Concave pyridines for bifunctional acid-base catalysis

Article abstract of DOI:10.1002/ejoc.200600842

Two bifunctional concave acid-base catalysts, 1 and 2, have been synthesized starting from 2,6-dibromopyridine (9) and 2,6-bis(ω- alkenyloxy)phenylboronic acids 8 and 10 which end up as bridgeheads in final bimacrocycles 1 and 2. One bridgehead contained

Full text of DOI:10.1002/ejoc.200600842

FULL PAPER
DOI: 10.1002/ejoc.200600842
Concave Pyridines for Bifunctional Acid–Base Catalysis[‡]
Timo Liebig,[a] Michael Abbass,[a] and Ulrich Lüning*[a]
Keywords: Acid catalysis / Base catalysis / Bifunctional catalysis / Heterocycles / Macrocycles / Supramolecular chemistry
Two bifunctional concave acid–base catalysts, 1 and 2, have
been synthesized starting from 2,6-dibromopyridine (9) and
2,6-bis(ω-alkenyloxy)phenylboronic acids 8 and 10 which
end up as bridgeheads in final bimacrocycles 1 and 2. One
bridgehead contained an additional substituent in the 4-posi-
tion. The respective protected 4-hydroxymethyl-substituted
phenylboronic acids 8 were synthesized from 4-bromo-3,5-
dihydroxybenzoic acid (3) in five steps. 4-Unsubstituted bo-
ronic acid 10 and 4-substituted boronic acid 8 were then at-
tached to 9 by subsequent Suzuki couplings to give tetra-ω-
alkenes 12. By ring-closing metathesis of 12, bimacrocyclic
dienes 13 and 17 were formed. After deprotection of the 4-
hydroxymethyl group of one bridgehead, a 3-hydroxybenzo-
ate was coupled to 14 to give ester 15 which gave bifunc-
tional acid–base catalyst 1 upon hydrolysis. Analogously,
homologue 2 was synthesized, but before coupling the bi-
macrocycle to the benzoate, tetraene 14 was hydrogenated
to 18. Acidic and basic centers in 1 (49% from 9) and 2 (19%
from 9) are at least 5 Å apart.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
structure with one bridge containing a pyridine ring. The
two necessary macrocyclizations can be performed sequen-
tially or in one pot. The synthesis of concave pyridines with
amide bridgeheads[5,6] used the first strategy (synthesis of a
macrocyclic pyridine-containing diamine which is then
bridged with a diacyl dichloride). Also, the syntheses of
concave pyridines based on calixarenes[7–9] used a two-step
strategy but there the pyridine-containing bridge was only
introduced in the final construction of the bimacrocycle
when a calixarene was treated with bis(bromomethyl)pyri-
dine. In the third approach, two aryl bridgeheads were con-
nected with the pyridine first, then both bridges were intro-
duced in a double macrocyclization in a one pot reaction.[10]
With other heterocycles such as 1,10-phenanthroline, a
highly efficient route that uses metal catalyzed C–C bond
formations has been established in the past years for the
synthesis of related bimacrocycles.[11] The key steps were:
(1) generation of the bridgeheads in the form of boronic
acids, (2) Suzuki coupling of the two bridgeheads to a dou-
bly halogenated heterocycle, and (3) bimacrocyclization by
ruthenium-catalyzed ring-closing metathesis (RCM). For
2,9-disubstituted 1,10-phenanthrolines, it has also been
demonstrated that a 4-substituted aryl bridgehead can be
introduced.[12]
Introduction
Among all catalysts, acid and bases are the most impor-
tant ones. Nature uses acidic and basic side chains of the
amino acids to carry out respective catalyses within en-
zymes. Aside from a single acid or a single base, a large
number of enzymes contain an acid–base array in the active
center. The special geometrical placement of an acid and a
base enables the enzymes to carry out bifunctional catalysis,
for example in proteases.[1] Bifunctional catalysis[2] can also
be carried out with small organic molecules, the simplest
model being the hydrogen bond donor–acceptor array in a
carboxylic acid or the prominent 2-pyridone.[3] Although
catalytically active in many reactions, the applicability of
these catalysts is limited for two reasons: the hydrogen-bond
donor and acceptor act in parallel, and their distance is
fixed to approximately 2.5 Å.
In order to imitate the concave shielding of the active site
in an enzyme, the bifunctional acid–base catalyst should be
placed in a cavity. Concave reagents imitate the geometry
of enzymes for acids, bases, or other catalysts and rea-
gents.[4] As a first example of concave bases, concave pyri-
dines had been synthesized.[5] By using different strategies,
several classes of concave pyridines are accessible. All
classes have in common that they consist of a bimacrocyclic
Building upon these findings, the synthetic scheme for
the synthesis of a bifunctional acid–base catalyst such as 1
or 2 based on a concave pyridine develops as follows: (1)
generation of aryl boronic acids as bridgeheads which have
alkenyloxy groups in the ortho position and an additional
protected functional group in the 4-position, (2) sequential
addition of a 4-unsubstituted and a 4-substituted aryl
[‡] Concave Reagents, 51. Part 50: S. Konrad, M. Bolte, C. Näther,
U. Lüning, Eur. J. Org. Chem. 2006, 4717–4730.
[a] Otto-Diels-Institut für Organische Chemie, Christian-Al-
brechts-Universität zu Kiel,
Olshausenstr. 40, 24098 Kiel, Germany
Fax: +49-431-880-1558
E-mail: luening@oc.uni-kiel.de
972
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Concave Pyridines for Bifunctional Acid–Base Catalysis
FULL PAPER
bridgehead into the 2- and 6-positions of a pyridine, (3) THP ether 7b in 88% yield. In the final reaction step, the
ring-closing metathesis (and possibly hydrogenation of the bromine atoms were exchanged with lithium atoms by using
double bonds), (4) deprotection of the additional functional n-butyllithium. Without isolation, the resulting aryllithium
group and connection with an acid.
compounds were treated with trimethylborate to yield bo-
ronic acids 8 after hydrolysis in 81% (8a) and 60% (8b)
yield.
By using boronic acids 8 and unsubstituted analogues
10 as described in the literature,[12] the connection of the
bridgeheads with the pyridine core was the next task.
2,6-Dibromopyridine (9) was chosen as the pyridine
building block, and the use of 1.1 equiv. of 4-unsubstituted
boronic acids 10a or 10b under standard Suzuki coupling
conditions gave 81% of 11a and 73% of 11b. Respective
boronic acids 8 with the protected functional groups in the
4-position were then coupled with the remaining bromide
functionality. tert-Butyldimethylsilyl (TBDMS) protected
tetrapentenyl derivative 12a was obtained in 92% yield,
whereas tetrahydropyranyl (THP) protected tetrahexenyl
derivative 12b could be isolated in 84% yield (Scheme 2).
Results and Discussion
A 4-substituted boronic acid with two ortho-methoxy
groups has already been described.[12] Its synthesis started
from commercially available 4-bromo-3,5-dihydroxybenzoic
acid (3) (Scheme 1).
Scheme 1. a) MeOH, H2SO4 (cat.), reflux, 18 h; b) (i) THF, PPh3,
diisopropyl azodicarboxylate (DIAD), 4-penten-1-ol, room temp.,
18 h (ii) DMF, K2CO3, KI, 6-bromohex-1-ene, 70 °C, 16 h; c) THF,
iBu2AlH, room temp., 3 h; d) (i) CH2Cl2, TBDMS–Cl, imidazole,
room temp., 1 h (ii) CH2Cl2, DHP, p-TsOH, room temp., 16 h; e)
THF, nBuLi, –78 °C, 1 h, (MeO)3B, –78 °CǞroom temp., 2 h,
dest. H2O.
Scheme 2. a) Dimethoxyethane, Pd(PPh3)4, 2  Na2CO3, reflux,
16–18 h; b) Dimethoxyethane, Pd(PPh3)4, Ba(OH)2·H2O, reflux,
16–19 h.
First, the carboxylic group of 3 was protected as methyl
ester 4 in 64% yield. To introduce the future chains of the
bimacrocycle, the phenolic groups of 3 had to be alkylated
Double ring-closing metatheses, deprotection, and con-
with the ω-alkenoxy residues. This connection between the nection with an acidic group remained to complete the syn-
phenolic groups of 4 and the alkenyl residue could be thesis. At this step of the synthesis, however, the decision as
achieved either by Williamson ether synthesis or by a Mit- to whether and when to hydrogenate the double bonds that
sunobu reaction and was dependent on the availability of resulted from the metathesis reaction needed to be made.
the alkenyl precursors. For 5a, we performed a Mitsunobu To elucidate saturated and unsaturated products, we left the
reaction with 4-penten-1-ol (97%). Compound 5b was ob- pentyl derivatives unsaturated, whereas in the hexenyl case,
tained by Williamson ether synthesis with the use of 6-bro- the double bonds of the bimacrocycle were hydrogenated to
mohex-1-ene (80%).
finally give decamethylene chains.
Next, the methyl esters were reduced to methanols 6a
Thus, tetrapentenyl ether 12a was mixed with GrubbsЈ
and 6b with the use of di-isobutylaluminium hydride (90 catalyst and the resulting mixture of (E,E)-, (E,Z)-, and
and 87%, respectively). For the transformation into boronic (Z,Z)-dialkene bimacrocycles 13 could be isolated in 92%
acids 8, the methanol function had to be protected. Two yield. Next, the tert-butyldimethylsilyl group was cleaved
protecting groups (PGs) were tested; pentenyl derivative 6a off with the use of tetrabutylammonium fluoride to give
was protected as tert-butyldimethylsilyl (TBDMS) ether 7a methanol 14 in 98% efficiency. Again, with the use of the
(87%), whereas hexenyl diether 6b was treated with 3,4-di- Mitsunobu protocol, the primary alcohol function was cou-
hydro-2H-pyran (DHP) under acidic conditions to give pled with methyl 3-hydroxybenzoate (87% of 15) before de-
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Scheme 3. a) CH2Cl2, Grubbs’ cat. (1st generation), room temp., 48 h; b) THF, NBu4F·3H2O, room temp., 45 min; c) THF, PPh3,
diisopropyl azodicarboxylate (DIAD), methyl 3-hydroxybenzoate, 0 °CǞroom temp., 18 h; d) THF, MeOH, LiOH, H2O, 40 °C, 4 h,
room temp., 18 h.
