An enaminone-directed benzannulation/macrocyclization approach to cyclophane ring systems

Article abstract of DOI:10.1021/jo0256181

A straightforward and modular preparative approach to 1,3,5-triaroylbenzene-based functionalized cyclophane ring systems has been developed. The key cyclophane-forming macrocyclization reaction was accomplished during the course of a regioselective cross-benzannulation between bis(aryl ethynyl) ketone and enaminone reactants. Macrocyclic products with ring sizes ranging from 18-to 22-membered were successfully constructed. The composition of the tether connecting the two aryl ethynyl ketone fragments can be easily varied; consequently, this method is suitable for construction of a diverse range of structurally distinct cyclophane products. To illustrate this feature, cyclophanes possessing xylyl, alkyl, di(ethylene triamine), and di(ethylene oxy) bridging units were synthesized in isolated yields of 11-46%. Three new cyclophanes (calixarene-like macrocyles 8 and 9, as well as crownophane 18) were structurally characterized by X-ray diffractometry.

Full text of DOI:10.1021/jo0256181

J . Org. Chem. 2002, 67, 4547-4552
4547
An En a m in on e-Dir ected Ben za n n u la tion /Ma cr ocycliza tion
Ap p r oa ch to Cyclop h a n e Rin g System s
F. Christopher Pigge,* Fatemeh Ghasedi, and Nigam P. Rath
Department of Chemistry and Biochemistry, University of MissourisSt. Louis,
8001 Natural Bridge Road, St. Louis, Missouri 63121-4499
piggec@jinx.umsl.edu
Received February 17, 2002
A straightforward and modular preparative approach to 1,3,5-triaroylbenzene-based functionalized
cyclophane ring systems has been developed. The key cyclophane-forming macrocyclization reaction
was accomplished during the course of a regioselective cross-benzannulation between bis(aryl
ethynyl) ketone and enaminone reactants. Macrocyclic products with ring sizes ranging from 18-
to 22-membered were successfully constructed. The composition of the tether connecting the two
aryl ethynyl ketone fragments can be easily varied; consequently, this method is suitable for
construction of a diverse range of structurally distinct cyclophane products. To illustrate this feature,
cyclophanes possessing xylyl, alkyl, di(ethylene triamine), and di(ethylene oxy) bridging units were
synthesized in isolated yields of 11-46%. Three new cyclophanes (calixarene-like macrocyles 8
and 9, as well as crownophane 18) were structurally characterized by X-ray diffractometry.
In tr od u ction
A common feature in the synthetic strategies described
above is the incorporation of preformed aromatic building
blocks into larger macrocyclic ring systems. In contrast,
examples of cyclophane construction via macrocyclization
accomplished during the course of a concomitant ben-
zannulation process are relatively rare. Importantly,
benzannulation-derived synthetic routes may provide
access to structurally unique cyclophane systems that are
difficult to prepare by other methods. Of the reported
benzannulation approaches toward cyclophane ring sys-
tems, most have relied on the use of transition metal
catalysts (e.g., Ziegler-type catalysts,5 Co,6 Pd7) to effect
the trimerization of alkyne derivatives. Cyclophane
structures also have been obtained from benzannulation
reactions of Fischer-type chromium carbenes.8 A common
drawback to metal-mediated benzannulation processes
is the generation of regioisomeric mixtures of benzene
derivatives (e.g., 1,3,5- and 1,2,4-substituted isomers).
Regioselective benzannulations that result in cyclophane
products have been achieved, however, in the Pd-
catalyzed cyclodimerization of enynes,9 in the aldol
condensation of nitromalonodialdehyde with various
The synthesis of new cyclophane ring systems remains
an active area of investigation. The impetus for much
recent work in this field stems from potential applications
of cyclophanes in, for example, materials science and
supramolecular chemistry. In addition, aesthetic char-
acteristics of relatively large (and oftentimes rigid) mac-
rocycles have long fascinated the preparative organic
chemist.1 Given the impressive structural diversity en-
countered in cyclophane ring systems, it is not surprising
that numerous synthetic strategies have emerged for
their construction. Among these, macrocyclizations ac-
complished via alkylation, acylation, cycloaddition, and
various condensation processes are frequently utilized,1,2
while phenol-derived cyclophanes (e.g., calixarenes and
calixresorcinarenes) are generated from a series of inter-
and intramolecular electrophilic aromatic substitutions.3
More recently, various transition-metal-mediated coup-
ling reactions have been successfully applied in the
synthesis of cyclophanes as well.4
(1) For overviews, see: (a) Diederich, F. Cyclophanes; Royal Society
of Chemistry: Cambridge, 1991. (b) Comprehensive Supramolecular
Chemistry, Vol. 2; Atwood, J . L., Davies, J . E. D., MacNicol, D. D.,
Vo¨gtle, F., Eds.; Pergamon: Oxford, 1996.
(4) (a) Lu¨ning, U.; Fahrenkrug, F.; Hagen, M. Eur. J . Org. Chem.
2001, 2161. (b) Smith, A. B., III; Adams, C. M.; Kozmin, S. A. J . Am.
Chem. Soc. 2001, 123, 990. (c) Wan, W. B.; Haley, M. M. J . Org. Chem.
