Ring Expansion Research Articles

Titanium-Catalyzed Reaction of Silacyclobutanes with Alkenes: Mimicking the Reactivity and Reversing the Selectivity Towards Late Transition Metals.

Transition metal-catalyzed ring opening and expansion reactions of silacyclobutanes (SCBs) constitute an atom- and step-economical strategy to construct value-added silicon-containing chemicals. Despite extensive studies, the reaction of SCBs with simple alkenes has only one precedent. Moreover, most reported reactions of SCBs use late transition metals (Pd, Ni, Rh) as catalysts. By contrast, there are no reports of using early transition metals. Herein, we report the first example, to our knowledge, of early-transition-metal-catalyzed reactions of SCBs using earth's second abundant titanium as a catalyst. Notably, orthogonal selectivity was observed. Selective activation of the relatively inert C(sp3)-Si bond was achieved in the case of benzosilacyclobutenes, a selectivity that has rarely been achieved using other metals. Even for silacyclobutanes with C(sp3)-Si bonds only, our titanium system also shows complementary selectivity towards late transition metals to give distinct products. Thus, structurally varied SCBs and alkenes were reacted in our system to afford structurally diverse silicon-containing products that are otherwise difficult to obtain using other transition metals.

Recent Advancement on Ring Expansion of Bicyclic Diaziridines to Access N‐Heterocyclic Compounds

Bicyclic diaziridines are important heterocyclic scaffolds, which can be cleaved into 1,3‐zwiterionic species to serve as a versatile precursor in fabricating biologically important N‐hetero‐ and spiro‐cyclic structural frameworks. Owing to their staple architecture, inherent ring strain and ease of synthesis, considerable advancements have been made by employing bicyclic diaziridines towards the construction of heterocyclic systems of biological importance. A significant surge with appreciable efforts in the adoption of such strategies has led to their implementation by the synthetic chemists. This article focuses on the developments in ring expansion of bicyclic diaziridines employed in N‐heterocycle synthesis.

Skeletal Editing via Transition-Metal-Catalyzed Nitrene Insertion.

Metal-nitrenes are valuable reactive intermediates for synthesis and are widely used to construct biologically relevant scaffolds, complexes and functionalized molecules. The ring expansion of cyclic molecules via single-nitrogen-atom insertion via nitrene or metal-nitrenoid intermediates has emerged as a promising modern strategy for driving advantageous nitrogen-rich compound synthesis. In recent years, the catalytic insertion of a single nitrogen atom into carbocycles, leading to N-heterocycles, has become an important focus of modern synthetic approaches with applications in medicinal chemistry, materials science, and industry. Catalytic single-nitrogen-atom insertions have been increasing in prominence in modern organic synthesis due to their capability to construct high-value added nitrogen-containing heterocycles from simple feedstocks. In this review, we will discuss the rapidly growing field of skeletal editing via single-nitrogen-atom insertion using transition metal catalysis to access nitrogen-containing heterocycles, with a focus on nitrogen insertion across a wide spectrum of carbocycles.

Macrocyclic Bridgehead Fluorophores, Pyrrolyl-diazabicyclo[8.3.1]tetradecadienones, with Giant Stokes Shifts.

A previously unknown class of fluorophores was discovered, which represents 14-membered bridgehead heterocycles, pyrrolyl-diazabicyclo[8.3.1]tetradecadienones, herein referred to as PY-14-ONEs. The new fluorophores are characterized by giant Stokes shifts of ∼8000-10,250 cm-1 and virtually zero overlap of the absorption and emission bands. They exhibit fluorescence maxima in the blue-green region (454 ≤ λem ≤ 513 nm, MeCN), which shift to the red side when converted to their water-soluble salts by alkylation with MeI (478 ≤ λem ≤ 516 nm, water). PY-14-ONEs were obtained by an original synthesis from DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene, which reacts with acylethynylpyrroles without catalysts under mild conditions to afford PY-14-ONEs in a 34-58% yield. The reaction represents a ring expansion of DBU. Since acylethynylpyrroles are readily available, the discovered reaction opens promising possibilities for the development of new fluorophores. The results of our time-dependent DFT calculations indicate that the pyrrole ring in PY-14-ONEs plays an important role in the formation of the Stokes shifts, which can be further enhanced by attaching appropriate substituents to it, capable of creating in S1 an extended conjugated system and causing a substantial alternation of the molecular structure via its planarization.

Synthesis of Dibenzoxasilepine Using Ring Expansion Reaction of a Pentacoordinate Silicon Intermediate

Dibenzoxasilepine is an important skeleton in both synthetic and medicinal chemistry. Here, we have succeeded in obtaining it in higher yield than the conventional method, elucidating for the first time the rearrangement tendency of the two aromatic rings during the ring expansion reaction on the cyclic pentacoordinate silicon intermediate.

