Synthesis of a novel benzocyclotrimer with one rigid and one flexible electron-rich cavity

Article abstract of DOI:10.1002/hlca.201500018

The straightforward synthesis of a novel benzocyclotrimer is herein presented. The syn-product is characterized by an electron-rich rigid aromatic cavity and a flexible electron-rich aromatic pocket. The molecule is a potential scaffold for supramolecular

Full text of DOI:10.1002/hlca.201500018

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Synthesis of a Novel Benzocyclotrimer with One Rigid and One Flexible
Electron-Rich Cavity
by Alceste Bolzana), Marco Bortoluzzia), Giuseppe Borsatoa), Chiara Fabbroa), Arif Das¸tanb),
Ottorino De Lucchia), and Fabrizio Fabris*a)
a) Dipartimento di Scienze Molecolari e Nanosistemi, Università Caꢀ Foscari di Venezia, IT-30123 Venezia
(phone: þ 39-41-2348908; fax: þ 39-41-2348517; e-mail: fabrisfa@unive.it)
b) Department of Chemistry, Ataturk University, Faculty of Sciences, TR-25240 Erzurum
The straightforward synthesis of a novel benzocyclotrimer is herein presented. The syn-product is
characterized by an electron-rich rigid aromatic cavity and a flexible electron-rich aromatic pocket. The
molecule is a potential scaffold for supramolecular applications.
Introduction. – Supramolecular applications in chemistry [1] have attracted the
interest of a large number of scientists, since the first applications described by D. J.
Cram, J.-M. Lehn, and C. J. Pedersen since 1987 [2]. The prerequisite for the
supramolecular phenomenon is the electronic and steric reciprocity between the host
and the guest partners. In order to form supramolecules with high selectivity, the
synthesis of hosts with specific shapes and finely tuned electronic surfaces is mandatory.
Benzocyclotrimers [3] are rigid molecules characterized by one or two cavities,
which have been successfully employed in supramolecular chemistry [4]. Among them,
benzocyclotrimers bearing aromatic rings are characterized by large stiff cavities. In
this report, we describe the synthesis of the electron rich benzocyclotrimer syn-1
displaying one rigid hemi-cavity in the lower part of the structure (Fig. 1).
Furthermore, the three tolyl residues form one flexible cavity at the upper part of
the central aromatic ring (Fig. 1).
Fig. 1. Benzocyclotrimer syn-1, displaying the upper gated-cavity and the lower hemi-cavity
ꢁ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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Results and Discussion. – The starting material for the synthesis of the benzo-
cyclotrimer syn-1 was 3,4-dibromo-N-tosylpyrrole 2, which can be obtained from
commercially available 1-(4-tolylsulfonyl)pyrrole [5]. Pyrrole 2 reacted in a [4 þ 2]
cycloaddition with the benzyne derived from the decomposition of the 2-diazonium-
4,5-dimethoxy benzoate zwitterion 3, acting as the dienophile1) (Scheme 1). The
benzyne intermediate was at first obtained in situ, by the action of isopentylnitrite in
CH2Cl2/acetone in the presence of the pyrrole, for safety reason. The yields of the
cycloadduct were disappointingly low (about 20% after chromatography). For this
reason, it was decided to isolate the diazonium salt by precipitation as chloride, which
turned out to be stable when moistened with Et2O and stored for a short time in a
refrigerator [7]. The diazonium chloride was conveniently converted into the benzyne
form in the presence of pyrrole 2, by the action of propylene oxide [7]. Several
experiments allowed to optimize the amount and rate of the addition of the hydrogen
chloride scavenger. Indeed, the rapid addition of 1 equiv. of propylene oxide led to the
formation of the cycloadduct in modest yield (20% yield of isolated product). The
addition of the scavenger in such an amount to completely consume the suspended
diazonium chloride (nearly two equiv.), led to an increase in the yield of the
cycloadduct (36%). Finally, 2.1 equiv. of scavenger was added at a slower rate
(27 mmol/h), to obtain the cycloadduct in a yield of 53% of isolated product 4
(Scheme 1).
Stannylation of the dibromide 4 was attempted at first by metalation with butyl-
lithium to obtain compound 5 and transmetalation with trimethyltin chloride,
furnishing the desired stannane 6 in low yields (about 20%), accompanied by non
negligible amounts of a tin free compound (Scheme 2). Characterization (1H- and
13C-NMR, HMQC, HMBC, COSY, NOESY) of this product allowed the assessment of
structure 9 to this compound. An obvious hypothesis for its formation is that at first the
addition of the lithiated intermediate 5 to a second molecule of 4 takes place to form 7.
The ring-opening of the aza-bridge, with simultaneous formation of a C¼C bond in the
saturated ring, is favoured by the release in strain in 8. A further gain in energy is
obtained by the elimination of a molecule of Ts-NLiBr (a compound analogous to
chloramine-T) and complete aromatization of the naphthyl moiety (Scheme 2).
In order to minimize this side product, the lithiation reaction was performed at
À 908 for a shorter time (3 – 4 min) before quenching with trimethyltin chloride. Owing
to this precaution, a nearly quantitative yield of trimethyltin derivative 6 was obtained.
Scheme 1. Synthesis of the Bicycle 4, via Cycloaddition Reaction of Pyrrole 2 with the Aryne from
Diazonium Salt 3
1
)
This compound is commercially available, but it is more convenient to prepare it from the less
expensive methyl ester, according to [6].

