Synthesis of inherently chiral azacalix[4]arenes and diazadioxacalix[4] arenes

Article abstract of DOI:10.1021/ol1017454

Figure Presented. Described are nucleophilic aromatic substitution reactions for the synthesis of inherently chiral azacalix[4]arenes and diazadioxacalix[4]arenes comprised of two or three different aromatic monomers. A variety of functional groups are tolerated at the 2-, 4-, and 5-positions on the nucleophilic-component monomers; reactions are run under ambient atmosphere; and the macrocycles are constructed without isolation of intermediate linear species.

Full text of DOI:10.1021/ol1017454

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4300-4303
Synthesis of Inherently Chiral
Azacalix[4]arenes and
Diazadioxacalix[4]arenes
Jeffrey L. Katz* and Brittany A. Tschaen
Department of Chemistry, Colby College, 5754 Mayflower Hill, WaterVille, Maine 04901
jlkatz@colby.edu
Received July 26, 2010
ABSTRACT
Described are nucleophilic aromatic substitution reactions for the synthesis of inherently chiral azacalix[4]arenes and diazadioxacalix[4]arenes
comprised of two or three different aromatic monomers. A variety of functional groups are tolerated at the 2-, 4-, and 5-positions on the
nucleophilic-component monomers; reactions are run under ambient atmosphere; and the macrocycles are constructed without isolation of
intermediate linear species.
Advances in heteracalixarene synthesis continue to spur
active investigation of these compounds as platforms for
molecular design and molecular recognition.1 Our laboratory2
and others3 have previously shown that nucleophilic aromatic
substitution (SNAr) reactions are highly efficient for the
synthesis of oxacalix[4]arene macrocycles by the condensa-
tion of diphenols with a variety of electron-deficient aromatic
1,3-dihalides. The high substrate scope provides access to
macrocycles that incorporate two different aromatic mono-
mers (two-component macrocycles) bearing a range of
functionality. Azacalix[4]arenes, in contrast, are more dif-
ficult to prepare in high yield and are most commonly
accessed via metal-catalyzed C-N coupling reactions.4
(3) (a) Lehmann, F. P. A. Tetrahedron 1974, 30, 727–733. (b) Gilbert,
E. E. J. Heterocycl. Chem. 1974, 11, 899–904. (c) Wang, M.-X.; Yang,
H.-B. J. Am. Chem. Soc. 2004, 126, 15412–15422. (d) Hao, E.; Fronczek,
F. R.; Vicente, M. G. H. J. Org. Chem. 2006, 71, 1233–1236. (e) Yang, F.;
Yan, L.; Ma, K.; Yang, L.; Li, J.; Chen, L.; You, J. Eur. J. Org. Chem.
2006, 1109–1112. (f) Maes, W.; Van Rossom, W.; Van Hecke, K.; Van
Meervelt, L.; Dehaen, W. Org. Lett. 2006, 8, 4161–4164. (g) Konishi, H.;
Mita, T.; Morikawa, O.; Kobayashi, K. Tetrahedron Lett. 2007, 48, 3029–
3032. (h) Li, M.; Ma, M.-L.; Li, X.-Y.; Wen, K. Tetrahedron 2009, 65,
4639–4643. (i) Hu, S.-Z.; Chen, C.-F. Chem. Commun. 2010, 46, 4199–
4201. See also 1d,e and references cited therein.
(4) (a) Ito, A.; Ono, Y.; Tanaka, K. New J. Chem. 1998, 22, 779–781.
(b) Ito, A.; Ono, Y.; Tanaka, K. J. Org. Chem. 1999, 64, 8236–8241. (c)
Selby, T. D.; Blackstock, S. C. Org. Lett. 1999, 1, 2053–2055. (d) Hauck,
S. I.; Lakshmi, K. V.; Harwig, J. F. Org. Lett. 1999, 1, 2057–2060. (e)
Miyazaki, Y.; Kanbara, T.; Yamamoto, T. Tetrahedron Lett. 2002, 43, 7945–
7948. (f) Wang, M.-X.; Zhang, X.-H.; Zheng, Q.-Y. Angew. Chem., Int.
