Nontemplated versus templated synthesis of a 56-membered macrocycle

Article abstract of DOI:10.1055/s-2007-985560

The amine-substituted quinquephenylene 1 was prepared in a Suzuki coupling approach and by reaction with terephthalic dialdehyde (7) it was transformed into the phenyl-connected diimine 8. Ring-closing metathesis with the Grubbs I or II catalyst led to the corresponding macrocycle 9. Hydrogenation resulted in the reduction of the double bonds as well as the removal of the template to yield the 56-membered macrocycle 6 in an overall yield of 43% (from 1). Direct metathesis reaction of 1 followed by hydrogenation afforded 6 in only 21% yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-985560

LETTER
2295
Nontemplated versus Templated Synthesis of a 56-Membered Macrocycle
5
6-Membered Macroc
a
a
Institut für Organische Chemie, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092385; E-mail: markus.albrecht@oc.rwth-aachen.de
b
Organisch-Chemisches Institut, Universität Münster, Corrensstraße 40, 49148 Münster, Germany
Received 1 June 2007
results in the formation of the boronic acid 4 (67%). The
amine 1 is finally obtained in 76% yield in a double
Suzuki coupling reaction7 with half an equivalent of the
dibromo aniline 58 in the presence of tetrakis(triphen-
Abstract: The amine-substituted quinquephenylene 1 was prepared
in a Suzuki coupling approach and by reaction with terephthalic di-
aldehyde (7) it was transformed into the phenyl-connected diimine
8. Ring-closing metathesis with the Grubbs I or II catalyst led to the
corresponding macrocycle 9. Hydrogenation resulted in the reduc- ylphosphane) palladium(0) (see Scheme 1).
tion of the double bonds as well as the removal of the template to
X-ray quality crystals of 1 are obtained from chloroform–
yield the 56-membered macrocycle 6 in an overall yield of 43%
methanol. The structure is shown in Scheme 1 (bottom).
(from 1). Direct metathesis reaction of 1 followed by hydrogenation
The curvature of the quinquephenylene with the amine
group located on the concave side is well recognized. In
addition, butenyloxy groups are located at the termini.9
afforded 6 in only 21% yield.
Key words: macrocycles, quinquephenylene, ring-closing meta-
thesis, preorganization, template effect
Since Pedersens discovery of the crown ethers in 1967
macrocyclic compounds play an important role as recep-
tors in supramolecular chemistry. The binding of guest
species in the interior of the compounds depends on the
size of the cavity, and also on appropriate functionalities,
which are able to interact with the guests.1
Today, the preparation of small and medium-sized macro-
cycles follows well-established procedures.2 However,
the specific high-yield synthesis of huge macrocycles,
which preferably bear internal functional groups, is still a
challenge. Investigations by Sanders,3 Höger,4 and many
others show that such macrocycles can be obtained in
template-directed syntheses.5
In 2004 Guan presented the synthesis of a ‘medium-sized’
26-membered macrocycle by a double ring-closing-
metathesis (RCM) approach using a bisimine as template.
The reaction yields an internally functionalized rigid
cyclophane with a rather small cavity.6
Now we describe the formation of a 56-membered macro-
cycle, which possesses two rigid quinquephenylene units
and two flexible hexyl bridges. The synthesis is per-
formed following a templated as well as nontemplated
strategy.
As the key building block in our synthesis, the amine-
substituted 1,1¢:4¢,1¢¢:3¢¢,1¢¢¢:4¢¢¢,1¢¢¢¢-quinquephenyle 1 is
initially prepared and structurally characterized as it is
shown in Scheme 1. Williamson ether synthesis of 4-bro-
mo-1-butene with 4-bromo-4¢-hydroxy biphenyl (2) af-
fords the ether 3 in 60%. Reaction of 3 with magnesium
and quenching with B(OMe)3 followed by sulfuric acid
SYNLETT 2007, No. 14, pp 2295–2297
Advanced online publication: 24.07.2007
DOI: 10.1055/s-2007-985560; Art ID: G17607ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.0
9
.2
0
0
7
Scheme 1 Synthesis and solid-phase structure of the quinque-
phenylene 1

