A versatile synthesis of heterocyclic analogues of neoflavonoids from enamino ketones

Article abstract of DOI:10.1055/s-0028-1088030

An efficient and versatile one-step method for the synthesis of heterocyclic analogues of neoflavonoids, such as pyrazolyl-, isoxazolyl-, pyrimidinyl-substituted 4-phenyl-2H-chromen-2-ones and fused 4-phenyl-2H,6H-pyrano[3,2-g]chromene-2,6-diones and 4-ph

Full text of DOI:10.1055/s-0028-1088030

PAPER
1279
A Versatile Synthesis of Heterocyclic Analogues of Neoflavonoids from
Enamino Ketones
H
eterocyclic Anal
i
o
k
f
N
eoflavono
t
ids fro
o
m
E
namino
r
Ketone
s
ia S. Moskvina,*a Volodymir P. Khilya,a Olexander V. Turov,a Ulrich M. Grothb
a
Kyiv National Taras Shevchenko University, Volodymyrska str. 60, Kyiv 01033, Ukraine
Fax +380(44)2351273; E-mail: V.Moskvina@gmail.com
b
Fachbereich Chemie, Universität Konstanz, Fach M-720, Universitätsstr. 10, 78457 Konstanz, Germany
Received 6 August 2008; revised 7 January 2009
It is known that enamino ketones can be used for the prep-
aration of substituted isoxazoles, pyrazoles, and pyrim-
idines.8 In each case, the cyclization reaction proceeds via
C–C–C + N–O, C–C–C + N–N, or C–C–C + N–C–N ring
Abstract: An efficient and versatile one-step method for the syn-
thesis of heterocyclic analogues of neoflavonoids, such as pyra-
zolyl-, isoxazolyl-, pyrimidinyl-substituted 4-phenyl-2H-chromen-
2-ones and fused 4-phenyl-2H,6H-pyrano[3,2-g]chromene-2,6-di-
ones and 4-phenyl-2H,10H-pyrano[2,3-f]chromene-2,10-diones, closure to yield the corresponding heterocycle. The ring
using the corresponding enamino ketones is described.
formation may proceed by two possible mechanisms dif-
fering in the order of their key steps, namely nucleophilic
attack and amine exchange reaction, which gives two re-
gioisomeric products.
Key words: heterocycles, 4-phenyl-2H-chromen-2-one, 2H-1-ben-
zopyran-2-one, neoflavone, enamino ketone, regioselectivity
Treatment of 6-acetyl-7-hydroxy-8-methyl-4-phenyl-2H-
chromen-2-one (1) and 8-acetyl-6-ethyl-7-hydroxy-4-
phenyl-2H-chromen-2-one (2) with N,N-dimethylform-
amide dimethyl acetal (DMFDMA) in refluxing toluene
gave the corresponding (dimethylamino)propenones 3
and 4 in good yields (Scheme 2). Subsequent reaction of
compounds 3 and 4 with equivalent amount of hydrazine
hydrate in absolute ethanol led to the corresponding
7-hydroxy-8-methyl-4-phenyl-6-(1H-pyrazol-3-yl)-2H-
chromen-2-one (5) and 6-ethyl-7-hydroxy-4-phenyl-8-
(1H-pyrazol-3-yl)-2H-chromen-2-one (6) in up to 50%
yields (Scheme 2). When a two- or threefold excess of the
nucleophile was used, the reaction yields increased to 80–
85%. Despite the fact that, according to the literature data,
2H-chromen-2-one derivatives are unstable in the pres-
ence of nucleophilic reagents,9 in our case the pyran ring
was not affected; this was confirmed by the presence of
characteristic 1H NMR signal of H3 at d = 6.1 in the spec-
Derivatives of 4-phenyl-2H-chromen-2-ones (4-phenyl-
2H-1-benzopyran-2-ones), or neoflavones, are wide-
spread in nature and possess a wide spectrum of biological
activity.1 Recent research in this field has confirmed that
compounds of this class are promising agents for medici-
nal use. For example, neoflavone derivatives act as NO in-
hibitors,2a exhibit cytotoxic2b and HIV-transcription
inhibitory2c activities, and can be used as leukotriene bio-
synthesis inhibitors.2d
On the other hand, compounds with pyrazole,3 isoxazole,4
or pyrimidine5 moieties or an annulated 4H-chromen-4-
one ring6 are of significant interest due to their diverse bi-
ological activity.7
In this paper, we wish to report a new convenient method
for the synthesis of neoflavones containing the aforemen-
tioned biogenic fragments, using the corresponding enam-
ino ketones as key intermediates (Scheme 1).
HO
O
O
Het
HO
O
O
HO
Me
O
O
Me2N
or
O
O
O
O
O
R
O
Scheme 1 Retrosynthetic analysis of heterocyclic and annulated analogues of neoflavonoids
SYNTHESIS 2009, No. 8, pp 1279–1286
x
x
.
x
x
.2
0
0
9
Advanced online publication: 25.03.2009
DOI: 10.1055/s-0028-1088030; Art ID: T13208SS
© Georg Thieme Verlag Stuttgart · New York

1280
V. S. Moskvina et al.
PAPER
R1
HO
Me
O
O
R1
R1
HO
O
O
HO
N
O
O
O
NH
N
O
1, R1 = 8-Me; 6-Ac
2, R1 = 6-C2H5; 8-Ac
5, R1 = 8-Me; 6-(pyrazol-5-yl), 81%
6, R1 = 6-Et; 8-(pyrazol-5-yl), 80%
C
d
a
11, R1 = 8-Me; 6-(isoxazol-5-yl), 79%
12, R1 = 6-Et; 8-(isoxazol-5-yl), 79%
R1
HO
O
O
b
Me2N
R1
HO
N
O
O
e
O
R2
c
N
3, R1 = 8-Me; 6-CO(CH)2NMe2, 83%
4, R1 = 6-Et; 8-CO(CH)2NMe2, 58%
14, R1 = 8-Me; 6-(pyrimidin-4-yl);
2 = NH2, up to 47%
15, R1 = 6-Et; 8-(pyrimidin-4-yl);
R1
R1
R
HO
N
O
O
HO
N
O
O
R
2 = NH2, up to 51%
16, R1 = 8-Me; 6-(pyrimidin-4-yl);
R2 = H, up to 41%
+
N
N
17, R1 = 6-Et; 8-(pyrimidin-4-yl);
Me
Me
R
2 = H, up to 45%
18, R1 = 8-Me; 6-(pyrimidin-4-yl);
2 = Me, up to 37%
19, R1 = 6-Et; 8-(pyrimidin-4-yl);
2 = Me, up to 38%
A
B
R
7, R1 = 8-Me; 6-(pyrazol-3-yl), 66%
9, R1 = 6-Et; 8-(pyrazol-3-yl), 61%
8, R1 = 8-Me; 6-(pyrazol-5-yl), 14%
10, R1 = 6-Et; 8-(pyrazol-5-yl), 11%
R
Scheme 2 Reagents and conditions: (a) DMFDMA (2 equiv), toluene, reflux, 5–7 h; (b) NH2NH2·x H2O (1–3 equiv), EtOH, reflux, 2–3 h;
(c) MeNHNH2 (1–2 equiv), EtOH, reflux, 2–3 h; (d) NH2OH (1.5 equiv) in H2O (1 mL), EtOH, reflux, 2–3 h; (e) Method A: 13a–c (1.1 equiv),
K2CO3 (1 equiv), DMF, reflux, 2–24 h; Method B: 13a–c (1.1 equiv), Na (0.4 equiv), EtOH, reflux, 20–40 h; Method C: 13a–c (1.1 equiv),
Et3N (1.5 equiv), DMF, 80 °C, 5–40 h.
