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.     

Green synthesis of new pyrimido[4,5‐d]pyrimidine derivatives using 7‐aminonaphthalene‐1,3‐disulfonic acid‐functionalized magnetic Fe3O4@SiO2 nanoparticles as catalyst

We, herein, describe a novel, simple, efficient and one‐pot multi‐component procedure for the synthesis of substituted pyrimido[4,5‐d]pyrimidines via reaction of N,N‐dimethyl‐6‐amino uracil, isothiocyanate and aromatic aldehydes promoted by 7‐aminonaphthalene‐1,3‐disulfonic acid (ANDSA)‐functionalized magnetic Fe₃O₄@SiO₂ in water as solvent and without using any other harmful organic reagents. Compared with other reactions, using these organic–inorganic hybrid heterogeneous catalysts can help us to achieve a green procedure, high catalytic activity, easy recovery with an external magnetic field, and short reaction times.     

Synthesis and reactions of 6‐methylsulfanyl‐2,4‐dithioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐carbonitrile

The synthesis of 6‐methylsulfanyl‐2,4‐dithioxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carbonitrile 4 is described. Compound 4 was reacted with various alkylants. The reaction with chloroacetic acid derivatives results in the formation of thieno[2,3‐d]pyrimidines 8 . When methyl iodide was used 2,4,6‐tris(methylsul‐fanyl)pyrimidine‐5‐carbonitrile 5 was obtained. The substitution of the methylsulfanyl groups in compound 5 by several N‐nuclophiles leads to amino substituted pyrimidines.     

Synthesis of Functionalized o‐, m‐, and p‐Terphenyl Derivatives by Consecutive Cross‐Coupling Reactions of Triazene‐Substituted Arylboronic Esters

Triazene‐substituted arylboronic esters were prepared readily from the corresponding aryl magnesium derivatives and shown to function as a new class of donor–acceptor‐substituted coupling reagents. The selective functionalization of these aromatic derivatives led to a wide variety of terphenyl derivatives in which the original bifunctional unit (often further substituted with another functional group) formed the central aromatic ring. The functionalized terphenyl derivatives were formed in two efficient cross‐coupling steps from the triazene‐substituted boronic esters: Suzuki cross‐coupling with an aryl halide was followed by BF₃?OEt₂‐induced palladium‐catalyzed coupling of the diazonium salt generated in situ from the triazene with an arylboronic acid.     

Cyclization–oxidation of Benzylidenehydrazinecarbothioamides by FeCl3.6H2O or ZnCl2.6H2O Catalysts and Synthesis of New 1,3,4‐Thiadiazolo‐[3,2‐ α]Pyrimidines

We report new method for preparation of 2‐amino‐5‐aryl‐1,3,4‐thiadiazoles by reaction of arylaldehyde with thiosemicarbazide and in the next step via cyclization of 2‐aryl hydrazinecarbothioamide in the presence of ZnCl₂.6H₂O or FeCl₃.6H₂O. Also, in this research, new substituted 1,3,4‐thiadiazolo‐[3,2‐α]pyrimidines were synthesized by the reaction of 2‐amino‐5‐aryl‐1,3,4‐thiadiazoles derivatives with DMAD or DEAD in the presence of K₂CO₃ under reflux conditions. The FT‐IR, ¹H‐NMR, ¹³C‐NMR, elemental analysis and single‐ crystal X‐ray analysis confirm the structures of the products.     

Convenient and Efficient Synthesis of 11‐Amino‐2,8‐substituted‐2,3,8,9‐tetrahydrobenzo[4,5]thieno[2,3‐b]quinolinone Derivatives

The Gewald reactions of 5‐substituted‐1,3‐cyclohexanedione, malononitrile, and powdered sulfur were carried out to give the corresponding products 2‐amino‐5‐substituted‐7‐oxo‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carbonitrile derivatives 1 . The intermediate enamines 2 were prepared by reaction of compounds 1 and 5‐substituted‐1,3‐cyclohexanedione with hydrochloric acid as catalyst. The title compounds 11‐amino‐2,8‐substituted‐2,3,8,9‐tetrahydrobenzo[4,5]thieno[2,3‐b]quinolinone 3 were synthesized by cyclization of compounds 2 in the presence of K₂CO₃ and Cu₂Cl₂. The structures of all compounds were characterized by elemental analysis, IR, MS, and ¹H‐NMR spectra.     

