Synthesis of 2,2,3,3-tetracyanocyclopropyl ketones and their reactions with oxygen-centered nucleophiles

A procedure for the synthesis of 2,2,3,3-tetracyanocyclopropyl ketones has been developed on the basis of three-component Wideqvist reaction of dihydroxymethyl ketones, 2-bromomalononitrile, and malononitrile. The presence of five electron-withdrawing groups in the resulting cyclopropyl ketones determines high acidity of proton in the cyclopropane ring. Facile deprotonation by the action of bases promotes opening of the three-membered ring with formation of either 1,1,3,3-tetracyanopropenides or (in the presence of alcohols or oximes), [2-alkoxy(aminooxy)-5-amino-4-cyanofuran-3(2H)-ylidene]malononitriles. The reaction with acetone oxime was not accompanied by cleavage of the three-membered ring, and nucleophilic attack was directed at the cyano groups in the trans position with respect to the carbonyl group to give the corresponding (1R*,5S*,6R*)-4-amino-2,2-bis(prop-2-ylideneaminooxy)-3-azabicyclo[3.1.0]hex-3-ene-1,5-dicarbonitriles.     

Synthesis and structure of 1-(buta-1,3-dien-2-yl)pyrazoles and their behavior in Diels-Alder reactions

A convenient procedure has been developed for the synthesis of cis-and trans-isomeric 1-(buta-1,3-dien-1-yl)-1H-pyrazoles by reaction of the corresponding pyrazoles with β-methylacrolein diethyl acetal and subsequent 1,4-cleavage of the nucleophilic substitution products. The behavior of the title compounds in Diels-Alder reactions with maleic anhydride has been studied. According to the ¹H NMR data, 1-(buta-1,3-dien-1-yl)-1H-pyrazole is a mixture of cis and trans isomers. Butadienylpyrazoles having methyl groups in the pyrazole ring do not react with maleic anhydride.     

New cascade reactions starting from acetylenic ω-ketoesters: an easy access to electrophilic allenes and to 1,3-bridgehead ketones

Acetylenic ω-ketoesters bearing a three carboncarbon bond spacer reacted smoothly with tetra-n-butylammonium fluoride and with potassium tert-butoxide to afford either electrophilic allenes or 1,3-bridgehead ketones, the latter being potentially useful molecules for the synthesis of biologically active compounds like Garsubellin A and Hispidospermidin.     

Asymmetric gamma-deprotonation and homoaldol reaction of 1,3-dien-2-yl carbamates: stereo- and regiochemistry

[reaction: see text] Lithium compounds 7 are configurationally stable intermediates obtained by deprotonation of 1,3-dien-2-yl carbamates 6 with n-butyllithium/(-)-sparteine with a high degree of enantiotopic differentiation at the gamma-position. They react with electrophiles regioselectively giving highly enantioenriched products. Starting with different isomers or changing the double-bond geometries in 6 leads to either of the enantiomers.     

Vinyl triflates derived from 1,3-dicarbonyl compounds and analogs: access and applications to organic synthesis

This review details the current methods used to prepare vinyl triflates derived from 1,3-dicarbonyl compounds and describes the reactivity of such functionalized vinyl triflates. α-Ketovinyl triflates can easily and stereoselectively be produced through three different ways. Enolization and triflation is the most common route, but direct triflation with triflic anhydride could also be used, each involving different mechanisms. Direct addition of triflic acid and related sulfonic acids to triple bond offers an alternative to the previous methods. With their peculiar set of functional groups, α-ketovinyl triflates can react in four different ways. The vinyl triflate part could be engaged in coupling reactions, while the carbonyl group as well as the enone motif could be subjected to nucleophilic additions. If a proton is available next to the triflate group, eliminations could occur under basic conditions. Upon addition, fragmentations could also be possible.     

Asymmetric organocatalytic direct aldol reactions of ketones with alpha-keto acids and their application to the synthesis of 2-hydroxy-gamma-butyrolactones

A variety of organocatalysts for the asymmetric direct aldol reactions of ketones with alpha-keto acids were designed on the basis of molecular recognition and prepared from proline and aminopyridines. The organic molecule 8e, derived from proline and 6-methyl-2-amino pyridine, was the best catalyst, affording excellent enantioselectivities (up to 98% ee) for the direct aldol reactions of acetone or 2-butanone with a wide range of alpha-keto acids and for the reactions of various acyclic aliphatic ketones with 3-(2-nitrophenyl)-2-oxopropanoic acid. The aldol adducts could be converted to 2-hydroxy-gamma-butyrolactones by reaction sequences of diastereoselective reduction and lactonization. Experimental and theoretical studies on the transition states revealed that the amide N-H and the pyridine N of the organocatalyst selectively form hydrogen bonds with the keto oxygen and the carboxylic acid hydroxy of the alpha-keto acid, respectively. These two hydrogen-bonding interactions are important for the reactivity and enantioselectivity of the direct asymmetric aldol condensation.     

