Mechanistic study of the titanocene(III)-catalyzed radical arylation of epoxides.

An atom-economical and catalytic arylation of epoxide-derived radicals is described. The key step of the catalytic system is a sequential electron and proton transfer for the rearomatization of the radical σ-complex and catalyst regeneration. Kinetic, computational, spectroscopic, and cyclovoltammetric investigations highlight the key issues of the reaction mechanism and catalyst stabilization by collidine hydrochloride. Studies employing radicophiles rule out the participation of cations as reactive intermediates.

Substituent effects and supramolecular interactions of titanocene(III) chloride: implications for catalysis in single electron steps.

The electrochemical properties of titanocene(III) complexes and their stability in THF in the presence and absence of chloride additives were studied by cyclic voltammetry (CV) and computational methods. The anodic peak potentials of the titanocenes can be decreased by as much as 0.47 V through the addition of an electron-withdrawing substituent (CO2Me or CN) to the cyclopentadienyl ring when compared with Cp2TiCl. For the first time, it is demonstrated that under the conditions of catalytic applications low-valent titanocenes can decompose by loss of the substituted ligand. The recently discovered effect of stabilizing titanocene(III) catalysts by chloride additives was analyzed by CV, kinetic, and computational studies. An unprecedented supramolecular interaction between [(C5H4R)2TiCl2](-) and hydrochloride cations through reversible hydrogen bonding is proposed as a mechanism for the action of the additives. This study provides the critical information required for the rational design of titanocene-catalyzed reactions in single electron steps.

Mechanistic studies on the CAN-mediated intramolecular cyclization of δ-aryl-ß-dicarbonyl compounds.

The synthesis of 2-tetralones through the cyclization of δ-aryl-ß-dicarbonyl substrates by using CAN is described. Appropriately functionalized aromatic substrates undergo intramolecular cyclizations generating 2-tetralone derivatives in moderate to good yields. DFT computational studies indicate that successful formation of 2-tetralones from δ-aryl-ß-dicarbonyl radicals is dependent on the stability of the subsequent cyclohexadienyl radical intermediates. Furthermore, DFT computational studies were used to rationalize the observed site selectivity in the 2-tetralone products.

Preparation and use of samarium diiodide (SmI(2)) in organic synthesis: the mechanistic role of HMPA and Ni(II) salts in the samarium Barbier reaction.

Although initially considered an esoteric reagent, SmI(2) has become a common tool for synthetic organic chemists. SmI(2) is generated through the addition of molecular iodine to samarium metal in THF.(1,2-3) It is a mild and selective single electron reductant and its versatility is a result of its ability to initiate a wide range of reductions including C-C bond-forming and cascade or sequential reactions. SmI(2) can reduce a variety of functional groups including sulfoxides and sulfones, phosphine oxides, epoxides, alkyl and aryl halides, carbonyls, and conjugated double bonds.(2-12) One of the fascinating features of SmI-(2)-mediated reactions is the ability to manipulate the outcome of reactions through the selective use of cosolvents or additives. In most instances, additives are essential in controlling the rate of reduction and the chemo- or stereoselectivity of reactions.(13-14) Additives commonly utilized to fine tune the reactivity of SmI(2) can be classified into three major groups: (1) Lewis bases (HMPA, other electron-donor ligands, chelating ethers, etc.), (2) proton sources (alcohols, water etc.), and (3) inorganic additives (Ni(acac)(2), FeCl(3), etc).(3) Understanding the mechanism of SmI(2) reactions and the role of the additives enables utilization of the full potential of the reagent in organic synthesis. The Sm-Barbier reaction is chosen to illustrate the synthetic importance and mechanistic role of two common additives: HMPA and Ni(II) in this reaction. The Sm-Barbier reaction is similar to the traditional Grignard reaction with the only difference being that the alkyl halide, carbonyl, and Sm reductant are mixed simultaneously in one pot.(1,15) Examples of Sm-mediated Barbier reactions with a range of coupling partners have been reported,(1,3,7,10,12) and have been utilized in key steps of the synthesis of large natural products.(16,17) Previous studies on the effect of additives on SmI(2) reactions have shown that HMPA enhances the reduction potential of SmI(2) by coordinating to the samarium metal center, producing a more powerful,(13-14,18) sterically encumbered reductant(19-21) and in some cases playing an integral role in post electron-transfer steps facilitating subsequent bond-forming events.(22) In the Sm-Barbier reaction, HMPA has been shown to additionally activate the alkyl halide by forming a complex in a pre-equilibrium step.(23) Ni(II) salts are a catalytic additive used frequently in Sm-mediated transformations.(24-27) Though critical for success, the mechanistic role of Ni(II) was not known in these reactions. Recently it has been shown that SmI(2) reduces Ni(II) to Ni(0), and the reaction is then carried out through organometallic Ni(0) chemistry.(28) These mechanistic studies highlight that although the same Barbier product is obtained, the use of different additives in the SmI(2) reaction drastically alters the mechanistic pathway of the reaction. The protocol for running these SmI(2)-initiated reactions is described.