Synthesis of three carbon atom bridged 2,4‐diaminopyrrolo[2,3‐d]‐pyrimidines as nonclassical dihydrofolate reductase inhibitors

A series of seven nonclassical three carbon atom bridged 2,4‐diamino‐5‐substituted‐pyrrolo[2,3‐d]‐pyrirnidines 1a‐g were synthesized as potential inhibitors of dihydrofolate reductase. Selective oxidation of diols 7a‐g affords α‐hydroxy ketones 8a‐g. Subsequent condensation with malononitrile gave the requisite 2‐amino‐3‐cyano‐4‐substituted furan precursors 9a‐g. Cyclocondensation with guanidine in refluxing ethanol in one step affords the three carbon atom bridged 2,4‐diamino‐5‐substituted‐pyrrolo[2,3‐d]‐pyrimidines 1a‐g. Preliminary biological results indicated that these compounds showed moderate inhibitory activities against dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium and rat liver with IC₅₀ values in the 0.66 μM ‐ 70.1 μM range and some compounds had marginal selectivity for T. gondii dihydrofolate reductase.     

Syntheses and properties of new herbicidal 2‐arylthio‐l,2,4‐triazolo [l,5‐a]pyrimidine derivatives

In search of novel herbicides with high activity, a series of 2‐arylthio‐1,4,2,‐triazolo[1,5‐a]pyrimidines (3) were synthesized by cyclization of 5‐amino‐3‐arylthio‐1,2,4‐triazoles with 1, 3‐diketones or by the nucleophilic substitution of substituted thiophenols with 2‐methylsulfonyl‐l,2,4‐triazolo [1,5‐a]‐pyrimidine. The structures of all compounds prepared were confirmed by ¹H NMR and MS spectroscopy along with elemental analyses. Preliminary bioassays indicated that some of the compounds 3 had good herbicidal activity against rape. In addition, the regioselectivity in the reaction of 5‐amino‐3‐substituted arylthio‐l,2,4‐triazoles with benzoylacetone was studied.     

Combination of Tetrabutylammonium Iodide (TBAI) with tert‐Butyl Hydroperoxide (TBHP): An Efficient Transition‐Metal‐Free System to Construct Various Chemical Bonds

In this account, we describe our recent progress on transition‐metal‐free‐catalyzed cross‐coupling reactions using tetrabutylammonium iodide (TBAI) as the catalyst and tert‐butyl hydroperoxide (TBHP) as the oxidant. A rich variety of important organic compounds including α‐acyloxy ethers, tert‐butyl peresters, allylic esters, amides, α‐amino nitriles, fully substituted pyrazoles, N‐sulfonyl formamidines, α‐amino acid esters, cyanomethyl esters, N‐nitrosamines, and 3‐acyloxy‐2,3‐dihydrobenzofurans have been successfully achieved in high chemoselectivity. Mechanistic studies suggested that TBAI could decompose TBHP to ^tBuO^. and ^tBuOO^. or be oxdized to (hypo)iodite by TBHP.     

C‐Selective and Diastereoselective Alkyl Addition to β,γ‐Alkynyl‐α‐imino Esters with Zinc(II)ate Complexes

Since umpolung α‐imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α‐amino acid derivatives. An unusual C‐alkyl addition to α‐imino esters using a Grignard reagent (RMgX)‐derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX]⁺ moiety, a nucleophilic [R₃Zn]^? moiety, and 2 [MgX₂]. Therefore, the ionically separated [R₃Zn]^? selectively attacks the imino carbon atom ,which is most strongly activated by chelation of [MgX]⁺. In particular, chiral β,γ‐alkynyl‐α‐imino esters can strongly promote highly regio‐ and diastereoselective C‐alkylation because of structural considerations, and the corresponding optically active α‐quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.     

A novel route to 4‐oxy/thio substituted‐1H‐pyrazol‐5(4H)‐ones via efficient cross‐Claisen condensation

α‐Oxy/thio substituted β‐keto esters were synthesized through an efficient cross‐Claisen condensation of oxy/thio substituted acetic acid ethyl esters with acid chlorides, which in turn converted in situ into 4‐oxy/thio substituted‐1H‐pyrazol‐5(4H)‐ones by the addition of hydrazine and its derivatives. This method has been found to be extremely fast, general, and useful toward the synthesis of inaccessible pyrazolones and synthetically demanding 4‐oxy/thio substituted pyrazolones. J. Heterocyclic Chem., (2011).     

