Computational study of the mechanism and selectivity of palladium-catalyzed propargylic substitution with phosphorus nucleophiles

The mechanism and sources of selectivity in the palladium-catalyzed propargylic substitution reaction that involves phosphorus nucleophiles, and which yields predominantly allenylphosphonates and related compounds, have been studied computationally by means of density functional theory. Full free-energy profiles are computed for both H-phosphonate and H-phosphonothioate substrates. The calculations show that the special behavior of H-phosphonates among other heteroatom nucleophiles is indeed reflected in higher energy barriers for the attack on the central carbon atom of the allenyl/propargyl ligand relative to the ligand-exchange pathway, which leads to the experimentally observed products. It is argued that, to explain the preference of allenyl- versus propargyl-phosphonate/phosphonothioate formation in reactions that involve H-phosphonates and H-phosphonothioates, analysis of the complete free-energy surfaces is necessary, because the product ratio is determined by different transition states in the respective branches of the catalytic cycle. In addition, these transition states change in going from a H-phosphonate to a H-phosphonothioate nucleophile.     

Catalytic Borylative Opening of Propargyl Cyclopropane,Epoxide, Aziridine,and Oxetane Substrates: Ligand Controlled Synthesis of Allenyl Boronates and Alkenyl Diboronates

A new copper‐catalyzed reaction for the stereo‐ and regioselective synthesis of alkenyl diboronates and allenyl boronates is presented. In this process propargyl derivatives of strained three/four‐membered rings were employed as substrates and B₂pin₂ was used as the boronate source. Selective formation of the alkenyl diboronate versus the allenyl boronate products was controlled by the choice of phosphine ligand.     

Catalytic Borylative Opening of Propargyl Cyclopropane,Epoxide, Aziridine,and Oxetane Substrates: Ligand Controlled Synthesis of Allenyl Boronates and Alkenyl Diboronates

A new copper‐catalyzed reaction for the stereo‐ and regioselective synthesis of alkenyl diboronates and allenyl boronates is presented. In this process propargyl derivatives of strained three/four‐membered rings were employed as substrates and B₂pin₂ was used as the boronate source. Selective formation of the alkenyl diboronate versus the allenyl boronate products was controlled by the choice of phosphine ligand.     

Ring opening insertion polymerization of ε‐caprolactone with hydrogen phosphonate initiators

In this work, ring opening insertion polymerization (ROIP) of ε‐caprolactone (ε‐CL) using a series of hydrogen phosphonates (H‐phosphonates) as initiators was investigated. The ROIP occurred by a coordination‐insertion mechanism containing two steps. First, the carbonyl carbon was attacked by the phosphorus atom of the H‐phosphonate tautomerization (a phosphine‐like structure) and the acyl‐oxygen bond was broken. An intermediate was formed by the coordination of the former carbonyl carbon and acyl‐oxygen of ε‐CL to phosphorus atom. Then the phosphorus‐alkoxide of H‐phosphonate was cleavaged to form acyl‐alkoxide bond. Poly(ε‐caprolactone) (PCL)‐inserted H‐phosphonates (PCL‐HPs), which was not only the product of the occurred ROIP but also the initiator for the next ROIP, were produced. After 60 min of microwave irradiation (510 W), PCL with a number‐average molar mass of 7800 g/mol and monomer conversion over 92% was obtained. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 6214–6222, 2009     

A free energy calculation study of the effect of H-->F substitution on binding affinity in ligand-antibody interactions

Changes in binding affinity to catalytic antibody 6D9 of chloramphenicol phosphonate derivatives (CPDs) containing H or F were investigated by performing free energy calculations based on molecular dynamics simulations. We calculated the binding free energy, enthalpy, and entropy changes (DeltaDeltaG, DeltaDeltaH, and -TDeltaDeltaS) attributable to H-->F substitution by comparing results for CPDs containing a trifluoroacetylamino group (CPD-F) or an acetylamino group (CPD-H). The calculated DeltaDeltaG, DeltaDeltaH, and -TDeltaDeltaS values were -2.9, -6.3, and 3.5 kcal mol(-1) and close to experimental values observed for a series of similar ligands, chloramphenicol phosphonates with F and H (-1.4, -3.5, and 2.1 kcal mol(-1)). Therefore, CPD-F binds more strongly to 6D9 than does CPD-H. To clarify the origin of the large difference in DeltaDeltaG, we apportioned the calculated values of DeltaDeltaG and DeltaG for the associated and dissociated states into contributions from various atomic interactions. We found that the H-->F substitution increased the binding affinity mainly by decreasing the hydration free energy and not by increasing favorable interactions with the antibody. The decreased hydration free energy of the ligand was mainly due to unfavorable coulombic interactions between the trifluoroacetylamino group and solvent waters, which increased the free energy of the dissociated state (by about 3.7 kcal mol(-1)). Also, the trifluoroacetylamino group slightly increased the free energy level of the associated state (about 0.8 kcal mol(-1)) because favorable van der Waals interactions compensated for unfavorable coulombic interactions with antibody atoms. In addition, the enthalpy and entropy changes, DeltaDeltaH and -TDeltaDeltaS (computationally -6.3 and 3.5 kcal mol(-1)), originated mainly from a decrease in hydration free energy in the dissociated state. The CPD-F and CPD-H ligands had substantially different structures in the dissociated and complexed states.     

