Plant coumarins: XIII. Synthesis of 2,3,9-trisubstituted furocoumarins

Article abstract of DOI:10.1134/S1070428013030159

Peucedanin reacted with methylideneiminium salt generated in situ from N,N,N′,N′-tetramethylmethanediamine and acetyl chloride to give 2-(dimethylaminomethyl)oreoselone. Reactions of peucedanin with aminomethylating agents generated in situ from formaldeh

Full text of DOI:10.1134/S1070428013030159

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 3, pp. 403–411. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © A.V. Lipeeva, E.E. Shul’ts, M.M. Shakirov, I.Yu. Bagryanskaya, G.A. Tolstikov, 2013, published in Zhurnal Organicheskoi Khimii,
2013, Vol. 49, No. 3, pp. 416–424.
Dedicated to Full Member of the Russian Academy of Sciences
I.P. Beletskaya on her jubilee
Plant Coumarins:
XIII.* Synthesis of 2,3,9-Trisubstituted Furocoumarins
A. V. Lipeeva, E. E. Shul’ts, M. M. Shakirov, I. Yu. Bagryanskaya, and G. A. Tolstikov
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: schultz@nioch.nsc.ru
Received December 27, 2012
Abstract—Peucedanin reacted with methylideneiminium salt generated in situ from N,N,N′,N′-tetramethyl-
methanediamine and acetyl chloride to give 2-(dimethylaminomethyl)oreoselone. Reactions of peucedanin with
aminomethylating agents generated in situ from formaldehyde and dimethylamine, N-methylpiperazine, or
N-Boc-piperazine in boiling methanol smoothly afforded the corresponding 9-aminomethyl derivatives whose
hydrolysis produced 9-aminomethyl-substituted oreoselones. 2,3,9-Trisubstituted linearly fused furocoumarins
were synthesized by reactions of 9-substituted oreoselone trifluoromethanesulfonates with arylboronic acids.
DOI: 10.1134/S1070428013030159
Psoralens are linearly fused furocoumarins that are
used as therapeutic agents in the PUVA treatment of
skin diseases such as psoriasis, vitiligo, and atopic
eczema. The mechanism of their action is based on
their ability to form photoadducts with DNAs and
other cellular (RNAs, proteins) and membrane com-
ponents (phospholipases A2 and C, Ca2+/calmodulin-
and AMP-dependent protein kinases, and epidermal
growth factor) [2]. On the other hand, some serious
side effects of PUVA therapy have been revealed, pri-
marily those related to the possibility for cross-linking
of two DNA molecules by one psoralen molecule. This
may be responsible for genotoxicity, keratoses, skin
cancer, and other cancer diseases. With a view to
minimize side effects of PUVA therapy, functionaliza-
tion of psoralens at the furan ring and C9 seems to be
promising provided that the ability to form adducts
with DNAs at the pyran fragment is retained [3].
In the present work we synthesized new nitrogen-
containing derivatives of an accessible furocoumarin,
peucedanin (I) [7], by the aminomethylation reaction
and studied transformations of 9-aminomethyl-substi-
tuted oreoselones via introduction of substituents into
the 3-position. Furocoumarins functionalized at C2
with aminomethyl groups can be obtained by con-
densation of psoralens with chloromethoxymethane,
followed by replacement of the halogen atom in
2-chloromethylfurocoumarins by the action of phthal-
imide potassium salt and subsequent cleavage of the
N-phthtalimidomethyl derivative with hydrazine
hydrate [8]. Aminomethylation of furocoumarins was
also performed with the use of N-hydroxymethyl-
phthalimide in the presence of strong protic or Lewis
acids [9]. In this case, the reaction involved position
2 or 3 in the furocoumarin molecule.
We found that peucedanin (I) did not undergo
aminomethylation under classical Mannich reaction
conditions [Me2NH, (CH2O)n, aqueous AcOH, 100°C]
[10], and 90% of the initial compound was recovered
from the reaction mixture. By reaction of I with
methylideneiminium salt generated in situ from
N,N,N′,N′-tetramethylmethanediamine (II) and acetyl
chloride we obtained 2-(dimethylaminomethyl)oreo-
selone (III) in 66% yield (Scheme 1).
Introduction of nitrogen-containing substituents
into furocoumarin molecules is known to enhance their
photoactivity toward DNA and RNA [4], whereas
9-(3-aminopropoxy)psoralens showed a long-term
effect in PUVA therapy [5]. In addition, amino-substi-
tuted furocoumarins are potential Kv1.3 potassium
channel blockers [6].
* For communication XII, see [1].
403

LIPEEVA et al.
404
Scheme 1.
O
4
9
5
[Me2N]2CH2 (II)–AcCl
CH2Cl2, 0–20°C
1'
4a
8a
3a
6
3
1
Me2N
2
7
8
O
i-Pr
9a
O
O
III
MeO
MeO
[Me2N]2CH2 (II) or
CH2O, Me2NH, MeOH, 65°C
i-Pr
i-Pr
O
O
O
O
O
O
NMe2
I
IV
NH
(V, VI)
N
MeO
R
CH2O, MeOH, 65°C
i-Pr
O
O
O
R
N
N
VII, VIII
O
O
II or V/CH2O
HCl, MeOH, 12 h
i-Pr
i-Pr
IV, VII
O
O
O
O
O
O
R
X, XI
IX
V, VII, R = Me; VI, VIII, R = t-BuOC(O); X, R = Me2N; XI, R = 4-methylpiperazin-1-yl.
