Template-directed synthesis of symmetric as well as unsymmetric macrocycles from rigid or flexible building blocks

Article abstract of DOI:10.1055/s-2008-1067128

'Arc'-shaped oligophenyl derivatives with terminal alkene moieties can be used to form macrocycles by 'dimerization' through ring-closing metathesis. Hereby the introduction of templates connecting the two building blocks favors the dimerization over oligomerization or polymerization reactions. Attachment of the template through imine formation allows the removal of the template simultaneous to the reduction of the double bonds formed during ring-closing metathesis. Unsymmetric macrocyles can be obtained either by successive attachment of different 'arc'-shaped molecules to the template or by direct imine connection of two different ring precursors. In the latter case, the imine unit cannot be cleaved in the case of the investigated examples but 'figure-8'-shaped macrobicycles are obtained. The studied template-directed macrocyclization depends on the one hand on the preorganization of the building blocks, and on the other on their flexibility. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067128

PAPER
2451
Template-Directed Synthesis of Symmetric as well as Unsymmetric Macro-
cycles from Rigid or Flexible Building Blocks
Template-Directed
S
yn
a
thesis of
M
r
acrocyc
k
les us Albrecht,* Yeni
Institut für Organische Chemie, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092385; E-mail: markus.albrecht@oc.rwth-aachen.de
Received 31 March 2008; revised 9 April 2008
Abstract: ‘Arc’-shaped oligophenyl derivatives with terminal alk-
ene moieties can be used to form macrocycles by ‘dimerization’
through ring-closing metathesis. Hereby the introduction of tem-
plates connecting the two building blocks favors the dimerization
over oligomerization or polymerization reactions. Attachment of
the template through imine formation allows the removal of the
template simultaneous to the reduction of the double bonds formed
during ring-closing metathesis. Unsymmetric macrocyles can be
obtained either by successive attachment of different ‘arc’-shaped
molecules to the template or by direct imine connection of two dif-
ferent ring precursors. In the latter case, the imine unit cannot be
cleaved in the case of the investigated examples but ‘figure-8’-
shaped macrobicycles are obtained. The studied template-directed
macrocyclization depends on the one hand on the preorganization of
the building blocks, and on the other on their flexibility.
Key words: macrocycles, template, ring closing metathesis, imines
Functionalized macrocyclic compounds are important for
Scheme 1 Nontemplated (a) and templated (b) approach towards
the preparation of not only novel receptor type molecules
but also for new materials and topologically interesting
species. Macrocycles were already important in the early
days of supramolecular chemistry in order to bind cation-
ic,1 neutral2 or, anionic guests.3 Later on they were used to
mimic active centers in naturally occurring systems (e.g.,
enzymes),4 to prepare catenanes or rotaxanes,5 and to pro-
mote or catalyze chemical reactions.6 Today they still play
a crucial role and some novel aspects like their interaction
with surfaces and two-dimensional self-assembly have
come into the focus of attention.7
macrocyclic compounds. Despite the higher number of reaction steps,
there are often advantages in the overall yields of the templated se-
quence.
cently, ring-closing metathesis (RCM) was shown to be
highly efficient for this purpose.10,11
Based on a template-directed RCM for the preparation of
inside-functionalized macrocycles communicated by us
recently,12 we now present a more thorough investigation,
in which we test rigid (‘preorganized’) building blocks
versus flexible ones and try to approach unsymmetric
macrocycles
(Scheme 1).
and
‘figure-8’-shaped
compounds
Although many preparative approaches towards macrocy-
cles were developed during the last decades, there is still
a need for new methodologies to obtain tailor-made com-
pounds for specific purposes.8 Templating proved to be an
efficient tool in the construction of macrocycles. Hereby,
the template can be noncovalently bound, as was already
demonstrated by Pedersen in his ground-breaking discov-
ery of the crown ethers. On the other hand, covalent at-
tachment of the template and cleavage after cyclization is
an important strategy for the synthesis of well-designed
huge cyclic compounds.9
Symmetric Macrocycles
Our recent study on the formation of a huge macrocycle 3
by ring-closing dimerization of an ‘arc’-shaped building
block 2 (which is obtained in a few steps from 1) is depict-
ed in Scheme 2. The compound 3 was obtained from 2 in
a nontemplated two-step procedure by RCM using the
Grubbs catalyst of the first or second generation13 fol-
lowed by hydrogenation of the double bond. In the tem-
plated procedure two units of 2 formed the bisimine with
terephthalic aldehyde, which was then cyclized by RCM.
Finally the double bonds were hydrogenated with subse-
quent reductive removal of the template. Despite more re-
action steps the templated sequence afforded the product
Despite the use of templates for the control of ring size,
appropriate coupling reactions have to be introduced for
mild but high-yielding formation of the ring systems. Re-
SYNTHESIS 2008, No. 15, pp 2451–2461
x
x.
x
x
.
2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1067128; Art ID: Z07708SS
© Georg Thieme Verlag Stuttgart · New York

2452
M. Albrecht, Yeni
PAPER
(CH2)9
(CH2)9
O
OH
Br
O
1. Mg
(CH2)9
O
2. B(OMe)3
Br
3. H2O, H+
KOH
62%
95%
OH
1. Grubbs I
2. PtO2, H2
21%
Br
B(OH)2
4
5
6
R
NH2
O(CH2)9
1. terephthal-
aldehyde
TiCl4, Et3N
2. Grubbs I
3. PtO2, H2
43%
Br
Br
7a/b
NH2
Br
1
2
Pd(PPh3)4
Na2CO3
R
NH2
O
R = H: 8a (86%)
R = t-Bu: 8b (78%)
O
O
O(CH2)9
Scheme 3 Preparation of the building blocks 8a/b.
served despite several attempts to perform the reaction un-
der different reaction conditions. Probably polymeric/
oligomeric compounds were formed.
NH2
H2N
On the other hand, the macrocycles 10a/b were obtained
in the template-directed reaction. Thus, two equivalents of
the aniline derivatives 8a/b were reacted with terephthalic
dialdehyde in the presence of titanium tetrachloride and
triethylamine16 to obtain the corresponding diimines in
40% (9a) or 46% (9b), respectively. RCM with Grubbs II
catalyst and subsequent hydrogenation with concomitant
removal of the template afforded the macrocycle 10a in
68% and 10b in 67% yield (Scheme 4).
3
O
O
Scheme 2 Macrocycle 3 was prepared recently, following a templa-
ted as well as nontemplated protocol (Grubbs I =
[(cyclohexyl)3P)2Cl2Ru=CHPh]).
a
The macrocycles were characterized by standard spectro-
scopic methods. For example, positive ESI-MS showed
the peak for [10a·H]+ at m/z = 1111.8 and for [10b·H]+ at
1
3 in 43% yield while the nontemplated approach yielded
m/z = 1223.9. H NMR spectroscopy (CDCl3) revealed
only 21%.12
the expected signals (see Experimental section and
Figure 1).
The introduced building block 2 is rigid and highly pre-
organized. We wondered if this is important for the forma-
tion of the macrocycle and prepared the more flexible
compounds 8a/b for comparison.
The synthesis of the ‘arc’-shaped building block 8 started
with 4-bromophenol (4), which reacted in a Williamson
ether synthesis with 11-bromoundec-1-ene to form the
corresponding alkyl aryl ether 5 in 62% yield. Compound
5 was transformed into the boronic acid 6 by generation of
the Grignard reagent, which in situ was trapped by
B(OMe)3. Compound 6 was obtained in 95% after hydro-
lytic workup. Finally, Suzuki coupling15 with the 2,6-di-
bromoanilinium derivatives 7a/b14 afforded the half
cycles 8a (86%) or 8b (78%) (Scheme 3).
In contrast to the more rigid macrocycle precursor 2, com-
pounds 8a or 8b could not be cyclized by RCM without
the support of a template. No ‘dimeric’ product was ob-
Figure 1 1H NMR spectrum of 10b in CDCl3.
