Carbonyl Addition Reactions Research Articles

A solventless carbonyl addition reaction as a guided inquiry laboratory activity for second-year undergraduate organic students

ABSTRACT A less hazardous, environmentally friendly, and energy-efficient Knoevenagel reaction performed using proline as a catalyst has been designed and implemented within a sophomore-level organic chemistry laboratory as a guided inquiry activity. The main learning objective is to enable students to identify and understand various green chemistry principles such as atom economy, use of safer chemicals, design for energy efficiency, and inherently safer chemistry for accident prevention. Students were successful in synthesizing α,β-unsaturated diesters using unknown substituted benzaldehydes (later identified by the students spectroscopically) and Meldrum’s acid at room temperature in the presence of proline as a catalyst without the need for an additional base. By analyzing 1H NMR spectroscopic data, infrared spectroscopy, and mass spectrometry to identify the synthesized product, the unknown benzaldehyde starting material, and the major reaction pathway, students have enhanced their spectroscopy skills and developed a deeper understanding of the mechanism of the reaction that may not be covered in the lecture course.

Unlocking the Nucleophilicity of Strong Alkyl C-H Bonds via Cu/Cr Catalysis.

Direct functionalization of inert C-H bonds is one of the most attractive yet challenging strategies for constructing molecules in organic chemistry. Herein, we disclose an unprecedented and Earth abundant Cu/Cr catalytic system in which unreactive alkyl C-H bonds are transformed into nucleophilic alkyl-Cr(III) species at room temperature, enabling carbonyl addition reactions with strong alkyl C-H bonds. Various aryl alkyl alcohols are furnished under mild reaction conditions even on a gram scale. Moreover, this new radical-to-polar crossover approach is further applied to the 1,1-difunctionalization of aldehydes with alkanes and different nucleophiles. Mechanistic investigations reveal that the aldehyde not only acts as a reactant but also serves as a photosensitizer to recycle the Cu and Cr catalysts.

Asymmetric Synthesis of Anti‐tuberculosis‐specific Drug TBAJ‐876 through Synergistic Li/Li Catalysis

Comprehensive SummaryTBAJ‐876, developed by TB Alliance, a novel anti‐tuberculosis‐specific drug, has entered Phase II clinical trials. Herein, the first asymmetric synthesis of TBAJ‐876 has been realized using synergistic Li/Li catalysis with excellent yield of 95% and 88 : 12 er (99.6 : 0.4 er, 10 : 1 dr after simple recrystallization). Furthermore, DFT calculations and 7Li‐NMR analysis illustrated the mechanism of the synergistic reaction: a chiral Li‐complex activates the nucleophile to control the stereoselectivity, while the other achiral Li‐complex activates the electrophile to catalyze the carbonyl addition reaction. Additionally, this protocol has been successfully carried out at 5 gram‐scale, showing its industrial potential.

Dirhodium(II)/Phosphine Catalyst with Chiral Environment at Bridging Site and Its Application in Enantioselective Atropisomer Synthesis.

A dirhodium(II)/phosphine catalyst with a chiral environment at the bridging site was developed for the asymmetric arylation of phenanthrene-9,10-diones with arylboronic acids. In contrast to the classic chiral bridging carboxylic acid (or derivatives) ligand strategy of bimetallic dirhodium(II) catalysis, in this reaction, tuning both axial and bridging ligands realized the first Rh2(OAc)4/phosphine-catalyzed highly enantioselective carbonyl addition reaction. The kinetic analysis reveals that dirhodium(II) and arylboronic acid follow the first-order kinetics, while phenanthrene-9,10-dione is zeroth-order. These data supported the proposed catalytic cycle, where the key intermediate in the rate-determining step involved the dirhodium(II) complex and arylboronic acid. Finally, axially chiral biaryls were prepared based on a newly developed oxidative ring-opening reaction of α-hydroxyl ketones with a base and molecular oxygen, which featured a central-to-axial chirality transfer radical β-scission step.

