Suzuki Yumiko

A molecular editing strategy to construct quinoxalinones from chromones and benzimidazolylidene N-heterocyclic carbenes (NHCs) was developed. The C2 atoms of the chromones were incorporated into the quinoxalinones via ring expansion of the NHCs.

The utility of acylals as building blocks for selective cross-benzoin synthesis was explored in this study. The synthesis of α-acetoxyketones (O-acyl cross-benzoins) was achieved via selective N-heterocyclic carbene-catalyzed cross-benzoin reactions using acylals as aldehyde equivalents. Thus, the combination of ortho-substituted phenyl acylals and aromatic/aliphatic aldehydes as coupling substrates using bicyclic triazolium salts as precatalysts and potassium carbonate as a base in THF at reflux temperature selectively yielded O-acyl cross-benzoins.

<p>The first total synthesis of the sesquiterpene lactone cynaropicrin, isolated from artichoke, was achieved starting from (<italic>S</italic>)-α-pinene. The synthesis involved a stereoselective Favorskii rearrangement and a diastereoselective Barbier reaction.</p>

This journal is © The Royal Society of Chemistry. Carbon quantum dots (CQDs; luminescent carbon nanoparticles, size < 10 nm) have attracted much attention with respect to their eco-friendliness and multi-functionality. The solvent-dependent photoluminescence of CQDs has been well investigated to optimize the synthesis process and homogeneous dispersion. Although some alkan-1-ol solvents, such as ethanol, have been well utilized empirically as good solvents when synthesizing highly photoluminescent CQDs, the role of alkan-1-ol solvents, particularly long-chain alkan-1-ols (e.g., 1-nonanol, 1-decanol), has not yet been clarified. Herein, we demonstrate a method for the synthesis of strongly yellow emitting CQDs using solvothermal treatment and elucidate the role of alkan-1-ol solvents in the photoluminescence of CQDs. These CQDs have been characterized using theoretical calculations, ex situ morphological observations using transmission electron microscopy (TEM) and dynamic light scattering (DLS), and 500 MHz 1H nuclear magnetic resonance (NMR) and 13C NMR spectroscopy. A comparative study of alkan-1-ol solvents suggests a mechanism for the agglomeration and aggregation of carbon precursors, intermediates, and CQDs, which is expected to lead to further synthesis studies on highly luminescent CQDs.

Organic reactions driven by microwaves have been subjected for several years to some enigmatic phenomenon referred to as the microwave effect, an effect often mentioned in microwave chemistry but seldom understood. We identify this microwave effect as an electromagnetic wave effect that influences many chemical reactions. In this article, we demonstrate its existence using three different types of microwave generators with dissimilar oscillation characteristics. We show that this effect is operative in photocatalyzed TiO2 reactions it negatively influences electro-conductive catalyzed reactions, and yet has but a negligible effect on organic syntheses. The relationship between this electromagnetic wave effect and chemical reactions is elucidated from such energetic considerations as the photon energy and the reactions' activation energies.

An alternative synthetic route to 1,4,5-trisubstituted imidazoles from α-imino ketone, which can be prepared from imidoyl chlorides and aromatic aldehydes via N-heterocycle carbene-catalyzed aroylation was developed. This methodology consists of simple transformations, allowing a rapid access to imidazole derivatives with various aryl substituents at the desired positions.

A combined experimental and computational study on the key intermediates of NHC-catalyzed acylation reaction, Breslow intermediates (BIs), has been conducted in order to achieve a direct nucleophilic alkanoylation of N-heterocycles. Various BI precursors are alternatively prepared and used in the reaction with 4-chloroquinazoline. The present study reveals that the intermediates having benzimidazole moiety serve as acylating agents for the introduction of straight-chain alkanoyl groups. Natural bond orbital analysis indicates that the reactivity of intermediates partly correlates to the occupancy of the πC-C bonds of the hydroxyl enamine moieties. The putative rate-determining step of the acylation reaction has been theoretically investigated. Several new 4-alkanoylquinazolines are synthesized using the BI precursors.

