Theoretical insights into the role of a counterion in copper-catalyzed enantioselective cyclopropanation reactions

The effect of a coordinating counteranion on the mechanism of Cu(I)-catalyzed cyclopropanation has been investigated extensively for a medium-sized reaction model by means of theoretical calculations at the B3LYP/6-31G(d) level. The main mechanistic features are similar to those found for the cationic (without a counteranion) mechanism, the rate-limiting step being nitrogen extrusion from a catalyst-diazoester complex to generate a copper-carbene intermediate. The cyclopropanation step takes place through a direct carbene insertion of the metal-carbene species to yield a catalyst-product complex, which can finally regenerate the starting complex. However, the presence of the counteranion has a noticeable influence on the calculated geometries of all the intermediates and transition structures. Furthermore, the existence of a preequilibrium with a dimeric form of the catalyst, together with a higher activation barrier in the insertion step, explains the lower yield of cyclopropane products observed experimentally in the presence of chloride counterion. The stereochemical predictions of a more realistic model (made by considering a chiral bis(oxazoline)-copper(i) catalyst) have been rationalized in terms of the lack of significant steric repulsions, and the model shows good agreement with the low enantioselectivities observed experimentally for these kinds of catalytic systems.     

Theoretical insights into enantioselective catalysis: the mechanism of the Kharasch-Sosnovsky reaction

The mechanism of the Kharasch-Sosnovsky reaction has been investigated using B3 LYP/6-31G* calculations on a chiral reaction model [cyclohexene+tert-butyl perbenzoate-->cyclohex-2-enyl benzoate+tert-butyl alcohol, catalyzed by a chiral bisoxazoline-copper(I) complex]. Although two previous reaction mechanisms have been considered, the results are consistent with a new mechanistic pathway. This path involves ligand exchange between the catalyst-cyclohexene complex with tert-butyl perbenzoate to give a catalyst-perester complex, which undergoes an (either one- or two-step) oxidative addition reaction to yield a copper(III) complex. The limiting step of the Kharasch-Sosnovsky reaction consists of an intramolecular step involving the abstraction of an allylic hydrogen from cyclohexene [which is pi-bound to the copper(III) complex]. The resulting allyl-copper(III) complex (subsequent to the loss of tert-butanol) can undergo a haptotropic rearrangement by means of an eta1-allyl/eta3-allyl equilibrium, leading to scrambling between vinylic and allylic positions when an isotopically labeled substrate is used. The allyl-copper(III) ion undergoes a stereospecific reductive elimination involving the pi-bond migration to yield a reaction product-catalyst complex, which can regenerate the alkene-copper(I) complex by ligand exchange. The proposed reaction mechanism is consistent with all known experimental results (including enantioselectivity data).     

Highly cis-selective Rh(I)-catalyzed cyclopropanation reactions

The performance of recently reported highly cis-diastereoselective Rh(I) cyclopropanation catalysts has been significantly improved by a systematic study of different reaction parameters (catalyst activation, solvent, temperature, stoichiometry). The catalyst efficiency and diastereoselectivity were enhanced by changing the activating agent from AgOTf to NaBArf. With this new system, the Rh(I) catalyst was shown to be a highly efficient and cis-diastereoselective cyclopropanation catalyst in reactions between α-diazoacetates and a range of different alkenes and substituted derivatives. Particularly noteworthy is the remarkable reactivity and cis-diastereoselectivity displayed in the reactions between ethyl diazoacetate and cyclopentene, 2,5-dihydrofuran, and benzofuran, with yields up to 99% and cis-selectivities greater than 99%.     

Gold(I)-catalyzed stereoselective olefin cyclopropanation

A triphenylphosphinegold(I)-catalyzed cyclopropanation of olefins using propargyl esters as gold(I)-carbene precursors is reported. This reaction provided the basis for the use of a DTBM-SEGPHOS gold(I) complex as a catalyst in the enantioselective (up to 94% ee) preparation of vinyl cyclopropanes with high cis-selectivity.     

DFT study of the mechanism of Cu(I)-catalyzed and uncatalyzed intramolecular cyclopropanation of iodonium ylides

The mechanism of the Cu(I)-catalyzed and uncatalyzed intramolecular cyclopropanation of ketoesteric and diesteric iodonium ylides has been thoroughly explored by means of electronic structure calculation methods (DFT). All crucial reaction steps encapsulated in the entire catalyzed and uncatalyzed reaction pathways were scrutinized, while the elementary steps, the intermediates and transition states were identified through monitoring the geometric and energetic reaction profiles. It was found that CuCl efficiently catalyze the cyclopropanation of iodonium ylides only for their diesteric derivatives and their diazo analogues via stabilization of the respective carbene upon complexation with the metal center. For the ketoesteric iodonium ylides the CuCl catalyst does not affect the kinetics of the intramolecular cyclopropanation reactions which could proceed easily without the catalyst, in line with available experimental observations.     