Successful aminomethylation of phenolic com-
pounds can be achieved by reacting them with
N,N,N′,N′-tetramethylmethanediamine (II) and formal-
dehyde in boiling methanol [11]. Treatment of
peucedanin with excess diamine II in boiling methanol
resulted in the formation of 9-(dimethylaminomethyl)-
peucedanin (IV, yield 68%). Also, compound IV was
smoothly synthesized in 80% yield by reaction of I
with dimethylamine (6 equiv) and formaldehyde in
boiling methanol, where the aminomethylating agent
was generated in situ. By reactions of I with 1-methyl-
piperazine (V) or tert-butyl piperazine-1-carboxylate
(VI) in the presence of formaldehyde under analogous
conditions we obtained 9-(4-R-piperazin-1-ylmethyl)-
furocoumarins VII and VIII in 76 and 83% yield,
respectively.
methanol. 9-(Dimethylaminomethyl)oreoselone (X)
and 9-(4-methylpiperazin-1-ylmethyl)oreoselone (XI)
were synthesized by hydrolysis of 9-substituted furo-
coumarins IV and VII with hydrochloric acid in meth-
anol according to [12] (Scheme 1).
Accessibility of 9-substituted oreoselone deriva-
tives X and XI has stimulated our interest in their
transformations involving the C3=O carbonyl group.
Compounds X and XI reacted with trifluoromethane-
sulfonic anhydride in the presence of pyridine to give
9-R-2-isopropyl-7-oxo-7H-furo[3,2-g]chromen-3-yl
trifluoromethansulfonates XII and XIII (yield 67–
74%) which turned out to be highly reactive in the
Suzuki–Miyaura reaction (Scheme 2). The reactions of
XII and XIII with o-tolylboronic acid (XIV) in the
presence of 5 mol % of PdCl2(dppf), 3 equiv of
K2CO3, and 0.1 equiv of Bu4N+Br– in acetonitrile [13]
afforded 76–80% of 9-R-2-isopropyl-3-(2-methyl-
phenyl)-7H-furo[3,2-g]chromen-7-ones XV and XVI.
When the reaction of XII with XIV was carried out in
We failed to synthesize the corresponding amino-
methyl derivatives by reaction of oreoselone (IX) with
diamine II or with dimethylamine or 1-methylpiper-
azine (V) in the presence of formaldehyde in boiling
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 3 2013

PLANT COUMARINS: XIII.
405
Scheme 2.
B(OH)2
Me
(XIV)
Me
PfCl2(dppf), K2CO3
i-Pr
Bu4NBr, MeCN, 80°C
O
O
O
R
TfO
XV, XVI
Tf2O, pyridine
B(OH)2
i-Pr
O
X, XI
O
O
O
(XVII)
O
R
PfCl2(dppf), K2CO3
Bu4NBr, MeCN, 80°C
i-Pr
XII, XIII
O
O
O
R
XVIII, XIX
TfO
i-Pr
O
O
O
XX
XII, XV, XVIII, R = Me2N; XIII, XVI, XIX, R = 4-methylpiperazin-1-yl.
dioxane in the presence of Pd(PPh3)4 which is widely
used in the Suzuki and Stille cross couplings of
4-sulfonyloxycoumarins [14–16], the yield of XVI was
considerably lower (50%). Replacement of potassium
carbonate by triethylamine reduced the yield of XVI to
18%. Potassium phosphate K3PO4 was also ineffective
as base in this reaction [16].
9-Aminomethyl-substituted 2-isopropyl-3-(furan-3-
yl)psoralens XVIII and XIX were synthesized in 65
and 57% yield, respectively, by reaction of furocou-
marins XII and XIII with furan-3-ylboronic acid
(XVII) in the presence of PdCl2(dppf). These data
show that the reactivity of trifluoromethanesulfonates
XII and XIII in the Suzuki reaction is comparable
with the reactivity of oreoselone trifluoromethanesul-
fonate (XX) [13].
The structure of the newly synthesized compounds
was determined on the basis of their spectral param-
eters and elemental compositions. In keeping with the
assumed structures, the 1H and 13C NMR spectra of the
isolated products contained only one set of signals cor-
responding to the furanocoumarin fragment and sub-
stituents therein.
furocoumarin fragment in molecule III is almost
planar: the mean-square deviation of atoms is 0.05 Å.
The bond lengths and bond angles in molecule IV are
similar to the corresponding standard values [17, 18]
and those found for its closest structural analog,
(3Z)-3-hydroxyimino-2-isopropyl-7H-furo[3,2-g]chro-
men-7(3H)-one [18]. Molecules III in crystal are
linked to form infinite chains along the a crystallo-
graphic axis through slightly shortened intermolecular
contacts (shorter than the sum of the corresponding
C2′
O2
C4
C9
C1′
C3
C5
C4a
C8a
C6
C3a
C9a
C2
O3
C3′
C7
C8
O1
N2″
C1″
C4″
C3″
Fig. 1. Molecular structure of (2R)-2-isopropyl-2-[(dimethyl-
amino)methyl]-2H-furo[3,2-g]chromene-3,7-dione (III)
according to the X-ray diffraction data.
The structure of furocoumarin III [(2R) isomer]
was proved by X-ray analysis (Fig. 1). The tricyclic
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 3 2013

LIPEEVA et al.
Elemental analysis was also performed using a Carlo
406
Erba-1106 CHN-analyzer.
The progress of reactions and the purity of the
isolated compounds were monitored by TLC on Silufol
UV-254 plates using chloroform and chloroform–
ethanol (50:2) as eluents; spots were visualized by
treatment with iodine vapor and under UV light.
Column chromatography was performed on silica gel
(0.035–0.070 mm, Acros) using chloroform and
chloroform–ethanol (50:3) as eluents.
Fig. 2. Infinite chains formed by molecules III in crystal
along the a crystallographic axis via weak intermolecular
interactions O···H (2.630, 2.668 Å) and O···C (3.210 Å).
1-Methylpiperazine (V), 1-Boc-piperazine (VI),
PdCl2(dppf), o-tolylboronic acid (XIV), and furan-3-
ylboronic acid (XVII) were commercial products (Alfa
Aesar). Acetonitrile, methanol, and triethylamine were
purified according to standard procedures and were
distilled in a stream of argon just before use.
N,N,N′,N′-Tetramethylmethanediamine (II) was syn-
thesized as described in [20].
van der Waals radii, N···O 2.68 Å, C···O 3.35 Å
[19]; Fig. 2).
