Tweezer-type catechol and resorcinol derivatives: Preparation, structures, and first investigations towards their hydrogen bonding abilities

Article abstract of DOI:10.1055/s-2002-33108

Tweezer-type molecules with an ester linkage between catechol or resorcinol and linear amino acid-based urea or amide derivatives are prepared. X-ray structures of representative compounds show, that the molecules are able to form intra- as well as intermolecular hydrogen bonds. In solution this hydrogen bonding donor/acceptor ability of the tweezers can be seen, on the one hand by interaction with anionic guest species (nitrate), and on the other hand by formation of gels in the case of the urea derivatives.

Full text of DOI:10.1055/s-2002-33108

1434
PAPER
Tweezer-Type Catechol and Resorcinol Derivatives: Preparation, Structures,
and First Investigations Towards their Hydrogen Bonding Abilities
Synthesis of
T
w
eezer-
T
a
ype Catec
r
R
k
esorcinol
D
u
erivatives s Albrecht,*a Jeanette Zauner,a Roland Fröhlich,b Olga Kataeva,b,c Elina Wegelius,d Kari Rissanend
a
Institut für Organische Chemie, RWTH Aachen, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
E-mail: markus.albrecht@oc.rwth-aachen.de
b
c
Organisch-Chemisches Institut, Universität Münster, Corrensstraße 40, 48149 Münster, Germany
E. Arbuzov Institute of Organic and Physical Chemistry, Russian Academy of Sciences, Arbuzov str. 8, Kazan 420088,
Russian Federation
d
Department of Chemistry, University of Jyväskylä, P.O. Box 35, 40351 Jyväskylä, Finland
Received 15 March 2002; revised 18 April 2002
Abstract: Tweezer-type molecules with an ester linkage between
catechol or resorcinol and linear amino acid-based urea or amide
derivatives are prepared. X-ray structures of representative com-
pounds show, that the molecules are able to form intra- as well as
intermolecular hydrogen bonds. In solution this hydrogen bonding
donor/acceptor ability of the tweezers can be seen, on the one hand
by interaction with anionic guest species (nitrate), and on the other
hand by formation of gels in the case of the urea derivatives.
Key words: amino acids, esters, hydrogen bonds, molecular recog-
nition, supramolecular chemistry
The selective recognition of cations, neutral molecules or
anions plays an important role in many biological process-
es. To understand the basic principles of molecular recog-
nition phenomena which occur in nature is an important
goal on the way to design efficient artificial receptors. The
selectivity of the binding of guest species hereby depends
on a perfect geometric and electronic match between the
host and the guest (receptor/substrate).1
Figure 1 Tweezer-type receptor molecules based on 2,2 -biphenol
and glycine derived side chains.
bone. The use of the two different backbones allows a fix-
ation of the tweezer-arms in an 60° (a) or 120° (b) angle
(Figure 2).
Very often cyclic molecules are used to model the recep-
tor abilities towards different guests.2 However, as an al-
ternative tweezer-type compounds, which possess a
higher flexibility, also can act as receptors.3 Recently we
started to study tweezer-type compounds which possess
an aromatic biphenol backbone to which two side chains
are attached via ester linkages. The side chains should
possess hydrogen bond donor/acceptor units to enable an
interaction with appropriate guest species. We have al-
ready reported, that the 2,2 -biphenol derivatives 1–3
(Figure 1) are able to bind nitrate in a 1:1 fashion and that
an additive effect of the number of hydrogen bonds4 is ob-
served in the binding of anions. Every additional hydro-
gen bond leads to an enhancement of the free enthalpy of
complexation of 2–3 kJ/mol.5
To enable some interaction with potential guest species,
we introduce different side arms which bear hydrogen
bond donor/acceptor moieties (indicated by the arrows in
Figure 2 A–E).6 The number of such potential binding
units can be varied by introducing either amides (B) and
carbamates (A, C) or ureas (D, E) and their distance can
be altered by using different spacers. Additionally the
steric hindrance (C) and the solubility (different substitu-
ents at the terminus D) of the system can be influenced
and chirality can be introduced (R = Me, D).
The very simple dicarbamate 5a is prepared by reaction of
catechol 4a with octyl isocyanate in acetonitrile and iso-
lated after column chromatography (silica gel, ethyl ace-
tate–hexane, 1:2) in 50% yield (Scheme 1).
However, the association constants which were observed
for the binding of nitrate by 1–3 are very low.5 In the
present study we substitute the flexible 2,2 -biphenol
backbone by the more rigid catechol and resorcinol back-
The compounds, which are based on a catechol or a resor-
cinol backbone and on two N-acetylglycine side chains
7a,b are prepared in a one-step procedure starting from
the corresponding dihydroxybenzene derivative 4a (cate-
Synthesis 2002, No. 10, 30 07 2002. Article Identifier:
1437-210X,E;2002,0,10,1434,1444,ftx,en;Z04102SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
chol) or 4b (resorcinol) and N-acetylglycine
6
(Scheme 2).

PAPER
Synthesis of Tweezer-Type Catechol and Resorcinol Derivatives
1435
Figure 2 Comparison of the catechol a and resorcinol b backbone (top) and of the hydrogen bond donor/acceptor ability of different side
arms (bottom).
material during the recrystallization. However, the com-
pounds are obtained in high purity.
Related tweezer-type derivatives of catechol and resorci-
nol, which bear urea moieties in the side arms, can be pre-
pared in three step sequences.
In the first step of the reaction sequence catechol (4a) or
resorcinol (4b) are coupled with N-BOC-glycine 8 using
the same coupling procedures as were applied to the cor-
responding N-acetyl derivatives 7a and 7b. The diester
10a is obtained in 66% by EDC/DMAP coupling, while
10b is formed in 58% by coupling with DCC/pyridine.
Additionally we prepared the chiral derivatives 11a (71%)
or 11b (65%) by reaction of catechol (4a) or resorcinol
(4b) with N-BOC-alanine 9 in the presence of DCC and
pyridine (Scheme 3). The BOC protecting groups are re-
moved quantitatively by reaction of 10a,b and 11b with
HCl in ether and the dihydrochlorides 12a,b and 13b are
coupled directly with N-methylmorpholine9 to liberate the
amino functions which are trapped by octyl isocyanate to
obtain the urea derivatives 14a (48%), 14b (50%) and 15b
(26%). The compounds precipitate from the reaction mix-
ture and can be isolated in analytically pure form by filtra-
Scheme 1
The double ester formation to form 7a proceeds in the
presence of EDC [N-ethyl(N -dimethylaminopropyl)car-
bodiimide] and DMAP (4-N,N-dimethylaminopyridine)7
in dichloromethane at 0 25 °C. The compound 7a is pu-
rified by crystallization from ethyl acetate–hexane and is
obtained in 25% yield as a white solid.
The resorcinol derivative 7b is obtained best with DCC
(N,N -dicyclohexylcarbodiimide) and pyridine as cou-
pling reagents.8 Recrystallization is done from ethyl ace-
tate–hexane 1:2 to obtain 7b in 40%. The yields in the
preparations of 7a/b are relatively low due to the loss of
Scheme 2
Synthesis 2002, No. 10, 1434–1444 ISSN 0039-7881 © Thieme Stuttgart · New York

1436
M. Albrecht et al.
PAPER
Scheme 3
tion. Attempts to deprotect 11a and subsequently couple prepared by coupling of catechol (4a) with only one
the resulting amine with isocyanate failed due to decom- equivalent of 6 in 72% yield.
position of the material.
