Reactions of Chlorosulfanyl Derivatives of Cyclobutanones with Different Nucleophiles

The reactions of 3‐chloro‐3‐(chlorosulfanyl)‐2,2,4,4‐tetramethylcyclobutan‐1‐one ( 2 ) with N, O, S, and P nucleophiles occur by substitution of Cl at the S‐atom. Whereas, in the cases of secondary amines, alkanols, phenols, thiols, thiophenols, and di‐ and trialkyl phosphates, the initially formed substitution products were obtained, the corresponding products with allyl and propargyl alcohols undergo a [2,3]‐sigmatropic rearrangement to give allyl and allenyl sulfoxides, respectively. Analogous substitution reactions were observed when 3‐chloro‐3‐(chlorodisulfanyl)‐2,2,4,4‐tetramethylcyclobutan‐1‐one ( 3 ) was treated with N, O, and S nucleophiles. The reaction of 3 with Et₃P led to an unexpected product via cleavage of the S? S bond (cf. Scheme 13). In the reactions of 2 with primary amines and H₂O, the substitution products react further via elimination of HCl to yield the corresponding thiocarbonyl S‐imides and the thiocarbonyl S‐oxide, respectively. Whereas the latter could be isolated, the former were not stable but could be intercepted by MeOH (Scheme 4) or adamantanethione (Scheme 5). The structures of some of the substitution products were established by X‐ray crystallography.     

Metallations and Reactions with Electrophiles of 4‐Isopropyl‐5,5‐diphenyloxazolidin‐2‐one (DIOZ) with N‐Allyl and N‐Propargyl Substituents: Chiral Homoenolate Reagents

N‐Allyl, N‐cinnamyl, and N‐(3‐trimethylsilyl)propargyl derivatives of 4‐isopropyl‐5,5‐diphenyloxazolidin‐2‐one (DIOZ) are prepared by lithiation of the parent DIOZ (with BuLi in THF) and reaction with the corresponding bromides (Scheme 1). Lithiation in the same solvent, with deprotonation by BuLi on the allylic or propargylic CH₂ group at dry‐ice temperature, provides colorful solutions, which are either combined with aldehydes or ketones directly or after addition (with or without warming) of (Me₂N)₃TiCl or (i‐PrO)₃TiCl. Conditions have thus been elaborated under which all three types of conjugated lithium compounds react in the γ‐position with respect to the oxazolidinone N‐atom: carbamoyl derivatives of enamines and allenyl amines are formed in yields ranging from 60 to 80% and with diastereoselectivities up to 98% (Schemes 2–5). The C=C bond of the N‐hydroxyalkenyl groups has (Z)‐configuration (products 5 and 8 ), the allene chirality axis has (M)‐configuration (products 9 ), and the addition to aldehydes and unsymmetrical ketones has taken place preferentially from the Si face. A mechanistic model is proposed that is compatible with the stereochemical outcome (assuming kinetic control and disregarding the presence of Li and Ti species in the reaction mixture; cf. L, M in Fig. 4). Hydrolysis of the enamine derivatives leads to lactols, oxidizable to γ‐lactones, with recovery of the crystalline oxazolidinone, as demonstrated in three cases (Scheme 6). Thus, the application of chiral oxazolidinone auxiliaries (cf. Figs. 1 and 2) has been extended to the overall enantioselective preparation of homoaldols.     

Using Calcium Carbide as an Acetylene Source for Cascade Synthesis of Pyrrolo[2,3‐b]quinoxalines via Copper‐Free Sonogashira Coupling Reaction

A palladium‐catalyzed cascade protocol has been established for the synthesis of 4‐methyl‐1‐(1H‐pyrrolo[2,3‐b]‐quinoxalin‐2‐yl)cyclohexanols and 2‐phenyl‐1‐(1H‐pyrrolo[2,3‐b]quinoxalin‐2‐yl)propan‐1‐ols through the reaction of N‐alkyl(aryl)‐3‐chloroquinoxalin‐2‐amines with calcium carbide and cyclohexanones or 2‐phenylpropanal. This one‐pot process, carried out without any copper salt in the key step of the Sonogashira coupling reaction, provides an efficient method for the synthesis of 2,3‐disubstituted pyrrolo[2,3‐b]quinoxalines in the presence of catalytic amounts of Pd(PPh₃)₂Cl₂ in DMSO/H₂O with high yields. The benefit of this strategy is the use of a commercially available, inexpensive, and less hazardous primary chemical feedstock, calcium carbide, as an acetylene source in a wet solvent.     

