Bimacrocyclic Pyridines and 1,8-Naphthyridines: Basicities and Application in Base Catalysis 1

Article abstract of DOI:10.1055/s-0034-1378384

Di-α-substituted N-heterocycles such as 2,6-halogenopyridines or 2,7-dichloro-1,8-naphthyridines can be coupled with 2,6-bis(alkenyloxy) substituted areneboronic acids. The resulting tetraenes are then cyclized by ring-closing metathesis to give bimacrocyclic concave pyridines or concave 1,8-naphthyridines. The relative basicity of the concave N-heterocycles was measured and their activity and selectivity was tested in the base-catalyzed addition of alcohols to diphenylketene.

Full text of DOI:10.1055/s-0034-1378384

PAPER
▌2799
paper
Bimacrocyclic Pyridines and 1,8-Naphthyridines: Basicities and Application in
Base Catalysis1
Bimacrocyclic Pyridines and 1,8-Naphthyridines
Timo Liebig, Ulrich Lüning*
Otto-Diels-Institut für Organische Chemie, Christian-Albrechts-Universität zu Kiel, Olshausenstraße 40, 24098 Kiel, Germany
Fax +49(431)8801558; E-mail: luening@oc.uni-kiel.de
Received: 27.05.2014; Accepted after revision: 12.06.2014
tions in one or the other lead to more unselective reac-
Abstract: Di-α-substituted N-heterocycles such as 2,6-halogeno-
tions,14,15 which is often observed with enzymes.
pyridines or 2,7-dichloro-1,8-naphthyridines can be coupled with
2,6-bis(alkenyloxy) substituted areneboronic acids. The resulting
tetraenes are then cyclized by ring-closing metathesis to give bi-
macrocyclic concave pyridines or concave 1,8-naphthyridines. The
relative basicity of the concave N-heterocycles was measured and
their activity and selectivity was tested in the base-catalyzed addi-
tion of alcohols to diphenylketene.
To enlarge the pool of concave bases, we have extended
the family of concave pyridines7,16,17 and have also syn-
thesized and analyzed respective concave 1,8-naphthyri-
dines.
Concave pyridines have been prepared by using a number
of different synthetic routes,7,16,17 and the same applies to
related compounds such as concave 1,10-phenanthro-
lines.9,18 The most efficient route involves the initial
preparation of a diarylheterocycle that carries four alkenyl
groups as substituents. Bimacrocyclization of the tetraene
is then performed by ring-closing metathesis (Scheme 1).
Key words: macrocycles, boronic acids, molecular recognition, ba-
sicity, base catalysis
Molecular recognition is the basis of many processes in
chemistry and in biology, from transport to catalysis.2,3
The high selectivity of enzymatic processes arises in a
large part from the concave shielding of the active site.4–6
Concave reagents7,8 copy this geometry but are not
restricted to the twenty or so naturally occurring amino ac-
ids. Based on artificial substructures, concave bases,7,9–11
concave acids,12 and even concave N-heterocyclic carben-
es13 have been prepared. Their overall shape resembles
that of a light bulb in a lamp shade,7 with the light bulb be-
ing the active center and the lamp shade being the concave
shielding (see Figure 1).
HaI
HaI
O
O
O
O
+
O
O
OH
OH
B
O
O
O
O
Scheme 1 General synthetic strategy to bimacrocyclic concave re-
agents employing cross-coupling and ring-closing metathesis, option-
ally followed by hydrogenation; the sphere represents a dihalogeno-
N-heterocycle in this work
The required building blocks are di-α-substituted hetero-
cycles (Figure 2) and 2,6-dialkenyloxy substituted arylbo-
ronic acids (Scheme 1). For solubility and other reasons,
in addition to di-α-substituted pyridines and 1,8-naph-
thyridines, heterocycles that were further substituted were
also used. 2,6-Dibromopyridine (1) is commercially
available, whereas 2,6-diiodo-3-methoxypyridine (2)19
and the boronic acids20 8 were prepared as described.
Mangini and Colonna21 developed a route to 4-substituted
naphthyridines in 1942. Accordingly, 2,6-diaminopyri-
dine (4) and ethyl benzoylacetate (5) were condensed in
concentrated sulfuric acid to give 7-amino-2-hydroxy-4-
phenyl-1,8-naphthyridine (6) as the hydrogensulfate in
75% yield (Scheme 2). Next, the amino group was substi-
tuted by a hydroxy group through diazotization and sub-
Figure 1 The ‘light bulb in a lamp shade’ model for concave re-
agents (see text)
In several applications, the necessity to tailor the active
site of concave reagents has become apparent. As prog-
nosticated by the blunt saying ‘one enzyme – one sub-
strate’ (or vice versa), good selectivities have only been
found when substrates and catalysts match. Slight varia-
SYNTHESIS 2014, 46, 2799–2807
Advanced online publication: 18.07.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0034-1378384; Art ID: ss-2014-t0754-op
© Georg Thieme Verlag Stuttgart · New York

2800
T. Liebig, U. Lüning
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Ph
N
Using Grubbs’ catalyst, tetraalkenes 9 and 10 were cy-
clized to form doubly unsaturated bimacrocycles 11 and
12 (Scheme 4). As found for related systems, the ring-
closing metatheses proceeded in good yields of up to 92%.
Products 11 and 12 were obtained as mixtures of E,E-,
E,Z-, and Z,Z-diastereoisomers.
OMe
Br
N
Br
I
N
I
Cl
N
Cl
1
2
3
Figure 2 Di-α-substituted N-heterocycles 1–3 as coupling partners
for Suzuki–Miyaura reactions (see Scheme 1)
X
R
R
n
nO
O
O
O
sequent decomposition in water. Finally, two chlorine
atoms were introduced by reaction of 7 with phosphorous
pentachloride in phosphoryl chloride. The formally hy-
droxy-substituted naphthyridines 6 and 7 are able to form
tautomers, therefore, intermediate 7 was not isolated and
the yield of dichloride 3 was determined to be 38% over
two steps. Although the yield was modest, the reaction
can be carried out on a multigram scale.
a
N
N
X
O
O
O
O
n
n
11, 12
13, 14
9, 10
b
a n = 3 9, 11, 13 R = H
b n = 4 10, 12, 14 R = OMe
11, 12 X = (CH2)nCH=CH(CH2)n
13, 14 X = (CH2)n+2
Ph
Ph
Scheme 4 (a) Ring-closing metatheses of tetraalkenyloxy-pyridines
9 and 10: Reagents and conditions: (a) Grubbs’ 1st generation cata-
lyst, CH2Cl2, 16–48 h, r.t.; (b) Hydrogenation of E,E-, E,Z-, and Z,Z-
mixtures of bimacrocyclic concave pyridines 11 and 12 to give con-
cave pyridines 13 and 14 with saturated chains.
O
a
+
H2N
N
NH2
H2N
N
N
OH
O
OEt
4
5
6
Ph
Ph
N
To transform the diastereoisomeric mixtures into a single
compound, the double bonds of the bimacrocycles 11 and
12 were hydrogenated, and bimacrocycles 13 and 14 with
saturated chains were obtained in yields of 88 to 97%.
b
c
HO
N
N
OH
Cl
N
Cl
7
3
Scheme 2 Synthesis of 4-phenyl substituted dichloro-1,8-naphthyri-
dine 3. Reagents and conditions: (a) H2SO4, <40 °C, 16 h; (b) H2SO4,
NaNO2, 0 °C, 15 min; H2O, 0–20 °C; (c) PCl5, POCl3, 0 °C; then re-
flux, 2.5 h.21
An analogous route was chosen for the synthesis of con-
cave bimacrocyclic 1,8-naphthyridines. Suzuki–Miyaura
cross-coupling reactions have been reported for unsubsti-
tuted dichloronaphthyridine.22 Not surprisingly, the cross
coupling between boronic acids 8 and 2,7-dichloro-4-phe-
nyl-1,8-naphthyridine (3) also went well. Tetrapentenyl
(15a) and tetrahexenyl (15b) derivatives could be isolated
in yields of 68 and 44%, respectively (Scheme 5). These
yields correspond to yields of up 67 to 83% per coupling.
En route to the desired bimacrocyclic concave heterocy-
cles, the next task was to introduce the bridgeheads. As
described for a related system,17 the Suzuki–Miyaura re-
action was used to couple 2,6-dihalogenopyridines 1 and
2 with boronic acids 8a and 8b. The twofold coupling
went well and tetraalkenes 9a,b and 10a,b were obtained
in yields between 63 and 76% (Scheme 3).
Ph
B(OH)2
O
O
a
n
n
+
Cl
N
N
Cl
R
3
8
Hal
N
1, 2
+
Hal
R
n
n O
O
X
Ph
Ph
a
n
n O
O
O
O
O
O
B(OH)2
b
N
N
O
O
N
N
n
n
n
n
a n = 3
b n = 4
O
O
O
O
9, 10
n
n
1, 9 R = H
2, 10 R = OMe
a n = 3
8
X
16 X = (CH2)nCH=CH(CH2)n
b n = 4
15
Scheme 3 Suzuki–Miyaura cross coupling of 2,6-dihalogenopyri-
dines 1 and 2 with dialkenyloxyboronic acids 8a,b. Reagents and con-
ditions: (a) Pd(PPh3)4, DME, H2O, Ba(OH)2, reflux, 16–48 h.