Synthesis 2008, No. 15, 2451–2461 © Thieme Stuttgart · New York

PAPER
Template-Directed Synthesis of Macrocycles
2453
CHO
O
(H2C)9
(CH2)9
(CH2)9
O
O
CHO
TiCl4, Et3N
R
NH2
R
N
N
R
O(CH2)9
R = H: 8a
R = t-Bu: 8b
O
O
(CH2)9
(H2C)9
R = H: 9a (40%)
R = t-Bu: 9b (46%)
1. Grubbs II
2. PtO2, H2
(H2C)9 (CH2)9
Grubbs II =
MesN
O
NH2
O
O
NMes
Cl2Ru CHPh
PCy3
R
H2N
R
R = H: 10a (68%)
R = t-Bu: 10b (67%)
O
(CH2)9
(CH2)9
Scheme 4 Template-directed synthesis of the macrocycles 10a/b.
Unsymmetric Macrocycles
addition of titanium tetrachloride and triethylamine. Al-
though the second imination with aniline 8a occurred also
The strategy used for the formation of unsymmetric mol- well, problems in the purification of the product were en-
ecules by successive attachment of two different half cir- countered. An amount of 20–30% of impurities (by NMR)
cles to a ditopic template followed by cyclization and could not be removed, due to simultaneous decomposition
cleavage of the template is illustrated in Scheme 5.
of the diimine. Therefore, we performed the macrocy-
clization by RCM with the crude product of 12 and imme-
diately reduced the double bonds with removal of the
template. Due to the impurities and extensive purification
of the product, the unsymmetric macrocycle 13 could be
obtained in only 17% yield (over 3 steps) (Scheme 6).
Compound 13 was characterized by positive ESI-MS
(m/z = 1123.5 [13·H]+) and showed the characteristic
1H NMR signals (see experimental section).
Thus, the reaction of only one equivalent of aniline deriv-
ative 2 with terephthalic aldehyde proceeded very well
and the monoimine 11 was obtained in 67% yield upon
Bicyclic ‘Figure-8’-Shaped Macrocycles
An alternative way to template the unsymmetric dimeriza-
tion between two ‘arc’-shaped building blocks is to use a
direct bond for connection of the two moieties. After cy-
clization, this bond has to be cleaved in order to obtain the
macrocycle. In our approach, which is outlined in
Scheme 7, the final bond cleavage did not occur.
Scheme 5 Formation of unsymmetric macrocycles by successive
attachment of two different half circles to a ditopic template followed
by cyclization and cleavage of the template.
Synthesis 2008, No. 15, 2451–2461 © Thieme Stuttgart · New York

2454
M. Albrecht, Yeni
PAPER
O
O
CHO
CHO
8a
TiCl4, Et3N
TiCl4, Et3N
N
NH2
O
67%
11
2
O
O
O
O
(CH2)9
(CH2)9
O
O
1. Grubbs II
2. PtO2, H2
N
N
NH2
17%
H2N
12
13
O
(CH2)9
O
(CH2)9
O
O
Scheme 6 Formation of the unsymmetric macrocycle 13.
CHO
O
14
Br
(CH2)9
Br
(CH2)9
O
Pd(PPh3)4
Na2CO3
OHC
78%
6
15
B(OH)2
(CH2)9
O
Scheme 8 Synthesis of the aldehyde 15.
Scheme 7 Formation of an unsymmetric ‘figure-8’-shaped macro-
cycle with the use of a direct bond as a template. Additional cleavage
of the central bond would result in the ‘open’ macrocycle.
boronic acid 6 and coupled it in a Suzuki coupling reac-
tion with 3,5-dibromobenzaldehyde (14). The aldehyde
15 was obtained in a yield of 78% (Scheme 8).
In order to follow the concept which is shown in
Scheme 7, we first had to prepare an appropriate building
block with a functional group on the convex face of the
‘arc’, which can be condensed with the amine of building
blocks 2 or 8a/b. Therefore, we used the already described
Aldehyde 15 was condensed with the rigid quinquephe-
nylene derivative 2 (in the presence or TiCl4 and Et3N) to
obtain the imine 16 in 68% yield. The following macrocy-
clization with subsequent reduction of the double bonds as
Synthesis 2008, No. 15, 2451–2461 © Thieme Stuttgart · New York

PAPER
Template-Directed Synthesis of Macrocycles
2455
O
(H2C)9
O
O
(H2C)9
O
TiCl4
Et3N
NH2
OHC
+
68%
N
O
2
(H2C)9
O
15
(H2C)9
16
O
O
O
(H2C)9
O
1. Grubbs II
2. PtO2, H2
N
H
87%
O
(H2C)9
17
O
Scheme 9 Synthesis of the ‘figure-8’-shaped compound 17.
well as of the imine proceeded to give 17 in 87% yield In this article, we have presented a simple approach for
(Scheme 9). To our surprise, the benzylic amine of 17 was the preparation of macrocyclic as well as macrobicyclic
not further reductively cleaved. Probably, the benzylic po- compounds. For this purpose, we connected two preorga-
sition, which can be recognized by the 1H NMR signal of nized ‘arc’-shaped building blocks through an appropriate
the methylene unit at d = 3.67, is hidden in the interior of template (terephthalic unit, direct bond) as imines to each
the ‘figure-8’-shaped molecule and is not accessible to the other. Ring-closing metathesis leads to macrocyclization.
heterogeneous PtO2 catalyst.
In the case of terephthalic diimine as the template, it is re-
moved upon reduction of the double bonds. In the case of
a direct bond, the imine is burrowed in the internal of the
macrocyle and it is only reduced to the amine, but the ben-
zylic amine is not further cleaved.
The analogous imine-condensation of 8a or 8b (a: R = H;
b: R = t-Bu) followed by RCM and reduction of the dou-
ble bond resulted in the formation of the macrobicycles
19a/b (a: 9%, b: 15%; over three steps) in which again the
central benzylamine unit was remained (Scheme 10). The Our studies show that the yield of the macrocyclization
low yields were caused by two factors: (1) The intermedi- depends on the preorganization and rigidity of the intro-
ate imines 18a and 18b could not be isolated in pure form duced building blocks. It will be of interest to use our in-
and had to be introduced into the ring closing reaction as side-functionalized macrocycles as receptors for guest
crude product, and (2) the high flexibility of the undecenyl species or to further functionalize them to perform and
chains led to a low preorganization of the two half circles control reactions inside of the macrocycles.17
for cyclization.
1H and 13C NMR spectra were recorded on a Varian Inova 400 or
Mercury 300 NMR spectrometer. FT-IR spectra were recorded on a
Bruker IFS spectrometer (KBr or neat). Mass spectra were taken on
a Varian MAT 212, Finnigan SSQ 7000 (EI, 70 eV) or LCQ Deca
XP Plus Thermo Finnigan (ESI). Elemental analyses were obtained
The bicyclic derivatives were characterized by positive
ESI MS (m/z = 1114.7 [19a·Li]+, 1164.4 [19b·H]+) and by
1H NMR (see experimental section).
Synthesis 2008, No. 15, 2451–2461 © Thieme Stuttgart · New York

2456
M. Albrecht, Yeni
PAPER
were dried (MgSO4). The solvent was removed and the residue was
purified by column chromatography on silica gel (Et2O–
hexane, 20:80) to give a colorless solid; yield: 4.41 g (60%); mp
128 °C.
(H2C)9
(CH2)9
O
O
IR (CDCl3): 1608 (w), 1481 (m), 1286 (w), 1247 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.44 (d, 3J = 8.5 Hz, 2 Harom), 7.39
3
3
(d, J = 8.5 Hz, 2 Harom), 7.32 (d, J = 8.6 Hz, 2 Harom), 6.88 (d,
EtOH,
HCl
3
3
3
3J = 8.6 Hz, 2 Harom), 5.84 (ddt, Jtrans = 17.1, Jcis = 10.1, J = 6.7
R
NH2
OHC
+
Hz, 1 H, HC=), 5.11 (dm, 3Jtrans = 17.1 Hz, 1 H, =CHtrans), 5.05 (dm,
3Jcis = 10.1 Hz, 1 H, =CHcis), 3.98 (t, J = 6.7 Hz, 2 H, CH2), 2.49
3
(qt, 3J = 6.7, 4J = 1.2 Hz, 2 H, CH2).
13C NMR (75 MHz, CDCl3): d = 158.8 (C), 139.8 (C), 134.4 (CH),
132.5 (C), 131.8 (CH), 128.3 (CH), 128.0 (CH), 120.8 (C), 117.2
(CH2), 115.0 (CH), 67.4 (CH2), 33.7 (CH2).
