N-heterocyclic Carbene Catalyst Research Articles

Organocatalytic and Chemoselective Polymerization of Multivinyl-Functionalized γ-Butyrolactones.

Achieving complete chemoselectivity in the polymerization of multivinyl polar monomers is an important yet challenging task, currently achievable only by metal- or metalloid-mediated polymerization processes but in a noncatalytic fashion. Now this work shows that organic N-heterocyclic carbene (NHC) catalysts effect rapid, chemoselective, and catalytic polymerization of multivinyl-functionalized γ-butyrolactones, particularly γ-vinyl-α-methylene-γ-butyrolactone (VMBL). Thus, the NHC-catalyzed polymerization of VMBL not only is quantitatively chemoselective, proceeding exclusively via polyaddition across the conjugated α-methylene double bond while leaving the γ-vinyl double bond intact, but also requires only an exceptionally low catalyst loading of 50 ppm, thus, exhibiting a remarkably high catalyst turnover frequency of 80000 h-1 and producing on average 33.6 polymer chains of Mn = 73.8 kg/mol per NHC molecule. The resulting PVMBL can be either thermally cured into cross-linked materials or postfunctionalized with the thiol-ene "click" reaction to achieve complete conversion of the pendant vinyl group on every repeat unit into the corresponding thioether.

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.

Telomerization of 1,3-butadiene with highly substituted alcohols using Pd/NHC-catalysts — Structure-reactivity-relationship of the O-nucleophile

Catalytic telomerization of 1,3-butadiene with alcohols is a catalytic reaction and an effective tool to synthesize 2,7-octadienyl ethers with different characteristics depending on the alcoholic substrate. While Pd/phosphine type catalysts were studied in depth, highly active Pd/NHC (=N-heterocyclic carbene) catalysts have been studied in the telomerization almost exclusively along with methanol. In the course of employing alcohols from renewables, e.g., lignin, cellulose or terpenes etc., a deeper understanding of the reactivity of these catalysts is needed.In this work, we present comprehensive investigations with linear and branched alcohols of different chain-lengths. Distinct tendencies in reaction behavior between primary and secondary alcohols were found and the lower reactivity of secondary alcohols could clearly be attributed to electronic properties, along with steric hindrance.Furthermore, the influence of double bonds in the alcohol chain has been studied. Interestingly, alcohols with double bonds that are not conjugated to the hydroxyl groups were shown to be more active than saturated alcohols. Allylic alcohols, however, are significantly less reactive than their saturated analogs.With the gathered information, we were able to deduce a structure reactivity-relationship of certain functional groups and substitution patterns. These findings were proved by employing terpenols to gain new allylic terpenol ethers.

Cooperative Asymmetric Catalysis by N-Heterocyclic Carbenes and Brønsted Acid in γ-Lactam Formation: Insights into Mechanism and Stereoselectivity

Current developments in the burgeoning area of cooperative asymmetric catalysis indicate the use of N-heterocyclic carbenes (NHCs) in conjunction with other catalysts such as a Bronsted acid. Herein, mechanistic insights derived through a comprehensive DFT (M06-2X) computational study on a dual catalytic reaction between an enal and an imine leading to trans-γ-lactams, catalyzed by a chiral NHC and benzoic acid, is presented. In the most preferred pathway, we note that the NHC catalyst activates one of the reactants (enal) in the form of a Breslow intermediate, whereas the electrophilic partner (imine) is activated by the benzoic acid through protonation of the imino nitrogen. In this article, we focus on the origin of cooperative action of both catalysts as well as on the stereoselectivity by identifying the stereocontrolling transition states. The explicit and cooperative participation of the Bronsted acid and NHC lowers the energetic barrier both in the Breslow intermediate formation and in the stereoc...

Enantioselective Assembly of Spirolactones through NHC-Catalyzed Remote γ-Carbon Addition of Enals with Isatins.

A chiral N-heterocyclic carbene (NHC)-catalyzed formal [4 + 2] annulation of β-methyl substituted enals with isatins was developed to construct six-membered spirolactones bearing highly congested quaternary carbon stereocentersin good yields and high enantioselectivities. The strategy realized a challenging remote γ-carbon addition of enals and chiral control of β-methyl substituted enals in the presence of the NHC catalyst only.

