Synthesis of 2‐amino‐7,8‐dihydro‐6(5H)‐quinazolinone, 2,4‐diamino‐7,8‐dihydro‐6(5H)‐quinazolinone, 5,6,7,8‐tetrahydro‐2,6‐quinazoline‐diamine and 5,6,7,8‐tetrahydro‐2,4,6‐quinazolinetriamine derivatives

N‐(2‐Amino‐5,6,7,8‐tetrahydro‐6‐quinazolinyl)acetamide ( 9 ) and N‐(2,4‐diamino‐5,6,7,8‐tetrahydro‐6‐quinazolinyl)acetamide ( 6 ) were synthesized from N‐(4‐oxocyclohexyl)acetamide ( 5 ) as novel peptidomimetic building blocks. With similar purpose, N‐(6‐oxo‐5,6,7,8‐tetrahydro‐2‐quinazolinyl)acetamide ( 18 ) and N‐[2‐(acetylamino)‐6‐oxo‐5,6,7,8‐tetrahydro‐4‐quinazolinyl]acetamide ( 14 ) were prepared from cyclohexane‐1,4‐dione monoethylene ketal ( 11 ).     

Identification of (6R)‐5,6,7,8‐Tetrahydro‐D‐monapterin (=(6R)‐2‐Amino‐5,6,7,8‐tetrahydro‐6‐[(1R,2R)‐1,2,3 ‐trihydroxypropyl]pteridin‐4(3H)‐one) as the Native Pteridine in Tetrahymena pyriformis

The structure of the native pteridine in Tetrahymena pyriformis was determined as (6R)‐5,6,7,8‐tetrahydro‐D ‐monapterin (=(6R)‐2‐amino‐5,6,7,8‐tetrahydro‐6‐[(1R,2R)‐1,2,3‐trihydroxypropyl]pteridin‐4(3H)‐one; 4 ). First, the configuration of the 1,2,3‐trihydroxypropyl side chain was confirmed as D ‐threo by the fluorescence‐detected circular dichroism (FDCD) spectrum of its aromatic pterin derivative 2 obtained by I₂ oxidation (Fig. 1). The configuration at the 6‐position of 4 was determined as (R) by comparison of its hexaacetyl derivative 6 with authentic (6R)‐ and (6S)‐hexaacetyl‐5,6,7,8‐tetrahydro‐D ‐monapterins 6 and 7 , respectively, in the HPLC, LC/MS, and LC‐MS/MS (Figs. 3 – 6). (6R)‐5,6,7,8‐Tetrahydro‐D ‐monapterin ( 4 ) is a newly discovered natural tetrahydropterin.     

A convenient one‐pot synthesis of new 3‐(4‐aryl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromen‐2‐yl)‐2H‐chromen‐2‐ones

Anhydrous zinc bromide catalysed reactions of arylidine‐3‐acetyl coumarins ( 1a‐c ) and 5,6‐benzoanalogs of arylidine 3‐acetyl coumarins ( 4a,4b ) with 1,3‐cyclohexanedione gives ‐(4‐aryl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromen‐2yl)‐2H‐chromen‐2‐ones ( 3a, 3c ) and 5,6‐benzoanalogs of 3‐(4‐aryl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromen‐2yl)‐2H‐chromen‐2‐one ( 5a,5b ). Under similar conditions arylidine‐3‐acetylcoumarins ( 1a, 1b,1d, 1e, 1f ) and 5,6‐benzoanalog of arylidine 3‐acetyl coumarin ( 4b ) react with 5,5‐dimethyl‐1,3‐cyclohexanedione (dimedone) yielding 3‐(4‐aryl‐7,7‐dimethyl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromen‐2‐yl)‐2H‐chromen‐2‐ones ( 3d‐3h ) and the 5,6‐benzoanalog of 3.(4‐aryl‐7,7‐dimethyl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromen‐2‐yl)‐2H‐chromen‐2‐one ( 5c ).     

Synthesis and reaction of 5,6,7,8‐tetrahydro‐4H‐oxazolo[4,5‐c]azepin‐4‐ones

The synthesis of 5,6,7,8‐tetrahydro‐4H‐oxazolo[4,5‐c]azepin‐4‐ones 5a,b and 1,3‐benzoxazol‐4‐amines 4a,b are described starting from 4,5,6,7‐tetrahydro‐1,3‐benzoxazol‐4‐ones. Thionation of 5a,b followed by alkylation with ethyl bromoacetate led to the corresponding S‐alkyl azepines 7a,b .     

