aza-Wittig Reaction Research Articles

ChemInform Abstract: One‐Pot Synthesis of 3‐Acetyl‐2‐aryl‐3,4‐dihydroquinazolines from N‐[2‐(Azidomethyl)phenyl]benzamides Utilizing Intramolecular Aza‐Wittig Reaction.

A new and convenient method for the preparation of 3,4-dihydroquinazolines 5 with aryl and Ac groups at C(2) and N(3), respectively, has been developed. The key sequence is the formation of aza-phosphorane intermediates by the reaction of N-[2-(azidomethyl)phenyl]benzamides 1 with Ph3P, followed by intramolecular aza-Wittig reaction and 3-acetylation, which can be conducted in one-pot.

Synthesis and biological activity of fused furo[2,3-d]pyrimidinone derivatives as analgesic and antitumor agents

Tumor growth is usually associated with persistent pain, especially during mid and terminal stages of cancer development. Nonetheless, a medicinal compound that possesses both anticancer and analgesic properties has not been identified. The 2-alkylthio-benzofuro[3,2-d]pyrimidin-4(3H)-ones (Code 5a–d) and 1-aryl-2-alkylthio-benzofuro[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-5(1H)-ones (Code 10a–g) were synthesized by using the bioisostere concept, which were obtained via the aza-Wittig reaction of functionalized iminophosphoranes reacted with carbon disulfide and further reaction of the product with alkyl halides or halogenated aliphatic esters. The analgesic properties of 5a–d and 10a–g were studied using rat chronic constriction injury model and the antitumor properties of these chemicals were assessed using MTS cell proliferation assay. Results showed that 5a–d and 10a–g were found to attenuate thermal and mechanical allodynia induced by neuropathy and inhibited the proliferation of three human cancer cell lines (A459, HepG2, and HeLa). Among these compounds, 10g showed highly positive effects in both assessments, and would be selected for future work.

The first asymmetric total synthesis of lycoposerramine-R.

The first asymmetric total synthesis of lycoposerramine-R, a Lycopodium alkaloid possessing a novel skeleton, was accomplished by a strategy featuring the stereoselective intramolecular aldol cyclization giving a cis-fused 5/6 bicyclic skeleton and a new method for the construction of the pyridone ring via the aza-Wittig reaction.

Synthesis of P-stereogenic compounds based on the diastereoselective ortho-lithiation of phosphinimidic amides

The extension of the diastereoselective functionalization of the Ph2P group of C-chiral P,P-diphenyl phosphinimidic amides via directed ortho-lithiation (DoLi)-electrophilic quench reactions as a method for the preparation of structurally diverse P-stereogenic compounds is described. Transformations at both the phosphorus-containing and the ortho-functional groups provide access to a large variety of P-stereogenic derivatives with excellent stereocontrol. These transformations include aza-Wittig reactions, N-alkylations, methanolysis, nucleophilic displacements with Grignard reagents, phosphine oxide reductions, azide to amine conversions, halogen/metal exchange, and Suzuki cross-coupling and condensation reactions. These transformations increase the diversity of functional groups at the ortho-disubstituted phenyl ring and enable the synthesis of enantiopure ortho-formyl- and ortho-stannyl-phosphinic amides that are difficult to prepare by other methods. The new products synthesized might be used as building blocks for the construction of high value added P-stereogenic compounds. This is illustrated by the synthesis of [1,5,2]diazaphosphinin-6(5H)-one 21, a phosphazenylphosphinate (SPN,RPO)-22 and the analogues of relevant bidentate and tridentate privileged structures such as PHOX-like 23 and the heteroatomic N,O,P-tridentate ligand 25.

Diaza-Wittig reaction of 4,5-disubstituted furan-2,3-diones with triphenylphosphazenes derived from 3-R-adamantanoyldiazomethane