ChemInform Abstract: N‐Heterocyclic Carbene‐Catalyzed Diastereoselective Vinylogous Michael Addition Reaction of γ‐Substituted Deconjugated Butenolides.

An efficient N-heterocyclic carbene (NHC)-catalyzed vinylogous Michael addition of deconjugated butenolides was developed. In the presence of 5 mol % of the NHC catalyst, both γ-alkyl- and aryl-substituted deconjugated butenolides undergo vinylogous Michael addition with various α, β-unsaturated ketones, esters, or nitriles to afford γ,γ-disubstituted butenolides containing adjacent quaternary and tertiary carbon centers in good to excellent yields with excellent diastereoselectivities. In this process, the free carbene is assumed to act as a strong Bronsted base to promote the conjugate addition.

Enantioselective Intermolecular Enamide-Aldehyde Cross-Coupling Catalyzed by Chiral N-Heterocyclic Carbenes.

The unprecedented N-heterocyclic carbene (NHC)-catalyzed intermolecular cross-coupling of enamides and aldehydes is described. Upon exposure of enamides to aldehydes in the presence of a NHC catalyst, catalytic C-C bond formation occurs, providing highly enantioselective N-protected amines, bearing a quaternary carbon center, in good yields and with high enantioselectivities.

1,4-Bis-Dipp/Mes-1,2,4-Triazolylidenes: Carbene Catalysts That Efficiently Overcome Steric Hindrance in the Redox Esterification of α- and β-Substituted α,β-Enals.

As reported by Scheidt and Bode in 2005, sterically nonencumbered α,β-enals are readily converted to saturated esters in the presence of alcohols and N-heterocyclic carbene catalysts, e.g., benzimidazolylidenes or triazolylidenes. However, substituents at the α- or β-position of the α,β-enal substrate are typically not tolerated, thus severely limiting the substrate spectrum. On the basis of our earlier mechanistic studies, a set of N-Mes- or N-Dipp-substituted 1,2,4-triazolium salts were synthesized and evaluated as (pre)catalysts in the redox esterification of various α- or β-substituted enals. In particular the 1,4-bis-Mes/Dipp-1,2,4-triazolylidenes overcome the above limitations and efficiently catalyze the redox esterification of a whole series of α/β-substituted enals hitherto not amenable to NHC-catalyzed transformations. The synthetic value of 1,4-bis-Mes/Dipp-1,2,4-triazolylidenes is further demonstrated by the one-step bicyclization of 10-oxocitral to (racemic) nepetalactone in diastereomerically pure form.

Organocatalytic Kinetic Resolution of Sulfoximines.

An efficient kinetic resolution of sulfoximines with enals was realized using chiral N-heterocyclic carbene (NHC) catalysts. The stereoselective amidation proceeds without additional acyl transfer agent. Both enantiomers of the sulfoximines can be obtained with excellent ee values (up to 99% ee and -97% ee, respectively). Performing the catalysis on a gram scale allowed using the recovered sulfoximine (+)-1j in an asymmetric synthesis of FXa inhibitor F.

Recyclable NHC Catalyst for the Development of a Generalized Approach to Continuous Buchwald–Hartwig Reaction and Workup

A generalized approach to the optimization and implementation of Buchwald–Hartwig reactions in flow is reported, through the combination of three key factors: a highly active palladium catalyst, a universal approach for continuous workup and purification, and a methodology for catalyst recycling and reuse. The palladium N-heterocyclic carbene (NHC) precatalyst [Pd(IPr*)(cin)Cl] 4 (IPr* = 1,3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene; cin = η3-cinnamyl) is an excellent choice for continuous Buchwald–Hartwig reactions, due to its inherent high activity and stability. In preparation for running this reaction in flow (published concurrently), a detailed study has been carried out into its water stability, ultimately allowing the recycling of the catalyst in the organic phase up to three times in batch mode. A “right-first-time” workup methodology has also been developed, resulting in a universal protocol that allows the selective extraction of the Buchwald–Hartwig product into the aqueous ...

