Synthetic exploration of oxacalix[2]arene[2]quinazolines

Article abstract of DOI:10.1002/ejoc.201000460

Oxacalix[2]arene[2]quinazoline macrocycles were prepared in good yields, as mixtures of syn and anti isomers, through nucleophilic aromatic substitution cyclocondensation reactions of 2, 4-dichloroquinazolines and m-dihydroxybenzenes. The macrocyclization

Full text of DOI:10.1002/ejoc.201000460

FULL PAPER
DOI: 10.1002/ejoc.201000460
Synthetic Exploration of Oxacalix[2]arene[2]quinazolines
Wim Van Rossom,[a] Lingam Kishore,[a] Koen Robeyns,[b] Luc Van Meervelt,[b]
Wim Dehaen,*[a] and Wouter Maes[a,c]
Keywords: Calixarenes / Nitrogen heterocycles / Aromatic substitution / Regioselectivity / Conformation analysis
Oxacalix[2]arene[2]quinazoline macrocycles were prepared
in good yields, as mixtures of syn and anti isomers, through
nucleophilic aromatic substitution cyclocondensation reac-
tions of 2,4-dichloroquinazolines and m-dihydroxybenzenes.
The macrocyclization conditions were optimized and the iso-
meric ratio was investigated by means of one-step and frag-
ment-coupling approaches. The oxacalixarene substitution
pattern could easily be varied by altering the dichloroquin-
azolinyl biselectrophilic and dihydroxyaryl bisnucleophilic
building blocks. The solid-state (1,3-alternate) conforma-
tional behavior and the oxacalix[4]arene cavity size were ex-
plored by X-ray diffraction studies.
In the presented work, we have expanded the scope of
our heteracalixarene research through application of an-
other heteroaromatic building block, 2,4-dichloroquinazo-
line. Because the reactivity of this (5,6-)annulated pyrimid-
ine analogue towards SNAr is enhanced compared to that
of the previously studied 4,6-dichloropyrimidines, it can be
envisaged that the macrocyclization reaction could provide
the thermodynamically favored oxacalix[4]arene predomi-
nantly (over linear oligomers and larger cyclooligomers)
Introduction
Heteracalix[n]arenes, in which the arene units are linked
by heteroatoms rather than methylene units, form a new
generation of less explored, yet promising calixarene macro-
cycles.[1–3] Among these heteracalixarenes, thiacalixarenes
have been studied most intensively,[4] mainly due to their
straightforward synthesis, whereas aza- and oxacalixarenes,
though (at least) equally attractive, have only been emerging
more recently.[5–9] To date, most reports on oxacalixarenes
describe the synthesis of oxacalix[4]arenes through facile
nucleophilic aromatic substitution (SNAr) strategies em-
ploying variously substituted m-dihydroxybenzenes and ac-
tivated arenes, either 1,5-difluoro-2,4-dinitrobenzene or
electrophilic m-dihalogenated heteroaromatic analogues
(e.g., 1,3,5-triazines or pyridines).[7,8] Previous work within
our group has focused on the synthesis of oxacalix[m]ar-
ene[m]pyrimidines (m = 2–6) through SNAr reactions of res-
orcinol derivatives and 4,6-dihalopyrimidines.[8f,8p,8w] It has
been demonstrated that oxacalix[m]arene[m]pyrimidines,
due to their high-yielding synthesis, tunable macrocycle size,
and ease of elaboration of the substitution pattern, are ver-
satile oxacalixarene platforms for the exploration of various
supramolecular applications.[7,10]
[a] Molecular Design and Synthesis, Department of Chemistry,
Katholieke Universiteit Leuven,
Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax: +32-16-327990
E-mail: wim.dehaen@chem.kuleuven.be
[b] Biomolecular Architecture, Department of Chemistry,
Katholieke Universiteit Leuven,
Celestijnenlaan 200F, 3001 Leuven, Belgium
[c] Institute for Materials Research (IMO), Research Group
Organic and (Bio)Polymer Chemistry, Hasselt University,
Universitaire Campus – Agoralaan Building D,
3590 Diepenbeek, Belgium
Scheme 1. Single-step and fragment-coupling approaches towards
oxacalix[2]arene[2]quinazolines 3a,b.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000460.
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Eur. J. Org. Chem. 2010, 4122–4129

Synthetic Exploration of Oxacalix[2]arene[2]quinazolines
under less forcing conditions, for example, at a lower tem- basis of symmetry through 1H NMR spectroscopy (see
perature. Moreover, 2,4-dichloroquinazoline is an unsym- Supporting Information), and the anti and syn regioisomers
metrical reaction partner, in contrast to most electrophilic were obtained as white solids in 42 and 32% yield, respec-
moieties used so far which contain two initially equally re- tively (74% overall oxacalix[4]arene yield).
active positions.[11] As a result, two oxacalix[4]arene config-
After this initial success, a systematic variation of the
urational (regio)isomers, with the heteroaromatic compo-
nents incorporated in either a syn or an anti arrangement,
can be expected on reaction with a resorcinol derivative
(Scheme 1).[12] Depending on the applied cyclocondensa-
tion conditions, the nature of the reaction (kinetic or
thermodynamic control) and the applied synthetic route
(direct or fragment-coupling SNAr approach), one of the
oxacalix[2]arene[2]quinazoline isomers may be formed pre-
dominantly.
different SNAr reaction parameters (solvent, base, reaction
time, and temperature) was performed to study their influ-
ence on the oxacalix[4]arene selectivity and the regioisom-
eric ratio (Table 1). In particular, conditions that were
proven to be effective for oxacalix[4]arene formation by
other research groups, for example, the Katz and Konishi
teams, have been tested.[8b,8e,8h,8k,8o] Solvent dryness was
shown to be essential to obtain high yields of the oxacalix-
[2]arene[2]quinazoline isomers.[17] The reaction temperature
has a profound effect on the reaction outcome. When the
cyclocondensation reaction was conducted at 100 °C, the
total oxacalix[4]arene amount decreased drastically (to
≈12%). On the other hand, the same reaction at room tem-
perature for 24 h afforded only trace quantities of macro-
cycles (≈1% 3a + 3b), whereas acyclic [1+1] adduct 4 was
obtained as the major product in 75% yield, together with
Results and Discussion
Oxacalixarene Synthesis and Exploration of the anti/syn
Ratio
The quinazolin(on)e framework, to which diverse phar- [2+1] adduct 5 in 7% yield (see structures in Scheme 1).
macological activities have been attributed,[13] is tradition- Care has to be taken while performing reactions at room
ally prepared through cyclization of appropriately substi- temperature, as vacuum evaporation of DMF at an elevated
tuted benzenes.[13–16] Many functional quinazolines found temperature (≈70 °C) to facilitate further workup initiates
in the literature are derived from substituted 2,4-dichlo- cyclooligomerization and inconsistent results may be ob-
roquinazoline precursors, structurally elaborated by SNAr tained. At shorter reaction times, increasing quantities of
reactions.[15] Because the 4-position is more reactive, se- noncyclic precursors 4 and 5 were identified in the crude
quential functionalization at both electrophilic positions mixture. On changing the base to Cs2CO3 (Table 1, Entry 2)
can easily be performed.
