Teresa M. V. D. Pinho e Melo

The Pyrolysis of Isoxazole Revisited: A New Primary Product and the Pivotal Role of the Vinylnitrene. A Low-Temperature Matrix Isolation and Computational Study

This paper describes the pyrolysis of parent isoxazole and of its 5-methyl and 3,5-dimethyl derivatives by the high-pressure pulsed pyrolysis method, where activation of the precursor molecules occurs predominantly by collisions with the host gas (Ar in our case), rather than with the walls of the pyrolysis tube, where catalyzed processes may occur. The products were trapped at 15 K in Ar matrices and were characterized by vibrational spectroscopy. Thereby, hitherto unobserved primary products of pyrolysis of isoxazole and of its 5-methyl derivative, 3-hydroxypropenenitrile or 3-hydroxybutenenitrile, respectively, were observed. E-Z photoisomerization could be induced in the above hydroxynitriles. On pyrolysis of isoxazole, ketenimine and CO were observed as decomposition products, but this process did not occur when the 5-methyl derivative was pyrolyzed. Instead, the corresponding ketonitrile was formed. In the case of 3,5-dimethylisoxazole, 2-acetyl-3-methyl-2H-azirine was detected at moderate pyrolysis temperatures, whereas at higher temperatures, 2,5-dimethyloxazole was the only observed rearrangement product (next to products of dissociation). These findings are rationalized on the basis of quantum chemical calculations. Thereby it becomes evident that carbonyl-vinylnitrenes play a pivotal role in the observed rearrangements, a role that had not been recognized in previous theoretical studies because it had been assumed that vinylnitrenes are closed-shell singlet species, whereas they are in fact open-shell singlet biradicaloids. Thus, the primary processes had to be modeled by the multiconfigurational CASSCF method, followed by single-point MR-CISD calculations. The picture that emerges from these calculations is in excellent accord with the experimental findings; that is, they explain why some possible products are observed while others are not.

Synthesis of 2-halo-2H-azirines

Abstract α-Oxophosphonium ylides react with N -chlorosuccinimide, N -bromosuccinimide and N -iodosuccinimide in the presence of azidotrimethylsilane giving the corresponding haloazidoalkenes which were completely converted to the 2-halo-2 H -azirines on heating in heptane.

Synthesis of isoquinolines by cycloaddition of arynes to 1,2,4-triazines

Abstract Benzyne has been generated from benzenediazonium-2-carboxylate in the presence of several 1,2,4-triazines 1 and isoquinolines 2 have been isolated in moderate yield. 1-Aminobenzotriazole was also used as the source of benzyne and isoquinolines were again isolated in moderate yield from these reactions. 4-Methylbenzyne, which was generated from 5-methylanthranilic acid, reacted unselectively with the triazines to give mixtures of 6- and 7-methylisoquinolines 3 and 4 On the other hand reactions of 3-methylbenzyne with the triazines 1d and 1e proceeded with high regioselectivity, giving only the 5-methylisoquinoline 5a and the 8-methylisoquinoline 6b, respectively.

Chiral 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles with anti-breast cancer properties.

The synthesis and biological evaluation of 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles as anticancer agents against MCF7 breast cancer cell lines is reported. The design of the new compounds has been guided considering (3R)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole as the lead compound due to its good performance against MCF7 breast cancer cell lines (IC(50) = 1.0 μM). The structural changes included the removal of the phenyl group at C-3, the replacement of this group by a 3,4,5-trimethoxyphenyl group, the removal of the methyl group at C-5 from the lead scaffold and the replacement of this group by a phenyl substituent. Overall, these studies showed that the combined presence of a phenyl group at C-3 and a methyl group at C-5 in the 1H,3H-pyrrolo[1,2-c]thiazole ring system is essential to ensure high cytotoxicty against MCF7 breast cancer cell lines. To probe whether the absolute configuration of the lead compound might affect the anticancer activity, its enantiomer was prepared and the activity against MCF7 cells was evaluated. (3S)-6,7-Bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole proved to be the most active compound so far studied, with IC(50) value of 0.5 μM.

UV-laser photochemistry of isoxazole isolated in a low-temperature matrix.

The photochemistry of matrix-isolated isoxazole, induced by narrowband tunable UV-light, was investigated by infrared spectroscopy, with the aid of MP2/6-311++G(d,p) calculations. The isoxazole photoreaction starts to occur upon irradiation at λ = 240 nm, with the dominant pathway involving decomposition to ketene and hydrogen cyanide. However, upon irradiation at λ = 221 nm, in addition to this decomposition, isoxazole was also found to isomerize into several products: 2-formyl-2H-azirine, 3-formylketenimine, 3-hydroxypropenenitrile, imidoylketene, and 3-oxopropanenitrile. The structural and spectroscopic assignment of the different photoisomerization products was achieved by additional irradiation of the λ = 221 nm photolyzed matrix, using UV-light with λ ≥ 240 nm: (i) irradiation in the 330 ≤ λ ≤ 340 nm range induced direct transformation of 2-formyl-2H-azirine into 3-formylketenimine; (ii) irradiation with 310 ≤ λ ≤ 318 nm light induced the hitherto unobserved transformation of 3-formylketenimine into 3-hydroxypropenenitrile and imidoylketene; (iii) irradiation with λ = 280 nm light permits direct identification of 3-oxopropanenitrile; (iv) under λ = 240 nm irradiation, tautomerization of 3-hydroxypropenenitrile to 3-oxopropanenitrile is observed. On the basis of these findings, a detailed mechanistic proposal for isoxazole photochemistry is presented.