Scheme 4. a) p-TsOH, MeOH, reflux, 90 min; b) CH2Cl2, Grubbs’ cat. (1st generation), room temp., 21 h; c) Pd/C, H2, MeOH, room
temp., 18 h; d) THF, PPh3, diisopropyl azodicarboxylate (DIAD), methyl 3-hydroxybenzoate, 0 °C, room temp. 18 h; e) THF, MeOH,
LiOH, H2O, 40 °C, 4 h, room temp., 18 h.
protection of the carboxylic acid with lithium hydroxide to 2 can be obtained in five or six reaction steps with overall
give final product 1 in 84% yield (Scheme 3).
yields of 49 and 19%, respectively. The geometry of 1 and
Spectroscopic analysis proved the structure of the final 2 was chosen in such a way that the acid and the base can-
product but also showed the (Z) and (E) isomers of the not react intramolecularly. The methylenoxy connection be-
double bonds. Of course, the ESI-MS spectra showed only tween bridgehead and benzoic acid assures some flexibility
one signal for the mixture of the isomers.
to allow for an induced fit in future catalysis. The distance
To avoid the problems arising from the (E) and (Z) between the acid and base functionalities was calculated to
double bonds, second tetraether 12b was transformed into be at least 5 Å, which guarantees that the acid and base
a bimacrocycle with saturated chains. For the synthesis of moieties cannot form an intramolecular hydrogen bond.[13]
2, first the protecting THP group of 12b was cleaved off by Thus, acid and base are favorably oriented for bifunctional
acid (98% of 16), then the ring-closing metathesis was car- acid–base catalysis.
ried out. The (E,E)-, (E,Z)-, and (Z,Z)-mixture of 17, ob-
Although separated by more than 5 Å, the pyridine and
tained in 89% yield, was then hydrogenated with palladium the carboxylic acid, in principle, can react with one another
on charcoal to give isomer-free macrocycle 18 in 96% yield. to give a zwitterion by proton transfer. Such a reaction can
The rest of the synthesis was carried out as follows: Mitsu- take place intra- or intermolecularly. In water, pyridine and
nobu coupling of 18 to methyl 3-hydroxybenzoate (65% of acetic acid possess almost identical pKa values, and thus a
19), and hydrolysis of the methyl ester with an aqueous lith- mixture of acid and base and conjugate acid and conjugate
ium hydroxide solution gave 57% of bifunctional acid–base base is expected. However, in less polar solvents, the acidity
catalyst 2 (Scheme 4).
of a neutral carboxylic acid is decreased more than that of
a protonated pyridine.[14,15] For instance, in ethanol the pKa
values of pyridines are only slightly altered,[16] whereas for
several benzoic acids, pKa values between 10 and 12 have
Conclusions
Compounds 1 and 2 are the first two examples of con- been determined[17] and correspond to a decrease in the
cave bases that carry an additional acidic function. Starting acidity by four orders of magnitude. This striking difference
from 2,6-dibromopyridine (9), bifunctional catalysts 1 and in solvent dependence of the acidity is not surprising. The
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Concave Pyridines for Bifunctional Acid–Base Catalysis
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dichlororuthenium (5–10 mol-%) was added, and the mixture was
stirred for 16–48 h at room temp. Afterwards, diisopropylamine (5–
10 mL) was added and after an additional 45 min of stirring at
room temp., the solvents were evaporated in vacuo, and the residue
was purified as detailed below.
difference in stabilization by polar and less polar solvents
is larger for charged species. In the case of carboxylic acids,
the base is charged, whereas for pyridines, the acid, the pyr-
idinium ion, is charged.[14] Thus, the formation of betaines
is not expected in organic solvents for bifunctional catalysts
1 and 2.
3-({2,11,13,22-Tetraoxa-1,12(1,3,2)-dibenzena-23(2,6)-pyridinabicy-
clo[10.10.1]tricosaphan-6,17-dien-15-yl}methyloxy)benzoic Acid (1):
Methyl 3-({2,11,13,22-tetraoxa-1,12(1,3,2)-dibenzena-23(2,6)-pyri-
dinabicyclo[10.10.1]tricosaphan-6,17-dien-15-yl}methyloxy)-
benzoate (15, 70.0 mg, 104 µmol) was dissolved in a mixture of
tetrahydrofuran and methanol (each 5 mL). Lithium hydroxide
(71.3 mg, 1.69 mmol) in water (3 mL) was added, and the reaction
mixture was stirred for 4 h at 40 °C. After an additional 18 h of
stirring at room temp., the solvents were evaporated in vacuo, and
the residue was dissolved in a mixture of dichloromethane and sat-
urated ammonium chloride (each 10 mL). The layers were sepa-
rated, and the aqueous layer was extracted with dichloromethane
and ethyl acetate (2ϫ25 mL each). The combined organic layer
was dried with magnesium sulfate, and the solvent was evaporated
in vacuo. The crude product was purified by recrystallization from
chloroform/n-pentane to yield 55.7 mg (84 %) of 1. 1H NMR
(500 MHz, CDCl3): δ = 7.78 (t, J = 7.7 Hz, 1 H, 4-H), 7.66–7.63
(m, 2 H, Ar-4-H, Ar-6-H), 7.33 (t, J = 7.9 Hz, 1 H, Ar-5-H), 7.26,
7.25 (2 d, J = 7.7 Hz, J = 7.7 Hz, 2 H, 3-H, 5-H), 7.22 (t, J =
8.4 Hz, 1 H, 4ЈЈ-H), 7.17–7.15 (m, 1 H, Ar-2-H), 6.34 (s, 2 H, 3Ј-
H, 5Ј-H), 6.55 (d, J = 8.4 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 5.36–5.30 (m,
4 H, CH=), 5.08 (s, 2 H, ArO-CH2), 3.91 (s, 3 H, Ar-COOCH3),
3.94–3.83 (m, 8 H, OCH2), 2.00–1.91, 1.89–1.81 (2 m, 8 H,
CH2CH=), 1.66–1.58, 1.56–1.48 (2 m, 8 H, OCH2CH2) ppm. 13C
NMR (125 MHz, CDCl3): δ = 168.5 (s, ArCOOH), 158.6 (Ar-C-
3), 157.6 (s, C-2Ј, C-6Ј), 157.5 (s, C-2ЈЈ, C-6ЈЈ), 153.8 (s, C-2), 153.5
(s, C-6), 138.1 (s, C-4Ј), 135.2 (d, C-4), 131.8 (s, Ar-C-1), 129.8,
129.7 (2 d, CH=), 129.3 (d, Ar-C-5), 129.2 (d, C-4ЈЈ), 124.1, 124.0
(2 d, C-3, C-5), 122.5 (d, Ar-C-6), 120.0 (d, Ar-C-2), 119.1 (s, C-
1ЈЈ), 118.6 (s, C-1Ј), 115.4 (d, Ar-C-4), 104.2 (d, C-3ЈЈ, C-5ЈЈ), 103.3
(d, C-3Ј, C-5Ј), 70.4 (t, ArO-CH2), 66.4, 66.3 (2 t, OCH2), 29.3,
29.2 (2 d, CH2CH=), 23.2, 23.1 (2 t, OCH2CH2) ppm. IR (KBr):
Unfortunately, in a first catalytic test, the rates of hydro-
lysis of a p-nitrophenyl ester catalyzed by these concave
acid–base catalysts were only marginally larger than the
background reaction. Application of these catalysts in hy-
drolyses, ring-opening reactions, and isomerizations are un-
der investigation.
Experimental Section
General Remarks: The following chemicals were obtained commer-
cially and used without further purification: barium hydroxide
octahydrate (Merck), benzylidenebis(tricyclohexylphosphane)di-
chlororuthenium (Fluka), 4-bromo-3,5-dihydroxybenzoic acid
(Aldrich), 6-bromohex-1-ene (Fluka), tert-butylchlorodimethylsil-
ane (Fluka), n-butyllithium (2.5  in hexanes, Aldrich), 2,6-dibro-
mopyridine (Aldrich), 3,4-dihydro-2H-pyran (Fluka), diisobutyl-
aluminium hydride (1.0  in hexanes, Aldrich), diisopropyl azodicar-
boxylate (Fluka), 1,2-dimethoxyethane (Aldrich), N,N-dimethyl-
formamide (Ն99.8%, Fluka), methyl 3-hydroxybenzoate (Aldrich),
Pd/C (10%) (Merck), 4-penten-1-ol (Alfa Aesar), tetrabutylammo-
nium fluoride trihydrate (Fluka), tetrakis(triphenylphosphane)pal-
ladium(0) (Aldrich), trimethyl borate (Fluka). 2,6-Bis(hex-5-enyl-
oxy)phenylboronic acid and 2,6-bis(pent-4-enyloxy)phenylboronic
acid were prepared according to literature procedures.[12] Dry sol-
vents were obtained with suitable desiccants: ethyl acetate and cy-
clohexane were distilled from calcium chloride, and tetra-
hydrofuran was distilled from lithium aluminium hydride. Column
chromatography was carried out with silica gel (Macherey–Nagel,
activity I). The preparative, centrifugally accelerated, thin layer
chromatograph (Chromatotron) was model 7924T from Harrison
Research. 1H and 13C NMR spectra were recorded with Bruker AC
200, ARX 300, DRX 500, or Avance 600 spectrometers with the
use of tetramethylsilane as the internal standard. IR spectra were
measured with a Perkin–Elmer 1600 Series spectrometer. Mass
spectra were recorded with Finnigan MAT 8200 or 8230 spectrom-
eters, or with an ESI mass spectrometer Mariner (Applied Biosys-
tems, by using methanol/dichloromethane, 1:1, as the solvent). Ele-
mental analyses were carried out with an Euro EA3000CHNS in-
strument (HEKAtech).
ν = 2936, 1700, 1595, 1438, 1248, 1109, 758 cm–1. MS (ESI): m/z
˜
(%) = 684 (13) [M + Na]+, 662 (100) [M + H]+. C41H43NO7
(661.78): calcd. C 74.41, H 6.55, N 2.21; found C 74.18, H 7.12, N
2.27.
