The first asymmetric synthesis of a 4-aryl-substituted 5-carboxy-3,4-dihydropyridin-2-one derivative

A simple and practical route for the asymmetric synthesis of (S)-4-(4-fluorophenyl)-1,4,5,6-tetrahydro-6-oxo-3-pyridinecarboxylic acid (1) is presented. The procedure comprises catalytic desymmetrization of a meso-anhydride using a chiral thiourea organocatalyst, followed by selective formylation and cyclization.     

Total synthesis of two novel 5,6,7,8-tetrahydroindolizine alkaloids, polygonatines A and B

The structures of polygonatines A and B, two simple but structurally novel alkaloids, have been substantiated by synthesis. Cyclisation of 4-(1H-pyrrol-1-yl)butanoic acid or its ethyl ester produced 6,7-dihydroindolizin-8(5H)-one , formylation of which at C-3 followed by reduction afforded polygonatine A . Acetylation of this alkaloid followed by displacement of the acetate with ethanol yielded polygonatine B , possibly via an azafulvenium cation.     

Functionalization of saturated hydrocarbons by aprotic superacids

The inefficient formylation of adamantane by CO initiated by superacid systems based on polyhalomethanes and aluminum halides becomes selective in the presence of methylcyclopentane and affords 1-adamantanecarbaldehyde in an almost quantitative yield under mild conditions.     

The Eschenmoser's Salt as a Formylation Agent for the Synthesis of Indolizinecarbaldehydes and Their Use for Colorimetric Nitrite Detection

C−H bond formylation is the most immediate way to incorporate the versatile formyl group into (hetero)aromatics. However, the type of reagents and severe conditions involved in the classical formylation methods often curtail their application, especially in the presence of other functional groups. Herein, we present the Eschenmoser's salt, a commercially available (dimethylamino)methylating chemical, as a useful reagent for the C−H formylation of indolizines and other compounds. The method is straightforward and mild, furnishing indolizinecarbaldehydes in modest-to-good yields with exclusive and remote regioselectivity. Furthermore, these compounds can be easily transformed into push-pull dyes and are highly selective in the colorimetric detection of nitrite, a substance extensively employed as preservative in the food industry, the concentration of which is crucial to control to prevent harmful effects in living organisms. The assay is simple, allowing the naked-eye detection of nitrite in solution or on a cotton swab for a wide range of concentrations.     

Synthesis and some transformations of 1-methyl-2-(thiophen-3-yl)-1<Emphasis Type="Italic">H</Emphasis>-benzimidazole

1-Methyl-2-(thiophen-3-yl)-1H-benzimidazole was synthesized by the Weidenhagen reaction, followed by N-methylation. Electrophilic substitution reactions of the title compound, in particular nitration, bromination, sulfonation, formylation, and acylation, were studied. The formylation and acylation in polyphosphoric acid afforded mixtures of 2- and 5-substituted isomers at the thiophene ring. The nitration of 1-methyl-2-(thiophen-3-yl)-1H-benzimidazole involved the thiophene ring or both thiophene and benzene fragments, depending on the conditions. Steric arrangement of the heterocycles in the 1-methyl-2-(thiophen-3-yl)-1H-benzimidazole molecule was analyzed by quantum chemical calculations.     

Synthesis of HKI 0231B

[reaction: see text] The total synthesis of HKI 0231B (1b) was completed in 12 linear steps and 15.6% overall yield. An unusual anionic cyclization provided access to intermediate 61 and the embedded benz[cd]indol-3-(1H)-one ring system 3. Directed ortho-lithiation in the presence of a ketone followed by formylation and finally acid-catalyzed methanolysis complete the synthesis. Studies directed toward the construction and reactivity of the lactam acetal functionality present in HKI 0231A (1a) are also reported.     

Unprecedented Vilsmeier formylation: expedient syntheses of the cruciferous phytoalexins sinalexin and brassilexin and discovery of a new heteroaromatic ring system

[reaction: see text]. A very concise first synthesis of sinalexin was achieved by regioselective formylation of 1-methoxyindoline-2-thione under Vilsmeier conditions followed by unprecedented ammonia workup. Similar formylation of indoline-2-thione yielded brassilexin and a novel pentacyclic heteroaromatic compound resulting from condensation of the Vilsmeier adduct of indoline-2-thione. Both sinalexin and brassilexin displayed strong antifungal activity against several pathogens of crucifers.     

