Chromone derivatives which bind to human hair

Article abstract of DOI:10.1016/j.tet.2005.05.081

Chromone derivatives bearing a quaternary ammonium functionality which bind to human hair were synthesised. The radical scavenging activity, according to the DPPH assay, of the chromone derivatives is considerably lower compared with flavonoids. The compounds show interesting UV absorption properties that depend on the position of a methoxy substituent. A bathochromic shift of 29 nm was observed when the methoxy group on the ammonium salts were shifted from position 7 to position 6.

Full text of DOI:10.1016/j.tet.2005.05.081

Tetrahedron 61 (2005) 7366–7377
Chromone derivatives which bind to human hair
a
Thomas Walenzyk, Christophe Carola, Herwig Buchholz and Burkhard Konig
b
b
a,
*
¨
aInstitute for Organic Chemistry, University of Regensburg, D-93040 Regensburg, Germany
bMerck KGaA, D-64293 Darmstadt, Germany
Received 21 March 2005; revised 19 May 2005; accepted 25 May 2005
Available online 16 June 2005
Abstract—Chromone derivatives bearing a quaternary ammonium functionality which bind to human hair were synthesised. The radical
scavenging activity, according to the DPPH assay, of the chromone derivatives is considerably lower compared with flavonoids. The
compounds show interesting UV absorption properties that depend on the position of a methoxy substituent. A bathochromic shift of 29 nm
was observed when the methoxy group on the ammonium salts were shifted from position 7 to position 6.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Many of these biological actions are attributed to the ability
of flavonoids to transfer electrons, chelate metal catalysts,7
activate antioxidant enzymes,8 reduce a-tocopherol radi-
cals,9 inhibit oxidases10 as well as through their possible
influences on the intracellular redox status, however, the
precise mechanisms remain unclear.11 Recent studies have
speculated that the classical hydrogen-donating antioxidant
activity of flavonoids12 is unlikely to be the sole explanation
for cellular effects.13
Chromones are a group of naturally occurring compounds
that are ubiquitous in nature especially in plants.1 They are
oxygen-containing heterocyclic compounds with a ben-
zoannelated g-pyrone ring, with the parent compound being
chromone (4H-chromen-4-one, 4H-1-benzopyran-4-one).2
Molecules containing the chromone structure (for example
chromones and flavonoids) have a wide range of biological
activities including tyrosine and protein kinase C inhibitors,
antifungal, antiallergenic, antiviral, antitublin, antihyper-
tensive and anticancer agents, as well being active at
benzoazepine receptors, lipoxygenase, cyclooxygenase and
modulating P-glycoprotein-mediated multidrug resistance
(MDR).2–5 Due to their abundance in plants and their low
mammalian toxicity, chromone derivatives are present in
large amounts in the diet of humans (Fig. 1).6
The antioxidant characteristics of flavonoids in combination
with their favourable UV absorption properties are also
exploited by plants to protect them from the suns UV
radiation and scavenge UV-generated reactive oxygen
species (ROS).14 For example, there is evidence that
flavonoids in leaves, deposited in either the epidermal
cells or in the waxy upper leaf surface provide protection
from the potential damage of UVB radiation.15 This use
could also be utilised in the protection of human hair from
UV-radiation. It is well known that exposure to UV-
radiation can damage hair fibres. UVB radiation is the
principal radiation responsible for hair protein loss (causing
dryness, reduced strength, rough surface texture, decreased
luster, stiffness and brittleness), while UVA radiation is
responsible for colour changes regardless of hair type.16
Hair melanins provide some photochemical protection to
hair proteins, especially at lower wavelengths where both
the hair pigments and proteins absorb radiation.17 These
melanins also immobilise many of the free radicals
generated by UV-radiation, however, in the process they
are often degraded or bleached.18 Here we reported the
synthesis of new chromone derivatives, bearing a cationic
functionality which bind to human hair.
Figure 1. Basic structure of flavonoids, flavones and chromones.
Keywords: Chromone; Hair substantivity; UV activity; Antioxidant;
Binding.
Corresponding author. Tel.: C49 941 943 4576; fax: C49 941 943 1717;
e-mail: burkhard.koenig@chemie.uni-regensburg.de
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.081

T. Walenzyk et al. / Tetrahedron 61 (2005) 7366–7377
7367
2. Results and discussion
expanded for other hydroxy-4-oxo-4H-chromene-2-car-
boxylic acid ethyl esters with other substitution patterns
(Scheme 2).
Quaternary ammonium compounds (cationic surfactants,
cationic polyelectrolytes and cationic quaternary derivatives
of hydrolyzed proteins) have been widely used as hair
conditioning agents.19 The deposition (substantivity) of
such compounds can effect the hair fibre friction, stiffness,
gloss, anti-static qualities and strength of hair.17 By
synthesising a chromone derivative with quaternary
ammonium functionality it was hoped that this compound
would show not only activity of cosmetic interest but also
hair substantivity.
Alternatively, the methoxy derivatives 12 were synthesized
(Scheme 3). Although in general hydroxyl groups give a
better radical scavenging activity,22 there are some
examples where a hydroxyl group is deleterious and
methoxy group beneficial to such activity.4,23,24 Compound
12 was prepared from the commercially available 11. The
methoxy derivatives 14 could now be easily synthesised and
purified without fear of zwitterion formation.
Numerous attempts with various conditions at O-demethyl-
ating 14a–c failed.25 Alternative protecting groups that can
withstand the reaction conditions and are industrially
feasible in order to readily synthesise hydroxyl derivatives
are currently being investigated.
The synthetic strategy chosen for the preparation of the
2-amido-chromone required the preparation of 2-ethylester-
chromone 2. Condensation of 1 with diethyl oxalate in the
presence of sodium ethanoxide in ethanol and followed by
acidic cyclisation afforded the ester 2.5,20 By reacting
different amines with 2, a variety of chromone amides were
synthesised (Scheme 1).
2.1. Hair substantivity
Reacting the ester 2 with either an n-alkyl amine (butylamine,
octylamine, dodecylamine) or 3-dimethylaminopropylamine
gave the amides 3 and 4, respectively. Treatment of the
latter with methyl iodide gave the trimethyl ammonium
salt 5.
Compounds 2, 3, and 5 served as models for hair binding
assay. Although there are various methods to measure the
substantivity of cationic species to hair,19,26 many are
complicated, require specialized instrumentation and are
time-consuming. As many compounds contained in
cosmetic products including cationic surfactants27 and
dyes28 can penetrate into hair fibres, it is important to
choose an analytical method which can quantitatively
recover the analyte.
Although numerous other methods exist for introducing a
new functionality at the C-2 position of chromone,3,4,21 the
chosen synthetic route is short, has two possibilities for
introducing diversity (variation of acetophenone and
variation of amine) needed to generate a small library and
utilises cheap reagents which is an important factor for
industrial applications.
Although a number of methods for hair substantivity were
tested,29 only two (MALDI MS30 and hair digestion
followed by HPLC analysis) could confirm the presence
of compound bound to hair. The practicality of HPLC
analysis and the large number of samples made the HPLC
method very feasible. The compound was dissolved in a
70:30 ethanol/water mixture, to which then sterile, washed
hair was added and allowed to stir for 1 h. The hair was then
In order to increase the radical scavenging activity of 3 and
5, the 7-hydroxy-4-oxo-4H-chromene-2-carboxylic acid
ethyl ester was synthesised. Due to the formation of a
zwitterion in compound 9 this synthetic route was not
Scheme 1. General synthesis of unsubstituted 2-amido chromones.

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T. Walenzyk et al. / Tetrahedron 61 (2005) 7366–7377
Scheme 2. General synthesis of hydroxyl substituted 2-amido chromones.
thoroughly washed with water and air dried. A sample of
this ‘treated’ hair was dissolved in sodium hydroxide
solution at 60 8C and then analysed via HPLC. This
method31 which was adapted from an analytical procedure
used for the detection of anabolic steroids in livestock has
the advantage that even small amounts of compounds can be
quantitatively recovered.
(generated due to the strong basic conditions) was observed.
Digested hair, which had previously been stirred with 5 and
then washed thoroughly, showed a peak at 5.47 min in
addition to the characteristic peaks of digested hair. On
spiking this sample with a small amount of the digested
product of 5, the peak at 5.47 min increased in intensity
confirming that 5 binds to human hair.
Digested blonde human hair was taken as a reference
showing characteristic peaks at 1.54, 1.77, 2.05 and
4.79 min. On digestion of 5 (without coming in contact
with any hair), only a peak at 5.47 min corresponding to the
carboxylic acid, 4-oxo-4H-chromene-2-carboxylic acid
In addition to 5, a number of other compounds were tested
for their hair substantivity (Table 1). Tests were carried out
on bleached human hair and on brown human hair. The hair
substantivity effect of all tested compounds was indepen-
dent of hair type.
Scheme 3. General synthesis of methoxy substituted 2-amido chromones.

