Metal-free synthesis of azacalix[4]arenes

Article abstract of DOI:10.1016/j.tetlet.2008.10.008

The facile preparation of N(H)-bridged azacalix[4]arenes has been achieved by stepwise nucleophilic aromatic substitutions assisted by hydrogen bonding interactions. The synthesis is uncatalyzed and affords previously unknown tetranitroazacalix[4]arenes.

Full text of DOI:10.1016/j.tetlet.2008.10.008

Tetrahedron Letters 49 (2008) 7250–7252
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal-free synthesis of azacalix[4]arenes
Mounia Touil a,b, Mohammed Lachkar b, Olivier Siri a,
*
a Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), UPR 3118 CNRS, Aix-Marseille Université, Campus de Luminy, Case 913, F-13288 Marseille cedex 09, France
b Université Sidi Mohamed Ben Abdellah, Faculté des Sciences Dhar El Mahraz Laboratoire d’Ingénierie des Matériaux Organométalliques et Moléculaires ‘L.I.M.O.M.’,
Département de Chimie, B.P. 1796, Atlas, 30000, Fès, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 July 2008
Revised 29 September 2008
Accepted 1 October 2008
Available online 7 October 2008
The facile preparation of N(H)-bridged azacalix[4]arenes has been achieved by stepwise nucleophilic aro-
matic substitutions assisted by hydrogen bonding interactions. The synthesis is uncatalyzed and affords
previously unknown tetranitroazacalix[4]arenes.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Calixarenes
Macrocycles
Nucleophilic aromatic substitution
Calix[n]arenes received much attention for decades in supra-
molecular chemistry due to their specific molecular structure,
which allowed the formation of host-guest complexes.1–3 Consid-
erable efforts are now devoted in derivatizing the basic calixarene
skeletons, and the more recent developments are the preparation
of analogs by replacing the methylenic bridges by heteroatoms in
order to tune and improve their properties.4–12 Among the het-
ero-bridged calixarenes, N(R)-bridged azacalix[4]arenes of type 1,
also called [14]metacyclophanes, are of growing interest owing to
the presence of the nitrogen bridges which: (i) conjugate with
the aromatic rings to increase the electron density of the pi-
cloud,12 (ii) may participate to the complexation of species,13 and
(iii) are the key sites for robust high spin polyradicals.7,14
N(H)-bridged aza[14]metacyclophanes such as 2 have been less
investigated,11,14,15 but are much more attractive owing to the
presence of additional hydrogen bonding and a possible tunable
functionalization of the NH sites which open new perspectives in
azacalixarene chemistry. Although the parent compound 2 (i.e.,
unsubstituted) was first reported by Smith in 1963,15 only two re-
cent articles—to the best of our knowledge—described the prepara-
tion of 2 or similar macrocyles.11,14 Both are based on palladium-
catalyzed aryl amination reactions, which were applied for the
synthesis of all azacalix[4]arenes of types 1 and 2 reported in the
literature.9,10,12
R
H
R
R
H
H
N
N
N
N
N
N
N
N
R
H
2
1
An alternative route that would not require the use of a catalyst
and which would give access to new functionalized N(H)-bridged
aza[14]metacyclophanes of type 2 could be useful to enlarge the
scope of this family of compounds. Herein, we report a synthetic
strategy that is based on stepwise nucleophilic aromatic substitu-
tions (SNAr), assisted by hydrogen bonding interactions for control-
ling the conformation of the key intermediates.
The commercially available 1,3-diaminobenzene derivatives
were used as nucleophilic components, for which introduction of
functionality could be achieved. 1,5-Fluoro-2,4-dinitrobenzene
was identified as their coupling partner of choice owing to the
presence of structural elements for SNAr and the possibility to pre-
pare N(H)-bridged aza[14]metacyclophanes of type 2 functional-
ized by nitro groups.
Molecule 3b was first reacted with 4 (1 equiv) in refluxing EtOH
in the presence of base to afford the [1+1] adduct 5,16 which precipi-
tated preventing the formation of polymeric materials (Scheme 1).
* Corresponding author. Tel.: +33 617 248 134; fax: +33 491 829 580.
E-mail address: siri@univmed.fr (O. Siri).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.008

M. Touil et al. / Tetrahedron Letters 49 (2008) 7250–7252
7251
O2N
F
NO2
F
CO2Me
R
4
(1 equiv.)
N(iPr)2Et
H2N
NH
NO2
NO2
H2N
NH2
EtOH, reflux (2h)
73%
3a R = H
5
3b R = CO2Me
F
4 (1 equiv.)
