PTABS: A Unique Water-Soluble π-Acceptor Caged Phosphine

Abstract

Caged phosphines have unique structure and provide many advantageous properties that could be fine-tuned to develop efficient catalytic systems. Our research group recently introduced a highly water-soluble caged phosphine PTABS (KapdiPhos), which is a derivatized form of triazaphosphaadamantane and explored its applicability as a strongly π-accepting ligand in combination with metals such as Pd or Cu in a variety of cross-coupling reactions of biologically relevant halonucleosides as well as chloroheteroarenes. This account will detail our journey from ideation to the various catalytic applications of the ligands eventually to its commercialization.

Rapid plugged flow synthesis of nucleoside analogues via Suzuki-Miyaura coupling and heck Alkenylation of 5-Iodo-2’-deoxyuridine (or cytidine)

“…The ease of employing and handling of the boronic acids as well as the ready availability of these reagents makes Suzuki-Miyaura couplings a preferred protocol. Several catalytic systems have been developed over the years for the functionalization of nucleosides in a variety of solvents and in many cases a single catalytic system wasn't available for transformation of all 4 natural nucleosides [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. This problem was overcome by our group through the development of catalytic systems that were able to functionalize all 4 nucleosides efficiently (see Scheme 1).…”

“…A typical catalytic protocol for the coupling of 5-iodo-2'-deoxycytidine (I-dC) with arlyboronic acid proceeds with relatively lower reactivity compared to its uridine counterpart partly due to the more electron-rich nature of the heterocyclic ring that resists the attack of the nucleophile as a part of the catalytic coupling pathway. We have in recent years demonstrated the capability of several of our catalytic systems to efficiently couple I-dC with different arylboronic acids [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. However, the reaction has been relatively slower than uridine coupling processes (up to 24 hrs).…”

“…However, the reaction has been relatively slower than uridine coupling processes (up to 24 hrs). Below, we have demonstrated one such Suzuki-Miyaura cross-coupling of I-dC (1b) with 3-methoxyphenylboronic acid (2a) with SerrKap palladacycle [34][35][36][37][38][39][40][41][42][43][44][45] (1.0 mol%) in a H 2 O:EtOH solvent system under an inert nitrogen atmosphere at 60 °C. Although good reactivity was observed under the conditions, the reaction takes 24 hrs to provide 76% of the coupled product (4a) with 14% of the dehalogenated product 4a'(Scheme 4).…”

“…We have also been active in the development of several catalytic systems (palladium-based) allowing efficient cross-coupling [23][24][25][26][27][28][29][30]. Starting with [Pd(imidate) 2 (PTA) 2 ] [ [31][32][33] allowing the Suzuki-Miyaura cross-coupling of all four nucleosides, PTABS (KapdiPhos) [34][35][36][37][38][39][40][41][42][43][44][45] in combination with Pd(II) precursor allowing the isolation via column-free procedure (as well as catalyst recyclability), SerrKap palladacycle [46,47] as a phosphine-free catalyst and recently, [Pd(sacc) 2 (THPEN)] [48] another example of water-soluble phosphine-free catalyst promoting the coupling to take place at ambient temperature (Scheme 1).…”

Cu(II)/PTABS-Promoted, Regioselective SNAr Amination of Polychlorinated Pyrimidines with Mechanistic Understanding

“…Despite the best efforts by researchers, there is still a long way to go to achieve very high selectivity for such synthetically viable substrates. Our research group has contributed significantly in the past decade to the functionalization of chloroheteroarenes using a variety of nucleophiles (including amines) at ambient or low temperatures owing to the identification of a unique Cu­(II)/PTABS (KapdiPhos)-promoted S N Ar. , The entire experience of working with our catalytic system and understanding the reactivity observed especially with heteroarenes (such as pyrimidine) provides us with an opportunity to address the site selectivity issue, and we therefore present herein our results for the efficient site-selective amination of polychlorinated pyrimidines using Cu­(II)/PTABS catalytic system and assisted by DFT analysis of the bond dissociation energies (BDEs) of the different C–Cl bonds. The difference in the BDE of regioisomeric C–Cl bonds (calculated by DFT) was exploited as the Cu/PTABS catalytic system via electronic and steric effects, which were able to enhance the reactivity of certain positions.…”