slightly diminished yields were obtained (53% 3a + 3b),
In a first attempt to prepare tetraoxacalix[2]arene[2]quin- whereas on applying anhydrous CsF (Table 1, Entry 3)
azolines, 2,4-dichloroquinazoline (1a) and orcinol (5-meth- mainly linear oligomers were produced (≈67% 4 and 23%
ylbenzene-1,3-diol, 2a) were mixed in equimolar amounts 5). For the reaction using CsF (2 equiv.) base, a shorter re-
with an excess amount of K2CO3 in dry DMF at 70 °C for action time (1 h) resulted in a similar mixture of linear
48 h, with the addition of 18-crown-6 (Scheme 1, Table 1, oligomers (53% 4, 20% 5; Table 1, Entry 4).[8h] The combi-
Entry 1). These conditions were chosen as they previously nation of Cs2CO3 or CsF base and DMSO as the solvent
afforded the best results (most thermodynamic control) for also caused a decrease in the oxacalix[4]arene yield (to 7
analogous 4,6-dichloropyrimidine biselectrophiles.[8f] 2,4- and 54%, respectively; Table 1, Entries 5 and 6).[8o] For the
Dichloroquinazoline was easily prepared by dehydroxychlo- reaction employing Cs2CO3 base, mainly linear oligomers
rination (POCl3) of 1H,3H-quinazoline-2,4-dione.[15b,16] were observed, whereas for the reaction with CsF larger
Analysis of the crude cyclooligomerization mixture revealed oxacalix[n]arenes (n Ͼ 4) were formed. The mixture con-
the presence of two major products, which, after flash chro- sisting of oxacalix[6]- up to oxacalix[12]arenes, as evidenced
matographic purification, were identified as oxacalix[4]- by electrospray mass spectrometry (ESI-MS), was found to
arene isomers. anti- and syn-Oxacalix[2]arene[2]quinazoline be inseparable by standard chromatography techniques. On
3a and 3b (Scheme 1) could easily be differentiated on the applying triethylamine (2.2 equiv.) as an organic base in
Table 1. Optimization of the one-pot SNAr conditions towards oxacalix[2]arene[2]quinazolines 3a,b.
Entry
Solvent
Base
t (h)
T (°C)
% anti
% syn
% Calix[4][a]
[b]
1
2
3
4
5
6
7
8
DMF
DMF
DMF
K2CO3
48
48
24
1
18
24
18
24
70
70
70
100
100
42
33
–
1
5
32
20
74
53
Cs2CO3
CsF
[c]
[c]
[c,d]
–
–
–
[c]
DMF
CsF
1[e]
7
DMSO
DMSO
CH3CN
dioxane
Cs2CO3
CsF
2
100
33
21
54[f]
[c]
[c]
[c,g]
Et3N
K2CO3
reflux
–
–
–
reflux[h]
35
54
89
[b]
[a] Isolated yield. [b] Addition of 18-crown-6. [c] Unidentifiable amount. [d] 4 (67%), 5 (23%). [e] 4 (53%), 5 (20%). [f] Larger oxacalix[n]-
arenes were formed as well. [g] 4 (30%), 5 (63%), unreacted 2a. [h] Preceded by 24 h at room temp.
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W. Dehaen et al.
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acetonitrile at reflux (Table 1, Entry 7),[8h] no macrocyclic
species were formed and only linear oligomers were ob-
served, that is, mainly 4 (30%) and 5 (63%).
As previously observed,[7] the oxacalix[4]arene seems to
be the thermodynamically favored (cyclo)oligomer and
high-dilution conditions are not required. Under most of
the conditions screened, the concurrent formation of analo-
gous enlarged O-bridged calix[n]arenes (n Ͼ 4) was not ob-
served (apart from trace signals in the ESI-MS). Only for
the DMSO/CsF system (Table 1, Entry 6) there seems to be
less thermodynamic control, as oxacalix[6]- up to oxaca-
lix[12]arenes were produced as well.
On the basis of previous work by Ponticelli and co-
workers, in which DFT calculations were used to confirm
that the orientation of an isoxazolopyridine building block
has only a minor effect on the stability of bicyclooxacalix-
[4]arene regioisomers,[8r] it may be presumed that both oxa-
calix[2]arene[2]quinazoline isomers will have almost the
same energy. From the performed reactions so far (Table 1,
Figure 1. anti-Heteracalix[4]arene isomers 6a–10a.
Entries 1–7), it can be seen that the anti-cyclotetramer is applied. 2,4-Dichloro-7-nitroquinazoline (1c) was synthe-
generally obtained in slight excess and the isomeric ratio is sized in two steps from 4-nitroanthranilic acid through fu-
undergoing rather small fluctuations. To gain more insight sion with urea and subsequent chlorination with POCl3.[18]
on the (relative) thermodynamic stability of the oxacalix[4]- Reaction of 1c and orcinol at 70 °C afforded only trace
arene isomers and their possible interconversion, a basic amounts of the oxacalix[4]arene isomers. When the reaction
equilibration study was performed.[8e,8h,8k,8m,8s] Upon treat- was, however, repeated at room temperature, desired oxaca-
ment of either anti or syn isomer 3a/b with a small amount lix[4]arenes 8a,b were obtained both in a moderate 18%
of orcinol (0.1 equiv.) under the currently optimal SNAr yield (Figure 1, Table 2). To modulate the size of the oxaca-
conditions (K2CO3, DMF, 70 °C, 24 h), only a very small lix[4]arene cavity and to modify its host–guest recognition
amount of macrocycle breakup and equilibration of the iso- abilities (e.g., through π–π interactions), 2,7-dihydroxy-
1
meric mixture was detected (Ͻ5% as judged by H NMR naphthalene (2c) was also used as a nucleophilic reaction
spectroscopy and TLC). Both oxacalix[4]arene isomers ap- partner.[8d,8o,8u,10] Although the reduced solubility of oxaca-
pear to be reasonably stable under the applied conditions lix[2]naphthalene[2]quinazoline isomers 9a,b in common
(very slow thermodynamic equilibration process).
organic solvents somewhat hampered the ease of purifica-
For comparison, a similar single-step cyclocondensation tion, both isomers could still be obtained in good yields
reaction was performed with 2,4-dichloropyrimidine (1b) as (36% anti/syn, Figure 1, Table 2).
