Visible‐Light‐Promoted Chelating N ‐Heterocyclic Carbene Palladium Catalysis for Amide Bond Formation From Aldehydes and Secondary Amines

Amides are valuable functional groups in biological, agrochemical, and pharmaceutical molecules. Several amides such as Weinreb amides, morpholine amides, and pyrrolidine amides are useful intermediates for the synthesis of aldehydes or ketones. Among them, morpholine amides are a cheap and good substitute for Weinreb amides. A large number of synthetic methods for making amides from various carboxylic acid derivatives have been reported. Among these, the aminolysis of acid chlorides in the presence of non-nucleophilic tertiary amines is generally considered to be the method of choice. Amides can also be synthesized using metals such as zinc, indium and samarium instead of tertiary amines from acid chlorides. Herein, we wish to report an alternative direct conversion of acid chlorides to secondary and tertiary amides (including morpholine amides), which proceeds under mild reaction conditions (0 °C) with an almost stoichiometric amount of amine and a short reaction time, and gives very good to excellent yields (Scheme 1). To demonstrate the feasibility of performing the desired reaction under a variety of conditions, we first carried out the synthesis of tertiary amides from benzoyl chloride. The corresponding morpholine amides could be obtained in 99% yield by reaction with benzoyl chloride under optimized reaction conditions in the presence of diisobutyl(morpholino)aluminum, which was easily prepared from morpholine and diisobutylaluminum hydride (DIBALH). The results are summarized in Table 1. We next synthesized various secondary and tertiary amides from other acid chlorides under the optimal conditions deduced from the previous experimental results. The results obtained for the reaction of benzoyl chloride with various primary and secondary amines are summarized in Table 2. As shown in Table 2, various noncyclic and cyclic primary amines underwent smooth conversion to the corresponding secondary amides in 90-99% yields (entries 1-5). Furthermore, the secondary amines also afforded the corresponding tertiary amides in 75-99% yields under similar reaction conditions (entries 6-10). From these results, we anticipated that the treatment of diisobutyl(morpholino)aluminum with representative acid chlorides would be effective for the direct synthesis of morpholine amides. Table 3 summarizes the results of the one-pot synthesis of morpholine amides from various acid chlorides. As expected, various aromatic acid chlorides with electronwithdrawing and electron-donating substituents underwent the conversion to the corresponding morpholine amides smoothly, in 89-99% yields (entries 1-7). A polyaromatic acid chloride such as naphthoyl chloride and a heterocyclic aromatic acid chloride such as furoyl chloride gave the corresponding morpholine amides in 92% and 91% yields, respectively, via the same methodology (entries 8 and 9). Furthermore, aliphatic acid chloride such as caproyl chloride smoothly afforded the corresponding morpholine amide in 96% under the same reaction conditions (entry 10). A proposed mechanism for this reaction is shown in Scheme 2 for the conversion of benzoyl chloride to the corresponding piperidine amide. Initially, the intermediate 2 is produced through the attack on the acid chloride by the secondary amino anion in diisobutyl(piperidino)aluminum 1 to give intermediate 3, with the release of an aluminum complex from intermediate 2. Finally, the hydrolysis of the Table 1. Optimization of reaction conditions for the synthesis of tertiary amides from acid chlorides

In this paper, a novel synthesis of tertiary amides from anionically activated aromatic trifluoromethyl groups is presented. Anionically activated trifluoromethyl groups react with secondary amines under aqueous conditions to afford tertiary amides. The mechanism involves initial elimination of hydrogen fluoride by an E1cB mechanism to afford an electrophilic quinone methide- or azafulvene-type intermediate that reacts with secondary amines under aqueous conditions to afford the tertiary amide in good yield (up to 99%).

