Synthesis of classical and nonclassical 2‐amino‐4‐oxo‐6‐benzylthieno‐[2,3‐d]pyrimidines as potential thymidylate synthase inhibitors

A series of seven nonclassical 2‐amino‐4‐oxo‐6‐substituted thieno[2,3‐d]pyrimidines 2‐8 and one classical N‐[4‐(2‐amino‐4‐oxo‐3,4‐dihydrothieno[2,3‐d]pyrimidin‐6‐ylmethyl)benzoyl]‐L‐glutamic acid 9 (Table I) were designed as the first in a series of 6‐substituted 6‐5 fused ring analogs as potential thymidylate synthase (TS) inhibitors and as antitumor agents. The target compounds were synthesized via a Heck coupling of appropriately substituted iodobenzenes and allyl alcohol followed by cyclization using cyanoacetate and sulfur powder to afford substituted thiophenes. The resulting thiophenes were then cyclocondensed with chloroformamidine hydrochloride to afford 2‐amino‐4‐oxo‐6‐substituted thieno[2,3‐d]pyrimidines 2‐8 and 26 . Hydrolysis of 26 followed by coupling with diethyl L‐glutamate afforded 28 . The classical analog 9 was obtained by hydrolysis of 28 . None of the target compounds inhibited human recombinant thymidylate synthase at 23 μm except 9 for which the IC₅₀ value was 100 μm.     

Copper(II)‐Catalyzed Synthesis of N‐Substituted‐3‐amino‐4‐cyano‐isoquinoline‐1(2H)‐ones by the Reaction of N‐Substituted‐2‐iodobenzamides with Malononitrile

A novel Cu(OAc)₂·H₂O catalyzed coupling reaction of N‐substituted‐2‐iodobenzamides with malononitrile to afford N‐substituted‐3‐amino‐4‐cyano‐isoquinoline‐1(2H)‐ones is described. The reaction proceeded in DMSO at 90°C for 5 h in nitrogen without external ligands.     

Copper‐Catalyzed Cascade Cyclization Reaction of 2‐Haloaryltriazenes and Sodium Azide: Selective Synthesis of 2 H‐Benzotriazoles in Water

A new approach to the synthesis of 2 H‐benzotriazoles is described. This strategy is based on the copper‐catalyzed C?N coupling of 2‐haloaryltriazenes or 2‐haloazo compounds with sodium azide and the intramolecular addition of nitrene to N?N bonds. This approach allows the synthesis of various N‐amino‐ and N‐aryl‐2 H‐benzotriazoles in water, in good to excellent yields. The procedure is simple and the starting materials and catalyst are easily available, offering a practical and convenient synthetic route to 2‐substituted benzotriazoles.     

Synthesis and stereochemical studies of 2‐substituted thiazolidine‐4‐carboxamide derivatives

A series of new 2‐substituted thiazolidine‐4‐carboxamide derivatives which have potentially useful immunological properties, have been synthesized in a stereoselective manner by coupling 2‐subsituted thiazolidine‐4‐carboxylic acids with amines or amino esters. The structure of these compounds was established by combination of NMR methods and by X‐ray analysis.     

tBuLi‐Mediated One‐Pot Direct Highly Selective Cross‐Coupling of Two Distinct Aryl Bromides

A Pd‐catalyzed direct cross‐coupling of two distinct aryl bromides mediated by tBuLi is described. The use of [Pd‐PEPPSI‐IPr] or [Pd‐PEPPSI‐IPent] as catalyst allows for the efficient one‐pot synthesis of unsymmetrical biaryls at room temperature. The key for this selective cross‐coupling is the use of an ortho‐substituted bromide that undergoes lithium–halogen exchange preferentially.     

Selective 1,2‐Aryl‐Aminoalkylation of Alkenes Enabled by Metallaphotoredox Catalysis

A highly chemo‐ and regioselective intermolecular 1,2‐aryl‐aminoalkylation of alkenes by photoredox/nickel dual catalysis is described here. This three‐component conjunctive cross‐coupling is highlighted by its first application of primary alkyl radicals, which were not compatible in previous reports. The readily prepared α‐silyl amines could be transferred to α‐amino radicals by photo‐induced single electron transfer step. The radical addition/cross‐coupling cascade reaction proceeds under mild, base‐free and redox‐neutral conditions with good functional group tolerance, and importantly, provides an efficient and concise method for the synthesis of structurally valuable α‐aryl substituted γ‐amino acid derivatives motifs.     

A Cascade Synthesis of Aminohydantoins Using In Situ‐Generated N‐Substituted Isocyanates

Nitrogen‐substituted isocyanates are rarely utilized but powerful building blocks for the development of cascade reactions in heterocyclic synthesis. These reactive amphoteric intermediates can be accessed in situ via an equilibrium that allows controlled reactivity in the presence of bifunctional partners such as α‐amino esters. A cascade reaction has been carried out that forms 3‐aminohydantoin derivatives using simple phenoxycarbonyl derivatives of hydrazides and hydrazones as precursors of N‐substituted‐isocyanates. This method allows rapid assembly of complex aminohydantoin derivatives, including analogues of medicinally‐relevant compounds, using simple reactants.     