Scheme 5 Synthesis of concave 1,8-naphthyridines 16 by Suzuki–
Miyaura cross-coupling between dichloronaphthyridine 3 and boron-
ic acids 8, followed by ring-closing metatheses of the resulting tet-
raenes 15. Reagents and conditions: (a) [Pd(PPh3)4], DME, H2O,
Ba(OH)2, reflux, 16–48 h; (b) Grubbs’ 1st generation catalyst,
CH2Cl2, r.t., 16–48 h.
Synthesis 2014, 46, 2799–2807
© Georg Thieme Verlag Stuttgart · New York

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Bimacrocyclic Pyridines and 1,8-Naphthyridines
2801
Tetraalkenes 15 were then subjected to ring-closing me-
tathesis using Grubbs’ 1st generation catalyst. In contrast
to some other dimacrocyclizations in which monomacro-
cycles were also obtained,23 the twofold metatheses pro-
ceeded smoothly with 15a and 15b, and the resulting
bimacrocyclic dienes 16 were isolated in 87 and 83%, re-
spectively.
Table 1 The log K Values for Concave Naphthyridines 16a and 16b,
Concave 11–14, and Other Pyridinesa
Base
log K
2,6-dimethylpyridine
1.3
2.1
3.2
3.1
3.5
3.3
3.5
3.3
0.9
1.4
2,4,6-trimethylpyridine
One application of concave N-heterocycles is in base ca- 11a (n = 3)
talysis. In a bimacrocyclic system, the concave shielding
has a distinct influence on the performance of the base. In
general, the nature of the basic center determines the ap-
proximate basicity, but the shielding can generate distinct
differences.24,25 When the base reacts as a Brønsted base,
it has to pick up a proton. In this process, the shielding will
have a small but not negligible influence. The main differ-
ence compared with a nonshielded parent system origi-
nate from differences in solvation.26–28
11b (n = 4)
12a (n = 3)
12b (n = 4)
13b (n = 4)
14b (n = 4)
16a (n = 3)
16b (n = 4)
In contrast, in reactions in which the base reacts as a nu-
cleophile or a Lewis base, the shielding has an enormous
influence on the performance of the base. In experiments
with concave pyridines, for instance, the different shield-
ings were responsible for the selectivities of base-cata-
lyzed reactions such as alcohol additions to ketenes.24,25
a The log K values are referenced to the first deprotonation of thymol
blue in ethanol. Larger log K values correspond to stronger bases.
parent compounds [pKa (pyridine): 5.25; pKa (1,8-naph-
thyridine): 3.36].33
The basicity constant Kb describes the basicity of a Brøn-
sted base quantitatively. To be able to compare all acids Finally, some of the pyridines were tested as catalysts in
and bases, it is more convenient to discuss the acidity of the base-catalyzed addition of alcohols to ketenes.24 1,2-
the conjugate acids of the bases in the form of their pKa Propanediol (18) was chosen as substrate and the regiose-
values. By definition, pKa values are based on water as lectivity of the mono-acylation by diphenylketene (17)
solvent with pKa + pKb = 14 at 25 °C.29 However, not all was measured (Scheme 6). The addition of different alco-
organic acids and bases are completely soluble in water. hols to ketenes has been studied with a variety of shielded
Therefore, related acidity constants have also been deter- pyridines. The catalysis occurs by hydrogen-bond forma-
mined in several organic solvents.30 In any case, each tion between the pyridine nitrogen atom and the OH
acidity constant reflects a relative acidity. In water, the groups thus enhancing the nucleophilicity of the alcohol.24
reference point is the acidity of water (pKa 15.5).
To study the influence of the bimacrocyclic structure of a
concave pyridine on the selectivity, the smallest bimacro-
cycle 11a34 and a respective non-bimacrocyclic pyridine
20 (which can be considered a bimacrocycle with infinite-
ly long chains) were first compared (Table 2).
To investigate the Brønsted basicity of the new bimacro-
cyclic bases in ethanol, they were titrated with an ac-
id/base indicator (thymol blue31) and the equilibrium
constants were determined as described.32 The resulting
log K values can be discussed as the basicities of the
bases, or as the acidities of the corresponding acids, with
the first deprotonation of thymol blue being the reference
point. Table 1 compiles these relative basicities log K for
concave naphthyridines 16a and 16b, for concave pyri-
dines 11–14 and other pyridines.
Ph
Ph
Ph
O
O
OH
Ph
O
17
19a
base
+
+
Ph
Ph
HO
O
2,6-Lutidine (2,6-dimethylpyridine) and 2,4,6-collidine
(2,4,6-trimethylpyridine) were included for comparison.
These compounds are both 2,6-disubstituted, and the dif-
ference in basicity arises from the +I effect of the addi-
tional methyl substituent in the 4-position of collidine.
HO
OH
O
18
19b
Scheme 6 Regioselective acylation of 1,2-propanediol (18) with di-
phenylketene (17) catalyzed by bases.
All concave pyridines 11–14 proved to be much more ba-
sic than the methylated pyridine analogues. One may
speculate whether the oxygen atoms of the bridgeheads
may stabilize the protonated form by hydrogen bonds.
When compared with the concave 1,8-naphthyridines 16,
the pyridines are approximately two orders of magnitude
more basic. This reflects the difference in basicity of the
Even without any catalyst, the primary alcohol function is
acylated fastest but only slightly less than three times as
fast as the secondary function. The strongly shielded and
less basic 2,6-di-tert-butylpyridine showed the same se-
lectivity. Presumably, only the background reaction is de-
tected in this case. The other pyridines, however, speed up
the reaction and lead to the preferred formation of 1-(di-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2799–2807

2802
T. Liebig, U. Lüning
PAPER
ed with an Applied Biosystems Mariner Spectrometry Workstation.
IR spectra were recorded with a Perkin–Elmer 1600 Series spec-
trometer. Elemental analyses were carried out with a Euro EA 3000
Elemental Analyzer from Euro Vector.
Table 2 Regioselectivities of the Monoacylation of 1,2-Propanediol
with Diphenylketene (17) Catalyzed by Concave and Nonconcave
Pyridines
Base
19a/19ba
Miyaura-Suzuki Cross-Coupling; General Procedure A
In DME and H2O (ca. 4:1), dihalogeno-N-heterocycle 1, 2, or 3 was
mixed with boronic acid 8 (2.5 equiv), barium hydroxide (1.5 equiv,
based on the amount of boronic acid 8), and Pd(PPh3)4 (5–10 mol%,
based on the amount of N-heterocycle 1, 2 or 3). The mixture was
heated to reflux for 16–48 h, then H2O (20–30 mL) and CHCl3 (20–
30 mL) were added and the layers were separated. The aqueous lay-
er was extracted with CHCl3 (3 × 20–30 mL) and brine (20 mL). Af-
ter drying with MgSO4, the solvent was evaporated in vacuo and the
product was purified by chromatography.
–
2.8b
6.5b
9.6b
6.9b
2.7
pyridine
2-methylpyridine
2,6-dimethylpyridine
2,6-di-tert-butylpyridine
20
10.3
10.0
Ring-Closing Metathesis; General Procedure B
Excluding oxygen, the tetraalkene precursor was dissolved in anhy-
drous CH2Cl2 (c = 0.01 mmol/l). After addition of benzyli-
denebis(tricyclohexylphosphine)-dichlororuthenium (Grubbs’ 1st
generation cat.; 5–10 mol-%), the mixture was stirred at r.t. for 16–
48 h. Diisopropylamine (5–10 mL) was then added and stirring was
continued for 45 min. The mixture was filtered through basic alumi-
num oxide using a mixture of CH2Cl2 and diisopropylamine as elu-
ent. No fractions were taken so that all E/Z isomers could be
collected. The crude product mixture was purified by chromatogra-
phy.
11a (n = 3)
a The selectivities are reported as the ratio of 1- to 2-acylated products.
b Selectivities comparable to reported values.25a
phenylacetoxy)-2-propanol (19a). By comparison to 2,6-
dimethylpyridine, introduction of aryl rings in the α-posi-
tion in the pyridine enhances the selectivity (11a and 20).
In this base-catalyzed reaction, however, it does not make
a difference whether a bimacrocyclic structure is used as
in 11a or the ‘open’ tetramethoxy analogue 20 is em-
ployed (Figure 3).
Hydrogenation; General Procedure C
The product of the ring-closing metathesis was dissolved in MeOH.
In case of low solubility, some CHCl3 was added. As catalyst, for
every 100 mmol of substrate, 10.0 mg of palladium on charcoal
(10%) was used. The catalyst was mixed with MeOH (5.0 mL) and
hydrogen was bubbled through the resulting suspension for 30 min
to activate the catalyst. The solution of the substrate was then added
and the resulting mixture was stirred under hydrogen at r.t. for 16–
24 h. The solvents were evaporated and the crude product was puri-
fied by chromatography.