2001, 66, 3893. (d) Collins, S. K.; Yap, G. P. A.; Fallis, A. G. Angew.
Chem., Int. Ed. Engl. 2000, 39, 385. (e) Pschirer, N. G.; Fu, W.; Adams,
R. D.; Bunz, U. H. F. Chem. Commun. 2000, 87.
(2) For selected recent examples, see: (a) Alcalde, E.; Ayala, C.;
Dinare`s, I.; Mesquida, N.; Sa´nchez-Ferrando, F. J . Org. Chem. 2001,
66, 2281. (b) Pascal, R. A., J r.; Barnett, L.; Qiao, X.; Ho, D. M. J . Org.
Chem. 2000, 65, 7711. (c) Butler, G. M., III; Brown, S. N.; Boger, R.
M.; Ferfolia, M. T.; Fitzgibbons, A. C.; J ongeling, A. C.; Kelleher, S.
J .; Malec, A. D.; Malerich, J .; Weltner, A. N. Org. Lett. 2000, 2, 4125.
(d) Sato, M.; Uehara, F.; Sato, K.; Yamaguchi, M.; Kabuto, C. J . Am.
Chem. Soc. 1999, 121, 8270. (e) Mascal, M.; Kerdelhue´, J .-L.; Blake,
A. J .; Cooke, P. A. Angew. Chem., Int. Ed. Engl. 1999, 38, 1968. (f)
Inouye, M.; Fujimoto, K.; Furusyo, M.; Nakazumi, H. J . Am. Chem.
Soc. 1999, 121, 1452. (g) Brody, M. S.; Williams, R. M.; Finn, M. G. J .
Am. Chem. Soc. 1997, 119, 3429. (h) Kim, B. H.; J eong, E. J .; J ung,
W. H. J . Am. Chem. Soc. 1995, 117, 6390.
(5) (a) Hubert, A. J . J . Chem. Soc., C 1967, 6. (b) Hubert, A. J .; Dale,
J . J . Chem. Soc. 1965, 3160.
(6) (a) Mascal, M.; Hansen, J .; Blake, A. J .; Li, W.-S. Chem.
Commun. 1998, 355. (b) Brisbois, R. G.; Fogel, L. E.; Nicaise, O. J .-C.;
DeWeerd, P. J . J . Org. Chem. 1997, 62, 6708. (c) Lofthagen, M.;
Chadha, R.; Siegel, J . S. J . Am. Chem. Soc. 1991, 113, 8785. See also:
(d) Moretto, A. F.; Zhang, H.-C.; Maryanoff, B. E. J . Am. Chem. Soc.
2001, 123, 3157.
(7) Granier, T.; Ca´rdenas, D. J .; Echavarren, A. M. Tetrahedron Lett.
2000, 41, 6775.
(8) (a) Wang, H.; Wulff, W. D.; Rheingold, A. L. J . Am. Chem. Soc.
2000, 122, 9862. (b) Do¨tz, K. H.; Gerhardt, A. J . Organomet. Chem.
1999, 578, 223.
(3) (a) Gutsche, C. D. Calixarenes; Royal Society of Chemistry:
Cambridge, 1989. (b) Cram, D. J .; Cram, M. Container Molecules and
Their Guests; Royal Society of Chemistry: Cambridge, 1994. (c)
Shorthill, B. J .; Granucci, R. G.; Powell, D. R.; Glass, T. E. J . Org.
Chem. 2002, 67, 904.
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Lett. 2000, 41, 4201.
10.1021/jo0256181 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/15/2002

4548 J . Org. Chem., Vol. 67, No. 13, 2002
Pigge et al.
Sch em e 1a
F igu r e 1. (a) The preparation of dendritic-like linked triar-
oylbenzenes via two independent enaminone-directed cross-
benzannulation reactions.12 (b) Schematic representation of a
proposed convergent enaminone-directed cross-benzannulation
affording cyclophane products.
substituted ketones,10 and in cycloaddition/dimerization
reactions between bis(allenes) and alkynes.11
A recent report from this laboratory described the
preparation of novel dendritic-like linked triaroylben-
zenes.12 The target compounds were obtained via the
independent cross-cyclotrimerization of two connected
aryl-substituted enaminones and aryl ethynyl ketones,13
as illustrated in Figure 1a. It was quickly realized during
the course of this study that a simple reformulation of
the reaction protocol could provide a synthetic entry into
cyclophane architectures if the enaminone-directed ben-
zannulation reaction also could be utilized as a method
for accomplishing macrocyclization. A general outline of
this strategy is shown in Figure 1b. Participation of two
tethered aryl ethynyl ketone moieties in a single conver-
gent enaminone-directed cyclotrimerization (depicted as
in 1) was envisioned to afford a 1,3,5-triaroylbenzene
product partially imbedded within a larger macrocyclic
ring system (i.e., 2). Additionally, this modular strategy
would offer a straightforward means of incorporating
functionalized tethers into the macrocyclic framework.
Reported herein are the results of initial studies along
these lines that have culminated with the successful
a
Conditions: (a) (i) HCCMgBr, THF; (ii) H2CrO4 (89% and 66%
for 5 and 6, respectively over two steps). (b) 7, PhMe, ∼0.002 M,
reflux, 120 h (12% and 11% for 8 and 9, respectively).
preparation and characterization of several novel cyclo-
phane ring systems possessing aryl, polyaza, and polyoxa
bridging units.
