Synthesis and structure of 1-substituted benzopyrano-[4′,3′-c] benzo[3″,4″-f]-2,8-dioxabicyclo[3.3.1]nonane

Article abstract of DOI:10.1515/znb-2006-0216

The base catalyzed condensation reaction between 4-hydroxycoumarin and 3-acetylcoumarin (3-benzoylcoumarin) in water at reflux led to the formation of 1-methyl (1-phenyl)-benzopyrano[4′,3′-c]-benzo[3″,4″-f]- 2,8-dioxabicyclo[3.3.1]nonane (2a, b) as final products. When 4-hydroxycoumarin and 3-acetylcoumarin reacted in a glacial acetic acid in the presence of potassium acetate the final product was 7-[3-acetyl-2-oxo-3,4-dihydro-2H-[1] benzopyran-4-yl]methyl-6H,14H,14bH-bis-([1]benzopyrano)[4,3-b:4′, 3′-d]pyran-6,14-dione (4). 4-Hydroxycoumarin and 4-(5-bromo-2- hydroxyphenyl)-3-buten-2-one were condensed in water at reflux and 1-methylcoumarino-[4′,3′-c]-bromobenzo[3″,4″-f]-2, 8-dioxabicyclo[3.3.1]nonane was a final product (3).

Full text of DOI:10.1515/znb-2006-0216

Synthesis and Structure of 1-Substituted Benzopyrano-
4’,3’-c]benzo[3”,4”-f]-2,8-dioxabicyclo[3.3.1]nonane
[
a
b
b
Ilia Manolov , Caecilia Maichle-Moessmer , and Elke Niquet
a
Department of Organic Chemistry, Faculty of Pharmacy, Medical University, 2, Dunav St.,
BG-1000 Sofia, Bulgaria
Institute of Inorganic Chemistry, Auf der Morgenstelle 18, D-72076 T u¨ bingen, Germany
b
Reprint requests to Assoc. Prof. Dr. Ilia Manolov. E-mail: imanolov@mbox.pharmfac.acad.bg.
Fax: 00359 2 9879874
Z. Naturforsch. 61b, 207 – 212 (2006); received August 17, 2005
The base catalyzed condensation reaction between 4-hydroxycoumarin and 3-acetylcoum-
arin (3-benzoylcoumarin) in water at reflux led to the formation of 1-methyl (1-phenyl)-
benzopyrano[4’,3’-c]-benzo[3”,4”-f]-2,8-dioxabicyclo[3.3.1]nonane (2a, b) as final products. When
4
-hydroxycoumarin and 3-acetylcoumarin reacted in a glacial acetic acid in the presence of potas-
sium acetate the final product was 7-[3-acetyl-2-oxo-3,4-dihydro-2H-[1]benzopyran-4-yl]methyl-
H,14H,14bH-bis-([1]benzopyrano)[4,3-b:4’,3’-d]pyran-6,14-dione (4). 4-Hydroxycoumarin
6
and 4-(5-bromo-2-hydroxyphenyl)-3-buten-2-one were condensed in water at reflux and 1-
methylcoumarino-[4’,3’-c]-bromobenzo[3”,4”-f]-2,8-dioxabicyclo[3.3.1]nonane was a final product
(3).
Key words: 4-Hydroxycoumarin, 3-Acetylcoumarin, Dioxabicyclononanes,
Benzopyranopyrandione
Introduction
-Hydroxycoumarin derivatives are of interest be-
4
cause of their anticoagulant [1 – 3], spasmolytic [4, 5],
and rodenticidal [6 – 9] activities. Some coumarin
derivatives are known for their antifungal and anti-HIV
activities [10, 11]. They are also extensively used as
analytical reagents [12– 14]. The most widely used an-
tithrombotic in the USA and Canada is racemic sodium
Warfarin. All compounds of this group inhibit vitamin
K 2,3-epoxide reductase.
Ikawa et al. [15] have established that when
α,β-unsaturated ketones derived from salicylaldehyde Jurd in 1981 [18]. Later Ruggiero and Valente [19, 20]
are condensed with 4-hydroxycoumarin, the Michael proved the structure by means of X-ray crystal struc-
condensation products undergo spontaneous dehy- ture analysis. Abd El-Rahman et al. [21] synthesized
dration to give products with high melting points, similar benzodioxocinone derivatives by condensation
which are insoluble in alkali and have low sol- of salicylidenacetone and hydroxyfurobenzopyran.
ubility in ethanol. The products, according to the
authors, are 6-oxo-7-substituted-6H,7H-[1]benzopyr- pounds. Instead of 2-hydroxybenzylidenacetone we
ano[4,3-b][1]-benzopyrans (1).
used 3-acetylcoumarin and 3-benzoylcoumarin and by
We now report a new synthesis for this class of com-
Porter and Trager [16, 17] have established in 1977 reaction of Michael addition we synthesized the same
that the base catalyzed condensation reaction between benzodioxocinones.