MeO
OMe
N
O
O
Me
Me
20
2,7-Dichloro-4-phenyl-1,8-naphthyridine (3)
Figure 3 2,6-Diarylpyridine 2035 as an ‘open’ comparison to con-
cave pyridines
While cooling with ice, crude 2,7-dihydroxy-4-phenyl-1,8-naph-
thyridine (7; 13.8 g, max. 57.9 mmol) and phosphorous pentachlo-
ride (10.5 g, 50.4 mmol) were added to phosphoryl chloride (50.0
mL, 536 mmol). The mixture was heated to reflux for 2.5 h. After
cooling to r.t., the mixture was poured on ice. A beige solid precip-
itated, which was purified by chromatography (silica gel, CH2Cl2).
In conclusion, starting from di-α-halogeno-N-heterocy-
cles (pyridines 1 or 2, or 1,8-naphthyridine 3) and 2,6-di-
alkenyloxyboronic acids 8, concave N-heterocycles 11–
14 and 16 can easily be synthesized by a reaction se-
quence involving Suzuki–Miyaura cross-coupling and
ring-closing metathesis. The basicity of the nitrogen at-
oms in the concave structures is conserved and they may
be used as catalysts in base catalysis.
Yield: 6.13 g (38%); mp 157–159 °C (Lit.21 158 °C).
IR (KBr): 2928, 1654, 1116 cm–1.
1H NMR (200 MHz, CDCl3): δ = 8.21 (d, J = 8.7 Hz, 1 H, H-5), 7.47
(s, 1 H, H-3), 7.45 (d, J = 8.7 Hz, 1 H, H-6), 7.62–7.40 (m, 5 H, Ph-
H).
MS (EI, 70 eV): m/z (%) = 276, 274 (60, 100) [M]+, 241, 239 (51,
54) [M – Cl]+, 203 (60) [M – 2Cl]+.
MS (CI, isobutane): m/z (%) = 277, 275 (69, 100) [M]+.
Commercially available chemicals were used without further puri-
fication. 2,6-Bis(pent-4-enyloxy)phenylboronic acid (8a),20 2,6-
bis(hex-5-enyloxy)phenylboronic acid (8b),20 2,7-dichloro-4-phe-
nyl-1,8-naphthyridine (3),21 and 2,6-diiodo-3-methoxypyridine
(2)19 were prepared according to literature procedures. Anhydrous
solvents were obtained with suitable desiccants. Column chroma-
tography was carried out on silica gel (0.04–0.063 mm, Macherey–
2-Hydroxy-4-phenyl-1,8-naphthyridin-7-yl-ammonium Hydro-
gensulfate (6·H2SO4)
2,6-Diaminopyridine (4; 10.9 g, 83.5 mmol) was added to ethyl
benzoylacetate (5; 24.7 g, 123 mmol) and the mixture was warmed
to 120 °C to give a homogeneous mixture. After cooling to –10 °C,
concd H2SO4 (25 mL) was added dropwise to the solid mass in such
a way that the temperature remained below 40 °C. The mixture was
stirred for 16 h at 35–40 °C and then poured on ice (100 g). The
mixture was made basic with concd ammonia (ca. 50 mL) and
stirred at r.t. for 1 h. The resulting solid was filtered off and washed
with hot EtOH to give the product.
1
Nagel). H and 13C NMR spectra were recorded with Bruker AC
200, ARX 300, DRX 500, or AV 600 instruments. Assignments
were supported by COSY, HSQC, and HMBC experiments. Even
when obtained by DEPT, the type of 13C signal is always listed as
singlet, doublet, etc. All chemical shifts are referenced to TMS or to
the residual proton or carbon signal of the solvent. If not stated oth-
erwise, coupling constants are 3J. Mass spectra were recorded with
a Finnigan MAT 8200 or MAT 8230. ESI mass spectra were record-
Yield: 16.9 g (max. 85%); green solid.
IR (KBr): 3325, 3135, 1619, 1369 cm–1.
Synthesis 2014, 46, 2799–2807
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Bimacrocyclic Pyridines and 1,8-Naphthyridines
2803
2,7-Dihydroxy-4-phenyl-1,8-naphthyridine (7)
mg, 78 μmol) in DME (50 mL) and H2O (6 mL). Purification by
chromatography on silica gel (cyclohexane–EtOAc, 6:1) gave 10a
as almost colorless flakes.
Compound 6·H2SO4 (16.9 g, 71.4 mmol) was added to concd
H2SO4 (140 mL). While cooling with ice, sodium nitrite (8.05 g,
116 mmol) was added and the solution was stirred for 15 min at 0 °C
and at r.t. for 10 min. Carefully, the mixture was poured on ice (300
mL) and the mixture was stirred for 10 min. To neutralize, (a large
amount of) sodium carbonate solution was added. The resulting sol-
id was separated, washed with deionized water, and dried in vacuo.
The crude product was poorly soluble and was therefore used with-
out further purification.
Yield: 310 mg (68%).
IR (KBr): = 2931, 2865, 1641, 1596, 1452, 1252, 1100 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.25 (d, J = 7.9 Hz, 1 H, H-4), 7.21
(d, J = 7.9 Hz, 1 H, H-5), 7.19 (t, J = 8.3 Hz, 1 H, H-4′), 7.17 (t, J =
8.3 Hz, 1 H, H-4′′), 6.56 (d, J = 8.3 Hz, 2 H, H-3′, H-5′), 6.55 (d, J =
8.3 Hz, 2 H, H-3′′, H-5′′), 5.72 (tdd, J = 6.7, 10.3, 17.0 Hz, 2 H,
CH′=CH2), 5.69 (tdd, J = 6.7, 10.3, 17.0 Hz, 2 H, CH′′=CH2), 4.96–
4.85 (m, 8 H, CH=CH2), ca. 3.88 (t, J = 6.5 Hz, 4 H, OCH2′), ca.
3.86 (t, J = 6.5 Hz, 4 H, OCH2′′), 3.76 (s, 3 H, OCH3), 2.04–1.94 (m,
8 H, CH2CH=), 1.69–1.59 (m, 8 H, OCH2CH2).
Crude yield: 13.8 g (ca. 81%).
IR (KBr): 3426, 1654, 1116 cm–1.
MS (ESI+, DMSO): m/z (%) = 239 (27) [M + H]+.
13C NMR (125 MHz, CDCl3): δ = 158.1 (s, C-2′′, C-6′′), 157.7 (s,
C-2′, C-6′), 152.7 (s, C-3), 145.6 (s, C-2), 144.4 (s, C-6), 138.1 (d,
CH=CH2), 129.1 (t, C-4′), 128.7 (d, C-4′′), 124.8 (d, C-5), 120.9 (s,
C-1′′), 117.8 (s, C-1′), 116.8 (d, C-4), 114.8 (t, CH=CH2′), 114.7 (t,
CH=CH2′′), 105.9 (d, C-3′′, C-5′′), 105.6 (d, C-3′, C-5′), 68.1 (t,
OCH2′′), 67.7 (t, OCH2′), 55.5 (q, OCH3), 29.9 (t, OCH2′CH2′CH2′),
29.8 (t, OCH2′′CH2′′CH2′′), 28.4 (t, OCH2′′CH2′′), 28.3 (t,
OCH2′CH2′).
2,6-Bis[2,6-bis(pent-4-enyloxy)phenyl]pyridine (9a)
Synthesized according to General Procedure A with 2,6-dibro-
mopyridine (1; 360 mg, 1.52 mmol), 2,6-bis(pent-4-enyl-
oxy)phenylboronic acid (8a; 1.11 g, 3.79 mmol) and Pd(PPh3)4 (178
mg, 150 μmol) in DME (95 mL) and H2O (15 mL). Purification by
chromatography on silica gel (cyclohexane–EtOAc, 6:1) gave 9a as
almost colorless flakes.
Yield: 540 mg (63%).
IR (KBr): 2940, 2866, 1641, 1598, 1456, 1246, 1101 cm–1.
MS (CI, isobutane): m/z (%) = 598 (100) [M + H]+.
Anal. Calcd for C38H47NO5: C, 76.34; H, 7.93; N, 2.34. Found: C,
76.36; H, 8.12; N, 2.33.
1H NMR (500 MHz, CDCl3): δ = 7.72 (t, J = 7.7 Hz, 1 H, H-4), 7.21
(t, J = 8.3 Hz, 2 H, H-4′, H-4′′), 7.20 (d, J = 7.7 Hz, 2 H, H-3, H-5),
6.55 (d, J = 8.4 Hz, 4 H, H-3′, H-3′′, H-5′, H-5′′), 5.72 (tdd, J = 6.7,
10.2, 17.2 Hz, 4 H, CH=CH2), 4.98–4.87 (m, 8 H, CH=CH2), 3.98
(t, J = 6.5 Hz, 8 H, OCH2), 2.01–1.91 (m, 8 H, CH2CH=CH2), 1.69–
1.59 (m, 8 H, OCH2CH2).
