Cyclotriveratrylene Dendrimers with a Fullerene C 60 in the Dendritic Branches

This work was carried out in collaboration between all authors. Authors KESM and MEMK made the synthesis. Author TK made the analysis of spectroscopy data, and revised the first draft of the manuscript. Author MMG wrote the paper. All authors read and approved the final manuscript. ABSTRACT Dendrons with dodecyl terminal groups joined to benzyloxy moieties were attached to a cyclotriveratrylene core. The dendrimers were used in Bingel cyclopropanation reaction with the fullerene C 60 . The structure of the synthesized dendrimers was confirmed by 1 H-and 13 C-NMR, MALDI-TOF mass spectrometry and elemental analysis. - groups of the cyclotriveratrylene. Signals at  H 4.61, 5.04, and at  H 5.08 were ascribed to the -CH 2 -O protons. For dendrimers 17 and 18, signals are also observed from the aromatic protons at the macrocycle and of the benzyloxy chains. In the 13 C


INTRODUCTION
The cup-shaped cyclotriveratrylene derivatives (CTV) are among the key structures that have been exploited for many years for the design of molecular hosts [1][2][3][4][5][6][7]. They are interesting starting compounds for the construction of new macromolecular architectures such as solid inclusion complexes [8], biosensors, bis-cryptophanes to study the guest

Research Article
exchange between closely bonded molecular cavities [9], chiral scaffolds for triple helix formation [10], organo-or metallo-gels [11], H 2 storage targets [12] or more recently, coordination polymer networks [13], self-assembled monolayers on gold surface [14] and dendrimers [15][16][17][18][19]. The three or six p-hydroxybenzyl substituents present on the wider rim of cyclotriveratrylenes are able to undergo modification to obtain dendrimers without steric restrictions. Dendrimers with polyamidoamine (PAMAM), Polyarylethyl or polyethers groups have applications in drug delivery [20][21][22][23] and dendrimers with polyethers in their structure could be used as biodegradable dendrimers with the appropriate enzyme in the drug delivery systems [24]. Recently, we reported the synthesis of cyclotriveratriyene-dendrimers and their supramolecular complexes with the fullerene C 60 [25]. In the present work we report the synthesis of cyclotriveratrylene-dendrimers with three and six fullerenes in the dendritic branches.

General
Solvents and reagents were purchased as reagent grade and used without further purification. Acetone was distilled over calcium chloride. Tetrahydrofuran was distilled from sodium and benzophenone. Column chromatography was performed on Merck silica gel 60Å (70-230 mesh). 1 H-and 13 C-NMR were recorded on a Varian-Unity-300 MHz with tetramethylsilane (TMS) as an internal reference. Infrared (IR) spectra were measured on a spectrophotometer Nicolet FT-SSX. Elemental analysis was determined by Galbraith Laboratories Inc. (Knoxville, TN, USA). FAB+ mass spectra were taken on a JEOL JMS AX505 HA instrument. Electrospray mass spectra were taken on a Bruker Daltonic, Esquire 6000. MALDI-TOF mass spectra were taken on a Bruker Omni FLEX.

(4-(Allyloxy)-3-methoxyphenyl) methanol 1
A mixture of vanillyl alcohol 10 g (65 mmol), allyl bromide (6.3 ml, 73 mmol) and potassium carbonate 10 g (65 mmol) in 100 ml of acetone was refluxed for 12 h with magnetic stirring. Then, after most of the solvent was stripped off, water was added and the organic material was extracted with dichloromethane. This product was recrystallized from 100 ml of diethyl ether to yield 14 g (80 %) of a white powder [25].

2,7,12-Trimethoxy-3,8,13-tris (2-propenyloxy)-10,15-dihydro -5 Htribenzo [a,d,g] cyclononene 2
p-Toluensulfonic acid 0.49 g (2.57 mmol) was mixed with the phenol protected vanillyl alcohol 0.5 g (2.57 mmol) in solid state and stirred for 20 min. The resulting purple solid was incubated at room temperature for 48 h. The reaction mixture was redissolved by addition of dichloromethane and the organic phase was thoroughly washed with water until neutral pH. The dichloromethane solution was partially dried over sodium sulphate and evaporated under vacuum, after which, ether was added, affording a crystalline residue, which was purified by digestion in 200 ml of ether overnight and finally isolated by suction filtration, to yield 0.22 g (37 %) of a white powder [25].

