Plant coumarins. 4. Synthesis of N-containing derivatives of oreoselone

Article abstract of DOI:10.1007/s10600-009-9347-5

Bromination of peucedanin by various reagents was studied. Conditions for forming 2-(1,3-dibromopropan-2-ylidene)-2H-furo[3,2-g][1]benzopyran-3,7-dione were found. Several 2-aminofuranocoumarins were synthesized by reaction of 2-bromoreoselone with deriva

Full text of DOI:10.1007/s10600-009-9347-5

Chemistry of Natural Compounds, Vol. 45, No. 3, 2009
PLANT COUMARINS. 4.* SYNTHESIS OF N-CONTAINING
DERIVATIVES OF OREOSELONE
A. V. Lipeeva, E. E. Shul′ts,* M. M. Shakirov, and G. A. Tolstikov
UDC 547.587.51
Bromination of peucedanin by various reagents was studied. Conditions for forming 2-(1,3-dibromopropan-
2-ylidene)-2H-furo[3,2-g][1]benzopyran-3,7-dione were found. Several 2-aminofuranocoumarins were
synthesized by reaction of 2-bromoreoselone with derivatives of pyrrolidine, piperidine, and piperazine.
The new compounds were interesting as potential biologically active compounds.
Key words: furanocoumarins, bromoreoselone, 2-(1-methylethylidene)-7H-furo[3,2-g][1]benzopyran-3,7-dione.
Linear dihydrofuranocoumarins are widely distributed plant metabolites with pronounced biological activity [2-4].
Thus, marmesin (1) is an effective c-AMP synthetase [5] and acetylcholinesterase [6] inhibitor. Propanediol (2) is used as an
antidote to snake venom [7]. The potential of coumarins for creating new antioxidants has recently been actively discussed
owing to their specific activity as selective MAO inhibitors [8]. Thus, the development of methods for modifying
furanocoumarins is of definite interest in medicinal chemistry.
H CO
3
O
HO
HO
O
O
O
O
O
O
O
O
O
O
O
O
OH
3
2
4
1
O
O
O
5
Br
Br
Br
e
a - d
e
3
3
7
O
O
O
O
O
O
O
O
O
1
6
7
5
a. Br -HCOOH; b. NBS-CCl ; c. PyHBrCl –MeOH; d. DDB-CCl ; e. NBS-(PhCO-) O, CCl
2
4
2
4
2
4
Scheme 1
An accessible source of furanocoumarins is Peucedanum morisonii Bess., which is widely distributed in western
Siberia. Its main metabolite peucedanin (3) can be isolated from roots of the plant in yields up to 4% of the dry raw material
mass [9]. The preparation of several derivatives of peucedanin and its hydrolysis product oreoselone (4) through modification
of the furan ring has been reported [10, 11]. Herein we describe the synthesis of new oreoselone derivatives.
The starting material for the transformations was 2-bromoreoselone (5), which was formed by bromination of 3 with
Br in CHCl , as previously reported [10]. We found that 5 was also the only product from bromination of peucedanin by Br
2
3
2
in formic acid (98% yield), by dioxanedibromide in CCl (94-98% yield), by N-bromosuccinimide in CCl (97-98% yield),
4
4
and by pyridine dichlorobromate (PyHBrCl ) in CH OH (94% yield).
2
3
Subsequent bromination of 5 by NBS (3 equiv.) in the presence of benzoyl peroxide in CCl formed 2-(1,3-
4
dibromopropan-2-ylidene)-2H-furo[3,2-g][1]benzopyran-3,7-dione (6) (73% yield). Obviously benzoyl peroxide enhances
dehydrobromination of 2-bromoreoselone and subsequent allylic bromination. This was confirmed by the fact that 6 was
formed by bromination of known 2-(1-methylethylidene)-7H-furo[3,2-g][1]benzopyran-3,7-dione (7) under these conditions
[10, 12] (51% yield).
______
*For Part 2, see [1].
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
Novosibirsk, Russia, fax: (383) 330 97 52, e-mail: schultz@nioch.nsc.ru. Translated from Khimiya Prirodnykh Soedinenii,
No. 3, pp. 289-294, May-June, 2009. Original article submitted December 30, 2008.
©
338
0009-3130/09/4503-0338 2009 Springer Science+Business Media, Inc.

