Synthesis of N‐(substituted phenylcarbonylamino)‐4‐ethyl‐1,2,3,6‐tetrahydropyridines as potential nonsteroidal anti‐inflammatory agents

Fourteen novel N‐(substituted phenylcarbonylamino)‐4‐ethyl‐1,2,3,6‐tetrahydropyridines 9 were synthesized in fair to good yields. 4‐Ethylpyridine 5 reacted with O‐mesitylenesulfonylhydroxylamine (O‐MSH) 4 to furnish N‐amino‐4‐ethylpyridinium mesitylenesulfonate 6 . The reaction of 6 with substituted acid chlorides 7 gave the stable crystalline pyridinium ylides 8a‐8n . A sodium borohydride reduction of 8 in absolute ethanol furnished the target compounds N‐(substituted phenylcarbonylamino)‐4‐ethyl‐1,2,3,6‐tetrahydropyridines 9a‐9n .     

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.     

Heterocycles Derived from 5‐(2‐Aminothiazol‐4‐yl)‐8‐hydroxyquinoline: Synthesis and Antimicrobial Activity

5‐(2‐Aminothiazol‐4‐yl)‐8‐hydroxyquinoline 2 has been synthesized by treating thiourea with 5‐chloroacetyl‐8‐hydroxyquinoline 1 . The amine 2 was treated with aromatic aldehydes to furnish schiff bases 6a‐c which on treatment with phenyl isothiocyanate gave the corresponding thiazolo‐s‐triazines 7a‐c . Reaction of 2 with phenyl isothiocyanate gave the corresponding aminocarbothiamide derivative 8 which on reaction with malonic acid in acetyl chloride afforded thiobarbituric acid derivative 9 . Coupling of 9 with diazonium salt gave the phenyl hydrazono derivative 10 . However, reaction of 2 with carbon disulphide and methyl iodide afforded dithiocarbamidate 12 which on treatment with ethylenediamine, o‐aminophenol and/or phenylenediamine gave the aminoazolo derivatives 13–15 , respectively. Other substituted fused thiazolopyrimidines 16–20 have been also prepared by the reaction of 2 with some selected dicarbonyl reagents. The characterisation of synthesized compounds has been done on the basis of elemental analysis, IR, ¹H‐NMR and mass spectral data. All the newly synthesized compounds have been screened for their antimicrobial activities.     

2‐Triazolylpyrimido[1,2,3‐cd]purine‐8,10‐diones via 1,3‐dipolar cycloadditions to 2‐ethynylpyrimido[1,2,3‐cd]purine‐8,10‐dione

This paper presents the synthesis of a series of 5,6‐dihydro‐4H,8H‐pyrimido[1,2,3‐cd]purine‐8,10(9H)‐dione ring system derivatives with a [1,2,3]triazole ring bonded in position 2. The procedure is based on cycloaddition of substituted alkyl azides to the terminal triple bond of 5,6‐dihydro‐2‐ethynyl‐9‐methyl‐4H,8H‐pyrimido[1,2,3‐cd]purine‐8,10(9H)‐dione ( 4 ). This cycloaddition produced two regioisomers ?5,6‐dihydro‐9‐methyl‐2‐(1‐substituted‐1H‐[1,2,3]triazol‐5‐yl)‐4H,8H‐pyrimido[1,2,3‐cd]purine‐8,10(9H)‐dione ( 7 ) and 2‐(1‐substituted‐1H‐[1,2,3]triazol‐4‐yl) derivative 8 . The required 2‐ethynyl deriva tive 4 was obtained from the starting 2‐unsubstituted compound 1 by bromination to yield the 2‐bromo derivative 2 , which was converted by Sonogashira reaction to trimethylsilylethyne 3 and finally, the protective trimethylsilyl group was removed by hydrolysis.     

