New approach to 5-arylsulfonyl-substituted 1,2-dihydropyrimidin-2-ones via base-induced chloroform elimination from 4-trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones

A four-step method for the synthesis of 5-arylsulfonyl-substituted 1,2-dihydropyrimidin-2-ones has been developed. The reaction of readily available N-[(1-acetoxy-2,2,2-trichloro)ethyl]ureas with sodium enolates of α-arylsulfonylketones followed by heterocyclization-dehydration of the oxoalkylureas formed gave 5-arylsulfonyl-4-trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones. The latter, in the presence of strong bases, eliminate CHCl₃ to give the target compounds.     

Highly diastereoselective alkylation,acylation and aldol condensation of cis- and trans-(N-acyloyl)hexahydrobenzoxazolidin-2-ones

The potential of hexahydrobenzoxazolidinones 1a–d as chiral auxiliaries was explored. N-Acylation of 1a–d, 2a–d and 3a–d was followed by methylation and benzylation via the corresponding sodium enolates generated by treatment with NaHMDS. Diastereoselectivities of 98% or higher were observed. The absolute configuration of the newly created stereogenic center was established by chemical correlation with 2-benzyl-1-propanol. The stereochemical results are congruent with addition to the electrophile from the less hindered face of a (Z)-configured enolate, the sodium cation being coordinated by both carbonyl oxygens of the substrate. cis- and trans-N-Propionyl derivatives 2a–d were treated with Bu₂BOTf/Et₃N to give dialkylboron enolates 6a–d, which were then reacted with acetaldehyde and benzaldehyde. ¹H and ¹³C NMR analyses showed the formation of a single diastereomeric aldol addition product, whose relative configuration was ascertained as syn from the measurement of the ³J_{H(2′)/H(3′)} coupling constants, and whose absolute configuration was determined by X-ray crystallographic analysis. The results are rationalized in terms of a Zimmerman–Traxler transition state, with a (Z)-configured enolate where boron is coordinated to the aldehyde carbonyl rather than the oxazolidinone carbonyl. Substrate 2a was also reacted with acyl chlorides via the sodium enolate (NaHMDS). The effect of reaction conditions on O- versus C-acylation, as well as the influence of solvent and additives on diastereoselectivity, are discussed.     

Palladium-catalyzed asymmetric allylic alkylation of acyclic ketones for synthesis of 2,2-disubsituted pyrrolidine derivatives

Palladium-catalyzed asymmetric allylic alkylation of acyclic ketones represents a significant challenge in organic synthesis. We report herein that the synthesis of chiral 2,2-disubsituted pyrrolidines from acyclic ketones has been accomplished by using catalytic asymmetric method in the presence of Pd(dba)₂ and (R)-binap ligand. Theses reactions occur between allyl methyl carbonate and unstabilized acyclic lithium enolates to provide the products in moderate to good enantioselectivity (up to 81% ee).     

The Acidity of Malondialdehyde and the Stability of its Complexes with Nickel(II) and Copper(II)

The acidity of malondialdehyde as well as the stability of its 1 :1-complexes with Ni^II and Cu^II have been determined (Table). In comparison with the enolates of aliphatic β-dike-tones the anion C₃H₃O₂? has not only a strikingly reduced basicity, but is also a grossly inferior ligand for metal cations.     

Zinc enolates: C- or O-metallation?