Ag Loaded on SiO2 as an Efficient and Recyclable Heterogeneous Catalyst for the Synthesis of Chloro‐8‐substituted‐9H‐purines

Ag support on silica has been used as an effective heterogeneous catalyst for the facile synthesis of chloro‐8‐substituted‐9H‐purine derivatives via the one‐pot reaction of 6‐chloro‐pyrimidines and substituted acids. The title compounds were formed as excellent yields with short reaction time under eco‐friendly conditions. The prepared catalyst (Ag/SiO₂) can be reused for a number of times with insignificant loss in its activity. This route has the advantage of being a cost‐effective, readily available, easy workup procedure.     

Synthesis of Pyrrolo[2,3‐d]pyrimidines by Copper‐Mediated Carbomagnesiations of N‐Sulfonyl Ynamides and Application to the Preparation of Rigidin A and a 7‐Azaserotonin Derivative

The treatment of readily available N‐alkynyl‐5‐iodo‐6‐sulfamido‐pyrimidines with iPrMgCl?LiCl followed by a transmetalation with CuCN?2 LiCl produces, after intramolecular carbocupration, metalated py r rolo[2,3‐d]pyrimidines. Quenching of these pyrimidines with allylic halides or acid chlorides results in polyfunctional pyrrolo[2,3‐d]pyrimidines. Further reaction with ICl and a Negishi cross‐coupling, using PEPPSI‐iPr as the catalyst, furnishes fully substituted N‐heterocycles. A formal synthesis of the marine alkaloid rigidin A has been achieved as well as the preparation of a derivative of 7‐azaserotonine, related to the natural hormone serotonin.     

1,3‐Dihydro‐2H‐imidazo[4,5‐c]pyridin‐2‐one

A facile acid catalysed cyclisation method for the preparation of the cyclic urea 2H‐imidazo[4,5‐c]pyridin‐2‐one ( 2 ) in > 95 % yield is reported. The biologically active compound 2 can be obtained by heating (3‐amino‐4‐pyridinyl)‐carbamic acid methyl, ethyl or tert‐butyl esters ( 1a‐c ) in sulfuric acid (0.1 %) or in aqueous HBF₄ (3.5 equivalents) for 10 min. ‐ 3 hrs at 90 °C. The corresponding microwave‐promoted (MW) reactions afforded the pure product 2 within few minutes. The 6‐butylamino‐substituted analogue ( 2a ) was correspondingly obtained by MW irradiation in 99 % yield by cyclisation of 2‐(butylamino)‐5‐amino‐4‐pyridylcarbamic acid isopropyl ester ( 1d ). Quantitative precipitation of product 2 was obtained by pH adjustment. The process represents a solvent‐free, “green” method for the preparation of 2 .     

Synthesis and Characterization of 11‐Amino‐3‐methoxy‐8‐substituted‐12‐aryl‐8,9‐dihydro‐7H‐chromeno[2,3‐b]quinolin‐10(12H)‐one Derivatives

A series of 2‐amino‐7‐methoxy‐4‐aryl‐4H‐chromene‐3‐carbonitrile compounds 2 were obtained by condensation of 3‐methoxyphenol with β‐dicyanostyrenes 1 in absolute ethanol containing piperidine. The intermediate enamines 3 were prepared by compounds 2 with 5‐substituted‐1,3‐cyclohexanedione using p‐toluenesuflonic acid (TsOH) as catalyst. The title compounds 11‐amino‐3‐methoxy‐8‐substituted‐12‐aryl‐8,9‐dihydro‐7H‐chromeno[2,3‐b]quinolin‐10(12H)‐one 4 were synthesized by cyclization of the intermediate enamines 3 in THF with K₂CO₃ /Cu₂Cl₂ as catalyst. The structures of all compounds were characterized by elemental analysis, IR, MS, and ¹H NMR spectra. The crystal structure of compound 4i was determined by single‐crystal X‐ray diffraction analysis.     

Lewis Acid‐Mediated Addition of Amino Acid‐Substituted α‐Allylsilanes to Aromatic Acetals

Unnatural amino acids extend the pharmacological formulator's toolkit. Strategies to prepare unnatural amino acid derivatives using Lewis acid‐activated allylsilane reactions are few. In this regard, we examined the utility of allylsilanes bearing an amino acid substituent in the reaction. Diastereoselective addition of methyl 2‐(N‐PG‐amino)‐3‐(trimethylsilyl)pent‐4‐enoate and methyl (E)‐2‐(N‐PG‐amino)‐3‐(trimethylsilyl)hex‐4‐enoate (PG=protecting group), 2 and 13 , respectively, to aromatic acetals in the presence of Lewis acids is described. Of those examined, TiCl₄ was found to be the most effective Lewis acid for promoting the addition. At least 1 equiv. of TiCl₄ was required to achieve high yields, whereas 2 equiv. of BF₃?OEt₂ were required for comparable outcomes. Excellent selectivity (>99% syn/anti) and high yield (up to 89%) were obtained with halo‐substituted aromatic acetals, while more electron‐rich electrophiles led to both lower yields and diastereoselectivities.     