Thus, we have synthesized 9-(R-aminomethyl)-sub-
stituted furocoumarins by reactions of peucedanin with
aminomethylating agents generated in situ from secon-
dary amines (dimethylamine, 1-methylpiperazine, or
1-Boc-piperazine) and formaldehyde in boiling metha-
nol. New 9-substituted 2-isopropyl-3-trifluoromethane-
sulfonyloxypsoralens have shown a high reactivity in
the Suzuki cross coupling reaction with aryl(hetaryl)-
boronic acids.
2-[(Dimethylamino)methyl]-2-isopropyl-2H-
furo[3,2-g]chromene-3,7-dione (III). A solution of
0.5 g (1.9 mmol) of peucedanin (I) and 0.27 g
(6 mmol) of N,N,N′,N′-tetramethylmethanediamine (II)
in 5 ml of methylene chloride was cooled to 0°C,
a solution of 0.36 g (4.75 mmol) of acetyl chloride in
5 ml of methylene chloride was added dropwise, and
the mixture was allowed to warm up to room tempera-
ture and left to stand for 24 h. It was then treated with
3 ml of water and extracted with methylene chloride
(3×4 ml), the combined extracts were washed with
water, dried over MgSO4, and evaporated, and the
residue was recrystallized from diethyl ether. Yield
0.41 g (72%), mp 95–96°C, [α]D20 = +11.6° (c = 1.0,
CHCl3). IR spectrum, ν, cm–1: 3429, 2972, 2951, 2936,
2882, 2826, 2775, 1738, 1724, 1628, 1574, 1485,
1472, 1393, 1352, 1288, 1202, 1138, 1103, 1026, 993,
EXPERIMENTAL**
The NMR spectra were recorded from solutions in
CDCl3 or CDCl3–CD3OD (10:1) (XVIII, XIX) on
1
Bruker AV-300 (300.13 MHz for H and 75.47 MHz
for 13C), AV-400 (400.13 MHz for 1H and 100.78 MHz
for 13C), and AV-600 spectrometers (600.30 MHz for
1H and 150.96 MHz for 13C); the chemical shifts were
measured relative to tetramethylsilane as internal
reference. Multiplicities of signals in the 13C NMR
spectra were determined using J modulation technique.
Signals in the NMR spectra of III, XI, XVI, and XIX
were assigned on the basis of carbon–proton shift
correlation experiments (COXH, COLOC). For atom
numbering used below in the description of the 1H and
13C NMR spectra, see structure III in Scheme 1.
899, 827, 745, 692, 594. UV spectrum (EtOH), λmax
,
nm (logε): 216 (3.91), 234 (4.14), 238 (4.15), 253
(4.24), 299 (3.93), 308 (3.92), 344 (3.92), 355 (3.94).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.82 d and
0.96 d [6H, (CH3)2CH, J = 6.9], 2.15 s [6H, N(CH3)2],
2.85 m [1H, CHCH3)2], 4.71 s (2H, CH2N), 6.29 d
(1H, 6-H, J = 9.6), 6.97 s (1H, 9-H), 7.66 d (1H, 5-H,
J = 9.6), 7.75 s (1H, 4-H). 13C NMR spectrum, δC,
ppm: 16.43 q and 16.46 q [(CH3)2CH], 33.15 d
[CH(CH3)2], 47.63 q [N(CH3)2], 62.54 t (CH2N),
98.20 s (C2), 100.22 d (C9), 113.96 s (C4a), 114.13 d
(C6), 120.34 s (C3a), 123.95 d (C4), 143.75 d (C5),
159.77 s (C9a), 160.87 s (C8a), 173.35 s (C7), 202.13 s
(C3). Found, %: C 68.05; H 6.70; N 4.54. m/z 301.1328
[M]+. C17H19NO4. Calculated, %: C 67.76; H 6.36;
N 4.65. Calculated: M 301.1309.
The molecular weights and elemental compositions
were determined from the high-resolution mass spectra
recorded on a DFS Thermo Scientific instrument
(electron impact, 70 eV; vaporizer temperature 270–
300°C). The IR spectra were recorded in KBr on
a Bruker Vector-22 instrument. The UV spectra were
measured on an HP 8453 UV-Vis spectrophotometer.
** Analytical and spectral studies were performed at the Chemical
Service Center, Siberian Branch, Russian Academy of Sciences.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 3 2013

PLANT COUMARINS: XIII.
407
the combined extracts were dried over MgSO4 and
evaporated, and the residue was subjected to column
chromatography on silica gel using chloroform as
eluent to isolate 0.54 g (76%) of compound VII as
an oily substance. IR spectrum, ν, cm–1: 3432, 2967,
2940, 2910, 2865, 2821, 2771, 1726, 1612, 1591,
1465, 1394, 1363, 1313, 1288, 1257, 1132, 1045,
9-[(Dimethylamino)methyl]-2-isopropyl-3-me-
thoxy-7H-furo[3,2-g]chromen-7-one (IV). a. A solu-
tion of 0.5 g (1.9 mmol) of peucedanin (I) in 5 ml of
methanol was heated to 65°C, 1.64 g (11.4 mmol) of
diamine II was added, and the mixture was heated for
3 h under reflux. When the reaction was complete
(TLC), the mixture was treated with 3 ml of water and
extracted with methylene chloride (3×4 ml), the
combined extracts were washed with water, dried, and
evaporated, and the residue was subjected to column
chromatography on silica gel using chloroform as
eluent to isolate 0.4 g (68%) of compound IV.
