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Here we described the behavior of phosphinyl nitrosoalkenes with indole, pyrrole and 2,5-dimethylpyrrole. 3-Substituted indoles have been prepared through the reaction of nitrosoalkenes with indole. The reaction of phosphinyl nitrosoalkenes with pyrrole leads to the formation of 2-substituted pyrroles, while the behavior of 2,5-dimethylpyrrole with these nitrosoalkenes affords bicyclic 1,2-oxazines. [ABSTRACT FROM AUTHOR]

This review summarizes the synthesis of γ-lactam ring using multicomponent reactions. 1 Introduction 2 Pyrrolidin-2-ones 3 Pyrrolin-2-ones (Dihydro-2H-pyrrol-2-ones) 4 Final Remarks [ABSTRACT FROM AUTHOR]

This review presents an overview on the recent advances in the catalytic enantioselective Darzens and aza‐Darzens reactions for the synthesis of enantiopure three‐membered oxygen and nitrogen containing heterocycles. Since the synthesis of epoxides is the most widely explored, compared to their nitrogen counterparts, particularly true when asymmetric synthesis are considered, in the last decades several methodologies have appeared or improved and are now available for the preparation of aziridines in a highly stereo‐ and enantioselective manner. Catalytic asymmetric Darzens and aza‐Darzens reaction constitute an important tool in modern organic chemistry, as there is an increased interest in bioactive natural products and pharmaceutical agents that contain these skeletons. Chiral epoxides and aziridines: In the last decades several methodologies have appeared or improved and are now available for the preparation of epoxides and aziridines in a highly stereo‐ and enantioselective manner. This review covers the most recent advances related to the catalytic enantioselective Darzens and aza‐Darzens reactions for the synthesis of chiral epoxides and aziridines. [ABSTRACT FROM AUTHOR]

A concise and eco-friendly synthesis of highly functionalized 1,2-oxazines from phosphinyl- and phosphonyl-nitroso alkenes has been developed. The key step of this process, which involves a two-step sequence of reactions on-water, is a regioselective hetero-Diels-Alder cycloaddition reaction of enol ethers to 4-phosphinyl or 4-phosphonyl nitroso alkenes mediated by water itself. The process has also been performed under solvent-free conditions and in organic solvents for comparison. [ABSTRACT FROM AUTHOR]

The reactivity of new three carbon synthon, generated in situ from the reaction of electrondeficient allenes with an appropriate phosphine as the catalyst, toward pronucleophilic reagents is described. Triphenylphosphine-catalyzed reaction of allenes derived from phosphine oxides with nitrogen- or carbonucleophiles gave the ?-addition product as a mixture of cis and trans isomers. [ABSTRACT FROM AUTHOR]

Phosphorylated nitroso alkenes react with cyclic dienes such as cyclopentadiene or cydohexadiene to afford hetero Diels--Alder-type cydoadducts where the nitroso alkene participates as dienophile component and the cyclic olefin acts as the 4π-electron (diene) system. Subsequent aza-Cope re-arrangement affords highly functionalized 5,6-dihydro-4H-1,2-oxazines. Conversely, the reaction of TMS-substituted cyclopentadiene (dienophile) with nitroso alkenes as heterodienes leads directly to bicyclic 1,2-oxazines. Theoretical studies are in agreement with the experimental results and with the new aza-Cope rearrangement proposed. [ABSTRACT FROM AUTHOR]

This review summarizes several reports concerning the synthesis and synthetic applications of hydroxylamines derived from phosphines, phosphine oxides and phosphonates, and phosphorus substituted hydroxamic acid derivatives. The first section outlines the synthesis and reactivity of phosphorus O-substituted and N-substituted hydroxylamines as well as several transformations of phosphorus substituted hydroxylamines including: rearrangement, hydrolysis, reduction and oxidation reactions. The second part of the review covers the synthesis and reactivity of phosphorus O-, N-, and C-substituted hydroxamic acid derivatives. [ABSTRACT FROM AUTHOR]

The synthesis of highly functionalized N-hydroxypyrrole derivatives by the formal [3+2] cycloaddition reaction of enamines and nitroso alkenes derived from phosphine oxides and phosphonates is reported. Intermediate phosphorylated nitrones, whose formation can be explained by a conjugate addition of enamines to phosphorylated nitroso alkenes and formation of the five-membered heterocycles, are isolated. [ABSTRACT FROM AUTHOR]

We disclose a direct approach to the diastereoselective synthesis of phosphorus substituted N-acylaziridines based on a one-pot ZnCl2-catalyzed Joullié–Ugi three-component reaction of phosphorylated 2H-azirines, carboxylic acids and isocyanides. Hence, this robust protocol offers rapid access to an array of N-acylaziridines in moderate-to-good yields and up to 98:2 dr for substrates over a wide scope. The relevance of this synthetic methodology was achieved via a gram-scale reaction and the further derivatization of the nitrogen-containing three-membered heterocycle. The diastereo- and regioselective ring expansion of the obtained N-acylaziridines to oxazole derivatives was accomplished in the presence of BF3·OEt2 as an efficient Lewid acid catalyst. [ABSTRACT FROM AUTHOR]