Organocatalyzed Enantioselective Synthesis of 2‐Amino‐4H‐chromene Derivatives

Optically active 2‐amino‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromene‐3‐carboxylates, 2‐amino‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromene‐3‐carbonitriles, and 2‐amino‐8‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromene‐3‐carbonitriles were synthesized. Using cinchona alkaloid‐derived bifunctional catalysts, the corresponding 2‐amino‐4H‐chromene derivatives were obtained in high yields and moderate to high ee values (up to 82% ee) from the tandem Michael addition–cyclization reaction between 1,3‐cyclohexanediones or 1,2‐cyclohexanediones and (E )‐3‐aryl‐2‐cyanoacrylate or alkylidene malononitrile derivatives.     

Synthesis of 5‐phenyl‐5,6,7,8‐tetrahydro‐1,6‐naphthyridines and 5‐phenyl‐6,7,8,9‐tetrahydro‐5H‐pyrido[3,2‐c]azepines as potential D1 receptor ligands

A new access to 5‐phenyl‐5,6,7,8‐tetrahydro‐1,6‐naphthyridines 25a‐28a (n=1) and 5‐phenyl‐6,7,8,9‐tetrahydro‐5H‐pyrido[3,2‐c]azepines 25b‐28b (n=2) has been developed by first preparing the functional pyridine moiety followed by intramolecular cyclization forming the partially reduced ring.     

Synthesis of 4‐Aryl‐1,7‐naphthyridine‐2(1H)‐thiones by the Electrocyclic Reaction of 4‐(1‐Arylalk‐1‐enyl)‐3‐isothiocyanatopyridines Generated in situ from the Corresponding Isocyanides

A convenient synthis for 4‐substituted and 3,4‐disubstituted 1,7‐naphthyridine‐2(1H)‐thiones 7 has been developed. The method is based on the electrocyclic reaction of 4‐(1‐arylalk‐1‐enyl)‐3‐isothiocyanatopyridines 6 , generated in situ by the treatment of the respective isocyanides 5 with S₈ in the presence of a catalytic amount of selenium. The isocyanides 5 can be easily prepared from commercially available pyridin‐3‐amine by conventional organic reactions.     

Studies on pyrazines. 36. A novel synthesis of 6‐(2‐hydroxyethyl)‐1,3‐dimethyllumazine

The titled compound was synthesized by cycloaddition of 5,6,7,8‐tetrahydro‐5,7‐dimethyl‐3,6,8‐trioxo‐3H‐pyrimido[5,4‐c][1,2,5]oxadiazine ( 1 ) with 2,3‐dihydrofuran ( 2a ).     

Asymmetric Ruthenium‐Catalyzed Hydrogenation of 2,6‐Disubstituted 1,5‐Naphthyridines: Access to Chiral 1,5‐Diaza‐cis‐Decalins

The first asymmetric hydrogenation (AH) of 2,6‐disubstituted and 2,3,6‐trisubstituted 1,5‐naphthyridines, catalyzed by chiral cationic ruthenium diamine complexes, has been developed. A wide range of 1,5‐naphthyridine derivatives were efficiently hydrogenated to give 1,2,3,4‐tetrahydro‐1,5‐naphthyridines with up to 99 % ee and full conversions. This facile and green protocol is applicable to the scaled‐up synthesis of optically pure 1,5‐diaza‐cis‐decalins, which have been used as rigid chelating diamine ligands for asymmetric synthesis.     

Synthesis of novel 1,7‐naphthyridines by Friedländer condensation of pyridine substrates

The general ability of appropriate pyridyl compounds (aldehyde or ketone) to undergo Friedländer condensation to give different 1,7‐naphthyridines has been demonstrated. 2,4‐Disubstituted 1,7‐naphthyridine 8 was prepared from 3‐amino‐4‐acetylpyridine ( 6 ) and ketone 4 (82%). The Friedländer self‐condensation of pyridyl substrate 6 is reported, as well. The dimer product, 2‐(3‐aminopyridin‐4‐yl)‐4‐methyl‐1,7‐naphthyridine ( 7 ), was obtained in 97% yield. 2‐Aryl‐ and 2,3‐diaryl‐1,7‐naphthyridines ( 16 , 17 , 18 ) were prepared from 3‐aminoisonicotinaldehyde ( 13 ) and arylketones 4 , 14 , and 15 (28–71%). The key substrates 6 and 13 are readily available via the improved pyridine nitration method. J. Heterocyclic Chem., (2011).     