An efficient synthesis of multisubstituted 4-nitrobuta-1,3-dien-1-amines and application in cyclisation reactions

The synthesis of multisubstituted 4-nitrobuta-1,3-dien-1-amines (nitrodienamines) from 3-aminocrotonates and nitroacetaldehyde potassium salt, has been performed in 45–89% yields. This one-step protocol works efficiently with a broad range of N-H and N-substituted 3-aminocrotonates and delivers both primary and secondary nitrodienamines. In addition, the possible variations of the substituents at the positions 2 and 3 of 4-nitrobuta-1,3-dien-1-amine have been shown. Generally, the yields of secondary 4-nitrobuta-1,3-dien-1-amines were lower than those of primary ones. The synthetic usefulness of obtained 4-nitrobuta-1,3-dien-1-amines has also been demonstrated by achieving the synthesis of multisubstituted 5-nitro-1,6-dihydropyridines in two-component cyclocondensation reactions of 4-nitrobuta-1,3-dien-1-amines with aromatic or aliphatic aldehydes. Lastly, diverse N-H and N-substituted 5-nitro-1,6-dihydropyridines have been obtained in 35–87% yields.     

1,3-Dipolar cycloaddition reactions of 1-methyl- and 1,3-dimethylindol-2-yl nitrile oxides

Reactions of the in situ prepared 1-methylindol-2-yl nitrile oxide ( 2a ) with dipolarophiles lead to isoxazolines 5 and isoxazoles 8 and to their chloro-derivatives 6 and 9 in good yields. Analogous reactions of the 1,3-dimethylindol-2-yl nitrile oxide ( 2b ) give the isoxazolines 10 and the isoxazoles 12 as main products as well as their oxidation products 11 and 13 in low yields. The mechanism of the reactions and the spectral elucidation of the cycloadducts are discussed.     

Configurationally stable,enantioenriched organometallic nucleophiles in stereospecific Pd-catalyzed cross-coupling reactions: an alternative approach to asymmetric synthesis

Several research groups have recently developed methods to employ configurationally stable, enantioenriched organometallic nucleophiles in stereospecific Pd-catalyzed cross-coupling reactions. By establishing the absolute configuration of a chiral alkyltin or alkylboron nucleophile prior to its use in cross-coupling reactions, new stereogenic centers may be rapidly and reliably generated with preservation of the known initial stereochemistry. While this area of research is still in its infancy, such stereospecific cross-coupling reactions may emerge as simple, general methods to access diverse, optically active products from common enantioenriched organometallic building blocks. This minireview highlights recent progress towards the development of general, stereospecific Pd-catalyzed cross-coupling reactions using configurationally stable organometallic nucleophiles.     

Direct preparation of arylethynylzinc bromides and their application to cross-coupling reactions

A novel synthetic protocol for the preparation of arylethynylzinc bromides has been developed. Thus-obtained organozinc reagents were successfully employed in the subsequent cross-coupling reactions with a broad range of aryl halides providing the corresponding alkynylated compounds in good to excellent yields.     

Electronic structure of organylthiochloroacetylenes and their reactions with O-containing nucleophiles

Conclusions Reactivity of organylthiochloroacetylenes toward O-containing nucleophiles was studied. It was established that phenolate anions attack the acetylenic C atom bound to the Cl atom and alcoholate anions attack the carbon atom bound to the S atom, which corresponds with the data of quantum chemical calculations.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya No. 3, pp. 612–616, March, 1988.     

2-Polyfluoroalkyl thiopyrylium salts: synthesis and reactions with nucleophiles

2-Polyfluoroalkylthiopyrylium salts have been synthesized by oxidative aromatization of 2-polyfluoroalkyl-2H-thiopyrans with triphenylmethane tetrafluoroborate. Nucleophilic addition of methanol, sodium azide, or urea to 2-trifluoromethylthiopyrylium tetrafluoroborate in a basic medium proceeds at the α-position to give the corresponding 2-substituted 6-trifluoromethyl-2H-thiopyrans whereas imidazoles, fluorine-containing 1,2,3-triazole, potassium thiolacetate, and sodium nitromethane afford mixtures of 2H- and 4H-thiopyrans. cis-Dihydroxylation of 6-trifluoromethyl-2-methoxy-2H-thiopyran affords the fluorine-containing thiohexenopyranoside derivative 8.     

