Unactivated Ketones Research Articles

Biocatalytic asymmetric aldol addition into unactivated ketones.

Enzymes are renowned for their catalytic efficiency and selectivity, but many classical transformations in organic synthesis have no biocatalytic counterpart. Aldolases are prodigious C-C bond-forming enzymes, but their reactivity has only been extended past activated carbonyl electrophiles in special cases. To probe the mechanistic origins of this limitation, we use a pair of aldolases whose activity is dependent on pyridoxal phosphate. Our results reveal how aldolases are limited by kinetically favourable proton transfer with solvent, which undermines aldol addition into ketones. We show how a transaldolase can circumvent this limitation, enabling efficient addition into unactivated ketones. The resulting products are highly sought non-canonical amino acids with side chains that contain chiral tertiary alcohols. Mechanistic analysis reveals that transaldolase activity is an intrinsic feature of pyridoxal phosphate chemistry and identifies principles for extending aldolase catalysis beyond its previous limits to enable convergent, enantioselective C-C bond formation from simple starting materials.

Samarium diiodide/samarium-mediated direct deoxygenative hydroborylation of ketones with hydroborane esters.

A direct deoxygenative hydroborylation of ketones with hydroborane ester promoted by a combination of samarium diiodide, samarium and nickel has been developed. In this method, secondary alkyl borate esters are synthesized from unactivated ketones with hydroborane esters in one step. A broad substrate scope and excellent selectivity toward CO cleavage has been demonstrated. This approach represents a general method for the construction of versatile secondary alkyl borate esters from unactivated ketones.

Synthesis of polysubstituted pyridazines via Cu-mediated C(sp3)-C(sp3) coupling/annulation of saturated ketones with acylhydrazones.

Pyridazine is a significant skeleton that widely exists in drugs and bioactive molecules. We herein describe expeditious approaches to access polysubstituted pyridazines from readily accessible unactivated ketones and acylhydrazones via Cu-promoted C(sp3)-C(sp3) coupling/cyclization sequences in a single-step fashion. Notably, the disparate 3,4,6-trisubstituted pyridazines and 3,5-disubstituted pyridazines could be obtained by tailoring the ketone's structure and reaction conditions. These transformations feature good functional group compatibility, excellent step-economy, and chemoselectivity. The potential synthetic utility of these conversions is illustrated by scale-up reactions and late-stage derivatizations of the as-prepared pyridazine products.

A Regioselective [3 + 2] Cycloaddition of Alkynols and Ketones To Access Diverse 1,3-Dioxolane Scaffolds.

This study presents a stepwise exoselective [3 + 2] cycloaddition reaction of alkynols with ketones, leading to the synthesis of 4-methylene-1,3-dioxolane derivatives. Remarkably, without any Thorpe-Ingold induced effect, the cyclization reaction was demonstrated with complete regio- and chemoselectivity, which was solely promoted by cesium carbonate. A wide range of unactivated ketones are viable under these mild reaction conditions, and both primary and tertiary alkynols are compatible with these cyclization reactions. We have prepared a diverse array of highly dense exomethylene 1,3-dioxolane rings demonstrating a remarkable tolerance for various functional groups.

Enantioselective Synthesis of Biphenyl-Bridged ϵ-Sultams by Organocatalytic Mannich Reactions of Cyclic N-Sulfonylimines with Unactivated Ketones.

A highly enantioselective Mannich reaction of biphenyl-bridged seven-membered cyclic N-sulfonylimines with methyl alkyl ketones is disclosed in this study. The reaction was performed under organocatalysis by using a quinine-derived primary amine as the catalyst in combination with a Brønsted acid as the co-catalyst. High yields (up to 89 %) and excellent enantioselectivities (up to 97 % ee) were observed. For methyl alkyl ketones containing a larger alkyl substituent, specific regioselective addition to the C=N bond is favored at the methyl group. On the contrary, ketones containing a smaller alkyl substituent or hydroxyacetone substrates gave major syn selective Mannich products at the methylene group.

