Imine-Palladacycles as Phosphine-Free Precatalysts for Low-Temperature Suzuki–Miyaura Synthesis of Nucleoside Analogues in Aqueous Media

Abstract

The synthesis and characterization of new water-soluble dinuclear palladacycles of the general formula [{Pd­(R-C^N-SO3Na)­(μ-AcO)}2] (R = H (1), OMe (2), Cl (3)) incorporating an ortho-metalated sodium 4-(N-benzylideneamino)­benzenesulfonate moiety is reported. These complexes have been revealed to be excellent phosphine-free catalysts for the synthesis of functionalized nucleoside analogues involving a low-temperature Suzuki–Miyaura coupling of 5-iodo-2′-deoxyuridine with different arylboronic acids in neat water. The potential of 1–3 as synthetic precursors was also tested, and bridging acetates were cleaved by reaction with neutral PPh3, yielding the corresponding mononuclear derivatives [Pd­(R-C^N-SO3Na)­(AcO)­(PPh3)] (R = H (4), MeO (5), Cl (6)). Analytical and spectroscopic techniques confirmed the proposed formulas and reactivities reported for complexes 1–6. Structural characterization by X-ray diffraction of single crystals grown from samples of 4 and 6 produced the unexpected but valuable crystallization-mediated compounds 4cm and 6cm that also supported the results presented here.

Suzuki‐Miyaura Coupling, Heck Alkenylation, and Amidation of DMTr‐Protected 5‐Iodo‐2′‐Deoxyuridine via Palladium‐catalyzed Reactions

“…Water-soluble catalytic systems are well known for modification of nucleosides, but conducting such reactions at close to ambient temperature has been challenging. Lower temperatures (<50°C or RT) were recently achieved by our research group using the Ser-rKap palladacyclic complex (Serrano et al, 2020). Here and in Figure 2, we present the synthesis of this complex, which will be used for coupling of 5 -O-DMTr-5-iodo-2deoxyuridine in Basic Protocols 2 and 3.…”

“…It is therefore necessary to develop catalytic protocols that can directly modify DMTr‐protected nucleosides and save both time and materials. To this end, we have employed the palladacycle (Serrano et al., 2020) and Pd/PTABS (Bhilare et al., 2016) catalytic systems (Fig. 1), which have worked efficiently for unprotected nucleosides.…”

Water‐Soluble Pd‐Imidate Complexes as Versatile Catalysts for the Modification of Unprotected Halonucleosides

“…The obtention of two unexpected crystal structures for them pointed out to the formation of neutral intermediates as tentative explanation for this behaviour. [62] Adjustment of relevant parameters such as solvent, temperature, base, and catalyst concentration were conducted with complex 3 c (SerrKap) that incorporated a chloride substituent in the benzylideneaniline ligand, since it was the one showing a better performance. The substrate scope for the modification of 5-Iodo-2'-deoxyuridine was next undertaken by Suzuki-Miyaura cross coupling with differently substituted arylboronic acids, using 0.5 mol % of this complex in water at 60 °C as the sole reaction solvent, using Et 3 N as base outperforming K 3 PO 4 , K 2 CO 3 , Cs 2 CO 3 , and DBU.…”

“…Synthesis of the dinuclear palladacyclic complexes and its PPh 3 derivatives. Reprinted (adapted) with permission from [62] J. L, Serrano, L. García, J. Pérez, P. Lozano, J. Correia, S. Kori, A. R. Kapdi, Y. S. Sanghvi, Organometallics 2020, 39, 4479-4490. Copyright {2020} American Chemical Society.…”

Palladium-catalyzed Suzuki–Miyaura cross-coupling with α-aminophosphonates based on 1,3,4-oxadiazole as ligands

“…Interestingly, several nitrogenated ligands have been also employed for the Suzuki-Miyaura cross-coupling. We can quote for example the use of Schiff bases [44][45][46][47][48][49][50], amines [51,52], azo compounds [53], pyridines [54][55][56][57][58], pyrimidines [59,60], triazoles [61] or benzimidazoles [62]. However, despite their relevance, these catalytic systems suffer from one or more drawbacks such as the use of expensive or difficultly accessible ligands, as well as high catalyst loading, hazardous solvents and harsh reaction conditions.…”