Synthesis of prenylated benzaldehydes and their use in the synthesis of analogues of licochalcone A

Article abstract of DOI:10.1016/j.ejmech.2004.07.004

In this paper, a general applicable synthesis of prenylated aromatic compounds exemplified by prenylated benzaldehydes starting from readily available acetophenones is described. The synthesized benzaldehydes are used to prepare a number of novel analogue

Full text of DOI:10.1016/j.ejmech.2004.07.004

European Journal of Medicinal Chemistry 39 (2004) 993–1000
www.elsevier.com/locate/ejmech
Short communication
Synthesis of prenylated benzaldehydes and their use in the synthesis
of analogues of licochalcone A
Hasse Kromann 1, Mogens Larsen 2, Thomas Boesen 1, Kristian Schønning,
Simon Feldbæk Nielsen * ,3
Lica Pharmaceuticals A/S, Symbion Science Park, Fruebjergvej 3, DK-2100 Copenhagen, Denmark
Received 6 May 2004; received in revised form 19 July 2004; accepted 30 July 2004
Available online 21 September 2004
Abstract
In this paper, a general applicable synthesis of prenylated aromatic compounds exemplified by prenylated benzaldehydes starting from
readily available acetophenones is described. The synthesized benzaldehydes are used to prepare a number of novel analogues of Licochalcone
A, a known antibacterial compound, and for the exploration of the pharmacophoric elements that are essential for the antibacterial activity. It
is shown that the hydroxyl group in the A ring is essential for the activity and that the hydroxyl group in the B ring has no influence on the
antibacterial effect of Licochalcone A. Furthermore, it is shown that the prenyl group at the position 5 of the B ring also has a dominating
influence on the activity. This aliphatic group can be replaced by other lipophilic long chained substituents in order to maintain the activity.
© 2004 Elsevier SAS. All rights reserved.
1. Introduction
The structure–activity relationship analysis of this type of
compounds has however been complicated by the difficult
accessible prenylated starting materials. Total synthesis of
e.g. LicochalconeA, has been performed by various Claisen-
type rearrangements of corresponding isoprenyloxy com-
pounds (Scheme 1) [8]. The conditions under which these
reactions have been performed are often very harsh, using
high pressure and elevated temperature. In addition, the syn-
thesis is limited to compounds having hydroxyl groups in a
favorable position in order for the rearrangement to occur
with the desired regioselectivity [9].
A large number of naturally occurring compounds contain
prenylated aromatic rings as an important part of their struc-
ture. These compounds are in many cases biological active
and are therefore interesting as potential drug candidates.
Examples of this type of compounds are the antibacterial
[1,2] oxygenated chalcone Licochalcone A (1) isolated from
the root of Chinese liquorice [3], the cytotoxic [4] Kazinol K
(2) isolated from the root bark of Broussonetia kazinoki [5]
and the antioxidant [6] Garciniaxanthone A (3) isolated from
heartwood of Garcinia subelliptica [7] (Chart 1).
In this paper, we describe a general applicable synthesis of
prenylated aromatic compounds exemplified by prenylated
benzaldehydes. This synthetic strategy is of general use,
starting from readily available acetophenones. The synthesi-
zed benzaldehydes are used to prepare a number of novel
analogues of Licochalcone A, which are used for the explo-
* Corresponding author. Tel.: +45-4494-5888.
E-mail address: sfn@licapharma.com (S.F. Nielsen).
1 Present address. MedChem Aps., Copenhagen, DK-2100, Denmark
2 Present address. H. Lundbeck A/S., Valby, DK-2500, Denmark
3 Present address. LEO Pharma., Ballerup, DK-2750, Denmark
0223-5234/$ - see front matter © 2004 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2004.07.004

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H. Kromann et al. / European Journal of Medicinal Chemistry 39 (2004) 993–1000
Chart 1. Chemical structures of Licochalcone A, Kazinol K, Garciniaxanthone A.
Scheme 1. Synthesis of Licochalcone A by Claisen rearrangement.
ration of the pharmacophoric elements that are essential for
the antibacterial activity.
the tetrahydropyranyl ether (THP) 16 [16] yielding chalco-
nes 18–19 (Scheme 3, RouteA). 4′-Dehydroxy chalcone (21)
was synthesized in 1.5 M solution of HCl in absolute ethanol
(Scheme 3, Route B).
