Synthetic studies of erythromycin derivatives: 6-O-methylation of (9S)-12,21-anhydro-9-dihydroerythromycin A derivatives

Synthetic studies on methylation of erythromycin derivatives were conducted. Methylation of 6 resulted in the formation of the C-3′ quaternary ammonium salts with a rate faster than 6-O-methylation. In dipolar aprotic solvent and under strong base conditions, 6-O-methylation, C-3′ quaternary ammonium salts formation and 2-C-methylation proceeded simultaneously to yield a mixture of three different products 7, 8 and 9. The quaternary ammonium salts were converted back to the corresponding tertiary amines 2, 10 and starting material 6 by employing sodium 4-pyridinethiolate as a N-demethylation reagent. The 6-O-methylation was eventually achieved in a good yield when a carbobenzyloxy (Cbz) group was utilized to protect the C-3′-dimethylamino group of 4. In this report, we will discuss the details of different reaction courses in the methylation of (9S)-12, 21-anhydro-9-dihydroerythromycin A derivatives.     

Highly stereoselective addition of organozinc reagents to pentopyranose derived glycals: effect of protecting group and assignment of C-glycoside stereochemistry

The nucleophilic addition of ethyl 3-propionylzinc iodide to a variety of differently protected pentopyranose derived d-glycals 6a-g proceeds with good to high levels of diastereoselectivity to provide the corresponding β-C-glycosides 7. The stereochemistry of the para-nitrobenzoate derivative 7d has been confirmed by X-ray crystallography, and the stereochemistry of the other β-C-glycoside products has been correlated to 7d. The stereochemical outcome observed supports the earlier suggestion by Isobe that through-space effects are important in stabilising and controlling the reactivity of the intermediate oxonium species represented by 11.     

Solvent-free reactions of N,N′-thiocarbonyldiimidazole with ferrocenylcarbinols

The efficient and simple routes for the synthesis of various ferrocenyl derivatives from ferrocenylcarbinols and N,N′-thiocarbonyldiimidazole (TCDI) are described. It involves grinding the two substrates in a Pyrex tube with a glass rod at room temperature. The reaction of ferrocenylmethanol (1a) provided S,S-bis(ferrocenylmethyl)dithiocarbonate (1b), whose crystal structure and a plausible mechanism for its formation are also reported. The reaction of 1-ferrocenyl-1-phenylmethanol (2a) and 1-ferrocenylbutanol (2b) gave the products 2c and 2d, respectively. The reaction of ω-ferrocenyl alcohols 4-ferrocenylphenol (3a) and 6-ferrocenylhexan-1-ol (3b) yielded the products 3c and 3d, respectively. Reaction of 1,1′-ferrocenedimethanol (3e) afforded 3f in moderate yield, and by contrast, it was not similar to 1b. Reaction of [4-(trifluoromethyl)phenyl]methanol (4a) provided the thiocarbonate 4b in good yield.     

Synthesis of 3-substituted-4-hydroxyquinoline N-oxides from the Baylis-Hillman adducts of o-nitrobenzaldehydes

The reaction of the Baylis-Hillman adducts 1b-f derived from o-nitrobenzaldehydes in trifluoroacetic acid in the presence of triflic acid (0.2 equiv.) afforded 3-substituted-4-hydroxyquinoline N-oxides 2b-e and 2a in good to moderate yields. The reaction mechanism was evidenced by the experiment with 1f, the Baylis-Hillman adduct of 2-nitrobenzaldehyde N-tosylimine, as the one involving N-hydroxyisoxazoline as the key intermediate.     

Synthesis and photochromic behaviour of new methyl induced linear and angular thieno-2H-chromenes

New methyl induced linear and angular thieno-2H-chromenes 4, 5 and 6 were prepared by reaction of new methylated 6-hydroxybenzo[b]thiophenes 2 (a, b and c) and propargylic alcohols 3a and 3b, using acidic Alumina Brockmann I as catalyst and drying agent. Compounds 2 were prepared in good to excellent yields in a ‘one pot’ three step reaction from the corresponding bromo compounds 1. The photochromic behaviour of compounds 4, 5 and 6b was evaluated with the aid of a classical set of spectrokinetic parameters, and compared to reference compounds that are benzoannellated in the 5,6 and 6,7 positions of the chromene (naphthopyrans) and also to thieno-2H-chromenes 7 and 8, previously prepared, which are analogues of 5a. The resistance to fatigue (photodegradation) under continuous irradiation was also evaluated.     

