Donor-acceptor Cyclopropanes Research Articles

1,3-Difunctionalization of Donor-Acceptor Cyclopropanes Enabled by Copper Nitrate: A Direct Approach to γ-Halonitrates.

1,3-Difunctionalization of donor-acceptor cyclopropanes with copper nitrate and N-halosuccinimide was developed to efficiently afford γ-halonitrates. The pivotal factor of this protocol lies in the dual role of copper nitrate as a Lewis acid and an ideal nitrooxy source. The given approach features easy handling, good functional group compatibility, and wide substrate scope. Furthermore, various transformations of the obtained γ-chloronitrates underscore the remarkable synthetic potential inherent in this method.

Highly efficient construction of angular polycycles

Angular tricyclic and polycyclic skeletons feature typical cores in an intriguing type of natural products. We herein report the Lewis acids-catalyzed dearomative (3 + 2) cycloadditions of donor-acceptor cyclopropanes with benzene ring, by which structurally complex and diverse angular tricyclic and polycyclic carbocycles were efficiently constructed from cheap and easily available feedstock and with convenient operation. This is also the example of (3 + 2) cycloaddition of a C3-synthon with the C = C of benzene. We believe this will demonstrate its potential in the total syntheses of natural products and drug discovery.

Ytterbium Triflate-Catalyzed Intramolecular Arylative Ring Opening of Arylaminomethyl-Substituted Donor-Acceptor Cyclopropanes: Access to Tetrahydroquinolines.

The treatment of arylaminomethyl-substituted donor-acceptor cyclopropanes with a catalytic amount of Yb(OTf)3 provides expedient access to tetrahydroquinoline derivatives. The transformation proceeds through an intramolecular SN2-type attack of the aminomethyl-containing aryl ring on the cyclopropane ring, leading to the formation of the products as single diastereomers.

Converting Strain Release into Aromaticity Loss for Activation of Donor-Acceptor Cyclopropanes: Generation of Quinone Methide Traps for C-Nucleophiles.

Here, we present a new approach for the activation of donor-acceptor cyclopropanes in ring-opening reactions, which does not require the use of a Lewis or Brønsted acid as a catalyst. Donor-acceptor cyclopropanes containing a phenolic group as the donor undergo deprotonation and isomerization to form the corresponding quinone methides. This innovative strategy was applied to achieve (4 + 1)-annulation of cyclopropanes with sulfur ylides, affording functionalized dihydrobenzofurans. Additionally, the generated ortho- and para-(aza)quinone methides can be trapped by various CH-acids.

Synthesis of Tetrasubstituted Enamines Using Secondary Amines and In Situ-Generated Allenes from Nitrocyclopropanes.

A novel reaction of cyclic and acyclic secondary amines with in situ-generated allene intermediate species from nitro-substituted donor-acceptor cyclopropanes is reported. In the presence of a simple inorganic base, NaOH, tetrasubstituted enamine derivatives can be obtained in moderate to excellent yields. The reaction is operationally easy, features mild reaction conditions and simple inorganic bases, and is free of transition metals.

Formal High-Order Cycloadditions of Donor-Acceptor Cyclopropanes with Cycloheptatrienes.

The design of various cycloaddition/annulation processes is one of the most intriguing challenges in the development of donor-acceptor (D-A) cyclopropane chemistry. In this work, a new class of formal high-order [6+n]-cycloaddition and annulation processes of D-A cyclopropanes with cycloheptatriene systems has been designed and reported, to fill a significant gap in the chemistry of D-A cyclopropanes. The reactivity of methylated cycloheptatrienes from Me1 to Me5 as well as unsubstituted cycloheptatriene was studied in detail under GaCl3 activation conditions, which makes it possible to efficiently generate gallium 1,2-zwitterionic complexes or 1,3-zwitterionic intermediates starting from D-A cyclopropanes, while other Lewis acids are ineffective and non-selective. New examples of formal [6+2]-, [6+3]-, [6+4]-, [6+1]-, and [4+2]-cycloaddition and annulation reactions with cycloheptatrienes along with more complex processes were discovered. Cycloheptatriene itself can also successfully act as a hydride anion donor, which allows the ionic hydrogenation of D-A cyclopropanes to be performed under mild conditions. As a result, a number of efficient and highly diastereoselective protocols for the synthesis of seven-membered carbocycles has been developed.

Enantioselective (3+2) Annulation of Donor-Acceptor Cyclopropanes with Aldehydes and Ketones Catalyzed by Brønsted Bases.

