Inter- and intramolecular hydrogen bonding in amide- and urea-substituted 8-hydroxyquinoline derivatives

Article abstract of DOI:10.1016/S0040-4020(01)01168-1

Amide- and urea-substituted 8-hydroxyquinoline derivatives 3, 5, and 7 are prepared by standard methods. In the solid state 3a, 5d, and 7 form 8-hydroxyquinoline dimers with bifurcated inter- and intramolecular hydrogen bonds.

Full text of DOI:10.1016/S0040-4020(01)01168-1

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 561±567
Inter- and intramolecular hydrogen bonding in amide-
and urea-substituted 8-hydroxyquinoline derivatives
a,p
Markus Albrecht, Karen Witt, Roland Frohlich and Olga Kataeva
a
b
b,²
È
a
È
È
Institut fur Organische Chemie, Universitat Karlsruhe, Richard-Willstatter-Allee, D-76131 Karlsruhe, Germany
b
È È
Organisch Chemisches Institut der Universitat, Corrensstraûe 40, D-48149 Munster, Germany
Received 27 August 2001;revised 26 October 2001;accepted 20 November 2001
AbstractÐAmide- and urea-substituted 8-hydroxyquinoline derivatives 3, 5, and 7 are prepared by standard methods. In the solid state 3a,
5d, and 7 form 8-hydroxyquinoline dimers with bifurcated inter- and intramolecular hydrogen bonds. q 2002 Elsevier Science Ltd. All
rights reserved.
1. Introduction
the above mentioned thymine±adenine base pair, 8-hydroxy-
quinoline possesses an alternating H-bonding donor/
acceptor motif which shows bifurcated hydrogen bond
interactions.4±6
Hydrogen bonding plays an important role in biology,
allowing the reversible formation of aggregates which are
non-covalently linked. Base pairing in DNA is only possible
due to the complementary binding sites of the nucleobases
guanine and cytosine or thymine and adenine. Due to the
higher number of hydrogen bonds, the Watson±Crick pair
of guanine and cytosine is more stable than the thymine±
adenine complex.1 More than ten years ago, Jorgensen
found out that the stability of multiple hydrogen bonded
`dimers' depends not only on the number of hydrogen
bonds but also on the hydrogen bonding pattern. Alternating
hydrogen bond donor and acceptor functionalities (e.g.
uracil/2,6-diaminopyridine) are less favored for complex
In this paper, we describe the synthesis of a series of
8-hydroxyquinoline derivatives which bear amide or urea
substituents as additional hydrogen bond donor/acceptor
moieties in 2- or 7-position. For two of the derivatives we
obtained X-ray structural analyses showing dimeric
8-hydroxyquinoline units with bifurcated H-bonds in the
solid state.
2. Results and discussion
formation than
guanine/cytosine) due to secondary repulsive or attractive
interactions between local charges.2
a non-alternating arrangement (e.g.
2.1. Preparation and characterization of the 8-hydroxy-
quinoline derivatives
The preparation of the amide- and urea-substituted 8-hydroxy-
quinoline derivatives 3, 5, and 7 follows standard proce-
dures. We already described the synthesis as well as the
crystal structure of 3a.6 The amide-substituted derivatives
3b±d are prepared similar to 3a. Therefore the carboxylic
acids 2b±d are activated with carbonyldiimidazole (CDI)7
and the activated esters by reaction with 7-amino-8-hydro-
xyquinoline (1) are transformed into the corresponding
amides 3b±d (yield: b 63%, c 63%, d 87%) (Scheme 1).
We are investigating in the supramolecular chemistry of
8-hydroxyquinoline derivatives regarding the metal coordi-
nation3 as well as the hydrogen bonding4±6 ability of these
molecules. In an ongoing project we study the dimerization
behavior of 8-hydroxyquinoline4 and of its derivatives to
use this for the formation of hydrogen bonded polymers in
the solid state.5 Introduction of further hydrogen bonding
donor/acceptor sites in the periphery of the 8-hydroxyquino-
line skeleton also leads to hydrogen bonded networks.6 Like
Reaction of the amine 1 with isocyanates 4a±d in chloro-
form leads to precipitation of the urea derivatives 5a±d
(yield: a 87%, b 37%, c 55%, d 76%). The compound 7
which bears an amide unit in 2-position of the 8-hydroxy-
quinolin skeleton is obtained from the amine 6 and acetic
acid by carbonyl diimidazole activation7 in 89% yield.
