Towards allosteric receptors - Synthesis of Resorcinarene-Functionalized 2,2′-Bipyridines and their metal complexes

FULL PAPER

DOI: 10.1002/ejoc.200900642

Towards Allosteric Receptors – Synthesis of Resorcinarene-Functionalized

2,2Ј-Bipyridines and Their Metal Complexes

Holger Staats,^[a]Friederike Eggers,^[b]Oliver Haß,^[a]Frank Fahrenkrug,^[b]Jens Matthey,^[a]

Ulrich Lüning,*^[b]and Arne Lützen*^[a]

Keywords: Macrocycles / Calixarenes / Nitrogen heterocycles / Supramolecular chemistry / Allosteric receptors

Based on a first example of an allosteric hemicarcerand (1)

two functional moieties on the central bipyridine. Among the

we prepared four new 2,2Ј-bipyridines that carry resorcinar- transition metal complexes that act as effectors for the confor-

ene moieties in a highly convergent manner. Upon coordina-

tion to suitable transition metal ions or their complexes these

compounds undergo conformational changes in a way that

they switch between “open” and “closed” forms (2, 3, and 4)

or vice versa (5), thus, bringing together or separating the

mational switching, [Re(CO)₅Cl] and monomeric copper(I)

complexes of sterically hindered 2,9-arylated 1,10-phenan-

throlines proved to be very effective.

Germany, 2009)

Introduction

The transfer of principles of regulating mechanisms such

as allosteric effects or self-assembly processes to artificial

systems is both challenging and promising.^[1]Our approach

aims at the use of coordination to metal centers to achieve

the formation of sophisticated supramolecular architectures

or change their conformation in a defined manner in order

to control a specific functional property.^[2]The latter one

can be achieved by employing cooperative effects in the se-

lective association of more than one substrate to different

binding sites of a single receptor.^[1b]These trigger confor-

mational rearrangements that switch on or off some func-

tion that is intrinsically embedded in different parts of the

molecule, but which have to be specially arranged in space

for an optimized cooperative action. Some time ago we

were able to develop a heterotropic positive cooperative al-

losteric analogon (1)^[3]of the well known resorcinarene-

based container molecules, also called carcerands and he-

micarcerands.^[4]Its recognition behaviour towards non-po-

lar substrates like the adamantyl ester of adamantyl carbox-

ylic acid can be changed dramatically upon coordination of

a transition metal ion as an effector or modulator to the

central 2,2Ј-bipyridine unit which serves as an allosteric

center (Scheme 1).^[5]

Scheme 1. “On”- (“closed”) and “off”-states (“open”) of allosteric

receptor 1 (1a R = C₅H₁₁; 1b R = C₁₁H₂₃).

[a] Kekulé-Institut für Organische Chemie und Biochemie, Rheini-

sche Friedrich-Wilhelms-Universität Bonn,

Gerhard-Domagk-Str. 1, 53121 Bonn, Germany

Fax: +49-228-73-9608

After having performed a conceptional theoretical study

on the influence of different substituents and substitution

patterns on the energetics of the conformational switching

of 2,2Ј-bipyridines between their syn- and anti-conforma-

tion,^[6]we now took this approach a step further. In this

E-mail: arne.luetzen@uni-bonn.de

[b] Otto-Diels-Institut für Organische Chemie, Christian-

Albrechts-Universität zu Kiel,

Olshausenstr. 40, 24098 Kiel, Germany

Fax: +49-431-880-1558

E-mail: luening@oc.uni-kiel.de

Eur. J. Org. Chem. 2009, 4777–4792

4777

U. Lüning, A. Lützen et al.

FULL PAPER

account we report on the synthesis of a series of four new

4, however, is a first example where we exchange one of

resorcinarene-functionalized

(Scheme 2) and their metal complexes.

2,2Ј-bipyridines

2–5 the resorcinarene moieties against an acetylated aminopyr-

idyl group to get a heterotopic system that offers two dif-

ferent binding sites for different functionalities of a sub-

strate. Whereas the resorcinarene group has an affinity for

non-polar alkyl or aryl groups the aminopyridine offers a

hydrogen bonding pattern to bind polar groups like carbox-

ylic acids.

Finally, 5 again has a different substitution pattern of the

2,2Ј-bipyridine. This leads to yet another concept because

5 is our first example designed to act as a heterotropic,

negative cooperative allosteric system because coordination

of the effector switches the conformation from a closed

“on” to an open “off” form.

Synthesis

The synthesis of 2–5 requires 2,2Ј-bipyridine building

blocks that are either symmetrically (4,4Ј- or 6,6Ј-) or non-

symmetrically 4,6Ј-disubstituted. Furthermore, they all

need a monofunctionalized resorcin[4]arene. In addition, 4

also needs the preparation of an acetylated aminopyridine

building block that can be coupled to the 2,2Ј-bipyridine.

4,4Ј-Dibromo-2,2Ј-bipyridine (10) was obtained in a four

step synthesis starting from 2,2Ј-bipyridine (6) (Scheme 3).

Adapting a protocol of Sheldon et al. developed for the

synthesis of 4,4Ј-dichloro-2,2Ј-bipyridine^[7]2,2Ј-bipyridine

was converted into the corresponding bis(N-oxide) 7 upon

reaction with peracetic acid. 7 was then subjected to a two-

fold nitration followed by nucleophilic substitution and re-

moval of the oxygen atoms to give 10 in an overall yield of

23%.

Scheme 2. Next generation of resorcinarene-functionalized 2,2Ј-bi-

pyridines 2–5 (R = alkyl chains).

Results and Discussion

Scheme 3. Synthesis of 4,4Ј-dibromo-2,2Ј-bipyridine (10).

Like 1, the new receptors 2, 3, and 4 were all designed

to act as heterotropic positive cooperative allosteric systems

(Scheme 2). 1 and 2 differ in the linker group between the

resorcinarenes and the bipyridine: whereas 1 has ester

groups we employed ethynylene groups in 2. 2 and 3 are

constitutional isomers which leads to an important concep-

tional difference between them: in 1 and 2 the substrate and

the effector binding sites are on different sides of the 2,2Ј-

bipyridine due to its 4,4Ј-substitution pattern. However, a

change of the substitution pattern from 4,4Ј to 6,6Ј in 3

leads to a situation where the binding sites of the substrate

and the effector are now on the same side of the bipyridine

thus bringing them in close contact.

6,6Ј-Dibromo-2,2Ј-bipyridine (11) was prepared in mod-

erate yield of 29% starting from commercially available 2,6-

dibromopyridine in a copper-mediated Ullmann-like cou-

pling reaction (Scheme 4) introduced by Holm et al. in

1973^[8]and modified by Butler and Soucy-Breau.^[9]

Scheme 4. Synthesis of 6,6Ј-dibromo-2,2Ј-bipyridine (11).

4778

www.eurjoc.org

Eur. J. Org. Chem. 2009, 4777–4792

Towards Allosteric Receptors

2,2Ј-Bipyridine-6,6Ј-dicarboxylic acid (14) was obtained atom (18).^[13]Interestingly, all Sonogashira as well as

in four steps starting from commercially available 2-chloro- Negishi protocols that we tested to prepare the ethynylated

4-methylpyridine

and

2-bromo-6-methylpyridine cavitand 19 failed. However, its synthesis could finally be

(Scheme 5). Modified Negishi cross-coupling^[10]of the two achieved by applying Suzuki cross-coupling conditions to

pyridines gave the corresponding dimethylated 2,2Ј-bipyr- the reaction of 18 with TMS-protected acetylene boronic

idine 12 which was converted into the dicarboxylic acid 14 acid dimethyl ester.^[13]

upon oxidation with potassium permanganate. Unfortu-

nately, this compound is very insoluble in common organic

solvents. Since the reaction did not work too well we had

to transform crude 14 into the corresponding dimethyl ester

13 in order to isolate and purify it in this form which is the

reason for the low yield. Subsequent saponification allowed

isolation of the dicarboxylic acid 14.

Scheme 7. Synthesis of monofunctionalized cavitands 17–19.

Scheme 5. Synthesis of 2,2Ј-bipyridine-6,6Ј-dicarboxylic acid (14).

Monohydroxylated and monoethynylated resorcinarenes

The aminopyridine building block 22 could be prepared

in three steps starting from commercially available 2-amino-

6-bromopyridine (Scheme 8). For this purpose, the amino

group was first acetylated before we introduced the TMS-

protected ethynyl group via Sonogashira cross-coupling. Fi-

nal fluoride-mediated deprotection of the silyl group gave

22 in excellent overall yield.

17 and 19 could both be prepared from non-functionalized

cavitand 16 which could be synthesized in two steps from

resorcinol (Scheme 6).^[11,12]

Scheme 8. Synthesis of 2-N-acetylamino-6-ethynylpyridine 22.

Sonogashira cross-coupling of 4,4Ј-dibromo-2,2Ј-bipyr-

Scheme 6. Synthesis of cavitand 16.

As shown in Scheme 7, monolithiation of 16 can then be

used to introduce a number of functional groups as, for idine (10) with ethynylated cavitand 19 gave target com-

example, a hydroxy group (17, via borylation) or a bromine pound 2 together with singly coupled bipyridine 23 which

Eur. J. Org. Chem. 2009, 4777–4792

www.eurjoc.org

4779

U. Lüning, A. Lützen et al.

FULL PAPER

could both be isolated in acceptable yields of 49% and

Target compound 3 was prepared in a similar way in a

51%, respectively.^[14]23 could be used directly for a second twofold Sonogashira reaction of resorcinarene 19 and bi-

Sonogashira reaction with 22 to yield 4 (Scheme 9).

pyridine 11 in a very good yield of 75% (Scheme 10).

In order to activate dicarboxylic acid 14 for a twofold

esterification it was transformed into the corresponding

dicarboxylic acid dichloride by reaction with thionyl

chloride and reacted without purification with hydroxylated

cavitand 17 to give target compound 5 in 55% isolated yield

(Scheme 11).

Scheme 11. Synthesis of resorcinarene-functionalized 2,2Ј-bipyr-

idine 5.

Scheme 9. Synthesis of resorcinarene-functionalized 2,2Ј-bipyr-

idines 2 and 4.

Metal Coordination

Having achieved the synthesis of our resorcinarene-func-

tionalized 2,2Ј-bipyridine ligands we studied their coordina-

tion behaviour towards a number of different transition

metal ions or complexes thereof. In our initial study^[3]sil-

ver(I) and copper(I) tetrafluoroborates were used to pre-

pare metal complexes [M1₂]BF₄. As expected these salts do

also form stable complexes with our new ligands 2–5 as

proven by NMR spectroscopy and ESI mass spectrometry.

However, only 2 and 4 having the same substitution pattern

of the central 2,2Ј-bipyridine as 1 do also form complexes

of the same 1:2 metal-to-ligand stoichiometry as 1. Chang-

ing the substitution pattern from 4,4Ј to 6,6Ј or 4,6Ј like in

3 and 5 makes it impossible to form a 1:2 complex due to

steric crowding. Thus, in these cases only 1:1 complexes

could be observed which seem to carry coordinated solvent

molecules to saturate the coordination sphere of the metal

ions (Figure 1).

Scheme 10. Synthesis of resorcinarene-functionalized 2,2Ј-bipyr-

idine 3.

4780

www.eurjoc.org

Eur. J. Org. Chem. 2009, 4777–4792

Towards Allosteric Receptors

Figure 1. Positive ESI MS of a 1:1 mixture of 3 and [Cu(CH₃CN)₄]-

BF₄in benzene/acetonitrile, 25:1.

Figure 2. NMR spectra (500.1 MHz in CDCl₃at 298 K) of a) li-

gand 4 and b) its rhenium complex [Re(CO)₃(4)Cl] (the upfield

region containing the alkyl signals is omitted).

The 1:2 metal-to-ligand stoichiometry found in the silver

and copper complexes of 2 and 4, however, is very inconve-

nient to study the host-guest chemistry of these compounds

because this could lead to a very complicated equilibrium

However, there are two important differences with the

between 1:2:2, 1:2:1, 1:2:0 and some more metal-to-ligand- rhenium complex compared to the other effectors: first, due

to-substrate assemblies which is very difficult to analyze. to the strongly coordinating chloride ion the resulting com-

Thus, it would be much more convenient if one could selec- plexes are neutral species and thus should have different

tively form 1:1 metal-to-ligand complexes. This can be properties compared to the other complexes with the hardly

achieved with metal complexes that offer only two coordi- coordinating anions that distribute more cationic charge

nation sites for the complexation of a single 2,2Ј-bipyridine into the ligand structure. Second, the binding of the rhe-

moiety. Scheme 12 shows two possibilities that we tested in nium to the 2,2Ј-bipyridine is usually thermodynamically

this context.

and kinetically very stable so that it is virtually inert and

survives even boiling in the presence of a 20-fold excess of

even better chelate ligands like 1,10-phenanthroline. Al-

though this is very nice to study the host-guest chemistry

of our ligands bound to this effector, it is of course not, if

it should act as an allosteric receptor that can be switched

on and off several times. The only exception to this is again

the rhenium complex of ligand 5. In this case the rhenium

can easily be removed from the ligand by adding EDTA

solution.

Therefore, we turned our attention to heteroleptic com-

plexes with two bidentate ligands.^[15]If for instance cop-

per(I) ions are mixed with two different bidentate ligands

L¹and L²in a 1:1:1 ratio, three possible complexes can

form: two homoleptic complexes L¹Cu⁺and L²Cu⁺and

2

a heteroleptic complex L¹L²Cu⁺. The statistical distribution

will be 1:2:1 but the use of sterically hindered ligands will

change the composition. When the hindered ligands (e.g.

L²) are too large to form a L²Cu⁺complex, the hetero-

2

leptic complex L¹L²Cu⁺will form exclusively even when

Scheme 12. Metal complexes that can only bind to a single 2,2Ј-

bipyridine ligand (L = 2,2Ј-bipyridine ligand): pentacarbonylrhe-

nium chloride (2,2Ј-bipyridine substitutes two carbonyl ligands)

and sterically hindered 1,10-phenanthrolines (phen).

L¹Cu⁺was quite stable because only the formation of

2

L¹L²Cu⁺ensures that all ligands and all coordination sites

of the copper(I) ion are occupied. Therefore, we have used

here copper(I) complexes of sterically hindered 1,10-phen-

Pentacarbonylrhenium chloride was found to form stable anthrolines that have originally been designed to be em-

orange 1:1 complexes with our ligands 2, 4, and 5 (Figure 2) ployed as concave reagents.^[16]With these, no 2:1 complexes

that could (except for the complex of 5 that was found to are formed, and the 1:1 complexes offer two remaining co-

undergo degradation when exposed to silica gel) even be ordination sites for the binding of a single 2,2Ј-bipyridine.

purified by column chromatography on silica gel.

These complexes are very promising since they do also form

Eur. J. Org. Chem. 2009, 4777–4792

www.eurjoc.org

4781

U. Lüning, A. Lützen et al.

FULL PAPER

cationic species from which the 2,2Ј-bipyridine can be

cleaved upon addition of an even stronger chelating ligand

like another phenanthroline or ethylene diamine tetraacetic

acid (EDTA). Furthermore, these compounds offer the pos-

sibility to fine-tune e.g. the solubility properties upon chem-

ical modification of the phenanthrolines periphery. Thus,

we chose previously prepared sterically hindered 2,9-aryl-

ated 1,10-phenanthroline 24^{[16b,16l,16m,16n]}as a first example.

In order to make this compound more soluble in polar sol-

vents like methanol which should be beneficial for the re-

cognition of hardly polar substrates because of additional

solvophobic effects, we decided to prepare also a new deriv-

ative carrying triethylene glycol chains (25) (Scheme 13).

Scheme 15. Synthesis of 2-iodo- (28) and 2-bromoresorcinol (30).

Scheme 13. 2,9-Arylated 1,10-phenanthrolines 24 and 25.

For the synthesis of 25, two building blocks were pre-

pared. One was 2,9-diiodo-1,10-phenanthroline (26) and

the other one the boronic acid 27 which contained ortho

triethylene glycol chains.

Scheme 16. Synthesis of triethylene glycolated resorcinols 32 and

33.

