Practical Synthesis of 6-Amino-1-hydroxy-2,1-benzoxaborolane: A Key Intermediate of DNDI-6148.

Visceral leishmaniasis (VL), a parasitic, poverty-linked, neglected disease, is endemic across multiple regions of the world and fatal if untreated. There is an urgent need for a better and more affordable treatment for VL. DNDI-6148 is a promising drug candidate being evaluated for the treatment of VL; however, the current process for producing the key intermediate of DNDI-6148, 6-amino-1-hydroxy-2,1-benzoxaborolane, is expensive and difficult to scale up. Herein, we describe two practical approaches to synthesizing 6-amino-1-hydroxy-2,1-benzoxaborolane from inexpensive and readily available raw materials. Starting with 4-tolunitrile, the first approach is a five-step sequence involving a Hofmann rearrangement, resulting in an overall yield of 40%. The second approach utilizes 2-methyl-5-nitroaniline as the starting material and features borylation of aniline and continuous flow hydrogenation as the key steps, with an overall yield of 46%. Both routes bypass the nitration of 1-hydroxy-2,1-benzoxaborolane, which is challenging and expensive to scale. In particular, the second approach is more practical and scalable because of the mild operating conditions and facile isolation process.

Metalloradical activation of carbonyl azides for enantioselective radical aziridination.

Organic azides have been increasingly employed as nitrogen sources for catalytic olefine aziridination due to their ease of preparation and generation of benign N2 as the only byproduct. Among common organic azides, carbonyl azides have not been previously demonstrated as effective nitrogen sources for intermolecular olefin aziridination despite the synthetic utilities of N-carbonyl aziridines. As a new application of metalloradical catalysis, we have developed a catalytic system that can effectively employ the carbonyl azide TrocN3 for highly asymmetric aziridination of alkenes at room temperature. The resulting enantioenriched N-Trocaziridines have been shown as valuable chiral synthons for stereoselective synthesis of other chiral aziridines and various chiral amines. The Co(II)-based metalloradical system, which proceeds with distinctive stepwise radical mechanism, may provide a general method for asymmetric synthesis of chiral aziridines from alkenes with organic azides.

Enantioselective Intermolecular Radical C-H Amination.

Radical reactions hold a number of inherent advantages in organic synthesis that may potentially impact the planning and practice for construction of organic molecules. However, the control of enantioselectivity in radical processes remains one of the longstanding challenges. While significant advances have recently been achieved in intramolecular radical reactions, the governing of asymmetric induction in intermolecular radical reactions still poses challenging issues. We herein report a catalytic approach that is highly effective for controlling enantioselectivity as well as reactivity of the intermolecular radical C-H amination of carboxylic acid esters with organic azides via Co(II)-based metalloradical catalysis (MRC). The key to the success lies in the catalyst development to maximize noncovalent attractive interactions through fine-tuning of the remote substituents of the D2-symmetric chiral amidoporphyrin ligand. This noncovalent interaction strategy presents a solution that may be generally applicable in controlling reactivity and enantioselectivity in intermolecular radical reactions. The Co(II)-catalyzed intermolecular C-H amination, which operates under mild conditions with the C-H substrate as the limiting reagent, exhibits a broad substrate scope with high chemoselectivity, providing effective access to valuable chiral amino acid derivatives with high enantioselectivities. Systematic mechanistic studies shed light into the working details of the underlying stepwise radical pathway for the Co(II)-based C-H amination.

Room Temperature Activation of Aryloxysulfonyl Azides by [Co(II)(TPP)] for Selective Radical Aziridination of Alkenes via Metalloradical Catalysis.

Aryloxysulfonyl azides can be effectively activated by commercially available cobalt(II) complex of meso-tetraphenylporphyrin ([Co(TPP)]) at room temperature under neutral and nonoxidative conditions for selective radical aziridination of alkenes via metalloradical catalysis. The [Co(TPP)]-catalyzed radical aziridination system is suitable for different combinations of olefin substrates and aryloxysulfonyl azides, producing various N-aryloxysulfonyl aziridine derivatives in good to excellent yields. In addition to generating the environmentally benign N2 as the only byproduct, this Co(II)-based metalloradical aziridination process features mild reaction conditions and operational simplicity.

Stereoselective Radical C-H Alkylation with Acceptor/Acceptor-Substituted Diazo Reagents via Co(II)-Based Metalloradical Catalysis.