3-({2,13,15,26-Tetraoxa-1,14(1,3,2)-dibenzena-27(2,6)-pyridinabicy-
clo[12.12.1]heptacosaphan-15-yl}methyloxy)benzoic Acid (2): Methyl
3-({2,13,15,26-tetraoxa-1,14(1,3,2)-dibenzena-27(2,6)-pyridinabicy-
clo[12.12.1]heptacosa-phan-15-yl}methyloxy)benzoate (19,
50.0 mg, 67.9 µmol) was dissolved in a mixture of tetrahydrofuran
and methanol (each 5 mL). Lithium hydroxide (71.3 mg,
1.69 mmol) in water (3 mL) was added, and the reaction mixture
was stirred for 4 h at 40 °C. After an additional 18 h of stirring at
room temp., the solvents were evaporated in vacuo, and the residue
was dissolved in a mixture of dichloromethane and saturated am-
monium chloride (each 10 mL). The layers were separated, and the
aqueous layer was extracted with dichloromethane and ethyl ace-
tate (2ϫ25 mL each). The combined organic layer was dried with
magnesium sulfate, and the solvent was evaporated in vacuo. The
crude product was purified by recrystallization from chloroform/n-
pentane to yield 28.0 mg (57%) of 2. 1H NMR (600 MHz, CDCl3):
δ = 7.73 (t, J = 7.7 Hz, 1 H, 4-H), 7.68–7.64 (m, 2 H, Ar-4-H, Ar-
6-H), 7.34 (t, J = 8.0 Hz, 1 H, Ar-5-H), 7.19 (t, J = 8.4 Hz, 1 H,
4ЈЈ-H), 7.18 (d, J = 7.7 Hz, 1 H, 3-H), 7.17 (d, J = 7.7 Hz, 1 H, 5-
H), 7.17–7.15 (m, 1 H, Ar-2-H), 6.63 (s, 2 H, 3Ј-H, 5Ј-H), 6.56 (d,
J = 8.4 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 5.08 (s, 2 H, ArO-CH2), 4.04–3.95,
3.90–3.81 (2 m, 8 H, OCH2), 1.62–1.51 (m, 8 H, OCH2CH2), 1.36–
General Procedure for the Synthesis of Boronic Acids 8: Aryl bro-
mide 7 was dissolved in dry tetrahydrofuran and then cooled to
–78 °C. n-Butyllithium (1.1 equiv., 2.5  in hexane) was added, and
the mixture stirred for 1 h at –78 °C. After the addition of ca.
3.3 equiv. of trimethyl borate, stirring was continued for 2 h. Dur-
ing this period, the mixture was warmed to room temp. After
quenching with water (20 mL), the layers were separated, and the
aqueous layer was extracted with diethyl ether (3ϫ20–30 mL). The
combined organic layers were washed with brine (20–30 mL) and
dried with magnesium sulfate. After evaporation of the solvent, the
crude product was purified as detailed below.
General Procedure for Ring Closing Metathesis (13, 17): 2,6-Disub-
stituted pyridinetetraene 12a or 16 was dissolved in dichlorometh-
ane (c
≈ 0.01 mol/L). Benzylidenebis(tricyclohexylphosphane)-
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T. Liebig, M. Abbass, U. Lüning
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1.07 (m, 24 H, CH2) ppm. 13C NMR (150 MHz, CDCl3): δ = 170.5
(s, ArCOOH), 158.6 (Ar-C-3), 157.9 (s, C-2Ј, C-6Ј), 157.8 (s, C-2ЈЈ,
C-6ЈЈ), 153.7 (s, C-2), 153.4 (s, C-6), 137.9 (s, C-4Ј), 135.1(d, C-4),
131.4 (s, Ar-C-1), 129.4 (d, Ar-C-5), 129.0 (d, C-4ЈЈ), 124.3, 124.1
(2 d, C-3, C-5), 122.8 (d, Ar-C-6), 120.6 (s, C-1ЈЈ), 120.5 (s, C-1Ј),
to yield 8.78 g (80 %) of 5b. M.p. 31 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.20 (s, 2 H, 2-H, 6-H), 5.84 (tdd, J = 6.7 Hz, J =
10.3 Hz, J = 17.1 Hz, 2 H, CH=), 5.05 (tdd, J = 1.5 Hz, J = 2.1 Hz,
J = 17.1 Hz, 2 H, =CH(Z)H), 4.98 (tdd, J = 1.2 Hz, J = 2.1 Hz, J
= 10.3 Hz, 2 H, CH=CH( E ) H), 4.09 (t, J = 6.4 Hz, 4 H,
120.2 (d, Ar-C-2), 115.6 (d, Ar-C-4), 104.9 (d, C-3ЈЈ, C-5ЈЈ), 103.9 OCH2CH2), 3.92 (s, 3 H, ArCOOCH3), 2.2–2.1 (m, 4 H,
(d, C-3Ј, C-5Ј), 70.5 (t, ArO-CH2), 68.5, 68.3 (2 t, OCH2), 28.0,
CH2CH=), 1.9–1.8 (m, 4 H, OCH2CH2), 1.7–1.5 (m, 4 H,
OCH2CH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.6 (s,
ArCOOCH3), 156.5 (s, C-3, C-5), 138.5 (d, CH=), 129.9 (s, C-1),
114.8 (t, =CH2), 106.3 (d, C-2, C-6), 107.7 (s, C-4), 69.3 (t, Ar-
OCH2), 52.4 (q, ArCOOCH3), 33.3(t, CH2CH=), 28.4 (t,
27.9, 26.9, 26.8, 25.7, 25.6, 24.4, 24.3 (8 t, CH ) ppm. IR (KBr): ν
˜
2
= 2936, 1700, 1595, 1438, 1248, 1109, 758 cm–1. MS (ESI): m/z (%)
= 722 (100) [M + H]+. C45H55NO7 (721.92): calcd. C 74.87, H 7.68,
N 1.94; found C 74.91, H 7.78, N 2.07.
OCH CH ), 25.2 (t, OCH CH CH ) ppm. IR (KBr): ν = 2947,
˜
2
2
2
2
2
Methyl 4-Bromo-3,5-dihydroxybenzoate (4):[18] 4-Bromo-3,5-dihy-
droxybenzoic acid (3, 10.0 g, 42.9 mmol) was dissolved in dry
methanol (100 mL). After addition of conc. sulfuric acid (2.5 mL),
the mixture was heated to reflux for 18 h. The solvent was removed
in vacuo, and the residue was dissolved in a mixture of water
(100 mL) and diethyl ether (400 mL). The water layer was extracted
with diethyl ether (3ϫ50 mL), and the combined organic layers
were dried with magnesium sulfate. The solvent was evaporated
in vacuo, and the residue was purified by recrystallization from
chloroform to yield 6.80 g (64 %) of 4. M.p. 230 °C. 1H NMR
1724, 1639, 1584, 1425, 1243, 1113 cm–1. MS (EI, 70 eV): m/z (%)
= 412, 410 (1, 1) [M]+, 381, 379 (2, 2) [M – CH3O]+, 331 (100)
[M – Br]+, 248, 246 (78, 78) [M – C12H20]+. C20H27BrO4 (411.33):
calcd. C 58.40, H 6.62; found C 58.50, H 6.73.
4-Bromo-3,5-bis(pent-4-enyloxy)phenylmethanol (6a): Methyl 4-
bromo-3,5-bis(pent-4-enyloxy)benzoate (5a, 6.86 g, 17.9 mmol) was
dissolved in tetrahydrofuran (50 mL). After the addition of a solu-
tion of diisobutylaluminium hydride (1.0  in hexanes, 40 mL,
40 mmol), the reaction mixture was stirred for 2 h at room temp.
(200 MHz, CDCl3): δ = 9.11 (s, 2 H, Ar-OH), 7.15 (s, 2 H, 2-H, 6- Water (15 mL) was added. The precipitated solid was filtered off
H), 3.83 (s, 3 H, ArCOOCH ) ppm. IR (KBr): ν = 3425, 1703, and washed with ethyl acetate (3ϫ25 mL). The filtrate was evapo-
˜
3
1600, 1424, 1373, 1273, 1036 cm–1. MS (EI, 70 eV): m/z (%) = 248, rated in vacuo and the residue was purified by column chromatog-
246 (52, 48) [M]+, 217, 215 (69, 61) [M–OCH3]+, 189, 187 (19, 13)
[M–COOCH3]+.
raphy (silica gel, cyclohexane/ethyl acetate, 2:1) to yield 5.70 g
(90%) of 6a. H NMR (300 MHz, CDCl3): δ = 6.52 (s, 2 H, 2-H,
1
6-H), 5.86 (tdd, J = 6.6 Hz, J = 10.2 Hz, J = 17.1 Hz, 2 H, CH=),
5.11 (tdd, J = 1.6 Hz, J = 2.1 Hz, J = 17.1 Hz, 2 H, CH=CH(Z)H),
5.02 (tdd, J = 1.2 Hz, J = 2.1 Hz, J = 10.2 Hz, 2 H, CH=CH(E)H),
4.61 (s, ArCH2O), 4.02 (t, J = 6.4 Hz, 4 H, OCH2), 2.36–2.22 (m,
4 H, CH2-CH=), 2.00–1.85 (m, 4 H, OCH2CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 156.6 (s, C-3, C-5), 141.4 (s, C-1), 137.7 (d,
CH=), 115.3 (t, =CH2), 104.1 (d, C-2, C-6), 100.9 (s, C-4), 68.5 (t,
HOCH2Ar), 65.1 (t, ArOCH2), 30.0 (t, CH2-CH=), 28.3 (t, Ar-
Methyl 4-Bromo-3,5-bis(pent-4-enyloxy)benzoate (5a): Methyl 4-
bromo-3,5-dihydroxybenzoate (4, 12.1 g, 48.9 mmol), 4-penten-1-ol
(9.22 g, 107 mmol), and triphenylphosphane (32.3 g, 123 mmol)
were dissolved in tetrahydrofuran (200 mL). At 0 °C, diisopropyl
azodicarboxylate (29.3 mL, 149 mmol) dissolved in tetrahydro-
furan (15 mL) was added, and the mixture was stirred for 18 h at
room temp. After addition of water (20 mL), the layers were sepa-
rated, and the aqueous layer was extracted with diethyl ether
(3ϫ20 mL). The combined organic layer was washed with brine
(2ϫ10 mL) and dried with magnesium sulfate. The solvent was
evaporated in vacuo, and the residue was purified by column
chromatography (silica gel, cyclohexane/ethyl acetate, 5:1) to yield
OCH CH ) ppm. IR (Film): ν = 3354, 2937, 1640, 1587, 1434,
˜
2
2
1237, 1114 cm–1. MS (ESI): m/z (%) = 356 (100) [M + H]+.
4-Bromo-3,5-bis(hex-5-enyloxy)phenylmethanol (6b): Methyl 4-
bromo-3,5-bis(hex-5-enyloxy)benzoate (5b, 823 mg, 2.00 mmol)
was dissolved in tetrahydrofuran (10 mL). After the addition of a
1
18.2 g (97%) of 5a. H NMR (300 MHz, CDCl3): δ = 7.20 (s, 2 H,
2-H, 6-H), 5.87 (tdd, J = 6.6 Hz, J = 10.2 Hz, J = 16.9 Hz, 2 H, solution of diisopropylaluminium hydride (1.0  in hexanes, 5 mL,
CH=), 5.11 (tdd, J = 1.5 Hz, J = 2.1 Hz, J = 16.9 Hz, 2 H, 5 mmol), the reaction mixture was stirred for 3 h at room temp.