1012, 935, 844, 825, 775. UV spectrum (EtOH), λmax
,
nm (logε): 206 (4.41), 259 (4.23), 302 (3.99), 341
1
(3.90). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
0.93 s [6H, (CH3)2CH, J = 7], 1.97 m (8H,
NCH2CH2N), 2.46 s (3H, 4′-CH3), 3.13 m [1H,
CH(CH3)2], 3.51 s (3H, OMe), 5.30 s (2H, CH2N),
5.90 d (1H, 6-H, J = 9.4), 6.85 s (1H, 4-H), 7.36 d (1H,
5-H, J = 9.4). 13C NMR spectrum, δC, ppm: 20.95 q
[(CH3)2CH], 23.37 d [CH(CH3)2], 45.52 q (NCH3),
49.41 t (CH2N), 52.13 t (C2′, C6′), 53.78 t (C3′, C5′),
61.96 q (OCH3), 109.10 s (C9), 112.36 d (C6), 112.89 s
(C4a), 119.18 d (C4), 124.69 s (C3a), 140.25 s (C3),
143.90 d (C5), 148.52 s (C8a), 152.98 s (C2), 154.53 s
(C9a), 159.65 s (C7). Calculated, %: C 68.69; H 7.07;
N 7.56. C21H26N2O4. Found, %: C 69.11; H 6.87;
N 7.21.
b. A solution of 0.5 g (1.9 mmol) of peucedanin (I)
and 0.75 ml (11.4 mol) of aqueous dimethylamine in
5 ml of methanol was heated to 65°C, 0.42 ml
(11.25 mmol) of formaldehyde was added, and the
mixture was heated for 3 h under reflux (TLC). The
mixture was cooled and evaporated, the residue was
treated with 3 ml of water and extracted with methy-
lene chloride (4×4 ml), the combined extracts were
dried over MgSO4 and evaporated, and the residue was
purified by column chromatography on alumina using
chloroform as eluent. Yield 0.47 g (80%), mp 97–98°C
(from Et2O). IR spectrum, ν, cm–1: 3432, 3025, 2971,
2931, 2871, 1856, 1726, 1635, 1577, 1465, 1390,
1365, 1305, 1284, 1180, 1141, 1120, 1039, 875, 823,
752, 599. UV spectrum (EtOH), λmax, nm (logε): 195
(3.50), 204 (4.31), 216 (4.23), 257 (4.36), 298 (4.04),
tert-Butyl 4-(2-isopropyl-3-methoxy-7-oxo-7H-
furo[3,2-g]chromen-9-ylmethyl)piperazine-1-car-
boxylate (VIII). A solution of 0.5 g (1.9 mmol) of
peucedanin (I) and 2.12 g (11.4 mmol) of 1-Boc-
piperazine (VI) in 5 ml of methanol was heated to
65°C, 0.42 ml (11.25 mmol) of formaldehyde was
added, and the mixture was heated for 5 h under reflux.
The mixture was then treated with 3 ml of water and
extracted with methylene chloride (4×4 ml), the com-
bined extracts were dried over MgSO4 and evaporated,
and the residue was purified by column chromatog-
raphy on silica gel using chloroform as eluent. Yield
0.71 g (83%), mp 105–106°C (from Et2O). IR spec-
trum, ν, cm–1: 3434, 2971, 2931, 2888, 2856, 2794,
1726, 1687, 1641, 1579, 1457, 1423, 1365, 1290,
1245, 1166, 1132, 1078, 1010, 867, 765. UV spectrum
(EtOH), λmax, nm (logε): 203 (4.27), 257 (3.95), 299
(3.66), 343 (3.41). 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 1.24 d [6H, (CH3)2CH, J = 7], 1.34 s (9H,
t-Bu), 2.16 m and 3.09 m (8H, NCH2CH2N), 3.70 m
[1H, CH(CH3)2], 3.80 s (3H, OMe), 4.03 s (2H,
CH2N), 6.21 d (1H, 6-H, J = 9.4), 7.49 s (1H, 4-H),
7.63 d (1H, 5-H, J = 9.4). 13C NMR spectrum, δC,
ppm: 20.95 q [(CH3)2CH], 23.37 d [CH(CH3)2],
28.29 q [9H, C(CH3)3]; 40.08 t, 45.44 t, 52.04 t,
53.85 t (C3′, C4′, C6′, C7′), 49.41 t (CH2N), 61.62 q
(OCH3), 82.42 s [C(CH3)3], 107.90 s (C9), 113.12 d
(C6), 114.50 s (C4a), 118.53 d (C4), 124.69 s (C3a),
1
333 (3.75). H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 1.22 d [6H, (CH3)2CH, J = 7.0], 2.20 s [6H,
N(CH3)2], 3.12 m [1H, CH(CH3)2], 3.80 s (2H, CH2N),
3.81 s (3H, OMe), 6.19 d (1H, 6-H, J = 9.4), 7.40 s
(1H, 4-H), 7.64 d (1H, 5-H, J = 9.4). 13C NMR
spectrum, δC, ppm: 20.41 q [(CH3)2CH], 25.85 d
[CH(CH3)2], 45.00 q [N(CH3)2], 49.35 t (CH2N),
61.22 q (OCH3), 109.40 d (C9), 113.77 d (C6), 114.44 s
(C4a), 115.57 d (C4), 120.60 s (C3a), 136.18 s (C3),
144.11 d (C5), 149.69 s (C8a), 151.84 s (C2), 152.63 s
(C9a), 160.45 s (C7). Mass spectrum: m/z 315.1467
[M]+. Found, %: C 69.65; H 6.71; N 4.44. C18H21NO4.
Calculated, %: C 70.01; H 6.23; N 4.21. M 315.1465.
2-Isopropyl-3-methoxy-9-[(4-methylpiperazin-
1-yl)methyl]-7H-furo[3,2-g]chromen-7-one (VII).
A solution of 0.5 g (1.9 mmol) of peucedanin (I) and
1.14 g (11.4 mmol) of 1-methylpiperazine (V) in 5 ml
of methanol was heated to 65°C, 0.42 ml (11.25 mmol)
of formaldehyde was added, and the mixture was
heated for 5 h under reflux. When the reaction was
complete (TLC), the mixture was treated with 3 ml of
water and extracted with methylene chloride (4×4 ml),
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LIPEEVA et al.