Photocatalytic Alkylation/Arylative Cyclization of N-Acrylamides of N-Heteroarenes and Arylamines with Dihydroquinazolinones from Unactivated Ketones.

We describe a visible-light photoredox-catalyzed alkylation/arylative cyclization of N-acrylamides─from 2-arylindoles, 2-arylbenzimidazoles, or N-substituted anilines─with ketone-derived dihydroquinazolinones, accessing indolo- and benzimidazolo[2,1-a]isoquinolines or 2-oxindoles. The consecutive incorporation of alkyl- and aryl-carbogenic motifs across a C=C bond via formal cleavage of ketone α-C-C and arene C-H bonds leads to the formation of five- and six-membered rings, with an all-carbon quaternary stereocenter. This dicarbofunctionalization elaborates aromatization-driven radical C-C functionalization of unactivated aliphatic ketones to construct diverse cyclic structures with functionality tolerance.

Direct insertion into the C–C bond of unactivated ketones with NaH-mediated aryne chemistry

•o-Diiodoarenes/NaH as an efficient system for aryne generation in a controlled manner •Neighboring-group-assisted metal-halogen exchange process •Sodium hydride as an iodophile reagent •Aryne insertion into C–C σ-bond of unactivated ketones Here, we document the reinvention of aryne chemistry with “old” o-diiodoarenes as aryne progenitors. We have established a NaH-mediated activation strategy for the generation of highly reactive aryne species in a controlled manner. The resulting arynes can efficiently participate in a C–C σ-bond-insertion reaction with unactivated ketones, which is difficult to achieve by existing methods. Density functional theory (DFT) calculations reveal that the two adjacent iodines in o-diiodoarenes play critical roles in the formation of aryne. The nucleophilic attack of hydride to the electrophilic iodine requires that the adjacent iodine act as a directing group to accelerate this process, whereas mono-substituted iodobenzene lacking the neighboring-group participation makes it difficult. The in-situ-formed enolates from ketones are proposed to adopt tetrameric aggregates to react with arynes, which accounts for the high regiochemistry for substrates with bulky substituents. Here, we document the reinvention of aryne chemistry with “old” o-diiodoarenes as aryne progenitors. We have established a NaH-mediated activation strategy for the generation of highly reactive aryne species in a controlled manner. The resulting arynes can efficiently participate in a C–C σ-bond-insertion reaction with unactivated ketones, which is difficult to achieve by existing methods. Density functional theory (DFT) calculations reveal that the two adjacent iodines in o-diiodoarenes play critical roles in the formation of aryne. The nucleophilic attack of hydride to the electrophilic iodine requires that the adjacent iodine act as a directing group to accelerate this process, whereas mono-substituted iodobenzene lacking the neighboring-group participation makes it difficult. The in-situ-formed enolates from ketones are proposed to adopt tetrameric aggregates to react with arynes, which accounts for the high regiochemistry for substrates with bulky substituents.

TfOH-catalyzed direct Michael addition and cascade cyclization reactions of unactivated ketones: A divergent route to functionalized benzofurans and benzofuro[3,2-b]pyridines

TfOH-catalyzed direct Michael addition and cascade cyclization reactions of azadienes with unactivated ketones have been developed by controlling the amount of TfOH, which provide a divergent approach to 2,3-disubstituted benzofurans and benzofuro[3,2-b]pyridines. Due to their weak nucleophilicity, unactivated ketones are used for the first time to react with azadienes instead of preactivated carbonyl compounds, in which the catalyst acidity is a key parameter. This approach with commercial ketones in mild reaction conditions shows synthetic and environmentally benign advantages including metal-free catalyst, atom economy and simple operation.

Electrochemical Cross-Dehydrogenative Coupling of Isochroman and Unactivated Ketones.