N-containing derivatives of coumarins are known to exhibit a broad spectrum of biological activity [4]. Thus,
8-piperazino-7-hydroxycoumarins exhibit high anti-inflammatory activity [13]. We studied the behavior of 5 upon reaction
with various amines. The reaction of 5 with pyrrolidine and (S)-prolinol was carried out by mixing the components in CHCl
3
or DMF and under phase-transfer catalysis conditions (organic phase EtOAc or CH Cl ; catalyst TEBAC with catalysis
2
2
promoter alcohol [14]). In all instances products of nucleophilic substitution of Br, compounds 8 and 9 (34-42% yield), and 7,
the product of HBr elimination from starting 5, were isolated. Table 1 gives the conditions and composition of reaction
products. It can be seen that performing the reaction of pyrrolidine with 5 in DMF increases the yield of the substitution
product 2-isopropyl-2-(pyrrolidin-1-yl)-2H-furo[3,2-g]chromen-3,7-dione (8). The reaction of the alkaloid anabasine (10)
with 5 gave high yields of the pure substitution product 2-isopropyl-2-[(S)-2-(pyridin-3-yl)piperidin-1-yl]-2H-furo[3,2-
g]chromen-3,7-dione (11) (61-65%). Reaction of 5 with 4-substituted piperazines gave low yields of 2-isopropyl-2-(4-R-
piperazin-1-yl)-2H-furo[3,2-g]chromen-3,7-diones 12-18 (18-48%). The reaction of N-(2-aminoethyl)-piperazine with 5 was
used as an example to show that performing the reaction under phase-transfer catalysis conditions increased the yield of
substitution product 13. A comparison of the reactions of various piperazines with 5 found that the yields of substitution
products were greatest for the reaction of 5 bromide with N-(4-methoxyphenyl)- and N-(4-nitrophenylpiperazines. The reaction
of 5 with alkaloids (-)-ephedrine (19) and (+)-pseudoephedrine (20) was carried out under phase-transfer catalysis conditions
using EtOAc and CH Cl as the organic phase. Using the latter could increase the yields of 21 and 22.
2
2
R
R
2''
R
2
O
O
1''
N
N1''
NH
R N
1
NH
R
N4''
5''
O
O
5
O
1'
O
O
O
iii
i - iii
H
8, 9
12 - 18
12: R = Me; 13: R = CH CH NH
2
8: R = H; 9: R = CH OH
N
H
2
2
2
i, iii
14: R = 4-NO C H ; 15:R = 4-MeOC H
2
6
6 4
4
6 4
N
N
10
16: R = 2-MeOC H
O
17: R =
O
H
18:R = 2-Me-3-MeC H
6
3
O
2'' N
5''
1'
H
H
H
HO
O
O
O
3''
2'C'
2''
Me
Me
C
C
C
Ph
HO
Ph
11
19
iv
O
O
3''
N1''
1'
N1''
H
20
iv
Me
Me
5
1'
O
O
O
O
O
O
Ph
Ph
21
22
H
HO
N
H
OH
H
C
C
C
Me
H
Me
C
H
N
H
Me
19
Me
20
i. CHCl , 20°C, 16 h; ii. DMFA, 20°C, 8 – 10 h; iii. EtOAc – 40% KOH, TEBAC–EtOH, 20°C, 8 h;
3
iv. CH Cl – 40% KOH, TEBAC– EtOH, 20°C, 8 h
2
2
Scheme 2
The compositions and structures of 2-substituted oreoselone derivatives 6, 8, 9, 11-18, 21, and 22 were confirmed by
elemental analyses and mass, IR, UV, and NMR spectra. Both dibromide 6 and products from reactions with amines 8, 9, 11-
18, 21, and 22 had UV spectra characteristic of furanocoumarins. For example, the spectrum of 6 had absorption bands with
maxima at 280, 309, 320 (sh), and 364 nm. UV spectra of amino-derivatives 8, 9, 11-18, 21, and 22 had four absorption bands,
13
the maxima of which, for example for 22, were located at 266, 274, 303, and 356 nm. PMR and C NMR spectra of the
products agreed fully with their structures and contained one set of resonances characteristic of the furanocoumarin backbone
and the corresponding substituent. Compounds 9, 11, 21, and 22 were formed as pure diastereoisomers. The principal
differences in PMR spectra of (1R,2S)- and (1S,2S)-2-{[(1-hydroxy-1-phenylpropan-2-yl](methyl)amino}-2-isopropyl-2H-
furo[3,2-g]chromen-3,7-diones 21 and 22 were the chemical shifts and SSCCs of side-chain protons H-2′′ and H-3′′.