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Scheme 2. Stannylation of 4 and Mechanistic Hypothesis for the Formation of By-Product 9
The cyclotrimerization of 6 was accomplished with freshly prepared copper(I) 2-
thiophenecarboxylate (CuTC) in dry NMP [8] (Scheme 3).
The isolation and purification of the benzocyclotrimers was accomplished by flash-
chromatograpy and trituration with AcOEt in order to remove some residual NMP.
The syn- and anti-diastereoisomers were obtained in 68% overall yield and in a 1:2.2
ratio. Attempts of demethylation of the phenolic moieties with boron tribromide in
CH2Cl2 at low temperature [9] invariably caused opening of the aza-bridge and
aromatization of the products, as witnessed by the disappearance of the signals
resonating at 5.70 ppm, concomitantly with the appearance of a set of signals at
8.95 ppm.
Scheme 3. Cyclotrimerization of vic-Bromostannane 6

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Conclusions. – In conclusion, a straightforward synthesis of a new benzocyclo-
trimer, characterized by two cavities, has been presented. Equilibrium geometry and
electronic structure of this compound have been investigated by means of DFT
calculations (see General in Exper. Part). In the most stable structure (syn-1-A),
depicted in Fig. 2, the relative positions of the tosyl groups do not allow the definition
of the gated-cavity sketched in Fig. 1. An equilibrium geometry (syn-1-B) having such a
cavity has been obtained by introducing three CÀC constrains among the tosyl-Me
groups, each one of 4.5 Š (see Fig. 2). This value allows the inter-atomic distances
among the Me fragments to be slightly higher than the sums of the Van der Waals radii,
as observable in the inset of Fig. 2. The Gibbs energy difference between syn-1-A and
syn-1-B is quite low, about 5.3 kcal/mol, this suggesting the facile formation of the
gated-cavity.
The minimum electron density values inside the rigid hemi-cavity and the gated-
cavity in syn-1-B are below 10À3 electronbohrÀ3, as observable in the slice reported in
Fig. 2. Syn-1-A and syn-1-B geometries and relative Gibbs energies. Inset: syn-1-B, Van der Waals spheres