2296
M. Albrecht et al.
LETTER
Derivative 1 represents a ‘semicircle’ and therefore seems generation catalyst reacting faster. Compound 9 is iso-
to be appropriate to form macrocycles in a dimerizing lated as mixture of the E and Z isomers (ratio 1:3). In the
RCM. The reaction cannot proceed intramolecularly; at case of this templated reaction the ring closing occurs
least two molecules of 1 have to take part. However, much faster as in the nontemplated case.
reacting 1 with Grubbs I catalyst results in the formation
The derivatives 9 possess the structure of a moleculare
of undefined, probably oligomeric material, which is still
turnstile, as it was described in 1995 by Moore. In contrast
soluble, but does not afford resolved NMR spectra.10
to his example, 9 possess flexible hexylidene bridges in
the outer circle.12
Hydrogenation (H2, PtO2) of the bisimine 9 results in the
reduction of the C=C double bonds and in the simulta-
neous reductive cleavage of the imines. The 56-membered
macrocycle 6 is isolated in 77% yield.
NH2
1
O
O
1. Grubbs catalyst
CH2Cl2
2. PtO2, H2
NH2
21%
1
O
O
terephthalic
dialdehyde (7),
TiCl4, Et3N, 63%
NH2
N
O
O
O
O
O
O
O
O
N
NH2
8
6
Grubbs catalyst
CH2Cl2
88%
Scheme 2 Nontemplated synthesis of macrocycle 6 using ring-clo-
sing metathesis
N
Reaction of 1 with the Grubbs catalyst of the second
generation results in the formation of the desired ‘un-
saturated’ macrocycle, which immediately is hydro-
genated (PtO2) to afford 6 in 21% yield (Scheme 2).
O
O
O
O
In order to improve the macrocyclization by RCM, the
reaction is intramolecularized by using terephthalic di-
aldehyde as a template. Reaction of two equivalents of 1
with terephthalic dialdehyde 7 in dichloromethane in the
presence of titanium tetrachloride and triethylamine11
results in the formation of the diimine 8 in 63% yield
(Scheme 3).
N
9
PtO2·H2
77%
6
Ring-closing metathesis of 8 results in the formation of
the macrocycle 9. The Grubbs I as well as Grubbs II cata- Scheme 3 Templated synthesis of 6 by RCM utilizing terephthalic
dialdehyde 7 as the template of choice
lysts are appropriate for this reaction with the second-
Synlett 2007, No. 14, 2295–2297 © Thieme Stuttgart · New York

