A Straightforward Synthesis of Six‐Membered‐Ring Heterocyclic α‐Aminophosphonic Acids from N‐Acyliminium Ions

A convenient synthesis of phosphonic analogues of pipecolic acid and its heterocyclic analogues is reported. The major step of the elaborated procedure is the introduction of the phosphonate group into the skeleton of the appropriate cyclic amide through N‐acyliminium ions. The former ones were obtained by preparation of the hemiaminals or their methyl ethers from the N‐protected cyclic amides. Finally, the reaction with trimethyl phosphite in the presence of BF₃·OEt₂ afforded the desired phosphonates, which were converted into phosphonic acids by the hydrolysis of phosphonate moiety with simultaneous cleavage of the nitrogen protecting groups.     

Synthesis of (3‐N‐substituted‐piperidin‐4‐ylidene)acetic Acid Ethyl Esters

A convenient preparation of skeletons 2A and 2B (cyclic γ,δ‐diamino‐α,β‐unsaturated esters) is reported by a three‐step synthetic route based on a sequence of NBS‐mediated one‐pot α‐bromination/Wittig olefination of piperidin‐4‐one 3 , nucleophilic addition with NaN₃, and followed by PPh₃‐promoted Staudinger reduction/substitution or CuI‐catalyzed Huisgen 1,3‐dipolar cycloaddition.     

Synthesis of Highly Functionalized γ‐Lactones via 1,5‐Electrocyclic Ring Closure

We have investigated 1,5‐electrocyclic ring‐closure reactions of conjugated esters with dimethyl diazomalonate in the presence of [Cu(acac)₂] as catalyst. Our new protocol offers an easy entry to various polyfunctionalized γ‐lactones in high yields. Their subsequent derivatives may be used as valuable intermediates, especially in the synthesis of natural products and their analogues.     

Synthesis and Anticancer and Antiviral Activities of New 2‐Pyrazoline‐Substituted 4‐Thiazolidinones

2‐(4,5‐Dihydropyrazol‐1‐yl)‐thiazol‐4‐ones ( 2–5 ) have been synthesized starting from 3‐phenyl‐5‐aryl‐1‐thiocarbamoyl‐2‐pyrazolines via [2+3]‐cyclization with 2‐bromopropionic acid, maleic anhydride, N‐arylmaleimides, and aroylacrylic acids. The in vitro anticancer activity of 2a , 3a , 4a , 5b , and 5c were tested by the National Cancer Institute. Compounds 4a , 5b , and 5c demonstrated selective inhibition of leukemia cell lines growth at a single concentration (10^?5 M). The screening of antiviral activity for a broad panel of viruses revealed that N‐(4‐methoxyphenyl)‐2‐{2‐[5‐(4‐methoxyphenyl)‐3‐phenyl‐4,5‐dihydropyrazol‐1‐yl]‐4‐oxo‐4,5‐dihydrothiazol‐5‐yl}‐acetamide 4a was highly active against Tacaribe TRVL 11 573 virus strain (EC₅₀ = 0.71 μg/mL, selectivity index = 130).     

N‐Heterocyclic Carbene Catalyzed Synthesis of δ‐Sultones via α,β‐Unsaturated Sulfonyl Azolium Intermediates

A limited array of reactive intermediates have enabled a wealth of discoveries in N‐heterocyclic carbene organocatalysis. In this study, the viability of α,β‐unsaturated sulfonyl azoliums as double electrophiles in new reactions is examined. Specifically, the (3+3) annulation of such species with the trimethylsilyl enol ethers of various 1,3‐dicarbonyl compounds has been developed. This reaction provides access to a range of novel unsaturated δ‐sultones (18 examples) in good yields (40–88 %) under mild reaction conditions. Mechanistic studies and the development of an enantioselective variant (55 % yield, 73:27 e.r.) support the intermediacy of an α,β‐unsaturated sulfonyl azolium species.     

Synthesis of Macrocyclic Lactones via Ring Transformation of 4‐(ω‐Hydroxyalkyl)‐1,3‐oxazol‐5(4H)‐ones

The synthesis of α‐benzamido‐α‐benzyl lactones 23 of various ring size was achieved either via ‘direct amide cyclization’ by treatment of 2‐benzamido‐2‐benzyl‐ω‐hydroxy‐N,N‐dimethylalkanamides 21 in toluene at 90 – 110° with HCl gas or by ‘ring transformation’ of 4‐benzyl‐4‐(ω‐hydroxyalkyl)‐2‐phenyl‐1,3‐oxazol‐5(4H)‐ones under the same conditions. The precursors were obtained by C‐alkylations of 4‐benzyl‐2‐phenyl‐1,3‐oxazol‐5(4H)‐one ( 15 ) with THP‐ or TBDMS‐protected ω‐hydroxyalkyl iodides. Ring opening of the THP‐protected oxazolones by treatment with Me₂NH followed by deprotection of the OH group gave the diamides 21 , whereas deprotection of the TBDMS series of oxazolones 25 with TBAF followed by treatment with HCl gas led to the corresponding lactones 23 in a one‐pot reaction.     