trum of the final product. The two characteristic doublets (Scheme 2). Thin-layer chromatography confirms the for-
of H4¢¢ and H5¢¢ of the pyrazole ring were also present in mation of two isomeric products, two spots with different
1H NMR spectra of the compounds at d = 6.39–7.94 with Rf values were observed; one of the spots gave dark-green
3JHH = 2.0 Hz. The exchangeable NH proton peak of the coloring with alcoholic solution of iron(III) chloride,
pyrazole ring was observed at d = 13.25–13.50.
which hints at the intramolecular hydrogen bond forma-
tion,11 possible for compounds 7 and 9. The latter assump-
tion is confirmed by 1H NMR spectra of compounds 7–10.
For example, the signal of the 7-OH group of 8 and 10 was
observed at d ~ 9.5, while the corresponding signal of 7
and 9 was shifted to a lower field down to d = 11.7–12.7.
The interaction of enamino ketones with methylhydrazine
was studied using different reagent molar ratios. Litera-
ture sources describe the formation of two regioisomeric
N-methylpyrazoles:
1-methyl-1H-pyrazol-3-yl
(type A)10a–d and 1-methyl-1H-pyrazol-5-yl (type B).10e,f
To definitely differentiate between 7, 9 and 8, 10, com-
pounds 9 and 10 were studied by means of C–H (HMQC
and HMBC) correlation spectroscopy. In compound 9, the
proton signals of the NCH3 group at d = 4.05 correlate
with the signal of the C5¢¢ atom of the CH group at
d = 132.9; the corresponding NCH3 proton signals
(d = 3.67) of compound 10 correlate with a nodal C5¢¢ sig-
nal at d = 133.6.
Reaction of compounds 3 and 4 with methylhydrazine in
a molar ratio of 1:1 in absolute ethanol proceeded to give
a sole product in each case, 7-hydroxy-8-methyl-6-(1-
methyl-1H-pyrazol-3-yl)-4-phenyl-2H-chromen-2-one (7)
and 6-ethyl-7-hydroxy-8-(1-methyl-1H-pyrazol-3-yl)-4-
phenyl-2H-chromen-2-one (9) in 44–54% yields. Using a
different molar ratio of reagents, 1:2, a mixture of regioi-
someric pyrazolylneoflavones was obtained: compound 7
and 7-hydroxy-8-methyl-6-(1-methyl-1H-pyrazol-5-yl)- Compounds 7–10 were separated by column chromatog-
4-phenyl-2H-chromen-2-one (8) in a 7:3 ratio, and com- raphy and characterized.
pound 9 and 6-ethyl-7-hydroxy-8-(1-methyl-1H-pyrazol-
5-yl)-4-phenyl-2H-chromen-2-one (10) in a 7:3 ratio
Exposure of enamino ketones 3 and 4 to a small excess of
hydroxylamine hydrochloride led to corresponding 7-hy-
Synthesis 2009, No. 8, 1279–1286 © Thieme Stuttgart · New York

PAPER
Heterocyclic Analogues of Neoflavonoids from Enamino Ketones
1281
Table 1 Formation of Substituted Chromenones 14–19 by Methods A–C (Scheme 2)
Reactant
Method A:
DMF, K2CO3
Method B:
NaOEt, EtOH
Method C:
DMF, Et3N
Time (h)
2–3
Yield (%)
Time (h)
20–24
Yield (%)
Time (h)
Yield (%)
NH
⋅H2CO3
33 (14)
43 (15)
25 (14)
18 (15)
47 (14)
51 (15)
5
NH2
H2N
13a
NH
28 (16)
30 (17)
41 (16)
45 (17)
a
⋅HAc
10–12
22–24
–
–
–
24–26
34–36
H2N
H
13b
NH
24 (18)
26 (19)
37 (18)
38 (19)
a
⋅HCl
–
H2N
Me
13c
a No reaction.
droxy-6-(isoxazol-5-yl)-8-methyl-4-phenyl-2H-chromen-
portant synthetic compounds.14 Their treatment with acids
2-one (11) and 6-ethyl-7-hydroxy-8-(isoxazol-5-yl)-4- led to an intramolecular cyclization, where the phenolic
phenyl-2H-chromen-2-one (12) in up to 80%. yields The hydroxy group attacks the aminopropenone moiety
1
presence of the H3 signal in H NMR spectra of com- (Scheme 3); a similar cyclization occurred when o-hy-
pounds 11 and 12 confirms the integrity of the pyran ring; droxyenamino ketones are exposed to halogen-containing
the doublets of H3¢¢ and H4¢¢ protons of the isoxazole ring electrophiles. In the latter case, electrophile (e.g., bromine
are located in the characteristic region of d = 6.7–8.6 atom) becomes a substituent at the position 3 of the 4H-
(3JHH = 1.2 Hz).
chromen-4-one ring (Scheme 4).
Two possible ways for the cyclization of enamino ketones Refluxing the enamino ketones 3 or 4 in ethanol in the
with hydroxylamine are known from the literature, result- presence of hydrochloric acid gave 10-methyl-4-phenyl-
ing in either isoxazol-5-yl10b,12 (type C) or isoxazol-3- 2H,6H-pyrano[3,2-g]chromene-2,6-dione (20) and 6-eth-
yl10c,d (type D) substituted products. Literature sources13 yl-4-phenyl-2H,10H-pyrano[2,3-f]chromene-2,10-dione
describe a method to differentiate these isoxazole regio- (21) in quantitative yields; when the same reaction was
isomers using the chemical shift of the nearby OH group carried out in acetic acid, the yields dropped to 86–89%
1
in the 1H NMR spectra, recorded in CDCl3. The hydroxy’s (Scheme 3). The doublets in H NMR spectra at d ~ 6.3
hydrogen atom in isomers of type D forms an intramolec- and ~8.3 with 3JHH = 6.0 Hz correspond to H7 and H8 sig-
ular bond of the chelate type with the nitrogen atom of the nals for 20 and to H8 and H9 signals for 21. The 13C NMR
isoxazole ring and absorbs at d = 9.5–12.0. Conversely, signal of C2 is located at d = 160.6–160.8; C6 of 20 and
the same hydrogen atom in type C isomers cannot form C10 of 21 at d = 175.8–175.9.
such a hydrogen bond, and absorbs in the upfield region
Treatment of enamino ketones 3 and 4 with bromine in
chloroform at 0 °C gave 7-bromo-10-methyl-4-phenyl-
2H,6H-pyrano[3,2-g]chromene-2,6-dione (22) and 9-bro-
mo-6-ethyl-4-phenyl-2H,10H-pyrano[2,3-f]chromene-
(d = 6.5–8.5). The 7-OH signal of the compounds 11 and
12 is observed at d = 7.1 and 8.6, correspondingly, which
allows them to be assigned a type C structure.