Keywords: hydrogen bonds;8-hydroxyquinoline derivative;urea deriva-
tive;amide derivatives.
p
Corresponding author. Fax: 149-721-698-529;
e-mail: albrecht@ochhades.chemie.uni-karlsruhe.de
²
Permanent address: A.E. Arbuzov Institute of Organic and Physical
Chemistry, Russian Academy of Sciences, Arbuzov str. 8, Kazan
420088, Russian Federation.
The 8-hydroxyquinoline derivatives 3a±d, 5a±d, and 7 are
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01168-1

562
M. Albrecht et al. / Tetrahedron 58 (2002) 561±567
1
Table 1. Comparison of the H NMR spectroscopic shifts (in ppm) of the
8-hydroxyquinoline protons
H2
H3
H4
H5
H6
H7
Solventa
CDCl3
CDCl3
1
8.68
8.72
8.83
8.81
8.79
8.81
8.77
8.78
8.70
±
7.15
7.33
7.56
7.46
7.44
7.41
7.36
7.37
7.35
6.78
8.21
8.00
8.11
8.28
8.28
8.21
8.25
8.20
8.22
7.90
7.85
8.24
7.09/7.22
±
±
±
±
±
±
±
±
3a
3b
3c
3d
5a
5b
5c
5d
6
7.35
7.47
7.35
7.37
7.40
7.33
7.34
7.35
7.08
7.30
8.58
8.06
8.67
8.10
8.51
8.45
8.46
8.16
6.98
7.04
CDCl3
DMSO-d6
Methanol-d4
DMSO-d6
DMSO-d6
DMSO-d6
Methanol-d4
DMSO-d6
DMSO-d6
±
6.86
7.27
7
±
a
Different solvents lead to shift differences which, however, are not sig-
ni®cant.
Scheme 1. Preparation of 3a±d, 5a±d, and 7 (CDIˆcarbonyldiimidazole).
characterized by NMR spectroscopic methods. The shifts of
the protons which are attached to the 8-hydroxyquinoline
moiety are listed in Table 1.
addition of DMSO-d6 (approx. 10%) the compounds
dissolve but only marginal shift differences are observed
depending on the concentration of the hydroxyquinoline
derivatives. 7 shows a better solubility in chloroform and
we observed a shifting of the amide proton depending on the
concentration of the sample. This indicates a dimerization of
7 in solution. However, the compound started to precipitate
before a ®nal shift could be reached and therefore no
thermodynamic data can be obtained.
The resonances of 3c, 6, and 7 are assigned by two-dimen-
sional NOESY NMR spectroscopy and the others by
comparison of the shifts and by analysis of the coupling
constants.
Most shifts of the compounds 3a±d and 5a±d with sub-
stituents in 7-position are found in typical regions (dˆ
8.7±8.8 (H2), 7.2±7.4 (H3), 7.9±8.2 (H4), 7.3±7.4 (H5),
7.1 (H6), 7.3 (H7) ppm).8 However, the signals of the protons
in 6-position are shifted to low ®eld (dˆ8.1±8.6 ppm)
compared to those of a derivative without an amide in this
position (e.g. 1, 6, 7). This is attributed to an anisotropic
effect of the CvOÐcarbonyl unit located in 7-position
(close to the 6-position) of the compounds. This indicates
that the CvO unit is orientated s-cis to CH6 as it is shown in
rotamer A and not s-trans as in B (see bonds presented as
bold lines).
As was shown, a series of 8-hydroxyquinolines, which bear
amide or urea substituents can be prepared. The example of
the glycine derivative 3d indicates that amino acids or
peptides can be introduced, which opens up the way to
chiral derivatives with additional hydrogen bonding func-
tionalities. All derivatives 3a±d and 5a±d can be used in
coordination studies to obtain trinuclear supramolecular
complexes which possess a hexahelical structure.3b The
coordination chemistry of the amide 7 with a substituent
in 2-position still has to be studied.