A Continuous Process for Buchwald–Hartwig Amination at Micro-, Lab-, and Mesoscale Using a Novel Reactor Concept

A continuous Buchwald–Hartwig reaction using the bulky N-heterocyclic carbene (NHC) precatalyst [Pd(IPr*)(cin)Cl] 4 has been developed for the synthesis of a key pharmaceutical intermediate 2. Using microreactor technology, the reaction could be optimized under dilute conditions with low material burden and the kinetic parameters investigated. For larger lab-scale operation (gram scale), process-relevant concentrations could be employed and the conditions developed for continuous workup effectively demonstrated (batch methodology published concurrently). The stability of the NHC catalyst allowed for a continuous acidic extraction of the product and on-stream recycling of the catalyst in the organic phase. At this scale, sonication is employed to prevent clogging in the reactor unit. Finally, a bespoke continuous flow reactor has been developed for carrying out the reaction beyond lab scale. This novel reactor concept for running heterogeneous reactions in flow combines the flexibility of continuously stir...

Recent Progress of Supported N-Heterocyclic Carbene Catalyst in Organic Reactions

The supported N-heterocyclic carbene (NHC) catalysts have been extensively applied in the catalysis of different organic reactions due to its unique characteristic such as high reactivity, easy separation, purification and recyclability. In this paper, the recent progresses in synthesis and application of supported N-heterocyclic carbene metal complexes based on various types of supports, such as polymer, magnetic nanoparticles, carbon and silica material have been reviewed.

Porous aromatic frameworks (PAFs) as efficient supports for N-heterocyclic carbene catalysts

Polymeric aromatic frameworks (PAFs), easily obtained from organic platforms, as excellent supports to yield robust well-defined organometallic heterogenized catalysts.

An N-heterocyclic carbene based MOF catalyst for Sonogashira cross-coupling reaction

The post-synthetic modification of azolium containing MOFs generated a new heterogeneous N-heterocyclic carbene catalyst (1-Pd), which is very active for Sonogashira cross coupling reaction.

N-Heterocyclic Carbene-Catalyzed Diastereoselective Vinylogous Michael Addition Reaction of γ-Substituted Deconjugated Butenolides

An efficient N-heterocyclic carbene (NHC)-catalyzed vinylogous Michael addition of deconjugated butenolides was developed. In the presence of 5 mol % of the NHC catalyst, both γ-alkyl- and aryl-substituted deconjugated butenolides undergo vinylogous Michael addition with various α, β-unsaturated ketones, esters, or nitriles to afford γ,γ-disubstituted butenolides containing adjacent quaternary and tertiary carbon centers in good to excellent yields with excellent diastereoselectivities. In this process, the free carbene is assumed to act as a strong Brønsted base to promote the conjugate addition.

Recyclable Supported Carbene Catalysts for High-Yielding Self-Condensation of Furaldehydes into C10 and C12 Furoins

Two highly efficient and recyclable heterogeneous azolium catalyst systems, one grafted (g) onto the inorganic oxide (Silica) and the other onto the organic polymer [Merrifield’s peptide or chloromethylated polystyrene (PS) resin], have been developed and employed to catalyze quantitative self-coupling (umpolung condensation) reactions of furfural and 5-hydroxymethylfurfural (HMF) into C10 and C12 furoins, respectively. Supported benzimidazolium ([BI]) salts bearing a long-chain alkyl substituent (i.e., C12 dodecyl) on the azolium nitrogen atom, upon activation with a suitable base to generate the corresponding N-heterocyclic carbene (NHC) catalyst, are found to be far more effective catalysts for furaldehyde self-coupling reactions than the analogous catalysts carrying a short-chain alkyl substituent (i.e., C1 methyl). Thus, supported NHC catalysts generated in situ from Silica-g-[BI]-C12 or PS-g-[BI]-C12-benzyl/base afford the C10 and C12 furoins in about 97% and 94% yield, respectively. By adopting a c...

N-Heterocyclic carbene-catalyzed dimerization, cyclotetramerization and polymerization of Michael acceptors