Synthesis of heterocycle‐substituted pyropheophorbide derivatives

Methyl pyropheophorbide‐a (MPPa) ( 1 ) was converted to two aldehydes, methyl 2‐formylmethyl‐2‐devinylpyropheophorbide‐a ( 2 ) and methyl 2‐formyl‐2‐devinylpyropheophorbide‐a ( 3 ). The former 2 reacted with active methylene compounds having a cyano function in the presence of sulfur to afford thiophene‐substituted chlorins 5a‐c and reacted with arylhydrazines to yield indole‐substituted chlorins 6a‐d . From the latter 3 , a α‐diketo chlorin 7 was obtained via Wittig reaction and oxidation. Compound 7 reacted with o‐phenylenediamine to afford 2‐quinoxalyl‐substituted pyropheophorbide‐a 8. The reaction of MPPa ( 1 ) with anthranilamide to give a spiro‐substituted compound 9 .     

A Facile Synthesis of Oxoindenothiazine and Dioxospiro(indene‐2,4′‐thiazine) Derivatives from (Substituted ethylidene)hydrazinecarbothioamides

(E)‐2‐[2‐(1‐Substituted ethylidene)hydrazinyl]‐5‐oxo‐9b‐hydroxy‐5,9b‐dihydroindeno[1,2‐d][1,3]‐thiazine‐4‐carbonitriles and (E)‐5‐oxo‐[(E)‐(1‐substituted ethylidene)hydrazinyl]‐2,5‐dihydroindeno[1,2‐d][1,3]thiazine‐4‐carbonitriles have been obtained from the reaction of 2‐(substituted ethylidene)hydrazinecarbothioamides with 2‐(1,3‐dioxo‐2,3‐dihydro‐1H‐inden‐2‐ylidene)propanedinitrile ( 1 ) in ethyl acetate solution. However, (Z)‐6′‐amino‐1,3‐dioxo‐3′‐substituted‐2′‐[(E)‐(1‐phenylethylidene)hydrazono]‐1,2′,3,3′‐tetrahydrospiro(indene‐2,4′‐[1,3]thiazine)‐5′‐carbonitriles were observed during the reaction of N‐substituted‐2‐(1‐phenylethylidene)hydrazinecarbothioamides with ( 1 ). The structure assignment of products has been confirmed on the basis of ¹H‐, ¹³C‐NMR, and mass spectrometry, as well as theoretical calculations.     

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.     

Metal‐Free Oxidative B−N Coupling of nido‐Carborane with N‐Heterocycles

A general method for the oxidative substitution of nido‐carborane (7,8‐C₂B₉H₁₂^?) with N‐heterocycles has been developed by using 2,3‐dichloro‐5,6‐dicyanobenzoquinone (DDQ) as an oxidant. This metal‐free B?N coupling strategy, in both inter‐ and intramolecular fashions, gave rise to a wide array of charge‐compensated, boron‐substituted nido‐carboranes in high yields (up to 97 %) with excellent functional‐group tolerance under mild reaction conditions. The reaction mechanism was investigated by density‐functional theory (DFT) calculations. A successive single‐electron transfer (SET), B?H hydrogen‐atom transfer (HAT), and nucleophilic attack pathway is proposed. This method provides a new approach to nitrogen‐containing carboranes with potential applications in medicine and materials.     

Copper‐catalyzed Synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde by Step‐wise and One‐pot Three‐component Huisgen's 1,3‐dipolar Cycloaddition Reaction

An efficient method for the synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde has been developed starting from oxindole and indole using Huisgen's 1,3‐dipolar cycloaddition reaction of organic azides to alkynes. The effect of catalysts and solvent on these reactions has been investigated. Among all these conditions, while using CuSO₄·5H₂O, DMF was found to be the best system for this reaction. It could also be prepared in a one‐pot three‐component manner by treating equimolar quantities of halides, azides, and alkynes. The Huisgen's 1,3‐dipolar cycloaddition reaction was performed using CuSO₄·5H₂O in DMF with easy work‐up procedure.     