339

TABLE 1. Conditions and Products from Reaction of 2-Bromoreoselone (5) with Amines
Amine
Reaction conditions
Yield, %
Pyrrolidine
Pyrrolidine
Pyrrolidine
S-Prolinol
S-Prolinol
(–)-Anabasine (10)
(10)
(10)
8 (38)
8 (42)
7 (51)
7 (49)
7 (50)
7 (51)
7 (52)
7 (24)
7 (25)
7 (27)
7 (41)
7 (57)
7 (56)
7 (58)
7 (54)
7 (40)
7 (48)
7 (59)
7 (60)
7 (48)
7 (50)
CHCl3, 20°C, 16 h (i)
DMF, 20°C, 8–10 h (ii)
EA-40% KOH, TEBAC–EtOH, 20°C, 8 h (iii)
8 (34)
9 (36)
(i)
(iii)
(i)
(ii)
(iii)
(i)
(ii)
(ii)
(iii)
(iii)
(iii)
(iii)
(iii)
(iii)
9 (36)
11 (64)
11 (61)
11 (65)
12 (33)
12 (30)
13 (18)
13 (27)
14 (34)
15 (48)
16 (46)
17 (37)
18 (34)
21 (41)
22 (40)
N-Methylpiperazine
N-Methylpiperazine
N-(2-Aminoethyl)-piperazine
N-(2-Aminoethyl)-piperazine
1-(3,4-Methylenedioxy)piperazine
1-(4-Nitrophenyl)piperazine
1-(4-Methoxyphenyl)piperazine
1-(2-Methoxyphenyl)piperazine
1-(2,3-Dimethylphenyl)piperazine
(–)-Ephedrine (19)
CH2Cl2–40% KOH, TEBAC–EtOH, 20°C, 8 h (iv)
(+)-Pseudoephedrine (20)
(iv)
13
TABLE 2. Chemical Shifts in C NMR Spectra of 6, 8, 9, and 11–14 (δ, ppm)
C atom
6
8
9
11
12
13
14
2
3
3a
4
4a
5
6
7
8a
9
9a
1′
2′
3′
2′′
3′′
4′′
5′′
6′′
145.05 s
181.80 s
119.31 s
125.12 d
115.52 s
143.09 d
115.48 d
165.73 s
160.51 s
101.22 d
158.88 s
126.08 s
26.13 ta
24.58 ta
–
111.86 s
198.21 s
120.47 s
124.35 d
113.28 s
143.41 d
114.60 d
159.30 s
161.67 s
100.55 d
169.64 s
34.70 d
15.63 qa
15.90 qa
45.58 tb
24.24 tc
25.91 tc
46.71 tb
–
111.93 s
197.55 s
118.10 s
123.90 d
114.11 s
142.98 d
114.01 d
158.75 s
161.09 s
99.85 d
171.39 s
33.63 d
15.24 qa
14.47 qa
59.32 d
29.03 t
114.69 s
197.87 s
120.76 s
124.45 d
115.72 s
143.13 d
115.39 d
158.83 s
161.13 s
101.62 d
169.60 s
31.81 d
16.67 q
17.52 q
36.47 d
29.59 ta
22.59 t
109.09 s
197.86 s
119.86 s
124.58 d
114.38 s
143.69 d
114.77 d
159.65 s
162.06 s
100.59 s
172.97 s
31.27 d
15.34 qa
16.94 qa
43.09 tb
54.66 t
111.95 s
197.50 s
120.64 s
124.18 d
113.83 s
143.05 d
114.04 d
158.68 s
161.11 s
100.23 s
171.70 s
31.29 d
15.27 qa
16.06 qa
41.19 tb
54.22 tc
–
108.73 s
197.32 s
119.54 s
124.24 d
114.01 s
143.27 d
112.71 d
159.13 s
161.64 s
100.02 s
172.49 s
29.27 d
14.00 qa
15.02 qa
45.45 tb
50.53 t
–
–
–
–
22.27 t
45.09 t
62.95 t
–
–
29.62 ta
36.47 t
54.66 t
56.64 tc
42.18 tb
50.53 t
44.48 tb
46.91 tb
For 21, these protons were situated at weaker field and had SSCC corresponding to cis protons [δ 2.90 (H-2′′) and
3
4.97 ppm (H-3′′), J = 3.0 Hz] as compared with their position in the spectrum of 22 [δ 2.57 (H-2′′) and 4.14 (H-3′′)]. The
3
SSCC between these protons in 22 ( J = 9.2 Hz) corresponded with their trans position. It was also interesting that the
chemical shifts of methyl protons of the isopropyl substituent in 20 and 21 were significantly different (Δδ 0.41 ppm). This
difference in the PMR spectra of 12-18 was Δδ 0.32-0.40 ppm; in those of 8 and 9, Δδ 0.17-0.19 ppm.
340

13
TABLE 2a. Chemical Shifts in C NMR Spectra of 15–18, 21, and 22 (δ, ppm)
C atom
15
16
17
18
21
22
2
3
3a
4
4a
5
6
7
8a
9
9a
1′
2′
3′
2′′
3′′
4′′
5′′
6′′
109.65 s
197.97 s
119.68 s
124.45 d
114.27 s
143.72 d
113.81 d
159.55 s
161.74 s
100.11 s
172.81 s
31.44 d
15.00 qa
16.53 qa
45.59 tb
50.91 t
109.68 s
197.88 s
119.69 s
124.05 d
113.98 s
143.33 d
113.98 d
159.32 s
161.43 s
99.84 s
172.61 s
31.32 d
14.87 qa
16.43 qa
45.72 tb
50.05 tc
–
109.87 s
198.00 s
119.81 s
123.77 d
113.36 s
143.53 d
113.70 d
159.51 s
161.57 s
100.82 s
172.77 s
31.50 d
15.01 qa
16.60 qa
45.71 t
109.38 s
197.78 s
119.07 s
125.84 d
114.68 s
143.64 d
115.43 d
160.78 s
162.25 s
100.43 s
171.49 s
29.60 d
15.45 qa
15.84 qa
44.72 t
114.99 s
196.67 s
120.54 s
125.27 d
115.19 s
143.91 d
114.28 d
159.31 s
160.09 s
100.20 s
166.09 s
30.52 d
17.17 qa
19.28 qa
73.14 d
60.26 d
–
115.47 s
197.48 s
116.54 s
126.81 d
116.16 s
143.93 d
116.16 d
158.73 s
161.93 s
101.19 s
170.39 s
32.86 d
17.47 qa
18.34 qa
78.03 d
61.83 d
–
52.47 t
51.43 t
–
–
–
50.91 t
51.53 tc
45.92 tb
52.47 t
45.71 t
51.43 t
44.72 t
–
–
–
–
45.90 tb
______
a,b,c,d
Chemical shifts denoted by the same letters may be switched within one column.