An unprecedented electrochemical cross-dehydrogenative coupling reaction between isochroman and unactivated ketones to directly synthesize α-substituted isochromans has been developed. This strategy provides a facile and efficient procedure to the direct activation of C(sp3)-H bond adjacent to the O atom of isochroman. The method features high atom economy, chemical oxidant-free, and mild conditions, in which methanesulfonic acid (MsOH) acts as both electrolyte and catalyst, making the process more convenient and environmentally friendly. Gram-scale experiment and synthesis of antitumor active compounds demonstrate the great potential of this protocol for practical applications.

Tandem Pd-catalyzed annulation/coupling of acetylenic enamines with aryl triflates.

A cascade of 5-exo-dig intramolecular nucleophilic addition of enamine to terminal alkyne followed by cross coupling has been demonstrated for the first time. Two new C-C bonds are stereoselectively forged by a single Pd-complex capable of catalyzing two mechanistically diverse transformations. Mechanistic investigations identified cyclization as the rate limiting step relying on the facile displacement of OTf, weakly bound to the Pd-center, by the alkyne.

Iron-Catalyzed Allylic Defluorinative Ketone Olefin Coupling.

In this protocol, we demonstrate our discovery that iron is able to efficiently catalyze the reductive allylic defluorinative ketyl olefin coupling reaction between α-trifluoromethyl alkenes and unactivated ketones. This operationally simple cross-electrophile reaction circumvents the use of pre-generated organometallics and allows for the synthesis of diverse functional-group-rich tertiary gem-difluorohomoallylic alcohols through a polarity-reversed strategy. Preliminary mechanistic studies support a mechanism that proceeds through a ketyl formation/olefin insertion/β-fluoro elimination sequence.

Synthesis and Catalysis of NHC Coordinated Cyclometalated Palladium(II) Complexes with Bridging Hydroxide Ligands

Abstract1,2‐Addition reactions using organoboron compounds are one of the useful syntheses of various functionalized alcohols, but they generally require a large quantity of bases. In this study, we attempted to solve this problem by synthesizing unsymmetrical 1,3‐diarylimidazoline‐type N‐heterocyclic carbene (NHC)‐coordinated C^C* cyclometalated palladium(II) complexes with bridging hydroxide ligands (CYPOHs) in two steps and one pot from the corresponding Cl bridged dimer and using them as catalysts. 2,6‐di(pentan‐3‐yl)aniline (IPent)‐based NHC coordinated PhS‐IPent‐CYPOH acted as a highly efficient catalyst for the 1,2‐addition of (hetero)arylboronates to a large number of aldehydes and ketones, including unactivated ketones, under base‐free conditions.magnified image

Electroreductive Olefin-Ketone Coupling.

A user-friendly approach is presented to sidestep the venerable Grignard addition to unactivated ketones to access tertiary alcohols by reversing the polarity of the disconnection. In this work a ketone instead acts as a nucleophile when adding to simple unactivated olefins to accomplish the same overall transformation. The scope of this coupling is broad as enabled using an electrochemical approach, and the reaction is scalable, chemoselective, and requires no precaution to exclude air or water. Multiple applications demonstrate the simplifying nature of the reaction on multistep synthesis, and mechanistic studies point to an intuitive mechanism reminiscent of other chemical reductants such as SmI2 (which cannot accomplish the same reaction).

Cover Feature: Brønsted Acid‐Catalyzed General Petasis Allylation and Isoprenylation of Unactivated Ketones (Chem. Eur. J. 45/2020)

General Petasis allylation and isoprenylation of unactivated ketones have been developed using a Brønsted acid catalyst, o-hydroxyaniline, and the corresponding pinacolyl boronates, which provided access to a broad variety of quaternary homoallylic amines and dienylamines, as well as a potentially bioactive quaternary homoallylic aminodiol. The Pegasus Statue as a symbol for Wuhan University of Technology (on the 20th anniversary of combination) encourages us to keep on discovering novel synthetic strategies. More information can be found in the Full Paper by U. Schneider, Y.-Y. Huang, et al. on page 10259.

Brønsted Acid-Catalyzed General Petasis Allylation and Isoprenylation of Unactivated Ketones.

