Immobilized Carbodiimide Assisted Flow Combinatorial Protocol to Facilitate Amide Coupling and Lactamization

Abstract

Through a screen of over one hundred and 30 permutations of reaction temperatures, solvents, carbodiimide resins, and carbodiimide molar equivalences, in the presence, absence, or combination of diisopropylamine and benzotriazole additives, a convenient and first reported carbodiimide polymer-assisted flow approach to effect amide coupling and lactamization was developed. The protocol entails injecting a single solution (1:9 dimethylformamide: dichloromethane) containing a carboxylic acid and an amine or linear peptide sequence into a continuous stream of dichloromethane. The protocol remained viable in the absence of base, did not require carboxylate preactivation which, and in concert with minimal workup requirements, enabled the isolation of products in high yields. Compared to the utilization of untethered carbodiimide reagents, the flow procedure was also observed to provide a degree of racemization safety.

A Comparison of Immobilised Triphenylphosphine and 1‐Hydroxybenzotriazole as Mediators of Catch‐and‐Release Acylation Under Flow Conditions

“…Nonetheless, through reductions of flow rates and increases in reaction column temperature (1.0-0.2 mL min À 1 , 40-140 °C, entries 1-4 and 5-9, respectively), conversions of 3 to amide 2 increased considerably to near 70%. Further, whilst varying the continuous flow solvent to toluene, tetrahydrofuran (THF), acetonitrile (ACN), and N,Ndimethylformamide (DMF) proved detrimental (i. e. < 10-58%, entries [10][11][12][13], the use of chloroform (CHCl 3 ) promoted an incremental increase in the conversion to 2 (74%, entry 14). Additionally, the absence or variation of base from Et 3 N to DIPEA or DMAP, and altering the activating agent from BrCCl 3 to trichloroacetonitrile (CCl 3 CN), imparted a minimal decrease to the affordance of 2 (66-70%, entries 15-18).…”

“…[5a] Moreover, we have previously observed PS-carbodiimide regeneration to be problematic, returning low conversions of the active carbodiimide coupling species. [10] On the other hand, the successful recycling of both the PS-triphenylphosphine-based (PS-PPh 3 ) [11] and benzotriazole-based (PS-HOBt) [8d,f] reagents has been described on prior occasions. Additionally, it is reported that the respective employment of both PS-PPh 3 and PS-HOBt, in concert with flow-based processing, can deliver tangible benefits to both reaction efficiency and protocol practicability.…”

A Solid‐Phase Assisted Flow Approach to In Situ Wittig‐Type Olefination Coupling

“…For example, the removal of excess materials, the release of final products, and even reagent regeneration by continuous flow are inherently more efficient than standard mixing strategies [6a,7] . As each of these procedures can be sequentially performed in‐line, flow methods can also minimise physical handling requirements [6a,8] . Moreover, these processes can all be monitored through spectrophotometric analysis of the elution stream [7–8] …”

“…As each of these procedures can be sequentially performed in‐line, flow methods can also minimise physical handling requirements [6a,8] . Moreover, these processes can all be monitored through spectrophotometric analysis of the elution stream [7–8] …”

“…[6a,8] Moreover, these processes can all be monitored through spectrophotometric analysis of the elution stream. [7][8] Fundamentally, the shift from solid-supported batch protocols to flow processing requires careful consideration regarding the reagent immobilisation matrix. [9] Specifically, the matrix should allow for optimal reactant diffusion to the polymer active sites to permit efficient polymer-substrate interactions.…”