Reaction of enamino ketones 3 and 4 with amidine salts 2,10-dione (23) in up to 60% yields (Scheme 4). As ex-
13a–c under different conditions (Method A: DMF, pected, the 1H NMR signal of H8 is observed in the lower
K2CO3; Method B: NaOEt, EtOH; Method C: DMF, field at d = 8.7–8.8. 13C NMR signals of C6 (22) and C10
Et3N) yielded the corresponding pyrimidines 14–19. The (23) are observed at d = 168.0–169.0.
progress of the reaction was monitored by TLC. It is
In conclusion, we have described an effective approach to
worth noting that reaction time and product yield depend-
utilizing the synthetic potential of enamino ketones for the
ed on the reaction conditions and activity of the corre-
preparation of new hetaryl-substituted and annulated
sponding amidine (Table 1).
neoflavones; the latter are highly valued for their chemical
1
In H NMR spectra of 14–19, signals at d = 7.77–8.47 and biological significance as 4-phenyl-2H-chromen-2-
with 3JHH = 5.2 Hz correspond to H4¢¢ and H5¢¢ of the py- one moiety is an essential component of natural products
rimidine ring; the amino group of 14 and 15 was observed and many medicinally useful molecules.
at d = 7.2.
In addition, o-hydroxyenamino ketones can be used to
construct a 4H-chromen-4-one (4H-1-benzopyran-4-one)
ring; the latter is found in many natural molecules, such as
flavones or isoflavones, and also in many medicinally im-
All solvents used were purified and dried by standard procedures.
Reaction progress and identity of obtained compounds were moni-
tored by TLC on Merck 60 F254 silica gel plates using CHCl3–
MeOH (9:1) and (95:5) systems and EtOAc–hexanes (3:7) mixtures
Synthesis 2009, No. 8, 1279–1286 © Thieme Stuttgart · New York

1282
V. S. Moskvina et al.
PAPER
3, 4
H+
a
O
Me
O
O
O
O
O
O
O
H
O
N HMe2
from 3
from 4
Et
– NHMe2
– H+
– NHMe2
– H+
O
20, 96%
21, 95%
Scheme 3 Reagents and conditions: (a) HCl, EtOH, reflux, 1–2 h.
3, 4
Br
a
O
Me
O
O
O
O
O
O
O
O
O
NMe2
from 3
from 4
Br
Et
Br
– NHMe2
– NHMe2
22, 59%
23, 60%
Scheme 4 Reagents and conditions: (a) Br2 (1 equiv), CHCl3, 0 °C, HCl, stirring, 30 min.
as eluents. Column chromatography was performed on silica gel
(63–200 mesh, Merck). Melting points were determined using a
Kofler-type Leica Galen III micro hot stage microscope. NMR
spectra were recorded on a Mercury-400 spectrometer (spectrome-
ter frequency for 1H: 400 MHz, 13C: 100 MHz) from DMSO-d6 (and
CDCl3 for compounds 11, 12) solns. The TMS signal was used as
an internal standard. HMQC spectra were acquired at 128 × 32 data
matrices with spectral ranges: for 1H: 4 kHz, for 13C: 21 kHz; mix-
13C NMR (DMSO-d6): d = 7.9, 45.5, 96.2, 111.0, 113.0, 121.3,
124.89, 128.74, 129.0, 129.9, 140.3, 153.6, 155.9, 157.6, 160.8,
163.1, 189.6.
MS: m/z (%) = 349 ([M + 1]+, 96.57).
8-[(2E)-3-(Dimethylamino)prop-2-enoyl]-6-ethyl-7-hydroxy-4-
phenyl-2H-chromen-2-one (4)
Recrystallized (i-PrOH), yellow solid; yield: 4.23 g (58%); mp 164–
166 °C.
1H NMR (DMSO-d6): d = 1.06 (t, 3JHH = 7.6 Hz, 3 H, CH3), 2.49 (q,
3JHH = 7.2 Hz, 2 H, CH2), 3.07 (s, 3 H, NCH3), 3.32 (s, 3 H, NCH3),
6.06 (s, 1 H, H3), 6.53 (d, 3JHH = 12 Hz, 1 H, COCH), 7.16 (s, 1 H,
H5), 7.42 (d, 3JHH = 8.6 Hz, 2 H, H2¢, H6¢), 7.54 (m, 3 H, H3¢, H4¢,
H5¢), 8.13 (d, 3JHH = 12 Hz, 1 H, CHNMe2), 16.57 (br s, 1 H, OH).
13C NMR (DMSO-d6): d = 12.4, 26.8, 43.2, 94.7, 112.3, 113.2,
117.3, 124.1, 126.4, 128.0, 128.8, 131.6, 140.0, 145.9, 152.9, 155.4,
156.9, 160.8, 189.7.
1
ing time corresponds to ICH = 140 Hz. HMBC spectra were ac-
quired as 400 × 32 data matrices with spectral ranges: for 1H: 4 kHz,
2-3
for 13C: 21 kHz; mixing time corresponds to
I
= 8 Hz. Spectra
CH
were measured with detection on protons and gradient selection of
signals. Elemental analyses for C, H, and N were performed using
Perkin-Elmer C, H, N Analyzer, their results were found to be in
good agreement ( 0.2%) with the calculated values. Mass spectra
were recorded on Agilent 1100 LC/MSD instrument with chemical
ionization (CI).
Compounds 1 and 2 were synthesized according to a procedure pub-
lished in the literature.15
MS: m/z (%) = 365 ([M + 2]+, 3.16), 364 ([M + 1]+, 96.84).
Enamino Ketones 3 and 4; General Procedure
Pyrazolyl-Substituted 4-Phenyl-2H-chromen-2-ones 5–10;
General Procedure
The corresponding acetylneoflavone 1 or 2 (20 mmol) and
DMFDMA (4.8 g, 3.4 mL, 40 mmol) were refluxed in anhyd tolu-
ene (50 mL) for 5–7 h. The solvent was evaporated under reduced
pressure and the solid product was recrystallized from an appropri-
ate solvent.
To a soln of the corresponding enamino ketone 3 or 4 (3 mmol) in
abs EtOH (15 mL) was added NH2NH2·x H2O (0.149–0.447 g,
0.14–0.42 mL, 3–9 mmol) or MeNHNH2 (0.138–0.276 g, 0.12–0.26
mL, 3–6 mmol) and the soln was refluxed with stirring for 2–3 h
(TLC monitoring). The solvent was evaporated under reduced pres-
sure, the residue was treated with H2O, filtered, and recrystallized
from an appropriate solvent or subjected to column chromatography
(silica gel).
6-[(2E)-3-(Dimethylamino)prop-2-enoyl]-7-hydroxy-8-methyl-
4-phenyl-2H-chromen-2-one (3)
Recrystallized (EtOH), yellow solid; yield: 5.77 g (83%); mp 256–
258 °C.
1H NMR (DMSO-d6): d = 2.24 (s, 3 H, CH3), 2.86 (s, 3 H, NCH3),
3.02 (s, 3 H, NCH3), 5.36 (d, 3JHH = 11.6 Hz, 1 H, COCH), 6.12 (s,
1 H, H3), 7.54 (d, 3JHH = 8.8 Hz, 2 H, H2¢, H6¢), 7.66 (m, 3 H, H3¢,
H4¢, H5¢), 7.87 (s, 1 H, H5), 8.13 (d, 3JHH = 11.6 Hz, 1 H, CHNMe2),
15.35 (br s, 1 H, OH).