Ed. 2004, 43, 838–842. (g) Suzuki, Y.; Yanagi, T.; Kanbara, T.; Yamamoto,
T. Synlett 2005, 263–266. (h) Fukushima, W.; Kanbara, T.; Yamamoto, T.
Synlett 2005, 2931–2934. (i) Tsue, H.; Ishibashi, K.; Takahashi, H.; Tamura,
R. Org. Lett. 2005, 7, 2165–2168. (j) Vale, M.; Pink, M.; Rajca, S.; Rajca,
A. J. Org. Chem. 2008, 73, 27–35. (k) Tsue, H.; Matsui, K.; Ishibashi, K.;
Takahashi, H.; Tokita, S.; Ono, K.; Tamura, R. J. Org. Chem. 2008, 73,
7748–7755.
(1) (a) Ko¨nig, B.; Fonseca, M. H. Eur. J. Inorg. Chem. 2000, 2303–
2310. (b) Vystotsky, M.; Saadioui, M.; Bo¨hmer, V. Calixarenes 2001; Kluwer
Academic Publishers: Dordrecht, Netherlands, 2001; pp 250-265. (c)
Morohashi, N.; Narumi, F.; Iki, N.; Hattori, T.; Miyano, S. Chem. ReV. 2006,
106, 5291–5316. (d) Wang, M.-X. Chem. Commun. 2008, 4541–4551. (e)
Maes, W.; Dehaen, W. Chem. Soc. ReV. 2008, 37, 2393–2402. (f) Tsue, H.;
Ishibashi, K.; Tamura, R. Top. Heterocycl. Chem. 2008, 17, 73–96.
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2758. (c) Katz, J. L.; Geller, B. J.; Foster, P. D. Chem. Commun. 2007,
1026–1028. (d) Wackerly, J. W.; Meyer, J. M.; Crannell, W. C.; King, S. B.;
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10.1021/ol1017454  2010 American Chemical Society
Published on Web 09/02/2010

Relatively few SNAr-based ring formations of either
azacalix[4]arenes or diazadioxacalix[4]arenes have been
reported. Yields are often modest, and preformation and
isolation of linear precursors is frequently required.5
Calix[4]arenes lacking planes of symmetry through op-
posing arenes are inherently chiral;6 in systems that lack
structural rigidity, rotation through the annulus leads to
enantiomerization. In principle, inherently chiral heteracalix[4]-
arenes are accessible by SNAr methods, simply by cyclizing
an aromatic monomer lacking an internal plane of symmetry
between reactive nucleophilic or electrophilic sites. However,
regioselectivity in such a cyclization has not been achieved
except by multistep fragment coupling.7 In this letter, we
describe a general strategy for the one-pot synthesis of
inherently chiral8 three-component azacalix[4]arenes and
diazadioxacalix[4]arenes. Furthermore, adaptation of the
method provides an entry into two-component azacalix[4]-
arenes, and we report that cyclizations using 4-substituted
1,3-diaminobenzenes are highly selective for the inherently
chiral anti-regioisomer.
diamine 2a with electrophile 1 (1:2 stoichiometric ratio,
DMF, (iPr)2NEt, 25 °C, 2 h) cleanly provided the corre-
sponding linear 1:2 adduct (trimer) 3a (R ) 4-OCH3). The
reaction remained homogeneous throughout, indicating that
control of speciation is likely due to the strong deactivating
ability of the amino substituent upon initial addition, sup-
pressing displacement of the second fluorine atoms on the
electrophilic rings.
In situ generated trimer 3a was cyclized simply by addition
of 1 equiv of resorcinol 4a and subsequent heating to 60 °C
1
for 2 h. H NMR analysis revealed high selectivity for
formation of diazadioxacalix[4]arene 5a over other linear and
cyclic oligomeric products (see Figure 2 and the Supporting
Information), and 5a was isolated in 72% yield following
chromatographic purification. Homogenous reaction condi-
tions were also maintained during the cyclization step;
solubility does not drive product selectivity, maximizing the
potential generality of the process.
The scope of this three-component macrocyclization
procedure is summarized in Table 1. 4-Methoxy diamine 2a
cyclized equally well with electron-rich and electron-poor
diphenols: condensation with 5-carbomethoxy-substitued 4a
(entry 1) and 5-methyl-substituted 4b (entry 2) furnished
diazadioxacalix[4]arenes 5a and 5b in 72% and 70% yield,
respectively. Both 4-methyl- and 4-aminophenyl-substituted
diamines 2b and 2c reacted analogously, furnishing three-
component macrocycles 5c-5e in 67-69% isolated yields
(entries 3-5). Electron-withdrawing groups, however, were
not tolerated at the 4-position on the 1,3-diamine coupling
partner. No significant formation of heteracalix[4]arenes was
observed with either 4-chloro- or 4-nitro-1,3-phenylenedi-
amine under analogous reaction conditions.
