Ring Expansion Reaction Research Articles

Design of new anti-Alzheimer drugs: ring-expansion synthesis and synchrotron X-ray diffraction study of dimethyl 4-ethyl-11-fluoro-1,4,5,6,7,8-hexa-hydro-azonino[5,6-b]indole-2,3-di-carboxyl-ate.

The title compound, C20H23FN2O4, is the product of a ring-expansion reaction from a seven-membered fluorinated hexa-hydro-azepine to a nine-membered azonine. The nine-membered azonine ring of the mol-ecule adopts a chair-boat conformation. The C=C and C-N bond lengths [1.366 (3) and 1.407 (3) Å, respectively] indicate the presence of conjugation within the enamine CH2-C=C-N-CH2 fragment. The substituent planes at the C=C double bond of this fragment are twisted by 16.0 (3)° as a result of steric effects. The amine N(Et) N atom has a trigonal-pyramidal configuration (sum of the bond angles = 346.3°). The inter-planar angle between the two carboxyl-ate substituents is 60.39 (8)°. In the crystal, mol-ecules form zigzag chains along [010] by inter-molecular N-H⋯O hydrogen-bonding inter-actions, which are further packed in stacks toward [100]. The title azonino-indole might be considered as a candidate for the design of new Alzheimer drugs.

Chiral Phosphoric Acid Catalyzed Enantioselective Ring Expansion Reaction of 1,3-Dithiane Derivatives: Case Study of the Nature of Ion-Pairing Interaction.

Chiral counterion controlled asymmetric catalysis via an ion-pairing interaction has attracted immense attention in recent years. Despite a number of successful studies, the mechanistic elucidation of the stereocontrolling element in the ion-pairing interaction is rarely conducted and hence its nature is still far from being well understood. Herein we report an in-depth mechanistic case study of a newly developed enantioselective ring expansion reaction of 1,3-dithiane derivatives catalyzed by chiral phosphoric acid (CPA). An unprecedented enantioselective 1,2-sulfur rearrangement/stereospecific nucleophilic addition sequence was proven to be the stereoselective pathway. More importantly, by thorough investigation of the intrinsic nature of the stereospecific nucleophilic addition to the cationic thionium intermediate, we discovered that the key interaction in this process is the nonclassical C-H···O hydrogen bonds formed between the conjugate base of the CPA catalyst and the cationic intermediate. These C-H···O hydrogen bonds not only bind the catalyst to the substrates to form energetically favored states throughout the overall processes but also firmly maintain the relative positions of these fragments as the "fixed" contact ion pair to sustain the chiral information generated at the initial sulfur rearrangement step. This mechanistic case study provides a very clear understanding of the nature of the ion-pairing interaction in organocatalysis. The conclusion encourages the further development of the research field with the focus to design new organocatalysts and cultivate novel organocatalytic transformations.

Asymmetric Formal Synthesis of (-)-Cephalotaxine via Palladium-Catalyzed Enantioselective Tsuji Allylation.

Asymmetric synthesis of the pentacyclic alkaloid (-)-cephalotaxine was accomplished via palladium-catalyzed enantioselective Tsuji allylation for construction of the aza-containing tetrasubstituted stereogenic center (95% yield, 93% ee). The allyl enol carbonate precursor was prepared from Hanaoka's ketone intermediate, which was formed by a novel formic acid promoted ring-expansion reaction.

Synthesis of sulfur-containing heterocycles via ring enlargement.

The current review deals with the use of ring expansion reactions for the synthesis of sulfur-containing heterocycles. Ring enlargement offers by far a convenient method for the synthesis of 'medium-sized ring systems', which are usually difficult to obtain or even produced in low yields. These reactions are often catalytically processed starting from a single cyclic precursor and, therefore, are superior to alternative classical iterative synthetic approaches in terms of atomic and conversion efficiency. The current review aims to shed light on the synthetic approaches that exist to afford medium-sized sulfur heterocycles from preexisting smaller rings (e.g., three-, four-, five-, six- and seven-membered rings).