7-Hydroxy-8-methyl-4-phenyl-6-(1H-pyrazol-3-yl)-2H-chrom-
en-2-one (5)
Recrystallized (MeOH–H2O, 5:1), colorless solid; yield: 0.74 g
(81%); mp 317–320 °C.
Synthesis 2009, No. 8, 1279–1286 © Thieme Stuttgart · New York

PAPER
Heterocyclic Analogues of Neoflavonoids from Enamino Ketones
1283
1H NMR (DMSO-d6): d = 2.34 (s, 3 H, CH3), 6.10 (s, 1 H, H3), 6.39
(d, 3JHH = 2 Hz, 1 H, H4¢¢), 7.52 (d, 3JHH = 8.6 Hz, 2 H, H2¢, H6¢),
7.56 (m, 3 H, H3¢, H4¢, H5¢), 7.57 (s, 1 H, H5), 7.76 (d, 3JHH = 2 Hz,
1 H, H5¢¢), 12.17 (br s, 1 H, OH), 13.24 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 8.8, 96.3, 101.6, 111.3, 111.4, 112.9,
114.3, 121.9, 128.9, 129.3, 130.0, 136.1, 150.0, 153.1, 155.9, 157.9,
160.4.
1H NMR (DMSO-d6): d = 1.13 (t, 3JHH = 7.6 Hz, 3 H, CH3), 2.63 (q,
3JHH = 7.6 Hz, 2 H, CH2), 4.05 (s, 3 H, NCH3), 6.11 (s, 1 H, H3),
3
7.09 (s, 1 H, H5), 7.29 (d, JHH = 2.4 Hz, 1 H, H4¢¢), 7.46 (d,
3JHH = 8.6 Hz, 2 H, H2¢, H6¢), 7.54 (m, 3 H, H3¢, H4¢, H5¢), 7.93 (d,
3JHH = 2.4 Hz, 1 H, H5¢¢), 12.76 (s, 1 H, OH).
13C NMR (DMSO-d6): d = 14.3, 23.5, 39.6, 105.1, 107.6, 110.9,
125.7, 128.6, 129.1, 129.2, 129.5, 130.2, 132.9, 136.1, 145.9, 151.3,
156.6, 158.1, 160.4.
MS: m/z (%) = 320 ([M + 2]+, 2.11), 319 ([M + 1]+, 100).
MS: m/z (%) = 347 ([M]+, 98.6).
6-Ethyl-7-hydroxy-4-phenyl-8-(1H-pyrazol-3-yl)-2H-chromen-
2-one (6)
Recrystallized (MeOH–H2O, 5:1), colorless solid; yield: 0.73 g
6-Ethyl-7-hydroxy-8-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-2H-
chromen-2-one (10)
(80%); mp 256 °C.
Obtained together with 9 when MeNHNH2 (6 mmol) was used; col-
orless solid; yield: 0.1 g (11%); mp 201–203 °C; Rf = 0.1 (EtOAc–
hexanes, 3:7).
1H NMR (DMSO-d6): d = 1.14 (t, 3JHH = 7.6 Hz, 3 H, CH3), 2.62 (q,
3JHH = 7.2 Hz, 2 H, CH2), 6.11 (s, 1 H, H3), 7.09 (s, 1 H, H5), 7.35
(d, 3JHH = 2 Hz, 1 H, H4¢¢), 7.48 (d, 3JHH = 8.8 Hz, 2 H, H2¢, H6¢),
7.54 (m, 3 H, H3¢, H4¢, H5¢), 7.94 (d, 3JHH = 2 Hz, 1 H, H5¢¢), 13.21
(br s, 1 H, OH), 13.48 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 14.3, 23.6, 96.4, 105.5, 106.9, 110.7,
110.8, 125.6, 128.7, 128.8, 129.3, 129.9, 136.4, 146.6, 151.7, 156.7,
159.04, 160.3.
1H NMR (DMSO-d6): d = 1.12 (t, 3JHH = 7.6 Hz, 3 H, CH3), 2.62 (q,
3JHH = 7.6 Hz, 2 H, CH2), 3.67 (s, 3 H, NCH3), 6.10 (s, 1 H, H3),
3
6.27 (d, JHH = 2.4 Hz, 1 H, H4¢¢), 7.24 (s, 1 H, H5), 7.46 (d,
3JHH = 8.8 Hz, 2 H, H2¢, H6¢), 7.51 (m, 3 H, H3¢, H4¢, H5¢), 7.56 (d,
3JHH = 2.4 Hz, 1 H, H3¢¢), 9.57 (s, 1 H, OH).
13C NMR (DMSO-d6): d = 14.6, 23.5, 37.5, 107.2, 108.9, 111.6,
111.7, 127.7, 128.9, 129.2, 129.6, 130.3, 133.6, 135.8, 138.6, 152.1,
156.1, 157.6, 160.4.
MS: m/z (%) = 334 ([M + 2]+, 3.17), 333 ([M + 1]+, 100).
7-Hydroxy-8-methyl-6-(1-methyl-1H-pyrazol-3-yl)-4-phenyl-
2H-chromen-2-one (7)
Obtained as the sole product when MeNHNH2 (3 mmol) was used;
recrystallized (acetone), colorless solid; yield: 0.51 g (54%) ; mp
223–224 °C.
MS: m/z (%) = 347 ([M + 1]+, 14.6), 346 ([M]+, 96.2).
Isoxazol-5-yl-Substituted 4-Phenyl-2H-chromen-2-ones 11 and
12; General Procedure
To a soln of the corresponding enamino ketone 3 or 4 (3 mmol) in
abs EtOH (15 mL), a suspension of NH2OH·HCl (0.246 g, 3.5
mmol) in H2O (1 mL) was added and the soln refluxed for 2–3 h
(TLC monitoring). The solvent was evaporated under reduced pres-
sure, the residue was treated with H2O, filtered, and recrystallized
from an appropriate solvent.
Obtained together with 8 when MeNHNH2 (6 mmol) was used; col-
orless solid; yield: 0.63 g (66%); mp 223–224 °C; Rf = 0.37
(EtOAc–hexanes, 3:7).
1H NMR (DMSO-d6): d = 2.32 (s, 3 H, CH3), 3.95 (s, 3 H, NCH3),
6.10 (s, 1 H, H3), 6.34 (d, 3JHH = 2 Hz, 1 H, H4¢¢), 7.44 (s, 1 H, H5),
7.50 (d, 3JHH = 8.8 Hz, 2 H, H2¢, H6¢), 7.56 (m, 3 H, H3¢, H4¢, H5¢),
7.77 (d, 3JHH = 2 Hz, 1 H, H5¢¢), 11.72 (s, 1 H, OH).
7-Hydroxy-6-(isoxazol-5-yl)-8-methyl-4-phenyl-2H-chromen-
2-one (11)
13C NMR (DMSO-d6): d = 8.5, 38.9, 96.0, 102.1, 111.1, 111.2,
112.6, 113.8, 121.4, 128.6, 129.0, 129.8, 132.8, 135.7, 149.5, 152.8,
155.6, 157.2, 160.0.