P-H activation using alkynylgold substrates: steric and electronic effects

The susceptibility of a prototypical hydrogen phosphonate to undergo P-H activation upon treatment with alkynylgold complexes has been studied. Dynamic solution behavior was observed during reactions involving triphenylphosphine ligated substrates and was attributed to rapid phosphine exchange between the alkynylgold starting material and the gold phosphonate product. The use of bulky biaryldialkylphosphine ligands eliminated the fluxional behavior, but did not significantly slow the rate of P-H activation. Similarly, changing the supporting ligand to an N-heterocyclic carbene did not significantly slow the rate of the reaction. Despite a number of reports outlining the functionalization of propargyl alcohols using gold catalysts, incorporating these groups into the architecture of the alkynylgold substrates did not alter the product distributions. Although the chemistry tolerated a range of supporting ligands, incorporating electron donating groups into the alkyne increased the rate of the reaction while electron-withdrawing groups slowed the reaction. A possible mechanism for the process includes a transition state containing significant pi-contribution from the alkyne. Due to the high yields of gold phosphonates obtained in this chemistry as well as the mild conditions of the reactions, the interception of intermediates/catalysts by substrates or ligands containing labile P-H donors is an issue that must be circumvented when designing or developing a gold catalyzed reaction that proceeds through alkynylgold intermediates.     

Enantioselective indole Friedel--Crafts alkylations catalyzed by bis(oxazolinyl)pyridine-scandium(III) triflate complexes

A highly enantioselective Friedel-Crafts alkylation of electron-rich aromatic nucleophiles catalyzed by scandium(III) triflate-pyridyl(bis)oxazoline complexes has been accomplished. The reaction involves alpha,beta-unsaturated acyl phosphonates as electrophiles and primarily substituted indoles as nucleophiles. The reactive acyl phosphonate product is converted to the corresponding ester or amide in good overall yield by adding an alcohol or amine directly to the reaction mixture.     

New direction in organopalladium chemistry: structure and reactivity of unsaturated hydrocarbon ligands bound to multipalladium units

Examination of the manner of interaction between Pd(0) and allylpalladium(II) complexes, both being involved as key intermediates in Pd-catalyzed allylic coupling, led us to discover a new role for such combinations in affecting the stereochemistry of the transformations. A similar investigation of the system involving Pd(0) and allenyl/propargyl complexes of Pd(II) led to the discovery of dinuclear Pd(I)bond;Pd(I) complexes containing bridging allenyl/propargyl ligands, which exhibited novel structural and reactivity aspects of great synthetic significance. A systematic comparison was made between the structure, stability, and reactivity of allyl and allenyl/propargyl ligands in dinuclear complexes and those in mononuclear counterparts. On the basis of MO calculations, coordination behavior specific to the ligands of the dinuclear complex is attributed to the occurrence of the back-donating interaction from filled Pdbond;Pd bonding orbitals to vacant ligand pi* orbitals. Similar bonding features are the origin of the ready synthesis of novel one-dimensional sandwich complexes composed of conjugated polyene ligands and linear polypalladium chains. A substitutionally labile dipalladium complex reacts with an equimolar amount of trienes or alkynes to give formal [4pi + 2sigma] or [2pi + 2sigma] adducts, respectively, which undergo further unique transformations with additional unsaturated substrates.     

