4-oksotiazolidin-2-alkiliden vinil-bromidi i α, α-dibrom-2-metoksiacetofenon : prekursori u sintetički korisnim transformacijama iniciranim retkim halofilnim napadom nukleofila
4-oxothiazolidine-2-alkylidene vinyl bromides and a,a-dibromo-2-methoxyacetophenone: precursors in synthetically useful transformations initiated by the rare halophilic attack of nucleophiles
Докторанд
Aleksić, JovanaМентор
Baranac-Stojanović, MarijaЧланови комисије
Pavlović, VladimirOpsenica, Dejan
Метаподаци
Приказ свих података о дисертацијиСажетак
Halofilne reakcije predstavljaju vrstu nukleofilnih supstitucionih reakcija do
kojih dolazi kada nukleofil reaguje sa atomom halogena, nakon ega se oslobaa
karbanjon kao odlazea grupa. To su relativno rijetke reakcije koje se dešavaju ukoliko
je klasina nukleofilna supstitucija (karbofilna reakcija) iz nekog razloga otežana i/ili
kada je karbanjon stabilizovan prisustvom elektron-privlanih supstituenata.
Cilj ovog rada je bio da se ispitaju halofilne reakcije i njihova sintetika
primena na dva sistema: 2-alkiliden-4-oksotiazolidin vinil-bromidima i ,-dibrom-2-
metoksiacetofenonu. Znaaj ovih reakcija u sluaju ispitivanih N-nesupstituisanih
tiazolidinskih jedinjenja je u dobijanju novih, potencijalno biološki aktivnih C-5
funkcionalizovanih derivata. Ovakvi derivati se ne mogu dobiti direktno reakcionom
sekvencom C-5 bromovanje/nukleofilna supstitucija, jer je bromovanje Nnesupstituisanih
2-alkiliden-4-oksotiazolidina visoko regioselektivno i kao proizvodi se
dobijaju iskljuivo vinil-bro...midi. Znaaj prouavanja ovakvih reakcija u sluaju a,a-
dibrom-2-metoksiacetofenona proistie iz injenice da se selektivno a-
monobromovanje metil-ketona esto teško postiže, a praeno je stvaranjem a,a-dibromderivata
kao sporednih, a ponekad i kao glavnih proizvoda. Mogua kaskadna
halofilna/karbofilna reakcija bi omoguila korišenje dibrom-derivata kao sintetikih
ekvivalenta monobromida, ime bi se izbegla dodatna faza selektivnog debromovanja
radi dobijanja monobrom-derivata, kao znaajnih sintetikih intermedijera. Razliiti
neutralni i anjonski nukleofili su uestvovali u halofilnoj reakciji sa tiazolidinskim vinilbromidima
dajui tri vrste proizvoda: i) proizvod reduktivnog debromovanja, ii)
proizvod supstitucije broma i iii) C-5 funkcionalizovan proizvod. Takoe je pokazano
da se ,-dibrom-2-metoksiacetofenon može upotrebiti kao sintetiki ekvivalent a-
monobromacetofenona.
Pored navedenih halofilnih reakcija, u ovom radu ispitivana je i mogunost
izvoenja Suzuki-Miyaura reakcije na vinil-bromidima, kao i mogua regioselektivnost
ove reakcije na N-supstituisanom tribrompirazolu, a u cilju dobijanja novih,
potencijalno biološki aktivnih jedinjenja. Suzuki-Miyaura reakcija sa derivatima
arilbornih kiselina izvedena na vinil-bromidima nije dala oekivani rezultat, ali je
uspešno izvedena sa N-supstituisanim tribrompirazolima uz visoku regioselektivnost,
pri emu su sintetisani 5-supstituisani 3,4-dibrompirazoli sa 1,1 ekvivalentom arilbornih
kiselina, 3,5-disupstituisani 4-brompirazoli sa 2,2 ekvivalenta arilbornih kiselina i 3,4,5-
trisupstituisani derivati sa 3,5 ekvivalenata arilbornih kiselina.
S obzirom da ispitivani tiazolidini spadaju u grupu push-pull alkena, kod kojih
elektronska delokalizacija izmeu donorskih i akceptorskih grupa na dvostrukoj vezi
ima znaajan uticaj na njihove osobine i hemijsku reaktivnost, uraena je i
kvantifikacija push-pull efekta dvostruke veze.
Halophilic reactions are nucleophilic substitution reactions in which
nucleophile attacks halogen atom with the carbanion acting as a leaving group. They are
relatively rare and usually take place if the classic nucleophilic substitution (carbophilic
reaction) is made difficult, and/or if the resulting carbanion is stabilized by electronwithdrawing
substituents.
The aim of the present work was to study halophilic reactions and their
synthetic application on two systems: 2-alkylidene-4-oxothiazolidines vinyl bromides
and ,-dibromo-2-methoxyacetophenone. The significance of the studied reactions in
the case of N-unsubstituited thiazolidine compounds would be the synthesis of novel,
potentially biologically active C-5 substituted derivatives. These derivatives are
impossible to obtain directly by the C-5 bromination/SNC substitution reaction
sequence, since bromination of N-unsubstituited 2-alkylidene-4-oxothiazolidines is
highly regioselective, resulting in the formation of vinyl bromide...s as sole products.
Significance of the studied reactions in the case of ,-dibromo-2-
methoxyacetophenone arises from the fact that selective a-monobromination of methyl
ketones of often difficult to achieve. ,-Dibromo derivatives can be formed as side
products, or even as major ones. A possible cascade halophilic/carbophilic reaction
would allow the use of dibromo derivatives as synthetic equivalents of monobromo
compounds, thus avoiding the additional step, selective debromination, necessary to
obtain synthetically useful monobromo derivatives. Various neutral and anionic
nucleophiles underwent a halophilic reaction with thiazolidine vinyl bromides yielding
three types of products: i) products of reductive debromination, ii) bromine susbtitution
products and iii) C-5 functionalized products. It has also been shown that ,-dibromo-
2-methoxyacetophenone can be used as synthetic equivalent of a-monobromo
acetophenone.
Apart from the mentioned halophilic reactions, a possibility of Suzuki-Miyaura
reaction to take place with the vinyl bromides was investigated, along with the possible
regioselectivity of the same reaction applied to N-substituted tribromopyrazoles, all with
the aim to obtaine new, potentially biologically active compounds. Suzuki-Miyaura
reaction of vinyl bromides with aryl boronic acid did not give the expected
tetrasubstituted alkenes. On the contrary, Suzuki-Miyaura reaction performed with the
N-substituted tribromopyrazoles showed high regioselectivity yielding 5-substituted
3,4-dibromopyrazoles with 1.1 equivalent of aryl boronic acids, 3,5-disubstituted 4-
bromo derivatives with 2.2 equivalents of aryl boronic acids and 3,4,5-trisubstituted
derivatives with 3.5 equivalents of aryl boronic acids.
Studied thiazolidine derivatives belong to the class of the so-called push-pull
alkenes in which electronic delocalization beween donor and acceptor groups attached
at the C=C double bond highly influences their properties and chemical reactivity. For
this reason, one aim of the present work was also to quantify this push-pull effect of the
studied compounds.