Two methods have been used for the generation of zinc enolates: the reaction of EtZnOMe with enol acetates, and that of lithium enolates with zinc chloride. Most of the zinc compounds prepared proved to be very reactive towards carbonyl functions, and so they cannot be isolated from the EtZnOMe/enol acetate system. The final products of these reactions are polymerisation and self-condensation products and β-diketonates, the latter being formed by condensation reactions of the zinc enolates with an acetate molecule. The structure of [EtZnOMe·Zn(Pac)₂]₂ (HPac = pivaloylacetone, (CH₃)₃CCOCH₂COCH₃), isolated in 20% yield from the reaction of EtZnOMe with CH₃COOC(t-Bu)CH₂, was determined by X-ray diffraction analysis. The compound forms monoclinic crystals, space group P2₁/c, with two dimers in a cell of dimensions a 11.677(4), b 18.299(9) and c 12.719(5) Å and β 117.26(3)°. The structure closely resembles that of the known complex [PhZnOPh·Zn(Pac)₂]₂.The complications involving reactions of zinc enolates with enol acetates were avoided by treating lithium enolates with zinc chloride. Polymerization and self-condensation could be prevented by using the very bulky enolate LiOC(t-Bu)CMe₂. In this way, the corresponding stable zinc enolate RZnCl·THF was obtained as a dissociating dimer. No replacement of the second chlorine atom by an enolate group occurred even when a large excess of lithium enolate was used.The reactivity of the zinc enolates suggests that they contain both zinccarbon and zincoxygen bonds. They are assumed to have a cyclic structure which resembles that of the Reformatsky reagent.     

On the Alkylation of 5-Fluorouracil-Some Recent Findings

Since its discovery 5-fluorouracil ¹(1,5-FU), an important anticancer drug, has been the subject of study for the preparation of some suitable derivatives² which may have better therapeutic efficacy. These are prepared through silylation method³, mercuri salt method⁴ and direct alkylation method⁵ of 5-FU. It was reported⁵ that the direct alkylation of 5-FU with saturated and allylic type halides under controlled conditions occur at N₃ (3-) and N₁ (1-) position respectively in contrast to alkylation of uracil where N₁ alkylated products are obtained in both cases. The position of alkylation in 5-FU was determined, with analogy from uracil⁶, by the bathochromic shift in UV from the neutral pH to alkaline pH of the 3-substituted product compared to no such shift of the 1-substituted product.     

Convergent syntheses of C(1→3)-linked disaccharides starting from isolevoglucosenone

Nucleophilic addition (Nu⁻M⁺) to isolevoglucosenone 1 generates enolates stereospecifically (exo face addition) that can be reacted with sugar-derived aldehydes to give C(1→3)-linked disaccharide precursors with high diastereoselectivity. Limitations of the method arising from unfavorable aldolate stability can be overcome by using Et₂AlI as the nucleophile. This leads to products of Baylis–Hillmann condensations. One example is presented and has led to the preparation of 2,3-anhydro-3-C-[(1S)-2,6-anhydro-d-glycero-d-gulo-heptitol-1-C-yl]-β-d-gulo-pyranose 5.     

Diastereoselectivity in the alkylation of 4-fluoroproline methyl esters

The reaction of alkylation of cis- and trans-4-fluoro-N-Boc-l-proline methyl esters has been examined by exposing their lithium enolates to a range of alkylating agents. The process showed a high degree of facial diastereoselectivity (except when methyl iodide was used as alkylating agent), invariably giving rise to products bearing the alkyl group in anti with respect to the fluorine atom. A tentative model to account for the observed stereoselectivity is also proposed.     

Enantioselective Copper‐Catalyzed Decarboxylative Propargylic Alkylation of Propargyl β‐Ketoesters with a Chiral Ketimine P,N,N‐Ligand

The first enantioselective copper‐catalyzed decarboxylative propargylic alkylation has been developed. Treatment of propargyl β‐ketoesters with a catalyst, prepared in situ from [Cu(CH₃CN)₄BF₄] and a newly developed chiral tridentate ketimine P,N,N‐ligand under mild reaction conditions, generates β‐ethynyl ketones in good yields and with high enantioselectivities without requiring the pregeneration of ketone enolates. This new process provides facile access to a range of chiral β‐ethynyl ketones in a highly enantioenriched form.     

Stereocontrolled synthesis of 2-aryl tetralones. Application in the synthesis of B/C hexahydrobenzo[c]phenanthridine alkaloids

Hexahydrobenzo[c]phenanthridines possessing a B/C cis ring junction have been synthesized in a stereoselective way starting from chiral non-racemic 2-aryl-tetralones prepared by asymmetric alkylation of (+)-(S,S)-pseudoephedrine based arylacetamide enolates with appropriately functionalized 2-aryl-1-iodoethane electrophiles. Subsequent transformations (intramolecular Friedel–Crafts acylation, stereocontrolled reductive amination and Pictet–Spengler cyclization) yielded the target heterocycles in good overall yields and in excellent stereoselectivities.     

