A new synthesis of cyanocyclopropanes by the intramolecular alkylation of magnesium carbenoids as the key reaction

Addition reaction of 1-chlorovinyl p-tolyl sulfoxides, derived from ketones and chloromethyl p-tolyl sulfoxide, with cyanomethyllithium gave adducts in quantitative yields. Treatment of the adducts with i-PrMgCl in THF resulted in the formation of cyanocyclopropanes via the intramolecular alkylation of the generated magnesium carbenoids. The intermediate of this reaction was proved to be a cyclopropylmagnesium chloride, and it was found to be reactive with electrophiles to give multi-substituted cyanocyclopropanes. The key reaction, intramolecular alkylation of magnesium carbenoid, is the first example for the reaction of the magnesium carbenoids with nitrile-stabilized carbanions.     

N-Tosylaziridine, a new substrate for chemical fixation of carbon dioxide via ring expansion reaction under atmospheric pressure

N-Tosylaziridine was found to be a useful substrate for cycloaddition reaction with carbon dioxide. The reaction was successfully catalyzed by lithium bromide under atmospheric pressure to give the corresponding five-membered cyclic urethane, N-tosyl-1,3-oxazolidin-2-one, selectively. It was found that electron-donating nature of the substituent at 2-position of N-tosylaziridine accelerated the reaction, and this tendency allowed us to estimate the reaction mechanism.     

Convenient synthesis and unusual reactivity of 2-oxo-2H,5H-pyrano[3,2-c]chromenes

The reaction of 4-oxo-4H-chromen-3-carbaldehydes with coumarin-4-acetic acids under the Perkin conditions follows an interesting pathway that involves aldol reaction and subsequent intramolecular lactonization to afford 2-oxo-2H,5H-pyrano[3,2-c]chromene skeleton. In contrast to chromone-3-carbaldehydes, the same reaction with chromone-2-carbaldehydes yielded only the aldol condensation product. The reaction was performed under thermal and microwave conditions. The reactivity of 2-oxo-2H,5H-pyrano[3,2-c]chromenes in water, alcohol and acetic acid was described.     

Reactivity and regioselectivity in the synthesis of spiroindoles via indole o-quinodimethanes. An experimental and computational study

The 1,3-dipolar cycloaddition reactions of stable nitrile oxides with indole o-quinodimethanes have been examined. In all cases the ‘exo-anti’ addition products, dispiroisoxazolines, were isolated in moderate to good yields (25-47%). In addition, from the reaction of one of the indole quinodimethanes with mesitonitrile oxide the ‘exo-syn’ addition product was isolated in 7% yield along with the remarkable indole quinodimethane dimerization and cycloaddition product, which was isolated in 13% yield. An analogous dimerization and cycloaddition product was isolated in 18% yield from the reaction of the N-acetyl-indole quinodimethane with mesitonitrile oxide. In the case of the reaction of the N-benzoylindole quinodimethane with the 2,6-dichlorobenzonitrile oxide an oxime was also isolated in 13% yield. The proposed reaction mechanism is supported by semiempirical (AM1) MO calculations via FMO interactions. The observed selectivity was explained by an investigation of the transition states carried out also for analogous dispiroisoxazolines.     

Chiral base-catalyzed aldol reaction of trimethoxysilyl enol ethers: effect of water as an additive on stereoselectivities

An aldol reaction of trimethoxysilyl enol ether catalyzed by lithium binaphtholate is described. The aldol reaction of trimethoxysilyl enol ether derived from cyclohexanone under anhydrous conditions predominantly afforded the anti-aldol adduct with moderate enantioselectivity, whereas the reaction under aqueous conditions predominantly resulted in the syn-adduct and the enantioselectivity of the syn-adduct was considerably improved. The best enantioselectivity was obtained in the reaction of trimethoxysilyl enol ether derived from 1-indanone with cyclohexanecarboxaldehyde (97% ee (syn)). This is the first example of an aldol reaction of trimethoxysilyl enol ether catalyzed by a chiral base.     

