Souvik Rakshit

Rh(III)-Catalyzed Directed C−H Olefination Using an Oxidizing Directing Group: Mild, Efficient, and Versatile

An efficient Rh(III)-catalyzed oxidative olefination by directed C-H bond activation of N-methoxybenzamides is reported. In this mild, practical, selective, and high-yielding process, the N-O bond acts as an internal oxidant. In addition, simply changing the substituent of the directing/oxidizing group results in the selective formation of valuable tetrahydroisoquinolinone products.

Pyrrole Synthesis via Allylic sp3 C−H Activation of Enamines Followed by Intermolecular Coupling with Unactivated Alkynes

A conceptually novel pyrrole synthesis is reported, efficiently merging enamines and (unactivated) alkynes under oxidative conditions. In an intermolecular Rh catalyzed process, the challenging allylic sp(3) C-H activation of the enamine substrates is followed by the cyclization with the alkyne (R(3) = CO(2)R). Alternatively, in some cases (R(3) = CN), the enamine can be utilized for a vinylic sp(2) C-H activation. A total of 17 examples with yields above 60% is presented, together with the results of an initial mechanistic investigation.

Palladium‐Catalyzed Oxidative Cyclization of N‐Aryl Enamines: From Anilines to Indoles

The indole unit is one of the most abundant and relevant heterocycles in natural products and pharmaceuticals. Despite the existence of numerous methods for the synthesis and derivatization of indoles, the development of new, more efficient methods is of great importance. In this context, direct oxidative C C coupling by the selective activation of two C H bonds is a promising synthetic strategy. In contrast to established cross-coupling methods, such as the Suzuki– Miyaura coupling, prefunctionalization of the reaction centers is not required. For example, electron-rich aniline substrates can be activated and functionalized by electrophilic aromatic palladation under acidic conditions to give indolequinones or carbazoles. However, the limited scope of these reactions, the frequent requirement of a stoichiometric amount of a palladium complex, and the low yields often observed limit the usefulness of these methods. Furthermore, simple non-annulated indoles could not be prepared under these acidic conditions. Herein, we report an efficient synthesis of functionalized indoles from commercially available anilines by palladiumcatalyzed, intramolecular oxidative coupling. As this cyclization does not proceed through electrophilic aromatic palladation, a large variety of anilines can be used in this reaction. Our investigation commenced with the cyclization of methyl (Z)-3-(phenylamino)but-2-enoate (1a) to give the corresponding indole 2a. In experiments to optimize the reaction, the best results were obtained with a catalytic amount of Pd(OAc)2, Cu(OAc)2 as the oxidant, and K2CO3 as the base in DMF (Table 1, entry 1). Under these conditions, conversion was complete within 3 h at 80 8C (72% yield of the isolated product), or within less than 15 min at 140 8C, even when only 5 mol% of Pd(OAc)2 was used (not shown). Variation of the oxidant (Table 1, entries 3–6), the base (Table 1, entries 7 and 8), or the solvent (Table 1, entries 9–11) led to a decrease in the yield. The use of acetic acid as the solvent resulted in the rapid decomposition of the substrate and therefore no product formation (Table 1, entry 11). The results with Pd(TFA)2 (TFA= trifluoroacetate) were similar to those observed under the optimal conditions (Table 1, entry 12), whereas the addition of PPh3 resulted in the formation of a less active catalyst (Table 1, entry 13). Interestingly, chloride anions do not influence the reaction at all (Table 1, entry 14). A great variety of substituted anilines can be transformed into the corresponding indoles under the optimized reaction conditions (Table 2). In some cases, an increased reaction temperature (and, consequently, a shorter reaction time) led to higher yields. Substrates with a variety of electron-donating (Table 2, entries 2–8) and electron-withdrawing substituents (Table 2, entries 9–19) were converted directly into the indole products, which are versatile building blocks for subsequent synthetic modification, for example, through modern crosscoupling reactions (Table 2, entries 12–14). The ability to vary the aniline moiety so broadly is a distinct advantage of this new indole synthesis. In the case of meta-substituted substrates 1, two regioisomeric indole products 2 can be formed. Intriguingly, exclusive Table 1: Optimization of the reaction conditions.

Palladium-Catalyzed Intermolecular Decarboxylative Coupling of 2-Phenylbenzoic Acids with Alkynes via C−H and C−C Bond Activation

A novel protocol for palladium-catalyzed intermolecular formal [4 + 2] annulation of 2-phenylbenzoic acids with alkynes is described. Acridine is shown to be essential for the high reaction efficiency. Phenanthrene derivatives are formed in moderate to good yields without coupling (pseudo)halides or organometallic species.

Exploring the Oxidative Cyclization of Substituted N‐Aryl Enamines: Pd‐Catalyzed Formation of Indoles from Anilines

The direct Pd-catalyzed oxidative coupling of two C-H-bonds within N-aryl-enamines 1 allows the efficient formation of differently substituted indoles 2. In this cross-dehydrogenative coupling, many different functional groups are tolerated and the starting material N-aryl-enamines 1 can be easily prepared in one step from commercially available anilines. In addition, the whole sequence can also be run in a one-pot fashion. Optimization data, mechanistic insight, substrate scope, and applications are reported in this full paper.

C–H Arylation of Pyridines: High Regioselectivity as a Consequence of the Electronic Character of C–H Bonds and Heteroarene Ring

We report a new catalytic protocol for highly selective C-H arylation of pyridines containing common and synthetically versatile electron-withdrawing substituents (NO(2), CN, F and Cl). The new protocol expands the scope of catalytic azine functionalization as the excellent regioselectivity at the 3- and 4-positions well complements the existing methods for C-H arylation and Ir-catalyzed borylation, as well as classical functionalization of pyridines. Another important feature of the new method is its flexibility to adapt to challenging substrates by a simple modification of the carboxylic acid ligand or the use of silver salts. The regioselectivity can be rationalized on the basis of the key electronic effects (repulsion between the nitrogen lone pair and polarized C-Pd bond at C2-/C6-positions and acidity of the C-H bond) in combination with steric effects (sensitivity to bulky substituents).

Constructing Iboga Alkaloids via C–H Bond Functionalization: Examination of the Direct and Catalytic Union of Heteroarenes and Isoquinuclidine Alkenes

The iboga alkaloids have attracted considerable attention in both the scientific community and popular media due to their reported ability to reverse or markedly diminish cravings for, and self-administration of, the major drugs of abuse. We have developed three new intramolecular C-H functionalization procedures leading to the core seven-membered ring of the iboga skeleton, a cyclization that proved to be highly challenging. The electrophilic palladium salt Pd(CH3CN)4(BF4)2 was effective for the cyclization of diverse N-(2-arylethyl)isoquinuclidines with yields of 10-35%. A two-step, bromination-reductive Heck reaction protocol was also effective for the synthesis of ibogamine in 42% yield. Finally, a direct Ni(0)-catalyzed C-H functionalization provided the benzofuran analogues of ibogamine (74%) and epi-ibogamine (38%). Although each approach suffers from significant shortcomings, in combination, the methods described provide practical routes to diverse ibogamine analogues.