408
137.21 s (C3), 143.90 d (C5), 148.52 s (C8a), 153.17 s
(C2), 154.24 s (C9a), 156.24 s [t-BuO(C)O], 159.92 s
(C7). Found, %: C 65.65; H 7.01; N 6.50. C25H32N2O6.
Calculated, %: C 65.77; H 7.07; N 6.14.
ppm: 21.05 q [(CH3)2CH], 23.57 d [CH(CH3)2],
46.52 q (NCH3), 51.41 t (CH2N), 53.13 t and 53.78 t
(C3′, C5′, C2′, C6′), 98.35 d (C2), 108.89 s (C9), 111.96 d
(C6), 113.09 s (C4a), 120.28 d (C4), 124.92 s (C3a),
144.90 d (C5), 146.82 s (C8a), 154.33 s (C9a), 161.65 s
(C7), 193.07 s (C3). Found, %: C 67.04; H 6.52; N 7.48.
C20H24N2O4. Calculated, %: C 67.40; H 6.79; N 7.86.
9-[(Dimethylamino)methyl]-2-isopropyl-2H-furo-
[3,2-g]chromene-3,7-dione (X). Compound IV, 0.5 g
(0.0016 mol), was dissolved in 3 ml of methanol, 5 ml
of concentrated aqueous HCl was added, and the
mixture was left to stand for 20 h at room temperature.
The mixture was diluted with water and extracted with
methylene chloride (4×5 ml), the combined extracts
were dried over MgSO4 and evaporated, and attempted
recrystallization of the residue from diethyl ether gave
0.3 g (62%) of X as a yellow oily substance. UV spec-
trum (EtOH), λmax, nm (logε): 205 (4.19), 223 (4.19),
251 (4.40), 299 (3.96), 308 (3.97), 343 (4.07), 353
(4.09). IR spectrum, ν, cm–1: 2970, 2945, 2881, 2823,
2775, 1745, 1724, 1624, 1573, 1485, 1467, 1393,
1352, 1288, 1228, 1197, 1137, 1099, 1031, 995, 902,
9-[(Dimethylamino)methyl]-2-isopropyl-7-oxo-
7H-furo[3,2-g]chromen-3-yl trifluoromethanesulfo-
nate (XII). A solution of 250 mg (0.8 mmol) of
9-[(dimethylamino)methyl]oreoselone (X) in 3 ml of
anhydrous pyridine was cooled to 0°C, 0.67 ml
(2.4 mmol) of trifluoromethanesulfonic anhydride was
added dropwise in a stream of argon, and the mixture
was stirred for 30 min on cooling, allowed to warm up
to room temperature, and stirred for 24 h under argon.
When the reaction was complete, the mixture was
treated with 3 ml of water and extracted with methy-
lene chloride (5×10 ml), the combined extracts were
washed with water (2×10 ml), dried over MgSO4, and
evaporated, and the residue was additionally dried by
azeotropic distillation with benzene. Recrystallization
from ethanol gave 0.25 g (74%) of XII, mp 101–
102°C. IR spectrum, ν, cm–1: 3437, 2970, 2941, 2879,
2798, 2495, 1699, 1625, 1462, 1427, 1342, 1292,
1247, 1218, 1139, 1049, 1031, 1002, 846, 767, 640,
1
827, 744. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
0.82 d and 0.96 d [3H each, (CH3)2CH, J = 7.0],
1.34 m [1H, (CH3)2CH], 2.15 s (6H, MeN), 2.83 s (2H,
CH2N), 4.52 m (1H, 2-H), 6.29 d (1H, 6-H, J = 9.4),
7.67 d (1H, 5-H, J 9.4), 7.75 s (1H, 4-H). 13C NMR
spectrum, δC, ppm: 16.53 q and 16.56 q [(CH3)2CH],
20.72 d [CH(CH3)2], 33.14 q and 35.45 q (NCH3),
47.62 t (CH2N), 95.72 d (C2), 100.22 s (C9), 110.19 s
(C4a), 114.15 d (C6), 120.35 s (C3a), 123.92 d (C4),
143.71 d (C5), 146.27 s (C8a), 160.89 s (C9a), 173.34 s
(C7), 202.03 s (C3). Found, %: C 67.84; H 6.25; N 4.38.
C17H19NO4. Calculated, %: C 67.76; H 6.36; N 4.65.
1
609. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
0.95 d and 1.12 d (3H each, CH3, J = 7.0), 1.70 m [1H,
(CH3)2CH)], 2.15 s (6H, NCH3), 2.85 s (2H, CH2N),
6.29 d (1H, 6-H, J = 9.4), 7.67 d (1H, 5-H, J = 9.4),
7.74 s (1H, 4-H). 13C NMR spectrum, δC, ppm: 20.23 q
(6H, CH3), 25.86 d (CH), 30.84 q and 32.02 q (CH3),
46.23 t (CH2N), 100.44 s (C9), 115.50 d (C6), 115.98 s
(C4a), 120.16 d (C4), 122.12 q (CF3), 126.13 s (C3a),
141.33 d (C3), 143.52 d (C5), 152.17 s (C8a), 152.98 s
(C2), 156.88 s (C9a), 172.31 s (C7). Found, %: C 49.60;
H 4.11; F 13.40; N 3.09; S 7.86. C18H18F3NO6S. Cal-
culated, %: C 49.88; H 4.19; F 13.15; N 3.23; S 7.40.