Similar observations are made for the derivatives 6 and 7
with a substituent in 2-position. The resonance of H3 of
compound 7 is signi®cantly low ®eld shifted compared to
6 indicating a location of the CvO double bond close to this
proton. The signal of H6 is found in the region which is
expected for a derivative without an amide substituent in
7-position (6: dˆ6.98; 7: dˆ7.04).8
2.2. The solid state structures of 5d and 7
The X-ray crystal structure of the acetamide 3a was already
described and it was shown that a double-stranded ladder-
type polymeric structure is formed in the solid state with
dimerization of the 8-hydroxyquinoline units. The backbone
of the double-stranded system is formed by hydrogen bond-
ing between amide NH and amide carbonyl units (Fig. 1).
In order to try to follow the dimerization of the 8-hydroxy-
quinoline units of compounds 3, 5, and 7 in solution, we
performed proton NMR studies with variable concentrations
of the compounds. However, the derivatives 3 or 5 show
only low solubility in non-polar solvents (e.g. CDCl3). Upon
The two hydroxyquinoline units of the 3a-dimer are in one
plane and intermolecular (a) as well as intramolecular (b)

M. Albrecht et al. / Tetrahedron 58 (2002) 561±567
563
Figure 1. Schematic representation of the dimeric structure of 3a in the
solid state.
hydrogen bonding occurs between the hydroxy group and
the quinoline nitrogen atom. The intermolecular hydrogen
Figure 3. The 8-hydroxyquinoline-dimer found in the solid state structure
of 5d.
Ê
bond distance aˆ2.16 A is shorter than the intramolecular
Ê
distance bˆ2.32 A. This observation was also made for
other 8-hydroxyquinoline dimers and might be due to an
unfavored small O±H±N angle of 113.78 (observed for
3a) for the intramolecular interaction.4,5 The corresponding
intermolecular O±H±N angle of 3a is 135.58.6
Similar as it was observed for 3a, 5d shows a separated
hydrogen bonding behavior of the hydroxyquinoline unit
and of the side chain in 7-position. The urea units form a
helical hydrogen bonded polymeric strand, which has a
fourfold screw-axis. Due to the S-con®gurated chiral sub-
stituent in the side chain only the right-handed helix is
formed. Hereby the urea NH moieties act as `tweezers'
which form two hydrogen bonds to the urea oxygen atom
X-Ray quality crystals of the chiral urea derivative 5d were
obtained. The compound crystallizes in the tetragonal space
group P41212 and was re®ned to Rˆ0.062. The positions of
the hydrogen atoms involved in hydrogen bonding were
located.
Ê
of the next molecule (d(H±O)ˆ2.23 and 1.97 A). The
hydroxyquinoline units are attached to this helix and by
dimerization connect the linear strands to form a three-
dimensional tetragonal network. For a schematic represen-
tation of one strand which is formed by hydrogen bonding of
the ureas, see Fig. 2b.
In 5d, the urea substituent is orientated with the carbonyl cis
to H6 and the urea NH are orientated parallel to the phenolic
C±O group. This is in accordance with the structure A
deduced from the results of the NMR spectra which were
discussed earlier.
Dimerization of the hydroxyquinoline units of 5d proceeds
Figure 2. (a) The urea-bridged helical polymer observed for 5d in the solid state. (b) A schematic representation of the structure of 5d.

564
M. Albrecht et al. / Tetrahedron 58 (2002) 561±567
3. Conclusions
In this publication we presented the syntheses of some new
8-hydroxyquinoline derivatives which bear amide (3a±d) or
urea moieties (5a±d) in 7-position or an acetamide in
2-position of the quinoline. 1H NMR spectroscopy indicates
that the amides and ureas are orientated with the N±H bonds
directed to the `face' of the molecule and the CvO double
bond to the `back'.
The crystal structure of 3a was described earlier6 and in
addition we now were able to obtain crystals of 5d and 7
for structure determination. All structures show dimeric
8-hydroxyquinoline units with bifurcated inter- and intra-
molecular hydrogen bonds. The compounds 3a and 5d with
substituents in 7-position show related H-bond length with a
long internal and a short intermolecular separation. This is
also found for other 8-hydroxyquinoline derivatives.4±6 The
amide or urea substituents of 3a and 5d form hydrogen
bonds leading to polymeric superstructures in the solid state.