CH=CH(Z)H), 4.98 (tdd, J = 1.2 Hz, J = 2.1 Hz, J = 10.2 Hz, 2 H, Water (5 mL) was added. The precipitated solid was filtered off and
CH=CH(E)H), 4.09 (t, J = 6.30, 4 H, OCH2), 3.91 (s, 3 H, OCH3),
2.36–2.26 (m, 4 H, CH2CH=), 2.01–1.90 (m, 4 H, OCH2CH2) ppm.
washed with ethyl acetate (3ϫ20 mL). The filtrate was evaporated
in vacuo, and the residue was purified by column chromatography
13C NMR (75 MHz, CDCl3): δ = 166.5 (s, ArCOOCH3), 156.5 (s, (silica gel, cyclohexane/ethyl acetate, 2:1) to yield 667 mg (87%) of
1
C-3, C-5), 137.6 (d, CH=CH2), 129.9 (s, C-1), 115.4 (t, CH=CH2), 6b. H NMR (300 MHz, CDCl3): δ = 6.55 (s, 2 H, 2-H, 6-H), 5.84
107.7 (s, C-4), 106.4 (d, C-2, C-6), 68.6 (t, OCH2CH2), 52.4 (q, (tdd, J = 6.6 Hz, J = 10.3 Hz, J = 17.1 Hz, 2 H, CH=), 5.04 (tdd,
ArCOOCH3), 29.9 (t, CH2CH=CH2), 28.2 (t, OCH2CH2) ppm. IR
J = 1.6 Hz, J = 2.1 Hz, J = 17.1 Hz, 2 H, CH=CH(Z)H), 4.97 (tdd,
(KBr): ν = 2946, 1723, 1640, 1586, 1426, 1243, 1110 cm–1. MS J = 1.2 Hz, J = 2.1 Hz, J = 10.3 Hz, 2 H, CH=CH(E)H), 4.64 (s,
˜
(ESI): m/z (%) = 405 (50) [M + Na]+, 384 (100) [M + H]+.
2 H, ArCH2OH), 4.03 (t, J = 6.4 Hz, 4 H, ArOCH2), 2.20–2.07 (m,
4 H, CH2CH=), 1.91–1.76 (m, 4 H, OCH2CH2), 1.67–1.53 (m, 4 H,
CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 156.7 (s, C-3, C-5),
141.4 (s, C-1), 138.6 (d, CH=CH2), 114.8 (t, CH=CH2), 104.0 (d,
C-2, C-6), 100.8 (s, C-4), 69.1 (t, ArOCH2), 65.2 (t, ArCH2O), 33.4
(t, CH2CH=), 28.6 (t, OCH2CH2), 25.2 (t, CH2) ppm. IR (Film):
Methyl 4-Bromo-3,5-bis(hex-5-enyloxy)benzoate (5b): Methyl 4-
bromo-3,5-dihydroxybenzoate (4, 6.61 g, 26.7 mmol) was dissolved
in dry N,N-dimethylformamide (120 mL). After the addition of po-
tassium carbonate (23.6 g, 170 mmol), potassium iodide (500 mg,
3.01 mmol), and 6-bromohex-1-ene (10.9 g, 66.7 mmol), the reac-
tion mixture was stirred for 16 h at 70 °C. The solvent was removed
in vacuo, and the residue was dissolved in a mixture of water
(20 mL) and diethyl ether (40 mL). The water layer was extracted
with diethyl ether (3ϫ20 mL), and the combined organic layer was
washed with brine (15 mL) and dried with magnesium sulfate. The
solvent was evaporated in vacuo, and the residue was purified by
column chromatography (silica gel, cyclohexane/ethyl acetate, 5:1)
ν = 3354, 2937, 1640, 1587, 1434, 1237, 1114 cm–1. MS (EI, 70 eV):
˜
m/z (%) = 384, 382 (4, 5) [M]+, 303 (100) [M – Br]+, 220, 218 (70,
72) [M – C12H20]+. C19H27BrO3 (383.32): calcd. C 59.53, H 7.10;
found C 59.24, H 7.14.
2-Bromo-4-(tert-butyldimethylsilyloxymethyl)-1,3-bis(pent-4-enyl-
oxy)benzene (7a): 4-Bromo-3,5-bis(pent-4-enyloxy)phenylmethanol
(6a, 5.70 g, 16.1 mmol) and imidazole (6.60 g, 96.9 mmol) were dis-
976
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 972–980

Concave Pyridines for Bifunctional Acid–Base Catalysis
FULL PAPER
solved in dry dichloromethane (200 mL). At 0 °C, tert-butylchloro-
dimethylsilane (2.51 g, 16.6 mmol) was added, and the mixture was
stirred for 1 h at room temp. After addition of water (20 mL), the
layers were separated, and the aqueous layer was extracted with
dichloromethane (3ϫ25 mL). The combined organic layers were
washed with brine (20 mL) and dried with magnesium sulfate. The
solvent was evaporated in vacuo, and the residue was purified by
column chromatography (silica gel, cyclohexane/ethyl acetate, 1:1)
to yield 6.57 g (87%) of 7a. 1H NMR (300 MHz, CDCl3): δ = 6.55
OCH2CH2), 0.96 [s, 9 H, C(CH3)3], 0.12 [s, 6 H, Si (CH3)2] ppm.
13C NMR (125 MHz, CDCl3): δ = 164.9 (s, C-2, C-6), 147.4 (s, C-
4), 136.9 (d, CH=), 115.8 (t, =CH2), 102.4 (d, C-3, C-5), 68.2 (t,
Si-OCH2Ar), 64.5 (t, ArOCH2-), 30.0 (t, CH2-CH=), 28.2 (t, Ar-
OCH2CH2), 25.1 [q, C(CH3)], 18.3 [s, C(CH3)], –5.28 [q, Si-(CH3)]
ppm. IR (KBr): ν = 3522, 2939, 2867, 164 1, 1567, 1445, 1335,
˜
1217, 1106 cm–1. Because of relaxation effects with 11B-isotopes,
the signal for C-1 is not detectable. MS (ESI): m/z (%) = 891 (100)
[2 M]+. C23H39BO5Si (434.45): calcd. C 63.59, H 9.05; found C
(s, 2 H, 4-H, 6-H), 5.88 (tdd, J = 6.6 Hz, J = 10.2 Hz, J = 17.1 Hz, 63.86, H 9.23.
2 H, CH=CH2), 5.11 (tdd, J = 1.6 Hz, J = 2.1 Hz, J = 17.1 Hz,
2,6-Bis(hex-5-enyloxy)-4-(2-tetrahydropyranyloxymethyl)phenyl-
2 H, CH=CH(Z)H), 5.02 (tdd, J = 1.2 Hz, J = 2.1 Hz, J = 10.2 Hz,
2 H, CH=CH(E)H), 4.70 (s, 2 H, ArCH2O), 4.05 (t, J = 6.4 Hz,
4 H, OCH2), 2.36–2.26 (m, 4 H, CH2-CH=), 2.01–1.90 (m, 4 H,
OCH2CH2), 0.97 [s, 9 H, C(CH3)3], 0.12 [s, 6 H, Si-(CH3)2] ppm.
13C NMR (75 MHz, CDCl3): δ = 156.4 (s, C-1, C-3), 142.1 (s, C-
5), 137.7 (d, CH=), 115.2 (t, =CH2), 103.2 (d, C-4, C-6), 99.9 (s,
C-2), 68.3 (t, Si-OCH2Ar), 64.6 (t, ArOCH2), 30.1 (t, CH2-CH=),
28.3 (t, ArOCH2CH2), 25.9 [q, C(CH3)], 18.4 [s, C(CH3)], –5.24 [q,
boronic Acid (8b): Synthesis according to the general procedure: 2-
Bromo-1,3-bis(hex-5-enyloxy)-5-(2-tetrahydropyranyloxymethyl)-
benzene (7b, 800 mg, 1.71 mmol) in tetrahydrofuran (45 mL) with
the use of n-butyllithium (2.5  in hexane, 1.00 mL, 2.50 mmol)
and trimethylborate (800 µL, 7.18 mmol). Purification by column
chromatography on silica gel eluting with cyclohexane/ethyl acetate
(3:1). Yield: 440 mg (60 %). M.p. Ͻ20 °C. 1H NMR (500 MHz,
CDCl3): δ = 7.30 [s, 2 H, ArB(OH)2], 6.61 (s, 2 H, 3-H, 5-H), 5.81
(tdd, J = 6.7 Hz, J = 10.2 Hz, J = 17.1 Hz, 2 H, CH=), 5.04, 4.99
(tdd, J = 1.2 Hz, J = 2.0 Hz, J = 10.2 Hz, CH=CH(E)H, tdd, J =
1.5 Hz, J = 2.0 Hz, J = 17.1 Hz, 4 H, CH=CH(Z)H), 4.76 (td, J =
0.7 Hz, J = 12.7 Hz, 1 H, ArCH2O), 4.69 (dd, J = 2.8 Hz, J =
4.5 Hz, 1 H, OCHO), 4.50 (td, J = 0.7 Hz, J = 12.7 Hz, 1 H, Ar-
CH2O-), 4.08 (t, J = 6.5 Hz, 4 H, ArOCH2CH2), 3.94–3.86, 3.58–
3.52 (m, 2 H, OCH2), 2.18–2.10 (m, 4 H, CH2CH=), 1.90–1.82 (m,
4 H, OCH2CH2), 1.61–1.54 (m, 4 H, OCH2CH2CH2) ppm. 13C
NMR (125 MHz, CDCl3): δ = 165.0 (s, C-2, C-6), 143.9 (s, C-4),
138.0 (d, CH=), 115.2 (t, =CH2), 104.2 (d, C-3, C-5), 97.9 (d,
OCHO), 68.9 (t, ArOCH2CH2), 68.5 (t, CH2O), 62.4 (t, ArCH2O),
33.3 (CH2-CH=), 30.6 (t, CH2), 28.5 (t, ArOCH2CH2), 25.4 (t,
Si-(CH )] ppm. IR (Film): ν = 3015, 2952, 2929, 1588, 1433, 1216,
˜
3
1108, 839 cm–1. MS (EI, 70 eV): m/z (%) = 470, 468 (5, 4) [M]+,
413, 411 (100, 96) [M – C4H9]+, 389 (39) [M – Br]+, 333 (83) [M –
C4H9 – Br]+.
2-Bromo-1,3-bis(hex-5-enyloxy)-5-(2-tetrahydropyranyloxymethyl)-
benzene (7b): 4-Bromo-3,5-bis(hex-5-enyloxy)phenylmethanol (6b,
3.73 g, 9.82 mmol) was dissolved in dry dichloromethane (60 mL).