Figure 3 shows the structure of the BOC-protected bis-
The derivative 16a with octadecyl instead of the decyl alanyl catechol ester 11a in the solid state. This compound
substituent is prepared in a similar way from 12a as a forms a monomeric structure in the solid state with one in-
crude product. However, 16a could not be purified and tramolecular NH–O hydrogen bond bridging the two side
was not obtained in analytically pure form.
arms (N...O = 2.902 Å). Hereby a 13 membered macrocy-
cle results, which forms a saddle shaped structure with the
two alanyl methyl groups more or less pointing towards
the concave face of the molecule. A weaker intermolecu-
lar hydrogen bond is formed with N...O = 3.075 Å lead-
ing to a one-dimensional band in [100] directions.
For comparison studies we also synthesized the catechol
derivative 20a with -alanine in the spacer. The com-
pound with -alanine urea moieties in the side arms 20a is
prepared starting from catechol 4a and forming the diester
with N-BOC- -alanine 17 in the presence of EDC and
DMAP. The diester 18a is obtained in 60% yield. The The monomeric structure of the bis(N-acetylglycine)ester
BOC protecting groups of 18a are removed by reaction of catechol 7a is presented in Figure 4a. The tweezer-type
with HCl and subsequently the dihydrochloride 19a is re- arrangement can be seen very nicely in this representa-
acted with N-methylmorpholine and octyl isocyanate. tion. No intramolecular hydrogen bonding can be ob-
Thus, the derivative 20a is obtained in 56% yield (over served for 7a in the solid state.
two steps) (Scheme 4).
Figure 4b on the other hand shows three molecules of 7a
As described, we have several tweezer-type catechol forming a polymeric strand by hydrogen bonding.6,11
(5a,7a,10a,14a,16a and 20a) and resorcinol derivatives Hereby the central molecule binds by its amide protons to
(7b,10b and 14b) in our hands, which we can now inves- two neighboring molecules. Additional hydrogen bonds
tigate for their ability to form hydrogen bonds.
are formed by the amide-oxygen atoms (Figure 4c) lead-
ing to a complicated three dimensional hydrogen bonded
network with two different types of hydrogen bonds
(N…O = 2.831 and 2.862 Å). The ester functionalities do
First we investigated representative X-ray structures of
the catechol derivatives 11a,7a and of the ‘single-armed’
intermediate 21a in the solid state.10 Compound 21a is
Synthesis 2002, No. 10, 1434–1444 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Tweezer-Type Catechol and Resorcinol Derivatives
1437
Scheme 4
gen bond in addition to the amide of the acetylglycine
moiety.
Figure 5a shows the monomeric structure of 21a in the
solid state. The acetylglycine is attached in a linear form
to the aromatic ring with the ester twisted out of plane and
the amide oriented in plane of the aromatic unit. The phe-
nolic hydrogen does not form an intramolecular hydrogen
bond to the neighboring ester unit but participates in inter-
molecular interactions. Hydrogen bonding between the
amide oxygen atoms and the OH groups of two molecules
21a leads to a macrocyclic dimer (Figure 5b), which by
additional interaction of the amide oxygens with amide
protons of neighboring molecules leads to a three-dimen-
sional network in the solid state (Figure 5b/c). Hereby the
O(2)-atom of the acetate undergoes two hydrogen bond-
ing interactions; one with the phenolic OH group
(O…O = 2.622 Å) and one with the amidic NH
(N…O = 2.914 Å). Another weaker hydrogen bond
(N...O = 3.142 Å) is observed between the amide proton
and O(5).
The X-ray structural results show, that our compounds are
able to undergo hydrogen bond interactions. Hereby bulky
groups in the periphery seem to suppress or weaken inter-
molecular binding, while sterically less demanding deriv-
atives lead to hydrogen-bridged polymeric structures in
the solid state. The results observed in the solid state en-
couraged us to investigate into the ability of the tweezer-
type complexes to form hydrogen bonds in solution: either
with guest species or with each other.
Figure 3 Molecular structure of 11a as found in the solid state.
not interfere with the hydrogen bonding interactions. Here
the ability of tweezer-type compounds like 7a to act
through their amide units of the side chains as hydrogen
bond donor as well as acceptor molecules is nicely dem-
onstrated.6
In a preliminary study we tested the anion binding12 by the
tweezer-type compounds using nitrate anions13 as guest
species, which can be fixed in the tweezer by hydrogen
bonding interaction. The results of the titration studies are
summarized in Table 1 and Figure 6 shows as a represen-
For comparison we prepared and crystallized compound
21a with only one N-acetylglycine attached by ester link-
age to catechol. One phenolic OH is able to form a hydro-
–
tative example the Job plot for the system 7a/NO3 and the
corresponding titration curve. [NMR titration experi-
Synthesis 2002, No. 10, 1434–1444 ISSN 0039-7881 © Thieme Stuttgart · New York

1438
M. Albrecht et al.
PAPER
Figure 4 Molecular structure of 7a as found in the solid state: a) the monomeric structure and b,c) different views of the hydrogen bonded
network.
ments were performed in CDCl3 at 297 K with subsequent The resorcinol derivatives are also able to bind nitrate in a
addition of tetrabutylammonium nitrate (TBAN)].14
1:1 fashion.15 Hereby an enhancement of the binding con-
stant is observed by switching from the simple bis-amide
7b (Ka = 59 mol–1) to the bis-urea derivative 14b
(Ka = 113 mol–1). Comparison of the very similar recep-
tors 14b and 15b shows that the methyl groups of the ala-
nine residues of 15b introduce conformations which are
not favorable for the formation of a host/guest complex
with nitrate. Binding of nitrate by the resorcinol derived
tweezers strongly influences the chemical shift of the pro-
ton in 2 position of the resorcinol which is directed to-
wards the anion binding site. Maximum high field shifts
of 67 Hz (7b), 22 Hz (14b), and 58 Hz (15b) are observed
in the titration experiments. For the protons H-4/6 and H-
5 a less pronounced shifting occurs.
Titration plots for 5a,7a,14a,20a,7b,14b, and 15b with ni-
trate using Jobs method14 show that a 1:1 complex is
formed between the tweezer-type receptor and the anion.
The titration experiments reveal, that the biscarbamate 5a
binds nitrate with a very low binding constant (Ka <25
mol–1) while the bis-acetylglycine 7a leads to a reasonable
– but still weak – binding (Ka = 158 mol–1). In the latter
the distance between the two amide NH units seems to be
more favorable for the binding of nitrate than in 5a
(Figure 7). Attempts to get stronger binding of the nitrate
by introduction of further hydrogen binding sites in the
ligands 14a,16a, and 20a does not lead to higher associa-
tion constants.5 Probably due to steric constrains in 14a
and poor preorganization in 20a Ka values of 126 mol–1 Although the observed association constants are all low,
(14a) and 102 mol–1 (20a) are observed for the binding of we can deduce some tendencies which should help us to
the anion. No association constant could be determined design more effective receptors for anions in the future.
for the interaction of nitrate with 16a (vide infra).
