Reactions of novel trifluoromethyl propargylic carbocation with carbon nucleophiles

Trifluoromethyl propargylic carbocation [I] generated from the reaction of 1-amino substituted 3-trifluoromethyl-2-propynyl trimethylsilyl ether 1 with TMSOTf in CH₂Cl₂ at −15 °C, followed by warming to room temperature reacted with 1.2 equiv of substituted benzenes, RMgBr and allylsilane to give the enones 3a-l and 5, respectively. The reaction of [I] with anisole, followed by treatment with Grignard reagents afforded the corresponding allyl amine derivatives 7, which underwent cyclization reaction to give indene derivatives 8 by using 2 equiv of TMSOTf.     

Imidomethylation of C-nucleophiles using O-phthalimidomethyl trichloroacetimidate and catalytic amounts of TMSOTf

The O-phthalimidomethyl trichloroacetimidate (1), as a latent aminomethylating agent, exhibits high electrophilicity towards a variety of C-nucleophiles in the presence of catalytic amounts of TMSOTf and mild reaction conditions. The nucleophiles include aromatics, alkenes and active methylene compounds 2-11 whereby a phthalimidomethyl group could be introduced to give compounds 12-22. Removal of the phthaloyl group gave the respective amines, β-amino ketones, and β-amino acids. The O-(trichloroacetamido)methyl trichloroacetimidate (35) was also found to be a good amidomethylating agent.     

Claisen rearrangements based on vinyl fluorides

2-Fluoroalk-1-en-3-ols (4), available from terminal alkenes (1) by bromofluorination, subsequent dehydrobromination of the 1-bromo-2-fluoroalkanes (2) to form 2-fluoroalkenes (3) and selenium dioxide mediated allylic oxidation with tert-butylhydroperoxide, undergo Johnson-Claisen rearrangement on treatment with trimethyl orthoacetate to give methyl 4-fluoroalk-4-enoates (7) in high yields. In contrast Ireland-Claisen rearrangement of 3-acetoxy-2-fluorodec-1-ene (9b) with triethylamine and TMSOTf in ether failed. Instead of the expected formation of a carboxylic acid, selective C-silylation of the α-position to the carboxyl group to form 14 occurred. However, Ireland-Claisen rearrangement was successful with corresponding chloroacetates 10 and propionates 11 of four 2-fluoroalk-1-en-3-ols (4) to give 2-chloro-4-fluoroalk-4-enecarboxylic acids (15) or its 2-methyl derivatives 16, respectively, in moderate yields. These [3,3]-sigmatropic rearrangements are diastereoselective giving trans-configured double bonds, exclusively. Corresponding esters derived from (Z)-2-fluorocyclododec-2-enol (22), did rearrange to yield mixtures of diastereomers much less selectively. Also 2-fluorodec-2-enol (6), which was prepared by rearrangement of 2-fluoro-2-octyloxirane (5) with TMSOTf and triethylamine, was successfully applied as a starting material for [3,3]-sigmatropic rearrangements. The corresponding 3-(1-fluoroethenyl)alkanoic acid derivatives 17 and 18 were formed in moderate yield.     

Synthesis of acyclic nucleoside analogues based on 1,2,4-triazolo[1,5-a]pyrimidin-7-ones by one-step Vorbrüggen glycosylation

New acyclovir analogues were obtained by reaction of 1,2,4-triazolo[1,5-a]pyrimidin-7-ones 4a–i with (2-acetoxyethoxy)methyl acetate 5 in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as catalyst (Vorbrüggen procedure). Coupling between compounds 4a–f and 5 led to a mixture of N3- and N4-isomers 6 and 7, respectively. On the contrary, the reaction of compounds 4g–i with 5 proceeded selectively with formation of N3-isomers only. It was found that the ratio of 6a–f and 7a–f depends on the presence or the absence of N,O-bis(trimethylsilyl)acetamide (BSA). Glycosylated products 6a–f and 7a–f underwent reversible isomerization under TMSOTf treatment. The ratio of glycosylated products of the coupling reaction between 4 and 5 was thermodynamically controlled. A similar reaction occurred if ZnCl₂ was chosen as a catalyst, although lower yields of the acyclic analogues of nucleosides were observed. The glycosylation of other purines (adenine and guanine) can be achieved via the non-BSA modification of the Vorbrüggen procedure.     