After the addition of 3,4-dihydro-2H-pyran (2.4 mL, 27 mmol) and
p-toluenesulfonic acid (100 mg, 526 µmol), the reaction mixture
was stirred for 16 h at room temperature. The solvent was removed,
and the residue was purified by column chromatography (silica gel,
cyclohexane/ethyl acetate, 6:1) to yield 4.03 g (88 %) of 7b. 1H
NMR (300 MHz, CDCl3): δ = 6.55 (t, J = 0.6 Hz, 2 H, 4-H, 6-H), CH ), 25.2 (t, ArOCH CH CH ), 19.4 (t, CH ) ppm. IR (KBr): ν
˜
2
2
2
2
2
5.84 (tdd, J = 6.6 Hz, J = 10.2 Hz, J = 17.1 Hz, 2 H, CH=), 5.04
= 3520, 2939, 2867, 1640, 1567, 1445, 1336, 1217, 1106 cm–1. Be-
(tdd, J = 1.6 Hz, J = 2.1 Hz, J = 17.1 Hz, 2 H, CH=CH(Z)H), 4.97 cause of relaxation effects with 11B-isotopes, the signal for C-1 is
(tdd, J = 1.2 Hz, J = 2.1 Hz, J = 10.2 Hz, 2 H, CH=CH(E)H), 4.71 not detectable. MS (EI, 70 eV): m/z (%) = 304 (11) [M – B(OH)2 –
(d, J = 0.6 Hz, J = 12.2 Hz, 1 H, ArCH2O), 4.67 (dd, J = 2.5 Hz,
J = 4.1 Hz, 1 H, OCHO), 4.46 (d, J = 0.6 Hz, J = 12.2 Hz, 1 H,
ArCH2O), 4.03 (t, J = 6.4 Hz, 4 H, ArOCH2CH2), 4.03–3.81 (m,
1 H, CH2O), 3.62–3.56 (m, 1 H, CH2O), 2.21–2.10 (m, 4 H,
CH2CH=), 1.91–1.57 (m, 14 H, CH2) ppm. 13C NMR (75 MHz,
CDCl3): δ = 156.5 (s, C-1, C-3), 138.7 (s, C-5), 138.6 (d, CH=),
114.7 (t, =CH2), 105.1 (d, C-4, C-6), 100.9 (s, C-2), 97.6 (d,
OCHO), 69.0 (t, ArOCH2CH2), 68.6 (t, CH2O), 62.3 (t, ArCH2O),
33.3 (t, CH2CH=), 30.6 (t, CH2), 28.5 (t, OCH2CH2), 25.4 (d, CH),
C6H11]+, 283 (100) [M – C5H9BO4]+.
2-[2,6-Bis(pent-4-enyloxy)-phenyl]-6-bromopyridine (11a): 2,6-Di-
bromopyridine (9, 487 mg, 2.06 mmol), 2,6-bis(pent-4-enyloxy)-
phenylboronic acid (10a, 660 mg, 2.27 mmol), and tetrakis(triphen-
ylphosphane)palladium(0) (235 mg, 206 µmol) were dissolved in di-
methoxyethane (50 mL). After the addition of aqueous sodium car-
bonate (2 , 2.3 mL), the reaction mixture was heated to reflux for
18 h. Water and chloroform (10 mL each) were added, the water
layer was extracted with chloroform (3ϫ15 mL), and the combined
organic layers were washed with brine (15 mL) and dried with mag-
nesium sulfate. The solvent was evaporated in vacuo, and the resi-
due was purified by column chromatography (silica gel, cyclohex-
ane/ethyl acetate, 9:1) to yield 680 mg (81%) of 11a. 1H NMR
(600 MHz, CDCl3): δ = 7.55 (t, J = 7.8 Hz, 1 H, 4-H), 7.39 (dd, J
= 7.8 Hz, J = 1.1 Hz, 1 H, 3-H), 7.28 (dd, J = 7.4 Hz, J = 1.1 Hz,
1 H, 5-H), 7.24 (t, J = 8.4 Hz, 1 H, 4Ј-H), 6.59 (d, J = 8.4 Hz, 2
25.2 (t, OCH CH CH ), 19.4 (t, CH ) ppm. IR (Film): ν = 2940,
˜
2
2
2
2
1587, 1433, 1232, 1114 cm–1. MS (EI, 70 eV): m/z (%) = 468, 466
(2, 3) [M]+, 387 (19) [M – Br]+, 368, 366 (31, 34) [M – C5H8O2]+,
204, 202 (98, 100) [M – C17H28O2]+. C24H35BrO4 (467.44): calcd.
C 61.67, H 7.55; found C 61.43, H 7.45.
4-(tert-Butyldimethylsilyloxymethyl)-2,6-bis(pent-4-enyloxy)phen-
ylboronic Acid (8a): Synthesis according to the general procedure:
2-Bromo-4-(tert-butyldimethylsilyloxymethyl)-1,3-bis(pent-4-enyl- H, 3Ј-H, 5Ј-H), 5.74 (tdd, J = 6.7 Hz, J = 10.2 Hz, J = 16.9 Hz,
oxy)benzene (7a, 7.20 g, 15.4 mmol) in tetrahydrofuran (110 mL)
with the use of n-butyllithium (2.5  in hexane, 8.00 mL,
2 H, CH=), 5.02–4.88 (m, 4 H, =CH2), 3.92 (t, J = 6.2 Hz, 4 H,
OCH2), 2.12–1.97 (m, 4 H, CH2CH=), 1.77–1.61 (m, 4 H,
20.0 mmol) and trimethylborate (7.00 mL, 62.8 mmol). Purification OCH2CH2) ppm. 13C NMR (150 MHz, CDCl3): δ = 157.4 (s, C-
by column chromatography on silica gel eluting with cyclohexane/
2Ј, C-6Ј), 155.7 (s, C-6), 140.8 (s, C-2), 137.9 (d, CH2CH=), 137.6
ethyl acetate (8:1). Yield: 5.41 g (81%). M.p. Ͻ20 °C. 1H NMR (d, C-4), 130.0 (d, C-4Ј), 125.7 (d, C-3), 125.2 (d, C-5), 118.4 (s, C-
(500 MHz, CDCl3): δ = 7.28 [s, 2 H, ArB(OH)2], 6.59 (s, 2 H, 3-H, 1Ј), 114.9 (t, =CH2), 105.2 (d, C-3Ј, C-5Ј), 67.8 (t, OCH2), 30.0 (t,
5-H), 5.81 (tdd, J = 6.7 Hz, J = 10.2 Hz, J = 16.9 Hz, 2 H, CH CH=), 28.3 (t, OCH CH ). IR (KBr): ν = 3053, 2985, 1640,
˜
2
2
2
CH=CH2), 5.08, 5.02 (tdd, J = 1.2 Hz, J = 2.0 Hz, J = 10.2 Hz,
=CH(E)H, tdd, J = 1.5 Hz, J = 2.0 Hz, J = 17.1 Hz, 4 H,
1598, 1421, 1101, 896 cm–1. HRMS: calcd. for C21H2479BrNO2
401.09903; found 401.09901 (δ =0.05 ppm), calcd. for
CH=CH(Z)H), 4.72 (s, 2 H, Ar-CH2-O), 4.08 (t, J = 6.5 Hz, 4 H, C2013CH2479BrNO2 402.10239; found 402.09972 (δ =6.64 ppm).
ArOCH2), 2.27–2.21 (m, 4 H, CH2-CH=), 1.98–1.92 (m, 4 H,
C2 1 H2 4BrNO2 (402.33): calcd. C 62.69, H 6.01, N 3.48,
Eur. J. Org. Chem. 2007, 972–980
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
977

T. Liebig, M. Abbass, U. Lüning
FULL PAPER
C21H24BrNO2·0.1C6H12: calcd. C 63.16, H 6.18, N 3.41; found C
63.26, H 6.18, N 3.43.
2-[2,6-Bis(hex-5-enyloxy)phenyl]-6-[2,6-bis(hex-5-enyloxy)-4-(2-
tetrahydropyranyloxymethyl)phenyl]pyridine (12b): 2,6-Bis(hex-5-en-
yloxy)-4-(2-tetrahydropyranyloxymethyl)phenylboronic acid (10b,
440 mg, 1.02 mmol), tetrakis(triphenylphosphane)palladium(0)
(94 mg, 82 µmol), barium hydroxide (300 mg, 1.75 mmol), and
water (5.00 mL) were added to a solution of 2-[2,6-bis(hex-5-en-
yloxy)phenyl]-6-bromopyridine (11b, 351 mg, 816 µmol) in 1,2-di-
methoxyethane (60 mL). The reaction mixture was heated to reflux
for 19 h. After the addition of water and chloroform (50 mL each),
the water layer was extracted with chloroform (3ϫ50 mL), and the
combined organic layer was washed with brine (20 mL). The sol-
vent was removed in vacuo, and the residue was purified by
chromatography (silica gel, cyclohexane/ethyl acetate, 6:1) to yield
2-[2,6-Bis(hex-5-enyloxy)phenyl]-6-bromopyridine (11b): 2,6-Dibro-
mopyridine (9, 500 mg, 2.11 mmol), 2,6-bis(hex-5-enyloxy)phe-
nylboronic acid (10b, 738 mg, 2.32 mmol), and tetrakis(triphenyl-
phosphane)palladium(0) (235 mg, 206 µmol) were dissolved in di-
methoxyethane (50 mL). After the addition of aqueous sodium car-
bonate (2 , 2.5 mL), the reaction mixture was heated to reflux for
16 h. Water and chloroform (10 mL each) were added, the water
layer was extracted with chloroform (3ϫ15 mL), and the combined
organic layers were washed with brine (15 mL) and dried with mag-
nesium sulfate. The solvent was evaporated in vacuo, and the resi-
due was purified by column chromatography (silica gel, cyclohex-
ane/ethyl acetate, 9:1) to yield 660 mg (73%) of 11b. 1H NMR
(600 MHz, CDCl3): δ = 7.53 (t, J = 7.7 Hz, 1 H, 4-H), 7.38 (dd, J
= 7.7 Hz, J = 0.9 Hz, 1 H, 3-H), 7.27 (dd, J = 7.7 Hz, J = 0.9 Hz,
1 H, 5-H), 7.24 (t, J = 8.4 Hz, 1 H, 4Ј-H), 6.58 (d, J = 8.4, 2 H, 3Ј-
H, 5Ј-H), 5.74 (tdd, J = 6.7 Hz, J = 10.2 Hz, J = 16.9 Hz, 2 H,
CH=), 4.97–4.89 (m, 4 H, =CH2), 3.91 (t, J = 6.3, 1 H, OCH2),
2.02–1.96 (m, 4 H, CH2CH=), 1.64–1.58 (m, 4 H, OCH2CH2),
1.41–1.35 (m, 4 H, CH2) ppm. 13C NMR (150 MHz, CDCl3): δ =
157.5 (s, C-2Ј, C-6Ј), 155.7 (s, C-6), 140.8 (s, C-2), 138.7 (d,
CH2CH=), 137.6 (d, C-4), 130.1 (d, C-4Ј), 125.3 (d, C-3), 125.2 (d,
C-5), 118.5 (s, C-1Ј), 114.5 (t, =CH2), 105.2 (d, C-3Ј, C-5Ј), 68.5 (t,
OCH2), 33.3 (t, CH2CH=), 28.5 (t, OCH2CH2), 25.2 (t, CH2) ppm.
