InBr3‐ and AgOTf‐catalyzed beckmann rearrangement of (E)‐benzoheterocyclic oximes

Beckmann rearrangement of (E)‐4‐chromanone oxime, (E)‐5‐oximino‐3,4‐dihydro‐1(2H)‐benzoxepines, and (E)‐5‐oximino‐3,4‐dihydro‐1(2H)‐benzothiepine are catalyzed by InBr₃ and AgOTf in refluxing acetonitrile resulting in the formation of pharmaceutically active heterocycles benzoxazepin‐4‐one, 5‐oxo‐benzoxazocines, and 5‐oxo‐benzothiazocine derivative, respectively, in excellent yield. J. Heterocyclic Chem., (2012).     

Synthesis and Antiplatelet‐Activity Evaluation of α‐Methylidene‐γ‐butyrolactones Bearing 3,4‐Dihydroquinolin‐2(1H)‐one Moieties

In continuation of our search for potent antiplatelet agents, we have synthesized and evaluated several α‐methylidene‐γ‐butyrolactones bearing 3,4‐dihydroquinolin‐2(1H)‐one moieties. O‐Alkylation of 3,4‐dihydro‐8‐hydroxyquinolin‐2(1H)‐one ( 1 ) with chloroacetone under basic conditions afforded 3,4‐dihydro‐8‐(2‐oxopropoxy)quinolin‐2(1H)‐one ( 2a ) and tricyclic 2,3,6,7‐tetrahydro‐3‐hydroxy‐3‐methyl‐5H‐pyrido[1,2,3‐de][1,4]benzoxazin‐5‐one ( 3a ) in a ratio of 1 : 2.84. Their Reformatsky‐type condensation with ethyl 2‐(bromomethyl)prop‐2‐enoate furnished 3,4‐dihydro‐8‐[(2,3,4,5‐tetrahydro‐2‐methyl‐4‐methylidene‐5‐oxofuran‐2‐yl)methoxy]quinolin‐2(1H)‐one ( 4a ), which shows antiplatelet activity, in 70% yield. Its 2′‐Ph derivatives, and 6‐ and 7‐substituted analogs were also obtained from the corresponding 3,4‐dihydroquinolin‐2(1H)‐ones via alkylation and the Reformatsky‐type condensation. Of these compounds, 3,4‐dihydro‐7‐[(2,3,4,5‐tetrahydro‐4‐methylidene‐5‐oxo‐2‐phenylfuran‐2‐yl)methoxy]quinolin‐2(1H)‐one ( 10b ) was the most active against arachidonic acid (AA) induced platelet aggregation with an IC₅₀ of 0.23 μM . For the inhibition of platelet‐activating factor (PAF) induced aggregation, 6‐{[2‐(4‐fluorophenyl)‐2,3,4,5‐tetrahydro‐4‐methylidene‐5‐oxofuran‐2‐yl]methoxy}‐3,4‐dihydroquinolin‐2(1H)‐one ( 9c ) was the most potent with an IC₅₀ value of 1.83 μM .     

Quinolone analogues 8 [1‐6]. Synthesis of 3‐aminopyridazino‐[3,4‐b]quinoxalin‐4(lH)‐one

The 3‐amino‐1‐methylpyridazino[3,4‐b]quinoxalin‐4(1H)‐one 6 and N‐(1,4‐dihydro‐1‐methyl‐4‐oxopyridazino[3,4‐b]quinoxalin‐3‐yl)carbamates 17a,b were synthesized from the 1,4‐dihydro‐1‐methyl‐4‐oxopyridazino[3,4‐b]quinoxa‐line‐3‐carboxylate 1b via the 1,5‐dihydro‐4‐hydroxy‐1‐methylpyridazino[3,4‐b]quinoxaline‐3‐carbohydrazide 13b and then 1,4‐dihydro‐1‐methyl‐4‐oxopyridazino[3,4‐b]quinoxaline‐3‐carboxazide 8 . Heating of compound 13b and arylalde‐hydes afforded the 1,4‐dihydro‐1‐methyl‐4‐oxopyridazino[3,4‐b]quinoxaline‐3‐carbo(2‐arylmethylene)hydrazides 14a‐d.     

