functionalized allyl tert -(hetero)cyclobutanols, the authors have achieved ring-opening reactions to synthesize thiolated 1,4-diketones and ring-expansion reactions to prepare seven-membered ring compounds.

Synthesis of Chiral o-Aminobenzylamines by Stereoselective Addition of Grignard Reagents to N-[(o-Aminophenyl)methylene] sulfinamides

AbstractChiral o-aminobenzylamines are synthons for many chiral ligands and catalysts that have been widely used in asymmetric synthesis. Here, we report a highly efficient and stereoselective addition of Grignard reagents to N-[(o-aminophenyl)methylene]sulfinamides to give a range of o-aminosulfinylimines in good yields with good to excellent diastereoselectivities.

A Robust Porphyrin‐Stabilized Triplet Carbon Diradical

AbstractThe synthesis of robust high‐spin carbon radicals is an important topic in organic chemistry. Toward this end, several porphyrin‐stabilized radicals have been systematically explored. A singly naphthalene‐fused porphyrin radical was synthesized by a reaction sequence consisting of a Suzuki–Miyaura coupling of β‐borylated porphyrin with 2‐bromobenzaldehyde, addition of mesityl Grignard reagent, intramolecular Friedel–Crafts alkylation, and final oxidation with DDQ or tBuOK/O2. This strategy was also used to synthesize doubly naphthalene‐fused porphyrins and syn‐ and anti‐fused‐anthracene‐bridged porphyrin dimers. While singly naphthalene‐fused porphyrin radical has been shown to be a stable monoradical, doubly naphthalene‐fused porphyrins and anti‐fused‐anthracene‐bridged porphyrin dimers have been shown to be closed‐shell molecules. Finally, the syn‐dimer was characterized as a surprisingly stable radical (t1/2=28 days under ambient air and at 80 °C) that is storable for more than several months, despite its high‐spin triplet ground‐state carbon diradical.

A Robust Porphyrin-Stabilized Triplet Carbon Diradical.

The synthesis of robust high-spin carbon radicals is an important topic in organic chemistry. Toward this end, several porphyrin-stabilized radicals have been systematically explored. A singly naphthalene-fused porphyrin radical was synthesized by a reaction sequence consisting of a Suzuki-Miyaura coupling of β-borylated porphyrin with 2-bromobenzaldehyde, addition of mesityl Grignard reagent, intramolecular Friedel-Crafts alkylation, and final oxidation with DDQ or tBuOK/O2 . This strategy was also used to synthesize doubly naphthalene-fused porphyrins and syn- and anti-fused-anthracene-bridged porphyrin dimers. While singly naphthalene-fused porphyrin radical has been shown to be a stable monoradical, doubly naphthalene-fused porphyrins and anti-fused-anthracene-bridged porphyrin dimers have been shown to be closed-shell molecules. Finally, the syn-dimer was characterized as a surprisingly stable radical (t1/2 =28 days under ambient air and at 80 °C) that is storable for more than several months, despite its high-spin triplet ground-state carbon diradical.

Pyrrolidine and Indolizidine Alkaloids from Chiral N-tert-Butanesulfinyl Imines Derived from 4-Halobutanal

AbstractAn efficient stereocontrolled preparation of 2-substituted pyrrolidines and 5-substituted indolizidin-7-ones, by using chiral N-tert-butanesulfinyl imines derived from 4-halobutanal as starting materials, is detailed. Addition of Grignard reagents and a decarboxylative Mannich­ reaction with β-keto acids involving these chiral imines proceeded with high diastereoselectivity. The synthesis of the pyrrolidinic alkaloids (–)-bgugaine, (+)-villatamine B, (–)-norhygrine, trans-dendrochrysanine, and (–)-ruspolinone demonstrated the utility of this methodology.

Synthesis of Quaternary Spirooxindole 2H-Azirines under Batch and Continuous Flow Condition and Metal Assisted Umpolung Reactivity for the Ring-Opening Reaction.

An efficient and new approach for the synthesis of spirooxindole 2H-azirines via intramolecular oxidative cyclization of 3-(amino(phenyl)methylene)-indolin-2-one derivatives in the presence of I2 and Cs2 CO3 under batch/continuous flow is described. This method is mild and facile to synthesize a variety of spirooxindole 2H-azirines derivatives in gram-scale. Furthermore, we have synthesized spiroaziridine derivatives from spirooxindole 2H-azirines derivatives via addition of Grignard reagent. In addition, we discloses an metal assisted attack of Grignard nucleophile at N-centre rather than C- of the spirooxindole 2H-azirines, which concurrently underwent ring opening of transient aziridines to afford N-substituted Z-3-(aminophenyl)indolin-2-one. A plausible mechanism for azirination and ring-opening reaction is also presented.

Preparation of spiro[indole-3,5'-isoxazoles] via Grignard conjugate addition/spirocyclization sequence.

A highly efficient one-pot procedure combining conjugate addition of Grignard reagents to (2-nitroalkenyl)indoles and sub-sequent Brønsted acid-assisted spirocyclization allowed for preparation of 4′H-spiro[indole-3,5′-isoxazoles] in a diastereomerically selective fashion. Utilization of alkyl Grignard reagents provided an easy access to 4′-alkylsubstituted derivatives hardly available by other means.

Stereoselective Synthesis of Oxabicyclic Pyrrolidines of Medicinal Relevance: Merging Chemoenzymatic and Catalytic Methods

AbstractTwo approaches to the synthesis of an oxabicyclic pyrrolidine‐6‐one are described using enzymatic resolution and gold‐mediated catalysis as key steps toward enantiopure compounds previously reported as racemic mixtures. Addition of Grignard reagents to the ketone afforded a variety of diversified tertiary alcohols of interest for their reported pharmacological activities.

Grignard Reagent Utilization Enables a Practical and Scalable Construction of 3-Substituted 5-Chloro-1,6-naphthyridin-4-one Derivatives.

A robust, practical, and scalable approach for the construction of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 via the addition of Grignard reagents to 4-amino-2-chloronicotinonitrile (15) was developed. Starting with various Grignard reagents, a wide range of 3-substituted 5-chloro-1,6-naphthyridin-4-one derivatives 13 were conveniently synthesized in moderate-to-good yields through addition–acidolysis–cyclocondensation. In addition, the robustness and applicability of this synthetic route was proven on a 100 g scale, which would enable convenient sample preparation in the preclinical development of 1,6-naphthyridin-4-one-based MET-targeting antitumor drug candidates.

Copper-Catalyzed Addition of Grignard Reagents to in situ Generated Indole-Derived Vinylogous Imines.

Chiral indole derivatives are ubiquitous motifs in pharmaceuticals and alkaloids. Herein, the first protocol for catalytic asymmetric conjugate addition of Grignard reagents to various sulfonyl indoles, offering a straightforward approach for the synthesis of chiral 3‐sec‐alkyl‐substituted indoles in high yields and enantiomeric ratios is presented. This methodology makes use of a chiral catalyst based on copper phosphoramidite complexes and in situ formation of vinylogous imine intermediates.