13C NMR (125 MHz, CDCl3): δ = 157.7 (s, C-2′, C-2′′, C-6′, C-6′′),
154.1 (s, C-2, C-6), 138.1 (d, CH=CH2), 134.7 (d, C-4), 128.9 (d, C-
4′, C-4′′), 123.7 (d, C-3, C-5), 121.1 (s, C-1′, C-1′′), 114.1 (t,
CH=CH2), 105.6 (d, C-3′, C-3′′, C-5′, C-5′′), 67.8 (t, OCH2), 29.9 (t,
OCH2CH2CH2), 28.3 (t, OCH2CH2).
2,6-Bis[2,6-bis(hex-5-enyloxy)phenyl]-3-methoxypyridine (10b)
Synthesized according to General Procedure A with 2,6-diiodo-3-
methoxypyridine (2; 180 mg, 500 μmol), 2,6-bis(hex-5-enyl-
oxy)phenylboronic acid (8b; 400 mg, 1.25 mmol) and Pd(PPh3)4
(58 mg, 50 μmol) in DME (30 mL) and H2O (4 mL). Purification by
chromatography on silica gel (cyclohexane–EtOAc, 7:1) gave 10b
as an almost colorless powder.
Yield: 250 mg (76%).
IR (KBr): 2932, 2865, 1642, 1595, 1456, 1250, 1100 cm–1.
MS (CI, isobutane): m/z (%) = 568 (100) [M + H]+.
1H NMR (300 MHz, CDCl3): δ = 7.22 (d, J = 8.0 Hz, 1 H, H-4), 7.19
(d, J = 8.0 Hz, 1 H, H-3, H-5), 7.17 (t, J = 8.2 Hz, 2 H, H-4′, H-4′′),
6.56 (d, J = 8.4 Hz, 4 H, H-3′, H-3′′, H-5′, H-5′′), 5.74 (tdd, J = 6.7,
10.3, 17.0 Hz, 2 H, CH′=CH2), 5.69 (tdd, J = 6.7, 10.3, 17.0 Hz,
2 H, CH′′=CH2), 4.98–4.86 (m, 8 H, CH=CH2), ca. 3.88 (t, J =
6.5 Hz, 4 H, OCH2′), ca. 3.86 (t, J = 6.5 Hz, 4 H, OCH2′′), 3.74 (s,
3 H, OCH3), 2.01–1.91 (m, 8 H, CH2CH=CH2), 1.64–1.51 (m, 8 H,
OCH2CH2), 1.40–1.26 (m, 8 H, OCH2CH2CH2).
13C NMR (125 MHz, CDCl3): δ = 158.1 (s, C-2′′, C-6′′), 157.9 (s,
C-2′, C-6′), 152.7 (s, C-3), 145.5 (s, C-2), 144.3 (s, C-6), 138.8 (d,
CH2C′H=CH2), 138.7 (d, CH2C′′H=CH2), 129.1 (d, C-4′), 128.7 (d,
C-4′′), 124.8 (d, C-5), 120.9 (s, C-1′′), 117.7 (s, C-1′), 116.9 (d, C-
4), 114.4 (t, CH=CH2′), 114.3 (t, CH=CH2′′), 105.9 (d, C-3′′, C-5′′),
105.5 (d, C-3′, C-5′), 68.6 (t, OCH2′′), 68.3 (t, OCH2′), 55.5 (t,
OCH3), 33.3 (t, CH2′CH=CH2), 33.2 (t, CH2′′CH=CH2), 28.6 (t,
OCH2′′CH2′′), 28.5 (t, OCH2′CH2′), 25.1 (t, OCH2′CH2′CH2′), 25.0
(t, OCH2′′CH2′′CH2′′).
Anal. Calcd for C37H45NO4: C, 78.27; H, 7.99; N, 2.47. Found: C,
77.97; H, 8.27; N, 2.55.
2,6-Bis[2,6-bis(hex-5-enyloxy)phenyl]pyridine (9b)
Synthesized according to General Procedure A with 2,6-dibro-
mopyridine (1; 300 mg, 1.26 mmol), 2,6-bis(hex-5-enyl-
oxy)phenylboronic acid (8b; 1.01 g, 3.14 mmol), Pd(PPh3)4 (145
mg, 125 μmol) in DME (75 mL) and H2O (10 mL). Purification by
chromatography on silica gel (cyclohexane–EtOAc, 7:1) gave 9b as
an almost colorless powder.
Yield: 589 mg (75%).
IR (KBr): 2938, 2869, 1640, 1598, 1455, 1244, 1101 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.66 (t, J = 7.7 Hz, 1 H, H-4), 7.21
(t, J = 8.3 Hz, 2 H, H-4′, H-4′′), 7.18 (d, J = 7.7 Hz, 2 H, H-3, H-5),
6.58 (d, J = 8.4 Hz, 4 H, H-3′, H-3′′, H-5′, H-5′′), 5.72 (tdd, J = 6.7,
10.2, 17.2 Hz, 4 H, CH=CH2), 5.01–4.87 (m, 8 H, CH=CH2), 3.88
(t, J = 6.5 Hz, 8 H, OCH2), 2.01–1.91 (m, 8 H, CH2CH=), 1.62–1.52
(m, 8 H, OCH2CH2), 1.38–1.30 (m, 8 H, OCH2CH2CH2).
MS (EI, 70 eV): m/z (%) = 653 (81) [M]+, 622 (59) [M – OCH3]+,
570 (100) [M – C6H11]+.
13C NMR (125 MHz, CDCl3): δ = 157.8 (s, C-2′, C-2′′, C-6′, C-6′′),
154.1 (s, C-2, C-6), 138.7 (d, CH=CH2), 134.6 (d, C-4), 128.9 (d, C-
4′, C-4′′), 123.7 (d, C-3, C-5), 121.3 (s, C-1′, C-1′′), 114.4 (t,
CH=CH2), 105.7 (d, C-3′, C-3′′, C-5′, C-5′′), 68.5 (t, OCH2), 33.2 (t,
CH2CH=CH2), 28.5 (t, OCH2CH2), 25.1 (t, OCH2CH2CH2).
MS (CI, isobutane): m/z (%) = 654 (100) [M + H]+.
2,11,13,22-Tetraoxa-1,12(1,3,2)-dibenzena-23(2,6)-pyridinabi-
cyclo[10.10.1]tricosaphan-6,17-diene (11a)
Synthesized according to General Procedure B with 9a (540 mg,
951 μmol) and benzylidenebis(tricyclohexylphosphine)dichlororu-
thenium (70 mg, 85 μmol, 9 mol%) in CH2Cl2 (210 mL). Purifica-
tion by chromatography on silica gel (cyclohexane–EtOAc, 6:1)
gave 11a as an almost colorless solidifying oil.
MS (ESI+, MeOH): m/z (%) = 624 (100) [M + H]+.
2,6-Bis[2,6-bis(pent-4-enyloxy)phenyl]-3-methoxypyridine
(10a)
Synthesized according to General Procedure A with 2,6-diiodo-3-
methoxypyridine (2; 274 mg, 760 μmol), 2,6-bis(pent-4-enyl-
oxy)phenylboronic acid (8a; 560 mg, 1.93 mmol) and Pd(PPh3)4 (90
Yield: 320 mg (66%).
IR (KBr): 2934, 1593, 1458, 1246, 1101 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2799–2807

2804
T. Liebig, U. Lüning
PAPER
1H NMR (500 MHz, CD2Cl2): δ = 7.75, 7.74 (2 × t, J = 7.7, 7.7 Hz,
1 H, H-4), 7.26, 7.22 (2 × d, J = 7.7, 7.7 Hz, 2 H, H-3, H-5), 7.21,
7.20 (2 × t, J = 8.3, 8.3 Hz, 2 H, H-4′, H-4′′), 6.55, 6.54 (2 × d, J =
8.4, 8.4 Hz, 4 H, H-3′, H-3′′, H-5′, H-5′′), 5.34–5.30, 4.98–4.95
(2 × m, 2 H, E- and Z-CH=CH), 4.04–3.97, 3.91–3.81 (2 × m, 8 H,
OCH2), 2.01–1.81 (m, 8 H, CH2CH=CH2), 1.67–1.43 (m, 8 H,
OCH2CH2).
13C NMR (125 MHz, CDCl3): δ = 158.0, 157.8 (2 × s, C-2′, C-2′′,
C-6′, C-6′′), 152.8 (s, C-3), 146.1 (s, C-2), 144.7 (s, C-6), 130.9,
130.7 (2 × d, Z- and E-CH=CH), 129.9 (d, C-4′), 129.1 (d, C-4′′),
125 (d, C-5), 120.9 (s, C-1′′), 117.3 (s, C-1′), 117.1 (C-4), 105.7,
104.7 (2 × d, C-3′′, C-5′′), 104.6, 104.2 (2 × d, C-3′, C-5′), 67.0,
66.6 (2 × t, OCH2CH2), 29.5, 29.0, 28.9, 28.5, 23.3, 23.2 (6 × t,
CH2).
