Krapcho Dealkoxycarbonylation Research Articles

Iridium-Catalyzed Branch-Selective Hydroalkylation of Simple Alkenes with Malonic Amides and Malonic Esters

We report the iridium-catalyzed branch-selective hydroalkylation of simple alkenes such as aliphatic alkenes and aromatic alkenes with malonic amides and malonic esters under neutral reaction conditions. A variety of aliphatic alkenes and aromatic alkenes bearing bromine, chlorine, ester, 2-thienylcarboxylate, silyl, and phthalimide groups were all found to be suitable for this hydroalkylation. The combination of this method with Krapcho dealkoxycarbonylation realized a one-pot synthesis of β-substituted amide and ester from β-amide ester and malonic ester. The hydroalkylated products derived from malonic amides are suitable for further transformation. The finely tuned reaction conditions realized the selective transformation of hydroalkylated products to 1,3-diamines or monoamides with the same reagent. Deuterium labeling experiments and measurement of the kinetic isotope effect indicated that the catalytic cycle involves a reversible step and cleavage of the C-H bond is not a rate-determining step. Density functional theory calculations provided insight into the reaction mechanism, where the carboiridation step is followed by C-H reductive elimination.

Iridium-Catalyzed Hydroalkylation of Aliphatic Alkenes with β-Ketoesters: Formal Hydroalkylation with Methyl Ketones

Transition-metal-catalyzed hydroalkylation of alkenes with 1,3-dicarbonyl compounds is a useful reaction to construct a C-C bond under neutral reaction conditions in a highly atom-economical manner. We found that hydroalkylation of aliphatic alkenes with β-ketoesters proceeded with the use of a cationic iridium complex and bidentate phosphine ligand to give selectively branched α-substituted β-ketoesters in high yields. The obtained hydroalkylated compounds can be converted to β-substituted ketones through one-pot Krapcho dealkoxycarbonylation.

Formal Synthesis of (±)-Aplykurodinone-1 Based on the Indium-Catalyzed Conia-Ene Reaction

A concise formal synthesis of (±)-aplykurodinone-1 starting from a commercially available material and based on the indium-catalyzed Conia-ene reaction has been accomplished. The synthesis features a Riley selenium dioxide oxidation, a Krapcho dealkoxycarbonylation, and a ring-closing metathesis approach. The synthetic strategy was also supported by a Saegusa oxidation and a classic Michael 1,4-conjugate addition.

Krapcho Dealkoxycarbonylation Strategy of Ethyl Cyanoacetate for the Synthesis of 3-Hydroxy-3-cyanomethyl-2-oxindoles and 3,3′-Dicyanomethyl-2-oxindoles in a Reaction with Isatin

A new strategy for the synthesis of 3-hydroxy-3-cyanomethyl-2-oxindoles and 3,3′-dicyanomethyl-2-oxindoles in a reaction of isatin with ethyl cyanoacetate by Krapcho dealkoxycarbonylation reaction in aqueous media is demonstrated. The reaction provides an easy access to synthetically and medicinally valuable oxindole alkylnitriles in good to very good yields. Wider substrate scope and operationally simple experimental procedures are highlighted features of the developed protocol. Based on control experiments, a plausible mechanism of reaction and synergistic effect of water is also rationalized.

Asymmetric Synthesis of Dihydropinidine Enabled by Concurrent Multienzyme Catalysis and a Biocatalytic Alternative to Krapcho Dealkoxycarbonylation

Dihydropinidine is a piperidine alkaloid found in spruce needles that has shown promising antifeedant activity against the large pine weevil, a widespread and economically relevant pest of conifero...

Formal synthesis of (±)-aplykurodinone-1 through an intramolecular Michael addition

A concise and straightforward formal synthesis of (±)-aplykurodinone-1, a degraded steroid natural product isolated from sea hare Syphonota geographica is described, based on an intramolecular Michael addition. The route also includes an intermolecular Michael addition, a Riley selenium dioxide oxidation, and a Krapcho dealkoxycarbonylation. The relative stereochemistries of key intermediates have been determined through single-crystal X-ray diffraction analysis.

Continuous high-pressure operation of a pharmaceutically relevant Krapcho dealkoxycarbonylation reaction

The synthesis of the pharmaceutically relevant scaffold 3,4-dihydro-1H-1-benzazepine-2,5-dione via Krapcho dealkoxycarbonylation in a continuous high temperature high pressure coil reactor is investigated and compared to results from batch experiments. In a first step, the continuous reactors residence time distribution (RTD) is characterized, followed by an initial comparison of batch and continuous reactant conversion profiles indicating a very good agreement between both reactors by means of conversion time. Reaction temperature is increased above the solvents atmospheric boiling point in the continuous reactor system to intensify the reaction and increase throughput. Optimal reaction parameters for complete conversion of the starting material in ≤ 3 min reaction time were estimated based on batch kinetics and confirmed by a continuous experiment. The system is able to generate around 12.2 g product per day.