Efficient synthesis of 2‐substituted thieno[2,3‐d]pyrimidin‐4(3H)‐ones via an iminophosphorane

The carbodiimides 4 , obtained from reactions of iminophosphorane 3 with aromatic isocyanates, were reacted with secondary amines to give 2‐dialkylamino‐5‐ethyl‐6‐methyl‐thieno[2,3‐d]pyrimidin‐4(3H)‐ones 6 in the presence of catalytic amount of EtONa. Reactions of 4 with phenols or ROH in the presence of the catalytic amount of K2CO₃ or RONa gave 2‐aryloxy‐ or 2‐alkoxy‐5‐ethyl‐6‐methyl‐thieno[2,3‐d]pyrimidin‐4(3H)‐ones 6 in satisfactory yields. The effects of the nucleophiles on cyclization have been investigated. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:266–270, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20424     

Eco‐friendly and Efficient Synthesis of 2,3‐Dihydroquinazolin‐4(1H)‐ones

A simple and facile method for the synthesis of 2,3‐dihydroquinazolin‐4(1H)‐ones through the direct cyclocondensation of one‐pot three‐component cyclocondensation of isatoic anhydride, ammonium acetate (or primary amines) and aldehydes; and anthranilamide and aldehydes using silica supported ferric chloride (SiO₂‐FeCl₃) as catalyst under solvent‐free conditions is described.     

Stereoselective Synthesis and Retentive Trapping of α‐Chiral Secondary Alkyllithiums Leading to Stereodefined α,β‐Dimethyl Carboxylic Esters

The treatment of α‐chiral secondary alkyl iodides with tBuLi at ?100 °C leads to the corresponding secondary alkyllithiums with high retention of configuration. Subsequent quenching with various electrophiles such as Bu₂S₂, DMF, MeOB(OR)₂, or Et₂CO provides the desired products with retention of configuration. Furthermore, a transmetalation with CuBr?P(OEt)₃ also allows retentive trapping with acid chlorides and ethylene oxide. The quenching of the resulting alkyllithiums with ClCO₂Et furnishes stereoselectively syn‐ and anti‐ethyl‐2,3‐dimethyl ester carboxylates (d.r.>94 %). Related esters bearing three adjacent stereo‐controlled centers (stereotriads) have also been prepared. This method has been applied to the synthesis of the ant pheromone (±)‐lasiol in 26 % overall yield (four steps) with d.r.=97:3 starting from commercially available cis‐2,3‐epoxybutane.     

Nickel(II)‐Catalyzed Asymmetric Propargyl [2,3] Wittig Rearrangement of Oxindole Derivatives: A Chiral Amplification Effect

A highly enantioselective [2,3] Wittig rearrangement of oxindole derivatives was realized by using a chiral N,N′‐dioxide/Ni^II complex as the catalyst under mild reaction conditions. A strong chiral amplification effect was observed, and allowed access to chiral 3‐hydroxy 3‐substituted oxindoles bearing allenyl groups in high yields and enantioselectivities (up to 92 % ee) by using a ligand with only 15 % ee. A reasonable explanation was given based on the experimental investigations and X‐ray crystal structures of enantiomerically pure and racemic catalysts. Moreover, the first catalytic kinetic resolution of racemic oxindole derivatives by a [2,3] Wittig rearrangement was realized with high efficiency and stereoselectivity.     

Azirine/Oxindole Ring Enlargement via Amidinium Intermediates

A novel general method for the synthesis of oxindoles, namely the ‘azirine/oxindole ring enlargement via amidinium‐intermediates’ has been established: the reaction of 2H‐azirin‐3‐amines 1 with BF₃?OEt₂ in THF solution at ?78° leads to 1,3,3‐trialkyl‐2‐amino‐3H‐indolium tetrafluoroborates 14 in good yields (Scheme 5). Treatment of aqueous solutions of 14 at 0° with aqueous NaOH (30%) and extraction with CH₂Cl₂ gives oily substances that are either hydrates of 1,3,3‐trialkyl‐2‐dihydroindol‐2‐imines 15 or the corresponding indolium hydroxides. These products are transformed to the corresponding 1,3,3‐trialkyl‐2,3‐dihydroindol‐2‐ones 17 in modest yields upon refluxing in H₂O/THF. Reaction of 14 with Ac₂O in pyridine at ca. 23° for 16 h followed by aqueous workup and chromatographic separation leads to mixtures of N‐(1,3,3‐trialkyl‐2,3‐dihydro‐indol‐2‐yliden)acetamides 16 and oxindoles 17 (Scheme 6). Hydrolysis of 16 with aqueous HCl under reflux for 1–2 h gives oxindoles 17 in a good yield. Several oxindoles, spiro‐oxindoles, and 5‐substituted oxindoles were synthesized by means of the reactions mentioned above.     

