Synthesis and structural revision of naturally occurring ayapin derivatives

Article abstract of DOI:10.1016/j.tet.2004.12.061

The synthesis of three highly oxygenated naturally occurring coumarins, 8-methoxy-6,7-methylenedioxycoumarin, 5-methoxy-6,7-methylenedioxycoumarin and 5,8-dimethoxy-6,7-methylenedioxycoumarin is described for the first time, together with a new method for the preparation of ayapin (6,7- methylenedioxycoumarin). Comparison of the spectroscopic data of the synthetic tetraoxygenated coumarin 5,8-dimethoxy-6,7-methylenedioxycoumarin with literature reports resulted in the structural revision of several natural coumarins. Two coumarins, both identified as 5,8-dimethoxy-6,7- methylenedioxycoumarin must have other structures, while the structure of another coumarin, described as the isomeric 7,8-dimethoxy-5,6- methylenedioxycoumarin has to be revised to 5,8-dimethoxy-6,7- methylenedioxycoumarin.

Full text of DOI:10.1016/j.tet.2004.12.061

Tetrahedron 61 (2005) 2505–2511
Synthesis and structural revision of naturally occurring
ayapin derivatives
Dominick Maes,a Stijn Vervisch,a Silvia Debenedetti,b Carlos Davio,c Sven Mangelinckx,a
Nicola Giubellinaa and Norbert De Kimpea,
*
aDepartment of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium
bDepartment of Biological Sciences, Faculty of Sciences, National University of La Plata, Calle 115 and 47, 1900 La Plata, Argentina
cLaboratory of Radioisotopes, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Junin 956, 1113 Buenos Aires, Argentina
Received 24 September 2004; revised 20 December 2004; accepted 22 December 2004
Available online 26 January 2005
Abstract—The synthesis of three highly oxygenated naturally occurring coumarins, 8-methoxy-6,7-methylenedioxycoumarin, 5-methoxy-
6,7-methylenedioxycoumarin and 5,8-dimethoxy-6,7-methylenedioxycoumarin is described for the first time, together with a new method for
the preparation of ayapin (6,7-methylenedioxycoumarin). Comparison of the spectroscopic data of the synthetic tetraoxygenated coumarin
5,8-dimethoxy-6,7-methylenedioxycoumarin with literature reports resulted in the structural revision of several natural coumarins. Two
coumarins, both identified as 5,8-dimethoxy-6,7-methylenedioxycoumarin must have other structures, while the structure of another
coumarin, described as the isomeric 7,8-dimethoxy-5,6-methylenedioxycoumarin has to be revised to 5,8-dimethoxy-6,7-methylenedioxy-
coumarin.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In the last decade, a large number of tri- and tetraoxygenated
coumarins have been isolated from plants. Examples
include purpurenol,1 purpurasol,2 purpurasolol,3 iso-
purpurasol,4 8-methoxy-6,7-methylenedioxycoumarin 2,5
5-methoxy-6,7-methylenedioxycoumarin 36,7 and 5,8-
dimethoxy-6,7-methylenedioxycoumarin 4 (Fig. 1). In this
article we report the synthesis of four coumarins bearing a
methylenedioxy substituent at C6 and C7. Hence they are all
derivatives of 6,7-methylenedioxycoumarin 1 (ayapin). 6,7-
Methylenedioxycoumarin 1 was first isolated from
Eupatorium ayapana (Asteraceae)8 and was given the
trivial name ayapin. Later, ayapin 1 was also isolated
from a number of other plants, including Helianthus
Figure 1.
annuus,9 Artemisia apiacea,10 Pterocaulon virgatum11 and
convenient way for the synthesis of coumarins is
the reaction of salicylaldehydes with alkoxycarbonyl-
methylenephosphorane in N,N-diethylaniline under
reflux.13–16 Although this method has been successfully
applied for the synthesis of simple mono- and dioxygenated
P. polystachyum.12
2. Results and discussion
coumarins,13–16 this is the first report on its application on
Different methods for the synthesis of coumarins from
o-hydroxybenzaldehydes were described in the literature. A
tri- and tetraoxygenated coumarins. The key feature of the
synthetic pathway was the synthesis of suitable o-hydroxy-
benzaldehydes which then are transformed to the corre-
Keywords: Coumarins; o-Hydroxybenzaldehydes; Wittig reaction; Natural
sponding coumarins via the Wittig reaction.
products; Structural revision; 6H-[1,3]Dioxolo[4,5-g]chromen-6-ones.
* Corresponding author. Tel.: C32 9 264 59 51; fax: C32 9 264 62 43;
e-mail: norbert.dekimpe@UGent.be
2-Hydroxy-4,5-methylenedioxybenzaldehyde
6
was
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.061