2. Results and discussion
Compounds 22–25 were prepared by methylation directly
on Licochalcone A using methyliodide under basic condi-
tions (Scheme 4). It has previously been described that the
4′-hydroxy group in the A ring of Licochalcone A is more
readily alkylated than the 4-hydroxy group in the B ring,
probably due to less sterical hindrance of the former [17].
The synthesis of compound 22 takes advantage of this fact,
using 1.2 equivalents methyl iodide. If a large excess of
methyl iodide is used alkylation of the hydroxyl groups in
both the A- and B rings is achieved yielding compound 23.
Compound 25 was prepared by THP-protection of the 4′-
hydroxy group in the A ring (Compound 24) followed by
methylation of the 4-hydroxy group in the B ring and subse-
quent cleavage of the THP-ether under acidic conditions.
The compounds shown in Table 2 were prepared as pre-
viously described [16,18,19].
2.1. Chemistry
The 4-chloro-5-(1,1-dimethyl-allyl)-2-methoxy-benzal-
dehyde 14 was prepared in six steps starting from 2′-chloro-
4′-methoxyacetophenone 4 as shown in Scheme 2. Reaction
of 4 with tosylmethylisocyanide under basic conditions gave
the nitrile 5, which was methylated in a-position with methy-
liodide resulting in 6. Bromination of 6 with N-bromo-
succinimide in trifluoroacetic acid gave 8, which was redu-
ced by DIBAL-H to yield the aldehyde 10. Subsequent
Wittig-reaction using methyltriphenylphosphonium bromide
gave the allylic compound 12 that after treatment with
n-BuLi and DMF gave the desired benzaldehyde 14.
The 5-(1,1-dimethyl-allyl)-2-methoxy benzaldehyde 15
was prepared from the nitrile 7 [10] (Scheme 2). Compound
7 was methylated using methyliodide and NaH. The fol-
lowing steps were equivalent to the steps used in the prepa-
ration of compound 14.
2.2. In vitro activity
Tables 1 and 2 summarize the antibacterial activity of the
synthesized chalcones, expressed in terms of antibacterial
minimum inhibitory concentrations (MIC) against a Gram-
positive bacteria strain—Staphylococus aureus.
Claisen-Schmidt condensations using hydroxy acetophe-
nones have been described in the literature, using either basic
[11,12] or acidic [13–15] catalysis. We obtained the best
results when the hydroxy acetophenones were protected as

H. Kromann et al. / European Journal of Medicinal Chemistry 39 (2004) 993–1000
995
Scheme 2
. Synthesis of prenylated benzaldehydes. Reagents and conditions: (a) Tosylmethylisocyanide, t-BuOK, DME, t-BuOH; (b) CH3I, NaH, DMF; (c)
NBS, TFA, rt.; (d) DIBAL-H, THF; (e) Methyl triphenylphosphonium bromide, n-BuLi, THF; (f) (i): n-BuLi, THF, –78 °C, (ii): DMF.
When the lipophilic prenyl group is removed (compound
27 [18]), a total loss of activity is observed (Table 2). Com-
pound 26 [19] in which only the two hydroxyl groups are
remaining is also inactive, in accordance with the results
above. If the prenyl group is exchanged by a propyl group
(compound 28 [16]) a moderate antibacterial effect is obser-
ved. The introduction of the longer hexyl group (compound
29 [16]) results in a compound that is more potent than
Licochalcone A. When comparing ClogP with the antibacte-
rial activity of the compounds (Table 2), a clear correlation
between lipophilicity and antibacterial activity, is seen.
These findings are in accordance with the findings by Hara-
guchi et al. [23] which reported that the presence of the
hydrophobic prenyl group is important for the antibacterial
activity of naturally occurring retrochalcones, isolated from
G. Inflate.
Scheme 3. Claisen–Schmidt condensation. Reagents and conditions: (a)
RouteA: (i) 0.1 eq. NaOH, prenylated benzaldehyde, EtOH, rt. (ii) 2 N HCl;
(b) Route B: 1.5 M HCl in EtOH, prenylated benzaldehyde, rt.