O
O
8a,b
(CH2)9
(H2C)9
MS (EI, 70 eV): m/z (%) = 302.0 (72, M+, C16H15BrO), 248 (100),
15
168 (4), 152 (16).
Anal. Calcd for C16H15BrO: C, 63.38; H, 4.99. Found: C, 63.38; H,
5.00.
(H2C)9
O
[4¢-(But-3-en-1-yloxy)biphenyl-4-yl]boronic Acid: One crystal of I2
was added to Mg turnings (218 mg, 8.97 mmol) in degassed anhyd
THF (0.5 mL) and the mixture was heated at reflux for 30 min. A
solution of 4¢-bromo-1,1¢-biphenyl-4-ylbut-3-enyl ether (1.80 g,
5.94 mmol, 1.0 equiv) in anhyd THF (3 mL) was added. Additional
anhyd THF (10 mL) was added and the mixture was heated for 3 h.
After cooling, trimethyl borate (0.86 mL, 7.72 mmol, 1.3 equiv) in
anhyd THF (32 mL) was added at –78 °C. The mixture was warmed
up to r.t. overnight and poured onto ice (30 g) containing concd
H2SO4 (1.5 mL). After stirring for 1 h, the mixture was extracted
with Et2O (5 × 60 mL). The organic phase was dried (Na2SO4) and
the solvent was removed under vacuum; yield: 1.07 g (67%); mp
179–186 °C.
(CH2)9
O
1. Grubbs II
2. PtO2, H2
R
N
87%
O
(H2C)9
O
(CH2)9
IR (KBr): 3360 (m), 1605 (s), 1526 (m), 1501 (m), 1346 (vs), 1285
(m), 1248 cm–1 (s).
18a,b
(CH2)9
O
(CH2)9
O
1H NMR (400 MHz, acetone-d6): d = 7.94 (d, 3J = 8.2 Hz, 2 Harom),
7.63 (d, 3J = 8.6 Hz, 2 Harom), 7.61 (d, 3J = 8.2 Hz, 2 Harom), 7.18 (s,
3
3
1 H, OH), 7.04 (d, J = 8.6 Hz, 2 Harom), 5.98 (ddt, Jtrans = 17.0,
3Jcis = 10.2, J = 6.6 Hz, 1 H, HC=), 5.19 (dm, Jtrans = 17.0 Hz, 1
H, =CHtrans), 5.09 (dm, 3Jcis = 10.2 Hz, 1 H, =CHcis), 4.10 (t, 3J = 6.6
Hz, 2 H, CH2), 2.55 (qt, 3J = 6.6, 4J = 1.4 Hz, 2 H, CH2).
3
3
13C NMR (100 MHz, acetone-d6): d = 159.5 (C), 143.0 (C), 135.5
(C), 135.4 (CH), 133.9 (C), 129.6 (CH), 128.6 (CH), 126.1 (CH),
117.0 (CH2), 115.6 (CH), 67.8 (CH2), 34.3 (CH2).
R
N
H
+
MS (EI, 70 eV): m/z (%) = 324.2 (100, C20H25BO3 ), 310.2 (4),
O
+
296.2 (4), 270.2 (28), 269.2 (2, MH+, C16H17BO3 ).
O
R = H: 19a (9%)
R = t-Bu: 19b (15%)
(CH2)9
Anal. Calcd for C16H17BO3: C, 71.67; H, 6.39. Found: C, 71.13; H,
6.30.
(CH2)9
Quinquephenylamine 2: The reaction was performed under N2 with
exclusion of light. [4¢-(But-3-en-1-yloxy)biphenyl-4-yl]boronic
acid (3.00 g, 0.01 mol, 3 equiv) and 2,6-dibromo-4-tert-butylaniline
(1.2 g, 3.8 mmol, 1 equiv) were dissolved in toluene (50 mL) con-
taining EtOH (7.5 mL). Aq 2 M Na2CO3 (11.5 mL, 0.02 mol, 6
equiv) and Pd(PPh3)4 (0.52 g, 0.45 mmol, 0.12 equiv) were added
successively and the mixture was heated at reflux for 4 d. After
cooling, toluene (50 mL) was added. The organic phase was sepa-
rated and the aqueous phase was extracted with CH2Cl2 (3 × 20 mL).
The combined organic phases were dried (MgSO4) and the residue
was purified by column chromatography (CH2Cl2); yield: 1.72 g
(76%); mp 198 °C.
Scheme 10 Synthesis of the ‘figure-8’-shaped compounds 19a/b.
with a Heraeus CHN-O-Rapid analyzer. Melting points: Büchi
B-540 (uncorrected). Preparative column chromatography: Merck
silica gel 60, particle size 0.040–0.063 mm (230–400 mesh, flash).
4,4¢¢¢¢-Bis(but-3-en-1-yloxy)-5¢¢-tert-butyl-
1,1¢:4¢,1¢¢:3¢¢,1¢¢¢:4¢¢¢,1¢¢¢¢-quinquephenyl-2¢¢-amine (2)
4¢-Bromo-1,1¢-biphenyl-4-ylbut-3-enyl Ether: To a solution of 4-(4-
bromophenyl)phenol (6.00 g, 24.09 mmol, 1.0 equiv) and NaOH
(1.18 g, 29.50 mmol, 1.2 equiv) in EtOH (70 mL) was added slowly
4-bromobut-1-ene (3.7 mL, 36.45 mmol, 1.5 equiv). The mixture
was heated at reflux for 50 h and the solvent was removed under
vacuum. The residue was dissolved in Et2O (100 mL) and the Et2O
phase was washed with brine (60 mL). The aqueous phase was ex-
tracted with Et2O (3 × 20 mL) and the combined organic phases
IR (KBr): 3444 (w), 3366 (m), 2949 (m), 2868 (m), 1606 (s), 1493
(s), 1466 (s), 1249 cm–1 (s).
1H NMR (400 MHz, CDCl3): d = 7.58 (d, 3J = 8.5 Hz, 4 Harom), 7.53
3
3
(d, J = 8.5 Hz, 4 Harom), 7.49 (d, J = 8.8 Hz, 4 Harom), 7.15 (s, 2
Synthesis 2008, No. 15, 2451–2461 © Thieme Stuttgart · New York

PAPER
Template-Directed Synthesis of Macrocycles
2457
3
Harom), 6.92 (d, 3J = 8.8 Hz, 4 Harom), 5.86 (ddt, Jtrans = 17.0,
IR (KBr): 3443 (s), 3028 (m), 2939 (vs), 2865 (s), 1609 (vs), 1524
3Jcis = 10.4, J = 6.7 Hz, 2 H, HC=), 5.12 (dm, Jtrans = 17.0 Hz, 2
H, =CHtrans), 5.05 (dm, 3Jcis = 10.4 Hz, 2 H, =CHcis), 4.00 (t, 3J = 6.7
Hz, 4 H, CH2), 2.51 (q, 3J = 6.7 Hz, 4 H, CH2), 1.28 (s, 9 H, t-C4H9).
13C 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).
(m), 1497 (vs), 1467 (s), 1391 (m), 1287 (s), 1246 (vs), 1176 cm–1
(s).
3
3
3
1H NMR (300 MHz, CDCl3): d = 7.53 (d, J = 8.4 Hz, 8 Harom),
3
7.49–7.40 (m, 16 Harom), 7.12 (s, 4 Harom), 6.86 (d, J = 8.7 Hz, 8
H
arom), 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-C4H9).
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).
+
MS (EI): 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.
MS (ESI, positive): 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.
Macrocycle 3
Diimine from Terephthalic Dialdehyde and 2: To a solution of quin-
quephenylamine 2 (100 mg, 0.168 mmol, 2 equiv), terephthalic al-
dehyde (11 mg, 0.082 mmol, 1 equiv), and Et3N (70 mL, 0.504
mmol, 6 equiv) in anhyd CH2Cl2 (10 mL) at 0 °C was added a solu-
tion of TiCl4 (11 mL, 0.101 mmol, 1.2 equiv) in CH2Cl2 (1 mL). Af-
ter stirring overnight, the mixture was filtered over Celite and the
solvent was removed under vacuum. The residue was dissolved in
toluene (50 mL), filtered again over Celite, and the solvent was re-
moved under vacuum. Precipitation of the product from toluene by
the addition of pentane afforded a yellow solid; yield: 67 mg (63%);
mp >250 °C.
