Sinteza derivata 1H-tetrazol-5-amina i 1H- pirazol-5-ola katalizovana kompleksnim jedinjenjima paladijuma

Abstract

Formiranje C–N veze katalizovano kompleksnim jedinjenjima paladijuma predstavlja veoma značajnu reakciju u medicinskoj hemiji i farmaceutskoj industiji. Imajući u vidu značaj N,1- disupstituisanih-1H-tetrazol-5-amina u farmaceutskoj industiji, industriji eksploziva, medicinskoj hemiji i fotohemiji, kao jedan od ciljeva ove doktorske disertacije postavljen je razvoj nove metode za sintezu N-aril-1-supstituisanih-1H-tetrazol-5-amina zasnovane na reakciji N-arilovanja 1- supstituisanih-1H-tetrazol-5-amina katalizovanoj kompleksnim jedinjenjima paladijuma. Iako se tetrazol-5-amin može smatrati manje reaktivnim sistemom za ovu reakciju, pronađeni su optimalni reakcioni uslovi i sintetisana su 23 derivata N-aril-1-alkil-1H-tetrazol-5-amina. Ustanovljeno je da prilikom sinteze N,1-diaril-1H-tetrazol-5-amina, primenom prethodno optimizovanih reakcionih uslova, dolazi i do reakcije Dimroth-ovog premeštanja proizvoda N-arilovanja. Snižavanjem reakcione temperature sa 105 ºC na 35 ºC, sintetisano je novih 19 derivata N,1-diaril-1H-tetrazol-5- amina, pri čemu reakcija premeštanja nije opažena. Primenom eksperimentalnih i in silico metoda određeni su reakcioni parametri, uticaj strukture na ishod reakcije i mehanizam reakcije Dimrothovog premeštanja N,1-diaril-1H-tetrazol-5-amina. U nastavku istraživanja reakcija je primenjena u sintezi novih derivata N,1-diaril-1H-tetrazol-5-amina. U poslednjem segmentu ove disertacije razvijena je metoda za sintezu hibridnih molekula koji sadrže fragmente privilegovanih struktura, 3- (trifluormetil)-1H-pirazola i izohromena. Primenom sinteze u dva koraka u jednom sudu sintetisano je devet derivata kao i jedan analog hibridnih molekula sa sumporom. Analizom 13C NMR spektara hibridnih molekula uočena je pojava 13C– 19F sprezanja kroz prostor.

Palladium catalyzed C–N bond formation is a very significant reaction in medicinal chemistry and pharmaceutical industry. Considering the importance of N,1-disubstituted-1H-tetrazol-5-amines in the industry of explosives and pharmaceuticals, medicinal chemistry and photochemistry, one of the goals set for this doctoral dissertation was the development of a new method for the synthesis of Naryl-1-substituted-1H-tetrazol-5-amines based on the N-arylation reaction of 1-substituted-1Htetrazol-5-amines catalyzed by palladium complexes. Even though the reactivity of tetrazol-5- amines in this reaction can be considered to be reduced, optimized reaction conditions were determined and 23 N-aryl-1-substituted-1H-tetrazol-5-amine derivatives were synthesized. During the synthesis of N,1-diaryl-1H-tetrazol-5-amines, under the previously optimized reaction conditions, Dimroth rearrangement of the N-arylation reaction products was observed. By lowering the reaction temperature from 105 ºC to 35 ºC, 19 N,1-diaryl-1H-tetrazol-5-amines were obtained while the rearrangement reaction did not occur. Reaction parameters, the relationship between the structure and the reaction outcome, as well as the mechanism of Dimroth rearrangement were determined with experimental and in silico methods. Additionally, the reaction was applied for the synthesis of new N,1-diaryl-1H-tetrazol-5-amine derivatives. A method for the synthesis of hybrid molecules containing two privileged fragments, 3-(trifluoromethyl)-1H-pyrazole and isochromene, was developed in the last segment of this dissertation. Nine hybrid derivatives and one sulfur analogue were obtained by applying a one-pot two-step method. Rare 13C– 19F through-space coupling was observed in all 13C NMR spectra of the hybrid molecules.