Regio- and enantioselective intermolecular rhodium-catalyzed [2+2+2] carbocyclization reactions of 1,6-enynes with methyl arylpropiolates

Transition metal-catalyzed [m+n+o] carbocyclization reactions provide powerful methods for the construction of complex polycyclic systems that are generally not accessible through classical pericyclic reactions. We have developed the first regio- and enantioselective crossed intermolecular rhodium-catalyzed [2+2+2] carbocyclization of carbon- and heteroatom-tethered 1,6-enynes with unsymmetrical 1,2-disubstituted alkynes. This study clearly delineates the ligand requirements for obtaining excellent regio- and enantioselectivity. Furthermore, the ability to utilize various electron-withdrawing groups, and to introduce quaternary carbon stereogenic centers, provides the level of versatility necessary for its application to target-directed synthesis. Additional studies on the development and application of this novel methodology to the total synthesis of natural products are currently underway.     

Diastereoselective synthesis of five- and seven-membered rings by [2+2+1], [3+2], [3+2+2], and [4+3] carbocyclization reactions of beta-substituted (alkenyl)(methoxy)carbene complexes with methyl ketone lithium enolates

beta-Substituted alkenylcarbene complexes react with methyl ketone lithium enolates to give different carbocyclization products depending on the structure of the lithium enolate, on the metal of the carbene complex, and on the reaction media. Thus, the reactions of aryl and alkyl methyl ketone lithium enolates with beta-substituted alkenyl chromium and tungsten carbene complexes in diethyl ether afford 1,3-cyclopentanediol derivatives derived from a formal [2+2+1] carbocyclization reaction. However, the lithium enolates of acetone and tungsten complexes furnish formal [3+2+2] carbocyclization products. In the case of alkynyl methyl ketone lithium enolates, competitive formal [2+2+1] and [3+2] carbocyclization reactions occur and 1,3-cyclopentanediol and 3-cyclopentenol derivatives are formed. Conversely, alkenyl methyl ketone lithium enolates react with alkenylcarbene complexes under the same reaction conditions to form 2-cycloheptenone derivatives by a formal [4+3] carbocyclization reaction. Finally, when the reaction was performed in the presence of a coordinating medium, the [3+2] carbocyclization pattern was observed independently of the nature of the methyl ketone lithium enolate used.     

Intermolecular rhodium-catalyzed [3+2+2] carbocyclization of alkenylidenecyclopropanes with activated alkynes: regio- and diastereoselective construction of cis-fused bicycloheptadienes

Polycyclic structures that contain seven-membered carbocycles constitute important structural motifs that are ubiquitous in several classes of bioactive natural products. We have developed the first regio- and diastereoselective intermolecular rhodium-catalyzed [3+2+2] carbocyclization of carbon- and heteroatom-tethered alkenylidenecyclopropanes with mono- and disubstituted alkynes for the construction of cis-fused bicycloheptadienes. This study delineates some of the critical features for controlling regioselectivity in this process and demonstrates that E-alkenes can be incorporated in a stereospecific manner to afford products with up to three new stereogenic centers. The latter feature is particularly significant given that related carbocyclization reactions are often limited in this respect.     

Ruthenium‐Catalyzed [2+2+2] Cycloaddition of 1,6‐Enynes and Unactivated Alkynes: Access to Ring‐Fused Cyclohexadienes

The [2+2+2] intermolecular carbocyclization reactions between 1,6‐enynes and alkynes catalyzed by [RuCl(cod)(Cp*)] (cod=1,5‐cyclooctadiene, Cp*=pentamethylcyclopentadienyl) are reported to provide bicyclohexa‐1,3‐dienes. The presented reaction conditions are compatible with internal and terminal alkynes and the chemo‐ and regioselectivity issues are controlled by the presence of substituents at the propargyl carbon center of the alkyne(s) partner(s).     

Intermolecular rhodium-catalyzed [2+2+2] carbocyclization reactions of 1,6-enynes with symmetrical and unsymmetrical alkynes

The crossed intermolecular rhodium-catalyzed [2+2+2] carbocyclization of carbon and heteroatom tethered 1,6-enynes can be accomplished with symmetrical and unsymmetrical alkynes, to afford the corresponding bicyclohexadienes in an efficient and highly selective manner.     

Diastereoselective metal-catalyzed [4 + 2 + 2] carbocyclization reactions utilizing a rhodium N-heterocyclic carbene (NHC) complex: the first example of a rhodium NHC-catalyzed [m + n + o] carbocyclization

The air and moisture stable rhodium N-heterocyclic carbene (NHC) complex, RhCl(IMes)(COD)(IMes =N,N[prime or minute]-bis(2,4,6-trimethylphenyl)imidazole-2-ylidine; COD = 1,5-cyclooctadiene), facilitates a diastereoselective metal-catalyzed [4 + 2 + 2] carbocyclization of 1,6-enynes in the presence of silver triflate and 1,3-butadiene.     