We initially investigated the formation of linear 1:2
adducts formed from condensation of 1,5-difluoro-2,4-
dinitrobenzene 1 and 1,3-diaminobenzenes 2 using exact
stoichiometric ratios (Table 1). Using air-dried glassware
under ambient atmosphere, reaction of 4-methoxy-substituted
Table 1. Synthetic Scope of Diazadioxacalix[4]arenes 5a
4-Hexyl resorcinol 4c also furnished good yields of
inherently chiral diazadioxacalix[4]arenes when paired with
internally symmetric diamine 2d, and macrocycle 5f was
isolated in 68% yield (Table 1, entry 6). Resorcinol 4c also
cyclized with diamine 2e, which bears a methyl group in
the 2-position (entry 7, 71% yield). 2-Substitution could also
be introduced on diphenol 4. The in situ generated trimer
(5) (a) Liu, S.-Q.; Wang, D.-X.; Zheng, Q.-Y.; Wang, M.-X. Chem.
Commun. 2007, 37, 3856–3858. (b) Touil, M.; Lachkar, M.; Siri, O.
Tetrahedron Lett. 2008, 49, 7250–7252. (c) Konishi, H.; Hashimoto, S.;
Sakakibara, T.; Matsubara, S.; Yasukawa, Y.; Morikawa, O.; Kobayashi,
K. Tetrahedron Lett. 2009, 50, 620–623. (d) Clayden, J.; Rowbottom,
S. J. M.; Ebenezer, W. J.; Hutchings, M. G. Tetrahedron Lett. 2009, 50,
3923–3925. (e) Tanaka, H.; Wada, A.; Shiro, M.; Hioki, K.; Morisaki, D.;
Kunishima, M. Heterocycles 2009, 79, 609–616. (f) Clayden, J.; Rowbottom,
S. J. M.; Hutchings, M. G.; Ebenezer, W. J. Tetrahedron Lett. 2009, 65,
4871–4880. (g) Xue, M.; Chen, C.-F. Org. Lett. 2009, 11, 5294–5297. (h)
Touil, M.; Haddoub, R.; Touil, M.; Raimundo, J.-M.; Siri, O. Org. Lett.
2010, 12, 2722–2725. (i) Wang, L.-X.; Wang, D.-X.; Huang, Z.-T.; Wang,
M.-X. J. Org. Chem. 2010, 75, 741–747.
product
entry
diamine 2
diphenol 4
(yield)b
1
2
3
4
5
6
7
8
2a (R1 ) 4-OCH3) 4a (R2 ) 5-CO2Me)
2a (R1 ) 4-OCH3) 4b (R2 ) 5-CH3)
2b (R1 ) 4-CH3)
2c (R1 ) 4-NHPh) 4a (R2 ) 5-CO2Me)
2c (R1 ) 4-NHPh) 4b (R2 ) 5-CH3)
2d (R1 ) 5-CO2Me) 4c (R2 ) 4-n-hexyl)
5a (72%)c
5b (70%)c
5c (68%)
5d (67%)
5e (69%)
5f (68%)
5g (71%)d
4a (R2 ) 5-CO2Me)
(6) (a) Bo¨hmer, V.; Kraft, D.; Tabatabai, M. J. Inclusion Phenom. Mol.
Recognit. Chem. 1994, 19, 17–39. (b) Cort, A. D.; Mandolini, L.; Pasquini,
C.; Schiaffino, L. New. J. Chem. 2004, 28, 1198–1199.
(7) (a) Hou, B.-Y.; Wang, D.-X.; Yang, H.-B.; Zheng, Q.-Y.; Wang,
M.-X. J. Org. Chem. 2007, 72, 5218–5226. (b) Hou, B.-Y.; Zheng, Q.-Y.;
Wang, M.-X. Tetrahedron 2007, 63, 10801–10808. (c) Van Rossom, W.;
Kishore, L.; Robeyns, K.; Van Meervelt, L.; Dehaen, W.; Maes, W. Eur.
J. Org. Chem. 2010, 4122–4129.
2e (R1 ) 2-CH3)
4c (R2 ) 4-n-hexyl)
2c (R1 ) 4-NHPh) 4d (R2 ) 2-OH, 5-CO2Et) 5h (66%)
a 1.0 equiv of diamine 2, 2.0 equiv of 1, 4.7 equiv of (iPr)2NEt; then
1.0 equiv of diphenol 4. b Isolated yield after chromatographic purification.
c 7.0 equiv of (iPr)2NEt. d Trimer formation run at 40 °C for 2 h, cyclization
at 70 °C for 2 h.