– We report on the synthesis of 7-benzoyl- and 7-heteroaroylquinazolines from 7-fluoroquinazolines and aromatic aldehydes by N-heterocyclic carbene (NHC)-catalyzed nucleophilic aromatic substitution, showing that the NHC derived from 1,3-dimethylimidazolium iodide outperformed those originating from other azolium (e.g., thiazolium and triazolium) salts. Additionally, the developed methodology allowed the preparation of 5- and 8-aroylquinazolines from the corresponding fluoroquinazolines.

Anticancer 2-aminoquinazolines were evaluated by their photophysical properties responding to media changes. By binding to the colchicine binding site of beta-tubulin, the fluorescence emission of 2-N-morpholino-derivative (1) was blue-shifted with enhanced intensity. These distinguished features were used for the development of a beta-tubulin colchicine site competition assay and visualization of the intracellular distribution of 1 by fluorescence microscopy.

A quinazoline derivative PVHD121 (1a) was shown to have strong antiproliferative activity against various tumor-derived cell lines, including A549 (lung), NCI-H460 (lung), HCT116 (colon), MCF7 (breast), PC3 (prostate), and HeLa (cervical) cells with IC50 values from 0.1 to 0.3 mu M. A structure activity relationship (SAR) study at the 2- and 4-position of the quinazoline core lead to the discovery of more potent anticancer agents (14, 16, 17, 19, 24, and 31). The results of an in vitro tubulin polymerization assay and fluorescent based colchicine site competition assay with purified tubulin indicated that la inhibits tubulin polymerization by binding to the colchicine site.

This article examined how and the possible effect microwaves may have on intramolecular reactions such as those of the Claisen-type rearrangement carried out in dimethyl sulfoxide (DMSO) solvent and in solvent-free, microwave irradiation conditions. For comparison, the reaction was also performed by conventional heating using an oil bath. 2-Allylphenol was synthesized from allylphenyl ether in DMSO solvent under stirring conditions as a model intramolecular reaction taking place via the Claisen rearrangement using a commercial microwave chemical apparatus together with conventional heating; no enhancement of the reaction occurred. To further examine the influence of microwave irradiation on Claisen rearrangement reactions, we also investigated the transformation of 1-allyloxy-4-methoxybenzene to 2-allyl-4-methoxyphenol under both solvent-free conditions (no stirring) and in DMSO medium; here also no reaction enhancement was observed. This notwithstanding, microwaves did impact the formation of a by-product formed in the latter reaction, which was identified by GC and GC/MS as 4-methoxyphenol, the yield of which was nearly fourfold greater (ca. 6%) under microwave irradiation than under oil-bath heating (ca. 1.5%). The latter suggests that under solvent-free conditions a microwave non-thermal effect influenced the formation of this by-product during the Claisen rearrangement process, contrary to the case where the reaction was performed in DMSO medium for which the yields were identical (ca. 2.5%), regardless of whether the reactant was microwave or oil-bath heated.

Synthesis of chiral ionic liquids containing an imidazole nucleus and chiral centers on N-substituents is reported. [(2S,3S)-2,3-Dihydroxybutane-1,4-bis(3-butylimidazolium)]-[bis(trifluoromethanesulfonyl)amide](2) and [(4S,5S)-2-phenyl-1,3-dioxolane-4,5-bis(1-methylimidazolium)]-[bis(trifluoromethanesulfonyl)amide](2) induced enantioselectivity in the Michael addition of malonic esters to chalcones. (c) 2013 Elsevier Ltd. All rights reserved.

An efficient one-pot synthesis of various unsymmetrical benzils via N-heterocyclic carbene (NHC)-catalyzed aroylation of N-phenylimidoyl chlorides with aromatic aldehydes followed by acidic hydrolysis has been developed. The one-pot procedure was extended to synthesis of quinoxalines and pyrazines by condensation/annulation of unsymmetrical benzils generated in situ with diamines. Crown Copyright (c) 2012 Published by Elsevier Ltd. All rights reserved.