4
-hydroxycoumarin and 2-hydroxybenzylidenacetone
Results and Discussion
yields 6-methyl-6,12-methano-6H,12H,13H-[1]benz-
opyrano[4,3-d][1,3]benzodioxocin-13-one (2a) as a fi-
Nearly ten years ago we investigated the interaction
nal product. An analogous structure was described by between 4-hydroxycoumarin and 3-acetylcoumarin or
0
932–0776 / 06 / 0200–0207 $ 06.00 ꢀc 2006 Verlag der Zeitschrift f u¨ r Naturforschung, T u¨ bingen · http://znaturforsch.com
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08
I. Manolov et al. · A Novel Route for the Synthesis of Dioxabicyclononane
Scheme 1.
the carbonyl group of the side chain and the hydroxyl
group of 4-hydroxycoumarin took place and a semi-
ketal was formed. The semi-ketal dehydrated sponta-
neously and the final product was formed. Products
1
and 2 are isomers (they have the same molecular
formula). The data of X-ray crystal structure analy-
ses were a proof that product 2 was formed and not
product 1.
The constitution of the dioxabicyclononanes can
be established also on the basis of the IR spec-
tra. Coumarin carbonyls are expected to absorb at
−
1
approximately 1720 cm . The observed carbonyl
−
1
stretch is found at 1703 cm and, therefore, all data
strongly suggest that the structure of coumarino-2,8-
dioxabicyclo[3.3.1]nonane (2a, b) must be assigned to
the products [16].
Fig. 1. ORTEP plot of 2b (50% probability level for el-
lipsoids of thermal vibration). Bond lengths [pm]: C1–
O1 136.6(5), C1–C2 133.8(7), C2–C15 149.8(8), C15–C14
The insolubility of the condensation product in di-
lute alkali is an indication that the hydroxyl group
of the 4-hydroxycoumarin fragments must have been
modified during the course of the reaction and that
1
1
52.4(7), C14–C13 138.3(7), C13–O12 137.6(6), C11–O12
44.9(6).
an intramolecular coumarin ketal has been formed
3
-benzoylcoumarinin water and an equimolar quantity
1
(
Scheme 1). In the H NMR spectrum signals are ob-
of sodium hydroxide at reflux. On the basis of elemen-
served at δ = 1.98 (methyl) and δ = 2.23 (methylene,
1
tal analyses, IR, H NMR and mass spectral data we
3
J = 3 Hz). The magnitude of the observed vicinal cou-
postulated similar to Ikawa et al. [15], that the product
had the structure of 1a [22].
pling is consistent with structure 2 since both methano
protons are constrained to be gauche to the benzylic
This assumption was wrong. In fact only product proton. Similar conclusions have already been made by
2
was formed. An intramolecular interaction between Porter and Trager [16]. The constitution of 2b has fi-
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I. Manolov et al. · A Novel Route for the Synthesis of Dioxabicyclononane
209
Scheme 2.
Fig. 2. ORTEP plot of 3 (50% probability
level for ellipsoids of thermal vibration).
Bond lengths [pm]: C1–O1 134.5(4),
C1–C2 134.7(4), C2–C15 151.1(5), C15–
C14 151.4(4), C14–C13 139.9(4), C13–
O12 138.0(4), C11–O12 142.8(4), C20–
Br1 190.5(4).
nally been established beyond doubt by an X-ray crys- and an equimolar quantity of sodium hydroxide),
tal structure determination (Fig. 1).
the final product was 7-[3-acetyl-2-oxo-3,4-dihydro-
H-[1]benzopyran-4-yl]methyl-6H,14H-14bH-bis-
2
The interaction between 4-hydroxycoumarin and
[1]benzopyrano-[4,3-b:4’,3’-d]pyran-6,14-dione (4)
4
-(5-bromo-2-hydroxyphenyl)-3-buten-2-one leads to
(
Scheme 3). The elemental analysis confirmed the
the formation of a new product, 1-methylcoum-
arino-[4’,3’-c]bromobenzo[3”,4”-f]-2 ,8-dioxabicyclo
1
molecular formula C H O . IR and H NMR data
31 20
8
confirmed the structure of the new product.
[3.3.1]nonane (3) (Scheme 2). The constitution was
confirmed by a crystal structure determination (Fig. 2).