The mechanism of the rhodium(I)-catalyzed [2 + 2 + 1] carbocyclization reaction of dienes and CO: a computational study

The rhodium(I) catalyzed [2 + 2 + 1] carbocyclization of tethered diene-enes to afford substituted hexahydropentalenones with high levels of diastereoselectivity was modeled using density functional theory. Previously, this transformation was observed to be facile, whereas the analogous bis-ene substrate could not be cyclized under any reasonable conditions. To establish a conceptual understanding of the carbocyclization mechanism and to identify the functional role of the diene fragment we analyzed the simulated reaction mechanisms using the two parent systems. We discovered a thus far unrecognized, but intuitively plausible, role of the CO ligand for controlling the electron density at the metal center, which affects the feasibility of oxidative addition and reductive elimination steps that are key components of the mechanism. Our calculations suggest that the diene moiety is unique and required because of its ability to undergo a eta(2)-->eta(4) reorganization allowing for the thermoneutral expulsion of one CO ligand, which in turn generates an electron-rich, coordinatively saturated Rh(I) center that can efficiently promote the oxidative addition with a low barrier. A number of functionalization strategies were considered explicitly to derive a rational plan for optimizing the catalysis and to expose the roles of the different components of the reactant-catalyst complex.     

Regio- and Chemoselective Formal (4+1) Carbocyclization of Chalcones with Internal Alkynes via Rhodium(III) Catalysis

A rhodium(III)-catalyzed oxidative cyclization of chalcones with internal alkynes is reported, generating biologically important 3,3-disubstituted 1-indanones along with reusable aromatic aldehydes. This transformation features unique (4+1) reaction mode, excellent regioselectivity in alkyne insertion, broad substrate scope, allows for the construction of quaternary carbon centers, and is scalable. Steric hindrance from substrate and ligand probably controls the chemoselectivity of this carbocyclization. Importantly, this discovery enables a practical two-step protocol switching the overall reaction of acetophenones with internal alkynes from a (3+2) to a (4+1) annulation.     

Mechanistic Study of the Rhodium‐Catalyzed [3+2+2] Carbocyclization of Alkenylidenecyclopropanes with Alkynes

A systematic theoretical study has been performed on the recently reported Rh^I‐catalyzed [3+2+2] carbocyclization reactions between alkenylidenecyclopropanes (ACPs) and alkynes. With the aid of theoretical calculations, two possible mechanisms, that is, alkene‐carbometalation‐first and alkyne‐carbometalation‐first mechanisms, are examined in this study. In the oxidative addition step, the possibility of reaction on either the distal or proximal C? C bond of the cyclopropane group has been evaluated. The calculations indicate that the alkene‐activation‐first mechanism is more favored for the overall catalytic cycle. This mechanism involves four steps, that is, oxidative addition of the distal (rather than the proximal) C? C bond of cyclopropane group, alkene carbometalation, alkyne carbometalation, and reductive elimination. The rate‐determining step in the overall catalytic cycle is the carbometalation of the alkyne (i.e., the alkyne‐insertion step) and this step also determines the regioselectivity. Finally, the origin of the regioselectivity is determined by the steric effect (i.e., the steric crowding between the electron‐withdrawing group on alkyne and other ligands on the rhodium center) in the alkyne‐insertion step.     

Palladium-catalyzed bisdiene carbocyclizations: a facile [3 + 2] cycloaddition reaction mode

[reaction: see text] In contrast to alkyl-substituted bisdienes, aryl-substituted substrates undergo surprisingly facile palladium-catalyzed carbocyclization via a novel [3 + 2] cycloaddition mode.     

Diastereoselective synthesis of three-, five-, six-, and seven-membered rings from Fischer carbene complexes and 4-unsubstituted 1-amino-1,3-dienes

Fischer carbene complexes react with 4-unsubstituted 1-amino-1,3-dienes to give different carbocyclization products depending on the nature of the carbene complex and on the substitution pattern of the aminodiene. Thus, the reaction of arylcarbene chromium complexes and 1-aminodienes diastereoselectively affords cyclopropane derivatives by means of a formal [2+1] carbocyclization reaction. In particular, pentacarbonyl[(2-furyl)(methoxy)methylene]chromium complex furnishes formal [4+1] carbocyclization products. Starting from beta-substituted alkenylcarbene complexes, formal [4+1] reactions occur and cyclopentenamine derivatives are diastereoselectively formed. However, when the alpha,beta-disubstituted alkenylcarbene complex pentacarbonyl[(5,6-dihydro-2H-pyran-2-yl)(methoxy)methylene]tungsten is used, the outcome of the reaction depends on the substitution on the carbon atom at the 3-position of the aminodiene, generating the [3+2] or [4+3]-cyclization products if the substituent is or is not a hydrogen atom, respectively. Finally, when the reaction is performed with alkynylcarbene complexes, benzaldehyde derivatives are obtained if the triple-bond substituent is a phenyl group or indene derivatives if the group is an alkenyl moiety.     