Dimethylzinc-mediated additions of alkenylzirconocenes to aldimines. New methodologies for allylic amine and C-cyclopropylalkylamine syntheses

Hydrozirconation of alkynes with zirconocene hydrochloride followed by in situ transmetalation to dimethylzinc provides access to reactive alkenyl organometallic reagents from readily available precursors. Upon addition of imines, 1,2-attack leads to synthetically useful allylic amine building blocks. In the presence of CH(2)I(2) or CH(2)Cl(2), the N-metalated allylic amide intermediate is cyclopropanated and C-cyclopropylalkylamines are formed in high yield and excellent diastereoselectivities favoring the anti products. The use of enynes as starting materials for this domino reaction provides conjugated biscyclopropanes and thus allows the stereoselective formation of five new carbon-carbon bonds. A transition state that explains the need for both zirconocene complex and alkyl zinc in the cyclopropanation reaction is proposed.     

A fluorous chiral dirhodium(II) complex as a recyclable asymmetric catalyst

[reaction: see text] The chiral fluorous complex tetrakis-dirhodium(II)-(S)-N-(n-perfluorooctylsulfonyl)prolinate has been prepared and used as a catalyst in homogeneous or fluorous biphasic fashion. The catalyst displays good chemo- and enantioselectivity in intermolecular cyclopropanation and C-H bond activation reactions. The catalyst can be simply and thoroughly separated from the reaction mixture and is recyclable.     

Intramolecular titanium-mediated aminocyclopropanation of terminal alkenes: easy access to various substituted azabicyclo[n.1.0]alkanes

[reaction: see text] A variety of substituted azabicyclo[n.1.0]alkanes were synthesized by intramolecular titanium-mediated cyclopropanation of N-benzyl-N-(2-alkylalk-3-enyl)formamides and N-benzyl-N-alkadienylformamides. N-Benzylpyrroline upon treatment with Grignard reagents undergoes a titanium-mediated carbomagnesiation to yield N-benzyl-N-(2-alkylbut-3-enyl)amines.     

Computational Insights into Different Mechanisms for Ag-, Cu-, and Pd-Catalyzed Cyclopropanation of Alkenes and Sulfonyl Hydrazones

The [2+1] cycloaddition reaction of a metal carbene with an alkene can produce important cyclopropane products for synthetic intermediates, materials, and pharmaceutical applications. However, this reaction is often accompanied by side reactions, such as coupling and self-coupling, so that the yield of the cyclopropanation product of non-silver transition-metal carbenes and hindered alkenes is generally lower than 50 %. To solve this problem, the addition of a low concentration of diazo compound (decomposition of sulfonyl hydrazones) to alkenes catalyzed by either CuOAc or PdCl₂ was studied, but side reactions could still not be avoided. Interestingly, however, the yield of cyclopropanation products for such hindered alkenes were as high as 99 % with AgOTf as a catalyst. To explain this unexpected phenomenon, reaction pathways have been computed for four different catalysts by using DFT. By combining the results of these calculations with those obtained experimentally, it can be concluded that the efficiency of the silver catalyst is due to the barrierless concerted cycloaddition step and the kinetic inhibition of side reactions by a high concentration of alkene.     

Iron(II)-catalyzed sulfimidation and [2,3]-sigmatropic rearrangement of propargyl sulfides with tert-butoxycarbonyl azide. Access to N-allenylsulfenimides

The iron(II)-catalyzed Bach reaction of tert-butoxycarbonyl azide (BocN(3)) and allyl sulfides has been extended to include propargyl sulfides, which give N-allenylsulfenimide products. Using 10 mol % dppeFeCl(2) as catalyst the reaction proceeds at 0 degrees C with a number of different propargyl sulfides in 31-73% isolated yield. The reaction is limited by product instability toward catalyst and termination of the catalytic cycle by excess BocN(3). N-Allenylsulfenimide 2b smoothly undergoes catalytic hydrogenation and a Diels-Alder reaction with cyclopentadiene.     