1-Bromo-4-(undec-10-enyloxy)benzene (5)
To a solution of KOH (7.17 g, 0.128 mol, 1.1 equiv) and 4-bro-
mophenol (4; 20 g, 0.116 mol, 1 equiv) in ethylene glycol mono-
methyl ether (60 mL) was added 11-bromoundec-1-ene (30.3 mL,
32.5 g, 0.139 mol, 1.2 equiv) and the mixture was heated at reflux
for 5 h. After cooling to r.t., H2O (120 mL) and petroleum ether (bp
30–60 °C, 95 mL) were added. The phases were separated and the
organic phase was washed with 15% aq KOH (3 × 50 mL) and H2O
(3 × 50 mL), and dried (K2CO3). The solvent was removed and the
residual oil was distilled under vacuum; yield: 23.5 g (62%).
IR (KBr): 3437 (vs), 2954 (m), 2865 (m), 1616 (s), 1496 (s), 1246
(vs), 1178 cm–1 (m).
IR (neat): 3378 (s), 2926 (vs), 2857 (s), 1587 (m), 1482 (s), 1286
(m), 1243 (s), 1069 (m), 1022 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 7.96 (s, 2 H, N=CH), 7.52–7.47
3
1H NMR (300 MHz, CDCl3): d = 7.32 (dt, J = 9.0, 5J = 2.2 Hz, 2
(m, 24 Harom), 7.45 (s, 4 Harom), 7.39 (s, 4 Harom), 6.94 (d, 3J = 8.8 Hz,
3
H
arom), 6.73 (d, 3J = 9.0 Hz, 2 Harom), 5.80 (ddt, Jtrans = 17.1,
3
3
8 Harom), 5.91 (ddt, Jtrans = 17.3, Jcis = 10.4, 3J = 6.8 Hz, 4 H,
3Jcis = 10.1, J = 6.7 Hz, 1 H, HC=), 4.98 (dm, Jtrans = 17.1 Hz, 1
3
3
3
HC=), 5.18 (dm, Jtrans = 17.3 Hz, 4 H, =CHtrans), 5.11 (dm,
3
H, =CHtrans), 4.92 (dm, Jcis = 10.1 Hz, 1 H, =CHcis), 3.87 (t,
3Jcis = 10.4 Hz, 4 H, =CHcis), 4.03 (t, 3J = 6.8 Hz, 8 H, CH2), 2.55 (q,
3J = 6.8 Hz, 8 H, CH2), 1.41 (s, 18 H, t-C4H9).
3J = 6.7, 2 H, CH2), 2.03 (q, J = 6.7 Hz, 2 H, CH2), 1.76 (quint,
3
3J = 6.7 Hz, 2 H, CH2), 1.50–1.20 (m, 12 H, CH2).
MS (ESI, positive): m/z = 1285.7 (MH+, C92H88N2O4 + H+).
13C NMR (75 MHz, CDCl3): d = 158.3 (C), 139.2 (CH), 132.2
(CH), 116.3 (CH), 114.2 (CH2), 112.6 (C), 68.2 (CH2), 33.9 (CH2),
29.6–29.0 (CH2), 26.1 (CH2).
Anal. Calcd for C92H88N2O4: C, 85.94; H, 6.90; N, 2.18. Found: C,
86.41; H, 6.98; N, 1.81.
Ring-Closing Metathesis: The diimine precursor of macrocycle 3
(60 mg, 0.047 mmol, 1 equiv) was heated at reflux in anhyd CH2Cl2
(100 mL) under N2 and a solution of Grubbs II catalyst (approxi-
mately 0.1–0.5 mg, 0.25–1.25 mol%) in anhyd CH2Cl2 (10 mL) was
added. The mixture was heated at reflux for 6 h and two-thirds of
the solvent was removed under vacuum. The precipitate was col-
lected by filtration and washed with pentane (30 mL); yield: 51 mg
(88%, E/Z = 1:3); mp >250 °C.
MS (EI, 70 eV): m/z (%) = 327.0 (9), 326.0 (M+ + 2), 325.1 (11),
324.0 (49, M+, C17H25BrO+), 173.9 (100), 171.9 (93).
4-(Undec-10-enyloxy)phenylboronic Acid (6)
A suspension of Mg turnings (2.55 g, 105 mmol, 1.5 equiv) in anhyd
THF (5 mL) was activated under N2 at reflux by adding a crystal of
I2. After 1 h, the bromide 5 (16.5 g, 70 mmol, 1.0 equiv) in anhyd
THF (15 mL) was added. An additional amount of anhyd THF (10
mL) was added and the mixture was heated at reflux for 3 h. After
cooling to r.t., trimethyl borate (10.3 mL, 91 mmol, 1.3 equiv) in an-
hyd THF (20 mL) was added at –78 °C. After warming overnight to
r.t., the mixture was poured onto ice (320 g) containing concd
H2SO4 (18 mL). After stirring for 1 h, the mixture was extracted
with Et2O (5 × 100 mL). The organic phase was dried (Na2SO4), the
solvent was removed under vacuum, and the residue was washed
with pentane (2 × 20 mL); yield: 19.3 g (95%); mp 78–83 °C.
IR (KBr): 3436 (m), 3033 (w), 2957 (m), 2898 (m), 1618 (s), 1497
(vs), 1245 (vs), 1180 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 8.02 (s, 2 H, N=CH), 7.56/7.54 (2
s, 4 Harom), 7.50–7.35 (m, 28 Harom), 6.86/6.82 (2 overlapping d,
3J = 8.7/8.9 Hz, 1:3 E/Z, 8 Harom), 5.64–5.60 (m, 4 H, HC=CH),
4.05–3.95 (m, 8 H, CH2), 2.58/2.42 (2 m, 1:3 E/Z, 8 H, CH2), 1.48
(s, 18 H, t-C4H9).
MS (ESI, positive): m/z = 1229.7 (MH+, C88H80N2O4 + H+).
IR (KBr): 3431 (m), 2924 (vs), 2855 (s), 1603 (vs), 1515 (m), 1356
(vs), 1243 (vs), 1168 (s), 1022 cm–1 (m).
Anal. Calcd for C88H80N2O4: C, 85.96; H, 6.56, N, 2.28. Found: C,
86.30; H, 6.91; N, 2.09.
1H NMR (400 MHz CDCl3): d = 8.07 (d, 3J = 8.2 Hz, 2 Harom), 6.92
3
3
(d, 3J = 8.2 Hz, 2 Harom), 5.76 (ddt, Jtrans = 17.0, Jcis = 10.2,
Macrocycle 3: A suspension of the unsaturated macrocyclic product
of the RCM (45 mg, 0.040 mmol) and PtO2 (5 mg) in CH2Cl2 (50
mL) was stirred for 2 d in an autoclave under an H2 atmosphere (20
bar). The mixture was filtered over Celite and the solvent removed
under vacuum. The product was purified by column chromatogra-
phy on silica gel (CH2Cl2); yield: 32 mg (77%); mp >250 °C.
3J = 6.6 Hz, 1 H, HC=), 4.93 (dm, 3Jtrans = 17.0 Hz, 1 H, =CHtrans),
4.86 (dm, Jcis = 10.2 Hz, 1 H, =CHcis), 3.96 (t, J = 6.6 Hz, 2 H,
CH2), 1.98 (q, 3J = 6.6 Hz, 2 H, CH2), 1.74 (quint, 3J = 6.6 Hz, 2 H,
CH2), 1.40–1.15 (m, 12 H, CH2).
3
3
13C NMR (100 MHz, CDCl3): d = 162.7 (C), 139.2 (CH), 137.4
(CH), 122.0 (C), 114.1 (CH2), 114.0 (CH), 67.9 (CH2), 33.9 (CH2),
29.6–29.1 (CH2), 26.2 (CH2).
Synthesis 2008, No. 15, 2451–2461 © Thieme Stuttgart · New York

2458
M. Albrecht, Yeni
PAPER
MS (EI, 70 eV): m/z (%) = 346.3 (58, C21H35BO3), 194.1 (100,
C10H15BO3).
the mixture was stirred for 1 d. The mixture was filtered over Celite
and the solvent was removed under vacuum. The residue was dis-
solved in toluene (40 mL) and filtered again over Celite. After re-
moval of the solvent, the residue was recrystallized from EtOH.