T. Walenzyk et al. / Tetrahedron 61 (2005) 7366–7377
7369
Table 1. Hair substantivity of chromones
2.3. Cyclic voltammetry
Compound
Hair substantivity
In flavonoids the reduction potential is strongly dependant
on the electron donating properties of the B-ring as this is
generally more electron rich as the A-ring.33 As chromones
do not possess the B-ring, the A-ring should influence the
electronic chemical properties of the chromone. The
electrochemical properties of compounds 15a, 15b, and
15c were measured by cyclic voltammetry34 in acetonitrile.
All three samples showed an electrochemical irreversible
behaviour. Relative to the half wave reduction potential of
Fc/FcC, a shift of C30, C60 and C50 mV were observed
for 15a, 15b, and 15c, respectively. Although these shifts
are small and close to the experimental error (G20 mV) the
general trend of increased reduction potential with increased
electron donating properties of the substitutent is indicated.
2
None
None
Possible
a
—
Possible
Yes
Yes
Yes
Yes
3a
3b
3c
8b
5
15a
15b
15c
a Could not be tested to due solubility problems.
These results show that compounds bearing a quaternary
ammonium salt bind well to hair. The HPLC chromatograph
shows a definite peak which corresponds to the added
compound (see Section 4 for more details concerning
analysis). An ester or butyl amide failed to show any
binding. There is some evidence to show that an octyl amide
functionality may bind to hair, however, due to their poor
solubility in ethanol/water mixtures, definite binding could
not be confirmed (The observed peak was within experi-
mental error). However, the use of long alkyl chains in hair
care products suggests that some interactions must take
place.
2.4. UV absorption of substituted chromones
The UV absorption properties of three different chromone
derivatives (ester, alkyl amide and ammonium salt) with
varying substitution patterns (methoxy substitution at
position 7-, 6- or 5-) were measured. Tables 2–4 summarise
the results.
A bathochromic shift was observed for the chromone
-esters, -alkyl amides and -ammonium salts upon substi-
tution of a methoxy group at either position 5, 6 or 7. As
expected the alkyl chain length has no effect on the UV
absorption. When compared to 5, a red shift of 29 and 15 nm
was observed for 15b and 15c, respectively, whilst 15a has
the same lmax (304 nm). Thus, by altering the chromone
substitution pattern, the UV absorption properties can be
tailored to individual needs. For example, 15a would protect
better against UVB radiation and thus hair protein loss,
whilst 15b would protect better against UVA radiation and
hair colour changes.
2.2. Antioxidant activities
The DPPH (2,2-diphenyl-1-picrylhydrazyl) assay was used
to screen the radical scavenging potential of the compounds.
The DPPH radical, DPPH% is a relatively stable para-
magnetic free radical, which accepts a hydrogen radical to
become a stable diamagnetic molecule. As chromones lack
the B-ring of flavonoids, which is responsible for much of
their antioxidant power, the radical scavenging ability of
chromones remain modest. However, interesting radical
scavenging properties were found for the amide derivatives.32
Table 2. Molar extinction coefficients for ethyl ester derivatives
Compound
R1
R2
R3
Wavelength, lmax (nm), Molar extinction coefficient (3)a
12a
12b
12c
OCH3
H
H
H
OCH3
H
H
H
OCH3
212 (4.44)
206 (4.45)
238 (4.29)
238 (4.22)
238 (4.22)
310 (4.01)
343 (3.77)
327 (3.64)
253 (4.31)
271 (4.00)
a Methanol was used as solvent.
Table 3. Molar extinction coefficients for alkyl amide derivatives
Compound
R1
R2
R3
Wavelength, lmax (nm), Molar extinction coefficient (3)a
13a
13b
13c
OCH3
H
H
H
OCH3
H
H
H
OCH3
212 (4.42)
205 (4.43)
236 (4.35)
230 (4.25)
238 (4.29)
255 (4.10)b
252 (4.36)
260 (4.16)
304 (4.04)
338 (3.75)
323 (3.71)
a Methanol was used as solvent.
b Present as a shoulder.
Table 4. Molar extinction coefficients for quaternary ammonium derivatives
Compound
R1
R2
R3
Wavelength, lmax (nm), Molar extinction coefficient (3)a
5
H
OCH3
H
H
H
OCH3
H
H
H
H
OCH3
204 (4.62)
210 (4.47)
205 (4.42)
246 (4.43)
242 (4.32)
248 (4.34)
242 (4.25)
304 (3.83)
304 (3.80)
333 (3.54)
319 (3.53)
15a
15b
15c
H
a CH3CN was used as solvent.

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T. Walenzyk et al. / Tetrahedron 61 (2005) 7366–7377
3. Conclusion
using a magnetic stirrer. Commercially available,36 washed,
sterile human hair (1.00 g, 0.4–0.7 cm pieces) was added to
the solution and allowed to stir vigorously for 1 h. The hair
was filtered and washed three times with fresh solvent. The
hair sample was dried overnight at 40 8C and 200 mbar,
yielding 1.00 g of treated hair.
Chromone derivatives containing a quaternary ammonium
functionality which bound to human hair were synthesised.
The substitution pattern of the methoxy group was system-
atically changed to probe its effect on the redox potential
and the UV absorption properties. The general radical
scavenger activity of all derivatives is lower if compared to
flavonoids. The UV absorption of the derivatives depends
on the position of the methoxy groups. If the substitutent is
shifted from the 7 to 6 position, a bathochromic shift of the
UV absorption of 29 nm results.
The treated hair (0.5 g) was added to a solution of NaOH
(1 M, 4 ml) and allowed to stir at 65 8C for 2 h, forming a
brown suspension. The reaction mixture was neutralised
with HCl (2 M, 2 ml) after which methanol (3 ml) and THF
(1 ml) were added and the mixture allowed to stir for a
further hour. A sample (5 mg) of only the substance to be
tested (no hair) was subjected to the same conditions to
control the stability of the substance. The suspension was
centrifuged (4000 rpm, 10 min) and the mother liquor
decanted. The mother liquor was then filtered (0.2 mm
polypropylene filter) to yield a clear light brown solution. A
sample of only hair (no substance) was subjected to the
same conditions and used as a reference. The hair
substantivity test was carried out using both bleached
European and natural light middle brown European hair. No
difference was noted in hair substantivity due to hair type.
4. Experimental
4.1. General
Purification and drying according to accepted general
procedures.35 If not otherwise stated, commercially available
solvent of the highest purity were used. UV–vis spectra were
measured using a Varian Cary BIO 50 UV/VIS/NIR
spectrometer, with a 1 cm quartz cell (Hellma) and Uvasol
solvents (Merck). Reported as: lmax in nm (3). IR spectra were
measured using a Bio-Rad FT-IR-Spectrometer FTS 155.
NMR spectra were measured using a Bruker Avance 300 (1H:
300.1 MHz, 13C: 75.5 MHz) and Bruker Avance 600 (1H:
600.1 MHz, 13C: 150.1 MHz). The chemical shifts are in d-
values (ppm) relative to the internal (or external) standard
TMS. Reported as: Chemical shift (multiplicity, coupling
constant, number of protons, assignment). Reported assign-
ments were determined with the help of COSY, HMQC,
HSQC, and NOESY 2D-Spectra. Mass spectra were measured
using a Varian CH-5 (EI), Finnigan MAT 95 (CI; FAB and
FD) and Finnigan MAT TSQ 7000 (ESI). Melting points are
uncorrected and were determined according to Tottoli using
instrumentation from Bu¨chi. Elemental analyses were
carried out by the microanalytical laboratory of the School
of Chemistry and Pharmacy, University of Regensburg.
4.5. X-ray crystallography
X-ray crystallography data for compounds 2, 13a, 13b and
13c are available under www.dekker.com.
4.6. Synthesis of new compounds
4.6.1. Ethyl-4-oxo-4H-chromene-2-carboxylate (2).37
Sodium (1.49 g, 65 mmol) was dissolved in absolute ethanol
(100 ml). Diethyloxalate (5.12 g, 35 mmol) and
2-hydroxyacetophenone (2.04 g, 15 mmol) were dissolved
in absolute ethanol (10 ml) and added to the sodium
ethanolate solution. The solution was allowed to reflux for
1 h. Concentrated HCl was added dropwise until the
reaction was acidic and a white precipitate formed. The
white precipitate was filtered and the yellow solution
concentrated to a slurry. The slurry was extracted with
ethyl acetate, dried over Na2SO4 and evaporated to give a
light yellow solid. The solid was recrystallised from
methanol/diisopropylether (4:1) to yield white needles
(3.20 g, 14.6 mmol, 98%).
4.2. HPLC
HPLC analyses were carried out using a Merck Hitachi
LaChrom (Interface L-7000, UV detector L-7400, Column
Oven L-7350, Autosampler L-7200, Pump L-7100) with a
Chromolith RP-18e 100-4.6 column. Wavelength 220–
400 nm; column temperature 30 8C; injection volume 50 ml;
acetonitrile and water buffered at pH 2.6 served as solvents.
Mp 63 8C; IR (KBr): n~ (cmK1)Z3447, 3067, 2985, 2938,
1734, 1647, 1466, 758; H NMR (600 MHz, CDCl3): d
1
(ppm)Z1.43 (t, JZ7.1 Hz, 3H, CH3), 4.46 (q, JZ7.1 Hz,
2H, CH2), 7.11 (s, 1H, H-3), 7.44 (ddd, JZ1.2, 7.1, 8.0 Hz,
1H, H-6), 7.61 (ddd, JZ0.4, 1.2, 8.5 Hz, 1H, H-8), 7.74
(ddd, JZ1.7, 7.1, 8.5 Hz, 1H, H-7), 8.20 (ddd, JZ0.4, 1.7,
8.0 Hz, 1H, H-5); 13C NMR (150 MHz, CDCl3): d (ppm)Z
14.1 (C, CH3), 63.0 (K, CH2), 114.8 (C, C-3), 118.8 (C,
C-8), 124.4 (Cquat, C-9), 125.7 (C, C-5), 125.9 (C, C-6),
134.7 (C, C-7), 152.2 (Cquat, C-2), 156.0 (Cquat, C-10),
160.6 (Cquat, C]O), 178.4 (Cquat, C-4); MS (ESI-MS,
EtOH/MeOHC10 mmol/l NH4OAc) m/z (%): 219 (100)
[MH]C. Elemental analysis: C12H10O4 Calcd: C, 66.05; H,
4.62. Found: C, 66.07; H, 4.72.
4.3. Cyclic voltammetry
The cyclic voltammetry measurements were conducted in
dry acetonitrile with 0.1 mol LK1 NBu4 BF4 as
electrolyte and under argon. The working electrode was a
graphite electrode, the counter electrode a platinum wire
and the reference electrode Ag/AgCl in LiCl saturated
ethanol. The PGSTAT 20 is from the company Eco Chemie
and is controlled by the program GPES V 3.0.
C
K
4.4. Hair substantitivity
The substance to be tested (1 mg) was dissolved in ethanol/
water (70:30, 50 ml) and allowed to stir at room temperature
4.6.2. 4-Oxo-4H-chromene-2-carboxylic acid butylamide
(3a). Ethyl-4-oxo-4H-chromene-2-carboxylate (655 mg,