A Dipleiadiene‐Embedded Aromatic Saddle Consisting of 86 Carbon Atoms

AbstractThis study presents a new type of negatively curved nanographene (C86H32) that contains an unprecedented pattern of heptagons. A tert‐butylated derivative of C86H32 was successfully synthesized using tetrabenzodipleiadiene as a key building block. This synthesis involved a ring expansion reaction as a key step to form the seven‐membered rings in the framework of tetrabenzodipleiadiene. The single‐crystal structure reveals a saddle‐shaped molecule with a highly bent naphthalene moiety at the center of the polycyclic backbone. As found from the DFT calculations, this aromatic saddle is flexible at room temperature and has a saddle‐shaped geometry as the dominant conformation. The DFT calculations along with experimental results show that the attachment of t‐butyl groups to the central tetrabenzodipleiadiene moiety of nanographene C86H32 can stabilize the saddle conformation and make this nanographene less flexible.

A Dipleiadiene-Embedded Aromatic Saddle Consisting of 86 Carbon Atoms.

This study presents a new type of negatively curved nanographene (C86 H32 ) that contains an unprecedented pattern of heptagons. A tert-butylated derivative of C86 H32 was successfully synthesized using tetrabenzodipleiadiene as a key building block. This synthesis involved a ring expansion reaction as a key step to form the seven-membered rings in the framework of tetrabenzodipleiadiene. The single-crystal structure reveals a saddle-shaped molecule with a highly bent naphthalene moiety at the center of the polycyclic backbone. As found from the DFT calculations, this aromatic saddle is flexible at room temperature and has a saddle-shaped geometry as the dominant conformation. The DFT calculations along with experimental results show that the attachment of t-butyl groups to the central tetrabenzodipleiadiene moiety of nanographene C86 H32 can stabilize the saddle conformation and make this nanographene less flexible.

Azaborines: synthesis and use in the generation of stabilized boron-substituted carbocations.

A formal N-heterocyclic carbene insertion into the B-H bond of 9-BBN followed by a ring expansion reaction is reported. NHC-9-BBN adducts were reacted in one or two steps to give the corresponding di- or triazaborines. Hydride abstraction of selected species with [Ph3C]+ is facile, giving rise to 6π-aromatic cations with Lewis acidity comparable to Lewis acids commonly employed in frustrated Lewis pairs.

Organic dye-catalyzed radical ring expansion reaction.

Herein, we reported an attractive method for synthesizing medium-sized rings that are catalyzed by erythrosine B under fluorescent light irradiation. This synthetic approach featured mild conditions, a facile procedure, a broad substrate scope, and moderate-to-good yields.

Gold-Catalyzed Ring Expansion Reaction: Highly Efficient Synthesis of Functionalized 2, 3-Benzodiazepine Scaffolds

Gold-Catalyzed Ring Expansion Reaction: Highly Efficient Synthesis of Functionalized 2, 3-Benzodiazepine Scaffolds

A Transient Vinylphosphinidene via a Phosphirene-Phosphinidene Rearrangement.

A room-temperature-stable crystalline 2H-phosphirene (1) was prepared by treatment of an electrophilic diamidocarbene with tert-butylphosphaalkyne. Compound 1 is shown to react as a vinylphosphinidene generated via phosphirene-phosphinidene rearrangement. Thermolysis is shown to affect C-N bond scission while reactions with C6Cl4O2 or (tht)AuCl afford formal oxidation of the phosphindene center and the phosphinidene-insertion into an aromatic C-C bond of a mesityl group, respectively. The latter reaction is the first example of a phosphorus analog of the Büchner ring expansion reaction.

β-Aminocarbonates in Regioselective and Ring Expansion Reactions.

The reactivity of β-aminocarbonates as anisotropic electrophiles has been investigated with several phenols. Products distribution shows that the regioselectivity of the anchimerically driven alkylation reaction depends on the nucleophiles. The results suggest that in the presence of nucleophiles that are also good leaving groups, the reaction takes place under thermodynamic control favoring the attack on the most sterically hindered carbon of the cyclic aziridinium intermediate. Furthermore, when an enantiomerically pure pyrrolidine-based carbonate was used, the reaction with phenols proceeds via a bicyclic aziridinium intermediate leading to the stereoselective synthesis of optically active 3-substituted piperidines via ring expansion reaction. These results were confirmed both by NMR spectroscopy and X-ray diffraction analysis.