Concise Synthesis and Cellular Evaluation of 3′-Formyl-4′,6′-dihydroxy-2′-methoxy-5′-methylchalcone (FMC) and Its Analogues

3′-Formyl-4′,6′-dihydroxy-2′-methoxy-5′-methylchalcone (FMC) was a natural product isolated from Cleistocalyx operculatus. A four-step synthetic strategy toward FMC and its four analogues (1b–1e) was first developed. All compounds were synthesized from commercially available 2,4,6-trihydroxyacetophenone; formylation at 3′ position under Vilsmeier–Haack conditions was followed by the introduction of a methyl group at 5′ position. The key step of selective methylation at 2′ position was achieved by trimethylsilyldiazomethane (TMSCHN₂). Then substituted aromatic aldehydes were condensed through Claisen–Schmidt reaction in the presence of potassium hydroxide. All structures were confirmed by ¹H NMR, ¹³C NMR, and high-resolution mass spectra. FMC and analogues were screened for their antiproliferative activity.     

Studies in iridoid synthesis. Chemoselective transformations of cis-1,2,4,6-tetrahydrophthalic anhydride

In the course of synthetic studies towards the development of diastereoselective routes to secoiridoid aglycones, cis-1,2,4,6-tetrahydrophthalic anhydride was transformed into the corresponding lactone cis-3a,4,7,7a-tetrahydro-3H-isobenzofuran-1-one, which served as a key precursor for a variety of chemoselective synthetic manipulations. Unsuccessful formylation of an ester intermediate resulted in a (E/Z) mixture of vinyl alcohols which were protected as acetates and as a single p-methoxybenzyl (PMB) ether (E) isomer. Dihydroxylation of the cyclohexene motif using OsO(4) led to the unexpected deprotection of the PMB ether. On the other hand, successful formylation of a suitably silyl protected lactonised intermediate was achieved using tert-butoxybis(dimethylamino)methane, or Bredereck's reagent. Tetrabutylammonium fluoride (TBAF) deprotection of a methoxyethoxymethyl (MEM)-ether intermediate serendipitously afforded an approximately 1 : 1 mixture of pyrano-pyranones, which are products of a seldom encountered intramolecular Michael addition, using an oxygen donor, to the terminus of an alpha,beta-unsaturated system, followed by beta-elimination of the MEM moiety.     

Intermolecular one-pot cyclization of formyl-pyrroles of amino acid esters with norephedrine: stereoselective routes to new tricyclic pyrrole–pyrazine–oxazole fused structures

The treatment of esters of amino acids with dimethoxytetrahydrofuran furnished pyrrole derivatives of amino acid esters. The Wilsmeier–Haack formylation followed by the reaction of the formylated pyrroles with norephedrine afforded a selective formation of the tricyclic pyrrole–pyrazine–oxazole fused structures in one step via the formation of an oxazoline structure and intramolecular lactam formation. Pyrrole–pyrazine–oxazole fused structures were achieved in good yields. The cyclization reaction for the formation of an oxazole ring worked selectively to form only one stereoisomer. The configuration of the newly generated stereogenic center in the oxazole ring is dependent on the stereogenic centers of norephedrine.     

Selective and Efficient Formylation of Indoles (C3) and Pyrroles (C2) Using 2,4,6‐Trichloro‐1,3,5‐Triazine/Dimethylformamide (TCT/DMF) Mixed Reagent

This study introduces an efficient method for the selective formylation of indoles and pyrroles at the positions of C(3) and C(2), respectively. The mixture of three equivalents of N ,N‐dimethylformamide and one equivalent of 2,4,6‐trichloro‐1,3,5‐triazine (cyanuric chloride) generates an easy handling formylating agent for the efficient formylation of these classes of compounds to give the corresponding aldehydes under mild reaction conditions. This procedure was highly efficient, and a range of formylated indoles and pyrroles were obtained in good to excellent yields.     

取代苯基吡唑醛缩邻氨基苯酚Schiff碱的合成与表征

取代苯肼与乙酰丙酮经过缩合反应合成取代苯基吡唑．取代苯基吡唑在Vilsmeier—Haak反应条件下,得到取代苯基吡唑醛．取代苯基吡唑醛与邻氨基苯酚作用生成取代苯基吡唑醛缩邻氨基酚Schiff碱．这些化合物的结构经IR光谱、质谱和^1H NMR确认．     

Synthesis of sterically hindered aromatic dialdehydes

A study was carried out on the formylation of a series of aromatic compounds containing two mesitylene or durene residues [dimesityl (I), dimesitylmethane (II), 1,2-dimesitylethane (III), 1,6-dimesitylhexane (IV), dimesityl sulfide (V), 1,1-dimesitylethylene (VI), 1,1-dimesityl-1-butene (VII), and didurylmethane (VIII)] by the action of dichloromethyl methyl ether (DCM) in the presence of A1C1₃ and TiCl₄. The corresponding dialdehydes are the major products. The formylation products when the reaction is carried out in the presence of A1C1₃ in the case of (I) and (V) contain significant amounts of monoaldehydes, while partial cleavage of the substrates with the formation of products containing only one benzene ring is observed in the case of (II) and (VIII) in addition to formylation.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 7, pp. 1700–1703, July, 1991.     