Reactions of 1-(3-R-adamantan-1-yl)-2-(triphenyl-λ-phosphanylidenehydrazono)ethanones with 4,5-disubstituted furan-2,3-diones gave 2-[2-(3-R-adamantan-1-yl)-5-acyl-2-oxoethylidenehydrazono]-4-Rfuran-3(2H)-ones. The diaza-Wittig reaction is very important for building up double carbon–nitrogen bonds [1–9]. A few examples of anomalous diaza-Wittig reaction involving the lactone carbonyl group in 5-arylfuran2,3-diones [10] and 1-benzofuran-2,3-dione [11] containing a ketone carbonyl group in the neighboring position have also been reported. Analogous pattern was observed in the reactions of 1-(9H-fluoren-9ylidene)-2-(triphenyl-λ-phosphanylidene)hydrazine with 5-aryl-4-benzoyl(or 3-arylquinoxalin-2-yl)furan2,3-diones [12]. In the present article we report the results of our study on the reactions of 4,5-disubstituted furan-2,3-diones IIa–IIi with 1-(3-R-adamantan1-yl)-2-(triphenyl-λ-phosphanylidenehydrazono)ethanones Ia–Ic prepared by the Staudinger reaction [13] (Scheme 1). Introduction of bulky substituents, including those containing a carbonyl group, into positions 4 and 5 of the furan ring, as well as structural modification of initial 1-acyl-2-(triphenylphosphanylidene)hydrazines Ia–Ic, was expected to not only get a deeper insight into theoretical aspects of the diazaWittig reaction but also obtain compounds possessing pharmacophoric fragments with a view to subsequent biological screening. By reaction of triphenylphosphazenes Ia–Ic with furan-2,3-diones IIa–IIi we obtained in good yields 2-[2-(3-R-adamantan-1-yl)-5-acyl-2-oxoethylidenehydrazono]-4-R-furan-3(2H)-ones IIIa–IIIl (Scheme 1). The reactions were carried out with equimolar amounts of the reactants at room temperature (method a). However, the synthesis of initial phosphazenes Ia–Ic is often accompanied by their hydrolysis during the isolation and purification procedures. In order to improve the yield of furanones IIIa–IIIl we tried to accomplish the Staudinger and diaza-Wittig reactions in a one-pot mode (method b). In this case, equimolar amounts of 3-R-adamantanoyldiazomethane IV, furandione II, and triphenylphosphine were used. Compounds IIIa–IIIl were isolated as yellow crystalline substances, which were readily soluble in DMSO, DMF, and acetone, poorly soluble in acetonitrile and diethyl ether, and insoluble in alkanes and water. The IR spectra of IIIa–IIIl contained absorption bands belonging to stretching vibrations of the ketone carbonyl group in the furan ring (C=O, 1701– 1720 cm), adamantanoyl carbonyl group (1668– 1697 cm), benzoyl carbonyl group (IIIf, IIIh, 1656– 1660 cm) , and C=C and C=N bonds (1580– 1623 cm). In the H NMR spectra of these compounds signals from protons in the adamantyl fragment were located at δ 1.65–2.82 ppm, the 4-H proton in the furan ring resonated at δ 6.17–7.03 m, a multiplet from aromatic protons was present in the region δ 6.85– 8.30 ppm, and the CH=N proton gave a singlet at δ 7.25–8.01 ppm. Compounds IIIa–IIIl are likely to be formed according to the aza-Wittig reaction mechanism [14] via attack by the phosphorus atom of phosphazene I on the lactone carbonyl oxygen atom of II to give interDOI: 10.1134/S1070428014120124

Synthesis of 4,6-Unsubstituted 2-Aminodihydropyrimidine-5-­carboxylates through Sequential Staudinger/Aza-Wittig/Cyclization Reactions

A novel method for constructing the dihydropyrimidine skeleton is developed. The method involves three sequential reactions: (1) the Staudinger reaction of (E)-ethyl 3-azido-2-{[(tert-butoxycarbonyl)amino]methyl}acrylate with triphenylphosphine; (2) aza-Wittig reaction of the resulting iminophosphorane with isocyanate; (3) intramolecular cyclization of the carbodiimide intermediate to give 4,6-unsubstituted 2-aminodihydropyrimidine-5-carboxylates in high overall yield. The method can be applied to various aromatic isocyanates, with substrates having electron-withdrawing groups showing high reactivities. In the case of aliphatic benzyl isocyanate, the reaction provides bicyclic dihydropyrimidine as the major product. The N-protecting group (Boc) can easily be removed to obtain N-unsubstituted dihydropyrimidines. All dihydropyrimidines in this study were previously unavailable and are difficult to synthesize by conventional methods.

Sequential multicomponent synthesis of α-ketoimides, from acyl chlorides, isocyanides, and silver salts of carboxylic acids

A sequential multicomponent synthesis among acyl chlorides, isocyanides, and silver salts of carboxylic acids was developed to synthesize α-ketoimides. The latter undergo an intramolecular aza-Wittig reaction to afford 2-acylquinazolinones.