Recent Progress in Chromium-Mediated Carbonyl Addition Reactions

AbstractOrganochromium(III) species are versatile nucleophiles in complex molecule synthesis due to their high functional group tolerance and chemoselectivity for aldehydes. Traditionally, carbonyl addition reactions of organochromium(III) species were performed through reduction of organohalides either using stoichiometric chromium(II) salts or catalytic chromium salts in the presence of stoichiometric reductants [such as Mn(0)]. Recently, alternative methods emerged involving organoradical formation from readily available starting materials (e.g., N-hydroxyphthalimide esters, alkenes, and alkanes), followed by trapping the radical with stoichiometric or catalytic chromium(II) salts. Such methods, especially using catalytic chromium(II) salts, will lead to the development of sustainable chemical processes minimizing salt wastes and number of synthetic steps. In this review, methods for generation of organochromium(III) species for addition reactions to carbonyl compounds, classified by nucleophiles are described.1 Introduction2 Alkylation2.1 Branch-Selective Reductive Alkylation of Aldehydes Using Unactivated Alkenes2.2 Linear-Selective Alkylation of Aldehydes2.2.1 Catalytic Decarboxylative Alkylation of Aldehydes Using NHPI ­Esters2.2.2 Catalytic Reductive Alkylation of Aldehydes Using Unactivated Alkenes2.2.3 Alkylation of Aldehydes via C(sp3)–H Bond Functionalization of Unactivated Alkanes2.3 Catalytic α-Aminoalkylation of Carbonyl Compounds3 Allylation3.1 Catalytic Allylation of Aldehydes via Three-Component Coupling3.2 Catalytic Allylation of Aldehydes via C(sp3)–H Bond Functionalization of Alkenes4 Propargylation: Catalytic Propargylation of Aldehydes via Three-Component Coupling5 Conclusion

CuH-Catalyzed Olefin Functionalization: From Hydroamination to Carbonyl Addition.

In organic synthesis, ligand-modified copper(I) hydride (CuH) complexes have become well-known reagents and catalysts for selective reduction, particularly toward Michael acceptors and carbonyl compounds. Recently, our group and others have found that these hydride complexes undergo migratory insertion (hydrocupration) with relatively unactivated and electronically unpolarized olefins, producing alkylcopper intermediates that can be leveraged to forge a variety of useful bonds. The resulting formal hydrofunctionalization reactions have formed the basis for a resurgence of research in CuH catalysis. This Account chronicles the development of this concept in our research group, highlighting its origin in the context of asymmetric hydroamination, evolution to more general C-X bond-forming reactions, and applications in the addition of olefin-derived nucleophiles to carbonyl derivatives.Hydroamination, the formal insertion of an olefin into the N-H bond of an amine, is a process of significant academic and industrial interest, due to its potential to transform widely available alkenes and alkynes into valuable complex amines. We developed a polarity-reversed strategy for catalytic enantioselective hydroamination relying on the reaction of olefins with CuH to generate chiral organocopper intermediates, which are intercepted by electrophilic amine reagents. By engineering the auxiliary ligand, amine electrophile, and reaction conditions, the scope of this method has since been extended to include many types of olefins, including challenging internal olefins. Further, the scope of amine reagents has been expanded to enable the synthesis of primary, secondary, and tertiary amines as well as amides, N-alkylated heterocycles, and anilines. All of these reactions exhibit high regio- and stereoselectivity and, due to the mild conditions required, excellent tolerance for heterocycles and polar functional groups.Though the generation of alkylcopper species from olefins was originally devised as a means to solve the hydroamination problem, we soon found that these intermediates could react efficiently with an unexpectedly broad range of electrophiles, including alkyl halides, silicon reagents, arylpalladium species, heterocycles, and carbonyl derivatives. The general ability of olefins to function as precursors for nucleophilic intermediates has proved particularly advantageous in carbonyl addition reactions because it overcomes many of the disadvantages associated with traditional organometallic reagents. By removing the need for pregeneration of the nucleophile in a separate operation, CuH-catalyzed addition reactions of olefin-derived nucleophiles feature improved step economy, enhanced functional group tolerance, and the potential for catalyst control over regio- and stereoselectivity. Following this paradigm, feedstock olefins such as allene, butadiene, and styrene have been employed as reagents for asymmetric alkylation of ketones, imines, and aldehydes.

Enantioselective Carbonyl 1,2- or 1,4-Addition Reactions of Nucleophilic Silyl and Diazo Compounds Catalyzed by the Chiral Oxazaborolidinium Ion.