Some aspects of the Lewis base and ligand behavior of N-heterocyclic carbenes

External Photocatalyst-Free Visible Light-Promoted 1,3-Addition of Perfluoroalkyl Iodides to Vinyldiazoacetates

Supramolecular Template-Assisted Catalytic [2+2] Photocycloaddition in Homogeneous Solution

• Synthesis and characterization of Pd(II) complexes with N-heterocyclic carbene ligands having a triazole pendant group. • Characterization of geometrical and rotational isomers for complexes of general formula [PdI 2 (NHC) 2 ]. • Evaluation of the energetics of the different isomers via DFT calculations. • Possibility to functionalize the triazole moiety affording a precursor of triazol-based N -heterocyclic carbenes. • Dinuclear complex formed by bridging coordination through the N-triazole and the C-imidazole atoms to two trans -PdI 2 units. A series of N -heterocyclic carbene (NHC) palladium complexes derived from N -methyl or N -mesityl-imidazolium salts bearing a triazole ring as pendant group to the second nitrogen atom, have been synthesized and characterized by NMR spectroscopy, mass spectrometry and single-crystal X-ray diffraction. Deprotonation of the imidazolium salt with palladium(II) acetate in acetonitrile affords square-planar Pd(II) complexes of general formula [PdI 2 (NHC) 2 ] with trans geometry. The steric hindrance of the NHC ligand substituents allows to characterize in solution both rotation syn and anti isomers. In contrast, in the crystallization process, the cis -[PdI 2 (NHC) 2 ] form was isolated, and its structure was determined by XRD. The stability of the possible geometrical and rotational isomers has been assessed also via DFT calculations (level of theory: COSMO-ZORA-BLYP(D3(BJ))/TZP). A second product forms along with the mononuclear complex and was identified as a dinuclear complex with the NHC and the nitrogen atom of the triazole ring bridging two trans -PdI 2 units. Finally, the nitrogen atom on the triazole ring was methylated affording a pendant triazolium salt, which can also give a carbene ligand upon deprotonation.

Imidazol(in)ium-2-carboxylates as Latent, Thermally Activated Organocatalysts for Transesterification Reactions

Oxidative amidation reaction of aldehydes with amines, by tert butyl hydrogen peroxide in toluene was achieved. The reaction utilised the in situ generated catalyst produced by Fe(II) – hydride complex [FeH 2 (PPh 3 ) 4 ], and N‐heterocyclic carbene (NHC) ligand. The catalytic system was found efficient for the synthesis of wide variety of mono and disubstiuted amides.

A series of N-heterocyclic carbene (NHC) ligands bearing aliphatic amino side groups were synthesized and reacted with the Grubbs first generation catalyst. Reactions involving symmetrical, aliphatic NHCs did not allow the isolation of any pure NHC substituted complexes due to their instability. Unsymmetrical NHCs having a planar mesityl group on one amino side reacted with Grubbs catalyst in a favorable manner, and the resulting complexes were stable enough to be isolated. X-ray crystallographic analysis demonstrated that the mesityl group is co-planar with the phenyl ring of the benzylidene, which indicates that a π–π interaction between the mesityl arm and the benzylidene moiety might constitute an important structural element. Catalysts substituted with an NHC derived from a primary or secondary amino-group were found to surpass the parent-complex for the ROMP of cycloocta-1,5-diene. The catalyst substituted with an NHC derived from tBu-NH2 was considerably less metathesis active. Also new N-alkyl-N′-(2,6-diisopropylphenyl) heterocyclic carbenes were synthesized. These NHC ligands revealed a different reactivity towards Grubbs complexes than the hitherto reported imidazolinylidenes: (i) facile bis(NHC) coordination was found, and (ii) both NHCs on the bis(NHC) complexes can be exchanged with a phosphine, thereupon regenerating the Grubbs first generation complex. Furthermore, a comparison between the classical Hoveyda–Grubbs complexes and complexes substituted with N-alkyl-N′-(aryl) heterocyclic carbenes demonstrates that the introduction of one aliphatic group into the NHC framework does not improve the catalytic activity in any of the tested metathesis reactions. The introduction of two aliphatic amino side groups enhances the reactivity in the ROMP reaction while the increase of steric interactions lowers the CM activity. The lower activity of the N-alkyl-N′-(2,6-diisopropylphenyl) heterocyclic carbene complexes compared with the N-alkyl-N′-mesityl heterocyclic carbene complexes, may analogously be attributed to a more demanding steric environment. While small differences in donor capacities might cause a significantly different catalytic behavior, it is thus plausible that subtle steric differences exert a more determining influence on the activity of the catalysts. In addition, the obtained results confirm that the NHC's amino side groups play a pivotal role in determining the reactivity, selectivity as well as the stability of the corresponding catalysts.