Conventional and Microwave‐Assisted Synthesis and Biological Activity Study of Novel Heterocycles Containing Pyran Moiety

Under both conventional and microwave methods, 2‐amino‐4H‐pyran‐3‐carbonitrile derivative 1 was synthesized and reacted with different reagents. Thus, 2‐amino‐4H‐pyran‐3‐carbonitrile derivative was treated with chloroacetyl chloride, phenyl isocyanate, cyanoacetic acid, benzoyl chloride, triethyl orthoformate, acetic anhydride/H₂SO₄, arylidene malononitrile, urea, and/or p‐aminosulphaguanidine producing chloroacetamide, 3‐phenylurea, cyanoacetamide, N‐benzoylpyran, ethylformimidate, pyranopyrimidin‐4‐one, pyranopyridine, pyranopyrimidin‐2‐one, and pyranopyrimidin‐2‐imine derivatives, respectively. Meanwhile, compound 1 was reacted with ethyl bromoacetate, phenacyl bromide, phthalic anhydride, different aromatic amines, and/or acetic acid/H₂SO₄ to produce 5‐aminopyrano[2,3‐b]pyrrole‐6‐carboxylate, dihydropyrano[2,3‐b]pyrrole‐6‐yl‐(phenyl)methanone, 1,3‐dioxoisoindolinyl pyran, 1,4‐dihydropyridine, and 2‐hydroxy‐1,4‐dihydropyridine derivatives, respectively. On the other hand, when compound 1 was allowed to react with maleic anhydride and/or hydrazine hydrate, pyran‐4‐oxobut‐2‐enoic acid and 3‐aminopyranopyrazole derivatives were obtained, respectively. Reaction of pyran‐4‐oxobut‐2‐enoic acid with malononitrile under different conditions gave 2‐(furan‐2‐yl)‐4H‐pyran and 2‐(4H‐pyran‐2‐yl)‐1H‐pyrrole derivatives, while condensation of 3‐aminopyranopyrazole with benzaldehyde gave 1,4‐dihydropyrano[2,3‐c]pyrazol‐3‐yl‐1‐phenylmethanimine derivative. The newly synthesized compounds were characterized by the spectroscopic tools IR, ¹H‐NMR, ¹³C‐NMR, MS, and elemental analysis. Some of these compounds have been screened in vitro for antimicrobial activity against different strains of bacteria and fungi and also were tested against two cancer cell lines: mammary gland breast cancer (MCF‐7) and colon cancer (HCT‐118).     

KAl(SO4)2·12H2O (Alum) Catalyzed One‐Pot Three‐Component Synthesis of 2‐Alkyl and 2‐Aryl‐4(3H)‐quinazolinone under Microwave Irradiation and Solvent Free Conditions

Twenty 2,3‐disubstituted‐4(3H)‐quinazolinones were synthesed by one‐pot three‐component method with isatoic anhydride, orthoesters and amines as raw materials in the presence of KAl(SO₄)₂·12H₂O (Alum) under microwave irradiation and solvent‐free conditions. 6‐Bromo‐2‐propyl‐3‐p‐tolylquinazolin‐4(3H)‐one ( 4m ), 6‐bromo‐2‐methyl‐3‐phenethylquinazolin‐4(3H)‐one ( 4n ) and 6‐bromo‐2‐ethyl‐3‐phenethylquinazolin‐4(3H)‐one ( 4o ) were characterized by IR, ¹H NMR, ¹³C NMR and elemental analysis.     

TiO2–SiO2 Catalyzed Eco‐friendly Synthesis and Antioxidant Activity of Benzopyrano[2,3‐d]pyrimidine Derivatives

A cost‐effective and eco‐friendly synthesis of benzopyrano[2,3‐d ]pyrimidine derivatives has been developed via three component one‐pot tandem approach by condensing different salicylaldehydes and secondary amines with malononitrile in the presence of TiO₂–SiO₂ catalyst at 80°C under solvent‐free conditions. Mild experimental conditions, reusability of the catalyst, and cost effectiveness are the merits of this procedure. Compounds 4g , 4h , and 4i bearing 2‐OMe group on the hydroxyphenyl group linked to the central carbon present in between the two nitrogen atoms of the pyrimidine ring were found to exhibit good antioxidant activity while other compounds have moderate antioxidant activity.     