the electrophilic building block. Using the conditions opti-
Thiacalixarenes can be synthesized by similar SNAr pro-
mized so far (DMF, K2CO3, 18-crown-6, 70 °C, 24 h), oxa- tocols when m-benzenedithiols are used as the nucleophilic
calix[2]arene[2]pyrimidine isomers 6a,b were obtained in components. Thiacalix[2]arene[2]quinazoline isomers 10a,b
85% overall yield and a similar isomeric ratio (47% anti, were prepared through reaction of 1,3-benzenedithiol (2d)
38% syn; Figure 1, Table 2), whereas the same reaction em- and 2,4-dichloroquinazoline (1a) by using the optimal SNAr
ploying 4,6-dichloropyrimidine as the biselectrophile af- conditions,[8f] and although the solubility of the thiacalixar-
forded 55% of the respective oxacalix[4]arene.[8f]
ene isomers is limited, they were isolated in 71 and 15%
Both reaction partners could be varied further to obtain yield, respectively, with a noteworthy preference for the anti
diversely functionalized heteracalixhetarene macrocycles. isomer (Figure 1, Table 2). From the above results it can
When resorcinol (2b) was applied as the bisnucleophile, be concluded that the isomeric ratio is rather nucleophile
anti- and syn-oxacalix[2]benzene[2]quinazolines 7a,b were dependent. The strong bias towards anti-thiacalix[4]arene
obtained in 47 and 27% yield, respectively (Figure 1, 10a seems to point to preferential diaryl coupling during
Table 2). Functionalized quinazoline moieties can also be the one-pot protocol towards 10a,b (see further).
Table 2. Newly synthesized heteracalix[4]hetarenes 6a,b–10a,b.[a]
Electrophilic component
Nucleophilic component
% anti
% syn
% Calix[4][b]
2,4-Dichloropyrimidine (1b)
2,4-Dichloroquinazoline (1a)
2,4-Dichloro-7-nitroquinazoline (1c)[c]
2,4-Dichloroquinazoline (1a)
2,4-Dichloroquinazoline (1a)
orcinol (2a)
resorcinol (2b)
6a (47)
7a (47)
8a (18)
9a (36)
10a (71)
6b (38)
7b (27)
8b (18)
9b (36)
10b (15)
85
74
36
72
86
orcinol (2a)
2,7-dihydroxynaphthalene (2c)
1,3-benzenedithiol (2d)
[a] General conditions: DMF, K2CO3, 18-crown-6, 70 °C, 24 h. [b] Isolated yield. [c] Reaction at room temp.
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Synthetic Exploration of Oxacalix[2]arene[2]quinazolines
In a next step, additional fragment-coupling experiments ited conversion to the thermodynamic oxacalix[4]arene sink
were conducted to achieve more knowledge on the regio- were also tested for dichloroquinazolines. Notably, the one-
selectivity
of
the
oxacalix[4]arene
formation pot synthesis approach under these conditions resulted in
(Scheme 1).[7,8a,8i,8k,8v,8w,9] Such stepwise procedures could an inversion of the regioisomeric ratio. Condensation of or-
also be advantageous for the selective synthesis of larger cinol (2a) and 2,4-dichloroquinazoline (1a) in the presence
oxacyclophanes or asymmetric (e.g., ABAC) derivatives. of K2CO3 base and 18-crown-6 in dioxane for 24 h at room
Upon autocyclization of [1+1] adduct 4, only anti isomer 3a temperature and subsequently 24 h at reflux temperature af-
would be expected if no ether bond scission and subsequent forded anti- and syn-oxacalix[4]arene 3a and 3b in 35 and
fragment recombination were involved (dynamic covalent 54% yield, respectively (Table 1, Entry 8). Both an excellent
chemistry), whereas treatment of [2+1] fragment 5 with or- overall yield (89%) and a larger syn content were observed,
cinol (1 equiv.) should in principle only provide syn-oxaca- although the selectivity is still rather poor. Similar results
lix[4]arene 3b and possibly larger (cyclo)oligomers under ki- (37% 3a, 46% 3b) were obtained when first aiming at pre-
netic conditions (Scheme 1). Diaryl precursor 4 could be paring [2+1] adduct 5 at room temperature in dioxane (2:1
obtained in good yield (75%) from the one-pot reaction in ratio 1a/2a, 5 h) and subsequently proceeding to cyclization
DMF (K2CO3 base) at room temperature, whereas linear by orcinol (2a) addition (1 equiv.) and reflux (24 h). A reac-
triaryl building block 5, composed of one orcinol unit that tion temperature of 70 °C was shown to be insufficient for
has reacted on the 4-position of two quinazoline molecules, complete precursor conversion.
was obtained under similar conditions (0 °C to room temp.)
in 91% yield through reaction of precursors 1a and 2a in
X-ray Diffraction Studies
stoichiometric 2:1 quantities. Alternatively, [2+1] adduct 5
was synthesized in a nearly quantitative yield on employing
2.2 equiv. of dichloroquinazoline 1a in acetone (2a, K2CO3,
18-crown-6, 48 h at room temp.).[8i,8w]
The solid-state conformational behavior of some of the
novel oxacalix[2]arene[2]quinazoline isomers, that is, anti
isomer 3a and syn isomer 9b, has been explored by X-ray
crystallography (Figure 2). Single crystals were obtained by
vapor diffusion of pentane into a CHCl3 solution of the
respective oxacalixarene. As for most oxacalix[4]arene
structures reported to date,[7,8] a 1,3-alternate conformation
was observed. The cavity structure, symmetry, and dimen-
sions vary of course depending on the respective isomer and
the nucleophilic component. The electrophilic character of
the quinazoline aromatic rings is clearly visible around the
bridging oxygen atoms. The C–O bond is noticeably (on
average 0.053 Å for 3a and 0.058 Å for 9b) shorter towards
the electrophilic quinazoline subunits (Figures S2 and S5,
Supporting Information). For anti isomer 3a, the planes
formed by the two benzene rings on opposite sides of the
oxacalix[4]arene cavity make an angle of 3.4°, which makes
In a first macrocyclization trial, diaryl precursor 4 was
subjected to the so far optimal SNAr conditions (DMF,
K2CO3, 18-crown-6, 70 °C, 24 h; Scheme 1). The reaction
outcome, anti- and syn-oxacalix[4]arenes were obtained in
48 and 29% yield, respectively, is clearly pointing to a ther-
modynamically controlled process with reversible bond for-
mation rather than a kinetically controlled process. The
anti/syn ratio is only slightly higher than that observed for
the direct synthesis (compare with Entry 1 in Table 1) and
the total oxacalix[4]arene yield is comparable. A shorter re-
action time and lower temperature were found ineffective
to improve the regioisomeric ratio, as major amounts of
unreacted [1+1] adduct 4 remained. Upon cyclization of
[2+1] fragment 5 with orcinol under identical conditions, 3a
and 3b were obtained in 25 and 15% yield, respectively
(10% unreacted 5). It is noteworthy that a higher amount
of anti isomer 3a was observed. This unexpected event was
attributed to the instability of [2+1] precursor 5, as forma-
tion of diaryl fragment 4 (isolated in 21%) by transetherifi-
cation was observed to be a major factor.[15a] From the
same reaction at room temperature over 60% of 4 was iso-
lated. Apparently the 4-position of the quinazoline hetero-
cycle is the most reactive locus, even when substituted with
a phenoxy moiety, causing quinazoline C–O bond cleavage.