Selective ruthenium-catalyzed transformations of enynes with diazoalkanes into alkenylbicyclo[3.1.0]hexanes

Reaction of a variety of CCH bond-containing 1,6-enynes with N2CHSiMe3 in the presence of RuCl(COD)Cp* as catalyst precursor leads, at room temperature, to the general formation of alkenylbicyclo[3.1.0]hexanes with high Z-stereoselectivity of the alkenyl group and cis arrangement of the alkenyl group and an initial double-bond substituent, for an E-configuration of this double bond. The stereochemistry is established by determining the X-ray structures of three bicyclic products. The same reaction with 1,6-enynes bearing an R substituent on the C1 carbon of the triple bond results in either cyclopropanation of the double bond with bulky R groups (SiMe3, Ph) or formation of alkylidene-alkenyl five-membered heterocycles, resulting from a beta elimination process, with less bulky R groups (R = Me, CH2CH=CH2). The reaction can be applied to in situ desilylation in methanol and direct formation of vinylbicyclo[3.1.0]hexanes and to the formation of some alkenylbicyclo[4.1.0]heptanes from 1,7-enynes. The catalytic formation of alkenylbicyclo[3.1.0]hexanes also takes place with enynes and N2CHCO2Et or N2CHPh. The reaction can be understood to proceed by an initial [2+2] addition of the Ru=CHSiMe3 bond with the enyne CCH bond, successively leading to an alkenylruthenium-carbene and a key alkenyl bicyclic ruthenacyclobutane, which promotes the cyclopropanation, rather than metathesis, into bicyclo[3.1.0]hexanes. Density functional theory calculations performed starting from the model system Ru(HCCH)(CH2=CH2)Cl(C5H5) show that the transformation into a ruthenacyclobutane intermediate occurs with a temporary eta3-coordination of the cyclopentadienyl ligand. This step is followed by coordination of the alkenyl group, which leads to a mixed alkyl-allyl ligand. Because of the non-equivalence of the terminal allylic carbon atoms, their coupling favors cyclopropanation rather than the expected metathesis process. A direct comparison of the energy profiles with respect to those involving the Grubbs catalyst is presented, showing that cyclopropanation is favored with respect to enyne metathesis.     

Cyclization reaction of cyano-substituted unsaturated esters prompted by conjugate addition of organoborons

[reaction: see text] Unsaturated esters possessing a pendent cyano moiety react with B-Ar-9-BBNs in the presence of a rhodium(I) catalyst to give the five- and six-membered beta-enamino esters in good yield. An (oxa-pi-allyl)rhodium(I) intermediate, formed by initial conjugate addition of an Ar-rhodium(I) species, undergoes a facile intramolecular addition to the cyano group to construct the carbocyclic skeletons.     

Asymmetric dearomative cyclopropanation of naphthalenes to construct polycyclic compounds

Catalytic asymmetric dearomatization (CADA) reactions is an important synthetic method for constructing enantioenriched complex cyclic systems from simple aromatic feedstocks. However, the CADA reactions of nonactivated arenes, such as naphthalenes and benzenes, have been far less explored than those of electronically activated arenes, such as phenols, naphthols and indoles. Herein, we disclose an asymmetric dearomative cyclopropanation of naphthalenes for the rapid construction of polycyclic compounds. With chiral dirhodium carboxylate as a catalyst, the dearomative cyclopropanation proceeded smoothly under mild conditions and afforded benzonorcaradiene-containing tetracycles in good yield and high enantioselectivity (up to 99% ee). Three stereogenic centers, including two all-carbon quaternary centers, were created in the dearomatization reaction. Moreover, a variety of functional groups are well-tolerated in the reaction. The products could be readily converted into other complex polycycles while maintaining the high ee value.

An enantioselective dearomative cyclopropanation of naphthalenes has been developed, which constructed a range of tetracyclic compounds bearing multichiral centers in high enantioselectivity.      

A density functional theory investigation of the Simmons-Smith cyclopropanation reaction: examination of the insertion reaction of zinc into the C-I bond of CH(2)I(2) and subsequent cyclopropanation reactions.

The insertion reaction of zinc into the C-I bond of CH(2)I(2) and subsequent cyclopropanation reactions with CH(2)CH(2) have been investigated using B3LYP level density functional theory calculations. The Simmons-Smith cyclopropanation reaction of olefins does not proceed easily due to the relatively large barriers on the insertion and cyclopropanation pathways. The computed results indicate that the IZnCH(2)I molecule is the active reagent in the Simmons-Smith reaction. This is consistent with the IZnCH(2)I reactive species being generated from diiodomethane and a Zn-Cu couple as proposed by several other research groups. The Simmons-Smith IZnCH(2)I carbenoid and CH(2)I-I carbenoid cyclopropanation reactions with olefins are compared. The reactions of olefins with the radicals from the decomposition of the IZnCH(2)I and CH(2)I-I species were also compared. We found that the chemical reactivity of the carbenoid species is dependent on its electrophilic behavior, steric effects, the leaving group character and the mechanism of the cyclopropanation reactions.     