Reactions of 2‐Pentynyl trimethylsilylethynyl selenides with primary amines via allenyl selenoketene

Reactions of 2‐pentynyl trimethylsilylethynyl selenide 3 with primary amines 5 via allenyl selenoketene 4 afforded the corresponding selenine 6 , selenophene 7 and β,γ‐unsaturated selenoamide 8 , respectively.     

Chromium(II) chloride as a highly selective (C(5)-dechlorinating agent for functionalized 2,3,5-trichlorocyclopent-2-en-1-ones

(±)-2,3,5-Trichloro-4,4-ethylenedioxy- and (±)-5-allyl(allenyl)-2,3,5-trichloro-4,4-dimethoxycyclopent-2-en-1-ones undergo regioselective reductive C(5)-dechlorination under the action of CrCl₂ to give the corresponding 2,3-dichlorocyclopentenones. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1699–1701, September, 1997.     

A β‐Enaminone‐Initiated Multicomponent Domino Reaction for the Synthesis of Indoloquinolizines and Benzoquinolizines from Acyclic Precursors

The cerium(IV) ammonium nitrate (CAN)‐catalyzed sequential multicomponent reaction between tryptamine, α,β‐unsaturated aldehydes, and β‐dicarbonyl compounds affords highly substituted indolo[2,3‐a]quinolizines in a single synthetic operation. Two rings are generated through the creation of two C? C and two C? N bonds by a domino process comprising initial β‐enaminone formation, followed by individual Michael addition, 6‐exo‐trig cyclization, iminium formation, and Pictet–Spengler steps. Furthermore, the reaction is diastereoselective and affords exclusively compounds with a trans relationship between the H‐2 and H‐12b protons. The use of amines bearing a less nucleophilic side chain aromatic ring (5‐bromotryptamine, 3,4‐dimethoxyphenylethylamine) prevents the Pictet–Spengler final step and leads to N‐indolylethyl or N‐phenylethyl‐1,4‐dihydropyridines, which are cyclized to the corresponding indolo[2,3‐a]quinolizines or benzo[a]quinolizines in the presence of HCl in methanol/water. Treatment of the fused quinolizine derivatives with sodium triacetoxyborohydride led to the corresponding indolo[2,3‐a]quinolizidines or benzo[a]quinolizidines, possessing four stereogenic centers, as mixtures of two diastereomers.     

An Enantioselective Bidentate Auxiliary Directed Palladium‐Catalyzed Benzylic C−H Arylation of Amines Using a BINOL Phosphate Ligand

A new enantioselective palladium(II)‐catalyzed benzylic C?H arylation reaction of amines is enabled by the bidentate picolinamide (PA) directing group. This reaction provides the first example of enantioselective benzylic γ‐C?H arylations of alkyl amines, and proceeds with up to 97 % ee. The 2,2′‐dihydroxy‐1,1′‐binaphthyl (BINOL) phosphoric acid ligand, Cs₂CO₃, and solvent‐free conditions are essential for high enantioselectivity. Mechanistic studies suggest that multiple BINOL ligands are involved in the stereodetermining C?H palladation step.     

Preparation of Silica Nanoparticles from Organic Laboratory Waste of Silica Gel HF254 and Their Use as a Highly Efficient Catalyst for the One‐Pot Synthesis of 2,3‐Dihydro‐1H‐isoindolone Derivatives

Reaction of an isocyanide with an iminium ion intermediate, formed by reaction between 6‐formyl‐2,3‐dimethoxybenzoic acid and secondary amines (dibenzyl‐ or benzyl(isopropyl)amine) in the presence of silica nanoparticles (silica NPs, ca. 70 nm) proceeds smoothly at room temperature to afford 2,3‐dihydro‐1H‐isoindolone derivatives in high yields.     