Several bis(α-aminophosphonates) have been conveniently prepared in good yields using a straightforward multicomponent Kabachnik–Fields reaction between ethane 1,2-diamine or propane 1,3-diamine, diethylphosphite and aldehydes under catalyst-free conditions. The nucleophilic substitution reaction of bis(α-aminophosphonates) prepared and ethyl (2-bromomethyl)acrylate under mild reaction conditions afforded an original synthetic approach to a new series of bis(allylic-α-aminophosphonates). [ABSTRACT FROM AUTHOR]

Cyclopenta[b]-pyrrole-2-phosphine oxides 4a and -phosphonates 4b,c are generated by the addition of cyclic enolates derived from ethyl 2-oxo-cyclopentanecarboxylate 2 to phosphorated 2H-azirines 1. However, the addition of enolate derived from acyclic 2-oxo-butanoate 10 to 2H-azirine phosphine oxide 1 led to vinylogous N-acyl-a-aminoalkyl phosphine oxides 12, involving the carbonyl group and the Ca of the keto ester 10. Ring closure of vinylogous derivative 12 in the presence of base afforded pyrrole-2-phosphine oxide 11. The addition of enolates derived from indenone-carboxylate 15 to 2H-azirines 1 led to the formation of functionalized N-substituted 1H-benzo[d]azepine derivatives 17. [ABSTRACT FROM AUTHOR]

Evaluates several methodologies for the construction of β-aminophosphonic and -phosphinic acid derivatives. Use of organophosphorus compounds for the synthesis of β-aminophosphonopeptides; Importance of these derivatives for the development of protease inhibitors; Biological activities of some representative β-aminophosphonates and -phosphinates.

We report efficient synthetic methodologies for the preparation of 3-amino and 3-hydroxy 3-pyrrolin-2-ones (unsaturated γ-lactams) through a multicomponent reaction of amines, aldehydes and acetylene or pyruvate derivatives. The densely substituted γ-lactam substrates show in vitro cytotoxicity, inhibiting the growth of the carcinoma human tumor cell lines RKO (human colon epithelial carcinoma), SKOV3 (human ovarian carcinoma) and A549 (carcinomic human alveolar basal epithelial cell). In view of the possibilities for the diversity of the substituents that offer a multicomponent, synthetic methodology, an extensive structure–activity profile is presented. In addition, the bioisosteric replacement of the flat ester group by a tetrahedral phosphonate or phosphine oxide moiety in γ-lactam substrates leads to increased growth inhibition activity. Cell morphology analysis and flow cytometry assays indicate that the main pathway by which our compounds induce cytotoxicity is based on the activation of the intracellular apoptotic mechanism. [ABSTRACT FROM AUTHOR]

Phosphinate pseudopeptide are analogs of peptides containing phosphinate moiety in a place of the amide bond. Due to this, the organophosphorus fragment resembles the tetrahedral transition state of the amide bond hydrolysis. Additionally, it is also capable of coordinating metal ions, for example, zinc or magnesium ions. These two properties of phosphinate pseudopeptides make them an ideal candidate for metal-related protease inhibitors. This research investigates the influence of additional residue in the P2 position on the inhibitory properties of phosphinopeptides. The synthetic strategy is proposed, based on retrosynthetic analysis. The N-C-P bond formation in the desired compounds is conveniently available from the three-component condensation of appropriate amino components, aldehydes, and hypophosphorous acid. One of the crucial synthetic steps is the careful selection of the protecting groups for all the functionals. Determination of the inhibitor activity of the obtained compounds has been done using UV-Vis spectroscopy and standard substrate L-Leu-p-nitroanilide toward the enzymes isolated from the porcine kidney (SsLAP, Sus scrofa Leucine aminopeptidase) and barley seeds (HvLAP, Hordeum vulgare Leucine aminopeptidase). An efficient procedure for the preparation of phosphinotripeptides has been performed. Activity test shown that introduction of additional residue into P2 position obtains the micromolar range inhibitors of SsLAP and HvLAP. Moreover, careful selection of the residue in the P2 position should improve its selectivity toward mammalian and plant leucyl aminopeptidases. [ABSTRACT FROM AUTHOR]