Figure 4. The dimer of 7 as found in the solid state: (a) top view and (b) side
view.
similar as observed for compound 3a. However in case of 5d
not a planar dimer is formed but the two aromatic planes are
twisted by approximately 27.48 against each other. Again a
The compound 7 with an amide in 2-position shows a
different behavior. Additional intermolecular hydrogen
bonds are formed upon dimer formation, which weaken
the intermolecular OH±Nquinoline bond strength. However,
the distance of the intramolecular interaction is not
in¯uenced.
Ê
relatively long intramolecular (d(H±N)ˆ2.31 A) and a short
intermolecular hydrogen bond interaction (d(H±N)ˆ
Ê
1.97 A) is observed (Fig. 3).
Thus the amide 3a and the urea derivative 5d in some
respect behave similar in the solid state. The amide and
urea moieties form a linear polymeric strand while the
hydroxyquinoline units interconnect the strands. However,
in 5d a helical twist is induced by the chiral substituents
leading to a three-dimensional network, while for 3a a linear
double-stranded structure is observed.
It is known, that hydroxyquinoline in solution shows a
monomer dimer equilibrium.9 Our results suggest, that in
the monomeric form a strong intramolecular hydrogen bond
is present.10 Two such monomers lead to the dimer by
formation of additional hydrogen bonding yielding the
bifurcated hydrogen bonds and H±N±H nitrogen bridges
(Fig. 5).
Shifting the amide unit from 7- to the 2-position results in a
different structure in the solid state. Compound 7 crystal-
lizes in the monoclinic space group P21/c and was re®ned to
Rˆ0.046. Again the positions of the hydrogen atoms that
are involved in hydrogen bonding could be located. As
indicated by NMR spectroscopy in solution the amide
CvO is orientated towards H3.
7 does not form a polymeric structure in the solid state but
dimeric units are observed. Hereby the hydroxy group, the
quinoline nitrogen atom, and the amide NH form hydrogen
bonds (Fig. 4).
In addition to the two bifurcated inter/intramolecular OH±N
hydrogen bonds, two more intermolecular hydrogen
bonding interactions are observed between the amide NH
and the phenolic oxygen atoms. The distance of this inter-
action is 2.05 A. This additional H-bonding does not
in¯uence the intramolecular H±N distance, which shows a
Figure 5.
The dimer is able to dissociate, while the intramolecular
interaction only can be broken if appropriate hydrogen
bond acceptors are attached which act as competitors to
the quinoline nitrogen atoms as was observed, e.g. for 8.5
Ê
Ê
typical separation of 2.20 A. However, the intermolecular
H±N interaction is weakened and a relatively long
Ê
distance of 2.78 A results. Reason for this might be the
4. Experimental
additional H-bond which in¯uences the hydrogen bonding
ability of the hydroxy group by electronic and/or steric
factors. The overall structure of the dimer is close to
planar with a slight shift of the two quinoline units from
the plane.
4.1. General remarks
1H and 13C NMR spectra were recorded on a Bruker DRX
500, AM 400, or WM 250 NMR spectrometer using DEPT

M. Albrecht et al. / Tetrahedron 58 (2002) 561±567
565
techniques for the assignment of the multiplicity of carbon
atoms. FT-IR spectra were recorded by diffuse re¯ection
(KBr) on a Bruker IFS spectrometer. Mass spectra (EI,
70 eV) were measured on a Finnigan MAT 90 mass spec-
trometer. Elemental analyses were obtained with a Heraeus
CHN-O-Rapid analyzer. Solvents were puri®ed by stan-
dard methods. Melting points: BuÈchi 535 (uncorrected).
