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Functionalization of pyrimidine nucleobases by direct C-H arylations.
Čerňová, Miroslava
Within presented dissertation thesis Pd-catalyzed direct C-H arylation of 1,3-dimethyluracil to position 5 or 6 was developed. An interesting dichotomy in the regioselectivity and mechanism of reactions were observed. A reaction of 1,3-dimethyluracil with diverse aryl halides performed in the absence of CuI led preferentially to 5-aryl-1,3-dimethyluracils, while with the addition of CuI 6-aryl-1,3-dimethyluracils were formed as the major products. Reactions mediated only in the presence of copper(I) iodide (in the absence of a Pd-catalyst) proceeded with lower yields but led exclusively to 6-arylated derivatives. In order to prepare free 5- and 6 arylated uracils for biological activity screening, the developed methodologies for the direct C-H arylations were applied to various 1,3-protected uracils. Benzyl-protected uracil was selected as the best candidate both in terms of stability during the arylations, as well as facile cleavage of the benzyl groups during deprotection of arylated uracils. Synthesis of various substituted 5- and 6-aryl-1,3-dibenzyluracils proceeded with the same regioselectivity as with the model compound 1,3-dimethyluracil. For deprotection of synthesized derivatives either transfer hydrogenolysis over Pd/C or treatment with BBr3 in case of uracils bearing bulky aromatic...
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Functionalization of pyrimidine nucleobases by direct C-H arylations.
Čerňová, Miroslava ; Hocek, Michal (advisor) ; Dvořák, Dalimil (referee) ; Rádl, Stanislav (referee)
Within presented dissertation thesis Pd-catalyzed direct C-H arylation of 1,3-dimethyluracil to position 5 or 6 was developed. An interesting dichotomy in the regioselectivity and mechanism of reactions were observed. A reaction of 1,3-dimethyluracil with diverse aryl halides performed in the absence of CuI led preferentially to 5-aryl-1,3-dimethyluracils, while with the addition of CuI 6-aryl-1,3-dimethyluracils were formed as the major products. Reactions mediated only in the presence of copper(I) iodide (in the absence of a Pd-catalyst) proceeded with lower yields but led exclusively to 6-arylated derivatives. In order to prepare free 5- and 6 arylated uracils for biological activity screening, the developed methodologies for the direct C-H arylations were applied to various 1,3-protected uracils. Benzyl-protected uracil was selected as the best candidate both in terms of stability during the arylations, as well as facile cleavage of the benzyl groups during deprotection of arylated uracils. Synthesis of various substituted 5- and 6-aryl-1,3-dibenzyluracils proceeded with the same regioselectivity as with the model compound 1,3-dimethyluracil. For deprotection of synthesized derivatives either transfer hydrogenolysis over Pd/C or treatment with BBr3 in case of uracils bearing bulky aromatic...
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Functionalization of pyrimidine nucleobases by direct C-H arylations.
Čerňová, Miroslava
Within presented dissertation thesis Pd-catalyzed direct C-H arylation of 1,3-dimethyluracil to position 5 or 6 was developed. An interesting dichotomy in the regioselectivity and mechanism of reactions were observed. A reaction of 1,3-dimethyluracil with diverse aryl halides performed in the absence of CuI led preferentially to 5-aryl-1,3-dimethyluracils, while with the addition of CuI 6-aryl-1,3-dimethyluracils were formed as the major products. Reactions mediated only in the presence of copper(I) iodide (in the absence of a Pd-catalyst) proceeded with lower yields but led exclusively to 6-arylated derivatives. In order to prepare free 5- and 6 arylated uracils for biological activity screening, the developed methodologies for the direct C-H arylations were applied to various 1,3-protected uracils. Benzyl-protected uracil was selected as the best candidate both in terms of stability during the arylations, as well as facile cleavage of the benzyl groups during deprotection of arylated uracils. Synthesis of various substituted 5- and 6-aryl-1,3-dibenzyluracils proceeded with the same regioselectivity as with the model compound 1,3-dimethyluracil. For deprotection of synthesized derivatives either transfer hydrogenolysis over Pd/C or treatment with BBr3 in case of uracils bearing bulky aromatic...
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Dichotomy in regioselectivity of Pd-catalyzed direct C-H arylation of protected uracils
Čerňová, Miroslava ; Hocek, Michal
Uracil bases and nucleosides bearing aryl groups in positions 5 or 6 are an important class of compounds and display wide range of biological activities1. In addition, arylation in position 5 is often used for labeling of nucleotides, oligonucleotides and DNA for applications in bioanalysis or chemical biology2. The 5- or 6-aryluracils can be prepared by heterocyclization or by cross-coupling reactions of halouracils with arylboronic acids or stannanes or metallated uracils with aryl halides. Direct C–H arylation of uracil is an alternative to classical cross-couplings where the preparation of reactive organometallic reagent is avoided. Recently, we have developed regioselective Pd-catalyzed and/or Cu-mediated direct C–H arylations of 1,3-dimethyluracil as a model compound for pyrimidine bases to position C-5 or C-6 3.
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