2,9-Diiodo-1,10-phenanthroline 26 was synthesized fol-

lowing the well known procedure described by Lewis et

al.^[17]and Yamada et al.^[18]Starting from 1,10-phenan-

throline, first chloro atoms were introduced in positions 2

and 9 (steps 1–3) and then a chloro-iodo exchange was ac-

complished^[16k,19](Scheme 14).

After alkylation, the boronic acid 27 was synthesized by

halogen-lithium exchange and work-up with trimethyl-

borate and hydrolysis (Scheme 17).

Scheme 14. Synthesis of 2,9-diiodo-1,10-phenanthroline (26).

Phenylboronic acid 27 was synthesized starting from res-

orcinol which was first halogenated with iodine or bromine

following literature procedures to yield 2-iodo-^[20]and 2-

Scheme 17. Synthesis of boronic acid 27.

Purification of the crude oily product by column

bromoresorcinol^[21,22](28) and (30) in one and in two steps, chromatography was not successful but resulted in cleavage

respectively, in about 70% (Scheme 15).

of the carbon–boron bond to give 1,3-bis(1,4,7,10-tetraoxa

The phenol groups of the halogenated resorcinols 28 and dodecyl)benzene (34). Therefore, crude 27 was used in the

30 were then alkylated using the strategy of Williamson subsequent Suzuki reaction with 2,9-diiodo-1,10-phenan-

with 3,6,9-trioxaundecyl-(4-methylbenzene)sulfonate (31) throline 26 (Scheme 18).^[24]The coupling was carried out in

(Scheme 16) to give triethylene glycolated 32 and 33. Sulf- a solution of 1,2-dimethoxyethane (DME) and water (4:1)

onate 31 was synthesized from triethylene glycol monoethyl with tetrakis(triphenylphosphane)palladium(0) ([Pd(PPh₃)₄])

ether following a literature procedure.^[23]

as catalyst and barium hydroxide as base.^[25]Unfortunately,

4782

www.eurjoc.org

Eur. J. Org. Chem. 2009, 4777–4792

Towards Allosteric Receptors

this reaction turned out to be quite difficult also because were designed as potential allosteric receptors. All of these

monoarylated byproducts (35 and 36) were obtained which ligands could be demonstrated to bind to different transi-

hampered the purification of 25 even more.

tion metal salts or complexes which causes long-range con-

formational changes within the ligand structure thus

switching between open and closed conformations (2, 3,

and 4) or vice versa (5) upon addition of these effectors.

Among these [Re(CO)₅Cl] and copper(I) complexes of steri-

cally hindered 1,10-phenanthrolines proved to be very ef-

ficient to ensure 1:1 metal-to-ligand stoichiometries. We are

currently evaluating the host-guest chemistry of these sys-

tems which will be reported in due course.

Experimental Section

Scheme 18. Synthesis of 2,9-arylated 1,10-phenanthroline 25.

General Remarks: All solvents were distilled and thoroughly dried

prior to use according to standard procedures. All syntheses with

air- and moisture-sensitive compounds were performed under

Schlenk conditions, with argon as the inert gas. For purification

purposes column chromatography on silica gel or on basic alumina

was applied. Solvents used as eluents for column chromatography

were distilled prior to use. The preparative, centrifugally ac-

celerated, thin-layer chromatograph (Chromatotron) was a model

7924T from Harrison Research. Detection was done under UV

light (254 and 366 nm). Gas chromatography was performed with

6890 N (Agilent); split/splitless injector, split ratio 11:1, injector

24 and 25 were then studied together with ligand 1b with

regard to their ability to form 1:1:1 complexes with cop-

per(I) ions. As 24, 25 could be proven to form only a 1:1

[Cu(25)]BF₄complex with copper(I) ions but no dimeric

species. Upon addition of 1b to solutions of [Cu24]BF₄and

[Cu25]BF₄, we observed the almost instant and quantitative

formation of [Cu(24)(1b)]BF₄and [Cu(25)(1b)]BF₄(Fig-

ure 3). As expected addition of an excess of 1b does not

lead to [Cu(1b)₂]BF₄complexes but the heteroleptic^[15]1:1:1

complexes remained intact.

1

temp. 240 °C, FID detector temp. 250 °C. H and ¹³C NMR spec-

tra were recorded at 298 K on a Bruker AC 200 (200 MHz), ARX

300 (300.1 MHz or 75.8 MHz), DMX 400 (400.1 MHz), DRX 500

(500.1 MHz or 125.8 MHz), or Avance 600 (600.1 MHz or

150 MHz) instruments, respectively. ¹H NMR chemical shifts are

reported as δ values (ppm) relative to residual non-deuterated sol-

vent as the internal standard. ¹³C NMR chemical shifts are given

in δ values (ppm) relative to the deuterated solvent as the internal

standard. Unless otherwise noticed, signals were assigned on the

basis of ¹H, ¹³C, H,H-COSY, HSQC or HMQC, and HMBC-

NMR experiments. IR spectra were measured on a Perkin–Elmer

1600 Series device. Mass spectra were taken on a Finnigan MAT

212 with data system MMS–ICIS (EI, CI, isobutane, ammonia), a

Finnigan MAT 95 with data system DEC-Station 5000 (CI, isobut-

ane or ammonia; HiRes-CI, isobutane or ammonia; FD), an A.E.I.

MS-50 (EI; HiRes-EI), a Thermoquest Finnigan LCQ (ESI), a Q-

ToF Ultima from Micromass (ESI, HiRes-ESI), a Finnigan MAT

8230 or MAT 8200 (EI, HiRes-EI), or on an Applied Biosystems

Mariner ESI-TOF MS 5280 (ESI). Melting points were measured

with a hot-stage microscope SM-Lux from Leitz or a SMP-20 from

Büchi and are not corrected. Elemental analyses were carried out

with a Fisons Instrument EA1108, an EuroVector instrument, or

a Heraeus Vario EL. Please note that CHN-analyses could only be

conducted with fluorine-free samples. Please also note that it is well

known that the cavitand compounds with long alkyl chains gen-

erally do not give sufficient elemental analyses because they always

contain some traces of solvent molecules. Thus, we did not perform

these but give high-resolution MS data instead in most cases.

Chemicals and reagents (except for the solvents) obtained from

commercial sources were used as received. The following com-

pounds were prepared according to published procedures: bis(re-

sorcinarene)-functionalized 2,2Ј-bipyridine 1b,^[3]2,2Ј-bipyridine

N,NЈ-dioxide (7),^[7]4,4Ј-dinitro-2,2Ј-bipyridine N,NЈ-dioxide (8),^[7]

6,6Ј-dibromo-2,2Ј-bipyridine (11),^[9]4,6Ј-dimethyl-2,2Ј-bipyridine

(12),^[10c]resorcin[4]arene 15a [2,8,14,20-tetrapentylpentacyclo-

(19. 3.1^3,7.1^9,13.1^15,19)-octacosa-1(25),3,5,7(28),9,11,13(27),15,17,

Figure 3. NMR spectra (500.1 MHz in [D₆]benzene/[D₃]acetonitrile

(1:1) at 298 K) of a) a 1:1 mixture of [Cu(24)]BF₄and 1b showing

only signals of the [Cu(24)(1b)]BF₄complex, b) a 1:0.5 mixture

[Cu(24)]BF₄and 1b showing signals of both the [Cu(24)(1b)]BF₄

complex and [Cu(24)]BF₄, and c) [Cu(24)]BF₄(the upfield region

containing the alkoxy and the alkyl signals is omitted, the star indi-

cate phenanthroline proton signals of the [Cu(24)]BF₄complex, the

dot indicate phenanthroline proton signals of the [Cu(24)(1b)]BF₄

complex).

Conclusions

We have synthesised four new resorcinarene-function-

alized 2,2Ј-bipyridines in a highly convergent manner that 19(26),21,23-dodecan-4,6,10,12,16,18,22,24-octol],^[26]resorcin[4]-

Eur. J. Org. Chem. 2009, 4777–4792

www.eurjoc.org

4783

U. Lüning, A. Lützen et al.

FULL PAPER

arene 15b [2,8,14,20-tetraundecylpentacyclo(19.3.1^3,7.1^9,13.1^15,19)-

octacosa-1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecan-

4,6,10,12,16,18,22,24-octol],^[26]cavitand 16b (1,21,23,25-tetraun-

decyl-2,20:3,19-dimetheno-1H,21H,23H,25H-bis[1,3]dioxocino-

[5,4-i:5Ј,4Ј-iЈ]benzo[1,2-d:5,4-dЈ]bis[1,3]benzodioxocin),^[13]bromi-

nated cavitand 18 (7-bromo-1,21,23,25-tetraundecyl-2,20:3,19-di-

metheno-1H,21H,23H,25H-bis[1,3]dioxocino[5,4-i:5Ј,4Ј-iЈ]-

benzo[1,2-d:5,4-dЈ]bis[1,3]-benzodioxocin),^[13]ethynylated cavitand

19 (7-ethynyl-1,21,23,25-tetraundecyl-2,20:3,19-dimetheno-

1H,21H,23H,25H-bis[1,3]dioxocino[5,4-i:5Ј,4Ј-iЈ]benzo[1,2-d:5,4-

dЈ]bis[1,3]benzodioxocin),^[13]2,9-bis[2,6-bis(methoxy)phenyl]-1,10-

phenanthroline (24),^[16a,16b]2,9-dichloro-1,10-phenanthroline,^[17,18]

and 2,9-diiodo-1,10-phenanthroline (26).^[17,18]

36.4 (cav-C_benzyl), 86.6 (C_alkyne), 94.5 (C_alkyne), 99.1 (cav-C_acetal),

99.5 (cav-C_acetal), 111.9 (cav-C_aryl), 116.4, 116.5 (cav-C_aryl), 120.7

(cav-C_aryl), 121.4 (cav-C_aryl), 123.1 (bipy-C_aryl), 124.8 (bipy-C_aryl),

125.9 (bipy-C_aryl), 127.3 (bipy-C_aryl), 132.4 (bipy-C_aryl), 134.1

(bipy-C_aryl), 138.2, 138.3, 138.4, 138.6, 138.7 (5ϫ cav-C_aryl) 149.2

(bipy-C_aryl), 149.8 (bipy-C_aryl), 154.7, 154.8, 155.0, 155.7 (4 ϫ

cav-C_aryl), 156.5 (2 ϫ bipy-C_aryl) ppm. MS (CI, isobutane, pos.

mode): m/z (%) = 1411.8 (100) [MH]⁺. HiRes-MS (pos. ESI) calcd.

for [C₈₈H₁₁₈⁸¹BrN₂O₈]⁺m/z = 1411.8081; found m/z = 1411.8170

(∆ = –6.0 ppm).

Bis(resorcinarene)-Functionalized 2,2Ј-Bipyridine 3: A two-neck

flask equipped with a septum and a reflux condenser was charged

with 25 mg of 19 (0.08 mmol), 190 mg of 11 (0.16 mmol, 2 equiv.),

1.5 mg (8 µmol, 10 mol-%) of copper(I) iodide, and 6 mg of

[Pd(PPh₃)₂Cl₂] (10 mol-%) and repeatedly evacuated and flushed

with argon. 15 mL of dry triethylamine and 10 mL of dry THF

were added via syringe and the resulting mixture was heated to

40 °C for 24 h. After that time 20 mL of diethyl ether were added

and the organic phase was washed four times with water and with

brine and dried with sodium sulfate. Removing of the organic sol-

vents in vacuo gave the crude product mixture which was subjected

to column chromatography on silica gel (eluent: n-hexane/ethyl ace-

tate, 5:1 + 0.5% triethylamine) to yield 150 mg of 3 as an amorph-

ous solid (60 µmol, 75%). R_f= 0.10 (n-hexane/ethyl acetate, 5:1 +

0.5% triethylamine). ¹H NMR (500.1 MHz, CDCl₃, 298 K): δ =

Bis(resorcinarene)-Functionalized 2,2Ј-Bipyridine 2 and Resorcinar-

ene-Functionalized 2,2Ј-Bipyridine 23: A two-neck flask equipped

with a septum and a reflux condenser was charged with 57 mg of 10

(0.18 mmol), 430 mg of 19 (0.36 mmol, 2 equiv.), 3.4 mg (18 µmol,

10 mol-%) of copper(I) iodide, and 13.6 mg [Pd(PPh₃)₂Cl₂] (10 mol-

%) and repeatedly evacuated and flushed with argon. 15 mL of dry

triethylamine and 10 mL of dry THF were added via syringe and

the resulting mixture was heated to 40 °C for 24 h. After that time

20 mL of diethyl ether were added and the organic phase was

washed four times with water and with brine and dried with potas-

sium carbonate. Removing of the organic solvents in vacuo gave

the crude product mixture which was subjected to column

chromatography on silica gel (eluent: n-hexane/ethyl acetate, 5:1 +

0.5% triethylamine) to yield 222 mg of 2 as an amorphous solid

(89 µmol, 49%) as well as 130 mg of 23 also as an amorphous solid

(92 µmol, 51%).

3

8.64 (d, J = 4.9 Hz, 2 H, bipy-H), 8.39 (s, 2 H, bipy-H), 7.31 (d,

³J = 4.9 Hz, 2 H, bipy-H), 7.16 (s, 2 H, cav-H_aryl), 7.11 (s, 4 H,

cav-H_aryl), 7.10 (s, 2 H, cav-H_aryl), 6.51 (s, 4 H, cav-H_aryl), 6.48 (s,

2

2 H, cav-H_aryl), 5.92 (d, J = 7.1 Hz, 4 H, cav-H_acetal), 5.74 (d, J

3

= 7.1 Hz, 4 H, cav-H_acetal), 4.80 (t, J = 8.0 Hz, 4 H, cav-H_benzyl),

1

4.73 (t, ³J = 8.0 Hz, 4 H, cav-H_benzyl), 4.54 (d, ²J = 7.1 Hz, 4 H,

cav-H_acetal), 4.43 (d, ²J = 7.1 Hz, 4 H, cav-H_acetal), 2.30–2.15 (m,

16 H, cav-H_alkyl), 1.50–1.19 (m, 144 H, cav-H_alkyl), 0.88 (t, ³J =

6.5 Hz, 24 H, cav-H_alkyl) ppm. ¹³C NMR (125.8 MHz, CDCl₃,

298 K): δ = 14.1 (cav-C_alkyl), 22.7 (cav-C_alkyl), 27.8, 27.9, 29.4, 29.7,

29.8, 29.9, 31.9 (cav-C_alkyl), 36.3 (cav-C_benzyl), 36.4 (cav-C_benzyl),

91.6, 94.4 (2ϫ C_alkyne), 99.1 (cav-C_acetal), 99.5 (cav-C_acetal), 112.0

(cav-C_aryl), 116.6 (2 ϫ cav-C_aryl), 120.5 (bipy-C_aryl), 120.7 (2 ϫ

cav-C_aryl), 121.0 (cav-C_aryl), 127.5 (bipy-C_aryl), 137.2 (bipy-C_aryl),

138.2, 138.3, 138.4, 138.6 (4ϫ cav-C_aryl), 142.3 (bipy-C_aryl), 154.7,

154.8, 155.0 (4ϫ cav-C_aryl), 155.7 (bipy-C_aryl) ppm. MS (pos. ESI):

m/z (%) = 2508.7 ([MH]⁺, 100). HiRes-MS (pos. ESI) calcd. for

[C₁₆₆H₂₂₉N₂O₁₆]⁺m/z = 2508.7234; found m/z = 2508.7327 (∆ =

3.7 ppm).

