Abstract
A regioselective Pd-mediated C–H bond arylation methodology for tryptophans, utilizing stable aryldiazonium salts, affords C2-arylated tryptophan derivatives, in several cases quantitatively. The reactions proceed in air, without base, and at room temperature in EtOAc. The synthetic methodology has been evaluated and compared against other tryptophan derivative arylation methods using the CHEM21 green chemistry toolkit. The behavior of the Pd catalyst species has been probed in preliminary mechanistic studies, which indicate that the reaction is operating homogeneously, although Pd nanoparticles are formed during substrate turnover. The effects of these higher order Pd species on catalysis, under the reaction conditions examined, appear to be minimal: e.g., acting as a Pd reservoir in the latter stages of substrate turnover or as a moribund form (derived from catalyst deactivation). We have determined that TsOH shortens the induction period observed when [ArN2]BF4 salts are employed with Pd(OAc)2. Pd(OTs)2(MeCN)2 was found to be a superior precatalyst (confirmed by kinetic studies) in comparison to Pd(OAc)2.
Highlights
Pd-catalyzed cross-couplings are well-established, versatile methods for the selective modification of natural products,[1] macrocycles,[2] and biomolecules.[3]
This problem was in part obviated by eliminating PhI(OAc)[2] as reagent/oxidant, using instead Cu(OAc)[2] as a cocatalyst along with PhB(OH)[2], with air serving a role as a terminal oxidant.10a Under such conditions specific tryptophan-containing peptides were susceptible to aromatic oxidation by CuII
The aryldiazonium salts employed within this study are readily available from the corresponding anilines by an oxidative process to generate the tetrafluoroborate salts in excellent yields.[15]
Summary
Pd-catalyzed cross-couplings are well-established, versatile methods for the selective modification of natural products,[1] macrocycles,[2] and biomolecules.[3]. [ArN2]BF4 salts share similarities with [Ar1IAr2]X, in terms of both their structure and reactivity.[12] As oxidative addition of [ArN2]BF4 to Pd0 is rapid,[13,14] we anticipated development of a mild and selective process, in the absence of an exogenous base In this context, a mild methodology for the arylation of mainly indole derivatives was reported by Noel et al, employing aryldiazonium salts and catalytic Pd(OAc)2.14d Noel et al further suggested a mechanism akin to Heck−Matsuda type coupling reactions.14d For several years we have independently been investigating synthetic protocols (Pd catalyst, solvent, temperatures) similar to those of Noel et al for tryptophan arylations.14h. Development of Conditions for the Direct C2Arylation of Tryptophan Derivatives and Peptides (Selected Examples)
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