Synthesis of 3-(2-hydroxyphenyl)-1,5-dialkyl-1<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazoles and their Zn(II) complexes

It has been demonstrated by ¹³C NMR and quantum-chemical calculations that alkylation of 5-(2-hydroxyphenyl)-3-methyl(vinylphenyl)-1H-1,2,4-triazoles with dialkyl sulfates in aqueous DMSO in the presence of alkali occurs exclusively in the 2-position of the triazole ring to give 3-(2-hydroxyphenyl)-1,5-dialkyl(alkylvinylphenyl)-1H-1,2,4-triazoles. Emission spectra of these compounds show two weak bands (λ _max ^fl = 317–346 and 430–447 nm, φ = 0.002–0.007), whereas their zinc complexes emit in the violet range of the visible spectrum (λ _max ^fl = 373–377 nm, φ = 0.20–0.25).     

Synthesis and asymmetric alkylation of glucose-derived bicyclic oxazinones: An evaluation of their use as “chiral glycines”

We have prepared structurally novel bicyclic oxazinones based on D-glucopyranose. The lithium enolates of these compounds undergo highly diastereoselective alkylation reactions with reactive alkyl halides, in modest yields. Use of the phosphazene P4 base enhances the yields of these processes, suggesting that metal enolate aggregation is at least partly responsible for the depressed yields. The stereochemistry of the products has been unequivocally ascertained by nOe measurements and ab initio calculations.     

N-Alkylation of 4-nitro-1,2,3-triazole revisited. Detection and characterization of the N3-ethylation product, 1-ethyl-5-nitro-1,2,3-triazole

The products of the alkylation of sodium 4-nitro-1,2,3-triazolate with ethyl bromide were investigated using ¹H, ¹³C, and ¹⁵N NMR spectroscopy. It was found that alkylation proceeds on the triazole nitrogen atoms giving a mixture of three isomeric N-ethyl-4-nitro-1,2,3-triazoles. The molar ratio of N1, N2, and N3-alkylation products was 4:8:1. The formation of a minor N3-isomer, namely 1-ethyl-5-nitro-1,2,3-triazole was confirmed by X-ray structural analysis of single crystals of its tetranuclear copper(II) complex obtained by reaction of copper(II) chloride dihydrate with a mixture of the N2 and N3-isomers.     

Oxidative Coupling of Carbon Acid Compounds by Means of Ag2O

Transition-metal catalyzed coupling of carbanions by means of transition metal compounds has constituted a convenient method of the carbon-carbon bond formation in organic synthesis.¹ Recently, CuCl₂-promoted coupling of lithium enolates of ketones² and esters³ has been reported, which provides new routes to 1,4-diketones and succinate derivatives, respectively. Now we found that some carbon acids, such as acylacetate and monosubstituted malonate, were readily oxidatively dimerized by Ag₂O without intervention of their carbanions in dimethyl sulfoxide (DMSO) according to eq. 1.     

Studies on SRN1 reactions-9 : A new access to the isoquinoline ring system

The S_RN1 reaction between o-halogeno-benzylamines and enolates derived from a series of ketones and aldehydes affords 1, 2 dihydro-isoquinolines from which are obtained (i)the isoquinoline derivatives, either spontaneously or by treatment on Pd-C and (ii) the 1,2,3,4 tetrahydro-isoquinoline derivatives after sodium borohydride reduction.     

Radical trifluoromethylation of Ti ate enolate: possible intervention of transformation of Ti(IV) to Ti(III) for radical termination

The radical trifluoromethylation of ketone Ti ate enolates gave α-CF₃ ketones in good yields. The use of excess amount of LDA and Ti(OⁱPr)₄ in the preparation of Ti ate enolates is the key to the efficient radical trifluoromethylation. Theoretical studies on the spin density of the Ti(IV) ate ketyl radical intermediate suggest the involvement of transformation from Ti(IV) ate ketyl radical intermediates to Ti(III) species in a radical termination step.     