New synthesis of multisubstituted cyanocyclopropanes by the intramolecular SN2 alkylation and 1,3-CC insertion reaction of magnesium carbenoids as the key reactions

Addition reaction of 1-chlorovinyl p-tolyl sulfoxides derived from ketones and aldehydes with lithium α-cyano carbanions gave nitrile adducts in high to quantitative yields. Treatment of the nitrile adducts derived from acetonitrile with excess i-PrMgCl in THF resulted in the formation of cyanocyclopropanes via the intramolecular S_N2 alkylation of the generated magnesium carbenoids. The intermediate of this reaction was proved to be a cyclopropylmagnesium chloride and was reactive with electrophiles to give multisubstituted cyanocyclopropanes. On the other hand, the reaction of the nitrile adducts derived from arylacetonitriles with i-PrMgCl resulted in the formation of 2-arylcyanocyclopropanes by the 1,3-carbon–carbon (1,3-CC) insertion reaction of the generated magnesium carbenoid intermediates. This reaction was found to proceed in a highly stereospecific manner. The key reactions, intramolecular S_N2 alkylation and 1,3-CC insertion reaction of the magnesium carbenoids, are the first examples for the reaction of the magnesium carbenoids bearing a nitrile functional group.     

Isocyanide based multicomponent reactions of oxazolidines and related systems

N-Alkyloxazolidines react in a multicomponent reaction with carboxylic acids and isocyanides to give N-acyloxyethylamino acid amides. The previously reported reaction conditions were improved using a design of experiments approach (DoE). Under the optimised conditions, good yields of the N-acyloxyethylamino acid amide products are obtained both via a three- or four-component approach from N-alkylethanolamines, aldehydes/ketones, isocyanides and carboxylic acids. The reaction of oxazolidines without a nitrogen substituent was found to give either the expected Ugi products or the N-acyloxyethylamino acid amides depending on the choice of reaction conditions. Optimised reaction conditions were also developed for the ring-expansion of oxazolidines to morpholin-2-ones via reaction with an isocyanide followed by hydrolysis. The mechanistic pathway of the multicomponent reaction was briefly investigated using an ¹⁸O labelling experiment. The carboxylic acid component can be replaced by a range of other acidic nucleophiles including thiobenzoic acid, thiophenol or 5-phenyltetrazole, which are incorporated via an alternative pathway. These latter reactions can also be applied to 2-aminotetrahydrofurans, 2-aminotetrahydropyrans or 4-hydroxybut-2-one, further extending the structural diversity of the multicomponent reaction products.     

Regioselective synthesis of β-fluoro-α,β-unsaturated ketones by the reaction of β-diketones with DFMBA

The deoxyfluorination reaction of β-diketones with N,N-diethyl-α,α-difluoro-m-methylbenzylamine (DFMBA) gave β-fluoro-α,β-unsaturated ketones in good yields. The reaction proceeded regioselectively, and only one regioisomer was obtained from the unsymmetrical 1-aryl-1,3-diketones. The reaction is applicable to diketones with a trifluoromethyl group, obtaining good yields of 3,4,4,4-tetrafluorobutenones. We used the resulting β-fluoro-α,β-unsaturated ketones for the reaction with lithium dialkyl cuprates.     

Preparation of cis-2-aminocyclopropanol: [2+1] cycloaddition reaction of bis(iodozincio)methane with α-ketoimine

A reaction of α-ketoimine with bis(iodozincio)methane gave a cis-2-aminocyclopropanol derivative via [2+1] cycloaddition. The reaction proceeded via a sequential nucleophilic attack of bis(iodozincio)methane to a couple of carbonyl groups in the substrate, which was fixed into s-cis conformation with a couple of zinc atoms in the reagent. The reaction proceeded with high diastereoselectivity.     

Synthetic transformations of isoquinoline alkaloids. 1-alkynyl-3,6-dimethoxy-N-methyl-4,5α-epoxy-6,18-endoethenobenzo[i]isomorphinans and their transformations

The reaction of thebaine with 2-bromo-6-methyl-1,4-benzoquinone regioselectively afforded 6,18-endo-etheno-9-methyldihydrothebainehydroquinone. Iodination of 6,18-endo-ethenodihydrothebainehydroquinones with N-iodosuccinimide in trifluoroacetic acid was also selective, and the corresponding 1-iodo derivatives were formed. The main reaction pathway in the halogenation of 6,18-endo-ethenodihydrothebainehydroquinone with iodine chloride was chlorination of the fused hydroquinone fragment. The Sonogashira reaction of 1-iodo-6,18-endo-ethenodihydrothebainehydroquinones with trimethylsilylacetylene and subsequent desilylation gave 1-ethynyl-6,18-endo-ethenodihydrothebainehydroquinones. 1-[3-(4-R-Piperazin-1-yl)-propynyl]- and 1-{3-[2-(pyridin-3-yl)piperidin-1-yl]propynyl}-6,18-endo-ethenodihydrothebainehydroquinones were synthesized by the Mannich reaction of acetylenic derivatives of dihydrothebainehydroquinone with piperazine and anabasine in the presence of formaldehyde, catalyzed by copper(I) compounds. The reaction of 1-iodo-6,18-endo-ethenodihydrothebainehydroquinone with N-methylpiperazine and formaldehyde was accompanied by copper-catalyzed oxidative homocoupling.     

