Sinteza derivata 1H-tetrazol-5-amina i 1H- pirazol-5-ola katalizovana kompleksnim jedinjenjima paladijuma
Synthesis of 1H-tetrazol-5-amine and 1Hpyrazol-5-ol derivatives catalyzed by palladium complexes
Author
Nikolić, Andrea M.Mentor
Opsenica, IgorCommittee members
Milić, DraganaGruden-Pavlović, Maja
Vulović, Bojan Z.
Ajdačić, Vladimir
Metadata
Show full item recordAbstract
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.