2: R_f= 0.22 (n-hexane/ethyl acetate, 5:1 + 0.5% triethylamine). H

3

NMR (500.1 MHz, CDCl₃, 298 K): δ = 8.64 (d, J = 4.9 Hz, 2 H,

3

bipy-H), 8.39 (s, 2 H, bipy-H), 7.31 (d, J = 4.9 Hz, 2 H, bipy-H),

7.16 (s, 2 H, cav-H_aryl), 7.11 (s, 4 H, cav-H_aryl), 7.10 (s, 2 H,

cav-H_aryl), 6.51 (s, 4 H, cav-H_aryl), 6.48 (s, 2 H, cav-H_aryl), 5.92 (d,

²J = 7.1 Hz, 4 H, cav-H_acetal), 5.74 (d, ²J = 7.1 Hz, 4 H, cav-H_acetal),

4.80 (t, ³J = 8.0 Hz, 4 H, cav-H_benzyl), 4.73 (t, ³J = 8.0 Hz, 4 H,

cav-H_benzyl), 4.54 (d, ²J = 7.1 Hz, 4 H, cav-H_acetal), 4.43 (d, ²J =

7.1 Hz, 4 H, cav-H_acetal), 2.30–2.15 (m, 16 H, cav-H_alkyl), 1.50–1.19

3

(m, 144 H, cav-H_alkyl), 0.88 (t, J = 6.5 Hz, 24 H, cav-H_alkyl) ppm.

¹³C NMR (125.8 MHz, CDCl₃, 298 K): δ = 14.1 (cav-C_alkyl), 22.7

(cav-C_alkyl), 27.8, 27.9, 29.4, 29.7, 29.8, 29.9, 31.9 (cav-C_alkyl), 36.3

(cav-C_benzyl), 36.4 (cav-C_benzyl), 86.4 (C_alkyne), 94.6 (C_alkyne), 99.1

(cav-C_acetal), 99.5 (cav-C_acetal), 111.9 (cav-C_aryl), 116.5 (2 ϫ

cav-C_aryl), 120.7 (cav-C_aryl), 121.3 (cav-C_aryl), 122.9 (cav-C_aryl),

125.6 (bipy-C_aryl), 132.2 (bipy-C_aryl), 138.2, 138.3, 138.6, 138.7 (4ϫ

cav-C_aryl) 149.1 (bipy-C_aryl), 154.7, 154.8, 155.0, 155.6 (4 ϫ

cav-C_aryl, bipy-C_aryl) ppm. MS (pos. ESI): m/z (%) = 2508.7

([MH]⁺, 100). HiRes-MS (pos. ESI) calcd. for [C₁₆₆H₂₂₉N₂O₁₆]⁺

m/z = 2508.7234; found m/z = 2508.7310 (∆ = 3.0 ppm).

Resorcinarene-Functionalized 2,2Ј-Bipyridine 4: A two-neck flask

equipped with a septum and a reflux condenser was charged with

70 mg of 23 (0.05 mmol), 16 mg of 22 (0.1 mmol, 2 equiv.), 1.0 mg

(5 µmol, 10 mol-%) of copper(I) iodide, and 3.5 mg (10 mol-%) of

[Pd(PPh₃)₂Cl₂] and repeatedly evacuated and flushed with argon.

10 mL of dry triethylamine were added via syringe and the resulting

23: R_f= 0.48 (THF/n-hexane, 2:3 + 0.5% triethylamine). ¹H NMR mixture was refluxed for 18 h. After that time 20 mL of ethyl ace-

(500.1 MHz, CDCl₃, 298 K): δ = 8.66 (³J = 4.4 Hz, 1 H, bipy-H),

8.62 (s, 1 H, bipy-H), 8.48 (br. s, 2 H, 2ϫ bipy-H), 7.50 (d, 1 H,

bipy-H), 7.31 (d, ³J = 4.4 Hz, 1 H, bipy-H), 7.16 (s, 1 H, cav-H_aryl),

7.11 (s, 2 H, cav-H_aryl), 7.10 (s, 1 H, cav-H_aryl), 6.52 (s, 2 H,

tate were added and the organic phase was washed four times with

water and with brine and dried with sodium sulfate. Removing of

the organic solvents in vacuo gave the crude product mixture which

was subjected to column chromatography on silica gel (eluent: n-

cav-H_aryl), 6.47 (s, 1 H, cav-H_aryl), 5.92 (d, ²J = 7.2 Hz, 2 H, hexane/ethyl acetate, 2:1 + 0.5% triethylamine) to yield 138 mg of

cav-H_acetal), 5.74 (d, ²J = 7.2 Hz, 2 H, cav-H_acetal), 4.79 (t, ³J =

4 as an amorphous solid (93 µmol, 69%). R_f= 0.21 (n-hexane/ethyl

7.7 Hz, 2 H, cav-H_benzyl), 4.73 (t, ³J = 7.7 Hz, 2 H, cav-H_benzyl), acetate, 2:1 + 0.5% triethylamine). H NMR (500.1 MHz, CDCl₃,

1

4.54 (d, ²J = 7.2 Hz, 2 H, cav-H_acetal), 4.43 (d, ²J = 7.2 Hz, 2 H,

298 K): δ = 8.70 (d, ³J = 5.2 Hz, 1 H, bipy-H), 8.65 (d, ³J = 4.9 Hz,

1 H, bipy-H), 8.61 (s, 1 H, bipy-H), 8.44 (s, 1 H, bipy-H), 8.25 (br.

cav-H_acetal), 2.29–2.13 (m, 8 H, cav-H_alkyl), 1.49–1.17 (m, 72 H,

3

cav-H_alkyl), 0.88 (t, J = 7.2 Hz, 12 H, cav-H_alkyl) ppm. ¹³C NMR s, 1 H, NH), 8.26 (d, J = 7.9 Hz, 1 H, py-H), 7.75 (dd, J = 7.9,

(125.8 MHz, CDCl₃, 298 K): δ = 14.1 (cav-C_alkyl), 22.7 (cav-C_alkyl), ³J = 7.6 Hz, 1 H, py-H), 7.48 (d, J = 5.2 Hz, 1 H, bipy-H), 7.32

3

27.8, 27.9, 29.4, 29.7, 29.8, 29.9, 31.9 (cav-C_alkyl), 36.3 (cav-C_benzyl),

(m, 2 H, py-H, bipy-H), 7.16 (1 H, cav-H_aryl), 7.11 (s, 2 H,

4784

www.eurjoc.org

Eur. J. Org. Chem. 2009, 4777–4792

Towards Allosteric Receptors

cav-H_aryl), 7.10 (s, 1 H, cav-H_aryl), 6.51 (s, 2 H, cav-H_aryl), 6.47 (s, dinitro-2,2Ј-bipyridine N,NЈ-dioxide in 60 mL of glacial acetic acid

2

1 H, cav-H_aryl), 5.93 (d, J = 7.3 Hz, 2 H, cav-H_acetal), 5.75 (d, J

and heated to 100 °C for 2 h. The resulting yellow-brownish solu-

tion was cooled to 0 °C and poured into 125 g of ice. Neutralisation

= 7.3 Hz, 2 H, cav-H_acetal),4.79 (t, ³J = 8.0 Hz, 2 H, cav-H_benzyl),

4.72 (t, ³J = 8.0 Hz, 2 H, cav-H_benzyl), 4.55 (d, ²J = 7.3 Hz, 2 H, with concd. sodium hydroxide solution resulted in precipitation of

2

cav-H_acetal), 4.43 (d, J = 7.3 Hz, 2 H, cav-H_acetal), 2.26–2.18 (m, 8

the product which was collected by filtration, washed with water

H, cav-H_alkyl), 2.21 [s, 3 H, –C(O)CH₃], 1.46–1.20 (m, 72 H, and dried in vacuo to yield 3.30 g of the desired product as a white

3

cav-H_alkyl), 0.88 (t, J = 6.7 Hz, 12 H, cav-H_alkyl) ppm. ¹³C NMR solid (9.5 mmol, 70%). The analytical data were in accordance with

(125.8 MHz, CDCl₃, 298 K): δ = 14.1 (cav-C_alkyl), 22.9 (cav-C_alkyl), the ones found in the literature.^[27b]

24.7 [–C(O)CH₃], 27.8, 27.9, 29.4, 29.7, 29.8, 29.9, 31.9 (cav-C_alkyl),

4,4Ј-Dibromo-2,2Ј-bipyridine (10):^[27]A suspension of 767 mg

36.3 (cav-C_benzyl), 36.4 (cav-C_benzyl), 86.6, 86.7, 94.5 (4ϫ C_alkyne),

(2.22 mmol) of 9 in 5 mL of phosphorus tribromide und 100 mL

99.1 (cav-C_acetal), 99.5 (cav-C_acetal), 111.9 (cav-C_aryl), 114.4

of anhydr. acetonitrile was heated to reflux for 4 h. After cooling

(py-C_aryl), 116.6 (2 ϫ cav-C_aryl), 120.7 (2 ϫ cav-C_aryl), 121.4

down to room temp., the solution was poured onto ice. The pH of

(cav-C_aryl), 123.0 (py-C_aryl), 123.8 (bipy-C_aryl), 125.8, 125.9 (2ϫ

the resulting mixture was adjusted to pH 11 with 6  aq. sodium

bipy-C_aryl), 131.5 (bipy-C_aryl), 132.5 (bipy-C_aryl), 138.2, 138.3, 138.6,

hydroxide. Then the mixture was extracted repeatedly with chloro-

138.7 (4ϫ cav-C_aryl, bipy-C_aryl), 139.1 (py-C_aryl), 139.7 (py-C_aryl),

form. The combined organic extract was dried with sodium carbon-

149.0 (bipy-C_aryl), 149.2 (bipy-C_aryl), 151.4 (py-C_aryl), 154.7, 154.8,

ate. Evaporation of the solvents gave the crude product which was

155.0, 155.7 (4ϫ cav-C_aryl, 2ϫ bipy-C_aryl), 168.8 [–C(O)CH₃] ppm.

recrystallised from a 1:1 mixture of ethanol and water to give

MS (CI, isobutane, pos. mode): m/z (%) = 1489.7 (100) [MH]⁺.

530 mg of 10 as a colourless crystalline solid (1.69 mmol, 76%);

HiRes-MS (pos. ESI) calcd. for [C₉₇H₁₂₅N₄O₉]⁺m/z = 1490.9480;

m.p. 140 °C ref.^[27a]141–142 °C. ¹H and ¹³C NMR spectroscopic

found m/z = 1490.9402 (∆ = –5.2 ppm).

data are in accordance with the literature data^[27b]MS (CI, isobut-

ane): m/z (%) = 315.0 (100) [MH]⁺.

Bis(resorcinarene)-Functionalized 2,2Ј-Bipyridine 5: A two-neck

flask equipped with a septum and a reflux condenser was charged

with 56.6 mg (0.232 mmol) of 14 and repeatedly evacuated and

flushed with argon. 10 mL of thionyl chloride were added via sy-

ringe and the resulting mixture was heated to reflux for 16 h. The

excess of thionylchloride was removed in vacuo and the residue

flushed with argon. A second two-neck flask equipped with a sep-

tum was charged with 400 mg (0.480 mmol, 2.2 equiv.) of 17 and

repeatedly evacuated and flushed with argon. 15 mL of dry dichlo-

romethane were added via syringe and the resulting solution was

transferred via syringe to the diacid chloride. After adding 5 mL

of dry triethylamine the mixture was refluxed for 2 d. The mixture

was diluted with dichloromethane, washed with water (3ϫ20 mL)

and brine, and dried with sodium sulfate. After removal of the sol-

vents the residue was subjected to column chromatography on silica

gel (eluent: n-hexane/ethyl acetate, 2:1) to give 239 mg of the de-

sired diester (128 µmol, 55%). R_f= 0.30 (n-hexane/ethyl acetate,

2:1). ¹H NMR (500.1 MHz, CDCl₃, 298 K): δ = 9.07 (d, ⁴J =

Methyl 6-[4-(Methoxycarbonyl)pyridin-2-yl]pyridine-2-carboxylate

(13): 1.00 g (5.43 mmol) of 10 and 6.00 g (38.0 mmol) of potassium

permanganate were suspended in 100 mL of water. The mixture

was stirred for 24 h at 70 °C. After filtration the precipitate was

washed with 10 mL of 1  aq. sodium hydroxide. The filtrate was

extracted with dichloromethane (2ϫ20 mL) and then neutralized

with 2  aq. hydrochloric acid. The solvents were evaporated in

vacuo and the residue was dissolved in 200 mL of methanol. 3 mL

of concd. sulfuric acid were added. The solution was stirred under

reflux for 12 h. After filtration the solvents were removed in vacuo,

the residue was dissolved in ethyl acetate, washed with water

(3ϫ20 mL) and with brine (1ϫ20 mL), and dried with sodium

sulfate. After evaporation of the solvents in vacuo, the crude prod-

uct was purified by column chromatography on silica gel (eluent:

n-hexane/ethyl acetate, 2:1 + 5% triethylamine) to give 193 mg of

the desired product as a colourless solid (0.71 mmol, 13%). R_f=

0.81 (n-hexane/ethyl acetate, 2:1 + 5% triethylamine); m.p. 205 °C.

¹H NMR (400 MHz, CDCl₃): δ = 4.04, 3.99 (s, 6 H, –COOCH₃),

3

1.4 Hz, 1 H, bipy-H), 8.91 (d, J = 4.8 Hz, 1 H, bipy-H), 8.71 (d,

3

³J = 7.2 Hz, 1 H, bipy-H), 8.26 (d, J = 7.2 Hz, 1 H, bipy-H), 8.06

3

7.89 (d, J = 4.9 Hz, 1 H, 5-H), 7.98 (dd, J = 7.7, J = 7.7 Hz, 1

3

4

(dd, J = 7.2, J = 7.2 Hz, 1 H, bipy-H), 7.96 (dd, J = 4.8, J =

1.4 Hz, 1 H, bipy-H), 7.13 (s, 2 H, cav-H_aryl), 7.12 (s, 2 H, cav-

H_aryl), 7.09 (s, 1 H, cav-H_aryl), 7.08 (s, 1 H, cav-H_aryl), 6.56 (s, 1 H,

cav-H_aryl), 6.55 (s, 1 H, cav-H_aryl), 6.43 (s, 2 H, cav-H_aryl), 6.41 (s,

2 H, cav-H_aryl), 5.74–5.70 (m, 4 H, cav-H_acetal), 5.60 (d, ²J = 7.1 Hz,

3

H, 4Ј-H), 8.16 (d, J = 7.7 Hz, 1 H, 5Ј-H), 8.60 (d, J = 7.7 Hz, 1

3

H, 3Ј-H), 8.82 (d, J = 4.9 Hz, 1 H, 6-H), 9.00 (s, 1 H, 3-H) ppm.

¹³C NMR (125 MHz, CDCl₃): δ = 52.7, 52.9 (–OCH₃), 121.1 (C-

3), 123.3 (C-5), 124.6 (C-3Ј), 125.4 (C-5Ј), 138.1 (C-4Ј), 138.9 (C-

4), 147.8 (C-6Ј), 149.8 (C-6), 155.5 (C-2Ј), 156.3 (C-2), 165.5 (C-4-

COO), 165.7 (C-6Ј-COO) ppm. MS (EI, 70 eV, pos. mode): m/z (%)

= 214.1 (100) [M – C₂H₂O₂]⁺, 272.1 (10) [M]^·+. HiRes-MS (EI,

70 eV, pos. mode): calcd. for [C₁₄H₁₂N₂O₄]^·+272.0797; found

272.0797 (∆ = 0.0 ppm).

2

2 H, cav-H_acetal), 5.56 (d, J = 7.1 Hz, 2 H, cav-H_acetal), 4.76–4.70

(m, 8 H, cav-H_benzyl), 4.65–4.63 (m, 4 H, cav-H_acetal), 4.40 (d, J =

2

7.1 Hz, 2 H, cav-H_acetal), 4.35 (d, ²J = 7.1 Hz, 2 H, cav-H_acetal),

2.24–2.20 (m, 16 H, cav-H_alkyl), 1.43–1.33 (m, 48 H, cav-H_alkyl),

0.94 (m, 24 H, cav-H_alkyl) ppm. ¹³C NMR (125.8 MHz, CDCl₃,

298 K): δ = 14.1 (cav-C_alkyl), 22.7 (cav-C_alkyl), 27.6 (cav-C_alkyl), 29.9

(cav-C_alkyl), 32.1 (cav-C_alkyl), 36.4 (cav-C_benzyl), 36.7 (cav-C_benzyl),

99.3 (cav-C_acetal), 99.8 (cav-C_acetal), 116.9 (cav-C_aryl), 117.4 (2ϫ cav-

C_aryl), 117.8 (cav-C_aryl), 120.5 (cav-C_aryl), 121.7 (bipy-C_aryl), 123.7

(bipy-C_aryl), 125.4 (bipy-C_aryl), 126.5 (bipy-C_aryl), 136.9 (bipy-C_aryl),

137.6, 138.7, 138.8, 139.1, 139.3 (8ϫ cav-C_aryl), 138.3 (bipy-C_aryl),

146.3 (bipy-C_aryl), 150.3 (bipy-C_aryl), 154.7, 155.0 (8ϫ cav-C_aryl),

155.8 (bipy-C_aryl), 156.6 (bipy-C_aryl), 164.0 (bipy-C_aryl), 164.6

(bipy-C_aryl) ppm. MS (pos. ESI): m/z (%) = 1875.0 ([MH]⁺, 100).