T. Walenzyk et al. / Tetrahedron 61 (2005) 7366–7377
7371
3 mmol) was dissolved in the butylamine (658 mg, 9 mmol)
allowed to stir at 50 8C for 10 min. The solvent was
evaporated leaving a yellow solid. Glacial acetic acid (5 ml)
was added and allowed to stir at 70 8C for 10 min. The
mixture was added to ice water and a white precipitate
formed which was filtered, washed with water and dried.
The white solid was recrystallised from ethyl acetate to
yield white needles (630 mg, 2.6 mmol, 86%).
for 10 min. The solvent was evaporated giving a light
yellow solid. Glacial acetic acid (10 ml) was added and
allowed to stir at 70 8C for 10 min. The mixture was added
to ice water and extracted with ethyl acetate. The organic
layer was dried over Na2SO4 and evaporated to give a
yellow solid. The solid was recrystallised from ethyl acetate
to yield white needles (2.30 g, 6.4 mmol, 71%).
Mp 108 8C; IR (KBr): n~ (cmK1)Z3319, 2959, 2932, 2850,
1982, 1642, 1522, 1387, 753; UV/vis (MeOH): lmax (nm)
(log 3)Z203 (4.37), 236 (4.29), 305 (3.83); 1H NMR
(300 MHz, DMSO): d (ppm)Z0.83 (t, JZ6.7 Hz, 3H,
CH3), 1.16–1.33 (m, 18H, 9!CH2), 1.48–1.60 (m, 2H,
CH2), 3.28 (m, 2H, CH2), 6.81 (s, 1H, H-3), 7.53 (ddd, JZ
1.0, 7.2, 8.0 Hz, 1H, H-6), 7.73 (dd, JZ0.6, 8.5 Hz, 1H,
H-8), 7.89 (ddd, JZ1.7, 7.2, 8.5 Hz, 1H, H-7), 8.05 (dd, JZ
1.7, 8.0 Hz, 1H, H-5), 9.12 (t, JZ5.8 Hz, 1H, N–H); 13C
NMR (75 MHz, DMSO): d (ppm)Z13.8 (C, CH3), 22.0 (K,
CH2), 26.3 (K, CH2), 28.6 (K, CH2), 28.7 (K, CH2), 28.8
(K, CH2), 28.9 (K, CH2), 28.9 (K, CH2), 28.9 (K, CH2),
31.2 (K, CH2), 39.2 (K, CH2), 39.4 (K, CH2), 110.2 (C,
C-3), 118.7 (C, C-8), 123.5 (Cquat, C-9), 124.8 (C, C-5),
125.9 (C, C-6), 134.9 (C, C-7), 155.0 (Cquat, C-2), 155.7
(Cquat, C-10), 158.7 (Cquat, C]O), 177.2 (Cquat, C-4); MS
(CI-MS, NH3) m/z (%): 375.2 (100) [MCNH3]C, 358.2
(56) [MH]C. Elemental analysis: C22H31NO3 Calcd: C
73.92; H 8.74; N, 3.92. Found: C, 73.75; H, 8.75; N, 3.74.
Mp 130 8C; IR (KBr): n~ (cmK1)Z3319, 3079, 2954, 2868,
1685, 1642, 1387, 755; UV/vis (MeOH): lmax (nm)
(log 3)Z202 (4.37), 236 (4.29), 305 (3.85); 1H NMR
(300 MHz, DMSO): d (ppm)Z0.91 (t, JZ7.2 Hz, 3H,
CH3), 1.34 (qd, JZ7.2, 14.1 Hz, 2H, CH2), 1.54 (XX, JZ
7.2 Hz, 2H, CH2), 3.30 (q, JZ7.2 Hz, 2H, CH2), 6.82 (s, 1H,
H-3), 7.53 (ddd, JZ1.0, 7.1, 8.0 Hz, 1H, H-6), 7.73 (dd, JZ
1.0, 8.5 Hz, 1H, H-8), 7.89 (ddd, JZ1.7, 7.1, 8.5 Hz, 1H,
H-7), 8.05 (dd, JZ1.7, 8.0 Hz, 1H, H-5), 9.10 (t, JZ5.6 Hz,
1H, N–H); 13C NMR (75 MHz, DMSO): d (ppm)Z13.6 (C,
CH3), 19.5 (K, CH2), 30.8 (K, CH2), 38.8 (K, CH2), 110.2
(K, C-3), 118.7 (C, C-8), 123.5 (Cquat, C-9), 124.8 (C,
C-5), 125.9 (C, C 6), 134.9 (C, C-7), 155.0 (Cquat, C-2),
155.7 (Cquat, C-10), 158.7 (Cquat, C]O), 177.2 (Cquat, C-4);
MS (CI-MS, NH3) m/z (%): 263.1 (100) [MCNH3]C, 246.1
(26) [MH]C. Elemental analysis: C14H15NO3 Calcd: C,
68.56; H, 6.16; N, 5.71. Found: C, 68.58; H, 6.04; N, 5.61.
4.6.3. 4-Oxo-4H-chromene-2-carboxylic acid octylamide
(3b). Ethyl-4-oxo-4H-chromene-2-carboxylate (655 mg,
3 mmol) and octylamine (1163 mg, 9 mmol) were dissolved
in dichloromethane (5 ml) and allowed to reflux for 10 min.
The solvent was evaporated leaving a light yellow solid.
Glacial acetic acid (5 ml) was added and allowed to stir at
70 8C for 10 min. The mixture was added to ice water and
extracted with ethyl acetate. The organic layer was dried
over Na2SO4 and evaporated to give a white solid. The solid
was recrystallised from ethyl acetate to yield white needles
(826 mg, 2.7 mmol, 91%).
4.6.5. 4-Oxo-4H-chromene-2-carboxylic acid (3-dimethyl-
amino-propyl)-amide (4). Ethyl-4-oxo-4H-chromene-2-
carboxylate (655 mg, 3 mmol) and 3-dimethylamino-propyl-
amine (920 mg, 9 mmol) were dissolved in dichloromethane
(5 ml) and allowed to reflux for 20 min. The solvent was
evaporated, glacial acetic acid (5 ml) was added and the
solution allowed to stir at 70 8C for 10 min. The mixture was
added to ice water and extracted with ethyl acetate. The
organic layer was dried over Na2SO4 and evaporated to give
a yellow solid. The solid was recrystallised from ethyl
acetate to yield white needles (691 mg, 2.5 mmol, 84%).
Mp 131 8C; IR (KBr): n~ (cmK1)Z3314, 2927, 2849, 1684,
1646, 1529, 1392, 751; UV/vis (MeOH): lmax (nm)
(log 3)Z202 (4.36), 236 (4.29), 305 (3.84); 1H NMR
(300 MHz, CDCl3): d (ppm)Z0.85–0.91 (m, 3H, CH3),
1.24–1.46 (m, 10H, 5!CH2), 1.61–1.72 (m, 2H, CH2), 3.49
(tq, JZ6.2, 7.2 Hz, 2H, CH2), 6.91 (s, 1H, N–H), 7.16 (s,
1H, H-3), 7.45 (ddd, JZ1.0, 7.2, 8.1 Hz, 1H, H-6), 7.52 (dd,
JZ0.5, 8.5 Hz, 1H, H-8), 7.73 (ddd, JZ1.7, 7.2, 8.5 Hz, 1H,
H-7), 8.22 (dd, JZ1.7, 8.0 Hz, 1H, H-5); 13C NMR
(75 MHz, CDCl3): d (ppm)Z14.1 (C, CH3), 22.6 (K,
CH2), 26.7 (K, CH2), 27.0 (K, CH2), 29.1 (K, CH2), 29.2
(K, CH2), 29.5 (K, CH2), 31.8 (K, CH2), 40.1 (K, CH2),
112.1 (C, C-3), 118.0 (C, C-8), 124.4 (Cquat, C-9), 126.0
Mp 125 8C; IR (KBr): n~ (cmK1)Z3289, 2976, 2946, 2805,
1686, 1640, 1534, 1460, 1392, 759; UV/vis (MeOH): lmax
(nm) (log 3)Z203 (4.37), 236 (4.29), 305 (3.84); H NMR
1
(300 MHz, DMSO): d (ppm)Z1.69 (p, JZ6.9 Hz, 2H, CH2),
2.15 (s, 6H, 2!CH3), 2.28 (t, JZ6.9 Hz, 2H, CH2), 3.33
(dd, JZ7.2, 12.7 Hz, 2H, CH2), 6.82 (s, 1H, H-3), 7.53 (ddd,
JZ1.0, 7.2, 8.0 Hz, 1H, H-6), 7.71 (dd, JZ0.7, 8.5 Hz, 1H,
H-8), 7.89 (ddd, JZ1.7, 7.2, 8.5 Hz, 1H, H-7), 8.05 (dd, JZ
1.7, 8.0 Hz, 1H, H-5), 9.25 (t, JZ5.5 Hz, 1H, N–H); 13C
NMR (75 MHz, DMSO): d (ppm)Z26.4 (K, CH2), 38.0 (K,
CH2), 45.1 (C, 2!CH3), 56.9 (K, CH2), 110.2 (C, C-3),
118.6 (C, C-8), 123.5 (Cquat, C-9), 124.9 (C, C-5), 125.9
(C, C-5), 126.2 (C, C-6), 134.5 (C, C-7), 154.8 (Cquat
C-2), 155.3 (Cquat, C-10), 159.2 (Cquat, C]O), 178.2 (Cquat
,
,
(C, C-6), 134.9 (C, C-7), 155.0 (Cquat, C-2), 155.6 (Cquat,
C-10), 158.7 (Cquat, C]O), 177.2 (Cquat, C-4); MS (PI-
EIMS) m/z (%): 58.1 (100) [Me2N]CH2]C, 274.1 (11)
[M]C%. Elemental analysis: C15H18N2O3 Calcd: C, 65.68;
H, 6.61; N, 10.21. Found: C, 65.63; H, 6.41; N, 10.08.
C-4); MS (CI-MS, NH3) m/z (%): 319.1 (100) [MCNH3]C,
302.1 (40) [MH]C. Elemental analysis: C18H23NO3 Calcd:
C, 71.73; H, 7.69; N, 4.65. Found: C, 71.62; H, 7.58; N,
4.43.
4.6.6. Trimethyl-{3-[(4-oxo-4H-chromene-2-carbonyl)-
amino]-propyl}-ammonium iodide (5). Iodomethane
(260 mg, 1.83 mmol) was dissolved in chloroform (5 ml)
and added to a solution of 4-oxo-4H-chromene-2-carboxylic
acid (3-dimethylamino-propyl)-amide (500 mg, 1.82 mmol)
4.6.4. 4-Oxo-4H-chromene-2-carboxylic acid dodecyla-
mide (3c). Ethyl-4-oxo-4H-chromene-2-carboxylate
(1.96 g, 9 mmol) and dodecylamine (5.0 g, 27 mmol) were
dissolved in dichloromethane (10 ml) and allowed to reflux