Resu lts a n d Discu ssion
A first approach toward cyclophane architectures via
enaminone-directed benzannulation is illustrated in
Scheme 1. In this synthetic route, a m- or p-xylyl moiety
serves as a tether connecting two ethynyl ketone frag-
ments. Thus, dialdehyde 3 and known dialdehyde14
4
were prepared from the corresponding dibromoxylenes
and 3-hydroxybenzaldehyde. Conversion of the aldehyde
residues to ethynyl ketones was then accomplished by a
two-step Grignard addition/oxidation sequence. With bis-
(ethynyl ketones) 5 and 6 in hand, the crucial benzan-
nulation/macrocyclization reaction was next attempted.
In the event, separate equimolar solutions of 5 or 6 and
phenolic enaminone 7 were added simultaneously to
refluxing toluene under moderately high-dilution condi-
tions (∼2 × 10-3 M). The reaction was monitored by TLC
until consumption of the starting materials was complete
(∼120 h). The desired cyclophane products 8 and 9 were
indeed formed under these conditions and were subse-
(10) (a) Dijkstra, P. J .; Skowronska-Ptasinska, M.; Reinhoudt, D.
N.; den Hertog, H. J ., J r.; van Eerden, J .; Harkema, S.; de Zeeuw, D.
J . Org. Chem. 1987, 52, 4913. (b) Berger, B.; Bo¨hmer, V.; Paulus, E.;
Rodriguez, A.; Vogt, W. Angew. Chem., Int. Ed. Engl. 1992, 31, 96.
(11) Bo¨hm, I.; Herrmann, H.; Menke, K.; Hopf, H. Chem. Ber. 1978,
111, 523.
(12) Pigge, F. C.; Ghasedi, F. Tetrahedron Lett. 2000, 41, 6545.
(13) For discussions concerning this method of benzannulation,
see: (a) Balasubramanian, K. K.; Selvaraj, S.; Vankataramani, P. S.
Synthesis 1980, 29. (b) Matsuda, K.; Nakamura, N.; Iwamura, H.
Chem. Lett. 1994, 1765.
(14) Wagner, R. W.; J ohnson, T. E.; Lindsey, J . S. Tetrahedron 1997,
53, 6755.

Enaminone-Directed Benzannulation/Macrocyclization
J . Org. Chem., Vol. 67, No. 13, 2002 4549
F igu r e 2. (a) Molecular structure (ORTEP) of 8 accompanied by a line drawing representation of the solid-state conformation.
(b) The molecular structure (ORTEP) of 9 accompanied by a line drawing representation of the solid-state conformation.
quently isolated by simple flash column chromatography
in yields of 12% and 11%, respectively. While disappoint-
ingly low, the isolated yields reported above are, however,
comparable to alternative macrocyclization protocols
encountered in cyclophane chemistry.1-8 Moreover, the
cyclophane products proved to be the only tractable
materials generated in the course of each benzannulation,
thus greatly simplifying product isolation and purifica-
tion. The bulk of the reactants appear to have been
consumed in the formation of sparingly soluble polymeric
materials, presumably a consequence of unwanted alkyne
oligomerization under the reaction conditions. In an
attempt to improve the yields of the cyclophane products,
several reaction parameters were varied. Adjusting the
ratio of 5 or 6 with respect to enaminone 7 from 1:1 to
2:1 to 4:1 had no effect on the outcome of the reaction.
The concentration of the reaction mixture and the rate/
order of reactant addition also were found to have little
effect on the reaction, so long as moderatly high dilution
was maintained. For example, combining 5 and 7 directly
in toluene at a concentration of 5 × 10-3 M produced
cyclophane 8 with equal efficiency.
Despite the modest yields encountered in the prepara-
tion of 8 and 9, there are several noteworthy features of
the cyclotrimerization process that merit further com-
ment. First, the benzannulation reaction proceeds with
complete regioselectivity such that the newly generated
arene ring possesses a 1,3,5-substitution pattern exclu-
sively. Second, the compatibility of the unprotected
phenol residue present in 7 with the trimerization process
permits direct incorporation of a synthetically versatile
functional group along the periphery of the cyclophane
products. Third, the straightforward means of assembling
the bis(ethynyl ketone) reactants lends itself to consider-
able structural variation, a feature responsible for spur-
ring additional synthetic studies (vide infra). Finally, 8
and 9 themselves bear an outward resemblance to certain
calix[4]arene derivatives. In fact, 8/9 can be viewed as
structural hybrids exhibiting features of so-called ex-
panded calixarenes15 and oxacalixarenes.16
9 were obtained through diffusion chamber techniques,
and their structures are illustrated in Figure 2, parts a
and b, respectively.17 The solid-state structure of cyclo-
phane 8 (Figure 2a) is difficult to describe, as it is
severely distorted from anything that resembles a “bowl”
or “saddle.” The approximate dimensions that define the
macrocycle opening are 5.6 Å (ring A to ring C distance)
by 4.5 Å (ring B to ring D distance). In contrast,
cyclophane 9 (Figure 2b) adopts a more defined saddle-
shaped solid-state conformation. The A and C rings are
superimposed across the cyclophane cavity at a slight
angle (∼30°), thereby creating a wider opening at the top
of the cyclophane (∼5.4 Å) than at the bottom (∼4.1 Å).