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D. Maes et al. / Tetrahedron 61 (2005) 2505–2511
Scheme 1.
synthesized from sesamol 5 in two different ways
has been described and different mechanisms have been
postulated.20–22 A problem that often occurs in this reaction
is that not only the substitution reaction takes place but also
the undesired reductive dehalogenation. This reductive
dehalogenation is probably due to the formation of
copper(0) in the reaction mixture.21 It has been proven
that polar co-solvents can improve the rate as well as the
final yield of the reaction, most probably because these
solvents increase the stability and solubility of the copper
salts, which have poor solubility in pure methanol.21–22
Amides such as N,N-dimethylformamide are sometimes
used as co-solvents and have been useful in the substitution
of aromatic aldehydes.23,24 In order to optimize the reaction,
the catalytic influence of different copper salts under the
same reaction conditions was compared (Table 1). When no
catalyst was added, no reaction could be observed (Table 1,
entry 1). Different copper(I) salts such as copper(I) iodide,
copper(I) bromide and copper(I) cyanide gave comparable
results (Table 1, entries 2–4). Copper(II) hydroxide and
basic copper(II) carbonate gave only complex reaction
mixtures. Copper(II) acetoacetate an copper(II) acetate were
lacking any catalytic activity (Table 1, entries 5 and 6).
Good results were obtained using copper(II) chloride as a
catalyst (Table 1, entry 9). Under the given circumstances,
after 14 h, 60% of the desired 2-hydroxy-3-methoxy-4,5-
methylenedioxybenzaldehyde 9 was formed in the reaction
mixture. Further optimization of the reaction procedure by
using 8 equiv of sodium methoxide, 0.2 equiv of catalyst
and a reaction time of 32 h gave 2-hydroxy-3-methoxy-4,5-
methylenedioxybenzaldehyde 9 in 69% isolated yield
(Table 1, entry 10).
(Scheme 1).18 Using the Gattermann formylation,17,18
2-hydroxy-4,5-methylenedioxybenzaldehyde
6
was
obtained in 76% yield. The Villsmeier–Haack reaction18,19
yielded 61% of the desired aldehyde 6. Different conditions
for the bromination of compound 6 were evaluated.
Treatment of 2-hydroxy-4,5-methylenedioxybenzaldehyde
6 with 2 equiv of bromine in dichloromethane resulted in no
reaction. Low yields of 3-bromo-2-hydroxy-4,5-methylene-
dioxybenzaldehyde 7 were obtained using bromine in acetic
acid. Best results were obtained when the reaction was
performed in dichloromethane with aluminium(III) chloride
as a Lewis catalyst. Thus, when 2-hydroxy-4,5-methylene-
dioxybenzaldehyde 6 was stirred for 6 h with 1.1 equiv of
bromine and 0.4 equiv of aluminium(III) chloride, 3-bromo-
2-hydroxy-4,5-methylenedioxybenzaldehyde
7
was
obtained in excellent yield (98%). Interestingly, it was
found that when more equivalents of bromine were used and
longer reaction times were applied, also the dibrominated
benzaldehyde 8 was present in the reaction mixture. This
was remarkable since it involved bromination at the
deactivated ortho position to the carbonyl. Optimization
of the latter side reaction by applying a large excess of
bromine (5 equiv), 0.4 equiv of aluminium(III) chloride and
an extended reaction time of 32 h resulted in a high yielding
procedure for the synthesis of 3,5-dibromo-2-hydroxy-4,5-
methylenedioxybenzaldehyde 8 (93%).
The next step involved the nucleophilic aromatic substi-
tution of these arylbromides with sodium methoxide. The
reaction of arylhalides with sodium methoxide in the
presence of copper(I) halides or pseudohalides as a catalyst