Synthesis and Mechanistic Study of Isoquinolinones from Cinnamoyl Azides

A series of isoquinolinones have been synthesized by one‐pot Curtius rearrangement and cyclization of the corresponding cinnamoyl azides using Hg(OAc)₂ as the catalyst under refluxing o‐dichlorobenzene. This is the first time that the intermediate carbamoylisoquinolinone 4 in the synthesis of isoquinolinones has been reported. The nature of the substituent on the aromatic ring was found to be crucial to obtaining high yields of isoquinolinone. The mechanism of the reaction was also discussed.     

Pinacol Rearrangement of 3,4‐Dihydro‐3,4‐dihydroxyquinolin‐2(1H)‐ones: An Alternative Pathway to Viridicatin Alkaloids and Their Analogs

3‐Alkyl/aryl‐3‐hydroxyquinoline‐2,4‐diones were reduced with NaBH₄ to give cis‐3‐alkyl/aryl‐3,4‐dihydro‐3,4‐dihydroxyquinolin‐2(1H)‐ones. These compounds were subjected to pinacol rearrangement by treatment with concentrated H₂SO₄, resulting in 4‐alkyl/aryl‐3‐hydroxyquinolin‐2(1H)‐ones. When a benzyl (Bn) group was present in position 3 of the starting compound, its elimination occurred during the rearrangement, and the corresponding 3‐hydroxyquinolin‐2(1H)‐one was formed. The reaction mechanisms are discussed for all transformations. All compounds were characterized by IR, ¹H‐ and ¹³C‐NMR spectroscopy, as well as mass spectrometry.     

A convenient synthesis of pyrazolo[3,4‐d]pyrimidine‐4,6‐dione and pyrazolo[4,3‐d]pyrimidine‐5,7‐dione derivatives

Pyrazolo‐[3,4‐d]pyrimidine‐4,6‐diones 5 and pyrazolo[4,3‐d]pyrimidine‐5,7‐diones 7 were synthesized by Curtius rearrangement of pyrazolic mono‐esters 2 and 3 followed by hetero‐cyclization via the ureas derivatives 4 and 6 under alkaline conditions.     

Reduction of 3‐Aminoquinoline‐2,4(1H,3H)‐diones and Deamination of the Reaction Products

3‐Aminoquinoline‐2,4‐diones were stereoselectively reduced with NaBH₄ to give cis‐3‐amino‐3,4‐dihydro‐4‐hydroxyquinolin‐2(1H)‐ones. Using triphosgene (=bis(trichloromethyl) carbonate), these compounds were converted to 3,3a‐dihydrooxazolo[4,5‐c]quinoline‐2,4(5H,9bH)‐diones. The deamination of the reduction products using HNO₂ afforded mixtures of several compounds, from which 3‐alkyl/aryl‐2,3‐dihydro‐1H‐indol‐2‐ones and their 3‐hydroxy and 3‐nitro derivatives were isolated as the products of the molecular rearrangement.     

Four Novel Dihydroisocoumarin (=3,4‐Dihydro‐1H‐2‐benzopyran‐1‐one) Glucosides from the Fungus Cephalosporium sp. AL031

Four novel dihydroisocoumarin (=3,4‐dihydro‐1H‐2‐benzopyran‐1‐one) glucosides were isolated from a culture broth of a strain of the fungus Cephalosporium sp. AL031. Their structures were elucidated as (2E,4E)‐5‐[(3S)‐5‐acetyl‐8‐(β‐D ‐glucopyranosyloxy)‐3,4‐dihydro‐6‐hydroxy‐1‐oxo‐1H‐2‐benzopyran‐3‐yl]penta‐2,4‐dienal ( 1 ), (2E,4E)‐5‐[(3S)‐5‐acetyl‐8‐(β‐D ‐glucopyranosyloxy)‐3,4‐dihydro‐6‐methoxy‐1‐oxo‐1H‐2‐benzopyran‐3‐yl]penta‐2,4‐dienal ( 2 ), (3S)‐8‐(β‐D ‐glucopyranosyloxy)‐3‐[(1E,3E,5E)‐hepta‐1,3,5‐trienyl]‐3,4‐dihydro‐6‐hydroxy‐5‐methyl‐1H‐2‐benzopyran‐1‐one ( 3 ), and (3S)‐8‐[(6‐O‐acetyl‐β‐D ‐glucopyranosyl)oxy]‐3‐[(1E,3E,5E)‐hepta‐1,3,5‐trienyl]‐3,4‐dihydro‐6‐methoxy‐5‐methyl‐1H‐2‐benzopyran‐1‐one ( 4 ) by spectroscopic methods, including 2D‐NMR techniques and chemical methods.     

