Copper-promoted regioselective synthesis of polysubstituted pyrroles from aldehydes, amines and nitroalkenes via1,2-phenyl/alkyl migration

The facile Copper-catalyzed synthesis of polysubstituted pyrroles from aldehydes, amines and β-nitroalkenesis reported. Remarkably, the use of α-methyl substituted aldehydes provide efficient access to a series of tetra- and pentasubstituted pyrroles via an overwhelming 1,2-phenyl/alkyl migration. The present methodology is also accessible to non α-substituted aldehydes yielding the corresponding trisubstituted pyrroles. On the contrary, the use of ketones, in place of aldehydes, does not promote the organic transformation signifying the necessity of α-substituted aldehydes. The reaction proceeds under mild catalytic conditions with low catalyst loading (0.3 – 1 mol %), a broad scope, very good functional-group tolerance, high yields and can be easily scaled up to more than 3 mmol of product, thus highlighting a useful synthetic application of the present catalytic protocol. Based on formal kinetic studies, a possible radical pathway is proposed that involves the formation of an allylic nitrogen radical intermediate, which in turn reacts with the nitroalkene to yield the desired pyrrole framework via a radical 1,2-phenyl or alkyl migration

Cu(II) coordination polymers as vehicles in the A³ coupling

A family of benzotriazole based coordination compounds, obtained in two steps and good yields from commercially available materials, formulated [CuII(L 1 )2(MeCN)2]·2(ClO4)·MeCN (1), [CuII(L 1 )(NO3)2]·MeCN (2), [ZnII(L 1 )2(H2O)2]·2(ClO4)·2MeCN (3), [CuII (L 1 )2Cl2]2 (4), [CuII 5(L 1 )2Cl10] (5), [CuII 2(L 1 )4Br2]·4MeCN·(CuII 2Br6) (6), [CuII(L 1 )2(MeCN)2]·2(BF4) (7), [CuII(L 1 )2(CF3SO3)2] (8), [ZnII(L 1 )2(MeCN)2]·2(CF3SO3) (9), [CuII 2(L 2 )4(H2O)2]·4(CF3SO3)·4Me2CO (10) and [CuII 2(L 3 )4(CF3SO3)2]·2(CF3SO3)·Me2CO (11) are reported. These air stable compounds were tested as homogeneous catalysts for the A3 coupling synthesis of propargyl amine derivatives from aldehyde, amine and alkyne under a non-inert atmosphere. Fine-tuning of the catalyst resulted in a one dimensional (1D) coordination polymer (CP) (8) with excellent catalytic activity in a wide range of substrates, avoiding any issues that would inhibit its performance

Supported gold nanoparticle-catalyzed selective reduction of multifunctional, aromatic nitro precursors into amines and synthesis of 3,4-dihydroquinoxalin-2-ones

The synthesis of 3,4-dihydroquinoxalin-2-ones via the selective reduction of aromatic, multifunctional nitro precursors catalyzed by supported gold nanoparticles is reported. The reaction proceeds through the in situ formation of the corresponding amines under heterogeneous transfer hydrogenation of the initial nitro compounds catalyzed by the commercially available Au/TiO2-Et3SiH catalytic system, followed by an intramolecular C-N transamidation upon treatment with silica acting as a mild acid. Under the present conditions, the Au/TiO2-TMDS system was also found to catalyze efficiently the present selective reduction process. Both transfer hydrogenation processes showed very good functional-group tolerance and were successfully applied to access more structurally demanding products bearing other reducible moieties such as chloro, aldehyde or methyl ketone. An easily scalable (up to 1 mmol), low catalyst loading (0.6 mol%) synthetic protocol was realized, providing access to this important scaffold. Under these mild catalytic conditions, the desired products were isolated in good to high yields and with a TON of 130. A library analysis was also performed to demonstrate the usefulness of our synthetic strategy and the physicochemical profile of the derivatives

Supported Gold Nanoparticle-Catalyzed Selective Reduction of Multifunctional, Aromatic Nitro Precursors into Amines and Synthesis of 3,4-Dihydroquinoxalin-2-Ones

The synthesis of 3,4-dihydroquinoxalin-2-ones via the selective reduction of aromatic, multifunctional nitro precursors catalyzed by supported gold nanoparticles is reported. The reaction proceeds through the in situ formation of the corresponding amines under heterogeneous transfer hydrogenation of the initial nitro compounds catalyzed by the commercially available Au/TiO2-Et3SiH catalytic system, followed by an intramolecular C-N transamidation upon treatment with silica acting as a mild acid. Under the present conditions, the Au/TiO2-TMDS system was also found to catalyze efficiently the present selective reduction process. Both transfer hydrogenation processes showed very good functional-group tolerance and were successfully applied to access more structurally demanding products bearing other reducible moieties such as chloro, aldehyde or methyl ketone. An easily scalable (up to 1 mmol), low catalyst loading (0.6 mol%) synthetic protocol was realized, providing access to this important scaffold. Under these mild catalytic conditions, the desired products were isolated in good to high yields and with a TON of 130. A library analysis was also performed to demonstrate the usefulness of our synthetic strategy and the physicochemical profile of the derivatives

Synthesis & biological evaluation of purine homo-n-nucleosides modified with coumarins