Catalytic Ni(II) in reactions of SmI2: Sm(II)- or Ni(0)-based chemistry?

The addition of catalytic amounts of Ni(II) salts provide enhanced reactivity and selectivity in numerous reactions of SmI(2), but the mechanistic basis for their effect is unknown. We report spectroscopic and kinetic studies on the mechanistic role of catalytic Ni(II) in the samarium Barbier reaction. The mechanistic studies presented herein show that the samarium Barbier reaction containing catalytic amounts of Ni(II) salts is driven solely by the reduction of Ni(II) to Ni(0) in a rate-limiting step. Once formed, Ni(0) inserts into the alkyl halide bond through oxidative addition to produce an organonickel species. During the reaction, the formation of colloidal Ni(0) occurs concomitantly with Ni(0) oxidative addition as an unproductive process. Overall, this study shows that a reaction thought to be driven by the unique features of SmI(2) is in fact a result of known Ni(0) chemistry.

A convenient pathway to Sm(II)-mediated chemistry in acetonitrile.

In this communication we show that the instability of samarium diiodide (SmI(2)) in acetonitrile is a consequence of ionization of the reductant in this solvent. Samarium triflate (Sm(OTf)(2)) is exceptionally stable in acetonitrile for periods over six months and can be used with appropriate additives to initiate a ketyl-olefin coupling reaction in high yield.

Uncovering the mechanistic role of HMPA in the samarium Barbier reaction.

The presence of HMPA is critical for the selective coupling of alkyl halides and ketones by SmI2. Although previous rate studies have shown that HMPA dramatically accelerates the reduction of alkyl halides over ketones, the basis of this rate acceleration is unknown. In this communication, we report experimental and computational evidence that demonstrate that the selectivity observed in the samarium Barbier reaction is in part a result of activation of the alkyl halide bond by HMPA.

Corrigendum to Solvent-dependent oxidative coupling of 1-aryl-1,3-dicarbonyls and styrene.

This report describes the scope and mechanism of the solvent-dependent, chemoselective oxidative coupling of 1-aryl-1,3-dicarbonyls with styrene using Ce(IV) reagents. Dihydrofuran derivatives are obtained when reactions are performed in methanol whereas nitrate esters can be selectively synthesized in acetonitrile and methylene chloride. Mechanistic studies are consistent with the rate of solvent-assisted deprotonation of a radical cation intermediate playing an integral role in the selective formation of products.

Dynamic ligand exchange in reactions of samarium diiodide.

Mechanistic studies show the importance of iodide displacement by additives that accelerate reactions of samarium diiodide. The key feature important for acceleration of reaction rate is the use of proton donors and other additives that have a high enough affinity for Sm(II) to displace iodide yet do not saturate the coordination sphere inhibiting substrate reduction.

Studies on the mechanism, selectivity, and synthetic utility of lactone reduction using SmI(2) and H(2)O.

Although simple aliphatic esters and lactones have long been thought to lie outside the reducing range of SmI(2), activation of the lanthanide reagent by H(2)O allows some of these substrates to be manipulated in an unprecedented fashion. For example, the SmI(2)-H(2)O reducing system shows complete selectivity for the reduction of 6-membered lactones over other classes of lactones and esters. The kinetics of reduction has been studied using stopped-flow spectrophotometry. Experimental and computational studies suggest that the origin of the selectivity lies in the initial electron-transfer to the lactone carbonyl. The radical intermediates formed during lactone reduction with SmI(2)-H(2)O can be exploited in cyclizations to give cyclic ketone (or ketal) products with high diastereoselectivity. The cyclizations constitute the first examples of ester-alkene radical cyclizations in which the ester carbonyl acts as an acyl radical equivalent.

Solvent-dependent oxidative coupling of 1-aryl-1,3-dicarbonyls and styrene.

