Michael Schnürch

Direct Functionalization of (Un)protected Tetrahydroisoquinoline and Isochroman under Iron and Copper Catalysis: Two Metals, Two Mechanisms

A highly facile, straightforward synthesis of 1-(3-indolyl)-tetrahydroisoquinolines was developed using either simple copper or iron catalysts. N-protected and unprotected tetrahydroisoquinolines (THIQ) could be used as starting materials. Extension of the substrate scope of the pronucleophile from indoles to pyrroles and electron-rich arenes was realized. Additionally, methoxyphenylation is not limited to THIQ but can be carried out on isochroman as well, again employing iron and copper catalysis.

Halogen dance reactions—A review

Halogen Dance (HD) reactions are a useful tool for synthetic chemists as they enable access to positions in aromatic and heteroaromatic systems for subsequent functionalization which are often difficult to address by other methods, hence, allowing entry to versatile scaffolds. While the method can be extremely useful, this transformation is often neglected upon designing synthetic sequences. This may be largely attributed to the lack of comprehensive reference works covering the general principles and outlining the versatility and limitations of the technique. The following review tries to present HD reactions in a clear and concise manner in order to convince more chemists of its advantages. It covers the field of HD reactions from their first observation in 1951 until the present. The important contributions leading to the elucidation of the mechanism are briefly outlined followed by a detailed mechanistic section and a discussion of factors which influence HD reactions. Finally, an overview of HD reactions on various carbocyclic and heterocyclic ring systems and its applications in the synthesis of complex compounds is given.

Tandem Catalysis: From Alkynoic Acids and Aryl Iodides to 1,2,3-Triazoles in One Pot

A tandem catalysis protocol based on decarboxylative coupling of alkynoic acids and 1,3-dipolar cycloaddition of azides enables a highly efficient synthesis of a variety of functionalized 1,2,3-triazoles. The three-step, one-pot method avoids usage of gaseous or highly volatile terminal alkynes, reduces handling of potentially unstable and explosive azides to a minimum, and furnishes target structures in excellent yields and a very good purity without the need for additional purification.

Direct Functionalization of C−H Bonds by Iron, Nickel, and Cobalt Catalysis

Non-precious-metal-catalyzed reactions are of increasing importance in chemistry due to the outstanding ecological and economic properties of these metals. In the subfield of metal-catalyzed direct C-H functionalization reactions, recent years have shown an increasing number of publications dedicated to this topic. Nickel, cobalt, and last but not least iron, have started to enter a field which was long dominated by precious metals such as palladium, rhodium, ruthenium, and iridium. The present review article summarizes the development of iron-, nickel-, and cobalt-catalyzed C-H functionalization reactions until the end of 2016, and discusses the scope and limitations of these transformations.

Ruthenium(0)-Catalyzed sp3 C–H Bond Arylation of Benzylic Amines Using Arylboronates

A Ru-catalyzed direct arylation of benzylic sp(3) carbons of acyclic amines with arylboronates is reported. This highly regioselective and efficient transformation can be performed with various combinations of N-(2-pyridyl) substituted benzylamines and arylboronates. Substitution of the pyridine directing group in the 3-position proved to be crucial in order to achieve high arylation yields. Furthermore, the pyridine directing group can be removed in high yields via a two-step protocol.

Mechanistic Investigations and Substrate Scope Evaluation of Ruthenium-Catalyzed Direct sp3 Arylation of Benzylic Positions Directed by 3-Substituted Pyridines

A highly efficient direct arylation process of benzylic amines with arylboronates was developed that employs Ru catalysis. The arylation takes place with greatest efficiency at the benzylic sp3 carbon. If the distance to the activating aryl ring is increased, arylation is still possible but the yield drops significantly. Efficiency of the CH activation was found to be significantly increased by use of 3-substituted pyridines as directing groups, which can be removed after the transformation in high yield. Calculation of the energy profile of different rotamers of the substrate revealed that presence of a substituent in the 3-position favors a conformation with the CH2 group adopting a position in closer proximity to the directing group and facilitating C–H insertion. This operationally simple reaction can be carried out in argon atmosphere as well as in air and under neutral reaction conditions, displaying a remarkable functional group tolerance. Mechanistic studies were carried out and critically compared to mechanistic reports of related transformations.

Single Operation Stereoselective Synthesis of Aerangis Lactones: Combining Continuous Flow Hydrogenation and Biocatalysts in a Chemoenzymatic Sequence

