Room‐Temperature Dialkylamination of Chloroheteroarenes Using a Cu(II)/PTABS Catalytic System

Abstract

The dimethylamino functionality has significant importance in industrially relevant molecules and methodologies to install these efficiently are highly desirable. We report herein a highly efficient, room‐temperature dimethylamination of chloroheteroarenes performed via the in‐situ generation of dimethylamine using N,N‐dimethylformamide (DMF) as precursor wiith a large substrate scope that includes various heteroarenes, purines as well as commercially relevant drugs such as altretamine, ampyzine and puromycin precursor.

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).…”

“…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).…”

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

“…Cu(OAc) 2 /PTABS was chosen for the catalytic transformation based on the optimization studies conducted by Harshita and Manisha. 83 In situ activation of DMF with KOt-Bu as the activator was previously described by the research groups of Shao 84 and Tu 85 but was applied for the amination of haloarenes. Our aim was to test the Cu(II)-promoted coordination/activation pathway using the in situ generated NHMe 2 as the nucleophile and performing the reaction at ambient temperature.…”

“…A large substrate scope was tolerated for the given transformation (Scheme 23). 83 The substrate scope was further extended to chloropurines by subjecting 6-chloropurine and 2-amino-6-chloropurine to the developed dialkylamination protocol at ambient temperature to provide the desired products in excellent yields (Scheme 24a). A regioselective dimethylamination was also performed on 2,6-dichloropurine with the reaction exclusively occurring at the C-6 position.…”