2-Isopropyl-9-[(4-methylpiperazin-1-yl)methyl]-
2H-furo[3,2-g]chromene-3,7-dione (XI). Compound
VII, 0.5 g (1.35 mmol), was dissolved in 2 ml of
methanol, 5 ml of aqueous HCl was added, and the
mixture was left to stand for 12 h. The mixture was
diluted with water and extracted with methylene
chloride (3×4 ml), and the combined extracts were
dried over MgSO4 and evaporated. Attempted recrys-
tallization gave 0.22 g (46%) of oily compound XI. IR
spectrum, ν, cm–1: 2962, 2935, 2877, 2836, 2792,
2740, 2682, 1739, 1629, 1616, 1456, 1413, 1359,
1168, 1141, 1095, 1010, 821. UV spectrum (EtOH),
2-Isopropyl-9-[(4-methylpiperazin-1-yl)methyl]-
7-oxo-7H-furo[3,2-g]chromen-3-yl trifluorometh-
anesulfonate (XIII) was synthesized in a similar way
from 280 mg (0.8 mmol) of 9-[(dimethylamino)meth-
yl]oreoselone (XI) and 0.67 g (2.4 mmol) of trifluoro-
methanesulfonic anhydride. Yield 0.26 g (67%),
mp 107–108°C (from Et2O). IR spectrum, ν, cm–1:
3420, 2992, 2913, 2818, 2814, 1726, 1645, 1630,
1570, 1489, 1462, 1414, 1308, 1303, 1244, 1213,
1187, 1140, 1100, 1030, 970, 944, 855, 823, 741, 604.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.28 d
[6H, (CH3)2CH, J = 7.0], 1.88 m [1H, (CH3)2CH)],
λ
max, nm (logε): 194 (3.55), 203 (4.10), 258 (3.79), 301
(3.51), 343 (3.28). 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 1.24 d [6H, (CH3)2CH, J = 7.0], 2.34 s (3H,
NCH3), 2.16 m and 3.09 m (8H, NCH2CH2N), 3.70 m
[1H, CH(CH3)2], 4.03 s (2H, CH2N), 4.50 m (1H,
2-H), 6.21 d (1H, 6-H, J = 9.4), 7.49 s (1H, 4-H),
7.63 d (1H, 5-H, J = 9.4). 13C NMR spectrum, δC,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 3 2013

PLANT COUMARINS: XIII.
409
2.16 m (4H, 3′-H, 5′-H, and 2H, 2′-H, 6′-H), 2.33 s
(3H, CH3), 3.09 m (2H, 2′-H, 6′-H), 4.00 s (2H,
CH2N), 6.19 d (1H, 6-H, J = 9.4), 7.47 s (1H, 4-H),
7.60 d (1H, 5-H, J = 9.4). 13C NMR spectrum, δC,
ppm: 20.23 q (6H, CH3), 25.86 d (CH), 46.37 t
(CH2N), 45.02 q (NCH3), 49.18 t and 51.32 t (C2′, C3′,
C5′, C6′), 100.44 s (C9), 115.50 d (C6), 115.98 s (C4a),
120.16 d (C4), 122.22 q (CF3), 126.13 s (C3a), 141.33 s
(C3), 143.52 d (C5), 152.17 s (C8a), 152.98 s (C2),
156.88 s (C9a), 160.31 s (C7). Found, %: C 51.68;
H 3.81; F 11.70; N 5.69; S 6.84. C21H19F3N2O6S. Cal-
culated, %: C 52.06; H 3.95; F 11.77; N 5.78; S 6.62.
2-Isopropyl-9-[(4-methylpiperazin-1-yl)methyl]-
3-(2-methylphenyl)-7H-furo[3,2-g]chromen-7-one
(XVI). a. Compound XIII, 0.2 g (0.4 mmol), was
dissolved in 3 ml of acetonitrile, 0.072 g (0.52 mmol,
1.3 equiv) of o-tolylboronic acid (XIV), 0.011 g
(0.05 equiv) of PdCl2(dppf), 0.12 g (3 equiv) of
K2CO3, and 0.01 g (10 mol %) of Bu4NBr were added
under stirring in a stream of argon, and the mixture
was stirred for 5 h at 80°C (TLC). The mixture was
cooled, treated with 3 ml of water, and extracted with
methylene chloride (4×5 ml), the combined extracts
were washed with water (2×5 ml), dried over MgSO4,
and evaporated under reduced pressure, and the residue
was purified by column chromatography on silica gel
using chloroform and chloroform–ethanol (50:2) as
eluent, followed by recrystallization from diethyl ether.
Yield 0.137 g (80%).
9-[(Dimethylamino)methyl]-2-isopropyl-3-(2-
methylphenyl)-7H-furo[3,2-g]chromen-7-one (XV).
Compound XII, 0.2 g (0.46 mmol), was dissolved in
3 ml of acetonitrile, 0.081 g (0.6 mmol, 1.3 equiv) of
o-tolylboronic acid (XIV), 0.016 g (0.025 mmol,
0.05 equiv) of PdCl2(dppf), 0.19 g (1.38 mol, 3 equiv)
of K2CO3, and 0.011 g (10 mol %) of Bu4NBr were
added under stirring in a stream of argon, and the
mixture was stirred for 4.5 h at 80°C (TLC). The mix-
ture was cooled, treated with 3 ml of water, and ex-
tracted with methylene chloride (4×5 ml), the com-
bined extracts were washed with water (2×10 ml) and
dried over MgSO4, the solvent was distilled under
reduced pressure, and the residue was subjected to
column chromatography on silica gel using chloroform
and chloroform–ethanol (50:2) as eluents. The product
was additionally recrystallized from diethyl ether.