The two-step convergent [3+1] approach under these condi-
tions is hence not applicable for more selective preparation
of the syn isomer, and suitable kinetic SNAr conditions lim-
iting breaking and reordering of the diaryl ether bonds have
not been found.
Because previous experiments with dichloropyrimidine-
based tri- and pentaaryl fragments have afforded good
selectivity for enlarged oxacalix[m]arene[m]pyrimidines (m
= 3, 4),[8w] the macrocyclization conditions showing the
most kinetic control (1,4-dioxane, K2CO3, 18-crown-6, re-
Figure 2. Single-crystal X-ray structures for 3a (upper structure)
flux, simultaneous addition of the precursors) and only lim- and 9b (lower structure).
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W. Dehaen et al.
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prior to use. Extra-dry DMSO (over molecular sieves, H2O Յ
0.005%) was purchased from Fluka. Extra-dry DMF (over molecu-
lar sieves, H2O Ͻ 50 ppm) was purchased from Acros. CH3CN was
freshly distilled from CaCl2 (and stored over 3 Å molecular sieves)
prior to use. 1,4-Dioxane (99.5%, for analysis) was purchased from
Acros (and kept over 4 Å molecular sieves).
them almost parallel, and the angle between the planes
formed by the two quinazoline heterocycles is 110.0°. The
cavity enclosed by the calixarene skeleton is about
4.53ϫ7.01 Å (distances taken between the centroids of the
benzene and pyrimidine rings, respectively; Figure S3, Sup-
porting Information). For syn isomer 9b, the planes formed
by the nucleophilic naphthalene rings on opposite sides of
the oxacalixarene cavity make an angle of 19.1°, and the
General Procedure for the Single-Step Synthesis of Oxacalix[2]ar-
ene[2]quinazoline Isomers 3a,b: 2,4-Dichloroquinazoline (200 mg,
angle between the planes formed by the quinazoline moie- 1.0 mmol, 1 equiv.), orcinol (125 mg, 1.0 mmol, 1 equiv.), K2CO3
(415 mg, 3.0 mmol, 3 equiv.), and 18-crown-6 (30 mg, 0.11 mmol)
were combined in dry DMF (10 mL), and the mixture was vigor-
ously stirred at 70 °C for 48 h under an argon atmosphere. DMF
was removed under vacuum, and the mixture was redissolved in
ethyl acetate and washed with distilled water. The organic fraction
was dried with Na2SO4, filtered, and concentrated under vacuum.
The respective oxacalix[4]arene isomers 3a (anti) and 3b (syn) were
separated and purified by column chromatography (silica; CH2Cl2/
ethyl acetate, 95:5), and obtained as pure-white solids. Whenever
linear oligomers remained in the reaction mixture (see Table 1), the
observed chromatographic elution order (silica; CH2Cl2/ethyl acet-
ate, 95:5) was 5–3a–4–3b. Data for anti-oxacalix[2]toluene[2]quinaz-
oline (3a): Yield 42% (105 mg). M.p. 305–307 °C. MS (APCI): m/z
= 501.5 [M + H]+. HRMS (EI): calcd. for C30H20N4O4 500.1485;
found 500.1484. 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ =
2.26 (s, 6 H, CH3), 6.58 (s, 2 H, 2-orc), 6.68 (s, 2 H, 4/6-orc), 6.76
(s, 2 H, 4/6-orc), 7.42–7.49 (m, 2 H, 6-quin), 7.79–7.86 (m, 4 H,
7,8-quin), 8.21 (d, JH,H = 8.1 Hz, 2 H, 5-quin) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): δ = 21.2 (CH3, orc), 113.1, 113.6
(CH, 2-orc), 119.3 (CH, 4/6-orc), 120.3 (CH, 4/6-orc), 124.0 (CH,
5-quin), 125.5 (CH, 6-quin), 126.6 (CH, 8-quin), 135.0 (CH, 7-
quin), 140.6 (C, Ci-CH3-Ph), 152.6 (C, 1/3-orc), 153.66, 153.73 (C,
1/3-orc), 161.3 (C, 2-quin), 169.6 (C, 4-quin) ppm. UV/Vis
(CH2Cl2): λmax (logε) = 316 (8250) nm. Data for syn-oxacalix[2]-
toluene[2]quinazoline (3b): Yield 32% (80 mg). M.p. 292–293 °C.
MS (APCI): m/z = 501.3 [M + H]+. HRMS (EI): calcd. for
C30H20N4O4 500.1485; found 500.1486. 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 2.26 (s, 3 H, CH3), 2.33 (s, 3 H, CH3),
6.54 (t, JH,H = 1.8 Hz, 2 H, 2-orc), 6.63 (t, JH,H = 1.8 Hz, 2 H, 2-
orc), 6.68 (d, JH,H = 1.5 Hz, 2 H, 4/6-orc), 6.78 (d, JH,H = 1.5 Hz,
2 H, 4/6-orc), 7.44–7.50 (m, 2 H, 6-quin), 7.81–7.88 (m, 4 H, 7,8-
quin), 8.22 (d, JH,H = 8.0 Hz, 2 H, 5-quin) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): δ = 21.3 (CH3, orc), 113.0, 114.0
(CH, 2-orc), 119.8 (CH, 4/6-orc), 120.2 (CH, 4/6-orc), 123.9 (CH,
5-quin), 125.4 (CH, 6-quin), 126.9 (CH, 8-quin), 135.0 (CH, 7-
quin), 140.2 (C, Ci-CH3-Ph), 140.9 (C, Ci-CH3-Ph), 152.9 (C, 1/3-
orc), 153.6, 154.0 (C, 1/3-orc), 161.6 (C, 2-quin), 169.5 (C, 4-quin)
ppm.
ties is 114.0°. The expanded cavity is about 4.16ϫ9.50 Å
(distances taken between the centroids of the naphthalene
and pyrimidine rings, respectively; Figure S6, Supporting
Information).