Synthesis of Dendrimers
A mixture of 12 or 14 (0.36 mmol), cesium carbonate (0.36 mmol) in N,N-dimethylformamide anhydrous (8 ml) was heated to reflux and stirred vigorously under nitrogen after 20 min. The cyclotriveratrylene 3 (0.07 mmol) dissolved in N,N-dimethylformamide anhydrous (10 ml) was added dropwise and the reaction was continued for 31 h at reflux. The mixture was allowed to cool and the precipitate was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed on silica gel with ethyl hexane as the eluent to afford the cyclotriveratrylene-dendrimer.

Synthesis of Fullerene Derivatives
DBU (0.43 mmol) and I 2 (0.020 mmol) were added at room temperature to a solution of C 60 (0.17 mmol) and 15 or 16 (0.17 mmol) in 17 ml of toluene anhydrous. The mixture was stirred for 3 days, filtered, evaporated under vacuum and purified by column chromatography (SiO 2 , CH 2 Cl 2 /methanol, 8:2).

RESULTS AND DISCUSSION
The synthesis of the cyclotriveratrylene derivatives is depicted in Scheme 1. Precursor CTV (OH) 3 was obtained in three steps from commercially available vanillyl alcohol, according to the subsequent multistep transformations. The (4-(allyloxy)-3-methoxyphenyl) methanol 1 undergoes smooth trimerisation in the presence of p-toluenesulfonic acid in solid state, affording the C3-cyclotriveratrylene derivative 2 in 24 % yield. The allyl ethers of 2 can then be cleaved back to phenols under mild condition, giving 3 in ca. 47 % [25].

Scheme 1. Synthesis of cyclotriveratrylene
Dendrons containing polybenzyl ether groups were prepared starting from the O-alkylation reaction of the commercially available methyl 3,5-dihydroxybenzoate 1 with 1bromododecane in acetone using potassium carbonate as a catalyst (Scheme 2) in agreement with the literature data [21][22][23][24][25]. The compound 9 was obtained from the diethyl 5-(hydroxymethyl) isophthalate 7, which first was protected with tert-butylchlorodimethylsilane to obtain the compound 8, followed by the reduction with LiAlH 4 in THF to give the compound 9 (Scheme 2).

Scheme 3. Synthesis of bismalonate 11
Bismalonate 11 was used to obtain the first generation activated dendron 12 upon treatment with SOCl 2 , which when coupled to the 3,5-dihydroxybenzyl alcohol was used to obtain the second generation activated dendron 14 (Scheme 4). agreement with the literature data [21][22][23][24][25]. The compound 9 was obtained from the diethyl 5-(hydroxymethyl) isophthalate 7, which first was protected with tert-butylchlorodimethylsilane to obtain the compound 8, followed by the reduction with LiAlH 4 in THF to give the compound 9 (Scheme 2).

Scheme 3. Synthesis of bismalonate 11
Bismalonate 11 was used to obtain the first generation activated dendron 12 upon treatment with SOCl 2 , which when coupled to the 3,5-dihydroxybenzyl alcohol was used to obtain the second generation activated dendron 14 (Scheme 4). agreement with the literature data [21][22][23][24][25]. The compound 9 was obtained from the diethyl 5-(hydroxymethyl) isophthalate 7, which first was protected with tert-butylchlorodimethylsilane to obtain the compound 8, followed by the reduction with LiAlH 4 in THF to give the compound 9 (Scheme 2).

Scheme 3. Synthesis of bismalonate 11
Bismalonate 11 was used to obtain the first generation activated dendron 12 upon treatment with SOCl 2 , which when coupled to the 3,5-dihydroxybenzyl alcohol was used to obtain the second generation activated dendron 14 (Scheme 4).