Synthesis of trifluoromethyl-promoted functional pyrazolo[1,5-a]pyrimidine and pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones

Ethyl 5-amino-3-trifluoromethyl-1H-pyrazole-4-carboxylate (1) was efficiently synthesized via the condensation of ethyl cyanoacetate and trifluoroacetic anhydride, followed by chloridization and the condensation with aqueous hydrazine. Its unique reactivity was exploited for the synthesis of trifluoromethylated pyrazolo[1,5-a]pyrimidine (5) and pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones (8a-j). Among them, 5 was firstly found to be a novel fluorescent molecule that might be exploited as an attractive fluorophore for possessing many binding sites, and its fluorescence intensity was obviously stronger than its methyl analogue. 8 were found to be a new chemical class of potential monocotyledonous Echinochloa crus-galli L. Beauv inhibitors, and were more active than their methyl analogues.     

Synthesis of N,N′-bis and N,N,N′,N′-tetra-[(3,5-di-substituted-1-pyrazolyl)methyl]para-phenylenediamines: new candidate ligands for metal complex wires

A series of tridentate ligands N,N-bis-[(di-substituted-1-pyrazolyl)methyl]arylamines 2-3a,b and benzylamine 4a,b, tetradentate N,N′-bis-[(di-substituted-1-pyrazolyl)methyl]para-phenylenediamines 7a,b and hexadentate N,N,N′,N′-tetra-[(di-substituted-1-pyrazolyl)methyl]para-phenylenediamines 8a,b has been prepared in good yield by condensation of arylamines, benzylamine or para-phenylenediamine with N-hydroxymethyl disubstituted pyrazoles 1a,b. The synthesis and characterisation of these various polydentate ligands are described.     

Acyclic tertiary diamines and 1,4,7,10-tetraazacyclododecane with fluorine-containing β-diketones: Leading to low melting ionic adducts

N,N,N′,N′-Tetramethylmethanediamine (1a), N,N,N′,N′-tetramethylethanediamine (1b), N,N,N′,N′-tetramethyl-1,3-propanediamine (1c), and N,N,N′,N′-tetramethyl-1,6-hexanediamine (1d) were reacted at 25 °C with 1,1,1,5,5,5-hexafluoro-2,4-pentanedione (2a), 2,2-dimethyl-6,6,7,7,8,8,8-heptafluoro-3,5-octanedione (2b), 2-thenoyltrifluoroacetone (2c), and 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (2d) to form the ionic adducts 3-18. 1,4,7,10-Tetraazacyclododecane (1e) reacted at 25 °C with β-diketones (2a-d) and 1,1,1-trifluoro-2,4-pentanedione (2e) to give ionic solids 19-23 in good yields. Some of the products are liquid at 25 °C and are thermally stable over long liquid ranges as determined by thermal gravimetric analyses. Single-crystal X-ray structure determinations show that compounds 9 and 21 crystallize in the monoclinic space groups P2(1)/c and P2(1)/n, respectively. All the new compounds were characterized by ¹H, ¹⁹F and ¹³C NMR, electrospray MS and/or elemental analyses.     

Cycloaddition of methyl 2-(2,6-dichorophenyl)-2H-azirine-3-carboxylate to electron-rich 2-azadienes

tert-Butyldimethylsililoxy-2-aza-1,3-butadienes react with 2H-azirine 3 leading to Diels-Alder cycloadducts in moderate yields. The reactions are endo- and regioselective with the azirine being added by its less hindered face. There is only one product in the case of 1b, 4b. There are two isomers (4 and 5) from 1a, 1c and 1d. A different result was obtained with the diene 1e. Diene 1e formed products 4e and 8. Some of compounds 4 and 5 have been hydrolysed leading to functionalised aziridines 7. Compound 8 gave aziridine 9.     

Substituent-induced regioselective synthesis of 1,2-teraryls and pyrano[3,4-c]pyran-4,5-diones from 2H-pyran-2-ones

Substituent-controlled regioselective synthesis of highly functionalized 1,2-teraryls 3a-k has been achieved through ring transformation of 6-aryl-4-(pyrrolidin-1-yl/piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1a-g by aryl acetones 2a-c in the presence of powdered KOH in DMF in very good yield. Under similar reaction conditions, 6-aryl-4-methylsulfanyl-2H-pyran-2-ones 5a-f afforded 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 6a-j as major products and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles as minor constituents 7a-j.     

