Chemicals and solvents (analytically pure) were purchased from Sigma-Aldrich and were used without further purification. Reactions were monitored by thin layer chromatography (Silica gel 60 on TLC Al foils, F254). Chromatography was performed on silica gel 60 column. NMR spectra were recorded on Bruker spectrometers (300 and 400 MHz). Chemical shifts (δ) are expressed in ppm and are measured by referring to the peak of TMS (singlet at δ = 0 ppm) and the solvent (residual CHCl₃: 7.26 ppm for ¹H; 77.16 ppm for ¹³C of CDCl₃) as an internal reference; the abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet. Fourier transform infrared (FTIR) measurements were performed on Perkin Elmer Spectrum 100 instrument, wavenumber range was measured from 400 cm⁻¹ to 4000 cm⁻¹. ESI-MS was performed on a Flexar SQ 300 MS instrument. NMR spectra of cavitands II, III and IV, IR spectra of III and IV, and mass spectrum of cavitand IV (ESI in positive and in negative modes) are given in the supplementary material [10] .

Scheme 1. Synthetic route of tetramethyl calix-[4]-resorcinarene derivatives.

1) Synthesis of cavitand I. This compound was prepared as described by Cram et al. [11] and was identified by comparison of its ¹H NMR spectrum with the one reported in literature, yield 88%, color: dark yellow, ¹H NMR (400 MHz, DMSO) δ [ppm]: 1.70 (d, 12H, CH₃CH), 2.00 (s, 12H, ArCH₃), 4.46 (q.4H, CH₃CH), 7.41 (s, 4H, ArH), 8.70 (s, 8H, ArOH). MS: m/z: 543 (M-H).

2) Synthesis of cavitand II. 6.0 g of cavitand I (9.87 mmol) was dissolved in 150 mL DMF. Then, 28.8 g of K₂CO₃ (0.20 mol) and 50 ml of CH₂Cl₂ were added in several portions to the previous mixture and this was agitated for 24 hours at 70˚C. The mixture was then cooled down to room temperature and filtered over Celite. The collected solvent was evaporated using a rotary evaporator, and the solid residue was purified over silica gel column chromatography using ethyl acetate/cyclohexane (30/70) as eluent. The cavitand II was obtained as a white powder (yield 84%). Final product was characterized by comparison of its ¹H NMR spectrum with the one reported in literature [11] . ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 1.73 (d, 12H, CH₃CH), 2.00 (s, 12H, ArCH₃), 4.29 (d, 4H, inner of OCH₂O), 5.20 (q, 4H, CH₃CH), 5.92 (d, 4H, outer of OCH₂O), 7.14 (s, 4H, ArH).

3) Synthesis of cavitand III. 3.0 g of Cavitand II (4.62 mmol) was dissolved in 200 mL of CH₂Cl₂. Then, 3.22 g of NBS (18.51 mmol) and a small quantity of benzoyl peroxide (15 mg, 0.06 mmol) were subsequently added to the solution. The mixture (clear orange color) was agitated and refluxed (40˚C) for 4 hours. The precipitation of succinimide was observed. The mixture was cooled to room temperature and the precipitate was eliminated by filtration over Celite. The volatiles were evaporated under vacuum giving withe solid. The crude was purified over silica gel column chromatography using ethyl acetate /cyclohexane (30/70) as eluent. The cavitand III was obtained as an off-white (cream) powder. The final product was characterized by comparison of its ¹H NMR spectrum with spectrum already reported in literature [9] . ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 1.75 (d, 12H, J = 7.4 Hz, CHCH₃), 4.42 (s, 8H, CH₂Br), 4.57 (d, 4H, J = 7.0 Hz, inner OCH₂O), 5.02 (q, 4H, J = 7.4 Hz, CH), 6.04 (d, 4H, J = 7.0 Hz, outer OCH₂O), 7.26 (s, 4H, ArH).