Conclusions
In conclusion, novel oxacalix[2]arene[2]quinazolines have
been synthesized by straightforward and efficient SNAr
macrocyclization strategies. Due to the asymmetry of the
applied quinazoline electrophilic precursors, two regioiso-
mers were obtained and the relative content of both isomers
could be varied (to a certain extent) by changing the reac-
tion conditions and the synthetic protocol. Some elements
controlling the isomeric distribution have been clarified, al-
though not everything is fully understood at this stage. Oxa-
calix[2]arene[2]quinazolines not merely expand the oxa-
calixarene structural diversity, but contribute to the con-
tinuous richness and complexity of the field. The induced
asymmetry in these novel oxacalix[4]arenes can be used as
a springboard towards increasingly complex macrocycles,
for example, inherently chiral macromolecules, with a wide
potential in general supramolecular chemistry. Additional
benefits of the quinazoline building block are the ease by
which the functionalization pattern can be elaborated and
likely extension to analogous, more sophisticated azahetero-
cyclic ring systems, for example, pyrido[3,2-d]pyrimidines,
pyrazolo[3,4-d]pyrimidines, or purines. Furthermore, as the
oxacalix[m]arene[m]quinazoline scaffold orients Lewis basic
nitrogen atoms inside the calixarene cavity, selective (metal)
ion complexation and supramolecular host–guest recogni-
tion (by hydrogen bonding) can be envisaged.[19]
2-Chloro-4-(3-hydroxy-5-methylphenoxy)quinazoline (4): Upon per-
forming the same reaction at room temperature for 24 h, [1+1] ad-
duct 4 was obtained in 75% yield (216 mg). M.p. 176–177 °C. MS
(CI): m/z (%) = 287.1/289.1 (100) [M + H]+, 251.1 (44) [M – Cl].
HRMS (EI): calcd. for C15H11ClN2O2 286.0509; found 286.0516.
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 2.35 (s, 3 H, CH3),
5.37 (br. s, 1 H, OH), 6.59 (s, 1 H, 2-orc), 6.61 (s, 1 H, 4/6-orc),
6.65 (s, 1 H, 4/6-orc), 7.61–7.67 (m, 1 H, 6-quin), 7.88–7.95 (m, 2
H, 7,8-quin), 8.30 (d, JH,H = 8.3 Hz, 1 H, 5-quin) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): δ = 21.6 (CH3, orc), 106.5 (CH,
2-orc), 114.5 (CH, 4/6-orc), 114.6 (CH, 4/6-orc), 115.1 (quin), 119.3
(CH, 4/6-orc), 120.3 (CH, 4/6-orc), 124.1 (CH, 5-quin), 127.3 (CH,
Experimental Section
General: NMR spectra were acquired with commercial instruments
(300/400/600 MHz) and chemical shifts (δ) are reported in parts per
million (ppm) referenced to tetramethylsilane (TMS) or residual
NMR spectroscopic solvent signals. In the 1H NMR spectra, some
signals are broadened due to unresolved 4J couplings. Detailed 13
C
NMR peak assignments were obtained by analysis of DEPT,
HSQC, and HMBC spectra. Mass spectra were obtained with spec-
trometers with a CI/EI (70 eV ionization energy) or APCI/ESI ion
source. Exact mass measurements were acquired in EI mode with
resolution 10000. For column chromatography 70–230 mesh silica
60 was used as the stationary phase. Chemicals received from com- 8-quin), 127.9 (CH, 6-quin), 135.3 (CH, 7-quin), 141.2 (C, Ci-CH3-
mercial sources were used without further purification. K2CO3 (an-
hydrous, granulated) was ground very well (with mortar and pestle)
Ph), 152.9 (C, 1/3-orc), 153.0 (C, 1/3-orc), 156.1, 156.6, 167.9 (C,
4-quin) ppm.
4126
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4122–4129

Synthetic Exploration of Oxacalix[2]arene[2]quinazolines
Single-Step Synthesis of Oxacalix[2]arene[2]quinazoline Isomers
3a,b (Procedure for Optimal syn-Oxacalix[4]arene Content): 2,4-
Dichloroquinazoline (50 mg, 0.25 mmol, 1 equiv.), orcinol (32 mg,
0.25 mmol, 1 equiv.), K2CO3 (87 mg, 1.25 mmol, 5 equiv.), and 18-
crown-6 (5 mg, 0.02 mmol) were combined in dry 1,4-dioxane
(3 mL). The mixture was vigorously stirred at room temperature
for 24 h under an argon atmosphere and subsequently brought to
reflux temperature and stirred for another 24 h. Dioxane was re-
moved under vacuum, and the mixture was redissolved in CH2Cl2
and washed with distilled water. The organic fraction was dried
with MgSO4, filtered, and concentrated under vacuum. The respec-
tive oxacalix[4]arene isomers 3a (22 mg, 35%) and 3b (34 mg, 54%)
were separated by column chromatography (silica; CH2Cl2/ethyl
acetate, 95:5) and obtained as pure-white solids.
Oxacalix[2]arene[2]quinazoline Isomers 7a,b: According to the ge-
neral procedure, 2,4-dichloroquinazoline (200 mg, 1.0 mmol,
1 equiv.), resorcinol (110 mg, 1.0 mmol, 1 equiv.), K2CO3 (415 mg,
3.0 mmol, 3 equiv.), 18-crown-6 (30 mg, 0.11 mmol), dry DMF
(10 mL), 70 °C, 24 h. Eluent: CH2Cl2/ethyl acetate, 92:8. Data for
anti-oxacalix[2]benzene[2]quinazoline (7a): Yield: 47% (111 mg).
M.p. Ͼ350 °C. MS (APCI): m/z = 473.4 [M + H]+. HRMS (EI):
calcd. for C28H16N4O4 472.1172; found 472.1160. 1H NMR
(400 MHz, CDCl3, 25 °C, TMS): δ = 6.76 (t, JH,H = 2.1 Hz, 2 H,
2-resorc), 6.85 (dd, JH,H = 8.0, 1.3 Hz, 2 H, 4/6-resorc), 6.94 (dd,
JH,H = 8.0, 1.2 Hz, 2 H, 4/6-resorc), 7.27 (t, JH,H = 8.1 Hz, 2 H, 5-
resorc), 7.47–7.53 (m, 2 H, 6-quin), 7.83–7.88 (m, 4 H, 7,8-quin),
8.25 (d, JH,H = 8.3 Hz, 2 H, 5-quin) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 113.2, 117.0 (CH, 2-resorc), 118.9 (CH,
4/6-resorc), 119.9 (CH, 4/6-resorc), 124.1 (CH, 5-quin), 125.6 (CH,
6-quin), 126.8 (CH, 8-quin), 130.1 (CH, 5-resorc), 135.2 (CH, 7-
quin), 153.0 (C, 1/3-resorc), 153.9, 154.0 (C, 1/3-resorc), 161.4 (C,
2-quin), 169.7 (C, 4-quin) ppm. Data for syn-oxacalix[2]benzene[2]-
quinazoline (7b): Yield: 27% (64 mg). M.p. 267–268 °C. MS
(APCI): m/z = 473.5 [M + H]+. HRMS (EI): calcd. for C28H16N4O4
472.1172; found 472.1162. 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 6.74 (t, JH,H = 2.1 Hz, 1 H, 2-resorc), 6.80–6.86 (m, 3
H, 2,4/6-resorc), 6.94 (dd, JH,H = 8.1, 2.1 Hz, 2 H, 4/6-resorc), 7.20
(t, JH,H = 8.0 Hz, 1 H, 5-resorc), 7.34 (t, JH,H = 8.0 Hz, 1 H, 5-
resorc), 7.47–7.53 (m, 2 H, 6-quin), 7.83–7.89 (m, 4 H, 7,8-quin),
8.24 (d, JH,H = 8.0 Hz, 2 H, 5-quin) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 113.0, 117.20 (CH, 2-resorc), 117.27 (CH,
2-resorc), 119.2 (CH, 4/6-resorc), 119.7 (CH, 4/6-resorc), 123.9
(CH, 5-quin), 125.5 (CH, 6-quin), 126.9 (CH, 8-quin), 129.8 (CH,
5-resorc), 130.3 (CH, 5-resorc), 135.2 (CH, 7-quin), 153.1 (C, 1/3-
resorc), 153.8 (C, 1/3-resorc), 161.6 (C, 2-quin), 169.5 (C, 4-quin)
ppm.