Hydrogen bonding in solution should not only occur with
guest species, but hydrogen bonds should also be formed
Synthesis 2002, No. 10, 1434–1444 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Tweezer-Type Catechol and Resorcinol Derivatives
1439
Figure 5 Molecular structure of 21a as found in the solid state: a) the monomeric structure and b,c) different fews of the hydrogen bonded
network.
between two or more tweezer-type molecules, leading to In conclusion, we have presented the syntheses of twee-
networks as observed in the solid state for 7a or 21a. zer-type compounds based on a catechol or resorcinol
Therefore we looked for possible gelating properties of backbone and on two side arms which possess amide or
the compounds and the results are summarized in Table 2. urea functionalities as hydrogen bond donor/acceptor
All experiments on the gelating properties were per- moieties. The use of either catechol or resorcinol as back-
formed with 5 mg compound/1 mL solvent at room or at bone allows the fixation of the arms at a defined angle to
low (253 K) temperature.16
each other.
For simple amides like 5a or 7a no gelating could be ob- The solid state structures of 7a, 11a and 21a show that the
served in a series of different solvents. However, urea de- compounds are able to undergo hydrogen bonding. How-
rivatives lead to gelation of a number of solvents. For ever, bulky groups like the BOC substituent of 11a seems
example 14a forms a gel in chloroform at room tempera- to prevent intermolecular hydrogen bonding.
ture, while a solution of 14a in dichloromethane or ethyl
In solution the ability of the tweezer-type compounds can
acetate gelates upon cooling. Introducing longer alkyl
be shown by host/guest interaction with nitrate. Low asso-
chains in the periphery of the molecules as shown with
ciation constants were obtained by NMR titrations but
compound 16a leads to strong gelation in benzene. In
some trends can be seen which might help in the design of
dichloromethane and chloroform gelation proceeds at low
more effective receptors. Additionally, in some cases ge-
temperature. Precipitation of 16a as a fluffy – probably
lation of solutions was observed, showing that the mole-
cules can interact with each other to build up network
hydrogen bridged – solid from chloroform at room tem-
perature is the reason, that no association constant with ni-
structures.
trate could be determined. Surprisingly, the -alanyl
In this paper we did not describe novel superior receptors
but we have investigated a class of interesting tweezer-
type compounds and showed that they are able to undergo
hydrogen bonding interactions. In future studies this sys-
derivative 20a does not gelate any of the tested solvents.
Layering the gel, which is formed from 14a in chloro-
form, with a few drops of a concentrated solution of tet-
rabutylammonium nitrate in chloroform, leads to a slow
tem has to be optimized and we hope that we can use the
dissolution of the gel. Here the nitrate anions break up the
labile aryl ester linkages between the backbone and the
hydrogen bonding network of the gel and form the already
side-arms to enter the field of ‘dynamic combinatorial
described 1:1 host guest complex [14a NO3]– with the re-
chemistry’ based on libraries of related receptor mole-
ceptor. The resorcinol derivatives 14b and 15b in chloro-
form only lead to organogels upon cooling the solutions.
cules.17
Synthesis 2002, No. 10, 1434–1444 ISSN 0039-7881 © Thieme Stuttgart · New York

1440
M. Albrecht et al.
PAPER
Table 2 Gelating Properties of the Tweezer-Type Compounds in
Different Solventsa
Compound CHCl3
CH2Cl2
EtOAc
Benzene
5a
7a
–
–
–
+
+
–
–
–
–
–
–
–
–
14a
16a
20a
14b
15b
++
+
–
+
–
insoluble
++
–
–
–
–
+
+
–
–
a – no gelating properties; + gelating at low temperatures; ++ gelating
at room temperature.
1H NMR and 13C NMR spectra were recorded on a Bruker DRX 500
spectrometer using DEPT techniques for the assignment of the mul-
tiplicity of carbon atoms. FT-IR spectra were recorded by diffuse
reflection (KBr) on a Bruker IFS spectrometer. Mass spectra (EI, 70
eV) were taken on a Finnigan MAT 90 mass spectrometer. Elemen-
tal analyses were obtained with a Heraeus CHN-O-Rapid analyzer.
Solvents were purified by standard methods. Melting points: Büchi
B-540 (uncorrected).
N-Octyl[(2-(N-octylcarbamoyloxy)phenoxy]formamide (5a)
Catechol (4a; 220 mg, 2.00 mmol) was dissolved in anhyd MeCN
(20 mL) and under argon octyl isocyanate (706 L, 4.00 mmol) was
added. The mixture was refluxed for 16 h before the solvent was re-
moved in vacuum. The residue was dissolved in EtOAc, washed
with sat. aq NaHCO3 (3 ), dried (MgSO4) and the solvent was re-
moved. The crude product was purified by chromatography over
silica gel (EtOAc–hexane, 1:2); yield: 420 mg (50%); white solid;
mp 105 °C.
Figure 6 Jobs plot for the interaction of the receptor 7a with tetra-
butylammonium nitrate showing that a 1:1 complex is formed
(X = molar fraction) (top). 1H NMR titration curve (500 MHz) for the
titration of 7a (amide proton) with tetrabutylammonium nitrate in
CDCl3 at 297 K (bottom).
IR (KBr): 3339, 2959, 2923 2853, 1718, 1541, 1495, 1262, 1188,
761 cm–1.
1H NMR (CDCl3, 500 MHz): = 7.19 (m, 4 H), 5.19 (br s, 2 H),
3.24–3.20 (m, 4 H), 1.53 (m, 4 H), 1.28 (m, 20 H), 0.88 (t, J = 6.9
Hz, 6 H).
13C NMR (CDCl3, 125 MHz): = 153.9 (C), 143.1 (C), 126.1 (CH),
123.5 (CH), 41.4 (CH2), 31.8 (CH2), 29.8 (CH2), 29.2 (CH2, double
intensity), 26.7 (CH2), 22.6 (CH2), 14.1 (CH3).
Table 1 Maximum 1H NMR Shift Differences max (500 MHz),
Association Constants Ka and Free Enthalpy of Complexation GHG
for the Formation of Receptor/Substrate Complexes with Nitrate
GHG (kJ mol–1)
Pos. FAB MS (DMSO/3-NBA): m/z = 421 [M + H]+, 443 [M +
Nitrate
Complex
max (CDCl3, Ka (296 K)
500 MHz)
(mol–1)
Na]+.
(Hz)
143
768
187
–
HRMS: m/z calcd for C24H41N2O4: 421.3066, found: 421.3057.
–
5a NO3
< 25
> –8.1
Anal. Calcd for C24H40N2O4 (420.59): C, 68.54; H, 9.59; N, 6.66:
Found: C, 68.53; H, 9.24; N, 6.84.
–
–
–
–
–
7a NO3
158 13
126 40
–
–12.5 0.2
–11.9 0.8
–
2-[2-(Acetylamino)acetyloxy]phenyl-2-(acetylamino)acetate
(7a)
14a NO3
16a NO3
20a NO3
Catechol (4a; 550 mg, 5.00 mmol), N-acetylglycine (6; 1.18 g, 10.0
mmol), and 4-N,N-dimethylaminopyridine (DMAP, 1.22 g, 10.0
mmol) were dissolved in CH2Cl2 at 0 °C. EDC (2.18 g, 11.4 mmol)
was added and after 2 h at 0 °C, the mixture was allowed to warm
to r.t. and stirred for additional 16 h. The solution was washed with
sat. aq NH4Cl (3 ), dried (MgSO4) and the solvent was removed in
vacuum. The crude product was purified by recrystallization from
EtOAc–hexane; yield: 384 mg (25%); white solid; mp 144 °C.