*For 11: Ar(Py)-C(2), 143.60 s; C(3), 143.67 d; C(4), 143.13 d; C(5), 125.99 d; C(6), 161.27 d; 12: N–CH , 44.78 q;
3
13: N–CH , 59.70 t; CH NH , 36.20 t; 14: Ar–C(1), 154.42 s; C(2,6), 112.72 d; C(4), 138.69 s; C(3,5), 125.74 d; 15: Ar–C(1),
2
2
2
145.50 s; C(2,6), 118.45 d; C(4), 154.11 s; C(3,5), 114.50 d; OCH (on C-4), 55.59 q; 16: Ar–C(1), 160.63 s; C(2), 140.69 s;
3
3
C(3), 117.94 d; C(4), 122.95 d; C(5), 120.84 d, C(6), 123.51 d; CH (on C-2), 55.24 q; 17: Ar–C(1), 146.62 s; C(2), 100.42 d;
C(3), 147.59 s; C(4), 143.50 s; C(5), 114.14 d; C(6), 107.80 d; (–O–CH –O), 110.05 t; 18: Ar–C(1), 150.39 s; C(2), 119.07 s;
2
C(3), 138.16 s; C(4), 118.48 d; C(5), 125.98 d; C(6), 114.44 d; CH (on C-2) 13.71 q; CH (on C-3), 20.54 q; 21: Ar–C(1),
3
3
139.51 s; C(2,6), 125.37 d; C(3,5), 128.14 d; C(4), 127.45 d; CH (on C′′), 14.48 q; 22: Ar–C(1), 142.10 s; C(2,6), 127.80 d;
3
C(3,5), 129.15 d; C(4), 118.48 d; CH (on C-2′′), 14.71 q.
3
EXPERIMENTAL
1
13
NMR spectra were recorded on Bruker AV-300 [operating frequency 300.13 ( H) and 75.47 MHz ( C)], AM-400
1
13
1
[operating frequency 400.13 ( H) and 100.78 MHz ( C)], and DRX-500 [operating frequency 500.13 ( H) and 125.76 MHz
13
13
( C)] instruments. The multiplicity of resonances in C NMR spectra were determined by standard methods of recording
spectra in JMOD and with off-resonance proton decoupling. Mass spectra were obtained in a DFS high-resolution mass
spectrometer. Specific rotations were measured on a Polar 3005 polarimeter at room (20-23°C) temperature. Elemental
analyses were performed on a Carlo Erba Model 1106 CHN-analyzer. IR spectra in KBr disks were recorded on a Vector-22
−4
instrument. UV absorption spectra in ethanol (c 10 M) were recorded on a HP 8453 UV—Vis spectrometer.
The course of reactions and purity of products were monitored by TLC on Silufol UV-254 plates with elution by
CHCl :C H OH (3:1), benzene, and benzene—EtOAc (1:1). Spots were detected in an iodine chamber and by using UV light.
3
2 5
Pyridinium dichlorobromate was prepared by the literature method [15]. Alkaloids used in the reactions were isolated
from plant material: (-)-anabasine [(2S)-3-(2-piperidinyl)-pyridine] (10), mp 104-105°C (2 Torr), lit. [16] n2D0 1.5430,
23
[α]
−62° (c 5, C H )] from the aerial part of Anabasis aphylla L. by the literature method [17]; (-)-ephedrine (19) [(1R,2S)-
578
6 6
2-methylamino-1-phenylpropan-1-ol], mp 38-39°C (hexane), lit. [18] mp 38-39°C (petroleum ether), from the hydrochloride
20
{mp 216-217°C (EtOH), [α]
−36° (c 2, H O), lit. [18] mp 216-217°C (EtOH), [α] −34.4° (c 1.5, H O)}. The latter was
578
2 589 2
prepared from ephedrine contained in the non-woody upper part of Ephedra equisetina Bunge by the literature method [19].
341

(+)-Pseudoephedrine (20) [(1S,2S)-2-methylamino-1-phenylpropan-1-ol] {mp 118-119°C (distilled at 100°C/12 Torr after
20
crystallization from C H ), [α]
+53° (c 3, EtOH), lit. [18] mp 118-119°C (purified as above), [α] +55.5° (c 8.1, EtOH)}
578
6
6
589
was isolated as the hydrochloride from ephedra without preliminary purification.
13
Tables 2 and 2a list the C NMR spectra of 6, 8, 9, 11-18, 21, and 22.
2-(1,3-Dibromopropan-2-ylidene)-2H-furo[3,2-g][1]benzopyran-3,7-dione (6). Method A. A solution of
bromoreoselone (5, 1 g, 3.1 mmol) in CCl (12 mL) was treated with NBS (1.6 g, 9.3 mmol) and benzoyl peroxide (5 mol%).
4
The mixture was refluxed for 10 h, cooled, and filtered to remove succinimide (1.18 g, identified by mp). The filtrate was
evaporated and treated with ether to afford a precipitate (1.34 g) from which column chromatography over silica gel (CHCl
3
eluent) and recrystallization of the product fraction from EtOAc afforded dibromide 6 (0.91 g, 73%).