3,5-Bis(2-chloroquinazolin-4-yloxy)toluene (5): A mixture of 2,4-
dichloroquinazoline (353 mg, 1.77 mmol, 2.2 equiv.), orcinol
(100 mg, 0.81 mmol, 1 equiv.), K2CO3 (278 mg, 2.12 mmol), and
18-crown-6 (8 mg, 0.03 mmol) in acetone (10 mL) was stirred under
an argon atmosphere at room temperature for 48 h. Acetone was
removed under vacuum, CH2Cl2 and water were added, the aque-
ous phase was discarded, and the organic solution was washed with
distilled water. The organic fraction was dried with MgSO4, fil-
tered, and concentrated under vacuum. The [2+1] adduct was puri-
fied by flash chromatography (silica; CH2Cl2/ethyl acetate, 95:5)
and obtained as a pure-white solid in a nearly quantitative yield
(351 mg, 97%). M.p. 186–187 °C. MS (APCI): m/z = 449.7 [M +
H]+. HRMS (EI): calcd. for C23H14Cl2N4O2 448.0494; found
1
448.0491. H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 2.48 (s,
3 H, CH3), 7.08–7.11 (m, 3 H, 2,4,6-orc), 7.62–7.69 (m, 2 H, 6-
quin), 7.91–7.94 (m, 4 H, 7,8-quin), 8.33 (d, JH,H = 8.0 Hz, 2 H, 5-
quin) ppm. 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 21.8
(CH3, orc), 112.9 (CH, 2-orc), 114.8, 120.3 (CH, 4,6-orc), 124.0
(CH, 5-quin), 127.3 (CH, 8-quin), 128.0 (CH, 6-quin), 135.3 (CH,
7-quin), 141.3 (C, Ci-CH3-Ph), 152.4 (C, 1,3-orc), 153.0, 155.9 (C,
2-quin), 167.6 (C, 4-quin) ppm.
Oxacalix[2]arene[2]quinazoline Isomers 8a,b: According to the ge-
neral
procedure,
2,4-dichloro-7-nitroquinazoline
(100 mg,
0.41 mmol, 1 equiv.), orcinol (50 mg, 0.41 mmol, 1 equiv.), K2CO3
(170 mg, 1.23 mmol, 3 equiv.), 18-crown-6 (15 mg, 0.06 mmol), dry
DMF (7 mL), room temp., 24 h. Eluent: CH2Cl2. Data for anti-
oxacalix[2]toluene[2]quinazoline (8a): Yield 18% (22 mg). M.p.
Ͼ350 °C. MS (ESI+): m/z = 591.4 [M + H]+. HRMS (EI): calcd.
for C30H18N6O8 590.1186; found 590.1199. 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 2.32 (s, 6 H, CH3), 6.58 (s, 2 H, 2-orc),
6.73 (s, 2 H, 4/6-orc), 6.81 (s, 2 H, 4/6-orc), 8.24 (dd, JH,H = 8.8,
1.5 Hz, 2 H, 6-quin), 8.41 (d, JH,H = 9.0 Hz, 2 H, 5-quin), 8.69 (d,
JH,H = 1.5 Hz, 2 H, 8-quin) ppm. 13C NMR (100 MHz, CDCl3,
25 °C, TMS): δ = 21.3 (CH3, orc), 113.5 (CH, 2-orc), 116.3, 119.1
(CH, 4/6-orc), 119.6 (CH, 4/6-orc), 120.8 (CH, quin), 122.5 (CH,
quin), 126.2 (CH, quin), 141.2 (C, Ci-CH3-Ph), 152.2, 152.3, 153.4,
154.0, 162.8 (C, 2-quin), 169.7 (C, 4-quin) ppm. Data for syn-ox-
acalix[2]toluene[2]quinazoline (8b): Yield: 18% (22 mg). M.p.
Ͼ350 °C. MS (ESI+): m/z = 591.2 [M + H]+. HRMS (EI): calcd.
for C30H18N6O8 590.1186; found 590.1173. 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 2.28 (s, 3 H, CH3), 2.36 (s, 3 H, CH3),
6.56 (s, 1 H, 2-orc), 6.65 (s, 1 H, 2-orc), 6.71 (s, 2 H, 4/6-orc), 6.83
(s, 2 H, 4/6-orc), 8.24 (d, JH,H = 9.0 Hz, 2 H, 6-quin), 8.40 (d,
JH,H = 9.0 Hz, 2 H, 5-quin), 8.70 (s, 2 H, 8-quin) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): δ = 21.27 (CH3, orc), 21.32 (CH3,
orc), 113.6 (CH, 2-orc), 113.7 (CH, 2-orc), 116.1, 119.0 (CH, 4/6-
orc), 120.1 (CH, 4/6-orc), 120.5 (CH, quin), 122.6 (CH, quin),
126.0 (CH, quin), 140.8 (C, Ci-CH3-Ph), 141.6 (C, Ci-CH3-Ph),
152.2, 152.5, 153.2, 154.1, 162.9 (C, 2-quin), 169.5 (C, 4-quin) ppm.
Oxacalix[2]arene[2]pyrimidine Isomers 6a,b: According to the gene-
ral procedure, 2,4-dichloropyrimidine (200 mg, 1.34 mmol,
1 equiv.), orcinol (166 mg, 1.34 mmol, 1 equiv.), K2CO3 (556 mg,
4.02 mmol, 3 equiv.), 18-crown-6 (30 mg, 0.11 mmol), DMF
(10 mL), 70 °C, 48 h. Eluent: CH2Cl2/ethyl acetate, 95:5. Data for
anti-oxacalix[2]toluene[2]pyrimidine (6a): Yield: 47% (124 mg).