The B and D rings (∼6.3 Å apart) are almost perpen-
dicular to the plane of the A ring, resulting in an overall
shape reminiscent of boatlike or flattened-cone conforma-
tions that are encountered in certain calixresorcinarene
derivatives.18 Both 8 and 9, however, exhibit substantial
conformational flexibility in solution, as evidenced by the
presence of a sharp singlet for the benzylic methylene
1
hydrogens in their room temperature H NMR spectra.
Low-temperature NMR studies (CD2Cl2, -90 °C) revealed
only slight broadening of these signals. Presumably,
conformational interconversion requires rotation of the
phenyl rings through the cyclophane cavity, and appar-
ently, significantly lower temperatures and/or additional
substituents on the phenyl rings will be required in order
to obtain discrete solution-phase conformations.19
(17) Crystal data for 8: monoclinic, P21/n, a ) 13.734(4) Å, b )
8.279(2) Å, c ) 23.601(9) Å, â ) 104.10(2)°, V ) 2602.7(14) Å3, Z ) 4,
Dcalc ) 1.379 g cm-3, µ ) 0.094 mm-1 (Mo KR), T ) 223(2) K, θ range
1.8-26.0°, 32 348 reflections, 5107 independent reflections, 374 par-
ameters, R1(F) ) 4.94%, wR2(F2) ) 12.68%, min./max. residual electron
density ) -0.185/0.167 e Å-3. Crystal data for 9: triclinic, P1h, a )
12.6130(7) Å, b ) 14.3665(8) Å, c ) 15.7132(9) Å, R ) 81.629(4)°, â )
89.924(3)°, γ ) 71.901(3)°, V ) 2674.7(3) Å3, Z ) 4, Dcalc ) 1.342 g
cm-3, µ ) 0.092 mm-1 (Mo KR), T ) 188(2) K, θ range ) 1.5-25.0°,
28 086 reflections, 9358 independent reflections, 739 parameters, R1-
(F) ) 14.86%, wR2(F2) ) 30.62%, min./max. residual electron density
) -0.367/0.494 e Å-3. The asymmetric unit contains two crystallo-
graphically independent, chemically similar molecules whose gross
conformations are identical. Structural differences between the two
molecules are observed in the relative orientations of the phenolic rings
that are not part of the core cyclophane macrocycle.
As a consequence of the nominal relationship between
8/9 and members of the calixarene family of cyclophanes,
the solid- and solution-phase structures of these macro-
cycles were further investigated. Single crystals of 8 and
(18) (a) Ho¨gberg, A. G. S. J . Org. Chem. 1980, 45, 4498. (b) Ho¨gberg,
A. G. S. J . Am. Chem. Soc. 1980, 102, 6046.
(19) Expanded calixarenes and oxacalixarenes are known to be much
more conformationally flexible than “traditional” calix[4]arenes: (a)
Masci, B.; Finelli, M.; Varrone, M. Chem. Eur. J . 1998, 4, 2018. (b)
Gutsche, C. D.; Bauer, L. J . J . Am. Chem. Soc. 1985, 107, 6052. (c)
Yamato, T.; Saruwatari, Y.; Yasumatsu, M.; Ide, S. Eur. J . Org. Chem.
1998, 309. (d) Ito, K.; Izawa, S.; Ohba, T.; Ohba, Y.; Sone, Y.
Tetrahedron Lett. 1996, 37, 5959.
(15) Ibach, S.; Prautzsch, V.; Vo¨gtle, F.; Chartroux, C.; Gloe, K. Acc.
Chem. Res. 1999, 32, 729 and references therein.
(16) (a) Tsubaki, K.; Morimoto, T.; Otsubo, T.; Kinoshita, T.; Fuji,
K. J . Org. Chem. 2001, 66, 4083. (b) Bo¨hmer, V. Liebigs Ann./ Recueil
1997, 2019.

4550 J . Org. Chem., Vol. 67, No. 13, 2002
Pigge et al.
Sch em e 2
Sch em e 3
refluxing toluene. The desired 20-membered macrocyclic
product 14 was subsequently isolated in 46% yield. Again,
evidence of successful benzannulation was provided by
the appearance of a downfield doublet (∼8.5 ppm, J )
∼1.5 Hz) corresponding to the unique aromatic hydrogen
of the 1,3,5-trisubstituted arene. Polyazacyclophanes are
widely utilized in supramolecular chemistry as molecular
receptors for neutral, cationic, and anionic substrates, as
well as novel metal-ligating agents.21 It is envisioned that
14 (and 17, vide infra) will serve as the first members of
a family of triaroylbenzene-derived azacyclophanes that
may be tuned to exhibit a range of useful host-guest
interactions with targeted substrates. Unfortunately, the
examination of host-guest and metal-ligating properties
of cyclophanes related to 14 has been thwarted by an
inability to remove the tosyl protecting groups. The
presence of numerous benzoyl rings precludes application
of reductive detosylation methods (e.g., Li-naphthalide),
and attempted hydrolyses of the sulfonamide groups
under standard conditions (concentrated H2SO4; aqueous
HBr/acetic acid/phenol) were unsuccessful. Consequently,
current efforts are focused on constructing analogues and
homologues of 14 with alternative (easily removable)
nitrogen protecting groups.