Photochemistry of 2-Formylphenylnitrene: A Doorway to Heavy-Atom Tunneling of a Benzazirine to a Cyclic Ketenimine.

The slippery potential energy surface of aryl nitrenes has revealed unexpected and fascinating reactions. To explore such a challenging surface, one powerful approach is to use a combination of a cryogenic matrix environment and a tunable narrowband radiation source. In this way, we discovered the heavy-atom tunneling reaction involving spontaneous ring expansion of a fused-ring benzazirine into a seven-membered ring cyclic ketenimine. The benzazirine was generated in situ by the photochemistry of protium and deuterated triplet 2-formylphenylnitrene isolated in an argon matrix. The ring-expansion reaction takes place at 10 K with a rate constant of ∼7.4 × 10-7 s-1, despite an estimated activation barrier of 7.5 kcal mol-1. Moreover, it shows only a marginal increase in the rate upon increase of the absolute temperature by a factor of 2. Computed rate constants with and without tunneling confirm that the reaction can only occur by a tunneling process from the ground state at cryogenic conditions. It was also found that the ring-expansion reaction rate is more than 1 order of magnitude faster when the sample is exposed to broadband IR radiation.

Theoretical study on DABCO-catalyzed ring expansion of cyclopropyl ketone: Mechanism, chemoselectivity, and role of catalyst

The possible mechanisms of 1,4-diazabicyclo[2.2.2]octane (DABCO)-catalyzed ring expansion of cyclopropyl ketone for forming dihydrofurans have been studied using density functional theory (DFT). According to the calculated results, the reaction occurs via two competing paths including paths A and B, which lead to two different products (i.e. 2-methyl-4,5-dihydrofuran and 2-phenyl-4,5-dihydrofuran), respectively. Path A is revealed to be more energetically favorable than path B, which is consistent with the experimental observation. Two reaction steps are contained in the favorable path: (1) nucleophilic addition of DABCO to cyclopropyl ketone coupled with three-membered ring opening; (2) five-membered ring closure process accompanied with dissociation of DABCO and product via the SN2-type transition state. Moreover, global reactivity index (GRI) and non-covalent interaction (NCI) analyses were performed to disclose the role of catalyst and explain the chemoselectivity. By analysing of the efficiency of different catalysts (i.e. tricyclohexylphosphine (PCy3), triphenylphosphine (PPh3), tributylphosphine (PBu3), 4-dimethylaminopyridine (DMAP), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)), it was found that the stronger nucleophilicity of amine catalyst would be corresponding to the lower energy barrier of the ring expansion reaction.

Recent applications of aziridine ring expansion reactions in heterocyclic synthesis

Recent applications of aziridine ring expansion reactions in heterocyclic synthesis

Gold-Catalyzed Ring Expansion of Enyne-Lactone: Generation and Transformation of 2-Oxoninonium.

An efficient gold-catalyzed ring-expansion reaction of enyne-lactones to form 2-oxoninonium intermediates is reported. The 2-oxoninonium generated in this work could undergo further 6π electrocyclization and aromatization reaction to produce different aromatic compounds.

From Five to Seven: Ring Expansion of Monoazadiene Titanium Complexes by Insertion of Aldehydes, Ketones and Nitriles.

The ring enlargement reactions at ambient temperatures of non C-terminus substituted monoazabutadiene (η4 -RN=CHCH=CH2 ) titanium complexes 2 are investigated. The insertion of aldehydes/ketones (five examples) and nitriles (four examples) into the Ti-C bonds result in expansion of the five-membered rings to uncommon seven-membered titanacycles 3 and 4 in good yields. These new compounds are fully characterized by NMR spectroscopy and single-crystal X-ray diffraction. In subsequent reactions, the seven-membered ring systems are protolyzed and the released organic fragments are isolated. Whereas the aldehyde/ketone insertion products 3 form substituted δ-amino alcohols 5 after reduction with NaBH3 CN, the nitrile insertion products 4 form substituted pyrroles 6 via cyclization.

Photochemically Switching Diamidocarbene Spin States Leads to Reversible Büchner Ring Expansions.