338
763
398
533
102
59
7
6
–11.4 1.7
–10.0 0.3
–11.7 0.2
–11.1 0.2
7b NO3
–
14b NO3
113 10
88
–
15b NO3
6
Synthesis 2002, No. 10, 1434–1444 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Tweezer-Type Catechol and Resorcinol Derivatives
1441
Figure 7 Comparison of possible nitrate binding modes of the catechol and resorcinol based receptors.
IR (KBr): 3247, 3069, 1794, 1653, 1571, 1490, 1407, 1376, 1242,
1158, 1149, 1119, 1038, 790, 781 cm–1.
removed in vacuum and the residue was recrystallized from
EtOAc–pentane; yield: 1.40 g (66%); white solid; mp 126 °C.
1H NMR (CDCl3, 500 MHz): = 7.27–7.24 (m, 2 H), 7.18–7.16 (m,
2 H), 6.93 (t, J = 5.9 Hz, 2 H), 4.22 (d, J = 5.9 Hz, 2 H), 2.06 (s, 6
IR (KBr): 3554, 3299, 3067, 3009, 2970, 2935, 2819, 1788, 1757,
1693, 1599, 1548, 1492, 983, 863, 846, 769, 667 cm–1.
H).
1H NMR (CDCl3, 500 MHz): = 7.29–7.27 (m, 2 H), 7.22–7.20 (m,
2 H), 5.51 (br s, 2 H), 4.15 (m, 4 H), 1.48 (s, 18 H).
13C NMR (CDCl3, 125 MHz): = 168.1 (C), 156.2 (C), 141.9 (C),
127.0 (CH), 123.3 (CH), 80.3 (C), 42.4 (CH2), 28.4 (CH3).
13C NMR (CDCl3, 125 MHz): = 171.3 (C), 167.6 (C), 141.8 (C),
127.1 (CH), 123.3 (CH), 41.3 (CH2), 22.9 (CH3).
Pos. FAB MS (DMSO/3-NBA): m/z = 309 [M + H]+.
Anal Calcd for C14H16N2O6 (308.29): C, 54.54; H, 5.23; N, 9.09.
Found: C, 54.09; H, 5.31; N, 8.75.
MS (EI/70 eV): m/z (%) = 425 (0.03) [M]+, 110 (100).
HRMS: m/z calcd for C20H29N2O8.: 425.1924, found: 425.1929.
X-Ray Structural Analysis of 7a18
Analysis Calcd for C20H28N2O8 (424.45): C, 56.60; H, 6.65; N, 6.60.
Found: C, 56.52; H, 6.69; N, 6.44.
Formula:
C14H16N2O6,
M = 308.29,
colorless
crystal
0.40 0.30 0.20 mm, a = b = 10.1776(2), c = 15.0922(3) Å,
V = 1563.30(5) Å3, calc = 1.310 g cm–3, = 0.104 cm–1, no absorption
correction (0.960 < T < 0.980), Z = 4, tetragonal, space group P41
(No. 76), = 0.71073 Å, T = 173 K, and scans, 9971 reflections
collected ( h, k, l), [sin / ]max = 0.59 Å–1, 2755 independent (Rint
= 0.033) and 2555 observed reflections [I 2 (I)], 208 refined pa-
rameters, R1 = 0.045, wR2 = 0.109, Flack parameter 0.6(15), maxi-
mum residual electron density 0.16 (–0.20) e Å–3.
2-(2-Aminoacetyloxy)phenyl-2-aminoacetate Dihydrochloride
(12a)
Bis(N-tert-butoxycarbonylgylcine)catecholate 10a (1.40 g, 3.30
mmol) was stirred overnight with a solution of sat. HCl in Et2O at
r.t. The solvent was removed in vacuum to obtain the product in
quantitative yield (981 mg); white solid; mp 197 °C.
IR (KBr): 3308, 2993, 2949, 2682, 2606, 1789, 1768, 1694, 1576,
1547, 1493, 1428, 4102, 1305, 1254, 1196, 1170, 1133, 1111, 1099,
1045, 887, 791, 768, 758 cm–1.
1H NMR (CD3OD, 500 MHz): = 7.39 (s, 4 H), 4.30 (s, 4 H).
13C NMR (CD3OD, 125 MHz): = 166.7 (C), 142.5(C), 128.7
(CH), 124.6 (CH), 41.3 (CH2).
Pos. FAB MS (3-NBA, DMSO): m/z = 225 [M – HCl2]+.
3-[2-(Acetylamino)acetyloxy]phenyl-2-(acetylamino)acetate
(7b)
Resorcinol (4b; 1.10 g, 10.0 mmol), N-acetylglycine (6; 2.36 g, 20.0
mmol), N,N -dicyclohexylcarbodiimide (DCC, 4.56 g, 21.0 mmol)
and pyridine (3 mL) in EtOAc (80 mL) were stirred for 3 d. Three
drops of AcOH were added and after 30 min, the mixture was heat-
ed and was filtered hot. The solvent was removed in vacuum and the
remaining crude product was recrystallized from hexane–EtOAc
(2:1); yield: 1.22 g (40%); white solid; mp 139 °C.
Anal. Calcd for C10H14Cl2N2O4 (297.14): C, 40.42; H, 4.75; N, 9.43:
Found: C, 40.41; H, 5.19; N, 9.19.
IR (KBr): 3275, 3089, 2981, 2929, 2851, 1777, 1765, 1645, 1601,
1560, 1370, 1252, 1188, 806, 799, 605 cm–1.
1H NMR (DMSO-d6, 500 MHz): = 8.46 (t, J = 5.7 Hz, 2 H), 7.46
(t, J = 8.2 Hz, 1 H), 7.03 (dd, J = 2.2, 8.2 Hz, 2 H), 6.94 (t, J = 2.2
Hz, 1 H), 4.06 (d, J = 5.7 Hz, 4 H), 1.88 (s, 6 H).
13C NMR (DMSO-d6, 125 MHz): = 170.5 (C), 169.3 (C), 151.2
(C), 130.6 (CH), 119.7 (CH), 116.0 (CH), 41.5 (CH2), 22.6 (CH3).
2-{2-[(Octylamino)carbonylamino]acetyloxy}phenyl-2-[(octy-
lamino)carbonylamino]acetate (14a)
The hydrochloride 12a (100 mg, 0.34 mmol) and N-methylmorpho-
line (74 L, 0.67 mmol) were stirred for 20 min in MeCN (10 mL)
under argon. Octyl isocyanate (118 L, 0.67 mmol) was added and
the mixture was refluxed for 16 h. The product crystallized upon
cooling and was isolated by filtration; yield: 87.1 mg (48%); white
solid; mp 157–164 °C.
Pos. FAB MS (DMSO/3-NBA): m/z = 309 [M + H]+.
IR (KBr): 3330, 2955, 2924, 2854, 1767, 1752, 1628, 1586, 1496,
1255, 1165, 1098, 621 cm–1.
