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.     

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 .     

3‐(α‐Chlorobenzyl)quinoxalin‐2(1H)‐ones as Versatile Reagents for the Synthesis of 3‐Benzylquinoxalin‐2(1H)‐ones and Thiazolo[3,4‐a]quinoxalin‐4(5H)‐ones

Facile and efficient methods for the synthesis of 3‐benzylquinoxalin‐2(1H)‐ones and thiazolo[3,4‐a]quinoxalin‐4(5H)‐ones by the reaction of the readily available 3‐(α‐chlorobenzyl)quinoxalin‐2(1H)‐ones and thiourea have been developed, with multiple roles of the latter. Possible mechanisms are discussed. These two‐step sequences can be performed in a one‐pot manner to produce the desired products in moderate to high yields.     

A Simple Multistep Conversion of 1,2‐Dihydro‐1,1‐dimethoxynaphthalen‐2‐ones to (3,4‐Dihydro‐3,4‐dioxonaphthalen‐2‐yl)acetates

On irradiation (λ=350 nm) in the presence of 1,1‐dimethoxyethene, naphthalene‐1,2‐dionemonoacetals 1 regioselectively afford 1,1,4,4‐tetramethoxycyclobuta[a]naphthalen‐3‐ones 3 . Sequential deprotection of these bis‐acetals first lead to 1,1‐dimethoxycyclobuta[a]naphthalene‐3,4‐diones 4 and then to cyclobuta[a]naphthalene‐1,3,4‐triones 6 , which, in turn, are converted into (3,4‐dihydro‐3,4‐dioxonaphthalen‐2‐yl)acetates 7 by treatment with SiO₂/MeOH/air.     

Synthesis of 3,4‐dihydro‐1(2H)‐isoquinolinonesxs

Approaches toward the preparative‐scale synthesis of target 3,4‐dihydro‐1(2H)‐isoquinolinones 1–3 are presented. Compounds 1 and 2 were prepared via a Schmidt rearrangement on easily obtained indanone precursors, but in low overall yield. A better method to make this class of compounds is exemplified by the large‐scale synthesis of 2 via a Curtius rearrangement sequence. Thus, high‐temperature thermal cyclization of an in situ formed styryl isocyanate from precursor 8 in the presence of tributylamine gave the corresponding 1(2H)‐isoquinolinone ( 9 ). Catalytic hydrogenation of 9 provided the desired 3,4‐dihydro‐5‐methyl‐1(2H)‐isoquinolinone ( 2 ) in 65 % overall yield. Similar reduction of a commercially available 5‐hydroxy‐1(2H)‐isoquinolinone precursor 10 followed by an O ‐alkylation/amination sequence gave target 3 in good overall yield. The route proceeding via the Curtius rearrangement is recommended for large scale synthesis of other 3,4‐dihydro‐1(2H)‐isoquinolinones. Only when deactivating substituents or sensitive functionality within the benzenoid ring render the high temperature ring closure of the intermediate isocyanate inefficient might a Schmidt rearrangement protocol be the method of choice.     

Synthesis of 5,6‐Diarylpyridin‐2(1H)‐ones from Isoflavones

A simple method for the cyclocondensation of substituted isoflavones with cyanoacetamide in the presence of sodium hydroxide to give an array of 3‐cyano‐5,6‐diarylpyridin‐2(1H)‐ones in good yields is reported.     

Synthesis and photochemical properties of trans‐2‐(2‐aryl‐ or heteroarylvinyl)‐4,5‐dichloropyridazin‐3(2H)‐ones

trans‐2‐(2‐Aryl‐ or heteroarylvinyl)‐4,5‐dichloropyridazin‐3(2H)‐ones 3 were synthesized from 4,5‐dichloropyridazin‐3(2H)‐one via 2 step. The photochemical behavior of 3 in THF, methylene chloride, acetonitrile and methanol is dependent on the kind of aryl or heterocyclic ring and the solvent polarity     

Interconversion of cis‐ and trans‐Fused Oxabicyclo[5.2.0]nonan‐2‐ones

On irradiation (350 nm) in the presence of alkenes (2,3‐dimethylbut‐2‐ene, 1,1‐dimethoxyethene, and 2,4,4‐trimethylpent‐1‐ene), benzoxepinone 1 and dioxepinone 2 are converted into mixtures of cis‐ and trans‐fused oxabicyclo[5.2.0]nonan‐2‐ones. Their relative thermodynamic stabilities (as reflected by the observed diastereoisomer ratios after equilibration with basic alumina) depend on the substitution pattern of the alkene moiety.     