N(iPr)2Et
MeCN, reflux
3 days
N(iPr)2Et
EtOH, reflux (24h)
74-78%
4
N(iPr)2Et
(0.5 equiv.)
MeCN, reflux
3 days
24%
R
R
H2N
H2N
NH
NH
NO2
NO2
O2N
NO2
HN
NH
NH
4
(1 equiv.)
N(iPr)2Et
MeCN, reflux
(8-24h)
O2N HN
NO2
67-75%
R
R
7a R = H
7b R = CO2Me
6a R = H
6b R = CO2Me
Scheme 1. Synthesis of calix[4]arenes 7a–7b.
The 1H NMR spectrum of 5 shows the NH resonance at
10.07 ppm, which suggests the presence of an intramolecular
hydrogen bond. X-ray analysis of 5 confirms the NHÁ Á ÁO2N interac-
tion, which preorganizes the backbone of the uncyclic intermediate
for the cylization step (Fig. 1).17
The cyclization reaction by dimerization of 5 in refluxing MeCN
was unsuccessful at C ꢀ 5 Á 10À4 M (starting material recov-
ered), but succeeded at C ꢀ 5 Á 10À2 M affording 7b in 24% yield
(Scheme 1). These observations suggest in one hand that high dilu-
tion conditions are not necessary to prevent the formation of poly-
mers or linear oligomers, and in other hand that higher
concentrations favor the formation of the target calix[4]arenes.
We also envisaged the use of 6a and 6b for which a similar confor-
mation controlled by two intramolecular H-bonds, instead of one
in 5, should favor the formation of the macrocycle.11 The reaction
between 3a or 3b and 4 (0.5 equiv) led to the formation of the
[2+1] products 6a or 6b, which precipitated in EtOH in good yields
(Scheme 1).18 Their 1H NMR spectra show two down-field NH at d
9.57 and 9.63 ppm for 6a and 6b, respectively, in agreement with
NHÁ Á ÁO2N hydrogen bonding interactions that restrict the rotation
of the uncyclized precursors. The macrocyclization from reactions
between 6a or 6b and 4 in refluxing MeCN (C ꢀ 5 Á 10À4 M) affor-
ded the target molecules 7a and 7b in 38% and 14% yield, respec-
tively (Scheme 1). These compounds are easily obtained pure as
yellow solids by precipitation (no need of purification by chroma-
tography).19 When the same reaction was carried out at C ꢀ
5 Á 10À2 M, the yields increased up to 75% and 67% for 7a and 7b,
respectively, which confirms the strong influence of the concentra-
tion on the formation of the macrocyles. It is noteworthy that 7a
could be directly obtained in 46% yield from 3a and 4 in refluxing
MeCN at C ꢀ 5 Á 10À2 M ( Scheme 1). The yield dropped to 15%,
Figure 1. ORTEP view of the crystal structure of 5. Displacement parameters
include 50% of the electron density. Selected bond distances (Å) and angles
(°): C(1)–N(1) = 1.345(4), C(2)–C(1) = 1.418(4), C(2)–C(3) = 1.380(5), C(3)–C(4) =
1.366(6), C(4)–C(5) = 1.397(6), C(6)–C(5) = 1.344(6), C(1)–C(6) = 1.413(5), C(2)–
N(3) = 1.433(5), C(4)–N(4) = 1.444(5); C(1)–C(2)–N(3) = 122.1(3), C(2)–C(1)–
N(1) = 123.8(3), N(4)–C(4)–C(3) = 119.2(4).

7252
M. Touil et al. / Tetrahedron Letters 49 (2008) 7250–7252
Nouvelles Technologies. We also thank Professor F. Fages for
fruitful discussions, and M. Giorgi for the crystal structure deter-
mination of 5.
References and notes
1. Baldini, L.; Casnati, A.; Sansone, F.; Ungaro, R. Chem. Soc. Rev. 2007, 36, 254–
266.
2. Kim, J. S.; Quang, D. T. Chem. Rev. 2007, 107, 3780–3799.
3. Ikeda, A.; Shinkai, S. Chem. Rev. 1997, 97, 1713–1734.
4. Katz, J. L.; Feldman, M. B.; Conry, R. R. Org. Lett. 2005, 7, 91–94.
5. Konishi, H.; Tanaka, K.; Teshima, Y.; Mita, T.; Morikawa, O.; Kobayashi, K.
Tetrahedron Lett. 2006, 47, 4041–4044.
