Aromatic Allylation via Diazotization: Metal-Free C−C Bond Formation

Native chemical ligation (NCL) is an invaluable tool in the total chemical synthesis of proteins. Ligation auxiliaries overcome the requirement for cysteine. However, the reported auxiliaries remained limited to glycine-containing ligation sites and the acidic conditions applied for cleavage of the typically applied N-benzyl-type linkages promote side reactions. With the aim to improve upon both ligation and cleavage, we systematically investigated alternative ligation scaffolds that challenge the N-benzyl dogma. The study revealed that auxiliary-mediated peptide couplings are fastest when the ligation proceeds via 5-membered rather than 6-membered rings. Substituents in α-position of the amine shall be avoided. We observed, perhaps surprisingly, that additional β-substituents accelerated the ligation conferred by the β-mercaptoethyl scaffold. We also describe a potentially general means to remove ligation auxiliaries by treatment with an aqueous solution of triscarboxyethylphosphine (TCEP) and morpholine at pH 8.5. NMR analysis of a C-labeled auxiliary showed that cleavage most likely proceeds through a radical-triggered oxidative fragmentation. High ligation rates provided by β-substituted 2-mercaptoethyl scaffolds, their facile introduction as well as the mildness of the cleavage reaction are attractive features for protein synthesis beyond cysteine and glycine ligation sites.

Section: Resultsmentioning

confidence: 99%

Features of Auxiliaries That Enable Native Chemical Ligation beyond Glycine and Cleavage via Radical Fragmentation

Loibl

Dallmann

Hennig

et al. 2018

“…Preliminary experiments with seven literature‐known Gomberg–Bachmann protocols,21 however, revealed that neither 4‐chlorophenyldiazonium chloride nor its corresponding tetrafluoroborate 1 (R 1 =Cl) were able to give more than trace amounts of the desired 2‐aminobiphenyl 9 upon reaction with 4‐fluoroaniline ( 7 , R 2 =NH 2 , R 3 =F) under any conditions 22. To now ensure a reaction course via an aryl diazotate 3 as a protected derivative of diazonium ion 1 , solutions of the specific diazotate 10 were prepared from 4‐chlorophenyldiazonium chloride and investigated spectroscopically 22–24. Selected results from the coupling of 10 with 4‐fluoroaniline ( 11 ) under various conditions are summarized in Table 1.…”

Section: Methodsmentioning

confidence: 99%

“…In this way, the equilibrium between the aryl diazonium salt 1 and the aryl diazotate 3 (Scheme ) can be shifted largely towards the diazotate 3 and otherwise prevailing ionic side reactions of diazonium ions with anilines are effectively suppressed 28. 29 Supported by the identification of the diazotates in NMR experiments,24 we therefore propose that not diazo anhydrides 4 , such as in classic Gomberg–Bachmann reactions, but more nucleophile‐resistant diazotates 3 or diazohydroxides 2 represent the major intermediates of this reaction type 20. 29, 30 Slightly modified standard conditions were then applied to determine the scope and limitations of the biaryl synthesis (Table 2).…”

Section: Methodsmentioning

confidence: 99%

The Gomberg–Bachmann Reaction for the Arylation of Anilines with Aryl Diazotates

Pratsch

Wallaschkowski

Heinrich

2012

Simply aqueous sodium hydroxide is sufficient to exclude ionic side reactions and to prepare 2-aminobiphenyls from aryl diazotates and anilines through a new variant of the Gomberg-Bachmann reaction (see scheme). The metal-free reaction under basic conditions allows to exploit the highly radical-stabilizing effect of the aniline's free amino function for the first time, which leads to a so far unreached regioselectivity.

“…[28] With the optimized conditions now available, we reevaluated the synthesis of as election of 2-aminobiphenyls 4.A comparison between the yields obtained from the previous protocol [19] and the newly developed procedure is summarized in Table 3. In less successful attempts, precipitate formation and the emergence of ay ellow color indicated the formation of undesired side products,s uch as diazo anhydrides.…”

Section: Resultsmentioning

confidence: 99%

Radical Arylation of Anilines and Pyrroles via Aryldiazotates

Hofmann

Gans

Clark

et al. 2017

The radical arylation of anilines and pyrroles can be achieved under transition-metal- and catalyst-free conditions by using aryldiazotates in strongly alkaline aqueous solutions. The aryldiazotates act as protected diazonium ions, which do not undergo azo coupling with electron-rich aromatic substrates, but can still serve as an aryl radical source at slightly elevated temperatures. Based on an improved preparation of aryldiazotates in aqueous solution, homolytic aromatic substitutions of anilines and pyrroles were conducted with good overall yields and high regioselectivity. Moreover, DFT calculations provided further mechanistic insights.