Recrystallized (MeOH); colorless solid; yield: 0.72 g (79%); mp
221–222 °C.
1H NMR (DMSO-d6): d = 2.38 (s, 3 H, CH3), 6.17 (s, 1 H, H3), 6.87
(d, 3JHH = 1.2 Hz, 1 H, H4¢¢), 7.51 (d, 3JHH = 8.8 Hz, 2 H, H2¢, H6¢),
7.58 (m, 3 H, H3¢, H4¢, H5¢), 7.73 (s, 1 H, H5), 8.43 (d, 3JHH = 1.2
Hz, 1 H, H3¢¢), 10.41 (br s, 1 H, OH).
1H NMR (CDCl3): d = 2.39 (s, 3 H, CH3), 6.14 (s, 1 H, H3), 6.48 (d,
3JHH = 1.6 Hz, 1 H, H4¢¢), 7.13 (s, 1 H, OH), 7.38 (m, 2 H, H2¢, H6¢),
7.48 (m, 3 H, H3¢, H4¢, H5¢), 7.62 (s, 1 H, H5), 8.24 (d, 3JHH = 1.6
Hz, 1 H, H3¢¢).
13C NMR (DMSO-d6): d = 12.8, 100.5, 112.7, 112.8, 113.2, 121.1,
125.6, 126.4, 127.8, 128.0, 140.1, 151.3, 151.8, 152.3, 155.4, 160.8,
167.3.
MS: m/z (%) = 334 ([M + 1]+, 2.19), 333 ([M]+, 100).
7-Hydroxy-8-methyl-6-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-
2H-chromen-2-one (8)
Obtained together with 7 when MeNHNH2 (6 mmol) was used; col-
orless solid; yield: 0.13 g (14%); mp 227–229 °C; Rf = 0.09
(EtOAc–hexanes, 3:7).
1H NMR (DMSO-d6): d = 2.34 (s, 3 H, CH3), 3.69 (s, 3 H, NCH3),
6.10 (s, 1 H, H3), 6.28 (d, 3JHH = 2 Hz, 1 H, H4¢¢), 7.22 (s, 1 H, H5),
7.49 (d, 3JHH = 8.6 Hz, 2 H, H2¢, H6¢), 7.55 (m, 3 H, H3¢, H4¢, H5¢),
7.60 (d, 3JHH = 2 Hz, 1 H, H3¢¢), 9.56 (s, 1 H, OH).
13C NMR (DMSO-d6): d = 9.4, 39.9, 104.8, 112.7, 113.2, 117.1,
121.1, 125.6, 125.6, 128.0, 128.7, 140.3, 140.8, 143.1, 151.6, 152.3,
155.4, 160.8.
MS: m/z (%) = 319 ([M]+, 10.31), 318 ([M+ – 1], 86.65).
6-Ethyl-7-hydroxy-8-(isoxazol-5-yl)-4-phenyl-2H-chromen-2-
one (12)
Recrystallized (MeOH), colorless solid; mp 204–206 °C; yield:
0.78 g (79%).
MS: m/z (%) = 334 ([M + 1]+, 6.13), 333 ([M]+, 83.6).
1H NMR (DMSO-d6): d = 1.12 (t, 3JHH = 7.6 Hz, 3 H, CH3), 2.64 (q,
3JHH = 7.2 Hz, 2 H, CH2), 6.13 (s, 1 H, H3), 6.72 (d, 3JHH = 1.2 Hz,
1 H, H4¢¢), 7.25 (s, 1 H, H5), 7.48 (d, 3JHH = 8.8 Hz, 2 H, H2¢, H6¢),
7.56 (m, 3 H, H3¢, H4¢, H5¢), 8.59 (d, 3JHH = 1.2 Hz, 1 H, H3¢¢), 9.97
(br s, 1 H, OH).
6-Ethyl-7-hydroxy-8-(1-methyl-1H-pyrazol-3-yl)-4-phenyl-2H-
chromen-2-one (9)
Obtained as the sole product when MeNHNH2 (3 mmol) was used;
recrystallized (acetone), colorless solid; yield: 0.43 g (44%); mp
196–197 °C.
3
1H NMR (CDCl3): d = 1.12 (t, JHH = 7.6 Hz, 3 H, CH3), 2.63 (q,
Obtained together with 10 when MeNHNH2 (6 mmol) was used;
colorless solid; yield: 0.58 g (61%) ; mp 196–197 °C; Rf = 0.38
(EtOAc–hexanes, 3:7).
3JHH = 7.2 Hz, 2 H, CH2), 6.18 (s, 1 H, H3), 7.23 (d, 3JHH = 1.6 Hz,
Synthesis 2009, No. 8, 1279–1286 © Thieme Stuttgart · New York

1284
V. S. Moskvina et al.
PAPER
1 H, H4¢¢), 7.25 (s, 1 H, H5), 7.37 (m, 2 H, H2¢, H6¢), 7.47 (m, 3 H,
H3¢, H4¢, H5¢), 8.39 (d, 3JHH = 1.6 Hz, 1 H, H3¢¢), 8.55 (s, 1 H, OH).
13C NMR (DMSO-d6): d = 14.4, 23.5, 96.3, 105.0, 106.4, 111.7,
128.5, 128.8, 129.3, 129.4, 130.1, 135.9, 151.0, 152.0, 155.9, 157.7,
159.8, 162.3.
H3¢, H4¢, H5¢), 8.61 (d, 3JHH = 5.2 Hz, 1 H, H5¢¢), 9.02 (d, 3JHH = 5.2
Hz, 1 H, H4¢¢), 9.34 (s, 1 H, H2¢¢), 15.06 (br s, 1 H, OH).
13C NMR (DMSO-d6): d = 9.3, 111.3, 112.3, 115.6, 117.1, 121.1,
125.6, 126.4, 127.8, 128.0, 139.8, 151.6, 152.3, 155.4, 157.3, 158.4,
159.8, 161.0.
MS: m/z (%) = 332 ([M]+, 100).
MS: m/z (%) = 332 ([M + 1]+, 4.08), 331 ([M]+, 87.14).
Pyrimidin-4-yl-Substituted 4-Phenyl-2H-chromen-2-ones 14–
19; General Procedures
6-Ethyl-7-hydroxy-4-phenyl-8-(pyrimidin-4-yl)-2H-chromen-
2-one (17)
Recrystallized (MeOH), yellow solid; mp 193–194 °C.
Method A: To a soln of the corresponding enamino ketone 3 or 4 (3
mmol) in anhyd DMF (10 mL), guanidine carbonate, formamidine
acetate, or acetamidine hydrochloride (3.1 mmol) was added, fol-
lowed by dry K2CO3 (0.42 g, 3 mmol). The mixture was refluxed for
2–24 h (TLC monitoring). The soln was cooled, treated with H2O,
and acidified with HCl to pH 6. The precipitate was filtered, washed
with cold H2O and recrystallized from an appropriate solvent.
1H NMR (DMSO-d6): d = 1.13 (t, 3JHH = 7.6 Hz, 3 H, CH3), 2.61 (q,
3JHH = 7.2 Hz, 2 H, CH2), 6.17 (s, 1 H, H3), 7.27 (s, 1 H, H5), 7.48
(d, 3JHH = 8.6 Hz, 2 H, H2¢, H6¢), 7.56 (m, 3 H, H3¢, H4¢, H5¢), 8.59
(d, 3JHH = 5.2 Hz, 1 H, H5¢¢), 9.04 (d, 3JHH = 5.2 Hz, 1 H, H4¢¢), 9.31
(s, 1 H, H2¢¢), 15.03 (br s, 1 H, OH).