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Fig. 3. Electron density (left, electrons/Bohr3) and electrostatic potential maps (right, kcal/mol) for syn-1-
B, slices taken perpendicular to the central aromatic ring
Fig. 3, taken perpendicular to the central aromatic ring. Greater differences between
the two cavities arise from the analysis of the electrostatic potential maps (see Fig. 3).
The value of electrostatic interaction energy for a charge inside the rigid hemi-cavity is
around À 15 kcal/mol, while less interaction is expected in the other cavity, where the
electrostatic interaction energy at the centre amounts to about À 10 kcal/mol. The
volume of the hemi-cavity and the volume included between the tosyl groups were
estimated to be about 34 and 64 Š3, respectively.
The authors wish to thank Università Caꢀ Foscari Venezia and MIUR (Rome) within PRIN national
framework.
Experimental Part
General. Solvents were dried over standard drying agents and freshly distilled prior to use. The
reagents were purchased from Aldrich and Acros, and were used without further purification unless
otherwise stated. All moisture-sensitive reactions were carried out under Ar. Flash chromatography
separations: silica gel (Machery-Nagel 60 M, 0.04 – 0.063 mm or 0.063 – 0.2 mm). IR Spectra: Perki-
nElmer Spectrum One spectrophotometer with NaCl optics. 1H- and 13C-NMR (300 and 75 MHz, resp.)
spectra: Bruker Avance 300 instrument with TMS as internal standard in CDCl3, except where defined
otherwise; J values in Hz. Computational details: all the ground-state geometry optimizations have been
carried out in vacuo using the hybrid DFT functional EDF 2 [10] in combination with the split-valence
double-z polarized basis set 6-31G(d,p) [11]. The ꢂrestrictedꢀ formalism has been used in all calculations.
No symmetry constrains have been applied, while geometry constrains have been introduced in selected
cases [12]. The software used is Spartan ꢀ082) [13]. Cartesian coordinates of syn-1-A and syn-1-B are
collected in a separated .xyz file. The volumes of the cavities were calculated with the program
DeepView/Swiss PdbViewer 4.0.4 by using a 1-N molecular probe on the minimized structure syn-1-B.
2
)
Except for molecular mechanics and semi-empirical models, the calculation methods used in
Spartan have been documented in [13b].