Fluoro-Promoted Thermal Ring Expansion of Cyclopropyl Carbenes to gem-Difluorinated Cyclobutenes.

Synthesis of gem-difluorinated cyclobutenes presents certain challenges for considering the compatibility of the fluorine atom introduction with four-membered ring retention. Herein, we develop a transition-metal-free synthetic strategy toward gem-difluorinated cyclobutenes from gem-difluorinated cyclopropyl N-tosylhydrazons via ring expansion reaction. The gem-difluoro substitution alters the properties of the cyclopropane, facilitating the thermal rearrangement of cyclopropyl carbenes into cyclobutenes. This reaction can be easily handled free from inert gas protection, thus offering an efficient route to synthesize gem-difluorinated cyclobutenes.

Cyclic amine ring expansion.

Cyclic amine ring expansion.

Diversified ring expansion of saturated cyclic amines enabled by azlactone insertion.

Saturated N-heterocycles are ubiquitous structures among natural products and biologically active compounds. Therefore, the development of synthetic methods for the construction of N-heterocycles is of great importance in the synthetic community. Altering the ring system of these motifs to analogues with different ring sizes by employing molecular editing techniques would be highly appealing in medicinal chemistry. We present herein the direct insertion of glycine derivatives as two-carbon synthons into unstrained five- or six-membered saturated cyclic amines at predictable sites, enabling the construction of synthetically challenging medium-sized azacycles through sequential Ru-catalysed C‒C bond formation, retro-aza-Michael addition and a lactamization process. Upon further derivation, we leverage this homologation platform to realize modular insertion of one- or two-carbon units into the aliphatic rings. The conversion of a single azacycle into up to five others provides a promising toolbox for diversifying existing drug candidates and increasing the prospects for clinical success.

Arene Ring Expansion by Ruthenium η6-Arene Complexes.

Transition metal π-arene complexes enable the dearomatization of benzene rings to access diversified unsaturated carbocycles through multistep synthetic procedures involving sequential addition of nucleophiles and electrophiles. This work details a single-step dearomatization process by reaction of Ru(η6-arene) complexes with enolates derived from α-halo or α-(tosyloxy)esters to directly transform π-coordinated arenes to ring-expanded cycloheptatrienes.

Smart and Efficient Synthesis of Cyclic Poly(N-isopropylacrylamide)s by Ring Expansion RAFT (RE-RAFT) Polymerization and Analysis of Their Unique Temperature-Responsive Properties.

Cyclic polymers have many interesting properties compared to their linear analogs, but there are very few examples of their synthesis. This is because most cyclic polymers have been synthesized by stepwise processes, including synthesizing homo- or hetero-telechelic end-functionalized precursor polymers and consecutive intramolecularly coupling of both ends of the polymers. This requires a complicated synthesis, and the product yields are very low because the target cyclic polymers are usually synthesized under highly dilute conditions, consequently, making it difficult to systematically analyze the properties of cyclic polymers. In the present research, we have synthesized cyclic polymers using a ring expansion polymerization method. Particularly, the ring expansion RAFT polymerization (RE-RAFT polymerization) that we have developed using a cyclic chain transfer agent is a smart method that can synthesize cyclic polymers very efficiently. In this paper, we successfully synthesized cyclic-poly(N-isopropylacrylamide), which is widely known as a thermo-responsive polymer, by RE-RAFT polymerization. Furthermore, we have compared the thermo-responsive properties of the cyclic-poly(N-isopropylacrylamide)s with those of their linear analogs.

Photochemical Ring Expansion of Cyclic Sulfoximines with Aryl Diazoacetates and Subsequent Diastereoconvergent Oxidation

Photochemical Ring Expansion of Cyclic Sulfoximines with Aryl Diazoacetates and Subsequent Diastereoconvergent Oxidation

π-Complexes Derived from Non-classical Diboriranes: Side-on vs. End-on Carbonylative Ring Expansion.

Unlike cyclopropanes, the analogous B2C species (diboriranes) tend to adopt non-classical Hückel-aromatic structures with bridging moieties R between the boron atoms. The coordination of the thus generated cyclic 2e- π-system to transition metals is completely unexplored. We here report that complexation of non-classical diboriranes cyclo-μ-RB2Dur2CPh (R=H, SnMe3; Dur=2,3,5,6-tetramethylphenyl) to Fe(CO)3 fragments allows for the carbonylative ring expansion of the B2C ring to either four- or five-membered rings depending on the nature of the BRB 3-center-2-electron bond (3c2e): The H-bridged diborirane (R=H) initially reacts with Fe2(CO)9 to the allylic π-complex with an agostic BH/Fe interaction. Subsequent formal hydroboration of CO from excess Fe2(CO)9 results in the side-on ring expansion under formation of a five-membered B2C2O ring, coordinated to the Fe(CO)3 moiety. In contrast, in case of the stannyl-bridged diborirane (R=SnMe3) under the same conditions, CO is added end-on to the B-B bond with the carbon terminus formally inserting into the B2Sn 3c2e-bond. The two carbonylative ring expansion products can also be described as nido and closo clusters, respectively, according to the Wade-Mingos rules.