This work describes a straightforward diastereoselective synthetic access to azirino[2,1- b ]benzo[ e ][1,3]oxazines containing phosphorus substituents such as phosphonate or phosphine oxide, by means of nucleophilic addition of functionalized phenols to the C–N double bond of 2 H -azirine derivatives. In addition, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and human embryonic kidney (HEK293) was also screened. Some azirino[2,1- b ]benzo[ e ][1,3]oxazines 4 and 6 exhibited very good activity against the A549 cell line in vitro. Furthermore, selectivity towards cancer cell (A549) over (HEK293), and non-malignant cells (MCR-5) has been detected. Image 1 • A new diastereoselective approach to phosphorylated azirino[2,1- b ]benzo[ e ] [1,3]oxazines with phosphorus substituents have been developed. • The process involve a nucleophilic addition of phenol derivatives to the C-N double bond of 2 H -azirines. • These heterocycles are merged hybrid substrates, holding aziridine, benzo[ e ] [1,3]oxazine and organophosphorus moieties. • Some compounds showed good in vitro cytotoxic effect against A549 cell line. [ABSTRACT FROM AUTHOR]

Abstract: Stereoselective inverse conjugate addition of carbonucleophiles to allenoates bearing a chiral auxiliary in the ester moiety afforded optically active α,β-unsaturated carboxylic esters bearing a new stereocenter at the δ position. The rationalization of the observed selectivity was supported by semi-empirical molecular orbital calculations. [Copyright &y& Elsevier]

Abstract: The synthesis of chiral functionalized β-amino esters via the hydride reductive amination of chiral allenes was explored. These compounds can be regarded as β-peptoids building blocks bearing a chiral side chain at the nitrogen and at the same time retaining the β-amino acid side chain. β-Enamino esters were obtained from the nucleophilic addition of α-amino esters (l-Ala, d-Ala, l-Phe, l-Leu, l-Trp and d-Trp methyl esters) to 2,3-allenoates bearing a chiral auxiliary, which determines the stereochemistry outcome of the subsequent reduction reaction. It was also demonstrated that in the reduction of β-enamino esters derived from l-Pro and d-Pro methyl esters the chirality of the new chiral center is controlled by the α-amino ester moiety. [Copyright &y& Elsevier]

Abstract: The synthesis of substituted 2,3-dihydro-1,4-thiazines, fused cycloalkyl-1,4-thiazines, 1,4-benzothiazines and fused cycloalkyl-1,4-benzothiazines by 1,4-addition of 1,2-aminothiols to 1,2-diaza-1,3-dienes bearing carboxylate, carboxamide, or phosphorylated groups and subsequent internal heterocyclization is described. The reaction of carboxylated 1,2-diaza-1,3-butadienes with 2-(butylamino)ethanethiol affords 1,4-thiazinan-3-ones. The solid-phase reaction of polymer-bound 1,2-diaza-1,3-butadienes with 1,2-aminothiols produces 2,3-dihydro-1,4-thiazines and 1,4-benzothiazines. [Copyright &y& Elsevier]

Abstract: A highly selective two-step approach to chiral β-amino esters via the hydride reductive amination of chiral allenes is reported. β-Enamino esters were obtained from the nucleophilic addition of amines to 2,3-allenoates bearing a chiral auxiliary. The reduction of the (1R)-(−)-10-phenylsulfonylisobornyl β-enamino esters gave the corresponding β-amino esters with S configuration whereas the reduction of the (1S)-(+)-10-phenylsulfonylisobornyl β-enamino esters led to β-amino esters with R configuration. The rationalization of the observed selectivity was supported by semi-empirical molecular orbital calculations (PM3). [Copyright &y& Elsevier]

Abstract: Recent advances in the aza-Wittig reaction of phosphazene derivatives with several carbonyl compounds are reviewed. Phosphazenes afford inter- and intramolecular aza-Wittig reactions with different compounds such as aldehydes, ketones, esters, thioesters, amides, anhydrides and sulfimides. One of the most important applications of this reaction is the synthesis of a wide range of acyclic and heterocyclic compounds, ranging from simple monocyclic compounds to complex polycyclic and macrocyclic systems. [Copyright &y& Elsevier]

The preparation of tetrahydropyrazines, dihydropyrazines, pyrazines, piperazinones, and quinoxalines by 1,4-addition of 1,2-diamines to 1,2-diaza-1,3-butadienes bearing carboxylate, carboxamide, or phosphorylated groups at the terminal carbon and subsequent internal heterocyclization is described. The solvent-free reaction of carboxylated 1,2-diaza-1,3-butadienes with the same reagents affords piperazinones, while phosphorylated 1,2-diaza-1,3-butadienes yield phosphorylated pyrazines. The solid-phase reaction of polymer-bound 1,2-diaza-1,3-butadienes with 1,2-diamines produces pyrazines. [ABSTRACT FROM AUTHOR]

