Reversible 1,4‐Insertion of Pyridine Into a Highly Polar Metal–Carbon Bond: Effect of the Second Metal

Abstract

Dihydropyridines (DHPs) serve as selective reducing agents, are useful building blocks in organic chemistry, and represent an important class of pharmacologically active compounds. Transition-metal catalyzed 1,4-selective hydrosilylations and silaborations of pyridine have recently been reported as two new methods for the synthesis of DHPs. Remarkably, the hydrosilylation was found to be reversible. In general, the phenomenon of reversibility has been recognized for few insertion reactions of organotransition metal complexes. Some of these processes have been turned into applications such as dynamic polymerizations. In contrast, reversible insertion reactions are unusual for polar organometallic compounds of Group 1 and Group 2 metals. To the best of our knowledge, reversible insertion reactions into metal–carbon bonds have not been studied in detail for organometallic compounds of the heavy elements of Groups 1 and 2. We are interested in the reaction of pyridine with allyl metal reagents to give N-metalated DHPs in a one-step reaction. We report here the reversible 1,4-selective insertion of pyridine into a potassium– carbon bond and the synergetic stabilization of the insertion product by divalent metals. The instantaneous reaction of allylpotassium 1 with pyridine in THF at ambient temperature exclusively gave the 1,4-insertion product 2 (Scheme 1). Side products due to 1,2-insertion, deprotonative metalations, or pyridine coupling were not observed. Remarkably, exposure of 2 to 100fold excess of [D5]pyridine resulted in rapid exchange of the C5H5N core for a C5D5N core in an equilibrium reaction as observed by H NMR spectroscopy. [Li ACHTUNGTRENNUNG(C3H5)ACHTUNGTRENNUNG(PMDTA)] and [Na ACHTUNGTRENNUNG(C3H5)] showed similar reactivity patterns (for details see the Supporting Information). The pyridine exchange most likely proceeds via elimination of C5H5N from 2 to form back starting material 1, which then undergoes 1,4-insertion with deuterated pyridine. Rearomatization and entropy could be driving forces for the potassium assisted elimination reaction. Reactions of pyridine with main group organometallics are relatively well studied: insertion reactions with 1,2-selectivity (M=Li, Al), 1,4-selectivity (M=Mg, Ca), and mixtures thereof (M=Mg, Sn) have been reported. However, the reversibility observed in reactions of 2 is unprecedented for insertion reactions involving highly polar organometallic reagents. Compound 2 was isolated and characterized, but is not stable in THF or pyridine, irrespective of the presence of neutral chelating ligands. To investigate the exchange of the pyridine core of N-metalated DHPs in more detail, we sought for a way of stabilizing compound 2 while preserving its striking characteristic of reversibility. Recently, organometallic alkali zincates have been established as powerful tools in organic synthesis, as they can combine the high reactivity of their organoalkali component and the high selectivity of their organozinc component. When [K([18]c-6)] [Zn ACHTUNGTRENNUNG(h1-C3H5)3] (3 ; [18]c-6= [18]crown-6) was treated with excess pyridine, one equivalent of 1, and [18]c-6 (Scheme 2), dianionic tetrakis ACHTUNGTRENNUNG(amido)zincate 4 was obtained in quantitative yield. This is in contrast to reactions [a] Dipl.-Chem. C. Lichtenberg, Dr. T. P. Spaniol, Prof. Dr. J. Okuda Institut f r Anorganische Chemie RWTH Aachen University Landoltweg 1, 52056 Aachen (Germany) Fax: (+49)241-80-92644 E-mail : jun.okuda@ac.rwth-aachen.de [b] Dr. L. Perrin, Prof. Dr. L. Maron Universit de Toulouse et CNRS, INSA, UPS, CNRS UMR 5215 LPCNO 135 avenue de Rangueil, 31077 Toulouse (France) Fax: (+33)561-559-697 E-mail : Laurent.maron@irsamc.ups-tlse.fr Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201200808. Scheme 1. Reaction of allylpotassium 1 with pyridine to give the 1,4-insertion product 2. In the presence of excess [D5]pyridine, the C5H5N core in 2 is exchanged rapidly for a C5D5N core to give [D5]-2.