When the condensation process between 4-hydr- Crystal Structure
oxycoumarin and 3-acetylcoumarin at a molar ratio
of 1:1 was carried out in glacial acetic acid and in
The crystallographic data are presented in Ta-
the presence of potassium acetate (instead of water ble 1. Compound 2b crystallized in the orthorhom-
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10
I. Manolov et al. · A Novel Route for the Synthesis of Dioxabicyclononane
Scheme 3.
bic space group Pna2 . The molecular struc- charge on application to CCDC, 12 Union Road,
1
ture is shown in Fig. 1. The two dihydropyr- Cambridge, CB 1EZ, UK (Fax:(+44) 1223-336-033;
an rings composed of C1/C2/C15/C16/C11/O1 and e-mail: deposit@ccdc.cam.ac.uk)
C13/C14/C15/C16/C11/O12 are constrained to a di-
axial configuration. The dihedral angle between these
two hydropyran rings is 69.7 (0.2). Both rings ex-
Experimental Section
◦
hibit half-chair conformation. The bond lengths C11-
O12 (144.9(6) pm) and C11-O1 (144.1(6) pm) are very
similar.
Chemicals were reagent grade and were purchased from
Fluka. Melting points were measured on a Boetius hot plate
microscope (Germany) and are uncorrected. IR spectra (nu-
jol) were recorded on an IR-spectrometer FTIR-8101M Shi-
madzu. H NMR spectra were recorded at ambient tem-
perature on a Bruker 250 WM (250 MHz) spectrometer in
The crystal system of 3 is monoclinic, the space
1
group is P2 /c. The molecular structure is shown in
1
Fig. 2. The structure shows the same characteristics as
structure 2b. All data are in good agreement with the
products described by Ruggiero et al. [19].
Crystallographic data (excluding structure factors)
have been deposited with the Cambridge Crystal-
lographic Data Center as supplementary publica-
[
D ]-acetone. Chemical shifts are given in ppm (σ) rela-
6
tive to TMS used as an internal standard. Mass spectra were
recorded on a Jeol JMS D 300 double focusing mass spec-
trometer coupled to a JMA 2000 data system. The com-
pounds were introduced by direct inlet probe, heated from
◦ ◦ ◦
5
0 C to 400 C at a rate of 100 /min. The ionization current
tion no. CCDC 284360 (2b) and CCDC 284361 was 300 mA, the accelerating voltage 3 kV and the cham-
◦
(
3). Copies of the data can be obtained free of ber temperature 150 C. TLC was performed on precoated
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I. Manolov et al. · A Novel Route for the Synthesis of Dioxabicyclononane
Table 1. Crystallographic data for 2b and 3.
211
the reaction. There was a pH change of the reaction medium,
so extra NaOH (0.4 g, 10 mmol) was added and as a result
the pH remained alkaline. After cooling, the reaction mixture
was acidified with diluted sulfuric acid and a brown heavy
residue was separated. The aqueous phase was separated and
the resin-like residue was dissolved in dioxane. After addi-
tion of water to the dioxane solution, white crystals were sep-
2b
3
Formula
C24H16O4
368.37
273
Mo-Kα
orthorhombic
Pna21
a = 757.35(14) 946.26(16)
b = 1965.8(4) 2245.8(3)
c = 1208.06(15) 775.8(9)
C19H13BrO4
385.20
213
Cu-Kα
monoclinic
P21/c
Molecular mass [g/mol]
Temperature [K]
Radiation
Crystal system
Space group
◦
arated and washed with methanol. Yield 1.51 g (41%). M. p.
Unit cell dimension [pm, ]
◦
2
40 C (dec.), R = 0.76 (toluene : chloroform : acetone =
f
8:8:1). – IR (KBr): ν = 1702, 1634, 1608, 1483, 1390, 1340,
1275, 1234, 1128, 981, 879, 758, 700. – MS (EI, 70 eV):
m/z (%) = 368 (100), 351 (6), 291 (4), 275 (11), 263 (7), 207
β = 90
1798.5(5)
4
111.47(13)
1534.2(19)
4
6
3
Volume [10 pm ]
Number of formula units, Z
(27), 194 (38), 178 (13), 121 (11), 92 (6), 77 (7). – C H O
24 4
16
Absorption coefficient µ [mm 1] 0.093
−
3.841
(368.4): calcd. C 78.26, H 4.35; found C 78.39, H 4.27.
