Ring-expanded Products Research Articles

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.

Scavenging of Alkylperoxyl Radicals by Addition to Ascorbate: An Alternative Mechanism to Electron Transfer.

Vitamin C (ascorbate; Asc) is a biologically important antioxidant that scavenges reactive oxygen species such as deleterious alkylperoxyl radicals (ROO•), which are generated by radical-mediated oxidation of biomolecules in the presence of oxygen. The radical trapping proprieties of Asc are conventionally attributed to its ability to undergo single-electron transfers with reactive species. According to this mechanism, the reaction between Asc and ROO• results in the formation of dehydroascorbate (DHA) and the corresponding hydroperoxides (ROOH). When studying the reactivity of DNA 5-(2'-deoxyuridinyl)methylperoxyl radicals, we discovered a novel pathway of ROO• scavenging by Asc. The purpose of this study is to elucidate the underlying mechanism of this reaction with emphasis on the characterization of intermediate and final decomposition products. We show that the trapping of ROO• by Asc leads to the formation of an alcohol (ROH) together with an unstable cyclic oxalyl-l-threonate intermediate (cOxa-Thr), which readily undergoes hydrolysis into a series of open-chain oxalyl-l-threonic acid regioisomers. The structure of products was determined by detailed MS and NMR analyses. The above transformation can be explained by initial peroxyl radical addition (PRA) onto the C2=C3 enediol portion of Asc. Following oxidation of the resulting adduct radical, the product subsequently undergoes Baeyer-Villiger rearrangement, which releases ROH and generates the ring expansion product cOxa-Thr. The present investigation provides robust clarifications of the peroxide-mediated oxidation chemistry of Asc and DHA that has largely been obscured in the past by interference with autooxidation reactions and difficulties in analyzing and characterizing oxidation products. Scavenging of ROO• by PRA onto Asc may have beneficial consequences since it directly converts ROO• into ROH, which prevents the formation of potentially deleterious ROOH, although it induces the breakdown of Asc into fragments of oxalyl-l-threonic acid.

Phosphine-Mediated Reductive Insertion of α-Keto Esters and Isatins into Phthalic Anhydride Derivatives.

Herein, we report an unprecedented P(NMe2)3-mediated reductive insertion of 1,2-dicarbonyl compounds including α-keto esters and isatins into phthalic anhydride-derived alkenes and phthalic anhydrides, which furnishes the corresponding isochroman-1-ones and isochroman-1,4-diones, respectively, in moderate to excellent yields with high chemo- and regioselectivity. Furthermore, the asymmetric version of the ring expansion reaction could be realized by using a chiral auxiliary strategy. Mechanistically, the nucleophilic attack of the Kukhtin-Ramirez adduct, generated from P(NMe2)3 and 1,2-dicarbonyl compound, to the anhydride derivative, followed by a cascade ring-opening and ring-closure process, affords the ring expansion product. The reaction represents a novel metal-free carbon insertion ring expansion of aliphatic rings and also the first [1 + 5] annulation involving the Kukhtin-Ramirez adducts.

Synthesis and Reactions of Pentacycloundecane Derivatives Related to Cookson’s Dione

AbstractIn this study, a pentacyclic keto-olefin was treated with thallium(III) nitrate trihydrate, resulting in the formation of mono ring-expanded product. However, when the corresponding dialkene was treated with thallium(III) nitrate trihydrate, an unexpected ring-closure product was obtained instead of the expected double ring-expanded product. The use of the Tebbe reagent facilitated the olefination of hindered and enolizable cage dione derivatives, converting both keto moieties into methylene groups and forming the desired diolefin. Notably, conventional Wittig reagents proved to be ineffective in the olefination sequence with cage diones.

Intramolecular 1,2-Aroyl Migration in Spiro Donor-Acceptor Cyclopropanes: Formation of 1,4-Naphthoquinones and 1-Naphthols as Ring-Expansion Products.