4) Synthesis of cavitand IV. Into a flask containing 80 ml of acetone, 2.0 g of cavitand III (2.40 mmol) and 0.9 g of sodium azide NaN₃ (15 mmol) were subsequently added. The mixture was agitated and refluxed for 3 h. After that, the mixture was filtered over Celite and the collected solution was evaporated using a rotary evaporator. The residue was purified over silica gel column chromatography with ethyl acetate/cyclohexane (65/35) as eluent. The cavitand IV was obtained as white powder (yield 85%). The final product was characterized by ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 1.75 (d, 12H, J = 7.4 Hz, CHCH₃), 4.3 (s, 8H, CH₂N₃), 4.42 (d, 4H, J = 7.0 Hz, inner OCH₂O), 5.0 (q, 4H, J = 7.4 Hz, CH₃CH), 6.0 (d, 4H, J = 7.0 Hz, outer OCH₂O), 7.3 (s, 4H, ArH). X. ¹³C-NMR (CDCl₃, 100 MHz), δ [ppm]: 153.326 (Ar-Cq), 139.058 (Ar-Cq), 122.19 (Ar-Cq), 120.277 (Ar-H), 99.677 (O-CH₂-O), 45.078 (Ar-CH₂-N₃), 31.211 (Ar-CH-Ar), 16.072 (CH₃). MS, ESI, in positive mode: m/z = 835 = [M + Na]⁺, m/z = 853 = [M + MeCN]⁺; in negative mode m/z = 847 = [M-H + 2H₂O]⁺ and m/z = 874 = [M⁺ + 4H₂O]⁺. FTIR: ν = 2100 cm⁻¹ (band of N₃).

5) Synthesis of cavitand V. 0.5 g of cavitand IV was dissolved in a toluene/ ethanol mixture (5 mL, 8 mL) followed by the addition of 0.3 g of Pt/C (5%). The mixture was agitated and refluxed for 24 h at 75˚C under one atmosphere of hydrogen pressure (or under 5 bars at 25˚C). The mixture was then filtered over Celite and the collected solvent was evaporated using a rotary evaporator. The cavitand V was obtained as white powder (yield 95%). The final product was characterized by comparison of its ¹H NMR spectrum with literature [12] [13] . ¹H NMR (400 MHz, CDCl₃) δ [ppm]: 7.1 (s, 4H; ArH), 5.8 (d, J = 7.2 Hz, 4H; outer OCHO), 4.9 (q, J = 7.35 Hz, 4H; CH₃CH), 4.3 (d, J = 7.2 Hz, 4H; inner OCHO), 3.5 (s, 8H; ArCH₂NH₂), 1.7 (d, J = 7.35 Hz, 12H; CH₃CH). ¹³C-NMR (CDCl3, 100 MHz), δ [ppm]: 152.8 (Ar-Cq), 138 (Ar-Cq), 129 (Ar-Cq), 118 (Ar-H), 99.4 (O-CH₂-O), 37 (Ar-CH₂-NH₂), 31 (Ar-CH-Ar), 15 (CH₃). ESI (in positive ionisation mode): m/z = 709 for [M + H]⁺, 727 for [M + H + H₂O]⁺, 765 [M + K + H₂O]⁺, FTIR: ν = 3370 cm⁻¹ (band of N-H).

The cavitand I was prepared as described by Cram et al., methylresorcinol and acetaldehyde were mixed in stoichiometric ratio in a proportional mixture of water and ethanol, in the presence of HCl as the catalyst. The resulting mixture was then refluxed for 16 h, and cavitand I was obtained with a high yield (88%) similar to that mentioned in the literature [11] .

Cavitand I was transformed into cavitand II cone structure by introducing methylene bridges between the oxygen atoms in ortho positions to the methyl groups of the methylresorcinol. Cram’s group has described the methylene insertion at the upper rim to form the bridged cavitand II by reacting the relaxed-open cavitand I with an excess amount of bromochloromethane in basic medium in DMA. They have demonstrated that a higher yield is obtained with CH₂BrCl as compared to using CH₂I₂ and CH₂Br₂ as methylene sources. Pellet Rostaing et al. [14] have realized the same insertion in basic medium in DMF instead of DMA. The key step of our methodology concerns the use of dichloromethane (DCM). Cavitand I was mixed with a large excess amount of CH₂Cl₂ in K₂CO₃/DMF mixture to afford cavitand II in a very good yield (84%); much better than that obtained by Cram’s group. The first use of CH₂Cl₂ as methylene bridges precursors as well as in the protection of aromatic diol, has two advantages: it is a very good replacer of Bromochloromethane which destroys the ozone layer and its production has been banned since 1^st January 2002, at the Eleventh Meeting of the Parties of Montreal Protocol on the substances that deplete the ozone layer. The second advantage is that the dichloromethane is less expensive and available in large quantities. In our protocol, DCM was used efficiently and its volatility (bp = 40˚C) was overcome by adding several portions during the progress of the refluxing process (70˚C) to establish the desired product.