7-Amino-8-hydroxyquinoline 1 was prepared as described
in the literature.11
(CDCl3): dˆ171.8 (C), 148.2 (CH), 139.3 (C), 137.4 (C),
136.5 (CH), 125.0 (CH), 123.8 (C), 121.4 (CH), 120.3 (CH),
118.0 (CH), 38.0 (CH2), 31.7 (CH2), 29.2 (CH2), 29.1 (CH2),
25.7 (CH2), 22.6 (CH2), 14.1 (CH3). IR (KBr): nˆ3306,
3050, 2950, 2035, 2917, 2869, 2850, 1941, 1918, 1897,
1661, 1630, 1583, 1535, 1506, 1468, 1430, 1409, 1376,
1357, 1332, 1290, 1280, 1253, 1224, 1191, 1134, 1111,
1094, 1066, 1044, 1032, 1002, 980, 948, 933, 891, 825,
799, 784, 766, 735, 722, 709, 684, 669 cm21. MS (EI,
70 eV): m/zˆ286 (26%) [M1], 160 (100%). HRMS calcd
for C17H22N2O2: 286.1681, found: 286.1685. Elemental
analysis calcd for C17H22N2O2: C, 71.30;H, 7.74;N, 9.78;
found: C, 71.13;H, 7.66;N, 9.75.
Data sets were collected with Enraf±Nonius CAD4 and
Nonius KappaCCD diffractometer, the later one equipped
with a rotating anode generator Nonius FR591. 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, absorp-
tion correction for CCD data SORTAV, structure solution
4.1.3. 8-Hydroxyqinoline-7-yl-N-acetylglycylamide 3d.
3d was prepared as described for 3b. Yield: 282 mg
(87%) gray solid. Mp: 1918C. 1H NMR (methanol-d4):
dˆ8.79 (dd, Jˆ4.2, 1.5 Hz, 1H), 8.21 (dd, Jˆ8.3, 1.5 Hz,
1H), 8.10 (d, Jˆ8.9 Hz, 1H), 7.44 (dd, Jˆ8.3, 4.2 Hz, 1H),
7.37 (d, Jˆ8.9 Hz, 1H), 4.12 (s, 2H), 2.08 (s, 3H). 13C NMR
(methanol-d4): dˆ174.1 (C), 170.3 (C), 149.8 (CH), 144.0
(C), 137.2 (CH), 127.6 (C), 123.9 (C), 122.1 (CH), 118.7
(CH), 44.3 (CH2), 22.4 (CH3). IR (KBr): nˆ3390, 3049,
2239, 1975, 1918, 1882, 1665, 1634, 1578, 1540, 1510,
1473, 1434, 1408, 1369, 1343, 1306, 1277, 1247, 1187,
1134, 1092, 1048, 1026, 1013, 916, 888, 834, 724, 674,
651, 609 cm21. MS (EI, 70 eV): m/zˆ259 (29%) [M1], 187
(100%). HRMS calcd for C13H13N3O3: 259.0957, found:
259.0948. Elemental analysis calcd for C13H13N3O3: C,
56.31;H, 5.45;N, 15.15;found: C, 56.36;H, 5.59;N, 14.95.
SHELXS-97, structure re®nement SHELXL-97 (G. M.
È È
Sheldrick, Universitat Gottingen, 1997).
13
Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication CCDC 168436 and 168437. Copies of
the data can be obtained free of charge on application to The
Director, CCDC, 12 Union Road, CambridgeCB2 1EZ, UK
(fax: 144-1223-336-033, e-mail: deposit@ccdc.cam.ac.uk).
4.1.1. 7-Benzoylamido-8-hydroxyquinoline 3b. Benzoic
acid (153 mg, 1.249 mmol) and CDI (222 mg, 1.369
mmol) are re¯uxed in dry THF (10 ml) for 1 h. After the
addition of 7-amino-8-hydroxyquinoline (200 mg, 1.249
mmol) the mixture is re¯uxed over night. Solvent is
removed and the residue is dissolved in dichloromethane,
which is washed with water. The organic phase is dried
(MgSO4), solvent is evaporated in vacuum and the crude
product is recrystallized from dichloromethane. Yield:
4.2. General procedure for the preparation of urea
derivatives
7-Amino-8-hydroxyquinoline (200 mg, 1.249 mmol) is
dissolved in 10 ml of dry chloroform and isocyanate
(1.249 mmol) is added. Re¯uxing over night results in
precipitation of a white solid material, which is isolated
by ®ltration.