Most of the known rearrangement reactions of donor-acceptor cyclopropanes (DACs) involve the migration of cationic carbon atom to anionic carbon or heteroatoms in 1,3- or 1,4-positions. In the present work, we observed that spiro DACs based on 1,3-indanedione or 1-indanone moiety undergo intramolecular 1,2-aroyl migration when treated with titanium(IV) chloride to afford 1,4-naphthoquinones and α-naphthols readily. The reactions take place through the formation of putative 1,3-dipolar intermediates, followed by cleavage and migration of the aroyl group to the adjacent carbon to afford the ring-expansion products.

Avenue to novel o-carboranyl boron compounds - reactivity study of o-carborane-fused aminoborirane towards organic azides.

Herein we report the reactivity study of o-carborane-fused bis(trimethylsilyl)aminoborirane towards three different types of organic azides, i.e., aryl, alkyl, and silyl azides. The reaction with ArN3 (Ar = 2,6-iPr2C6H4, 2,6-C6H3Cl2, 2,4,6-C6H2Br3, C6F5) resulted in the cycloaddition of ArN3 to the borirane BN unit accompanied by silyl migration. Conversely, in the reaction with BnN3, only the BnN3 : borirane 1 : 2 ring expansion product was obtained. Finally, the reaction with Me3SiN3 resulted in a formal nitrene insertion product under thermal conditions. All of the newly obtained o-carborane-fused BN-containing heterocycles were fully characterized, and the mechanism of these substituent-dependent reactions was studied using DFT calculations.

Aluminyl derived ethene functionalization with heteroallenes, leading to an intramolecular ligand rearrangement.

The aluminacyclopropane K[Al(NON)(η-C2H4)] ([NON]2- = [O(SiMe2NDipp)2]2-, Dipp = 2,6-iPr2C6H3) reacts with CO2 and iPrNCNiPr to afford ring-expanded products of C-C bond formation. The latter system undergoes a 1,3-silyl retro-Brook rearrangement of the NON-group, to afford the [NNO]2- ligand ([NNO]2- = [N(Dipp)SiMe2N(Dipp)SiMe2O]2-). The mechanism of transformation was examined by density functional theory (DFT).

Selective ring expansion and C−H functionalization of azulenes

We report a transition metal-catalyzed ring expansion of azulene that can be contrasted with C–H functionalization. This study represents the first example of the successful ring expansion of azulene using Cu(hfacac)2 (hfacac: hexafluoroacetylacetonate) with a diazo reagent. This result is notable for extending the Buchner reaction, previously limited to benzenoid aromatics, to nonbenzenoid compounds. The chemoselectivity of the reaction can be directed towards C–H functionalization by substituting the Cu catalyst with AgOTf. This approach does not require the addition of phosphine, NHC, or related ligands, and prefunctionalization of azulenes is unnecessary. Furthermore, the method exhibits excellent functional group tolerance, allowing for the synthesis of a wide range of 6,7-bicyclic compounds and C–H functionalized azulenes. We also present a theoretical study that explains the experimental observations, explaining why copper afford the ring expansion product while silver forms the C–H alkylation product.

Photochemically Mediated Ring Expansion of Indoles and Pyrroles with Chlorodiazirines: Synthetic Methodology and Thermal Hazard Assessment.

We demonstrate that arylchlorodiazirines serve as photo-activated halocarbene precursors for the selective one-carbon ring expansion of N-substituted pyrroles and indoles to the corresponding pyridinium and quinolinium salts. Preliminary investigations indicate that the same strategy also enables the conversion of N-substituted pyrazoles to pyrimidinium salts. The N-substituent of the substrate plays an essential role in: (1) increasing substrate scope by preventing product degradation, (2) enhancing yields by suppressing co-product inhibition, and (3) activating the azinium products towards subsequent synthetic manipulations. This latter point is illustrated by subjecting the quinolinium salts to four complementary partial reductions, which provide concise access to ring-expanded products with different degrees of increased C(sp3 ) character. Thermal analysis of the diazirines by differential scanning calorimetry (DSC) provides detailed insight into their energetic properties, and highlights the safety benefits of photolyzing-rather than thermolyzing-these reagents.

