Seven-membered Ring Products Research Articles

Synthesis of Acylation Polycyclic Derivatives via Regioselective Acylation/Cyclization of 1,7-Dienes with Acyl Oxime Esters.

A visible-light-induced radical cascade regioselective acylation/cyclization of 1,7-dienes with acyl oxime esters for the preparation of acylation polycyclic compounds via NCR-mediated C-C σ-bond cleavage is established. The transformation involves the cleavage of the C-C σ-bond in acyl oxime esters and selective addition of the electron neutral C═C bonds in 1,7-dienes for the synthesis of acyl polycyclic quinolinone derivatives, not the traditional seven-membered ring products. The strategy offers several advantages, including broad substrate tolerance, no need for bases, hyperstoichiometric radical initiators, and other auxiliaries.

Nickel-catalyzed switchable arylative/endo-cyclization of 1,6-enynes

Carbo- and heterocycles are frequently used as crucial scaffolds in natural products, fine chemicals, and biologically and pharmaceutically active compounds. Transition-metal-catalyzed cyclization of 1,6-enynes has emerged as a powerful strategy for constructing functionalized carbo- and heterocycles. Despite significant progress, the regioselectivity of alkyne functionalization is entirely substrate-dependent. And only exo-cyclization/cross-coupling products can be obtained, while endo-selective cyclization/cross-coupling remains elusive and still poses a formidable challenge. In this study, we disclose a nickel-catalyzed switchable arylation/cyclization of 1,6-enynes in which the nature of the ligand dictates the regioselectivity of alkyne arylation, while the electrophilic trapping reagents determine the selectivity of the cyclization mode. Specifically, using a commercially available 1,10-phenanthroline as a ligand facilitates trans-arylation/cyclization to obtain seven-membered ring products, while a 2-naphthyl-substituted bisbox ligand promotes cis-arylation/cyclization to access six-membered ring products. Diastereoselective cyclizations have also been developed for the synthesis of enantioenriched piperidines and azepanes, which are core structural elements of pharmaceuticals and natural products possessing important biological activities. Furthermore, experimental and density functional theory studies reveal that the regioselectivity of the alkyne arylation process is entirely controlled by the steric hindrance of the ligand; the reaction mechanism involves exo-cyclization followed by Dowd-Beckwith-type ring expansion to form endo-cyclization products.

Recent advances in transition-metal-catalyzed Büchner reaction of alkynes.

Medium-sized ring-containing organic molecules, especially seven-membered rings, are significant structural motifs. However, such frameworks are considered difficult structures to access owing to entropic effects and transannular interactions. Compared to the construction of five and six-membered rings, the synthesis of seven-membered rings can be more challenging through traditional cyclization pathways. Büchner reactions are particularly attractive and efficient synthetic strategies to construct functionalized seven-membered ring products from the benzenoid double bond with carbene. In recent years, the field of transition-metal-catalyzed Büchner ring expansion reactions of alkynes has experienced a speedy development and a diverse array of efficient synthetic procedures have been disclosed under mild experimental conditions, as the synthesis of synthetically challenging seven-membered rings is easily achieved. In this review, we will focus on the recent progress in the transition-metal-catalyzed Büchner reaction of alkynes and the mechanistic rationale is depicted where possible, with the reactions being sorted according to the type of catalyst.

β-Chloroaldehydes from Trapping Zirconium Enolates Produced in Asymmetric 1,4-Additions.

Zirconium enolates, derived from copper-catalyzed asymmetric conjugate additions, are trapped with the Vilsmeier-Haack reagent. Asymmetric additions generate quaternary carbon centers with high enantioselectivity (generally ∼90% ee), and the enolates are converted to unsaturated β-chloroaldehydes (41-57% yields). The reaction tolerates changes to the nucleophile, can be used to form five-, six-, or seven-membered ring products, and is scalable to 5 mmol, and the products are readily elaborated by condensation, cross coupling, and addition reactions.