Lewis acid mediated reactions of cyclopropyl aryl ketones with arylaldehydes, facile preparation of 2-(2-hydroxyethyl)-1,3-diarylpropenones

In the presence of Lewis acid TMSOTf, ring-opening reaction of aryl cyclopropyl ketone with arylaldehyde took place under mild conditions to give 2-(2-hydroxyethyl)-1,3-diarylpropenone in good yield. By protection of hydroxy group with triethylsilyl group (TES), the corresponding ring-opened product 7 was obtained in high yield with good geometrical selectivity.     

Highly facialselective synthesis of pyranose 1,3-oxazines and their ring opening with nucleophiles: a novel entry to 2-C-branched glycosides

A TMSOTf-promoted cycloaddition of N-benzoyl-N,O-acetals with various glycals and 3-deoxy glycals affords pyranose 1,3-oxazines with high facial selectivity. In addition, a highly diastereoselective ring opening of the resulting pyranose 1,3-oxazines is reported. With diverse nucleophiles, these reactions take place upon heating at 80 °C. This novel ring-opening reaction affords structurally diversified 2-C-branched glycosides with three newly formed contiguous stereocenters.     

Electrophilic additions to allenes—II : The reaction of benzeneselenenyl chloride with some 1,3-disubstituted allenes

Benzeneselenenyl chloride reacts with 1,3-dialkyl-substituted allenes in methylene chloride solution to give 1:1-adducts. Attack by selenium is found to occur exclusively at the central allenic carbon. In contrast to the analogous reaction of arenesulphenyl chlorides, the preferential formation of the Z-alkene is observed. A mechanism involving the preequilibrium formation of alkylideneseleniranium ions and/or alkylideneepiselenuranes which, in the product-determining step, collapse to products via an anti attack of chloride at the methine carbon of the ring is proposed to account for the preferential formation of the Z-isomers.     

Chloromethyl chlorosulfate: a new, catalytic method of preparation and reactions with some nucleophiles

The reaction of liquid (gamma-) SO3 with CH2Cl2 at room temperature leads to SO3 insertion into the C-Cl bonds, giving the useful chloromethylating agent chloromethyl chlorosulfate (CMCS). The process is very slow but becomes rapid on addition of catalytic quantities of trimethyl borate. The product mixture consists almost entirely of CMCS and the product of further sulfation, methylene bis(chlorosulfate)(MBCS), in a ratio of ca. 2 : 1, but typical yields of CMCS, isolated by distillation, are only 30-35%. The catalysed reaction in the homogeneous liquid phase at -45 degrees C has been followed as a function of time and of reactant concentration by 1H nmr spectroscopy. It is observed that, besides CMCS and MBCS, three additional, transient products (designated A, B and C) are formed. Products A, B and C decompose slowly at -45 degrees C but much more rapidly if the reaction mixture is raised to room temperature, giving additional CMCS and MBCS. From an analysis of the SO3 balance, it is inferred that products A, B and C arise from the reaction of one molecule of CH2Cl2 with respectively two, three and four molecules of SO3; they are suggested to be chloromethyl chloropolysulfates. By measuring initial rates of CMCS formation or total CH2Cl2 consumption, it is shown that the reaction is first order in the catalyst and roughly third order in SO3. A mechanistic scheme is proposed in which SO3 forms equilibrating zwitterionic molecular complexes with CH2Cl2. of 1 : 1, 2 : 1 and higher stoichiometries. The boron-containing catalyst can activate these complexes towards nucleophilic attack at carbon by the negatively charged oxygen of another zwitterion. An analogous mechanism can be written for the conversion of CMCS into MBCS by SO3 in the presence of trimethyl borate. CMCS reacts rapidly with anionic nucleophiles, such as halide or acetate ions (X-), in homogeneous solution of their tetrabutylammonium salts in CD3CN, or in a two-phase system (CDCl3/H2O) using alkali-metal salts in conjunction with a phase-transfer catalyst. In both situations the products (ClCH2X) arise by rapid nucleophilic displacement of the chlorosulfate moiety; this then more slowly liberates chloride ion, which converts further CMCS into CH2Cl2. The reactivity of CMCS has been compared with that of MBCS and methyl chlorosulfate (MCS) in competitive experiments; the reactivity order is MCS > MBCS > CMCS > CH2Cl2. Evidence is also presented suggesting that, in contrast to the halide nucleophiles, reaction of CMCS with sodium phenoxide in tetrahydrofuran solution leads to nucleophilic displacement of the sulfur-bound chloride.     

