Tris(4-azidophenyl)methanol – a novel and multifunctional thiol protecting group

The novel tris(4-azidophenyl)methanol, a multifunctionalisable aryl azide, is reported. The aryl azide can be used as a protecting group for thiols in peptoid synthesis and can be cleaved under mild reaction conditions via a Staudinger reduction. Moreover, the easily accessible aryl azide can be functionalised via copper-catalysed cycloaddition reactions, providing additional opportunities for materials chemistry applications.

Inspired by the versatile azides, we report a multifunctional and spatially oriented aryl azide, which can be converted to triazoles via cycloaddition reaction and utilised as a protecting group for thiols in peptoid synthesis.
The novel aryl azide, tris(4-azidophenyl)methanol (1, Fig. 1), was synthesised according to a modied procedure by Kutonova et al. 44 The arylamine was rst diazotised with tert-butyl nitrite in the presence of p-toluenesulfonic acid, followed by the reaction with sodium azide in a one-pot procedure (Scheme 1).
A set of cycloaddition reactions were performed utilising Cu(I) as catalyst to assess the potential functionalities of the synthesised aryl azide 1 (Scheme 2). The active hydroxyl group can be attached to other functional systems, such as the modication of the lipophilicity or the introduction of the other functional groups leading to a more sophisticated system.
Triphenylmethane and its derivatives, such as 4-methoxytrityl and 4-methyltrityl, were reported as excellent protecting groups for thiols. 45 To evaluate the application of the newly discovered aryl azide 1, we explored a new strategy for protecting thiols with aryl azide 1, accomplishing deprotection under mild reaction conditions, in which the thioether bond was cleaved by a Staudinger reduction (Fig. 2).
The studied thiols were rst protected with aryl azide 1. The reaction was carried out either in TFA or in a TFA/CHCl 3 mixture, which led to the desired products 3a-f in excellent yield (Scheme 3).
The deprotection was based on the Staudinger reduction, where the aryl azide-protected thiols were treated with trimethyl phosphine in THF/1 M HCl mixtures for 5 min at room temperature. The rst step of the deprotection process involves the reduction of the azide groups to amines by reaction with trimethyl phosphine. The positive mesomeric effect (+M effect) renders the thioether bond labile, thus facilitating the cleavage of the thiols group under acidic conditions. This deprotection process based on aryl azide 1 is promising to protect thiols in solid-state synthesis.
We then utilised aryl azide 1 as protecting group for thiols in peptoid synthesis (see ESI † for details). As shown in Scheme 4, Fmoc-Phe-OH was rst loaded to the polystyrene resin 5, then deprotected from the Fmoc group to obtain amine 6. Aer acetylation with 2-bromoacetic acid, the secondary amines 8a-e were formed by reacting primary amines with acetylated resin 7. By reacting 3f with 8a-e, a series of short peptoids 9a-e with aryl azide protected thiols were synthesised. Following the described procedure, the peptoid-peptide hybrids 14a-c were synthesized. In contrast to the peptoids 9a-e, the protected aminothiol was not incorporated at the end of the chain, but rather in the middle. Aer elongation, peptoids with a protected aminothiol as building block were obtained. In the case of 16f, the Fmoc-protecting group of the terminal amino acid was removed using common deprotection conditions, showing that the azide protecting group remains intact under the applied basic conditions. The deprotection and cleavage process of the peptoids involves two orderly steps: the aryl azide protecting group was rst deprotected using trimethyl phosphine in a THF/1 M HCl mixture within 5 min at room temperature to afford 10a-e and 15a-c. Aerward, the nal peptoids (11a-e and 16a-c) were cleaved from the resin using a 33% solution of hexauoro-2-   propanol (HFIP) in dichloromethane, the successful synthesis was conrmed by LC-MS and ESI-MS.
In conclusion, a novel multifunctional aryl azide was efficiently synthesised in a one-pot reaction from a commercially available pararosaniline base. Thereby, a new strategy for protecting thiols in peptoid synthesis with the aryl azide 1 was established, for which deprotection can be accomplished by a Staudinger reduction under acid catalysis. Moreover, the spacious aryl azide can be functionalised by cycloaddition reaction, which provides additional options for use in materials chemistry.

Conflicts of interest
No conicts of interest to declare.