The dearomative dicarboxylation of stable heteroaromatics using CO 2 is highly challenging but represents a very powerful method for producing synthetically useful dicarboxylic acids, which can potentially be employed as intermediates of biologically active molecules such as natural products and drug leads. However, these types of transformations are still underdeveloped, and concise methodologies with high efficiency (e.g., high yield and high selectivity for dicarboxylations) have not been reported. We herein describe a new electrochemical protocol using the CO 2 radical anion (E 1/2 of CO 2 = −2.2 V in DMF and −2.3 V in CH 3 CN vs SCE) that produces unprecedented trans-oriented 2,3-dicarboxylic acids from N-Ac-, Boc-, and Ph-protected indoles that exhibit highly negative reduction potentials (−2.50 to −2.94 V). On the basis of the calculated reduction potentials, Nprotected indoles with reduction potentials up to −3 V smoothly undergo the desired dicarboxylation. Other heteroaromatics, including benzofuran, benzothiophene, electron-deficient furans, thiophenes, 1,3-diphenylisobenzofuran, and N-Boc-pyrazole, also exhibit reduction potentials more positive than −3 V and served as effective substrates for such dicarboxylations. The dicarboxylated products thus obtained can be derivatized into useful synthetic intermediates for biologically active compounds in few steps. We also show how the dearomative monocarboxylation can be achieved selectively by choice of the electrolyte, solvent, and protic additive; this strategy was then applied to the synthesis of an octahydroindole-2-carboxylic acid (Oic) derivative, which is a useful proline analogue.

The radical anion of CO 2 (CO 2 •− ) is a strongly nucleophilic radical species with rapidly emerging applications in contemporary organic chemistry. This radical species exhibits high reactivity in single-electron reduction reactions due to the concomitant release of stable CO 2 , or Giese-type reactions, especially for electron-deficient alkenes and styrene derivatives. In contrast to previous reports, we herein disclose the development of a robust method for the introduction of CO 2•− , which can be generated from cesium formate under photoredox/hydrogen atom transfer (HAT) catalysis, into stable heteroaromatics such as benzofuran, benzothiophene, and indole derivatives to afford synthetically useful α-oxy, α-thio, and α-amino acid derivatives in moderate to high yield. In addition, when using electron-deficient naphthalene derivatives, both single-electron reduction and Giese-type nucleophilic addition occur simultaneously to produce carboxylated tetrahydronaphthalene derivatives in good yield. Moreover, one of the tetrahydronaphthalenes that bear a cyano group was transformed into the corresponding γ-butyrolactam via reduction of the cyano functionality through hydrogenation followed by cyclization. To the best of our knowledge, these dearomative carboxylation reactions with metal formates under photoredox/HAT conditions are unprecedented, thus providing a synthetic option for the introduction of a C1 source into stable (hetero)aromatics.

Abstract1,2-Bis(diphenylphosphino)ethane (DPPE) and its synthetic analogues are important structural motifs in organic synthesis, particularly as diphosphine ligands with a C2-alkyl-linker chain. Since DPPE is known to bind to many metal centers in a bidentate fashion to stabilize the corresponding metal complex via the chelation effect originating from its entropic advantage over monodentate ligands, it is often used in transition-metal-catalyzed transformations. Symmetric DPPE derivatives (Ar12P−CH2−CH2−PAr12) are well-known and readily prepared, but electronically and sterically unsymmetric DPPE (Ar12P−CH2−CH2−PAr22; Ar1≠Ar2) ligands have been less explored, mostly due to the difficulties associated with their preparation. Here we report a synthetic method for both symmetric and unsymmetric DPPEs via radical difunctionalization of ethylene, a fundamental C2 unit, with two phosphine-centered radicals, which is guided by the computational analysis with the artificial force induced reaction (AFIR) method, a quantum chemical calculation-based automated reaction path search tool. The obtained unsymmetric DPPE ligands can coordinate to several transition-metal salts to form the corresponding complexes, one of which exhibits distinctly different characteristics than the corresponding symmetric DPPE–metal complex.