1
500 mg (84%) of 12b. H NMR (500 MHz, CDCl3): δ = 7.66 (t, J
= 7.7 Hz, 1 H, 4-H), 7.19 (t, J = 8.3 Hz, 1 H, 4ЈЈ-H), 7.16 (d, J =
7.7 Hz, 2 H, 3-H, 5-H), 6.58 (s, 2 H, 3Ј-H, 5Ј-H), 6.57 (d, J =
8.3 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 5.70 (tdd, J = 6.7 Hz, J = 10.2 Hz, J =
16.9 Hz, 4 H, CH=), 4.95–4.87 (m, 8 H, =CH2), 4.74 (td, J =
0.7 Hz, J = 12.7 Hz, 1 H, ArCH2O), 4.67 (dd, J = 2.8 Hz, J =
4.5 Hz, 1 H, OCHO), 4.52 (td, J = 0.7 Hz, J = 12.7 Hz, 1 H, Ar-
CH2O), 3.94–3.86, 3.56– 3.50 (2 m, 1 H, CH2O), 3.85 (t, J = 6.5 Hz,
4 H, ArOCH2CH2), 2.01–1.84 (m, 8 H, CH2CH=), 1.62–1.50, 1.38–
1.30 (2 m, 22 H, CH2) ppm. 13C NMR (125 MHz, CDCl3): δ =
157.8 (s, C-2Ј, C-6Ј), 157.7 (s, C-2ЈЈ, C-6ЈЈ), 154.1 (s, C-2), 153.9 (s,
C-6), 139.4 (s, C-4Ј), 138.7 (d, CH2CH=), 134.6 (d, C-4), 128.9 (d,
C-4ЈЈ), 123.7 (d, C-3, C-5), 121.3 (s, C-1Ј), 120.4 (s, C-1ЈЈ), 114.4
(t, =CH2), 105.7 (d, C-3ЈЈ, C-5ЈЈ), 105.4 (d, C-3Ј, C-5Ј), 97.2 (d,
OCHO), 68.8 (t, ArOCH2CH2), 68.5 (t, CH2O), 62.4 (t, ArCH2O),
33.2 (CH2-CH=), 30.7, 29.0, 28.5, 25.5, 19.6 (5 t, CH2) ppm. IR
IR (KBr): ν = 3053, 2985, 1649, 1598, 1421, 1100, 896 cm–1. MS
˜
(EI, 70 eV): m/z (%) = 431, 429 (28, 27) [M]+, 350 (100) [M –
Br]+, 267, 264 (64, 68) [M – 2–C6H11]+. MS (CI, Isobutane): m/z
(%) = 432, 430 (89, 100) [M + H]+, 352, 350 (8, 13) [M + H –
Br]+. C23H28BrNO2 (430.38): calcd. C 64.19, H 6.56, N 3.25,
C23H28BrNO2·0.1CH3COOEt calcd. C 63.99, H 6.61, N 3.19;
found C 63.76, H 6.59, N 3.15.
(KBr): ν = 3053, 2986, 1640, 1598, 1432, 1102, 895 cm–1. MS (ESI):
˜
m/z (%) = 738 (100) [M + H]+.
15-[(tert-Butyldimethylsilyloxy)methyl]-2,11,13,22-tetraoxa-
1,12(1,3,2)-dibenzena-23(2,6)-pyridinabicyclo[10.10.1]tricosaphan-
6,17-diene (13): Synthesis according to the general procedure:
Benzylidenebis(tricyclohexylphosphane)dichlororuthenium
(112 mg, 137 µmol) and 2-[2,6-bis(pent-4-enyloxy)phenyl]-6-[2,6-
bis(pent-4-enyloxy)-4-(tert-butyldimethylsilyloxymethyl)phenyl]pyr-
idine (12a, 1.22 g, 1.71 mmol). Purification: column chromatog-
raphy on silica gel eluting with cyclohexane/ethyl acetate (9:1).
2-[2,6-Bis(pent-4-enyloxy)-phenyl]-6-[2,6-bis(pent-4-enyloxy)-4-(tert-
butyldimethylsilyloxymethyl)phenyl]pyridine (12a): 2,6-Bis(pent-4-
enyloxy)-4-(tert-butyldimethylsilyloxymethyl)phenylboronic acid
(8a, 900 mg, 2.07 mmol), tetrakis(triphenylphosphane)palla-
dium(0) (115 mg, 99.5 µmol), barium hydroxide (1.41 g,
8.22 mmol), and water (20.0 mL) were added to a solution of 2-
[2,6-bis(pent-4-enyloxy)phenyl]-6-bromopyridine (11a, 650 mg,
1.62 mmol) in 1,2-dimethoxyethane (120 mL). The reaction mix-
ture was heated to reflux for 19 h. After the addition of water and
chloroform (50 mL each), the water layer was extracted with chlo-
roform (3 ϫ50 mL), and the combined organic layer was washed
with brine (20 mL). The solvent was removed in vacuo, and the
residue was purified by column chromatography (silica gel, cyclo-
hexane/ethyl acetate, 6:1) to yield 1.07 g (92%) of 12a. 1H NMR
(500 MHz, CDCl3): δ = 7.69 (t, J = 7.7 Hz, 1 H, 4-H), 7.19 (t, J =
8.3 Hz, 1 H, 4ЈЈ-H), 7.18 (d, J = 7.7 Hz, 2 H, 3-H, 5-H), 6.57 (t, J
= 8.3 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 6.56 (s, 2 H, 3Ј-H, 5Ј-H), 5.71, 5.70
(2 tdd, J = 6.7 Hz, J = 10.2 Hz, J = 16.9 Hz, 4 H, CH=), 4.95–4.86
(m, 8 H, =CH2), 4.72 (s, 2 H, Ar-CH2-O), 3.87 (t, J = 6.5 Hz, 8 H,
OCH2), 2.03–1.96 (m, 8 H, CH2CH=), 1.69–1.61 (m, 4 H,
OCH2CH2), 0.95 [s, 9 H, SiC(CH3)3], 0.11 [s, 6 H, Si-(CH3)2] ppm.
1
Yield: 1.03 g (92%). H NMR (500 MHz, CDCl3): δ = 7.71 (t, J =
7.7 Hz, 1 H, 4-H), 7.19 (t, J = 8.3 Hz, 1 H, 4ЈЈ-H), 7.18 (d, J =
7.7 Hz, 2 H, 3-H, 5-H), 6.54 (d, J = 8.3 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 6.53
(s, 2 H, 3Ј-H, 5Ј-H), 5.37–5.30 (m, 4 H, CH=), 4.72 (s, 2 H, Ar-
CH2-O), 3.91–3.84 (m, 8 H, OCH2), 2.01–1.92, 1.89–1.81 (2 m, 8 H,
CH2CH=), 1.67–1.58, 1.56–1.49 (2 m, 8 H, OCH2CH2), 0.95 [s,
9 H, SiC(CH3)3], 0.11 [s, 6 H, Si-(CH3)2] ppm. 13C NMR
(125 MHz, CDCl3): δ = 157.7 (s, C-2ЈЈ, C-6ЈЈ), 157.5 (s, C-2Ј, C-
6Ј), 154.4 (s, C-2), 154.3 (s, C-6), 142.7 (s, C-4Ј), 134.6 (d, C-4),
129.9 (d, =CH), 128.9 (d, C-4ЈЈ), 123.7 (d, C-3), 123,5 (d, C-5),
120.5 (s, C-1ЈЈ), 118.9 (s, C-1Ј), 104.3 (d, C-3ЈЈ, C-5ЈЈ), 101.8 (d, C-
3Ј, C-5Ј), 66.5, 66.4 (2 t, OCH2), 65.2 (t, Ar-CH2-O), 29.5, 29.4 (2
t, OCH2CH2), 25.9 [q, C(CH3)], 23.3 (t, CH2CH=), 18.4 [s,
C(CH )], –5.14 [q, Si-(CH )] ppm. IR (KBr): ν = 2939, 2867, 1597,
˜
3
3
1431, 1248 cm–1. MS (ESI): m/z (%) = 656 (100) [M + H]+.
13C NMR (125 MHz, CDCl3): δ = 157.8 (s, C-2ЈЈ, C-6Ј), 157.6 (s, 15-(Hydroxymethyl)-2,11,13,22-tetraoxa-1,12(1,3,2)-dibenzena-
C-2Ј, C-6Ј), 154.2 (s, C-2), 154.0 (s, C-6), 142.82 (s, C-4Ј), 138.0 (d, 23(2,6)-pyridinabicyclo[10.10.1]tricosaphan-6,17-diene (14): 15-
CH=), 134.5 (d, C-4), 128.9 (d, C-4ЈЈ), 123.8 (d, C-3), 123.6 (d, C- [(tert-Butyldimethylsilyloxy)methyl]-2,11,13,22-tetraoxa-
5), 121.3 (s, C-1ЈЈ), 119.6 (s, C-1Ј), 114.8 (t, =CH2), 105.7 (d, C-
3ЈЈ, C-5ЈЈ), 103.1 (d, C-3Ј, C-5Ј), 67.9, 67.8 (2 t, OCH2), 65.1 (t,
1,12(1,3,2)-dibenzena-23(2,6)-pyridinabicyclo[10.10.1]tricosaphan-
6,17-diene (13, 1.14 g, 1.73 mmol) was dissolved in tetrahydrofuran
Ar-CH2-O), 30.0, 29.9 (2 t, CH2CH=), 28.3, 28.2 (2 t, OCH2CH2), (20 mL) and tetrabutylammonium fluoride trihydrate (723 mg,
25.9 [q, C(CH3)], 18.4 [s, C(CH3)], –5.17 [q, Si-(CH3)] ppm. IR
1.91 mmol) was added. After 45 min stirring at room temp., the
solvent was evaporated in vacuo, and the residue was purified by
column chromatography (silica gel, cyclohexane/ethyl acetate, 1:3)
(KBr): ν = 3053, 2986, 1640, 1598, 1432, 1102, 895 cm–1. MS (ESI):
˜
m/z (%) = 712 (100) [M + H]+.