A general method for the synthesis of 2-arylpyrroles

Reaction of methyl azidoacetate with β-arylacroleins, followed by cyclisation of the obtained derivatives easily leads to arylpyrroles. N M R and mass spectra data are given and the Vilsmeier formylation of some arylpyrroles is described.     

Solvent-dependent oxidations of 5- and 6-azaindoles to trioxopyrrolopyridines and functionalised azaindoles

A regioselective synthesis of 4,7-dimethoxy 5- and 6-azaindoles 2 has been achieved, based on the appropriate choice of ortho-directing or ortho-repulsing groups in the formylation of a pyridine ring. Studies on the regioselectivity of the formylation step and on the preparation of azidoacrylate intermediates 4 are described in this paper. The reactivity of the 5- and 6-azaindole structures towards BBr3-mediated selective monodemethylation and oxidative demethylation reactions were also investigated. The regioselectivity of the deprotection was confirmed using a chemical approach. Oxidation reactions were then carried out on either dimethoxy- or hydroxymethoxyazaindoles, in different solvents, using [bis(trifluoroacetoxy)iodo]benzene. In acetonitrile-water, trioxopyrrolopyridines 12 were obtained, whereas the formation of functionalised azaindoles 17 was observed in acetonitrile-methanol. The tautomeric structure of the trioxopyrrolopyridines was proved by X-ray diffraction analysis.     

Synthesis of dimethoxybenz[g]isoquinolines

Stobbe condensation of 2,3-dimethoxybenzaldehyde with diethyl succinate, followed by reduction and cyclization, gave 3-carbethoxy-5,6-dimethoxy-l-tetralone (7a). Subsequent reduction, aromatization and side chain conversion yielded the key intermediate 7,8-dimethoxy-2-naphthalenecarboxaldehyde (8c). 6,7-Dimethoxybenz[g]isoquinoline (1) was prepared from 8c via condensation with nitromethane, reduction, formylation, cyclization, and aromatization reactions; the isomeric 8,9-dimethoxybenz[g]isoquinoline (2) was obtained by the condensation of 8c with the diethyl acetal of aminoacetaldehyde (12) followed by reduction, tosylation, cyclization and aromatization. The methiodides of both compounds were also prepared.     

Synthesis of formyl-thienylpyrroles: versatile building blocks for NLO materials

Several formyl-substituted 1-alkyl(aryl)-2-(2′-thienyl)pyrroles 3-7 were synthesized by functionalization of the pyrrole or thiophene ring of thienylpyrroles 2 using different methods: Vilsmeier formylation or metalation followed by reaction with DMF.     

Concise syntheses of the cruciferous phytoalexins brassilexin, sinalexin, wasalexins, and analogues: expanding the scope of the vilsmeier formylation

Efficient syntheses of the phytoalexins brassilexin, sinalexin, and analogues are demonstrated through the application of the Vilsmeier formylation to indoline-2-thiones followed by a new aqueous ammonia workup procedure. Similarly, a very concise two-pot synthesis of the phytoalexins wasalexins using sequential formylation-amination of indolin-2-ones is described. Remarkably, this novel aqueous ammonia workup allows the sequential one-pot formylation-amination, expanding substantially the scope of the Vilsmeier formylation of both indoline-2-thiones and indolin-2-ones. The examination of the formylation-amination reaction and optimization of conditions, as well as the syntheses and antifungal activities of several brassilexin analogues, are reported.     

A divergent synthesis of functionalized unsaturated delta-lactones from alpha-alkenoyl-alpha-carboxyl ketene dithioacetals

A divergent synthesis of functionalized unsaturated delta-lactones 2, 3, 4, and 5 has been developed starting from the readily available alpha-alkenoyl-alpha-carboxyl ketene dithioacetals 1 in high to excellent yields under mild reaction conditions. Thus, 6-substituted 3-(1,3-dithiolan/dithian-2-ylidene)-3H-pyran-2(6H)-ones 2, obtained from a consecutive reduction with NaBH4 and acidic workup of 1 via a novel vinylogous Pummerer cyclization, can be further transformed into alpha-pyranones 3, 4, and 5 upon a sequential isomerization catalyzed by triethylamine (to give 3), followed by dethioacetalization (to give 4) or a formylation with Vilsmeier reagent (to give 5).     

A new formylation reagent : 4-formyl-2-methyl-1,3,4-thiadiazolin-5-thione.

4-Formyl-2-methyl-1,3,4-thiadiazolin-5-thione, prepared from acetic formic anhydride, is found to act as a selective formylation reagent under mild conditions. The synthesis of some N-formyl antibiotics with this reagent is reported.