Photochemical and Atom-Economical Sulfonylimination of Alkenes with Bifunctional N-Sulfonyl Ketimine

An organo-photocatalytic sulfonylimination of alkenes was developed by employing readily available N-sulfonyl ketimines as bifunctional reagents. This transformation, featuring prominent functional group tolerance, provides a direct and atom-economic approach for the synthesis of valuable β-amino sulfone derivatives as a single regioisomer. In addition to terminal alkenes, internal alkenes participate in this reaction with high diastereoselectivity. N-Sulfonyl ketimines with aryl or alkyl substituents were found to be compatible with this reaction condition. This method could be applied in the late-stage modifications of drugs. Additionally, a formal insertion of alkene into cyclic sulfonyl imine was observed, affording a ring expansion product.

Snapshots of sequential polyphosphide rearrangement upon metallatetrylene addition.

Insertion and functionalization of gallasilylenes [LPhSi-Ga(Cl)LBDI] (LPh = PhC(NtBu)2; LBDI = [{2,6-iPr2C6H3NCMe}2CH]) into the cyclo-E5 rings of [Cp*Fe(η5-E5)] (Cp* = η5-C5Me5; E = P, As) are reported. Reactions of [Cp*Fe(η5-E5)] with gallasilylene result in E-E/Si-Ga bond cleavage and the insertion of the silylene in the cyclo-E5 rings. [(LPhSi-Ga(Cl)LBDI){(η4-P5)FeCp*}], in which the Si atom binds to the bent cyclo-P5 ring, was identified as a reaction intermediate. The ring-expansion products are stable at room temperature, while isomerization occurred at higher temperature, and the silylene moiety further migrates to the Fe atom, forming the corresponding ring-construction isomers. Furthermore, reaction of [Cp*Fe(η5-As5)] with the heavier gallagermylene [LPhGe-Ga(Cl)LBDI] was also investigated. All the isolated complexes represent rare examples of mixed group 13/14 iron polypnictogenides, which could only be synthesized by taking advantage of the cooperativity of the gallatetrylenes featuring low-valent Si(ii) or Ge(ii) and Lewis acidic Ga(iii) units/entities.

Apparent 6‐endo‐trig Carbofluorination of Alkenes Enabled by Palladium‐Based Dyotropic Rearrangement

AbstractAlkene difunctionalization featuring an intramolecular carbometallation step has been developed into a powerful transformation in organic synthesis. The 5‐exo‐trig carbometallation is in general highly favored over the alternative 6‐endo‐trig cyclization. We report herein a formal 6‐endo‐trig carbofluorination protocol by combining the conventional 5‐exo‐trig carbopalladation with a chemoselective 1,2‐aryl/Pd dyotropic rearrangement. Treatment of 2‐(2‐alkylallyloxy)phenyl boronic acid derivatives in the presence of a catalytic amount of Pd(dba)2, 4,4′‐di‐tert‐butyl‐2,2′‐bipyridine and Selectfluor affords chromanes with concurrent generation of a tertiary alkyl fluoride function. A σ‐alkyl‐PdII species resulting from the 5‐exo‐trig carbopalladation process is isolated and characterized by X‐ray crystallographic analysis. Its oxidation to PdIV complex triggers the chemoselective dyotropic rearrangement leading to the ring expansion product.

Apparent 6-endo-trig Carbofluorination of Alkenes Enabled by Palladium-Based Dyotropic Rearrangement.

Alkene difunctionalization featuring an intramolecular carbometallation step has been developed into a powerful transformation in organic synthesis. The 5-exo-trig carbometallation is in general highly favored over the alternative 6-endo-trig cyclization. We report herein a formal 6-endo-trig carbofluorination protocol by combining the conventional 5-exo-trig carbopalladation with a chemoselective 1,2-aryl/Pd dyotropic rearrangement. Treatment of 2-(2-alkylallyloxy)phenyl boronic acid derivatives in the presence of a catalytic amount of Pd(dba)2 , 4,4'-di-tert-butyl-2,2'-bipyridine and Selectfluor affords chromanes with concurrent generation of a tertiary alkyl fluoride function. A σ-alkyl-PdII species resulting from the 5-exo-trig carbopalladation process is isolated and characterized by X-ray crystallographic analysis. Its oxidation to PdIV complex triggers the chemoselective dyotropic rearrangement leading to the ring expansion product.