Terphenylamines 8a and 8b
To a solution of boronic acid 6 (500 mg, 1.72 mmol, 3 equiv) and
2,6-dibromoaniline (7a; 142 mg, 0.57 mmol, 1 equiv) or 2,6-dibro-
mo-4-tert-butylaniline (7b; 175 mg, 0.57 mmol, 1 equiv) in a mix-
ture of EtOH (3 mL) and toluene (25 mL) was added aq 2 M
Na2CO3 (1.71 mL, 3.42 mmol, 6 equiv). After the addition of
Pd(PPh3)4 (80 mg, 0.068 mmol, 0.12 equiv), the mixture was heated
at reflux under N2 for 3 d. Toluene (50 mL) was added and the or-
ganic phase was washed with aq NaOH (3 × 30 mL). The combined
aqueous phases were back-extracted with CH2Cl2 (3 × 50 mL). The
combined organic phases were dried (MgSO4) and the solvent was
removed under vacuum. The crude product was purified by chroma-
tography over silica gel using CH2Cl2 as solvent.
9a
Yield: 34 mg (40%).
1H NMR (300 MHz, CDCl3): d = 7.87 (s, 2 H, N=CH), 7.36 (s, 4
H
arom), 7.30–7.22 (m, 14 Harom), 6.77 (d, 3J = 8.6 Hz, 8 Harom), 5.73
3
3
3
(ddt, Jtrans = 16.8, Jcis = 10.1, J = 6.7 Hz, 4 H, HC=), 4.91 (dm,
3Jtrans = 16.8 Hz, 4 H, =CHtrans), 4.85 (dm, Jcis = 10.1 Hz, 4
3
H, =CHcis), 3.85 (t, 3J = 6.7 Hz, 8 H, CH2), 1.96 (q, 3J = 6.7 Hz, 8 H,
3
CH2), 1.69 (quint, J = 6.7 Hz, 8 H, CH2), 1.40–1.15 (m, 48 H,
CH2).
MS (ESI, positive): m/z = 1262.0 (MH+, C88H112N2O4 + H+).
9b
8a
Yield: 42 mg (46%); mp 104 °C.
Yield: 286 mg (86%); mp 85 °C.
IR (KBr): 3426 (vs), 3074 (m), 2926 (vs), 2853 (s), 2550 (m), 1634
(s), 1510 (s), 1461 (m), 1285 (m), 1247 (s), 1180 (m), 1056 cm–1
(m).
IR (KBr): 3853 (vs), 3743 (vs), 3671 (m), 3617 (m), 3071 (m), 2922
(vs), 2853 (s), 2361 (vs), 1835 (m), 1698 (m), 1640 (m), 1618 (m),
1518 (vs), 1458 (s), 1391 (m), 1248 (vs), 1003 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.86 (s, 2 H, N=CH), 7.34 (s, 4
1H NMR (400 MHz, CDCl3): d = 7.34 (d, 3J = 8.8 Hz, 4 Harom), 7.01
arom), 7.30–7.23 (m, 12 Harom), 6.78 (d, 3J = 8.9 Hz, 8 Harom), 5.73
3
3
H
(d, J = 7.4 Hz, 2 Harom), 6.90 (d, J = 8.8 Hz, 4 Harom), 6.77 (t,
3
3
3
3J = 7.4 Hz, 1 Harom), 5.74 (ddt, Jtrans = 17.0, Jcis = 10.2 J = 6.6
Hz, 2 H, HC=), 4.92 (dm, 3Jtrans = 17.0 Hz, 2 H, =CHtrans), 4.86 (dm,
3Jcis = 10.2 Hz, 2 H, =CHcis), 3.92 (t, 3J = 6.6 Hz, 4 H, CH2), 3.80 (s,
2 H, NH2), 1.98 (q, 3J = 6.6 Hz, 4 H, CH2), 1.73 (quint, 3J = 6.6 Hz,
4 H, CH2), 1.40–1.15 (m, 24 H, CH2).
3
3
3
(ddt, Jtrans = 17.1, Jcis = 10.2, J = 6.5 Hz, 4 H, HC=), 4.91 (dm,
3Jtrans = 17.1 Hz, 4 H, =CHtrans), 4.85 (dm, Jcis = 10.2 Hz, 4
3
H, =CHcis), 3.86 (t, 3J = 6.5 Hz, 8 H, CH2), 1.95 (q, 3J = 6.5 Hz, 8 H,
CH2), 1.75–1.64 m, 8 H, CH2), 1.40–1.15 (m, 66 H, CH2 + t-C4H9).
MS (ESI, positive): m/z = 1374.3 (MH+, C96H128N2O4 + H+).
13C NMR (100 MHz, CDCl3): d = 158.3 (C), 141.1 (C), 139.2 (CH),
131.8 (C), 130.3 (CH), 129.4 (CH), 127.6 (C), 118.0 (CH), 114.7
(CH), 114.1 (CH2), 68.1 (CH2), 33.9 (CH2), 29.6–29.0 (CH2), 26.2
(CH2).
Anal. Calcd for C96H128N2O4·H2O: C, 82.83; H, 9.41; N, 2.01.
Found: C, 82.75; H, 9.51; N, 1.88.
Two-Step Procedure for the Preparation of Macrocycles 10a
and 10b
+
MS (EI, 70 eV): m/z (%) = 581.5 (100, M+, C40H55NO2 ), 429.2 (5),
Metathesis Reaction: Bisimine 9a (10 mg, 0.008 mmol, 1 equiv) or
9b (10 mg, 0.007 mmol, 1 equiv) was dissolved in anhyd CH2Cl2
(20 mL) under N2. At reflux, Grubbs II catalyst (0.1–0.5 mg, 1.5–
7.5 mol%) in anhyd CH2Cl2 (5 mL) was slowly added. The mixture
was heated at reflux for 2 d and then filtered over Celite. Removal
of the solvent resulted in the macrocyclic precursors for 10a/b as
crude products, which were used further without purification.
277.0 (17).
Anal. Calcd for C40H55NO2: C, 82.57; H, 9.53; N, 2.41. Found: C,
82.84; H, 9.17; N, 2.13.
8b
Yield: 285 mg (78%); mp 130 °C.
IR (KBr): 3389 (s), 2921 (vs), 2852 (vs), 1609 (s), 1509 (s), 1468
(s), 1283 (m), 1243 (vs), 1173 (m), 1109 (m), 1032 cm–1 (m).
Precursor of 10a
1H NMR (300 MHz, CDCl3): d = 7.87 (s, 2 H, N=CH), 7.39 (s, 4
1H NMR (400 MHz, CDCl3): d = 7.47 (d, 3J = 8.8 Hz, 4 Harom), 7.15
Harom), 7.29–7.21 (m, 12 Harom), 6.90 (t, 3J = 8.6 Hz, 2 Harom), 6.77
3
3
(s, 2 Harom), 6.98 (d, J = 8.8 Hz, 4 Harom), 5.82 (ddt, Jtrans = 17.0,
3
(d, J = 8.6 Hz, 8 Harom), 5.33–5.26 (m, 4 H, HC=CH), 3.84 (t,
3Jcis = 10.2, J = 6.6 Hz, 2 H, HC=), 5.00 (dm, Jtrans = 17.0 Hz, 2
H, =CHtrans), 4.93 (dm, 3Jcis = 10.2 Hz, 2 H, =CHcis), 3.99 (t, 3J = 6.6
Hz, 4 H, CH2), 2.04 (q, 3J = 6.6 Hz, 4 H, CH2), 1.80 (quint, 3J = 6.6
Hz, 4 H, CH2), 1.50–1.28 (m, 33 H, CH2 + t-C4H9).
3
3
3J = 6.7 Hz, 8 H, CH2), 2.00–1.86 (m, 8 H, CH2), 1.75–1.62 (m, 8
H, CH2), 1.44–1.15 (m, 48 H, CH2).
MS (ESI, positive): m/z = 1205.9 (MH+, [C84H104N2O4 + H]+).