HiRes-MS (pos. ESI) calcd. for [C₁₁₆H₁₃₂N₂O₂₀+ H]⁺m/z =

1874.9485; found m/z = 1875.0000 (∆ = 27.5 ppm).

2,2Ј-Bipyridine-4,6Ј-dicarboxylic Acid (14): Diester 13 could be sa-

ponified in quantitative manner upon treatment with 6  aq. so-

dium hydroxide in boiling THF/methanol for 1 h. Acidifying of the

mixture with aq. hydrochloric acid led to precipitation of the de-

sired product. Due to the very low solubility of this compound it

was not characterised further but used directly for the synthesis of

5.

Cavitand 16a (1,21,23,25-Tetrapentyl-2,20:3,19-dimetheno-1H,

21H,23H,25H-bis[1,3]dioxocino[5,4-i:5Ј,4Ј-iЈ]benzo[1,2-d:5,4-dЈ]bis-

[1,3]benzodioxocin):^[28]7.69 g (10.0 mmol) of resorcinarene 15a

were dissolved in 150 mL of anhydr. DMF. 22.1 g (160 mmol,

16 equiv.) of anhydr. potassium carbonate and 6.5 mL (100 mmol,

10 equiv.) of bromochloromethane were added and the resulting

4,4Ј-Dibromo-2,2Ј-bipyridine N,NЈ-Dioxide (9):^[27b]40 mL of acetyl

bromide were added to a suspension of 3.8 g (13.6 mmol) of 4,4Ј-

Eur. J. Org. Chem. 2009, 4777–4792

www.eurjoc.org

4785

U. Lüning, A. Lützen et al.

FULL PAPER

mixture was heated to 70 °C for 4 d. Every 24 h another 6.5 mL

(100 mmol, 10 equiv.) of bromochloromethane were added. The re-

action mixture was quenched with brine and filtered. The filtrate

was washed repeatedly with water, washed with brine, and dried

with magnesium sulfate. 15 mL of methanol was added and the

mixture was reduced until the product precipitated as a slightly

brownish solid which was collected and dried in vacuo; yield 1.80 g

(2.1 mmol, 22%). The analytical data are in accordance with the

ones found in the literature.^[28]

charged with 430 mg (2.00 mmol) of 20, 70 mg of [Pd(PPh₃)₂Cl₂]

(10 mol-%), and 38 mg (200 µmol, 10 mol-%) of copper(I) iodide

and repeatedly evacuated and flushed with argon. 20 mL of dry

triethylamine and 0.74 mL (2.2 mmol, 1.1 equiv.) of trimethyl-

silylacetylene were added via syringe and the resulting solution was

heated to 50 °C for 18 h. After that time, 20 mL of water and

20 mL of ethyl acetate were added. The layers were separated and

the organic layer was washed twice with water, washed with brine,

and dried with sodium sulfate. After removal of the solvents in

vacuo the residue was subjected to column chromatography on sil-

ica gel (eluent: n-hexane/ethyl acetate, 3:1 + 0.5% triethylamine) to

give 405 mg of the desired product (1.74 mmol, 87%). R_f(n-hexane/

ethyl acetate, 3:1 + 0.5% triethylamine): 0.48; m.p. 191 °C. ¹H

NMR (500.1 MHz, CDCl₃, 298 K): δ = 8.31 (br. s, 1 H, –NH), 8.15

Hydroxy-Functionalized Cavitand 17a (7-Hydroxy-1,21,23,25-tet-

rapentyl-2,20:3,19-dimetheno-1H,21H,23H,25H-bis[1,3]dioxocino-

[5,4-i:5Ј,4Ј-iЈ]benzo[1,2-d:5,4-dЈ]bis[1,3]benzodioxocin): In order to

eliminate traces of dichloromethane which tends to associate with

these kind of cavitands 3.00 g (3.67 mmol) of cavitand 16a were

dissolved in 20 mL of dry THF. The solvent was evaporated and

the residue was heated to 80 °C at 10^–3mbar for 1 h. This pro-

cedure was repeated twice. The remaining cavitand was dissolved

in 60 mL of dry THF. 0.60 mL (4.0 mmol, 1.1 equiv.) of N,NЈ-tetra-

methylethylenediamine (TMEDA) was added and the mixture was

cooled down to –78 °C. At this temperature, 2.61 mL (4.04 mmol

of a 1.55  solution in n-hexane, 1.1 equiv.) of n-butyllithium was

added slowly via syringe. The resulting mixture was stirred for

30 min at –78 °C. 0.46 mL (4.0 mmol, 1.1 equiv.) of trimethylborate

was added and the cooling bath was removed. After one hour of

stirring at room temp., 3 mL of 3  aq. sodium hydroxide and 3 mL

of 30% aq. hydrogen peroxide were added and the resulting mixture

was stirred for 18 h before it was poured into 10% aq. sodium

disulfite. The organic layer was separated and the aqueous phase

was extracted twice with ethyl acetate (2ϫ25 mL). The combined

organic phases were washed with sat. aq. sodium hydrogen carbon-

ate, water, and brine, dried with magnesium sulfate, and concen-

trated in vacuo. The resulting residue was subjected to column

chromatography on silica gel (eluent: n-hexane/ethyl acetate, 3:1)

to give 1.50 g of the desired product (1.8 mmol, 49%). R_f= 0.36 (n-

hexane/ethyl acetate, 3:1). ¹H NMR (500.1 MHz, CDCl₃, 298 K): δ

3

(d, J = 8.2 Hz, 1 H, 3-H), 7.64 (dd, J = 8.2, J = 7.7 Hz, 1 H, 4-

3

H), 7.19 (d, J = 7.7 Hz, 1 H, 5-H), 2.16 [s, 3 H, –C(O)CH₃], 0.25

[s, 9 H, –Si(CH₃)₃] ppm. ¹³C NMR (125.8 MHz, CDCl₃, 298 K): δ

= 168.7 [C(O)CH₃], 151.2 (C-2), 140.7 (C-6), 138.6 (C-4), 123.4 (C-

5), 113.8 (C-3), 102.9 (C_alkyne), 95.1 (C_alkyne), 24.6 [C(O)CH₃], –0.3

[–Si(CH₃)₃] ppm. MS (EI, 70 eV, pos. mode): m/z (%) = 232.0 (74)

[M]^·+, 189.9 (94) [M – CH₃]⁺, 174.9 (100) [M – NHC(O)CH₃]⁺.

HiRes-MS (CI, isobutane) calcd. for [C₁₂H₁₇N₂OSi]⁺m/z =

233.1110; found m/z = 233.1107 (∆ = –1.3 ppm).

N-(6-Ethynylpyridin-2-yl)acetamide (22): 70 mg (0.30 mmol) of 21

and 50 mg (ca. 3 equiv.) of KF were dissolved in 10 mL of a 1:1

mixture of THF and methanol and stirred at room temp. until TLC

monitoring revealed complete consumption of the starting mate-

rial. The solvents were evaporated in vacuo and the residue was

dissolved in 20 mL of diethyl ether. The solution was washed twice

with water, washed with brine (20 mL each), and dried with sodium

sulfate. The solvent was removed in vacuo and the residue subjected

to column chromatography on silica gel (eluent: n-hexane/ethyl ace-

tate, 1:1 + 0.5% triethylamine) to give the crude product as a

brownish solid. This was further purified by flash chromatography

(eluent: n-hexane/ethyl acetate, 5:1 + 0.5% triethylamine) to give

48 mg (0.3 mmol, quant.) of 22 as colourless crystals. R_f= 0.52 (n-

hexane/ethyl acetate, 1:1 + 0.5% triethylamine); m.p. 119 °C. ¹H

= 9.4 (br. s, 1 H, –OH), 7.10 (s, 3 H, cav-H_aryl), 6.64 (s, 1 H, cav-

2

H

_aryl), 6.49 (s, 2 H, cav-H_aryl), 6.47 (s, 1 H, cav-H_aryl), 5.83 (d, J

2

= 7.1 Hz, 2 H, cav-H_acetal), 5.73 (d, J = 7.1 Hz, 2 H, cav-H_acetal),

4.72 (t, ³J = 8.2 Hz, 2 H, cav-H_benzyl), 4.70 (t, ³J = 8.2 Hz, 2 H,

cav-H_benzyl), 4.43 (d, ²J = 7.1 Hz, 2 H, cav-H_acetal), 4.42 (d, ²J =

7.1 Hz, 2 H, cav-H_acetal), 2.23–2.19 (m, 8 H, cav-H_alkyl), 1.45–1.30

3

NMR (500.1 MHz, CDCl₃, 298 K): δ = 8.20 (d, J = 8.2 Hz, 1 H,

3

3-H), 8.14 (br. s, 1 H, –NH), 7.68 (dd, J = 6.6, J = 8.2 Hz, 1 H,

3

4-H), 7.22 (d, J = 6.6 Hz, 1 H, 5-H), 3.13 (s, 1 H, –CϵCH), 2.18

(s, 3 H, –CH₃) ppm. ¹³C NMR (125.8 MHz, CDCl₃, 298 K): δ =

168.8 [–C(O)CH₃], 151.4 (C-2), 139.9 (C-6), 138.7 (C-4), 123.4 (C-

5), 114.2 (C-3), 82.1 (–CϵCH), 77.3 (–CϵCH), 24.7 [–C(O)CH₃]

ppm. MS (EI, 70 eV, pos. mode): m/z (%) = 160.2 (23) [M]^·+, 118.2

(100) [M – Ac]⁺. HiRes-MS (EI, 70 eV, pos. mode) calcd. for

[C₉H₈N₂O]^·+m/z = 160.0637; found m/z = 160.0637 (∆ = 0.0 ppm).

3

(m, 24 H, cav-H_alkyl), 0.91 (t, J = 7.1 Hz, 12 H, cav-H_alkyl) ppm.

¹³C NMR (125.8 MHz, CDCl₃, 298 K): δ = 14.1 (cav-C_alkyl), 22.7

(cav-C_alkyl), 27.5 (cav-C_alkyl), 29.7 (cav-C_alkyl), 29.8 (cav-C_alkyl), 32.0

(cav-C_alkyl), 36.3 (cav-C_benzyl), 36.6 (cav-C_benzyl), 99.5, 99.7 (2ϫ cav-

C_acetal), 109.5 (cav-C_aryl), 116.3, 116.5 (2ϫ cav-C_aryl), 120.6, 120.9

(2ϫ cav-C_aryl), 138.4, 138.5, 138.6, 140.9, 142.0, 154.8, 154.9 (9ϫ

cav-C_aryl) ppm. MS (neg. ESI): m/z (%) = 813.5 ([M – H]^–, 100).

2,9-Bis[2,6-bis(1,4,7,10-tetraoxadodecyl)phenyl]-1,10-phenanthroline

(25). Method A: Crude 2,6-bis(1,4,7,10-tetraoxadodecyl)phenyl-

boronic acid (27, 382 mg, max. 805 µmol) and 2,9-dichloro-1,10-

phenanthroline (65.6 mg, 267 µmol) were dissolved in 1,2-di-

methoxyethane (8 mL) and water (2 mL). After addition of tetrakis-

(triphenylphosphane)palladium(0) (32.7 mg, 28.4 µmol) and

barium hydroxide octahydrate (389 mg, 1.21 mmol), the mixture

was stirred under nitrogen at 60 °C for 16 h. Cooling to room temp.

was followed by addition of dichloromethane and water (5 mL

each) and separation of the layers. The water layer was extracted

with dichloromethane (5 mL). The combined organic layer was

washed with brine (10 mL) and dried with magnesium sulfate. After

evaporation of the solvent in vacuo, the crude product was purified

by column chromatography [silica gel, ethyl acetate, R_f(16) ≈ 0.10].

It was only possible to isolate the monoaryl-substituted phen-

anthroline. MS (ESI, pos. mode, CHCl₃/MeOH, crude product):

N-(6-Bromopyridin-2-yl)acetamide (20):^[29]

A

two-neck flask

equipped with a septum and a reflux condenser was charged with

1.04 g (6.00 mmol) of 2-amino-6-bromopyridine and repeatedly

evacuated and flushed with argon. After dissolving the compound

in 20 mL of anhydr. pyridine and 0.47 mL (6.6 mmol, 1.1 equiv.)

of freshly distilled acetyl chloride were added via syringe. After

30 min, TLC control revealed complete consumption of the starting

material and the mixture was quenched with 20 mL of water. The

pH was adjusted to 7 and the resulting mixture was cooled to

–30 °C. The precipitate was collected, washed twice with water, and

dried in vacuo to give 910 mg of the product as a crystalline solid

(4.2 mmol, 71%). The analytical data were in accordance with the

ones found in the literature.^[29]

N-(6-{2-[Trimethylsilyl]ethynyl}pyridin-2-yl)acetamide (21): A two-

neck flask equipped with a septum and a reflux condenser was

4786

www.eurjoc.org

Eur. J. Org. Chem. 2009, 4777–4792

Towards Allosteric Receptors

m/z (%) = 1059 (42) [M + Na]⁺, 1037 (12) [M + H]⁺, 665 (100) [16

for 1 h. After addition of trimethylborate (1.62 mL, 16.4 mmol),

the solution was stirred for 2 h while it was warmed to room temp.

The mixture was hydrolyzed with water (20 mL) and the layers were

separated. The water layer was extracted with diethyl ether

(3ϫ10 mL) and the combined organic layer was washed with brine

(10 mL) and dried with magnesium sulfate. The solvent was evapo-

rated in vacuo to yield 1.90 g of the light yellow crude liquid (yield

+ Na]⁺.

Method B: 2,9-Diiodo-1,10-phenanthroline (26, 212 mg, 869 µmol)

was dissolved in 1,2-dimethoxyethane (23 mL) and crude 2,6-

bis(1,4,7,10-tetraoxadodecyl)phenylboronic acid (27, 1.25 g, max.

2.63 mmol), [Pd(PPh₃)₄] (106 mg, 86.9 µmol), barium hydroxide oc-

tahydrate (1.27 g, 3.94 mmol) and water (5.8 mL) were added, and

the suspension was stirred under nitrogen at 60 °C for 18 h. After

cooling to room temp., additional [Pd(PPh₃)₄] (20 mg, 16 µmol)

and crude 2,6-bis(1,4,7,10-tetraoxadodecyl)phenylboronic acid (26,

300 mg, max. 631 mmol) was added, and the mixture was stirred

under nitrogen at 60 °C for another 42 h. Dichloromethane and

water (25 mL each) were added at room temp. and the layers were

separated. The water layer was extracted with dichloromethane

(3ϫ20 mL). The combined organic layer was washed with brine

(20 mL) and dried with magnesium sulfate. The solvent was evapo-

rated in vacuo and the crude material was purified by column

chromatography on silica gel [eluent: ethyl acetate Ǟ dichlorometh-

ane/5% methanol, R_f(ethyl acetate) = 0.05] to yield 84 mg of a

product mixture, which was again purified by chromatography

(chromatotron 1 mm, silica gel, dichloromethane/3% methanol) to

yield 20 mg of brown oil (19.3 µmol, 2%). R_f= 0.05 (ethyl acetate).

approx. 80%). IR (film): ν = 3507 (OH), 2869 (aliph. C–H), 1596,

˜

1453 (arom. C=C), 1256, 1101 (C–O–C) cm^–1. ¹H NMR (300 MHz,

3

CDCl₃): δ = 1.20 (t, J = 7.0 Hz, 6 H, –CH₃), 3.52 (q, J = 7.0 Hz,

4 H, –OCH₂CH₃), 3.56–3.75 (m, 16 H, –CH₂O–), 3.93 (m_c, 4 H,

3

2,6-C_ArOCH₂CH₂O), 4.10 (m_c, 4 H, 2,6-C_ArOCH₂), 6.59 (d, J =

8.3 Hz, 2 H, 4,6-C_ArH), 7.21 (t, ³J = 8.3 Hz, 1 H, 5-C_ArH), 7.33 [s,

2 H, -B(OH)₂] ppm. MS (CI, isobutane, pos. mode): m/z (%) = 474

(1) [M]^·+, 431 (100) [C₂₂H₃₈O₈+ H]⁺, 117 (24) [C₆H₁₃O₂]⁺.