Methylation of the hydroxyl group in the A ring of Lico-
chalcone A (compound 22) and synthesis of the 4′-
dehydroxy analogue (compound 21) show that the free hy-
droxyl group in position 4′ of the A ring is necessary for the
antibacterial activity of Licochalcone A. On the other hand,
no change in activity is observed when the hydroxyl group in
the 4-position of the B ring is removed (compound 18),
blocked by a methyl (compound 25), or replaced by a chlo-
rine (compound 19). Removal of both hydroxyl groups (com-
pound 20) or blockage of both hydroxyl groups by methyla-
tion (compound 23) eliminates the activity completely in
accordance with the observations above.
In this paper, the results show that the lipophilic character
of Licochalcone A is essential for the antibacterial activity.
Furthermore, it is shown that the prenyl group in position
5 can be replaced by other aliphatic groups, if they mimic the
lipophilic character of it.
3. Conclusion
In this article, we described the synthesis of novel preny-
lated benzaldehydes from readily available acetophenones.

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H. Kromann et al. / European Journal of Medicinal Chemistry 39 (2004) 993–1000
Table 1
The prenylated benzaldehydes were used to identify the
pharmacophoric elements that are responsible for the anti-
bacterial activity of Licochalcone A. It was shown that the
hydroxyl group at position 4′ of the A ring was essential for
the activity. On the other hand, the hydroxyl group at position
4 of the B ring has no effect on the antibacterial activity of
Licochalcone A. Furthermore it was shown that the prenyl
group at position 5 of the B ring has also a dominating
influence on the activity. The aliphatic group can be replaced
by other lipophilic long chained aliphatic substituents. It is
believed that the strong lipophilic character of the molecule
plays an essential role in the antibacterial effect.
In vitro antibacterial activity of prepared analogues of Licochalcone A
(MIC, µM). Each value represents the mean of three experiments
Compound
R1
R2
MIC (µm) S. aureus
ATCC29213
1
18
25
22
19
20
21
OH
OH
OH
OCH3
OH
H
OH
H
20
20
OCH3
OH
Cl
20
>300
10
4. Experimental section
H
>300
>300
2
H
OH
4.1. Chemistry
Ciprofloxacin [20]
Linezolid [21,22]
2
Thin-layer chromatography (TLC) was performed on si-
lica gel F254 plates (Merck). All compounds were detected
using UV light. 1H-NMR and 13C spectra were recorded on a
400 MHz Varian Gemini spectrometer or a Bruker AC-300 F
spectrometer, using CDCl3 or DMSO-d6 as the solvent. Che-
mical shifts are given in ppm (d) using TMS as internal
standard, and coupling constants (J) are given in Hertz. Mass
spectra (GC-MS) were recorded using a Agilent Technolo-
gies 6890N and were all >95% pure. Mass spectra (LC-MS)
were recorded using a Waters Alliance HPLC-system cou-
pled to a Quatro Micro triple quadropol mass spectrometer
(Micromass) operating in positive (ESI) mode. Separation
was performed on a XTerra MS C18 column (150 × 2.1 mm
I.D., 3,5 µm particle size). Purity of the final products (>95%)
was determined using a Waters Alliance 2690 separation
module and Waters 996 PDA-detector. Separation was per-
formed on a XTerra MS C18 column (150 × 2.1 mm I.D.,
3.5 µm particle size) using 40% mobile phaseA (acetonitrile)
and 60% mobile phase B (10 mM ammonium acetate pH
9.5). During the first 20 min, the mobile phase was changed
Table 2
In vitro antibacterial activity of selected analogues of LicochalconeA (MIC,
µM). Each value represents the mean of three experiments
Compound
R1
R2
ClogP
MIC (µm) S. aureus
ATCC29213
1
OCH3
H
Prenyl
H
4.9
3.1
3.2
4.7
6.3
20
26 [19]
27 [18]
28 [16]
29 [16]
>300
>300
75
OCH3
OCH3
OCH3
H
Propyl
Hexyl
10
Scheme 4
. Synthesis of methylated analogues of LicochalconeA. Reagents and conditions: (a) 1.2 eq. CH3I, 2.0 eq. NaOH, DMSO, rt; (b) 2.4 eq. CH3I, 2.0 eq.
