Lewis Base Catalyst Research Articles

ChemInform Abstract: Formamides as Lewis Base Catalysts in SN Reactions — Efficient Transformation of Alcohols into Chlorides, Amines, and Ethers.

AbstractA simple formamide catalyst facilitates the efficient transformation of alcohols into alkyl chlorides with benzoyl chloride as the sole reagent.

Construction of polycyclic spirooxindoles through [3+2] annulations of Morita–Baylis–Hillman carbonates and 3-nitro-7-azaindoles

A mild and efficient dearomatic [3+2] annulation reaction of 3-nitro-7-azaindoles and Morita−Baylis−Hillman carbonates from isatins was developed catalyzed by DMAP, affording the corresponding polycyclic spirooxindoles containing fused azaindoline architectures and vicinal quaternary centers in excellent yields (up to 96%) with high regio- and diastereoselectivity (dr>19:1). Moderate enantioselectivity (79% ee) was obtained by employing a chiral DMAP-type Lewis base catalyst.

Asymmetric cyanation of imines via dipeptide-derived organophosphine dual-reagent catalysis.

Over the past few decades, enantioselective phosphine organocatalysis has evolved rapidly into a highly efficient catalytic strategy for a range of useful reactions. However, as restricted by the traditional catalytic modes, some important reactions, such as asymmetric Strecker-type reactions, have thus far been out of reach of this strategy. Reported herein is an application of enantioselective phosphine organocatalysis for asymmetric Strecker-type reactions, enabled by a dual-reagent catalyst system in which the key organophosphorus zwitterion intermediate, generated in situ by mixing a chiral dipeptide-derived multifunctional organophosphine with methyl acrylate, is used as a highly efficient chiral Lewis base catalyst. The high efficiency of this catalytic system is demonstrated in the asymmetric cyanation of isatin-derived ketimines and azomethine aldimines as well as in the kinetic resolution of racemic 3-substituted azomethines. Mechanistic studies provide experimental evidence for the intermediacy of the putative zwitterion and its role as a catalytically active Lewis base.

ChemInform Abstract: Bifunctional AgOAc/ThioClickFerrophos Catalyzed Asymmetric 1,3‐Dipolar Cycloaddition Reaction of Azomethine Ylides to Nitroalkenes

Abstract18 examples

Organocatalysis: Fundamentals and Comparisons to Metal and Enzyme Catalysis

Catalysis fulfills the promise that high-yielding chemical transformations will require little energy and produce no toxic waste. This message is carried by the study of the evolution of molecular catalysis of some of the most important reactions in organic chemistry. After reviewing the conceptual underpinnings of catalysis, we discuss the applications of different catalysts according to the mechanism of the reactions that they catalyze, including acyl group transfers, nucleophilic additions and substitutions, and C–C bond forming reactions that employ umpolung by nucleophilic additions to C=O and C=C double bonds. We highlight the utility of a broad range of organocatalysts other than compounds based on proline, the cinchona alkaloids and binaphthyls, which have been abundantly reviewed elsewhere. The focus is on organocatalysts, although a few examples employing metal complexes and enzymes are also included due to their significance. Classical Brønsted acids have evolved into electrophilic hands, the fingers of which are hydrogen donors (like enzymes) or other electrophilic moieties. Classical Lewis base catalysts have evolved into tridimensional, chiral nucleophiles that are N- (e.g., tertiary amines), P- (e.g., tertiary phosphines) and C-nucleophiles (e.g., N-heterocyclic carbenes). Many efficient organocatalysts bear electrophilic and nucleophilic moieties that interact simultaneously or not with both the electrophilic and nucleophilic reactants. A detailed understanding of the reaction mechanisms permits the design of better catalysts. Their construction represents a molecular science in itself, suggesting that sooner or later chemists will not only imitate Nature but be able to catalyze a much wider range of reactions with high chemo-, regio-, stereo- and enantioselectivity. Man-made organocatalysts are much smaller, cheaper and more stable than enzymes.

Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N‐Oxide Lewis Base Catalysts

AbstractAtropisomeric biaryl pyridine and isoquinoline N‐oxides were synthesized enantioselectively by dynamic kinetic resolution (DKR) of rapidly racemizing precursors exhibiting free bond rotation. The DKR was achieved by ketoreductase (KRED) catalyzed reduction of an aldehyde to form a configurationally stable atropisomeric alcohol, with the substantial increase in rotational barrier arising from the loss of a bonding interaction between the N‐oxide and the aldehyde. Use of different KREDs allowed either the M or P enantiomer to be synthesized in excellent enantiopurity. The enantioenriched biaryl N‐oxide compounds catalyze the asymmetric allylation of benzaldehyde derivatives with allyltrichlorosilane.

Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N-Oxide Lewis Base Catalysts.

Atropisomeric biaryl pyridine and isoquinoline N-oxides were synthesized enantioselectively by dynamic kinetic resolution (DKR) of rapidly racemizing precursors exhibiting free bond rotation. The DKR was achieved by ketoreductase (KRED) catalyzed reduction of an aldehyde to form a configurationally stable atropisomeric alcohol, with the substantial increase in rotational barrier arising from the loss of a bonding interaction between the N-oxide and the aldehyde. Use of different KREDs allowed either the M or P enantiomer to be synthesized in excellent enantiopurity. The enantioenriched biaryl N-oxide compounds catalyze the asymmetric allylation of benzaldehyde derivatives with allyltrichlorosilane.

Formamides as Lewis Base Catalysts in SN Reactions-Efficient Transformation of Alcohols into Chlorides, Amines, and Ethers.

A simple formamide catalyst facilitates the efficient transformation of alcohols into alkyl chlorides with benzoyl chloride as the sole reagent. These nucleophilic substitutions proceed through iminium-activated alcohols as intermediates. The novel method, which can be even performed under solvent-free conditions, is distinguished by an excellent functional group tolerance, scalability (>100 g) and waste-balance (E-factor down to 2). Chiral substrates are converted with excellent levels of stereochemical inversion (99 %→≥95 % ee). In a practical one-pot procedure, the primary formed chlorides can be further transformed into amines, azides, ethers, sulfides, and nitriles. The value of the method was demonstrated in straightforward syntheses of the drugs rac-Clopidogrel and S-Fendiline.

Computational Insights into the Central Role of Nonbonding Interactions in Modern Covalent Organocatalysis.

The flexibility, complexity, and size of contemporary organocatalytic transformations pose interesting and powerful opportunities to computational and experimental chemists alike. In this Account, we disclose our recent computational investigations of three branches of organocatalysis in which nonbonding interactions, such as C-H···O/N interactions, play a crucial role in the organization of transition states, catalysis, and selectivity. We begin with two examples of N-heterocyclic carbene (NHC) catalysis, both collaborations with the Scheidt laboratory at Northwestern. In the first example, we discuss the discovery of an unusual diverging mechanism in a catalytic kinetic resolution of a dynamic racemate that depends on the stereochemistry of the product being formed. Specifically, the major product is formed through a concerted asynchronous [2 + 2] aldol-lactonization, while the minor products come from a stepwise spiro-lactonization pathway. Stereoselectivity and catalysis are the results of electrophilic activation from C-H···O interactions between the catalyst and the substrate and conjugative stabilization of the electrophile. In the second example, we show how knowledge and understanding of the computed transition states led to the development of a more enantioselective NHC catalyst for the butyrolactonization of acyl phosphonates. The identification of mutually exclusive C-H···O interactions in the computed major and minor TSs directly resulted in structural hypotheses that would lead to targeted destabilization of the minor TS, leading to enhanced stereoinduction. Synthesis and evaluation of the newly designed NHC catalyst validated our hypotheses. Next, we discuss two works related to Lewis base catalysis involving 4-dimethylaminopyridine (DMAP) and its derivatives. In the first, we discuss our collaboration with the Smith laboratory at St Andrews, in which we discovered the origins of the regioselectivity in carboxyl transfer reactions. We disclose how different Lewis base catalysts (NHC or DMAP) can lead to different regiomeric products as a result of differing magnitudes of aromatic and C-H···O interactions present in the respective transition states. In the second example, we discuss the mechanism and origins of the stereoselectivity of a reaction catalyzed by a planar-chiral 4-(pyrrolidino)pyridine derivative, namely, the coupling of ketenes with cyanopyrrole. We discovered that the chiral base mechanism is operative, in contrast to the originally proposed Brønsted acid mechanism. The selectivity is determined by the ease with which the major and minor TSs can realize strong stabilizing C-H···N interactions between the pyrrole cyano group and the catalyst. These interactions induce increased catalyst distortion in the minor TS, thereby leading to enantioselectivity. Finally, we discuss our computations related to amine-based organocatalysis in collaboration with the Carter laboratory at Oregon State. We probed the mechanism and stereoselectivity of a bifunctional amine thiourea-catalyzed Michael reaction. Our computations led to the design of an improved catalyst. However, synthesis and tests revealed that this catalyst was prone to degradation to side products that also catalyze the reaction, ultimately reducing the observed enantioselectivity. Lastly, we discuss our study of the mechanism and stereoselectivity of a proline sulfonamide-catalyzed Robinson annulation, in which we discovered that the enantioselectivity is controlled by the first Michael step but the diastereoselectivity is controlled by the following Mannich step.