Synthesis of 6‐Alkylidene‐5,6‐dihydro‐4H‐1,3‐thiazine Derivatives via the Cyclization of N‐3‐Bromo‐3‐alkenylthioamides

By the treatment of N‐3‐bromo‐3‐alkenylthioamides with sodium hydroxide in DMF‐H₂O in the presence of tetra‐butylammonium bromide, series of 6‐alkylidene‐5,6‐dihydro‐4H‐1,3‐thiazine derivatives were prepared in moderate to good yields. The cyclization is supposed to proceed via both the intramolecular vinylic nucleophilic substitution and the elimination‐addition mechanisms (formation of acetylenic intermediates) in a competitive manner.     

Synthesis of phosphorylated 1,3,5‐oxadiazines via N‐acyltrifluoroacetimidoylphosphonates

N‐Benzoyl‐ and N‐methoxycarbonyltrifluoroacetimidoylphosphonates react with dimethylcyanamide in a [4+2]‐cycloaddition to give 4‐phosphorylated 1,3,5‐oxadiazines. The structures of the products were confirmed by NMR (¹H, ¹³C, ¹⁹F, ³¹P) and IR spectra and by XRD analysis. © 2002 John Wiley & Sons, Inc. Heteroatom Chem 13:22–26, 2002; DOI 10.1002/hc.1102     

Synthesis of 3‐Carbamoyl β‐Lactams via Manganese(III)‐Promoted Cyclization of N‐Alkenylmalonamides

Manganese(III)‐promoted cyclization of N‐alkenylmalonamides (=N‐alkenylpropanediamides) gave 3‐(aryl/(alkylamino)carbonyl) β‐lactams as well as 3‐(aryl/(alkylamino)thiocarbonyl) β‐lactams. The relative configuration of the obtained products was unambiguously determined by X‐ray crystallography. The proposed method is very useful for the one‐pot synthesis of a number of 3‐(aryl/(alkylamino)carbonyl) β‐lactams, especially those containing an amino(thiocarbonyl) moiety, which are not selectively accessible by other methods.     

Diastereoselective Synthesis of Novel Pyrrolidine or Pyrrolizine‐Fused Benzo‐δ‐sultams via 1,3‐Dipolar Cycloadditions

The synthesis of novel pyrrolidine or pyrrolizine‐fused benzosultams is described. A number of (E)‐N‐(2‐formylphenyl)‐N‐alkyl‐2‐phenylethenesulfonamides derivatives were synthesized and subjected to intramolecular [3 + 2] cycloaddition with azomethine ylides derived in situ from the reaction with sarcosine, phenylglycine, and L‐proline.     

Synthesis of N‐methyl‐4‐pyridyl‐1,2,3,4‐tetrahydroisoquinolines via a pictet‐spengler cyclisation

The synthesis of N‐methyl‐4‐pyridyl‐1,2,3,4‐tetrahydroisoquinolines (6a,b,c) was achieved via a Pictet‐Spengler cyclization of an activated amino group derivatized in a carbamate form. The obtained compounds have been designed as potential serotonin analogs.     

Synthesis and antioxidant activities of novel N‐aryl (and N‐alkyl) γ‐ and δ‐imino esters and ketimines

Novel N‐aryl (and N‐alkyl) γ‐ and δ‐imino esters 2a–g ( 3a–g ) and N‐aryl (and N‐alkyl) ketimines 2h–j ( 3h–j ) were synthesized in high yields (80–99%) from their corresponding γ‐ and δ‐keto esters and ketones in this study. The structures of the synthesized compounds were clarified by Fourier transform infrared (FT‐IR), NMR (¹H and ¹³C), mass spectrometry, and elemental analyses. Isomerizations [E/Z] were also determined by their ¹H NMR spectra. The free‐radical scavenging activity of imines was evaluated using the 1,1‐diphenyl‐2‐picryl‐hydrazyl (DPPH) method. The relationships between the structure and antioxidant activity of these compounds are discussed. Among these compounds, 2a–c (at the concentration 1000 μg/mL) exhibit high antioxidant activity similar to those of the standards (butylated hydroxyanisole [ BHA], butylated hydroxytoluene [ BHT], and ascorbic acid).