Zhang et al.
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one-pot reaction fashions starting from cheap and readily
available (hetero)aromatic dinucleophilic and dielectrophilic
reactants.1 Surprisingly, however, NH-bridged calixaro-
matics still remain largely unexplored. For example, using
the fragment coupling method, we3a previously prepared
NH-bridged calix[2]arene[2]triazines from 1,3-phenylene-
diamine and cyanuric chloride. Siri9 and Konishi10 indepen-
dently reported the synthesis of NH-bridged calix[4]arenes
by reacting 1,3-phenylenediamine with 1,5-difluoro-2,4-di-
nitrobenzenes. The use of 1,3-dibromobenzenes as dielectro-
philes in the reaction with 1,3-phenylenediamine led to none
or very low yields of NH-bridged calixaromatics.2h Recently,
Rajca and co-workers11a and Tsue and co-workers11b,c
reported the synthesis of NH-bridged calix[n]arenes from
exhaustive debenzylation of NBn-bridged calix[n]arenes.
For years, we have been interested in the heterocalix[n]-
pyridine derivatives because of their intriguing cavity struc-
tures and versatile properties in recognizing various metal
cations and neutral molecules.1a It is highly desirable to have
the NH-bridged calix[n]pyridine derivatives in order to
understand the substituent effect of the bridging nitrogen
atoms on the structure and property of azacalix[n]pyridines.
Very recently, combining the fragment coupling method and
N-Boc protection/deprotection strategy, we have synthe-
sized NH-bridged calix[m]arene[n]pyridines (m = 1, n = 3;
m = n = 2).12 The method, unfortunately, does not work for
the synthesis of NH-bridged calix[4]pyridine. We report
herein the efficient synthesis of a series of (NH)m(NMe)4-m
-
(2) For recentexamplesofnitrogen-bridged calixaromatics, see: (a) Ito, A.;
Ono, Y.; Tanaka, K. New J. Chem. 1998, 779. (b) Ito, A.; Ono, Y.; Tanaka, K.
J. Org. Chem. 1999, 64, 8236. (c) Miyazaki; Kanbara, T.; Yamamoto, T
Tetrahedron Lett. 2002, 43, 7945. (d) Wang, M.-X.; Zhang, X.-H.; Zheng,
Q.-Y. Angew. Chem., Int. Ed. 2004, 43, 838. (e) Gong, H.-Y.; Zhang, X.-H.;
Wang, D.-X.; Ma, H.-W.; Zheng, Q.-Y.; Wang, M.-X. Chem.;Eur. J. 2006,
12, 9262. (f) Gong, H.-Y.; Zheng, Q.-Y.; Zhang, X.-H.; Wang, D.-X.; Wang,
M.-X. Org. Lett. 2006, 8, 4895. (g) Tsue, H.; Ishibashi, K.; Takahashi, H.;
Tamura, R. Org. Lett. 2005, 7, 11. (h) Fukushima, W.; Kanbara, T.;
Yamamoto, T. Synlett 2005, 19, 2931. (i) Selby, T. D.; Blackstock, S. C.
Org. Lett. 1999, 1, 2053. (j) Suzuki, Y.; Yanagi, T.; Kanbara, T.; Yamamoto,
T. Synlett 2005, 2, 263. (k) Ishibashi, K.; Tsue, H.; Tokita, S.; Matsui, K.;
Takahashi, H.; Tamura, R. Org. Lett. 2006, 8, 5991. (l) Gong, H.-Y.; Wang,
D.-X.; Xiang, J.-F.; Zheng, Q.-Y.; Wang, M.-X. Chem.;Eur. J. 2007, 13,
7791. (m) Liu, S.-Q.; Wang, D.-X.; Zheng, Q.-Y.; Wang, M.-X. Chem.
Commun. 2007, 3856. (n) Zhang, E.-X.; Wang, D.-X.; Zheng, Q.-Y.; Wang,
M.-X. Org. Lett. 2008, 10, 2565. (o) Gong, H.-Y.; Wang, D.-X.; Zheng, Q.-Y.;
Wang, M.-X. Tetrahedron 2009, 65, 87.
