Mechanistic Study of the N-Formylation of Amines with Carbon Dioxide and Hydrosilanes

N-formylation of amines with CO2 and hydrosilane reducing agents proceeds via fast and complex chemical equilibria, which hinder easy analysis of the reaction pathways. In situ reaction monitoring and kinetic studies reveal that three proposed pathways, via direct- and amine assisted formoxysilane formation (pathways 1 and 2, respectively) and via a silylcarbamate intermediate (pathway 3), are possible depending on the reaction conditions and the substrates. While pathway 1 is favored for non-nucleophilic amines in the absence of a catalyst, a base catalyst results in noninnocent behavior of the amine in the CO2 reduction step toward the formoxysilane intermediate. The reaction pathway is altered by strongly nucleophilic amines, which form stable adducts with CO2. Silylcarbamate intermediates form, which can be directly reduced to the N-formylated products by excess hydrosilane. Nevertheless, without excess hydrosilane, the silylcarbamate is an additional intermediate en route to formoxysilanes along pathway 2. Exchange NMR spectroscopy (EXSY) revealed extensive substituent exchange around the hydrosilane silicon center, which confirms its activation during the reaction and supports the proposed reaction mechanisms. Numerous side reactions were also identified, which help to establish the reaction equilibria in the N-formylation reactions

Synthesis of cyclic carbonates from diols and CO2 catalyzed by carbenes

The synthesis of cyclic carbonates from epoxides and CO2 is a well-established reaction, whereas the synthesis of cyclic carbonates from diols and CO2 is considerably more challenging, and few efficient catalysts are available. Here, we describe heterocyclic carbene catalysts, including one derived from a cheap and efficient thiazolium salt, for this latter reaction. The reaction proceeds at atmospheric pressure in the presence of an alkyl halide and Cs2CO3. Reaction mechanisms for the transformations involved are also proposed

Intricacies of Cation-Anion Combinations in Imidazolium Salt-Catalyzed Cycloaddition of CO2 Into Epoxides

The cycloaddition of CO2 into epoxides catalyzed by imidazolium and related salts continues to attract attention due to the industrial importance of the cyclic carbonate products. The mechanism of the imidazolium-catalyzed transformation has been proposed to require the participation of the acidic C2 proton. However, other simple salts without acidic protons, such as N,N,N,N-tetrabutylammonium chloride, are also efficient catalysts for the reaction. Hence, we decided to investigate the role of the ring protons of imidazolium salts in this reaction. To this end, we systematically studied the catalytic activity of a series of methyl substituted imidazolium cations, in the presence of various halide anions, both by experiment and in silico. Our results demonstrate that, while stabilization of intermediates by C2, C4, or C5 protons in imidazolium salts takes place, it is the nucleophilicity of the anion that governs the overall activity, which is intimately related to the strength of the interactions between the cation and anion. Consequently, the reactivity of the halide anion strongly depends on the nature of the cation and cosolvents. This study completes the (known) mechanism and should facilitate the development of highly efficient catalysts

Organocatalysts in C-N Bond Forming Reactions of Amines with CO2

The thesis describes a simple approach for N-formylation of amines with CO2 and hydrosilane reducing agents, the use of organic salts as N-formylation catalysts, their physical properties required for high catalytic activity and their role in the catalytic cycle. The investigation is then extended to the synthesis of quinazoline-2,4(1H,3H)-dione from 2-aminobenzonitrile and CO2 as well as other C-N bond forming reactions. Basicity, as measured by pKb, is identified as the key property required for high catalytic activity of organic salt catalysts. Minor variations in catalytic activity among salts of equal basicity are assigned to the ion pairing energy, hydrogen bonding ability and steric factors. The N-formylation reaction catalysed by organic salts proceeds by the activation of the hydrosilane reducing agent. Although, the catalytic activity was originally assigned to the nucleophilicity of the anion, a detailed investigation of the reaction mechanism and physical parameters of numerous salt catalysts revealed that they are more active as bases. Extensive substituent exchange around the hydrosilane silicon centre confirms its activation and supports the proposed reaction mechanism, where in-situ formed carbamate salt acts as the reaction nucleophile. Accounting for small detrimental effect of ion paring, a linear relationship between the pKa of the salt and catalytic activity is observed. The onset of the base catalysed reaction mechanism is substrate dependent with further variations for amines of high basicity. Nevertheless, highly basic salt catalysts, such as tetra-n-butylammonium fluoride ([TBA]F), promote rapid N-formylation of all types of amines under extremely mild conditions. A linear relationship between the basicity of salt catalysts and their catalytic activity was also observed in the synthesis of quinazoline-2,4(1H,3H)-dione. Similarly, the reaction proceeds by in-situ formation of a carbamate salt, which requires a base catalyst. However, here the reaction mechanism is limited by the acidity of the quinazoline-2,4(1H,3H)-dione product. Quinazoline-2,4(1H,3H)-dione is deprotonated by more basic catalysts (pKa of conjugate acid > 14.7 in DMSO) leading to the neutralization of the base catalyst and the formation of the quinazolide anion, which then acts as the reaction catalyst. Analysis of the reported literature reveals that the findings are directly applicable to the vast majority of C-N bond forming reactions of amines with CO2 and to almost all types of organocatalysts. The reactions proceed by carbamate salt formation in the form [BaseH][RR'NCOO]. The anion of the carbamate salt then acts as a nucleophile in hydrosilane reductions of CO2 towards formamides, N-methylamines and aminals or internal cyclization reactions to quinazoline-2,4-diones, oxazolidinones and oxazin-2-ons or after dehydration as an electrophile in the synthesis of urea derivatives. The role of organocatalysts in the reactions indicates that all bases of sufficient strength should be able to catalyse the reactions