Structural characteristics of triaroylbenzene-derived
cyclophanes can be easily altered simply by using a linear
bis(ethynyl ketone) reactant exhibiting a para substitu-
tion pattern. As illustrated in Scheme 3, reaction of tri-
(aza)-linked bis(ethynyl ketone) 15 and enaminone 12
afforded the corresponding cyclophane product 17 in a
serviceable 34% isolated yield. Likewise, di(ethylene
glycol) derivative 16 was smoothly converted to the tri-
(oxa) macrocycle 18. Both of these products possess 22-
membered macrocyclic rings and represent the largest
cyclophanes thus far prepared by this method. Macrocycle
18 exhibits structural features common to both cyclo-
While the feasibility of utilizing an enaminone-directed
benzannulation reaction as a means of constructing
cyclophane ring systems has been established on the
basis of the results described above, the isolated yields
of macrocyclic products encountered in these initial
studies are such that this process is unlikely to be of great
synthetic value. A possible explanation for the inef-
ficiency of macrocyclization observed in the preparation
of 8 and 9 is that the xylyl tether connecting the ethynyl
ketone moieties is too rigid to easily permit assembly of
an arene ring via the molecular arrangement illustrated
schematically in 1 (Figure 1b). Accordingly, then, incorpor-
ation of a longer and/or more flexible tether may result
in higher yielding benzannulative macrocyclizations.
Toward this end, bis(ethynyl ketone) 10 was prepared
from the corresponding dialdehyde precursor2g,14 and
treated with an equimolar amount of enaminone 7 in
refluxing toluene (0.004 M). Gratifyingly, the expected
cyclophane product 13 was isolated in quite respectable
44% yield after flash column chromatography (Scheme
2). The structure of 13 was assigned on the basis of NMR
spectroscopy and high-resolution mass spectral data. In
particular, the generation of an unsymmetrical 1,3,5-
triaroylbenzene ring gives rise to a characteristic set of
finely coupled downfield signals in the 1H NMR spectrum
(7.98 and 8.56 ppm) that correspond to the hydrogens at
the 2, 4, and 6 positions. It should be noted that
cyclophanes 8 and 13 both possess 18-membered mac-
rocyclic rings; thus, the increased flexibility of the pen-
tamethylene tether in 10 appears to be responsible for
the significant improvement in the benzannulation-
macrocyclization process.
It has proven possible to construct functionalized
cyclophane ring systems via this method as well, and the
preparation of a tri(aza)-bridged triaroylbenzene-based
macrocycle is also shown in Scheme 2. The linear
cyclophane building block 11 (easily prepared via routine
transformationsssee the Supporting Information) was
treated with methoxy-substituted enaminone20 12 in
(21) For examples and leading references, see: (a) Lamarque, L.;
Navarro, P.; Miranda, C.; Ara´n, V. J .; Ochoa, C.; Escart´ı, F.; Garc´ıa-
Espan˜a, E.; LaTorre, J .; Luis, S. V.; Miravet, J . F. J . Am. Chem. Soc.
2001, 123, 10560. (b) Albelda, M. T.; Burguete, M. I.; Fr´ıas, J . C.;
Garc´ıa-Espan˜a, E.; Luis, S. V.; Miravet, J . F.; Querol, M. J . Org. Chem.
2001, 66, 7505. (c) Burguete, M. I.; Escuder, B.; Fr´ıas, J . C.; Garc´ıa-
Espan˜a, E.; Luis, S. V.; Miravet, J . F. J . Org. Chem. 1998, 63, 1810
and references therein.
(20) Tseng, S.-S.; Epstein, J . W.; Brabander, H. J .; Francisco, G. J .
Heterocycl. Chem. 1987, 24, 837.

Enaminone-Directed Benzannulation/Macrocyclization
J . Org. Chem., Vol. 67, No. 13, 2002 4551
from 11% to 46%. An important feature that appears to
significantly influence the efficiency of the benzannula-
tion process is the flexibility of the tether used to link
the ethynyl ketone reaction partners. The applicability
of this synthetic protocol for the construction of structur-
ally more complex cyclophanes is currently being ex-
plored, as are methods for improving the efficiency of the
benzannulation process. It is envisioned that concomitant
enaminone-directed benzannulation-macrocyclization may
be developed into a general method for the construction
of functionalized cyclophanes and, in turn, new molecular
hosts and/or metal-ligating species.