The effect of crown ethers on the alkylation of a cyclic β-keto ester

The effects of crown ethers (6 and 7) on the reactions of sodium (2a) and potassium enolates (2b) of 2-ethoxycarbonylcyclohexanone (1) with isopropyl iodide in dimethylsulfoxide and dimethoxyethane have been investigated. When the addition of crown ether promoted dissociation of ion pair 2 in either of the two solvents, the total rate of reaction (k_t) increased and the ratio of carbon- (3) to oxygen-alkylation (4 and 5) products decreased. The results are consistent with the involvement of both the ion pair and more dissociated species in alkylation and with greater reactivity for the latter.     

Palladium-catalyzed asymmetric allylic substitution using novel phosphino-ester (PHEST) ligands with 1,1′-binaphthyl skeleton

The asymmetric allylic alkylation of rac-1,3-diphenyl-2-propenyl acetate 1 with dimethyl malonate 2a proceeded smoothly in the presence of lithium acetate, BSA (N,O-bis(trimethylsilyl)acetamide), [Pd(η³-C₃H₅)Cl]₂, and the chiral ligand (R)-i-Pr₂N-PHEST (R)-5a to give the allylic alkylation product (R)-3a in 89% yield with 99% ee. Furthermore, the asymmetric allylic amination of 1 with potassium phthalimide 2c has been carried out using the same ligand to give the allylic amination product (S)-3c in 10% yield with 66% ee.     

Reaction of N-substituted 2-oxochromen-3-carboxamides with bromoderivatives of zinc enolates prepared from alkyl 2,2-dialkyl-4,4-dibromo-3-oxoalkanoates and zinc

Zinc enolates obtained from ethyl 2,2-dialkyl-4,4-dibromo-3-oxobutanoates and zinc react with N-substituted 2-oxochromen-3-carboxamides forming ethyl 3-{1a-(R³-carbamoyl)-2-oxo-1a,7b-dihydrocyclopropa[c]chromen-1-yl}-2,2-dialkyl-3-oxopropanoate isomer with a Z-position of methine hydrogens. Zinc enolates prepared from alkyl 2,2-dialkyl-4,4-dibromo-3-oxopentanoates and-hexanoates and zinc react with N-substituted 2-oxochromen-3-carboxamides to give rise to esters of 3-{1-alkyl-1a-(R³-carbamoyl)-2-oxo-1a,7b-dihydrocyclopropa-[c]chromen-1-yl}-2,2-dialkyl-3-oxopropanoic acid as isomers with the E-position of the methine proton and the alkyl substituent. The reaction carried out in the presence of small quantities of THF and HMPA leads to the formation of 9c-alkyl-2-R³-9b,9c-dihydro-5-oxa-2-azacyclopenta[2,3]-cyclopropa[1,2-a]naphthalene-1,3,4-triones. Zinc enolates from alkyl 2,2-dialkyl-4,4-dibromo-3-oxopentanoates and-hexanoates and zinc with the secondary amides of 2-oxochromen-3-carboxylic acid form alkyl 3-{2-oxo-1a-(piperidinocarbonyl)-and 3-{6-R¹-1a-(morpholinocarbonyl)-2-oxo-1a,7b-dihydrocyclopropa[c]chromen-1-yl}-2,2-R²,R²-3-oxopropanoates as single geometrical isomers.     

A new efficient synthetic strategy for N-(dialkylamino)azacycle as a tetrasubstituted hydrazine derivative using sodium triacyloxyborohydride

A new efficient and convergent method has been developed to construct a N-(dialkylamino)azacyclic system as a tetrasubstituted hydrazine via reductive alkylation of the corresponding hydrazone using sodium triacyloxyborohydride [NaBH(OCOR)₃], which is tolerant of various substituents (e.g., phenol, conjugated olefin, amide, and thioamide) on the substrate and useful for organization of the N-aminoazacycle array.