13C NMR (125 MHz, CD2Cl2): δ = 157.8, 157.6, 157.1 (3 × s, C-2′,
C-2′′, C-6′, C-6′′), 154.3, 154.1 (2 × s, C-2, C-6), 134.6 (d, C-4),
130.6, 129.9 (2 × d, Z- and E-CH=CH), 128.9 (2 × d, C-4′, C-4′′),
123.9, 123.6 (2 × d, C-3, C-5), 120.9, 120.3 (2 × s, C-1′,C-1′′),
105.5, 104.5, 104.2 (3 × d, C-3′, C-3′′, C-5′, C-5′′), 67.2, 66.5 (2 × t,
OCH2), 29.4, 29.3, 29.2, 28.2, 23.2, 23.1 (6 × t, CH2).
MS (ESI+, CHCl3–MeOH): m/z (%) = 564 (10) [M + Na]+, 542
(100) [M + H]+.
Anal. Calcd for: C34H39NO5: C, 75.39; H, 7.26; N, 2.59. Found: C,
75.09; H, 7.14; N, 2.48.
273-Methoxy-2,13,15,26-tetraoxa-1,14(1,3,2)-dibenzena-
27(2,6)-pyridinabicyclo[12.12.1]heptacosaphan-7,20-diene
(12b)
Synthesized according to General Procedure B with 10b (250 mg,
382 μmol), benzylidenebis(tricyclohexylphosphine)dichlororuthe-
nium (15 mg, 18 μmol, 5 mol%) in CH2Cl2 (100 mL). Purification
by chromatography on silica gel (cyclohexane–EtOAc, 7:1) gave
12b as an almost colorless solid.
MS (ESI+, MeOH): m/z (%) = 534 (100) [M + Na]+, 512 (52) [M +
H]+.
Anal. Calcd for C33H37NO4: C, 77.47; H, 7.29; N 2.74; Calcd for
C33H37NO4·0.2CH2Cl2: C, 75.43; H, 7.13; N, 2.65. Found: C, 75.50;
H, 7.33; N, 2.73.
2,13,15,26-Tetraoxa-1,14(1,3,2)-dibenzena-27(2,6)-pyridinabi-
cyclo[12.12.1]heptacosaphan-7,20-diene (11b)
Yield: 196 mg (86%).
IR (KBr): 2930, 1592, 1454, 1252, 1101 cm–1.
Synthesized according to General Procedure B with 9b (300 mg,
480 μmol), benzylidenebis(tricyclohexylphosphine)-dichlororuthe-
nium (21 mg, 18 μmol, 9 mol%) in CH2Cl2 (120 mL). Purification
by chromatography on silica gel (cyclohexane–EtOAc, 6:1) gave
11b as an almost colorless solid.
1H NMR (500 MHz, CDCl3): δ = 7.24, 7.23 (2 × d, 8.5 Hz, 1 H, H-
4), 7.19, 7.18 (2 × t, J = 8.3, 8.3 Hz, 2 H, H-4′, H-4′′), 7.16, 7.15
(2 × d, J = 8.5, 8.5 Hz, 1 H, H-5), 6.53 (d, J = 8.4 Hz, 2 H, H-3′, H-
5′), 6.52 (d, J = 8.4 Hz, 2 H, H-3′′, H-5′′), 5.30–5.26, 5.21–5.17
(2 × m, 2 H, Z- and E-CH=CH), 3.94–3.84, 3.80–3.70 (2 × m, 8 H,
OCH2), 3.75 (s, 3 H, OCH3), 2.12–1.90 (m, 8 H, CH2CH=CH2),
1.64–1.46 (m, 8 H, OCH2CH2), 1.44–1.22 (m, 8 H, CH2).
13C NMR (125 MHz, CDCl3): δ = 158.2, 158.0 (2 × s, C-2′, C-2′′,
C-6′, C-6′′), 152.9 (s, C-3), 146.0 (s, C-2), 144.8 (s, C-6), 130.7,
130.2 (2 × d, Z- and E-CH=CH), 128.9 (d, C-4′), 128.6 (d, C-4′′),
124.5 (d, C-5), 117.1 (d, C-4), 104.9, 104.8 (2 × d, C-3′, C-5′),
104.7, 104.6 (2 × d, C-3′′, C-5′′), 68.8, 68.7 (2 × t, OCH2CH2), 55.7
(q, OCH3), 31.5 (t, CH2CH=CH2), 28.5, 28.3, 27.6, 27.5, 26.9, 26.7
(6 × t, OCH2CH2), 25.1, 25.0, 24.9 (3 × t, CH2).
Yield: 250 mg (92%).
IR (KBr): 2935, 1593, 1458, 1246, 1102 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.68, 7.66 (2 × d, J = 7.7, 7.7 Hz,
1 H, H-4), 7.19, 7.18 (2 × t, J = 8.3, 8.3 Hz, 2 H, H-4′, H-4′′), 7.15,
7.13 (2 × d, J = 7.7, 7.7 Hz, 2 H, H-3, H-5), 6.53 (d, J = 8.3 Hz, 4 H,
H-3′, H-3′′, H-5′, H-5′′), 5.29–5.26, 5.21–5.17 (2 × m, 2 H, Z and E-
CH=CH), 3.94–3.84, 3.80–3.70 (2 × m, 8 H, OCH2), 2.12–1.90 (m,
8 H, CH2CH=CH2), 1.64–1.46 (m, 8 H, OCH2CH2), 1.44–1.22 (m,
8 H, CH2).
13C NMR (125 MHz, CDCl3, TMS): δ = 157.9, 157.8 (2 × s, C-2′,
C-2′′, C-6′, C-6′′), 154.4 (s, C-2, C-6), 134.6 (d, C-4), 130.7, 130.2
(2 × d, Z- and E-CH=CH), 128.8 (d, C-4′, C-4′′), 123.5 (d, C-3, C-
5), 120.6 (s, C-1′, C-1′′), 104.8, 104.7, 104.6 (3 × d, C-3′, C-3′′, C-
5′, C-5′′), 68.7, 68.6, 68.5 (3 × t, OCH2CH2), 31.5 (t, CH2CH=CH2),
27.6, 26.9, 26.6, 25.0, 24.9, 24.8 (6 × t, CH2).
MS (EI, 70 eV): m/z (%) = 597 (53) [M]+, 566 (100) [M – OCH3]+.
MS (CI, isobutane): m/z (%) = 598 (100) [M + H]+.
Anal. Calcd for C38H47NO5: C, 76.35; H, 7.92; N, 2.34. Found: C,
76.11; H, 7.78; N, 2.24.
MS (ESI+, CHCl3–MeOH): m/z (%) = 564 (10) [M + Na]+, 542
2,11,13,22-Tetraoxa-1,12(1,3,2)-dibenzena-23(2,6)-pyridinabi-
cyclo[10.10.1]tricosaphan (13a)
(100) [M + H]+.
Synthesized according to General Procedure C with 11a (130 mg,
254 μmol), palladium (10%) on charcoal (42 mg) in MeOH (15
mL). Purification by chromatography on silica gel (cyclohexane–
EtOAc, 1:1) gave 13a as almost colorless crystals.
Anal. Calcd for C37H45NO4: C, 78.27; H, 7.99; N, 2.47. Found: C,
78.08; H, 7.72; N, 2.36.
233-Methoxy-2,11,13,22-tetraoxa-1,12(1,3,2)-dibenzena-
23(2,6)-pyridinabicyclo[10.10.1]tricosaphan-6,17-diene (12a)
Synthesized according to General Procedure B with 10a (120 mg,
200 μmol), benzylidenebis(tricyclohexylphosphine)dichlororuthe-
nium (16 mg, 19 μmol, 9 mol%) in CH2Cl2 (50 mL). Purification by
chromatography on silica gel (cyclohexane–EtOAc, 6:1) gave 12a
as an almost colorless solidifying oil.
Yield: 115 mg (88%).
IR (KBr): 2931, 2860, 1591, 1459, 1250, 1101 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.68 (t, J = 7.7 Hz, 1 H, H-4), 7.21
(t, J = 8.3 Hz, 2 H, H-4′, H-4′′), 7.18 (d, J = 7.7 Hz, 2 H, H-3, H-5),
6.54 (d, J = 8.3 Hz, 4 H, H-3′, H-5′, H-3′′, H-5′′), 3.98–3.95, 3.86–
3.80 (2 × m, 8 H, OCH2CH2), 1.66–1.48 (m, 8 H, OCH2CH2), 1.32–
1.08 (m, 16 H, CH2).
13C NMR (125 MHz, CDCl3): δ = 157.9 (s, C-2′, C-6′, C-2′′, C-6′′),
154.1 (s, C-2, C-6), 134.2 (d, C-4), 128.8 (d, C-4′, C-4′′), 123.8 (d,
C-3, C-5), 120.2 (s, C-1′,C-1′′), 104.3 (d, C-3′, C-3′′, C-5′, C-5′′),
67.7 (t, OCH2CH2), 28.1, 26.7, 24.4 (3 × t, CH2).
Yield: 97 mg (90%).
IR (KBr): 2930, 2865, 1593, 1456, 1253, 1100 cm–1.
