HFIP as a versatile solvent in resorcin[ n ]arene synthesis

Herein, we present 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as an efficient solvent for synthesizing resorcin[ n ]arenes in the presence of catalytic amounts of HCl at ambient temperature and within minutes. Remarkably, resorcinols with electron-withdrawing groups and halogens, which are reported in the literature as the most challenging precursors in this cyclization, are tolerated. This method leads to a variety of 2-substituted resorcin[ n ]arenes in a single synthetic step with isolated yields up to 98%.

We began by screening various solvents and combinations of solvents including HFIP.
Those experiments revealed that the most favorable outcomes are achieved in the presence of HFIP in its pure form in the presence of HCl as the catalyst (Table 1, entries 1-4).The removal of HCl from the reaction conditions unveiled the crucial role of the catalyst in the process (Table 1, entry 5), which was expected; however, note that here we use the acid in catalytic amounts and not in excess as reported in the literature.[73][74][75] Variations in catalyst nature between a Brønsted and Lewis acid, and the acid's pKa (Table 1, entries 6-8) did not improve the yield compared to HCl (Table 1, entry 4).Last, further exploration of the condition using HFIP/HCl revealed that the reaction progress achieves its maximum conversion early on at just 20 minutes (Figure S1).Remarkably these results demonstrate that reaction times can be decreased from 72-144 [26] to approximately 1 hour.

Substrate scope
To demonstrate the limitations and scope of the reaction, we first used resorcinol in the presence of various aldehydes featuring different alkyl chains, all of which exhibited high isolated yields (Scheme 2, 1a-e).Interestingly, literature reports commonly show lower yields as the aldehyde alkyl chain increases in length where commonly refluxing temperatures are required; [9,74,76] in contrast, the protocol reported herein provides 94-98% yield when employing longer aldehydes (1c-e).In addition to resorcinol, 2-methylresorcinol is commonly used in resorcin[n]arene synthesis as radical oxidation of the methyl unit in the ArCH3 fragments provides a benzyl synthon, which is used conveniently towards other applications, e.g., metal cluster synthesis, and halogen and hydrogen-bonded cavitands.[77][78][79] Our protocol works well with 2-methylresorcinol, as shown for products 1f and 1g, with significant yields around 80%.
Electron deficient and halogenated 2-substitued resorcinols are notoriously difficult to engage in the cyclization reaction towards resorcin[n]arenes since the nucleophilic character of the attacking aromatic carbon is diminished.Specifically, there is no literature information on 2-chlororesorcinol or 2-iodoresorcinol being used in this manner, and from the few reports using 2-bromoresorcinol, it has been described to yield inseparable mixtures of oligomers.[9,59] Electron withdrawing groups like carboxylic acids are another useful functional group instead of the halogen that provides a divergent route to other functional materials, e.g., polymers and capsules.[80] In that regard, 2,6-dihydroxybenzoic acid is known to also yield inseparable mixtures; [9,81] however, a couple of reports describe successful syntheses with reaction yields <10% using 2,6-dihydroxybenzoic acid and formaldehyde, or acetaldehyde, under basic conditions.[38,82] Recently, similar conditions using basic media have been employed successfully with 2-nitroresorcinol in the formation of resorcin[n]arenes.[83] We applied our protocol using 2haloresorcinols and aliphatic aldehydes of varying lengths.Our findings indicate that chlorinated species 1h-j are formed with reasonable yields ranging from 48 to 69% in 24 hours (Scheme 2).Remarkably, brominated compounds 1k-n are also formed in significant yields reaching up to 94% for the n-pentyl containing species 1m.Note that species 1l and 1m are extensively used in the field and are prepared through the twostep synthesis described in the introduction (Scheme 1a-b).[56,58,59,63,66,80,[84][85][86][87][88]] Furthermore, we successfully synthesized carboxylic acid-containing resorcin [4]arenes 1o-s employing HFIP under an optimized reaction time of 48 hours.
Compounds 1o-s are reported here for the first time.Their tetracarboxylic acid head group and short-to-long aliphatic tails from ethyl to n-undecyl may find applications in the development of novel materials, e.g., as ligands in nanoparticle synthesis.We were surprised to find out that 2-iodoresorcinol did not produce the desired resorcin[n]arene.Repeated experiments showed resorcinol in the reaction mixture.
This observation led us to run a control experiment in the absence of aldehyde, which showed that HFIP leads to metal-free deiodination of 2-iodoresorcinol (Figure 1a).
Finally, while all new compounds reported herein have full spectroscopic characterization, chlorinated species 1h and 1i developed high quality crystals from standing solutions in dimethyl sulfoxide.Their molecular crystal structures were determined and are shown in Figure 1b displaying the classic cone conformation.[89] Overall, access to electron deficient and halogenated resorcin [4]

Conclusion
Introduction of HFIP to the synthesis of resorcin[n]arenes accelerates their reaction time significantly to under one hour for simple and commonly used starting materials, and most importantly establishes the production of new species unavailable in the past, e.g., halogenated and electron deficient resorcin [4]arenes.Our studies suggest that the benefits of short reaction times and substrate scope obtained from the protocol developed herein may be translated to the formation of other macrocycles as long as they share a similar reaction mechanism.

Table 1 :a
Optimization of resorcin[n]arene synthesis using HFIP a The reaction was performed with resorcinol (1.0 mmol), valeraldehyde (1.0 mmol), and catalyst (30 mol%) in solvent (5 mL) at room temperature for 2 h; b Yields were determined by 1 H NMR analysis of the unpurified reaction mixture using CH2Br2 as an internal standard; c The reaction yields no product at room temperature or under reflux conditions.TfOH = triflic acid.

Scheme 2 :
Scheme 2: Scope of resorcin[n]arene synthesis using HFIP.a All reactions were