Yield 0.13 g (76%), mp 97–98°C. UV spectrum
(EtOH), λmax, nm (logε): 203 (4.51), 251 (4.05), 298
(3.63), 309 (3.64), 342 (3.75), 352 (3.75). IR spectrum,
ν, cm–1: 3429, 3062, 3051, 2966, 2927, 1720, 1625,
1600, 1570, 1483, 1442, 1344, 1299, 1278, 1199,
1132, 1095, 1066, 1041, 987, 897, 734, 688, 601.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.22 d
[6H, (CH3)2CH], 2.21 s (6H, MeN), 2.81 s (3H,
2′-CH3), 3.12 m [1H, (CH3)2CH], 3.52 d (2H, CH2N),
6.33 d (1H, 6-H, J = 9.4), 7.29 m (2H, 3′-H, 4′-H),
7.44 m (2H, 5′-H, 6′-H), 7.76 s (1H, 4-H), 8.19 d (1H,
5-H, J = 9.4). 13C NMR spectrum, δC, ppm: 23.30 q
[(CH3)2CH], 26.10 d [CH(CH3)2], 41.52 q (2′-CH3),
45.21 q and 48.32 q (NCH3), 49.47 t (CH2N), 109.91 s
(C9), 112.40 s (C6), 113.95 s (C4a), 117.37 d (C6′),
119.51 d (C4), 123.73 s (C3a), 125.18 d (C3′), 127.26 d
(C4′), 129.01 d (C5′), 130.56 s (C2′), 137.21 s (C1′),
140.45 s (C3), 143.46 d (C5), 149.14 s (C8a), 152.86 s
(C2), 154.94 s (C9a), 161.57 s (C7). Found, %: C 73.45;
H 6.35; N 3.55. C24H25NO3 ·H2O. Calculated, %:
C 73.26; H 6.92; N 3.56.
b. Compound XIII, 0.2 g (0.4 mmol), was dis-
solved in 3 ml of anhydrous dioxane, 0.072 g
(0.52 mmol, 1.3 equiv) of o-tolylboronic acid (XIV),
14 mg (0.025 mmol) of Pd(PPh3)4, 200 mg (1.5 mmol)
of K2CO3, and 11 mg (10 mol %) of Bu4N+ Br– were
added under argon, and the mixture was stirred for 6 h
at 100°C (TLC). The mixture was cooled, treated with
3 ml of water, and extracted with methylene chloride
(4×3 ml), the combined extracts were washed with
water, dried over magnesium sulfate, and evaporated,
and the residue was purified by column chromatog-
raphy on silica gel, followed by recrystallization from
diethyl ether. Yield 85 mg (50%).
c. Compound XIII, 0.2 g (0.4 mmol), was dissolved
in 3 ml of acetonitrile, 0.072 g (0.52 mmol, 1.3 equiv)
of o-tolylboronic acid (XIV), 18 mg (0.025 mmol,
0.05 equiv) of PdCl2(dppf), and 318 mg (1.5 mmol,
3 equiv) of K3PO4 were added under argon, and the
mixture was stirred for 6 h at 80°C (TLC). The mixture
was cooled, treated with 3 ml of water, and extracted
with methylene chloride (4×3 ml), and the combined
extracts were dried over magnesium sulfate and evap-
orated. Chromatographic purification of the residue on
a column charged with silica gel, followed by recrys-
tallization from hexane, gave 30 mg (18%) of com-
pound XVI and a large amount of tars.
Compound XVI. mp 100–101°C (from Et2O). IR
spectrum, ν, cm–1: 3417, 3066, 2970, 2937, 2877,
2842, 2802, 2742, 1726, 1637, 1577, 1458, 1415,
1388, 1363, 1286, 1217, 1168, 1141, 1120, 1097, 1037,
1008, 979, 875, 821, 781, 734. UV spectrum (EtOH),
λ
max, nm (logε): 220 (4.01), 224 (4.02), 257 (4.32), 297
(3.89), 342 (3.32). 1H NMR spectrum (CDCl3), δ, ppm
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 3 2013

LIPEEVA et al.
410
(XIX) was synthesized in a similar way from 0.15 g
(0.30 mmol) of compound XIII and 0.043 g
(0.6 mmol) of acid XVII in 3 ml of acetonitrile in the
presence of 0.011 g of PdCl2(dppf), 0.12 g of K2CO3,
and 0.01 g of Bu4NBr. Yield 0.07 g (57%), oily sub-
stance. IR spectrum, ν, cm–1: 3433, 3062, 2979, 2879,
2814, 1732, 1635, 1579, 1500, 1429, 1388, 1284,
1249, 1211, 1199, 1139, 1114, 1049, 871, 819, 601.
1H NMR spectrum (CDCl3–CD3OD), δ, ppm (J, Hz):
1.16 d [6H, (CH3)2CH, J = 7.0], 1.42 m [1H,
(CH3)2CH], 2.23 s (3H, NCH3), 2.71 m (8H,
NCH2CH2N), 5.03 s (2H, CH2N), 6.20 d (1H, 6-H, J =
9.4), 6.38 s (1H, 4″-H), 7.16 br.s (1H, 5″-H), 7.44 br.s
(1H, 2″-H), 7.52 s (1H, 4-H), 7.69 d (1H, 5-H, J = 9.4).
13C NMR spectrum, δC, ppm: 20.32 q [(CH3)2CH],
25.68 d [CH(CH3)2], 46.09 q (NCH3), 47.20 t (CH2N),
50.73 t and 54.82 t (C2′, C3′, C4′, C5′), 99.14 s (C9),
112.86 d (C4), 113.85 s (C6), 116.32 d (C4), 121.40 s
(C3a), 123.97 s (C3′), 124.86 s (C4a), 135.94 d (C2′),
142.11 s (C3), 142.78 d (C5′), 144.12 d (C5), 149.20 s
(C8a), 151.19 s (C2), 153.42 s (C9a), 161.30 s (C7).
Found, %: C 71.36; H 5.11; N 6.68. C24H22N2O4. Cal-
culated, %: C 71.63; H 5.51; N 6.96.