Co(II)-based metalloradical catalysis has been, for the first time, successfully applied for asymmetric intramolecular C-H alkylation of acceptor/acceptor-substituted diazo reagents. Through the design and synthesis of a new D2-symmetric chiral amidoporphyrin as the supporting ligand, the Co(II)-based metalloradical system, which operates at room temperature, is capable of 1,5-C-H alkylation of α-methoxycarbonyl-α-diazosulfones with a broad range of electronic properties, providing the 5-membered sulfolane derivatives in high yields with excellent diastereoselectivity and enantioselectivity. In addition to complete chemoselectivity toward allylic and allenic C-H bonds, the Co(II)-based metalloradical catalysis for asymmetric C-H alkylation features a remarkable degree of functional group tolerance.

Synthesis of chiral N-phosphoryl aziridines through enantioselective aziridination of alkenes with phosphoryl azide via Co(II)-based metalloradical catalysis.

The Co(II) complex of a new D 2-symmetric chiral porphyrin 3,5-DiMes-QingPhyrin, [Co(P6)], can catalyze asymmetric aziridination of alkenes with bis(2,2,2-trichloroethyl)phosphoryl azide (TcepN3) as a nitrene source. This new Co(II)-based metalloradical aziridination is suitable for different aromatic olefins, producing the corresponding N-phosphorylaziridines in good to excellent yields (up to 99%) with moderate to high enantioselectivities (up to 85% ee). In addition to mild reaction conditions and generation of N2 as the only byproduct, this new metalloradical catalytic system is highlighted with a practical protocol that operates under neutral and non-oxidative conditions.

Selective Radical Amination of Aldehydic C(sp2)-H Bonds with Fluoroaryl Azides via Co(II)-Based Metalloradical Catalysis: Synthesis of N-Fluoroaryl Amides from Aldehydes under Neutral and Nonoxidative Conditions.

The Co(II) complex of the D2h-symmetric amidoporphyrin 3,5-Di t Bu-IbuPhyrin, [Co(P1)], has proven to be an effective metalloradical catalyst for intermolecular amination of C(sp2)-H bonds of aldehydes with fluoroaryl azides. The [Co(P1)]-catalyzed process can employ aldehydes as the limiting reagents and operate under neutral and non-oxidative conditions, generating nitrogen gas as the only byproduct. The metalloradical aldehydic C-H amination is suitable for different combinations of aldehydes and fluoroaryl azides, producing the corresponding N-fluoroaryl amides in good to excellent yields. A series of mechanistic studies support a stepwise radical mechanism for the Co(II)-catalyzed intermolecular C-H amination.

Thermal processing as a means to prepare durable, submicron thickness ionomer films for study by transmission infrared spectroscopy.

A high temperature solution processing method was adapted to prepare durable, freestanding, submicrometer thickness films for transmission infrared spectroscopy studies of ionomer membrane. The materials retain structural integrity following cleaning and ion-exchange steps in boiling solutions, similar to a commercial fuel cell membrane. Unlike commercial membrane, which typically has thicknesses of >25 µm, the structural properties of the submicrometer thickness materials can be probed in mid-infrared spectral measurements with the use of transmission sampling. Relative to the infrared attenuated total reflection (ATR) technique, transmission measurements can sample ionomer membrane materials more uniformly and suffer less distortion from optical effects. Spectra are reported for thermally processed Nafion and related perfluoroalkyl ionomer materials containing phosphonate and phosphinate moieties substituted for the sulfonate end group on the side chain. Band assignments for complex or unexpected features are aided by density functional theory (DFT) calculations.

Synthesis of novel thermally reversible photochromic axially chiral spirooxazines.

The Suzuki reactions of diboronic acid 1 and bromo-spirooxazine 2, under N(2) atmosphere and aerobic conditions, gave the dispirooxazine-substituted binaphthyl product 3 and the monospirooxazine-substituted binaphthyl derivative 4, respectively. The thermally reversible photochromic behavior of the target axially chiral spirooxazines 3 was investigated, and both the ring-opening process upon irradiation with 365 nm light and the thermally reverse ring-closing process were fast. These chiral spirooxazines were found to impart their chirality to an achiral liquid crystal host, at low doping levels, to form a self-organized photoresponsive helical superstructure.

Self-assembly and liquid-crystalline properties of 5-fluoroalkylporphyrins.