LETTER
56-Membered Macrocycle
(9) (a) Characterization of 1
2297
The macrocycle 6 obtained by either of the two protocols
is characterized by its 1H NMR and 13C NMR, elemental
analysis as well as positive ESI-MS spectrum. The latter
shows the dominating peak at m/z = 1135.4 which is as-
signed to the protonated species [6·H]+ (sprayed from
chloroform–methanol).13
Mp 198 °C. 1H NMR (400 MHz, CDCl3): d = 7.58 (d,
3J = 8.5 Hz, 4 H, Har), 7.53 (d, 3J = 8.5 Hz, 4 H, Har), 7.49 (d,
3J = 8.8 Hz, 4 H, Har), 7.15 (s, 2 H, Har), 6.92 (d, 3J = 8.8 Hz,
4 H, Har), 5.86 (ddt, 3Jtrans = 17.0 Hz, 3Jcis = 10.4 Hz, 3J = 6.7
Hz, 2 H, HC=), 5.12 (dm, 3Jtrans = 17.0 Hz, 2 H, =CHtrans),
5.05 (dm, 3Jcis = 10.4 Hz, 2 H, =CHcis), 4.00 (t, 3J = 6.7, 4 H,
CH2), 2.51 (q, 3J = 6.7, 4 H, CH2), 1.28 (s, 9 H, t-Bu). 13
C
Our results show that the huge cyclophane 6 can be ob-
tained in a ring-closing metathesis with subsequent reduc-
tion of the double bonds in 21% yield starting with the
simple pre-organized building block 1. On the other hand,
the templated reaction is superior to this short-step proto-
col due to avoiding oligomeric/polymeric side products
during the ring-closing metathesis. Imination of 1 (2
equiv) with terephthalic dialdehyde followed by RCM
and subsequent hydrogenation of the double bond accom-
panied by removal of the template affords the macrocycle
6 in an overall yield of 43%.
NMR (100 MHz, CDCl3): d = 158.5 (C), 141.7 (C), 139.7
(C), 138.3 (C), 137,5 (C), 134.4 (CH), 133.2 (C), 129.8
(CH), 128.0 (CH), 127.8 (C), 127.0 (CH), 126.9 (CH), 117.1
(CH2), 114.9 (CH), 67.4 (CH2), 34.2 (C), 33.8 (CH2), 31.7
(CH3). MS (EI, 70 eV): m/z (%) = 593.3 (100) [M+,
+
C42H43NO2 ], 578.2 (97), 538.2 (3), 523.2 (12). Anal. Calcd
for C42H43NO2·0.5 H2O: C, 83.68; H, 7.36; N, 2.32. Found:
C, 83.76; H, 7.35; N, 2.11. X-ray crystal structure analysis
for 1: formula C42H43NO2, M = 593.77, colorless crystal
0.30 × 0.10 × 0.10 mm, a = 9.656(1), b = 35.774(1),
c = 9.666(1) Å, V = 3339.0(5) Å3, rcalc = 1.181 g cm–3,
m = 0.549 mm–1, empirical absorption correction (0.853 ≤ T
≤ 0.947), Z = 4, orthorhombic, space group Pnma (No. 62),
l = 1.54178 Å, T = 223 K, ω and ϕ scans, 13160 reflections
collected (±h, ±k, ±l), [(sinq)/λ] = 0.60 Å–1, 2693
independent (Rint = 0.047) and 2683 observed reflections [I
≤ 2 σ(I)], 215 refined parameters, R = 0.081, wR2 = 0.246,
max. residual electron density 0.35 (–0.20) e Å–3, hydrogen
atoms are calculated and refined riding.
The presented building block 1 and its macrocyclization
will be further studied by us in order to get a deeper in-
sight in the underlying templating process, and to apply
the findings in the preparation of topologically interesting
molecules. In addition, 6 will be tested as macrocyclic
receptor for small organic molecules.
Data set was collected with a Nonius KappaCCD
diffractometer. Programs used: data collection COLLECT
(Nonius B.V., 1998), data reduction Denzo-SMN,9b
absorption correction Denzo,9c structure solution SHELXS-
97,9d structure refinement SHELXL-97 (G. M. Sheldrick,
Universität Göttingen, 1997), graphics SCHAKAL (E.
Keller, Universität Freiburg, 1997).
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(Al 410/13-1) and the Fonds der Chemischen Industrie.
CCDC 649216 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033, E-mail:
deposit@ccdc.cam.ac.uk]. (b) Otwinowski, Z.; Minor, W.
Methods in Enzymology 1997, 276, 307. (c) Otwinowski,
Z.; Borek, D.; Majewski, W.; Minor, W. Acta Crystallogr.,
Sect. A: Fundam. Crystallogr. 2003, 59, 228. (d) Sheldrick,
G. M. Acta Crystallogr., Sect. A: Fundam. Crystallogr.
1990, 46, 467.
References and Notes
(1) (a) Pedersen, C. Angew. Chem., Int. Ed. Engl. 1988, 27,
1021; Angew. Chem. 1988, 100, 1053. (b) Macrocyclic
Chemistry – Current Trends and Future Perspectives; Gloe,
K., Ed.; Springer: Dordrecht, 2005.
(2) Parker, D. Macrocycle Synthesis: A Practical Approach;
Oxford University Press: Oxford, 1996.
(3) Anderson, S.; Anderson, H. L.; Bashall, A.; McPartlin, M.;
Sanders, J. K. M. Angew. Chem., Int. Ed. Engl. 1995, 34,
1096; Angew. Chem. 1995, 107, 1196.
(10) Grubbs, R. H. Angew. Chem. Int. Ed. 2006, 45, 3760;
Angew. Chem. 2006, 118, 3845.
(11) Lautens, M.; Tayama, E.; Herse, C. J. Am. Chem. Soc. 2005,
127, 72.
(12) Bedard, T. C.; Moore, J. S. J. Am. Chem. Soc. 1995, 117,
10662.
(13) Characterization of 6
(4) For a recent example, see: Becker, K.; Lagoudakis, P. G.;
Gaefke, G.; Höger, S.; Lupton, J. M. Angew. Chem. Int. Ed.
2007, 46, 3450; Angew. Chem. 2007, 119, 3520.
(5) For selected reviews, see: (a) Laughrey, Z. R.; Gibb, B. C.
Top. Curr. Chem. 2005, 249, 67. (b) Hoss, R.; Vögtle, F.
Angew. Chem., Int. Ed. Engl. 1994, 33, 375; Angew. Chem.
1994, 106, 389.
Mp >250 °C. 1H NMR (300 MHz, CDCl3): d = 7.53 (d,
3J = 8.4 Hz, 8 H, Har), 7.49–7.40 (m, 16 H, Har), 7.12 (s, 4 H,
Har), 6.86 (d, 3J = 8.7 Hz, 8 H, Har), 3.98 (t, 3J = 6.2 Hz, 8 H,
CH2), 1.82 (m, 8 H, CH2), 1.53 (m, 8 H, CH2), 1.26 (s, 18 H,
t-Bu). 13C NMR (75 MHz, CDCl3): d = 158.7 (C), 141.0 (C),
139.6 (C), 138.5 (C), 138.4 (C), 133.1 (C), 129.8 (CH),
128.0 (CH), 127.3 (C), 127.0 (CH), 126.6 (CH), 115.0 (CH),
67.5 (CH2), 34.1 (C), 31.6 (CH3), 28.6 (CH2), 25.0 (CH2).
ESI-MS (+): m/z = 1135.4 [MH+, C80H82N2O4 + H+]. Anal.
Calcd for C80H82N2O4·H2O: C, 83.30; H, 7.34; N, 2.43.
Found: C, 83.47; H, 7.37; N, 1.99.
(6) Camacho, D. H.; Salo, E. V.; Guan, Z. Org. Lett. 2004, 6,
865.
(7) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh,
M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314.
(8) Miura, Y.; Oka, H.; Momoki, M. Synthesis 1995, 1419.
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