Simple preparation of phenylpropenoid β-d-glucopyranoside congeners by Mizoroki-Heck type reaction using organoboron reagents

Palladium(II)-catalyzed carbon-carbon bond formation between allyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (3) and arylboronic acid congeners gave the corresponding cinnamyl 2,3,4,6-tetra-O-acetyl- β-d-glucopyranosides (4a-m) in good yield. Among them, coupling products 4a-m were converted to not only the naturally occurring phenylpropenoid β-d-glucopyranoside analogues (1a-e) but also the unnaturally ones (1f-m).     

Stabilization of (N-methyleneamino)imidoylketenes: synthesis of dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazines

Thermolysis of substituted methyl 1-methyleneamino-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates 2a,b led to substituted dimethyl 3,9-dioxo-1,5,7,11-tetrahydro-1H,7H-dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazine-1,7-dicarboxylates 4a,b and methyl 2,5-dihydro-5-oxo-1H-pyrazole-3-carboxylates 5a,b as minor products. The structure of compound 4a was determined by X-ray crystallography. The proposed mechanism of this conversion includes generation of (N-methyleneamino)imidoylketenes 6a,b and its intramolecular transformation to azomethine imines—5-oxo-2,5-dihydropyrazole-1-methylium-2-ides 7a,b, which undergo dimerization in head-to-tail manner yielding products 4a,b and partially hydrolyse to compounds 5a,b.     

Racemic [1SR,2RS,(RS)]-N-cyano(phenyl)methyl-1-aminoindan-2-ol: crystal structure and reactivity towards thermal epimerization in the solid state

A diastereomeric mixture of racemic α-amino nitriles [1SR,2RS,(SR)]- (1) and [1SR,2RS,(RS)]-N-cyano(phenyl)methyl-1-aminoindan-2-ol (2) was thermally epimerized in the solid state to give diastereopure [1SR,2RS,(SR)]-1. The reaction was about 26 times slower than the same reaction of a mixture of their enantiopure counterparts, showing that different mechanisms operated between the two transformations. X-ray crystallographic analysis revealed that in the former transformation, racemic-compound crystals of 2 were converted into conglomerate crystals of 1, while in the latter, enantiomeric crystals of 2 were converted into enantiomeric crystals of 1. The difference in the reactivity toward the epimerization between the racemic and the enantiopure mixture could be rationalized by the difference in the stability of compound 2 in the two crystal forms.     

Copper-mediated coupling of aminopurines and aminopyrimidines with arylboronic acids

Selective N-arylation of aminopurines and aminopyrimidines 1-3 with arylboronic acids 4-6 was explored using copper(II) acetate and the corresponding N-arylated purine and pyrimidine derivatives 7-15 were obtained in moderate to good yields.     

Synthesis and reactivity of N-aryl substituted N-heterocyclic silylenes

The synthesis of two N-aryl substituted 2-silaimidazolidenes 9a, b by metal-reduction of the appropriate silicon(IV) heterocycles is reported. Structural as well as spectroscopic data obtained for the N-aryl substituted N-heterocyclic silylenes (NHSi) are very close to those obtained previously for their N-alkyl substituted counterparts. NHSis 9a, b are used as starting materials for the synthesis of a series of dichalcogenadisiletanes 19-24 and for of a mono silylene tungsten complex 29. The reactivity studies revealed only marginally differences between the N-aryl substituted NHSis 9a, b and previously described N-alkyl substituted silylenes.     

Effect of π-accepting substituent on the reactivity and spectroscopic characteristics of triarylbismuthanes and triarylbismuth dihalides