Brønsted acid-catalyzed general Petasis allylation and isoprenylation of unactivated ketones were developed by using o-hydroxyaniline and the corresponding pinacolyl boronic esters. This robust methodology provided access to a broad variety of quaternary homoallylic amines and dienyl amines in high yields, proved to be applicable to a gram-scale synthesis, and allowed the synthesis of a potentially bioactive quaternary homoallylic aminodiol.

Nickel-Catalyzed Asymmetric Addition of Aromatic Halides to Ketones: Highly Enantioselective Synthesis of Chiral 2,3-Dihydrobenzofurans Containing a Tertiary Alcohol.

A highly enantioselective and straightforward synthetic procedure to chiral 3-hydroxy-2,3-dihydrobenzofurans has been developed by nickel/bisoxazoline-catalyzed intramolecular asymmetric addition of aryl halides to unactivated ketones, giving 2,3-dihydrobenzofurans with a chiral tertiary alcohol at the C-3 position in good yields and excellent enantioselectivities (up to 92% yield and 98% ee). The gram-scale reaction also proceeded smoothly without a loss of yield and enantioselectivity.

Asymmetric Michael Addition of Unactivated Ketones with β‐Nitrostyrenes Mediated by Bifunctional L‐Prolinamide Organocatalysts

AbstractThe catalytic activity of two types of L‐prolinamide organocatalysts was investigated for asymmetric Michael addition reaction of cyclic/acyclic ketones with β‐nitrostyrens. L‐Prolinamides bearing amino groups on phenyl ring worked well, though their catalytic efficiency as well as selectivity was found to be dependent upon the position of amine group to the amide bond. Organocatalyst having –NH2 group ortho to amide bond provided the best results. Substrate scope was also studied by performing the reaction of various β‐nitrostyrenes with ketones to afford the corresponding Michael adducts in excellent yields with very high diastereoselectivities and enantioselectivities in almost all cases.

One-pot access to tetrahydrobenzo[c]carbazoles from simple ketones by using O2 as an oxidant.

An effective and operationally simple one-pot Brønsted acid catalyzed cascade method is demonstrated for the synthesis of diversely functionalized carbazole frameworks starting from protecting group free 2-alkenyl indoles. The employment of easily available unactivated ketones as annulating partners, mostly unexplored for the synthesis of carbazoles, is the major highlight of this protocol. This protocol is step- and atom-economical, uses molecular oxygen as the green oxidant, and gives water as the only by-product and is amenable to different functional groups. Moreover, gram-scale synthesis and downstream modification of the obtained products demonstrate the synthetic applicability of this protocol.

Cu(i)-Catalyzed asymmetric intramolecular addition of aryl pinacolboronic esters to unactivated ketones: enantioselective synthesis of 2,3-dihydrobenzofuran-3-ol derivatives

An (S,S)-QuinoxP*-supported Cu(i) catalyst has been disclosed for highly enantioselective intramolecular addition of aryl pinacolboronic esters to unactivated ketones under mild reaction conditions. This protocol showcases a broad substrate tolerance and allows access to various chiral 2,3-dihydrobenzofuran-3-ol derivatives in generally good yields with excellent enantioselectivities.

CeCl3⋅7H2O-catalysed hydrophosphonylation of aldehydes and ketones: An expeditious route to α-hydroxyphosphonates under solvent-free conditions

A cerium(III) chloride-catalysed expeditious synthesis of α-hydroxyphosphonates via a modified Abramov synthetic protocol has been developed. The scope of the current protocol is broad, with a range of aromatic, α,β-unsaturated and heterocyclic aldehydes being efficiently converted to the anticipated products in very good to excellent yields (89–96%) in 15 min using low catalytic loading. The protocol was efficiently extended to hitherto unactivated cyclic ketones such as cyclopentanone and cyclohexanone to afford the required products in excellent yields. However, the reaction with cyclohexenone delivered a Michael product instead of the anticipated α-hydroxyphosphonates. The solvent-free conditions, low catalytic loadings, avoidance of toxic reagents and good to excellent yields are significant advantages of this protocol.