Synthesis of Fused 9,10‐Dihydro‐6H‐Azepino‐ and 9,10‐Dihydro‐6H‐[1,3]Diazepino[1,2‐e]Purines via Ring Closing Metathesis as Antilipid Peroxidation Agents

Ring closing metathesis of 8‐allyl‐9‐butenylpurines or N,9‐diallyl‐N‐methyl‐9H‐purin‐8‐amines with the Grubbs second generation catalyst resulted in fused 9,10‐dihydro‐6H‐azepino[1,2‐e]purines or 9,10‐dihydro‐6H‐[1,3]diazepino[1,2‐e]purines, respectively. The 8‐allyl‐9‐butenylpurines were prepared from 8‐bromo‐9‐butenylpurines after Stille coupling with allyltributyltin. The N,9‐diallyl‐N‐methyl‐9H‐purin‐8‐amines were synthesized from 9‐allyl‐8‐bromopurines after treatment with allylamine in H₂O under MW irradiation, followed by methylation with MeI in KOH. The new compounds were tested as inhibitors of lipid peroxidation. 6‐Methyl‐4‐(morpholin‐4‐yl)‐7,10‐dihydro‐6H‐[1,3]diazepino[1,2‐e]purine presents interesting results and could serve as a lead compound.     

The Synthesis of 1,4‐Bis[N‐(4/6‐Substituted Benzothiazole‐2‐yl)‐N′‐Glycosylguanidino]Benzenes

The starting material O‐protected glycosyl isothiocyanate ( 1?3 ) was refluxed with 1,4‐diaminobenzene in CHCl₃ under nitrogen atmosphere to give 1,4‐bis(N‐glycosyl)thioureidobenzene ( 4?6 ). Then 1,4‐bis[N‐(4/6‐substituted benzothiazole‐2‐yl)‐N′‐glycosylguanidino]benzenes ( 8a?8e , 9a?9e , 10a?10e ) were obtained in good yield by reaction of compounds ( 4?6 ) with 2‐amino‐4/6‐benzothizoles ( 7a?7e ) and HgCl₂ in the presence of TEA in DMF. The structures of all 18 new compounds were confirmed by IR, ¹H NMR, LC‐MS and elemental analysis. The bioactivity of anti‐HIV‐1 protease (HIV‐1 PR) and against angiotensin converting enzyme (ACE) have been evaluated.     

Synthesis of 3‐Alkoxybenzo[c]thiophen‐1(3H)‐ones by Hydrolysis of N‐Substituted 3‐Alkoxybenzo[c]thiophen‐1(3H)‐imines Derived from 1‐Bromo‐2‐(dialkoxymethyl)benzenes and Isothiocyanates

A convenient procedure for the preparation of a new type of thiophthalides, 3‐alkoxybenzo[c]thiophen‐1(3H)‐ones 4 and 9 has been developed. Thus, 1‐(dialkoxymethyl)‐2‐lithiobenzenes, generated by Br/Li exchange between 2‐bromo‐1‐(dialkoxymethyl)benzenes 1 and 6 , and BuLi, react with isothiocyanates to afford N‐substituted 2‐(dialkoxymethyl)benzothioamides 2 and 7 , which, on treatment with a catalytic amount of TsOH?H₂O, give N‐substituted 3‐alkoxybenzo[c]thiophen‐1(3H)‐imines 3 and 8 . The latter are hydrolyzed under acidic conditions to the desired products 4 and 9 , respectively.     

On the Reaction of Thiazole‐2,4‐diamines with Isothiocyanates – Preparation and Transformation of 2,4‐Diaminothiazole‐5‐carbothioamides

In the reaction of thiazole‐2,4‐diamines 8 with isothiocyanates 1 , 2,4‐diaminothiazole‐5‐carbothioamides 9, 10, 18 , and 19 as well as thiazolo[4,5‐d]pyrimidine‐7(6H)‐thiones 21 were formed. The carbothioamides 9, 10 , and 18 were transformed by reaction with different types of monofunctional and bifunctional electrophiles into hitherto unknown acceptor‐substituted 4,4′‐([2,5′‐bithiazole]‐2′,4′‐diyl)bis[morpholines] 24 and 29 , the 2′,4′‐bis(dialkylamino)[2,5′‐bithiazol]‐4‐(5H)‐ones 30 , and the 4‐substituted 2′,4′‐bis(dialkylamino)‐2,5′‐bithiazoles 31 . From 30 and 31 new 4‐mono‐ or 4,5‐disubstituted 2′,4′‐bis(dialkylamino)‐2,5′‐bithiazoles 34, 35, 38 , and 39 as well as 5‐substituted 2′,4′‐bis(dialkylamino)[2,5′‐bithiazol]‐4(5H)‐ones 33, 36 , and 37 were prepared.     

