Ring Expansion Step Research Articles

One-pot synthesis of fused-rings heterocyclic systems based on symmetrically benzofuran annulated 1,8-naphthalimides

A useful and straightforward synthetic approach to afford heteroarenes by symmetrical annulation of two benzofuran units to 1,8-naphthalene anhydrides, through a regioselective one-pot Sn–Ar/C–H activation tandem reaction is introduced herein. Two synthetic pathways are compared, highlighting that the utilization of diester derivatives improves: (i) the compatibility with the key ring expansion step, (ii) the solubility of the intermediate thus facilitating its purification, and (iii) the versatility of the final imidization. The electrochemical and spectral properties of this new class of compounds are investigated.

Ring Expansion Strategies for the Synthesis of Medium Sized Ring and Macrocyclic Sulfonamides

AbstractTwo new ring expansion strategies are reported for the synthesis of medium sized ring and macrocyclic sulfonamides. Both methods can be performed without using classical protecting groups, with the key ring expansion step initiated by nitro reduction and amine conjugate addition respectively. Each method can be used to make diversely functionalised cyclic sulfonamides in good to excellent yields, in a range of ring sizes. The ring size dependency of the synthetic reactions is in good agreement with the outcomes modelled by Density Functional Theory calculations.

Ring Expansion Strategies for the Synthesis of Medium Sized Ring and Macrocyclic Sulfonamides.

Two new ring expansion strategies are reported for the synthesis of medium sized ring and macrocyclic sulfonamides. Both methods can be performed without using classical protecting groups, with the key ring expansion step initiated by nitro reduction and amine conjugate addition respectively. Each method can be used to make diversely functionalised cyclic sulfonamides in good to excellent yields, in a range of ring sizes. The ring size dependency of the synthetic reactions is in good agreement with the outcomes modelled by Density Functional Theory calculations.

Toward the Scale-Up of a Bicyclic Homopiperazine via Schmidt Rearrangement and Photochemical Oxaziridine Rearrangement in Continuous-Flow.

The scale-up of a chiral bicyclic homopiperazine of pharmaceutical interest was investigated. The outcome and safety profile of a key batch ring-expansion step via Schmidt rearrangement was improved using continuous-flow chemistry. The selectivity of nitrogen insertion for the ring expansion was improved via an alternative photochemical oxaziridine rearrangement under mild conditions, which when converted to continuous-flow in a simple and efficient flow reactor allowed the first photochemical scale-up of a homopiperazine.

Theoretical Investigation of Main-Group Element Hydride Insertion into Phosphorus-Heterocyclic Carbenes (PHCs)

Initial reports of ring expansion reactions (RER) of N-heterocyclic carbenes (NHCs) with main-group element hydrides have led to several synthetic and theoretical investigations, which include reports of insertion by Be, B, Al, Si, and Zn hydrides. The RERs generally lead to insertion of the heteroatom into the endocyclic C–N bond with formation of an expanded heterocyclic ring. Following the recent isolation of a P-heterocyclic carbene (PHC), here we report results from a computational study (RI-SCS-MP2/def2-TZVP//M06–2X/def2-TZVP) of RERs with a series of PHCs for the ring-insertion of silicon (SiH4, SiH2Ph2) and boron (BH3, BH2NMe2) hydrides. In order to explore the roles of both electronic and steric effects on PHCs and their reactivity, a series of P-substituent PHCR (R=H, Me, Ph, and bulky Ar groups) were investigated. Bulky R groups serve to maximise ring planarity and the σ-donating capability of the PHC. For RER, the PHC analogues exhibit facile initial hydride transfer from the main-group hydrides to the carbene carbon, with barriers that are substantially lower than with NHCs. However, the full ring insertion mechanisms for PHCs are, in general, kinetically unfavourable due to a large barrier associated with the ring-expansion step. While bulky P-substituents maximise heterocycle planarity towards that of NHCs, the RER reactivity with bulky PHCs does not reflect that of an NHC.

Second-Generation Synthesis of (+)-Fastigiatine Inspired by Conformational Studies.