In this paper, we propose a novel and efficient method for the preparation of various unsymmetrical benzils. We first demonstrate the nucleophilic aroylation of N-phenylbenzimidoyl chlorides with aromatic aldehydes using N-heterocyclic carbene as the catalyst to afford 1-aryl-2-phenyl-2-(phenylimino)ethanones. These iminoethanones were then converted to 1,2-diaryl-1,2-diketones by acid-promoted hydrolysis. (C) 2011 Elsevier Ltd. All rights reserved.

The total synthesis of atroviridin has been accomplished by a linear route involving the N-heterocyclic carbene (NHC)-catalyzed aroylation of the fluorobenzene derivative, Claisen cyclization of the O-propargylated benzo-phenones, and intramolecular 1,4-addition of the quinone intermediates. The result provides a viable route to xanthone natural products.

Aromatic aldehydes and ketones react with ketene under Lewis acid catalysis to produce beta-lactones, which in situ react with another molecule of ketene to produce 3-arylglutaric anhydrides. The mechanism, scope, and limitation of this one-pot synthesis of 3-substituted glutaric anhydrides are discussed. (C) 2009 Elsevier Ltd. All rights reserved.

Rh-N-heterocyclic carbene (NHC) complexes were generated in situ from imidazolium salts, [RhCl(cod)](2) and t-BuOK in dioxane. In the presence of a catalytic amount of Rh-NHC complexes, the addition reaction of phenylboronic acid to N-sulfonylarylimines and N-phosphinyolarylimines gave the corresponding amines in high yields.

A highly efficient total synthesis of (R)-(+)-muscopyridine 1 has been accomplished in 12 steps with 40% overall yield. A highlight of the synthesis is the intramolecular [4+2] cycloaddition of bisketene to afford a bridged pyrone and ring transformation of the pyrone to afford pyridine derivatives. (c) 2007 Elsevier Ltd. All rights reserved.

N-Heterocyclic carbenes (NHCs) were generated in-situ from imidazolium and imidazolinium salts by deprotonation of C-2 hydrogen and were used as ligands in the copper-catalyzed addition of diethylzinc to N-sulfonylimines. The copper - NHC complexes were shown to possess an efficient ligand acceleration effect (LAE).

Xanthones and acridones were synthesized from 3,4-difluoronitrobenzene and 2-fluorobenzaldehydes in two or three steps. The key step was nucleophilic aroylation catalyzed by imidazolidenyl carbene. The nucleophilic aroylation of 3,4-difluoronitrobenzene afforded 2,2'-difluoro-4-nitrobenzophenones. The cyclization of the difluorobenzophenones with O-nucleophile and N-nucleophile yielded 3-nitroxanthones and 3-nitroacridones, respectively. Indazole, quinolino[2,3-b]quinoxaline, and thianaphtho[2,3-b]quinoxaline derivatives were also synthesized via nucleophilic aroylation of 2,3-dichloroquinoxaline followed by cyclization with nucleophiles.

Benzoin reactions are catalyzed by N,N-dialkylbenzimidazole to yield alpha-hydroxy ketones; the reaction proceeds in water as an aqueous medium under mild conditions. The utility of these salts as pre-catalysts in these reactions has been demonstrated. (c) 2006 Elsevier Ltd. All rights reserved.

N-Heterocyclic carbenes produced in situ from salts of imidazolium. benzimidazolium, pyrido[1,2-c]imidazolium, imidazolinium, thiazolium, and triazolium catalyze the addition of trimethylsilylcyanide to aldehydes to yield cyanohydrin trimethylsilyl ethers. The use of C-2-symmetric imidazolidenyl carbene derived from (R,R)-1,3-bis[(1-naphthyl)ethyl]imidazolium chloride led to enantioselective cyanosilylation. (c) 2006 Elsevier Ltd. All rights reserved.