Regioselective Synthesis of Amino Substituted Indazolo[2,1‐b]phthalazine‐triones and Pyrazolo[1,2‐b]phthalazine‐2‐carbonitriles Catalyzed by 2‐1′‐Methylimidazolium‐3‐yl‐1‐ethyl Sulfate

The regioselective reactions of luminol with 1,3‐cyclohexanedione (or malononitrile) and aromatic aldehydes catalyzed by 2‐1′‐methylimidazolium‐3‐yl‐1‐ethyl sulfate were developed to synthesize 7‐amino‐3,4‐dihydro‐2H‐indazolo[2,1‐b]phthalazine‐1,6,11(13H)‐triones and 3,9‐diamino‐5,10‐dihydro‐5,10‐dioxo‐1H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitriles in good to excellent yields in short times.     

Attempted synthesis of ethyl 3,4‐dihydro‐2H‐1,4‐benzoxazine‐3‐carboxylate and 3‐acetate derivatives

Ethyl 3,4‐dihydro‐2H‐1,4‐benzoxazine‐3‐carboxylate derivatives 2 were obtained and isolated in low yields from the condensation of 2‐aminophenol and ethyl 2,3‐dibromopropanoate. They can be obtained by hydrogenation of ethyl 2H‐1,4‐benzoxazine‐3‐carboxylate in satisfactory yield. Using 2‐iminophenol did not direct the condensation with ethyl 2,3‐dibromopropanoate towards 2 but was fruitfull for the preparation of ethyl 2‐(4‐benzyl‐3,4‐dihydro‐2H‐1,4‐benzoxazin‐3‐yl)acetate from ethyl bromocrotonate.     

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.     

N,N′‐Dioxide/Nickel(II)‐Catalyzed Asymmetric Inverse‐Electron‐Demand Hetero‐Diels–Alder Reaction of β,γ‐Unsaturated α‐Ketoesters with Enecarbamates

N,N′‐Dioxide/nickel(II) complexes have been developed to catalyze the inverse‐electron‐demand hetero‐Diels–Alder reaction of β,γ‐unsaturated α‐ketoesters with acyclic enecarbamates. After detailed screening of the reaction parameters, mild optimized reaction conditions were established, affording 3,4‐dihydro‐2H‐pyranamines in up to 99 % yield, 99 % ee and more than 95:5 d.r. The catalytic system was also efficient for β‐substituted acyclic enecarbamates, affording more challenging 2,3,4‐trisubstituted 3,4‐dihydro‐2H‐pyranamine with three contiguous stereogenic centers in excellent yields, diastereoselectivities, and enantioselectivities. The reaction could be scaled up to a gram scale with no deterioration of either enantioselectivity or yield. Based on these experiments and on previous reports, a possible transition state was proposed.     

Two‐Step Synthesis of 1,3‐Disubstituted 3,4‐Dihydro‐4‐thioxoquinazolin‐2(1H)‐ones from 1‐Bromo‐2‐fluorobenzenes

An efficient synthesis of 3‐alkyl‐3,4‐dihydro‐4‐thioxobenzoquinazolin‐2(1H)‐ones 3 has been accomplished in two steps and in satisfactory yields from 1‐bromo‐2‐fluorobenzenes 1 . Thus, the reaction of 1‐fluoro‐2‐lithiobenzenes, generated by the Br/Li exchange between 1 and BuLi, with alkyl isothiocyanates, gives N‐alkyl‐2‐fluorobenzothioamides 2 , which, in turn, react with a series of isocyanates in the presence of NaH to give the desired products 3 .     