NaOH, DMSO, rt.; (c) 3,4-dihydro-2H-pyran, pyridinium p-toluenesulfonate; (d) i: CH3I, NaOH, DMSO, rt, ii: HCl (ag).

H. Kromann et al. / European Journal of Medicinal Chemistry 39 (2004) 993–1000
997
via a linear gradient to 90%A and 10% B. The accurate mass
measurements were obtained on a VG AutoSpec mass spec-
trometer (Micromass, Manchester, UK) equipped with an EI
source. The instrument was operated at a resolution of
10000 FWHM.
was stirred vigorously for 1 h. The crude product was filtered
off and recrystallized from boiling MeOH. The pure product
was isolated as white needles. Yield: 13 g (54%). GC-MS:
289 (M). 1H-NMR (DMSO-d6): d 7.56 (s, 1H), 7.23 (s, 1H),
3.84 (s, 3H), 1.70 (s, 6H).
Column chromatography (CC) was performed on Merck
silica gel 60 (0.063–0.200 mm). All solvents and reagents
were obtained from Fluka or Aldrich and used without fur-
ther purification except DMF and THF, which was stored
over 3 Å molecular sieves. Compound 26–29 (>95% pure)
were prepared as described previously [24,25].
4.5. 2-(3-Bromo-4-methoxyphenyl)-2-methylpropionitrile
(9)
Same procedure as described for compound 8. Recrystal-
lisation from n-heptane gave 9 as white needles.Yield: 19.3 g
1
(76%). GC-MS: 254 (M). H NMR (DMSO-d6): d 7.68 (d,
4.2. 2-(2-Chloro-4-methoxyphenyl)propionitrile (5)
J = 2.5 Hz, 1H), 7.50 (dd, J = 8.7 Hz, J = 2.4 Hz, 1H), 7.16 (d,
J = 8.8 Hz, 1H), 3.86 (s, 3H), 1.70 (s, 6H).
A solution of 2-chloro-4-methoxyacetophenone (4)
(18.5 g, 0.10 mol) and tosylmethylisocyanide (TOSMIC,
21.5 g, 0.11 mol) in dry DME (100 ml) was cooled to –10 °C.
A solution of t-BuOK (22.4 g, 0.20 mol) in dry t-BuOH
(250 ml) was added slowly keeping the temperature below
5 °C. The homogeneous orange solution was stirred for 2 h at
0 °C and 1 h at 25 °C. The resulting suspension was evapo-
rated to a slurry. Water (200 ml) was added and extracted
with Et2O (3 × 150 ml). The organic phase was dried
(Na2SO4) and the solvent was removed under reduced pres-
sure leaving an orange oil. Yield: 19 g (97%). GC-MS: 196
(M). 1H-NMR (DMSO-d6): d 7.49 (d, J = 8.7 Hz, 1H), 7.12
(d, J = 2.7 Hz, 1H), 7.02 (dd, J = 8.7 Hz, J = 2.7 Hz, 1H), 4.42
(q, J = 7.2 Hz, 1H), 3.80 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H).
4.6. 2-(5-Bromo-2-chloro-4-methoxyphenyl)-2-methyl-
propionaldehyde (10)
A solution of 2-(5-bromo-2-chloro-4-methoxyphenyl)-2-
methylpropionitrile (8) (13.0 g, 0.045 mol) in dry THF
(80 ml) was cooled to –10 °C under argon. DIBAL-H (1 M in
THF, 100 ml, 0.10 mol) was added keeping the temperature
below 0 °C. The mixture was stirred for 30 min at 0 °C and
then 2 h at 25 °C. The clear solution was carefully poured into
icecold HCl (2 M, 100 ml). THF was removed under reduced
pressure. The aqueous phase was cooled and the crude pro-
duct was filtered off and recrystallized from MeOH. GC-MS:
292 (M).Yield: 7.8 g (59%). 1H-NMR (DMSO-d6): d 9.61 (s,
1H), 7.68 (s, 1H), 7.27 (s, 1H), 3.89 (s, 3H), 1.40 (s, 6H).