Practical synthesis of 4′-selenopyrimidine nucleosides using hypervalent iodine

We report herein a synthesis of 4′-selenouridine 12 and 4′-selenocytidine 14, substrates for the synthesis of 4′-selenoRNA. The Pummerer-like reaction between the selenoxide 9 and a silylated uracil afforded the desired 4′-selenouridine derivative 10; however, the chemical yield of 10 was rather low. In addition, the reproducibility of this reaction was poor because of the instability of the selenoxide 9. Improvement of this Pummerer-like reaction to give 10 was achieved when the 4-selenosugar 8 was treated with TMSOTf, 2,6-lutidine and the silylated uracil in the presence of iodosylbenzene.     

Synthesis of procyanidins by stepwise- and self-condensation using 3,4-cis-4-acetoxy-3-O-acetyl-4-dehydro-5,7,3′,4′-tetra-O-benzyl-(+)-catechin and (−)-epicatechin as a key building monomer

3,4-cis-4-Acetoxy-3-O-acetyl-4-dehydro-5,7,3′,4′-tetra-O-benzyl-(+)-catechin (1a) or (−)-epicatechin (1b) reacted high regio- and stereo-selectively with 1.5 equiv of the 5,7,3′,4′-tetra-O-benzyloxyflavan-3-ol (4a or 4b) in the presence of 1 equiv of TMSOTf to give the corresponding procyanidins. On the other hand, the self-condensation of 1a in the presence of a catalytic amount of B(C₆F₅)₃ afforded wide-range procyanidins from dimer to 15-mer like a biomass.     

The reaction of 2-fluoroalkyl-1-iodoethylenes with arylamines: a facile method for the synthesis of fluoroalkylated quinolines and enaminoketones

The reaction of 2-fluoroalkyl-1-iodoethylenes with arylamines (1) and the subsequent acid promoted transformation of the products were described. In the presence of ZnCl₂ and triethylamine, 1 reacted readily with various p-substituted anilines in HMPA under a vacuum of 60-70 mmHg to give the corresponding enaminoaldehydes (2) as a mixture of E- and Z-isomers. Cyclization of 2, without further purification in refluxing toluene, catalyzed by strong acids such as p-toluene sulfonic acid and trifluoromethanesulfonic acid gave 2-fluoroalkylquinolines (3) in good yields, while fluoroalkylated enaminoketones (4) were obtained predominantly when 2 was treated with acids in aqueous THF solution. A possible mechanism was proposed for the formation of 3 and 4.     

Synthesis of polycyclic and 4,5-diacylthiophene-2-carboxylates via intramolecular Friedel-Crafts alkylations and unusual autooxidative fragmentation of the derivatives obtained from the samarium diiodide-promoted coupling reactions of thiophene-2-carboxylate with carbonyl compounds

Our present study provides an expedient method for the synthesis of novel polycyclic and multi-substituted thiophene derivatives. A series of 4,5-di(hydroxyalkyl)-4,5-dihydrothiophene-2-carboxylates (e.g., 4a-c and 10) were prepared by the SmI₂-promoted three-component coupling reactions of thiophene-2-carboxylate with aromatic aldehydes and 4-methoxyacetophenone. Diol 4a was oxidized by DDQ or pyridinium dichromate to give 5-acyl-4-hydroxyalkyl-4,5-dihydrothiophene-2-carboxylate 6a, which was subjected to dehydration to give either alkene 7 with terminal CC double bond or alkene 15a having conjugation with the ester group, depending on the reaction conditions using different quantities of p-toluenesulfonic acid. Alkene 7 underwent an intramolecular Friedel-Crafts alkylation to give a tetralone-fused thiophene-2-carboxylate 9. By the similar procedure, a carbazole-fused thiophene 14 was also prepared. Alkenes 15a-c underwent autooxidative fragmentation to give 4,5-diacylthiophene-2-carboxylates 5a-c that were elaborated to pyridazine-fused thiophenes.     