Synthesis of Pyrrolo[3, 4-d]Pyrimidine Thiono Derivatives via Aza Wittig Reaction

New pyrolo [3,4-d] pyrimidine derivatives were obtained from the aza-Wittig reactions of iminophosphorane with phenylisocyanates via of amino compounds with triphenylphosphine, hexachloroethane and triethyl-amine produced iminophosphorane.

Nitrogen-rich multinuclear ferrocenophanes as multichannel chemosensor molecules for transition and heavy-metal cations.

[m.n] Multinuclear ferrocenophanes prepared by aza-Wittig reaction of bisiminophosphoranes derived from 1,1′-diazidoferrocene and isophthaladelhyde or 2,5-diformylthiophene, behave as efficient electrochemical and chromogenic chemosensor molecules for Zn2+, Pb2+, and Hg2+ metal cations. Whereas the OSWV of receptor 3, bearing two m-phenylene units in the bridges, display one oxidation peak, receptor 4 incorporating two thiophene rings in the bridges, exhibits two well-separated oxidation peaks. In both receptors only the addition of Zn2+, Pb2+, and Hg2+ metal cations induced a remarkable anodic shift of ferrocene/ferrocenium redox couple. Likewise, in the absorption spectra of these receptors the low energy band is red-shifted by Δλ = 165 − 209 nm, and these changes promoted a significant color changes which could be used for the naked eye detection of these metal cations. The coordination modes for two representative cases were unveiled by DFT calculations that show an unsual coordination in the [42Pb]2+ complex with the Pb2+ cation in a distorted cubic N4S4 donor cage.

A novel access to pyrido[4,3-d]pyrimidine scaffold via Staudinger/intramolecular aza-Wittig reaction of 5-acyl-4-(β-azidoalkyl)-1,2,3,4-tetrahydropyrimidin-2-ones

A general four-step approach to 1,2,3,7,8,8a-hexahydropyrido[4,3-d]pyrimidin-2-ones via Staudinger/intramolecular aza-Wittig reaction of 5-acyl-4-(β-azidoalkyl)-1,2,3,4-tetrahydropyrimidin-2-ones promoted by PPh3 was developed. Synthesis of the starting pyrimidinones included preparation of 3-azidoaldehydes by the addition of hydrazoic acid to α,β-unsaturated aldehydes, transformation of 3-azidoaldehydes into N-[(3-azido-1-tosyl)alkyl]ureas followed by the reaction with enolates of dibenzoylmethane, benzoylacetone, acetylacetone, or ethyl 2,4-dioxo-4-phenylbutanoate and dehydration of the resulting products under acidic conditions.

Revisiting Wittig Olefination and Aza-Wittig Reaction for Carbohydrate Transformations and Stereocontrol in Sugar Chemistry

Recent advances in stereocontrolled Wittig olefination of sugars with stabilized and semi-stabilized phosphoranes are reviewed. Transformations of free and protected sugars for chain elongation at both reducing and terminal ends, and branched chain construction at the carbon atoms 2, 3 and 5 demonstrate the usefulness of this reaction in the preparation of a number of biologically active molecules and their precursors, starting from readily available sugars. Higher sugars, bicyclic structures, and C-C linked oligosaccharides lie amongst the diversity of compounds shown in this review that are synthesized by this reaction, easily carried out and efficient in terms of reaction yield and stereoselectivity, depending on reagents and reaction conditions. The analogy of aza-Wittig reaction, based on reaction of N-alkyl-triphenyl-λ5-phosphanimines with aldehydes or ketones, encouraged us to consider its contribution for the synthesis of N-linked sugars and imino sugars, which have biological and - some of them - industrial application as inhibitors of glycoprocessing enzymes. The use of this reaction for the preparation of pseudonucleosides with the N-linked appendages, N-linked and thiazolidinone-linked saccharides, and a diversity of imino sugars will be highlighted and the reaction stereocontrol discussed. Keywords: Aza-Wittig reaction, stereocontrol, Wittig olefination.

ChemInform Abstract: Synthesis of Functionalized Pyridine‐2,6‐bis(imidazolines) by Ring Transformation of 4‐(Aminomethyl)oxazoline Derivatives.

Optically active pyridine-2,6-bis(4-azidomethyloxazoline) was prepared by starting from L-serine and pyridine 2,6-dicarboxylic acid. Reduction of the azide moieties gave pyridine-2,6-bis(4-aminomethyloxazoline), which was not a stable compound, but readily underwent a ring-transforming rearrangement to furnish the pyridine-2,6-bis(4-hydroxymethylimidazoline). After Boc protection of the amidine functionalities, this compound could be further converted into the pyridine-2,6-bis(4-aminomethylimidazoline) via the corresponding bis(azidomethyl) compound. The azide functions of the bis(oxazoline) and the bis(imidazoline) intermediate products could also be further derivatized with an alkyne to give triazoles or through aza-Wittig reactions with benzaldehyde to give imines.