(J, Hz): 1.17 d [6H, (CH3)2CH, J = 7.0], 2.07 s (3H,
NCH3), 2.22 m and 2.32 m (8H, NCH2CH2N), 2.71 s
(2′-CH3), 3.12 m [1H, (CH3)2CH], 5.02 d (2H, CH2N),
6.15 d (1H, 6-H, J = 9.4), 6.92 m (3H, 3′-H, 4′-H,
5′-H), 7.10 d (1H, 6′-H), 7.38 s (1H, 4-H), 7.60 d (1H,
5-H, J = 9.4). 13C NMR spectrum, δC, ppm: 20.36 q
[(CH3)2CH], 25.63 d [CH(CH3)2], 29.21 q (2′-CH3 ),
45.45 q (NCH3), 48.78 t (CH2N), 50.05 t and 53.47 t
(C2″, C3″, C5″, C6″), 109.24 s (C9), 113.92 d (C6),
114.29 s (C4a), 116.24 d (C4), 120.51 d (C6′), 121.21 s
(C3a), 124.00 d (C3′), 128.54 d (C4′), 129.09 d (C5′),
130.62 s (C3′), 135.87 s (C1′), 143.65 s (C3), 145.78 d
(C5), 151.15 s (C8a), 152.15 s (C2), 153.16 s (C9a),
160.44 s (C7). Found, %: C 75.13; H 6.79; N 6.44.
C27H30N2O3. Calculated, %: C 75.32; H 7.02; N 6.51.
9-[(Dimethylamino)methyl]-3-(furan-3-yl)-2-iso-
propyl-7H-furo[3,2-g]chromen-7-one (XVIII). Com-
pound XII, 0.2 g (0.46 mmol), and furan-3-ylboronic
acid (XVII), 0.07 g (0.6 mmol), were dissolved in 3 ml
of acetonitrile, 0.016 g (0.025 mmol, 0.05 equiv) of
PdCl2(dppf), 0.18 g K2CO3, and 0.011 g (10 mol %) of
Bu4NBr were added under stirring in a stream of
argon, and the mixture was stirred for 4.5 h at 80°C
(TLC). The mixture was cooled, treated with 3 ml of
water, and extracted with methylene chloride (4×5 ml),
the combined extracts were washed with water (2×
10 ml), dried over MgSO4, and evaporated under
reduced pressure, and the residue was subjected to
chromatography on silica gel using chloroform and
chloroform–ethanol (50:2) as eluents. Yield 0.1 g
(65%), oily substance. IR spectrum, ν, cm–1: 3271,
2968, 2881, 2777, 2132, 2075, 1745, 1722, 1622,
1566, 1502, 1485, 1390, 1353, 1332, 1288, 1226,
1137, 1099, 1066, 1020, 995, 933, 877, 825, 744, 690,
X-Ray analysis of compound III. The X-ray dif-
fraction data were acquired on a Bruker Kappa Apex II
diffractometer equipped with a two-coordinate CCD
detector (MoKa irradiation, graphite monochromator,
ω-j scanning up to 2q < 55.2°) from a 0.20 ×0.20×
0.94-mm colorless single crystal of III. Triclinic
crystal system, space group P1; C17H19NO4; unit cell
parameters: a = 6.3978(4), b = 11.1848(8), c =
11.4605(8) Å; α = 79.122(2), β = 82.087(2), γ =
84.060(2)°; V = 795.15(9) Å3; Z = 2; dcalc = 1.259 g×
cm–3; μ = 0.090 mm–1. Total of 8966 reflection inten-
sities were measured, 3553 of which were independent
(Rint = 0.046). A correction for absorption was intro-
duced using SADABS program [21]. The structure was
solved by the direct method and was refined by the
full-matrix least-squares procedure in anisotropic ap-
proximation for non-hydrogen atoms using SHELX-97
software [22]. Hydrogen atoms were placed into cal-
culated positions which were refined according to the
riding model (coordinates of hydrogen atoms were
calculated at each iteration from the coordinates of the
corresponding carbon atoms). The final divergence
factors were wR2 = 0.2032 (against F2 for all reflec-
tions) and R = 0.0669 (for 3237 reflections with
F > 4σ); 292 variable parameters; goodness of fit
S = 1.04; maximal and minimal residual electron
densities 0.22 and –0.16 ē/Å3. The complete set of
crystallographic data for compound III was deposited
to the Cambridge Crystallographic Data Centre
1
603. H NMR spectrum (CDCl3–CD3OD), δ, ppm
(J, Hz): 0.81 d and 0.95 d [3H each, (CH3)2CH, J =
7.0], 1.21 m [1H, (CH3)2CH], 2.13 s [6H, (CH3)2N],
3.85 s (2H, CH2N), 6.53 s (2H, 4′-H), 6.29 d (1H, 6-H,
J = 9.4), 7.39 br.s (1H, 5′-H), 7.68 br.s (1H, 2′-H),
7.77 d (1H, 5-H, J = 9.4), 7.79 s (1H, 4-H). 13C NMR
spectrum, δC, ppm: 15.8 q [(CH3)2CH], 21.86 d
[CH(CH3)2], 32.40 q and 33.14 q (NCH3), 46.87 t
(CH2N), 99.48 s (C9), 109.44 s (C4a), 113.40 s (C6),
119.60 s (C3a), 123.17 d (C4), 124.75 d (C2′), 124.07 t
(C3′), 138.91 s (C3), 140.64 d (C2′), 142.42 d (C5′),
142.96 d (C5), 145.53 s (C8a), 158.97 (C2), 160.15 s
(C9a), 172.60 s (C7). Found, %: C 71.12; H 5.94;
N 3.78. C21H21NO4. Calculated, %: C 71.78; H 6.02;
N 3.99.
3-(Furan-3-yl)-2-isopropyl-9-[(4-methylpiper-
azin-1-yl)methyl]-7H-furo[3,2-g]chromen-7-one
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 3 2013

PLANT COUMARINS: XIII.
411
10. Tramontini, M. and Angiolini, L., Tetrahedron, 1990,
(entry no. CCDC 909 587) and is available at
www.ccdc.cam.ac.uk/data_request/cgi-bin/catreq.cgi.
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11. Niyazov, N.A., Timofeev, V.P., Surkov, V.D., and Lyubi-
mov, N.V., Russian Patent no. 2144529, 2000; Byull.
Izobret., 2000, no. 4.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 12-03-92200-a, 12-03-31096).
12. Osadchii, S.A., Shul’ts, E.E., Shakirov, M.M., and Tol-
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