M.p. 249–250 °C. MS (APCI): m/z = 401.3 [M + H]+. HRMS (EI):
calcd. for C22H16N4O4 400.1172; found 400.1178. 1H NMR
(400 MHz, CDCl3, 25 °C, TMS): δ = 2.19 (s, 6 H, CH3), 6.42 (s, 2
H, 2-orc), 6.54 (s, 2 H, 4/6-orc), 6.59–6.64 (m, 4 H, 4/6-orc and
5-pyrim), 8.38 (d, JH,H = 5.5 Hz, 2 H, 6-pyrim) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): δ = 21.1 (CH3, orc), 102.6 (CH,
5-pyrim), 113.6 (CH, 2-orc), 119.5 (CH, 4/6-orc), 120.0 (CH, 4/6-
orc), 140.4 (C, Ci-CH3-Ph), 152.4 (C, 1/3-orc), 153.0 (C, 1/3-orc),
160.9 (CH, 6-pyrim), 165.3 (C, 2-pyrim), 171.1 (C, 4-pyrim) ppm.
Data for syn-oxacalix[2]toluene[2]pyrimidine (6b): Yield: 38%
(101 mg). M.p. 96–98 °C. MS (APCI): m/z = 401.4 [M + H]+.
1
HRMS (EI): calcd. for C22H16N4O4 400.1172; found 400.1174. H
NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 2.23 (s, 3 H, CH3),
2.25 (s, 3 H, CH3), 6.42 (s, 1 H, 2-orc), 6.48 (s, 1 H, 2-orc), 6.59–
6.66 (m, 6 H, 4,6-orc and 5-pyrim), 8.42 (d, JH,H = 5.6 Hz, 2 H, 6-
pyrim) ppm. 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 21.18
(CH3, orc), 21.20 (CH3, orc), 102.5 (CH, 5-pyrim), 113.76 (CH, 2-
orc), 113.81 (CH, 2-orc), 119.8 (CH, 4/6-orc), 120.0 (CH, 4/6-orc),
140.4 (C, Ci-CH3-Ph), 140.6 (C, Ci-CH3-Ph), 152.5 (C, 1/3-orc), Oxacalix[2]naphthalene[2]quinazoline Isomers 9a,b: According to
153.1 (C, 1/3-orc), 161.0 (CH, 6-pyrim), 165.5 (C, 2-pyrim), 171.1 the general procedure, 2,4-dichloroquinazoline (200 mg, 1.0 mmol,
(C, 4-pyrim) ppm.
1 equiv.), 2,7-dihydroxynaphthalene (161 mg, 1.0 mmol, 1 equiv.),
Eur. J. Org. Chem. 2010, 4122–4129
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4127

W. Dehaen et al.
K2CO3 (415 mg, 3.0 mmol, 3 equiv.), 18-crown-6 (30 mg, diffractometer equipped with a CCD detector by using Cu-Kα radi-
FULL PAPER
0.11 mmol), dry DMF (10 mL), 70 °C, 24 h. Extraction solvent
CHCl3. Eluent: CHCl3/ethyl acetate, 90:10. Data for anti-oxaca-
lix[2]naphthalene[2]quinazoline (9a): Yield: 36% (120 mg). M.p.
Ͼ350 °C. MS (APCI): m/z = 573.3 [M + H]+. HRMS (EI): calcd.
for C36H20N4O4 572.1485; found 572.1487. 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 6.96 (dd, JH,H = 8.8, 2.0 Hz, 2 H, 3/6-
naphth), 7.02 (dd, JH,H = 8.8, 2.0 Hz, 2 H, 3/6-naphth), 7.18–7.21
(m, 4 H, 1,8-naphth), 7.51–7.61 (m, 6 H, 6-quin/4,5-naphth), 7.86–
7.94 (m, 4 H, 7,8-quin), 8.31 (d, JH,H = 8.3 Hz, 2 H, 5-quin) ppm.
ation (λ = 1.54178 Å). The images were interpreted and integrated
with the program SAINT from Bruker.[20] Both structures were
solved by direct methods and refined by full-matrix least-squares
on F2 by using the SHELXTL program package.[21] Non-hydrogen
atoms were refined anisotropically, with hydrogen atoms placed in
the riding mode with isotropic temperature factors fixed at 1.2
times U(eq) of the parent atoms (1.5 times for methyl groups).
CCDC-688453 (for 3a) and -688454 (for 9b) contain the supple-
mentary crystallographic data for this paper. These data can be
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 113.2, 118.2 (CH, obtained free of charge from The Cambridge Crystallographic
1/8-naphth), 118.4 (CH, 1/8-naphth), 120.8 (CH, 3/6-naphth), 121.9
(CH, 3/6-naphth), 124.1 (CH, 5-quin), 125.5 (CH, 6-quin), 126.9
(CH, 8-quin), 129.0 (CH, 4/5-naphth), 129.1, 129.2 (CH, 4/5-
naphth), 134.1, 135.1 (CH, 7-quin), 150.5 (C, 2/7-naphth), 151.4
(C, 2/7-naphth), 154.1, 161.8 (C, 2-quin), 169.9 (C, 4-quin) ppm.
Data for syn-oxacalix[2]naphthalene[2]quinazoline (9b): Yield: 36%
(120 mg). M.p. Ͼ350 °C. MS (APCI): m/z = 573.3 [M + H]+.
HRMS (EI): calcd. for C36H20N4O4 572.1485; found 572.1474. H
NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 6.95 (dd, JH,H = 8.8,
2.3 Hz, 2 H, 3/6-naphth), 7.01 (dd, JH,H = 8.8, 2.3 Hz, 2 H, 3/6-
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Single-Crystal Structure of 3a: C30H20N4O4·CHCl3, crystal size
0.3ϫ0.3ϫ0.1 mm, M = 619.87, monoclinic, C2/c, a = 38.262(8) Å,
b = 9.0671(18) Å, c = 18.639(4) Å, β = 118.35(3)°, V = 5691(3) Å3,
T = 100(2) K, Z = 8, ρcalcd. = 1.447 gcm–3, µ(Cu-Kα) = 3.293 mm–1,
F(000) = 2544, R1 = 5.21%, ωR2 = 12.85 for 4370 reflections with
Io Ͼ2σ(I) and GOOF = 1.051. The crystal structure was determined
by using two datasets with insufficient completeness from two dif-
ferent crystals, 96.6 and 95.9% complete up to 135.4° (2θ). Rint for
dataset one after absorption correction (SADABS) was 8.45% for
17136 reflections (5578 unique). Rint for dataset two after absorp-
tion correction (SADABS) was 8.28% for 16413 reflections (5502
unique). The Rmerge between the two datasets is 7.74 (Rsigma 0.0456)
for a total of 33549 reflections (5821 unique). Both crystals were
similar in size and shape.