ChemInform Abstract: Highly Enantioselective Bromocyclization of Allylic Amides with a P/P=O Double‐Site Lewis Base Catalyst.

AbstractThe role of the BINAP monoxide catalyst in the enantioselective bromocyclization of allylic amides affording enantioenriched oxazolines is examined in detail.

Enantioselective Aerobic Oxidative C(sp3)–H Olefination of Amines via Cooperative Photoredox and Asymmetric Catalysis

A cooperative photoredox and asymmetric catalysis for the enantioselective aerobic oxidative C(sp3)–H olefination of tetrahydro-β-carbolines (THCs) is reported. This method, which is also effective for tetrahydroisoquinolines (THIQs), features a triple-catalyst strategy, involving a dicyanopyrazine-derived chromophore (DPZ) as the metal-free photoredox catalyst, a chiral Lewis base catalyst, and an inorganic salt cocatalyst. The current protocol provides straightforward access to a series of valuable α-substituted THCs and THIQs in high yields with excellent regio- and enantioselectivities (up to 95% ee).

P-Chiral phosphine oxide catalysed reduction of prochiral ketimines using trichlorosilane

Twelve P-chiral phosphine oxides were screened for their ability to act as a chiral Lewis base catalyst for the asymmetric hydrosilylation of ketimines, providing chiral amines in good conversion and yield, but relatively poor enantioselectivity (ee <30%). Mechanistic studies paralleling work on chiral sulfinamides have shown a non-linear relationship of catalyst enantioselectivity and the chiral amine product.

Highly Enantioselective Bromocyclization of Allylic Amides with a P/P=O Double‐Site Lewis Base Catalyst

The enantioselective bromocyclization of allylic amides catalyzed by phosphorus-containing Lewis bases was examined in detail. A series of control experiments and NMR studies showed that a partially oxidized bis-phosphine generated in situ serves as the actual enantioselective catalyst. The reaction mechanism involves distinct roles of two Lewis basic sites, P and P=O, with P+ Br serving as a fine-tuning element for substrate fixation in the chiral environment, and P+ OBr as the Br+ transfer agent to the olefin. Catalyst loading could be reduced to as little as 1 mol %, and the reaction affords enantioenriched oxazolines with up to >99.5 % ee.

Chiral Cobalt(III) Complexes as Bifunctional Brønsted Acid–Lewis Base Catalysts for the Preparation of Cyclic Organic Carbonates

Stereochemically inert cationic cobalt(III) complexes were shown to be one-component catalysts for the synthesis of cyclic carbonates from epoxides and carbon dioxide at 50 °C and 5 MPa carbon dioxide pressure. The optimal catalyst possessed an iodide counter anion and could be recycled. A catalytic cycle is proposed in which the ligand of the cobalt complexes acts as a hydrogen-bond donor, activating the epoxide towards ring opening by the halide anion and activating the carbon dioxide for subsequent reaction with the halo-alkoxide. No kinetic resolution was observed when terminal epoxides were used as substrates, but chalcone oxide underwent kinetic resolution.