The origin of the ligand-controlled regioselectivity in Rh-catalyzed [(2 + 2) + 2] carbocyclizations: steric vs. stereoelectronic effects

Density functional theory calculations demonstrate that the reversal of regiochemical outcome of the addition for substituted methyl propiolates in the rhodium-catalyzed [(2 + 2) + 2] carbocyclization with PPh₃ and (S)-xyl-binap as ligands is both electronically and sterically controlled. For example, the ester functionality polarizes the alkyne π* orbital to favor overlap of the methyl-substituted terminus of the alkyne with the p_π-orbital of the alkenyl fragment of the rhodacycle during alkyne insertion with PPh₃ as the ligand. In contrast, the sterically demanding xyl-binap ligand cannot accommodate the analogous alkyne orientation, thereby forcing insertion to occur at the sterically preferred ester terminus, overriding the electronically preferred orientation for alkyne insertion.     

One-pot Zn/CuI/TFA-catalyzed domino three-component-carbocyclization reaction involving biphenyl-2-carbaldehydes/alkynes/piperidine: allenes-mediated construction of phenanthrenes

A one-pot protocol involving Zn/CuI/TFA-catalyzed domino three-component and subsequent carbocyclization reactions is described. The reaction proceeds via formation of propargyl amines from biphenyl-2-carbaldehydes/terminal alkynes/piperidine followed by the elimination of piperidine and ring closure to furnish phenanthrene derivatives in good yields. The strategy involves C(sp)-H activation-CH functionalization with imine-alkyne activation-1,5 hydride shift-β-elimination of piperidine-allene formation-6π cycloaddition-isomerization domino sequence. Evidence for the involvement of allenes as an intermediate during carbocyclization is discussed.     

Metal‐Free Radical [2+2+1] Carbocyclization of Benzene‐Linked 1,n‐Enynes: Dual C(sp3)?H Functionalization Adjacent to a Heteroatom

A new metal‐free oxidative radical [2+2+1] carbocyclization of benzene‐linked 1,n‐enynes with two C(sp³) H bonds adjacent to the same heteroatom is described. This method achieves two C(sp³) H oxidative functionalizations and an annulation, thus providing efficient and general access to a variety of fused five‐membered carbocyclic hydrocarbons.     

The fascinating construction of pyridine ring systems by transition metal-catalysed [2 + 2 + 2] cycloaddition reactions

Cycloaddition reactions compose one of the most important classes of reactions when it comes to the simultaneous formation of several bonds in one reaction step. The de novo construction of carbocyclic aromatic systems from acetylenes was also found as an excellent possibility for the assembly of heteroaromatic systems. The transition metal-catalysed [2 + 2 + 2] cycloaddition reaction constitutes a fascinating tool for the synthesis of pyridines from nitriles and the most recent developments demonstrate the ability to control the substitution pattern as well as the possibility of introducing chirality by the use of achiral substrates and a chiral catalyst under mild conditions. In this tutorial review we are focusing on the de novo construction of pyridine ring systems by the transition metal-catalysed [2 + 2 + 2] cycloaddition reaction. After surveying the mechanistic features and intermediates of the reaction depending on the different metal complexes used, we depict the preparation of achiral pyridine derivatives. The last section describes the advances in the synthesis of chiral pyridines and biaryls using the cyclotrimerization method. The various possibilities of introducing chirality by catalytic means are presented and illustrated by instructive examples. This review will be of interest for people active in: Organic Chemistry, Organometallic Chemistry, Transition Metal Chemistry, Stereoselective Synthesis, Heterocyclic Chemistry.     

Diastereoselective intermolecular rhodium-catalyzed [4 + 2 + 2] carbocyclization reactions: computational and experimental evidence for the intermediacy of an alternative metallacycle intermediate

Intermolecular rhodium-catalyzed [m + n + o] reactions of 1,6-enynes and various pi-components (carbon monoxide, alkynes, 1,3-butadienes, etc.) provide an expeditious approach for the construction of polycyclic fragments that represent important synthons for target-directed synthesis. We present computational and experimental evidence for the existence of a previously undescribed reaction pathway for the rhodium-catalyzed [4 + 2 + 2] reaction involving a 1,6-enyne. This model clearly demonstrates the origin of the excellent diastereoselectivity in this type of reaction and the remarkable tolerance of both (E)- and (Z)-isomers within the 1,6-enyne, which is generally prone to competitive ene-cycloisomerization.     