(8) The term “inherently chiral” is used to identify macrocycles that
lack internal planes of symmetry due to asymmetrically disposed substit-
uents. The inherently chiral heteracalix[4]arenes described in this letter
undergo enantiomerization at ambient temperature. Future work will address
post-cyclization derivativization to furnish resolvable enantiomers.
Org. Lett., Vol. 12, No. 19, 2010
4301

derived from diamine 2c reacted with ethyl gallate 4d
selectively across the meta-disposed phenols, providing
macrocycle 5h in 66% yield, which bears a lower-rim
hydroxyl group (entry 8).
produced a single major product azacalix[4]arene macrocycle,
and isomerically pure anti-azacalix[4]arene 7a was isolated in
62% yield (Scheme 2). No syn-azacalix[4]arene regioisomer
Consistent with the observations of Siri,5b formation of
diazadioxacalix[4]arenes 5 was optimal at unusually high
reaction concentrations (approximately 0.40 M with respect
to diamine 2). The lack of oligomeric mixtures observed in
single-step oxacalix[4]arene formation reactions is attributed
to reversible C-O bond formation leading to thermodynamic
product distributions.1d,e,2d Analogous C-N bond cleavage
is unlikely, and we have not observed C-N bond cleavage
under our macrocyclization conditions: product distributions
reflect kinetic mixtures. Thus, there exists a strong kinetic
bias for diazadioxacalix[4]arene formation over oligomer-
ization for the sequence leading to macrocycles 5. Intramo-
lecular hydrogen bonding between the bridging diaryl amines
and adjacent nitro groups has been proposed as a confor-
mational constraint in similar systems.5b The observed kinetic
bias for heteracalix[4]arene formation is also consistent with
our electrophile-dependent conformational model for ox-
acalixarene versus poly(meta-phenylene oxide) formation2d>
and that electrophiles such as 1 bearing sterically bulky
groups in the 2- and 4-positions are sufficient to gear linear
oligomers into favorable conformations for cyclization.
We next sought to adapt our three-component coupling
procedure to accommodate nitrogen atoms at all four bridging
positions. In situ generated trimer 3a reacted with diami-
nobenzene 2d at 85 °C over 18 h and furnished inherently
chiral azacalix[4]arene 6a in 61% yield after chromatographic
purification (Scheme 1). Analogously, trimer formation using
Scheme 2.
Anti-Selective Synthesis of Azacalix[4]arenes 7a
a 1.0 equiv of diamine 2, 1.0 equiv of 1, 4.7 equiv of (iPr)2NEt. b Isolated
yield after chromatographic purification. c 7.0 equiv of (iPr)2NEt. d 90 °C
reaction temperature.
was detectable, and the remainder of the material consisted
of higher oligomers (see Supporting Information). The
structure of 7a was confirmed by X-ray crystallography
(Figure 1), which also revealed substantial gearing of the
Scheme 1. Synthesized Three-Component Azacalix[4]arenes 6
Figure 1. X-ray crystal structure of 7a (thermal ellipsoids at the
30% probability level; oxygen ) red, nitrogen ) blue, carbon )
gray, hydrogen ) black).
diamine 2c, followed by cyclization with 2d, formed three-
component azacalix[4]arene 6b in 57% isolated yield. Thus,
by simply modulating temperature to match substrate nu-
cleophilicity, a variety of inherently chiral three-component
azacalix[4]arenes and diazadioxacalix[4]arenes are readily
accessed in a single reaction vessel, without the need for
inert atmosphere, and using exact stoichiometric quantities
of the aromatic monomers.
The ability of diaminobenzene 2d to successfully displace
the fluorine atoms on trimers 3 suggested that an analogous
procedure would also furnish two-component azacalix[4]arenes.
Reaction of equimolar quantities of diaminobenzene 2a and 1,5-
difluoro-2,4-dinitrobenzene 1 at 85 °C (DMF, (iPr)2NEt, 18 h)
aromatic framework (27° average dihedral angle between
opposing aromatic rings). Equally selective formation of the
inherently chiral anti-regioisomer was observed in cycliza-
tions using diamines 2b or 2c, furnishing azacalix[4]arenes
7b and 7c in 56% and 54% isolated yield, respectively.