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3,4-Dibromo-1-tosyl-1H-pyrrole (¼ 3,4-Dibromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole; 2). A
soln. of Br2 (7.4 ml, 140 mmol) in glacial AcOH (80 ml) was added dropwise in 30 min to a soln. of 1-
tosyl-1H-pyrrole [5] (13.50 g, 60 mmol) in glacial AcOH (200 ml), and the mixture was maintained at
1208 for 1.5 h. The resulting dark soln. was poured onto H2O and ice (1 l), and the pH was adjusted to
neutral with aq. sat. NaHCO3. The resulting solid material was filtered and dissolved in CH2Cl2, dried
over Na2SO4, and decolorized with charcoal. The soln. was filtered over a Celite pad, concentrated at
i
reduced pressure. The resulting solid material was crystallized from hot PrOH to afford 5.76 g of tan
crystals (25% yield). M.p. 135 – 1378. 1H-NMR: 7.76 (d, J ¼ 8.5, 2 H); 7.34 (d, J ¼ 8.5, 2 H); 7.17 (s, 2 H);
2.43 (s, 3 H).
2-Carboxy-4,5-dimethoxybenzenediazonium Chloride (3). Aq. HCl (37%, 5 ml) and isopentylnitrite
(10.4 ml, 124.32 mmol) were sequentially added to an ice cooled soln. of 2-amino-4,5-dimethoxybenzoic
acid [6][7] (10.00 g, 50.60 mmol) in EtOH (80 ml). The mixture was maintained under vigorous stirring,
until the solid appeared completely dispersed in the soln. (30 min). Et2O (50 ml) was added in order to
complete the precipitation of the salt, which was washed with small amounts of cold Et2O (2 Â 10 ml) and
partially dried by suction in the funnel (CAUTION! Dry diazonium salts are explosive!), to obtain
1
11.30 g of tan solid material (91% yield). H-NMR ((D6)DMSO): 8.66 (s, 1 H); 7.73 (s, 1 H); 4.10 (s,
3 H); 3.93 (s, 3 H).
2,3-Dibromo-1,4-dihydro-6,7-dimethoxy-9-tosyl-1,4-epiminonaphthalene (¼2,3-Dibromo-1,4-dihy-
dro-6,7-dimethoxy-9-[(4-methylphenyl)sulfonyl]-1,4-epiminonaphthalene; 4). Propylene oxide (3.46 ml,
95.83 mmol) was added via a syringe-pump during 3.5 h to a slurry of 3 (11.16 g, 45.63 mmol) and 2
(8.61 g, 22.71 mmol) in 1,2-dichloroethane (100 ml) maintained at 1008. Heating was maintained until N2
evolution ceased (nearly 4.5 h). The resulting soln. was diluted with CH2Cl2, washed with aq sat.
NaHCO3 (3 Â 50 ml), dried over Na2SO4, decolorized with charcoal, and concentrated at reduced
pressure. The resulting dark oil was crystallized from Et2O to obtain a first crop of tan crystals (3.76 g).
M.p. 168 – 1738. Mother liquors were concentrated and purified by flash-chromatography (eluent
CH2Cl2) and crystallized from Et2O what gave a second crop of colorless crystals (2.46 g; overall yield
53%). M.p. 170 – 1748. IR (KBr): 1482, 1345, 1160, 1071, 707, 576. 1H-NMR: 7.59 (d, J ¼ 8.4, 2 H); 7.24 (d,
J ¼ 8.4, 2 H); 6.93 (s, 2 H); 5.31 (s, 2 H); 3.83 (s, 6 H); 2.40 (s, 3 H). 13C-NMR: 146.6; 143.9; 137.5; 134.9;
133.6; 129.8; 128.5; 107.4; 74.3; 56.5; 21.5. Anal. calc. for C19H17Br2NO4S: C 44.29, H 3.33; found: C 44.25,
H 3.39.
2-Bromo-1,4-dihydro-6,7-dimethoxy-9-tosyl-3-(trimethylstannyl)-1,4-epiminonaphthalene (¼2-Bro-
mo-1,4-dihydro-6,7-dimethoxy-9-[(4-methylphenyl)sulfonyl]-3-(trimethylstannanyl)-1,4-epiminonaph-
thalene; 6). A soln. of butyl lithium in hexane (2.5m, 2.1 ml, 5.15 mmol) was added to a soln. of 4 (2.20 g,
4.29 mmol) in dry THF (14 ml) maintained at À 908 under Ar. After 3 min, trimethyltin chloride (1.03 g,
5.15 mmol) was added in one portion and the temp. was left to rise to r.t. in 4 h. The mixture was diluted
in CH2Cl2, washed with H2O (3 Â 20 ml), dried over Na2SO4, and concentrated at reduced pressure to
afford 2.41 g (94% yield) of crystalline material. M.p. 638. IR (KBr): 1479, 1339, 1158, 1071, 693, 573.
1H-NMR: 7.48 (d, J ¼ 8.1, 2 H); 7.14 (d, J ¼ 8.1, 2 H); 6.83 (s, 2 H); 6.65 (s, 2 H); 5.45 (s, 1 H); 5.17 (s,
1 H); 3.78 (s, 3 H); 3.76 (s, 3 H); 2.35 (s, 3 H); 0.13 (s, 9 H). 13C-NMR: 152.8; 146.5; 145.8; 145.5; 143.3;
139.4; 138.7; 135.5; 129.4; 128.5; 107.8; 106.8; 74.5; 74.2; 56.5; 56.3; 21.4; À 9.1. Anal. calc. for
C22H26BrNO4SSn: C 44.10, H 4.37; found: C 43.97, H 4.33.
2-Bromo-3-(3-bromo-6,7-dimethoxynaphthalen-2-yl)-1,4-dihydro-6,7-dimethoxy-9-tosyl-1,4-epimi-
nonaphthalene (¼2-Bromo-3-(3-bromo-6,7-dimethoxynaphthalen-2-yl)-1,4-dihydro-6,7-dimethoxy-9-
[(4-methylphenyl)sulfonyl]-1,4-epiminonaphthalene; 9). Compound 9 was obtained in 34% yield, when
the previous reaction was performed at À 788 and waiting 30 min before quenching with trimethyltin
chloride. M.p. 140 – 1448. IR (KBr): 2993, 1503, 1254, 1173, 1057, 698, 580. 1H-NMR: 7.92 (s, 1 H); 7.51 (d,
J ¼ 8.3, 2 H); 7.23 (s, 1 H); 7.09 (d, J ¼ 8.3, 2 H); 6.99 (s, 1 H); 6.97 (s, 1 H); 6.87 (s, 1 H); 6.71 (s, 1 H); 5.75
(d, J ¼ 1.7, 1 H); 5.37 (d, J ¼ 1.7, 1 H); 3.98 (s, 3 H); 3.95 (s, 3 H); 3.82 (s, 3 H); 3.72 (s, 3 H); 2.35 (s, 3 H).
13C-NMR: 151.6; 150.9; 150.2; 146.4; 146.3; 143.3; 139.0; 138.4; 135.2; 132.5; 130.4; 130.0; 129.1; 128.7;
128.6; 128.4; 127.6; 117.2; 108.6; 107.6; 106.3; 105.2; 74.3; 72.9; 56.4; 56.3; 56.0; 55.9; 21.4. Anal. calc. for
C31H27Br2NO6S: C 53.08, H 3.88; found: C 53.20, H 3.85.
Cyclotrimerization of 6 with CuTC. Copper(I) 2-thiophenecarboxylate (CuTC) (405 mg,
2.36 mmol) was added to a soln. of 6 (940 mg, 1.57 mmol) in dry NMP (4.0 ml) maintained at À 208

