Synthesis Of Novel Nitrogen Heterocycles By Sequential Ugi/Staudinger/Aza-Wittig Reaction

Heterocyclic compounds not only widely distributed in nature, but also exhibit a variety of unique biological activity, widely used in medicine and pesticides, such as various clinical synthetic drugs and natural drugs, low toxicity fungicides, pesticides and herbicides. Therefore, how to quickly and efficiently build a structure of diverse, multi-substituted heterocyclic compounds to filter out new pesticides and pharmaceuticals, has always been one of the important area of organic chemistry and medicinal chemistry research. In this paper, a series of new multi-substituted nitrogen-containing heterocyclic compounds were synthesized by sequential Ugi/Staudinger/intramolecular aza-Wittig reactions, starting from easily accessible o-azidobenzaldehyde, a-amino ketone hydrochloride, isocyanide,2-azido-3-aromatic acrylic acid, and a-amino acid ester hydrochloride et al. The structues of every target compounds were all comfirmded by1H NMR,13C NMR, MS and elemental analysis. At the same time, we measured the antibacterial activity of target compounds against Penicillium digitatum, Penicillium italicum, Magnaporthe oryzae and Fusarium graminearum at the50mg/L concentration, the human cervical cancer Caski cells growth inhibitory activities of some compounds, at100μM,50μM and25μM concentrations. Details are as follows:1. The azides2, obtained from Ugi reactions of a-amino ketone hydrochloride, o-azido benzaldehyde, caroboxylic acid and isocyanides, reacted with triphenylphosphine to give various2,3,4,5-Tetrasubstituted4,5-dihydro-3H-1,4-benzodiazepines4in moderate to good yields via sequential Staudinger and intramolecular aza-Wittig reaction. The synthetic conditions and the spectral properties of the target compounds were studied and discussed. By X-Ray diffraction confirms the single crystal of Compound5and4a, further confirmed the structure of the compound4. The fungicidal activities and the Caski human cervical cancer cells growth inhibitory activity of the compound4were measured. The results show that at the50mg/L concentration, compound4showed relatively obvious inhibitory activity on the Penicillium digitatum, most of the compounds, which inhibition rate at45%. Such as4d,4g,4n and4o, their inhibition rate reached50%. But they showed weak antibacterial activitis on Penicillium italicum and Magnaporthe oryzae, and poor inhibitory activity on Fusarium graminearum.2. Starting from the2-azido-3-aromatic acrylic acid, a-amino ketone hydrochloride, aldehydes and isocyanurate, the azide intermediate14were synthesized by Ugi reaction, which reacted with triphenylphosphine to give the compounds1,6-dihydropyrazin-2(3H)-one15or their isomer pyrazin-2(1H)-one18by sequential Staudinger and intramolecular aza-Wittig reaction. The structures of the target compounds were characterized via1H NMR,13C NMR, MS and elemental analysis, and the spectral properties were also studied.We tested the fungicidal activities and the human cervical cancer Caski cells growth inhibitory activity of target compounds. The results show that at50mg/L concentration, the inhibition activity on Penicillium digitatum is relatively good, some compounds inhibiton rate up to45%and above, such as compound15m, which antibacterial rate at50%. But the inhibition activity on Penicillium italicum, Magnaporthe oryzae and Fusarium graminearum is not high, inhibition rate at around30%. The effect of Compound15on human cervical cancer Caski cells growth is weak. Only compound15g shows obvious effect at100μM concentration, which inhibition rate reached44.9%.3. Vinyl azides19, obtained from Ugi-type reaction of a-azidovinylacids, sencondary amine, aldehyde and isocyanides, reacted with triphenylphosphine to give various4-arylidene-1H-imidazol-5(4H)-ones20in high yields via sequential Staudinger and intramolecular aza-Wittig reaction. Their structures were confirmed by1H NMR,13C NMR, MS and elemental analysis. The antibacterial activity and the human cervical cancer Caski cells growth inhibitory activity of target compounds20were measured. The results show that at50mg/L concentration, the inhibition activity on Penicillium digitatum, Penicillium italicum and Fusarium graminearum is better than the Magnaporthe oryzae. The first three inhibitory rate is about35%, and the later inhibitory rate is30%or less. Compound20d and20e show significant inhibition on Penicillium digitatum. Their inhibition rate were53%and58%respectively. Compound20has no significant inhibition.activity on human cervical cancer Caski cell growth..4. Various2,3-disubstitutedquinazolin-4(3H)-ones26were prepared from corresponding azides25by catalytic Staudinger/aza-Wittig sequence based on in situ reduction of tertiary phosphine oxides by tetramethyldisiloxane (TMDS) and a stoichiometric amount of Ti(OiPr)4. The azides25were readily obtained by Ugi-type reaction of o-azido benzoic acid, sencondary amine, aldehyde and isocyanides. The most suiltable catalytic conditions for the synthesis of the target compounds were studied, and the the mechanism of this catalytic recycle was also discussed. The fungicidal activities and the human cervical cancer Caski cells growth inhibitory activity of target compounds26were tesed. At50mg/L concentration, the target compound26showed significant inhibitory activity on Penicillium digitatum, the majority inhibition rate up to50%or more. The fungicidal activities to the Penicillium italicum of compounds26is weaker, inhibition rate at about35%. The inhibitory activitis on Magnaporthe oryzae, Fusarium graminearum and human cervical cancer Caski cell were not obvious. 5. The azides29, obtained from a-amino acid ester hydrochloride, o-azido benzoic acid, aldehyde and isocyanides by Ugi reaction, reacted with catalytic amount of tertiary phosphine oxides (TPO) via catalytic Staudinger/aza-Wittig sequence to give a series of1,4-benzodiazepin-5(4H)-ones30. Structures of the target compounds were characterized via1H NMR,13C NMR, MS and elemental analysis, and the spectral properties were also studied. The most suiltable phousphine reagent and catalytic conditions for the synthesis of the target compounds were studied and discussed. Through X-Ray single crystal diffraction by one representative compound, the structure of the1,4-benzodiazepin-5(4H)-one derivatives were further confirmed.Target compounds30were measured fungicidal activities and inhibition of cell growth of human cervical cancer Caski. The results show that, most compounds have poor growth inhibitory activities on Penicillium digitatum, Penicillium italicum, Magnaporthe oryzae, Fusarium graminearum and human cervical cancer Caski cells. But individual compounds showed obvious activities, such as compound30k, at50mg/L concentration, which inhibition rate to Penicillium digitatum was43%. Compound30n, at50μM. oncentration, its inhibition rate for human cervical cancer cell growth inhibition Caski was48.8%. Compound30o, at100μM concentration, which inhibition rate for human cervical cancer cells inhibited Caski was50.9%.