An expedient method for the synthesis of 6-substituted uracils under microwave irradiation in a solvent-free medium

Condensation of malonic acid 1 and ureas 2a-f proceeds smoothly in the presence of acetic anhydride 3 under microwave irradiation in solvent-free conditions to give 6-hydroxy-uracils 4 in excellent yields. Under identical conditions, the condensation of cyanoacetic acid 5 and ureas 2a,b,g and h in the presence of acetic anhydride 3, followed by cyclization in the presence of sodium hydroxide affords 6-amino-uracils 6 in high yields. The work-up procedures are simple and products need no purification.     

Thermal rearrangements of tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylates. Synthesis of 3H-imidazol-1-ium ylides and their silver derivatives

Isoxazolines 2 from the cycloaddition of imidazoline 3-oxides 1 with DMAD undergo rearrangement to 3,4-dihydro-2H-imidazol-1-ium-1-(1,2-bis-methoxycarbonyl-2-oxo-ethanides) 3, which spontaneously undergo elimination to give 3H-imidazol-1-ium-1-(1,2-bis-methoxycarbonyl-2-oxo-ethanides) 5 or 1H-imidazoles 6 when heated in toluene at reflux. The presence of the aromatic ring at C-6 decelerated the conversion and enhanced the yield of 5. Solvents more polar than toluene (e.g., DMSO) provided quantitative conversion of 2 into 6 in mild conditions, while in less polar solvents such as CCl₄, the reaction rate was lowered and the yield of 5 enhanced. C-2 unsubstituted ylides 5 were treated with Ag₂O or AgNO₃ in the presence of Et₃N at room temperature to give C-2 metallated derivatives 9 in excellent yields.     

Synthesis and reactivity of a putative biogenetic precursor to tricholomenyns B, C, D and E

A chemoenzymatic synthesis of the putative biogenetic precursor, 6, to the epoxy-quinol type natural products, tricholomenyns B, C, D and E (2-5, respectively), has been achieved. However, treatment of compound 6 under a variety of conditions failed to effect its conversion into any of the natural products 2-5. In contrast, the simple model system 22 reacts with acetic acid in the presence of stoichiometric quantities of Ti(OPr-i)₄ to give the diacetate 23.     

Synthesis of the 5-hydroxymethyl-6-aryl-8-oxabicyclo[3.2.1]oct-3-en-2-one natural products descurainin and cartorimine

Reaction of pyranulose 6 with styrenes 12c or 13 and Et₃N in CH₂Cl₂ at 25 °C afforded the [5+2] cycloadducts 14c and 15, which were hydrolyzed to give the natural products 1 and descurainin (2) in 24 and 27% overall yield, respectively. Heating pyranulose 6 with cinnamate ester 21 in the presence of 2,6-di-t-butylpyridine in CH₃CN at 175 °C afforded the [5+2] cycloadduct, which was hydrolyzed to give cartorimine (3) in 13% yield.     

The synthesis of 2,4-dienyl fluoroalkyl ketones by a tandem three-stage sequence of propargyl 2-fluoroalkylvinyl ether formation, Claisen rearrangement, and allene-to-conjugated diene isomerization

A tandem three stages process to a series of trifluoromethyl and halodifluoromethyl 2,4-unsaturated ketones 4a-c is described. This process started with the preparation of 2-fluoroalkyl substituted propargyl vinyl ether 3a-d by treatment of a mixture of individual ethyl α-per(poly)fluoroalkyl acetates 1a-d and propargyl alcohol 2 in CH₂Cl₂ with the mixed base (Na₂CO₃/TEA) at ambient temperature. When heated in toluene at 80°C, these ethers readily underwent a tandem propargyl-allenyl Claisen rearrangement and isomerization of the resultant 3,4-dienone to give 2,4-unsaturated fluoroalkyl ketones 4a-c (Z/E mixture). The reaction of ethyl α-per(poly)fluoroalkyl acetate 1 with 1-phenyl propargyl alcohol 5 in refluxing CH₂Cl₂ in the presence of the mixed base (Na₂CO₃/TEA) directly afforded the corresponding unsaturated fluoroalkyl ketone 6a-c in one pot. In the presence of NaH, the reaction of ethyl 3-halo-3-fluoroalkylacrylates 8a-b with 1,1-dimethyl propargyl alcohol 9 at −50°C to 0°C also gave the unsaturated fluoroalkyl ketones 10a-b in one pot. The difluorovinyl propargyl ether 11 produced by reduction of 2-bromodifluoromethyl substituted propargyl vinyl ether 3b rearranged in hot benzene to give the corresponding allene 12 bearing a gem-difluoromethylene group in the middle of the aliphatic chain.     