(3) For recent examples of oxygen-bridged calixaromatics, see: (a) Wang,
M.-X.; Yang, H.-B. J. Am. Chem. Soc. 2004, 126, 15412. (b) Katz, J. L.;
Feldman, M. B.; Conry, R. R. Org. Lett. 2005, 7, 91. (c) Katz, J. L.; Selby, K.
J.; Conry, R. R. Org. Lett. 2005, 7, 3505. (d)Katz, J. L.; Geller, B. J.; Conry, R.
R. Org. Lett. 2006, 8, 2755. (e) Maes, W.; Van Rossom, W.; Van Hecke, K.;
Van Meervelt, L.; Dehaen, W. Org. Lett. 2006, 8, 4161. (f) Hao, E.; Fronczek,
F. R.; Vicente, M. G. H. J. Org. Chem. 2006, 71, 1233. (g) Chambers, R. D.;
Hoskin, P. R.; Kenwright, A. R.; Khalil, A.; Richmond, P.; Sandford, G.;
Yufit, D. S.; Howard, J. A. K. Org. Biomol. Chem. 2003, 2137. (h) Chambers,
R. D.; Hoskin, P. R.; Khalil, A.; Richmond, P.; Sandford, G.; Yufit, D. S.;
Howard, J. A. K. J. Fluorine Chem. 2002, 116, 19. (i) Li, X. H.; Upton, T. G.;
Gibb, C. L. D.; Gibb, B. C. J. Am. Chem. Soc. 2003, 125, 650. (j) Yang, F.;Yan,
L.-W.; Ma, K.-Y.; Yang, L.; Li, J.-H.; Chen, L.-J.; You, J.-S. Eur. J. Org.
Chem. 2006, 1109. (k) Wang, Q.-Q.; Wang, D.-X.; Zheng, Q.-Y.; Wang, M.-X.
Org. Lett. 2007, 9, 2847. (l) Katz, J. L.; Geller, B. J.; Foster, P. D. Chem.
Commun. 2007, 1026. (m) Zhang, C.; Chen, C.-F. J. Org. Chem. 2007, 72, 3880.
(n) Van Rossom, W.; Maes, W.; Kishore, L.; Ovaere, M.; Van Meervelt, L.;
Dehaen, W. Org. Lett. 2008, 10, 585.
bridged calix[4]pyridines (m = 1-4) from 2þ2 and 1þ3 frag-
ment coupling reactions followed by deallylation reaction. It
has been found indeed that NH bridge(s) played an impor-
tant role in determining the conformational structures and
properties of the resulting macrocycles.
Results and Discussion
We started our study with the synthesis of (NH)(NMe)3-
bridged calix[4]pyridine. The strategy was based on the
deprotection of the N-protection group of azacalix-
[4]pyridine. We envisioned that the introduction of an allyl
group on bridging nitrogen would afford the formation of
(NAllyl)(NMe)3-bridged calix[4]pyridine from the cross-
coupling reaction between diamine fragment 4 and dibro-
mide fragment 7. Deprotection of the allyl group on bridging
nitrogen of the resulting (NAllyl)(NMe)3-bridged calix-
[4]pyridine would then give the desired (NH)(NMe)3-
bridged calix[4]pyridine. Scheme 1 shows the preparation
of fragments 4 and 7. Nucleophilic substitution reaction of
2,6-dibromopyridine 1 with methylamine at 190 °C in an
autoclave gave 6-bromo-2-methylaminopyridine 2 in 92%
yield. Treatment of 2 with sodium hydride followed by 2,6-
dibromopyridine produced dibromide intermediate 3 in 98%
yield. Diamination of 3 with methylamine in an autoclave
afforded product 4 in an almost quantitative yield. A similar
monoamination reaction of 1 with ammonia in an autoclave
gave 6-bromo-2-aminopyridine 5, which underwent nucleo-
philic reaction with 1 in the presence of sodium hydride to
afford bis(6-bromopyridin-2-yl)amine 6 in 88% yield. Reac-
tion between 6 and allyl bromide with the aid of sodium
hydride yielded N-allylbis(6-bromopyridin-2-yl)amine 7
almost quantitatively (Scheme 1).