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T. Walenzyk et al. / Tetrahedron 61 (2005) 7366–7377
in chloroform (5 ml). The solution was allowed to stir at
room temperature for 30 min and then at reflux for 15 min
upon which a precipitate formed. The yellow precipitate
was filtered and washed with chloroform yielding a light
yellow solid (578 mg, 1.39 mmol, 76%).
filtered off, washed with water and dried. The solid was
recrystallised from ethyl acetate/diisopropylether (4:1) to
yield a light brown solid (573 mg, 2.2 mmol, 88%).
Mp 240 8CC; IR (KBr): n~ (cmK1)Z3340, 3195, 3081,
2960, 2875, 1639, 1618, 1394, 829; UV/vis (MeOH): lmax
Mp 240 8CC; IR (KBr): n~ (cmK1)Z3404, 3022, 2956,
1673, 1643, 1458, 740; UV/vis (CH3CN): lmax (nm)
(log 3)Z204 (4.62), 246 (4.43), 304 (3.83); 1H NMR
(300 MHz, DMSO): d (ppm)Z1.95–2.06 (m, 2H, CH2),
3.07 (s, 9H, 3!CH3), 3.34–3.44 (m, 6H, 2!CH2), 6.86 (s,
1H, H-3), 7.55 (ddd, JZ1.0, 7.2, 8.0 Hz, 1H, H-6), 7.75 (d,
JZ8.5 Hz, 1H, H-8), 7.92 (ddd, JZ1.7, 7.2, 8.5 Hz, 1H,
H-7), 8.06 (dd, JZ1.7, 8.0 Hz, 1H, H-5), 9.25 (t, JZ5.9 Hz,
1H, N–H); 13C NMR (75 MHz, DMSO): d (ppm)Z22.6 (K,
CH2), 36.3 (K, CH2), 52.1 (C, CH3), 52.2 (C, CH3), 52.2
(C, CH3), 63.2 (K, CH2), 110.5 (C, C-3), 118.6 (C, C-8),
123.5 (Cquat, C-9), 124.9 (C, C-5), 126.0 (C, C-6), 135.0
(C, C-7), 155.0 (Cquat, C-2), 155.4 (Cquat, C-10), 159.2
(Cquat, C]O), 177.2 (Cquat, C-4); MS (ESI, H2O/AcN) m/z
(%): 289.0 (100) [K]C. Elemental analysis: C16H21N2O3I
Calcd: C, 46.17; H, 5.08; N, 6.73. Found: C, 45.79; H, 4.70;
N, 6.51.
(nm) (log 3)Z211 (4.41), 238 (4.31), 307 (3.98); H NMR
1
(300 MHz, DMSO): d (ppm)Z0.90 (t, JZ7.2 Hz, 3H, CH3),
1.32 (qd, JZ7.2, 14.2 Hz, 2H, CH2), 1.47–1.58 (m, 2H, CH2),
3.28 (dd, JZ6.9, 13.2 Hz, 2H, CH2), 6.69 (s, 1H, H-3), 6.94
(dd, JZ2.3, 8.7 Hz, 1H, H-6), 6.99 (d, JZ2.2 Hz, 1H, H-8),
7.88 (d, JZ8.7 Hz, 1H, H-5), 9.06 (t, JZ5.8 Hz, N–H), 10.98
(s, 1H, OH); 13C NMR (75 MHz, DMSO): d (ppm)Z13.6 (C,
CH3), 19.5 (K, CH2), 30.9 (K, CH2), 38.8 (K, CH2), 102.6
(C, C-8), 110.1 (C, C-3), 115.6 (C, C-6), 116.4 (Cquat, C-9),
126.6 (C, C-5), 155.1 (Cquat, C-2), 156.9 (Cquat, C-10), 158.8
(Cquat, C]O), 163.1 (Cquat, C-7), 176.3 (Cquat, C-4); MS
(CI-MS, NH3) m/z (%): 262.2 (100) [MH]C. Elemental
analysis: C14H15NO4 Calcd: C, 64.36; H, 5.79; N, 5.36.
Found: C, 64.12; H, 5.48; N, 5.11.
4.6.9. 7-Hydroxy-4-oxo-4H-chromene-2-carboxylic acid
octylamide (8b). Ethyl-7-hydroxy-4-oxo-4H-chromene-2-
carboxylate (585 mg, 2.5 mmol) and octylamine (905 mg,
7 mmol) were dissolved in dichloromethane (10 ml) and
allowed to reflux for 10 min. The solvent was evaporated
upon which a brown solid formed. Glacial acetic acid
(10 ml) was added and allowed to stir at 70 8C for 10 min.
The mixture was added to ice water yielding a precipitate,
which was filtered off, washed with water and dried. The
solid was recrystallised from ethyl acetate to yield a white
solid (642 mg, 2.0 mmol, 81%).
4.6.7.
Ethyl-7-hydroxy-4-oxo-4H-chromene-2-car-
boxylate (7).38 Sodium (1.84 g, 80 mmol) was dissolved
in absolute ethanol (100 ml). Diethyloxalate (7.31 g,
50 mmol) and 2,4-dihydroxyacetophenone (2.28 g,
15 mmol) were dissolved in absolute ethanol (10 ml) and
added to the sodium ethanolate solution. The solution was
allowed to reflux for 1 h. Concentrated HCl was added
dropwise until the reaction was acidic and a white
precipitate formed. The white precipitate was filtered off
and the yellow/brown filtrate concentrated to a slurry. The
slurry was extracted with ethyl acetate, dried over Na2SO4
and evaporated to give a light orange solid. The solid was
recrystallised from methanol/diisopropylether (3:1) to yield
white needles (2.78 g, 12 mmol, 79%).
Mp 215 8C; IR (KBr): n~ (cmK1)Z3256, 3155, 2947, 2919,
2853, 1634, 1598, 1530, 1388, 1242, 838; UV/vis (MeOH):
1
lmax (nm) (log 3)Z210 (4.44), 238 (4.33), 308 (3.99); H
NMR (600 MHz, DMSO): d (ppm)Z0.84 (t, JZ6.7 Hz, 3H,
CH3), 1.20–1.31 (m, 10H, 5!CH2), 1.50–1.56 (m, 2H,
CH2), 3.27 (dd, JZ6.7, 13.4 Hz, 2H, CH2), 6.69 (s, 1H, H-3),
6.94 (dd, JZ1.9, 8.7 Hz, 1H, H-6), 6.99 (d, JZ1.9 Hz, 1H,
H-8), 7.88 (d, JZ8.7 Hz, 1H, H-5), 9.03 (t, JZ5.5 Hz, 1H,
N–H), 10.96 (s, 1H, OH); 13C NMR (150 MHz, DMSO): d
(ppm)Z13.8 (C, CH3), 22.0 (K, CH2), 26.3 (K, CH2), 28.5
(K, CH2), 28.6(K, CH2), 28.7(K, CH2),31.1(K, CH2), 39.1
(K, CH2), 102.6 (C, C-8), 110.1 (C, C-3), 115.6 (C, C-6),
116.4 (Cquat, C-9), 126.6 (C, C-5), 155.1 (Cquat, C-2), 156.9
(Cquat, C-10), 158.8 (Cquat, C]O), 163.1 (Cquat, C-7), 176.2
(Cquat, C-4); MS (ESI, DCM/MeOH C10 mmol/l NH4Ac)
m/z (%): 318.1 (100) [MH]C. Elemental analysis: C18H23NO4
Calcd: C, 68.12; H, 7.30; N, 4.41. Found: C, 67.85; H, 7.30; N,
4.24.
Mp 210–211 8C; IR (KBr): n~ (cmK1)Z3521, 3109, 1742,
1640, 1601, 1570, 1456, 1253, 829; UV/vis (MeOH): lmax
1
(nm) (log 3)Z211 (4.44), 239 (4.24), 313 (3.96); H NMR
(600 MHz, DMSO): d (ppm)Z1.34 (t, JZ7.1 Hz, 3H, CH3),
4.37 (q, JZ7.1 Hz, 2H, CH2), 6.82 (s, 1H, H-3), 6.90 (d, JZ
2.2 Hz, 1H, H-8), 6.96 (dd, JZ2.2, 8.7 Hz, 1H, H-6), 7.89
(d, JZ8.7 Hz, 1H, H-5), 11.02 (s, 1H, OH); 13C NMR
(150 MHz, DMSO): d (ppm)Z13.8 (C, CH3), 62.5 (K,
CH2), 102.4 (C, C-8), 113.6 (C, C-3), 115.8 (C, C-6),
116.6 (Cquat, C-9), 126.7 (C, C-5), 151.5 (Cquat, C-2), 157.1
(Cquat, C-10), 159.9 (Cquat, C]O), 163.5 (Cquat, C-7), 176.1
(Cquat, C-4); MS (EI-MS, 70 eV) m/z (%): 234.1 (100) [M]C%
;
HRMS (C12H10O5)C% Calcd: 234.0528. Found: 234.0528G
0.76 ppm. Elemental analysis: C12H10O5 Calcd: C, 61.54;
H, 4.30. Found: C, 60.97; H, 4.21.
4.6.10. 7-Hydroxy-4-oxo-4H-chromene-2-carboxylic
acid (3-dimethylamino-propyl)-amide (9). Ethyl-7-
hydroxy-4-oxo-4H-chromene-2-carboxylate (1.17 g, 5 mmol)
and 3-dimethylaminopropylamine (1.53 g, 15 mmol) were
dissolved in dichloromethane (10 ml) and allowed to reflux
for 1 h. The solvent was evaporated, glacial acetic acid
(10 ml) was added and allowed to stir at 70 8C for 10 min.
The mixture was added to ice water and extracted with ethyl
acetate. The aqueous layer was neutralised with sodium
hydrogen carbonate and extracted with ethyl acetate. The
aqueous layer was made basic with sodium carbonate and
4.6.8. 7-Hydroxy-4-oxo-4H-chromene-2-carboxylic acid
butylamide (8a). Ethyl-7-hydroxy-4-oxo-4H-chromene-2-
carboxylate (585 mg, 2.5 mmol) and butylamine (512 mg,
7 mmol) were dissolved in dichloromethane (10 ml) and
allowed to reflux for 10 min. The solvent was evaporated
upon which a light yellow solid formed. Glacial acetic acid
(10 ml) was added and allowed to stir at 70 8C for 10 min.
The mixture was added to ice water. The precipitate was