Figure 2. 1H NMR spectra in DMSO-d6 of 7a (a) and 7b (b). The range 0–3.5 ppm is
omitted for clarity.
6. Matsumiya, H.; Terazono, Y.; Iki, N.; Miyano, S. J. Chem. Soc., Perkin Trans. 2
2002, 1166–1172.
7. Ishibashi, K.; Tsue, H.; Sakai, N.; Tokita, S.; Matsui, K.; Yamauchi, J.; Tamura, R.
Chem. Commun. 2008, 2812–2814.
8. Morohashi, N.; Narumi, F.; Iki, N.; Hattori, T.; Miyano, S. Chem. Rev. 2006, 106,
5291.
9. Ito, A.; Ono, Y.; Tanaka, K. New J. Chem. 1998, 779–781.
10. Ito, A.; Ono, Y.; Tanaka, K. J. Org. Chem. 1999, 64, 8236–8241.
11. Fukushima, W.; Kanbara, T.; Yamamoto, T. Synlett 2005, 2931–2934.
12. Tsue, H.; Ishibashi, K.; Takahashi, H.; Tamura, R. Org. Lett. 2005, 7, 2165–2168.
13. Takemura, H. J. Inclusion Phenom. Macrocycl. Chem. 2002, 42, 169–182.
14. Vale, M.; Pink, M.; Rajca, S.; Rajca, A. J. Org. Chem. 2008, 73, 27–35.
15. Smith, G. W. Nature (London, UK) 1963, 198, 879.
16. Synthesis of 5: A mixture of 4 (100 mg, 0.49 mmol, 1 equiv), methyl 3,5-
diaminobenzoate (114.8 mg, 0.69 mmol, 1 equiv) and N(iPr)2Et (0.21 ml,
1.2 mmol, 2.5 equiv) in refluxing EtOH was stirred for 2 h. The obtained
precipitate was isolated by filtration and washed with water affording 5 as an
orange solid (m = 250 mg, 73% yield). 1H RMN (250 MHz, acetone-d6) d 3.85 (s,
3H, CH3), 5.30 (br s, 2H, NH2), 6.95 (m, 1H, aromatic H), 7.01 (d, 1H,
3JHF = 12.6 Hz, aromatic H), 7.22 (m, 1H, aromatic H), 7.33 (m, 1H, aromatic H),
9.07 (d, 4JHF = 8.0 Hz, 1H, aromatic H), 10.07 (br s, 1H, NH). MS (ESI)+: m/z = 351
[M+H]+. Calcd for C14H11FN4O6Á1/6EtOH: C, 48.10; H, 3.38; N, 15.65. Found: C,
48.46; H, 3.32; N, 15.91.
Figure 3. View of the 1,3-alternate conformation of 7a and 7b.
when the same reaction occurs in a protic solvent such as EtOH.
Similarly, the macrocyclization from reactions between 6a and 4
(C ꢀ 5 Á 10À2 M) gave 7a in lower yield (17%) in EtOH than in MeCN
(75% yield). These observations are consistent with SNAr reactions
assisted by H-bonding interactions, which are more favored at
higher concentrations and which prevent the formation of poly-
meric materials in spite of low dilution conditions.
17. Crystal data for 5: monoclinic, space group P21/c with a = 11.4771(4),
b = 9.6376(4), c = 14.1523(5),
a = 90, b = 95.901, c = 90 at 293(2) K with Z = 4,
R1 = 0.0977, R2 = 0.1472, GOF = 1.127. Crystallographic data for the structures
5 has been deposited at the Cambridge Crystallographic Data Centre (CCDC
693854). Copy of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +40(0)-1223-336033 or e-
mail: http://www.wdeposit@ccdc.cam.ac.uk].
The 1H NMR spectra of 7a and 7b show unusual high-field
chemical shifts of the intraannular aromatic protons Ha at d 5.38
and 5.53 ppm for 7a and 7b, respectively (Fig. 2). These 1H NMR
data suggest that 7a and 7b adopt the 1,3-alternate conformation,
in which Ha protons are located inside the anisotropic shielding
cone of the adjacent aromatic rings (Fig. 3).4,14 This conformation
is supported by the resonance of the corresponding Ha proton in
6a and 6b (d 6.63 and 6.40 ppm, respectively), which are poorly
influenced by the adjacent aromatic rings due to a higher degree
of freedom.