2-Iodoresorcinol (28): Was synthesized following a literature pro-

cedure^[20]starting from resorcinol (6.00 g, 54.4 mmol, recrystallized

from toluene), and iodine (14.8 g, 58.3 mmol) in 50 mL of water to

yield 8.52 g (36.1 mmol, 67%) of colourless crystals, ref.^[20]72%;

m.p. 91 °C, ref.^[20]93 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.34 (s,

2 H, OH), 6.53 (d, ³J = 8.1 Hz, 2 H, 4,6-C_ArH), 7.10 (t, ³J = 8.2 Hz,

1 H, 5-C_ArH) ppm. MS (EI, 70 eV, pos. mode): m/z (%) = 236 (100)

[M]^·+.

IR (KBr): ν = 2926 (aliph. C–H), 1593, 1459 (arom. C=C), 1250,

˜

1

3

1111 (C–O–C) cm^–1. H NMR (500 MHz, CDCl₃): δ = 1.05 (t, J

2,4,6-Tribromoresorcinol (29): Was synthesized from resorcinol

(10.0 g, 90.8 mmol) in chloroform (91 mL), bromine (14.5 mL,

45.5 g, 285 mmol) in chloroform (22 mL) following a literature pro-

cedure^[22]to yield colourless crystals (21.7 g, 62.7 mmol, 69%),

ref.^[3]97%; m.p. 110 °C, ref.^[22]111 °C. ¹H NMR (200 MHz,

CDCl₃): δ = 5.95 (s, 2 H, OH), 7.60 (s, 1 H, 5-C_ArH) ppm. MS (EI,

70 eV, pos. mode): m/z (%) = 350, 348, 346, 344 (31, 95, 100, 32)

[M]^·+, 332, 330, 328, 326 (2, 6, 7, 2) [M – H₂O]^·+.

3

= 7.0 Hz, 12 H, –CH₃), 3.32–3.47 (m, 40 H, –OCH₂–), 3.63 (t, J

= 4.6 Hz, 8 H, ArOCH₂CH₂–), 4.05–4.20 (m, 8 H, ArOCH₂–), 6.83

(d, ³J = 8.4 Hz, 4 H, 3,5-C_ArH), 7.43 (t, ³J = 8.2 Hz, 2 H, 4-C_ArH),

3

7.89 (d, J = 8.2 Hz, 2 H, 3,8-C_PhenH), 7.94 (s, 2 H, 5,6-C_PhenH),

3

8.39 (d, J = 8.3 Hz, 2 H, 4,7-C_PhenH) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 14.9 (q, CH₃), 66.5 (t, OCH₂CH₃), 67.5, 68.4, 69.0,

69.4, 70.0, 70.3 (t, –OCH₂–), 106.9 (d, 3,5-C_Ar), 118.9 (s, 2,6-C_Ar),

126.6 (d, 5,6-C_Phen), 127.6 (d, 3,8-C_Phen), 127.8 (s, 2,9-C_Phen), 131.2

(d, 4-C_Ar), 136.3 (d, 4,7-C_Phen), 144.8 (s, 4a,6a-C_Phen), 154.5 (s,

10a,10b-C_Phen), 157.0 (s, 1-C_Ar) ppm. MS (EI, 70 eV, pos. mode):

m/z (%) = 1037 (54) [M]^·+, 992 (14) [M – C₂H₅O]⁺, 963 (9) [M –

C₄H₉O]⁺, 947 (11) [M – C₄H₉O₂]⁺, 919 (5) [M – C₆H₁₃O]⁺, 903

(68) [M – C₆H₁₃O]⁺, 890 (66) [M – C₇H₁₄O₃]⁺, 877 (47) [M –

C₈H₁₆O₃]⁺, 832 (13) [C₄₆H₄₉N₂O₁₂]⁺, 847 (10) [C₄₆H₅₉N₂O₁₃]⁺, 787

(14) [C₄₄H₅₅N₂O₁₁]⁺, 730 (12) [C₄₀H₄₅N₂O₁₁]⁺, 729 (10)

[C₄₁H₄₉N₂O₁₀]⁺. MS (ESI, pos. mode, CHCl₃/MeOH): m/z (%) =

1059.5 (99) [M + Na]⁺, 1037.5 (100) [M + H]⁺. HiRes-MS (ESI,

pos. mode, CHCl₃/MeOH): calcd. for [C₅₆H₈₀N₂O₁₆+ H]⁺m/z =

1037.5581; found m/z = 1037.5518 (∆ = –6.1 ppm), calcd. for

[C₅₅¹³CH₈₀N₂O₁₆+ H]⁺m/z = 1038.5614; found m/z = 1038.5609

(∆ = 0.6 ppm).

2-Bromoresorcinol (30): Was synthesized from 1,3,5-tribromo-2,4-

dihydroxybenzene (19.3 g, 55.5 mmol) using sodium sulfite (13.8 g,

111 mmol) and sodium hydroxide (4.33 g, 111 mmol) in water

(139 mL) and methanol (28 mL) following a literature procedure^[21]

to yield 9.00 g (47.6 mmol, 86%) of colourless needles, ref.^[16a]65%;

m.p. 98 °C, ref.^[21]102.5 °C. ¹H NMR (200 MHz, CDCl₃): δ = 5.41

(s, 2 H, OH), 6.60 (d, ³J = 8.4 Hz, 2 H, 4,6-C_ArH), 7.12 (t, ³J =

8.4 Hz, 1 H, 5-C_ArH) ppm. MS (EI, 70 eV, pos. mode): m/z (%) =

190, 188 (98, 100) [M]^·+.

3,6,9-Trioxaundecyl-(4-methylbenzene)sulfonate (31): Was synthe-

sized following a literature procedure^[23]from triethylenglycol mono-

ethyl ether (3.84 mL, 22.0 mmol) in pyridine (4 mL) with p-tolu-

enesulfonic chloride (4.20 g, 22.0 mmol) in pyridine (12 mL). After

work-up, the crude material was dried at 100 mbar for 2.5 h to yield

6.06 g of a colourless liquid (18.2 mmol, 83%), ref.^[23]97%. ¹H

NMR (300 MHz, CDCl₃): δ = 1.20 (t, ³J = 7.0 Hz, 2 H,

2,6-Bis(1,4,7,10-tetraoxadodecyl)phenylboronic Acid (27). Method

A: 2-Bromo-1,3-bis(1,4,7,11-tetraoxadodecyl)benzene (32, 410 mg,

805 µmol) was dissolved in dry THF (11 mL) and cooled to –78 °C.

After addition of n-butyllithium (0.35 mL, 0.89 mmol, 2.6  in hex-

anes), the solution was stirred at –78 °C for 1 h, before adding tri-

methylborate (0.28 mL, 2.7 mmol) and stirring for another 1.5 h.

During this time, the solution was warmed to room temp. The mix-

ture was hydrolyzed with water (20 mL) and the layers were sepa-

rated. The water layer was extracted with diethyl ether (3ϫ20 mL)

and the combined organic layer was washed with brine (20 mL)

and dried with magnesium sulfate. The solvent was evaporated in

vacuo to yield 360 mg of the colourless crude liquid (yield approx.

90%).

3

–OCH₂CH₂–), 2.45 (s, 3 H, 4-C_ArCH₃), 3.51 (q, J = 7.0 Hz, 2 H,

–OCH₂CH₃), 3.56–3.64 [m, 8 H, (–OCH₂CH₂)₂O–], 3.69 (t, ³J =

4.9 Hz,

2 = 4.9 Hz, 2 H,

H, –SO₂OCH₂CH₂), 4.16 (t, ³J

–SO₂OCH₂), 7.34 (d, ³J = 8.3 Hz, 2 H, 3,5-C_ArH), 7.80 (d, ³J =

8.3 Hz, 2 H, 2,6-C_Ar) ppm. MS (EI, 70 eV, pos. mode): m/z (%)

= 332 (1) [M]^·+, 243 (7) [M – OCH₂CH₂OCH₂CH₃]⁺, 199 (100)

[C₉H₁₁O₃S]⁺, 155 (58) [C₇H₇O₂S]⁺, 91 (84) [C₇H₇]⁺. MS (CI, isobu-

tane, pos. mode): m/z (%) = 333 (100) [M + H]⁺.

2-Bromo-1,3-bis(1,4,7,10-tetraoxadodecyl)benzene (32): 2-Bromo-

resorcinol (30) (2.00 g, 10.6 mmol) was dissolved in dry N,N-di-

methylformamide (45 mL). After addition of 8.72 g (62.9 mmol) of

potassium carbonate and 8.73 g (26.3 mmol) of 3,6,9-trioxaun-

decyl-(4-methylbenzene)sulfonate (31), the mixture was stirred at

60 °C under nitrogen for 16 h. The solvent was then evaporated in

vacuo and the residue was dissolved in 2  sodium hydroxide solu-

Method B: 2-Iodo-1,3-bis(1,4,7,10-tetraoxadodecyl)benzene (33,

2.75 g, 4.96 mmol) was dissolved in dry THF (37 mL) under nitro-

gen and cooled to –78 °C. n-Butyllithium (2.15 mL, 5.44 mmol,

2.6  in hexanes) was added and the solution was stirred at –78 °C

Eur. J. Org. Chem. 2009, 4777–4792

www.eurjoc.org

4787

U. Lüning, A. Lützen et al.

FULL PAPER

tion and ethyl ether (20 mL each). After separation of the layers,

the water layer was extracted with ethyl ether (3ϫ20 mL). The

combined organic layer was washed with 2  sodium hydroxide

solution (2ϫ20 mL) and with brine (20 mL). After drying with

magnesium sulfate, the solvent was evaporated in vacuo. The crude

material was purified by column chromatography on silica gel (elu-

ent: cyclohexane/ethyl acetate, 1:2) to yield 4.30 g of a colourless

liquid (8.48 mmol, 80%). R_f= 0.26 (cyclohexane/ethyl acetate, 1:2).

over silica gel. All attempts only resulted in decomposition. Also,

variations of solvents, of composition of the solvent mixture or of

the amount of silica gel did not allow a successful purification.

The only isolated product was colourless liquid 1,3-bis(1,4,7,10-

tetraoxadodecyl)benzene (silica gel, ethyl acetate, R_f= 0.50). IR

(film): ν = 2869 (aliph. C–H), 1592, 1452 (arom. C=C), 1123 (C–

˜

3

O–C) cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 1.21 (t, J = 7.0 Hz,

6 H, –CH₃), 3.52 (q, ³J = 7.0 Hz, 4 H, –OCH₂CH₃), 3.57–3.60 (m,

IR (film): ν = 2972, 2869 (aliph. C–H), 1597, 1452 (arom. C=C), 4 H, –CH₂OCH₂CH₃), 3.64–3.70 (m, 8 H, –OCH₂–), 3.72–3.75 (m,

˜

1177, 1109 (C–O–C), 775 (C_Ar–H) cm^–1. ¹H NMR (300 MHz, 4 H, –CH₂OCH₂CH₂OAr), 3.85 (m_c, 4 H, –OCH₂CH₂OAr), 4.10

3

CDCl₃): δ = 1.21 (t, J = 7.0 Hz, 6 H, –CH₃), 3.52 (q, J = 7.0 Hz, (m_c, 4 H, –CH₂OAr), 6.49–6.52 (m, 3 H, 2,4,6-C_ArH), 7.14 (m_c, 1

4 H, –OCH₂CH₃), 3.57–3.61 (m, 4 H, –CH₂OCH₂CH₃), 3.64–3.71 H, 5-C_ArH) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 15.1 (q,

(m, 8 H, –OCH₂–), 3.79–3.83 (m, 4 H, –OCH₂–), 3.92 (m_c, 4 H, – –CH₃), 66.6, 67.3, 69.6, 69.8, 70.6, 70.7, 70.8 (t, –CH₂–), 101.7 (d,

3

OCH₂–), 4.18 (m_c, 4 H, –CH₂OAr), 6.57 (d, J = 8.3 Hz, 2 H, 4,6- 2-C_Ar), 107.0 (d, 4,6-C_Ar), 129.7 (d, 5-C_Ar), 159.9 (s, 1,3-C_Ar) ppm.

C_ArH), 7.17 (t, ³J = 8.3 Hz, 1 H, 5-C_ArH) ppm. ¹³C NMR

MS (EI, 70 eV): m/z (%) = 430 (100) [M]^·+, 371 (4) [M – C₃H₇O]⁺,

(125 MHz, CDCl₃): δ = 16.4 (q, –CH₃), 67.9 (t, –CH₂CH₃), 70.5, 358 (7) [M – C₄H₈O]⁺, 270 (6) [C₁₄H₂₂O₅]⁺, 117 (73) [C₆H₁₃O₂]⁺,

70.8, 71.1, 71.9, 72.0, 72.5 (t, –CH₂–), 103.7 (s, 2-C_Ar), 107.7 (d,

4,6-C_Ar), 129.4 (d, 5-C_Ar), 158.0 (s, 1,3-C_Ar) ppm. MS (EI, 70 eV,

pos. mode): m/z (%) = 511, 509 (2) [M + H]⁺, 510, 508 (6,5) [M]^·+,

429 (3) [M – Br]⁺, 179 (7) [C₈H₁₈O₄+ H]⁺, 161 (30) [C₈H₁₇O₃]⁺,

117 (44) [C₆H₁₃O₂]⁺, 73 (100) [C₄H₉O]⁺. MS (CI, isobutane,

pos. mode): m/z (%) = 511, 509 (38, 36) [M + H]⁺, 161 (48)

[C₈H₁₇O₃]⁺, 117 (73) [C₆H₁₃O₂]⁺, 73 (100) [C₄H₉O]⁺. HiRes-MS

(EI, 70 eV, pos. mode): calcd. for [C₂₂H₃₇⁷⁹BrO₃]^·+m/z = 508.1671;

found m/z = 508.1672 (∆ = 0.1 ppm), calcd. for [C₂₂H₃₇⁸¹BrO₃]^·+

m/z = 510.1655; found m/z = 510.1651 (∆ = –0.4 ppm). C₂₂H₃₇BrO₃

(508.17), calcd. C 51.87, H 7.32; found C 51.75, H 7.29.

111 (28) [C₆H₆O₂]⁺. HiRes-MS (ESI, pos. mode, CHCl₃/MeOH):

C₂₂H₃₈O₈(430.26); calcd. for [C₂₂H₃₈O₈+Na]⁺m/z = 453.2459;

found m/z = 453.2455 (∆ = –0.9 ppm), calcd. for [C₂₁¹³CH₃₈O₈+

Na]⁺m/z = 454.2493; found m/z = 454.2459 (∆ = –7.5 ppm).

C₂₂H₃₈O₃(430.26), calcd. C 61.37, H 8.90. C₂₂H₃₈O₃·0.05 CH₂Cl₂,

calcd. C 60.91, H 8.83; found C 60.72, H 8.96.