(+)-Fastigiatine is a complex alkaloid isolated from the alpine club moss Lycopodium fastigatum, most commonly found in New Zealand. It has been the subject of two successful synthetic campaigns. A second-generation route toward fastigiatine was developed to resolve two problematic steps from our initial synthesis. Selective reduction and protection of the C13 ketone improved the yield and reliability of the dibromocarbene ring expansion step. In the prior synthesis, cuprate addition to the C10 enone generated a 1:1 mixture of isomers in an advanced intermediate. Protection of the C13 alcohol with a large silyl group changed the conformational preference of the enone and led to a more selective conjugate addition to produce the desired β-epimer at C10. MacMillan's decarboxylative photoredox addition method proved to be more practical than the prior aminomethyl cuprate addition chemistry. The second-generation synthesis is longer than the original but improves the selectivity and reproducibility of the overall route.

Ni(II)-catalyzed asymmetric alkenylations of ketimines

Chiral allylic amines are not only present in many bioactive compounds, but can also be readily transformed to other chiral amines. Therefore, the asymmetric synthesis of chiral allylic amines is highly desired. Herein, we report two types of Ni(II)-catalyzed asymmetric alkenylation of cyclic ketimines for the preparation of chiral allylic amines. When ketimines bear alkyl or alkoxycarbonyl groups, the alkenylation gives five- and six-membered cyclic α-tertiary allylic amine products with excellent yields and enantioselectivities under mild reaction conditions. A variety of ketimines can be used and the method tolerates some variation in alkenylboronic acid scope. Furthermore, with alkenyl five-membered ketimine substrates, an alkenylation/rearrangement reaction occurs, providing seven-membered chiral sulfamide products bearing a conjugated diene skeleton with excellent yields and enantioselectivities. Mechanistic studies reveal that the ring expansion step is a stereospecific site-selective process, which can be catalyzed by acid (Lewis acid or Brønsted acid).

Rh2(II)-Catalyzed Ring Expansion of Cyclobutanol-Substituted Aryl Azides To Access Medium-Sized N-Heterocycles.

A new reactivity pattern of Rh2(II)-N-arylnitrenes was discovered that facilitates the synthesis of medium-sized N-heterocycles from ortho-cyclobutanol-substituted aryl azides. The key ring-expansion step of the catalytic cycle is both chemoselective and stereospecific. Our mechanistic experiments implicate the formation of a rhodium N-arylnitrene catalytic intermediate and reveal that sp3 C-H bond amination of this electrophilic species is competitive with the ring-expansion process.

Synthesis of 3‐Benzazepines by Metal‐Free Oxidative C–H Bond Functionalization–Ring Expansion Tandem Reaction

AbstractA metal‐free synthesis of biologically important benzazepines is achieved through a single synthetic operation involving an oxidative C–H bond functionalization and ring expansion with diazomethanes as key reagent. This represents a new, strong methodology for the straightforward construction of the seven‐ring N‐heterocyclic structures under mild conditions using a 2,2,6,6‐tetramethylpiperidine 1‐oxyl (TEMPO) oxoammonium salt as oxidant. Moderate to good yields are achieved from simple, readily available tetrahydroisoquinolines, and this methodology has been further successfully applied for the synthesis of the 3‐benzazepine drug Lorcaserin. A possible mechanistic pathway for the ring expansion step, comprising the extrusion of nitrogen in a concerted asynchronic process, is proposed based on both mechanistic proof and density function theory (DFT) calculations.magnified image

Cover Picture: Journal of the Chinese Chemical Society 5/2013

AbstractThe computational study of gold(I)‐catalyzed ring expansion reactions of unactivated alkynylcyclopropanes is reported. The main finding of this work is that when unactivated alkynylcyclopropane with a smaller singlet‐triplet splitting (ΔEST) is utilized, the gold(I)‐catalyzed ring expansion step has a smaller activation energy and a larger exothermicity. For more information about this figure, turn to pp 473∼480 in this issue.