D. Maes et al. / Tetrahedron 61 (2005) 2505–2511
2507
Table 1. Comparison of the catalytic activity of different copper salts for the synthesis of 2-hydroxy-3-methoxy-4,5-methylenedioxybenzaldehyde 9 from
3-bromo-2-hydroxy-4,5-methylenedioxybenzaldehyde 7 (analysis of the reaction mixture based on H NMR)
1
Entry
7
6
9
1a
2a
3a
4a
5a
6a
7a
8a
9a
10b
No catalyst
CuI
CuBr
100
60
62
66
0
7
6
6
0
33
32
28
CuCN
Cu(OH)2
Cu2CO3(OH)2
Cu(CH3COO)2
Cu(acac)2
CuCl2
Complex reaction mixture
Complex reaction mixture
100
100
35
0
0
5
17
0
0
60
CuCl2
6
77 (69c)
a Reaction conditions: 2 N NaOMe (20 equiv), catalyst (0.5 equiv), MeOH/DMF (3/1), 6, 14 h.
b Reaction conditions: 2 N NaOMe (8 equiv), catalyst (0.2 equiv), MeOH/DMF (3/1), 6, 32 h.
c Isolated yield after purification of the reaction mixture by column chromatography.
In a similar way 2-hydroxy-3,6-dimethoxy-4,5-methylene-
dioxybenzaldehyde 10 was synthesized in 52% isolated
yield from 3,6-dibromo-2-hydroxy-4,5-methylenedioxy-
benzaldehyde 8 and sodium methoxide in MeOH/DMF in
the presence of copper(II) chloride under reflux for 32 h.
2-Hydroxy-4,5-methylenedioxybenzaldehyde 6 (3%),
2-hydroxy-3-methoxy-4,5-methylenedioxybenzaldehyde 9
(18%) and 2-hydroxy-6-methoxy-4,5-methylenedioxy-
benzaldehyde 11 (3%) were isolated as side products in
this reaction (Scheme 1).
methylenedioxycoumarin do not correspond with those
reported for the natural coumarin, nor with our own
findings. However, the spectroscopic data we obtained for
this coumarin are in full agreement with those published for
the natural coumarin.5
The isomeric 5-methoxy-6,7-methylenedioxycoumarin 3
was first isolated from Simsia cronquistii (Asteracea),6
and from two Pterocaulon species, P. virgatum and
P. polystachyum.7 Very recently, it was found that
5-methoxy-6,7-methylenedioxycoumarin 3 is an inhibitor
of cellular proliferation in human promyelocytic leukemia
U-937 cells, and could therefore be a promising option for
the treatment of several forms of leukemia.27,28 5,8-
Dimethoxy-6,7-methylenedioxycoumarin 4 was reported
The o-hydroxybenzaldehydes 6, 9, 10 and 11 were
converted to the corresponding coumarins using the Wittig
reaction of methoxycarbonylmethylenetriphenylphosphor-
ane in N,N-diethylaniline.13–16 In this way ayapin 1,
8-methoxyayapin 2, 5-methoxyayapin 3 and 5,8-dimethoxy-
ayapin 4 were synthesized in high yields (77–82%,
Scheme 2). Special attention was paid to the optimization
of the workup procedure. In an earlier report we described a
workup procedure that involved a crystallization from the
reaction mixture.25 An improved method involved the
removal of the solvent through distillation under reduced
pressure, followed by chromatography of the residue over
silica gel. In this way high yields of the corresponding
coumarins were obtained, as outlined in Scheme 2.
1
twice in the literature.29,31 Based on H NMR and mass
spectrometric data, 5,8-dimethoxy-6,7-methylenedioxy-
coumarin 4 was proposed as the structure of sabandin, a
natural coumarin isolated from Ruta pinnata (Rutaceae).29,30
Recently, structure 4 was also assigned to artemicapin A, a
coumarin from Artemisia capillaris (Asteraceae) based on
1H NMR, 13C NMR, NOESY and HMBC experiments.31
Since the spectroscopic data from both references differ
substantially, an unambiguous synthesis of this compound
was desirable. The spectroscopic data for the synthesized
5,8-dimethoxy-6,7-methylenedioxycoumarin 4 do not
match with those reported for sabandin29,30 or artemicapin
A.31 Moreover, the 13C NMR and 1H NMR correspond very
well with those reported for a coumarin isolated from a
Brazilian plant, Metreodorea flavida (Rutaceae).32 This
coumarin was identified as the regioisomeric structure 7,8-
dimethoxy-5,6-methylenedioxycoumarin 12 (Fig. 2).
Because no NOE correlation was found between the
hydrogen at position 4 and the methoxy protons, the authors
concluded that the methylenedioxy substituent was posi-
tioned at carbons 5 and 6.32 Our own findings with the
natural compound 5-methoxy-6,7-methylenedioxycoumarin
36,7 revealed the absence of NOE correlation between H4
8-Methoxy-6,7-methylenedioxycoumarin 2 is a naturally
occurring coumarin identified in Asterolasia trymalioides
(Rutaceae), a shrub from South-East Australia.5 Although
the synthesis of 8-methoxy-6,7-methylenedioxycoumarin 2
from 6,7-dihydroxy-8-methoxycoumarin has been
reported,26 the published data for 8-methoxy-6,7-
Scheme 2.
Figure 2.