Ethyl 1,4‐Dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylates by a Tandem SNAr‐Addition‐Elimination Reaction

A series of N‐substituted 1,4‐dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylate esters has been prepared in two steps from ethyl 2‐(2‐chloronicotinoyl)acetate. Treatment of the β‐ketoester with N,N‐dimethylformamide dimethyl acetal in N,N‐dimethylformamide (DMF) gave a 95% yield of the 2‐dimethylaminomethylene derivative. Subsequent reaction of this β‐enaminone with primary amines in DMF at 120^oC for 24 h then afforded the target compounds in 47–82% yields by a tandem S_NAr‐addition‐elimination reaction. Synthetic and procedural details as well as a mechanistic rationale are presented.     

Microwave Induced Synthesis of 3‐Aryl‐6‐(6‐/8‐substituted 4‐chloroquinoline‐3‐yl) ‐ s ‐triazolo [3,4‐b] −1,3,4‐thiadiazoles

The condensation of 4‐amino‐3‐aryl‐5‐mercapto‐1, 2, 4‐triazoles (1a‐f) with 6‐/8‐substituted 1,4‐dihydro‐4‐oxo‐quinoline‐3‐carboxylic adds (2a‐d) in the presence of phosphorus oxychloride on refluxng or under microwave irradiation gave twenty four novel 3‐aryl‐6‐ (6‐/8‐substituted 4‐chloroquinoline‐3‐yl)‐s‐triazolo[3,4‐b]‐1, 3,4‐thiadiazoles (4a‐x), Considerable increase in the reaction rate has been observed with improved yields under microwave irradiation. The structures of the compounds synthesized were determined by elemental analyses, IR, ¹H NMR and MS spectra. Their spectral properties and the reaction mechanism were also discussed. The preliminary biological test showed that some of compounds bad moderate antibacterial activities.     

Preparation of new N6, 9‐disubstituted 2‐phenyl‐adenines and corresponding 8‐azaadenines.: A feasibility study for application to solid‐phase Synthesis. I

A suitably substituted pyrimidine 1 was converted to a number of title compounds. Nucleophilic substitu tion involving the chlorine atoms in 1 by treatment with phenylmethanethiol yielded 2 or 3 , depending on the reaction temperature. Treatment of 3 with an amine afforded 6‐phenylmethanesulfanyl‐N⁴‐substituted‐2‐phenyl‐pyrimidine‐4,5‐diamines 4–7 . These pyrimidines were converted into 2‐phenylpurines 8–11 and 2‐phenyl‐8‐azapurines 12–14 , by treatment with triethyl orthoformate in the presence of hydrochloric acid (or acetic anhydride), or with potassium nitrite and acetic acid respectively. The thioether function on C(6) was then converted into a sulfonyl group by oxidation with m‐chloroperoxybenzoic acid affording purines 15–18 and their 8‐azaanalogs 19–21 ; these compounds, as crude products, were treated with an amine to yield the corresponding adenines 22–25 or 8‐azaadenines 26–31. All reactions were performed under conditions com patible with the possible use of a thiomethyl resin in place of phenylmethanethiol to bind the pyrimidine ring of 1 to a solid phase.     

Synthesis of new spiro‐[isothiochromene‐3,5′‐isoxazolidin]‐4(1H)‐ones

A series of seven new 2′,3′,4′‐substituted spiro[isothiochromene‐3,5′‐isoxazolidin]‐4(1H)‐ones ( 7‐13 ) has been prepared in the reaction of benzylidene(phenyl)azane oxide ( 5 ) or benzylidene(methyl)azane oxide ( 6 ) with (3Z)‐3‐(4‐substituted‐benzylidene)‐1H‐isothio‐ chromen‐4(3H)‐one ( 1‐4 ). The reaction occurs by a 1,3‐dipolar cycloaddition mechanism that leads to the regiospecific formation of various spiroisoxazolidines ( 7‐13 ).     