4.3. 2-(2-Chloro-4-methoxyphenyl)-2-methylpropionitrile
(6)
4.7. 2-(3-Bromo-4-methoxyphenyl)-2-methyl-
propionaldehyde (11)
A solution of 2-(2-chloro-4-methoxyphenyl)propionitrile
(5) (19 g, 0.097 mol) and methyl iodide (7 ml, 0.11 mol) in
dry DMF (100 ml) was flushed with argon for 2 min and
cooled to 0 °C. Sodium hydride (60% oil susp., 4.4 g,
0.11 mol) was added in small portions. The thick suspension
was stirred for another 18 h at 25 °C and then poured into
water (300 ml) and extracted with Et2O (3 × 100 ml). The
organic phase was dried (Na2SO4) and the solvent was remo-
ved under reduced pressure leaving yellow oil, which was
distilled. b.p. 103–106 °C/0.06 mbar, clear oil that solidifies
Same procedure as described for compound 10. THF was
removed under reduced pressure to give clear oil. The oil was
distilled (b.p. 114–130 °C at 4.3 × 10–3 mbar) Yield: 7.40 g
(58%). GC-MS: 257 (M). 1H-NMR (CDCl3): d 9.44 (s, 1H),
7.45 (d, J = 2.3 Hz, 1H), 7.15 (dd, J = 8.6 Hz, J = 2.4 Hz, 1H),
6.90 (d, J = 8.7 Hz, 1H), 3.89 (s, 3H), 1.43 (s, 6H).
4.8. 1-Bromo-4-chloro-5-(1,1-dimethylallyl)-
2-methoxybenzene (12)
1
on standing. Yield: 17.5 g (83%). GC-MS: 210 (M). H-
NMR (DMSO-d6): d 7.43 (d, J = 8.9 Hz, 1H), 7.13 (d,
J = 2.9 Hz, 1H), 6.98 (dd, J = 8.9 Hz, J = 2.8 Hz, 1H), 3.80 (s,
3H), 1.77 (s, 6H).
A suspension of methyltriphenylphosphonium bromide
(11.4 g, 0.032 mol) in dry THF (100 ml) was cooled to 0 °C
under argon. n-BuLi (2.5 M, 12 ml, 0.030 mol) was added
slowly. The resulting clear orange solution of the ylide was
stirred for another 15 min at 0 °C. 2-(3-Bromo-4-
methoxyphenyl)-2-methylpropionaldehyde (10) (7.8 g,
0.027 mol) was dissolved in dry THF (50 ml) and added to
ylide solution. The mixture was stirred for 3 h at 25 °C and
the resulting suspension was quenched with MeOH (10 ml).
The solvent was removed under reduced pressure and the
crude product was purified by CC using n-heptane as eluent.
4.4. 2-(5-Bromo-2-chloro-4-methoxyphenyl)-2-methyl-
propionitrile (8)
A solution of 2-(2-chloro-4-methoxyphenyl)-2-methyl-
propionitrile (6) (17.5 g, 0.084 mol) in TFA (100 ml) was
cooled to 0 °C. N-bromosuccinimide (14.9 g, 0.084 mol) was
added in small portions keeping the temperature below 5 °C.
The orange solution was stirred for 2 h at 25 °C and evapo-
rated to dryness. Water (200 ml) was added and the mixture
1
Yield: 3.92 g (50%) as a clear oil. GC-MS: 290 (M). H-
NMR (DMSO-d6): d 7.55 (s, 1H), 7.14 (s, 1H), 6.05 (dd,

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H. Kromann et al. / European Journal of Medicinal Chemistry 39 (2004) 993–1000
J = 17.5 Hz, J = 10.5 Hz, 1H), 5.04 (dd, J = 10.5 Hz,
J = 1.2 Hz, 1H), 4.92 (dd, J = 9.3 Hz, J = 0.9 Hz, 1H), 3.87 (s,
3H), 1.45 (s, 6H).
and the solution was extracted with EtOAc (3 × 20 ml). The
organic phase was dried (Na2SO4) and concentrated under
reduced pressure. The crude product was purified by CC
using EtOAc/n-heptane as eluent.
