ABSTRACT
5,10-Dihydroindeno[1,2-b]indole has served as an important starting precursor for BARAC-fluor reagent in medicinal chemistry. Herein, an unprecedented p-TsOH assisted intramolecular C2-arylation of NH-indoles via C(sp2)-CN/C(sp2)-H coupling, offering a series of 5,10-dihydroindeno[1,2-b]indoles with moderate to good yields, has been showcased under redox-neutral conditions. Furthermore, successful scalability and synthetic applications highlight the practical nature of the method.
ABSTRACT
An anion-relay double aza-Michael-Michael addition strategy has been reported for the synthesis of intricate scaffolds from enone-tethered cyclohexadienones and primary amines. This method discloses the base-catalyzed synthesis of highly valued bridged aza-tricyclic frameworks with a high level of product selectivity and stereoselectivity. Gram scale synthesis and synthetic transformation were shown to afford structurally diverse bridged aza-polycyclic amines. Control experiments and the kinetic profile were studied to determine a plausible reaction mechanism.
ABSTRACT
By tapping into the divergent reactivity of diazocarboxylates under thermal and photocatalytic conditions, we could develop chemodivergent phosphonylation protocols for α-diazocarboxylates with trialkyl phosphites. While the thermal reaction led to N-P bond formation affording phosphonylated hydrazones, the visible light-mediated reaction furnished phosphonylated aryl carboxylates through C-P bond formation. Both reactions are notable for their operational simplicity and mild conditions affording products in good yields without the requirement of a metal, base or photocatalyst.
ABSTRACT
The hydrogen bonding interaction between an amide N-H and the amide N of the preceding residue is prevalent in proline-containing proteins and peptides. However, the N-Hâ â â N hydrogen bonding interaction is rare in non-prolyl natural peptides due to restricted dihedral angles. Herein, we stabilize this type of interaction in 8-aminoquinoline appended non-prolyl peptides through bifurcated Nâ â â Hâ â â N hydrogen bond. The 8-aminoquinoline-incorporated model peptides 2 a-i were designed, synthesized, and the crystal structures of 2 a-c and 2 i were solved. Analysis of crystal data reveals that the amide N-H of aminoquinoline is involved in bifurcated hydrogen bonding interaction with the nitrogen of the preceding amino acid residue and the nitrogen in quinoline. Analysis of crystal packing, Hirshfeld surface and fingerprint plots confirms that the intermolecular Oâ â â H contacts significantly contribute to stabilizing bifurcated Nâ â â Hâ â â N hydrogen bonding interaction. Furthermore, NMR experiments and CD spectroscopy were conducted to examine the preferred conformation in solution, and the data corroborate with the crystal structure conformation.
Subject(s)
Aminoquinolines , Hydrogen Bonding , Peptides , Peptides/chemistry , Peptides/chemical synthesis , Aminoquinolines/chemistry , Aminoquinolines/chemical synthesis , Crystallography, X-Ray , Models, MolecularABSTRACT
Herein, a one-pot desulfonylative protocol enabled by copper(II)/zinc(II) salts to access pyrrolo[2,3-b]quinolines in good to excellent yields from 2-carbonylanilines and ynamide-derived buta-1,3-diynes has been reported. Significantly, various 2-carbonylanilines carrying reactive functional groups are well tolerated. Moreover, a gram-scale synthesis and synthetic application highlight the practical utility of the current protocol. Notably, the fluorescence properties of pyrrolo[2,3-b]quinolines have been recorded, and their potential use as a fluorescent probe in the imaging of live cells has been demonstrated.
ABSTRACT
We have developed the first I2/base-catalyzed regio- and stereoselective intermolecular ß-amidosulfonylation of terminal alkynes using sodium sulfinates and quinoxalinone derivatives. The present methodology is compatible with a broad spectrum of various heterocyclic amides, terminal alkynes, and sodium sulfinates. It provides rapid access to valuable (Z)-ß-amidovinyl sulfones at mild conditions. Moreover, the synthetic application of this methodology was demonstrated by the late-stage functionalization of numerous bioactive molecules.