Chiral N-heterocyclic carbenes are generated from C-2-symmetric 1,3-bis(1-arylethyl)imidazolium salts and potassium tert-butoxide. These C2-symmetric imidazolidenyl carbenes catalyze enantioselective acylation of racemic secondary alcohols. The asymmetric acylation of 1-(1-naphthyl)ethanol was achieved in up to 68% cc of the acylated product, using (R,R)-1,3-bis[(1-naphthyl)ethyl]imidazolium tetrafluoroborate as a precursor of the chiral N-heterocyclic carbene and vinyl propionate as the acyl donor. (c) 2005 Elsevier Ltd. All rights reserved.

Synthesis of 4-hydroxy-2-pyrones bridged at the 3- and 6-positions by ring-closing metathesis was studied. The reaction of 6-(9-decenyl)-4-methoxy-3(10-undecenoyl)pyran-2-one (6b) by the first generation ruthenium catalyst (7) gave 3,6-bridged 2-pyrone (10b) in 62% yield. The reaction of 3-(6-heptenoyl)-6(5-hexenyl)-4-methoxypyran-2-one (6a) (n = 4) under the same conditions afforded the 3,6-bridged 2-pyrone (10a) in 6% yield together with considerable amounts of intermolecular metathesis products.

A convenient one-pot synthesis of alpha-fluoro-alpha,beta-unsaturated esters from ethoxy- and tert-butoxycarbonylmethyltriphenylphosphoniurn bromide was developed. The fluorinated phosphoranes, generated in situ from alkoxycarbonylmethyltriphenylphosphoniurn bromides and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor(R)), undergo a Wittig reaction with aldehydes to yield alpha-fluoro-alpha,beta-misaturated esters with (Z)-selectivity. (C) 2003 Elsevier Ltd. All rights reserved.

Chiral N-heterocyclic carbenes, which are derived from C-2-symmetric 1,3-bis(1-arylethyl) imidazolium salts, catalyze enantioselective acylation of racemic secondary alcohols.

Imidazolidenyl carbene catalyzes nucleophilic acylation reaction of arylfluorides with electron withdrawing groups to give benzophenone derivatives.

2-Aroylquinoxalines (5, 6), 1-aroylphthalazines (10, 11), and 4-aroylcinnolines (13) were synthesized by using arenecarbaldehydes (2) in the presence of an azolium salt (1) in moderate to good yields. 1,3-Dimethylimidazolium iodide (1a) and sodium sulfinate (7) were also effective catalysts in this aroylation.

In the presence of 1,3-dimethylimidazolium iodide (1), 6-chloro-9-phenyl-9H-purine (7) and 4-chloro-5,6-dimethylpyrrolo[2,3-d]pyrimidines 40-42 underwent nucleophilic aroylation with arenecarbaldehydes (5) to give the corresponding fused aroylpyrimidines 8 and 43-45. 1,3-Dimethylbenzimidazolium iodide (2) was an effective catalyst for the similar synthesis of 7-aroyl-3-phenyl-3H-1,2,3-triazolo[4,5-d]pyrimidines 16-21. In the synthesis of 4-aroyl-1H-pyrazolo[3,4-d]pyrimidines 26-32, both azolium salts 1 and 2 were effective as catalysts. Moreover, 4-aroyl-7H-pyrrolo[2,3-d]pyrimidines 43-45 were obtained in good yields via the 4-tosyl derivatives, in the presence of catalytic amounts of sodium p-toluenesulfinate (46) and the imidazolium salt 1, This catalytic aroylation,vas found to be a facile and useful method for the synthesis of 6-aroyl-9H-purines and their analogues.

4-(alpha-Benzyl-alpha-hydroxybenzyl)quinazoline (4a) underwent retro-benzoin condensation catalyzed by cyanide ion to give deoxybenzoin (2a) and quinazoline (5a), Similarly, several nitrogen-containing heteroarenes (4, 9, 12, 16-19) having an alpha-hydroxybenzyl group at the alpha-position of the nitrogen underwent retro-benzoin type condensation to afford ketones (2) and heteroarenes (5), However, similar reaction of pyrazolopyrimidines (13, 14, 15) having an alpha-benzyl-alpha-hydroxybenzyl group resulted in benzyl migration, giving benzylpyrazolopyrimidines (8) and arenecarbaldehydes (3), Tetrabutylammonium cyanide (11, Bu4NCN) was a more effective cyanide ion donor than KCN (10). The retro-benzoin condensation was applied to the synthesis of 2-substituted quinazolines (38) from 2-chloro-4-aroylquinazolines (34), using the aroyl group as a protecting and electron-withdrawing group.