Ready access to 7,8‐dihydro‐ and 1,2,3,4‐tetrahydro‐1,6‐naphthyridine‐5(6H)‐ones from simple pyridine precursors

Short pathways are described for the synthesis of a representative example of each of the 7,8‐dihydro‐and 1,2,3,4‐tetrahydro‐1,6‐naphthyridine‐5(6H)‐one ring systems from simple pyridine precursors. An attempted synthesis of the related 4,6‐dihydro‐1,6‐naphthyridin‐5(1H)‐one ring system from a common intermediate was unsuccessful.     

Process‐Scale Total Synthesis of Nature‐Identical (−)‐(S,S)‐7‐Hydroxycalamenal in High Enantiomeric Purity through Catalytic Enantioselective Hydrogenation

A process‐scale stereoselective synthesis of nature‐identical (−)‐(S,S)‐7‐hydroxycalamenal (=(−)‐(5S,8S)‐5,6,7,8‐tetrahydro‐3‐hydroxy‐5‐methyl‐8‐(1‐methylethyl)naphthalene‐2‐carbaldehyde; (−)‐ 1a ) in 96% enantiomeric excess (ee) with the aid of chiral Ru complexes has been developed. The key step was the enantioselective hydrogenation of easily accessible 2‐(4‐methoxyphenyl)‐3‐methylbut‐2‐enoic acid ( 10 ) to (+)‐ 11 in a 86% ee (Scheme 5 and Table 1). A substantial increase in optical purity (96% ee) was achieved by induced crystallization of the intermediate (+)‐3,4‐dihydro‐4‐(1‐methylethyl)‐7‐methoxy‐2H‐naphthalen‐1‐one ((+)‐ 3 ). Computational conformation analysis carried out on the analog (−)‐ 9 rationalized the high diastereoselectivity achieved in the catalytic hydrogenation of the CC bond.     

The Synthesis of New Organoselenium Heterocyclic Compounds: 2‐aryl‐4‐phenyl‐5,6,7,8‐tetrahydro‐4H‐selenochromenes

We have explored the reactions of 2‐(3‐oxo‐1‐aryl‐3‐phenylpropyl)cyclohexanone ( 1–3 ) with hydrogen selenide in situ in conditions of acid catalysis, and synthesized new 2‐aryl‐4‐phenyl‐5,6,7,8‐tetrahydro‐4H‐selenochromenes ( 4–6 ).     

One‐step synthesis of aminopyrimidines from 5‐Oxo‐4H‐benzopyrans

Novel 4‐amino‐6‐aryl‐2‐phenylpyrimidine‐5‐carbonitriles have been prepared in one step procedure from the readily available 4‐aryl‐2‐amino‐3‐cyano‐5,6,7,8‐tetrahydro‐7,7‐dimethyl‐5‐oxo‐4H‐benzopyrans. The mass spectroscopy study under EI conditions shows molecular peaks with high intensity corresponding to the loss of benzonitrile from the C2 position of the pyrimidine ring. Semiempirical (AMI and PM3) and ab initio HF/6–31G* calculations reveal a favored distorted geometry where the three rings are not in the same plane.     

Synthesis of 2H‐chromeno[4,3‐b]pyridine‐2,5(1H)‐diones and related heterocycles via the erlenmeyer‐ploechl reaction

1,2‐Dihydro‐5H‐[1]benzopyrano[4,3‐b]pyridine‐2,5‐diones 4a‐j were synthesized from 4‐alkylamino‐coumarin‐3‐carbaldehydes 1 and 5(4H)‐oxazolinones (azalactones) derived from N‐acetylglycine ( 2a ) and hippuric acid ( 2b ). The intermediates 3 ( 3j isolated only) underwent spontaneous recyclization via opening of the azalactone and successive formation of the fused 2‐pyridones 4 . Attempts to synthesize the selected 2H‐chromeno[3,4‐f]‐1,7‐naphthyridine 6 by Vilsmeier reaction of 4e failed. Instead, N‐deacetylation took place, followed by formylation of the amino group to the formamidine 7a . In addition, pyranopyridine 9a was obtained by condensation of the 3‐formyl‐2‐pyridone 8 with the azalactone derived from 2a and acetic anhydride.     