Scheme 4. Synthesis of activated dendrons 12 and 14; a) SOCl 2 , pyridine, CH 2 Cl 2 b) 3,5-dihydroxybenzyl alcohol, Cs 2 CO 3 , DMF
The dendrons of first and second generation 12 and 14, respectively, were attached to the cyclotriveratrylene 3 to obtain the dendrimers 15 and 16 (Scheme 5). The reaction was carried out in DMF and Cs 2 CO 3 at reflux for 2 days, and the dendrimers 15 and 16 were obtained in good yields.

Scheme 5. Synthesis of dendrimers 15 and 16
The 1 H NMR spectra of dendrimers 15 and 16 showed one broad signal at  H 0.87, 1.26, 1.71 and at d  3.80, due to the aliphatic chain, at  H 3.45 due to the CO-CH 2 -CO. The signal at  H 3.84 is assigned to the O-CH 3 and signals at  H 4.61, 5.04 and 5.08 are ascribed to the -CH 2 -O protons. For dendrimers 15 and 16, the aromatic protons give singlets and multiplets at  H 6.46, 7.50, and at 7.70. In both cases, two doublets were observed at  H 3.63, and at  H 4.70 due to the protons at the CH 2 groups of the cyclotriveratrylene with a coupling constant J= 15.00 Hz. The dendrons of first and second generation 12 and 14, respectively, were attached to the cyclotriveratrylene 3 to obtain the dendrimers 15 and 16 (Scheme 5). The reaction was carried out in DMF and Cs 2 CO 3 at reflux for 2 days, and the dendrimers 15 and 16 were obtained in good yields.  The dendrons of first and second generation 12 and 14, respectively, were attached to the cyclotriveratrylene 3 to obtain the dendrimers 15 and 16 (Scheme 5). The reaction was carried out in DMF and Cs 2 CO 3 at reflux for 2 days, and the dendrimers 15 and 16 were obtained in good yields. The functionalization of C 60 was made using the double Bingel cyclopropanation [26][27][28][29][30][31]. Treatment of C 60 with dendrimers 15 or 16, I 2 , and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in toluene at room temperature gave the fullerene derivatives 17 and 18 in 21 and 18 % yield, respectively (Scheme 6). All the spectroscopic studies and elemental analysis results were consistent with the proposed molecular structures assigned to the fullerene derivatives. All the compounds were characterized by 1 H and 13 C NMR, IR, and mass spectrometry (Electrospray and MALDI-TOF).

Scheme 6. Synthesis of fullerene derivatives 17 and 18
In the 1 H NMR spectra of compounds 17a and 18b ( Fig. 1a and 1b respectively) are observed at  H 0.85-1.70 and 3.80 signals due to the aliphatic chain. Two doublets at  H 3.50 and 4.60 assigned to the -CH 2 -groups of the cyclotriveratrylene. Signals at  H 4.61, 5.04, and at  H 5.08 were ascribed to the -CH 2 -O protons. For dendrimers 17 and 18, signals are also observed from the aromatic protons at the macrocycle and of the benzyloxy chains. In the 13 C NMR spectra of the cyclotriveratrylene-fullerene-dendrimers, 35 signals were ascribed to the fullerene.

Scheme 6. Synthesis of fullerene derivatives 17 and 18
In the 1 H NMR spectra of compounds 17a and 18b ( Fig. 1a and 1b respectively) are observed at  H 0.85-1.70 and 3.80 signals due to the aliphatic chain. Two doublets at  H 3.50 and 4.60 assigned to the -CH 2 -groups of the cyclotriveratrylene. Signals at  H 4.61, 5.04, and at  H 5.08 were ascribed to the -CH 2 -O protons. For dendrimers 17 and 18, signals are also observed from the aromatic protons at the macrocycle and of the benzyloxy chains. In the 13 C NMR spectra of the cyclotriveratrylene-fullerene-dendrimers, 35 signals were ascribed to the fullerene. The functionalization of C 60 was made using the double Bingel cyclopropanation [26][27][28][29][30][31]. Treatment of C 60 with dendrimers 15 or 16, I 2 , and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in toluene at room temperature gave the fullerene derivatives 17 and 18 in 21 and 18 % yield, respectively (Scheme 6). All the spectroscopic studies and elemental analysis results were consistent with the proposed molecular structures assigned to the fullerene derivatives. All the compounds were characterized by 1 H and 13 C NMR, IR, and mass spectrometry (Electrospray and MALDI-TOF).

