Shapiro Reaction Research Articles

Preparation of Vinylic Lithium Reagents from Silyl Enolates of Alkyl Aryl Ketones Using Lithium Arenide

AbstractThe preparation of vinylic lithium reagents from vinylic halides is a common practice in organic synthesis. However, the preparation of vinylic halides is not always straightforward. In this study, we propose the use of silyl enolates of alkyl aryl ketones as a readily available and efficient alternative for generating vinylic lithium species. Treatment of triisopropylsilyl enolates of alkyl aryl ketones with lithium naphthalenide or lithium 4,4’‐di‐t‐butylbiphenylide affords the corresponding vinylic lithium species. This preparation represents a reductive transformation of electron‐rich silyl enolates, which had remained unexplored. This process provides an alternative to the Shapiro reaction and has great potential for various applications in organic synthesis.

Nickel-Catalyzed Stereoselective Alkenylation of Ketones Mediated by Hydrazine

The direct conversion of naturally abundant carbonyl compounds provides a powerful platform for the efficient synthesis of valuable chemicals. In particular, the conversion of ketones to alkenes is a commonly encountered chemical transformation, often achieved via the multistep Shapiro reaction with tosylhydrazone and over stoichiometric organolithium or Grignard reagent. Herein, we report an earth abundant nickel-catalyzed alkenylation of naturally abundant methylene ketones to afford a wide range of alkene derivatives, mediated by hydrazine. The protocol features a broad substrate scope (including alkyl ketones, aryl ketones, and aldehydes), good functional group compatibility, mild reaction conditions, water tolerance, and only environmentally friendly N2, H2, and H2O as theoretical byproducts. Moreover, gram-scale synthesis with good yield and generation of pharmaceutical intermediates highlighted its practical applicability.

Synthesis of a deuterated probe for the confocal Raman microscopy imaging of squalenoyl nanomedicines.

The synthesis of ω-di-(trideuteromethyl)-trisnorsqualenic acid has been achieved from natural squalene. The synthesis features the use of a Shapiro reaction of acetone-d6 trisylhydrazone as a key step to implement the terminal isopropylidene-d6 moiety. The obtained squalenic acid-d6 has been coupled to gemcitabine to provide the deuterated analogue of squalenoyl gemcitabine, a powerful anticancer agent endowed with self-assembling properties. The Raman spectra of both deuterated and non-deuterated squalenoyl gemcitabine nanoparticles displayed significant Raman scattering signals. They revealed no differences except from the deuterium peak patterns in the silent spectral region of cells. This paves the way for label-free intracellular trafficking studies of squalenoyl nanomedicines.

A Facile Route to Ursodeoxycholic Acid Based on Stereocontrolled Conversion and Aggregation Behavior Research

A facile route to ursodeoxycholic acid (UDCA) and its aggregation behavior in aqueous phase solution, which is rarely known, are reported. The starting material, hyodeoxycholic acid (HDCA), is a relatively less expensive material and more easily obtained compared with chenodeoxycholic acid (CDCA). A facile route was developed to synthesize UDCA from HDCA with a Shapiro reaction as the key step and in 26% overall yield. A new strategy using organosilane reagent considering its stability, nontoxicity, and abundance in nature was carried out for a more rapid route and higher yield. It was found that the critical micelle concentration value, which is a critical value for surfactants of bile salts, was influenced by the number of hydroxyl groups.

ChemInform Abstract: Cs2CO3‐Promoted Carboxylation of N‐Tosylhydrazones with Carbon Dioxide Toward α‐Arylacrylic Acids.

AbstractThe procedure includes Cs2CO3 as the base at +80 °C and is thus quite different from the traditional Shapiro reaction (BuLi at ‐78 °C).

On the mechanism of the Shapiro reaction: understanding the regioselectivity

A DFT computational exploration of the mechanism of the Shapiro reaction is presented together with some suggestions to control the regiochemistry of the main isomer.

ChemInform Abstract: Preparation of Fluoroalkenes via the Shapiro Reaction: Direct Access to Fluorinated Peptidomimetics.

Fluoroalkenes represent a useful class of peptidomimetics with distinct biophysical properties. Current preparations of this functional group commonly provide mixtures of E- or Z-fluoroalkene diastereomers, and/or mixtures of nonfluorinated products. To directly access fluoroalkenes in good stereoselectivity, a Shapiro fluorination reaction was developed. Fluoroalkene products were accessed in one- or two-step sequences from widely available ketones. This strategy should be useful for the preparation of fluorinated analogs of peptide-based therapeutics, many of which would be challenging to prepare by alternate strategies.