T. Walenzyk et al. / Tetrahedron 61 (2005) 7366–7377
7373
extracted with ethyl acetate. The aqueous layer was made
acidic with concentrated HCl and then evaporated to
dryness giving a yellow solid. The yellow solid was added
to methanol and a white solid crystallised out, which was
filtered off. The yellow filtrate was evaporated to dryness
and repeatedly dissolved in methanol until no further white
solid crystallised. The yellow mother liquor was evaporated
to dryness yielding a yellow solid, which was dissolved in
boiling ethanol, filtered and evaporated to dryness yielding a
yellow solid (1.37 g, 4.7 mmol, 94%).
precipitate formed. The white precipitate was filtered and
the yellow solution concentrated to a slurry. The slurry was
extracted with ethyl acetate, dried over Na2SO4 and
evaporated to give a light yellow solid. The solid was
recrystallised from methanol/diisopropylether (4:1) to yield
a yellow solid (3.65 g, 14.7 mmol, 98%).
Mp 109 8C; IR (KBr): n~ (cmK1)Z3459, 3110, 2997, 2856,
1742, 1664, 1628, 1442, 1258, 838; UV/vis (MeOH): lmax
1
(nm) (log 3)Z212 (4.44), 238 (4.29), 310 (4.01); H NMR
(300 MHz, DMSO): d (ppm)Z1.34 (t, JZ7.1 Hz, 3H, CH3),
3.91 (s, 3H, O–CH3), 4.38 (q, JZ7.1 Hz, 2H, CH2), 6.85 (s,
1H, H-3), 7.07 (dd, JZ2.4, 8.9 Hz, 1H, H-6), 7.19 (d, JZ
2.4 Hz, 1H, H-8), 7.91 (d, JZ8.9 Hz, 1H, H-5); 13C NMR
(75 MHz, DMSO): d (ppm)Z13.8 (C, CH3), 56.2 (C, O–
CH3), 62.5 (K, CH2), 100.8 (C, C-8), 113.8 (C, C-3),
115.6 (C, C-6), 117.5 (Cquat, C-9), 126.7 (C, C-5), 151.5
(Cquat, C-2), 157.1 (Cquat, C-10), 159.9 (Cquat, C]O), 163.5
(Cquat, C-7), 176.1 (Cquat, C-4); MS (EI-MS, 70 eV) m/z (%):
248.1 (100) [M]C%. Elemental analysis: C13H12O5 Calcd: C,
62.9; H, 4.87. Found: C, 62.67; H, 4.67.
Mp 240 8CC; IR (KBr): n~ (cmK1)Z3455, 3273, 3064,
2999, 1683, 1650, 1619, 1548, 1468, 1272, 786; UV/vis
(MeOH): lmax (nm) (log 3)Z210 (3.92), 237 (3.80), 307
(3.46); 1H NMR (300 MHz, DMSO): d (ppm)Z2.00 (t, JZ
7.2 Hz, 2H, CH2), 2.72 (s, 6H, 2!CH3), 2.89 (t, JZ7.2 Hz,
2H, CH2), 3.02–3.18 (m, 2H, CH2), 6.72 (s, 1H, H-3), 7.00
(dd, JZ2.2, 8.8 Hz, 1H, H-6), 7.16 (d, JZ2.2 Hz, 1H, H-5),
7.86 (d, JZ8.8 Hz, 1H, H-8), 9.40 (t, JZ5.9 Hz, 1H, N–H),
11.36 (s, 1H, OH); 13C NMR (75 MHz, DMSO): d (ppm)Z
21.8 (K, CH2), 36.0 (K, CH2), 41.8 (C, 2!N–CH3), 53.3
(K, CH2), 102.7 (C, C-8), 110.2 (C, C-3), 115.8 (C, C-6),
116.3 (Cquat, C-9), 126.5 (C, C-5), 154.8 (Cquat, C-2), 156.9
(Cquat, C-10), 159.2 (Cquat, C]O), 163.4 (Cquat, C-7), 176.3
(Cquat, C-4); MS (ESI, DCM/MeOH C10 mmol/l NH4Ac)
m/z (%): 291.1 (100) [MH]C. HRMS (C15H18N2O4)C%
Calcd: 290.1266. Found: 290.1266G0.7 ppm.
4.6.13. 7-Methoxy-4-oxo-4H-chromene-2-carboxylic
acid butylamide (13a). Ethyl-7-methoxy-4-oxo-4H-chro-
mene-2-carboxylate (590 mg, 2.4 mmol) and butylamine
(512 mg, 7 mmol) were dissolved in dichloromethane
(10 ml) and allowed to reflux for 10 min. The solvent was
evaporated yielding a light yellow solid. Glacial acetic acid
(10 ml) was added and allowed to stir at 70 8C for 10 min.
The mixture was poured into ice water, the precipitate was
filtered off, washed with water and dried. The solid was
recrystallised from dichloromethane/diisopropylether (1:1)
to yield white needles (562 mg, 2.0 mmol, 86%).
4.6.11. {3-[(7-Hydroxy-4-oxo-4H-chromene-2-carbonyl)-
amino]-propyl}-trimethyl-ammonium iodide (10). 7-
Hydroxy-4-oxo-4H-chromene-2-carboxylic acid (3-
dimethylamino-propyl)-amide (436 mg, 1.5 mmol) was
added to acetonitrile (30 ml) containing sodium carbonate
(415 mg, 5 mmol). Iodomethane (227 mg, 1.6 mmol) was
added to the suspension and allowed to stir at room
temperature overnight. The reaction mixture was evapor-
ated to dryness and resuspended in methanol. A white
precipitate was filtered off and the resulting yellow mother
liquor evaporated to dryness yielding a light yellow solid
(439 mg, 1 mmol, 68%).
Mp 130 8C; IR (KBr): n~ (cmK1)Z3349, 2959, 2869, 1655,
1610, 1357, 843; UV/vis (MeOH): lmax (nm) (log 3)Z212
(4.42), 236 (4.35), 255 (sh 4.10), 304 (4.04); 1H NMR
(300 MHz, CDCl3): d (ppm)Z0.97 (t, JZ7.3 Hz, 3H, CH3),
1.43 (qd, JZ7.3, 14.4 Hz, 2H, CH2), 1.64 (td, JZ7.3,
14.9 Hz, 2H, CH2), 3.48 (dd, JZ6.9, 13.4 Hz, 2H, CH2),
3.91 (s, 3H, O–CH3), 6.89 (d, JZ2.3 Hz, 1H, H-8), 6.99 (dd,
JZ1.9, 8.9 Hz, 1H, H-6), 7.09 (s, 1H, H-3), 8.10 (d, JZ
8.9 Hz, 1H, H-5); 13C NMR (75 MHz, CDCl3): d (ppm)Z
13.8 (C, CH3), 20.1 (K, CH2), 31.5 (K, CH2), 39.8 (K,
CH2), 56.0 (C, O–CH3), 100.4 (C, C-8), 112.2 (C, C-3),
115.0 (C, C-6), 118.2 (Cquat, C-9), 127.4 (C, C-5), 154.6
(Cquat, C 2), 157.0 (Cquat, C-10), 159.3 (Cquat, C]O), 164.7
(Cquat, C-7), 177.5 (Cquat, C 4); MS (CI-MS, NH3) m/z (%):
276.2 (100) [MH]C. Elemental analysis: C15H17NO4 Calcd:
C, 65.44; H, 6.22; N, 5.09. Found: C, 65.43; H, 5.82; N,
4.91.
Mp 240 8CC; IR (KBr): n~ (cmK1)Z3445, 3266, 3064,
2979, 1681, 1645, 1252, 832; 1H NMR (300 MHz, DMSO):
d (ppm)Z1.90–2.02 (m, 2H, CH2), 3.07 (s, 9H, 3!CH3),
3.27–3.40 (m, 4H, 2!CH2), 6.66 (s, 1H, H-3), 6.80 (d, JZ
2.2 Hz, 1H, H-8), 6.83 (dd, JZ2.2, 8.6 Hz, 1H, H-6), 7.79
(d, JZ8.6 Hz, 1H, H-5), 9.15 (t, JZ5.9 Hz, 1H, N–H); 13C
NMR (75 MHz, DMSO): d (ppm)Z22.7 (K, CH2), 36.2 (K,
CH2), 52.1 (C, 3!N–CH3), 63.2 (K, CH2), 102.3 (C, C-8),
110.2 (C, C-3), 114.5 (Cquat, C-9), 117.2 (C, C-6), 126.2 (C,
C-5), 154.3 (Cquat, C-2), 157.4 (Cquat, C-10), 159.4 (Cquat, C]
O), 167.1 (Cquat, C-7), 175.9 (Cquat, C-4); MS(ESI, H2O/AcN)
m/z (%): 305.0 (100) [M]C; HRMS (C16H21N2O4)C Calcd:
305.1501. Found: 305.1500G1.23 ppm.
4.6.14. 7-Methoxy-4-oxo-4H-chromene-2-carboxylic
acid (3-dimethylamino-propyl)-amide (14a). Ethyl-7-
methoxy-4-oxo-4H-chromene-2-carboxylate (620 mg,
2.5 mmol) and 3 dimethylaminopropylamine (766 mg,
7.5 mmol) were dissolved in dichloromethane (10 ml) and
the reaction mixture was refluxed for 1 h. The solvent was
evaporated, glacial acetic acid (10 ml) was added and the
solution allowed to stir at 70 8C for 10 min. The mixture was
added to ice water and extracted with ethyl acetate. The
aqueous layer was neutralised with sodium hydrogen
carbonate and extracted with ethyl acetate. The aqueous
4.6.12. Ethyl-7-methoxy-4-oxo-4H-chromene-2-car-
boxylate (12a).37 Sodium (1.49 g, 65 mmol) was dissolved
in absolute ethanol (100 ml). Diethyloxalate (5.12 g,
35 mmol) and 2-hydroxy-4-methoxyacetophenone (2.49 g,
15 mmol) were dissolved in absolute ethanol (10 ml) and
added to the sodium ethanolate solution. The solution was
allowed to reflux for 1 h. Concentrated HCl was added
dropwise until the reaction was acidic and a white