(Invited, Digital Presentation) Carbocation Generation By Organophotoredox Catalyzed Radical-Polar Crossover

Carbocation is one of the most common and reactive chemical species in organic chemistry, which has been broadly utilized for alkylation of various nucleophiles and rearrangement reaction. Conventionally, carbocation is generated from alkyl electrophiles or alkenes in the presence of strong Lewis acids and Brønsted acids, which narrows usable nucleophiles and coexistable functional groups. The requirement of strong acidic conditions would originate from the difficulty of two electron abstraction from carbocation precursors at once. Recently, to solve this problem, activation of substrates via single electron transfer was presented. Knowles and co-workers reported the carbocation generation from the mesolytic cleavage of alkoxyamine-derived radical cation, that is generated by a visible-light mediated photoredox catalysis. Although this protocol does not require the strong acids, the low accessibility of alkoxyamine substrates restricted the introducible alkyl groups. In this presentation, a new approach to catalytic generation of carbocation by a visible light-mediated organophotoredox catalysis is provided. We were interested in an organocatalysis merging with the radical-polar crossover (RPC) mechanism as an approach to non-acidic and catalytic generation of carbocations. Details of our scenario for the RPC are described in Figure. We selected N-Ph-benzo[b]phenothiazine (PTH) as a suitable organophotoredox RPC catalyst due to three features: excitation in the UV-visible area, high reduction potential and potential persistent properties of the corresponding radical cation. Aliphatic carboxylic acid-derived redox active esters were chosen as carbocation precursors due to the availability and the well-studied reactivity. The catalytic system is initiated by single electron transfer from a phenothiazine catalyst to a redox active ester under irradiation of a blue light-emitting diode (LED) to generate the radical cation form of the catalyst (A) and an alkyl radical (B). Then, recombination process between A and B affords an alkylsulfonium intermediate C, which acts as a carbocation equivalent. The carbocation equivalent was applied to alkylation of various nucleophiles and the semipinacol rearrangement reactions. First, the catalytic system was exploited to alkylation of various nucleophiles. After screening of reaction conditions, the combination of N-phenyl benzo[b]phenothiazine and lithium tetrafluoroborate was found to be effective in this alkylation protocol. Aliphatic alcohol, water, amide, thiol, fluoride anion and allylsilane could participate in this organophotoredox catalysis as nucleophiles. This protocol allowed to use secondary or tertiary aliphatic carboxylic acid-derived redox active esters as alkylating reagents, providing sterically hindered molecules with functional group compatibility.Subsequently, we applied the photochemically-generated carbocation equivalent to the semipinacol rearrangement reaction. Although the semipinacol rearrangement reaction has been utilized in key steps for construction of complex carbon frameworks in total synthesis of natural products, the conventional methods require specific design of the substrates and harsh reaction conditions to control the reactivity and regioselectivity. Since our method has the advantage of using carboxylic acids as the carbocation precursors, the substrates are easily synthesized from the corresponding enolate species derived from aliphatic carboxylic acids and carbonyl compounds. Then, we found the b-hydroxy redox active ester derivatives underwent the decarboxylative semipinacol rearrangement reaction, affording the complex carbonyl compounds. For example, the reaction with substrate prepared from aromatic aldehyde and secondary aliphatic carboxylic acid proceeded to give the aldehyde bearing an a-quaternary carbon center through migration of the aromatic ring. The reactions with cyclic ketone-derived substrates also occurred to furnish the ring expansion products. Figure 1

Significant Broadening of the Substrate Scope for the Hydrated Imidazoline Ring Expansion (HIRE) via the Use of Lithium Hexamethyldisilazide

AbstractSubstrates that are insufficiently activated towards the hydrated imidazoline ring expansion (HIRE) process have been previously found to deliver exclusively the products of aminoalkyl side-chain ring expansion. Attempted reversal of the process by thermal activation towards HIRE failed. We have found that for such problematic substrates the HIRE-type ring expansion can be effectively achieved by applying lithium hexamethyldisilazide (LHMDS) in toluene. LHMDS is thought to promote intramolecular transamidation, which leads to ring-expanded 10- and 11-membered heterocyclic products in modest to good yields. The process significantly broadens the substrate scope amenable to the HIRE strategy.

Sulfur Oxidation Increases the Rate of HIRE-Type [1.4]Thiazepinone Ring Expansion and Influences the Conformation of a Medium-Sized Heterocyclic Scaffold.