ChemInform Abstract: A New Synthesis of Pyrido[4,3‐d]pyrimidin‐2‐ones.

AbstractTitle compounds [(V) and (VIII)] are synthesized using the Staudinger—aza—Wittig reaction of dihydropyrimidinone derivatives (IV) or (VII), respectively.

Facile Synthesis of 4-Arylidene-1H-imidazol-5(4H)-ones by an Ugi–Aza-Wittig Sequence

Vinyl azides, obtained from the Ugi-type reaction of 2-azido-3-arylacrylic acid, secondary amine, aldehyde, and isocyanide, react with triphenylphosphine to give a variety of 4-arylidene-1H-imidazol-5(4H)-ones in high yields via sequential Staudinger and intramolecular aza-Wittig reaction.

One-pot sequential synthesis of isocyanates and urea derivatives via a microwave-assisted Staudinger–aza-Wittig reaction

A fast and efficient protocol for the synthesis of N,N'-disubstituted urea derivatives from alkyl halides and primary or secondary amines has been developed. The synthetic pathway combines nucleophilic substitutions and a Staudinger–aza-Wittig reaction in the presence of polymer-bound diphenylphosphine under 14 bar of CO2 pressure and has been performed in a one-pot two-step process. The protocol has been optimized under microwave irradiation and the scale-up experiment has been conducted under conventional conditions in a Parr reactor. The final compounds were isolated after simple filtration in almost quantitative overall yields which makes this procedure facile and rapid to execute.

Synthesis of bicyclic y-lactam derivatives by intramolecular carbene insertion and aza-Wittig reaction

Synthesis of bicyclic y-lactam derivatives by intramolecular carbene insertion and aza-Wittig reaction

ChemInform Abstract: Four‐Component Synthesis of Disubstituted 1,3,4‐Oxadiazoles from N‐Isocyaniminotriphenylphosphorane, Phenylacetylenecarboxylic Acid, Chloroacetone Derivatives, and Primary Amines.

Abstract The 1:1 imine intermediate generated by the addition of primary amine to chloroacetone derivatives is trapped by N-isocyaniminotriphenylphosphorane in the presence of phenylacetylenecarboxylic acid, leading to the formation of the corresponding iminophosphorane intermediate. Disubstituted 1,3,4-oxadiazole derivatives are formed via intramolecular aza-Wittig reaction of the iminophosphorane intermediate. The reactions were completed in neutral conditions at room temperature. The disubstituted 1,3,4-oxadiazole derivatives were prepared in excellent yields. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.

A new synthesis of pyrido[4,3-d]pyrimidin-2-ones

Title compounds [(V) and (VIII)] are synthesized using the Staudinger—aza—Wittig reaction of dihydropyrimidinone derivatives (IV) or (VII), respectively.

Synthesis of 2-Alkylamino/Alkoxy-3-Arylthieno[3,2-d]Pyrimidin-4(3<i>H</i>)-One Derivatives

The title compounds 2-alkylamino/alkoxy-3-arylthieno [3,2-pyrimidin-4(3H)-ones were synthesized by base catalytic reactions of primary amines or alcohols with carbodiimides,which were obtained from the aza-wittig reaction of iminophosphorane 2 and arylisocyanates.The conditions of cyclization and spectral properties were researched.

Model support studies toward the total synthesis of the stemona alkaloid stemocurtisine

Herein we report the results of a furan-based approach toward the synthesis of the Stemona alkaloid, stemocurtisine 1 via the linearly fused tricyclic intermediate 3, representing the key A,B,C-ring structural feature of the target molecule. A highly diastereoselective synthesis of compound 3 was achieved starting from 3-furfural 6, in a synthetic sequence that involved; (1) a rapid in situ conversion of an O-mesylate to the corresponding chloride with inversion of configuration from assistance of the neighbouring 3-furanyl group; (2) an intramolecular aza-Wittig reaction to prepare the azepine ring; and (3) a base promoted lactam ring forming step. While methods were established to oxidize the furan ring of 3 to the corresponding γ-hydroxy-α,β-unsaturated lactone we were unable to affect cyclization of the lactam ring hydroxyl group to the γ-position of the lactone to create the cyclic ether feature of the natural product. Model studies were also unsuccessful.