Pd-catalyzed arylation reactions with phenol diazonium salts: application in the synthesis of diarylheptanoids

The first total synthesis of the natural product (3S,7R)-5,6-dehydro-de-O-methyl centrolobine and various analogues is reported, using a highly regio- and diastereoselective Mizoroki-Heck reaction of phenol diazonium salts and enantiopure dihydropyrans. The assigned relative configuration was confirmed by single-crystal X-ray structure analysis, but a revision of the absolute configuration is proposed based on polarimetric measurement.     

Cycloaddition reactions of allenylphosphonates and related allenes with dialkyl acetylenedicarboxylates, 1,3-diphenylisobenzofuran, and anthracene

Cycloaddition reactions of allenylphosphonates [(RO)(2)P(O)[(R(1))C═C═CR(2)(2)] with dialkyl acetylenedicarboxylates, 1,3-diphenylisobenzofuran, and anthracene have been investigated and compared with those of allenoates [(EtO(2)C)RC═C═CH(2)] and allenylphosphine oxides [Ph(2)P(O)(R(1))C═C═CR(2)(2)] in selected cases. Allenylphosphonates (RO)(2)P(O)(Ar)C═C═CH(2) with an α-aryl group preferentially undergo [4 + 2] cycloaddition with DMAD/DEAD under thermal activation, but in addition to the expected 1:1 (allene: DMAD) product, the reaction also leads to 1:2 as well as 2:1 products that were not reported before. When an extra vinyl group is present at the γ-carbon of allenylphosphonate [e.g., (OCH(2)CMe(2)CH(2)O)P(O)(Ph)C═C═CH(C═CHMe)], [4 + 2] cycloaddition takes place utilizing either the vinylic or the aryl end, but additionally a novel cyclization wherein complete opening of the [β,γ] carbon-carbon double bond of the allene is realized. In contrast to these, the reaction of allenylphosphonate (OCH(2)CMe(2)CH(2)O)P(O)(H)C═C═CMe(2) possessing a terminal ═CMe(2) group with DMAD occurs by both [2 + 2] cycloaddition and ene reaction. While the reaction of ═CH(2) terminal allenylphosphonates as well as allenylphosphine oxides with 1,3-diphenylisobenzofuran afforded preferentially endo-[4 + 2] cycloaddition products via [α,β] attack, the analogous allenoates [(EtO(2)C)RC═C═CH(2)] underwent exo-[4 + 2] cyclization. Under similar conditions, allenylphosphonates with a terminal ═CR(2) group gave only [β,γ]-cycloaddition products. An unusual ring-opening of a [4 + 2] cycloaddition product followed by ring-closing via [4 + 4] cycloaddition, as revealed by (31)P NMR spectroscopy, is reported. Anthracene reacted in a manner similar to 1,3-diphenylisobenzofuran, albeit with lower reactivity. Key products, including a set of exo- and endo- [4 + 2] cycloaddition products, have been characterized by single crystal X-ray crystallography.     

Regio- and diastereoselective reactions of chiral secondary alkylcopper reagents with propargylic phosphates: preparation of chiral allenes

The diastereoselective S_N2′-substitution of secondary alkylcopper reagents with propargylic phosphates enables the preparation of stereodefined alkylallenes. By using enantiomerically enriched alkylcopper reagents and enantioenriched propargylic phosphates as electrophiles anti-S_N2′-substitutions were performend leading to α-chiral allenes in good yields with excellent regioselectivity and retention of configuration. DFT-calculations were performed to rationalize the structure of these alkylcopper reagents in various solvents, emphasizing their configurational stability in THF.

The diastereoselective S_N2′-substitution of secondary alkylcopper reagents with propargylic phosphates enables the preparation of stereodefined alkylallenes.     

Diamidophosphites with remote P1-stereocentres and their performance in Pd-catalyzed enantioselective reactions

Diamidophosphite ligands based on 1,1′-bis(hydroxymethyl)ferrocene or N¹,N²-bis((S)-1-hydroxy-3,3-dimethylbutan-2-yl)oxalamide and bearing 1,3,2-diazaphospholidine rings with stereogenic phosphorus atoms were obtained. The use of these ligands provides up to 96% ee in Pd-catalyzed asymmetric allylations of (E)-1,3-diphenylallyl acetate, up to 70% ee in Pd-catalyzed desymmetrizations of N,N′-ditosyl-meso-cyclopent-4-ene-1,3-diol bis-carbamate and up to 80% ee in Pd-catalyzed allylic alkylations of cinnamyl acetate with ethyl 2-oxocyclohexane-1-carboxylate. Results obtained with a diamidophosphite containing an oxalamide framework show the considerable potential of such ligands in enantioselective catalysis.