π‐Komplexe aus Nicht‐Klassischen Diboriranen: Side‐on vs. End‐on Carbonylierende Ringerweiterung

AbstractIm Gegensatz zu Cyclopropanen neigen die analogen B2C‐Spezies (Diborirane) dazu, nicht‐klassische Hückel‐aromatische Strukturen mit verbrückenden Resten R zwischen den Boratomen auszubilden. Die Koordination des so erzeugten zyklischen 2e− π‐Systems an Übergangsmetalle ist völlig unerforscht. Wir berichten, dass die Komplexierung von nicht‐klassischen Diboriranen cyclo‐μ‐RB2Dur2CPh (R=H, SnMe3; Dur=2,3,5,6‐Tetramethylphenyl) mit Fe(CO)3‐Fragmenten eine carbonylierende Ringerweiterung des B2C‐Rings zu vier‐ oder fünfgliedrigen Ringen ermöglicht, abhängig von der Art der BRB‐3‐Zentren‐2‐Elektronenbindung (3c2e): Das H‐verbrückte Diboriran (R=H) reagiert zunächst mit Fe2(CO)9 zum allylischen π‐Komplex mit einer agostischen BH/Fe‐Wechselwirkung. Die anschließende formale Hydroborierung von CO aus überschüssigem Fe2(CO)9 führt zur side‐on Ringerweiterung unter Ausbildung eines fünfgliedrigen B2C2O‐Rings, der an eine Fe(CO)3‐Einheit koordiniert ist. Im Gegensatz dazu wird im Falle des stannylverbrückten Diborirans (R=SnMe3) unter denselben Bedingungen CO endständig an die B−B‐Bindung addiert, wobei das Kohlenstoffende formal in die B2Sn 3c2e‐Bindung insertiert. Die beiden carbonylierenden Ringerweiterungsprodukte können auch als nido‐ bzw. closo‐Cluster nach den Wade‐Mingos‐Regeln beschrieben werden.

Borole Ring Expansion Reactions with Boron Azides: A Versatile Pathway to Borylated Azaborinines

Borole Ring Expansion Reactions with Boron Azides: A Versatile Pathway to Borylated Azaborinines

Ring Expansion toward Fused Diazabicyclo[3.1.1]heptanes through Lewis Acid Catalyzed Highly Selective C−C/C−N Bond Cross‐Exchange Reaction between Bicyclobutanes and Diaziridines

The synthesis of bicyclic scaffolds has garnered considerable interest in drug discovery because of their ability to mimic benzene bioisosteres. Herein, we introduce a new approach that utilizes a Lewis acid (Sc(OTf)3)‐catalyzed σ‐bond cross‐exchange reaction between the C−C bond of bicyclobutanes and the C−N bond of diaziridines to produce multifunctionalized and medicinally interesting azabicyclo[3.1.1]heptane derivatives. The reaction proceeds well with different bicyclobutanes and a broad range of aryl‐ as well as alkenyl‐, but also alkyl‐substituted diaziridines (up to 98% yield). Conducting a scale‐up experiment and exploring the synthetic transformations of the cycloadducts emphasized the practical application of the synthesis. Furthermore, a zinc‐based chiral Lewis acid catalytic system was developed for the enantioselective version of this reaction (up to 96% ee).

Ring Expansion toward Fused Diazabicyclo[3.1.1]heptanes through Lewis Acid Catalyzed Highly Selective C-C/C-N Bond Cross-Exchange Reaction between Bicyclobutanes and Diaziridines.

The synthesis of bicyclic scaffolds has garnered considerable interest in drug discovery because of their ability to mimic benzene bioisosteres. Herein, we introduce a new approach that utilizes a Lewis acid (Sc(OTf)3)-catalyzed σ-bond cross-exchange reaction between the C-C bond of bicyclobutanes and the C-N bond of diaziridines to produce multifunctionalized and medicinally interesting azabicyclo[3.1.1]heptane derivatives. The reaction proceeds well with different bicyclobutanes and a broad range of aryl- as well as alkenyl-, but also alkyl-substituted diaziridines (up to 98% yield). Conducting a scale-up experiment and exploring the synthetic transformations of the cycloadducts emphasized the practical application of the synthesis. Furthermore, a zinc-based chiral Lewis acid catalytic system was developed for the enantioselective version of this reaction (up to 96% ee).