1
naphth), 7.17 (d, JH,H = 2.2 Hz, 2 H, 1/8-naphth), 7.22 (d, JH,H
=
2.2 Hz, 2 H, 1/8-naphth), 7.49–7.55 (m, 4 H, 6-quin/4,5-naphth),
7.63 (d, JH,H = 8.8 Hz, 2 H, 4,5-naphth), 7.86–7.94 (m, 4 H, 7,8-
quin), 8.30 (d, JH,H = 8.0 Hz, 2 H, 5-quin) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): δ = 113.1, 118.2 (CH, 1/8-
naphth), 118.6 (CH, 1/8-naphth), 121.3 (CH, 3/6-naphth), 121.5
(CH, 3/6-naphth), 124.0 (CH, 5-quin), 125.4 (CH, 6-quin), 127.0
(CH, 8-quin), 128.8, 128.9 (CH, 4/5-naphth), 129.3 (CH, 4/5-
naphth), 129.4, 133.9, 135.1 (CH, 7-quin), 150.7 (C, 2/7-naphth),
151.2 (C, 2/7-naphth), 154.2, 161.9 (C, 2-quin), 169.7 (C, 4-quin)
ppm.
Single-Crystal Structure of 9b: C36H20N4O4, crystal size
0.2ϫ0.2ϫ0.1 mm,
M = 572.56, monoclinic, C21/n, a =
9.9834(6) Å, b = 18.7663(11) Å, c = 14.7223(9) Å, β = 105.087(4)°,
V = 2663.2(3) Å3, T = 100(2) K, Z = 4, ρcalcd. = 1.428 gcm–3, µ-
(Cu-Kα) = 0.775 mm–1, F(000) = 1184, R1 = 6.09%, ωR2 = 15.02
for 4370 reflections with Io Ͼ2σ(I) and GOOF = 1.053.
Thiacalix[2]arene[2]quinazoline Isomers 10a,b: According to the ge-
neral procedure, 2,4-dichloroquinazoline (200 mg, 1.0 mmol,
1 equiv.), 1,3-benzenedithiol (150 mg, 1.0 mmol, 1 equiv.), K2CO3
(415 mg, 3.0 mmol, 3 equiv.), 18-crown-6 (30 mg, 0.11 mmol), dry
DMF (10 mL), 70 °C, 24 h. Extraction solvent CHCl3 (large vol-
umes). Eluent: CHCl3/ethyl acetate, 96:4. Data for anti-thiacalix[2]-
benzene[2]quinazoline (10a): Yield: 71% (192 mg). M.p. Ͼ350 °C.
MS (APCI): m/z = 537.2 [M + H]+. HRMS (EI): calcd. for
C28H16N4S4 536.0258; found 536.0271. 1H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 7.32 (t, JH,H = 7.8 Hz, 2 H, 5-benz), 7.39
(d, JH,H = 7.8 Hz, 2 H, 4/6-benz), 7.46–7.55 (m, 6 H, 6-quin and
2,4/6-benz), 7.81–7.85 (m, 4 H, 7,8-quin), 8.07 (d, JH,H = 8.3 Hz, 2
H, 5-quin) ppm. 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ =
120.8, 124.0 (CH, 5-quin), 126.6 (CH, 6-quin), 126.9, 127.7 (CH,
8-quin), 130.3 (CH, 5-benz), 130.7, 134.7 (CH, 7-quin), 137.5 (CH,
4/6-benz), 137.9 (CH, 4/6-benz), 141.5 (CH, 2-benz), 149.1, 166.7
(2-quin), 172.2 (4-quin) ppm. Data for syn-thiacalix[2]benzene[2]-
quinazoline (10b): Yield: 15% (40 mg). M.p. Ͼ350 °C. MS (APCI):
m/z = 537.4 [M + H]+. HRMS (EI): calcd. for C28H16N4S4
536.0258; found 536.0258. 1H NMR (600 MHz, CDCl3, 25 °C,
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra for all novel heteracalix[4]arenes
and precursors and additional X-ray figures for 3a and 9b.
Acknowledgments
The authors thank the Fund for Scientific Research – Flanders
(FWO) for financial support and a postdoctoral fellowship to W.M.
The Katholieke Universiteit Leuven and the Ministerie voor Wet-
enschapsbeleid are also thanked for continuing financial support.
[1] a) Z. Asfari, V. Böhmer, J. Harrowfield, J. Vicens (Eds.), Ca-
lixarenes 2001, Kluwer Academic Publishers, Dordrecht, 2001;
b) J. Vicens, J. Harrowfield (Eds.), Calixarenes in the
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[2] We prefer the term heteracalixarenes to distinguish the class of
heteroatom-bridged metacyclophanes from heterocalixarenes,
the heterocyclic analogues of classical C-bridged calixarenes,
for example, calixpyrroles (calixhetarenes).
TMS): δ = 7.29 (t, JH,H = 7.7 Hz, 2 H, 5-benz), 7.35 (t, JH,H
=
7.7 Hz, 2 H, 5-benz), 7.42–7.45 (m, 4 H, 4,6-benz), 7.48–7.52 (m,
3 H, 6-quin and 2-benz), 7.57 (t, JH,H = 1.6 Hz, 1 H, 2-benz), 7.81–
7.86 (m, 4 H, 7,8-quin), 8.06 (d, JH,H = 8.2 Hz, 2 H, 5-quin) ppm.
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 120.7, 123.9 (CH,
5-quin), 126.5 (CH, 6-quin), 127.4, 127.7 (CH, 8-quin), 130.2 (CH,
5-benz), 130.5 (CH, 5-benz), 134.7 (CH, 7-quin), 137.1 (CH, 4/6-
benz), 138.3 (CH, 4/6-benz), 141.3 (CH, 2-benz), 141.7 (CH, 2-
benz), 149.2, 167.0 (2-quin), 171.7 (4-quin) ppm.
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4122–4129

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[17] On using regular DMF (not extra dry or carefully dried prior
to use), yields dropped dramatically and noncyclic oligomers
(sometimes partially hydrolyzed, as in ref.[8k]) were identified in
the reaction mixture.
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[19] Some of the reported oxacalix[2]arene[2]quinazolines (3a/b, 9a/
b) have very recently been investigated as potential hosts for
spherical fullerenes C60 and C70 (within the framework of a
study on oxacalix[2]arene[2]pyrimidine-bisporphyrinoid tweez-
ers as selective receptors towards fullerene C70, see ref.[10]). Un-
fortunately, no binding was observed for these macrocycles, as
1
evidenced by H NMR titration experiments.
[20] SAINT, Manual Version 5/6.0, Bruker Analytical X-ray System
Inc., Madison, Wisconsin, 1997.
[21] SHELXTL-NT, Manual Version 5.1, Bruker Analytical X-ray
System Inc., Madison, Wisconsin, 1997.
Received: April 6, 2010
Published Online: May 27, 2010
Eur. J. Org. Chem. 2010, 4122–4129
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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