Enantioselective reaction of α-lithiated thiazolidines as new chiral formyl anion equivalents

The reaction of lithiated N-Boc-thiazolidine and N-Boc-benzothiazolidine with benzophenone in the presence of (−)-sparteine afforded the products with up to 97% ee and 93% ee, respectively. The reaction with various aromatic and aliphatic aldehydes also afforded the products with high enantioselectivity and moderate diastereoselectivity. Each diastereomer could be converted to optically active diols. Consequently, lithiated N-Boc-thiazolidine and N-Boc-benzothiazolidine serve as chiral formyl anion equivalents. The reaction was confirmed to proceed through a dynamic thermodynamic resolution pathway.     

Novel enantiocontrol system with aminoacyl derivatives of glucoside as enamine-based organocatalysts for aldol reaction in aqueous media

Introduction of carbohydrate auxiliary into enanine-based catalyst provided a novel enantiocontrol for aqueous aldol reaction. Methyl 2-(l-prolyl)amido-2-deoxy-α-d-glucopyranosides led to the enantiocontrol as parent amino acids did in the reaction of acetone with 4-nitrobenzaldehyde, and provided R-aldol in an improved efficiency compared with that of l-proline in aqueous media. The enantioreversal control of that with parent amino acid was observed in the reaction with methyl 2-(l-tert-leucyloxy)-α-d-glucopyranoside, which provided S-aldol predominantly in moderate efficiency. The novel enantiocontrol system was proposed to occur as a result of the generation of the transition state through the reaction of enamine with hydroxyl group on glucoside auxiliary.     

Unexpected regioselectivity observed in the bromination and epoxidation reactions of p-benzoquinone-fused norbornadiene: An experimental and computational study

The bromination reaction of p-benzoquinone-fused norbornadiene was studied at various temperatures (?78, ?50, 0, 25, and 77 °C). At room temperature, the double bonds of the p-benzoquinone units were mainly brominated. The double bond of the norbornene unit also underwent a bromination reaction in a yield of only 2%. However, the reaction at ?78 °C resulted in the formation of products derived from the attack of bromine on the norbornene double bond with higher charge density. In contrast to the bromination reaction, the epoxidation reaction of the same compound with m-chloroperbenzoic acid and dimethyldioxirane exclusively resulted in the formation of products derived from the addition to the double bond of norbornadiene. The regioselectivity observed was investigated and the results were supported by theoretical calculations.     

Experimental and DFT study of the aza-Diels-Alder reaction between cyclopentadiene and protonated benzylimine derivated from glyoxylates

The Diels-Alder reaction of protonated N-benzyl imine of methyl glyoxylate with cyclopentadiene in different solvents gave mixtures of exo/endo adducts. The exo/endo selectivity of the reaction was elucidated by NMR experiments. Theoretical calculations by means of density functional theory (DFT) at the B3LYP/6-31G(d) level have also been performed to elucidate the molecular mechanism of this reaction. The DFT results suggest a highly asynchronous concerted mechanism, which in turn can explain the preferred exo stereoselectivity of the reaction. Inclusion of solvent effects enhances the exo selectivity, and this effect increases with the polarity of the solvent, in good agreement with the experimental findings.     

Stereospecific deoxydichlorocyclopropanation of expoxides by dichlorocarbene generated in an emulsifying system

The reaction of epoxides with dichlorocarbene generated in an emulsifying system was investigated. The products were the corresponding dichlorocyclopropane derivatives. The reaction of cis- and trans-β-methylstyrene oxides showed the reaction was completely stereospecific. Styrene oxide gave the corresponding dichlorocyclopropane and styrene, where the concentration of the latter was kept in the nearly stationary state during the reaction. Further the competitive reaction of α- and β-methylstyrene oxide showed that introduction of an additional Me group at the α-position accelerated the reaction only 12 times. From these observations the reaction was concluded to involve the two step process, namely, the deoxygenation process and dichlorocyclopropanation process, both of which were stereospecific and practically concerted.     