Preparation of Fluoroalkenes by the Shapiro Reaction

Preparation of Fluoroalkenes by the Shapiro Reaction

Preparation of Fluoroalkenes via the Shapiro Reaction: Direct Access to Fluorinated Peptidomimetics

Fluoroalkenes represent a useful class of peptidomimetics with distinct biophysical properties. Current preparations of this functional group commonly provide mixtures of E- or Z-fluoroalkene diastereomers, and/or mixtures of nonfluorinated products. To directly access fluoroalkenes in good stereoselectivity, a Shapiro fluorination reaction was developed. Fluoroalkene products were accessed in one- or two-step sequences from widely available ketones. This strategy should be useful for the preparation of fluorinated analogs of peptide-based therapeutics, many of which would be challenging to prepare by alternate strategies.

Use of RCM Reactions for Construction of Eight-Membered Carbocycles and Introduction of a Hydroxy Group at the Juncture between Five- and Eight-Membered Carbocycles

Model studies for total synthesis of YW3699 were carried out in order to introduce a hydroxy group at the ring juncture between 5- and 8-membered carbocycles. The five-membered ring part, hydrazone, and aldehyde with a cyclohexane ring were connected by the Shapiro reaction, followed by conversion to diketones, which were treated with IBX to afford hydroxylated models.

Diazo Compounds and N-Tosylhydrazones: Novel Cross-Coupling Partners in Transition-Metal-Catalyzed Reactions

Transition-metal-catalyzed carbene transformations and cross-couplings represent two major reaction types in organometallic chemistry and organic synthesis. However, for a long period of time, these two important areas have evolved separately, with essentially no overlap or integration. Thus, an intriguing question has emerged: can cross-coupling and metal carbene transformations be merged into a single reaction cycle? Such a combination could facilitate the development of novel carbon-carbon bond-forming methodologies. Although this concept was first explored about 10 years ago, rapid developments inthis area have been achieved recently. Palladium catalysts can be used to couple diazo compounds with a wide variety of organic halides. Under oxidative coupling conditions, diazo compounds can also react with arylboronic acids and terminal alkynes. Both of these coupling reactions form carbon-carbon double bonds. As the key step in these catalytic processes, Pd carbene migratory insertion plays a vital role in merging the elementary steps of Pd intermediates, leading to novel carbon-carbon bond formations. Because the diazo substrates can be generated in situ from N-tosylhydrazones in the presence of base, the N-tosylhydrazones can be used as reaction partners, making this type of cross-coupling reaction practical in organic synthesis. N-Tosylhydrazones are easily derived from the corresponding aldehydes or ketones. The Pd-catalyzed cross-coupling of N-tosylhydrazones is considered a complementary reaction to the classic Shapiro reaction for converting carbonyl functionalities into carbon-carbon double bonds. It can also serve as an alternative approach for the Pd-catalyzed cross-coupling of carbonyl compounds, which is usually achieved via triflates. The combination of carbene formation and cross-coupling in a single catalytic cycle is not limited to Pd-catalyzed reactions. Recent studies of Cu-, Rh-, Ni-, and Co-catalyzed cross-coupling reactions with diazo compounds or N-tosylhydrazones show that these transformations also work with other transition metals, demonstrating the generality of the diazo compounds as new cross-coupling partners in transition-metal-catalyzed coupling reactions.

Modified Shapiro Reactions with Bismesitylmagnesium As an Efficient Base Reagent

Bismesitylmagnesium has been shown to successfully mediate the Shapiro reaction. A range of tosylhydrazones has been subjected to the developed system, which furnishes exceptionally high incorporation of the introduced electrophiles and good yields of the functionalized styrenes. At conveniently accessible temperatures and with a comparably small excess of base reagent, this protocol offers an efficient alternative to the lithium-mediated process. Importantly, 1.05 equiv of Weinreb amides are sufficient to obtain aryl enones in good yields.

Concise Synthesis of Norrisolide

AbstractThe marine natural product norrisolide has been synthesized in a convergent manner with a longest linear sequence of 14 steps. The hydrindane portion of the molecules is prepared through conjugate addition of a functionalized allyl group into cyclopentenone, followed by stereoselective trapping of the enolate generated from the resulting enol silyl ether with an allyl electrophile. Ring‐closing metathesis then establishes the 6–5 ring system. Likewise, selective preparation of the side chain features an enantioselective cyclopropanation of furan‐2‐one, followed by rearrangement and hydrogenation. Coupling of the two major fragments through a Shapiro reaction, followed by reduction and olefination then completes the carbon framework of the natural product. The final steps of the synthesis involve adjustments to the oxidation state of the side chain. New strategies to generate both the hydrindane core and the oxidized side chain has allowed for the more concise and efficient preparation of the natural product.