Pivotal Role of the Basic Character of Organic and Salt Catalysts in C-N Bond Forming Reactions of Amines with CO2

Organocatalysts promote a range of C-N bond forming reactions of amines with CO2. Herein, we review these reactions and attempt to identify the unifying features of the catalysts that allows them to promote a multitude of seemingly unrelated reactions. Analysis of the literature shows that these reactions predominantly proceed by carbamate salt formation in the form [BaseH][RR ' NCOO]. The anion of the carbamate salt acts as a nucleophile in hydrosilane reductions of CO2, internal cyclization reactions or after dehydration as an electrophile in the synthesis of urea derivatives. The reactions are enhanced by polar aprotic solvents and can be either promoted or hindered by H-bonding interactions. The predominant role of all types of organic and salt catalysts (including ionic liquids, ILs) is the stabilization of the carbamate salt, mostly by acting as a base. Catalytic enhancement depends on the combination of the amine, the base strength, the solvent, steric factors, ion pairing and H-bonding. A linear relationship between the base strength and the reaction yield has been demonstrated with IL catalysts in the synthesis of formamides and quinazoline-2,4-diones. The role of organocatalysts in the reactions indicates that all bases of sufficient strength should be able to catalyze the reactions. However, a physical limit to the extent of a purely base catalyzed reaction mechanism should exist, which needs to be identified, understood and overcome by synergistic or alternative methods

Carbon Dioxide Based N-Formylation of Amines Catalyzed by Fluoride and Hydroxide Anions

We described herein a simple approach for N-formylation with CO2 and hydrosilane reducing agents. Fluoride and hydroxide salts efficiently catalyzed the reaction, principally through activation of the hydrosilanes, which led to hydrosilane reactivities comparable to those of NaBH4/LiAlH4. Consequently, the N-formylation of amines with CO2 could be achieved at room temperature and atmospheric pressure. The mechanism of these anionic catalysts contrasts that of the currently reported systems, for which activation of CO2 is the key mechanistic step. Using tetrabutylammonium fluoride as a simple ammonium salt catalyst, the N-formylated products of both aliphatic and aromatic amines could be obtained in excellent yields with high selectivities

The dilemma between acid and base catalysis in the synthesis of benzimidazole from o-phenylenediamine and carbon dioxide

The tandem synthesis of benzimidazole and other azoles can be achived by the N-formylation of ortho-substituted anilines followed by a cyclization reaction. However, CO2-based N-formylations with hydrosilane reducing agents are base catalyzed whereas the cyclization reaction is acid catalyzed. The mismatch in catalytic conditions means that only one of the steps can be catalyzed in a single pot reaction. While the N-formylation reaction is frequently the target of catalyst development, the cyclization reaction requires comparably much harsher reaction conditions. Identification of these difficulties lead us to the development of a one-pot, two-step synthesis of benzimidazole under mild reaction conditions employing acid catalysts

Delineation of the Critical Parameters of Salt Catalysts in the N-Formylation of Amines with CO2

N-formylation of amines with CO2 is base-catalyzed and studies of salt catalysts reveal that the reaction is efficiently catalyzed by "free" floating anions of high basicity, as represented in the cover image. More information can be found in the Full Paper by P. J. Dyson et al. (DOI: 10.1002/chem.201901686)