Scheme 6. Synthesis of fullerene derivatives 17 and 18
In the 1 H NMR spectra of compounds 17a and 18b ( Fig. 1a and 1b respectively) are observed at  H 0.85-1.70 and 3.80 signals due to the aliphatic chain. Two doublets at  H 3.50 and 4.60 assigned to the -CH 2 -groups of the cyclotriveratrylene. Signals at  H 4.61, 5.04, and at  H 5.08 were ascribed to the -CH 2 -O protons. For dendrimers 17 and 18, signals are also observed from the aromatic protons at the macrocycle and of the benzyloxy chains. In the 13 C NMR spectra of the cyclotriveratrylene-fullerene-dendrimers, 35 signals were ascribed to the fullerene.

H NMR spectra of dendrimers a) 17 and b) 18 in CDCl 3
In the Fig. 2 the MALDI-TOF mass spectra for dendrimers 17 and 18 contain a peak at m/z= 6295 (M+Na) and 12513 respectively.

H NMR spectra of dendrimers a) 17 and b) 18 in CDCl 3
In the Fig. 2 the MALDI-TOF mass spectra for dendrimers 17 and 18 contain a peak at m/z= 6295 (M+Na) and 12513 respectively.

H NMR spectra of dendrimers a) 17 and b) 18 in CDCl 3
In the Fig. 2 the MALDI-TOF mass spectra for dendrimers 17 and 18 contain a peak at m/z= 6295 (M+Na) and 12513 respectively.

CONCLUSION
The cyclotriveratrylene dendrimers were obtained from dendrons 12 and 14, and then the fullerene C 60 was introduced in the dendritic branches by a cyclization reaction. Adding the fullerene C 60 in the last step of the synthesis gave good yields. The cycloadditions could occur in different places as show in Fig. 3. The cis cycloadditions gives 30 to 35 signals in the 13 C NMR spectrum. The trans cycloadditions gives in the 13 C NMR spectrum more than 35 signals. In our case the 1 H, 13 C NMR and UV-vis studies showed that the double Bingel cyclopropanation reaction afforded only cis-2 adducts, in agreement with the literature data [32,33].

CONCLUSION
The cyclotriveratrylene dendrimers were obtained from dendrons 12 and 14, and then the fullerene C 60 was introduced in the dendritic branches by a cyclization reaction. Adding the fullerene C 60 in the last step of the synthesis gave good yields. The cycloadditions could occur in different places as show in Fig. 3. The cis cycloadditions gives 30 to 35 signals in the 13 C NMR spectrum. The trans cycloadditions gives in the 13 C NMR spectrum more than 35 signals. In our case the 1 H, 13 C NMR and UV-vis studies showed that the double Bingel cyclopropanation reaction afforded only cis-2 adducts, in agreement with the literature data [32,33].

CONCLUSION
The cyclotriveratrylene dendrimers were obtained from dendrons 12 and 14, and then the fullerene C 60 was introduced in the dendritic branches by a cyclization reaction. Adding the fullerene C 60 in the last step of the synthesis gave good yields. The cycloadditions could occur in different places as show in Fig. 3. The cis cycloadditions gives 30 to 35 signals in the 13 C NMR spectrum. The trans cycloadditions gives in the 13 C NMR spectrum more than 35 signals. In our case the 1 H, 13 C NMR and UV-vis studies showed that the double Bingel cyclopropanation reaction afforded only cis-2 adducts, in agreement with the literature data [32,33].