We report three crystal structures of a synthetic 5-fluoroalkylporphyrin molecule that was programmed for self-assembly. All the X-ray structures of zincated and free-base porphyrins Zn2 b, Zn5 a, and 2 b revealed rigorous pi-pi stacking and extremely hydrophobic interactions. Other the other hand, the strong aggregation of 5-fluoroalkylporphyrins in solution was also found. Interestingly, the regular nanopore formation of the 5-fluoroalkylporphyrin was visualized by atomic force microscopy (AFM). Importantly, the 5-fluoroalkylporphyrins possess liquid-crystalline properties that were confirmed by using a combination of differential scanning calorimetry (DSC) and polarizing optical microscopy (POM) techniques. By comparison, the self-assembly of non-fluorine-containing porphyrins with similar structure showed much lower aggregation ability, as investigated by NMR techniques. Additionally, no birefringent mesophase was observed for the non-fluorine-containing porphyrin.

Reactions of fullerenes with reactive methylene organophosphorus reagents: efficient synthesis of organophosphorus group substituted C60 and C70 derivatives.

Treatment of C70 with cycloalkylaminomethylenebisphosphonates in the presence of NaH gave corresponding C70 dimers 1 in good yield, while the methanofullerenes, C70>CH(PO3Et2) (3) and C70>C(PO3Et2)2 (4) or C60>CH(PO3Et2) (5) and C60>C(PO3Et2)2 (6), were obtained, respectively, by the reaction of C70 or C60 with tetraethyl methylenediphosphonate in the presence of NaH. Diethyl cyanomethylphosphonate reacted with C60 or C70 under similar conditions to afford C60>C(PO3Et2)CN (7) and C70>C(PO3Et2)CN (8). Furthermore, the presence of weak electronic interactions between two fullerene cages of fullerene dimers was demonstrated by cyclic voltammetry. A radical mechanism was proposed for the formation of the fullerene derivatives on the basis of the ESR studies.

Rational synthesis of meso- or beta- fluoroalkylporphyrin derivatives via halo-fluoroalkylporphyrin precursors: electronic and steric effects on regioselective electrophilic substitution in 5-fluoroalkyl-10,20-diarylporphyrins.

[reaction: see text] Electrophilic nitration, formylation or bromination of metalated 5-fluoroalkyl-10,20-diphenylporphyrin (fluoroalkyl = CF3, ClCF2CF2, n-C6F13) proceeded with high regioselectivity, exclusively affording corresponding meso-substituted porphyrins, while the iodination reaction mainly took place at the adjacent beta site giving 2-iodo-10-fluoroalkyl-5,15-diphenylporphyrin. Suzuki, Sonogashira, and trifluoromethylation reactions of the obtained 5-bromo-15-fluoroalkyl-10,20-diphenylporphyrins or 2-iodo-10-fluoroalkyl-5,15-diphenylporphyrins could perform smoothly to give the corresponding various meso- or beta-functionalized fluoroalkylated porphyrin derivatives. Accordingly, two meso-to-meso butadiyne-bridged bisporphyrin dimers and two beta-to-beta butadiyne-linked dimeric porphyrins were prepared by the coupling reactions of 5-ethynyl-15-fluoroalkyl-10,20-diphenylporphyrins and 2-ethynyl-10-fluoroalkyl-5,15-diphenylporphyrins, respectively.

Facile and potent synthesis of carbon bridged fullerene dimers (HC60-CR2-C60H type).

Novel carbon bridged fullerene dimers (HC60-CR2-C60H type) are obtained in high yield by the reaction of aminomethylenebis(phosphonate) anions with [60]fullerene.

Fluoroalkylation of porphyrins: synthesis and reactions of beta-fluoroalkyltetraarylporphyrins.

Treatment of 5,10,15,20-tetraarylporphyrins (1) with perfluoroalkyl iodides (2) in the presence of Na(2)S(2)O(4)/NaHCO(3) in DMSO-CH(2)Cl(2) at 30-40 degrees C for several hours gives the corresponding 2-perfluoroalkylporphyrins (3). Nucleophilic attack on 3 with dimethyl malonate, diethyl malonate, malonitrile, or cyano acetate (Nu) anion results in the formation of (E)-3-Nu-2-perfuoroalkyl(methylenyl)chlorins. Electrophilic substitution on 3 with NBS or NO(2) affords regioselectively the corresponding 12(or 13)-bromo- and 12,13-dibromo- or nitroporphyrins.