Pericyclic reactions, which involve cyclic concerted transition states without ionic or radical intermediates, have been extensively studied since their definition in the 1960s, and the famous Woodward–Hoffmann rules predict their stereoselectivity and chemoselectivity. Here, we describe the application of a fully automated reaction-path search method, that is, the artificial force induced reaction (AFIR), to trace an input compound back to reasonable starting materials through thermally allowed pericyclic reactions via product-based quantum-chemistry-aided retrosynthetic analysis (QCaRA) without using any a priori experimental knowledge. All categories of pericyclic reactions, including cycloadditions, ene reactions, group-transfer, cheletropic, electrocyclic, and sigmatropic reactions, were successfully traced back via concerted reaction pathways, and starting materials were computationally obtained with the correct stereochemistry. Furthermore, AFIR was used to predict whether the identified reaction pathway can be expected to occur in good yield relative to other possible reactions of the identified starting material. In order to showcase its practical utility, this state-of-the-art technology was also applied to the retrosynthetic analysis of a natural product with a relatively high number of atoms (52 atoms: endiandric acid C methyl ester), which was first synthesized by Nicolaou in 1982 and provided the corresponding starting polyenes with the correct stereospecificity via three pericyclic reaction cascades (one Diels–Alder reaction as well as 6π and 8π electrocyclic reactions). Moreover, not only systems that obey the Woodward–Hoffmann rules but also systems that violate these rules, such as those recently calculated by Houk, can be retrosynthesized accurately.

Theory‐driven organic synthesis is a powerful tool for developing new organic transformations. A palladacycle(II), generated from 8‐methylquinoline via C(sp3)−H activation, is frequently featured in the scientific literature, albeit that the reactivity toward CO2, an abundant, inexpensive, and non‐toxic chemical, remains elusive. We have theoretically discovered potential carboxylation pathways using the artificial force induced reaction (AFIR) method, a density‐functional‐theory (DFT)‐based automated reaction path search method. The thus obtained results suggest that the reduction of Pd(II) to Pd(I) is key to promote the insertion of CO2. Based on these computational findings, we employed various one‐electron reductants, such as Cp*2Co, a photoredox catalyst under blue LED irradiation, and reductive electrolysis ((+)Mg/(−)Pt), which afforded the desired carboxylated products in high yields. After screening phosphine ligands under photoredox conditions, we discovered that bidentate ligands such as dppe promoted this carboxylation efficiently, which was rationally interpreted in terms of the redox potential of the Pd(II)‐dppe complex as well as on the grounds of DFT calculations. We are convinced that these results could serve as future guidelines for the development of Pd(II)‐catalyzed C(sp3)−H carboxylation reactions with CO2.

1,2-Bis(diphenylphosphino)ethane (DPPE) and its synthetic analogues are important structural motifs in organic synthesis, particularly as novel diphosphine ligands with a C2-alkyl-linker chain. Since DPPE is known to bind to many metal centers in a bidentate fashion to stabilize the corresponding metal complex via the chelation effect originating from its entropic advantage over monodentate ligands, it is often used in transition-metal-catalyzed transformations, and many unique reactions have been developed using this bidentate ligand. Symmetric DPPE derivatives (Ar12P−CH2−CH2−PAr12) are well-known and readily prepared, but electronically and sterically unsymmetric DPPE (Ar12P−CH2−CH2−PAr22; Ar1 ≠ Ar2) ligands have been less explored, mostly due to the difficulties associated with their preparation. In this study, we disclose a novel synthetic method for not only symmetric but also unsymmetric DPPE derivatives using two phosphine-centered radicals and gaseous ethylene, the latter of which is a useful and fundamental C2 unit that is ubiquitous in industrial processes. The thus obtained unsymmetric DPPE ligands can coordinate to several transition-metal salts in a bidentate fashion to form the corresponding complexes, one of which exhibits distinctly different characteristics than the corresponding symmetric DPPE–metal complex. A feasible radical reaction pathway toward DPPE was successfully designed using the artificial force induced method (AFIR) method, a DFT-based automated reaction path search tool.

Integrated circuits (IC) shown in this cover represent the brain of supercomputers. Several potential three‐dimensional structures of palladacycles derived from 8‐methylquinoline and triphenylphosphine via C(sp3)–H activation were randomly created by the AFIR method with a supercomputing system. One of the proposed structures was reacted with CO2 (abundant, inexpensive, non‐toxic, and renewable C1 source) to afford the targeted carboxylic acid. This series of computation followed by experimentation is a powerful tool for the development of new chemical reactions. More information can be found in the Full Paper by Tsuyoshi Mita, Satoshi Maeda et al.