◦
Theta range [ ]
3.34 – 30.95
5.02 – 65.04
1.13/−0.62
3107
2235
218
Largest peak and hole [pm·10−6] 0.18/−0.21
1-Methylcoumarino-[4’,3’-c]bromobenzo[3”,4”-f]-2,8-di-
Reflections collected
Reflections observed I > 2(σ)
Parameters
5675
1445
317
0.893
oxabicyclo[3.3.1]nonane (3)
4-Hydroxycoumarin (1.62 g, 10 mmol) and 4-(5-bromo-
GOOF
1.066
Absorption correction
Transmission Tmax/Tmin
R1[I > 2σ(I)]
DIFABS
0.604/0.133
0.0737
0.1084
none
2-hydroxyphenyl)-3-buten-2-one (2.41 g, 10 mmol) were
dissolved in water and the reaction mixture was refluxed
for 14 h. After cooling the crude product was separated
and recrystallized from ethyl acetate. White crystals, suitable
for X-ray crystal structure analyses, were obtained. Yield
0.0417
0.0464
R2 [all data]
◦
plates Kieselgel 60 F254 Merck (Germany) with layer thick- 2.73 g (71%). M. p. 275 – 277 C. – MS (EI, 70 eV): m/z
ness 0.25 mm and UV detection (254 nm). Yields of TLC- (%) = 385/387 (32), 384/386 (100), 369/371 (69), 327/329
homogeneous isolated products are given. The analyses indi- (13), 305 (52), 213 (38), 144 (18), 121 (20), 92 (8). –
1
cated by the symbols of the elements were within ± 0.3% of
H NMR (CDCl ): δ = 1.99 s (3H), 2.18 – 2.30 d (2H),
3
the theoretical values.
4.24 – 4.26 t (1H), 6.73 – 7.81 m (7H arom). – C H BrO
1
9
13
4
(385.2): calcd. C 59.22, H 3.38, Br 20.78; found C 59.35,
1
-Methylcoumarino-[4’,3’-c]benzo[3”,4”-f]-2,8-dioxabi-
H 3.51, Br 21.07.
cyclo[3.3.1]nonane (2a)
7
-[3-Acetyl-2-oxo-3,4-dihydro-2H-(1)benzopyran-4-
4
-Hydroxycoumarin (1.62 g, 10 mmol) was treated with
-acetylcoumarin (1.88 g, 10 mmol) and a solution of NaOH
0.4 g, 10 mmol) in 30 ml of water. The reaction mixture was
yl]methyl-6H,14H,14bH-bis-(1)benzopyrano[4,3-b:4’,3’-
d]pyran-6,14-dione (4)
3
(
Anhydrous potassium acetate (30 mmol), 4-hydroxy-
coumarin (30 mmol) and 3-acetylcoumarin (30 mmol) were
dissolved in glacial acetic acid (30 ml). The reaction mixture
was refluxed for 7 h. After cooling a yellow-redish precipi-
tate was separated. The precipitate was washed with glacial
acetic acid. The filtrate was poured in a large volume of wa-
ter. The red precipitate was separated. The crude product was
heated at reflux and stirred for 20 h. CO was liberated during
the reaction. The reaction was monitored by TLC. The crude
2
product was recrystallized from ethyl acetate. Yield 1.78 g
◦
(
58%). M. p. 263 C (dec.), R = 0.74 (toluene : chloroform :
f
acetone = 8:8:1). – IR (KBr): ν = 1703, 1638, 1615, 1578,
−
150 cm . – H NMR (CDCl ): δ = 2.00 s (3H), 2.28 d
3
1
1
1
(
2H), 4.31 t (1 H), 6.8 – 7.9 m (8 H – arom.). – C H14O4
19
recrystallized from acetic acid. Yield 3.40 g (65%). M. p.
(306.3): calcd. C 74.51, H 4.58; found C 74.65, H 4.71.
◦
3
8
9
2
05 C (dec.). R = 0.59 (toluene : chloroform : acetone 8 :
f
: 1). – IR (chloroform): ν = 1780, 1720, 1630, 1555, 1160,
1
-Phenylcoumarino-[4’,3’-c]benzo[3”,4”-f]-2,8-dioxabi-
−1
1
80, 910 cm . – H NMR (CDCl ): δ = 2.38 s (3H), 2.50 –
3
cyclo[3.3.1]nonane (2b)
.80 m (2H, diastereotopic CH ), 2.96 – 3.33 d,d (two CH),
2
To a solution of 3-benzoylcoumarin (2.5 g, 10 mmol) 5.40 s (1H), 7.2 – 8.4 m (12H-arom.). – MS (EI, 70 eV): m/z
and NaOH (0.4 g, 10 mmol) in water (30 ml) was added 4- (%) = 520 (13), 505 (7), 375 (54), 332 (27), 188 (100), 162
hydroxycoumarin (1.62 g, 10 mmol), and the reaction mix- (11), 120 (74), 92 (83), 77 (19). – C31H20O8 (520.5): calcd.
ture was boiled at reflux for 15 h. CO was liberated during C 71.54, H 3.85; found C 71.77, H 4.04.
2
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I. Manolov et al. · A Novel Route for the Synthesis of Dioxabicyclononane
[
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