Method B. A solution of 7 (0.5 g, 2.05 mmol) in CCl (12 mL) was treated with NBS (0.73 g, 4.1 mmol) and benzoyl
4
peroxide (5 mol %). The mixture was refluxed for 10 h. Succinimide (0.4 g, identified by mp) was filtered off after the
reaction was finished. The mother liquor was evaporated and treated with ether to afford a precipitate (0.61 g) from which
column chromatography over silica gel (CHCl eluent) and recrystallization of the product fraction from EtOAc afforded
3
−1
dibromide 6 (0.41 g, 51%), mp 189°C. IR spectrum (ν, cm ): 828, 856, 890, 1138, 1353, 1600, 1620, 1658, 1709, 1744. UV
spectrum (CHCl , λ , nm, log ε): 280 (4.25), 309 (4.49), 320 sh (3.45), 364 (3.48).
3
max
PMR spectrum (δ, ppm, J/Hz): 4.47 (2H, s, CH Br), 4.95 (2H, s, CH Br), 6.42 (1H, d, J = 9.6, H-6), 7.15 (1H, s,
2
2
H-9), 7.74 (1H, d, J = 9.6, H-5), 7.91 (1H, s, H-4).
+
+
+
Mass spectrum (m/z, I , %): 399 (25) [M] , 321 (40) [M - Br] , 240 (100) [M - 2Br] , 211 (100), 188 (10). Found
rel
[M] 397.8783. C H Br O . Calcd 397.8784. C H Br O .
14
8
2
4
14
8
2 4
Reaction of 2-Bromoreoselone with Amines. i: a solution of 5 (5.3 mmol, 1.7 g) in CHCl (4 mL) was stirred,
3
treated with a solution of the amine (10.6 mmol) in CHCl (4 mL), and held at room temperature for 16 h. When the reaction
3
was finished (TLC monitoring), the reaction mixture was diluted with water (10 mL). The organic layer was separated. The
aqueous layer was extracted with CHCl (3 × 4 mL). The organic layer was dried over MgSO and evaporated. The solid was
3
4
dissolved in acetone and cooled. The majority of 7 was filtered off. The mother liquor was evaporated. The solid was
chromatographed over aluminum oxide (activity level II) with elution by CHCl . The product fraction was treated with ether.
3
Recrystallization from the appropriate solvent afforded 8, 9, 11, and 12.
ii: a solution of 5 (3.9 mol) in DMF (10 mL) was stirred, treated with amine (7.8 mmol), and stirred for 8-10 h at
25°C. When the reaction was finished, saturated NH Cl solution (10 mL) was added. Products were extracted by CH Cl
4
2
2
(4 × 5 mL). Solvent was evaporated in vacuo. The solid was dried in a Petri dish and treated with hexane. The resulting
precipitate was recrystallized from acetone to afford 7. The mother liquor was evaporated. Compounds 8 and 11-13 were
isolated by column chromatography over aluminum oxide.
iii: a mixture of KOH (4 mL, 30%), EtOAc (20 mL), and TEBAC (0.006 mg) in alcohol (0.5 mL) was stirred, treated
with 5 (3.1 mmol) and amine (6.2 mmol), and stirred for 8 h at room temperature. The organic layer was separated. The
aqueous layer was extracted with CH Cl (3 × 4 mL). Solvent was evaporated in vacuo. The solid was treated with hexane
2
2
and recrystallized from acetone to afford 7. The mother liquor was evaporated. The solid was crystallized from EtOAc or
chromatographed over aluminum oxide (CHCl eluent) to afford 8, 9, 11, and 13-18.
3
iv: a mixture of KOH (4 mL, 30%), EtOAc (20 mL), and TEBAC (0.006 mg) in alcohol (0.5 mL) was stirred, treated
with 5 (3.1 mmol) and amine (6.2 mmol), and stirred for 8 h at room temperature. The organic layer was separated. The
aqueous layer was extracted with CH Cl (3 × 4 mL). Solvent was evaporated in vacuo. The solid was treated with hexane
2
2
and recrystallized from acetone to isolate 7. The mother liquor was evaporated. The solid was chromatographed twice over
aluminum oxide (CHCl eluent). The product fraction was crystallized from EtOAc to afford 21 and 22.
3
2-Isopropyl-2-(pyrrolidin-1-yl)-2H-furo[3,2-g]chromen-3,7-dione (8). Mp 158-161°C (EtOAc). IR spectrum
−1
(KBr, ν, cm ): 908, 1096, 1142, 1170, 1298, 1343, 1622, 1708, 1724. UV spectrum (EtOH, λ , nm, log ε): 257 (3.94), 278
max
(3.88), 314 (3.72), 337 (3.67).
PMR spectrum (δ, ppm, J/Hz): 0.84, 1.02 (both d, 3H each, J = 7.0, Me-2′,3′), 1.56, 1.75 (both m, 4H, H-3′′,4′′), 1.87-
2.10 (2H, m, H-2′′,5′′), 2.70-2.90 (2H, m, H-2′′,5′′), 3.17 m (1H, m, H-1′), 6.33 (1H, d, J = 9.6, H-6), 6.94 (1H, s, H-9), 7.67
(1H, d, J = 9.6, H-5), 7.76 (s, 1H, H-4). C H NO .