1H NMR (500 MHz, CD2Cl2): δ = 7.33, 7.31 (2 × d, J = 8.5, 8.5 Hz,
1 H, H-4), 7.25, 7.24 (2 × t, J = 8.3, 8.3 Hz, 2 H, H-4′, H-4′′), 7.20,
7.19 (2 × d, J = 8.5, 8.5 Hz, 1 H, H-5), 6.59 (d, J = 8.4 Hz, 2 H, H-
3′, H-5′), 6.57 (d, J = 8.4 Hz, 2 H, H-3′′, H-5′′), 5.39–5.34, 5.03–
4.96 (2 × m, 2 H, Z- and E-CH=CH), 4.04–3.90, 3.89–3.80 (2 × m,
8 H, OCH2), 3.79 (s, 3 H, OCH3), 2.01–1.73 (m, 8 H, CH2CH=),
1.67–1.45 (m, 8 H, OCH2CH2).
MS (ESI+, MeOH): m/z (%) = 538 (60) [M + Na]+, 516 (100) [M +
H]+.
HRMS (ESI+, MeOH): m/z [M + H]+ calcd for C33H41NO4:
515.30359; found: 515.30329; m/z [M
+
H]+ calcd for
C3213CH41NO4: 516.30688; found: 516.30616.
Synthesis 2014, 46, 2799–2807
© Georg Thieme Verlag Stuttgart · New York

PAPER
Bimacrocyclic Pyridines and 1,8-Naphthyridines
2805
2,13,15,26-Tetraoxa-1,14(1,3,2)-dibenzena-27(2,6)-pyridinabi-
cyclo[12.12.1]heptacosaphan (13b)
3.80 (m, 4 H, OCH′′2CH2), 3.74 (s, 3 H, OCH3), 1.60–1.46 (m, 8 H,
OCH2CH2), 1.38–1.08 (m, 24 H, CH2).
Synthesized according to General Procedure C with 11b (48.0 mg,
84.6 μmol), palladium (10%) on charcoal (20 mg) in MeOH (10
mL). Purification by chromatography on silica gel (cyclohexane–
EtOAc, 1:1) gave 13b as an almost colorless solidifying oil.
13C NMR (75 MHz, CDCl3): δ = 158.2 (s, C-3′′, C-5′′), 158.1 (s, C-
3′, C-5′), 152.6 (s, C-3), 145.7 (s, C-2), 144.6 (s, C-6), 129.0 (d, C-
4′), 128.6 (d, C-4′′), 124.9 (d, C-5), 119.9 (s, C-1′′), 117.4 (d, C-4),
116.4 (s, C-1′), 105.2 (d, C-3′′, C-5′′), 105.0 (d, C-3′, C-5′), 68.6 (t,
OCH′′2), 68.5 (t, OCH′2), 55.1 (q, OCH3), 28.0 (t, OCH2CH2), 26.9,
26.8, 25.7, 25.6, 24.4, 24.2 (6 × t, CH2).
Yield: 47 mg (97%).
IR (KBr): 2931, 2860, 1591, 1459, 1250, 1101 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.69 (t, J = 7.7 Hz, H-4), 7.21 (d,
J = 7.7 Hz, 2 H, H-3, H-5), 7.20 (t, J = 8.3 Hz, 2 H, H-4′, H-4′′),
6.57 (d, J = 8.3 Hz, 4 H, H-3′, H-5′, H-3′′, H-5′′), 4.03–3.95, 3.89–
3.82 (2 × m, 8 H, OCH2CH2), 1.60–1.49 (m, 8 H, OCH2CH2), 1.35–
1.10 (m, 24 H, CH2).
MS (ESI+, MeOH): m/z (%) = 624 (44) [M + Na]+, 602 (100) [M +
H]+.
HRMS (ESI+, MeOH): m/z [M]+ calcd for C38H51NO5: 601.37671;
found: 601.37669; m/z [M]+ calcd for C3713CH51NO5: 602.38007;
found: 602.38007.
13C NMR (125 MHz, CDCl3): δ = 157.9 (s, C-2′, C-6′, C-2′′, C-6′′),
154.2 (s, C-2, C-6), 134.4 (d, C-4), 128.8 (d, C-4′, C-4′′), 123.8 (d,
C-3, C-5), 120.9 (s, C-1′,C-1′′), 104.9 (d, C-3′, C-3′′, C-5′, C-5′′),
68.5 (t, OCH2CH2), 28.1, 26.7, 25.7, 24.4 (4 × t, CH2).
MS (EI, 70 eV): m/z (%) = 571 (100) [M]+, 458 (56) [M – C8H16]+.
MS (CI, isobutane): m/z (%) = 572 (100) [M + H]+.
HRMS (ESI+, MeOH): m/z [M]+ calcd for C37H49NO4: 571.36615;
found: 571.36605; m/z [M]+ calcd for C3613CH49NO4: 572.36951;
found: 572.36958.
Anal. Calcd for C38H51NO5: C, 75.84; H, 8.54; N, 2.33. Found: C,
75.98; H, 8.63; N, 2.32.
2,7-Bis[2,6-bis(pent-4-enyloxy)phenyl]-4-phenyl-1,8-naphthy-
ridine (15a)
Synthesized according to General Procedure A with 3 (591 mg, 2.15
mmol), 8a (1.50 g, 5.16 mmol) and Pd(PPh3)4 (250 mg, 216 μmol)
in DME (120 mL) and H2O (6 mL). Purification by chromatography
on silica gel (cyclohexane–EtOAc, 2:1) gave 15a as an almost col-
orless solidifying oil.
Yield: 310 mg (68%).
IR (KBr): 2926, 1596, 1458, 1252, 1100 cm–1.
Anal. Calcd for C37H49NO4: C, 77.72; H, 8.64; N, 2.45. Found: C,
77.53; H, 8.73; N, 2.37.
1H NMR (500 MHz, CDCl3): δ = 8.30 (d, J = 8.5 Hz, 1 H, H-5),
7.59–7.47 (m, 5 H, PhH), 7.57 (d, J = 8.5 Hz, 1 H, H-6), 7.53 (s,
1 H, H-3), 7.29, 7.28 (2 × t, J = 8.4 Hz, 2 H, H-4′, H-4′′), 6.63 (d,
J = 8.4 Hz, 4 H, H-3′, H-5′, H-3′′, H-5′′), 5.66, 5.61 (2 × tdd, J = 6.6,
10.3, 16.9 Hz, 2 H, CH=CH2), 4.88–4.77 (m, 8 H, CH=CH2), ca.
3.95, 3.94 (2 × t, J = 6.4 Hz, 8 H, OCH2CH2), 1.98–1.90 (m, 8 H,
CH2CH=), 1.71–1.62 (m, 8 H, OCH2CH2).
13C NMR (125 MHz, CDCl3): δ = 157.9 (s, C-7), 157.6 (s, C-2′, C-
6′, C-2′′, C-6′′), 157.5 (s, C-2), 156.2 (s, C-8a), 147.5 (s, C-4), 137.7,
137.6 (2 × d, CH2CH=), 137.5 (s, 4a), 133.1 (d, C-5), 129.5 (d, Ph-
C-2, Ph-C-6), 129.4 (s, Ph-C-1), 129.3, 129.2 (2 × d, C-4′, C-4′′),
128.3 (d, Ph-C-3, Ph-C-5), 128.0 (d, C-3), 124.8 (d, Ph-C-4), 124.7
(d, C-6), 120.4 (s, C-1′), 117.9 (s, C-1′′), 114.5, 114.4 (2 × t,
CH=CH2), 105.4 (d, C-3′, C-5′, C-3′′, C-5′′), 67.9, 67.8 (2 × t,
OCH2), 29.8 (2 × t, CH2CH=), 28.0 (2 × t, OCH2CH2).
233-Methoxy-2,11,13,22-tetraoxa-1,12(1,3,2)-dibenzena-
23(2,6)-pyridinabicyclo[10.10.1]tricosaphan (14a)
Synthesized according to General Procedure C with 12a (140 mg,
258 μmol), palladium (10%) on charcoal (65 mg) in MeOH (20
mL). Purification by chromatography on silica gel (cyclohexane–
EtOAc, 1:1) gave 14a as an almost colorless solidifying oil.
Yield: 128 mg (92%).
IR (KBr): 2934, 2858, 1593, 1456, 1250, 1102 cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.25 (d, J = 8.4 Hz, 1 H, H-4), 7.21
(t, J = 8.3 Hz, 1 H, H-4′), 7.19 (t, J = 8.3 Hz, 1 H, H-4′′), 7.18 (d, J =
8.4 Hz, 1 H, H-5), 6.54 (d, J = 8.3 Hz, 2 H, H-3′, H-5′), 6.53 (d, J =
8.3 Hz, 2 H, H-3′′, H-5′′), 4.02–3.94 (m, 4 H, OCH′2CH2), 3.85–
3.78 (m, 4 H, OCH′′2CH2), 3.77 (s, OCH3), 1.67–1.44 (m, 8 H,
OCH2CH2), 1.34–1.04 (m, 16 H, CH2).