4.9. 2-Bromo-4-(1,1-dimethylallyl)-1-methoxybenzene (13)
Same procedure as described for compound 12. Yield:
4.13. 3-[5-(1,1-Dimethylallyl)-2-methoxyphenyl]-1-
(4-hydroxyphenyl)-propenone (18)
1
3.1 g (84%) as a clear oil. GC-MS: 255 (M). H-NMR
(CDCl3): d 7.50 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.6 Hz,
J = 2.4 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 5.97 (dd,
J = 17.7 Hz, J = 10.3 Hz, 1H), 5.06 (dd, J = 17.7 Hz,
J = 1.4 Hz, 1H), 5.02 (dd, J = 10.4 Hz, J = 1.2 Hz, 1H), 3.87
(s, 3H), 1.44 (s, 6H).
General procedure A gave the desired product 18 as yel-
low crystals. Yield: 12%. LC-MS: 323.4 (M + 1). 1H-NMR
(DMSO-d6): d 10.40 (bs, 1H), 8.03 (d, J = 7.0 Hz, 2H), 7.98
(d, J = 15.8 Hz, 1H), 7.82 (d, J = 15.4 Hz, 1H), 7.79 (s, 1H),
7.36 (dd, J = 8.7 Hz, J = 2.5 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H),
6.91 (d, J = 8.7 Hz, 2H), 6.08 (dd, J = 17.7 Hz, J = 10.2 Hz,
1H), 5.07–5.01 (m, 2H), 3.87 (s, 3H), 1.41 (s, 6H). 13C-NMR
(CDCl3): 190.4; 160.5; 157.2; 147.9; 140.9; 131.3; 131.1;
129.6; 127.6; 123.5; 122.8; 115.6; 111.1; 111.0; 55.7; 40.6;
28.4. HRMS (C21H22O3) calculated. 322.1569; found:
322.1580.
4.10. 4-Chloro-5-(1,1-dimethylallyl)-2-methoxy-
benzaldehyde (14)
A solution of 1-bromo-4-chloro-5-(1,1-dimethylallyl)-2-
methoxybenzene (12) (3.9 g, 0.014 mol) in dry THF (30 ml)
was cooled to –78 °C under argon. n-BuLi (2.5 M, 6 ml,
0.0145 mol) was added keeping the temperature below
–70 °C. The yellow mixture was stirred for another 15 min
and quenched with dry DMF (1.2 ml, 0.015 mol). The coo-
ling bath was removed and the mixture was allowed to warm
to 25 °C. Saturated NaHCO3 (30 ml) was added and the
solution was extracted with EtOAc (3 × 50 ml). The organic
phase was dried (Na2SO4) and evaporated to dryness. The
crude product was recrystallized from MeOH. Yield: 3.00 g
(93%). GC-MS: 239 (M). 1H-NMR (DMSO-d6): d 10.30 (s,
1H), 7.80 (s, 1H), 7.30 (s, 1H), 6.08 (dd, J = 17.3 Hz,
J = 10.5 Hz, 1H), 5.06 (dd, J = 10.5 Hz, J = 1.2 Hz, 1H), 4.91
(dd, J = 17.3 Hz, J = 0.9 Hz, 1H), 3.93 (s, 3H), 1.49 (s, 6H).
4.14. 3-[4-Chloro-5-(1,1-dimethylallyl)-2-methoxyphenyl]-
1-(4-hydroxyphenyl)-propenone (19)
General procedure A gave the desired product 19 as yel-
low crystals. Yield: 42%. LC-MS: 357.8 (M + 1). 1H-NMR
(DMSO-d6): d 10.41 (bs, 1H), 8.03 (d, J = 8.7 Hz, 2H),
7.88–7.83 (m, 3H), 7.14 (s, 1H), 6.91 (d, J = 8.9 Hz, 2H),
6.09 (dd, J = 17.5 Hz, J = 8.7 Hz, 1H), 5.03 (dd, J = 10.7 Hz,
J = 1.3 Hz, 1H), 4.93 (dd, J = 17.6 Hz, J = 1.1 Hz, 2H), 3.92
(s, 3H), 1.53 (s, 6H). 13C (DMSO-d6): 196.6; 162.1; 156.8;
146.7; 136.8; 136.6; 135.7; 131.0; 130.2; 129.1; 122.7;
121.7; 115.3; 114.9; 111.1; 56.1; 55.5; 40.9; 28.0. HRMS
(C21H21ClO3) calculated: 356.1179; found: 356.1183.