Boron Lewis acid catalysis has a long history and has become one of the most powerful methods for organic synthesis. In addition to achiral boron catalysts such as BX3 (X = F, Cl, Br) and B(C6F5)3, chiral boron catalysts are also significant synthetic tools used by organic chemists in academic laboratories and industry. Since first reported by Corey et al. in 2002( Corey et al. J. Am. Chem. Soc. 2002 , 124 , 3808 ), the chiral oxazaborolidinium ion (COBI), an activated form of proline-derived oxazaborolidine, has been used as a strong Lewis acid catalyst. Although the early examples of asymmetric synthesis through COBI-catalyzed nucleophilic 1,2- or 1,4-carbonyl additions were reported in 2004-2006, Diels-Alder and cycloaddition reactions of various carbonyl compounds were mostly developed over the next several years to afford enantioenriched cyclized products. The power of COBI in catalyzing carbonyl 1,2- or 1,4-addition reactions triggered our interest in developing asymmetric synthetic methodologies to generate versatile enantiomerically enriched compounds. In this Account, we summarize our recent studies on COBI-catalyzed asymmetric nucleophilic carbonyl addition and tandem reactions. Logical mechanistic explanations of asymmetric COBI catalysis are also discussed. The proton-activated COBI catalyst, which can activate various carbonyl compounds such as aldehydes, ketones, acroleins, and enones through Lewis acid-base interactions and synergistic hydrogen bonds, facilitates asymmetric 1,2- or 1,4-carbonyl additions of nucleophiles. Nucleophiles bearing trialkylsilyl groups successfully reacted with aromatic, aliphatic, and α,β-unsaturated aldehydes through 1,2-addition reactions resulting in chiral β-hydroxy esters. In addition, efficient asymmetric hydrosilylation of ketones was achieved with a TfOH-activated COBI catalyst. Optically active β-keto esters and all-carbon quaternary aldehydes were synthesized successfully through asymmetric 1,2-addition of diazo compounds and tandem H- or C-migration, respectively. In some cases, epoxide products were obtained as side products via the Darzens reaction pathway. Solvent and π-π interactions played important roles in favoring C-migration over H-migration. Nucleophilic 1,4-addition of diazo compounds and chemoselective ring-closure afforded an efficient approach to cyclopropanes, and their tandem rearrangements provided four- and seven-membered cyclic compounds with excellent stereoselectivity. After a Michael addition of diazo compounds, the selective β-hydride shift pathway afforded the β-substituted cyclic enones with high diastereo- and enantioselectivity. The presence of π-bond(s) in the substituents at the α-position of the diazo compound hindered the β-hydride shift pathway and, as a result, favored the cyclopropanation pathway. While there still remain challenges to be overcome, these results further understanding of COBI catalysis and open a window for future development of new asymmetric synthetic methods using carbonyl addition and tandem reactions.

A Divergent Approach to the Marine Diterpenoids (+)‐Dictyoxetane and (+)‐Dolabellane V

We present a full account of the development of a strategy that culminated in the first total syntheses of the unique oxetane-containing natural product (+)-dictyoxetane and the macrocyclic diterpene (+)-dolabellane V. Our retrosynthetic planning was guided by both classical and nonconventional strategies to construct the oxetane, which is embedded in an unprecedented 2,7-dioxatricyclo[4.2.1.03,8 ]nonane ring system. Highlights of the successful approach include highly diastereoselective carbonyl addition reactions to assemble the full carbon skeleton, a Grob fragmentation to construct the 11-membered macrocycle of (+)-dolabellane V, and a bioinspired 4-exo-tet, 5-exo-trig cyclization sequence to form the complex dioxatricyclic framework of (+)-dictyoxetane. Furthermore, an unprecedented strain-releasing type I dyotropic rearrangement of an epoxide-oxetane substrate was developed.

ChemInform Abstract: Development of Highly Active Chiral Titanium Catalysts for the Enantioselective Addition of Various Organometallic Reagents to Aldehydes

AbstractReview: [56 refs.

Development of Highly Active Chiral Titanium Catalysts for the Enantioselective Addition of Various Organometallic Reagents to Aldehydes.

The catalytic enantioselective carbonyl addition reaction has long attracted the interest of chemists because of its synthetic importance. Although many highly enantioselective reactions have been developed, with few exceptions the reactions are carried out at relatively high catalyst loadings, making them less practical for scale-up applications. In addition, organometallic reagents employed as carbon nucleophiles have been limited to those with relatively low reactivity, such as diorganozincs and arylboronic acids. In an effort to enhance the practicality, a highly active and enantioselective chiral titanium catalyst system was recently developed in our laboratory, enabling the enantioselective carbonyl addition reaction to aldehydes using various organometallic reagents (RM; M = MgX, Li, BY2 , ZnX, AlMe2 ) at lower catalyst loadings (≤5 mol %).

Experimental study on a new plugging agent during CO2 flooding for heterogeneous oil reservoirs: A case study of Block G89-1 of Shengli oilfield

In oilfield operations, CO2 has been applied to enhance oil recovery (EOR). However, CO2 injection in heterogeneous oil reservoirs lacks acceptable sweep efficiency due to the high mobility of CO2. A suitable composite organic granule plugging agent was developed to control CO2 mobility and hence, improve sweep efficiency and oil recovery. The reaction mechanism involved hydroquinone, formaldehyde, furfural and heptyl alcohol catalyzed by p-toluene sulfonic acid at supercritical CO2 to initiate carbonyl addition and condensation reaction via sol-gel polymerization to form granulated polymer. This system is suitable for low permeability and low water-cut oil reservoirs. The core experiments show that the system is easy for injection, and the plugging ratio is more than 98% after injecting 1PV. The parallel sand pack model experiments show that the system can enter the high permeability reservoirs first and as the increase of permeability ratio, the profile modification becomes better. The core flooding experiment shows that the system had good performance of sealing for CO2 and the EOR can be further improved 11.9% at the same time.