ChemInform Abstract: Chiral Phosphine Oxide Aziridinyl Phosphonate as a Lewis Base Catalyst for Enantioselective Allylsilane Addition to Aldehydes.

Abstract A series of chiral Lewis bases, phosphine oxide ferrocenyl aziridinyl methanol 1–4, phosphinyl aziridinyl phosphonates 5 and 6, and phosphine oxide aziridinyl phosphonates 7 and 8 were screened for allylsilane additions to aldehydes. Among the Lewis bases, 8 was found to catalyze the reaction by forming the product in up to 94% yield and with 77% ee.

ChemInform Abstract: Stereoselective Electrophilic Cyclization

AbstractReview: [rational design of monofunctionalized chiral Lewis base catalysts for enantioselective iodo‐ and protocyclizations as well as nucleophilic phosphite‐urea cooperative catalysts for the stereoselective promotion of electrophilic bromocyclizations; 31 refs.

Bifunctional AgOAc/ThioClickFerrophos catalyzed asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides to nitroalkenes

AgOAc/ThioClickFerrophos (TCF) complex catalyzed the 1,3-dipolar cycloaddition of azomethine ylides (glycine imino ester) to nitroalkenes. The corresponding endo-cycloadducts (88:12–98:2 endo/exo) were afforded in good yields with high enantioselectivities, up to 98% ee, without addition of external amine. AgOAc/TCF works as a bifunctional (Lewis acid and base) catalyst.

Chiral phosphine oxide aziridinyl phosphonate as a Lewis base catalyst for enantioselective allylsilane addition to aldehydes

A series of chiral Lewis bases, phosphine oxide ferrocenyl aziridinyl methanol 1–4, phosphinyl aziridinyl phosphonates 5 and 6, and phosphine oxide aziridinyl phosphonates 7 and 8 were screened for allylsilane additions to aldehydes. Among the Lewis bases, 8 was found to catalyze the reaction by forming the product in up to 94% yield and with 77% ee.

Stereoselective Electrophilic Cyclization.

Electrophilic cyclizations of unactivated alkenes play highly important roles in the synthesis of useful building blocks. This account describes our contributions to the rational design of monofunctionalized chiral Lewis base catalysts for enantioselective iodo- and protocyclizations. For the stereoselective promotion of electrophilic bromocyclizations, nucleophilic phosphite-urea cooperative catalysts have been designed.

A DFT study on the competing mechanisms of PPh3-catalyzed [3 + 3] and [3 + 2] annulations between 5-acetoxypenta-2,3-dienoate and 1C,3O-bisnucleophiles

In this paper, the competing mechanisms of PPh3-catalyzed [3+3] annulation reaction (including possible pathways a, b and c) and [3+2] annulation reaction (including possible pathways a′, b′ and c′) between 5-acetoxypenta-2,3-dienoate and 1C,3O-bisnucleophile have been theoretically investigated using density functional theory (DFT). Among the six possible pathways, our computational results indicate that pathway c is the most energy favorable pathway at acid condition, whereas pathway b′ is the most energy favorable pathway at base condition. Thus, the different acid/base condition would be the switch for the two competing reactions, which is in agreement with the experiment results. Moreover, the analysis of global reactivity indexes has been carried out to explore the role of the catalyst PPh3, which demonstrates that Lewis base catalyst PPh3 noticeably strengthens the nucleophilicity of the reactant and makes the annulation reactions easier to occur. This work should be helpful for not only understanding the role of PPh3 catalyst in the [3+3] and [3+2] annulations, but also the role of the real switch (i.e., the acid/base additives) in the competing [3+3] and [3+2] annulations, and thus provides valuable insights on the rational design of more efficient catalysts for this kind of reactions.