2-[2,6-Bis(1,4,7,10-tetraoxadodecyl)phenyl]-9-chloro-1,10-phen-

anthroline (35): Monoaryl-substituted phenanthroline 35 was iso-

lated from the reaction following method A (see above) after col-

umn chromatography on silica gel (eluent: ethyl acetate); yield:

20 mg (31 µmol, 12%) as a yellow oil. R_f= 0.10 (ethyl acetate). IR

2-Iodo-1,3-bis(1,4,7,10-tetraoxadodecyl)benzene (33): 2-Iodoresor- (KBr): ν = 2867 (aliph. C–H), 1589, 1453 (arom. C=C), 1260, 1118

˜

cinol (28) (434 mg, 1.84 mmol) was dissolved in dry N,N-dimethyl-

formamide (8 mL), and potassium carbonate (1.52 g, 11.0 mmol)

and 3,6,9-trioxaundecyl-(4-methylbenzene)sulfonate (31) (1.52 g,

4.57 mmol) were added. The mixture was stirred at 60 °C under

nitrogen for 16 h and the solvent was evaporated in vacuo. The

residue was dissolved in 2  sodium hydroxide solution and diethyl

ether (20 mL each). After separation of the layers, the water layer

was extracted with diethyl ether (3ϫ15 mL). The combined or-

ganic layer was washed with 2  sodium hydroxide solution

(2ϫ15 mL) and with brine (15 mL), dried with magnesium sulfate

and the solvent was evaporated in vacuo. The crude product was

purified by column chromatography on silica gel (eluent: cyclohex-

ane/ethyl acetate, 1:2) to yield 500 mg of a colourless liquid

(899 µmol, 49%). R_f= 0.34 (cyclohexane/ethyl acetate, 1:2). IR

(C–O–C) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.16 (t, ³J =

7.0 Hz, 6 H, –CH₃), 3.32–3.36 (m, 4 H, –OCH₂CH₃), 3.38–3.49 (m,

3

16 H, –OCH₂–), 3.67 (t, J ≈ 4.9 Hz, 4 H, ArOCH₂CH₂–), 4.20 (t,

³J ≈ 4.9 Hz, 4 H, ArOCH₂–), 6.73 (d, ³J = 8.4 Hz, 2 H, 3,5-C_ArH),

7.32 (t, ³J = 8.3 Hz, 1 H, 4-C_ArH), 7.58 (d, ³J = 8.3 Hz, 1 H, 3-

C_PhenH), 7.77 (d, ³J = 8.7 Hz, 1 H, 8-C_PhenH), 7.81 (d, ³J = 8.3 Hz,

3

1 H, 5-C_PhenH*), 7.85 (d, J = 8.8 Hz, 1 H, 7-C_PhenH), 8.19 (d, J

= 8.4 Hz, 1 H, 6-C_PhenH*), 8.23 (d, ³J = 8.3 Hz, 1 H, 4-C_PhenH) ppm

(* assignments might be interchanged). ¹³C NMR (75 MHz,

CDCl₃): δ = 15.1 (q, –CH₂–), 66.5 (t, –CH₂CH₃), 69.4, 69.5, 69.6,

70.35, 70.37, 70.5 (t, –OCH₂–), 107.2 (d, 3,5-C_Ar), 121.2 (s, 1-C_Ar),

123.8 (d, 3-C_Phen), 125.1 (d, 8-C_Phen), 127.0 (s, 6a-C_Phen), 127.2 (s,

4a-C_Phen), 127.3 (d, 5-C_Phen), 127.6 (d, 6-C_Phen), 130.1 (d, 4-C_Ar),

134.8 (d, 4-C_Phen), 138.6 (d, 7-C_Phen), 144.5 (s, 10b-C_Phen), 146.1 (s,

(film): ν = 2970, 2867 (aliph. C–H), 1587, 1450 (arom. C=C), 1253,

9-C_Phen), 150.9 (s, 10a-C_Phen), 155.5 (s, 2,6-C_Ar), 157.8 (s, 2-C_Phen)

˜

1

3

1103 (C–O–C) cm^–1. H NMR (600 MHz, CDCl₃): δ = 1.20 (t, J

ppm (please note that the assignment of the protons of the phenan-

throline unit and of the aromatic carbon signals has been carried

4 H, –CH₂OCH₂CH₃), 3.65–3.70 (m, 8 H, out parallel to known signals for related phenanthrolines, but is

= 7.0 Hz, 6 H, –CH₃), 3.52 (q, ³J = 7.0 Hz, 4 H, –OCH₂CH₃),

3.57–3.60 (m,

–OCH₂–), 3.80–3.83 (m, 4 H, –CH₂OCH₂CH₂OAr), 3.92 (m_c, 4 not proved by HSQC or HMBC spectra). MS (ESI, pos. mode,

H, –OCH₂CH₂OAr), 4.17 (m_c, 4 H, –CH₂OAr), 6.49 (d, ³J =

8.3 Hz, 2 H, 4,6-C_ArH), 7.20 (t, ³J = 8.3 Hz, 1 H, 5-C_ArH) ppm.

¹³C NMR (150 MHz, CDCl₃): δ = 15.1 (q, –CH₃), 66.5, 69.2, 69.4,

69.8, 70.6, 70.7, 71.2 (t, –CH₂–), 79.2 (s, 2-C_Ar), 105.6 (d, 4,6-C_Ar),

129.6 (d, 5-C_Ar), 159.0 (s, 1,3-C_Ar) ppm. MS (EI, 70 eV, pos. mode):

m/z (%) = 556.6 (16) [M]^·+, 429.5 (4) [M – I]⁺, 161 (27) [C₈H₁₇O₃

+ H]⁺, 117 (49) [C₆H₁₃O₂]⁺, 73 (100) [C₄H₉O]⁺. MS (CI, isobutane,

pos. mode): m/z (%) = 557.6 (71) [M + H]⁺, 117 (100) [C₆H₁₃O₂]⁺.

HiRes-MS (ESI, pos. mode, MeOH): C₂₂H₃₇IO₈(556.15); calcd.

for [C₂₂H₃₇IO₈+Na]⁺m/z = 579.1425; found m/z = 579.1419 (∆ =

–1 ppm), calcd. for [C₂₁¹³CH₃₇IO₈+Na]⁺m/z = 580.1460; found

m/z = 580.1449 (∆ = –1.9 ppm). C₂₂H₃₇IO₈(556.15), calcd. C 47.49,

H 6.70. C₂₂H₃₇IO₈·0.2 CH₂Cl₂, calcd. C 46.50, H 6.57; found C

46.46, H 6.64.

CHCl₃/MeOH): m/z (%) = 667, 665 (39, 100) [M + Na]⁺. MS (EI,

70 eV, pos. mode): m/z (%) = 644, 642 (9, 15) [M]^·+, 599, 597 (3, 9)

[M – C₂H₅O]⁺, 555, 553 (14, 20 [M – C₄H₉O₂]⁺, 511, 509 (24, 47)

[C₂₈H₃₀ClN₂O₅]⁺, 497, 495 (46, 100) [C₂₇H₂₈ClN₂O₅]⁺.

C₃₄H₄₃ClN₂O₈(642.27), calcd.

C 63.49, H 6.74, N 4.36.

C₃₄H₄₃ClN₂O₈·1H₂O, calcd. C 61.76, H 6.86, N 4.24; found C

61.78, H 6.76, N 3.97.

2-[2,6-Bis(1,4,7,10-tetraoxadodecyl)phenyl]-9-iodo-1,10-phen-

anthroline (36): Monoaryl-substituted phenanthroline 36 was isolated

from the reaction following method B (see above) after column

chromatography on silica gel (eluent: ethyl acetate); yield: 56 mg

(76 µmol, 19%) of a yellow oil. R_f= 0.10 (ethyl acetate). IR (KBr):

ν = 2868 (aliph. C–H), 1573, 1472 (arom. C=C), 1252, 1110 (C–

˜

3

O–C) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.17 (t, J = 7.0 Hz,

1,3-Bis(1,4,7,10-tetraoxadodecyl)benzene (34): It was not possible

to purify the crude boronic acid 18 by column chromatography

6 H, –CH₃), 3.35–3.40 (m, 4 H, –OCH₂CH₃), 3.42–3.50 (m, 16 H,-

–OCH₂–), 3.71 (t, J ≈ 4.9 Hz, 4 H, ArOCH₂CH₂–), 4.25 (t, J ≈

3

4788

www.eurjoc.org

Eur. J. Org. Chem. 2009, 4777–4792

Towards Allosteric Receptors

4.9 Hz, 4 H, ArOCH₂–), 6.76 (d, ³J = 8.4 Hz, 2 H, 3,5-C_ArH), 7.33

(t, ³J = 8.3 Hz, 1 H, 4-C_ArH), 7.73 (d, ³J = 8.8 Hz, 1 H, 6-C_PhenH*),

to 40 °C for 30 min to give the deep red solution of the desired

copper(I) complex which was characterised by ¹H NMR spec-

7.835 (d, J = 8.3 Hz, 1 H, 8-C_PhenH), 7.84 (d, J = 8.3 Hz, 1 H, troscopy and ESI MS. ¹H NMR (400.1 MHz, CDCl₃/[D₄]MeOH

3

3-C_PhenH), 7.86 (d, ³J = 8.8 Hz, 1 H, 5-C_PhenH*), 7.96 (d, ³J =

2:1, 298 K): δ = 8.43 (d, J = 8.3 Hz, 2 H, phen-H_phen), 8.31 (d, J

= 5.2 Hz, 2 H, bipy-H), 8.23 (s, 2 H, bipy-H), 7.95 (s, 2 H, phen-

3

8.3 Hz, 1 H, 7-C_PhenH), 8.22 (d, J = 8.4 Hz, 1 H, 4-C_PhenH) ppm

(* assignments might be interchanged). ¹³C NMR (75 MHz,

H_phen), 7.82 (d, J = 5.2 Hz, 2 H, bipy-H), 7.70 (d, J = 8.3 Hz, 2

3

CDCl₃): δ = 15.2 (t, –CH₂–), 66.6 (t, –CH₂CH₃), 69.6, 69.7, 69.9, H, phen-H_phen), 6.95 (s, 4 H, cav-H_aryl), 6.93 (s, 2 H, cav-H_aryl),

3

70.4, 70.5, 70.6 (t, –OCH₂–), 107.8 (d, 3,5-C_Ar), 118.6 (s, 9-C_Phen), 6.87 (s, 2 H, cav-H_aryl), 6.59 (t, J = 8.4 Hz, 2 H, phen-H_aryl), 6.32

3

121.5 (s, 1-C_Ar), 125.4 (d, 3-C_Phen), 127.35 (s, 6a-C_Phen), 127.37 (d,

5-C_Phen), 127.5 (d, 6-C_Phen), 127.5 (s, 4a-C_Phen), 130.2 (d, 4-C_Ar),

(s, 2 H, cav-H_aryl), 6.28 (s, 4 H, cav-H_aryl), 5.79 (d, J = 8.4 Hz, 4

2

H, phen-H_aryl), 5.50 (d, J = 7.2 Hz, 4 H, cav-H_acetal), 5.41 (d, J =

133.3 (d, 8-C_Phen), 134.8 (d, 4-C_Phen), 137.0 (d, 7-C_Phen), 144.4 (s, 7.1 Hz, 4 H, cav-H_acetal), 4.52 (t, ³J = 7.9 Hz, 4 H, cav-H_benzyl),

10b-C_Phen), 147.5 (s, 10a-C_Phen), 155.5 (s, 2-C_Phen), 158.0 (s, 2,6- 4.51 (t, ³J = 7.6 Hz, 4 H, cav-H_benzyl), ≈ 4.3–4.2 (m, 8 H, cav-H_acetal

,

C_Ar) ppm (please not that the assignment of the protons of the

phenanthroline unit and of the aromatic carbon signals has been

carried out parallel to known signals for related phenanthrolines,

but is not proved by HSQC or HMBC spectra.). MS (ESI, pos.

buried under the water signal), 3.57–3.53 (m, 4 H, –OCH₂–), 3.40–

3.20 (m, 52 H, –OCH₂–), 2.05–1.97 (m, 16 H, cav-H_alkyl), 1.25–1.00

(m, 144 H, cav-H_alkyl), 0.82 (m, 12 H, –OCH₂CH₃), 0.63 (m, 24 H,

cav-H_alkyl) ppm (referenced on residual CHCl₃, please note that the

1

mode, CHCl₃/MeOH): m/z (%) = 757 (100) [M + Na]⁺, 734 (62) assignment was done solely on the basis of the H NMR spectro-

[M + H]⁺. C₃₄H₄₃IN₂O₈(734.21), calcd. C 55.59, H 5.90, N 3.81.

scopic data and the comparison with known complexes). MS (ESI,

C₃₄H₄₃IN₂O₈·0.5H₂O, calcd. C 54.91, H 5.96, N 3.77; found C pos. mode): m/z (%) = 3648.3 (100, matching isotope pattern)

54.77, H 5.94, N 3.74.

[Cu(25)(1b)]⁺.

[Cu(24)(1b)]BF₄: 12.7 mg (5.0 µmol) of 1b were dissolved in 0.5 mL

of a 1:1 mixture of [D₆]benzene/[D₃]acetonitrile. 3.0 mg (5.0 µmol,

1 equiv.) of [Cu(24)]BF₄were dissolved in 0.5 mL of a 1:1 mixture

of [D₆]benzene/[D₃]acetonitrile. The solutions were combined and

heated to 40 °C for 30 min to give the deep red solution of the

desired copper(I) complex which was characterised by ¹H NMR

[Re(CO)₃(2)Cl]: 250.8 mg of 2 (100 µmol) and 36.2 mg (100 µmol,

1 equiv.) of pentacarbonylrhenium chloride were dissolved in 5 mL

of chloroform and heated to 50 °C for 1 h. 280 mg (quant.) of the

desired complex could be isolated after column chromatography on

silica gel (eluent: n-hexane/ethyl acetate, 1:1 + 0.5% triethylamine).

R_f= 0.95 (n-hexane/ethyl acetate, 1:1 + 0.5% triethylamine). ¹H

1

spectroscopy and ESI MS. H NMR (500.1 MHz, C₆D₆/CD₃CN,

3

NMR (500.1 MHz, CDCl₃, 298 K): δ = 8.95 (d, J = 6.1 Hz, 2 H,

1:1, 298 K): δ = 8.59 (m, 2 H, phen-H_phen), 8.46 (m, 2 H, bipy-H),

3

bipy-H), 8.08 (s, 2 H, bipy-H), 7.42 (d, J = 6.1 Hz, 2 H, bipy-H),

8.41 (s, 2 H, bipy-H), 8.13 (s, 2 H, phen-H_phen), 7.95 (d, ³J = 4.4 Hz,

7.24 (s, 2 H, cav-H_aryl), 7.11 (s, 4 H, cav-H_aryl), 7.10 (s, 2 H, cav-

3

2 H, bipy-H), 7.79 (d, J = 8.2 Hz, 2 H, phen-H_phen), 7.34 (s, 4 H,

H_aryl), 6.54 (s, 2 H, cav-H_aryl), 6.53 (s, 2 H, cav-H_aryl), 6.47 (s, 2 H,

cav-H_aryl), 7.33 (s, 2 H, cav-H_aryl), 7.13 (s, 2 H, cav-H_aryl), 6.81 (m,

2 H, phen-H_aryl), 6.52 (m, 2 H, cav-H_aryl), 6.50 (m, 2 H, cav-H_aryl),

5.97 (s, 4 H, phen-H_aryl), 5.71 (d, ²J = 7.4 Hz, 4 H, cav-H_acetal), 5.63

(d, ²J = 7.1 Hz, 4 H, cav-H_acetal), 4.68 (t, ³J = 8.0 Hz, 8 H,

cav-H_benzyl), 4.45 (d, ²J = 7.4 Hz, 4 H, cav-H_acetal), 4.36 (d, ²J =

7.1 Hz, 4 H, cav-H_acetal), 3.29 (br. s, 12 H, –OCH₃), 2.32 (m, 16 H,

cav-H_alkyl), 1.42–1.24 (m, 144 H, cav-H_alkyl), 0.84 (m, 24 H,

cav-H_alkyl) ppm (please note that the assignment was done solely

cav-H_aryl), 5.92 (d, ²J = 7.2 Hz, 4 H, cav-H_acetal), 5.72 (d, ²J =

7.2 Hz, 2 H, cav-H_acetal), 5.71 (d, ²J = 7.2 Hz, 2 H, cav-H_acetal),

4.80 (t, ³J = 8.2 Hz, 4 H, cav-H_benzyl), 4.73 (t, ³J = 8.2 Hz, 4 H,

cav-H_benzyl), 4.54 (d, ²J = 7.2 Hz, 4 H, cav-H_acetal), 4.41 (d, ²J =

7.2 Hz, 2 H, cav-H_acetal), 4.40 (d, ²J = 7.2 Hz, 2 H, cav-H_acetal),

2.30–2.17 (m, 16 H, cav-H_alkyl), 1.49–1.19 (m, 144 H, cav-H_alkyl),

0.87 (m, 24 H, cav-H_alkyl) ppm. ¹³C NMR (125.8 MHz, CDCl₃,

298 K): δ = 14.1 (cav-C_alkyl), 22.7 (cav-C_alkyl), 27.9, 29.4, 29.7, 29.8,

29.9, 31.9 (cav-C_alkyl), 36.3, 36.4 (cav-C_benzyl), 92.4 (2ϫ C_alkyne),

99.1 (cav-C_acetal), 99.5 (cav-C_acetal), 110.9 (cav-C_aryl), 116.6 (cav-C_a-

_ryl), 120.5, 120.6 (cav-C_aryl), 122.8 (cav-C_aryl), 124.9 (bipy-C_aryl),

128.8 (bipy-C_aryl), 134.6 (bipy-C_aryl), 137.9, 138.3, 138.9, 139.0

(cav-C_aryl) 152.9 (bipy-C_aryl), 154.6, 154.9, 155.2, 155.3, 155.9 (4ϫ

cav-C_aryl, bipy-C_aryl), 189.0, 196.8 (CO) ppm. MS (ESI, neg. mode):

m/z (%) = 2541.5 (100, matching isotope pattern) [(Re(CO)₃Cl(2)

+ CH₃O)₂]^2–.