N-Heterocyclic carbenes (NHCs), which were first isolated in the early 1990s, have received a great deal of scientific attention as ligands for transition metal complexes and organocatalysts for more than a decade. Organocatalysis by NHCs primarily involves the reaction of carbonyl compounds, particularly the umpolung of aldehydes, although we and others have been developing the reactions and the polymerizations of Michael acceptors. This review focuses on the NHC-catalyzed transformations of Michael acceptors that were developed by our research group, including (1) tail-to-tail dimerization of a wide variety of substrates, (2) cyclotetramerization of acrylates, (3) tandem oxa-Michael addition and head-to-tail dimerization of methacrolein and (4) oxa-Michael addition polymerization of hydroxyl-functionalized acrylates. For the former two reactions, the NHCs turn the β-carbon of the Michael acceptors into nucleophilic sites (umpolung), thereby generating the deoxy-Breslow intermediate and enabling bond formation between the β-carbon and electrophiles. The latter two reactions are based on the O–C bond formation between alcohols and Michael acceptors, in which the NHC catalysts act as a Lewis base. Thus, the use of NHC catalysts allowed new modes of reactivity of Michael acceptors other than the conventional addition polymerizations. This review describes the N-heterocyclic carbene-catalyzed transformations of Michael acceptors that were developed by our research group, including (1) tail-to-tail dimerization of a wide variety of substrates, such as vinyl pyridines, acrylates, methacrylates and methacrylonitrile, (2) cyclotetramerization of acrylates to form trisubstituted cyclopentenones, (3) tandem oxa-Michael addition and head-to-tail dimerization of methacrolein and (4) oxa-Michael addition polymerization of hydroxyl-functionalized acrylates.

The Real Role of N-Heterocyclic Carbene in Reductive Functionalization of CO2: An Alternative Understanding from Density Functional Theory Study.

The mechanisms of reductive functionalization of CO2 to formamide catalyzed by N-heterocyclic carbene (NHC) were comprehensively studied with DFT calculations. New activation mode with much lower energy barrier than those proposed before was discovered. In this reaction, NHC acts as neither a CO2 nor a silane activator, but as a precursor of the real catalyst, i.e., the in situ formed ionic liquid [NHCH](+)[Carbamate](-). In this loose contact ion pair, the negatively charged O atom of the carbamate anion becomes the new active site and is free to do nucleophilic attack. When amine is absent, CO2 will be converted into methanol. In this case, the NHC-CO2 adduct is the real catalytic species, the active site shifted from the carbene C atom to the negatively charged O atom. These new activation modes follow a pattern of "S(N)2@Si-Acceptor", in which the Si-H bond is activated via concerted backside S(N)2 nucleophilic attack by the negatively charged O atom, and the leaving hydride is directly accepted by a free CO2 molecule. The advantages of these new activation modes originate from the following points: (1) The ionic liquid [NHCH](+)[Carbamate](-) and NHC-CO2 adduct are thermodynamically more stable than NHC. (2) The active site of the NHC catalyst is extended outside a lot. Consequently, the large steric effect between the NHC arms and the substrates in transition state can be avoided to some extent. (3) The O atom has good silicon affinity. In addition, a free CO2 molecule, whose carbon atom is more electrophilic than those of the CO2 moieties in NHC-CO2 adduct and carbamate, acts as an efficient hydride acceptor.

Gas Phase Studies of N-Heterocyclic Carbene-Catalyzed Condensation Reactions.

N-Heterocyclic carbenes (NHCs) catalyze Umpolung condensation reactions of carbonyl compounds, including the Stetter reaction. These types of reactions have not heretofore been examined in the gas phase. Herein, we explore the feasibility of examining these reactions in the absence of solvent. A charge-tagged thiazolylidene catalyst is used to track the reactions by mass spectrometry. We find that the first Umpolung step, the addition of the NHC catalyst to a carbonyl compound to form the "Breslow intermediate", does not readily proceed in the gas phase, contrary to the case in solution. The use of acylsilanes in place of the carbonyl compounds appears to solve this issue, presumably because of a favorable Brook rearrangement. The second addition reaction, with enones, does not occur under our gas phase conditions. These reactions do occur in solution; the differential reactivity between the condensed and gas phases is discussed, and calculations are used to aid in the interpretation of the results.

ChemInform Abstract: Iron‐Catalyzed Directed C2‐Alkylation and Alkenylation of Indole with Vinylarenes and Alkynes.

An iron–N-heterocyclic carbene catalyst generated from an iron(III) salt, an imidazolinium salt, and a Grignard reagent promotes alkylation and alkenylation reactions at the indole C2-position with vinylarenes and internal alkynes, respectively, via imine-directed C–H activation. The former reaction affords 1,1-diarylalkane derivatives with exclusive regioselectivity. Deuterium-labeling experiments suggest that these reactions involve oxidative addition of the C–H bond to the iron center, insertion of the unsaturated bond into the Fe–H bond, and C–C reductive elimination.