4.11. 5-(1,1-Dimethylallyl)-2-methoxybenzaldehyde (15)
4.15. 3-[5-(1,1-Dimethylallyl)-2-methoxyphenyl]-1-phenyl-
propenone (20)
Same procedure as described for compound 14. Evapora-
tion of the organic phase gave yellow oil.Yield: 2.31 g (94%).
GC-MS: 204 (M). 1H-NMR (CDCl3): d 10.48 (s, 1H), 7.84
(d, J = 2.5 Hz, 1H), 7.55 (dd, J = 8.8 Hz, J = 2.6 Hz, 1H), 6.94
(d, J = 8.7 Hz, 1H), 6.00 (dd, J = 17.7 Hz, J = 10.2 Hz, 1H),
5.05–5.01 (m, 2H), 3.93 (s, 3H), 1.41 (s, 6H).
General procedure A gave the desired product 20 as yel-
low oil. Yield: 51%. LC-MS: 307.4 (M + 1). 1H-NMR
(CDCl3): d 8.08 (d, J = 16.1 Hz, 1H), 8.05–8.02 (m, 2H), 7.64
(d, J = 16.1 Hz, 1H), 7.60–7.50 (m, 4H), 7.38 (dd, J = 8.6 Hz,
J = 2.4 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 6.04 (dd,
J = 17.5 Hz, J = 10.3 Hz, 1H), 5.10 (dd, J = 17.6 Hz,
J = 2.4 Hz, 2H), 5.08 (dd, J = 10.4 Hz, J = 1.4 Hz, 1H), 3.92
(s, 3H), 1.44 (s, 6H). 13C (CDCl3): 191.5; 157.2; 147.9;
141.1; 140.9; 132.4; 129.6; 129.1 (2 × C); 128.6; 128.5;
128.2; 127.8; 127.7; 123.2; 111.1; 111.0; 55.7; 40.6; 28.4;
28.1. HRMS (C21H22O2) calculated 306.1620; found:
306.1637.
4.12. General procedures for the Claisen–Schmidt
condensation
4.12.1. Route A
To a solution of acetophenone (2 mmol) and prenylated
benzaldehyde (2 mmol) in EtOH (10 ml) was added a small
NaOH pellet (50 mg). The reaction was stirred overnight at
rt. Addition of aqueous HCl (2 M, 10 ml) gave a slurry of
crystals that was filtered off.
4.16. 3-[5-(1,1-Dimethylallyl)-4-hydroxy-2-methoxy-
phenyl]-1-phenylpropenone (21)
4.12.2. Route B
A solution of acetophenone (2 mmol) and prenylated
benzaldehyde (2 mmol) in a 1.5 M solution of HCl in EtOH
(10 ml) was stirred at rt over night. Water (30 ml) was added
General procedure B gave the desired product 21 as yel-
low crystals. Yield: 16%. LC-MS: 323.4 (M + 1). 1H-NMR
(CDCl3): d 8.03–7.98 (m, 3H), 7.59–7.47 (m, 5H), 6.45 (s,

H. Kromann et al. / European Journal of Medicinal Chemistry 39 (2004) 993–1000
999
1H), 6.25 (s, 1H), 6.20 (dd, J = 17.7 Hz, J = 8.8 Hz, 1H),
5.43–5.34 (m, 2H), 3.88 (s, 3H), 1.55 (s, 6H).
were added. The reaction was stirred at rt overnight and HCl
(2M, 40 ml) was added. The aqueous solution was extracted
with CH2Cl2 (3 × 20 ml) and the combined organic phases
were dried (Na2SO4) and evaporated under reduced pressure.
The crude product was purified by CC using EtOAc/n-
heptane as eluent and recrystallized from EtOAc/n-heptane.
Yield: 180 mg (36%) as yellow crystals. LC-MS: 353.4 (M +
13C NMR (DMSO-d6): 196.5; 160.2; 148.3; 141.1; 138.2;
130.4; 129.3; 129.1; 127.3; 127.1; 127.0; 126.3; 125.1;
122.2; 111.4; 111.1; 55.4; 40.6; 28. HRMS (C21H22O3) cal-
culated 322.1569; found: 322.1578.