Helvetica Chimica Acta – Vol. 98 (2015)
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under Ar. The mixture was left to rise to r.t. in 18 h, diluted with CH2Cl2 (100 ml) and 10% aq. NH3
(50 ml) and vigorously stirred for 1 h. Layers were separated and the org. phase was washed with 10% aq.
NH3 (3 Â 20 ml), dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by
flash-chromatography (eluent AcOEt/cyclohexane with a gradient from 4 :1 to pure AcOEt). First
eluate: anti-5,6,11,12,17,18-hexahydro-2,3,8,9,14,15-hexamethoxy-19,20,21-tritosyl-5,18 :6,11:12,17-trie-
piminotrinaphthylene (anti-1) was triturated with AcOEt to eliminate residual NMP to afford 262 mg
of tan solid material (47% yield). M.p. 948. IR (KBr): 1485, 1337, 1295, 1158, 1068, 693, 567. 1H-NMR:
7.11 (d, J ¼ 8.3, 4 H); 6.96 (s, 2 H); 6.93 (d, J ¼ 8.3, 2 H); 6.75 (s, 2 H); 6.63 (d, J ¼ 8.1, 4 H); 6.53 (s, 2 H);
6.06 (d, J ¼ 8.1, 2 H); 5.80 (s, 2 H); 5.71 (s, 2 H); 5.62 (s, 2 H); 3.85 (s, 6 H); 3.67 (s, 6 H); 3.64 (s, 6 H);
2.18 (s, 6 H); 1.82 (s, 3 H). 13C-NMR: 147.4; 147.2; 146.9; 143.4; 142.6; 138.0; 137.8 (2 overlapping C);
134.1; 133.9; 133.8; 133.7; 133.6; 129.3; 128.6; 127.5; 127.4; 107.0; 106.7; 106.4; 66.4; 66.2; 65.8; 56.5; 56.3;
56.2; 21.2; 20.7. Anal. calc. for C57H51N3O12S3: C 64.21, H 4.82; found: C 64.39, H 4.89.
Second
eluate:
syn-5,6,11,12,17,18-hexahydro-2,3,8,9,14,15-hexamethoxy-19,20,21-tritosyl-
5,18 :6,11:12,17-triepiminotrinaphthylene (syn-1) was triturated with AcOEt to eliminate residual
NMP to afford 117 mg of tan solid material (21% yield). M.p. 908. IR (KBr): 1331, 1295, 1163, 1074, 693,
1
579. H-NMR: 7.43 (d, J ¼ 7.9, 6 H); 7.09 (d, J ¼ 7.9, 6 H); 6.44 (s, 6 H); 3.55 (s, 18 H); 2.34 (s, 9 H).
13C-NMR: 147.3; 143.6; 137.9; 134.7; 133.6; 129.5; 128.0; 106.5; 66.3; 56.1; 21.3. Anal. calc. for
C57H51N3O12S3: C 64.21, H 4.82; found: C 63.86, H 4.90.
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Received January 21, 2015