13C NMR (150 MHz, CDCl3): δ = 158.2 (s, C-2′′, C-6′′), 158.1 (s,
C-2′, C-6′), 152.8 (s, C-3), 145.9 (s, C-2), 144.6 (s, C-6), 129.0 (d,
C-4′), 128.6 (d, C-4′′), 124.8 (d, C-5), 119.9 (s, C-1′′), 117.1 (d, C-
4), 117.0 (s, C-1′), 104.8 (d, C-3′′, C-5′′), 104.3 (d, C-3′, C-5′), 67.8
(t, OCH′′2CH2), 67.7 (t, OCH′2CH2), 55.9 (q, OCH3), 28.8 (t,
OCH′′2CH2), 28.5 (t, OCH′2CH2), 26.7, 26.6, 23.8, 23.6 (4 × t,
CH2).
MS (CI, isobutane): m/z (%) = 598 (100) [M + H]+.
Anal. Calcd for C46H50N2O4·0.1CHCl3: C, 78.33; H, 7.14; N, 3.96.
Found: C, 78.13; H, 7.27; N, 3.94.
2,7-Bis[2,6-bis(hex-5-enyloxy)phenyl]-4-phenyl-1,8-naphthyri-
dine (15b)
Synthesized according to General Procedure A with 3 (362 mg, 1.32
mmol), 8b (1.01 g, 3.14 mmol) and Pd(PPh3)4 (145 mg, 125 μmol)
in DME (75 mL) and H2O (10 mL). Purification by chromatography
on silica gel (cyclohexane–EtOAc, 7:1 to 1:1) gave 15b as an almost
colorless solidifying oil.
MS (ESI+, MeOH): m/z (%) = 568 (56) [M + Na]+, 546 (100) [M +
H]+.
Anal. Calcd for C34H43NO5: C, 74.83; H, 7.94; N, 2.57. Found: C,
74.81; H, 8.02; N, 2.55.
Yield: 440 mg (44%).
IR (KBr): 2940, 1596, 1458, 1250, 1102 cm–1.
273-Methoxy-2,13,15,26-tetraoxa-1,14(1,3,2)-dibenzena-
27(2,6)-pyridinabicyclo[12.12.1]heptacosaphan (14b)
Synthesized according to General Procedure C with 12b (90.0 mg,
150 μmol), palladium (10%) on charcoal (35 mg) in MeOH (15
mL). Purification by chromatography on silica gel (cyclohexane–
EtOAc, 1:1) gave 14b as an almost colorless solidifying oil.
1H NMR (500 MHz, CDCl3): δ = 8.26 (d, J = 8.51 Hz, 1 H, H-5),
7.57–7.42 (m, 5 H, PhH), 7.49 (s, 1 H, H-3), 7.47 (d, J = 8.5 Hz,
1 H, H-6), 7.25, 7.24 (2 × t, J = 8.4 Hz, 2 H, H-4′, H-4′′), 6.62 (d, J
= 8.4 Hz, 4 H, H-3′, H-5′, H-3′′, H-5′′), 5.61, 5.57 (2 × tdd, J = 6.6,
10.3, 16.9 Hz, 2 H, CH=CH2), 4.84–4.74 (m, 8 H, CH=CH2), ca.
3.94, 3.92 (2 × t, J = 6.4 Hz, 8 H, OCH2CH2), 1.90–1.84 (m, 8 H,
CH2CH=), 1.62–1.54 (m, 8 H, OCH2CH2), 1.34–1.26 (m, 8 H,
OCH2CH2CH2).
Yield: 87 mg (96%).
IR (KBr): 2934, 2858, 1593, 1456, 1250, 1102 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.22 (d, J = 8.4 Hz, 1 H, H-4), 7.21
(d, J = 8.4 Hz, 1 H, H-5), 7.19 (t, J = 8.3 Hz, 1 H, H-4′), 7.17 (t, J =
8.3 Hz, 1 H, H-4′′), 6.55 (d, J = 8.3 Hz, 2 H, H-3′, H-5′), 6.54 (d, J =
8.3 Hz, 2 H, H-3′′, H-5′′), 4.04–3.97 (m, 4 H, OCH′2CH2), 3.87–
13C NMR (125 MHz, CDCl3): δ = 157.9 (s, C-7), 157.6 (s, C-2′, C-
6′, C-2′′, C-6′′), 157.5 (s, C-2), 156.3 (s, C-8a), 147.6 (s, C-4), 138.4,
138.3 (2 × d, CH2CH=), 137.6 (s, C-4a), 133.2 (d, C-5), 129.5 (d,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2799–2807

2806
T. Liebig, U. Lüning
PAPER
Ph-C-2, Ph-C-6), 129.4 (s, Ph-C-1), 129.3, 129.2 (2 × d, C-4′, C-
4′′), 128.3 (d, Ph-C-3, Ph-C-5), 128.0 (d, C-3), 124.8 (d, Ph-C-4),
124.7 (d, C-6), 120.4 (s, C-1′), 118.1 (s, C-1′′), 114.1, 114.0 (2 × t,
CH=CH2), 105.2 (d, C-3′, C-5′, C-3′′, C-5′′), 68.5, 68.4 (2 × t,
OCH2), 32.9, 32.8 (2 × t, CH2CH=), 28.3, 28.2 (2 × t, OCH2CH2),
25.0, 24.9 (2 × t, OCH2CH2CH2).
MS (ESI+, MeOH): m/z (%) = 717 (33) [M + Na]+, 695 (100) [M +
H]+.
Anal. Calcd for C46H50N2O4: C, 79.51; H, 7.25; N, 4.03. Found: C,
79.67; H, 7.42; N, 4.17.
MS (ESI+, MeOH): m/z (%) = 624 (100) [M + H]+.
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
Anal. Calcd for C50H58N2O4: C, 79.96; H, 7.78; N, 3.73. Found: C,
79.87; H, 7.87; N, 3.72.
10.1055/s-00000084.SunogIpimrfiantoSuIpg
n
fonirtat
ori
234-Phenyl-2,11,13,22-tetraoxa-1,12(1,3,2)-dibenzena-23(2,7)-
1,8-naphthyridinabicyclo[10.10.1]tricosaphan-6,17-diene (16a)
Synthesized according to General Procedure B with 15a (310 mg,
446 μmol), benzylidenebis(tricyclohexylphosphine)dichlororuthe-
nium (37 mg, 45 μmol, 10 mol%) in CH2Cl2 (300 mL). Purification
by chromatography on silica gel (cyclohexane–EtOAc, 1:1) gave
16a as an almost colorless solidifying oil.
References
(1) Concave Reagents, part 65. Part 64: Reimers, T.;
Haberhauer, G.; Benkhäuser, C.; Schmidtchen, F. P.;
Lützen, A.; Lüning, U. Eur. J. Org. Chem. 2013, 7556.
(2) (a) Steed, J. W.; Atwood, J. L. Supramolecular Chemistry,
2nd ed.; John Wiley & Sons: Chichester, 2009.
(b) Supramolecular Chemistry, From Molecules to
Nanomaterials; Vol. 1–8; Steed, J. W.; Gale, P. A., Eds.;
John Wiley & Sons: Chichester, 2012.
(3) (a) Lehn, J.-M. Supramolecular Chemistry: Concepts and
Perspectives; Wiley-VCH: Weinheim, 1995. (b) Vögtle, F.
Supramolekulare Chemie; Teubner: Stuttgart, 1989.
(4) See textbooks of biochemistry, for example: Voet, D.; Voet,
J. G.; Pratt, C. W. Lehrbuch der Biochemie; Wiley-VCH:
Weinheim, 2002.
(5) Concave geometry is a major factor in host–guest
recognition. Most molecules are ‘potato shaped’ and thus
convex. To be complementary to such a guest molecule, host
molecules have to possess concave areas. For references, see
books on supramolecular chemistry such as refs. 2, 6 and 8.
(6) (a) Lehn, J.-M. Supramolecular Chemistry; Wiley-VCH:
Weinheim, 1995. (b) Davis, F.; Higson, S. Macrocycles;
John Wiley & Sons: Chichester, 2011.
(7) Lüning, U. Liebigs Ann. Chem. 1987, 949.
(8) Lüning, U. Concave Reagents, In Molecular Encapsulation;
Brinker, U. H.; Mieusset, J.-L., Eds.; John Wiley & Sons:
New York, 2010.
(9) Lüning, U.; Müller, M.; Gelbert, M.; Peters, K.; v.
Schnering, H. G.; Keller, M. Chem. Ber. 1994, 127, 2297;
and cited references.
(10) Ross, H.; Lüning, U. Tetrahedron Lett. 1997, 38, 4539.
(11) Lüning, U.; Liebig, T. Eur. J. Org. Chem. 2012, 1346.
(12) Lüning, U.; Baumgartner, H.; Wangnick, C. Tetrahedron
1996, 52, 599; and cited references.
(13) Winkelmann, O.; Lüning, U. Supramolecular Chemistry
2009, 21, 223; and cited references.
(14) For unprecedented hemiacetal formation by NHC
organocatalysis, see: Winkelmann, O.; Näther, C.; Lüning,
U. Org. Biomol. Chem. 2009, 7, 553.
(15) For exclusive 2-acylation of a glucose derivative catalyzed
by a concave pyridine, see: Petersen, S.; Lüning, U. Eur. J.