Enyne [4+4] Cycloaddition/Oxidation: Ring Contraction via Cyclopropanones and Their Anionic Ring-Opening Reactions.

Irradiation of a 1,3-enyne tethered to a 2-pyridone, in the presence of oxygen, leads to formation of a seven-membered ring product, an overall [4+4-1] reaction. This transformation involves two unstable intermediates and a sequence of unusual reactions. An initial [4+4] photocycloaddition of the enyne with the pyridone yields a 1,2,5-cyclooctatriene. Photooxidation of this triene forms a cyclopropanone and subsequent photoextrusion of carbon monoxide gives the observed 1,4-cycloheptadiene product. The first-formed cyclooctatriene and the cyclopropanone could be observed and characterized spectroscopically. The cyclopropanone underwent CO extrusion both photochemically and thermally to give the cycloheptadiene product. Addition of fluoride or acetylide to the most stable cyclopropanone occurred chemoselectively at the two different silicon groups rather than the carbonyl group. The resulting cyclopropanone ring openings gave unsaturated aldehydes.

Highly Selective Ring Expansion of Bicyclo[3.1.0]hexenes.

A Ru-carbene-promoted ring expansion of bicyclo[3.1.0]hexenes with terminal alkynes is reported. The reaction delivers seven-membered carbocycles starting from readily available starting materials and was found to be highly regioselective. The resulting seven-membered ring products contain both conjugated diene and cyclopropane substructures that could be selectively reacted in subsequent transformations.

Intermolecular/Intramolecular Sequential Aldol Reaction

The first example of intermolecular/intramolecular sequential aldol reaction of disilyl enol ethers is described. This strategy enables the formation of five-, six-, and seven-membered ring products. Four or more contiguous stereogenic centers are created with high levels of relative stereochemical control.

Mechanism and Origins of Selectivity in Ru(II)-Catalyzed Intramolecular (5+2) Cycloadditions and Ene Reactions of Vinylcyclopropanes and Alkynes from Density Functional Theory

The mechanism, solvent effects, and origins of selectivities in Ru(II)-catalyzed intramolecular (5+2) cycloaddition and ene reaction of vinylcyclopropanes (VCPs) and alkynes have been studied using density functional theory. B3LYP/6-31G(d)/LANL2DZ optimized structures were further evaluated with the M06 functional, 6-311+G(2d,p) and LANL2DZ basis sets, and the SMD solvent model. The favored mechanism involves an initial ene-yne oxidative cyclization to form a ruthenacyclopentene intermediate. This mechanism is different from that found earlier with rhodium catalysts. The subsequent β-hydride elimination and cyclopropane cleavage are competitive, determining the experimental selectivity. In trans-VCP, the cyclopropane cleavage is intrinsically favored and leads to the (5+2) cycloaddition product. Although the same intrinsic preferences occur with the cis-VCP, an unfavorable rotation is required in order to generate the cis-double bond in seven-membered ring product, which reverses the selectivity. Acetone solvent is found to facilitate the acetonitrile dissociation from the precatalyst, destabilizing the resting state of the catalyst and leading to a lower overall reaction barrier. In addition, the origins of diastereoselectivities when the allylic hydroxyl group is trans to the bridgehead hydrogen are found to be the electrostatic interactions. In the pathway that generates the favored diastereomer, the oxygen lone pairs from the substituent are closer to the cationic catalyst center and provide stabilizing electrostatic interactions. Similar pathways also determine the regioselectivities, that is, whether the more or less substituted C-C bond of cyclopropane is cleaved. In the trans-1,2-disubstitued cyclopropane substrate, the substituent from the cyclopropane is away from the reaction center in both pathways, and low regioselectivity is found. In contrast, the cleavage of the more substituted C-C bond of the cis-1,2-disubstituted cyclopropane has steric repulsions from the substituent, and thus higher regioselectivity is found.