The discovery of thermal and photochemical control by Woodward and Hoffmann revolutionized how we understand chemical reactivity. Similarly, we now describe the first example of a carbene that exhibits differing thermal and photochemical reactivity. When a singlet ground-state N,N'-diamidocarbene 1 was photolyzed at 380 nm, excitation to a triplet state was observed. The triplet-state electronic structure was characteristic of the expected biradical σ1pπ1 spin configuration according to a combination of spectroscopic and computational methods. Surprisingly, the triplet state of 1 was found to engage a series of arenes in thermally reversible Büchner ring expansion reactions, marking the first examples where both cyclopropanation and ring expansion of arenes were rendered reversible. Not only are these photochemical reactions different from the known thermal chemistry of 1, but the reversibility enabled us to perform the first examples of photochemically induced arene exchange/expansion reactions at a single carbon center.

Convergent Synthesis of Fused Ring Systems in Large Polycyclic Ethers.

This article reviews our studies on the oxiranyl anion-based, [X+2+Y]-type convergent strategy for the synthesis of polycyclic ether natural products. The strategy is noteworthy for its flexibility, which allows for the generation of different-sized fused ring systems based on a ring expansion reaction. For a precise understanding of this key ring expansion, we first focused on the reaction mechanism, in which an equatorial attack of TMS-diazomethane was determined to be the crucial step. In the later part of this review, the application of our oxiranyl anion-based strategy to large fused ring systems is described. The advantageous flexibility is highlighted in the divergent synthesis of five octacyclic ethers involving the CDEFGHIJ-ring skeleton of yessotoxin and its ring-modified analogs. Total synthesis of gymnocin-A was achieved using the oxiranyl anion convergent strategy, which furnished its large system of fourteen contiguous ether rings.

Recent Advances in the Synthesis of Hydrogenated Azocine-Containing­ Molecules

This review covers recent advances in synthesis of azocine-containing systems. The most approaches towards azocines are discussed.1 Introduction2 Ring-Expansion Reaction2.1 Ring-Expansion Reaction of Cyclopentane Containing the 1,4-Diketone Moiety with Primary Amines (from 5 to 8)2.2 Ring-Expansion Reaction of Annulated Tetrahydropyridines under the Action of Activated Alkynes (from 6 to 8)2.3 Reductive Ring-Expansion Reaction of Cyclic Oximes2.4 Other Ring-Expansion Reactions3 Heck Reaction4 Cycloaddition5 Ring-Closing Metathesis (RCM)6 Cyclization6.1 Metal-Catalyzed Cyclization6.2 Radical Cyclization6.3 Friedel–Crafts Cyclization6.4 Other Examples of Cyclizations7 Microwave- and Photo-Assisted Reactions8 Other Methods8.1 Cascade and Tandem Reactions8.2 Aldol Condensation8.3 Thermolysis8.4 Ring Opening8.5 Other Methods9 Conclusion

Nucleophile-Mediated Ring Expansion of 5-Acyl-substituted 4-Mesyloxymethyl-1,2,3,4-tetrahydropyrimidin-2-ones in the Synthesis of 7-Membered Analogues of Biginelli Compounds and Related Heterocycles.

A general six-step approach to alkyl 2-oxo-2,3,6,7-tetrahydro-1H-1,3-diazepine-5-carboxylates and 5-acyl-2,3,6,7-tetrahydro-1H-1,3-diazepin-2-ones based on the nucleophile-mediated ring expansion reaction of 5-functionalized 4-mesyloxymethyl-1,2,3,4-tetrahydropyrimidin-2-ones has been developed. Synthesis of the latter involved nucleophilic substitution of tosyl group in readily available N-[(2-benzoyloxy-1-tosyl)ethyl]urea with sodium enolates of β-oxoesters or 1,3-diketones, followed by dehydration or heterocyclization-dehydration of resulting products, removal of benzoyl protection, and conversion of hydroxymethyl group into mesyloxymethyl group. Conformations of the obtained tetrahydro-1H-1,3-diazepin-2-ones in solid state and solutions were established using X-ray diffraction and NMR spectroscopy. A plausible mechanism of tetrahydropyrimidine ring expansion based on DFT calculation at B3LYP/6-31+G(d,p) level and NMR monitoring experiments was discussed. The ring contraction reaction of methoxy- or phenylthio-diazepinones under acidic conditions resulted in the corresponding 3-functionalized 1-carbamoyl-1H-pyrroles.