1

on the basis of the H NMR spectroscopic data and the compari-

son with known complexes). MS (ESI, pos. mode): m/z (%) =

3062.8 ([Cu(24)(1b)]⁺, 100, matching isotope pattern). HiRes-MS

(pos. ESI) calcd. for [C₁₉₂H₂₅₂N₄O₂₄Cu]⁺m/z = 3062.7971; found

m/z = 3062.8315 (∆ = 11.2 ppm).

[Cu(25)]BF₄: 5.2 mg (5.0 µmol) of 25 were dissolved in 800 µL of a

2:1 mixture of [D₁]chloroform/[D₄]MeOH. 1.6 mg (5.0 µmol,

1 equiv.) of [Cu(CH₃CN)₄]BF₄were dissolved in 200 µL of a 2:1

mixture of [D₁]chloroform/[D₄]MeOH. The solutions were com-

bined and heated to 40 °C for 30 min to give the deep red solution

of the desired copper(I) complex which was characterised by ¹H

NMR spectroscopy and ESI MS. ¹H NMR (400.1 MHz, CDCl₃/

[Ag(2)₂]BF₄: 25.1 mg (10.0 µmol) of 2 were dissolved in 1 mL of

[D₆]benzene. 1.4 mg (5.0 µmol, 0.5 equiv.) of [Ag(NCCH₃)₂]BF₄

were dissolved in 40 µL of [D₃]acetonitrile. The solutions were

combined and heated to 40 °C for 30 min to give the slightly yellow

solution of the desired silver(I) complex which was characterised by

NMR spectroscopy. Please note that the mass of the 2:1 complex

(M([C₃₃₂H₄₅₆AgN₄O₃₂]⁺) = 5123.05 g/mol) was beyond the mass

which we could measure accurately with our equipment. However,

no signal for a [Ag(2)]BF₄complex carrying only one ligand could

3

[D₄]MeOH 2:1, 298 K): δ = 8.29 (d, J = 8.2 Hz, 2 H, H_phen), 7.79

(s, 2 H, H_phen), 7.74 (m, ³J = 8.2 Hz, 2 H, H_phen), 7.13 (m, ³J =

3

8.3 Hz, 2 H, H_aryl), 6.46 (d, J = 8.3 Hz, 4 H, H_aryl), 3.93–3.88 (m,

16 H, –OCH₂–), 3.42–3.22 (m, 40 H, –OCH₂–), 0.93 (m, 12 H,

–OCH₂CH₃) ppm (referenced on residual CHCl₃, please note that

1

the assignment was done solely on the basis of the H NMR spec-

1

be detected. H NMR (500.1 MHz, C₆D₆/CD₃CN, 25:1, 298 K): δ

troscopic data and the comparison with known complexes). MS

(ESI, pos. mode): m/z (%) = 1099.4 ([Cu(25)]⁺, 45, matching iso-

tope pattern), 1037.6 [25 + H]⁺, (100).

= 8.49 (m, 2 H, bipy-H), 8.42 (m, 2 H, bipy-H), 7.61 (s, 2 H,

cav-H_aryl), 7.54 (s, 6 H, cav-H_aryl), 7.24 (m, 2 H, bipy-H), 6.73 (s, 4

H, cav-H_aryl), 6.59 (s, 2 H, cav-H_aryl), 6.08 (d, ²J = 7.1 Hz, 4 H,

cav-H_acetal), 5.72 (d, ²J = 7.1 Hz, 4 H, cav-H_acetal), 5.21 (t, ³J =

7.7 Hz, 4 H, cav-H_benzyl), 5.14 (t, ³J = 7.7 Hz, 4 H, cav-H_benzyl),

4.78 (d, ²J = 7.1 Hz, 4 H, cav-H_acetal), 4.49 (d, ²J = 7.1 Hz, 4 H,

[Cu(25)(1b)]BF₄: 5.1 mg (2.0 µmol) of 1b were dissolved in 0.5 mL

of a 2:1 mixture of [D₁]chloroform/[D₄]MeOH. 400 µL of the 5 m

solution of [Cu(25)]BF₄(2.0 µmol, 1 equiv.) was added and heated

Eur. J. Org. Chem. 2009, 4777–4792

www.eurjoc.org

4789

U. Lüning, A. Lützen et al.

FULL PAPER

3

cav-H_acetal), 2.45–2.28 (m, 16 H, cav-H_alkyl), 1.50–1.13 (m, 144 H,

py-H), 8.08 (s, 1 H, bipy-H), 7.86 (dd, J = 8.0, J = 7.7 Hz, 1 H,

3

cav-H_alkyl), 0.92 (t, J = 6.6 Hz, 24 H, cav-H_alkyl) ppm.

py-H), 7.53 (d, J = 5.5 Hz, 1 H, bipy-H), 7.52 (d, J = 8.0 Hz, 1

H, py-H), 7.39 (d, ³J = 5.5 Hz, 1 H, bipy-H), 7.25 (s, 1 H, cav-

H_aryl), 7.12 (s, 2 H, cav-H_aryl), 7.11 (s, 1 H, cav-H_aryl), 6.55 (s, 1 H,

cav-H_aryl), 6.54 (s, 1 H, cav-H_aryl), 6.47 (s, 1 H, cav-H_aryl), 6.12 (d,

²J = 7.1 Hz, 1 H, cav-H_acetal), 6.00 (d, ²J = 7.1 Hz, 1 H, cav-H_acetal),

5.74 (d, ²J = 7.1 Hz, 2 H, cav-H_acetal), 4.84 (t, ³J = 8.2 Hz, 1 H,

cav-H_benzyl), 4.81 (t, ³J = 8.2 Hz, 1 H, cav-H_benzyl), 4.73 (t, ³J =

8.2 Hz, 2 H, cav-H_benzyl), 4.57–4.51 (m, 2 H, cav-H_acetal), 4.41 (d,

²J = 7.1 Hz, 2 H, cav-H_acetal), 2.29–2.18 (m, 8 H, cav-H_alkyl), 2.25

[Cu(2)₂]BF₄: 25.1 mg (10.0 µmol) of 2 were dissolved in 1 mL of

[D₆]benzene. 1.6 mg (5.0 µmol, 0.5 equiv.) of [Cu(NCCH₃)₄]BF₄

were dissolved in 40 µL of [D₃]acetonitrile. The solutions were

combined and heated to 40 °C for 30 min to give the deep red solu-

tion of the desired copper(I) complex which was characterised by

NMR spectroscopy. Please note that the mass of the 2:1 complex

(M([C₃₃₂H₄₅₆CuN₄O₃₂]⁺) = 5078.73 g/mol) was beyond the mass

which we could measure accurately with our equipment. However,

no signal for a [Cu(2)]BF₄complex carrying only one ligand could

3

[s, 3 H, –C(O)CH₃], 1.49–1.20 (m, 72 H, cav-H_alkyl), 0.88 (t, J =

7.2 Hz, 12 H, cav-H_alkyl) ppm. ¹³C NMR (125.8 MHz, CDCl₃,

298 K): δ = 14.1 (cav-C_alkyl), 22.7 (cav-C_alkyl), 24.7 [–C(O)CH₃],

27.9, 29.4, 29.7, 29.8, 29.9, 31.9 (cav-C_alkyl), 36.3, 36.4 (cav-C_benzyl),

86.5 (C_alkyne), 92.5 (2ϫ C_alkyne), 95.0 (C_alkyne), 99.3 (cav-C_acetal),

99.5 (cav-C_acetal), 110.9 (cav-C_aryl), 116.6 (py-C_aryl), 120.5, 120.6

(cav-C_aryl), 122.9 (cav-C_aryl), 124.5 (py-C_aryl), 124.8 (bipy-C_aryl),

126.0 (bipy-C_aryl), 128.8 (bipy-C_aryl), 129.1 (bipy-C_aryl), 133.2 (bipy-

C_aryl), 134.5 (bipy-C_aryl), 137.9, 138.3, 138.4, 138.8 (cav-C_aryl) 139.0

(py-C_aryl), 151.6 (py-C_aryl), 152.8 (bipy-C_aryl), 153.0 (bipy-C_aryl),

154.7, 154.8, 155.1, 155.2, 155.3, 156.0, 156.1 (3ϫ cav-C_aryl, 2ϫ

bipy-C_aryl, py-C_aryl), 168.9 [–C(O)CH₃], 188.9, 196.8 (CO) ppm. MS

(ESI, pos. mode): m/z (%) = 1818.8 ([Re(CO)₃Cl(4) + Na]⁺, 100,

matching isotope pattern).

1

be detected. H NMR (500.1 MHz, C₆D₆/CD₃CN, 25:1, 298 K): δ

= 9.04 (m, 2 H, bipy-H), 8.55 (m, 2 H, bipy-H), 7.98 (m, 2 H, bipy-

H), 7.70–7.50 (m, 8 H, cav-H_aryl), 6.69 (br. s, 4 H, cav-H_aryl), 6.44

(br. s, 2 H, cav-H_aryl), 5.97 (m, 4 H, cav-H_acetal), 5.76 (m, 4 H,

cav-H_acetal), 5.31–5.10 (m, 8 H, cav-H_benzyl), 4.70 (m, 4 H,

cav-H_acetal), 4.53 (m, 4 H, cav-H_acetal), 2.54–2.33 (m, 16 H, cav-

H_alkyl), 1.58–1.27 (m, 144 H, cav-H_alkyl), 1.02 (m, 24 H, cav-H_alkyl

)

ppm.

[Ag(3)]BF₄: 25.1 mg (10.0 µmol) of 3 were dissolved in 1 mL of [D₆]-

benzene. 1.4 mg (5.0 µmol, 0.5 equiv.) of [Ag(NCCH₃)₂]BF₄were

dissolved in 40 µL of [D₃]acetonitrile. The solutions were combined

and heated to 40 °C for 30 min to give the slightly yellow solution

of the desired silver(I) complex which was characterised by NMR

spectroscopy and ESI MS. ¹H NMR (500.1 MHz, C₆D₆/CD₃CN,

[Ag(4)₂]BF₄: 14.9 mg (10.0 µmol) of 4 were dissolved in 1 mL of

[D₆]benzene. 1.4 mg (5.0 µmol, 0.5 equiv.) of [Ag(NCCH₃)₂]BF₄

were dissolved in 40 µL of [D₃]acetonitrile. The solutions were

combined and heated to 40 °C for 30 min to give the slightly yellow

solution of the desired silver(I) complex which was characterised

3

25:1, 298 K): δ = 8.04 (d, J = 5.5 Hz, 2 H, bipy-H), 7.67 (br. s, 2

H, bipy-H), 7.55–7.42 (m, 10 H, cav-H_aryl, bipy-H), 6.79 (br. s, 6 H,

cav-H_aryl), 6.30 (d, ²J = 5.4 Hz, 4 H, cav-H_acetal), 5.92 (d, ²J =

5.4 Hz, 4 H, cav-H_acetal), 5.29 (m, 4 H, cav-H_benzyl), 5.21–5.08 (m,

8 H, cav-H_acetal, cav-H_benzyl4), 4.75 (d, ²J = 5.4 Hz, 4 H,

cav-H_acetal), 2.55–2.25 (m, 16 H, cav-H_alkyl), 1.68–1.10 (m, 144 H,

1

by NMR spectroscopy and ESI MS. H NMR (500.1 MHz, C₆D₆/

CD₃CN, 25:1, 298 K): δ = 9.03–8.84, 8.71–8.51, 8.397, 8.272, 7.60,

7.52, 7.36 (m, 10 H, –NH, 6ϫ bipy-H, 3ϫ py-H), 7.03 (br. s, 3 H,

cav-H_aryl), 6.78 (br. s, 2 H, cav-H_aryl), 6.61 (br. s, 1 H, cav-H_aryl),

6.21 (m, 2 H, cav-H_acetal), 5.76 (m, 2 H, cav-H_acetal), 5.20 (m, 2 H,

cav-H_benzyl), 5.14 (m, 2 H, cav-H_benzyl), 4.89 (m, 2 H, cav-H_acetal),

4.52 (m, 2 H, cav-H_acetal), 2.46–2.28 [br. s, 3 H, –C(O)CH₃], 2.01–

1.86 (m, 8 H, cav-H_alkyl), 1.50–1.00 (m, 72 H, cav-H_alkyl), 0.95–0.88

(m, 12 H, cav-H_alkyl) ppm. MS (ESI, pos. mode): m/z (%) =

3087.8 (100) [Ag(4)₂]⁺. HiRes-MS (pos. ESI) calcd. for

[C₁₉₄H₂₄₇AgN₈O₁₈]⁺m/z = 3087.7852; found m/z = 3087.7810 (∆

= –1.4 ppm).

3

cav-H_alkyl), 0.92 (t, J = 6.6 Hz, 24 H, cav-H_alkyl) ppm. MS (ESI,

pos. mode): m/z (%) = 2617.5 ([Ag(3)]⁺, 100, matching isotope

pattern, just a trace signal for a [Ag(3)₂]⁺ion could be detected in

an ESI-QToF experiment which resulted most likely from non-spe-

cific aggregation).

[Cu(3)]BF₄: 25.1 mg (10.0 µmol) of 3 were dissolved in 1 mL of [D₆]-

benzene. 1.6 mg (5.0 µmol, 0.5 equiv.) of [Cu(NCCH₃)₄]BF₄were

dissolved in 40 µL of [D₃]acetonitrile. The solutions were combined

and heated to 40 °C for 30 min to give the deep red solution of

the desired copper(I) complex which was characterised by NMR

spectroscopy and ESI MS. ¹H NMR (500.1 MHz, C₆D₆/CD₃CN,

25:1, 298 K): δ = 8.02 (m, 2 H, bipy-H), 7.72–7.42 (m, 12 H, 3ϫ

cav-H_aryl, 2ϫ bipy-H), 6.60 (br. s, 2 H, cav-H_aryl), 6.53 (br. s, 4 H,

cav-H_aryl), 5.71 (m, 4 H, cav-H_acetal), 5.56 (m, 4 H, cav-H_acetal), 5.08

(m, 4 H, cav-H_benzyl), 4.87 (m, 4 H, cav-H_benzyl), 4.43 (m, 4 H,

cav-H_acetal), 4.36 (m, 4 H, cav-H_acetal), 2.63–2.26 (m, 16 H,

cav-H_alkyl), 1.67–1.11 (m, 144 H, cav-H_alkyl), 0.92 (t, ³J = 7.2 Hz,

24 H, cav-H_alkyl) ppm. MS (ESI, pos. mode): m/z (%) = 2572.8

([Cu(3)]⁺, 100, matching isotope pattern, just a trace signal for a

[Cu(3)₂]⁺ion could be detected in an ESI-QToF experiment which

resulted most likely from non-specific aggregation).