Diversity oriented synthesis of indole-based peri-annulated compounds via allylic alkylation reactions

Diverse indole-based peri-annulated compounds were synthesized via transition-metal-catalyzed allylic alkylation reaction. With palladium catalyst, indole-based nine-membered ring products were obtained in 40–70% yields. When iridium catalyst was used, highly enantioenriched seven-membered ring products were obtained in 40–78% yields and 91–97% ee. Meanwhile, when 3-substituted indole substrates were employed with a palladium catalyst, asymmetric allylic dearomatization of indoles occurred with products obtained in 48–78% yields and 35–78% ee with a chiral ferrocene-based Phox ligand. Interestingly, with an iridium catalyst, Friedel–Crafts type allylic alkylation reaction proceeded at the C5 position of indole, affording the products with 40–60% yields and 56–97% ee.

Gas-Phase Chemical Dynamics Simulations on the Bifurcating Pathway of the Pimaradienyl Cation Rearrangement: Role of Enzymatic Steering in Abietic Acid Biosynthesis.

The biosynthesis of abietadiene is the first biosynthetically relevant process shown to involve a potential energy surface with a bifurcating reaction pathway. Herein, we use gas-phase, enzyme-free direct dynamics simulations to study the behavior of the key reaction (bifurcating) step, which is conversion of the C20 pimaradienyl cation to the abietadienyl cation. In a previous study (J. Am. Chem. Soc.2011, 133, 8335), a truncated C10 model was used to investigate this reaction. The current work finds that the complete C20 pimaradienyl cation gives reaction dynamics similar to that reported for the truncated C10 model. We find that in the absence of the enzyme, the C20 abietadienyl cation is generated in almost equal quantity (1.3:1) as an unobserved (in nature) seven-membered ring product. These simulations allude to a need for abietadiene synthase to steer the reaction to avoid generation of the seven-membered ring product. The methodology of post-transition state chemical dynamics simulations is also considered. The trajectories are initiated at the rate-controlling transition state (TS) separating the pimaradienyl and abietadienyl cations. Accurate results are expected for the short-time direct motion from this TS toward the abietadienyl cation. However, the dynamics may be less accurate for describing the unimolecular reactions that occur in moving toward the pimaradienyl cation, due to the unphysical flow of zero-point energy.

Cyclopropyl Carbinol Rearrangement for Benzo‐Fused Nitrogen Ring Synthesis

A synthetic method that relies on gold-catalysed cyclopropyl carbinol rearrangement of 2-tosylaminophenyl cyclopropylmethanols to prepare 2,3-dihydro-1H-benzo[b]azepines and 2-vinylindolines efficiently is reported. The reactions were shown to be chemoselective, with secondary and tertiary alcohol substrates exclusively providing benzo-fused five- and seven-membered ring products, respectively. The ring-forming process was also found to proceed in moderate to excellent yields under mild conditions only in the presence of the gold and silver catalyst combination. The mechanism is thought to involve activation of the alcohol by the (p-CF(3)C(6)H(4))(3)PAuCl/AgOTf (Tf = triflate) catalyst, resulting in ionization of the starting material. The tertiary carbocationic intermediate generated in situ in this manner then triggers ring-opening of the cyclopropane moiety and trapping by the tethered aniline group to give the 2,3-dihydro-1H-benzo[b]azepine. Cyclopropane ring fragmentation of the secondary carbocationic analogue, on the other hand, results in diene formation followed by subsequent intramolecular hydroamination to afford the 2-vinylindoline.

Nitrile insertion into a boryl-substituted five-membered zirconacycloallenoid: unexpected formation of a zwitterionic boratirane product

Nitrile insertion into a zirconacycloallenoid complex leads to the formation of a seven-membered ring product with an attached boratirane unit.