Exp er im en ta l Section 24
m eta -Xylyloxy-Br id ged Bis(a r yl eth yn yl k eton e) 5. A
solution of 3 (1.25 g, 3.61 mmol) in THF (10 mL) was cooled
to 0 °C in an ice bath. Ethynylmagnesium bromide (0.5 M in
THF, 19.0 mL, 9.50 mmol) was added via syringe and the
reaction mixture was stirred at room temperature. The reac-
tion was complete after 2 h (TLC) and was quenched by
addition of saturated aq NH4Cl solution (∼30 mL). The
reaction mixture was extracted with several portions of ether,
and the combined ether extracts were washed with brine. The
ether solution was next dried over anhydrous MgSO4, filtered,
and concentrated to afford a dark oil. Purification by flash
column chromatography (1:1 hexane:EtOAc) yielded the cor-
responding diol (1.35 g, 94%) as a pale yellow solid. Without
further characterization, the diol (1.30 g, 3.26 mmol) was
dissolved in ∼20 mL of acetone. A solution of the J ones reagent
was added dropwise via pipet until the red color indicative of
excess Cr(VI) salts persisted. The reaction was quenched by
addition of an excess of 2-propanol, and the insoluble Cr(III)
salts were removed by filtration through a pad of Celite. The
filtrate was diluted with ether and washed sequentially with
satd aq NaHCO3 solution, water, and brine, and dried over
anhydrous MgSO4. Filtration and removal of the solvent
yielded a dark oil that was then purified by flash column
chromatography (1:1 hexanes:EtOAc). The bis(ethynyl ketone)
5 (1.22 g, 95%, 89% from 3) was isolated as a white solid: mp
F igu r e 3. Molecular structure (ORTEP) of 18.
phanes and crown ethers, and Nishimura has coined the
term “crownophane” to describe such compounds.22 Re-
crystallization from hexanes/EtOAc deposited X-ray qual-
ity single crystals and the molecular structure of 18 is
shown in Figure 3.23 An elliptical-shaped macrocycle is
clearly evident with a long axis of 8.08 Å (C26-O3). The
short axis as defined by the distance between the
centroids of the two para-substituted arenes is 5.78 Å
and the O2-O4 distance in the di(ethylene oxy) unit is
∼4.6 Å. The para-substituted arene rings are each tilted
∼45° with respect to the 1,3,5-triaroyl-substituted ring,
and this results in a shallow cyclophane cavity with a
wider opening at the top (∼7.5 Å) than at the bottom
(∼4.1 Å). While the presence of only three crownophane
ether oxygen atoms is expected to be insufficient for
binding alkali and alkaline metal ions, the construction
of homologous crownophanes with additional ethylene
oxy bridging units in close proximity to a putative
cyclophane “pocket” has the potential to afford new
molecular receptors suitable for binding various inorganic
and organic salts and zwitterions. Studies along these
lines are currently in progress.
In conclusion, a new and concise synthetic approach
suitable for the preparation of functionalized cyclophane
ring systems has been developed. Macrocyclization is
achieved during the course of a regioselective benzan-
nulation reaction between two connected aryl ethynyl
ketone groups and an aryl enaminone reactant. The
nature of the tether connecting the aryl ethynyl ketone
fragments can be easily varied and triaroylbenzene-based
cyclophanes with tri(aza), tri(oxa), and xylyl bridges have
been constructed. In addition, this synthetic approach
results in placement of an arene ring on the periphery
of the cyclophane macrocycle that is potentially available
for further synthetic elaboration. Indeed, while only
hydroxy- and methoxy-substituted enaminones were
employed in these initial studies, alternative function-
alized enamines should display similar reactivity.12 The
yields observed for the key macrocyclization step range
1
95-97 °C; H NMR (300 MHz, CDCl3) δ 3.44 (s, 2H), 5.16 (s,
4H), 7.23-7.28 (m, 2H), 7.40-7.45 (m, 5H), 7.55 (br s, 1H),
7.73-7.84 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 70.24, 80.49,
80.92, 114.23, 122.19, 123.37, 126.73, 127.49, 129.18, 129.98,
136.98, 137.62, 158.92, 177.11; IR (thin film) ν (cm-1) 3275,
2082, 1642. Anal. Calcd for C26H18O4: C 79.17, H 4.60.
Found: C 79.27, H 4.59.
pa r a -Xylyloxy-Br id ged Bis(a r yl eth yn yl k eton e) 6.
Using the procedure described above for the preparation of 5,
dialdehyde14 4 was converted to bis(ethynyl ketone) 6 in 66%
overall yield after purification by flash column chromatography
(1:1 hexanes:EtOAc) to yield a white solid: mp 153-154 °C;
1H NMR (300 MHz, CDCl3) δ 3.43 (s, 2H), 5.51 (s, 4H), 7.20-
7.27 (m, 2H), 7.43 (t, J ) 7.8 Hz, 2H), 7.49 (s, 4H), 7.74 (t, J
) 2.1 Hz, 2H), 7.82 (d, J ) 7.5 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 70.17, 80.50, 80.90, 114.30, 122.30, 123.40, 128.10,
130.0, 136.6, 137.3, 159.1, 177.3; IR (thin film) ν (cm-1) 3253,
2093, 1636. Anal. Calcd for C26H18O4: C 79.17, H 4.60.
Found: C 78.73, H 4.63.
Cyclop h a n e 8. Enaminone 7 (0.100 g, 0.523 mmol) dis-
solved in 50 mL of 4:1 PhMe:CH2Cl2 and 5 (0.206 g, 0.523
mmol) dissolved in 50 mL of PhMe were simultaneously added
dropwise over 2 h to 150 mL of refluxing PhMe. The reaction
was monitored by TLC, and after 5 d the starting materials
were completely consumed. The solvent was evaporated and
the residue was purified by flash column chromatography (2:1
hexanes:EtOAc) to afford 8 (0.033 g, 12%) as a white solid.