Reaction mechanism and chemoselectivity of gold(I)-catalyzed cycloaddition of 1-(1-alkynyl) cyclopropyl ketones with nucleophiles to yield substituted furans

The mechanisms of gold(I)-catalyzed cycloaddition of 1-(1-alkynyl) cyclopropyl ketones with nucleophiles have been investigated using density functional theory calculations at the B3LYP/6-31G (d, p) level of theory. A polarizable continuum model (PCM) has been established in order to evaluate the effects of solvents on the reactions. The results of the calculations indicate that the first step of the catalytic cycle is the cyclization of the carbonyl oxygen onto the triple bond which forms a new and stable resonance structure of an oxonium ion and a carbocation intermediate. The subsequent ring expansion step results in the formation of the final product and regeneration of the catalyst. Furthermore, the regioselectivity and effect of substituents has been discussed, including an analysis of energy, bond length, and natural bond orbital (NBO) charge distributions in the rate-determining step. Our computational results are consistent with earlier experimental observations.

Exploitation of Furanoid 5‐Azido‐3‐C‐Branched‐Chain Sugars Towards Highly Functionalized Nitrogen‐Containing Carbohydrate Derivatives

AbstractThe ability of easily accessed 1,2‐O‐protected 5‐azido‐3‐C‐(ethoxycarbonyl)methylenefuranoses to serve as precursors for the generation of imino sugar derivatives containing an α,β‐unsaturated lactone or ketone functionality has been investigated. A key aspect was the propensity of the corresponding deprotected δ‐amino α,β‐unsaturated esters to undergo 5‐aminofuranose/iminopyranose isomerization. Acid hydrolysis of the δ‐amino (Z)‐α,β‐unsaturated ester followed by treatment with base led to a butenolide‐containing N‐ethylformamide arising from a rearrangement of the imino‐sugar‐fused butenolide intermediate induced by the conjugated system. When carrying out the ring expansion step under neutral conditions, a 2‐keto imino sugar was obtained that was readily converted into a 1,2‐dihydropyridin‐3‐one by acetylation. Furthermore, reduction of the δ‐azido (E)‐α,β‐unsaturated ester to the amine was followed by spontaneous intramolecular cyclization, providing the related furanose‐fused unsaturated δ‐lactam.

Synthesis and In Vitro Evaluation of Taxol oxetane ring D precursors.

A series of potential taxoid substrates was prepared in radiolabelled form to probe in vitro for the oxirane formation step and subsequent ring expansion step to the oxetane (ring D) presumably involved in the biosynthesis of the anticancer agent Taxol. None of the taxoid test substrates underwent transformation in cell-free systems from Taxus suggesting that these surrogates bore substitution patterns inappropriate for recognition or catalysis by the target enzymes, or that taxoid oxiranes and oxetanes arise by independent biosynthetic pathways.

A One‐Pot Synthesis of 1,4‐Dithiins and 1,4‐Benzodithiins from Ketones Using the Recyclable Reagent 1,1′‐(Ethane‐1,2‐diyl)dipyridinium Bistribromide (EDPBT).

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A one-pot synthesis of 1,4-dithiins and 1,4-benzodithiins from ketones using the recyclable reagent 1,1′-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT)

A novel access to 1,4-dithiins and 1,4-benzodithiins from the corresponding ketones in one-pot using the recyclable reagent, 1,1′-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT) is described. This method is mild, simple, environmentally benign and is applied successfully for the ring expansion of 1,3-dithiolane to 1,4-dithiins and the ring expansion associated with aromatisation of cyclic ketones with or without double bonds in the ring. The main feature of this method is that EDPBT acts as a promoter in the formation of 1,3-dithiolane and as a reagent in the ring expansion step. The spent reagent can be recovered, regenerated and reused.

One-Pot Synthesis of Fluorescent 2,5-Dihydro-1,2,3-triazine Derivatives from a Cascade Rearrangement Sequence in the Reactions of 1,2,3-Triazolium-1-aminide 1,3-Dipoles with Propiolate Esters

The reactions of 1,2,3-triazolium-1-aminides 1 (readily available from benzil bishydrazones) with propiolate esters leads to fluorescent 2,5-dihydro-1,2,3-triazine derivatives 2, 3 in one pot. These synthetic reactions can be carried out in acetone, in water, or under solvent-free conditions. The reactions involve a Huisgen cycloaddition followed by a sequence of rearrangements. The final ring-expansion step was blocked by linking a six-methylene hydrocarbon chain between the prospective 1,2,3-triazine C-4 and C-6 atoms, using substrate 8 which gave the fused tricyclic azapropellane product 9 exclusively. X-ray crystal structures were determined for two 2,5-dihydro-1,2,3-triazine derivatives and for compound 9. The UV absorption of the 1,2,3-triazine derivatives showed a dual absorption at ca. 310 and ca. 390 nm with fluorescent emission at ca. 480 and 528 nm (for excitation at 317 nm). The significant Stokes shift of ca. 200 nm shows the potential for biological fluorescent labeling experiments.