This report describes the scope and mechanism of the solvent-dependent, chemoselective oxidative coupling of 1-aryl-1,3-dicarbonyls with styrene using Ce(IV) reagents. Dihydrofuran derivatives are obtained when reactions are performed in methanol whereas alpha-tetralones can be selectively synthesized in acetonitrile and methylene chloride. Mechanistic studies are consistent with the rate of solvent-assisted deprotonation of a radical cation intermediate playing an integral role in the selective formation of products.

Mechanistic study of samarium diiodide-HMPA initiated 5-exo-trig Ketyl-Olefin coupling: the role of HMPA in post-electron transfer steps.

The mechanistic importance of HMPA and proton donors (methanol, 2-methyl-2-propanol, and 2,2,2-trifluoroethanol) on SmI2-initiated 5-exo-trig ketyl-olefin cyclizations has been examined using stopped-flow spectrophotometric studies. In the presence of HMPA, the rate order of proton donors was zero and product studies showed that they had no impact on the diastereoselectivity of the reaction. Conversely, reactions were first-order in HMPA, and the additive displayed saturation kinetics at high concentrations. These results were consistent with HMPA being involved in a rate-limiting step before cyclization, where coordination of the intermediate ketyl to the sterically congested Sm(III)HMPA both stabilizes the intermediate and inhibits cyclization. Liberation of the contact ion pair through displacement by an equivalent of HMPA provides a solvent-separated ion pair releasing the steric constraint to ketyl-olefin cyclization. The mechanism derived from rate studies shows that HMPA is important not only in increasing the reduction potential of Sm(II) but also in enhancing the inherent reactivity of the radical anion intermediate formed after electron transfer through conversion of a sterically congested contact ion pair to a solvent-separated ion pair. The mechanistic complexity of the SmI2-HMPA-initiated ketyl-olefin cyclization is driven by the high affinity of HMPA for Sm(III), and these results suggest that simple empirical models describing the role of HMPA in more complex systems are likely to be fraught with a high degree of uncertainty.

A computational study of the formation and dimerization of benzothiet-2-one.

A computational B3LYP/6-31G(d,p) study of the formation of benzothiet-2-one (4) from benzothiophenedione (2) and its subsequent dimerization to 5 was performed. The proposed intermediate ketene 3 has no gas-phase barrier to ring closure to 4. Three transition structures for dimerization were located. The geometry of the lowest energy one (TS8a) has a geometry corresponding to a two atom + two atom, face-to-face addition of the two thiolactone moieties. The orbital interactions suggest that the reaction is pseudopericyclic.

Stopped-flow kinetics of tetrazine cycloadditions; experimental and computational studies toward sequential transition states.

The Diels-Alder cycloadditions of tetrazines (1) with alkynes (2) are expected to give bicyclic adducts (3). Kinetic measurements of the cycloadditions of 1a and 1b with 2a give DeltaG(++) = 19.2 +/- 1.0 and 11.5 +/- 1.2 kcal/mol, respectively. Stopped-flow UV studies on the reaction of 1b with 2a show an isosbestic point at 428 nm; this places an upper limit of 11.6 +/- 2.6 kcal/mol on DeltaG(++) for loss of N(2) from the putative bicyclic intermediate 3b. Calculations (B3LYP/6-31G(d,p) + ZPVE) of transition structures for the reaction of tetrazinediacid 1d with propynylamine 2c are consistent with the experimental results for the reaction of 1b with 2a. This and several related model systems reveal two interesting features of the calculated energy surfaces. First, there may be no barrier for the loss of nitrogen from structures 3 and thus there may be two sequential transition states. This also extends Berson's correlation of activation energy with reaction energy in pericyclic reactions to significantly lower barriers. Second, for the cycloaddition of 4e and 2c, there is neither an intermediate nor a transition state between TS3e and the final product 6e. It appears that the energy surface "turns a corner" in the vicinity of a structure resembling 5e. This is not a mathematically well-defined point but has chemical consequences in that the overall exothermicity of the reaction from 4e to 6e is not felt in TS3e.

A theoretical study of the [4 + 4] dimerization of thioformylketene.

[reaction and structure: see text] A theoretical study (B3LYP and G3MP2B3) of the dimerization of thioformylketene (1) was performed. Four pathways-two [4 + 2] pathways with thioformylketene (1), one [4 + 4] pathway with 1, and one [4 + 2] pathway involving 1 and thietone (11)-were considered. Interestingly, the [4 + 4] pathway with 1 had the lowest barrier (3.8 kcal/mol). The geometry of the transition state TS14 is unusual, with the forming bonds in the plane of the ketene. This suggests that the reaction is pseudopericyclic.