Highly Efficient [3 + 2] Cycloaddition: Click Synthesis of Novel 1H‐indol‐3‐yl‐benzo[d]imidazole Bis‐triazoles

A series of novel 1‐((1H‐1,2,3‐triazol‐4‐yl)methyl)‐2‐(1‐((1H‐1,2,3‐triazol‐4‐yl)methyl)‐5‐substituted‐1H‐indol‐3‐yl)‐6‐substituted‐1H‐benzo[d]imidazoles 5a – i have been prepared using click chemistry as an ideal strategy where [3 + 2] cycloaddition of azides with terminal alkynes has been developed as the target compounds. In route‐II, 5‐substituted‐1H‐indole‐3‐carbaldehydes 1a – c react with 5‐substituted orthophenylenediamine 8 to give desired products, that is, 6‐substituted‐2‐(5‐substituted‐1H‐indol‐3‐yl)‐1H‐benzo[d]imidazole 6a – i . Here, 6a – i react with 2 equiv of propargylbromide 7 to give novel 6‐substituted 2‐(5‐substituted‐1‐(prop‐2‐yn‐1‐yl)‐1H‐indol‐3‐yl)‐1‐(prop‐2‐yn‐1‐yl)‐1H‐benzo[d]imidazole 4a – i . 4a – i were reacted with 2 equiv of NaN₃ in t‐butanol/water (1:2) and add catalytic amount of CuSO₄.5H₂O. Stir the reaction mixture at room temperature to get the target products 5a – i . Here, obtained products contain four rings, that is, one indole, two triazoles, and one benzimidazole. The main advantages of this method are short reaction times, easy workup, higher yields (88–92%), and no by‐products formation.     

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.     

Asymmetric Synthesis of Densely Functionalized Medium‐Ring Carbocycles and Lactones through Modular Assembly and Ring‐Closing Metathesis of Sulfoximine‐Substituted Trienes and Dienynes

An asymmetric synthesis of densely functionalized 7–11‐membered carbocycles and 9–11‐membered lactones has been developed. Its key steps are a modular assembly of sulfoximine‐substituted C‐ and O‐tethered trienes and C‐tethered dienynes and their Ru‐catalyzed ring‐closing diene and enyne metathesis (RCDEM and RCEYM). The synthesis of the C‐tethered trienes and dienynes includes the following steps: 1) hydroxyalkylation of enantiomerically pure titanated allylic sulfoximines with unsaturated aldehydes, 2) α‐lithiation of alkenylsulfoximines, 3) alkylation, hydroxy‐alkylation, formylation, and acylation of α‐lithioalkenylsulfoximines, and 4) addition of Grignard reagents to α‐formyl(acyl)alkenylsulfoximines. The sulfoximine group provided for high asymmetric induction in steps 1) and 4). RCDEM of the sulfoximine‐substituted trienes with the second‐generation Ru catalyst stereoselectively afforded the corresponding functionalized 7–11‐membered carbocyles. RCDEM of diastereomeric silyloxy‐substituted 1,6,12‐trienes revealed an interesting difference in reactivity. While the (R)‐diastereomer gave the 11‐membered carbocyle, the (S)‐diastereomer delivered in a cascade of cross metathesis and RCDEM 22‐membered macrocycles. RCDEM of cyclic trienes furnished bicyclic carbocycles with a bicyclo[7.4.0]tridecane and bicyclo[9.4.0]pentadecane skeleton. Selective transformations of the sulfoximine‐ and bissilyloxy‐substituted carbocycles were performed including deprotection, cross‐coupling reaction and reduction of the sulfoximine moiety. Esterification of a sulfoximine‐substituted homoallylic alcohol with unsaturated carboxylic acids gave the O‐tethered trienes, RCDEM of which yielded the sulfoximine‐substituted 9–11‐membered lactones. RCEYM of a sulfoximine‐substituted 1,7‐dien‐10‐yne showed an unprecedented dichotomy in ring formation depending on the Ru catalyst. While the second‐generation Ru catalyst gave the 9‐membered exo 1,3‐dienyl carbocycle, the first‐generation Ru catalyst furnished a truncated 9‐membered 1,3‐dieny carbocycle having one CH₂ unit less than the dienyne.