The product was crystallized by slow diffusion of hexanes into
an EtOAc solution: mp 198-199 °C; 1H NMR (300 MHz,
CDCl3) δ 5.22 (s, 4H), 5.42 (br s, 1H), 7.00 (m, 2H), 7.07-7.16
(22) (a) Inokuma, S.; Sakai, S.; Nishimura, J . Top. Curr. Chem.
1994, 172, 87 and references therein. (b) Nishimura, J .; Nakamura,
Y.; Hayashida, Y.; Kudo, T. Acc. Chem. Res. 2000, 33, 679.
(23) Crystal data for 21: triclinic, P1h, a ) 10.4673(8) Å, b ) 11.8925-
(9) Å, c ) 12.6585(9) Å, R ) 68.641(5)°, â ) 70.745(4)°, γ ) 88.954(5)°,
V ) 1376.1(2) Å3, Z ) 2, Dcalc ) 1.329 g cm-3, µ ) 0.093 mm-1 (Mo
KR), T ) 203(2) K, θ range 1.85-26.43°, 24 187 reflections, 5599
independent reflections, 371 parameters, R1(F) ) 5.27%, wR2(F2) )
(24) For general experimental details, see the Supporting Informa-
tion.
11.24%, min./max. residual electron density ) -0.191/0.141 e Å-3
.

4552 J . Org. Chem., Vol. 67, No. 13, 2002
Pigge et al.
(m, 3H), 7.20 (br s, 1H), 7.23 (br s, 1H), 7.30-7.42 (m, 9H),
7.82 (t, J ) 1.5 Hz, 1H), 8.47 (d, J ) 1.5 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 69.65, 116.72, 118.06, 119.13, 120.91, 121.51,
122.93, 123.70, 125.69, 129.05, 130.19, 130.27, 133.34, 134.30,
137.69, 138.11, 138.30, 139.05, 156.28, 157.85, 194.64, 195.34
(one C signal was not observed); IR (thin film) ν (cm-1) 3250,
1701; HRMS (FAB+, NBA) calcd for C35H25O6 [M + H]+
541.1651, found 541.1652.
Dieth ylen etr ia m in e-Br id ged Cyclop h a n e 17. Using the
procedure described above, reaction of 0.581 g (0.683 mmol)
of 15 and 0.143 g (0.683 mmol) of 12 gave 0.234 g (34%) of 17
as a colorless solid after purification by flash column chroma-
tography (2:1 hexanes:EtOAc). An analytical sample was
obtained by recrystallization from CH3CN: mp 241-243 °C;
1H NMR (500 MHz, CDCl3) δ 1.95 (s, 3H), 2.37 (br t, J ) 7.6
Hz, 4H), 2.50 (s, 6H), 3.27 (br t, J ) 7.6 Hz, 4H), 3.91 (s, 3H),
4.36 (s, 4H), 6.97 (d, J ) 8.1 Hz, 2H), 7.12 (d, J ) 8.1 Hz, 2H),
7.21-7.23 (m, 1H), 7.39-7.48 (m, 7H), 7.58 (d, J ) 8.2 Hz,
4H), 7.64 (s, 1H), 7.75 (d, J ) 8.2 Hz, 4H), 7.87 (d, J ) 8.2 Hz,
4H), 8.65 (d, J ) 1.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ
21.19, 21.85, 48.93, 49.82, 54.53, 55.77, 114.50, 120.15, 123.19,
127.46, 129.65, 129.94, 130.28, 130.78, 133.16, 134.67, 134.90,
135.54, 136.30, 137.07, 137.87, 140.24, 143.11, 143.98, 144.27,
160.14, 193.74, 194.79; IR (thin film) ν (cm-1) 1661, 1153.
HRMS (FAB+, NBA) calcd for C55H52N3O10S3 1010.2815 [M +
H]+, found 1010.2810. Anal. Calcd for C55H51N3O10S3: C 65.39,
H 5.09, N 4.16, S 9.52. Found: C 65.16, H 5.16, N 4.25, S 9.32.
Cyclop h a n e 9. Using the procedure described above for the
preparation of 8, reaction of 7 (0.114 g, 0.596 mmol) and 6
(0.235 g, 0.596 mmol) afforded 9 (0.037 g, 11%) as a white solid
after flash column chromatography (2:1 hexanes:EtOAc). A
crystalline sample was obtained by slow diffusion of hexanes
1
into a CDCl3 solution: mp 147-148 °C; H NMR (300 MHz,
CDCl3) δ 5.17 (s, 4H), 5.98 (br s, 1H), 6.66 (m, 2H), 7.12-7.15
(m, 1H), 7.17 (s, 4H), 7.25-7.43 (m, 10H), 8.26 (d, J ) 1.8 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ 71.87, 116.86, 118.14, 121.02,
122.24, 122.94, 123.47, 127.64, 130.23, 130.35, 132.42, 132.88,
137.12, 137.89, 138.19, 138.45, 139.01, 156.31, 158.33, 194.64,
196.31. Anal. Calcd for C35H24O6‚(H2O)0.5: C 76.49, H 4.40.
Found: C 76.16, H 4.56.