Novel and Stereospecific Synthesis of (2S)‐3‐(2,4,5‐Trifluorophenyl)propane‐1,2‐diol from D‐Mannitol

A stereospecific synthesis of (2S)‐3‐(2,4,5‐trifluorophenyl)propane‐1,2‐diol from D ‐mannitol has been developed. The reaction of 2,3‐O‐isopropylidene‐D ‐glyceraldehyde with 2,4,5‐trifluorophenylmagnesium bromide gave [(4R)‐2,2‐dimethyl‐1,3‐dioxolan‐4‐yl](2,4,5‐trifluorophenyl)methanol in 65% yield as a mixture of diastereoisomers (1 : 1). The Ph₃P catalyzed reaction of the latter with C₂Cl₆ followed by reduction with Pd/C‐catalyzed hydrogenation gave (2S)‐3‐(2,4,5‐trifluorophenyl)propane‐1,2‐diol with >99% ee and 65% yield.     

Sequential Intramolecular Diels–Alder Reaction of 3‐Heteroaryl‐2‐propenylamides of Ethenetricarboxylate

The reaction of 1,1,2‐ethenetricarboxylic acid 1,1‐diethyl ester with E‐3‐(2‐furyl)‐2‐propenylamines under the amide condensation conditions (EDCI/HOBt/Et₃N) on heating at 80–110°C afforded cis‐fused tricyclic compounds, furo[2,3‐f]isoindoles as major product. On the other hand, the reaction with E‐3‐(3‐furyl)‐2‐propenylamines afforded trans‐fused tricyclic compounds predominantly. The formation of amide/[4 + 2] cycloaddition/hydrogen‐shift reactions proceed sequentially. The observed stereoselectivity of the fused rings has been investigated by the density functional theory calculations. The reaction of 1,1,2‐ethenetricarboxylic acid 1,1‐diethyl ester with 3‐(3‐pyridinyl)‐2‐propen‐1‐amine under the amide condensation conditions afforded HOBt‐incorporated 3,4‐trans‐pyrrolidine selectively. The chemoselectivity and stereoselectivity of the reactions with (3‐heteroaryl)‐2‐propen‐1‐amines depend on the nature of heteroarenes.     

Unprecedented Spectroscopic and Computational Evidence for Allenyl and Propargyl Titanocene(IV) Complexes: Electrophilic Quenching of Their Metallotropic Equilibrium

The synthesis and structural characterization of allenyl titanocene(IV) [TiClCp₂(CH=C=CH₂)] 3 and propargyl titanocene(IV) [TiClCp₂(CH₂?C≡C?(CH₂)₄CH₃)] 9 have been described for the first time. Advanced NMR methods including diffusion NMR methods (diffusion pulsed field gradient stimulated spin echo (PFG‐STE) and DOSY) have been applied and established that these organometallics are monomers in THF solution with hydrodynamic radii (from the Stokes–Einstein equation) of 3.5 and 4.1 Å for 3 and 9 , respectively. Full ¹H, ¹³C, Δ¹H, and Δ¹³C NMR data are given, and through the analysis of the Ramsey equation, the first electronic insights into these derivatives are provided. In solution, they are involved in their respective metallotropic allenyl–propargyl equilibria that, after quenching experiments with aromatic and aliphatic aldehydes, ketones, and protonating agents, always give the propargyl products P (when carbonyls are employed), or allenyl products A (when a proton source is added) as the major isomers. In all the cases assayed, the ratio of products suggests that the metallotropic equilibrium should be faster than the reactions of 3 and 9 with electrophiles. Indeed, DFT calculations predict lower Gibbs energy barriers for the metallotropic equilibrium, thus confirming dynamic kinetic resolution.     

Reversible Transformation between Amorphous and Crystalline States of Unsaturated Polyesters by Cis–Trans Isomerization

An aliphatic polyester has been prepared from ethylene oxide and maleic anhydride that undergoes reversible transformation between amorphous (T_g=18 °C) and crystalline (T_m=124 °C) states through cis–trans isomerization of the C=C bonds in the polymer backbone without any change in either the molecular weight or dispersity of the polymer. A similar transformation was also observed in chiral unsaturated polyesters formed from enantiopure terminal epoxides, such as epichlorohydrin, phenyl glycidyl ether, and (2,3‐epoxypropyl)benzene. These unsaturated polyesters with 100 % E‐configuration in the crystalline state were prepared by quantitative isomerization of their Z‐configuration analogues in the presence of a catalytic amount of diethylamine, while in the presence of benzophenone, irradiation with 365 nm UV light resulted in the transformation of about 30 % trans‐alkene to cis‐maleate form, thereby affording amorphous polyesters.