Solvent‐Free Synthesis of Diphenyl [2‐(Aminocarbonyl)‐1,2‐dihydroisoquinolin‐1‐yl]phosphonates from Isoquinoline,Isocyanates, and Diphenyl Phosphonate

The 1 : 1 intermediates generated by addition of isoquinoline to isocyanates were trapped by diphenyl phosphonate to yield diphenyl [2‐(aminocarbonyl)‐1,2‐dihydroisoquinolin‐1‐yl]phosphonates in good yields under solvent‐free conditions.     

Synthesis and Functionalization of Allenes by Direct Pd‐Catalyzed Organolithium Cross‐Coupling

A palladium‐catalyzed cross‐coupling between in situ generated allenyl/propargyl‐lithium species and aryl bromides to yield highly functionalized allenes is reported. The direct and selective formation of allenic products preventing the corresponding isomeric propargylic product is accomplished by the choice of SPhos or XPhos based Pd catalysts. The methodology avoids the prior transmetalation to other transition metals or reverse approaches that required prefunctionalization of substrates with leaving groups, resulting in a fast and efficient approach for the synthesis of tri‐ and tetrasubstituted allenes. Experimental and theoretical studies on the mechanism show catalyst control of selectivity in this allene formation.     

Theoretical Study on the Mechanism of the Gas-phase Reaction of Sc＋ with Propargyl Alcohol

In order to elucidate the reaction mechanisms of reaction Sc^＋ with propargyl alcohol (PPA), the triplet potential energy surface for the reactions has been theoretically investigated using a DFT method. The geometries for the reactants, intermediates, transition states and products were completely optimized at B3LYP/DZVP level. The single point energy of each stationary point was calculated at MP4/(6-311＋G** for C, H, O and Lanl2dz for Sc^＋) level. All the transition states were verified by the vibrational analysis and the internal reaction coordinate (IRC) calculations. The present results show that the reaction takes an insertion-elimination mechanism both along the O—H and C—O bond activation branches, but the C—O bond activation is much more favorable in energy than the O—H bond activation. All theoretical results not only support the existing conclusions inferred from early experiment, but also complement the pathway and mechanism for this reaction.     

Solvent Effects on Acyl Transfers to Phosphonates

Abstract

The nucleophilic reactivity of the phosphate dianion in aqueous solution is unusually low, relative to that of other nucleophiles of comparable pK₄,s. For example, in the reaction with g-nitrophenyl acetate (pNPA), phosphate shows a negative deviation of over two orders of magnitude from the Bransted correlation (β_nuc ≈ 0.7) obtained with other oxygen nucleophiles [l]. Since there are over 1 3 0 enzymatic reactions which catalyze nucleophilic reactions of phosphate, we were interested in exploring the possible sources of this catalytic efficiency. By using phosphonates (Rpo₃ ^?2) as phosphate analogs we have shown an unusual insensitivity of the rate of acetyl transfer from E- nitrophenol to the phosphonate dianion (β_nuc = 0.3). These observations, along with the more favorable entropy of activation for the reaction of pNPA with phosphonates (ΔS? ≈ ?13 eu) than with most other nucleophiles (e.g., with imidazole or with acetate, δS? ≈ ?30 eu) suggest a significant contribution of desolvation to the activation energy. To investigate this further we looked at the effect of DMSO/water mixtures on the reaction rate. The second-order rate constant for acetyl transfer from E-nitrophenol to chloromethylphosphonate increases over 5,000-fold as the DMSO concentration is increased to 90% (v/v). This sensitivity to DMSO concentration is greater than that reported for acetyl transfer to a variety of phenoxide nucleophiles [2] and is greater than can be accounted for simply from the increase in the effective pK_a2 of the phosphonate nucleophile. This suggests a significant role for desolvation in the enzyme-catalyzed nucleophilic reactions of inorganic phosphate.     

Synthesis of (3,6-dihydro-2H-pyran-2-yl)phosphonate derivatives and investigation of catalyst effect on frontier molecular orbitals using DFT method

Hetero Diels-Alder (HDA) reactions between 2,3-dimethyl-1,3-butadiene and diethyl ester of aroyl phosphonates catalyzed by AlCl₃ to afford (3,6-dihydro-2H-pyran-2-yl) phosphonate derivatives were investigated. Aroyl phosphonates with electron-withdrawing groups generally resulted in better isolated chemical yields. A stoichiometric amount of AlCl₃ rather than a catalytic amount was necessary to activate the cycloaddition reaction. The amount of AlCl₃ catalyst and its effect on LUMO of ethyl ester benzoyl phosphonate were also investigated by performing density functional theory (DFT) (B97D/6-31+G(d,p)) computations in dichloromethane. An increased loading of AlCl₃ induced a considerable decrease in the LUMO energy of ethyl ester of benzoyl phosphonate. The computed Gibbs free activation energy is 17.03 kcal/mol in DCM at 0°C using the same computational level.     