[Cu(4)₂]BF₄: 14.9 mg (10.0 µmol) of 4 were dissolved in 1 mL of

[D₆]benzene. 1.6 mg (5.0 µmol, 0.5 equiv.) of [Cu(NCCH₃)₄]BF₄

were dissolved in 40 µL of [D₃]acetonitrile. The solutions were

combined and heated to 40 °C for 30 min to give the deep red solu-

tion of the desired copper(I) complex which was characterised by

NMR spectroscopy and ESI MS. Unfortunately, the NMR spectra

showed only very broad signals (even at low temperatures) which

did not allow any assignment of individual signals. MS (ESI, pos.

mode): m/z (%) = 3041.8 (100) [Cu(4)₂]⁺. HiRes-MS (pos. ESI)

calcd. for [C₁₉₄H₂₄₇CuN₈O₁₈]⁺m/z = 3041.8008; found m/z =

3041.7556 (∆ = –14.9 ppm).

[Re(CO)₃(4)Cl]: 149.0 mg (100 µmol) of 4 and 36.2 mg (100 µmol,

1 equiv.) of pentacarbonylrhenium chloride were dissolved in 5 mL

of chloroform and heated to 50 °C for 1 h. Evaporation of the sol-

vent and purification of the orange residue by column chromatog-

raphy of silica gel (eluent: n-hexane/ethyl acetate, 1:1 + 0.5% tri-

ethylamine) gave 62 mg of the pure complex as an orange solid

(35 µmol, 35%). R_f= 0.50 (n-hexane/ethyl acetate, 1:1 + 0.5% tri-

ethylamine). ¹H NMR (500.1 MHz, CDCl₃, 298 K): δ = 8.99 (d, ³J

[Re(CO)₃(5)Cl]: 50.0 mg (26.7 µmol) of 5 and 9.7 mg (26.7 µmol,

1 equiv.) of [Re(CO)₅Cl] were dissolved in 5 mL of chloroform and

heated to 60 °C for 24 h. The solution was diluted with 25 mL of

dichloromethane, extracted twice with water (2 mL). Evaporation

of the solvent gave 58 mg (quant.) of the pure complex as an orange

solid. ¹H NMR (500.1 MHz, CDCl₃, 298 K): δ = 9.35 (d, ³J =

4

4.8 Hz, 1 H, bipy-H), 8.89 (d, J = 1.4 Hz, 1 H, bipy-H), 8.59 (d,

3

³J = 7.2 Hz, 1 H, bipy-H), 8.48 (d, J = 7.2 Hz, 1 H, bipy-H), 8.33

3

4

= 5.5 Hz, 1 H, bipy-H), 8.90 (d, ³J = 5.5 Hz, 1 H, bipy-H), 8.54 (dd, J = 7.2, J = 7.2 Hz, 1 H, bipy-H), 8.13 (dd, J = 4.8, J =

3

(br. s, 1 H, –NH), 8.44 (s, 1 H, bipy-H), 8.39 (d, J = 7.7 Hz, 1 H,

1.4 Hz, 1 H, bipy-H), 7.14–7.10 (m, 6 H, cav-H_aryl), 6.58 (s, 1 H,

4790

www.eurjoc.org

Eur. J. Org. Chem. 2009, 4777–4792

Towards Allosteric Receptors

Chem. 2003, 3948–3957; c) U. Kiehne, J. Bunzen, H. Staats, A.

Lützen, Synthesis 2007, 1061–1069; d) M. Hapke, H. Staats, I.

Wallmann, A. Lützen, Synthesis 2007, 2711–2719; e) M.

Hapke, L. Brandt, A. Lützen, Chem. Soc. Rev. 2008, 37, 2782–

2797.

K. Paek, K. Joo, M. Kim, Y. Kim, Bull. Korean Chem. Soc.

1995, 16, 477–478.

Please note that monofunctionalized cavitands can also be pre-

pared in a functionalization-defunctionalization approach: a)

J. L. Irwin, M. S. Sherburn, J. Org. Chem. 2000, 65, 602–605;

b) J. L. Sherburn, M. S. Sherburn, J. Org. Chem. 2000, 65,

5846–5848; c) J. L. Irwin, M. S. Sherburn, Org. Lett. 2001, 3,

225–227.

cav-H_aryl), 6.57 (s, 1 H, cav-H_aryl), 6.51 (s, 2 H, cav-H_aryl), 6.42 (s,

2 H, cav-H_aryl), 5.77 (m, 2 H, cav-H_acetal), 5.69 (m, 2 H, cav-H_acetal),

5.59 (m, 2 H, cav-H_acetal), 5.58 (m, 2 H, cav-H_acetal), 4.82–4.63 (m,

8 H, cav-H_benzyl), 4.47 (m, 4 H, cav-H_acetal), 4.38 (m, 2 H, cav-

H_acetal), 4.32 (m, 2 H, cav-H_acetal), 2.24–2.20 (m, 16 H, cav-H_alkyl),

[11]

[12]

1.43–1.33 (m, 48 H, cav-H_alkyl), 0.91 (m, 24 H, cav-H_alkyl) ppm.

MS (ESI, neg. mode): m/z (%) = 2259.0 ([Re(CO)₃Cl(5) + Br]^–, 30,

matching isotope pattern).

[Ag(5)]BF₄: 20.0 mg (10.7 µmol) of 5 were dissolved in 2 mL of [D₆]-

benzene. From this solution 400 µL was transferred into an NMR

tube. 5.9 mg (21.4 µmol) of [Ag(NCCH₃)₂]BF₄were dissolved in

1 mL of [D₃]acetonitrile. 100 µL of the silver(I) salt’s solution was

also transferred to the NMR tube. The resulting mixture was

heated to 40 °C for 30 min to give an almost colourless solution

of the desired silver(I) complex which was characterised by NMR

spectroscopy and ESI MS. Unfortunately, the NMR spectra

showed only very broad signals (even at low temperatures) which

did not allow any assignment of individual signals. MS (ESI, pos.

mode): m/z (%) = 1981.0 (100) [Ag(5)]⁺. HiRes-MS (pos. ESI)

calcd. for [C₁₁₆H₁₃₂AgN₂O₂₀]⁺m/z = 1981.8449; found m/z =

1981.7807 (∆ = –32.3 ppm).

[13]

[14]

O. Hass, A. Schierholt, M. Jordan, A. Lützen, Synthesis 2006,

519–526.

Compound 23 could also be prepared selectively by using a

slight excess of bipyridine 10 compared to cavitand 19. How-

ever, the yield obtained in this approach was almost identical.

Since the separation of 2 and 23 did not cause any severe trou-

ble we sticked to the method depicted in Scheme 9.

a) M. Schmittel, U. Lüning, M. Meder, A. Ganz, C. Michel,

M. Hederich, Heterocycl. Commun. 1997, 3, 493–498; b) M.

Schmittel, A. Ganz, Synlett 1997, 710–712; c) M. Schmittel,

A. Ganz, Chem. Commun. 1997, 999–1000. The formation of

heteroleptic complexes can also be seen through the eyes of

dynamic combinatorial chemistry. There, numerous investi-

gations have been carried out to study the influence of the rela-

tive stabilities of individual components on the final composi-

tion of the dynamic combinatorial libraries. The final mixture

will be that with the lowest total free enthalpy and thus the

most stable member need not exist in highest concentration.

Some examples: d) P. T. Corbett, J. K. M. Sanders, S. Otto, J.

Am. Chem. Soc. 2005, 127, 9390–9392; e) P. T. Corbett,

J. K. M. Sanders, S. Otto, Chem. Eur. J. 2008, 14, 2153–2166;

f) K. Severin, Chem. Eur. J. 2004, 10, 2565–2580; g) V. Saggi-

omo, U. Lüning, Chem. Commun. 2009, 3711–3713.

a) U. Lüning, Liebigs Ann. Chem. 1987, 949–955; b) U. Lüning,

M. Müller, Chem. Ber. 1990, 123, 643–645; c) U. Lüning, M.

Müller, M. Gelbert, K. Peters, H. G. von Schnering, M. Keller,

Chem. Ber. 1994, 127, 2297–2306; d) M. Hagen, U. Lüning,

Chem. Ber./Recueil 1997, 130, 231–234; e) F. Löffler, M. Hagen,

U. Lüning, Synlett 1999, 1826–1828; f) B. Meynhardt, U.

Lüning, C. Wolff, C. Näther, Eur. J. Org. Chem. 1999, 2327–

2335; g) M. Gelbert, U. Lüning, Supramol. Chem. 2001, 12,

435–444; h) M. Bühl, F. Terstegen, F. Löffler, B. Meynhardt,

S. Kierse, M. Müller, C. Näther, U. Lüning, Eur. J. Org. Chem.

2001, 2151–2160; i) U. Lüning, F. Fahrenkrug, Eur. J. Org.

Chem. 2006, 916–923; j) S. Konrad, M. Bolte, C. Näther, U.

Lüning, Eur. J. Org. Chem. 2006, 4717–4730; k) F. Eggers, U.

Lüning, Eur. J. Org. Chem. 2009, 2328–2341; l) U. Lüning, M.

Abbass, F. Fahrenkrug, Eur. J. Org. Chem. 2002, 3294–3303;

m) R. Cacciapaglia, S. Di Stefano, F. Fahrenkrug, U. Lüning,

L. Mandolini, J. Phys. Org. Chem. 2004, 17, 350–355; n) U.

Lüning, F. Fahrenkrug, Eur. J. Org. Chem. 2004, 3119–3127.

J. Lewis, T. D. O’Donoghue, J. Chem. Soc., Dalton Trans. 1980,

736–742.

[15]

[Cu(5)]BF₄: 20.0 mg (10.7 µmol) of 5 were dissolved in 2 mL of [D₆]-

benzene. From this solution 400 µL was transferred into an NMR

tube. 6.7 mg (21.4 µmol) of [Cu(NCCH₃)₄]BF₄were dissolved in

1 mL of [D₃]acetonitrile. 100 µL of the copper(I) salt’s solution was

also transferred to the NMR tube. The resulting mixture was

heated to 40 °C for 30 min to give the deep red solution of the

desired copper(I) complex which was characterised by NMR spec-

troscopy and ESI MS. Unfortunately, the NMR spectra showed

only very broad signals (even at low temperatures) which did not

allow any assignment of individual signals. MS (ESI, pos. mode):

m/z (%) = 1977.9 (100) [Cu(5)(CH₃CN)]⁺. HiRes-MS (pos. ESI)

calcd. for [C₁₁₈H₁₃₅CuN₃O₂₀]⁺m/z = 1978.8967; found m/z =

1978.9160 (∆ = 9.8 ppm).

[16]

Acknowledgments

We would like to thank the Deutsche Forschungsgemeinschaft

(DFG) (SFB 624) for financial support.

[1] a) F. Hof, S. L. Craig, C. Nuckolls, J. Rebek Jr., Angew. Chem.

2002, 114, 1556–1578; Angew. Chem. Int. Ed. 2002, 41, 1488–

11508; b) L. Kovbasyuk, R. Krämer, Chem. Rev. 2004, 104,

3161–3187; c) D. M. Vriezema, M. C. Aragonès, J. A. A. W.

Elemans, J. J. L. M. Cornelissen, A. E. Rowan, R. J. M. Nolte,

Chem. Rev. 2005, 105, 1445–1489.

[2] C. A. Schalley, A. Lützen, M. Albrecht, Chem. Eur. J. 2004,

10, 1072–1080.

[3] A. Lützen, O. Haß, T. Bruhn, Tetrahedron Lett. 2002, 43, 1807–

[17]

[18]

[19]

[20]

1811.

[4] a) D. J. Cram, M. J. Cram, Container Molecules and Their

Guests, Royal Society of Chemistry, Cambridge, 1994; b) J. C.

Sherman, Tetrahedron 1995, 51, 3395–3422.

M. Yamada, Y. Nakamura, S. Kuroda, I. Shimao, Bull. Chem.

Soc. Jpn. 1990, 63, 2710–2712.

F. Fahrenkrug, Ph. D. Thesis, Christian-Albrechts-Universität

[5] For a comprehensive list of references using 2,2Ј-bipyridines as

zu Kiel, 2003.

allosteric centres, see references 7–16 in ref.^[6]

.

T. Hamura, T. Hosoya, H. Yamaguchi, Y. Kuriyama, M. Tan-

abe, M. Miyamoto, Y. Yasui, T. Matsumoto, K. Suzuki, Helv.

Chim. Acta 2002, 85, 3589–3604.

E. Kiehlmann, R. W. Lauener, Can. J. Chem. 1989, 67, 335–

344.

T. L. Davis, J. W. Hill, J. Am. Chem. Soc. 1929, 51, 493–504.

F. Bellouard, F. Chuburu, J.-J. Yaouanc, H. Handel, Y. LeMest,

Eur. J. Org. Chem. 1999, 3257–3261.

Please note that experiments with 2,9-dichloro-1,10-phen-

anthroline and related boronic acids were not successful even

[6] S. Zahn, W. Reckien, B. Kirchner, H. Staats, J. Matthey, A.

Lützen, Chem. Eur. J. 2009, 15, 2572–2580.

[7] G.-J. ten Brink, I. W. C. E. Arends, M. Hoogenrad, G. Verspui,

R. A. Sheldon, Adv. Synth. Catal. 2003, 345, 497–505.

[8] J. E. Parks, B. E. Wagner, R. H. Holm, J. Organomet. Chem.

1973, 56, 53–66.

[21]

[22]

[23]

[9] I. R. Butler, C. Soucy-Breau, Can. J. Chem. 1991, 69, 1117–

1123.

[24]

[10] a) A. Lützen, M. Hapke, Eur. J. Org. Chem. 2002, 2292–2297;

b) A. Lützen, M. Hapke, H. Staats, J. Bunzen, Eur. J. Org.

Eur. J. Org. Chem. 2009, 4777–4792

www.eurjoc.org

4791

U. Lüning, A. Lützen et al.

FULL PAPER

with broad variation of the reaction conditions, so the iodo

compound 26 has to be used instead.

Am. Chem. Soc. 1958, 80, 2745–2748; b) D. Wenkert, R. B.

Woodward, J. Org. Chem. 1983, 48, 283–289.

[25] Please note that because of the unknown amount of boronic

acid 27 in the crude product and incomplete conversion, ad-

ditional crude boronic acid 27 and tetrakis(triphenylphos-

phane)palladium(0) were added after 18 h and the mixture was

stirred for another 20 h to yield the desired product 25.

[28]

This compound has been described before. However, it was

synthesised in a different way: a) Y. Aoyama, Y. Tanaka, S.

Sugahara, J. Am. Chem. Soc. 1989, 111, 5397–5404; b) D. J.

Cram, L. M. Tunstad, C. B. Knobler, J. Org. Chem. 1992, 57,

528–535.

[26] a) L. M. Tunstad, J. A. Tucker, E. Dalcanale, J. Weiser, J. A.

Bryant, J. C. Sherman, R. C. Helgeson, C. B. Knobler, D. J.

Cram, J. Org. Chem. 1989, 54, 1305–1312; b) D. J. Cram, S.

Karbach, H.-E. Kim, C. B. Knobler, E. F. Maverick, J. L. Eric-

son, R. C. Helgeson, J. Am. Chem. Soc. 1988, 110, 2229–2237.

[27] This compound has been described before. However, it was

synthesised in a different way: a) G. Maerker, F. H. Case, J.

[29] This compound has been described before. However, it was

synthesised in a different way: P. L. Ferrarini, G. Biagi, O. Livi,

G. Primofiore, M. Carpene, J. Heterocycl. Chem. 1981, 18,

1007–1010.

Received: June 12, 2009

Published Online: August 27, 2009

4792

www.eurjoc.org

Eur. J. Org. Chem. 2009, 4777–4792

Article Doi

Towards allosteric receptors - Synthesis of Resorcinarene-Functionalized 2,2′-Bipyridines and their metal complexes

DOI: 10.1002/ejoc.200900642

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.200900642

Full text of DOI:10.1002/ejoc.200900642

Products guided by the article

R&D Labs maybe for 1195761-43-3

Relevant to this article

Hot Product