Synthesis of Polycyclic Heterocycles via a One-Pot Ortho Alkylation/Direct Heteroarylation Sequence

[reaction: see text] Polycyclic thiophenes and furans were synthesized using a one-pot ortho alkylation/direct heteroarylation reaction sequence. Under the optimized reaction conditions, aryl iodides were coupled with 3-(bromoalkyl)thiophenes or -furans, affording six- and seven-membered annulated ring products via formation of two C-C bonds from two aryl C-H bonds.

Reaction of Dilithiosilane R2SiLi2 and Dilithiogermane R2GeLi2 (R = SiMetBu2) with MesBCl2 (Mes = 2,4,6-trimethylphenyl): Evidence for the Formation of Silaborene R2Si=BMes and Germaborene R2Ge=BMes

Abstract 1,1-Dilithiosilane and -germane, R2SiLi2 and R2GeLi2 (R = SiMetBu2) reacted with MesBCl2 to give the unexpected seven-membered ring products, [1,3,2]oxasila- and -germaborepanes, through the intermediate formation of >Si=B– and >Ge=B– doubly bonded species.

Cyclooctatetraene (COT)-Coordinated Diiron Carbene Complexes and Their Remarkable Thermolysis Reactions

The reactions of the COT-coordinated diiron cationic bridging carbyne complexes [Fe 2 (μ-CAr)(CO) 4 (η 8 -C 8 H 8 )]BF 4 (1, Ar = C 6 H 5 ; 2, Ar = p-CH 3 C 6 H 4 ; 3, Ar = p-CF 3 C 6 H 4 ) with p-methylaniline gave the COT-coordinated diiron Fischer-type carbene complexes [Fe 2 {= C(Ar)NHC 6 H 4 CH 3 -p}(μ-CO)(CO) 3 (η 8 -C 8 H 8 )] (7, Ar = C 6 H 5 ; 8, Ar = p-CH 3 C 6 H 4 ; 9, Ar = p-CF 3 C 6 H 4 ). Heating the solution of diiron carbene complexes [Fe 2 {=C(Ar)NHC 6 H 5 }(μ-CO)-(CO) 3 (η 8 -C 8 H 8 )] (4, Ar = C 6 H 5 ; 5, Ar = p-CH 3 C 6 H 4 ; 6, Ar = p-CF 3 C 6 H 4 ) in benzene in a sealed tube at 85-90 °C for 72 h afforded the chelated diiron carbene complex [Fe 2 {=C(C 6 H 5 )-NC 6 H 5 }(η 2 :η 3 :η 2 -C 8 H 9 )(CO) 4 ] (4a), C 8 ring addition products [Fe 2 {N(C 6 H 5 )=C(Ar)(η 1 :η 3 :η 2 -C 8 H 9 )}(CO) 5 ] (10, Ar = C 6 H 5 ; 12, Ar = p-CH 3 C 6 H 4 ; 14, Ar = p-CF 3 C 6 H 4 ), and C 7 contraction ring products [Fe 2 {N(C 6 H 5 )=C(Ar)CH(η 2 :η 3 -C 7 H 8 )(CO) 4 }] (11, Ar = C 6 H 5 ; 13, Ar = p-CH 3 C 6 H 4 ; 15, Ar = p-CF 3 C 6 H 4 ), respectively. The similar thermolysis of complexes 7 and 8 afforded corresponding thermolysis products [Fe 2 {=C(C 6 H 5 )NC 6 H 4 CH 3 -p}(η 2 :η 3 :η 2 -C 8 H 9 )(CO) 4 ] (7a), [Fe 2 {N(C 6 H 4 CH 3 -p)=C(Ar)(η 1 :η 2 :η 3 -C 8 H 9 )}(CO) 5 ] (16, Ar = C 6 H 5 ; 18, Ar = p-CH 3 C 6 H 4 ), and [Fe 2 {N(C 6 H 4 CH 3 -p)=C(Ar)CH(η 2 :η 3 -C 7 H 8 )}(CO) 4 ] (17, Ar = C 6 H 5 ; 19, Ar = p-CH 3 C 6 H 4 ), respectively. Interestingly, products 4a and 7a were transformed into the eight-membered ring products 10 and 16 and seven-membered ring products 11 and 17, respectively, under similar conditions. Surprisingly, compounds 10, 16, and 18 can also be partially transformed into compounds 11, 17, and 19, respectively, by further thermolysis at higher temperature (100-105 °C). The structures of complexes 7, 10, 11, 18, and 19 have been established by X-ray diffraction studies.