Expedient Synthesis of Fused Azepine Derivatives Using a Sequential Rhodium(II)‐Catalyzed Cyclopropanation/1‐Aza‐Cope Rearrangement of Dienyltriazoles

A general method for the formation of fused dihydroazepine derivatives from 1‐sulfonyl‐1,2,3‐triazoles bearing a tethered diene is reported. The process involves an intramolecular cyclopropanation of an α‐imino rhodium(II) carbenoid, leading to a transient 1‐imino‐2‐vinylcyclopropane intermediate which rapidly undergoes a 1‐aza‐Cope rearrangement to generate fused dihydroazepine derivatives in moderate to excellent yields. The reaction proceeds with similar efficiency on gram scale. The use of catalyst‐free conditions leads to the formation of a novel [4.4.0] bicyclic heterocycle.     

A non-fluorous copper catalyst for the styrene cyclopropanation reaction in a fluorous medium

The complex Tp(Br3)Cu(NCMe) (1), containing no fluorine atoms, can be dissolved in the perfluoropolyether FOMBLIN and employed as a catalyst for the styrene cyclopropanation reaction with ethyl diazoacetate, with activities and diastereo-selectivities identical to those observed under homogeneous conditions with the advantage of being able to use a fluorous separation technique for catalyst recycling.     

壳聚糖希夫碱铜多相催化剂催化苯乙烯环丙烷化反应研究

壳聚糖希夫碱铜催化剂催化苯乙烯环丙烷化反应，得到了非常好的化学收率，同时还得到了17.1%ee和33.3:66.7的顺反比。此外，催化剂重复使用数次仍保持很高的活性。     

双环笼状磷酸酯衍生物的研究Ⅵ:4-取代-2,6,7-三氧杂-1-磷杂双环[2.2.2]辛烷的反应研究

双环笼状亚磷酸酯类衍生物由于其笼状结构所引起的张力及高位阻性 ,使得它同一般直链亚磷酸酯类化合物相比,在亲核取代反应性等方面有关明显的不同.本文用化合物1分别同SO~2Cl~2,Cl~2, Br~2, PCl~5等反应,结果表明,1均发生了类Arbuzov反应,生成具有相同立体构型的开环产物.本文还对化合物2的磷酰化反应进行了研究,发现在这类高位阻性的双环笼状亚磷酸酯衍生物的磷酰化反应中,DMAP是一个较有效的催化剂.     

Copper(I) chloride initiated decomposition of 7-phosphanorbornadiene. Evidence for a solvent-assisted catalytic mechanism

Density functional theory is used to explore the mechanism of the copper(I)-chloride-catalyzed decomposition of W(CO)(5)-complexed 7-phosphanorbornadiene and the subsequent olefin trapping of the terminal phosphinidene complex. CuCl lowers the activation barrier by interacting directly with the breaking P-C bond. Contrary to the prevailing notion that a free terminal phosphinidene complex (W(CO)(5)=PR) is generated in the CuCl-catalyzed cheletropic elimination of the 7-phosphanorbornadiene-W(CO)(5) complex, the present mechanism suggests that CuCl is attached to the terminal phosphinidene. Furthermore, a "chloride shuttle" takes place where the chloride first migrates to the phosphorus center and then is returned back to the copper center by the incoming olefin in an S(N)2 reaction step. When the substituent on phosphorus is a phenyl group (R = Ph), the uncatalyzed reaction has an activation barrier of 17.9 kcal/mol, which is reduced by 10.9 kcal/mol on including the CuCl catalyst. The CuCl-catalyzed decomposition of 7-phosphanorbornadiene followed by olefin trapping of the terminal phosphinidene complex has a close parallel with the Cu(I)-catalyzed cyclopropanation reaction of diazoalkane. In both catalyzed reactions, copper(I) is coordinated to the phosphinidene/carbene as a Lewis acid, while a Lewis base is displaced from the phosphorus/carbon center as the olefin is added.     

A molecular orbital analysis of Cu(I)-catalysed cyclopropanation using diazoalkanes with CH3 and CF3 substituents

The mechanism of cyclopropanation catalysed by Cu(I) complexes has been investigated by calculation using a series of diazoalkanes containing inductive electron donating (methyl) and withdrawing (CF3) substituents and a range of metal fragments (Cu+, [(DAB)Cu]+, ClCu and (triflate)Cu). Copper-diazoalkane complexes exist as an equilibrium of C- and N-bonded isomers. Catalysis occurs through lowering of the activation energy for rate determining C-N bond cleavage of the C-bonded isomer; this is most marked for (triflate)Cu. Direct reaction of the copper-carbene complex occurs to yield stable cupracyclobutanes in all but one case. Associative substitution of the cupracyclobutane by diazoalkane completes the catalytic cycle.