1
195 mg (63%) white solid. Mp: 1808C. H NMR (metha-
nol-d4): dˆ8.83 (dd, Jˆ4.3, 1.6 Hz, 1H), 8.27 (dd, Jˆ8.3,
1.6 Hz, 1H), 8.06 (d, Jˆ8.9 Hz, 1H), 8.04±8.02 (m, 2H),
7.64±7.61 (m, 1H), 7.58±7.54 (m, 2H), 7.48 (dd, Jˆ8.3,
4.3 Hz, 1H), 7.45 (d, Jˆ8.9 Hz, 1H). 13C NMR (methanol-
d4): dˆ168.8 (C), 149.9 (CH), 145.4 (CH), 140.3 (C), 137.4
(C), 135.7 (C), 133.2 (CH), 129.8 (CH), 128.7 (CH), 125.0
(CH), 123.7 (CH), 122.3 (CH), 118.8 (CH). IR (KBr): nˆ
3312, 1952, 1899, 1875, 1763, 1650, 1627, 1582, 1504,
1466, 1431, 1408, 1377, 1332, 1304, 1279, 1252, 1187,
1135, 1125, 1092, 1076, 1040, 1027, 1000, 972, 958, 940,
922, 903, 826, 791, 722, 690, 673, 658 cm21. MS (EI,
70 eV): m/zˆ264 (59%) [M1], 105 (100%). HRMS calcd
for C16H12N2O2: 264.0899, found: 264.0893. Elemental
analysis calcd for C16H12N2O2´0.25H2O: C, 71.50;H,
4.68;N, 10.42;found: C, 71.61;H, 4.59;N, 10.40.
4.2.1. N-(8-Hydroxyqinolin-7-yl)-N0-phenyl urea 5a.
Yield: 305 mg (87%) white solid. Mp: 3708C (decomp.).
1H NMR (DMSO-d6): dˆ10.2 (br, 1H), 9.44 (s, 1H), 8.81
(dd, Jˆ4.2, 1.6 Hz, 1H), 8.56 (s, 1H), 8.51 (d, Jˆ9.0 Hz,
1H), 8.25 (dd, Jˆ8.3, 1.6 Hz, 1H), 7.47 (d, Jˆ7.4 Hz, 2H),
7.41 (dd, Jˆ8.3, 4.2 Hz, 1H), 7.40 (d, Jˆ9.0 Hz, 1H), 7.28
(t, Jˆ7.4 Hz, 2H), 6.96 (t, Jˆ7.4 Hz, 1H). 13C NMR
(DMSO-d6): dˆ152.5 (C), 148.4 (CH), 139.8 (C), 139.6
(C), 137.9 (C), 136.0 (CH), 128.8 (CH), 125.4 (C), 123.8
(C), 121.8 (CH), 120.2 (CH), 119.7 (CH), 118.0 (CH), 117.3
(CH). IR (KBr): nˆ3313, 3033, 1937, 1880, 1646, 1632,
1597, 1557, 1507, 1499, 1473, 1447, 1434, 1409, 1378,
1333, 1297, 1280, 1254, 1225, 1190, 1159, 1135, 1095,
1050, 960, 902, 889, 786, 753, 742, 712, 694, 665 cm21
.
MS (EI, 70 eV): m/zˆ279 (28%) [M1], 160 (100%). HRMS
calcd for C18H25N3O2: 279.1008, found: 279.0996. Ele-
mental analysis calcd for C16H13N3O2´0.25H2O: C, 67.71;
H, 4.79;N, 14.81;found: C, 68.00;H, 4.72;N, 14.79.