The substituted tetrahydrofuran core is a structural motif in many biologically active and natural compounds. However, the scarcity of enantioselective methods developed towards its synthesis makes this field challenging and attractive to explore. Herein, the first Brønsted-base catalyzed enantioselective (3+2) annulation of donor-acceptor cyclopropanes with aldehydes and ketones affording enantioenriched 2,3,5-substituted tetrahydrofurans is reported. The reaction concept is based on activation of racemic β-cyclopropyl ketones by a chiral bifunctional Brønsted base which catalyzes the (3+2) annulation for a range of aldehydes and ketones. For aldehydes, the annulation furnished tetrahydrofurans in excellent yield, good diastereoselectivity and with excellent enantioselectivity up to >99 % ee. Surprisingly, aromatic aldehydes afforded the cis-2,5-substituted tetrahydrofurans as the major diastereoisomer, while for aliphatic aldehydes the trans-cycloadduct was favored. The reaction also proceeds well for ketones affording spiro tetrahydrofurans in excellent yields and enantioselectivities (up to 99 % ee). Hammett studies have been conducted to elucidate the influence of the electronic nature of benzaldehydes on the stereoselectivity. Based on the diastereochemical outcome for the aldehydes, two reaction paths for aromatic and aliphatic aldehydes are proposed. Finally, two diastereoselective synthetic transformations have been conducted to demonstrate the synthetic potential of the obtained products.

Ring-Opening of Donor-Acceptor Cyclopropane Diester for the Synthesis of Oxime Esters and 2,3-Dihydroazete Ester

AbstractA simple and efficient approach for the synthesis of privileged oxime esters by employing donor-acceptor cyclopropane diesters (DACs) as one of the potential precursors is reported. The strategy involves Lewis acid catalyzed ring-opening of DACs, resulting in an open-chain intermediate followed by the base-mediated construction of the corresponding oxime esters in a one-pot reaction. Moreover, the process also features the synthesis of diethyl 4-(4-methoxyphenyl)azete-2,2(3H)-dicarboxylate.

Esterification and Etherification of Aliphatic Alcohols Enabled by Catalytic Strain-Release of Donor-Acceptor Cyclopropane.

We herein disclose a highly efficient protocol for the esterification and etherification of alcohols, leveraging a Sc(OTf)3-catalyzed ring-strain release event in the meticulously designed, chromatographically stable mixed anhydrides or benzyl esters that incorporate an intramolecular donor-acceptor cyclopropane (DAC). This versatile method facilitates the straightforward functionalization of sugar, terpene, and steroid alcohols under mild acidic conditions, as showcased by the single-catalyst-driven, dual protection of sugar diol.

Template-Directed In Crystallo Photopolymerization of a Donor-Acceptor Cyclopropane: When Everything Falls into Place!

A single-crystal-to-single-crystal solid-state reaction of vinylogous donor-acceptor cyclopropanes is documented. The enantiospecific synthesis of new products, distinct from those obtained in solution, is achieved for the target compounds. Photopolymerization occurred upon X-ray exposure to the crystals. Notably, in one case, this reactivity exhibits selectivity since an ordered arrangement of polymers and unreacted cocrystallized monomeric conformers has been observed. Structural characterization of the complete transformation monitored through single-crystal X-ray diffraction and supported by molecular dynamics simulations sheds light on the subtle role of crystal packing in the reaction process. Moreover, the X-ray diffraction (XRD)-resolved structure of a donor-acceptor cyclopropane intermediate reveals an elongation in bond length that corroborates the existence of the so-called "push-pull effect".

Chiral Brønsted Base Activation of Donor-Acceptor Cyclopropanes toward Diastereo- and Enantioselective [3 + 2] Cycloaddition with Isatin-Derived Ketimines.

Organocatalyzed diastereo- and enantioselective [3 + 2] cycloaddition reactions of donor-acceptor (D-A) cyclopropanes with isatin-derived ketimines are presented. Different from well-developed Lewis acid activation protocols which promote the reactivity of D-A cyclopropanes through coordinating to the acceptor group, in this reaction, dicyanocyclopropylmethyl ketones can be activated through nucleophilic activation of the donor group by using dihydroquinine-derived squaramide as Brønsted base catalyst. The reaction affords functionalized spiro[oxindole-3,2'-pyrrolidines] with two nonadjacent tetra- and tri-substituted stereocenters in 83-99% yields, moderate to excellent diastereoselectivities (up to >20:1 diastereomeric ratio (dr)), and excellent enantioselectivities (up to >99% enantiomeric excess (ee)) under mild conditions.

Hydro-phosphorothiolation of Styrene and Cyclopropane with S-Hydrogen Phosphorothioates under Ambient Conditions.

A metal-free hexafluoroisopropanol-mediated hydro-phosphorothiolation of styrenes and donor-acceptor cyclopropanes with S-hydrogen phosphorothioates in a Markovnikov fashion has been developed under ambient reaction conditions to afford a library of S-alkyl phosphorothioates. Notably, this strategy provides a simple and efficient way to produce biologically significant kitazin and iprobenfos derivatives. Mechanistic studies disclose that the reaction proceeds through a carbocation intermediate.

BF3·OEt2-Mediated (3+2) Cycloaddition Reactions of Donor-Acceptor Cyclopropanes (DACs) with Cyanamides: Access to Cyclic Amidines

AbstractA BF3·OEt2-promoted facile synthesis of cyclic amidines (2-amino-1-pyrrolines) has been developed via the (3+2)-cycloaddition of cyanamides with donor-acceptor cyclopropanes (DACs). In addition to this, the protocol has been successfully extended to construct a dimerized amidine derivative and gram-scale synthesis with great efficiency.

