Synthesis of Fluoroalkylated β-Aminophosphonates and Pyridines from Primary β-Enaminophosphonates

Abstract

A simple and efficient stereoselective synthesis of fluorine containing beta-aminophosphonates by reduction of beta-enaminophosphonates is described. Reduction with sodium cyanborohydride in the presence of zinc chloride and the catalytic hydrogenation of beta-enaminophosphonates gives beta-aminophosphonates. beta-Enaminophosphonates are also used as intermediates for the regioselective synthesis of fluoroalkyl-substituted pyridines.

Fluorine–Protein Interactions and 19F NMR Isotropic Chemical Shifts: An Empirical Correlation with Implications for Drug Design

“…Shielded CF 3 moieties include those with an a-carbonyl, or a hydroxy or amino group in the b (vicinal) position. [47] Trifluoromethyl ketones are sometimes present in equilibrium with their hydrated form, with the 19 F signal of the hydrated form~8 ppm more shielded than the corresponding ketone, resonating in the range between~À80 tõ À90 ppm. There are several structures of trifluoroacetate (TFA) and trifluoroethanol (TFE) in complex with various receptors, where the CF 3 groups participate in hydrogen bonds with the protein.…”

Fluoroalkylated α,β-Unsaturated Imines as Synthons for the Preparation of Fluorinated Triazinane-2,4-diones and Dihydropyrimidin-2(1H)-ones

“…Unsaturated imines 1 were prepared in good yields by olefination reaction of phosphorated enamines and aldehydes, , and DHPMs are a class of important heterocycles used not only in preparative organic chemistry but also in medicinal chemistry. − Our initial approach to fluorinated DHPMs was based on the ADA reaction of 1-azadiene 1 and phenyl isocyanate . However, the treatment of α,β-unsaturated imine 1a (R 1 = p -CH 3 C 6 H 4 , R F = CF 3 ) with phenyl isocyanate 2a at room temperature did not give the fluorinated DHPMs 3a , and the corresponding vinylogous triazinane-2,4-dione 4a (R 1 = p -CH 3 C 6 H 4 , R F = CF 3 , Scheme ) was obtained instead in a regioselective fashion in low yield.…”

“…We also reported an efficient procedure for the synthesis of electron-poor 1-azadienes derived from αamino acids or α-aminophosphonates using an aza-Wittig approach, as well as successful normal ADA reactions of α,βunsaturated N-arylimines, hydrazones, and ADA reaction of α,β-unsaturated sulfinylmines with electron-rich dienophiles and Michael additions (1,4 addition) of α,β-unsaturated Narylimines. In the development of new fluorinated substrates, we prepared the first stable N-unsubstituted α,β-unsaturated imine 27 Ia (Scheme 2) from primary fluorine-substituted enaminophosphonates, 28,29 and we used these derivatives for the preparation of vinylogous α-aminonitriles IIIa, 30 βaminonitriles IIIb (X = CN), 30 and β-aminoesters IIIb (X = CO 2 Et), 31 obtained by 1,2-addition of trimethylsilyl cyanide, acetonitrile, or ethyl acetate, while the regioselective Michael addition of α-carbanions derived from carboxylic esters and nitriles to fluorinated imines I may afford functionalized pyridine derivatives IV. 31,32 In this context, the development of new methods for the preparation of fluorine-substituted heterocycles is an interesting goal in synthetic organic chemistry not only because of their use in medicinal chemistry 22 but also for the development of active ingredients for crop protection 23 and materials.…”

A Multicomponent Protocol for the Synthesis of Highly Functionalized γ-Lactam Derivatives and Their Applications as Antiproliferative Agents

“…Likewise, we have been recently involved in the development of strategies for the preparation of fluorine [ 41 , 42 , 43 , 44 ] and phosphorus [ 45 , 46 , 47 , 48 , 49 ] containing derivatives, as well as for the design of new biologically active simple and fused heterocycles with anticancer and antileishmanial activity [ 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. Due to the potential of five-membered heterocycles containing the 1,5-dihydro-2 H -pyrrol-2-one skeleton as anticancer agents, we thought that γ-lactam derivatives, obtained by multicomponent methodologies, may be excellent candidates for the development of new antiproliferative agents.…”