18 19
4
2-[(R)-(2-Hydroxymethyl)pyrrolidin-1-yl]-2-isopropyl-2H-furo[3,2-g]chromen-3,7-dione (9). Mp 212-215°C
(ether), [α]2D0 −7.6° (c 1.0, CHCl :EtOH, 1:1). IR spectrum (KBr, ν, cm ): 826, 856, 1140, 1351, 1451, 1624, 1731, 2929,
−1
3
3007, 3330. UV spectrum (EtOH, λ , nm, log ε): 257 (4.04), 273 (3.84), 301 (3.80), 350 (3.65).
max
342

PMR spectrum (δ, ppm, J/Hz): 0.83, 1.02 (both d, 3H each, J = 7.0, Me-2′,3′), 1.52-1.67 (2H, m, H-3′′,4′′), 1.78-2.10
(4H, m, H-3′′,4′′,5′′,5′′), 2.32 (1H, m, H-1′), 3.32-3.60 (3H, m, H-2′′,6′′,6′′), 4.16 (1H, m, OH), 6.32 (1H, d, J = 9.6, H-6), 6.95
(1H, s, H-9), 7.67 (1H, d, J = 9.6, H-5), 7.76 (s, 1H, H-4). C H NO ×CHCl .
19 21
5
3
2-Isopropyl-2-[(S)-2-(pyridin-3-yl)piperidin-1-yl]-2H-furo[3,2-g]chromen-3,7-dione (11).
Mp 200-201°C,
[α]2D0 −3.2° (c 0.5, CHCl ). IR spectrum (KBr, ν, cm ): 854, 908, 1100, 1125, 1140, 1353, 1483, 1579, 1627, 1655, 1737,
−1
3
3230. UV spectrum (EtOH, λ , nm, log ε): 257 (4.31), 277 (4.19), 299 (4.04), 345 (3.88).
max
PMR spectrum (δ, ppm, J/Hz): 1.01, 1.06 (both d, 3H each, J = 7.0, Me-2′,3′), 1.42-1.55 (m, 2H, H-5′′), 1.70-1.84 (m,
3H, 2H, H-4′′ and 1H, H-3′′), 1.98 (m, 1H, H-3′′), 2.37 (1H, m, H-1′′), 2.83 (m, 1H, H-6′′), 3.21 (m, 1H, H-6′′), 3.88 (m, 1H,
H-2′′), 6.27 (1H, d, J = 9.6, H-6), 6.85 (1H, s, H-9), 7.22 [t, 1H, H(5)-Py, J = 7.6, 7.5], 7.64 (1H, d, J = 9.6, H-5), 7.69 (s, 1H,
H-4), 7.84 [d, 1H, H(4)-Py, J = 7.5], 8.42 [d, 1H, H(6)-Py, J = 7.6], 8.56 [d, 1H, H(2)-Py, J = 1.2]. C H N O .
24 24
2 4
2-Isopropyl-2-(4-methylpiperazin-1-yl)-2H-furo[3,2-g]chromen-3,7-dione (12). Mp 214-216°C. IR spectrum (KBr,
−1
ν, cm ): 825, 859, 909, 1091, 1136, 1350, 1391, 1574, 1624, 1650, 1722, 2975. UV spectrum (EtOH, λ , nm, log ε): 257
max
(4.31), 299 (3.99), 313 (3.89), 354 (3.91).
PMR spectrum (δ, ppm, J/Hz): 0.74, 1.12 (both d, 3H each, J = 7.0, Me-2′,3′), 2.30 (3H, s, N–Me), 2.57 (1H, m, H-1′),
2.52 (2H, m, H-2′′,6′′), 2.60-2.88 (4H, m, H-2′′,3′′,5′′,6′′), 3.27 (2H, m, H-3′′,5′′), 6.30 (1H, d, J = 9.6, H-6), 6.88 (1H, s, H-9),
7.66 (1H, d, J = 9.6, H-5), 7.73 (s, 1H, H-4). C H N O ×CHCl .
19 22
2
4
3
2-[4-(2-Aminoethyl)piperazin-1-yl]-2-isopropyl-2H-furo[3,2-g]chromen-3,7-dione (13). Mp 181-183°C. IR
−1
spectrum (KBr, ν, cm ): 826, 855, 911, 954, 1102, 1120, 1142, 1292, 1351, 1484, 1574, 1626, 1650, 1732, 2855. UV
spectrum (EtOH, λ , nm, log ε): 256 (4.26), 273 (4.08), 301 (4.06), 349 (3.90).
max
PMR spectrum (δ, ppm, J/Hz): 0.80, 1.12 (both d, 3H each, J = 7.0, Me-2′,3′), 1.90 (2H, m, NH ), 2.45 (2H, m,
2
CH –N), 2.50 (2H, m, H-2′′,6′′), 2.57 (1H, m, H-1′), 2.60-2.88 (4H, m, H-2′′,3′′,5′′,6′′), 3.31 (2H, m, H-3′′,5′′), 3.44 (2H, m,
2
CH –NH ), 6.29 (1H, d, J = 9.6, H-6), 6.91 (1H, s, H-9), 7.68 (1H, d, J = 9.6, H-5), 7.74 (s, 1H, H-4). C H N O . Found:
2
2
20 25 3 4
m/z 371.37. C H N O . Calcd 371.3711.
