Tri(Amino-PEG3-amide)-amine

The use of dynamic covalent reactions (DCRs) is gaining popularity for the construction of self-assembling architectures. We have recently introduced DCRs that exchange alcohols and aldehydes to create hemiaminal ethers within tri(2-picolyl)amine (TPA) ligands, all of which are templated by Zn(II). To expand the scope of this assembly, aromatic imines derived from pyridine-2-carboxyaldehyde were explored as dynamic covalent receptors for di(2-picolyl)amine in the presence of Zn(II) to create TPA ligands that contain aminal linkages. This represents another metal-templated in situ multicomponent assembly. The stability of the assembly was successfully modulated through substituent effects, and the equilibrium constants from imines to aminals were correlated by a linear free energy relationship (LFER) with σ(+) values. Dynamic component exchange was investigated as a means of probing multiple equilibriums quantitatively in the system. Further, the mechanism was analyzed with a qualitative kinetics study. NMR spectra reveal the different extents of two competing pathways for assembly depending upon whether the aromatic amine has electron-withdrawing or electron-donating groups on the ring. Finally, mass spectral evidence supports the presence and differing extents of dominance of the two pathways as a function of the substituents.

Palladium-catalyzed para-C-H bond amination of 2-aryl chloromethylbenzenes is described for the first time. The reactions of 2-aryl chloromethylbenzenes with cyclic amines proceeded smoothly in the presence of Pd(acac)2, tri(2-furyl)phosphine, and NaH in tetrahydrofuran at 40 °C to provide para-C-H bond aminated products in satisfactory to high yields with acceptable regioselectivity in most cases. The electronic property of the substituents linked to the benzene rings did not significantly influence the reactivity of the 2-aryl chloromethylbenzene substrates and the reaction regioselectivity.

Among the C6-halo purine ribonucleosides, the readily accessible 6-chloro derivative has been known to undergo slow SNAr reactions with amines, particularly aryl amines. In this work, we show that in 0.1 M AcOH in EtOH, aryl amines react quite efficiently at the C6-position of 2',3',5'-tri-O-(t-BuMe2Si)-protected 6-chloropurine riboside (6-ClP-riboside), with concomitant cleavage of the 5'-silyl group. These two-step processes proceeded in generally good yields, and notably, reactions in the absence of AcOH were much slower and/or lower yielding. Corresponding reactions of 2',3',5'-tri-O-(t-BuMe2Si)-protected 6-ClP-riboside with alkyl amines proceeded well but without desilylation at the primary hydroxyl terminus. These differences are likely due to the acidities of the ammonium chlorides formed in these reactions, and the role of AcOH was not desilylation but possibly only purine activation. With 50% aqueous TFA in THF at 0 °C, cleavage of the 5'-silyl group from 2',3',5'-tri-O-(t-BuMe2Si)-protected N6-alkyl adenosine derivatives and from 6-ClP-riboside was readily achieved. Reactions of the 5'-deprotected 6-ClP-riboside with alkyl amines proceeded in high yields and under mild conditions. Because these complementary methodologies yielded N6-aryl and -alkyl adenosine derivatives containing a free 5'-hydroxyl group, a variety of product functionalizations were undertaken to yield N6,C5'-doubly modified nucleoside analogues.