The hydrated imidazoline ring expansion (HIRE-type) reaction was investigated for a series of di(hetero)arene-fused [1.4]thiazepinones in comparison with their sulfone counterparts. The sulfones were found to undergo ring expansion at a much higher rate compared to the thioethers, much in line with the current mechanistic understanding of the process. Moreover, the amide bond cis- and trans-isomers of the ring-expanded products were found, in the case of sulfones, to be stabilized through an intramolecular hydrogen bond. The latter phenomenon was studied in detail by NMR experiments and corroborated by X-ray crystallographic information.

The Fluoride Anion-Catalyzed Sulfurization of Thioketones with Elemental Sulfur Leading to Sulfur-Rich Heterocycles: First Sulfurization of Thiochalcones.

Fluoride anion was demonstrated as a superior activator of elemental sulfur (S8) to perform sulfurization of thioketones leading to diverse sulfur-rich heterocycles. Due to solubility problems, reactions must be carried out either in THF using tetrabutylammonium fluoride (TBAF) or in DMF using cesium fluoride (CsF), respectively. The reactive sulfurizing reagents are in situ generated, nucleophilic fluoropolysulfide anions FS(8−x)−, which react with the C=S bond according to the carbophilic addition mode. Dithiiranes formed thereby, existing in an equilibrium with the ring-opened form (diradicals/zwitterions) are key-intermediates, which undergo either a step-wise dimerization to afford 1,2,4,5-tetrathianes or an intramolecular insertion, leading in the case of thioxo derivatives of 2,2,4,4-tetramethylcyclobutane-1,3-dione to ring enlarged products. In reactions catalyzed by TBAF, water bounded to fluoride anion via H-bridges and forming thereby its stable hydrates is involved in secondary reactions leading, e.g., in the case of 2,2,4,4-tetramethyl-3-thioxocyclobutanone to the formation of some unexpected products such as the ring enlarged dithiolactone and ring-opened dithiocarboxylate. In contrast to thioketones, the fluoride anion catalyzed sulfurization of their α,β-unsaturated analogues, i.e., thiochalcones is slow and inefficient. However, an alternative protocol with triphenylphosphine (PPh3) applied as a catalyst, offers an attractive approach to the synthesis of 3H-1,2-dithioles via 1,5-dipolar electrocyclization of the in situ-generated α,β-unsaturated thiocabonyl S-sulfides. All reactions occur under mild conditions and can be considered as attractive methods for the preparation of sulfur rich heterocycles with diverse ring-size.

Diverse Reactivity of Hypersilylsilylene with Boranes and Three-Component Reactions with Aldehyde and HBpin.

The recently reported hypersilylsilylene PhC(NtBu)2SiSi(SiMe3)3 (1) reacts with BH3, 9-BBN, and PhBCl2 to yield the respective Lewis acid base adducts 2-4, respectively. Compound 4 undergoes isomerization to form a ring expansion product 5. The same silylene was found to initially form an adduct with HBpin (6) and subsequently isomerized to 7 via the rupture of the B-H bond of HBpin (7), where the hydride was bound to the carbon atom of the amidinate ligand and the Bpin unit was attached to the silicon center. Surprisingly, the reaction of 1 with HBcat results in PhC(NtBu)2Bcat (8). Subsequently, we have shown that HBcat forms the same product when it reacts with related silylene PhC(NtBu)2SiN(SiMe3)3 (1'). With all of these reactions in hand, we ponder if silylene can activate two small molecules at one time. In this work, we delineate the three-component reactions of silylenes 1 and 1' with 4-fluorobenzaldehyde and HBpin, which afforded unusual coupling products, 9 and 10, respectively. Note that 9 and 10 were prepared from the cleavage of the B-H and C═O bonds by silylene in a single reaction and are the first structurally attested Si-C-O-B coupled products.

Electrochemical Ring Expansion to Synthesize Medium-Sized Lactams Through C–C Bond Cleavage

Medium-sized nitrogen heterocycles are prevalent motifs in many kinds of bioactive molecules and natural products. Owing to the unfavorable enthalpic and entropic barriers during the transition sta...