4-Aroyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidines (5) were formed in low yields by reaction of 4-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (4) with arenecarbaldehydes (3) in the presence of potassium cyanide. Similar reaction of 4-tosyl-1-phenyl-1H-pyrazolo [3,4-d]pyrimidine (9) with 3 gave the ketones (5) in higher yields (60-74%). In the presence of catalytic amounts of both sodium p-toluenesulfinate (10) and potassium cyanide, the reaction of 4 with 3 gave the ketones (5) in good yields.

When alpha-benzylbenzoin (3a, alpha-benzyl-alpha-hydroxybenzyl phenyl ketone) was treated with potassium cyanide (1) in N,N-dimethylformamide at 80 degrees C for 1h, the carbon-carbon bond was cleaved, resulting in the formation of deoxybenzoin (4a, benzyl phenyl ketone) and benzaldehyde (2a). This carbon-carbon bond cleavage proceeds through a retro-benzoin condensation mechanism. This method of synthesizing ketones was applied to several alpha-substituted benzoins (3), and the corresponding ketones (4) were formed in good yields. Further, we found that the cyanide ion-donating ability of tetrabutylammomium cyanide (6, Bu4NCN) is more effective than that of potassium cyanide (1, KCN). As expected from the chemical analogy between cyanide ion and azolium ylide, several azolium salts (7) can also be employed in the retro-benzoin condensation as catalysts. The benzoin derivatives 3 were synthesized in the following three ways; reaction of alkyl halide (9) with benzoin (5), Michael addition of benzoin (5) with accepters (10), and Grignard reaction of benzils (8). Alkylation of the benzoins without isolation, followed by carbon-carbon bond cleavage, readily afforded the corresponding ketones (4).

Several heteroarenecarbonitriles (5) were synthesized in moderate yields from heteroarenes (3) through metalation, followed by electrophilic cyanation using p-toluenesulfonyl cyanide. Similarly, trimethylsilylheteroarenes (8) were converted to heteroarenecarbonitriles (5) in good yields by treatment with p-toluenesulfonyl cyanide.

4-Aroylfuro[2,3-d]-(4), 4-aroylthieno[2,3-d]-(7 and 8), and 4-aroylisoxazolo[5,4-d]pyrimidines (13) were synthesized by aroylation of the fused chloro-(3a and 12) or bromopyrimidines (3b, 5, and 6) with arenecarbaldehydes (2) catalyzed by an imidazolium salt (1a). The fused aroylpyrimidines (4 and 7) were also synthesized by oxidative decyanation of alpha-phenylheteroareneacetonitriles (10 and 11).

Refluxing of a mixture of benzaldehyde (la), 1,3-dimethylbenzimidazolium iodide (7), p-nitroaniline (9b) as an oxidizing agent, and 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) in MeOH afforded methyl benzoate (2a) in good yield, Other methyl arenecarboxylates 2 were similarly obtained from arenecarbaldehydes 1, We showed that this aroylation proceeds via the 2-aroyl-1,3-dimcthylbenzimidazolium salt (8), The 1,2,4-triazolium salt (18) and the naphtho[1,2-d]imidazolium salt (19) were also effective catalysts for this oxidative aroylation, However, the aroylation did not proceed with the imidazolium salt (20), Tn the presence of flavins (25a-c), arenecarbaldehydes 1 reacted in MeOH under aerobic conditions catalyzed by the benzimidazolium salt 7 to give the corresponding methyl arenecarboxylates 2, 1-Methyl-3-[3-(10-phenylisoalloxazin-3-yl)propyl]benzimidazolium bromide (27) is an effective complex catalyst for this oxidative aroylation.