Enantioselective synthesis of a taxol C ring

An enantioselective synthesis of a C ring of taxol has been accomplished. The key step is an oxidative cleavage of a derivative of the Wieland–Miescher ketone. A first attempt of a Shapiro reaction modelling the coupling of the C ring with the A fragment of taxol was also successful.

Synthesis of a Novel Taxa‐Oxa‐Sugar Hybrid Core Structure by Tandem Cross‐Enyne Metathesis/IMDA

AbstractThis paper describes our design and efforts in synthesizing new scaffolds with taxol‐eleutherobin hybrid core structures and a taxol‐sugar hybrid. The synthesis of taxol‐eleutherobin hybrids involved the synthesis of the A‐ring fragment from carvone and the C‐ring fragment from either D‐mannose or D‐glucose. The Shapiro reaction was used as the key reaction to couple the A‐ and C‐ring fragments of these hybrid structures. Unfortunately, another key reaction (RCM) failed to form the B‐ring and essentially the core unit. However, a tandem enyne cross‐metathesis/intramolecular Diels–Alder strategy was utilized for the synthesis of a taxa‐oxa‐sugar hybrid.

Synthesis of Vinigrol

The important biological properties, such as platelet aggregation inhibition, antihypertensive activity, and tumor necrosis factor antagonism, coupled with a high degree of structural complexity have rendered vinigrol a target of widespread interest in the synthetic community. Key transformations in the present approach include a highly selective 1,3-dipolar cycloaddition to give tetracycle C, a Saegusa deamination of bromo­isoxazole E and a Shapiro reaction to complete the carbon skeleton.

Convenient Preparation of Cycloalkenyl Boronic Acid Pinacol Esters

A practical method for the preparation of cycloalkenyl boronic acid pinacol esters is described. These important synthetic intermediates are typically made using more expensive methods like transition metal-catalyzed borylation of alkenyl halides or triflates. In this work, they are obtained from the simple corresponding cycloalkanones, which are subjected to Shapiro reaction conditions followed by trapping with a borate ester. The requisite products are obtained in very good to excellent yields, and the reactions can be scaled up to multigram amounts. By providing a simple alternative to common methods that make use of expensive transition-metal catalysts and formation of sensitive intermediates, this convenient method will be useful for the synthesis of ring-containing partners for Suzuki–Miyaura cross-coupling and other reactions employing boronic esters as substrates.

Synthesis, Stability, and Crystal Structure of an Azulenium Cation Containing an Adamantyl Group

AbstractStarting from the trimethylsilyl enol ether of 1‐acetyl‐1,3,5‐cycloheptatriene, the title 1H‐azulenium cation was synthesized by a five‐step sequence that involved a Noyori–Mukaiyama aldol reaction, a Nazarov cyclization, a Shapiro reaction, and a hydride abstraction. The Nazarov reaction of the aldol‐type adduct resulted in the formation of an unusual double‐bond position isomer, which has never been obtained in similar reactions forming tetrahydroazulenones. The pKR+ value of the title cation was found to be 9.8, which is less than that expected by inductive stabilization from the number of carbons at the 1‐position. The X‐ray crystal structure of the title cation (ClO4– salt) reveals CH–O interactions and deformation of the azulenyl ion part.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

The Shapiro reaction of barrelene derivatives: the influence of annelation on acene formation

The possible formation of pentacene from a tosylhydrazone of 6,13-dihydro-6,13-ethenopentacene under the conditions of the Shapiro reaction is explored, as previous work demonstrated that the tosylhydrazone of barrelene (bicyclo[2.2.2]octatriene) yields benzene under these conditions [C. Weitemeyer, T. Preuss, and A. de Meijere, Chem. Ber., 1985, 118, 3993]. The computational analyses based on homodesmotic equations involving the anions, and monomeric (including the dimethyl ether solvate) and dimeric organolithium compounds reveals that benzene formation is exothermic, but pentacene formation is endothermic due to the increased stability of the lithium derivative and the decreased stability of pentacene. The computational predictions are confirmed by experimental investigations.

Synthesis of 3‐Phenyl‐4‐piperidones from Acetophenone by Shapiro and Aza‐Michael Reactions and Their Further Derivatization

AbstractThe Shapiro reaction of acetophenone is the key in a convenient three‐step access to a divinyl ketone which is further transformed by double aza‐Michael reactions with primary amines into N‐substituted 3‐phenyl‐4‐piperidones. In the case of N‐benzyl and N‐allyl derivatives, the piperidine nitrogen atom can be deprotected and further functionalized, for example, by carboxamide, carbamate, or urea formation.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)