Sulfoxide‐Directed Metal‐Free ortho‐Propargylation of Aromatics and Heteroaromatics

A sulfoxide‐directed, metal‐free ortho‐propargylation of aromatics and heteroaromatics exploits intermolecular delivery of a propargyl nucleophile to sulfur followed by an intramolecular relay to carbon. The operationally simple cross‐coupling procedure is general, regiospecific with regard to the propargyl nucleophile, and shows complete selectivity for products of ortho‐propargylation over allenylation. The use of secondary propargyl silanes allows metal‐free ortho‐coupling to form carbon–carbon bonds between aromatic and heteroaromatic rings and secondary propargylic centres. The ‘safety‐catch’ nature of the sulfoxide directing group is illustrated in a selective, iterative double cross‐coupling process. The products of propargylation are versatile intermediates and they have been readily converted into substituted benzothiophenes.     

Palladium‐Catalyzed One‐Pot Three‐ or Four‐Component Coupling of Aryl Iodides,Alkynes, and Amines through CN Bond Cleavage: Efficient Synthesis of Indole Derivatives

An efficient synthesis of N‐substituted indole derivatives was realized by combining the Pd‐catalyzed one‐pot multicomponent coupling approach with cleavage of the C(sp³)?N bonds. Three or four components of aryl iodides, alkynes, and amines were involved in this coupling process. The cyclopentadiene–phosphine ligand showed high efficiency. A variety of aryl iodides, including cyclic and acyclic tertiary amino aryl iodides, and substituted 1‐bromo‐2‐iodobenzene derivatives could be used. Both symmetric and unsymmetric alkynes substituted with alkyl, aryl, or trimethylsilyl groups could be applied. Cyclic secondary amines such as piperidine, morpholine, 4‐methylpiperidine, 1‐methylpiperazine, 2‐methylpiperidine, and acyclic amines including secondary and primary amines all showed good reactivity. Further application of the resulting indole derivatives was demonstrated by the synthesis of benzosilolo[2,3‐b]indole.     

金催化的炔烃羟基化反应: 合成2取代苯并呋喃化合物

本文报道了一种以邻炔基苯酚为原料,通过金催化的炔烃羟基化反应合成2取代苯并呋喃的方法. 该方法可以在温和的条件下快速以高产率得到各种2取代苯并呋喃. 关键前体邻炔基苯酚可以很容易由Sonogashira 反应制备.     

Synthesis of N‐Substituted Condensed Tetrahydropyridine‐Based Enaminones via Palladium‐Catalyzed Intramolecular C–N Cross‐coupling

A number of β‐enaminones with secondary amino group (alkyl, cyclopropyl, and aryl) were prepared from corresponding β‐diketones. Two general protocols for their palladium‐catalyzed intramolecular C–N cross‐coupling were established to give corresponding N‐substituted condensed tetrahydropyridines in good yields. The methodology is applicable for a wide variety of structural motifs. The work also extends the applicability of novel, recently established, palladium precatalysts to new substrates.     

Copper‐Catalyzed Cross‐Coupling of Boronic Esters with Aryl Iodides and Application to the Carboboration of Alkynes and Allenes

Copper‐catalyzed Suzuki–Miyaura‐type cross‐coupling and carboboration processes are reported. The cross‐couplings function well with a variety of substituted aryl iodides and aryl boronic esters and allows for orthogonal reactivity compared to palladium‐catalyzed processes. The carboboration method includes both alkynes and allenes and provides access to highly substituted and stereodefined vinyl boronic esters. The alkyne carboboration method is highlighted in the simple one‐pot synthesis of Tamoxifen.     

Copper‐Mediated ortho‐Nitration of (Hetero)Arenecarboxylates

Various (hetero)arenecarboxylic acids were converted to the corresponding Daugulis amides and nitrated selectively in the ortho‐position in the presence of [CuNO₃(PPh₃)₂] and AgNO₂ at 50 °C. A microwave‐assisted saponification allows regenerating the carboxylate group within minutes, which may then be removed tracelessly by protodecarboxylation, or substituted by aryl‐ or alkoxy‐groups via decarboxylative cross‐coupling.     

A Novel Iron‐catalyzed One‐pot Synthesis of 3‐Amino‐1,2,4‐triazoles

A novel one‐pot synthesis of 3‐amino‐1,2,4‐triazole developed via iron (III) catalyzed route is reported. The new method is more efficient, simple, and convenient and presents a concise new strategy for the synthesis of 3‐amino‐1,2,4‐triazole derivatives. The iron (III) complex intermediate assisted in the intramolecular bond cyclization owing to its Lewis acidity or oxidizing properties. A series of aromatic nitriles bearing different electron‐donating and electron‐withdrawing groups substituted at para and/or ortho positions were also investigated. The position of the substituents affected the yield of the final compound, with the para‐substituted substrates giving relatively higher yields.     

