Multicomponent One‐pot Reactions Towards the Synthesis of Stereoisomers of Dipicolylamine Complexes

Abstract

Reported are multi-component one-pot syntheses of chiral complexes [M(L(R) OR')Cl2 ] or [M(L(R) SR')Cl2 ] from the mixture of an N-substituted ethylenediamine, pyridine-2-carboxaldehyde, a primary alcohol or thiol and MCl2 utilizing in-situ formed cyclized Schiff bases where a C-O bond, two stereocenters, and three C-N bonds are formed (M=Zn, Cu, Ni, Cd; R=Et, Ph; R'=Me, Et, nPr, nBu). Tridentate ligands L(R) OR' and L(R) SR' comprise two chiral centers and a hemiaminal ether or hemiaminal thioether moiety on the dipicolylamine skeleton. Syn-[Zn(L(Ph) OMe)Cl2 ] precipitates out readily from the reaction mixture as a major product whereas anti-[Zn(L(Ph) OMe)Cl2 ] stays in solution as minor product. Both syn-[Zn(L(Ph) OMe)Cl2 ] and anti-[Zn(L(Ph) OMe)Cl2 ] were characterized using NMR spectroscopy and mass spectrometry. Solid-state structures revealed that syn-[Zn(L(Ph) OMe)Cl2 ] adopted a square pyramidal geometry while anti-[Zn(L(Ph) OMe)Cl2 ] possesses a trigonal bipyramidal geometry around the Zn centers. The scope of this method was shown to be wide by varying the components of the dynamic coordination assembly, and the structures of the complexes isolated were confirmed by NMR spectroscopy, mass spectrometry, and X-ray crystallography. Syn complexes were isolated as major products with Zn(II) and Cu(II) , and anti complexes were found to be major products with Ni(II) and Cd(II) . Hemiaminals and hemiaminal ethers are known to be unstable and are seldom observed as part of cyclic organic compounds or as coordinated ligands assembled around metals. It is now shown, with the support of experimental results, that linear hemiaminal ethers or thioethers can be assembled without the assistance of Lewis acidic metals in the multi-component assembly, and a possible pathway of the formation of hemiaminal ethers has been proposed.

Mechanism of Evolution of Koneramine Complexes from One‐Pot Reactions: Snapshots of Intermediates Offer Facile Routes to New Dipicolylamines

“…The koneramine complexes syn ‐[Cu(L Ph OMe)Cl 2 ], syn ‐[Zn(L Ph OMe)Cl 2 ], anti ‐[Ni(L Ph OMe)(H 2 O)Cl 2 ], and anti ‐[Cd(L Ph OMe)(μ‐Cl)Cl] 2 were isolated when methanol was used as the solvent, where methanol easily attacked the iminium ion 10 . We have equilibrated a mixture of an equivalent of N ‐phenylethylenediamine and two equivalents of pyridine‐2‐carboxaldehyde in isopropanol (Scheme ) . The Cu‐koneramine complex formation at the conditions reported by us recently was performed by adding an equivalent of copper(II) salt as an isopropanol solution .…”

“…We have also reported the stereoselective self‐sorting of koneramines and thiokoneramines by using transition metal ions as external stimuli (Ni 2+ , Cu 2+ , Zn 2+ , Cd 2+ ) . The Cu II ions coordinate with syn forms of koneramines specifically in equatorial fashion; Ni II and Cd II ions facially coordinate with anti ‐koneramines specifically . The Zn II ions predominantly coordinate with syn forms of koneramines specifically in equatorial fashion at room temperature.…”

“…Koneramines are potential tridentate chelates that include a hemi‐aminal ether backbone, two stereogenic centers, and a fourth tertiary nitrogen center, which cannot participate in coordination (Scheme ). Our group recently reported a protocol involving multiple components forming complexes of koneramines . We have also reported the stereoselective self‐sorting of koneramines and thiokoneramines by using transition metal ions as external stimuli (Ni 2+ , Cu 2+ , Zn 2+ , Cd 2+ ) .…”

“…The Zn II ions predominantly coordinate with syn forms of koneramines specifically in equatorial fashion at room temperature. However Zn II complexes of facially bound anti ‐koneramines were isolated at low temperature in low yields . On the other hand, only anti ‐thiokoneramines are known to coordinate to transition metal ions (Ni 2+ , Cu 2+ , Zn 2+ , Cd 2+ ) in equatorial fashion; complexes of syn ‐thiokoneramines have not been isolated yet .…”

“…We have hypothesized that the multicomponent system recently reported by us (Scheme ) produces 2‐(1‐phenylimidazolidin‐2‐yl)pyridine (6 ) as the first checkpoint, which eventually yields the next checkpoint (3‐phenyl‐2‐(pyridin‐2‐yl)imidazolidin‐1‐yl)(pyridin‐2‐yl)methanol ( 8 ); this hemi‐aminal ( 8 ) ultimately delivers the strategic component of the system—3‐phenyl‐2‐(pyridin‐2‐yl)‐1‐(pyridin‐2‐ylmethylene)imidazolidin‐1‐ium cation ( 10 )—which could be attacked by nucleophilic solvent molecules such as alcohols to yield the 2‐(methoxy(3‐phenyl‐2‐(pyridin‐2‐yl)imidazolidin‐1‐yl)methyl)pyridine ( 12 ), a hemi‐aminal ether called a koneramine (R=Ph; R′=Me) . In this paper, we provide unequivocal support for the proposed intermediacy of metastable imidazolidine ( 6 ), hemi‐aminal ( 8 ), and iminium ion ( 10 ) in the formation of koneramines ( 12 ) by tweaking the multicomponent system to divert the equilibrium towards a different emergent.…”