Abstract: 3-Phosphinyl 1-aza-1,3-butadienes 2 are obtained by aldol condensation between hydrazonoalkyl phosphine oxides and N,N-dimethylformamide dimethyl acetal. Transamination reaction of these azadienes with amines yields functionalized 1-aza-1,3-butadienes 3 . Cycloaddition processes of these azadienes 2a with electron-poor dienophiles to give phosphorylated pyridine derivatives 9 and 15 are also reported, while intramolecular cyclization reaction of heterodiene 2b affords phosphorylated pyrazole 17 . [Copyright &y& Elsevier]

Abstract: 1,2-Diaza-1,3-butadienes derived from phosphine oxides and phosphonates and with optically active substituents on N-1 and C-3 are obtained by 1,4-elimination from chlorohydrazonoalkyl-phosphine oxides and -phosphonates in the presence of bases. Michael addition (1,4-addition) of ammonia, aliphatic and aromatic amines and aminoesters to these azo-alkenes gives functionalized α-amino-phosphine oxides and -phosphonates. [Copyright &y& Elsevier]

Achiral and chiral 1,2-diaza-1,3-butadienes derived from phosphine oxides and phosphonates are obtained from hydrazonoalkyl-phosphine oxides and -phosphonates. Michael addition (1,4-addition) of ammonia, aminoesters and aminoalcohols to these azo-alkenes gives functionalized α-amino-phosphine oxides and -phosphonates. [Copyright &y& Elsevier]

A simple and efficient method for asymmetric synthesis of 2H-azirine-2-phosphonates 6 is described. The key step is a base-mediated Neber reaction of p-toluenesulfonyloximes 4 derived from phosphonates. Triethylamine 5, alkaloids 7 and solid-phase bound achiral 8 or chiral amines 9 are used. Reduction of 2H-azirines 6 with sodium borohydride in ethanol gives cis-aziridine-phosphonates 10. Ring opening of aziridines 10 and 11 leads to the formation of enantiomerically enriched β-12 and 14 and α-aminophosphonates 13 and 15. [Copyright &y& Elsevier]

Examines the asymmetric synthesis of azirines derived from phosphine oxides using solid-supported amines. Identification on the ring opening of azirines with carboxylic acids; Formation of phosphorylated oxazoles; Class of compounds with high reactivity; Modification of molecules influencing biological activity.

Several phosphorus-substituted N-acylated cyanoaziridines 2 and N-carbamoylated cyanoziridines 5 were prepared in good to high yields. N-Acylated cyanoaziridines 2 were used, after ring expansion, in an efficient synthesis of oxazoline derivative 3a and in a completely regio-controlled reaction in the presence of NaI. Conversely, N-carbamoyl cyanoaziridines 5 reacted with NaI to obtain a regioisomeric mixture of 2-aminocyanooxazolines 7. Mild acidic conditions can be used for the isomerization of N-thiocarbamoyl cyanoaziridine 6a into a 2-aminocyanothiazoline derivative 8a by using BF3·OEt2 as a Lewis acid. Likewise, a one pot reaction of NH-cyanoaziridines 1 with isocyanates obtained 2-iminocyanooxazolidines 9 regioselectively. This synthetic methodology involves the addition of isocyanates to starting cyanoaziridines to obtain N-carbamoyl cyanoaziridines 5, which after the ring opening, reacts with a second equivalent of isocyanate to give the final 2-imino cyanooxazolidines 9. In addition, the cytotoxic effect on the cell lines derived from human lung adenocarcinoma (A549) was also screened. 2-Iminooxazolidines 9 exhibited moderate activity against the A549 cell line in vitro. Furthermore, a selectivity towards cancer cells (A549) over non-malignant cells (MCR-5) was detected. [ABSTRACT FROM AUTHOR]

This work reports a straightforward regioselective synthetic methodology to prepare α-aminophosphine oxides and phosphonates through the addition of oxygen and sulfur nucleophiles to the C–N double bond of 2H-azirine derivatives. Determined by the nature of the nucleophile, different α-aminophosphorus compounds may be obtained. For instance, aliphatic alcohols such as methanol or ethanol afford α-aminophosphine oxide and phosphonate acetals after N–C3 ring opening of the intermediate aziridine. However, addition of 2,2,2-trifluoroethanol, phenols, substituted benzenthiols or ethanethiol to 2H-azirine phosphine oxides or phosphonates yields allylic α-aminophosphine oxides and phosphonates in good to high general yields. In some cases, the intermediate aziridine attained by the nucleophilic addition of O- or S-nucleophiles to the starting 2H-azirine may be isolated and characterized before ring opening. Additionally, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and non-malignant cells (MCR-5) was also screened. Some α-aminophosphorus derivatives exhibited very good activity against the A549 cell line in vitro. Furthermore, selectivity towards cancer cell (A549) over non-malignant cells (MCR-5) has been detected in almost all compounds tested. [ABSTRACT FROM AUTHOR]