Di(eth ylen e oxy)-Br id ged Cyclop h a n e 18. Using the
procedure for benzannulation-macrocyclization described above,
bis(aryl ethynyl) ketone 16 (0.200 g, 0.512 mmol) and enami-
none 12 (0.105 g, 0.512 mmol) reacted to afford cyclophane 18
(0.110 g, 39%) as a yellow solid after purification by flash
column chromatography (1:1 hexanes:EtOAc). An analytical
sample was obtained by slow diffusion of hexanes into an
EtOAc solution: mp 186-187 °C; 1H NMR (300 MHz, CDCl3)
δ 3.75 (s, 8H), 3.90 (s, 3H), 4.63 (s, 4H), 7.19-7.23 (m, 1H),
7.40-7.48 (m, 3H), 7.54 (d, J ) 8.2 Hz, 4H), 7.85 (d, J ) 8.2
P en ta m eth ylen e-Br id ged Cyclop h a n e 13. Using the
procedure described for the preparation of 8, reaction of
phenolic enaminone 7 (0.212 g, 1.11 mmol) and 10 (0.400 g,
1.11 mmol) in 250 mL of refluxing toluene for 5 d gave
cyclophane 13 (0.247 g, 44%) after purification by flash column
chromatography (2:1 hexanes:EtOAc). An analytical sample
was obtained as a colorless solid by recrystallization from
CHCl3/hexanes: mp 98-105 °C (dec); 1H NMR (CDCl3, 300
MHz) δ 1.84-1.90 (m, 6H), 4.10 (t, J ) 5.0 Hz, 4H), 6.22 (br
s, 1H), 7.09-7.21 (m, 5H), 7.38-7.55 (m, 7H), 7.98 (t, J ) 1.5
Hz, 1H), 8.56 (d, J ) 1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ 21.35, 27.95, 67.27, 116.92, 117.85, 118.09, 120.96, 121.53,
122.96, 130.23, 130.65, 133.40, 134.49, 137.86, 137.96, 138.02,
Hz, 4H), 8.04 (t, J ) 1.6 Hz, 1H), 8.65 (d, J ) 1.6 Hz, 2H); 13
C
NMR (75 MHz, CDCl3) δ 55.78, 70.07, 70.61, 72.51, 114.41,
120.14, 123.29, 127.62, 129.90, 130.35, 134.50, 135.81, 136.10,
137.24, 137.98, 140.17, 144.41, 160.11, 194.31, 195.06; IR (thin
film) ν (cm-1) 1661, 1270. Anal. Calcd for C34H30O7‚(H2O)0.25
C 73.56, H 5.54. Found: C 73.46, H 5.45.
:
139.94, 156.41, 158.58, 194.81, 195.24; IR (thin film) ν (cm-1
)
3500, 1663; HRMS (FAB+, thioglycerol) calcd for C32H27O6
507.1808 [M + H]+, found 507.1811. Anal. Calcd for C32H26O6‚
(H2O)0.25: C 75.20, H 5.23. Found: C 75.19, 5.24.
Ack n ow led gm en t. Financial support for this work
was provided by the UMsSt. Louis Department of
Chemistry. Support for instrumentation facilities (NMR,
X-ray, MS) was provided by the NSF (CHE-9974801,
CHE-9101834, CHE-9708640). We thank Dr. J anet
Braddock-Wilking for assistance in obtaining low-tem-
perature NMR spectra, and Dr. R. E. K. Winter and Mr.
J . Kramer for assistance in obtaining mass spectral
data.
Dieth ylen etr ia m in e-Br id ged Cyclop h a n e 14. Using the
procedure described for the preparation of cyclophane 8,
enaminone 12 (0.188 g, 0.918 mmol) and 11 (0.780 g, 0.918
mmol) reacted to give cyclophane 14 as a pale yellow solid
(0.426 g, 46%) after purification by flash column chromatog-
raphy (2:1 hexanes:EtOAc). An anlytical sample was obtained
1
by recrystallization from CH3CN: mp 175-179 °C; H NMR
(300 MHz, CDCl3) δ 2.41 (s, 3H), 2.49 (s, 6H), 2.63 (br t, J )
6.9 Hz, 4H), 3.01 (br t, J ) 6.9 Hz, 4H), 3.89 (s, 3H), 4.21 (s,
4H), 7.16-7.23 (m, 5H), 7.32-7.44 (m, 9H), 7.66 (d, J ) 7.7
Hz, 2H), 7.72 (d, J ) 7.7 Hz, 2H), 7.77-7.80 (m, 6H), 8.23 (br
s, 1H), 8.57 (d, J ) 1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
21.70, 21.80, 50.09, 51.29, 54.95, 55.76, 114,40, 120.06, 123.21,
127.38, 127.62, 128.97, 129.80, 129.94, 130.27, 131.28, 134.10,
134.28, 134.35, 134.97, 135.31, 137.45, 137.52, 137.57, 138.00,
139.87, 144.00, 144.20, 160.06, 194.49, 195.01; IR (thin film)
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures and detailed descriptions for the preparation
of 3, 7, 10-11, and 15-16; copies of 1H NMR spectra for
compounds 8, 10, 15, and 16; and details of X-ray data
collection and structure refinement. This material is available
free of charge via the Internet at http://pubs.acs.org.
ν (cm-1) 1664, 1159. Anal. Calcd for C55H51N3O10S3‚(H2O)0.5
C 64.81, H 5.14, N 4.12. Found: C 64.76, H 5.08, N 4.13.
:
J O0256181