Over the last two decades, biocatalysis has matured into a generally accepted approach for laboratory-scale reactions and industrial processes. Selectivity and environmental sustainability of enzymatic transformations are often superior relative to their chemical counterparts, and these transformations ultimately offer the prospect of reducing production costs by minimizing waste and maximizing product output. This competition, however, can never designate a single champion. In many cases, chemical catalysts, especially when paired with a continuous flow reactor design, are difficult to beat in terms of volumetric productivity with state of the art technology. For a long time, laboratory chemistry was confined to the domain of batch reactors. With the emergence of continuous flow reactor devices for research, the field was open for the development of reactions that can rather easily be scaled up to higher volumes without the need for extensive engineering. Within this study, it was our particular aim to combine the two worlds of heterogeneous catalysis and biocatalysis into one simple process that features the excellent selectivity of enzymes and the high productivity of heterogeneous catalytic entities in continuous flow. We identified the aroma compound Aerangis lactone [(S,S)-3] as a suitable target for our proof-of-concept case study: Its two chiral centers allow the selectivity of an integrated chemoenzymatic process to be demonstrated, and its synthetic accessibility from a cheap starting material enables the simplicity of our approach to be outlined (Scheme 1). The target compound possesses highly interesting olfactory properties: it was characterized as the main odor component of African white-flowering orchids and is widely used in the perfume and cosmetics industries. The immediate advantages of our concept involving the integration of chemoenzymatic processes can easily be reasoned by comparison to previous routes towards the asymmetric product. Various multistep stereoselective syntheses consisting of a minimum of seven steps have been reported for (S,S)-3, but their complexity and elaborate protecting group chemistry prohibits efficient production of (S,S)-3 on a larger scale. A simple but completely unselective two-step approach to Aerangis lactone was described in a patent by Kaiser starting from cheap dihydrojasmone (1; <150 E kg , Sigma–Aldrich) through catalytic hydrogenation to saturated ketone 2 and subsequent Baeyer–Villiger oxidation (BVOx); however, this route yielded a mixture of all four possible stereoisomers of 3. We based our process design on this principal approach by additionally employing diastereoand enantioselective catalysts to specifically produce natural (5S,6S)-3 in a single operation by hydrogenation in continuous flow and enzymatic BVOx in a subsequent batch reactor. This approach should overcome safety issues by limiting the amount of pressurized reaction volume during the hydrogenation phase. Furthermore, hazardous reagents (such as peracids) can be replaced by alternatively utilizing Baeyer–Villiger monooxygenases (BVMOs), which operate with molecular oxygen as a primary oxidant at ambient pressure. Finally, application of a flow chemical setting also enabled single-operation access to epimer (5R,6S)-3. The design of the envisioned single-operation procedure demanded that certain prerequisites be met for the single reaction steps and further required additional adaptations to facilitate the direct coupling of the reactors in-line without interScheme 1. Stereoselective synthesis of natural Aerangis lactone [(S,S)-3] and its epimer (R,S)-3 via nonisolated saturated ketones 2. Reagents and conditions: a) 5 % Rh/C, Cs2CO3 1:5; H2; 0.5 m 1 in heptane; 30 8C; 1.0 mL min 1 c.f. ; quant. b) Amberlyst 15, 0.5 m cis-2 in heptane, 25 8C, 1.0 mL min 1 c.f. , quant. c) Up to 20 mm cis-2, G6P (0.5 equiv.), 2 % w/v CDMO crude cell extract, 5 U ml 1 G6PDH, 2 % w/v Triton X-100, 200 mm NADP , 50 mm TrisHCl pH 7.1, water. d) Same conditions as those given in c) by using CPMO instead of CDMO. c.f. = continuous flow, CDMO = cyclododecanone monooxygenase, CPMO = cyclopentanone monooxygenase, G6PDH = glucose-6-phosphate dehydrogenase, G6P = glucose-6-phosphate.

Ruthenium(II)-Catalyzed sp3 C–H Bond Arylation of Benzylic Amines Using Aryl Halides

A ruthenium(II)-catalyzed protocol for the direct arylation of benzylic amines was developed. Employing 3-substituted pyridines as directing groups, arylation was achieved using aryl bromides or aryl iodides as the aryl source. Potassium pivalate proved to be an important additive in this transformation. The arylation took place selectively in the benzylic sp(3) position, and no significant competitive sp(2) arylation was observed. Arylated imines were observed as byproducts in minor amounts. Additionally, reaction conditions for cleaving the pyridine group were established, enabling access to bis-arylated methylamines.

Direct Arylation of Benzo[b]furan and Other Benzo‐Fused Heterocycles

The direct arylation of benzo[b]furan, benzo[b]thiophene, and indole has been studied by using aromatic bromides as the aryl source. The protocol employing common reagents and a Pd catalyst has led to the regioselective arylation of these heterocycles at the 2-position. A range of functional groups were tolerated, providing quick access to a variety of arylated benzo-fused heterocycles that would be accessible more elaborately using classical synthetic strategies. This is the first systematic study of the direct arylation of benzo[b]furan.

Selective Ru(0)-catalyzed deuteration of electron-rich and electron-poor nitrogen-containing heterocycles.

A highly selective Ru(3)(CO)(12)-catalyzed deuteration method using t-BuOD as deuterium source is reported. Electron-rich and electron-poor N-heteroarenes such as indoles, azaindoles, deazapurines, benzimidazole, quinolines, isoquinolines, and pyridines were efficiently deuterated at specific positions with high selectivity; in most cases, deuterium incorporation was close to the theoretically possible values. To further increase deuteration degrees, several cycles of the reaction protocol can be carried out which gave superior deuteration degrees employing a much lower excess of deuterating agent compared to established protocols. It was proved that the same protocol can in principle be applied to tritiation reactions important for radioactive labeling of bioactive molecules.