Synthetic Applications of Molybdenum and Tungsten Dearomatization Agents

Author: ORCID icon
Wilde, Justin, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Harman, Walter, Chemistry, University of Virginia

Many aromatic molecules are inexpensive and naturally abundant. While these compounds might seem to be ideal starting materials in the synthesis of saturated derivatives, such chemistry is hindered by aromatic stabilization energy, which is often considerable. The goal of this research was to develop dearomatization chemistry using pi-basic transition metal complexes.

Initially, pyridine dearomatization was explored with a second-row metal system, {MoTp(NO)(DMAP)} (DMAP = 4-(dimethylamino)pyridine; Tp = tris(pyrazolyl)borate). The η2/κN equilibrium was of particular interest, as the similarity of a molybdenum complex to the previously-reported heavy metal analogs was uncertain. A dihapto-coordinate molybdenum pyridine-borane complex was synthesized, however its sensitivity to oxidation made organic reactions impractical. A similar challenge was evident for pyridines bearing electron-donating groups. Nevertheless, 2-(trifluoromethyl)pyridine, with its strong inductively-withdrawing substituent, proved very suitable for organic transformations. Methylation followed by nucleophilic addition (with organomagnesiums, organozincs, amines, etc.) yielded a diverse range of dihydropyridines. The addition was found to occur stereo- and regioselectively.

The second electrophilic, nucleophilic tandem addition was stymied by an unexpected, though not unprecedented, ring-opening reaction. Nevertheless, the dihydropyridines were useful in their own right. Following facile oxidative decomplexation with iodine, the liberated dihydropyridines were shown to participate in Diels-Alder reactions, generating novel bridgehead CF3-substituted isoquinuclidines. This chemistry was then conducted enantioselectively by use of an enantioenriched molybdenum complex, yielding the final isoquinuclidine in >94:6 er. The isoquinuclidine core, which appears in a number of natural products and medicinally-useful substances, prompted us to begin exploring other practical applications of this dearomatization chemistry.

Tungsten was employed to access a parent pyridine complex, via the established chemistry of WTp(NO)(PMe3)(3,4-η2-pyridine borane). Due to the prevalence of amines in biologically-active substances, this class of nucleophiles was investigated in detail. The amine addition was found to have a wide scope, allowing the synthesis of nearly a dozen aminotetrahydropyridine derivatives. A range of substituents including progargyl, azetidinyl, and benzyl groups were found to be tolerated on the amine.

In a related project, several derivatives of a known drug, methylphenidate, were also produced. An assortment of nitrogen protecting groups were screened, and functionalized tetrahydropyridine organics were synthesized with a tosyl substituent on nitrogen, eliminating the characterization issues that are caused by acetyl rotamers. The wide range of tetrahydropyridines accessible from a single η2-pyridine-borane precursor thus demonstrates the potential utility of transition metal-promoted dearomatization in chemical library synthesis.

PHD (Doctor of Philosophy)
dearomatization, organometallic, tungsten, molybdenum, pyridine, isoquinuclidine, synthesis
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