20 25
3 4
2-Isopropyl-2-[4-(4-nitrophenyl)piperazin-1-yl]-2H-furo[3,2-g]chromen-3,7-dione (14). Mp 181-185°C. IR
−1
spectrum (KBr, ν, cm ): 648, 826, 854, 875, 906, 910, 949, 1035, 1092, 1117, 1144, 1246, 1291, 1331, 1340, 1504, 1598,
1625, 1721, 1746. UV spectrum (EtOH, λ , nm, log ε): 256 (4.02), 301 (3.74), 311 (3.56), 361 (3.87).
max
PMR spectrum (δ, ppm, J/Hz): 0.86, 1.20 (both d, 3H each, J = 7.0, Me-2′,3′), 2.42 (2H, m, H-2′′,6′′), 2.60 (1H,
m, H-1′), 2.78 (2H, m, H-2′′,6′′), 2.98 (2H, m, H-3′′,5′′), 3.42 (2H, m, H-3′′,5′′), 6.34 (1H, d, J = 9.6, H-6), 6.76 (2H, d, J = 8.6,
H-2,6-Ar), 6.91 (1H, s, H-9), 7.67 (1H, d, J = 9.6, H-5), 7.74 (1H, s, H-4), 8.10 (2H, d, J = 8.6, H-3,5-Ar). C H N O ×CHCl .
24 23
3
6
3
Found m/z 449.1583. C H N O . Calcd 449.1581.
24 23
3 6
2-Isopropyl-2-[4-(4-methoxyphenyl)piperazin-1-yl]-2H-furo[3,2-g]chromen-3,7-dione (15). Mp 147-149°C. IR
−1
spectrum (KBr, ν, cm ): 661, 702, 827, 908, 1010, 1034, 1100, 1145, 1292, 1307, 1349, 1500, 1512, 1624, 1668, 1720, 1746.
UV spectrum (EtOH, λ , nm, log ε): 244 (4.55), 297 (3.87), 347 (3.59).
max
PMR spectrum (δ, ppm, J/Hz): 0.74, 1.13 (both d, 3H each, J = 7.0, Me-2′,3′), 2.72 (1H, m, H-1′), 2.76 (2H, m,
H-2′′,6′′), 2.85 (2H, m, H-2′′,6′′), 3.06 (2H, m, H-3′′,5′′), 3.42 (2H, m, H-3′′,5′′), 3.69 (3H, s, OCH ), 6.25 (1H, d, J = 9.6,
3
H-6), 6.74 (2H, d, J = 8.6, H-2,6-Ar), 6.77 (1H, s, H-9), 6.84 (2H, d, J = 8.6, H-3,5-Ar), 7.63 (1H, d, J = 9.6, H-5), 8.01 (1H,
s, H-4).
Mass spectrum (m/z, I , %): 435.2 (11), 434.2 (37), 392 (5), 391 (17), 243 (5), 242 (18), 192 (32), 191 (18), 190 (16),
rel
+
150 (100). Found m/z 434.1829 [M] . C H N O . Calcd MW = 434.1836. C H N O .
25 26
2
5
25 26 2 5
2-Isopropyl-2-[4-(2-methoxyphenyl)piperazin-1-yl]-2H-furo[3,2-g]chromen-3,7-dione (16). Mp 196-199°C. IR
−1
spectrum (KBr, ν, cm ): 660, 826, 907, 1010, 1028, 1120, 1145, 1243, 1296, 1310, 1500, 1582, 1625, 1668, 1721, 1746. UV
spectrum (EtOH, λ , nm, log ε): 208 (4.39), 249 (4.10), 284 (3.81), 308 (3.63), 338 (3.56), 350 sh (3.52).
max
PMR spectrum (δ, ppm, J/Hz): 0.78, 1.18 (both d, 3H each, J = 7.0, Me-2′,3′), 2.64 (1H, m, H-1′), 2.84 (2H, m,
H-2′′,6′′), 2.95-3.11 (4H, m, H-2′′,3′′,5′′,6′′), 3.53, 3.73 (2H, m, H-3′′,5′′), 3.73 (3H, s, OCH ), 6.31 (1H, d, J = 9.6, H-6), 6.82
3
(2H, m, H-4,6-Ar), 6.89 (1H, s, H-9), 6.90 (1H, ddd, J = 8.2, 8.0, 1.8, H-5-Ar), 7.02 (1H, t, J = 8.6, H-3-Ar), 7.67 (1H, d,
J = 9.6, H-5), 7.75 (1H, s, H-4).
Mass spectrum (m/z, I , %): 435.1 (20), 434.1 (65), 391 (58), 341 (41), 242 (13), 220 (38), 192 (43), 191 (58), 190
rel
+
(37), 162 (91), 150 (100). Found m/z 434.1846 [M] . C H N O . Calcd MW = 434.1836. C H N O .