A luminescent bimetallic AuI complex comprised of N-heterocyclic carbene (NHC) and carbazole (Cz) ligands, that is, (NHC')Au(NHC)AuCz has been synthesized and studied. Both carbene ligands in the bimetallic complex act as electron acceptors in tandem to increase the energy separation between the ground and excited state, which is higher than those found in either monometallic analogue, (NHC)AuCz and (NHC')AuCz. A coplanar geometry designed into the tandem complex ensures sufficient electronic coupling between the π-orbitals of the ligands to impart a strong oscillator strength to the singlet intra-ligand charge-transfer (1 ICT) transition. Theoretical modelling indicates that the emissive ICT excited state involves both NHC ligands. The tandem complex gives blue luminescence (λmax =480 nm) with a high photoluminescent quantum yield (ΦPL =0.80) with a short decay lifetime (τ=0.52 μs). Temperature-dependent photophysical studies indicate that emission is via thermally assisted delayed fluorescence (TADF) and give a small singlet-triplet energy difference (ΔEST =50 meV, 400 cm-1 ) consistent with the short TADF lifetime.

N-Heterocyclic carbene catalyzed C-acylation reaction for access to linear aminoenones

Fluorescent N‐heterocyclic carbene (NHC) metal complexes are useful for various chemical and biological applications. In this study, we developed a simple strategy to synthesize BODIPY‐linked NHC metal complexes involving Ag, Cu, Ni, and Pd. The synthesis began with the preparation of BODIPY‐imidazolium salt as a precursor ligand. This ligand was used to obtain BODIPY‐imidazolium silver carbene complex, which subsequently facilitated the syntheses of BODIPY‐linked NHC transition metal complexes (Cu, Ni, and Pd) via the transmetalation method. This approach offers a versatile pathway for the synthesis of various other fluorescent carbene metal complexes. The applications of these BODIPY‐linked NHC metal complexes were also explored. Chemotherapeutic anti‐cancer activity of BODIPY‐imidazolium silver carbene complex showed high cancer cell killing efficacy as compared to its precursor ligand. This outcome confirmed that the attachment of the silver atom is essential to enhance the cytotoxic activities. Additionally, the fluorescence property of the BODIPY moiety is highly useful for cellular imaging, which establishes the silver complex as a potential chemotheranostic agent for cancer management. Furthermore, BODIPY‐imidazolium copper carbene complex was explored as a non‐noble metal‐based catalyst for ammonia borane (AB) hydrolysis to generate hydrogen. This catalytic system was further applied for chemoselective reduction of the aromatic formyl groups in the presence of other reducible functional groups. Overall, this investigation presents a simple and efficient design strategy for the synthesis of different BODIPY‐linked metal carbene complexes with potential applications in catalysis, cellular imaging, and cancer therapy.