18. General procedure for the synthesis of 6a and 6b: To a solution of 3 (1.96 mmol,
2 equiv) in ethanol containing N(iPr)2Et (2.45 mmol, 2.5 equiv), was added 1,5-
difuoro-2,4-dinitrobenzene
4 (0.98 mmol, 1 equiv). The mixture was then
stirred for 24 h under reflux affording 6a and 6b, which were isolated as orange
precipitates by filtration.
Compound 6a: m = 378 mg, 78% yield. 1H NMR (250 MHz, DMSO-d6) d 5.28 (br
s, 4H, NH2), 6.40 (m, 3H, aromatic H), 6.63 (s, 1H, HN–C@CH–C–NH), 7.02 (m,
2H, aromatic CH), 9.01 (s, 1H, O2N–C@CH–C–NO2), 9.57 (br s, 2H, NH). MS
(MALDI-TOF)+: m/z = 381 [M+H]+. Calcd for C18H16N6O4Á1/4EtOH: C, 56.70; H,
4.50; N, 21.45. Found: C, 56.53; H, 4.35; N, 21.67.
Interestingly, the comparison between the resonances of the in-
tra- and extraannular aromatic protons (Ha and Hb) for 7a and 7b
shows rare chemical shift differences between two aromatic pro-
Compound 6b: m = 360 mg, 74% yield. 1H NMR (250 MHz, acetone-d6) d 3.78 (s,
6H, CH3), 5.53 (br s, 4H, NH2), 6.40 (s, 1H, HN–C@CH–C–NH), 6.68 (m, 2H,
aromatic H), 6.90 (m, 2H, aromatic H), 7.01 (m, 2H, aromatic H), 9.01 (s, 1H,
O2N–C@CH–C–NO2), 9.63 (br s, 2H, NH). 13C NMR (DMSO-d6) d 51.9 (OCH3),
96.3, 112.1, 112.5, 113.5, 125.0, 128.2, 131.2, 138.6, 146.0, 149.9 (aromatic C),
165.9 (C@O). MS (ESI)+: m/z = 497 [M+H]+. Calcd for C22H20N6O8Á1/2H2O: C,
52.28; H, 4.19; N, 16.63. Found: C, 52.02; H, 4.01; N, 16.33.
tons linked to the same benzene ring (Dd = 3.66 and 3.50 ppm,
respectively).
In summary, we described the first metal-free synthesis of
azacalix[4]arenes, which allowed the access to new N(H)-bridged
aza[14]metacyclophanes 7a and 7b. 1H NMR analysis clearly dem-
onstrated that these macrocycles adopt an 1,3-alternate conforma-
tion in solution. In addition to the NH-bridging sites, the potential
presence of four NH2 functions (reduction of the NO2 groups) open
unprecedented pespectives in azacalixarene chemistry, currently
under investigations.
19. General procedure for the synthesis of 7a and 7b: To a solution of 6a or 6b in
CH3CN in the presence of N(iPr)2Et (5 equiv), was added dropwise 1,5-difuoro-
2,4-dinitrobenzene
4 (1 equiv) at room temperature. After stirring under
reflux, the solution was concentrated under vacuum to afford
a yellow
precipitate of 7a or 7b, which was isolated by filtration.
Compound 7a: m = 38 mg, 75% yield. 1H RMN (250 MHz, DMSO-d6) d 5.38 (s,
2H, HN–C@CH–C–NH, called Ha), 7.14 (m, 6H, aromatic H), 7.47 (m, 2H,
aromatic H), 9.04 (m, 2H, O2N–C@CH–C–NO2, called Hb), 9.72 (br s, 4H, NH).
MS (MALDI-TOF)+: m/z = 545 [M+H]+. Calcd for C24H16N8O8: C, 52.95; H, 2.96;
N, 20.58. Found: C, 53.09; H, 3.12; N, 20.31.
Compound 7b: m = 180 mg, 67% yield. 1H RMN (250 MHz, DMSO-d6) d 3.81 (s,
6H, CH3), 5.53 (s, 2H, HN–C@CH–C–NH, called Ha), 7.52 (m, 2H, aromatic H),
7.65 (m, 4H, aromatic H), 9.03 (s, 2H, O2N–C@CH–C–NO2, called Hb), 9.78 (br s,
4H, NH); MS (ESI)+: m/z = 661 [M+H]+. Calcd for C28H20N8O12: C, 50.92; H, 3.05;
N, 16.96. Found: C, 50.60; H, 3.33; N, 16.56.
Acknowledgments
This work was supported by the Centre National de la
Recherche Scientifique, the Ministère de la Recherche et des