4.1.2. 7-Caproylamido-8-hydroxyquinoline 3c. 7-Caproyl-
amido-8-hydroxyquinoline is prepared similar to 7-benzoyl-
amido-8-hydroxyquinoline. The crude product is puri®ed by
column chromatography (silica gel, hexane/ethyl acetate
1:1). Yield: 223 mg (63%) white solid. Mp: 134±1378C
1
4.2.2. N-(8-Hydroxyqinolin-7-yl)-N0-n-octyl urea 5b.
Yield: 147 mg (37%) gray solid. Mp: 183±1908C. 1H
NMR (DMSO-d6): dˆ10.05 (br, 1H), 8.77 (dd, Jˆ4.1,
1.6 Hz, 1H), 8.45 (d, Jˆ9.0 Hz, 1H), 8.21 (s, 1H), 8.20
(decomp.). H NMR (CDCl3): dˆ8.72 (br, 1H), 8.64 (d,
Jˆ8.1 Hz, 1H), 8.13 (d, Jˆ8.1 Hz, 1H), 7.92 (br, 1H),
7.36 (d, Jˆ9.1 Hz, 1H), 7.34 (d, Jˆ9.1 Hz, 1H), 2.47 (br,
2H), 1.40±1.29 (m, 8H), 0.88 (t, Jˆ6.5 Hz, 3H). 13C NMR

566
M. Albrecht et al. / Tetrahedron 58 (2002) 561±567
(dd, Jˆ8.1, 1.6 Hz, 1H), 7.36 (dd, Jˆ8.1, 4.1 Hz, 1H), 7.33
(d, Jˆ9.0 Hz, 1H), 6.96 (t, Jˆ5.6 Hz, 1H), 3.09 (dt, Jˆ6.7,
5.6 Hz, 2H), 1.41 (q, Jˆ6.7 Hz, 2H), 1.25±1.27 (m, 10H),
0.84 (t, Jˆ6.6 Hz, 3H). 13C NMR (DMSO-d6): dˆ155.3
(C), 148.2 (CH), 138.8 (C), 137.9 (C), 135.8 (CH), 126.3
(C), 123.3 (C), 120.3 (CH), 119.3 (CH), 117.1 (CH), 39.0
(CH2), 31.3 (CH2), 29.7 (CH2), 28.8 (CH2), 28.7 (CH2), 26.4
(CH2), 22.1 (CH2), 14.0 (CH3). IR (KBr): nˆ3339, 2959,
2854, 1941, 1689, 1639, 1587, 1555, 1504, 1479, 1464,
1435, 1408, 1373, 1331, 1273, 1233, 1203, 1184, 1140,
1120, 1089, 1052, 943, 888, 825, 790, 771, 751, 723, 707,
675 cm21. MS (EI, 70 eV): m/zˆ315 (6%) [M1], 160
(100%). HRMS calcd for C18H25N3O2: 315.1947, found:
315.1953. Elemental analysis calcd for C18H25N3O2: C,
68.54;H, 7.99;N, 13.32;found: C, 68.22;H, 7.80;N, 12.83.
N13 from difference Fourier map, others calculated and
all re®ned as riding atoms.
4.2.5. 2-Acetamido-8-hydroxyquinoline 7. 2-Amino-8-
hydroxyquinoline (200 mg, 1.249 mmol) and 1-acetyl imi-
dazole (137 mg, 1.249 mmol) in dry THF (10 ml) are
re¯uxed over night. Solvent is removed, the residue is
dissolved in dichloromethane, washed with water, dried
(Na2SO4) and dichloromethane is evaporated again. Yield:
226 mg (89%) white solid. Mp: 1898C. 1H NMR (methanol-
d4): dˆ8.19 (d, Jˆ9.0 Hz, 1H), 8.15 (d, Jˆ9.0 Hz, 1H),
7.31±7.26 (m, 2H), 7.05 (dd, Jˆ6.9, 1.9 Hz, 1H), 2.22 (s,
3H). 13C NMR (methanol-d4): dˆ172.2 (C), 153.0 (C),
151.1 (C), 139.4 (CH), 138.0 (C), 128.0 (C), 126.9 (CH),
118.0 (CH), 115.8 (CH), 112.4 (CH), 24.2 (CH3). IR (KBr):
nˆ3422, 333, 3238, 3124, 3080, 3059, 1985, 1920, 1841,
1764, 1704, 1598, 1544, 1508, 1437, 1398, 1374, 1357,
1329, 1296, 1266, 1245, 1228, 1202, 1168, 1135, 962,
863, 851, 764, 733, 724, 696 cm21. MS (EI, 70 eV):
m/zˆ202 (56%) [M1], 160 (100%). HRMS calcd for
C11H10N2O2: 202.0742, found: 202.0729. Elemental analy-
sis calcd for C11H10N2O2: C, 65.35;H, 4.99;N, 13.68;
found: C, 65.13;H, 4.98;N, 13.72.