13C NMR (DMSO-d6): d = 14.8, 26.9, 112.7, 113.2, 115.5, 116.4,
124.5, 126.4, 127.1, 128.0, 128.7, 139.6, 144.6, 151.0, 155.0, 157.3,
158.4, 160.1, 160.8.
Method B: To a soln of Na (27 mg, 1.2 mmol) in abs EtOH (50 mL),
guanidine carbonate, formamidine acetate, or acetamidine hydro-
chloride (3.1 mmol) was added, followed by the corresponding
enamino ketone 3 or 4 (3 mmol). The mixture was refluxed for 20–
40 h (TLC monitoring). The soln was cooled, treated with H2O and
acidified with HCl to pH 6. The precipitate was filtered, washed
with cold H2O, and recrystallized from an appropriate solvent.
MS: m/z (%) = 345 ([M + 1]+, 96.68).
7-Hydroxy-8-methyl-6-(2-methylpyrimidin-4-yl)-4-phenyl-2H-
chromen-2-one (18)
Recrystallized (EtOH); yellow solid; mp 259–260 °C.
Method C: To a soln of the corresponding enamino ketone 3 or 4 (3
mmol) in DMF (10 mL), guanidine carbonate, formamidine acetate,
or acetamidine hydrochloride (3.1 mmol) was added, followed by
Et3N (0.254 g, 0.48 mL, 3.5 mmol) in DMF (5 mL). The mixture
was kept at 80 °C with stirring for 5–40 h (TLC monitoring). The
soln was cooled, treated with H2O and acidified with HCl to pH 6.
The precipitate was filtered, washed with cold H2O, and recrystal-
lized from an appropriate solvent.
1H NMR (DMSO-d6): d = 2.32 (s, 3 H, CH3), 2.39 (s, 3 H, CH3),
3
6.09 (s, 1 H, H3), 6.89 (d, JHH = 5.2 Hz, 1 H, H5¢¢), 7.48 (d,
3JHH = 8.6 Hz, 2 H, H2¢, H6¢), 7.52 (m, 3 H, H3¢, H4¢, H5¢), 7.66 (s,
1 H, H5), 8.31 (d, 3JHH = 5.2 Hz, 1 H, H4¢¢), 14.38 (br s, 1 H, OH).
13C NMR (DMSO-d6): d = 12.8, 25.5, 111.8, 112.6, 113.2, 117.1,
121.1, 125.6, 126.4, 128.1, 128.7, 140.1, 151.8, 152.3, 155.4, 158.0,
159.8, 160.2, 167.3.
MS: m/z (%) = 346 ([M + 1]+, 2.16), 345 ([M]+, 92.68).
Reaction times (h) and yields (%) are presented in Table 1.
6-(2-Aminopyrimidin-4-yl)-7-hydroxy-8-methyl-4-phenyl-2H-
chromen-2-one (14)
Recrystallized (i-PrOH); yellow solid; mp 329–332 °C.
6-Ethyl-7-hydroxy-8-(2-methylpyrimidin-4-yl)-4-phenyl-2H-
chromen-2-one (19)
Recrystallized (EtOH), yellow solid; mp 203–205 °C.
1H NMR (DMSO-d6): d = 2.30 (s, 3 H, CH3), 6.11 (s, 1 H, H3), 6.62
1H NMR (DMSO-d6): d = 1.19 (t, 3JHH = 7.6 Hz, 3 H, CH3), 2.36 (s,
3 H, CH3), 2.59 (q, 3JHH = 7.2 Hz, 2 H, CH2), 6.13 (s, 1 H, H3), 7.18
(s, 1 H, H5), 7.43 (d, 3JHH = 8.6 Hz, 2 H, H2¢, H6¢), 7.51 (m, 3 H,
H3¢, H4¢, H5¢), 7.63 (d, 3JHH = 5.2 Hz, 1 H, H5¢¢), 8.34 (d, 3JHH = 5.2
Hz, 1 H, H4¢¢), 16.36 (br s, 1 H, OH).
13C NMR (DMSO-d6): d = 14.8, 25.5, 26.9, 112.5, 112.7, 113.2,
115.6, 124.5, 125.6, 127.1, 128.0, 128.7, 140.0, 144.6, 151.0, 155.4,
157.8, 158.6, 160.8, 167.3.
3
(d, JHH = 5.2 Hz, 1 H, H5¢¢), 7.16 (br s, 2 H, NH2), 7.51 (d,
3JHH = 8.6 Hz, 2 H, H2¢, H6¢), 7.56 (m, 3 H, H3¢, H4¢, H5¢), 7.69 (s,
1 H, H5), 8.23 (d, 3JHH = 5.2 Hz, 1 H, H4¢¢), 15.3 (br s, 1 H, OH).
13C NMR (DMSO-d6): d = 8.4, 96.0, 103.3, 110.7, 111.3, 113.4,
113.7, 123.4, 128.5, 128.6, 129.1, 129.9, 135.4, 154.8, 155.6, 159.7,
160.0, 161.1, 162.6, 163.3.
MS: m/z (%) = 346 ([M + 1]+, 87.64).
MS: m/z (%) = 359 ([M]+, 87.82).
8-(2-Aminopyrimidin-4-yl)-6-ethyl-7-hydroxy-4-phenyl-2H-
chromen-2-one (15)
Recrystallized (EtOH); yellow solid; mp 285–288 °C.
10-Methyl-4-phenyl-2H,6H-pyrano[3,2-g]chromene-2,6-dione
(20) and 6-Ethyl-4-phenyl-2H,10H-pyrano[2,3-f]chromene-
2,10-dione (21); General Procedure
A soln of the corresponding enamino ketone 3 or 4 (3 mmol) in abs
EtOH (30 mL) was treated with concd HCl (2 mL) and refluxed for
1–2 h. The solvent was evaporated under reduced pressure and the
solid product was recrystallized (MeOH).
1H NMR (DMSO-d6): d = 1.13 (t, 3JHH = 7.6 Hz, 3 H, CH3), 2.59 (q,
3JHH = 7.2 Hz, 2 H, CH2), 6.09 (s, 1 H, H3), 7.15 (br s, 2 H, NH2),
7.19 (s, 1 H, H5), 7.46 (d, 3JHH = 8.6 Hz, 2 H, H2¢, H6¢), 7.55 (m, 3
3
H, H3¢, H4¢, H5¢), 7.79 (d, JHH = 5.2 Hz, 1 H, H5¢¢), 8.47 (d,
3JHH = 5.2 Hz, 1 H, H4¢¢), 16.41 (br s, 1 H, OH).
13C NMR (DMSO-d6): d = 14.0, 23.3, 96.0, 105.3, 109.5, 109.7,
109.9, 128.2, 128.5, 129.0, 129.5, 129.6, 129.7, 135.9, 153.6, 156.5,
159.3, 160.5, 160.7, 160.8, 164.0.
10-Methyl-4-phenyl-2H,6H-pyrano[3,2-g]chromene-2,6-dione
(20)
Colorless solid; yield: 0.84 g (96%); mp 292–295 °C.