Random cross-linked poly(styrene-co-maleic anhydride): Characterization of cross-linking intermediates by size exclusion chromatography

The cross-linking reaction of poly(styrene-co-maleic anhydride) (SMA) with ethylene glycol (EG) was monitored using size exclusion chromatography. On-line viscosity and static light scattering detection provided [η] and R_g for structural analysis of the cross-linking intermediates. With increasing reaction time a decrease of the expansion exponent α of the Kuhn-Mark-Houwink-Sakurada relationship was observed. A change from coiled structures to spherical molecules during the cross-linking reaction was confirmed by analyzing the fractal dimensions of the molecules after different reaction times. The calculation of the branching parameters g and g′ revealed the formation of contracted branched molecules. The connection of SMA chains by EG leads to a contraction of the polymers with increasing molecular weight.     

Synthesis of unsymmetrical biaryl ureas from N-carbamoylimidazoles: kinetics and application

N-Carbamoylimidazoles dissociate in solution to yield imidazole and an isocyanate that may be reacted with another aryl amine to form an unsymmetrical biaryl urea. This paper investigates the reaction kinetics and the influence of electron withdrawing/donating substituents on the reaction of N-carbamoylimidazoles with aniline. The overall reaction mechanism involves two zwitterionic intermediates, formed during dissociation and upon reaction of the liberated isocyanate with aniline. The rate limiting step for the reaction is a base catalysed proton transfer from the second zwitterionic intermediate. Although electron withdrawing substituents on the aryl group hinder dissociation, they significantly increase reaction rates compared to compounds bearing electron donating substituents. The imidazole liberated upon dissociation catalyses the rate determining step so that reactions of dissociated N-carbamoylimidazoles proceed more rapidly than those involving only isocyanates. In addition, the imidazole eliminates the need for anhydrous reaction conditions. The N-carbamoylimidazole methodology was demonstrated by preparing sorafenib, a biaryl urea kinase inhibitor, in good yield and excellent purity.     

Study of plant coumarins: X. Peurutenicin triflate in cross-coupling reactions

By Suzuki cross-coupling reaction of peurutenicin triflate with arylboric, furanylboric, pyridinylboric, and indolylboric acids the corresponding 7-aryl(hetaryl)coumarins were synthesized. The high activity of hetaryl-substituted boric acids in the Suzuki reaction was observed. Heck reaction of 7-O-trifluoromethylsulfonylpeur utenicin with terminal olefins (styrene, vinylpyridines, vinylpyrazine, vinyltriazole) was used to prepare (E)-7-[aryl(hetaryl)vinyl]coumarins. The dependence of reaction products yield on the nature of the catalytic system was found.     

Reaction of strontium sulfate with anatase and rutile below and above the phase transition temperature of strontium sulfate

The solid-state reaction of strontium sulfate with anatase and rutile was examined by isothermal and non-isothermal TGA/DTA and X-ray diffraction. The endothermic peak due to the reversible phase transition of SrSO₄ was observed by DTA in the vicinity of the endothermic peak due to the reaction. The product was only SrTiO₃ in all cases. The reaction mechanism was described by the Jander model. The rate constant for anatase was about twice as large as that for rutile. The relation between In k_j and T⁻¹ for anatase and rutile was discontinuous being linear either side of the phase transition temperature of SrSO₄. The rate constant just above the transition temperature was enhanced 1.5 times with respect to that just below the temperature. The activation energy for the reaction of strontium sulfate with rutile was 354 and 435 kJ mol⁻¹ in the higher and lower temperature regions respectively. In the reaction with anatase, the phase transition of anatase to rutile was also observed in about 30% of the fraction reacted at any temperature, and the rate constant was scattered from the In k_j vs. T⁻¹ curve, especially at high temperatures.     

Kinetic study of oxidation of galactose by N-bromo phthalimide in the presence of cationic micelle in acidic medium

The kinetics of micellar catalyzed oxidation of galactose by N-bromophthalimide was studied in the presence of acidic medium at 308?K. The oxidation reaction exhibits first-order kinetics with respect to oxidant (N-bromophthalimide), fractional order with respect to substrate (galactose) and positive fractional order with respect to HClO₄ on the rate of reaction. The rate of the reaction increased with decreasing the dielectric constant of the medium. With a progressive increase in the concentration of CTAB, the rate of reaction increased and after reaching peak k _obs, decreased at higher concentrations of CTAB. There catalytic roles are best explained by Berezin??s model. The influence of salts on the reaction rate was also studied. The various activation parameters have been calculated. The rate constant and binding constant with the surfactant have also been evaluated. A suitable mechanism consistent with the experimental findings has been proposed.