4-Substituted nucleophiles have not previously found
general utility for the construction of heteracalix[4]arenes,
presumably due to the problematic formation of regioiso-
meric mixtures. Regioselective monoarylation of both di-
amines 2a and 2b, however, is well precedented in the
literature.9 The high anti-regioselectivity obtained in the
synthesis of azacalix[4]arenes 7 is consistent with formation
4302
Org. Lett., Vol. 12, No. 19, 2010

of a single regioisomeric dimer in the initial linear coupling
step (Scheme 2). Subsequent coupling of dimers (2 + 2
pathway), under conditions of kinetic product control, then
furnishes macrocycles with anti-regiochemistry. Supporting
this mechanism, selectivity was not observed in the formation
of diazadioxacalix[4]arenes 5 (3 + 1 pathway) using two
different 4-substituted nucleophiles: attempted coupling of
diamine 2c, diphenol 4c, and electrophile 1 under the reaction
conditions described in Table 1 led to the formation of a
mixture of regioisomers.
It has been documented that azacalix[4]arenes similar to
6 and 7 have low solubility in organic solvents and that this
can complicate purification and lower obtained product
yields.5b,c,h All heteracalixarenes described above are isolated
via precipitation of reaction mixtures (by addition of aqueous
acid), followed by chromatographic purification. In many
cases, 1H NMR analysis of the precipitated reaction residues
revealed nominally “pure” products without discrete single
contaminants present in >5% quantity. We suspected that
higher oligomers accounted for the remaining mass balance
for reactions leading to macrocycles 5-7 but that these
impurities were difficult to identify and quantify by 1H NMR.
GPC analysis performed on the unpurified reaction residues
of 5a and 7a indeed revealed significant quantities of
oligomers, which were removed upon chromatographic
purification (see Figure 2 and the Supporting Information).
Thus, our reported yields appear to accurately reflect the
kinetic cyclization selectivity versus oligomerization inherent
under the reaction conditions. Furthermore, we urge caution
in identifying heteracalixarenes as analytically pure without
GPC verification when obtained by precipitation methods
under conditions of kinetic product control, as significant
quantities of oligomeric contaminants can be difficult to
detect by NMR.
Figure 2.
Partial 1H NMR spectra (10.0-5.7 ppm range) and GPC
chromatograms of heteracalixarene 5a (from Table 1, entry 1) before
1
and after chromatographic purification. (a) H NMR spectrum of
1
unpurified 5a (* denotes residual DMF resonance). (b) H NMR
spectrum of purified 5a. (c) GPC chromatogram of unpurified 5a.
(d) GPC chromatogram of purified 5a. GPC baselines are shown
with a gray line below chromatogram peaks.
different aromatic monomers. In addition, we have shown
that single-step azacalix[4]arene formation using 4-substi-
tuted 1,3-diaminobenzenes can proceed with high selectivity
for the inherently chiral anti-regioisomer. Investigations to
expand substrate scope, and to structurally rigidify the
synthesized macrocycles to permit resolution of enantiomers,
are ongoing and will be reported in due course.
Acknowledgment. This work is supported by the National
Science Foundation (CHE-0640729), the Petroleum Research
Fund (45440-B1), and Colby College. Special thanks are due
to the Bowdoin College MALDI HRMS facility (MRI-
0116416).
In conclusion, we have described one-pot methods for the
construction of inherently chiral azacalix[4]arenes and
diazadioxacalix[4]arenes comprised of either two or three
(9) (a) Chang, J.-Y.; Lin, C.-F.; Pan, W.-Y.; Bacherikov, V. A.; Chou,
T.-C.; Chen, C.-H.; Dong, H.; Cheng, S.-Y.; Tsai, T.-J.; Lin, Y.-W.; Chen,
K.-T.; Chen, L.-T.; Su, T.-L. Bioorg. Med. Chem. 2003, 11, 4959–4969.
(b) Bacherikov, V. A.; Chang, J.-Y.; Lin, Y.-W.; Chen, C.-H.; Pan, W.-Y.;
Dong, H.; Lee, R.-Z.; Chou, T.-C.; Su, T.-L. Bioorg. Med. Chem. 2005,
13, 6513–6520. (c) Su, T.-L.; Lin, Y.-W.; Chou, T.-C.; Zhang, X.;
Bacherikov, V. A.; Chen, C.-H.; Liu, L. F.; Tsai, T.-J. J. Med. Chem. 2006,
49, 3710–3718. (d) Touil, M.; Raimundo, J.-M.; Lachkar, M.; Marsal, P.;
Siri, O. Tetrahedron 2010, 66, 4377–4382.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 3a, 5a-h,
6a-b, and 7a-c and X-ray crystallographic data for
compound 7a (CIF format). This material is available free
of charge via the Internet at http://pubs.acs.org.
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