Allenes as building blocks in heterocyclic chemistry

Allenes have a unique structural feature characterized by having two cumulated double bonds. The inherent instability associated with these 1,2-dienes has been widely exploited for various synthetic purposes. Allenes have thus become important and versatile building blocks in organic chemistry. In this paper some illustrative examples of the chemistry of these building blocks in the synthesis of heterocyclic compounds are presented.Graphical abstract

Synthesis and reactivity of 2-halo-2H-azirines towards nucleophiles

Nucleophilic substitution reactions of 2-halo-2H-azirine with potassium phthalimide and aniline allowed the preparation of new substituted 2H-azirines. The reactions of 2-bromo-3-phenyl-2H-azirine-2-carboxylate with methylamine led to the synthesis of a-diimines and from the reaction with water, a 3-oxazoline was obtained. # 2000 Published by Elsevier Science Ltd.

Recent Developments in the Synthesis of Dipyrromethanes. A Review

Introduction ................................................................................. 184 I. Synthesis of Dipyrromethanes ....................................................... 184 1. Dipyrromethane Synthesis via Condensation of Pyrroles with Aldehydes and Ketones .........................................................................................184 a) Synthesis of 5-Substituted Dipyrromethanes.........................................184 Preparation of 5-Aryldipyrromethanes TFA-catalyzed Condensation of Pyrrole with Aldehydes...................................................................187 Preparation of Dipyrromethane via TFA-catalyzed Condensation of Pyrrole with Aldehydes...................................................................187 Preparation of 5-Aryldipyrromethanes via BF3·Et2 O-catalyzed Condensation of Pyrrole with Aldehydes ..........................................187 Preparation of 5-(Hydroxymethyl)dipyrromethane (13) via InCl3-catalyzed Condensation of Pyrrole with Glycolaldehyde ...........190 Preparation of 5-(2-Furyl)-, 5-(3-Furyl)and of 5-(2-Selenenyl)dipyrromethanes via TFA-catalyzed Condensation of Pyrrole with Heteroaromatic Aldehydes ..............................................................192 Preparation of Dipyrromethanes via Condensation of Pyrrole with Pyridine-, Quinoline-, and 1H-Imidazole-derived Aldehydes ..............193 “On Water” Synthesis of 5-Phenyldipyrromethanes via Condensation of Pyrrole with Benzaldehyde ..........................................................197 Preparation of 5,5-Daryldipyrromethanes via BF3·Et2O-catalyzed Condensation of Pyrrole with Aromatic Ketones ...............................198 b) Synthesis of Polysubstituted Dipyrromethanes......................................199 II. Dipyrromethanes from α-Acylpyrroles.......................................... 202 Preparation of 5-Phenyldipyrromethane via TFA-catalyzed Condensation of Pyrrole with 2-(α-Hydroxy-α-phenylmethyl)pyrrole ......203 III. Dipyrromethane Synthesis via Other Approaches.......................... 205 Preparation of 5-(Trifluoromethyl)dipyrromethane from 1-Bromo1-chloro-2,2,2-trifluoroethane and Pyrrole.............................................209 Conclusion.................................................................................... 209 Acknowledgements ....................................................................... 209 References .................................................................................... 209

2H-Azirines as dipolarophiles

2H-Azirine-3-carboxylates unsubstituted at C-2 act as dipolarophiles in the reaction with diazomethane giving new 4,5-dihydro-3H-pyrazole derivatives. The synthesis of a pyrimidine was also achieved via 1,3-dipolar cycloaddition of methyl 2-bromo-3-phenyl-2H-azirine-2-carboxylate with an azomethine ylide.

Photochemistry and Vibrational Spectra of Matrix-Isolated Methyl 4-Chloro-5-phenylisoxazole-3-carboxylate

Methyl 4-chloro-5-phenylisoxazole-3-carboxylate (MCPIC) has been synthesized, isolated in low temperature argon and xenon matrices, and studied by FTIR spectroscopy. The characterization of the low energy conformers of MCPIC was made by undertaking a systematic investigation of the DFT(B3LYP)/6-311++G(d,p) potential energy surface of the molecule. The theoretical calculations predicted the existence of three low energy conformers. Two of them (I and II) were observed experimentally in the cryogenic matrices. The third one (III) was found to be converted into conformer II during deposition of the matrices, a result that is in agreement with the predicted low III → II energy barrier (<0.3 kJ mol(-1)). In situ UV irradiation (λ > 235 nm) of matrix-isolated MCPIC yielded as final photoproduct the corresponding oxazole (methyl 4-chloro-5-phenyl-1,3-oxazole-2-carboxylate). Identification of the azirine and nitrile-ylide intermediates in the spectra of the irradiated matrices confirmed their mechanistic relevance in the isoxazole → oxazole photoisomerization.