1H NMR (CDCl3, 500 MHz): = 7.22 (m, 2 H), 7.16 (m, 2 H), 4.19
(s, 4 H), 3.15 (t, J = 7.2 Hz, 4 H), 1.47 (m, 4 H), 1.28–1.24 (m, 24
H), 0.87 (t, J = 6.9 Hz, 6 H).
13C NMR (CDCl3, 125 MHz): = 168.4 (C), 159.1 (C), 141.7 (C),
127.0 (CH), 123.3 (CH), 42.2 (CH2), 40.8 (CH2), 31.8 (CH2), 30.0
(CH2), 29.3 (CH2), 29.2 (CH2), 26.9 (CH2), 22.6 (CH2), 14.1 (CH3).
Anal. Calcd for C14H16N2O6 3/2 H2O (335.29): C, 50.15; H, 5.71; N,
8.35. Found: C, 49.92; H, 5.73; N, 8.28.
2-{2-[(tert-Butoxy)carbonylamino]acetyloxy}phenyl-2-[(tert-
butoxy)carbonylamino]acetate (10a)
Catechol (4a; 220 mg, 5.00 mmol) and N-BOC protected glycine 8
(1.93 g, 11.0 mmol) were dissolved in CH2Cl2 (10 mL) at 0 °C.
EDC (2.18 g, 11.0 mmol) and DMAP (1.22 g, 10 mmol) were add-
ed. After warming to r.t., the mixture was stirred for 16 h, washed
with sat. aq NaHCO3 and brine and dried (MgSO4). The solvent was
Pos. FAB MS (DMSO/3-NBA): m/z = 535 [M + H]+.
Synthesis 2002, No. 10, 1434–1444 ISSN 0039-7881 © Thieme Stuttgart · New York

1442
M. Albrecht et al.
PAPER
3-{2-[(tert-Butoxy)carbonylamino]acetyloxy}phenyl-2-[(tert-
butoxy)carbonylamino]acetate (10b); Typical Procedure
Resorcinol (4b; 1.10 g, 10.0 mmol), N-BOC-glycine (8; 3.50 g, 20.0
mmol), DCC (4.56 g, 21.0 mmol) and pyridine (3 mL) were stirred
for 16 h in EtOAc (80 mL). After addition of 3 drops of AcOH and
additional stirring for 30 min, the precipitated urea was filtered off,
the solvent was removed and the residue was purified by column
chromatography (silica gel, hexane–EtOAc, 2:1); yield: 2.45 g
(58%); white solid; mp 145 °C.
Anal. Calcd for C28H46N4O6 1/2 H2O (543.70): C, 61.85; H, 8.71; N,
10.30: Found: C, 61.90; H, 8.40; N, 10.55.
2-{2-[(tert-Butoxy)carbonylamino]propanoyloxy}phenyl-2-
[(tert-butoxy)carbonylamino]propanoate (11a)
Catechol (4a; 1.10 g, 10.0 mmol) and N-BOC-L-alanine (9; 3.78 g,
20.0 mmol) were dissolved in EtOAc (40 mL). DCC (4.56 g, 21.0
mmol) and pyridine (1.45 mL, 18.0 mmol) were added and the mix-
ture was stirred at r.t. for 14 h. Three drops of AcOH were added
and after stirring for another 30 min the precipitate was filtered off
and the solvent was removed in vacuum. The crude product was pu-
rified by column chromatography (hexane–EtOAc, 2:1); yield: 3.21
g (71%); white solid; mp 93 °C.
IR (KBr): 3365, 2980, 2936, 1777, 1699, 1602, 1519, 1485, 1456,
1393, 1368, 1287, 1251, 1149, 1055, 965 cm–1.
1H NMR (CDCl3, 500 MHz): = 7.36 (t, J = 8.2 Hz, 1 H), 7.01(dd,
J = 2.1, 8.2 Hz, 2 H), 6.94 (t, J = 2.1 Hz, 1 H), 5.14 (br s, 2 H), 4.14
(d, J = 5.7 Hz, 4 H), 1.46 (s, 18 H).
13C NMR (CDCl3, 125 MHz): = 168.7 (C), 155.8 (C), 150.7 (C),
129.9 (CH), 119.1 (CH), 115.1 (CH), 80.4 (C), 42.6 (CH2), 28.3
(CH3).
IR (KBr): 3391, 3366, 2976, 2935, 1780, 1757, 1691, 1598, 1525,
1493, 1457, 1394, 1367, 1324, 1299, 1242, 1123, 1061, 1015, 949,
902, 884, 864, 846, 803, 788, 776, 756, 648 cm–1.
1H NMR (CDCl3): = 7.27–7.22 (m, 2 H), 7.18–7.16 (m, 2 H), 5.44
(d, J = 7.4 Hz, 2 H), 4.53 (quin, J = 7.4 Hz, 2 H), 1.55 (d, J = 7.4 Hz,
6 H), 1.45 (s, 18 H).
Pos. FAB MS (DMSO/3-NBA): m/z = 447 [M + Na]+.
13C NMR (CDCl3): = 171.1 (C), 155.5 (C), 142.0 (C), 126.9 (CH),
123.3 (CH), 80.1 (C), 49.3 (CH3), 28.4 (CH3), 18.0 (CH).
Anal. Calcd for C20H28N2O8 (424.45): C, 56.60; H, 6.65; N, 6.60:
Found: C, 56.25; H, 6.85; N, 6.10.
Pos. FAB MS (DMSO/3-NBA): m/z = 453 [M + H]+.
3-{2-[(Octylamino)carbonylamino]acetyloxy}phenyl-2-[(octyl-
amino)carbonylamino]acetate (14b); Typical Procedure
The bis(N-tert-butoxycarbonylgylcine)resorcinolate 10b (2.45 g,
5.76 mmol) was first stirred in a sat. solution of HCl in Et2O for 3 h
at r.t. to quantitativly remove the BOC protecting group. The pre-
cipitated dihydrochloride 12b (1.71 g) was used without character-
ization. The dihydrochloride 12b (100 mg, 0.34 mmol) was stirred
under argon for 20 min in MeCN (10 mL) in the presence of N-me-
thylmorpholine (74 L, 0.67 mmol). Octyl isocyanate (118 L, 0.67
mmol) was added and the mixture was refluxed for 16 h . Upon
cooling the product precipitated and was isolated by filtration;
yield: 90.0 mg (50%); white solid; mp 147 °C.
Anal. Calcd for C22H32N2O8 (452.51): C, 58.40; H, 7.13; N, 6.19:
Found: C, 58.08; H, 7.11; N, 6.11.
X-Ray Structural Analysis of 11a18
Formula
C22H32N2O8,
M = 452.50,
colorless
crystal
0.25 0.25 0.10 mm, a = 9.925(1), b = 12.997(1), c = 19.471(1)
Å, V = 2511.7(3) Å3, calc = 1.197 g cm–3, = 7.61 cm–1, absorption
correction via scan data (0.833 < T < 0.928), Z = 4, orthorhombic,
space group P212121 (No. 19), = 1.54178 Å, T = 223 K, /2
scans, 2906 reflections collected (+h, +k, +l), [sin / ]max = 0.62
Å–1, 2906 independent (Rint = 0.000) and 2495 observed reflections
[I
2 (I)], 304 refined parameters, R1 = 0.035, wR2 = 0.094, Flack
IR (KBr): 3322, 2956, 2925, 2852, 1752, 1625, 1580, 1234, 918,
780, 685, 618 cm–1.