The rigidified-bridged cavitand II was subjected to a bromination reaction using N-bromosuccinimide (NBS) as a source of bromide in dichloromethane (DCM) or in acetone to obtain cavitand III. The use of acetone as a solvent for this reaction has been described by Bourgeois and Evans for the bromination on aromatic of resorcinarene derived from resorcinol [15] .

The bromination takes place through a free radical mechanism in the presence of traces of benzoyl peroxide as initiator. The most electron-rich methyl groups on the upper rim between two donor alkoxy functions are the most reactive sites towards the radical reaction since the generated radicals are stabilized by the neighboring electron donating groups. The obtained yield (80%) was better than the one attained in the literature (60%) [9] . Cavitand III was collected as a pure cream powder. It is noteworthy to mention that only traces of benzoyl peroxide must be added as initiator since its excess prevents the reaction from proceeding to completion and conduces to the formation of benzoyl bromide as a side product, as detected by proton NMR (See Supp. Materials.).

Alkyl halides are usually very reactive toward nucleophilic substitution. Bromide is a very good leaving group, and N 3 − is a strong nucleophile. Thus, a substitution reaction on cavitand III occurs easily.

To achieve the synthesis of cavitand IV, we used sodium azide NaN₃. This substitution needs a solvent with a high dielectric constant in order to dissociate NaN₃. We have recently realized in our laboratory the azide substitution of chlorinated products using NaN₃ in acetone. Therefore, we have adopted this method for the preparation of cavitand IV. These conditions proved to be successful for this bromide substitution reaction establishing the desired azido cavitand with no side products or impurities. A simple filtration over Celite followed by evaporation of the solvent affords the product with a very good yield (85%) and purity. Hence, the purification of this step is avoided in this synthetic route. It is important to note the versatility of the azido cavitand IV for further functionalization via click chemistry highlighting the importance of straightforward synthesis for this type of cavitands. For instance, Hooley’s group has published the synthesis of a compound similar to cavitand IV as precursor to advanced cavitands substituted with tri-azole groups which have been used as iron-coordinate water-soluble catalysts for C-H Oxidation [16] . Their method of synthesis consisted on using THF as a solvent mixed with a solution of NaN₃ in DMSO. This method allows obtaining the corresponding compound in good yield but it is more demanding than our described method. Furthermore, acetone is much less toxic, less odorous, and more volatile than THF and DMSO; and hence, its elimination by evaporation is much easier.

The traditional routes to introduce amino groups into the aromatic scaffolds of calixarene chemistry are i) nitration of cavitands followed by reduction of the nitro group with common reducing agents [17] [18] [19] , or ii) formation of azo compound followed by reduction with Na₂S₂O₄ [20] [21] . An amino resorcinarene similar to cavitand V, is recently used by Sheela et al. (2011) as a stabilizer for the dispersion of nanodiamonds in organic solvents for the purpose of growing diamond films [12] . This group uses synthetic procedures already described in the literature to prepare the tetra-amino cavitand in two steps from tetra-brominated cavitand [13] [22] . Their described method enables the transformation of the tetra-brominated cavitand into tetrakis (phthalimidomethyl), and then the phthalimido group is hydrolyzed by hydrazine hydrate under reflux in ethanol/THF. In fact, we have realized the reduction reaction of the tetraazide adduct into its corresponding tetra-amine product with molecular hydrogen. The hydrogenation reaction was catalyzed by Platinum on charcoal Pt/C in toluene/ethanol at 75˚C under one atmosphere of hydrogen, to afford to product V in 95% yield. The developed Pt/C catalytic hydrogenation is an advantageous alternative to the classical methods used to synthesize the tetrakis(aminomethyl)- calix-[4]-resorcinare; It is a simpler, cleaner, atom-economical, and higher yielding method with no side products or impurities.