Photorearrangement of Propargyl Bromide as a Probe to Study Propargylic and Allenic Radicals by Infrared Matrix Isolation Technique

The photolysis of propargyl bromide in Ar matrix to form allenyl bromide proceeded with a radical mechanism. The deuterium label study and radical scavenger were used to investigate the mechanism. Neither propargyl nor allenyl radical was trapped in Ar matrix at 8 K. The rates of propargyl and allenyl radicals coupled with bromo radical are significantly fast. The stability of propargyl and allenyl radicals is discussed.     

Unprecedented Spectroscopic and Computational Evidence for Allenyl and Propargyl Titanocene(IV) Complexes: Electrophilic Quenching of Their Metallotropic Equilibrium

The synthesis and structural characterization of allenyl titanocene(IV) [TiClCp₂(CH=C=CH₂)] 3 and propargyl titanocene(IV) [TiClCp₂(CH₂?C≡C?(CH₂)₄CH₃)] 9 have been described for the first time. Advanced NMR methods including diffusion NMR methods (diffusion pulsed field gradient stimulated spin echo (PFG‐STE) and DOSY) have been applied and established that these organometallics are monomers in THF solution with hydrodynamic radii (from the Stokes–Einstein equation) of 3.5 and 4.1 Å for 3 and 9 , respectively. Full ¹H, ¹³C, Δ¹H, and Δ¹³C NMR data are given, and through the analysis of the Ramsey equation, the first electronic insights into these derivatives are provided. In solution, they are involved in their respective metallotropic allenyl–propargyl equilibria that, after quenching experiments with aromatic and aliphatic aldehydes, ketones, and protonating agents, always give the propargyl products P (when carbonyls are employed), or allenyl products A (when a proton source is added) as the major isomers. In all the cases assayed, the ratio of products suggests that the metallotropic equilibrium should be faster than the reactions of 3 and 9 with electrophiles. Indeed, DFT calculations predict lower Gibbs energy barriers for the metallotropic equilibrium, thus confirming dynamic kinetic resolution.     

Stereochemical inversion of phosphonothioate methanolysis by La(III) and Zn(II): mechanistic implications for the degradation of organophosphate neurotoxins

The utility of phosphonothioate methanolysis to degrade organophosphate neurotoxins has prompted the stereochemical investigation of this useful transformation. The methanolysis of enantiomerically pure O,S-diethyl phenylphosphonothioate (5) was studied both in the presence and in the absence of metal ions known to catalyze the phosphonothioate → phosphonate transformation. This report outlines the syntheses of enantiomerically pure 5 and its methanolysis product O-ethyl O-methyl phenylphosphonate (7). Compound 7 results from exclusive P-S scission of 5, which is the desired mode of phosphonothioate methanolysis (E(a) = 14.5 ± 0.5 kcal/mol). The stereochemical analysis of the phosphonothioate methanolysis was done for the first time with β-cyclodextrin, and it shows complete inversion on the phosphorus center upon methoxide displacement of ethanethiolate. The presence of La(III) or Zn(II) complexes do not alter this S(N)2-like substitution which sheds new light on the mechanism of methanolysis of phosphonothioates.     

alpha-fluorinated phosphonates as substrate mimics for glucose 6-phosphate dehydrogenase: the CHF stereochemistry matters