ChemInform Abstract: Concise Approach to Pyrrolizino[1,2‐b]indoles from Indole‐Derived Donor—Acceptor Cyclopropanes.

AbstractThe ring opening of cyclopropanes (I) with sodium azide followed by Krapcho dealkoxycarbonylation and a subsequent Vilsmeier—Haack formylation of resulting azides (II) gives rise to azido aldehydes (IV).

ChemInform Abstract: I2/Cu‐Mediated Self‐Sorting Domino Reaction of Aryl β‐Ketoesters into Symmetrical 2‐Carboalkoxy‐1,4‐enediones: Application to Synthesis of Pyrazine, β‐Carboline and Quinoxalines.

AbstractSymmetrical 1,4‐enediones (II) are obtained from aryl‐β‐ketoesters (I) by a self‐sorting domino reaction involving tandem iodination, self‐dimerization, and Krapcho dealkoxycarbonylation in one‐pot.

ChemInform Abstract: The Krapcho Dealkoxycarbonylation Reaction of Esters with α‐Electron‐withdrawing Substituents

AbstractReview: 1913 refs.

Advances in the Krapcho Decarboxylation

Po. S. Poon, who received her Doctorate degree in 2007 from Venezuelan Institute of Scientific Research (IVIC), is working at IVIC as an Investigator in the Department of Chemistry. Her research encompases the synthesis of terpenoid and bioactive compounds. She was received the Paula Prize from IVIC for her high academic achievement. Manuel S. Laya obtained his MSc degree in 1997 from IVIC and is now working as Research Associate in the Department of Organic Chemistry, IVIC. He has published more than 30 papers, most of which are related to synthetic studies on terpenoid compounds. Ajoy K. Banerjee, who received his PhD in 1965 from the University of Kolkata (India), joined IVIC in 1968. Since 1982 he has been working as Senior Research Scientist. Most of his work is related to synthetic studies on terpenoid compounds (diterpenes and sesquitepenes). He teaches organic chemistry and supervises students who join IVIC for MSc or PhD degrees. Dr Banerjee is the author of two books on organic chemistry, written in Spanish, and several papers. 1. Modifications 2. General features 3. Mechanism 4. Synthetic applications 5. Conclusion 6. References This review provides a brief description of the Krapcho dealkoxycarbonylation and its recent applications in the synthesis of organic compounds and natural products. The general features of the Krapcho reaction, its mechanism and several modifications of the Krapcho reaction are discussed.

Efficient Route to (S)-Azetidine-2-carboxylic Acid

A new and efficient route to (S)-azetidine-2-carboxylic acid (>99.9% ee) in five steps and total yield of 48% via malonic ester intermediates was established. As the key step, efficient four-membered ring formation (99%) was achieved from dimethyl (S)-(1'-methyl)benzylaminomalonate by treating with 1,2-dibromoethane (1.5 eq) and cesium carbonate (2 eq) in DMF. Krapcho dealkoxycarbonylation of dimethyl (1'S)-1-(1'-methyl)benzylazetidine-2,2-dicarboxylate, the product of this cyclization procedure, proceeded with preferential formation (2.7:1, 78% total yield) of the desired (2S,1'S)-monoester, with the help of a chiral auxiliary which was introduced on the nitrogen atom. The undesired (2R,1'S)-isomer could be converted to that with proper stereochemistry, by a deprotonation and subsequent re-protonation step. Finally, lipase-catalyzed preferential hydrolysis of the (2S,1'S)-monoester and subsequent deprotection provided enantiomerically pure (S)-azetidine-2-carboxylic acid in a 91% yield from the mixture of (2S,1'S)- and (2R,1'S)-isomers.

A Convenient Preparation of 4‐Carboxamide Derivatives of Pyridazino[4,5‐b]indoles and Pyridazino[4,5‐b]benzo[b]furans.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Convenient Preparation of 4-Carboxamide Derivatives of Pyridazino[4,5-b]indoles and Pyridazino[4,5-b]benzo[b]furans

Diels-Alder reaction of indole or 3-coumaranone with 3,6-dicarbomethoxy-1,2,4,5-tetrazine followed by MgCl 2 -mediated C-4 regioselective amidation of the tricyclic diester and subsequent Krapcho dealkoxycarbonylation, provided a convenient route to 4-carboxamide derivatives of pyridazino]4,5-b]indoles and pyridazino]4,5-b]benzo]b]furans. 1,4-Biscarboxamide derivatives were also obtained by full amidation of diester intermediates with an excess of the amine.