13C NMR (100 MHz, CDCl3): d = 158.5 (C), 141.1 (C), 139.2 (CH),
133.2 (C), 131.6 (C), 130.5 (CH), 126.6 (CH), 114.8 (CH), 114.1
(CH2), 68.1 (CH2), 33.9 (CH2), 31.6 (CH3), 29.6–29.0 (CH2), 26.2
(CH2).
Precursor of 10b
1H NMR (400 MHz, CDCl3): d = 7.88 (s, 2 H, N=CH), 7.38 (s, 4
H
arom), 7.30–7.24 (m, 12 Harom), 6.77 (d, 3J = 8.8 Hz, 8 Harom), 5.30–
5.27 (m, 4 H, HC=CH), 3.86 (t, 3J = 6.6 Hz, 8 H, CH2), 2.00–1.85
(m, 8 H, CH2), 1.75–1.64 (m, 8 H, CH2), 1.40–1.17 (m, 66 H, CH2
+ t-C4H9).
+
MS (EI, 70 eV): m/z (%) = 637.7 (100, M+, C44H63NO2 ), 622.6
(52), 484.4 (4), 470.4 (5).
Anal. Calcd for C44H63NO2·0.5 H2O: C, 81.68; H, 9.97; N, 2.16.
Found: C, 81.91; H, 9.97; N, 1.98.
Reduction: The crude product of the RCM and PtO2 (3 mg) were
stirred in CH2Cl2 (50 mL) under an H2 atmosphere (20 bar) for 2 d
and then the mixture was filtered over Celite. The solvent was re-
moved and the residue was purified by column chromatography on
silica (CH2Cl2).
Terephthalic Diimines 9a and 9b
The aniline 8a (80 mg, 0.137 mmol, 2 equiv) or the tert-butyl-sub-
stituted 8b (87 mg, 0.136 mmol, 2 equiv), terephthalic dialdehyde
(9 mg, 0.067 mmol, 1 equiv), and Et3N (57 mL, 0.412 mmol, 6
equiv) were dissolved in anhyd CH2Cl2 (10 mL) under N2. At 0 °C,
TiCl4 (9 mL, 0.08 mmol, 1.2 equiv) in CH2Cl2 (1 mL) was added and
10a
Yield: 6 mg (68% over two steps); mp 152 °C.
Synthesis 2008, No. 15, 2451–2461 © Thieme Stuttgart · New York

PAPER
Template-Directed Synthesis of Macrocycles
2459
IR (CHCl3): 2924 (vs), 2853 (s), 1604 (m), 1510 (m), 1453 (m),
1286 (m), 1244 (s), 1178 (m), 1114 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 7.37–7.28 (m, 10 Harom), 7.03 (d,
3J = 6.9 Hz, 4 Harom), 6.90 (d, 3J = 8.7 Hz, 8 Harom), 3.91 (t, 3J = 6.4
Hz, 8 H, CH2), 1.73 (quint, 3J = 6.4 Hz, 8 H, CH2), 1.34–1.17 (m,
64 H, CH2).
MS (ESI, positive): m/z = 1111.8 (MH+, C76H106N2O4 + H+).
HRMS (ESI, positive): m/z calcd for [C76H106N2O4 + H]+:
RCM of 12 Followed by Reduction: A solution of the crude product
12 (40 mg) in anhyd CH2Cl2 (50 mL) was heated at reflux under N2.
A solution of Grubbs II catalyst (0.1–0.5 mg) in anhyd CH2Cl2 (2
mL) was added and the mixture was heated at reflux for 6 d. During
this time, additional catalyst was added (2 × 0.5 mg). The mixture
was filtered and the solvent was removed. The residue was dis-
solved in CH2Cl2 (50 mL), PtO2 (3 mg) was added and reduction
took place overnight in an autoclave at 30 bar H2 pressure. The mix-
ture was filtered over Celite, the solvent removed, and the residue
purified by column chromatography on silica gel (CH2Cl2–
hexane, 2:1) to give 13; yield: 6 mg (17% over three steps); mp
>250 °C.
1111.82254; found: 1111.82476.
10b
Yield: 6 mg (67% over 2 steps); mp 87–95 °C.
IR (CHCl3): 3548 (s), 3405 (s), 3040 (m), 2930 (vs), 2859 (s), 1607
(s), 1496 (s), 1445 (vs), 1384 (m), 1361 (w), 1338 (w), 1318 (m),
1286 (m), 1247 (s), 1180 (m), 1162 (m), 1121 (m), 1064 (m), 1021
(m), 1005 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.60–7.46 (m, 12 Harom), 7.30 (d,
3J = 8.5 Hz, 4 Harom), 7.17 (s, 2 Harom), 6.98 (d, 3J = 7.4 Hz, 2 Harom),
6.92 (d, 3J = 8.9 Hz, 4 Harom), 6.87 (d, 3J = 8.5 Hz, 4 Harom), 6.74 (t,
3J = 7.4 Hz, 1 Harom), 3.98 (t, 3J = 6.4 Hz, 4 H, CH2), 3.89 (t, 3J = 6.4
Hz, 4 H, CH2), 1.80–1.65 (m, 8 H, CH2), 1.60–1.20 (m, 45 H, CH2
+ CH3).
IR (CHCl3): 2925 (vs), 2853 (s), 1609 (m), 1509 (s), 1466 (m), 1286
(m), 1245 (s), 1175 (m), 1110 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 7.36 (d, 3J = 8.7 Hz, 8 Harom), 7.04
(s, 4 Harom), 6.90 (d, 3J = 8.7 Hz, 8 Harom), 3.92 (t, 3J = 6.4 Hz, 8 H,
CH2), 1.73 (quint, 3J = 6.4 Hz, 8 H, CH2), 1.45–1.35 (m, 8 H, CH2),
1.28–1.17 (m, 74 H, CH2 + t-C4H9).
MS (ESI, positive): m/z = 1223.9 (MH+, [C84H122N2O4 + H]+).
HRMS (ESI, positive): m/z calcd for [C84H122N2O4 + H]+:
1223.94774; found: 1223.94799.
MS (ESI, positive): m/z = 1123.5 (100%, MH+, C78H94N2O4 + H+).
Terephthalic Aldehyde Monoimine 11
Convex Aldehyde 15
At 0 °C, a solution of TiCl4 (11 mL, 0.101 mmol, 0.6 equiv) in
CH2Cl2 (1 mL) was added to a solution of tert-butylquinquephenyl-
amine 2 (100 mg, 0.168 mmol, 1 equiv), terephthalic aldehyde (23
mg, 0.171 mmol, 1 equiv), and Et3N (70 L, 0.504 mmol, 3 equiv) in
anhyd CH2Cl2 (40 mL) under N2. The mixture was allowed to warm
to r.t. overnight and then filtered over Celite. Half of the solvent was
removed under vacuum and cold pentane was added to precipitate
the product as a yellow solid; yield: 80 mg (67%).; mp 145 °C.
To a solution of 4-(undec-10-enyloxy)phenylboronic acid (6; 500
mg, 1.72 mmol, 3 equiv), 3,5-dibromobenzaldehyde (14; 152 mg,
0.57 mmol, 1 equiv), EtOH (3 mL), and aq 2 M Na2CO3 (1.7 mL,
3.42 mmol, 6 equiv) in toluene (25 mL) was added Pd(PPh3)4 (80
mg, 0.068 mmol, 0.12 equiv) under N2. The mixture was heated at
reflux for 3 d and then toluene (50 mL) was added. The mixture was
washed with aq NaOH (3 × 50 mL) and dried (MgSO4). Removal of
solvent and column chromatography of the residue using CH2Cl2 as
eluent afforded the terphenyl aldehyde 15; yield: 263 mg (78%); mp
78 °C.
IR (KBr): 3442 (vs), 3250 (m), 2947 (m), 2868 (m), 1698 (s), 1607
(s), 1495 (s), 1384 (m), 1245 (vs), 1190 (s), 1034 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 10.07 (s, 1 H, CHO), 7.99 (s, 4
Harom), 7.61 (s, 8 Harom), 7.54 (s, 1 H, N=CH), 7.50 (d, 3J = 8.8 Hz,
4 Harom), 7.22 (s, 2 Harom), 6.93 (d, 3J = 8.8 Hz, 4 Harom), 5.87 (m, 2
IR (KBr): 3439 (m), 2925 (vs), 2853 (s), 1698 (vs), 1641 (w), 1606
(s), 1514 (s), 1462 (m), 1386 (m), 1336 (m), 1283 (m), 1251 (vs),
1167 (s), 1114 (w), 1017 cm–1 (s).