Theoretical study of protonated xylenes: ethene elimination and H,C‐scrambling reactions

AbstractQuantum chemical calculations have been carried out to investigate various unimolecular rearrangements that can take place in protonated gas‐phase xylenes. Hydrogen and methyl group ring migrations were investigated. The barriers for hydrogen migrations are lower than the barriers for methyl group migrations. Mechanisms for ring expansion to seven‐membered rings, and for contraction to five‐membered rings were studied. Both of these mechanisms can eventually lead to ethene elimination. The most favourable ring expansion step goes through a 1,3‐hydrogen shift from a methyl group onto the arenium ring, forming a protonated methylcycloheptatriene. Interconversions between various ring‐expanded forms have been investigated. Re‐contraction can lead to an ethylbenzenium ion that could subsequently split off ethene. Alternatively, the xylenium ion can contract to a five‐membered ring. The immediate product is a bicyclic ion (bicyclo[3.1.0]hexane skeleton) that can rearrange further to give an ethylbenzenium ion, or the five‐ring system can split off ethene, and be converted into a cyclopentadienyl ion that can isomerize into a benzenium ion. Stable structures and transition states are calculated both at the B3LYP/cc‐pVTZ//B3LYP/6‐311G(d,p) and at the MP2/cc‐pVTZ//MP2/6‐31G(d) levels. The energies needed for ring expansion or ring contraction are not very different, and the calculations suggest that both reaction paths are possible, but the energy needed for actually splitting off an ethene molecule is lower along the expansion path. Copyright © 2004 John Wiley & Sons, Ltd.

Equilibrium position, kinetics, and reactor concepts for the adipyl-7-ADCA-hydrolysis process.

One of the building blocks of cephalosporin antibiotics is 7-amino-deacetoxycephalosporanic acid (7-ADCA). It is currently produced from penicillin G using an elaborate chemical ring-expansion step followed by an enzyme-catalyzed hydrolysis. However, 7-ADCA-like components can also be produced by direct fermentation. This is of scientific and economic interest because the elaborate ring-expansion step is performed within the microorganism. In this article, the hydrolysis of the fermentation product adipyl-7-ADCA is studied. Adipyl-7-ADCA can be hydrolyzed in an equilibrium reaction to adipic acid and 7-ADCA using glutaryl-acylase. The equilibrium reaction yield is described as a function of pH, temperature, and initial adipyl-7-ADCA concentration. Reaction rate equations were derived for adipyl-7-ADCA-hydrolysis using three (pH-independent) reaction rate constants and the apparent equilibrium constant. The reaction rate constants were calculated from experimental data. Based on the equilibrium position and reaction rate equations the hydrolysis reaction was optimized and standard reactor configurations were evaluated. It was found that equilibrium yields are high at high pH, high temperature and low-initial adipyl-7-ADCA concentration. The course of the reaction could be described well as a function of pH (7-9), temperature (20-40 degrees C) and concentration using the reaction rate equations. It was shown that a series of CSTR's is the best alternative for the process.

New cyclization mechanism for squalene: a ring-expansion step for the five-membered C-ring intermediate in hopene biosynthesis.

Three triterpenes having the 6/6/5-fused tri- and 6/6/6/5-fused tetracyclic skeletons were isolated from an incubation mixture of the mutated F601A enzyme, these products being in accordance with a Markovnikov closure. Successful trapping of the tricyclic cationic intermediate by using the squalene analog having a highly nucleophilic hydroxyl group leads us to propose that the ring expansion process of the 5-membered C-ring is involved in the squalene cyclization cascade.

Biosynthesis. Part 29.1 Colchicine: studies on the ring expansion step focusing on the fate of the hydrogens at C-3 of autumnaline

Biosynthesis. Part 29.1 Colchicine: studies on the ring expansion step focusing on the fate of the hydrogens at C-3 of autumnaline