The novel transition metal free synthesis of 1,1′-biazulene

Reaction of 1-azulenyl methyl sulfoxide (1) under acidic conditions gave the 1,1′-biazulene derivative 3. Methylmercapt groups of 3 were readily converted to formyl groups by Vilsmeier reaction to afford 3,3′-diformyl-1,1′-biazulene (4), which reacted with pyrrole in the presence of acetic acid to give the parent 1,1′-biazulene (5). Reaction of 5 with pyridine in the presence of Tf₂O gave 3,3′-dihydropyridyl-1,1′-biazulene derivative 6. 3,3′-(4-Pyridyl)-1,1′-biazulene (7) was obtained by the reaction of 3 with KOH in EtOH at room temperature in good yield.     

Reaction of quinine, 9-epiquinine and their acetates in superacid in the presence of hydrogen peroxide: an access to new fluorhydrins and/or ketones

In HF-SbF₅, in the presence of H₂O₂ (source of OH⁺ equivalent) quinine 1a yields 10-keto derivatives 4a and 5a and cyclic ether 3 as the major product. In the same conditions 1b, 2a, and 2b give the 10-keto and 10-fluoro-3-hydroxy analogs.     

Regioselective hydrodehalogenation of 3,5-dihaloisothiazole-4-carbonitriles: synthesis of 3-haloisothiazole-4-carbonitriles

3,5-Dibromoisothiazole-4-carbonitrile 1 treated with Zn or In dust (5 equiv) and HCO₂H undergoes regioselective hydrodebromination to give 3-bromoisothiazole-4-carbonitrile 3 in 70-74% yield. Similarly, 5-bromo and iodo 3-chloroisothiazole-4-carbonitriles 8 and 9 give 3-chloroisothiazole-4-carbonitrile 4 in 77 and 85% yields, respectively. Also hydrodeamination of 5-amino-3-chloroisothiazole-4-carbonitrile 7 using isoamyl nitrite gives the latter in 95% yield. The dibromoisothiazole 1 reacts with Zn dust in either DCO₂D or HCO₂D to give 3-bromo-5-deuterioisothiazole-4-carbonitrile 10 in 71 and 58% yields, respectively. The 3-bromoisothiazole 3 reacts with cyclic dialkylamines to give the corresponding 2-(dialkylaminomethylene)-malononitriles and not the expected 3-dialkylaminoisothiazole-4-carbonitriles. Finally, the 3-bromoisothiazole 3 is readily converted into both 3-bromoisothiazole-4-carboxamide 19 and the carboxylic acid 20. All products are fully characterized.     

Total synthesis of puerarin, an isoflavone C-glycoside

We completed the first total synthesis of puerarin (1), an isoflavone C-glycoside. The key intermediate, β-d-glucopyranosyl-2,6-dimethoxybenzene (9), was obtained by coupling of a lithiated aromatic reagent (3) with pyranolactone (2) in 56% yield. Condensation of (16) with p-methoxybenzaldehyde gave the chalcone (17). The protected chalcone (18) was cyclized to (19) in the presence of Tl(NO₃)₃. Demethylation of (19) was accomplished by refluxing with TMSI in CH₃CN to give puerarin (1).     

Comparative reactivity studies of dppf-containing CpRu and (C6Me6)Ru complexes towards different donor ligands (dppf=1,1-bis(diphenylphosphino)ferrocene)