25 26
2
5
25 26 2 5
343

2-[4-(Benzo[d][1,3]dioxol-5-yl)piperazin-1-yl]-2-isopropyl-2H-furo[3,2-g]chromen-3,7-dione (17). Mp 126-
−1
128°C. IR spectrum (KBr, ν, cm ): 824, 846, 863, 906, 1036, 1100, 1144, 1192, 1350, 1395, 1572, 1623, 1654, 1699, 1727,
3075.
PMR spectrum (δ, ppm, J/Hz): 0.74, 1.12 (both d, 3H each, J = 7.0, Me-2′,3′), 2.30 (3H, s, N–Me), 2.48 (1H, m, H-1′),
2.64 (4H, m, H-2′′,6′′), 2.83 (2H, m, H-3′′,5′′), 3.30 (2H, m, H-3′′,5′′), 5.90 (2H, m, O–CH –O), 6.27 (1H, d, J = 9.8, H-6), 6.34
2
(1H, d, J = 7.8, H-6-Ar), 6.69 (1H, s, H-2-Ar), 6.86 (1H, d, J = 7.8, H-5-Ar), 7.07 (1H, s, H-9), 7.64 (1H, d, J = 9.6, H-5), 7.72
(s, 1H, H-4). C H N O .
25 24
2 6
2-(4-(2,3-Dimethylphenyl)piperazin-1-yl)-2-isopropyl-2H-furo[3,2-g][1]benzopyran-3,7-dione (18). Mp 166-
−1
168°C. IR spectrum (KBr, ν, cm ): 661, 702, 827, 908, 1010, 1034, 1100, 1145, 1292, 1307, 1349, 1500, 1512, 1624, 1668,
1720, 1746. UV spectrum (EtOH, λ , nm, log ε): 241 (4.01), 266 (4.08), 274 (4.18), 303 (4.27), 356 (3.59).
max
PMR spectrum (δ, ppm, J/Hz): 0.88, 1.26 (both d, 3H each, J = 7.0, Me-2′,3′), 2.10 (3H, s, CH ), 2.16 (3H, s, CH ),
3
3
2.45 (1H, m, H-1′), 2.90 (4H, m, H-2′′,6′′), 3.08 (2H, m, H-3′′,5′′), 3.16 (2H, m, H-3′′,5′′), 6.32 (1H, d, J = 9.6, H-6), 6.78 (1H,
d, J = 8.2, H-6-Ar), 6.81 (1H, s, H-9), 6.86 (1H, d, J = 8.0, H-2-Ar), 6.97 (1H, t, J = 8.2, 8.0, H-5-Ar), 7.72 (1H, d, J = 9.6,
H-5), 7.98 (1H, s, H-4). C H N O .
26 28
2 4
2-{[(1R,2S)-1-Hydroxy-1-phenylpropan-2-yl](methyl)amino}-2-isopropyl-2H-furo[3,2-g]chromen-3,7-dione
(21). Mp 210-211°C, [α]2D0 −27° (c 1.0, EtOH, 1:1). UV spectrum (EtOH, λ , nm, log ε): 231 (3.71), 271 (4.16), 301 (4.28),
max
357 (3.55).
PMR spectrum (δ, ppm, J/Hz): 0.82 (3H, d, J = 7.0, Me on C-2′′), 0.91, 1.31 (both d, 3H each, J = 7.0, Me-2′,3′), 2.40
(3H, s, CH ), 2.41 (1H, m, H-1′), 2.90 (1H, m, H-2′′), 4.97 (1H, d, J = 3.0, H-3′′), 5.22 (1H, m, OH), 6.33 (1H, d, J = 9.6,
3
H-6), 6.97 (1H, s, H-9), 7.15 (2H, m, H-Ar), 7.28 (3H, m, H-Ar), 7.68 (1H, d, J = 9.6, H-5), 7.87 (1H, s, H-4). C H NO .
24 25
5
2-{[(1S,2S)-1-Hydroxy-1-phenylpropan-2-yl](methyl)amino}-2-isopropyl-2H-furo[3,2-g]chromen-3,7-dione
(22). Mp 223-224°C, [α]2D0 +12.4° (c 0.5, EtOH, 1:1). IR spectrum (KBr, ν, cm ): 661, 702, 827, 908, 1010, 1034, 1100,
−1
1145, 1292, 1307, 1349, 1500, 1512, 1624, 1668, 1720, 1746. UV spectrum (EtOH, λ , nm, log ε): 266 (4.18), 274 (4.29),
max
303 (4.40), 356 (3.71).
PMR spectrum (δ, ppm, J/Hz): 0.86 (3H, d, J = 7.0, Me on C-2′′), 0.90, 1.30 (both d, 3H each, J = 7.0, Me-2′,3′), 2.33
(3H, s, CH ), 2.48 (1H, m, H-1′), 2.57 (1H, m, H-2′′), 3.57 (1H, m, OH), 4.14 (1H, d, J = 9.2, H-3′′), 6.31 (1H, d, J = 9.6,
3
H-6), 6.97 (1H, s, H-9), 7.19 (2H, m, H-Ar), 7.25 (3H, m, H-Ar), 7.66 (1H, d, J = 9.6, H-5), 7.86 (1H, s, H-4). C H NO .
24 25
5
ACKNOWLEDGMENT
The work was supported financially by the Russian Foundation for Basic Research (Project No. 08-03-90200-Mong_a).
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