978
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 972–980

Concave Pyridines for Bifunctional Acid–Base Catalysis
FULL PAPER
280 mg (98%) of 16. H NMR (500 MHz, CDCl3): δ = 7.67 (t, J
to yield 918 mg (98 %) of 14. 1H NMR (500 MHz, CDCl3/
1
CD3OD): δ = 7.79 (t, J = 7.7 Hz, 1 H, 4-H), 7.27, 7.26 (4 d, each = 7.7 Hz, 1 H, 4-H), 7.19 (t, J = 8.3 Hz, 1 H, 4ЈЈ-H), 7.17 (d, J =
J = 7.7 Hz, 2 H, 3-H, 5-H), 7.24 (t, J = 8.4 Hz, 1 H, 4Ј-H), 6.57 (s,
2 H, 3Ј-H, 5Ј-H), 6.56 (d, J = 8.4 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 5.36–5.27
7.7 Hz, 2 H, 3-H, 5-H), 6.57 (d, J = 8.3 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 6.54
(s, 2 H, 3Ј-H, 5Ј-H), 5.71, 5.70 (2 tdd, J = 6.7 Hz, J = 10.2 Hz, J
(m, 4 H, =CH, E/Z), 4.60 (s, 2 H, Ar-CH2-OH), 3.95–3.81 (m, 8 H, = 16.9 Hz, 4 H, CH=), 4.95–4.87 (m, 8 H, =CH2), 4.63 (s, 2 H, Ar-
OCH2), 1.98–1.80 (m, 8 H, CH2CH=), 1.70–1.60, 1.56–1.46 (2 m, CH2-O), 3.88–3.83 (m, 8 H, OCH2), 2.01–1.92, (m, 8 H, CH2CH=),
8 H, OCH2CH2) ppm. 13C NMR (125 MHz, CDCl3/CD3OD): δ = 1.64–1.54 (m, 8 H, OCH2CH2), 1.38–1.30 (m, 8 H, CH2) ppm. 13C
157.4 (s, C-2Ј, C-6Ј), 157.3 (s, C-2ЈЈ, C-6ЈЈ), 153.7 (s, C-2), 153.6 (s,
NMR (125 MHz, CDCl3): δ = 157.8 (2 s, C-2Ј, C-6Ј, C-2ЈЈ, C-6ЈЈ),
C-6), 142.9 (s, C-4Ј), 135.2 (d, C-4), 129.6 (d, =CH), 129.3 (d, C- 154.1 (s, C-2), 153.9 (s, C-6), 142.6 (s, C-4Ј), 138.7 (d, CH=), 134.7
4ЈЈ), 124.1, 124.0 (2 d, C-3, C-5), 118.9 (s, C-1Ј), 117.4 (s, C-1ЈЈ),
103.9 (d, C-3ЈЈ, C-5ЈЈ), 102.3 (d, C-3Ј, C-5Ј), 66.2 (t, OCH2), 64.8
(t, Ar-CH2-OH), 29.1 (t, CH2CH=), 22.9 (t, OCH2CH2) ppm. IR
(d, C-4), 128.9 (d, C-4ЈЈ), 123.8 (d, C-3, C-5), 121.1 (s, C-1ЈЈ), 120.1
(s, C-1Ј), 114.4 (t, =CH2), 105.7 (d, C-3ЈЈ, C-5ЈЈ), 103.9 (d, C-3Ј,
C-5Ј), 68.5 (t, OCH2), 65.4 (t, Ar-CH2-OH), 33.2 (t, CH2CH=),
(KBr): ν = 3405, 2928, 2856, 1598, 1458, 1432, 1102 cm–1. MS 28.5 (t, OCH CH ), 25.1 (t, CH ) ppm. IR (KBr): ν = 2937, 2865,
˜
˜
2
2
2
(ESI): m/z (%) = 564 (72) [M + Na]+, 542 (100) [M + H]+.
1639, 1598, 1458, 1431, 1249, 1121 cm–1. MS (ESI): m/z (%) = 654
(100) [M + H]+.
Methyl 3-({2,11,13,22-Tetraoxa-1,12(1,3,2)-dibenzena-23(2,6)-pyri-
dinabicyclo[10.10.1]tricosaphan-6,17-dien-15-yl}methyloxy)benzoate
(15): 15-(Hydroxymethyl)-2,11,13,22-tetraoxa-1,12(1,3,2)-di-
benzena-23(2,6)-pyridinabicyclo[10.10.1]tricosaphan-6,17-diene
(14, 332 mg, 612 µmol), methyl-3-hydroxybenzoate (94.0 mg,
614 µmol) and triphenylphosphane (204 mg, 776 µmol) were dis-
solved in tetrahydrofuran (20 mL). At 0 °C, diisopropyl azodicar-
boxylate (184 µL, 946 µmol) was added and the mixture was stirred
for 18 h at room temp. After addition of water (10 mL), the layers
were separated and the aqueous layer was extracted with diethyl
ether (3ϫ15 mL). The combined organic layer was washed with
brine (2ϫ15 mL) and dried with magnesium sulfate. The solvent
was evaporated in vacuo, and the residue was purified by column
chromatography (silica gel, cyclohexane/ethyl acetate, 3:1) and by
chromatography with a chromatotron (silica gel, cyclohexane/ethyl
acetate, 9:1 to 3:1) to yield 360 mg (87 %) of 15. 1H NMR
(600 MHz, CDCl3): δ = 7.73 (t, J = 7.7 Hz, 1 H, 4-H), 7.67–7.64
(m, 2 H, Ar-4-H, Ar-6-H), 7.35 (t, J = 7.9 Hz, 1 H, Ar-5-H), 7.20
(t, J = 8.3 Hz, 1 H, 4ЈЈ-H), 7.19 (2 d, J = 7.7 Hz, J = 7.7 Hz, 2 H,
3-H, 5-H), 7.17–7.15 (m, 1 H, Ar-2-H), 6.62 (s, 2 H, 3Ј-H, 5Ј-H),
6.55 (d, J = 8.3 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 5.36–5.30 (m, 4 H, =CH),
5.08 (s, 2 H, ArO-CH2), 3.91 (s, 3 H, Ar-COOCH3), 3.90–3.84 (m,
8 H, OCH2), 2.01–1.92, 1.89–1.81 (2 m, 8 H, CH2CH=), 1.66–1.58,
1.56–1.48 (2 m, 8 H, OCH2CH2) ppm. 13C NMR (125 MHz,
CDCl3): δ = 166.9 (s, ArCOOCH3), 158.7 (Ar-C-3), 157.7 (s, C-2Ј,
C-6Ј), 157.6 (s, C-2ЈЈ, C-6ЈЈ), 154.3 (s, C-2), 154.0 (s, C-6), 137.6 (s,
C-4Ј), 134.8 (d, C-4), 131.4 (s, Ar-C-1), 129.9, 129.8 (2 d, =CH),
129.5 (d, Ar-C-5), 128.9 (d, C-4ЈЈ), 123.8, 123.7 (2 d, C-3, C-5),
122.2 (d, Ar-C-6), 120.2 (d, Ar-C-2), 120.1 (s, C-1ЈЈ), 119.8 (s, C-
1Ј), 115.3 (d, Ar-C-4), 104.2 (d, C-3ЈЈ, C-5ЈЈ), 103.3 (d, C-3Ј, C-5Ј),
70.6 (t, ArO-CH2-), 66.6, 66.5 (2 t, OCH2), 52.2 (q, ArCOOCH3),
29.4, 29.3 (2 d, CH2CH=), 23.2, 23.1 (2 t, OCH2CH2-) ppm. IR
15-(Hydroxymethyl)-2,13,15,26-tetraoxa-1,14(1,3,2)-dibenzena-
27(2,6)-pyridinabicyclo[12.12.1]heptacosaphan-7,20-diene (17): Syn-
thesis according to the general procedure: Benzylidenebis(tricy-
clohexylphosphane)dichlororuthenium (41 mg, 50 µmol) and 2-
[2,6-bis(hex-5-enyloxy)phenyl]-6-[2,6-bis(hex-5-enyloxy)-4-(hy-
droxymethyl)phenyl]pyridine (16, 405 mg, 621 µmol). Purification:
column chromatography on silica gel eluting with cyclohexane/
ethyl acetate (1:3). Yield: 330 mg (89 %). 1H NMR (500 MHz,
CDCl3): δ = 7.69 (t, J = 7.7 Hz, 1 H, 4-H), 7.21 (t, J = 8.3 Hz, 1 H,
4Ј-H), 7.16, 7.12 (4 d, each J = 7.7 Hz, 2 H, 3-H, 5-H), 6.56 (d, J
= 8.4 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 6.44 (s, 2 H, 3Ј-H, 5Ј-H), 5.29–5.16
(m, 4 H, =CH, E/Z), 4.55 (3 s, 2 H, Ar-CH2-OH), 3.96–3.68 (m,
8 H, OCH2), 2.14–1.89 (m, 8 H, CH2CH=), 1.60–1.24 (m, 20 H,
CH2) ppm. 13C NMR (125 MHz, CDCl3/CD3OD): δ = 157.9 (s, C-
2Ј, C-6Ј), 157.7 (s, C-2ЈЈ, C-6ЈЈ), 154.4 (s, C-2), 154.3 (s, C-6), 143.3
(s, C-4Ј), 134.8 (d, C-4), 130.7 (d, =CH), 129.0 (d, C-4ЈЈ), 123.8,
123.7 (2 d, C-3, C-5), 120.2 (s, C-1Ј), 118.8 (s, C-1ЈЈ), 104.6 (d, C-
3ЈЈ, C-5ЈЈ), 102.6 (d, C-3Ј, C-5Ј), 68.7 (t, OCH2), 64.6 (t, Ar-CH2-
OH), 31.6 (t, CH2CH=), 27.6 (t, OCH2CH2), 26.6, 24.9 (3 t, CH2)
ppm. IR (KBr): ν = 2936, 1641, 1598, 1458, 1431, 1249, 1109 cm–1.
˜
MS (ESI): m/z (%) = 598 (100) [M + H]+.