Photo-cycloaddition reactions of vinyldiazo compounds

Heterocyclic rings are important structural scaffolds encountered in both natural and synthetic compounds, and their biological activity often depends on these motifs. They are predominantly accessible via cycloaddition reactions, realized by either thermal, photochemical, or catalytic means. Various starting materials are utilized for this purpose, and, among them, diazo compounds are often encountered, especially vinyldiazo compounds that give access to donor-acceptor cyclopropenes which engage in [2+n] cycloaddition reactions. Herein, we describe the development of photochemical processes that produce diverse heterocyclic scaffolds from multisubstituted oximidovinyldiazo compounds. High chemoselectivity, good functional group tolerance, and excellent scalability characterize this methodology, thus predisposing it for broader applications. Experimental and computational studies reveal that under light irradiation these diazo reagents selectively transform into cyclopropenes which engage in cycloaddition reactions with various dipoles, while under thermal conditions the formation of pyrazole from vinyldiazo compounds is favored.

Methanesulfonic Acid‐Catalyzed Friedel‐Crafts Alkylation: Towards Sustainable Synthesis of Arylalkanes from Donor–Acceptor Cyclopropane Ketones

AbstractWe present herein Brønsted acid‐catalyzed Friedel‐Crafts alkylation of phenols with Donor–Acceptor cyclopropane ketones. The presence of the 1,4‐diphenyl butan‐1‐one and 1,3‐diphenyl propane‐1‐one motifs in various naturally occurring biologically significant molecules inspired us to pursue the direct synthesis of these structural frameworks. Utilizing methanesulfonic acid (MeSO3H) as a catalyst, we achieved a more environmentally friendly and high‐yielding synthesis, owing to its cost‐effectiveness, biodegradability, transition–metal and additives free conditions. Furthermore, we have successfully extended our developed methodology to thiophenols, resulting in the production of sulfur–based butan‐1‐one derivatives in good yields.

Competition of (3+2) annulation and (3+2) cycloaddition in the reaction of alkenes with donor-acceptor cyclopropanes

Competition of (3+2) annulation and (3+2) cycloaddition in the reaction of alkenes with donor-acceptor cyclopropanes

Hexafluoroisopropanol Promoted Ring‐Opening‐Cyclization of Donor–Acceptor Cyclopropanes with Primary Amines

AbstractWe reveal here a catalyst‐free, ring‐opening‐cyclization of donor‐acceptor cyclopropanes with primary amines to synthesize functionalized dihydropyrroles. This protocol avoids inert conditions and solvents promoted by hexafluoroisopropanol (HFIP). The reaction is quite general with aryl, alkyl, and alicyclic amines. A good number of cyclopropanes bearing keto groups reacted excellently to produce the desired products. Further, we complemented this method with Meldrum's acid‐derived cyclopropanes for synthesizing γ‐lactams. We have demonstrated the post‐synthetic applications of the products and gram‐scale synthesis to highlight the adaptability of this synthetic protocol.

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.

Nickel(II)-Catalyzed Formal [3+2] Cycloadditions between Indoles and Donor-Acceptor Cyclopropanes.

This article describes the development of a nickel-catalyzed regio- and diastereoselective formal [3+2] cycloaddition between N-substituted indoles and donor-acceptor cyclopropanes to synthesize cyclopenta[b]indoles. Optimized reaction conditions provide the desired nitrogen-containing cycloadducts in up to 93% yield and dr 8.6:1 with complete regioselectivity. The substrate scope showed high tolerance to various substituted indoles and cyclopropanes, resulting in the synthesis of six new cyclopenta[b]indoles and the isolation of five derivatives previously reported in the literature. In addition, a mechanistic proposal for the reaction was studied through online reaction monitoring by ESI-MS, allowing for the identification of the reactive intermediates in the Ni(II) catalyzed process. X-ray crystallography confirmed the structure and relative endo stereochemistry of the products. This method enables the fast and efficient construction of fused indolines from readily accessible starting materials.

Synthesis and biological evaluation of 3‐hydroxypyrazoles as aquaporin 9 inhibitors

AbstractA series of 3‐hydroxypyrazole derivatives have been synthesized by a base‐promoted reaction of nitro‐substituted donor–acceptor cyclopropanes with hydrazines. The synthesized compounds have been investigated for their ability to inhibit aquaporin 9 (AQP9) in rat Leydig cells (LC‐540). The protein data bank structure for AQP9 was predicted using homology modeling; and the protein–ligand interaction for the synthesized hydroxyl pyrazole derivatives were analyzed using molecular modeling and docking studies. The results of in silico analyses showed that compound 5b had a higher binding affinity with AQP9 than other compounds. Further, in vitro studies conducted in LC‐540 cells confirmed that compound 5b effectively inhibits AQP9. Hence, compound 5b may be used as an inhibitor in enhancing our understanding of AQP9 function, and in the treatment of several diseases.