Assessing the viability of biosynthetic pathways for calophyline A formation—are pericyclic reactions involved?

The results of quantum chemical calculations on a previously proposed biosynthetic pathway for the formation of calophyline A from rhazimol, which features formally forbidden 4-electron [1,2] and [1,3] sigmatropic shifts, are discussed. The proposed pathway was not found to be energetically viable, despite a surprisingly low predicted barrier for the [1,3] shift, but an alternative route involving a series of tautomerizations and carbonyl addition reactions is shown to be more energetically feasible.

Anionic cyclopolymerization of methacrylic anhydride with the aid of bulky aluminum Lewis acid

Methacrylic anhydride was anionically polymerized for the first time by a lithium ester enolate with the aid of the bulky aluminum bisphenoxides in dichloromethane at −78 °C to afford polymers consisting of six-membered cyclized units as confirmed by NMR and IR spectroscopy, while a less bulky trialkylaluminum was ineffective. At higher temperatures, no polymeric product formed partly due to the carbonyl addition reaction of the alkyl group in the aluminum compound to the monomer. From the model reactions in the presence and absence of the aluminum compounds, importance of formation of an enolate–aluminate type species is suggested. Tacticity of PMMA derived from poly(MAAn) is rich in syndiotacticity in comparison to radically prepared one.

ChemInform Abstract: Preparation of Solid Salt Stabilized Functionalized Organozinc Compounds and Their Application to Cross‐Coupling and Carbonyl Addition Reactions.

AbstractNovel zinc pivalates are prepared as is shown for substrates (III) and isolated as stable powders which can be easily handled.

Preparation of Solid Salt‐Stabilized Functionalized Organozinc Compounds and their Application to Cross‐Coupling and Carbonyl Addition Reactions

Powdered organozinc reagents: Various aryl and heteroaryl bromides as well as benzylic chlorides react with Mg and Zn(OPiv)2⋅2 LiCl (OPiv=pivalate) to provide solid organozinc reagents after solvent evaporation. These powders can be stored at room temperature under argon for months and can be manipulated in air for a short time. They undergo smooth Negishi cross-coupling and carbonyl addition reactions (see scheme).

Expanding the pleuromutilin class of antibiotics by de novo chemical synthesis.

New pleuromutilin-like compounds were synthesized in approximately 11 steps from 3-allylcyclopent-2-enone by a strategy featuring sequential carbonyl addition reactions. Several analogs possessing the C14 tiamulin ester side chain displayed activity in a Mycobacterium tuberculosis mc(2)7000 assay. The results described herein provide a basis for further efforts to expand the structural and stereochemical diversity of the pleuromutilin class of bacterial protein synthesis inhibitors through advances in chemical synthesis.

ChemInform Abstract: Transition Metal Catalyzed Reactions of Organosilicon Reagents Through Intramolecular Activation

AbstractReview: ca. 60 refs.

ChemInform Abstract: Intramolecular [1 + 2] and [3 + 2] Cycloaddition Reactions of Cyclopropenone Ketals.

The first intramolecular thermal reactions of cyclopropenone ketals are reported and the work examined substrates tethered to an electron-deficient olefin bearing a single electron-withdrawing substituent. Whereas the intermolecular variants of the reactions provide only the products of an endo-selective [1 + 2] cycloaddition or a carbonyl addition reaction of a thermally generated π-delocalized singlet vinylcarbene, the intramolecular variants provide either [1 + 2] or [3 + 2] cycloadducts in reactions that depend on the reaction conditions, the alkene-activating substituent, and the nature of the tethering. In addition to providing key mechanistic insights into the thermal [3 + 2] cycloaddition reaction for such substrates, they were also found to proceed under conditions that reflect the ease and regioselectivity of the cyclopropenone ketal cleavage for π-delocalized singlet vinylcarbene generation. The most effective combination of structural features that impact the reactivity was observed with subst...

ChemInform Abstract: Reductive Radical Cyclization of Haloalkenes Promoted by Samarium Diiodide. Sequential Cyclization/Intermolecular Carbonyl Addition Reactions.

ChemInform Abstract: Reductive Radical Cyclization of Haloalkenes Promoted by Samarium Diiodide. Sequential Cyclization/Intermolecular Carbonyl Addition Reactions.

ChemInform Abstract: Sequential Radical Cyclization/Intermolecular Carbonyl Addition Reactions Initiated by Samarium(II) Iodide.

ChemInform Abstract: Sequential Radical Cyclization/Intermolecular Carbonyl Addition Reactions Initiated by Samarium(II) Iodide.