Reported is a systematic study of the "fitness" (in terms of kcat/Km) of a series of phosphonate mimics of glucose 6-phosphate (G6P) as unnatural substrates for G6P dehydrogenase from Leuconostoc mesenteroides. The four G6P analogues (9, 10, 15a, and 15b) differ only in the degree of fluorination at the "bridging" phosphonate carbon. All have been synthesized from benzyl 6-O-trifluoromethanesulfonyl-2,3,4-tri-O-benzyl beta-D-glucopyranoside (6). The phosphonates with bridging CH2 (9) and CF2 (10) groups are cleanly obtained by direct displacements with the appropriate LiX2CP(O)(OEt)2 reagents (X = H, F) in 15 min at -78 degrees C. For the (alpha-monofluoro)alkylphosphonates (15a/b), homologation of 6 is achieved via lithiodithiane-mediated triflate displacement, followed by aldehyde unmasking [CaCO3, Hg(ClO4)2, H2O]. Addition of diethyl phosphite anion produces diastereomeric, (alpha-hydroxy)phosphonates 13a/b (1.4:1 ratio) which may be readily separated by chromatography. The stereochemistry of the minor diastereomer was established as 7(S) via X-ray crystallographic structure determination of its p-bromobenzoate derivative, 16b. Treatment of the major 7(R) diastereomer with DAST produces alpha-fluorinated phosphonate 14a, in modest yield, with inversion of configuration, as established, again, by X-ray crystallography. To our knowledge, this is first example of DAST-mediated fluorination of a (nonbenzylic, nonpropargylic) secondary (alpha-hydroxy)phosphonate and thus establishes the stereochemical course of this transformation. alpha-Deprotonation/kinetic quenching of 14a provides access to the 7(R)-epimer (14b). For all four protected phosphonates (7, 8, 14a, and 14b), diethyl phosphonate ester deprotection was carried out with TMSBr, followed by global hydrogenolytic debenzylation to produce the free phosphonates, as alpha/beta anomeric mixtures. Titrations of G6P itself and the free phosphonic acids provides second pKa values of 6.5 (1, bridging-O), 5.4 (10, bridging-CF2), 6.2 (14a, bridging-CHF), and 7.6 (9, bridging-CH2). Leuconostoc mesenteroides G6PDH-mediated oxidation and Lineweaver-Burk analysis yields normalized kcat/Km values of 0.043 (14b, bridging-7(R)-CHF), 0.11 (10, bridging-CF2), 0.23 (14b, bridging-CH2), and 0.46 (14a, bridging-7(S)-CHF) relative to G6P itself, largely reflecting differences in Km. The fact that kcat/Km increases by more than an order of magnitude in going from the 7(R)-alpha-monofluoroalkyl phosphonate (worst substrate) to the 7(S)-diastereomer (best substrate) is especially notable and is discussed in the context of the known phosphate binding pocket of this enzyme as revealed by X-ray crystallography (Adams, M. J. et al. Structure 1994, 2, 1073-1087).     

Electrocatalytic Fast and Efficient Multicomponent Approach to Medicinally Relevant (2‐Amino‐4H‐chromen‐4‐yl) phosphonate Scaffold

‘One‐pot’ electrocatalytic transformation of salicylaldehydes, malononitrile, and triethyl phosphite in an undivided cell results in the formation of diethyl (2‐amino‐3‐cyano‐4H‐chromen‐4‐yl)phosphonates in 88–93% substance yields and 880–930% current efficiency via complex multicomponent process. This novel electrocatalytic chain process opens an effective, fast, and convenient way to cyano‐functionalized (2‐amino‐4H‐chromen‐4‐yl)phosphonate systems which are promising compounds for biomedical applications. This efficient electrocatalytic approach to the (2‐amino‐4H‐chromen‐4‐yl)phosphonate scaffold represents novel synthetic concept for multicomponent reactions (MCR) strategy and allows to combine the synthetic virtues of conventional MCR with ecological benefits and convenience of facile electrocatalytic procedure.     

锡存在下取代的炔丙基溴与醛反应的选择性

报道三甲基硅基和苯基取代的炔丙基溴在锡存在下与醛的反应, 并讨论了反应的选择性。三甲基硅基炔丙基溴与醛的反应产率约为71-84%。产物中丙二烯醇与高炔丙基醇之比在44 :56到25 : 75之间, 苯基炔丙基溴的反应得到了产物丙二烯醇。     

Concise Total Synthesis of Enigmazole A

An efficient entry into the phosphorylated marine macrolide enigmazole A is described. Enigmazole A interferes with c‐Kit signaling by an as yet unknown mode of action and is therefore a potential lead in the quest for novel anticancer agents. Key to success is a gold‐catalyzed cascade comprising a [3,3]‐sigmatropic rearrangement of a propargyl acetate along the periphery of a macrocyclic scaffold, followed by a transannular hydroalkoxylation of the resulting transient allenyl acetate. This transformation mandated the use of a chiral gold catalyst to ensure a matching double‐asymmetric setting. Other noteworthy steps are the preparation of the oxazole building block by a palladium‐catalyzed C?H activation, as well as the smooth ring‐closing alkyne metathesis of a diyne substrate bearing a propargylic leaving group, which has only little precedent.