Investigation On Alkynes Halogenation

Organic halides have found broad and varied uses in the pharmaceutical,agricultural and materials industries.In the present work,we highlight three key points: 1)organic halides have received much attention in synthetic chemistry,since they are considered valuable building blocks in transition metal catalyzed cross coupling reactions,among others;2)organic halides are prevalent in the structures of natural products,pesticides and materials;and 3)the incorporation of halides,in particular fluorine,into organic molecules can strongly affect the chemical and physical properties,such as the acidity,polarity,and metabolic stability.Therefore,the development of a general and efficient strategy to construct carbon-halogen bonds is of great importance in the field of organic synthesis.This work includes the following six parts,with a focus on the hydrohalogenation of alkynes.We developed procedures for both the gold-catalyzed hydrofluorination and hydrochlorination of alkynes.Although the metalfree halogenation of alkynes is well established,we successfully synthesized various polysubstituted haloalkenes via hydrogen bonding assisted Br?nsted acid catalysis.Furthermore,we have shown the potential applicability of the resulting organic halides to subsequent transformations to form other desirable target molecules.In Chapter 1 we highlighted the significant role of organic halides in the field of organic synthesis.We summarized the approach to carbon-halides bonds via halogenation of alkynes.The direct halogenation of alkynes has been well established.However,the harsh reaction conditions and complexity of the process limit its application.Herein,we propose the goal of the project: develop convenient and practical methodologies to synthesize desirable organic halide containing products.In Chapter 2 we developed an efficient route towards the synthesis of α-fluoroketones.Employing the readily available alkynes as the starting materials,we found that treatment with N-oxides and in the presence of a homogeneous gold catalyst,the intermediate gold carbene could be inserted into the H—F bond,leading to desirable products.Our method is safe,practical and functional group tolerant.Aliphatic,aromatic and complex natural product derived alkynes were well tolerated and gave high yields.We also carried out mechanistic studies,which proved that the intermediate gold carbene plays an important role during the course of the reaction.Due to the high reactivity of the α-fluoroketone moiety,the resulting compounds could be used in subsequent transformations to produce further useful organofluorine compounds.In Chapter 3 we described gold catalysis and hydrogen bonding assisted hydrohalogenation of haloalkynes.Both(E)-and(Z)-chlorohaloalkenes were obtained by controlling the reaction conditions.Hydrogen bond network assisted Br?nsted acid catalyzed addition of DMPU/HCl to haloalkynes gave exclusively syn-products.On the contrary,raising the temperature to 80-100°C and using an acetic acid/lithium chloride system to generate the chloride in situ gave solely the anti-addition products when activated by gold catalysis.We also proposed the mechanism of the reaction according to DFT calculations,which indicated that the more acidic HCl favored chloride attack in syn to the H atom.The gold-catalyzed process gave the expected anti-selectivity consistent with typical homogeneous gold catalysis,and we proved this with a deuterium-labeling experiment;using d4-Ac OH as the solvent,the deuterated product was obtained in 92% yield.Taking advantage of the difference in reactivity between chloro-and bromo/chloro-alkenes,we were able to conduct sequential cross-coupling reactions to synthesize both E-and Z-trisubstituted alkenes.In Chapter 4 we reported the(radio)hydrofluoration of ynamides.The hydrogen-bond donor HFIP is able to form a network that activates alkali metal fluorides(KF)to release HF in situ,which can then add across the triple bond of ynamides in the absence of any other reagents.The reactions exhibited high functional groups tolerance and even worked well in an ambient atmosphere.Most importantly,this is the first metal free 18 F addition protocol to C-C unsaturated bonds with extraordinarily high radiochemical yields.This strategy provides potential practical value in pharmaceuticals and hospitals where fast and robust radiolabelling experiments are essential.In Chapter 5 we reported a hydrogen bonding cluster promoted addition of sulfonic acids to haloalkynes.The reactivity of sulfonic acids could be significantly enhanced in the presence of strong hydrogen bonding donors.This metal-free method resulted in good chemical yields for a wide range of haloalkyne substrates and demonstrated good functional group tolerance,providing both E-and Z-alkenyl sulfonates depending on the steric hindrance of the sulfonic acid.We also carried out DFT calculations.In this case,aromatic sulfonic acids led to cis-addition products,while aliphatic sulfonic acid gave the opposite trans-addition products.In Chapter 6 we disclosed an atom-economical and metal-free method for the regio-and stereo-selective hydrohalogenation of ynones and ynamides using easy to handle DMPU/HX(X = Br or Cl)reagents.The reaction operated under mild conditions and a range of functional groups were well tolerated.We found that the hydrohalogenation of ynones gave the anti-addition product whereas the same reaction with ynamides produced the syn-addition products.The resulting alkenyl halides could be converted to multisubstituted alkenes using palladium catalysis cross coupling reactions.