4.2.3. N-(8-Hydroxyqinolin-7-yl)-N0-benzyl urea 5c.
Yield: 200 mg (55%) white solid. Mp: 212±2148C
1
(decomp.). H NMR (DMSO-d6): dˆ10.06 (br, 1H), 8.78
(d, Jˆ3.9 Hz, 1H), 8.46 (d, Jˆ8.9 Hz, 1H), 8.38 (s, 1H),
8.22 (d, Jˆ8.1 Hz, 1H), 7.45 (t, Jˆ5.5 Hz, 1H), 7.38±7.30
(m, 6H), 7.25 (m, 1H), 4.33 (d, Jˆ5.5 Hz, 2H). 13C NMR
(DMSO-d6): dˆ155.4 (C), 148.2 (CH), 140.2 (C), 139.0
(C), 137.9 (C), 136.0 (CH), 128.4 (CH), 127.1 (CH),
126.8 (CH), 126.1 (C), 123.5 (C), 120.4 (CH), 119.4
(CH), 117.2 (CH), 42.8 (CH2). IR (KBr): nˆ3318, 1731,
1639, 1588, 1556, 1506, 1469, 1433, 1408, 1378, 1335,
1277, 1232, 1191, 1134, 1091, 969, 822, 786, 749, 703,
664 cm21. MS (EI, 70 eV): m/zˆ293 (14%) [M1], 160
(100%). HRMS calcd for C17H15N3O2: 293.1164,
found: 293.1170. Elemental analysis calcd for
C17H15N3O2´0.25H2O: C, 68.56;H, 5.25;N, 14.11;found:
C, 68.28;H, 5.09;N, 13.77.
X-Ray structural analysis of 7:12 formula C11H10N2O2,
Mˆ202.21, colorless crystal 0.25£0.15£0.10 mm3, aˆ
Ê
11.211(1), bˆ6.542(31), cˆ13.965(1) A, bˆ110.16(1)8,
Vˆ961.5(2) A , rcalcdˆ1.397 g cm23, mˆ0.99 cm21, no
Ê 3
absorption correction (0.976#T#0.990), Zˆ4, monoclinic,
Ê
space group P21/c (No. 14), lˆ0.71073 A, Tˆ198 K, v and
w scans, 3381 re¯ections collected (^h, ^k, ^l), [(sin u)/
l]ˆ0.62 A , 1922 independent (Rintˆ0.039) and 1227
Ê 21
observed re¯ections [I$2s(I)], 143 re®ned parameters,
Rˆ0.046, wR2ˆ0.107, max. residual electron density 0.16
Ê 23
4.2.4. N-(8-Hydroxyquinolin-7-yl)-N0-(S)-1-phenylethyl
urea 5d. Yield: 290 mg (76%) slightly yellow solid. Mp:
3508C (decomp.). 1H NMR (methanol-d4): dˆ8.74 (d,
Jˆ3.6 Hz, 1H), 8.16 (d, Jˆ8.7 Hz, 2H), 7.90 (s, 1H),
7.39±7.31 (m, 7H), 7.23 (t, Jˆ7.1 Hz, 1H), 4.97±4.93 (m,
1H), 1.49 (d, Jˆ6.9 Hz, 3H). 13C NMR (methanol-d4):
dˆ157.5 (C), 149.7 (CH), 146.1 (C), 141.3 (C), 139.8
(C), 137.2 (CH), 129.6 (CH), 128.0 (CH), 126.9 (CH),
126.1 (C), 126.0 (C), 122.4 (CH), 120.9 (CH), 118.7
(CH), 50.8 (CH), 23.5 (CH3). IR (KBr): nˆ3337, 3291,
3030, 2974, 1947, 1645, 1622, 1587, 1553, 1505, 1465,
1431, 1408, 1374, 1348, 1268, 1233, 1210, 1186, 1137,
1090, 952, 825, 789, 753, 701, 672 cm21. MS (EI, 70 eV):
m/zˆ307 (6%) [M1], 160 (100%). HRMS calcd for
C18H17N3O2: 307.1321, found: 307.1331. Elemental analy-
sis calcd for C18H17N3O2´0.25H2O: C, 69.33;H, 5.66;N,
13.47;found: C, 69.45;H, 5.59;N, 13.20.
(20.21) e A , hydrogens at O4 and N12 from difference
Fourier map, others calculated and all re®ned as riding
atoms.
Acknowledgements
Financial support by the Fonds der Chemischen Industrie
and the Deutsche Forschungsgemeinschaft is gratefully
acknowledged.
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