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T. Walenzyk et al. / Tetrahedron 61 (2005) 7366–7377
layer was made basic with sodium carbonate and extracted
with ethyl acetate. The organic layer was dried over Na2SO4
and evaporated to give a yellow solid (654 mg, 2.1 mmol,
86%).
Mp 98 8C; IR (KBr): n~ (cmK1)Z3455, 3114, 3078, 2984,
2844, 1740, 1657, 1610, 1488, 1288, 839; UV/vis (MeOH):
lmax (nm) (log 3)Z206 (4.45), 238 (4.22), 253 (4.31), 343
(3.77); 1H NMR (600 MHz, CDCl3): d (ppm)Z1.42 (t, JZ
7.1 Hz, 3H, CH3), 3.89 (s, 3H, O–CH3), 4.45 (q, JZ7.1 Hz,
2H, CH2), 7.10 (s, 1H, H-3), 7.32 (dd, JZ3.2, 9.2 Hz, 1H,
H-7), 7.53 (dd, JZ0.4, 3.2 Hz, 1H, H-5), 7.54 (dd, JZ0.4,
9.2 Hz, 1H, H-8); 13C NMR (150 MHz, CDCl3): d (ppm)Z
14.1 (C, CH3), 56.0 (C, O–CH3), 62.9 (K, CH2), 104.6 (C,
C-5), 113.8 (C, C-3), 120.2 (C, C-8), 125.0 (C, C-7),
125.2 (Cquat, C-9), 150.8 (Cquat, C-10), 152.0 (Cquat, C-2),
157.5 (Cquat, C-6), 160.6 (Cquat, C]O), 178.3 (Cquat, C 4);
Mp 127–128 8C; IR (KBr): n~ (cmK1)Z3440, 3257, 3032,
2950, 1667, 1630, 1442, 845; 1H NMR (300 MHz, CDCl3):
d (ppm)Z1.79 (td, JZ5.9, 11.8 Hz, 2H, CH2), 2.36 (s, 6H,
2!CH3), 2.51–2.58 (m, 2H, CH2), 3.58 (td, JZ5.2, 5.9 Hz,
2H, CH2), 3.91 (s, 3H, O–CH3), 6.80 (d, JZ2.3 Hz, 1H,
H-5), 6.99 (dd, JZ2.3, 8.9 Hz, H-6), 7.05 (s, 1H, H-3), 8.11
(d, JZ8.9 Hz, 1H, H-8), 9.28 (s, 1H, N–H); 13C NMR
(75 MHz, CDCl3): d (ppm)Z24.8 (K, CH2), 40.6 (K, CH2),
45.6 (C, 2!N–CH3), 55.8 (C, O–CH3), 59.2 (K, CH2),
MS (PI-EIMS, 70 eV) m/z (%): 248.0 (100) [M]C%
.
Elemental analysis: C13H12O5 Calcd: C, 62.90; H, 4.87.
Found: C, 62.67; H, 4.66.
100.5 (C, C-8), 111.8 (C, C-3), 114.5 (C, C-6), 118.3 (Cquat
,
C-9), 127.5 (C, C-5), 155.1 (Cquat, C-2), 157.1 (Cquat, C-10),
159.2 (Cquat, C]O), 164.6 (Cquat, C-7), 177.7 (Cquat, C-4); MS
(ESI, H2O/AcN) m/z (%): 305.0 (100) [MH]C; HRMS
(C16H20N2O4)C% Calcd: 304.1423. Found: 304.1421G
0.44 ppm.
4.6.17. 6-Methoxy-4-oxo-4H-chromene-2-carboxylic
acid butylamide (13b). Ethyl-6-methoxy-4-oxo-4H-chro-
mene-2-carboxylate (590 mg, 2.4 mmol) and butylamine
(512 mg, 7 mmol) were dissolved in dichloromethane
(10 ml) and the reaction mixture was refluxed for 10 min.
The solvent was evaporated upon which a light yellow solid
formed. Glacial acetic acid (10 ml) was added and allowed
to stir at 70 8C for 10 min. The mixture was added to ice
water, the precipitate was filtered off, washed with water
and dried. The solid was recrystallised from dichloro-
methane/diisopropylether (1:3) to yield white needles
(572 mg, 2.1 mmol, 87%).
4.6.15. {3-[(7-Methoxy-4-oxo-4H-chromene-2-carbonyl)-
amino]-propyl}-trimethyl-ammonium iodide (15a). 7-
Methoxy-4-oxo-4H-chromene-2-carboxylic acid (3-
dimethylamino-propyl)-amide (456 mg, 1.5 mmol) was
dissolved in chloroform (10 ml), iodomethane (284 mg,
2 mmol) added and the reaction mixture was allowed to stir
at room temperature for 1 h. The solution was heated to
reflux for 10 min, the formed precipitate filtered off and
washed with chloroform. The precipitate was dried yielding
a white solid (575 mg, 1.3 mmol, 86%).
Mp 146 8C; IR (KBr): n~ (cmK1)Z3305, 3091, 2956, 2869,
1639, 1610, 1359, 833; UV/vis (MeOH): lmax (nm)
1
(log 3)Z205 (4.43), 230 (4.25), 252 (4.36), 338 (3.75); H
Mp 208 8C (decomposition); IR (KBr): n~ (cmK1)Z3490,
3411, 3257, 3012, 2954, 1676, 1633, 1604, 1442, 848; UV/
vis (CH3CN): lmax (nm) (log 3)Z210 (4.47), 242 (4.32),
NMR (300 MHz, CDCl3): d (ppm)Z0.98 (t, JZ7.3 Hz, 3H,
CH3), 1.43 (qd, JZ7.3, 14.3 Hz, 2H, CH2), 1.65 (td, JZ7.3,
14.9 Hz, 2H, CH2), 3.49 (dd, JZ7.1, 13.3 Hz, 2H, CH2),
3.90 (s, 3H, O–CH3), 7.15 (s, 1H, H-3), 7.31 (dd, JZ3.1,
9.2 Hz, 1H, H-7), 7.45 (d, JZ9.2 Hz, 1H, H-8), 7.56 (d, JZ
3.0 Hz, 1H, H-5); 13C NMR (75 MHz, CDCl3): d (ppm)Z
13.8 (C, CH3), 20.1 (K, CH2), 31.5 (K, CH2), 39.8 (K,
CH2), 56.0 (C, O–CH3), 105.1 (C, C-5), 111.2 (C, C-3),
119.4 (C, C-8), 124.6 (C, C-7), 125.1 (Cquat, C-9), 150.0
(Cquat, C-10), 154.6 (Cquat, C-2), 157.5 (Cquat, C-6), 159.3
(Cquat, C]O), 178.1 (Cquat, C-4); MS (CI-MS, NH3) m/z
(%): 276.2 (100) [MH]C. Elemental analysis: C15H17NO4
Calcd: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.33; H, 5.92;
N, 4.80.
1
304 (3.80); H NMR (600 MHz, DMSO): d (ppm)Z1.97–
2.03 (m, 2H, CH2), 3.07 (s, 9H, 3!CH3), 3.35–3.39 (m, 2H,
CH2), 3.36–3.41 (m, 2H, CH2), 3.93 (s, 3H, O–CH3), 6.78
(s, 1H, H-3), 7.13 (dd, JZ2.4, 8.9 Hz, H-6), 7.18 (d, JZ
2.4 Hz, 1H, H-8), 7.97 (d, JZ8.9 Hz, 1H, H-5), 9.19 (s, 1H,
N–H); 13C NMR (150 MHz, DMSO): d (ppm)Z22.7 (K,
CH2), 36.3 (K, CH2), 52.2 (C, 3!N–CH3), 56.1 (C, O–
CH3), 63.3 (K, CH2), 100.8 (C, C-8), 110.6 (C, C-3),
115.3 (C, C-6), 117.5 (Cquat, C-9), 126.5 (C, C-5), 155.1
(Cquat, C-2), 156.9 (Cquat, C-10), 159.3 (Cquat, C]O), 164.3
(Cquat, C-7), 176.4 (Cquat, C-4); MS (ESI, H2O/AcN) m/z
(%): 319.0 (100) [M]C; HRMS (C17H23N2O4)C Calcd:
319.1657. Found: 319.1661G1.16 ppm.
4.6.18. 6-Methoxy-4-oxo-4H-chromene-2-carboxylic
acid (3-dimethylamino-propyl)-amide (14b). Ethyl-6-
methoxy-4-oxo-4H-chromene-2-carboxylate (620 mg,
2.5 mmol) and 3-dimethylaminopropylamine (766 mg,
7.5 mmol) were dissolved in dichloromethane (10 ml) and
the reaction mixture was refluxed for 1 h. The solvent was
evaporated, glacial acetic acid (10 ml) was added and the
solution allowed to stir at 70 8C for 10 min. The mixture was
added to ice water and extracted with ethyl acetate. The
aqueous layer was neutralised with sodium hydrogen
carbonate and extracted with ethyl acetate. The aqueous
layer was made basic with sodium carbonate and extracted
with ethyl acetate. The organic layer was dried over Na2SO4
and evaporated to give a yellow solid (615 mg, 2.1 mmol,
81%).
4.6.16. Ethyl-6-methoxy-4-oxo-4H-chromene-2-car-
boxylate (12b). Sodium (1.49 g, 65 mmol) was dissolved
in absolute ethanol (100 ml). Diethyloxalate (5.12 g,
35 mmol) and 2-hydroxy-5-methoxyacetophenone (2.49 g,
15 mmol) were dissolved in absolute ethanol (10 ml) and
added to the sodium ethanolate solution. The solution was
allowed to reflux for 1 h. Concentrated HCl was added
dropwise until the reaction was acidic and a white
precipitate formed. The white precipitate was filtered off
and the yellow solution was concentrated to a slurry. The
slurry was extracted with ethyl acetate, dried over Na2SO4
and evaporated to give a light yellow solid. The solid was
recrystallised from methanol/diisopropylether (3:1) to yield
a yellow solid (3.66 g, 14.8 mmol, 98%).