15-(Hydroxymethyl)-2,13,15,26-tetraoxa-1,14(1,3,2)-dibenzena-
27(2,6)-pyridinabicyclo[12.12.1]heptacosaphane (18): Palladium on
charcoal (10%, 110 mg) was mixed with methanol (50 mL) and hy-
drogen gas was bubbled through the mixture for 30 min. This acti-
vated mixture was then mixed with a solution of 15-(hydroxy-
methyl)-2,13,15,26-tetraoxa-1,14(1,3,2)-dibenzena-27(2,6)-pyridina-
bicyclo[12.12.1]heptacosaphan-7,20-diene (17, 300 mg, 503 µmol)
in methanol/chloroform (1:1, 6 mL), and hydrogen gas was bubbled
through the solution for 3 h while stirring at room temperature was
continued. Stirring of the solution under an atmosphere of hydro-
gen was continued for 18 h at room temperature. The solvent was
evaporated in vacuo and the residue was purified by column
chromatography (silica gel, cyclohexane/ethyl acetate, 1:3) and by
chromatography with a chromatotron (silica gel, cyclohexane/ethyl
acetate, 1:1 to 1:3) to yield 290 mg (96 %) of 18. 1H NMR
(500 MHz, CDCl3): δ = 7.68 (t, J = 7.7 Hz, 1 H, 4-H), 7.20 (t, J =
8.3 Hz, 1 H, 4ЈЈ-H), 7.18, 7.16 (2 d, J = 7.7 Hz, 1 H, 3-H, 5-H),
6.56 (d, J = 8.3 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 6.46 (s, 2 H, 3Ј-H, 5Ј-H),
4.62 (s, 2 H, Ar-CH2-OH), 4.03–3.94, 3.90–3.81 (2 m, 8 H, OCH2),
1.62–1.50, 1.34–1.08 (m, 32 H, CH2) ppm. 13C NMR (125 MHz,
CDCl3): δ = 157.8 (s, C-2Ј, C-6Ј), 157.6 (s, C-2ЈЈ, C-6ЈЈ), 154.2 (s,
C-2), 154.1 (s, C-6), 143.2 (s, C-4Ј), 134.5 (d, C-4), 128.9 (d, C-4ЈЈ),
123.9 (d, C-3), 123.8 (d, C-5), 120.5 (s, C-1ЈЈ), 119.1 (s, C-1Ј), 104.9
(d, C-3ЈЈ, C-5ЈЈ), 103.1 (d, C-3Ј, C-5Ј), 68.5 (t, OCH2), 64.7 (t, Ar-
CH2-OH), 28.1 (t, OCH2CH2), 26.7, 25.7, 24.3 (3 t, CH2) ppm. IR
(KBr): ν = 2922, 2867, 1721, 1582, 1455, 1435, 1290, 1279, 1116,
˜
1103 cm–1. MS (ESI): m/z (%) = 698 (19) [M + Na]+, 676 (100) [M
+ H]+. C42H46NO7 (675.81): calcd. C 74.64, H 6.71, N 2.07; found
C 74.68, H 6.91, N 2.12.
2-[2,6-Bis(hex-5-enyloxy)phenyl]-6-[2,6-bis(hex-5-enyloxy)-4-(hy-
droxymethyl)phenyl]pyridine (16): A solution of p-toluenesulfonic
acid (100 mg, 525 µmol) in dry methanol (5 mL) was added drop-
wise over 5 min to a solution of 2-[2,6-bis(hex-5-enyloxy)phenyl]-6-
[2,6-bis(hex-5-enyloxy)-4-(2-tetrahydropyranyloxymethyl)phenyl]-
pyridine (12b, 321 mg, 437 µmol) heated to reflux in dry methanol
(20 mL). Heating was continued for 90 min. The volume was re-
duced to 5 mL. After the addition of saturated aqueous sodium
hydrogen carbonate (5 mL) and chloroform (20 mL), the water
layer was extracted with chloroform (3ϫ20 mL), and the combined
organic layers were washed with brine (15 mL). The solvent was
removed in vacuo, and the residue was purified by column
chromatography (silica gel, cyclohexane/ethyl acetate, 1:3) to yield
(KBr): ν = 3405, 2928, 2856, 1598, 1458, 1432, 1102 cm–1. MS
˜
Eur. J. Org. Chem. 2007, 972–980
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
979

T. Liebig, M. Abbass, U. Lüning
FULL PAPER
(ESI): m/z (%) = 602 (100) [M + H]+. C38H51NO5 (601.81): calcd.
C 75.84, H 8.54, N 2.33; found C 75.92, H 8.71, N 2.32.
[1]
[2]
V. E. Anderson, M. W. Ruszczycky, M. E. Harris, Chem. Rev.
2006, 106, 3236–3251.
For a recent example of bifunctional acid–base catalysis and
corresponding references, see: J. D. Bass, A. Solovyov, A. J.
Pascall, A. Katz, J. Am. Chem. Soc. 2006, 128, 3737–3747.
For a theoretical and experimental study, see: L.-H. Wang, H.
Zipse, Liebigs Ann. 1996, 1501–1509.
U. Lüning “Concave Reagents” in Encyclopedia of Supramolec-
ular Chemistry (Eds.: J. L. Atwood, J. W. Steed), Marcel
Dekker, New York, 2004, pp. 311–318.
U. Lüning, Liebigs Ann. Chem. 1987, 949–955.
U. Lüning, R. Baumstark, K. Peters, H. G. v. Schnering, Lie-
bigs Ann. Chem. 1990, 129–143.
H. Ross, U. Lüning, Angew. Chem. 1995, 107, 2723–2725; An-
gew. Chem. Int. Ed. Engl. 1995, 34, 2555–2557.
H. Ross, U. Lüning, Liebigs Ann. 1996, 1367–1373.
Methyl 3-({2,13,15,26-Tetraoxa-1,14(1,3,2)-dibenzena-27(2,6)-pyri-
dinabicyclo[12.12.1]heptacosaphan-15-yl}methyloxy)benzoate (19):
15-(Hydroxymethyl)-2,13,15,26-tetraoxa-1,14(1,3,2)-dibenzena-
27(2,6)-pyridinabicyclo[12.12.1]heptacosaphane (18, 150 mg,
249 µmol), methyl 3-hydroxybenzoate (38.0 mg, 249 µmol) and tri-
phenylphosphane (83 mg, 316 µmol) were dissolved in tetra-
hydrofuran (10 mL). At 0 °C, diisopropyl azodicarboxylate
(75.0 µL, 385 µmol) was added, and the mixture was stirred for
18 h at room temp. After addition of water (5 mL), the layers were
separated and the aqueous layer was extracted with diethyl ether
(3ϫ15 mL). The combined organic layer was washed with brine
(2ϫ15 mL) and dried with magnesium sulfate. The solvent was
evaporated in vacuo, and the residue was purified by column
chromatography (silica gel, cyclohexane/ethyl acetate, 3:1) and by
chromatography with a chromatotron (silica gel, cyclohexane/ethyl
acetate, 9:1 to 3:1) to yield 120 mg (65 %) of 19. 1H NMR
(600 MHz, CDCl3): δ = 7.69 (t, J = 7.7 Hz, 1 H, 4-H), 7.67–7.64
(m, 2 H, Ar-4-H, Ar-6-H), 7.34 (t, J = 7.9 Hz, 1 H, Ar-5-H), 7.19
(t, J = 8.3 Hz, 1 H, 4ЈЈ-H), 7.18 (d, J = 7.7 Hz, 1 H, 3-H), 7.17 (d,
J = 7.7 Hz, 1 H, 5-H), 7.17–7.15 (m, 1 H, Ar-2-H), 6.63 (s, 2 H, 3Ј-
H, 5Ј-H), 6.55 (d, J = 8.3 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-H), 5.08 (s, 2 H, ArO-
CH2), 3.91 (s, 3 H, Ar-COOCH3), 4.04–3.95, 3.90–3.81 (2 m, 8 H,
OCH2), 1.59–1.50 (m, 8 H, OCH2CH2), 1.36–1.07 (m, 24 H, CH2)
ppm. 13C NMR (125 MHz, CDCl3): δ = 166.9 (s, ArCOOCH3),
158.6 (Ar-C-3), 157.9 (s, C-2Ј, C-6Ј), 157.8 (s, C-2ЈЈ, C-6ЈЈ), 154.4
(s, C-2), 154.0 (s, C-6), 137.5 (s, C-4Ј), 134.5 (d, C-4), 131.4 (s, Ar-
C-1), 129.4 (d, Ar-C-5), 128.8 (d, C-4ЈЈ), 123.8, 123.7 (2 d, C-3, C-
5), 122.2 (d, Ar-C-6), 120.8 (s, C-1ЈЈ), 120.5 (s, C-1Ј), 120.2 (d, Ar-
C-2), 115.2 (d, Ar-C-4), 104.9 (d, C-3ЈЈ, C-5ЈЈ), 103.9 (d, C-3Ј, C-
5Ј), 70.6 (t, ArO-CH2-), 68.6, 68.5 (2 t, OCH2), 52.2 (q, Ar-
COOCH3), 28.0, 27.9, 26.9, 26.8, 25.7, 25.6, 24.4, 24.3 (8 t, CH2)
[3]
[4]
[5]
[6]
[7]
[8]
[9]
S. Konrad, C. Näther, U. Lüning, Eur. J. Org. Chem. 2005,
2330–2337, and refs. cited.
[10] U. Lüning, R. Baumstark, W. Schyja, Tetrahedron Lett. 1993,
34, 5063–5066.
[11] U. Lüning, F. Fahrenkrug, Eur. J. Org. Chem. 2004, 3119–3127.
[12] U. Lüning, M. Abbass, F. Fahrenkrug, Eur. J. Org. Chem. 2002,
3294–3303.
[13] Single hydrogen bonds are weak interactions, the typical bond
energy is 10 to 30 kJ/mol. Therefore, at room temperature in
solution, only a fraction of hydrogen-bond donor and ac-
ceptors will exist in the hydrogen bonded state. In contrast to
the intermolecular formation of a single hydrogen bond, intra-
molecular hydrogen bonds are formed to a much larger extent
due to the vicinity of hydrogen-bond donor and hydrogen-bond
acceptor. The “effective concentration” of both centers is high
in the intramolecular case.
[14] C. Reichardt, Solvents and Solvent Effects in Organic Chemis-
try, 2nd ed., VCH, Weinheim, 1988. See especially Table 4–1,
p. 83.
ppm. IR (KBr): ν = 2922, 2867, 1721, 1582, 1455, 1435, 1290, 1279,
˜
1116, 1103 cm–1. MS (ESI): m/z (%) = 736 (100) [M + H]+.
C46H57NO7 (735.95): calcd. C 75.07, H 7.81, N 1.90; found C
75.01, H 7.96, N 2.01.
[15] K. Izutsu, Acid-Base Dissociation Constants in Dipolar Aprotic
Solvents, Chemical Data Series No. 35, Blackwell Scientific
Publications, Oxford, 1990.
[16] See ref.[6] and cited references.
[17] U. Lüning, H. Baumgartner, C. Wangnick, Tetrahedron 1996,
Acknowledgments
52, 599–604.
[18] J. R. Cannon, T. M. Cresp, B. W. Metcalf, M. V. Sargent, G.
Vinciguerra, J. Chem. Soc., C 1971, 3495–3499.
Received: September 26, 2006
The support of this work by the Schwerpunktsprogramm der Deut-
schen Forschungsgemeinschaft SPP 1179 is gratefully acknowl-
edged.
Published Online: December 12, 2006
980
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 972–980