Copper‐Catalyzed Carbocyclization of Silyl Enol Ether Tethered Ynamides for Efficient and Practical Synthesis of 2‐Azabicyclo[3.2.0] Compounds†

An efficient copper‐catalyzed carbocyclization of silyl enol ether tethered ynamides has been developed, allowing rapid and practical construction of diverse 2‐azabicyclo[3.2.0] compounds in generally good to excellent yields with broad substrate scope under mild reaction conditions. Importantly, this protocol not only constitutes a rare example of non‐noble metal‐catalyzed alkyne carbocyclization, but also represents a rare cyclization on the β‐position of π‐tethered ynamides. The possibility of asymmetric carbocyclization via kinetic resolution also emerges.     

Alkylative Carbocyclization of ω‐Iodoalkynyl Tosylates with Alkynyllithium Compounds Through a Carbenoid‐Chain Process Leading to (1‐Iodoprop‐2‐ynylidene)tetrahydrofurans and ‐cyclopropanes

Alkylative carbocyclization reactions of ω‐iodoalkynyl tosylates with alkynyllithium compounds to give products with incorporated iodine atoms are described. Slow addition of 2‐(3‐iodoprop‐2‐ynyloxy)ethyl tosylates to 1‐alkynyllithium compounds in tetrahydrofuran at 40 °C followed by additional stirring at this temperature gives (Z)‐3‐(1‐iodoprop‐2‐ynylidene)tetrahydrofurans stereoselectively in good to moderate yields. Under similar conditions at 0 °C, 4‐iodobut‐1‐ynyl tosylates react with 1‐alkynyllithium compounds to give (1‐iodoprop‐2‐ynylidene)cyclopropanes. The carbocyclization reactions are proposed to proceed through a new carbenoid‐chain process involving the exo cyclization of a lithium acetylide intermediate and the vinylic substitution of the resulting TsO,Li‐cycloalkylidenecarbenoids (Ts=tosyl) by 1‐alkynyllithium compounds.     

Rhodium N-heterocyclic carbene-catalyzed [4 + 2] and [5 + 2] cycloaddition reactions

[reactions: see text] A rhodium complex of N-heterocyclic carbene (NHC) has been developed for intra- and intermolecular [4 + 2] and intramolecular [5 + 2] cycloaddition reactions. This is the first use of a transition-metal NHC complex in a Diels-Alder-type reaction. For the intramolecular [4 + 2] cycloaddition reactions, all the dienynes studied were converted to their corresponding cycloadducts in 91-99% yields within 10 min. Moreover, up to 1900 turnovers have been obtained for the intramolecular [4 + 2] cycloaddition at 15-20 degrees C. For the intermolecular [4 + 2] cycloadditions, high yields (71-99%) of the corresponding cycloaddition products were obtained. The reaction time and yield were highly dependent upon the diene and the dienophile. For the intramolecular [5 + 2] cycloaddition reactions, all the alkyne vinylcyclopropanes studied were converted to their corresponding cycloadducts in 91-98% yields within 10 min. However, the catalytic system was not effective for an intermolecular [5 + 2] cycloaddition reaction.     

Reflected shock tube studies of high-temperature rate constants for OH + NO2 --> HO2 + NO and OH + HO2 --> H2O + O2

The motivation for the present study comes from the preceding paper where it is suggested that accepted rate constants for OH + NO2 --> NO + HO2 are high by approximately 2. This conclusion was based on a reevaluation of heats of formation for HO2, OH, NO, and NO2 using the Active Thermochemical Table (ATcT) approach. The present experiments were performed in C2H5I/NO2 mixtures, using the reflected shock tube technique and OH-radical electronic absorption detection (at 308 nm) and using a multipass optical system. Time-dependent profile decays were fitted with a 23-step mechanism, but only OH + NO2, OH + HO2, both HO2 and NO2 dissociations, and the atom molecule reactions, O + NO2 and O + C2H4, contributed to the decay profile. Since all of the reactions except the first two are known with good accuracy, the profiles were fitted by varying only OH + NO2 and OH + HO2. The new ATcT approach was used to evaluate equilibrium constants so that back reactions were accurately taken into account. The combined rate constant from the present work and earlier work by Glaenzer and Troe (GT) is k(OH+NO2) = 2.25 x 10(-11) exp(-3831 K/T) cm3 molecule(-1) s(-1), which is a factor of 2 lower than the extrapolated direct value from Howard but agrees well with NO + HO2 --> OH + NO2 transformed with the updated equilibrium constants. Also, the rate constant for OH + HO2 suitable for combustion modeling applications over the T range (1200-1700 K) is (5 +/- 3) x 10(-11) cm3 molecule(-1) s(-1). Finally, simulating previous experimental results of GT using our updated mechanism, we suggest a constant rate for k(HO2+NO2) = (2.2 +/- 0.7) x 10(-11) cm3 molecule(-1) s(-1) over the T range 1350-1760 K.