One‐Pot Synthesis of 4‐Substituted 3,4‐Dihydro‐3‐methoxyisocoumarins via Carboxylation of α‐Substituted 2‐Lithio‐β‐methoxystyrenes with Carbon Dioxide

A new type of isocoumarins (=1H‐isochromen‐1‐ones=1H‐2‐benzopyran‐1‐ones), 4‐substituted 3,4‐dihydro‐3‐methoxyisocoumarins 2 , can be obtained by a one‐pot process from α‐substituted 2‐bromo‐β‐methoxystyrenes 1 . Thus, lithium 2‐(1‐aryl(or methyl)‐2‐methoxyethenyl)benzoates are conveniently generated via the Br/Li exchange between 1 and BuLi, followed by the action of CO₂ on the resulting α‐substituted 2‐lithio‐β‐methoxystyrenes. Upon treating with concentrated HCl at room temperature, these lithium benzoates undergo lactonization to provide the desired 3,4‐dihydroisocoumarins 2 in relatively good yields.     

An Efficient Synthesis of 3‐(3‐benzyl‐2‐(phenylimino)‐2,3‐dihydrothiazol‐4‐yl)‐6‐methyl‐4‐(2‐oxo‐2‐phenylethoxy)‐3,4‐dihydro‐2H‐pyran‐2‐one Derivatives via Multi‐Component Approach

An easy, highly efficient and a new convenient one‐pot, two‐step approach to the synthesis of 3‐(3‐benzyl‐2‐(phenylimino)‐2,3‐dihydrothiazol‐4‐yl)‐6‐methyl‐4‐(2‐oxo‐2‐phenylethoxy)‐3,4‐dihydro‐2H‐pyran‐2‐one is described. These compounds were synthesized from 3‐(3‐benzyl‐2‐(phenylimino)‐2,3‐dihydrothiazol‐4‐yl)‐4‐hydroxy‐6‐methyl‐3,4‐dihydro‐2H‐pyran‐2‐one and α‐bromoketones in good yields. The compounds 4 were synthesized by a multi‐component reaction between 1 , 2 , and 3 and the prominent features of this protocol are mild reaction conditions, operation simplicity, and good to high yields of products.     

A Convenient Synthetic Route of Diethyl (4‐Oxo‐chromeno[2,3‐d]pyrimidin‐2(5)‐yl)phosphonates

Novel diethyl (4‐oxo‐3,4‐dihydro‐2H‐chromeno[2,3‐d]pyrimidin‐2‐yl)phosphonate as two enantiomers and diethyl (4‐oxo‐1,5‐dihydro‐4H‐chromeno[2,3‐d]pyrimidin‐5‐yl) phosphonate were obtained in easy procedure via reaction of 2‐imino‐2H‐chromene‐3‐carboxamide, dimethylformamide dimethyl‐acetal, and diethyl phosphite in a simple one pot. Possible reaction mechanisms were proposed. The structures of the obtained products were confirmed by elemental analyses and spectral tools.     

Catalytic Enantioselective Synthesis of a 3‐Aryl‐3‐benzyloxindole (=3‐Aryl‐3‐benzyl‐1,3‐dihydro‐2H‐indol‐2‐one) Exhibiting Antitumor Activity

A palladium‐catalyzed intramolecular α‐arylation of an amide in the presence of a bulky chiral N‐heterocyclic carbene ligand is the key step in the first catalytic synthesis of (3R)‐6‐chloro‐3‐(3‐chlorobenzyl)‐1,3‐dihydro‐3‐(3‐methoxyphenyl)‐2H‐indol‐2‐one ((R)‐ 5 ). This oxindole, in racemic form, had been shown previously to be an anticancer agent. (R)‐ 5 was obtained with an overall yield of 45% and with 96% enantioselectivity.     

An efficient one‐pot synthesis of pyrazolo[3,4‐b]pyridinone derivatives catalyzed by L‐proline

A series of 3‐methyl‐1,4‐disubstituted‐4,5‐dihydro‐1H‐pyrazolo[3,4‐b]pyridine‐6(7H)‐ones was synthesized via the three‐component reaction of aldehyde, 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐amine, and Meldrum's acid catalyzed by L ‐proline. This protocol has the advantages of easier work‐up, milder reaction conditions, and high yields. J. Heterocyclic Chem., (2011).