Competitive chlorination of p-substituted triarylbismuthanes 1 [(p-XC₆H₄)₃Bi; a: X = OMe, c: Cl, d: CO₂Et, e: CF₃, f: CN, g: NO₂] and trimesitylbismuthane (2,4,6-Me₃C₆H₂)₃Bi 1h by sulfuryl chloride was carried out against 1b (X = H) and the effect of these substituents on the formation of triarylbismuth dichlorides 2 was studied. The relative ratios 2/2b decreased with increasing electron-withdrawing ability of the substituents (2a/2b = 53/47, 2c/2b = 33/67, 2d/2b = 35/65, 2e/2b = 29/71, 2f/2b = 16/84, 2g/2b = 0/100, 2h/2b = 46/54), indicating a lowering of reactivity of the lone pair on the bismuth atom. Pd-Catalyzed degradation of 2a-g and their difluorides 3 giving biaryls 4 was promoted by the electron-withdrawing p-substituents in the equatorial aryl groups but suppressed by the more electronegative fluorine atoms in the apical positions. This is in fairly good accord with the stability of the trigonal bipyramidal geometry. The ¹³C NMR study of 1-3 showed that the signals due to the ipso carbons (C1) attached to the bismuth atom shift downfield with increasing electron-withdrawing nature of the p-substituents. No such tendency was observed in other aromatic ring carbons. The electronic effect on the C1 atoms, similar to that on the chlorination of 1 and degradation of 2 and 3, indicates the significant participation of the C1 atoms in these reactions through the Bi-C1 bonds.     

Synthesis and combinatorial approach of the reactivity of 6- and 7-arylthieno[3,2-d][1,3]oxazine-2,4-diones

This paper describes a general procedure for the synthesis of new substituted thiaisatoic anhydrides or 6- or 7-aryl-1H-thiéno[3,2-d][1,3]oxazine-2,4-diones 3a-j and 4a-f. They were synthesized in large scale under microwave heating conditions with high yields. The reactivity vs nucleophilic reagents of these compounds was studied and permitted to develop a simple combinatorial procedure to synthesize a library of new thiophene ureidoacids 7a-j and 8a-j.     

Synthesis of aluminium complexes bearing a piperazine-based ligand system

Aluminium complexes bearing the N,N-chelating ligand 1,4-bis(2-hydroxy-3,5-di-tert-butyl)piperazine (1) have been synthesised. Both monometallic and bimetallic aluminium methyl complexes (2 and 3, respectively) were prepared by treatment of 1 with the appropriate amount of AlMe₃. Complex 2 can be converted to 3 by addition of excess AlMe₃. Bimetallic aluminium-ethyl complex 4 was also prepared. Treatment of 1 with AlEt₂Cl afforded the monometallic chloride complex 5. Treatment of this latter complex with potassium alkoxides (KOR, R = Me, Et, ⁱPr, ^tBu) or AgOTf afforded the corresponding aluminium alkoxide complexes (6, R = Et; 7, R = Me; 8, R = ⁱPr; 9, R = ^tBu; 10, R = OTf) in good yields. Aluminium ethoxide complex 6 was also synthesised by treatment of 1 with AlEt₂OEt. All of these complexes were tested as potential catalysts in the ring-opening polymerisation of rac-lactide and caprolactone with limited success.     

A simple approach for the regioselective synthesis of imidazo[1,2-a]pyrimidiones and pyrimido[1,2-a]pyrimidinones

Several imidazo and pyrimido[1,2-a]pyrimidinones of type 1 and 2 were synthesized through intramolecular cyclization of pyrimidines 9 or pyrimidinones 10 bearing a variety of β and γ-aminoalcohols at the 2-position. Ring closure of the pyrimidinones of type 10 under Mitsunobu conditions lead to mixtures of both bicyclic regioisomers 1 and 2. Treatment of pyrimidines of type 9 with H₂SO₄ provided an efficient and operationally simple one-pot hydrolysis-cyclization procedure for obtaining imidazo and pyrimido[1,2-a]pyrimidinones 1 in good yields as the sole regioisomeric bicyclic product.     

Synthesis and reactivity of pyrrolo[3,2-d][1,3]oxazine-2,4-dione. Access to new pyrrolo[3,2-e][1,4]diazepine-2,5-diones

A convenient synthesis of pyrrolo[3,2-d][1,3]oxazine-2,4-dione 4 is described and its reactivity towards various nucleophiles studied. The regioselective ring opening of anhydride 4 or its N-alkylated analog 25 in the presence of alanine or proline afforded, respectively, imidazolidinedione 22 and N-protected pyrrolo[3,2-e][1,4]diazepines 30 and 31 in a one-pot process. In a last part of this study, an alternative route to produce a library of eight non protected pyrrolo[3,2-e][1,4]diazepine-2,5-diones 35a–h is described to overcome the limited reactivity of anhydride 4.