Sulfur Groups as Directing Tethers in C-H-Bond Functionalizations
Final Report Abstract
The main purpose of this research project was the development of general and synthetically useful C-H bond functionalization reactions. Selective C-H bond functionalization reactions have lately attracted great interest among synthetic chemists, since they avoid the prefunctionalization and transmetallation step of the classical coupling methods. Despite the enormous advances already achieved, there are still some unsolved issues. Initially, an important limitation on the directed C-H functionalization of arenes was addressed. Most of the directing groups used cannot be removed or further modified after the C-H functionalization reaction and, therefore, it constraints the synthetic applicability of these methods. To overcome this important issue, C-S-based detachable and/or modifiable directing groups in the ortho-directed C-H functionalization of arenes were designed. Several aryl sulfones, sulfides and sulfoxides containing different coordinating heterocycles were explored. After systematic studies, the 2-pyridylsulfoxide was identified as an effective directing group. The Pd-catalyzed directed acetoxylation reaction was studied for a variety of arenes with 2-pyridylsulfoxide as the directing group. This reaction proceeded with a high mono-acetoxylation selectivity, broad functionality tolerance, oxido-redox stability and no catalyst poisoning. Moreover, it was demonstrated that the 2-pyridyl group can be easily removed or further modified to generate structural valuable phenolic derivatives such as ortho thiols and disulfides. Furthermore, the development of efficient functionalization of C(sp3)-H bonds under mild reaction conditions was also challenged. In this particular research area, interesting findings in our group redirected the studies from sulfur-directing groups to the use of oxoammonium salts as mild, non-toxic oxidants for the C(sp3)-H bonds functionalization in alpha position to animes and ethers. These types of oxidative C-H transformations are very interesting and with broader applicability since the compounds generated are valuable motifs present in numerous natural and synthetic bioactive compounds. Thus, we have recently introduced the use of TEMPO oxoammoinum salts as mild and efficient oxidants for coupling reactions of C(sp3)-H bonds with enolizable C-nucleophiles such as malonates, β-ketoesters, β-nitroketones and alkyl or α,β-unsaturated aldehydes, as well as with simple olefins. The new methodologies developed provide new synthetic tools for the straightforward modular access to important classes of heterocyclic compounds with potential bioactive properties such as substituted isochromanes, tetrahydroisoquinolines, quinolines, oxazinones or dihydroquinazolines.
Publications
- TEMPO Oxoammoninum Salt Mediated Dehydrogenative Povarov – Oxidation Tandem Reaction of N-Alkyl Anilines”. Org. Lett. 2011, 13, 6066-6069
Heinrich Richter, Olga García Mancheño
- “Catalyzed Selective Direct α- and γ-Alkylation of Aldehydes with Cyclic Benzyl Ethers Using T+BF4- in the Presence of an Inexpensive Organic Acid or Anhydride”. Chem. Eur. J. 2011, 17, 11622-11627
Heinrich Richter, Renate Rohlmann, Olga García Mancheño
- “Modifiable Sulfur Tethers as Directing Groups for Aromatic C–H Acetoxylation Reactions”. Adv. Synth. Catal. 2011, 353, 295-302
Heinrich Richter, Stephan Beckendorf, Olga García Mancheño
- “Mild Metal-free Tandem α-Alkylation/Cyclization of N-Benzyl Carbamates with Simple Olefins”. Chem. Int. Ed. 2012, 51, 8656-8660
Heinrich Richter, Roland Fröhlich, Constantin G. Daniliuc, Olga García Mancheño
(See online at https://doi.org/10.1002/anie.201202379) - “Iron-Catalyzed Oxidative Tandem Reactions with TEMPO Oxoammonium Salts: Synthesis of Dihydroquinazolines and Quinolines”. J. Org. Chem. 2013, 78, 6050-6064
Renate Rohlmann, Tobias Stopka, Heinrich Richter, Olga García Mancheño
(See online at https://doi.org/10.1021/jo4007199) - “Metal-Free Oxidative C(sp3)–H Bond Couplings as Valuable Synthetic Tools for C–C Bond Formations”. Synlett 2013, 24, 6-10
Renate Rohlmann, Olga García Mancheño
(See online at https://doi.org/10.1055/s-0032-1317673)