(4) For review on thiacalixarenes, see: Morohashi, N.; Narumi, F.; Iki,
N.; Hattori, T.; Miyano, S. Chem. Rev. 2006, 106, 5291.
(5) For examples of other heteroatom-bridged calixaromatics, see: (a)
€
€
Konig, B.; Rodel, M.; Bubenitschek, P.; Jones, P. G.; Thondorf, I. J. Org.
€
€
Chem. 1995, 60, 7406. (b) Konig, B.; Rodel, M.; Bubenitschek, P.; Jones, P.
G. Angew. Chem., Int. Ed. 1995, 34, 661. (c) Yoshida, M.; Goto, M.;
Nakanishi, F. Organometallics 1999, 18, 1465. (d) Avarvari, N.; Mezailles,
N.; Ricard, L.; Le Floch, P.; Mathey, F. Science 1998, 280, 1587. (e)
Avarvari, N.; Maigrot, N.; Ricard, L.; Mathey, F.; Le Floch, P. Chem.;
Eur. J. 1999, 5, 2109.
We then investigated the macrocyclic cross-coupling reac-
tion between 4 and 7 (Scheme 2). The effects of catalyst,
ligand, base, reaction temperature, ratio between reactants,
and concentration of reactants were examined (see Table S1
in the SI). It has been found that Pd2(dba)3 showed higher
catalytic efficiency than Pd(PPh)4, PdCl2(PPh)2, and PdCl2
(entries 1-6, Table S1 in the SI). Bidentate ligand dppp was a
better ligand than dppf, dppb, and P(c-Hex)3 (entries 6-10,
Table S1 in the SI). While a polar solvent such as DMF,
DMSO, and DME had a detrimental effect on the cross-
coupling reaction, toluene turned out to be the best solvent
(6) Wang, D.-X.; Zheng, Q.-Y.; Wang, Q.-Q.; Wang, M.-X. Angew.
Chem., Int. Ed. 2008, 47, 7485.
(7) (a) Yang, H.-B.; Wang, D.-X.; Wang, Q.-Q.; Wang, M.-X. J. Org.
Chem. 2007, 72, 3757. (b) Hou, B.-Y.; Wang, D.-X.; Yang, H.-B.; Zheng,
Q.-Y.; Wang, M.-X. J. Org. Chem. 2007, 72, 5218. (c) Hou, B.-Y.; Zheng,
Q.-Y.; Wang, D.-X.; Wang, M.-X. Tetrahedron 2007, 63, 10801. (d) Hou,
B.-Y.; Zheng, Q.-Y.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Chem.
Commun. 2008, 3864. (e) Yao, B.; Wang, D.-X.; Huang, Z.-T.; Wang,
M.-X. Chem. Commun. 2009, 2899.
(8) The N-arylation of NH-bridged calix[2]arene[2]triazine was reported:
Wang, Q.-Q.; Wang, D.-X.; Ma, H.-W.; Wang, M.-X. Org. Lett. 2006, 8, 5967.
(9) Touil, M.; Lachkar, M.; Siri, O. Tetrahedron Lett. 2008, 49, 7250.
(10) Konishi, H.; Hashimoto, S.; Sakakibara, T.; Matsubara, S.; Yasukawa,
Y.; Morikawa, O.; Kobayashi, K. Tetrahedron Lett. 2009, 50, 620.
(11) (a) Vale, M.; Pink, M.; Rajca, S.; Rajca, A. J. Org. Chem. 2008, 73,
27. (b) Tsue, H.; Ishibashi, K.; Tokita, S.; Takahashi, H.; Matsui, K.;
Tamura, R. Chem.;Eur. J. 2008, 14, 6125. (c) Tsue, H.; Matsui, K.;
Ishibashi, K.; Takahashi, H.; Tokita, S.; Ono, K.; Tamura, R. J. Org. Chem.
2008, 73, 7748.
(12) Yao, B.; Wang, D.-X.; Gong, H.-Y.; Huang, Z.-T.; Wang, M.-X.
J. Org. Chem. 2009, 74, 5361.
8596 J. Org. Chem. Vol. 74, No. 22, 2009