Synthesis of Morphlinotetrahydrothieno[2,3‐c]Isoquinolines

1‐Morpholin‐4‐yl‐5,6,7,8‐tetrahydroisoquinoline‐4‐carbonitrile ( 2 ) was synthesized from 3‐amino‐1‐thioxo‐5,6,7,8‐tetrahydro‐1H‐isothiochromene‐4‐carbonitrile ( 1 ) and used as starting material to synthesize many thienotetrahydroisoquinolines ( 4 ), which in turn were used in the synthesis of many pyrimidothienotetrahydroisoquinolines.     

A Convenient Synthesis and Biological Research of Novel 5,6,7,8‐Tetrahydro‐1,6‐naphthyridin‐2(1H)‐one Derivatives Hydrochloride as Cytotoxic Agents

A series of 5,6,7,8‐tetrahydro‐1,6‐naphthyridin‐2(1H)‐one derivatives hydrochloride were obtained using a convenient and mild method from 4‐piperidone monohydrate hydrochloride. The newly synthesized compounds and their derivatives were characterized by ¹H NMR, ¹³C NMR, and high‐resolution mass spectrometry. Furthermore, cytotoxicity in vitro of the synthesized compounds were screened using MTT or CCK8 assay. The results showed that some of the compounds showed potential antitumor activity. Among of them, compound 10a had effects against tumor cells (MOLM‐13), and the half maximal inhibitory concentration value was 76 μmol/L.     

Synthesis and characterization of new complexes of the type [Ru(CO)2Cl2 (2‐phenyl‐1,8‐naphthyridine‐kN) (2‐phenyl‐1,8‐naphthyridine‐kN′)]. Preliminary applications in homogeneous catalysis

Novel ruthenium (II) complexes were prepared containing 2‐phenyl‐1,8‐naphthyridine derivatives. The coordination modes of these ligands were modified by addition of coordinating solvents such as water into the ethanolic reaction media. Under these conditions 1,8‐naphthyridine (napy) moieties act as monodentade ligands forming unusual [Ru(CO)₂Cl₂(η¹‐2‐phenyl‐1,8‐naphthyridine‐ kN )(η¹‐2‐phenyl‐1,8‐naphthyridine‐kN′)] complexes. The reaction was reproducible when different 2‐phenyl‐1,8‐naphthyridine derivatives were used. On the other hand, when dry ethanol was used as the solvent we obtained complexes with napy moieties acting as a chelating ligand. The structures proposed for these complexes were supported by NMR spectra, and the presence of two ligands in the [Ru(CO)₂Cl₂(η¹‐2‐phenyl‐1,8‐naphthyridine‐ kN )(η¹‐2‐phenyl‐1,8‐naphthyridine‐kN′)] type complexes was confirmed using elemental analysis. All complexes were tested as catalysts in the hydroformylation of styrene showing moderate activity in N,N′‐dimethylformamide. Copyright © 2008 John Wiley & Sons, Ltd.     

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 .     

4‐Hydroxy‐2‐vinyl‐2,3,4,5‐tetrahydro‐1‐benzazepine and its 7‐fluoro and 7‐chloro analogues are isomorphous but not strictly isostructural

4‐Hydroxy‐2‐vinyl‐2,3,4,5‐tetrahydro‐1‐benzazepine, C₁₂H₁₅NO, (I), and its 7‐fluoro and 7‐chloro analogues, namely 7‐fluoro‐4‐hydroxy‐2‐vinyl‐2,3,4,5‐tetrahydro‐1‐benzazepine, C₁₂H₁₄FNO, (II), and 7‐chloro‐4‐hydroxy‐2‐vinyl‐2,3,4,5‐tetrahydro‐1‐benzazepine, C₁₂H₁₄ClNO, (III), are isomorphous, but with variations in the unit‐cell dimensions which preclude in compound (III) one of the weaker intermolecular interactions found in compounds (I) and (II). Thus the compounds are not strictly isostructural in terms of the structurally significant intermolecular interactions, although the corresponding atomic coordinates are very similar. The azepine rings adopt chair conformations. The molecules are linked by a combination of N—H...O and O—H...N hydrogen bonds into chains of edge‐fused R³₃(10) rings, which in compounds (I) and (II) are further linked into sheets by a single C—H...π(arene) hydrogen bond. The significance of this study lies in its observation of isomorphism in compounds (I)–(III), and its observation of a sufficient variation in one of the cell dimensions effectively to alter the range of significant hydrogen bonds present in the crystal structures.