3
H, HC=), 5.13 (dm, Jtrans = 17.3 Hz, 2 H, =CHtrans), 5.06 (dm,
1H NMR (300 MHz, CDCl3): d = 10.05 (s, 1 H, CHO), 7.91 (s, 3
3Jcis = 10.4 Hz, 2 H, =CHcis), 4.01 (t, 3J = 6.7 Hz, 4 H, CH2), 2.53 (q,
3J = 6.7 Hz, 4 H, CH2), 1.30 (s, 9 H, CH3).
Harom), 7.53 (d, 3J = 8.9 Hz, 4 Harom), 6.94 (d, 3J = 8.9 Hz, 4 Harom),
3
3
3
5.75 (ddt, Jtrans = 17.1, Jcis = 10.1, J = 6.7 Hz, 2 H, HC=), 4.92
MS (ESI, positive): m/z = 742.3 (C51H51NO4 + H+), 710.2 (MH+,
3
3
(dm, Jtrans = 17.1 Hz, 2 H, =CHtrans), 4.86 (dm, Jcis = 10.1 Hz, 2
C50H47NO3 + H+).
H, =CHcis), 3.94 (t, 3J = 6.7 Hz, 4 H, CH2), 1.97 (q, 3J = 6.7 Hz, 4 H,
3
CH2), 1.74 (quint, J = 6.7 Hz, 4 H, CH2), 1.35–1.20 (m, 24 H,
Anal. Calcd for C50H47NO3·H2O: C, 82.50; H, 6.78; N, 1.92. Found:
C, 82.98; H, 6.58; N, 1.74.
CH2).
13C NMR (75 MHz, CDCl3): d = 192.5 (CHO), 159.3 (C), 142.3
(C), 139.2 (CH), 137.4 (C), 132.1 (C), 130.9 (CH), 128.2 (CH),
126.1 (CH), 115.0 (CH), 114.1 (CH2), 68.2 (CH2), 33.8 (CH2),
29.5–29.1 (CH2), 26.0 (CH2).
Macrocycle 13
Unsymmetric Bisimine 12: At 0 °C, monoimine 11 (80 mg, 0.1128
mmol, 1 equiv), terphenylamine 8a (250 mg, 0.4296 mmol, 3.8
equiv), and Et3N (70 mL, 0.504 mmol) were dissolved in anhyd
CH2Cl2 (30 mL) under N2. A solution of TiCl4 (11 mL, 0.101 mmol,
0.6 equiv) in CH2Cl2 (1 mL) was slowly added and the solution
warmed to r.t. overnight. The mixture was filtered over Celite, the
solvent removed, and the residue dissolved in toluene (40 mL). Af-
ter filtering over Celite, the solvent was removed again and the solid
material was dissolved in toluene (30 mL). This solution was slowly
added to cold pentane (50 mL). The mixture was reduced in volume
to 20 mL and hexane (100 mL) was added. After filtration, the fil-
trate was concentrated to 10 mL. To the residue were added EtOH
(40 mL), Et2O (50 mL), and hexane (40 mL). The precipitate
formed was removed and the filtrate was taken to dryness. The
crude product obtained was directly used in the next step for RCM.
+
MS (EI, 70 eV): m/z (%) = 594.6 (100, M+, C41H54O3 ), 442.3 (10),
290.0 (62).
Anal. Calcd for C41H54O3·0.5 H2O: C, 81.55; H, 9.18. Found: C,
81.74; H, 9.08.
Imine 16
tert-Butylquinquephenylamine 2 (50 mg, 0.084 mmol, 1 equiv), ter-
phenylaldehyde 15 (50 mg, 0.084 mmol, 1 equiv), and Et3N (35 mL,
0.251 mmol, 3 equiv) were dissolved in anhyd CH2Cl2 (10 mL) un-
der N2. At 0 °C, a solution of TiCl4 (5 mL, 0.045 mmol, 0.5 equiv)
in CH2Cl2 (2 mL) was added. The mixture was stirred for 3 d at r.t.
and then filtered over Celite. The solvent was removed under vac-
uum, the residue was dissolved in toluene (50 mL) and filtered again
over Celite. The solvent was removed and the residue was dissolved
in CH2Cl2 (30 mL). The product precipitated upon addition of pen-
MS (ESI, positive): m/z = 1273.5 (MH+, [C90H100N2O4 + H]+).
Synthesis 2008, No. 15, 2451–2461 © Thieme Stuttgart · New York

2460
M. Albrecht, Yeni
PAPER
tane (50 mL). The latter procedure was repeated with the remaining
solution to optimize the yield; yield: 67 mg (68%); mp 179 °C.
MS (ESI, positive): m/z = 1114.7 (100%, M + Li+, [C77H105NO4 +
Li]+).
IR (KBr): 3420 (s), 2937 (vs), 2861 (s), 1715 (vs), 1606 (m), 1501
(m), 1456 (m), 1349 (vs), 1237 (m), 1165 (vs), 1034 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 8.02 (s, 1 H, N=CH), 7.63 (s, 1
Bicycle 19b
Yield: 15 mg (15%, over 3 steps); mp >250 °C.
IR (KBr): 3430 (vs), 3003 (m), 2941 (m), 2872 (w), 1742 (vs), 1623
(m), 1522 (m), 1383 (w), 1354 (m), 1261 (m), 1164 (m), 1104 (w),
1055 (w), 1028 cm–1 (m).
H
arom), 7.49–7.46 (m, 12 Harom), 7.43 (d, 3J = 8.5 Hz, 4 Harom), 7.38
3
3
(d, J = 8.8 Hz, 4 Harom), 6.88 (d, J = 8.8 Hz, 4 Harom), 6.79 (d,
3J = 8.5 Hz, 4 Harom), 5.85 (ddt, Jtrans = 17.0, Jcis = 10.2, J = 6.7
3
3
3
3
3
3
Hz, 2 H, HC=), 5.73 (ddt, Jtrans = 17.0, Jcis = 10.2, J = 6.7 Hz, 2
1H NMR (300 MHz, CDCl3): d = 7.44–7.30 (m, 9 Harom), 7.10 (s, 2
3
H, HC=), 5.11 (dm, Jtrans = 17.0 Hz, 2 H, =CHtrans), 5.04 (dm,
H
arom), 6.93–6.83 (m, 10 Harom), 3.94 (t, 3J = 6.4 Hz, 4 H, CH2), 3.86
3Jcis = 10.2 Hz, 2 H, =CHcis), 4.92 (dm, Jtrans = 17.0 Hz, 2
(t, 3J = 6.4 Hz, 4 H, CH2), 3.76 (br s, 2 H, NH2), 3.63 (s, 2 H, CH2),
3
H, =CHtrans), 4.86 (dm, 3Jcis = 10.2 Hz, 2 H, =CHcis), 3.98 (t, 3J = 6.7
Hz, 4 H, CH2), 3.88 (t, 3J = 6.7 Hz, 4 H, CH2), 2.50 (q, 3J = 6.7 Hz,
4 H, CH2), 1.97 (q, 3J = 6.7 Hz, 4 H, CH2), 1.72 (quint, 3J = 6.7 Hz,
4 H, CH2), 1.30–1.20 (m, 24 H, CH2).
1.80–1.65 (m, 8 H, CH2), 1.45–1.16 (m, 73 H, CH2 + CH3).
MS (ESI, positive): m/z = 1164.4 (100%, MH+, [C81H113NO4
+
H]+).
Anal. Calcd for C81H113NO4·H2O: C, 82.25; H, 9.80; N, 1.18.
Found: C, 82.24; H, 9.21; N, 1.22.
MS (ESI, positiv): m/z = 1170.9 (100%, MH+, C83H95NO4 + H+).