ABSTRACT
An efficient method for the stereoselective synthesis of "all center substituted" polycyclic pyrazoles from alkynyl cyclohexa-2,5-dienones and nonstabilized diazoalkanes via sequential [3 + 2]-cycloaddition/[1,5]-sigmatropic rearrangement and aza-Michael reactions is reported. The developed process is highly regioselective and stereoselective. It employs a wide substrate scope to furnish structurally diverse linear and bridged [4.4.n.0] ring-fused pyrazoles in moderate to good yields. One-pot and gram-scale syntheses and synthetic transformations have also been showcased.
ABSTRACT
A straightforward and atom-economical one-pot protocol catalyzed by gold(I) and zinc(II) for the synthesis of amine-substituted diaryl[c,h][1,6]naphthyridines from two different aromatic nitriles has been showcased. This dual-catalytic strategy is highly efficient, offering an array of tetracyclic heteroaromatic products in good to excellent yields. Furthermore, the base can efficiently catalyze the second annulation step, yielding structurally unique thiophene-fused [1,6]naphthyridines in good yields.
ABSTRACT
A palladium(II)-catalyzed regio- and stereoselective difunctionalization of alkynoic acids has been achieved using sodium sulfinates and isocyanides to synthesize (E)-ß-sulfonylacrylamides. The reaction proceeds via decarboxylative isocyanide addition, followed by sulfonylation. This three-component process works well with aromatic, heteroaromatic, and aliphatic alkynoic acids with good functional group tolerance and excellent regio- and stereoselectivity. DFT calculations were carried out to explain the reaction mechanism and the stereoselective formation of (E)-ß-sulfonylacrylamides.
ABSTRACT
The first multicomponent regio- and stereoselective difunctionalization of alkynes via concomitant C-O and C-S bond formation using 1,3-diketones and sodium sulfinate has been developed for the synthesis of various sulfonated enethers. The viability of this strategy is unveiled by gram-scale, various synthetic modifications and late-stage functionalization. This transformation does not require any prefunctionalization, metal catalysts, and oxidants. The present operationally simple, efficient, and sustainable approach provides various functionalized olefins in a one-pot protocol with high Z-selectivity.
ABSTRACT
A robust synthesis of phenanthridines has been described via Pd(II)-catalyzed domino C(sp2)-H activation/N-arylation using oxime esters with aryl acyl peroxides in a highly regioselective manner. This protocol is compatible with acetophenone as well as benzophenone-derived oxime esters and allows modular construction of functionalized phenanthridines with wide tolerance of electronic functionality. Further transformations were conducted to synthesize key building blocks, and control experiments were performed to understand the plausible reaction mechanism.
ABSTRACT
Herein, we present a Zn(II)-catalyzed (3 + 3) heteroannulation reaction between aromatic amines and 1,3-diynamides for the synthesis of amidoquinolines. A large number of aromatic amines are well tolerated, furnishing quinoline derivatives in up to excellent yield. Notably, various reactive functional groups have survived under the optimal reaction conditions, highlighting the mildness of the developed protocol. In addition, amines derived from bioactive molecules show modest reactivity.
ABSTRACT
Herein, a catalytic synthetic transformation offering a series of -NH2 group-bearing aminoisoquinolines with moderate to good yields has been showcased. Interestingly, the nitrogen atom of the isoquinoline ring is coming from the reaction medium upon metal-assisted C≡N bond cleavage. Moreover, this (5+1) annulation reaction shows broad substrate variation. Furthermore, the derivatization of the isoquinoline core via functional group interconversions and mechanistic studies to identify the reaction intermediate have been carried out successfully.
Subject(s)
Isoquinolines , Nitrogen , CatalysisABSTRACT
The current regime for leishmaniasis is associated with several adverse effects, expensive, parenteral treatment for longer periods and the emergence of drug resistance. To develop affordable and potent antileishmanial agents, a series of N-acyl and homodimeric aryl piperazines were synthesized with high purity, predicted druggable properties by in silico methods and investigated their antileishmanial activity. The in vitro biological activity of synthesized compounds against clinically validated intracellular amastigote and extracellular promastigote form of Leishmania donovani parasite showed eight compounds inhibited 50% amastigotes growth below 25 µM. The half maximal inhibitory concentration (IC50) and cytotoxicity assessment of eight active compounds, 4a, 4d and 4e demonstrated activity with an IC50 2.0 - 9.1 µM and selectivity index 10 - 42. Compound 4d (IC50 2.0 µM, SI = 42) found to be the best among them with four-folds more potent and eight-folds less toxic than the control drug miltefosine. Overall, results demonstrated that compound 4d is a promising lead candidate for further development as antileishmanial drug.