Ιn the present dissertation, the synthesis and biological evaluation of purine homo-N-nucleosides modified with coumarins, have been developed. Τhe first cross metathesis of purine analogues using microwave irradation has been reported. Especially, the reactions in the presence of Grubbs 2nd or Hoveyda-Grubbs 2nd catalyst (2 portions), took place at 100oC and led to the desired E-alkenes. The Wittig reactions of (purin-9-yl)-acetaldehydes were examined for the first time. Moreover, the first Wittig reactions of (purin-9-yl)ethylidenetriphenylphosphoranes were described. Notably, Z-alkenes were isolated at low temperature (-30oC). The first (purin-9-yl)-acetaldehyde oximes and coumarinyloxy-acetaldehyde oximes were synthesized starting from the corresponding acetaldehydes. Besides, the 1,3-dipolar cycloaddition reactions of nitriloxides which formed in situ from the corresponding acetaldehyde oximes, have been developed for the first time. The reactions led to the synthesis of 3,5-isoxazolines or 3,5-isoxazoles. Additionally, the reactions of 4-hydroxycoumarin with various (purin-9-yl)-acetaldehyde derivatives were studied. Τhe desired E-isomers were synthesized. Furthermore, the expected 2:1 adducts analogous to dicoumarol according to the literature, were not isolated. Finally, the biological experiments in vitro were developed for the activity of the new compounds, as inhibitors: of lipid peroxidation, οf thrombin, of soybean lipoxygenase, of monoamine-oxidase (MAO-A and MAO-B) and of acetylo-or butyrylcholinesterase.Σκοπός της παρούσης διδακτορικής διατριβής είναι η σύνθεση και η μελέτη τροποποιημένων με κουμαρίνες νουκλεοζιτικών παραγώγων πουρινών με πιθανό βιολογικό ενδιαφέρον. Αρχικά, αναλύονται οι πρώτες αντιδράσεις διασταυρούμενης μετάθεσης ολεφίνης πουρινικών παραγώγων. Oι αντιδράσεις παρουσία καταλύτη Grubbs 2ης γενιάς ή Hoveyda-Grubbs 2ης γενιάς σε φούρνο μικροκυμάτων στους 100oC παρέχουν Ε-αλκένια. Περιγράφονται για πρώτη φορά οι αντιδράσεις Wittig ακεταλδεϋδών πουρινικών παραγώγων. Επίσης, αναπτύσσονται οι πρώτες αντιδράσεις Wittig υλιδίων πουρινικών παραγώγων. Μάλιστα οι αντιδράσεις δίνουν στους -30οC, εκλεκτικά Ζ-αλκένια. Από τις αντίστοιχες ακεταλδεΰδες σχηματίζονται για πρώτη φορά οι ακεταλδεϋδο-οξίμες πουρινικών και κουμαρινικών παραγώγων. Παράλληλα, μελετώνται οι πρώτες αντιδράσεις 1,3-διπολικής κυκλοπροσθήκης νιτριλοξειδίων που προκύπτουν in situ από τις αντίστοιχες ακεταλδεϋδο-οξίμες, οι οποίες οδηγούν στην παρασκευή 3,5-ισοξαζολινικών και ισοξαζολικών προϊόντων. Ακόμα, περιγράφονται οι αντιδράσεις συμπύκνωσης μεταξύ της 4-υδροξυκουμαρίνης και διαφόρων ακεταλδεϋδών πουρινικών παραγώγων. Τα επιθυμητά προϊόντα συντίθενται με Ε-στερεοχημεία. Σε αντίθεση με τη βιβλιογραφία δεν απομονώνονται τα αντίστοιχα δικουμαρινικά παράγωγα. Τέλος, εκτελούνται βιολογικά πειράματα in vitro, για την δράση των εξεταζόμενων ενώσεων ως αναστολέων: της λιπιδικής υπεροξείδωσης, της θρομβίνης, της φυτικής λιποξυγονάσης, της μονοαμινο-οξειδάσης (ΜΑΟ-Α και ΜΑΟ–Β) και της ακετυλο- και βουτυλοχολινεστεράσης

Selective photoinduced reduction of nitroarenes to n-arylhydroxylamines

We report the selective photoinduced reduction of nitroarenes to N-arylhydroxylamines. The present methodology facilitates this transformation in the absence of catalyst or additives and uses only light and methylhydrazine. This noncatalytic photoinduced transformation proceeds with a broad scope, excellent functional-group tolerance, and high yields. The potential of this protocol reflects on the selective and straightforward conversion of two general antibiotics, azomycin and chloramphenicol, to the bioactive hydroxylamine species

Synthesis and Biological Evaluation of Novel Hybrid Molecules Containing Purine, Coumarin and Isoxazoline or Isoxazole Moieties

Introduction: The 1,3-dipolar cycloaddition reactions of nitrile oxides formed in situ (in the presence of NCS and Et3N) from the oximes of (purin-9-yl)acetaldehyde or (coumarinyloxy)acetaldehyde with allyloxycoumarins or 9-allylpurines, respectively resulted in 3,5- disubstituted isoxazolines. The similar reactions of propargyloxycoumarins or 9-propargylpurines led to 3,5-disubstituted isoxazoles by treatment with PIDA and catalytic amount of TFA. Methods: The new compounds were tested in vitro as antioxidant agents and inhibitors of soybean lipoxygenase LO, AChE and MAO-B. Results: The majority of the compounds showed significant hydroxyl radical scavenging activity. Compounds 4k and 4n presented LO inhibitory activity. Conclusion: Compound 13e presents an antioxidant significant profile combining anti-LO, anti-AChE and anti-MAO-B activities