Bicycle 17
To a refluxing solution of the imine 16 (12 mg, 0.01025 mmol, 1
equiv) in anhyd CH2Cl2 (20 mL) was added Grubbs II catalyst (0.1–
0.5 mg, 1–5 mol%) in anhyd CH2Cl2 (1 mL). After being heated at
reflux for 2 d under N2, the mixture was allowed to cool to r.t. and
filtered over Celite. The solvent was removed, the residue was dis-
solved in CH2Cl2 (30 mL) and PtO2 (3 mg) was added. After stirring
for 3 d under 40 bar of H2 atmosphere, the mixture was filtered over
Celite, the solvent was removed and the residue was purified by col-
umn chromatography (silica gel, CH2Cl2); yield: 10 mg (87%, over
2 steps); mp >250 °C.
Acknowledgment
Support by the Deutsche Forschungsgemeinschaft and the Fonds
der Chemischen Industrie is gratefully acknowledged.
References
(1) Pedersen, C. Angew. Chem., Int. Ed. Engl. 1988, 27, 1021;
Angew. Chem. 1988, 100, 1053.
(2) Chung, S. K.; Hamilton, A. D. J. Am. Chem. Soc. 1988, 110,
1318.
IR (KBr): 3434 (vs), 2926 (s), 2853 (m), 1616 (s), 1507 (m), 1455
(m), 1391 (w), 1250 (s), 1176 (m), 1116 cm–1 (m).
(3) (a) Park, C. H.; Simmons, H. E. J. Am. Chem. Soc. 1968, 90,
2431. (b) Graf, E.; Lehn, J.-M. J. Am. Chem. Soc. 1975, 97,
5022.
(4) (a) Royer, G. P. Adv. Catal. 1980, 29, 197. (b) Lippard, S.
J.; Berg, J. M. Principles of Bioinorganic Chemistry;
University Science Books: Mill Valley, 1994. (c) Albrecht,
M. Naturwissenschaften 2007, 94, 951.
(5) Amabilino, D. B.; Stoddart, J. F. Chem. Rev. 1995, 95, 2725.
(6) (a) Hosseini, M. W.; Lehn, J.-M.; Maggiora, L.; Mertes, K.
B.; Mertes, M. P. J. Am. Chem. Soc. 1987, 109, 537.
(b) Karakhanov, E. A.; Maksimov, A. L.; Runova, E. A.
Russ. Chem. Rev. 2005, 74, 97. (c) Zhang, X. X.; Bradshaw,
J. S.; Izatt, R. M. Chem. Rev. 1997, 97, 3313.
(7) Tahara, K.; Johnson, C. A.; Fujita, T.; Sonoda, M.;
De Schryver, F. C.; De Feyter, S.; Haley, M. M.; Tobe, Y.
Langmuir 2007, 23, 10190.
(8) (a) Macrocyclic Chemistry – Current Trends and Future
Perspectives; Gloe, K., Ed.; Springer: Berlin, 2005.
(b) Parker, D. Macrocycle Synthesis: A Practical Approach;
Oxford University Press: Oxford, 1996. (c) Dietrich, B.;
Viout, P.; Lehn, J.-M. Macrocyclic Chemistry; VCH:
Weinheim, 1993. (d) Hisaki, I.; Eda, T.; Sonoda, M.; Niino,
H.; Sato, T.; Wakabayashi, T.; Tobe, Y. J. Org. Chem. 2005,
70, 1853.
(9) (a) 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. (b) Höger, S.
J. Polym. Sci. A 1999, 37, 2685. (c) Becker, K.;
Lagoudakis, P. G.; Gaefke, G.; Höger, S.; Lupton, J. M.
Angew. Chem. Int. Ed. 2007, 46, 3450; Angew. Chem. 2007,
119, 3520. (d) Laughrey, Z. R.; Gibb, B. C. Top. Curr.
Chem. 2005, 249, 67. (e) Hoss, R.; Vögtle, F. Angew.
Chem., Int. Ed. Engl. 1994, 33, 375; Angew. Chem. 1994,
106, 389.
1H NMR (400 MHz, CDCl3): d = 7.65 (s, 8 Harom), 7.52 (d, 3J = 8.8
Hz, 4 Harom), 7.42 (s, 1 Harom), 7.29 (d, 3J = 8.5 Hz, 4 Harom), 7.27 (s,
3
2 Harom), 6.96 (d, J = 8.8 Hz, 4 Harom), 6.88 (s, 2 Harom), 6.73 (d,
3J = 8.5 Hz, 4 Harom), 3.98 (t, 3J = 6.3 Hz, 4 H, CH2), 3.87 (t, 3J = 6.3
Hz, 4 H, CH2), 3.67 (s, 2 H, CH2), 1.80–1.65 (m, 8 H, CH2), 1.32 (s,
9 H, t-C4H9), 1.31–1.20 (m, 36 H, CH2).
MS (ESI, positive): m/z = 1122.9 (100%, C79H95NO4 + H+).
Anal. Calcd for C79H93NO4·4 H2O: C, 79.56; H, 8.54; N, 1.17.
Found: C, 79.44; H, 8.57; N, 0.90.
Macrobicycles 19a and 19b
Terphenylamine 8a or 8b (0.0842 mmol, 1 equiv), terphenyl alde-
hyde 15 (50 mg, 0.0841 mmol, 1 equiv), and one drop of HCl were
heated at reflux overnight in anhyd EtOH (30 mL). The volume of
the solvent was reduced and the precipitate formed was heated at re-
flux in anhyd CH2Cl2 (25 mL) under N2. Grubbs II catalyst (0.1–0.5
mg) in anhyd CH2Cl2 (2 mL) was added and the mixture was heated
at reflux for 4 d. The mixture was filtered over Celite and the solvent
removed. The residue was dissolved in CH2Cl2 (30 mL) and PtO2 (3
mg) was added. The mixture was stirred under H2 atmosphere (40
bar) for 1 d and then filtered over Celite. After removal of the sol-
vent, the crude product was purified by chromatography (silica gel,
CH2Cl2–hexane, 2:1).
Bicycle 19a
Yield: 8 mg (9%, over three steps); mp >250 °C.
IR (KBr): 3420 (vs), 3089 (m), 3052 (m), 2936 (s), 2870 (m), 1633
(s), 1459 (m), 1384 (m), 1250 (m), 1112 (m), 1076 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.43–7.32 (m, 9 Harom), 7.07 (d,
3J = 7.7 Hz, 2 Harom), 6.95–6.84 (m, 11 Harom), 3.94 (t, 3J = 6.4 Hz,
4 H, CH2), 3.86 (t, 3J = 6.4 Hz, 4 H, CH2), 3.64 (s, 2 H, CH2), 1.80–
1.67 (m, 8 H, CH2), 1.45–1.16 (m, 64 H, CH2).
(10) Camacho, D. H.; Salo, E. V.; Guan, Z. Org. Lett. 2004, 6,
865.
Synthesis 2008, No. 15, 2451–2461 © Thieme Stuttgart · New York

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Template-Directed Synthesis of Macrocycles
2461
(11) For a recent example of macrocycle directed macro-
cyclization, see: Song, K. H.; Kang, S. O.; Ko, J. Chem.
Eur. J. 2007, 13, 5129.
(14) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh,
M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314.
(15) Miura, Y.; Oka, H.; Momoki, M. Synthesis 1995, 1419.
(16) Lautens, M.; Tayama, E.; Herse, C. J. Am. Chem. Soc. 2005,
127, 72.
(17) (a) Lehn, J.-M. Pure Appl. Chem. 1979, 51, 979.
(b) Breslow, R. Science 1982, 218, 532.
(12) Albrecht, M.; Yeni, ; Fröhlich, R. Synlett 2007, 2295.
(13) For selected examples on macrocyclization by ring-closing
metathesis, see: (a) Grubbs, R. H. Angew. Chem. Int. Ed.
2006, 45, 3760; Angew. Chem. 2006, 118, 3845. (b) Bajwa,
N.; Jennings, M. P. Tetrahedron Lett. 2008, 49, 390.
(c) Conrad, J. C.; Fogg, D. E. Curr. Org. Chem. 2006, 10,
185. (d) Gradillas, A.; Perez-Castells, J. Angew. Chem. Int.
Ed. 2006, 45, 6086; Angew. Chem. 2006, 118, 6232.
(e) Gaich, T.; Mulzer, J. Curr. Top. Med. Chem. 2005, 5,
1473.
Synthesis 2008, No. 15, 2451–2461 © Thieme Stuttgart · New York