1H NMR (DMSO-d6): d = 2.55 (s, 3 H, CH3), 6.31 (d, 3JHH = 6 Hz,
1 H, H7), 6.45 (s, 1 H, H3), 7.53 (d, 3JHH = 8.8 Hz, 2 H, H2¢, H6¢),
7.63 (m, 3 H, H3¢, H4¢, H5¢), 7.97 (s, 1 H, H5), 8.31 (d, 3JHH = 6 Hz,
1 H, H8).
MS: m/z (%) = 360 ([M + 1]+, 3.15), 359 (M+, 93.7).
7-Hydroxy-8-methyl-4-phenyl-6-(pyrimidin-4-yl)-2H-chrom-
en-2-one (16)
Recrystallized (MeOH); yellow solid; mp 246–248 °C.
13C NMR (DMSO-d6): d = 8.6, 96.0, 112.3, 115.1, 116.6, 120.8,
122.1, 128.6, 129.2, 130.2, 134.8, 155.0, 155.9, 157.3, 158.7, 175.7.
1H NMR (DMSO-d6): d = 2.31 (s, 3 H, CH3), 6.13 (s, 1 H, H3), 7.24
(s, 1 H, H5), 7.46 (d, 3JHH = 8.6 Hz, 2 H, H2¢, H6¢), 7.55 (m, 3 H,
Synthesis 2009, No. 8, 1279–1286 © Thieme Stuttgart · New York

PAPER
Heterocyclic Analogues of Neoflavonoids from Enamino Ketones
1285
MS: m/z (%) = 306 ([M + 1]+, 2.74), 305 ([M]+, 97.26).
References
(1) (a) Liang, X.-T.; Fang, W.-S. Medical Chemistry of
6-Ethyl-4-phenyl-2H,10H-pyrano[2,3-f]chromene-2,10-dione
(21)
Colorless solid; yield: 1.08 g (95%); mp 256–257 °C.
Bioactive Natural Products; John Wiley & Sons: Chichester,
2006. (b) Murray, R. D. H.; Mendez, J.; Brown, S. A. The
Natural Coumarins. Occurrence, Chemistry and
Biochemistry; John Wiley & Sons: Chichester, 1982.
(c) Garazd, M. M.; Garazd, Ya. L.; Khilya, V. P. Chem. Nat.
Compd. 2003, 39, 54. (d) Moskvina, V. S.; Garazd, Ya. L.;
Garazd, M. M.; Khilya, V. P. Chem. Nat. Compd. 2006, 42,
129.
1H NMR (DMSO-d6): d = 1.20 (t, 3JHH = 7.2 Hz, 3 H, CH3), 2.80 (q,
3JHH = 7.2 Hz, 2 H, CH2), 6.32 (d, 3JHH = 6 Hz, 1 H, H8), 6.37 (s, 1
3
H, H3), 7.50 (d, JHH = 8.8 Hz, 2 H, H2¢, H6¢), 7.53 (s, 1 H, H5),
7.57 (m, 3 H, H3¢, H4¢, H5¢), 8.18 (d, 3JHH = 6 Hz, 1 H, H9).
13C NMR (DMSO-d6): d = 14.1, 22.9, 96.0, 111.8, 114.6, 114.8,
119.9, 123.1, 128.7, 129.2, 129.7, 130.0, 135.1, 154.7, 154.8, 156.9,
159.1, 175.4.
(2) (a) Awale, S.; Shrestha, S. P.; Tezuka, Y.; Ueda, J. J. Nat.
Prod. 2005, 68, 858. (b) Lopez-Perez, J. L.; Olmedo, D. A.;
del Olmo, E.; Vasquez, Y.; Solis, P. N.; Gupta, M. P.;
San Feliciano, A. J. Nat. Prod. 2005, 68, 369. (c) Bedoya,
L. M.; Beltran, M.; Sancho, R.; Olmedo, D. A.; Sanchez-
Palomino, S.; del Olmo, E.; Lopez-Perez, J. L.; Munoz, E.;
San Feliciano, A.; Alcami, J. Bioorg. Med. Chem. Lett.
2005, 15, 4447. (d) Blouin, M.; Grimm, E.; Gareau, Y.;
Gagnon, M.; Juteau, H.; Laliberte, S.; Mackay, B.; Friesen,
R. WO 2006,099,735, 2006.
(3) (a) Menozzi, G.; Mosti, L.; Merello, L.; Piana, A.; Armani,
U.; Ghia, M.; Angiola, M.; Mattioli, F. Farmaco 2000, 55,
219. (b) Menozzi, G.; Schenone, P.; Mosti, L. J. Heterocycl.
Chem. 1993, 30, 997. (c) Singh, S. P.; Naithani, R.;
Aggarwal, R.; Prakesh, O. Indian J. Heterocycl. Chem.
2001, 11, 27. (d) Nargund, L. V. G.; Hariprasad, V.; Reddy,
G. R. N. J. Pharm. Sci. 1992, 81, 892. (e) Bauer, V. J.;
Dalalian, H. P.; Fanshawe, W. J.; Safir, S. R.; Tocus, E. C.;
Boshart, C. R. J. Med. Chem. 1968, 11, 981. (f) Ashton,
W. T.; Hutchins, S. M.; Greenlee, W. J.; Doss, G. A.; Chang,
R. S. L.; Lotti, V. J.; Faust, K. A.; Chen, T. B.; Zingaro,
G. J.; Kivlighn, S. D.; Siegl, P. K. S. J. Med. Chem. 1993, 36,
3595.
MS: m/z (%) = 320 ([M + 1]+, 3.03), 319 ([M]+, 96.97).
7-Bromo-10-methyl-4-phenyl-2H,6H-pyrano[3,2-g]chromene-
2,6-dione (22) and 9-Bromo-6-ethyl-4-phenyl-2H,10H-pyra-
no[2,3-f]chromene-2,10-dione (23); General Procedure
To a soln of the corresponding enamino ketone 3 or 4 (3 mmol) in
CHCl3 (40 mL) was added a soln of Br2 (0.479 g, 0.154 mL, 3
mmol) in CHCl3 (5 mL) dropwise at 0 °C. After complete addition
of Br2 the mixture was diluted with 5% HCl (50 mL) and vigorously
stirred for 30 min. The organic layer was separated, the aqueous lay-
er extracted with CHCl3 (2 × 10 mL), and the combined organic ex-
tracts dried (MgSO4). The solvent was evaporated under reduced
pressure and the solid product was recrystallized from an appropri-
ate solvent.
7-Bromo-10-methyl-4-phenyl-2H,6H-pyrano[3,2-g]chromene-
2,6-dione (22)
Recrystallized (EtOH), colorless solid; yield: 0.65g (59%); mp
259–262 °C.
1H NMR (DMSO-d6): d = 2.52 (s, 3 H, CH3), 6.43 (s, 1 H, H3), 7.51
(d, 3JHH = 8.8 Hz, 2 H, H2¢, H6¢), 7.60 (m, 3 H, H3¢, H4¢, H5¢), 7.99
(s, 1 H, H5), 8.80 (s, 1 H, H8).