T. Walenzyk et al. / Tetrahedron 61 (2005) 7366–7377
7375
1
Mp 108–109 8C; IR (KBr): n~ (cmK1)Z3434, 3305, 3041,
2945, 1680, 1641, 1385, 830; 1H NMR (300 MHz, DMSO):
d (ppm)Z1.68 (p, JZ6.9 Hz, 2H, CH2), 2.15 (s, 6H, 2!
CH3), 2.28 (t, JZ6.9 Hz, 2H, CH2), 3.32 (dd, JZ6.9,
13.3 Hz, 2H, CH2), 3.86 (s, 3H, O–CH3), 6.79 (s, 1H, H-3),
7.40 (d, JZ3.1 Hz, 1H, H-5), 7.48 (dd, JZ3.1, 9.1 Hz, 1H,
H-7), 7.66 (d, JZ9.1 Hz, 1H, H-8), 9.23 (t, JZ5.6 Hz, 1H,
N–H); 13C NMR (75 MHz, DMSO): d (ppm)Z26.4 (K,
CH2), 37.9 (K, CH2), 45.0 (C, 2!CH3), 55.7 (C, O–CH3),
56.8 (K, CH2), 104.5 (C, C-5), 109.3 (C, C-3), 120.2 (C,
C-8), 124.1 (C, C-7), 124.3 (Cquat, C-9), 149.6 (Cquat, C-10),
155.4 (Cquat, C-2), 156.8 (Cquat, C-6), 158.7 (Cquat, C]O),
176.9 (Cquat, C-4); MS (CI-MS, NH3) m/z (%): 305.2 (100)
[MH]C; HRMS (C16H20N2O4)C% Calcd: 304.1423. Found:
304.1425G0.71 ppm.
(nm) (log 3)Z238 (4.22), 271 (4.00), 327 (3.64); H NMR
(300 MHz, CDCl3): d (ppm)Z1.40 (t, JZ7.1 Hz, 3H, CH3),
3.97 (s, 3H, O–CH3), 4.42 (q, JZ7.1 Hz, 2H, CH2), 6.83 (d,
JZ8.5 Hz, 1H, H-6), 6.99 (s, 1H, H-3), 7.14 (dd, JZ0.9,
8.5 Hz, 1H, H-8), 7.59 (t, JZ8.5 Hz, 1H, H-7); 13C NMR
(75 MHz, CDCl3): d (ppm)Z14.1 (C, CH3), 56.5 (C, O–
CH3), 62.8 (K, CH2), 106.9 (C, C-6), 110.6 (C, C-8),
115.3 (Cquat, C-9), 116.5 (C, C-3), 134.7 (C, C-7), 150.3
(Cquat, C-2), 158.0 (Cquat, C 10), 159.8 (Cquat, C-5), 160.6
(Cquat, C]O), 178.0 (Cquat, C-4); MS (PI-EIMS, 70 eV) m/z
(%): 248.0 (100) [M]C%. Elemental analysis: C13H12O5
Calcd: C, 62.90; H, 4.87. Found: C, 62.84; H, 4.75.
4.6.21. 5-Methoxy-4-oxo-4H-chromene-2-carboxylic
acid butylamide (13c). Ethyl-5-methoxy-4-oxo-4H-chro-
mene-2-carboxylate (590 mg, 2.4 mmol) and butylamine
(512 mg, 7 mmol) were dissolved in dichloromethane
(10 ml) and the reaction mixture was allowed to reflux for
10 min. The solvent was evaporated giving a light yellow
solid. Glacial acetic acid (10 ml) was added, the solution
was allowed to stir at 70 8C for 10 min, added to ice water,
the precipitate filtered off, washed with water and dried.
The solid was recrystallised from dichloromethane/diiso-
propylether (2:1) to yield white needles (607 mg, 2.2 mmol,
93%).
4.6.19. {3-[(6-Methoxy-4-oxo-4H-chromene-2-carbonyl)-
amino]-propyl}-trimethyl-ammonium iodide (15b). 6-
Methoxy-4-oxo-4H-chromene-2-carboxylic acid (3-
dimethylamino-propyl)-amide (456 mg, 1.5 mmol) was
dissolved in chloroform (10 ml), iodomethane (284 mg,
2 mmol) was added and the reaction mixture was allowed to
stir at room temperature for 1 h. The solution was heated to
reflux for 10 min, the formed precipitate filtered off and
washed with chloroform. The precipitate was dried yielding
a white solid (620 mg, 1.4 mmol, 93%).
Mp 128 8C; IR (KBr): n~ (cmK1)Z3314, 3090, 2961, 1650,
1605, 1387, 794; UV/vis (MeOH): lmax (nm) (log 3)Z238
(4.29), 260 (4.16), 323 (3.71); 1H NMR (300 MHz, CDCl3):
d (ppm)Z0.96 (t, JZ7.3 Hz, 3H, CH3), 1.35–1.47 (m, 2H,
CH2), 1.63 (td, JZ7.3, 15.0 Hz, 2H, CH2), 3.47 (dd, JZ6.8,
13.6 Hz, 2H, CH2), 3.97 (s, 3H, O–CH3), 6.84 (d, JZ
8.4 Hz, 1H, H-6), 7.03 (s, 1H, H-3), 7.05 (d, JZ8.4 Hz, 1H,
H-8), 7.60 (t, JZ8.4 Hz, 1H, H-7); 13C NMR (75 MHz,
CDCl3): d (ppm)Z13.8 (C, CH3), 20.1 (K, CH2), 31.5 (K,
CH2), 39.7 (K, CH2), 56.6 (C, O–CH3), 107.0 (C, C-6),
109.8 (C, C-8), 113.7 (C, C 3), 115.0 (Cquat, C-9), 134.5
(C, C-7), 152.8 (Cquat, C-2), 157.3 (Cquat, C-10), 159.2
(Cquat, C-5), 160.1 (Cquat, C]O), 177.9 (Cquat, C-4); MS
(CI-MS, NH3) m/z (%): 276.1 (100) [MH]C. Elemental
analysis: C15H17NO4 Calcd: C, 65.44; H, 6.22; N, 5.09.
Found: C, 65.40; H, 6.00; N, 4.96.
Mp 240 8CC; IR (KBr): n~ (cmK1)Z3422, 3298, 3031,
3013, 2945, 1680, 1651, 1615, 1485, 828; UV/vis (CH3CN):
lmax (nm) (log 3)Z205 (4.42), 248 (4.34), 333 (3.54); H
NMR (300 MHz, DMSO): d (ppm)Z1.93–2.06 (m, 2H,
CH2), 3.07 (s, 9H, 3!CH3), 3.30–3.41 (m, 4H, 2!CH2),
3.87 (s, 3H, O–CH3), 6.83 (s, 1H, H-3), 7.42 (d, JZ3.1 Hz,
1H, H-5), 7.51 (dd, JZ3.1, 9.2 Hz, 1H, H-7), 7.70 (d, JZ
9.2 Hz, 1H, H-8), 9.24 (t, JZ5.9 Hz, 1H, N–H); 13C NMR
(75 MHz, DMSO): d (ppm)Z22.6 (K, CH2), 36.2 (K,
CH2), 52.1 (C, 3!CH3), 55.7 (C, O–CH3), 63.2 (K, CH2),
104.5 (C, C-5), 109.5 (C, C-3), 120.3 (C, C-8), 124.2 (C,
1
C-7), 124.3 (Cquat, C-9), 149.6 (Cquat, C-10), 155.1 (Cquat
,
,
C-2), 156.8 (Cquat, C-6), 159.2 (Cquat, C]O), 176.9 (Cquat
C-4); MS (ESI, H2O/AcN) m/z (%): 319.0 (100) [M]C.
Elemental analysis: C17H23N2O4I Calcd: C, 45.75; H, 5.19;
N, 6.28. Found: C, 45.40; H, 5.14; N, 6.51. HRMS
(C17H23N2O4)C Calcd: 319.1658. Found: 319.1660G
0.76 ppm.
4.6.22. 5-Methoxy-4-oxo-4H-chromene-2-carboxylic
acid (3-dimethylamino-propyl)-amide (14c). Ethyl-5-
methoxy-4-oxo-4H-chromene-2-carboxylate (620 mg,
2.5 mmol) and 3-dimethylaminopropylamine (766 mg,
7.5 mmol) were dissolved in dichloromethane (10 ml) and
the reaction mixture was refluxed for 1 h. The solvent was
evaporated, glacial acetic acid (10 ml) was added and the
solution allowed to stir at 70 8C for 10 min. The mixture was
added to ice water and extracted with ethyl acetate. The
aqueous layer was neutralised with sodium hydrogen
carbonate and extracted with ethyl acetate. The aqueous
layer was made basic with sodium carbonate and extracted
with ethyl acetate. The organic layer was dried over Na2SO4
and evaporated to give a yellow solid (627 mg, 2.1 mmol,
83%).
4.6.20. Ethyl-5-methoxy-4-oxo-4H-chromene-2-car-
boxylate (12c).37 Sodium (1.49 g, 65 mmol) was dissolved
in absolute ethanol (100 ml). Diethyloxalate (5.12 g,
35 mmol) and 2-hydroxy-6-methoxyacetophenone (2.49 g,
15 mmol) were dissolved in absolute ethanol (10 ml) and
added to the sodium ethanolate solution. The solution was
allowed to reflux for 1 h. Concentrated HCl was added
dropwise until the reaction was acidic and a white
precipitate formed. The white precipitate was filtered off
and the yellow solution concentrated to a slurry. The slurry
was extracted with ethyl acetate, dried over Na2SO4 and
evaporated to give a light yellow solid. The solid was
recrystallised from methanol/diisopropylether (2:1) to yield
a yellow solid (2.99 g, 12.1 mmol, 80%).
Mp 87–88 8C; IR (KBr): n~ (cmK1)Z3420, 3312, 3080,
2955, 1650, 1603, 798; H NMR (300 MHz, DMSO): d
1
Mp 124 8C; IR (KBr): n~ (cmK1)Z3433, 3084, 2988, 2844,
1728, 1659, 1507, 1478, 1269, 800; UV/vis (MeOH): lmax
(ppm)Z1.67 (p, JZ6.9 Hz, 2H, CH2), 2.15 (s, 6H, 2!CH3),
2.27 (t, JZ6.9 Hz, 2H, CH2), 3.31 (dd, JZ6.9, 13.3 Hz, 2H,