Highly Enantioselective Protonation of the 3,4‐Dihydro‐2‐ methylnaphthalen‐1(2H)‐one Li‐Enolate by TADDOLs

A series of nine TADDOLs (=α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanols) 1a – 1i , have been tested as proton sources for the enantioselective protonation of the Li‐enolate of 2‐methyl‐1‐tetralone (=3,4‐dihydro‐2‐methylnaphthalen‐1(2H)‐one). The enolate was generated directly from the ketone (with LiN(i‐Pr)₂ (LDA)/MeLi) or from the enol acetate (with 2 MeLi) or from the silyl enol ether (with MeLi) in CH₂Cl₂ or Et₂O as the solvent (Scheme). The Li‐enolate (associated with LiBr/LDA, or LiBr alone) was combined with 1.5 – 3.0 equiv. of the TADDOL at −78° by addition of the latter or by inverse addition. 2‐Methyl‐1‐tetralone of (S)‐configuration is formed (≤80% yield) with up to 99.5% selectivity if and only if (R,R)‐TADDOLs ( 1d , e , g ) with naphthalen‐1‐yl groups on the diarylmethanol unit are employed (Table). The reactions were carried out on the 0.1‐ to 1.0‐mM scale. The selectivity is subject to non‐linear effects (NLE) when an enantiomerically enriched TADDOL 1d is used (Fig. 1). The performance of TADDOLs bearing naphthalen‐1‐yl groups is discussed in terms of their peculiar structures (Fig. 2).     

Convenient synthesis and biological activities of pyridine derivatives of 3,4‐dihydropyrimidin‐2(1H)‐ones

2‐Chloro‐5‐(chloromethyl)‐pyridine reacted with 3,4‐dihydropyrimidin‐2(1H)‐ones 1 to afford 1‐[6‐aryl‐1‐(6‐chloropyridin‐3‐yl‐methyl)‐2‐(6‐chloropyridin‐3‐yl‐methylthio)‐4‐methyl‐1,6‐dihydropyrimidin‐5‐yl] carboxylates or ethanones 2 in good yields. The structure of the target compounds 2 was confirmed by IR, ¹H NMR, EI‐MS, and elemental analyses, and compound 2a was further characterized by single crystal X‐ray diffraction. The preliminary bioassay indicated that some of the title compounds possess moderate insecticidal and fungicidal activities. J. Heterocyclic Chem., (2011).     

Reactions of 4‐Hydroxyquinolin‐2(1H)‐ones with Acenaphthoquinone: Synthesis of New 1,2‐Dihydroacenaphthylene‐spiro‐tetrakis(4‐hydroxyquinolin‐2(1H)‐ones)

Reaction of four equivalents of 4‐hydroxyquinolin‐2(1H)‐ones with one equivalent of acenaphthoquinone in absolute ethanol, containing catalytic triethylamine, gave 3,3′,3″,3?‐(1,2‐dihydroacenaphthylene)‐1,1,2,2‐tetrayl‐tetrakis(4‐hydroxyquinolin‐2(1H)‐ones) in a good to excellent yields. The structures of the products were elucidated by ¹H NMR, ¹³C NMR, NMR, IR, mass spectra, and elemental analyses.     

Green Biginelli‐type Reaction: Solvent‐free Synthesis of 5‐unsubstituted 3,4‐dihydropyrimdin‐2(1H)‐ones

The Biginelli‐type compounds, 5‐unsubstituted 3,4‐dihydropyrimdin‐2(1H)‐ones were synthesized by a one‐pot three‐component condensation of aromatic aldehydes, aromatic ketones and urea in the presence of SnCl₄ · 5H₂O under solvent‐free conditions. The advantages of this method are short reaction time (4–10 min), excellent yields (74–97%), inexpensive catalyst and solvent‐free conditions. A plausible mechanism was proposed.     

One‐pot Synthesis of 3,4‐Dihydropyrimidin‐2(1H)‐ones Catalysed by Cupric Acetate under Solvent‐free Conditions

A solvent‐free synthesis of 3,4‐dihydropyrimidin‐2(1H)‐ones from aromatic aldehydes, β‐keto ester/acetyl acetone and urea catalysed by cupric acetate under thermal condition is reported as a simple and an efficient protocol. Compared with classical Biginelli reaction reported in 1893, this new method provides much improved modification in terms of yield and reaction time. The usage of milder catalyst, environmental friendly procedures and excellent yields within a very short time (5–15 min) are the advantages of the method in which the involvement of solvent‐free condition adds an edge to the method. Thus, the efficiency of the protocol enabled the rapid synthesis of 3,4‐dihydropyrimidin‐2(1H)‐one derivatives in a short duration.     

One‐pot,Green and Efficient Synthesis of 3,4‐Dihydropyrimidin‐2(1H)‐ones or Thiones Catalyzed by Citric Acid

One‐pot three‐component condensation of ethyl acetoacetate, aldehyde and urea or thiourea in refluxing ethanol in the presence of catalytic amounts of citric acid afforded the corresponding 3,4‐dihydropyrimidin‐2(1H)‐ones/thiones in high yields. The catalyst is reusable and can be applied several times without any decrease in product yield.     

A One‐Pot Biginelli Synthesis of 6‐Unsubstituted 5‐Aroylpyrimidin‐2(1H)‐ones and 6‐Acetyl‐1,2,4‐triazin‐3(2H)‐ones

The three‐component Biginelli‐like cyclocondensation reaction of enamines 1 , urea, and aldehydes in dioxane/acetic acid efficiently afforded the corresponding 6‐unsubstituted 3,4‐dihydropyrimidin‐2(1H)‐ones 2 in good yields (Scheme 1, Table). The corresponding reaction of azaenamine (=hydrazone) 7 with benzaldehyde and urea afforded 6‐acetyl‐1,2,4‐triazin‐3(2H)‐ones in good yields (Scheme 3).