13C NMR (DMSO-d6): d = 10.3, 96.1, 112.3, 112.7, 114.8, 115.1,
128.7, 128.8, 129.2, 130.0, 129.6, 134.6, 151.3, 153.4, 154.6, 156.9,
159.8, 169.7.
(4) (a) Natale, N. R.; Rogers, M. E.; Staples, R.; Triggle, D. J.;
Rutledge, A. J. Med. Chem. 1999, 42, 3087. (b) Kang,
Y. K.; Shin, K. J.; Yoo, K. H.; Seo, K. J.; Hong, C. Y.; Lee,
C. S.; Park, S. Y.; Kim, D. G.; Park, S. W. Bioorg. Med.
Chem. Lett. 2000, 10, 95. (c) Conti, P.; Dallanoce, C.;
Amici, M. D.; Micheli, C. D.; Klotz, K.-N. Bioorg. Med.
Chem. 1998, 6, 401.
MS: m/z (%) = 385 ([M + 1]+, 3.11), 384 ([M]+, 98.03).
(5) (a) Progress in Nucleic Acid Research and Molecular
Biology, Vols. 1-26; Academic: New York, 1963-1981.
(b) Collis, A. J.; Foster, M. L.; Haley, F.; Maslen, C.;
McLay, I. M.; Page, K. M.; Redford, E. J.; Souness, J. E.;
Wilsher, N. E. Bioorg. Med. Chem. Lett. 2001, 11, 693.
(c) Bruno, O.; Schenone, S.; Ranise, A.; Bondavalli, F.;
Barocelli, E.; Ballabeni, V.; Chiavarini, M.; Bertoni, S.;
Tagnolini, M.; Impicciatore, M. Bioorg. Med. Chem. 2001,
9, 629. (d) Sisko, J. J. Org. Chem. 1998, 63, 4529.
(6) (a) Philipp, A.; Jirkovsky, I.; Martel, R. R. J. Med. Chem.
1980, 23, 1372. (b) Zwaagstra, M. E.; Timmerman, H.;
Abdoelgafoer, R. S.; Zhang, M.-Q. Eur. J. Med. Chem.
1996, 31, 861. (c) Bois, F.; Desfougeres, A.; Boumendjel,
A.; Mariotte, A.-M.; Bessard, G.; Caron, F.; Devillier, P.
Bioorg. Med. Chem. Lett. 1997, 7, 1323. (d) Ismail, K. A.;
Abd El Aziem, T. Eur. J. Med. Chem. 2001, 36, 243.
(e) Lin, Y.-M.; Flavin, M. T.; Cassidy, C. S.; Mar, A.; Chen,
F.-C. Bioorg. Med. Chem. Lett. 2001, 11, 2101.
(f) Walenzyk, T.; Carola, C.; Buchholz, H.; König, B.
Tetrahedron 2005, 61, 7366.
(7) Silverman, R. B. The Organic Chemistry of Drug Design,
and Drug Action, 2nd ed.; Elsevier/Academic Press: New
York, 2004, 617.
(8) (a) Abdulla, R. F.; Brinkmeyer, R. S. Tetrahedron 1979, 35,
1675. (b) Elassar, A.-Z. A.; El-Khair, A. A. Tetrahedron
2003, 59, 8463.
9-Bromo-6-ethyl-4-phenyl-2H,10H-pyrano[2,3-f]chromene-
2,10-dione (23)
Recrystallized (i-PrOH), colorless solid; yield: 0.72 g (60%); mp
264–266 °C.
1H NMR (DMSO-d6): d = 1.19 (t, 3JHH = 7.2 Hz, 3 H, CH3), 2.80 (q,
3JHH = 7.2 Hz, 2 H, CH2), 6.40 (s, 1 H, H3), 7.50 (d, 3JHH = 8.8 Hz,
2 H, H2¢, H6¢), 7.52 (m, 3 H, H3¢, H4¢, H5¢), 7.58 (s, 1 H, H5), 8.77
(s, 1 H, H8).
13C NMR (DMSO-d6): d = 14.0, 22.8, 96.0, 112.3, 112.3, 114.9,
115.1, 128.7, 129.1, 129.2, 130.0, 130.2, 134.9, 151.2, 153.7, 154.6,
156.5, 158.8, 169.1.
MS: m/z (%) = 399 ([M + 1]+, 2.19), 398 ([M]+, 96.85).
Acknowledgment
V. M. thanks the DAAD, Euler program, for a fellowship. The au-
thors acknowledge Thomas K. Huhn (Fachbereich Chemie der Uni-
versität Konstanz) for technical support. Also
a special
acknowledgement to Prof. Dr. Igor Komarov (Department of Che-
mistry, Kyiv National Taras Shevchenko University) for help du-
ring the preparation of the manuscript.
Synthesis 2009, No. 8, 1279–1286 © Thieme Stuttgart · New York

1286
V. S. Moskvina et al.
PAPER
(11) Jork, H.; Funk, W.; Fischer, W.; Wimmer, H. Thin-Layer
(9) (a) Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Addison
Wesley: Essex, 1997. (b) Comprehensive Organic
Chemistry, Vol. 4; Barton, D.; Ollis, D. W., Eds.; Pergamon:
Oxford, 1979.
(10) (a) Westman, J.; Lundin, R.; Stalberg, J.; Ostbye, M.;
Franzen, A.; Hurynowicz, A. Comb. Chem. High
Chromatography: Reagents and Detection Methods, Vol.
1a; VCH: Weinheim, 1990.
(12) (a) Molteni, V.; Hamilton, M. W.; Mao, L.; Crane, C. M.;
Termin, A. P.; Wilson, D. M. Synthesis 2006, 90.
(b) Dominquez, E.; Ibeas, E.; Martinez de Margorta, E.;
Palacias, J. K.; SanMartin, R. J. Org. Chem. 1996, 61, 5435.
(c) Keshk, E. M. Heteroat. Chem. 2004, 15, 85.
(13) Khilya, V. P.; Ishchenko, V. V. Chem. Heterocycl. Compd.
2002, 38, 883.
(14) Andersen, M.; Markham, K. R. Flavonoids: Chemistry,
Biochemistry and Applications; CRC Press/Taylor Francis:
Boca Raton, 2006.
Throughput Screening 2002, 5, 565. (b) Chimichi, S.;
Boccalini, M.; Hassan, M. M. M.; Viola, G.; Dall’Acqua, F.;
Curini, M. Tetrahedron 2006, 62, 90. (c) El-Taweel,
F. M. A. A.; Einagdi, M. M. J. Heterocycl. Chem. 2001, 38,
981. (d) Hassanien, A. Z. A. E. l. B. J. Chem. Res. 2004, 8,
536. (e) Uber, J. S.; Vogels, Y.; Helder, D.; Mutikainen, I.;
Turpeinen, U.; Fu, W. T.; Roubeau, O.; Gamez, P.; Reedijk,
J. Eur. J. Inorg. Chem. 2007, 4197. (f) Tanaka, A.;
Terasawa, T.; Hagihara, H.; Sakuma, Y.; Ishibe, N.; Sawada,
M.; Takasugi, H.; Tanaba, H. J. Med. Chem. 1998, 41, 2390.
(15) Moskvina, V. S.; Khilya, V. P. Chem. Nat. Compd. 2008, 44,
16.
Synthesis 2009, No. 8, 1279–1286 © Thieme Stuttgart · New York