Redox-Tunable Ring Expansion Enabled By A Single-Component Electrophilic Nitrogen Atom Synthon.

Controllable installation of a single nitrogen atom is central to many major goals in skeletal editing, with progress often gated by the availability of an appropriate N-atom source. Here we introduce a novel reagent, termed DNIBX, based on dibenzoazabicycloheptadiene (dbabh), which allows the electrophilic installation of dbabh to organic substrates. When indanone β-ketoesters are aminated by DNIBX, the resulting products undergo divergent ring expansions depending on the mode of activation, producing heterocycles in differing oxidation states under thermal and photochemical conditions. The mechanism of each transformation is discussed, and the different reactivity modes of the indanone-dbabh adducts are compared to other nitrogenous precursors.

Redox‐Tunable Ring Expansion Enabled By A Single‐Component Electrophilic Nitrogen Atom Synthon

Controllable installation of a single nitrogen atom is central to many major goals in skeletal editing, with progress often gated by the availability of an appropriate N‐atom source. Here we introduce a novel reagent, termed DNIBX, based on dibenzoazabicycloheptadiene (dbabh), which allows the electrophilic installation of dbabh to organic substrates. When indanone β‐ketoesters are aminated by DNIBX, the resulting products undergo divergent ring expansions depending on the mode of activation, producing heterocycles in differing oxidation states under thermal and photochemical conditions. The mechanism of each transformation is discussed, and the different reactivity modes of the indanone‐dbabh adducts are compared to other nitrogenous precursors.

Ring Expansion Reactions via C-N Bond Cleavage in the Synthesis of Medium-sized Cycles and Macrocycles

The literature review discusses and systematizes synthetic approaches to medium-sized cycles and macrocycles based on ring expansion reactions of bi- or polycyclic systems via C-N bond cleavage. Ring expansion reactions of bicyclic ammonium salts proceed via thermal decomposition or the action of strong bases. Bi- or polycyclic systems containing a common amine group can be reduced with strong reducing reagents, e.g. lithium aluminum hydride. Ammonium derivatives are much more prone to nucleophilic attack and quite often are used as starting materials for the synthesis of medium-sized cycles. Bicyclic systems containing a common aminal or amidine group are used for the synthesis of medium-sized rings and macrocycles via cleavage of the endocyclic C-N bond. Various methods of their activation and reduction are discussed in the review.

Can OPAH ions be a source of CO and HCO in the interstellar medium? Lessons learned from the unimolecular dissociation of dibenzofuran and dibenz[b,f]oxepin radical cations

Unlike polycyclic aromatic hydrocarbons (PAHs), which are recognized to be key players in interstellar and astrochemistry, less is known about the astrochemical relevance of oxygen-containing PAHs (OPAHs). Small O-containing molecules such as CO and HCO are ubiquitous in the interstellar medium and understanding how OPAHs may be a source for these critical small molecules is important. To this end, we have studied the unimolecular reactions of two ionized OPAHs, dibenzofuran (1+•) and dibenz[b,f]oxepin (2+•) with tandem mass spectrometry (collision-energy resolved dissociation) and imaging photoelectron photoion coincidence spectroscopy (iPEPICO). Collision-induced dissociation (CID) results show the competition between the loss of carbon monoxide (CO) and loss of 29 Da (either the formyl radical (HCO) or sequential H loss), with the latter being the dominant reaction. Rice–Ramsperger–Kassel–Marcus (RRKM) modeling of the iPEPICO data, on the other hand, is consistent with the loss of CO from the parent ion at the dissociative ionization onset, and, in the case of 2+•, sequential H-atom loss from this product. There is significant difference between the two structurally similar systems. In 1+•, dissociation requires around 4 eV of ion internal energy, while only 2.5 eV internal energy is required for 2+• to fragment. Calculations at the CAM-B3LYP/6–311++G(d,p) level of theory were used to examine the reaction pathways. For CO loss in 1+•, the reaction is initiated by a ring expansion followed by contraction of the central ring forming an ion–molecule complex between protonated cyclopenta[3,4]cyclobuta[1,2]benzene and CO. HCO loss is preceded by H migration to a bridging carbon vicinal to the oxygen atom and subsequent ring re-organization to form a low energy cyclopenta[c][1]benzopyran cation. This channel is higher enough in energy to preclude its participation near threshold, but not at higher internal energies reached in the CID experiment, which could therefore involve both sequential H loss and HCO loss. In 2+•, the reaction starts with an opening of the central O-containing ring, lowering the energy demand relative to 1+•.