Engaging Alkenes and Alkynes in Deaminative Alkyl-Alkyl and Alkyl-Vinyl Cross-Couplings of Alkylpyridinium Salts.
ABSTRACT: An alkyl-alkyl cross-coupling of Katritzky alkylpyridinium salts and organoboranes, formed in situ via hydroboration of alkenes, has been developed. This method utilizes the abundance of both alkyl amine precursors and alkenes to form C(sp3)-C(sp3) bonds. This strategy is also effective with alkynes, enabling a C(sp3)-C(sp2) cross-coupling. Under these mild conditions, a broad range of functional groups, including protic groups, is tolerated. As seen with previous alkylpyridinium cross-couplings, mechanistic studies support an alkyl radical intermediate.
Project description:A Negishi cross-coupling of alkylpyridinium salts and alkylzinc halides has been developed. This is the first example of alkyl-alkyl bond formation via cross-coupling of an alkyl amine derivative with an unactivated alkyl group, and allows both primary and secondary alkylpyridinium salts to react with primary alkylzinc halides with high functional group tolerance. When combined with formation of the pyridinium salts from primary amines, this method enables the noncanonical transformation of NH2 groups into a wide range of alkyl substituents with broad functional group tolerance.
Project description:The reductive cross-coupling of sp3-hybridized carbon centers represents great synthetic values and insurmountable challenges. In this work, we report a nickel-catalyzed deaminative cross-electrophile coupling reaction to construct C(sp)?C(sp3), C(sp2)?C(sp3), and C(sp3)?C(sp3) bonds. A wide range of coupling partners including aryl iodides, bromoalkynes, or alkyl bromides are stitched with alkylpyridinium salts that derived from the corresponding primary amines. The advantages of this methodology are showcased in the two-step synthesis of the key lactonic moiety of (+)-compactin and (+)-mevinolin. The one-pot procedure without isolation of alkylpyridinium tetrafluoroborate salt is also proven to be successful. This cross-coupling strategy of two electrophiles provides a highly valuable vista for the convenient installation of alkyl substituents and late functionalizations of sp3 carbons.
Project description:A nickel-catalyzed reductive cross-coupling of alkylpyridinium salts and aryl bromides has been developed using Mn as the reductant. Both primary and secondary alkylpyridinium salts can be used, and high functional group and heterocycle tolerance is observed, including for protic groups. Mechanistic studies indicate the formation of an alkyl radical, and controlling its fate was key to the success of this reaction.
Project description:Alkynes are amongst the most valuable functional groups in organic chemistry and widely used in chemical biology, pharmacy, and materials science. However, the preparation of alkyl-substituted alkynes still remains elusive. Here, we show a nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts. Key to the success of this coupling is the development of an easily accessible and bench-stable amide-type pincer ligand. This ligand allows naturally abundant alkyl amines as alkylating agents in Sonogashira reactions, and produces diverse alkynes in excellent yields under mild conditions. Salient merits of this chemistry include broad substrate scope and functional group tolerance, gram-scale synthesis, one-pot transformation, versatile late-stage derivatizations as well as the use of inexpensive pre-catalyst and readily available substrates. The high efficiency and strong practicability bode well for the widespread applications of this strategy in constructing functional molecules, materials, and fine chemicals.
Project description:A Suzuki-Miyaura cross-coupling of ?-pyridinium esters and arylboroxines has been developed. Combined with formation of the pyridinium salts from amino acid derivatives, this method enables amino acid derivatives to be efficiently transformed into ?-aryl esters and amides. Under the mild conditions, broad functional group tolerance on both the amino acid derivatives and the arylboroxine are observed, including protic functional groups. Mechanistic studies support an alkyl radical intermediate, similar to other cross-couplings of alkylpyridinium salts.
Project description:By employing an N-heterocyclic carbene (NHC) catalyst, we developed a versatile catalytic system that enables deaminative cross-coupling reactions of aldehydes with redox-active pyridinium salts. Katritzky pyridinium salts behave as single-electron oxidants capable of generating alkyl radicals enabled by the redox properties of the enolate form of Breslow intermediates. The resultant alkyl radical undergoes efficient recombination with the NHC-bound aldehyde-derived carbonyl carbon radical for the formation of a C-C bond. The mild and transition metal-free reaction conditions tolerate a broad range of functional groups, and its utility has been further demonstrated by the modification of a series of peptide feedstocks and application to the three-component dicarbofunctionalization of olefins.
Project description:We developed a strategy to harness alkyl amines as alkylating agents via C-N bond activation. This Suzuki-Miyaura cross coupling of alkylpyridinium salts, readily formed from primary amines, is the first example of a metal-catalyzed cross coupling via C-N bond activation of an amine with an unactivated alkyl group. This reaction enjoys broad scope and functional group tolerance. Primary and secondary alkyl groups can be installed. Preliminary studies suggest a NiI/NiIII catalytic cycle.