Mechanism of Anionic Dearomatizing Reactions of Diphenylphosphinamide Derivatives: A Theoretical and Experimental Study

The mechanism of the anionic dearomatisation of phosphinamide derivatives has been investigated both theoretically and experimentally. The potential-energy surface of model reactions was studied at the Becke3LYP/6-31+G* level of theory, and according to this study, a pre-reactive complex is formed between the alkyllithium and the phosphinamide. This complex evolves preferentially through NC(alpha)-metalation of the phosphinamide. The intramolecular nucleophilic addition of the carbanion to the ortho position of the aromatic ring leads to the dearomatised products, in a reaction that has been shown to be under thermodynamic control. Coordinating co-solvents, such as hexamethyl phosphoramide (HMPA) or N,N'-dimethyl-N,N'-propylene urea (DMPU), appear to influence the reaction by favouring the formation of solvent-separated ion pairs. The cyclisation reaction of allylphosphinamide derivatives was also studied. It was found that both the alpha- and gamma-attack of the allyl anion can take place, however the formation of the seven-membered ring products derived from the gamma-attack are clearly favoured.

Rhodium(II)‐Catalyzed Aziridination of Allyl‐Substituted Sulfonamides and Carbamates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Rhodium(II)-catalyzed aziridination of allyl-substituted sulfonamides and carbamates.

Several unsaturated sulfonamides underwent intramolecular aziridination when treated with PhI(OAc)(2), MgO, and catalytic Rh(2)(OAc)(4) to give bicyclic aziridines in excellent yield. Treatment of the resulting azabicyclic sulfonamides in methanol in the presence of p-TsOH resulted in exclusive opening of the aziridine ring at the most substituted position affording six- and seven-membered ring products in high yield. In contrast, the intramolecular aziridination of several cycloalkenyl-substituted carbamates did not require a Rh(II) catalyst and proceeded via an iminoiodinane intermediate. The resulting tricyclic aziridines underwent ring opening when treated with various nucleophiles to give anti-derived products as expected for nucleophilic attack at the three-membered ring. The iodine(III)-mediated reaction of a 3-indolyl-substituted carbamate, however, required a Rh(II) catalyst. The expected aziridine was not observed, but rather simultaneous spirocyclization of C(3) and stereoselective syn-acylation at C(2) occurred to give compound 41, whose structure was unequivocally established by an X-ray crystallographic study. The reaction proceeds in a stepwise manner via a metal-free zwitterionic intermediate which is attacked by a nucleophilic reagent on the same side of the amide anion. Related reactions occurred with both a 2-indolyl- and 3-benzofuranyl-substituted carbamate but with lower stereoselectivity.

Base-Promoted Ring Contractionof Eight-Membered Cyclic Acyloins and their Ethers toC s-Symmetric α-Ketols

In the presence of potassium hexamethyldisilazide and 18-crown-6 in THF at room temperature, 2-benzyloxycyclo-octanone and its Δ 5 -unsaturated congener undergo a two-stage rearrangement to give symmetrical seven-membered ring products. The pathway consists of the sequential operation of an O → C 1,2-shift and an u-ketol rearrangement. The greater thermodynamic stability of the cycloheptane or cycloheptene generated in this fashion is substantiated by MM3 calculations.

7- endo Selective Friedel–Crafts type cyclization of vinyloxiranes linked to an ester group

Treatment of arylpropyl vinyloxiranes linked to ester with BF 3 was found to produce seven-membered ring products in excellent yields. This reaction proceeded in an inversion fashion.