Final Report Summary - NEW ORGANOMETALLICS (Preparation of polyfunctional organometallics: new key intermediates for synthetic organic chemistry)
In our Advanced ERC grant “New Organometallics” we have developed a range of new preparations of highly functionalized organometallics mainly of magnesium, zinc, aluminum, indium and manganese and have demonstrated their high synthetic utility for the construction of complex molecules of interest in the pharmaceutical and agrochemical industry. These preparation methods can be devised in three general methods: (1) metal insertions (20 publications); halogen-metal exchange (7 publications); and (3) directed metalations (39 publications). These methods are now commonly used by pharmaceutical, agrochemical and chemical companies (kilogram- to ton-scale production). In the course of this grant, we have discovered a preparation method of solid organozinc reagents which are air-stable and display low moisture sensitivity. These reagents have a real industrial potential; have been patented by the Ludwig-Maximilians-University Munich. Thus, we have demonstrated that LiCl accelerates dramatically the insertion of metals to an organic halide. This allows a smooth preparation of polyfunctional magnesium reagents. By using the cocktail Mg, LiCl, ZnCl2, the reaction scope can be further extended. The activation effect of LiCl for metal insertion can be applied to many other metals. We have studied in some details the insertion of aluminum to aromatic and heterocyclic iodides and bromides. We have discovered that iPrMgCl•LiCl is a very active reagent for performing efficient I/Mg- and Br/Mg-exchange reactions. It is now used at the ton-scale for the production of pharmaceutical intermediates. Finally, we have discovered reaction conditions allowing a stereoselective I/Li-exchange reaction. This reaction is very promising and allows the stereoselective preparation of a range of highly functionalized cyclohexan rings. The reaction has been extended recently in our laboratory to acyclic iodides with great success. We have developed a simple synthesis of sterically hindered TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl) complexed with LiCl. These bases are not only highly soluble, but also kinetically highly active for the performance of stoichiometric C-H activation of a broad range of unsaturated molecules. Thus, a broad range of functionalized aromatic molecules can undergo selective C-H activation reaction using TMPZnCl•LiCl or TMPMgCl•LiCl. The use of microwave irradiation has further extended the reaction scope and zincation with TMPZnCl•LiCl can be successfully performed under microwave irradiation at temperatures up to 160 °C. The use of BF3 as promotor for metalation allowed us to functionalize the quinine skeleton and to prepare regioselective alkaloid derivatives. The activation of TMP-Zn bases with the Lewis-acid (MgCl2) has allowed functionalization of the chromone and thiochromone heterocycles. All these new bases have found numerous applications and have allowed to prepare for the first time a range of polyfunctional aryl and heteroaryl derivatives of Al, Zr, Fe, Mn and La. One highlight of this research grant is certainly the preparation of air stable solid organozinc reagents. Organozincs are highly pyrophoric and hygroscopic organometallic reagents which are dangerous to manipulate neat due to their high tendency to ignite in air, especially Me2Zn, Et2Zn and iPr2Zn which can be handle only by experienced organometallic chemists. In this ERC grant, we have discovered that the combination of various zinc reagents with zinc pivalate (Zn(OCOtBu)2) or related metal carboxylates lead to stable organometallic solids (after removal of the solvents), moreover these reagents have an excellent air stability. These reagents have been patented by the LMU Munich. Although this chemistry is still in its infancy, its synthetic potential is enormous, since it could on a long run, replace the expensive organoboronates. Preliminary applications in their use for high-throughput screenings for the search of pharmaceutically active molecules are most promising.
We have also shown that polyfunctional zinc and magnesium organometallics can be readily aminated using a transmetalation to the corresponding amido-copper reagents and subsequent oxidation with PhI(OAc)2. The discovery of a cobalt-catalyzed sulfonate/copper exchange led us to study in more detail the possibility of using cobalt and related metals such as iron or chromium for the performance of cross-coupling reactions. We found that iron(III) salts also catalyze in the presence of quinoline or isoquinoline a range of cross-couplings with heterocyclic substrates (for which the Pd-catalyzed cross-couplings are much more difficult). Very recently we have discovered that CrCl2 is also an excellent catalyst for the cross-coupling between Csp2-centers.
We have also shown that polyfunctional zinc and magnesium organometallics can be readily aminated using a transmetalation to the corresponding amido-copper reagents and subsequent oxidation with PhI(OAc)2. The discovery of a cobalt-catalyzed sulfonate/copper exchange led us to study in more detail the possibility of using cobalt and related metals such as iron or chromium for the performance of cross-coupling reactions. We found that iron(III) salts also catalyze in the presence of quinoline or isoquinoline a range of cross-couplings with heterocyclic substrates (for which the Pd-catalyzed cross-couplings are much more difficult). Very recently we have discovered that CrCl2 is also an excellent catalyst for the cross-coupling between Csp2-centers.