1H NMR (DMSO-d6, 500 MHz): = 7.42 (t, J = 8.2 Hz, 1 H), 7.00
(m, 2 H), 6.91 (s, 1 H), 6.28 (m, 2 H), 6.20 (t, J = 5.7 Hz, 2 H), 4.00
(d, J = 5.7 Hz, 4 H), 2.97 (q, J = 6.5 Hz, 4 H), 1.30 (m, 4 H), 1.22
(m, 20 H), 0.83 (t, J = 6.8 Hz, 6 H).
13C NMR (DMSO-d6, 125 MHz): = 170.5 (C), 158.4 (C), 151.3
(C), 130.5 (CH), 119.6 (CH), 116.0 (CH), 42.3 (CH2), 39.5 (CH2),
31.7 (CH2), 30.4 (CH2), 29.2 (CH2), 29.1 (CH2), 26.8 (CH2), 22.5
(CH2), 14.4 (CH3).
parameter –0.3(2), maximum residual electron density 0.15 (–0.19)
e Å–3.
2-{2-[(Octadecylamino)carbonylamino]acetyloxy}phenyl-2-
[(octadecylamino)carbonylamino]acetate (16a)
Under argon, the dihydrochloride 12a (200 mg, 0.67 mmol) and N-
methylmorpholine (148 L, 1.35 mmol) were stirred for 20 min at
r.t. in MeCN (10 mL). Octadecyl isocyanate was added and the mix-
ture was stirred for an additional 16 h. The crude product precipitat-
ed and was isolated by filtration. However, the material upon
cooling gelated in several organic solvents and therefore could not
be purified by crystallization and was not obtained in an analytically
pure form; yield: 300 mg (55%); white solid as a crude product; mp
165 °C.
Pos. FAB MS (DMSO/3-NBA): m/z = 535 [M + H]+, 557 [M +
Na]+.
Anal. Calcd for C28H46N4O6 (534.70): C, 62.90; H, 8.67; N, 10.48:
Found: C, 62.90; H, 8.27; N, 10.37.
IR (KBr): 3338, 2955, 2919, 2849, 1762, 1749, 1620, 1584, 1500,
1467, 1253, 1169, 1100 cm–1.
1H NMR (CDCl3/CD3OD (313 K), 500 MHz): = 7.17–7.14 (m, 2
H), 7.12–7.10 (m, 2 H), 4.06 (s, 4 H), 3.05 (m, 4 H), 1.35 (m, 4 H),
1.17 (m, 60 H), 0.79 (t, J = 7.0 Hz, 6 H).
13C NMR (CDCl3, 125 MHz): = 168.9 (C), 159.0 (C), 141.7 (C),
126.6 (CH), 123.1 (CH), 41.8 (CH2), 40.1 (CH2), 31.7 (CH2, double
intensity), 30.0 (CH2), 29.5 (CH2, quadruple intensity), 29.5 (CH2,
triple intensity), 29.3 (CH2), 29.2 (CH2, double intensity), 26.8
(CH2), 22.5 (CH2, double intensity), 13.8 (CH3).
3-{2-[(tert-Butoxy)carbonylamino]propanoyloxy}phenyl-2-
[(tert-butoxy)carbonylamino]propanoate (11b)
Compound 11b was prepared from 4b (550 mg, 5.00mol) and 9
(1.89 g, 10.0 mol) as described for 10b; yield: 1.46 g (65%); white
solid; mp 120 °C.
IR (KBr): 3523, 3382, 3077, 2986, 2938, 1775, 1690, 1603, 1518,
1483, 1451, 1393, 1370, 1336, 1303, 1282, 1256, 1147, 1125, 1099,
1068, 1023, 1004, 963, 930, 904, 788, 756, 682 cm–1.
1H NMR (CDCl3, 500 MHz): = 7.37 (t, J = 8.2 Hz, 1 H), 7.01 (d,
J = 2.2 Hz, 2 H), 6.96 (m, 1 H), 5.10 (m, 2 H), 4.51 (m, 2 H), 1.52
(d, J = 7.2 Hz, 6 H), 1.45 (s, 18 H).
Pos. FAB MS (DMSO/3-NBA): m/z = 816 [M + H]+.
HRMS: m/z calcd for C48H87N4O6: 815.6626, found: 815.6648.
13C NMR (CDCl3, 125 MHz): = 171.6 (C), 155.1 (C), 150.9 (C),
129.8 (CH), 119.0 (CH), 115.0 (CH), 80.2 (C), 49.4 (CH), 28.3
(CH3), 18.3 (CH3).
Synthesis 2002, No. 10, 1434–1444 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Tweezer-Type Catechol and Resorcinol Derivatives
1443
Pos. FAB MS (DMSO/3-NBA): m/z = 453 [M + H]+, 475 [M +
HRMS: m/z calcd for C22H33N2O8: 453.2237, found: 453.2227.
Na]+.
Anal. Calcd for C22H32N2O8 (452.51): C, 58.40; H, 7.13; N, 6.19.
Found: C, 58.26; H, 7.26; N, 5.68.
Anal. Calcd for C22H32N2O8 H2O (470.52): C, 56.16; H, 7.28; N,
5.95. Found: C, 56.29; H, 6.92; N, 5.73.
3-{3-[(Octylamino)carbonylamino]propanoyloxy}phenyl-3-
[(octylamino)carbonylamino]propanoate (20a)
3-(2-Aminopropanoyloxy)phenyl-2-aminopropanoate Dihydro-
chloride (13b)
Compound 13b was prepared from 11b (1.00 g, 2.21mmol) similar
to the corresponding glycine derivative 12b; yield: 717 mg (quant.);
white solid; mp 225 °C.
The BOC-protecting group of 18a was removed quantitatively by
stirring the compound in a sat. solution of HCl in Et2O for 3 h at r.t.
After removal of the solvent the dihydrochloride 19a was obtained
as a white solid which was used without characterization. The dihy-
drochloride 19a (200 mg, 0.62 mmol) and N-methylmorpholine
(135 L, 1.23 mmol) were stirred for 20 min at r.t. under argon in
MeCN (20 mL). After addition of octyl isocyanate (217 L, 1.23
mmol), the mixture was refluxed for 16 h. The product precipitated
upon cooling and was collected by filtration; yield: 195 mg (56%);
white solid; mp 156 °C.
IR (KBr): 3414, 2918, 1933, 1768, 1599, 1483, 1238, 1182, 1126,
1098, 884, 747, 685 cm–1.
1H NMR (DMSO-d6, 500 MHz): = 8.89 (br s, 6 H), 7.55 (t, J = 8.1
Hz, 1 H), 7.20 (m, 1 H), 7.18 (m, 2 H), 4.33 (m, 2 H), 1.57 (d, J = 7.2
Hz, 6 H).
13C NMR (DMSO-d6, 125 MHz): = 168.5 (C), 150.2 (C), 130.5
(CH), 119.7 (CH), 115.3 (CH), 40.0 (CH), 15.5 (CH3).
IR (KBr): 3347, 2954, 2923, 2850, 1755, 1623, 1584, 1252, 776
cm–1.