[CpRu(dppf)Cl] (Cp=η⁵-C₅H₅) (1) and [(HMB)Ru(dppf)Cl]PF₆ ((HMB)=η⁶-C₆Me₆) (3) react with different donor ligands to give rise to N-, P- and S-bonded complexes. The stoichiometric reactions of 1 and 3 with NaNCS give the mononuclear complexes [CpRu(dppf)(NCS)] (2) and [(HMB)Ru(dppf)(NCS)]PF₆ (4), respectively, in yields above 80%, while 3 also gives a dppf-bridged diruthenium complex [(HMB)Ru(NCS)₂]₂(μ-dppf) (5) in 67% yield from reaction with four molar equivalents of NaNCS. Compound 5 is also obtained in 70% yield from the reaction of 4 with excess NaNCS. With CH₃CN in the presence of salts, both 1 and 3 give their analogous solvento derivatives [CpRu(dppf)(CH₃CN)]BPh₄ (6) and [(HMB)Ru(dppf)(CH₃CN)] (PF₆)₂ (7). With phosphines, the reaction of 1 gives chloro-displaced complexes [(CpRu(dppf)L]PF₆ (L =PMe₃ (8), PMe₂Ph(9)), whereas the reaction of 3 with PMe₂Ph leads to substitution of dppf, giving [(HMB)Ru(PMe₂Ph)₂Cl] PF₆ (10). The reaction of 1 with NaS₂CNEt₂ gives a dinuclear dppf-bridged complex [{CpRu(S₂CNEt₂)}₂(μ-dppf)] (11), whereas that of 3 results in loss of the HMB ligand giving a mononuclear complex [Ru(dppf)(S₂CNEt₂)₂] (12). With elemental sulfur S₈, 1 is oxidized to give a dinuclear CpRu^III dppf-chelated complex [{CpRu(dppf)}₂(μ-S₂)](BPh₄)Cl (13), whereas 3 undergoes oxidation at the ligand, giving a dppf-displaced complex [(HMB)Ru(CH₃CN)₂Cl]PF₆ (14) and free dppfS₂. The structures of 1, 2, 5-9, 11, 13 and 14 were established by X-ray single crystal diffraction analyses. Of these, 5 and 11 both contain a dppf-bridge between Ru^II centers, while 13 is a dinuclear CpRu^III disulfide-bridged complex; all the others are mononuclear. All complexes obtained were also spectroscopically characterized.     

The use of two optically active N-sulfinyl α-imino esters in the stereoselective aza-Diels-Alder reaction

Diastereoselective aza-Diels-Alder (aza-DA) reactions of ethyl (S)-N-(tert-butanesulfinyl)iminoacetate (2a) and ethyl (S)-N-(p-toluenesulfinyl)iminoacetate (2b) with different dienes including activated, non-activated, cyclic, and acyclic dienes in the presence of Lewis acids are described. Reactions with 2a were found to be more selective. Reactions of unactivated dienes (acyclic and cyclic) with stoichiometric amounts of TMSOTf as Lewis acid afforded the aza-DA adducts in modest yields and in diastereoselectivities up to 99%. A strong preference for Re-approach was observed for 2a. Cyclic dienes gave the exo adducts as major products. For the aza-DA reaction with activated Danishefsky type dienes poor diastereoselectivities were observed. In these cases, the best results were obtained using stoichiometric amounts of BF₃·Et₂O as Lewis acid (up to 69% de, 76% yield). The absolute configurations of six of the addition products were established by chemical correlation with known compounds. Acidic cleavage of the sulfinyl group occurred without racemization to optically active non-proteinogenic α-amino acid ethyl esters.     

Syntheses and crystal structures of diorganotin (IV) moieties with 3-hydroxy-2-pyridinecarboxylic acid

A series of new organotin (IV) complexes with 3-hydroxy-2-pyridinecarboxylic acid (3-OH-2-picH) of two types: R₂SnCl(3-OH-2-pic) (I) (R = Me 1, n-Bu 2, Ph 3, PhCH₂4) and R₂ Sn(3-OH-2-pic)₂ (II) (R = Me 5, n-Bu 6, Ph 7, PhCH₂8)have been synthesized by reactions of diorganotin (IV) dichloride with 3-hydroxy-2-pyridinecarboxylic acid in the presence of sodium ethoxide. All complexes are characterized by elemental analyses, IR spectra and NMR spectra analyses. Among them, complexes 1, 5, 6 and 7 are also characterized by X-ray crystallography diffraction analyses. Complex 1 is a 1D polymeric chain with six-coordinate tin atoms and the packing of complex 1 is stabilized by the C-H?Cl intermolecular weak interactions, thus a 2D network of 1 is formed. Complex 5 is also a 1D polymeric chain with seven-coordinate tin atoms. Complex 6 is a zigzag polymeric chain linked by Sn?O intermolecular weak interactions. Complex 7 is a monomeric complex with distorted octahedral geometry.