Subject(s)
Antiprotozoal Agents , Leishmania donovani , Leishmaniasis , Humans , Leishmaniasis/drug therapyABSTRACT
The difficulty in isolating cyclic enamines emanating from their intrinsic instability has impeded their exploration in cycloaddition reactions. Here, we achieved a metal-free domino reaction providing quinoline and isoquinoline-derived cyclic amidines by the cycloaddition of azides with in situ generated enamines via dearomatization.
ABSTRACT
A catalyst-controlled divergent synthesis of bridged [3.3.1] bis(indolyl)-oxanes and cis-[6.7] fused bis(indolyl) oxepanes via diastereoselective desymmetrization of bis(indolyl)-cyclohexadienones is presented for the first time. The reaction is highly atom- and step-economic, furnishing sp3-rich functionalized bis(indolyl) derivatives in good to excellent yields with wide substrate scope. The reaction proceeds through Friedel-Crafts alkylation followed by catalyst-controlled selective C-C bond formation/rearrangement. Gram scale synthesis and synthetic utility to generate bis(indolyl) alkaloid-like molecular diversity were also illustrated.
ABSTRACT
Herein, we disclose the first report on the generation of cyanonitrone in situ from diazoacetonitrile and nitrosoarene, and its subsequent [3+2] cycloaddition with oxabicyclic alkenes to access fused tricyclic cyanoisoxazolidines. Further, this methodology could be extended to access fused tricyclic trifluoromethylated and phosphonylated isoxazolidines. Surprisingly, the reductive ring-opening of cyanoisoxazolidines was followed by a spontaneous lactonization to produce fused tricyclic amino lactones. Moreover, the N-O bond of the obtained tricyclic trifluoromethylated isoxazolidines could be cleaved to obtain 1,3-amino alcohols.
Subject(s)
Alkenes , Amino Alcohols , Cyclization , Alkenes/chemistry , Lactones/chemistry , Cycloaddition ReactionABSTRACT
An efficient method for the construction of hydrocarbazoles bearing three continuous sterically hindered stereocenters, two quaternary and one tertiary, via a highly diastereoselective palladium-catalyzed [4 + 2]-cycloaddition/dearomatization of 3-nitroindoles has been developed. The cycloaddition of 3-nitroindoles occurs at ambient conditions with a 1,4-zwitterionic intermediate, in situ generated from γ-methylidene-δ-valerolactones. The further synthetic utility of this method is demonstrated by the multifaceted transformations possible from the products. The catalytic asymmetric aspect of this transformation has also been explored.
Subject(s)
Palladium , Cycloaddition Reaction , Molecular Structure , Stereoisomerism , CatalysisABSTRACT
We report herein the first systematic crystal structural investigation of azaproline incorporated in homo- and heterochiral diprolyl peptides. The X-ray crystallography data of peptides 1-5 illustrates that stereodynamic nitrogen in azaproline adopted the stereochemistry of neighbouring proline residue without depending on its position in the peptide sequence. Natural bond orbital analysis of crystal structures indicates OazPro -C'Pro of peptides 4 and 5 participating in nâπ* interaction with stabilization energy about 1.21-1.33â kcal/mol. Density functional theory calculations suggested that the endo-proline ring puckering favoured over exo-conformation by 6.72-7.64â kcal/mol. NBO and DFT data reveals that the nâπ* interactions and proline ring puckering stabilize azaproline chirality with the neighbouring proline stereochemistry. The CD, solvent titration, variable-temperature and 2D NMR experimental results further supported the crystal structures conformation.
Subject(s)
Nitrogen , Proline , Protein Conformation , Proline/chemistry , Peptides/chemistry , Magnetic Resonance SpectroscopyABSTRACT
An interesting substrate-controlled reactivity switch has been observed in the reaction of α-fluoro-ß-ketoamides with arynes. The reaction of secondary α-fluoro-ß-ketoamides with arynes provided access to α-aryl-α-fluoroacetamides through an arylation/deacylation sequence. Interestingly, the reaction of tertiary α-fluoro-ß-ketoamides resulted in the C-C σ-bond insertion reaction to afford 1,2-disubstituted arenes.