1H NMR (CDCl3, 500 MHz): = 7.24–7.21 (m, 2 H), 7.19–7.17 (m,
2 H), 5.48 (br s, 2 H), 5.38 (br s, 2 H), 3.44 (t, J = 5.5 Hz, 4 H), 3.12
(t, J = 7.1 Hz, 4 H), 2.78 (t, J = 5.5 Hz, 4 H), 1.44 (quin, J = 7.1 Hz,
4 H), 1.29–1.24 (m, 20 H), 0.86 (t, J = 7.0 Hz, 6 H).
Pos. FAB MS (DMSO/3-NBA): m/z = 254 [M – HCl2]+.
Anal. Calcd for C12H18Cl2N2O4 2 H2O (361.22): C, 39.90; H, 6.14;
N, 7.76: Found: C, 39.73; H, 5.51; N, 6.96.
13C NMR (CDCl3, 125 MHz): = 170.3 (C), 158.9 (C), 141.7 (C),
126.4 (CH), 123.4 (CH), 40.3 (CH2), 35.5 (CH2), 34.6 (CH2), 31.8
(CH2), 30.3 (CH2), 29.3 (CH2), 29.3 (CH2), 27.0 (CH2), 22.6 (CH2),
14.1 (CH3).
3-{2-[(Octylamino)carbonylamino]propanoyloxy}phenyl-2-
[(N-octylcarbamoyl)amino]propanoate (15b)
Compound 15b was synthesiszed from 13b (150 mg, 0.47 mmol) as
described for the corresponding glycine derivative 14b; yield: 68.7
mg (26%); white solid; mp 185 °C.
Pos. FAB MS (DMSO/3-NBA): m/z = 563 [M + H]+, 585 [M +
Na]+.
IR (KBr): 3328, 2955, 2925, 2854, 1767, 1747, 1630, 1604, 1578,
1484, 1468, 1242, 1132 cm–1.
1H NMR (CDCl3, 500 MHz): = 7.32 (t, J = 7.9 Hz, 1 H), 6.96 (m,
3 H), 5.77 (br s, 2 H), 5.54 (br s, 2 H), 4.60 (d, J = 6.1 Hz, 2 H), 3.16
(m, 2 H), 3.06 (m, 2 H), 1.41 (m, 10 H), 1.23 (m, 20 H), 0.86 (t,
J = 6.4 Hz, 6 H).
13C NMR (CDCl3, 125 MHz): = 172.4 (C), 158.2 (C), 151.0 (C),
129.6 (CH), 119.0 (CH), 115.7 (CH), 49.2 (CH), 40.4 (CH2), 31.8
(CH2), 30.2 (CH2), 29.3 (CH2), 29.2 (CH2), 26.9 (CH2), 22.6 (CH2),
17.9 (CH3), 14.1 (CH3).
Anal Calcd for C30H50N4O6 (562.75): C, 64.03; H, 8.96; N, 9.96:
Found: C, 63.98; H, 8.63; N, 9.98.
2-Hydroxyphenyl-2-(acetylamino)acetate (21a)
Catechol (4a; 1.10 g, 10.0 mmol) and N-acetylglycine (6; 1.18 g,
10.0 mmol) were dissolved in EtOAc (40 mL). After addition of
DCC (2.16 g, 10.5 mmol) and pyridine (1.45 mL, 18.0 mmol), the
mixture was stirred for 14 h at r.t. Three drops of AcOH were added,
the mixture was stirred for another 30 min, the precipitated urea was
filtered off and the solvent was removed in vacuum. The crude
product was purified by column chromatography (silica gel,
EtOAc); yield: 1.50 g (72%); mp 133 °C.
Pos. FAB MS (DMSO/3-NBA): m/z = 563 [M + H]+, 585 [M +
Na]+.
HRMS: m/z calcd for C30H51N4O6: 563.3809, found: 563.3821.
IR (KBr): 3949, 3386, 3116, 2587, 1777, 1638, 1590, 1577, 1524,
1514, 1460, 1417, 1365, 1315, 1295, 1260, 1235, 1163, 1151, 1130,
1098, 1035, 941, 785, 759, 741, 633 cm–1.
Anal. Calcd for C30H50N4O6 1/2 CHCl3 (622.44): C, 58.85; H, 8.18;
N, 9.00. Found: C, 58.44; H, 8.14; N, 9.54.
1H NMR (CDCl3): = 7.17–7.13 (m, 1 H), 7.03–7.01 (m, 2 H),
6.89–6.86 (m, 1 H), 6.24 (br s, 1 H), 4.17 (d, J = 5.3 Hz, 2 H), 2.11
(s, 2 H).
13C NMR (CDCl3): = 172.4 (C), 167.8 (C), 147.9 (C), 137.7 (C),
127.6 (CH), 122.2 (CH), 120.2 (CH), 117.9 (CH), 42.7 (CH2), 22.8
(CH3).
3-{3-[(tert-Butoxy)carbonylamino]propanoyloxy}phenyl-3-
[(tert-butoxy)carbonylamino]propanoate (18a)
A solution of catechol (4a; 1.10 g, 10.0 mmol) and N-BOC- -ala-
nine (17; 3.78 g, 20.0 mmol) in CH2Cl2 (40 mL) was cooled to 0 °C.
EDC (4.03 g, 21.0 mmol) and DMAP (2.57 g, 21.0 mmol) were add-
ed and the reaction mixture was stirred for 16 h at r.t. The organic
phase was successively washed with sat. aq NH4Cl, sat. aq NaHCO3
and brine. After drying (MgSO4) the solvent was removed in vacu-
um and the residue is purified by column chromatography (silica
gel, EtOAc–hexane, 1:5); yield: 2.73 g (60%); colorless waxy solid.
MS (EI/70 eV): m/z (%) = 209 (2.72, [M]+), 100 (100).
HRMS: m/z calcd for C10H11NO4: 209.0688, found: 209.0677.
Anal. Calcd for C10H11NO4 (209.20): C, 57.41; H, 5.30; N, 6.70.
Found: C, 57.55; H, 5.42; N, 6.53.
IR (KBr): 3360, 2978, 2917, 2849, 1769, 1712, 1516, 1494, 1458,
1392, 1367, 1275, 1243, 1167, 1103, 1074, 972, 922, 783, 757 cm–1.
1H NMR (CDCl3, 500 MHz): = 7.25–7.20 (m, 2 H), 7.18–7.15 (m,
2 H), 5.18 (br s, 2 H), 3.42 (m, 4 H), 2.72 (t, J = 5.5 Hz, 4 H), 1.40
(s, 18 H).
13C NMR (CDCl3, 125 MHz): = 169.8 (C), 155.8 (C), 141.7 (C),
126.7 (CH), 123.4 (CH), 79.5 (C), 36.0 (CH2), 34.5 (CH2), 28.4
(CH3).
X-Ray Structural Analysis of 21a18
Formula
C10H11NO4,
M = 209.20,
colorless
crystal
0.70 0.50 0.20 mm, a = 12.804(1), b = 9.005(4), c = 9.176(2) Å,
= 94.33(1)°, V = 1055.0(5) Å3,
= 1.317 g cm–3, = 8.70
calc
cm–1, absorption correction via scan data (0581 < T < 0.845), Z =
4, monoclinic, space group P21/c (No. 14), = 1.54178 Å, T = 223
K, /2 scans, 2244 reflections collected (+h, –k, l), [(sin )/ ]max
= 0.62 Å–1, 2148 independent(Rint = 0.038) and 2022 observed re-
Pos. FAB MS (DMSO/3-NBA): m/z = 453 [M + H]+.