Highly Enantioselective Synthesis of Orthogonally Protected (2S)‐2,3‐Diaminopropanoates through Catalytic Phase‐Transfer Aza‐Henry Reaction

The syntheses of enantiomer‐enriched orthogonally protected different (2S)‐2,3‐diaminopropanoates and unnatural furyl‐substituted (tert‐butoxy)carbonyl (Boc) as well as (benzyloxy)carbonyl (Cbz) protected amino acid esters are accomplished by means of an enantioselective aza‐Henry reaction. A key feature of this protocol is organocatalysis as a genesis of chirality to ensure high enantioselectivity.     

Diastereo‐ and Enantioselective anti‐Selective Hydrogenation of α‐Amino‐β‐keto Ester Hydrochlorides and Related Compounds Using Transition‐Metal–Chiral‐Bisphosphine Catalysts

This review describes our recent works on the diastereo‐ and enantioselective synthesis of anti‐β‐hydroxy‐α‐amino acid esters using transition‐metal–chiral‐bisphosphine catalysts. A variety of transition metals, namely ruthenium (Ru), rhodium (Rh),iridium (Ir), and nickel (Ni), in combination with chiral bisphosphines, worked well as catalysts for the direct anti‐selective asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides, yielding anti‐β‐hydroxy‐α‐amino acid esters via dynamic kinetic resolution (DKR) in excellent yields and diastereo‐ and enantioselectivities. The Ru‐catalyzed asymmetric hydrogenation of α‐amino‐β‐ketoesters via DKR is the first example of generating anti‐β‐hydroxy‐α‐amino acids. Complexes of iridium and axially chiral bisphosphines catalyze an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides via dynamic kinetic resolution. A homogeneous Ni–chiral‐bisphosphine complex also catalyzes an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides in an anti‐selective manner. As a related process, the asymmetric hydrogenation of the configurationally stable substituted α‐aminoketones using a Ni catalyst via DKR is also described.     

Oxazoline chemistry part III. Synthesis and characterisation of [2‐(2′‐anilinyl)‐2‐oxazolines] and some related compounds

The syntheses and characterisation of a series of chiral and achiral 2‐(aminophenyl)‐2‐oxazolines and some related compounds is reported. All of the derivatives have been produced by a one‐step procedure involving the treatment of isatoic anhydride (i.e. [2H]‐3, 1‐benzoxazine‐[1H‐2,4‐dione: 1 ) or its 5‐chloro analogue with a slight excess of appropriate amino‐alcohols. In most cases, anhydrous ZnCl₂ is shown to be an effective Lewis acid catalyst for this reaction at reflux temperature in high boiling aromatic solvents (PhCl or PhMe). Oxazolines have been readily formed using rac‐2‐amino‐1‐butanol, (S)‐phenylglycinol, 2‐methyl‐2‐amino‐1‐propanol and (1S,2R) or (IR,2S)‐cis‐ 1 ‐amino‐2‐indanol; yields range from 85% to 22%. The use of aminoalcohols such as 2‐ethanolamine, (±)‐2‐amino‐1‐phenyl‐1‐propanol or 3‐amino‐1‐propanol (to give the corresponding 4,5‐dihydro‐1,3‐oxazine) results in poor yields. The use of other Lewis acid catalysts (silicic acid, Cd(acac)₂·2H₂O, CuCl₂·2H₂O, InCl₃) or higher temperatures did not improve the yields with these latter two substrates. Benzoxazoles and N‐substituted benzoxazoles can also be obtained in reasonable yields from 1 using 2‐aminophenol (36%) or 2‐amino‐3‐hydroxypyridine (45%).     

One‐Pot Synthesis of 2‐Substituted 4‐Aryl‐4,5‐dihydro‐3,1‐benzoxazepines from 2‐(2‐Aminophenyl)‐1‐arylethanols via Dehydration of the Corresponding Amides

An efficient method for the preparation of 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepine derivatives under mild conditions has been developed. The reaction of 2‐(2‐aminophenyl)ethanols 1 with acid chlorides in the presence of excess Et₃N in THF at room temperature gave the corresponding N‐acylated intermediates 2 , which were dehydrated by treatment with POCl₃ to give 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepines 3 in a one‐pot reaction.