Theoretical Studies On The Mechanism And Selectivity Of Transition Metal Catalyzed Cyclization Reactions Of Alkynes

Homogeneous transition metal-catalyzed reactions in the area of organic synthesis have received considerable attention over the past decade,which provided an effective strategy for constructing a diverse range of useful complex molecules.In particular,transition metal-catalyzed cycloisomerization reactions of alkynes have developed into a powerful approach for producing carbo-and heterocycles,which are widely applied to the synthesis of complex molecules and natural products.However,controlling the selectivity to enable the selective formation of diverse carbo-and heterocycles is a considerable challenge.In recent years,theory and computational chemistry have become an important means of interpreting and predicting experimental results and understanding the performance of chemical reactions,which occupies an important position in the field of metal organic chemistry.In this dissertation,we present a systematic DFT mechanistic study on some important alkynes cycloisomerization reactions catalyzed by transition metals such as Au,Pt.Through DFT calculation,we discussed the mechanistic details of reactions,studied the thermodynamic and kinetic properties of the reaction,elucidated influences of ligands,counterions,and catalysts as well as reactant stoichiometric ratio on reaction selectivity at the molecular level,clarified the origins of selectivity of the reaction,and reasonably explained a series of experimental phenomena.It is expected that these calculated results can provide an important theoretical foundation for the design and development of new catalytic systems.The main contributions and valuable innovations of this dissertation are summarized as follows:1.With the aid of density functional theory(DFT)calculations,we have performed a systematic study of Au(I)-catalyzed regiodivergent cycloisomerizations of boron-containing alkynyl epoxides toward C2-and C3-borylated furans.The calculations clarified the mechanistic details of the reaction and the regiodivergence induced by two gold catalysts.The proposed catalytic cycle involves two major stages:ring expansion of alkynyl epoxide accompanied by B(MIDA)group migration to form a m-boron furyl heterocyclic intermediate and a formal 1,2-H or a 1,2-B migration to form a C3-or C2-borylated furan.The former is identified as the bottleneck of the reaction,which proceeds via ? activation of the oxirane moiety rather than ? activation of the alkynyl moiety proposed in experimental work,and the latter controls the regiodivergence.Calculations show that the counterion and ligand in the gold catalyst play less important roles in the ring expansion,but they are crucial for the divergent formation of borylated furans:an OTf-counterion with an(ArO)3P ligand favors the 1,2-H migration,leading to the formation of C3-borylated furan,whereas an SbFes anion with an IPr ligand promotes the 1,2-B migration,supporting the predominant formation of C2-borylated furan.The theoretical results rationalize the observed regioselectivity and provide key insights into the mechanism of the migratory cycloisomerization of boron-containing alkynyl epoxides.2.We have performed a DFT calculation study on Au(?)-catalyzed intramolecular hydroarylation of alkynes reported by Jiang et al.(J.Am.Chem.Soc.2016,138,5218-5221).Focusing on a representative alkyne,N-propargyl-N-tosylaniline,we conducted a detailed study on the ortho-and para-position hydroarylation of the alkyne catalyzed by gold(I)catalysts with different ligands.Both the ortho-and para-position hydroarylation reactions are found to follow a similar three-stage mechanism:electrophilic cyclization,proton loss,and protiodeauration.The initial electrophilic cyclization was identified as the rate-and regiochemistry-deternining step.With the flexible electrondeficient phosphite ligand,the ortho-position cyclization is identified as the energetically more favorable pathway,while with the rigid electron-abundant phosphine(Xphos)ligand,the dominant pathway turns to the para-position cyclization.The theoretical results are in good agreement with the experimental observations.The ?-? interaction between alkynyl phenyl and the directing acylamino group are found to be mainly responsible for the observed ortho-selectivity,while a combination of favorable noncovalent CH…? interaction and steric repulsion between Xphos ligand and alkynyl group contributes to the observed exclusive para-selectivity.The present calculations provide deeper insight into the mechanism and origin of regioselectivity of the title reaction.3.The mechanisms and chemoselectivities on the Au(I)-catalyzed intermolecular condensation between homopropargyl alcohols and terminal alkynes were investigated by performing DFT calculations.The reaction was indicated to involve three stages:transformation of the homopropargyl alcohol(Ri)via intramolecular cyclization to the cyclic vinyl ether(R1'),formation of the C-2-arylalkynyl cyclic ether(P1)via hydroalkynylation of R1' with phenylacetylene(R2),and conversion from Pi to 2,3-dihydro-oxepine(P2).The results revealed the origin of the reaction divergence and rationalized the experimental observations that a 1:3 reactant stoichiometric ratio affords P1 as the major product,whereas the 1:1.1 ratio results in P2 in high yield.The reactant stoichiometric ratio-controlled divergent reactivity is attributed to different catalytic activities of the gold catalyst toward different reaction stages.In the 1:3 situation,the excess R2 induces the Au catalyst toward its dimerization and/or hydration,inhibiting the conversion of Pi to P2 and resulting in product Pi.Without excess R2,the Au catalysis follows a general cascade reaction,leading to product P2.Theoretical results described a general strategy controlling the reaction divergence by a different reactant stoichiometric ratio.This strategy may be enlightening for chemists who are exploring various synthesis methods with high chemo-,regio-,and enantioselectivities.4.We present a DFT study on the catalyst-controlled synthesis of benzo-heterocycles from o-alkynylbenzamides,which challenges four different products via the N-/O-attack with 5-exo/6-endo-dig pathway.The calculated results reproduce experimental observations,i.e.,Au(?)catalysts induced the O-attack,in which the phosphite ligand favors O-5-exo-dig cyclization,and the Xphos ligand favors O-6-endo-dig cyclization;in contrast,with PtCl4 or a base as the catalyst,the N-cyclization mode was preferred,resulting in N-6-endo-dig cyclization or N-5-exo-dig cyclization.In Au(?)catalysis,the preferred O-attack mode mainly originates from the symmetry match in the dominant bond forming interaction between the lone-pair orbital of carbonyl-0 and the in-plane alkyne ?*-orbital,and the electronic property of the ligand controls the selective O-5-exo-dig or O-6-endo-dig cyclization.The preference for the N-attack mode in PtCl4 catalysis is attributed to the stronger coordinate capability of carbonyl-0 than amino-N in the substrate to PtCl4,blocking the O-attack pathway,and the regioselectivity(N-6-endo-dig vs N-5-exo-dig)depends on the stronger electrostatic interaction between the amino-N and Cp atom of the alkynyl group.However,in the situation of the base catalysis,the preference for N-5-exo-dig cyclization over O-5-exo-dig can be explained by the larger configuration distortion in the O-5-exo-dig cyclization than that in the N-5-exo-dig cyclization.The present calculations provide deeper insight into the mechanism and origin of chemo-and regioselectivity of the title reaction.