Synthesis 2002, No. 10, 1434–1444 ISSN 0039-7881 © Thieme Stuttgart · New York

1444
M. Albrecht et al.
PAPER
flections [I
2
(I)], 144 refined parameters, R1 = 0.052, wR2
(12) (a) Beer, P. D. Chem. Commun. 1996, 689. (b) Snowden, T.
S.; Anslyn, E. V. Curr. Opin. Chem. Biol. 1999, 3, 740.
(c) Werner, F.; Schneider, H.-J. Helv. Chim. Acta 2000, 83,
465.
= 0.156, maximum residual electron density 0.30 (–0.28) e Å–3.
Titration Experiments
The association constants Ka were obtained by stepwise addition of
tetrabutylammonium nitrate to solutions of the receptors 5a (0.027
molar), 7a (0.030 molar), 14a (0.032 molar), 20a (0.028 molar), 7b
(0.032 molar), 14b (0.028 molar), or 15b (0.018 molar) in CDCl3 at
297 K and the obtained data were analyzed with Wilcoxs method
using Origin 6.0 (Microcal Software) for data fitting.
(13) Bisson, A. B.; Lynch, V. M.; Monahan, M.-K. C.; Anslyn, E.
V. Angew. Chem., Int. Ed. Engl. 1997, 36, 2340; Angew.
Chem. 1997, 109, 2435.
(14) (a) Wilcox, C. S. In Frontiers in Supramolecular Chemistry
and Photochemistry; Schneider, H.-J.; Dürr, H., Eds.; VCH:
Weinheim, 1991, 123. (b) Fielding, L. Tetrahedron 2000,
56, 6151.
(15) (a) Snellink-Ruel, B. H. M.; Antonisse, M. M. G.;
Engbersen, J. F. J.; Timmerman, P.; Reinhoudt, D. N. Eur. J.
Org. Chem. 2000, 165. (b) Shioya, T.; Nishizawa, S.;
Teramae, N. J. Am. Chem. Soc. 1998, 120, 11534.
(c) Nishizawa, S.; Bühlmann, P.; Iwao, M.; Umezawa, Y.
Tetrahedron Lett. 1995, 36, 6483.
Acknowledgement
This work was supported by the Fonds der Chemischen Industrie
and the Deutsche Forschungsgemeinschaft. Financial support from
the Finnish Ministry of Education is gratefully acknowledged by
E.W.
(16) (a) Terech, P.; Weiss, R. G. Chem. Rev. 1997, 97, 3133.
(b) van Esch, J. H.; Feringa, B. L. Angew. Chem. Int. Ed.
2000, 39, 2263; Angew. Chem. 2000, 112, 2351. (c) de
Loos, M.; Ligtenbarg, A. G. J.; van Esch, J. H.; Kooijman,
H.; Spek, A. L.; Hage, R.; Kellog, R. M.; Feringa, B. L. Eur.
J. Org. Chem. 2000, 3675. (d) Mieden-Gundert, G.; Klein,
L.; Fischer, M.; Vögtle, F.; Heuzé, K.; Pozzo, J.-L.; Vallier,
M.; Fages, F. Angew. Chem. Int. Ed. 2001, 40, 3164; Angew.
Chem. 2001, 113, 3266.
(17) (a) de Miguel, Y. R.; Sanders, J. K. M. Curr. Opin. Chem.
Biol. 1998, 2, 417. (b) Lehn, J.-M. Chem.–Eur. J. 1999, 5,
2455. (c) Albrecht, M. J. Inclusion Phenom. Macrocyclic
Chem. 2000, 36, 127.
References
(1) Lehn, J.-M. Supramolecular Chemistry - Concepts and
Perspectives; VCH: Weinheim, 1995.
(2) (a) Pedersen, C. Angew. Chem., Int. Ed. Engl. 1988, 27,
1021; Angew. Chem. 1988, 100, 1053. (b) Lehn, J.-M.
Angew. Chem., Int. Ed. Engl. 1988, 27, 90; Angew. Chem.
1988, 100, 92.
(3) Zimmerman, S. C. Top. Curr. Chem. 1993, 165, 71.
(4) Schneider, H.-J. Angew. Chem., Int. Ed. Engl. 1991, 30,
1417; Angew. Chem. 1991, 103, 1419.
(5) Albrecht, M.; Zauner, J.; Burgert, R.; Röttele, H.; Fröhlich,
R. Mater. Sci. Eng., C 2001, 18, 185.
(18) Data sets were collected with Enraf-Nonius CAD4 and
Nonius KappaCCD diffractometer. Programs used: data
collection EXPRESS (Nonius B.V., 1994) and COLLECT
(Nonius B.V., 1998), data reduction MolEN (K. Fair, Enraf-
Nonius B.V., 1990) and Denzo-SMN, absorption correction
for CCD data SORTAV, structure solution SHELXS-97,
structure refinement SHELXL-97 (G.M. Sheldrick,
Universität Göttingen, 1997).19 Crystallographic data
(excluding structural factors) for the structures reported in
this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
CCDC 180408, 180409 and 180410. Copies of the data can
be obtained free of charge on application to The Director,
CCDC, 12 Union Road, CambridgeCB2 1EZ, UK [fax: int.
code: +44(1223)336-033, e-mail: deposit@ccdc.cam.ac.uk].
(19) (a) Programs used: Blessing, R. H. J. Appl. Cryst. 1997, 30,
421. (b) Blessing, R. H. Acta Cryst. 1995, A51, 33.
(c) Keller, E. Universität Freiburg: Germany, 1997.
(d) Otwinowski, Z.; Minor, W. Methods in Enzymology
1997, 276, 307. (e) Sheldrick, G. M. Acta Cryst., Sect. A
1990, A46, 467.
(6) Prins, L. J.; Reinhoudt, D. N.; Timmerman, P. Angew. Chem.
Int. Ed. 2001, 40, 2382; Angew. Chem. 2001, 113, 2446.
(7) (a) König, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
(b) Dhaon, M. K.; Olsen, R. K.; Ramasamy, K. J. Org.
Chem. 1982, 47, 1962.
(8) Galpin, I. J.; Hardy, P. M.; Kenner, G. W.; McDermott, J.
W.; Ramage, R.; Seely, J. H.; Tyson, R. G. Tetrahedron
1979, 35, 2577.
(9) Kapoor, A.; Gerencser, L. W. J. Pharm. Sci. 1969, 58, 976.
(10) (a) Desiraju, G. R. In Comprehensive Supramolecular
Chemistry, Vol. 6; Macnicol, D. D.; Toda, F.; Bishop, R.,
Eds.; Pergamon: New York, 1996, 1–21. (b) Albrecht, M.;
Blau, O.; Witt, K.; Wegelius, E.; Nissinen, M.; Rissanen, K.;
Fröhlich, R. Synthesis 1999, 1819.
(11) Schmuck, C.; Wienand, W. Angew. Chem. Int. Ed. 2001, 40,
4363; Angew. Chem. 2001, 113, 4493.
Synthesis 2002, No. 10, 1434–1444 ISSN 0039-7881 © Thieme Stuttgart · New York