7376
T. Walenzyk et al. / Tetrahedron 61 (2005) 7366–7377
10. Cos, P.; Ying, L.; Calomme, M.; Hu, J. P.; Cimanga, K.; Van
Poel, B.; Pieters, L.; Vlietnck, A. J.; Vanden Berghe, D. J. Nat.
Prod. 1998, 61, 71.
CH2), 3.86 (s, 3H, O–CH3), 6.61 (s, 1H, H-3), 7.02 (d, JZ
8.4 Hz, 1H, H-6), 7.20 (dd, JZ0.7, 8.4 Hz, 1H, H-8), 7.75 (t,
JZ8.4 Hz, 1H, H-7), 9.17 (t, JZ5.6 Hz, 1H, N–H); 13C
NMR (75 MHz, DMSO): d (ppm)Z26.4 (K, CH2), 37.9 (K,
CH2), 45.0 (C, 2!CH3), 56.0 (C, O–CH3), 56.8 (K, CH2),
107.4 (C, C-6), 109.9 (C, C-8), 111.8 (C, C-3), 114.0
(Cquat, C-9), 134.9 (C, C-7), 153.3 (Cquat, C-2), 156.9
(Cquat, C-10), 158.7 (Cquat, C-5), 159.1 (Cquat, C]O), 176.4
(Cquat, C-4); MS (CI-MS, NH3) m/z (%): 305.2 (100)
[MH]C. HRMS (C16H20N2O4)C% Calcd: 304.1424. Found:
304.1425G1.1 ppm.
11. Williams, R. J.; Spencer, J. P. E.; Rice-Evans, C. Free Radical
Biol. Med. 2004, 36, 838.
12. Rice-Evans, C. Curr. Med. Chem. 2001, 8, 797. Rice-Evans,
C.; Miller, N. J.; Paganga, G. Free Radic. Biol. Med. 1996, 20,
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4.6.23. {3-[(5-Methoxy-4-oxo-4H-chromene-2-carbonyl)-
amino]-propyl}-trimethyl-ammonium iodide (15c). 5-
Methoxy-4-oxo-4H-chromene-2-carboxylic acid (3-
dimethylamino-propyl)-amide (456 mg, 1.5 mmol) was
dissolved in chloroform (10 ml), iodomethane (284 mg,
2 mmol) was added and the reaction mixture was allowed to
stir at room temperature for 1 h. The solution was heated to
reflux for 10 min, the formed precipitate filtered off and
washed with chloroform. The precipitate was dried yielding
a white solid (625 mg, 1.4 mmol, 93%).
14. Shirley, B. W. Trends Plant Sci. 1996, 31, 377.
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18. Tolgyesi, E. Cosmet. Toiletr. 1983, 98, 29.
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Mp 240 8CC; IR (KBr): n~ (cmK1)Z3433, 3244, 3018,
2940, 1683, 1650, 1602, 1475, 802; UV/vis (CH3CN): lmax
(nm) (log 3)Z242 (4.25), 319 (3.53); H NMR (300 MHz,
DMSO): d (ppm)Z1.92–2.04 (m, 2H, CH2), 3.06 (s, 9H,
3!CH3), 3.30–3.41 (m, 4H, 2!CH2), 3.87 (s, 3H, O–CH3),
6.65 (s, 1H, H-3), 7.04 (d, JZ8.4 Hz, 1H, H-6), 7.23 (dd,
JZ0.7, 8.4 Hz, 1H, H-8), 7.77 (t, JZ8.4 Hz, 1H, H-7), 9.17
(t, JZ5.9 Hz, 1H, N–H); 13C NMR (75 MHz, DMSO): d
(ppm)Z22.6 (K, CH2), 36.2 (K, CH2), 52.1 (C, 3!CH3),
56.1 (C, O–CH3), 63.2 (K, CH2), 107.5 (C, C-6), 109.9
(C, C-8), 112.0 (C, C-3), 114.0 (Cquat, C-9), 135.0 (C,
20. Bantick, J. R.; Cairns, H.; Chambers, A.; Hazard, R.; King, J.;
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1
´ ´ ´ ˇ ´
22. Amic, D.; Davidovic-Amic, D.; Beslo, D.; Trinajstic, N.
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1921. Chiba, P.; Holzer, W.; Landau, M.; Bechmann, G.;
Lorenz, K.; Plagens, B.; Hitzler, M.; Richter, E.; Ecker, G.
C-7), 153.1 (Cquat, C-2), 156.9 (Cquat, C-10), 159.1 (Cquat
,
C-5), 159.2 (Cquat, C]O), 176.3 (Cquat, C-4); MS ESI, H2O/
AcN) m/z (%): 319.0 (100) [M]C. HRMS (C17H23N2O4)C
Calcd: 319.1658. Found: 319.1660G1.02 ppm.
´
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´
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chromone derivatives see: Horton, D. A.; Bourne, G. T.;
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27. Wortmann, F.-J.; Gotsche, M.; Schmidt-Lewerku¨hne, H. Int.
J. Cosmet. Sci. 2004, 26, 61.
4. Hadjeri, M.; Barbier, M.; Ronot, X.; Mariotte, A.-M.;
Boumendjel, A.; Boutonnat, J. J. Med. Chem. 2003, 46, 2125.
5. Ellis, G. P.; Barker, G. Prog. Med. Chem. 1972, 9, 65.
6. Beecher, G. R. J. Nutr. 2003, 133, 3248S. Hoult, J. R. S.;
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28. Kelch, A.; Wessel, S.; Will, T.; Hintze, U.; Wepf, R.;
Wiesendanger, R. J. Microsc. 2000, 200, 179.
29. The compound was dissolved in ethanol/water (70:30),
commercially available, washed, sterile human hair was
added and allowed to stir at room temperature for 1 h.
Samples (100 ml) were taken at 0 min (before the addition of
the hair), 5, 15 and 60 min and UV absorption was measured.
Parallel to this, samples were taken from a solution containing
only hair (and no active substance) and used as a reference. No
9. Hirano, R.; Sasamoto, W.; Matsumoto, A.; Itakura, H.;
Igarashi, O.; Kondo, K. J. Nutr. Sci. Vitaminol. 2001, 47, 357.

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7377
changes in UV absorption within experimental error were
noted, regardless of substance tested or hair type (brown or
bleached hair). After 60 min the hair was filtered and washed
three times with fresh solvent. The hair sample was dried
overnight at 40 8C and 200 mbar, placed into a crucible
containing liquid nitrogen and ground to a fine powder. Due to
the small quantities of substance on the hair, IR analysis of the
ground sample could not confirm the presence of the substance
when compared to the reference (for neither brown nor
bleached hair).
32. The antioxidant results will be published elsewhere (patent
pending).
33. Jovanovic, S. V.; Steenken, S.; Tosic, M.; Marjanovic, B.;
Simic, M. G. J. Am. Chem. Soc. 1994, 116, 4846.
34. Speiser, B. Chemie in unsere Zeit 1981, 15, 62. Heinze, J.
Angew. Chem., Int. Ed. Engl. 1984, 96, 823.
¨
¨
35. Hu¨nig, S.; Markl, G.; Sauer, J. Einfuhrung in die apparativen
methoden in der organischen chemie, 2nd ed.; Wu¨rzburg:
Regensburg, 1994. Author Collective Organikum, 17th ed.;
VEB Deutscher Verlag der Wissenschaften: Berlin, 1988.
36. Hair was bought from Kerling International Haarfabrik
GmbH—bleached European hair (washed) and natural light-
middle brown European hair (washed). The hair was cut into
0.4–0.7 cm pieces prior to use.
30. A sample of the treated hair (bleached) and the corresponding
reference sample were analysed using MALDI-MS. Here a
definite peak at MC can be seen, when compared to the
reference sample.
31. Hubbard, D. L.; Wilkins, D. G.; Rollins, D. E. Drug Metab.
Dispos. 2000, 28, 1464. Haasnoot, W.; Stouten, P.; Schilt, R.;
Hooijerink, D. Analyst 1998, 123, 2707. Nielen, M. W. F.;
Hooijerink, H.; Essers, M. L.; Lasaroms, J. J. P.; van Bennekom,
E. O.; Brouwer, L. Anal. Chim. Acta 2003, 483, 11.
37. Has been previously synthesised: Ellis, G. P.; Shaw, D. J. Med.
Chem. 1972, 15, 865.
38. Has been previously synthesised: Fiton, A. O.; Hatton, B. T.
J. Chem. Soc. C: Org. 1970, 18, 2609.