Org. Chem. 1999, 847.
(16) Lüning, U.; Baumstark, R.; Schyja, W. Tetrahedron Lett.
1993, 34, 5063.
(17) Liebig, T.; Abbass, M.; Lüning, U. Eur. J. Org. Chem. 2007,
972.
(18) Lüning, U.; Fahrenkrug, F. Eur. J. Org. Chem. 2004, 3119.
(19) (a) Koch, V.; Schnatterer, S. Synthesis 1990, 497.
(b) Bojarska-Dahlig, H.; Swirska, A. Roczniki Chemii 1953,
27, 258; Chem. Abstr. 1954, 48, 6439i.
(20) Lüning, U.; Abbass, M.; Fahrenkrug, F. Eur. J. Org. Chem.
2002, 3294.
(21) Mangini, A.; Colonna, M. Gazz. Chim. Ital. 1942, 72, 190.
(22) Ehlers, P.; Petrosyan, A.; Ghochikyan, T. V.; Saghyan, A.
S.; Neubauer, A.; Lochbrunner, S.; Langer, P. Synlett 2013,
359.
Yield: 248 mg (87%).
IR (KBr): 2925, 1599, 1456, 1249, 1101 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.33, 8.31 (2 × d, J = 8.4 Hz, 1 H,
H-5), 7.61–7.43 (m, 5 H, PhH), 7.47 (s, 1 H, H-3), 7.45 (d, J =
8.4 Hz, 1 H, H-6), 7.28, 7.27 (2 × t, J = 8.3 Hz, 2 H, H-4′, H-4′′),
6.67, 6.66 (2 × d, J = 8.3 Hz, 4 H, H-3′, H-5′, H-3′′, H-5′′), 5.13–
5.02, 4.88–4.83 (2 × m in ratio 5:1, 4 H, CH2CH=), 4.09–3.75 (m,
8 H, OCH2CH2), 1.91–1.44 [m, 16 H, OCH2(CH2)2].
13C NMR (125 MHz, CDCl3): δ = 158.3, 158.2 (2 × s, C-7), 157.9,
157.8 (2 × s, C-2), 157.7, 157.6 (2 × s, C-8a), 157.7, 157.6 (2 × s,
C-2′, C-6′, C-2′′, C-6′′), 148.3, 148.2 (2 × s, C-4), 137.7, 137.6
(2 × s, C-4a), 133.9, 133.8 (2 × d, C-5), 129.9 (s, Ph-C-1), 129.9,
129.8 (2 × d, Ph-C-2, Ph-C-6, C-4′, C-4′′), 129.7, 129.6 (2 × d,
CH2CH=CH2), 128.6, 128.4 (2 × d, C-3), 124.9, 124.8 (2 × d, C-6),
124.7 (d, C-4), 122.5 (s, C-1′), 118.2 (s, C-1′′), 107.7, 107.5, 107.3,
107.1 (4 × d, C-3′, C-5′, C-3′′, C-5′′), 69.7, 69.5 (2 × d, OCH2CH2),
29.6, 29.5, 29.4, 24.2, 24.1, 24.0 (6 × t, CH2).
MS (ESI+, MeOH): m/z (%) = 661 (15) [M + Na]+, 639 (100) [M +
H]+.
Anal. Calcd for C42H42N2O4: C, 78.97; H, 6.63; N, 4.39. Found: C,
79.01; H, 6.81; N, 4.32.
274-Phenyl-2,13,15,26-tetraoxa-1,14(1,3,2)-dibenzena-27(2,7)-
1,8-naphthyridinabicyclo[12.12.1]heptacosaphan-7,20-diene
(16b)
Synthesized according to General Procedure B with 15b (400 mg,
532 μmol), benzylidenebis(tricyclohexylphosphine)dichlororuthe-
nium (45 mg, 54 μmol, 10 mol%) in CH2Cl2 (210 mL). Purification
by chromatography on silica gel (cyclohexane–EtOAc, 2:1) gave
16b as an almost colorless solidifying oil.
Yield: 307 mg (83%).
IR (KBr): 2927, 1597, 1457, 1248, 1101 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.26 (d, J = 8.5 Hz, 1 H, H-5),
7.58–7.44 (m, 5 H, PhH), 7.48 (s, 1 H, H-3), 7.46 (d, J = 8.5 Hz,
1 H, H-6), 7.26, 7.24 (2 × t, J = 8.3 Hz, 2 H, H-4′, H-4′′), 6.61, 6.60
(2 × d, J = 8.4 Hz, 4 H, H-3′, H-5′, H-3′′, H-5′′), 5.08–5.02, 4.92–
4.86 (2 × m in ratio of 1:2, 4 H, CH2CH=), 3.96–3.86 (m, 8 H,
OCH2CH2), 1.74–1.64 (m, 8 H, CH2CH=), 1.62–1.46 (m, 8 H,
OCH2CH2), 1.22–1.08 (m, 8 H, CH2).
13C NMR (125 MHz, CDCl3): δ = 158.4 (s, C-7), 157.9 (s, C-2),
157.8 (s, C-2′, C-6′, C-2′′, C-6′′), 156.5 (s, C-8a), 147.7 (s, C-4),
138.0 (s, C-4a), 133.3 (d, C-5), 129.8, 129.7 (2 × d, CH2CH=CH2),
129.6 (s, Ph-C-1, 2 × d, Ph-C-2, Ph-C-6), 129.5 (2 × d, C-4′, C-4′′),
128.6 (d, Ph-C-3, Ph-C-5), 128.2 (d, C-3), 125.0 (d, Ph-C-4), 124.8
(d, C-6), 120.5, 118.1 (2 × s, C-1′, C-1′′), 105.0 (d, C-3′, C-5′, C-3′′,
C-5′′), 68.9 (t, OCH2), 31.8 (2 × t, CH2CH=), 28.2 (2 × t,
OCH2CH2), 26.1 (2 × t, CH2).
Synthesis 2014, 46, 2799–2807
© Georg Thieme Verlag Stuttgart · New York

PAPER
Bimacrocyclic Pyridines and 1,8-Naphthyridines
2807
(23) Stoltenberg, D.; Näther, C.; Meyer, H.; Machay, S.; Lüthje,
S.; Lüning, U. Synthesis 2012, 3095.
(24) Lüning, U.; Baumstark, R.; Schyja, W. Liebigs Ann. Chem.
1991, 999.
(25) (a) Schyja, W.; Petersen, S.; Lüning, U. Liebigs Ann. 1996,
2009. (b) Petersen, S.; Lüning, U. Eur. J. Org. Chem. 1999,
847; and cited references. (c) Lüning, U.; Hacker, W.
J. Prakt. Chem. 1999, 341, 662; and cited references.
(26) A remarkable change in basicity due to different solvation
has been found for 2,6-dialkylpyridines. Di-tert-butyl-
pyridine is considerably less basic then other dialkyl-
pyridines. See refs. 27 and 28.
(30) Izutsu, K. Acid-base dissociation constants in dipolar
aprotic solvents, IUPAC chemical data series, no. 35;
Blackwell: Oxford, 1990.
(31) Thymol blue is blue only in strongly basic media when it is
deprotonated to the dianionic form. In the described titration,
the equilibrium between the neutral red form and the yellow
mono-anion was measured by UV/Vis spectroscopy.
(32) Lüning, U.; Baumstark, R.; Peters, K.; v. Schnering, H. G.
Liebigs Ann. Chem. 1990, 129.
(33) (a) Perrin, D. D. Dissociation constants of organic bases in
aqueous solution; Butterworths: London, 1965. (b) Oae, S.;
Kadoma, Y. Can. J. Chem. 1986, 64, 1184.
(27) Brown, H. C.; Kanner, B. J. Am. Chem. Soc. 1953, 75, 3865;
pKa (in H2O–EtOH 50:50, 25 °C): 2,6-dimethylpyridine:
5.77, 2,6-diisopropylpyridine: 5.34, 2,6-di-tert-butyl-
pyridine: 3.58.
(28) Heintz, A.; Wandschneider, D.; Lüning, U.; Marczak, W.
Fluid Phase Equilibria 2006, 248, 123.
(34) Saturated bimacrocycle 13a and unsaturated precursor 11a
possess the same number of carbon atoms in the chains
between the bridgeheads. However, due to the geometry of
the double bond, the Z-unsaturated chains are slightly
shorter. Therefore, the unsaturated mixture 11a was studied
because it contains, in the mixture, the smallest
(29) pKa values are logarithms of the equilibrium constants of the
dissociation of acids (including protonated bases) in water.
The water concentration of 55.5 M is part of the Ka values
resulting in acid constants Ka with the dimension of M. Thus,
all tabled pKa values are water-based and calculated from M
concentrations.
bimacrocycle(s).
(35) (a) Lüning, U.; Baumstark, R.; Schyja, W. Tetrahedron Lett.
1993, 34, 5063. (b) Schyja, W. Dissertation; Universität
Freiburg: Germany, 1995.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2799–2807