1
1) H-NMR (CDCl3): d 8.04 (d, J = 15.8 Hz, 1H), 7.97 (d,
4.17. 3-[5-(1,1-Dimethylallyl)-4-hydroxy-2-methoxy-
J = 8.7 Hz, 2H), 7.53 (d, J = 15.7 Hz, 1H), 7.51 (s, 1H), 6.93
(d, J = 8.6 Hz, 2H), 6.45 (s, 1H), 6.16 (dd, J = 17.4 Hz,
J = 8.6 Hz, 1H), 6.15 (bs, 1H), 4.97 (dd, J = 16.8 Hz,
J = 1.4 Hz, 1H), 4.93 (dd, J = 13.4 Hz, J = 1.3 Hz, 1H), 3.91
(s, 3H), 3.86 (s, 3H), 1.45 (s, 6H). 13C NMR (DMSO-d6):
197.2; 161.7; 161.4; 161.5; 158.6; 157.1; 155.9; 147.9;
138.2; 130.7; 130.1; 128.2; 125.8; 118.9; 114.6; 109.4; 96.7;
55.8; 55.1; 37.3; 27.3. HRMS (C22H24O4) calculated
352.1675; found: 352.1690.
phenyl]-1-(4-methoxyphenyl)-propenone (22)
To a solution of Licochalcone A (500 mg, 1.5 mmol) in
DMSO (5 ml) were added methyl iodide (110 µl, 1.8 mmol)
and NaOH (120 mg, 3.0 mmol). The reaction was stirred at rt
for 3 h and water was added (40 ml). The aqueous solution
was extracted with CH2Cl2 (3 × 20 ml) and the combined
organic phases were dried (Na2SO4) and evaporated under
reduced pressure. The crude product was purified by CC
using EtOAc/n-heptane as eluent and recrystallized from
EtOAc/n-heptane. Yield: 250 mg (50%) as yellow crystals.
LC-MS: 353.4 (M + 1). 1H-NMR (CDCl3): d 8.03 (d,
J = 9.0 Hz, 2H), 7.98 (d, J = 15.8 Hz, 1H), 7.58 (d,
J = 15.8 Hz, 1H), 7.48 (s, 1H), 7.97 (d, J = 9.0 Hz, 2H), 6.45
(s, 1H), 6.26 (s, 1H), 6.21 (dd, J = 17.8 Hz, J = 8.6 Hz, 1H),
5.37 (dd, J = 17.6 Hz, J = 1.0 Hz, 2H), 5.34 (dd, J = 10.6 Hz,
5. Determination of MIC
MIC was determined in triplicate in a microdilution assay
using MH-broth as described by NCLLS (National Commit-
tee for Clinical Laboratory Standards. Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria that Grow
Aerobically; Approved Standard—Fifth Edition. M7-
A5 NCCLS 2000). This method was modified to include
uninoculated dilution series of test compounds to facilitate
MIC determination if the test compound should precipitate.
MIC was determined as the lowest concentration of test
compound able to inhibit visible growth of bacteria.
J = 1.0 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 1.46 (s, 6H). 13
C
(CDCl3): 189.8; 163.1; 159.6; 158.2; 147.9; 140.6; 131.9;
131.0; 130.8; 128.7; 124.7; 120.6; 116.8; 113.9; 113.8;
101.3; 55.7; 55.5; 39.8; 27.4; 27.2. HRMS (C22H24O4) cal-
culated: 352.1675; found: 352.1677.
4.18. 3-[5-(1,1-Dimethylallyl)-2,4-dimethoxyphenyl]-1-
(4-methoxyphenyl)-propenone (23)
References
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2.3 eq. methyl iodide gave the desired compound as yellow
crystals. Yield: 15%. LC-MS: 367.5 (M + 1) 1H-NMR
(CDCl3): d 8.03 (d, J = 15.9 Hz, 1H), 8.02 (d, J = 9.0 Hz, 2H),
7.53 (d, J = 15.8 Hz, 1H), 7.52 (s, 1H), 6.98 (d, J = 9.0 Hz,
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110.1; 96.3; 55.7; 55.5; 55.3; 43.5; 40.1; 27.4. HRMS
(C23H26O4) calculated: 366.1831; found: 366.1810.
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