Project description:The chemical inertness of abundant and commercially available alkyl chlorides precludes their widespread use as reactants in chemical transformations. Presented in this work is a metallaphotoredox methodology to achieve the catalytic intramolecular reductive cyclization of unactivated alkyl chlorides with tethered alkenes. The cleavage of strong C(sp3 )-Cl bonds is mediated by a highly nucleophilic low-valent cobalt or nickel intermediate generated by visible-light photoredox reduction employing a copper photosensitizer. The high basicity and multidentate nature of the ligands are key to obtaining efficient metal catalysts for the functionalization of unactivated alkyl chlorides.
Project description:The use of pyridinium-activated primary amines as photoactive functional groups for deaminative generation of alkyl radicals under catalyst-free conditions is described. By taking advantage of the visible light absorptivity of electron donor-acceptor complexes between Katritzky pyridinium salts and either Hantzsch ester or Et<sub>3</sub> N, photoinduced single-electron transfer could be initiated in the absence of a photocatalyst. This general reactivity platform has been applied to deaminative alkylation (Giese), allylation, vinylation, alkynylation, thioetherification, and hydrodeamination reactions. The mild conditions are amenable to a diverse range of primary and secondary alkyl pyridiniums and demonstrate broad functional group tolerance.
Project description:The design of nanoparticle delivery materials possessing biological activities is an attractive strategy for the development of various therapies. In this study, 11 cationic amphiphilic 4-(<i>N</i>-alkylpyridinium)-1,4-dihydropyridine (1,4-DHP) derivatives differing in alkyl chain length and propargyl moiety/ties number and position were selected for the study of their self-assembling properties, evaluation of their cytotoxicity in vitro and toxicity on microorganisms, and the characterisation of their interaction with phospholipids. These lipid-like 1,4-DHPs have been earlier proposed as promising nanocarriers for DNA delivery. We have revealed that the mean diameter of freshly prepared nanoparticles varied from 58 to 513 nm, depending upon the 4-(<i>N</i>-alkylpyridinium)-1,4-DHP structure. Additionally, we have confirmed that only nanoparticles formed by 4-(<i>N</i>-dodecylpyridinium)-1,4-DHP derivatives <b>3</b> and <b>6,</b> and by 4-(<i>N</i>-hexadecylpyridinium)-1,4-DHP derivatives <b>10</b> and <b>11</b> were stable after two weeks of storage. The nanoparticles of these compounds were found to be homogenous in size distribution, ranging from 124 to 221 nm. The polydispersity index (PDI) values of 1,4-DHPs samples <b>3</b>, <b>6</b>, <b>10</b>, and <b>11</b> were in the range of 0.10 to 0.37. We also demonstrated that the nanoparticles formed by 4-(<i>N</i>-dodecylpyridinium)-1,4-DHP derivatives <b>3</b>, <b>6</b>, and <b>9,</b> and 4-(<i>N</i>-hexadecylpyridinium)-1,4-DHP derivatives <b>10</b> and <b>11</b> had zeta-potentials from +26.07 mV (compound <b>6</b>) to +62.80 mV (compound <b>11</b>), indicating a strongly positive surface charge and confirming the relative electrostatic stability of these nanoparticle solutions. Transmission electron microscopy (TEM) images of nanoaggregates formed by 1,4-DHPs <b>3</b> and <b>11</b> confirmed liposome-like structures with diameters around 70 to 170 nm. The critical aggregation concentration (CAC) value interval for 4-(<i>N</i>-alkylpyridinium)-1,4-DHP was from 7.6 µM (compound <b>11</b>) to 43.3 µM (compound <b>6</b>). The tested 4-(<i>N</i>-alkylpyridinium)-1,4-DHP derivatives were able to quench the fluorescence of the binary 1,6-diphenyl-1,3,5-hexatriene (DPH)-1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) system, demonstrating hydrophobic interactions of 1,4-DHPs with phospholipids. Thus, 4-(<i>N</i>-dodecylpyridinium)-1,4-DHP derivative <b>3</b> quenched the fluorescence of the DPH?DPPC system more efficiently than the other 4-(<i>N</i>-alkylpyridinium)-1,4-DHP derivatives. Likewise the compound <b>3</b>, also 4-(N-dodecylpyridinium)-1,4-DHP derivative <b>9</b> interacted with the phospholipids. Moreover, we have established that increasing the length of the alkyl chain at the quaternised nitrogen of the 4-(<i>N</i>-alkylpyridinium)-1,4-DHP molecule or the introduction of propargyl moieties in the 1,4-DHP molecule significantly influences the cytotoxicity on HT-1080 (human fibrosarcoma) and MH-22A (mouse hepatocarcinoma) cell lines, as well as the estimated basal cytotoxicity. Additionally, it was demonstrated that the toxicity of the 4-(<i>N</i>-alkylpyridinium)-1,4-DHP derivatives on the Gram-positive and Gram-negative bacteria species and eukaryotic microorganism depended on the presence of the alkyl chain length at the <i>N</i>-alkyl pyridinium moiety, as well as the number of propargyl groups. These lipid-like compounds may be proposed for the further development of drug formulations to be used in cancer treatment.