A comparative study between para‐aminophenyl and ortho‐aminophenyl benzothiazoles using NMR and DFT calculations

Ortho‐substituted and para‐substituted aminophenyl benzothiazoles were synthesised and characterised using NMR spectroscopy. A comparison of the proton chemical shift values reveals significant differences in the observed chemical shift values for the NH protons indicating the presence of a hydrogen bond in all ortho‐substituted compounds as compared to the para compounds. The presence of intramolecular hydrogen bond in the ortho amino substituted aminophenyl benzothiazole forces the molecule to be planar which may be an additional advantage in developing these compounds as Alzheimer's imaging agent because the binding to amyloid fibrils prefers planar compounds. The splitting pattern of the methylene proton next to the amino group also showed significant coupling to the amino proton consistent with the notion of the existence of slow exchange and hydrogen bond in the ortho‐substituted compounds. This is further verified by density functional theory calculations which yielded a near planar low energy conformer for all the o‐aminophenyl benzothiazoles and displayed a hydrogen bond from the amine proton to the nitrogen of the thiazole ring. A detailed analysis of the ¹H, ¹³C and ¹⁵N NMR chemical shifts and density functional theory calculated structures of the compounds are described. Copyright © 2014 John Wiley & Sons, Ltd.     

Ruthenium‐Catalyzed C7 Amidation of Indoline CH Bonds with Sulfonyl Azides

A ruthenium‐catalyzed direct C7 amidation of indoline C?H bonds with sulfonyl azides was developed. This procedure allows the synthesis of a variety of 7‐amino‐substituted indolines, which are useful in pharmaceutical. The good functional tolerances, as well as the mild conditions, are prominent feature of this method.     

Microwave‐mediated synthesis and antibacterial activity of some novel 2‐(substituted biphenyl) benzimidazoles via Suzuki‐Miyaura cross coupling reaction and their N‐substituted derivatives

A series of some novel 2‐(substituted biphenyl) benzimidazoles and their N‐substituted derivatives were synthesized via microwave‐mediated Suzuki‐Miyaura coupling of 2‐(4‐iodophenyl)‐1H‐benzimidazole or 2‐(4‐iodophenyl)‐6‐amino‐1H‐benzimidazole and arylboronic acids. The method reported herein offers advantageous shorter reaction times, higher yields and is applicable to a large set of substrates. All the synthesized compounds were screened for their antibacterial activity against Staphylococcus aureus and Salmonella typhimurium bacterial species. J. Heterocyclic Chem., (2011).     

Protecting‐group‐free palladium‐catalyzed hydroxylation,C–O and C–N coupling of chiral 6‐bromo‐ and 6,6’‐dibromo‐ 1,1’‐binaphthols

A straightforward, protecting‐group‐free protocol for the synthesis of chiral 6‐substituted and 6,6’‐disubstituted binols (binol = 1,1’‐bi‐2‐naphthol) by palladium‐catalyzed hydroxylation, C–N and C–O coupling of chiral 6‐bromo‐ and 6,6’ ‐dibromo‐1,1’‐binaphthols is developed. The protecting group free palladium‐catalyzed hydroxylation, C–O and C–N cross‐coupling protocol affords a straightforward and general method for the synthesis of chiral 6‐substituted and 6,6’‐disubstituted binols with good yields, avoiding the tedious procedures of introduction and removal of protecting groups. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis of (+) or (-)-2-(8′-Diphenylphosphino-1′-naphthyl)oxazoline Ligands and Their Application in Pd-Catalyzed Allylic Alkylation Reaction

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Chemical Synthesis of Burkholderia Lipid A Modified with Glycosyl Phosphodiester‐Linked 4‐Amino‐4‐deoxy‐β‐L‐arabinose and Its Immunomodulatory Potential

Modification of the Lipid A phosphates by positively charged appendages is a part of the survival strategy of numerous opportunistic Gram‐negative bacteria. The phosphate groups of the cystic fibrosis adapted Burkholderia Lipid A are abundantly esterified by 4‐amino‐4‐deoxy‐β‐L ‐arabinose (β‐L ‐Ara4N), which imposes resistance to antibiotic treatment and contributes to bacterial virulence. To establish structural features accounting for the unique pro‐inflammatory activity of Burkholderia LPS we have synthesised Lipid A substituted by β‐L ‐Ara4N at the anomeric phosphate and its Ara4N‐free counterpart. The double glycosyl phosphodiester was assembled by triazolyl‐tris‐(pyrrolidinyl)phosphonium‐assisted coupling of the β‐L ‐Ara4N H‐phosphonate to α‐lactol of β(1→6) diglucosamine, pentaacylated with (R)‐(3)‐acyloxyacyl‐ and Alloc‐protected (R)‐(3)‐hydroxyacyl residues. The intermediate 1,1′‐glycosyl‐H‐phosphonate diester was oxidised in anhydrous conditions to provide, after total deprotection, β‐L ‐Ara4N‐substituted Burkholderia Lipid A. The β‐L ‐Ara4N modification significantly enhanced the pro‐inflammatory innate immune signaling of otherwise non‐endotoxic Burkholderia Lipid A.