N‐heterocyclic carbenes (NHCs) have been dominating the world of homogeneous catalysis in an unprecedented manner in the last two decades. Understanding the underlying reasons behind catalysis with NHC ligands has thus become of significant interest. Subscribing to this view, we strive to identify the key attributes of N‐heterocyclic carbene ligands through a combination of experimental and computational studies. Rational catalyst design, by appropriate functionalization of N‐heterocyclic carbene ligands to investigate their utility in a host of catalytically relevant transformations of interest to contemporary organic synthesis, is thus central to our efforts. From this perspective, a variety of C–C and C–N bond forming reactions, namely, the Suzuki–Miyaura, Sonogashira, and Hiyama cross‐couplings, the base‐free Michael additions, the alkene and alkyne hydroaminations, the formation of β‐enaminones from 1,3‐dicarbonyl compounds and primary amines, and the environmentally important ring‐opening polymerizations (ROP) of L‐lactides, which produce biodegradable polylactide polymers from renewable resources, have been studied. The metal–carbene interaction in these catalysts has been probed with the aid of computational studies, which suggest that strong σ‐donor N‐heterocyclic carbene ligands bind tightly to the metal center and thereby impart the much needed stability to these catalysts. Even going beyond catalysis, we investigated the potential of N‐heterocyclic carbene complexes in biomedical applications particularly for their antimicrobial and anticancer properties.

Amides are valuable functional groups in biological, agrochemical, and pharmaceutical molecules. Several amides such as Weinreb amides, morpholine amides, and pyrrolidine amides are useful intermediates for the synthesis of aldehydes or ketones. Among them, morpholine amides are a cheap and good substitute for Weinreb amides. A large number of synthetic methods for making amides from various carboxylic acid derivatives have been reported. Among these, the aminolysis of acid chlorides in the presence of non-nucleophilic tertiary amines is generally considered to be the method of choice. Amides can also be synthesized using metals such as zinc, indium and samarium instead of tertiary amines from acid chlorides. Herein, we wish to report an alternative direct conversion of acid chlorides to secondary and tertiary amides (including morpholine amides), which proceeds under mild reaction conditions (0 °C) with an almost stoichiometric amount of amine and a short reaction time, and gives very good to excellent yields (Scheme 1). To demonstrate the feasibility of performing the desired reaction under a variety of conditions, we first carried out the synthesis of tertiary amides from benzoyl chloride. The corresponding morpholine amides could be obtained in 99% yield by reaction with benzoyl chloride under optimized reaction conditions in the presence of diisobutyl(morpholino)aluminum, which was easily prepared from morpholine and diisobutylaluminum hydride (DIBALH). The results are summarized in Table 1. We next synthesized various secondary and tertiary amides from other acid chlorides under the optimal conditions deduced from the previous experimental results. The results obtained for the reaction of benzoyl chloride with various primary and secondary amines are summarized in Table 2. As shown in Table 2, various noncyclic and cyclic primary amines underwent smooth conversion to the corresponding secondary amides in 90-99% yields (entries 1-5). Furthermore, the secondary amines also afforded the corresponding tertiary amides in 75-99% yields under similar reaction conditions (entries 6-10). From these results, we anticipated that the treatment of diisobutyl(morpholino)aluminum with representative acid chlorides would be effective for the direct synthesis of morpholine amides. Table 3 summarizes the results of the one-pot synthesis of morpholine amides from various acid chlorides. As expected, various aromatic acid chlorides with electronwithdrawing and electron-donating substituents underwent the conversion to the corresponding morpholine amides smoothly, in 89-99% yields (entries 1-7). A polyaromatic acid chloride such as naphthoyl chloride and a heterocyclic aromatic acid chloride such as furoyl chloride gave the corresponding morpholine amides in 92% and 91% yields, respectively, via the same methodology (entries 8 and 9). Furthermore, aliphatic acid chloride such as caproyl chloride smoothly afforded the corresponding morpholine amide in 96% under the same reaction conditions (entry 10). A proposed mechanism for this reaction is shown in Scheme 2 for the conversion of benzoyl chloride to the corresponding piperidine amide. Initially, the intermediate 2 is produced through the attack on the acid chloride by the secondary amino anion in diisobutyl(piperidino)aluminum 1 to give intermediate 3, with the release of an aluminum complex from intermediate 2. Finally, the hydrolysis of the Table 1. Optimization of reaction conditions for the synthesis of tertiary amides from acid chlorides

Copper-Catalyzed Ligand-Controlled Selective Borocarbonylation of α-Substituted Styrenes Toward β-Boryl Aldehydes and Cyclopropyl Boronate Esters