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D. Maes et al. / Tetrahedron 61 (2005) 2505–2511
Table 2. 1H and 13C NMR data for the natural coumarin from Metreodorea flavida and for 5,8-dimethoxy-6,7-methylenedioxycoumarin 4
Coumarin from Metreodorea flavida32
5,8-Dimethoxy-6,7-methylenedioxycoumarin
1H NMR (CDCl3)
13C NMR (CDCl3)
3.99 (3H, s)
4.04 (3H, s)
6.01 (2H, s)
6.20 (1H, d, JZ9.7 Hz)
7.91 (1H, d, JZ9.7 Hz)
61.1 (–OCH3)
61.1 (–OCH3)
102.1 (–OCH2O–)
107.0 (Cq)
4.02 (3H, s)
4.06 (3H, s)
6.03 (2H, s)
6.22 (1H, d, JZ9.7 Hz)
7.93 (1H, d, JZ9.7 Hz)
60.3 (–OCH3)
61.2 (–OCH3)
102.2 (–OCH2O–)
107.1 (Cq)
112.0 (CH)
126.9 (Cq)
112.2 (CH)
127.0 (Cq)
132.8 (Cq)
133.4 (Cq)
132.9 (Cq)
133.5 (Cq)
138.8 (CH)
142.9 (Cq)
138.9 (CH)
143.1 (Cq)
143.7 (Cq)
160.5 (C]O)
143.8 (Cq)
160.6 (C]O)
and the protons of the methoxy substituent at C5. This was
confirmed by the fact that no NOE correlation could be
found between the H4 proton of the synthesized 5,8-
dimethoxy-6,7-methylenedioxycoumarin 4 and any of the
methoxy groups. These observations prove that the presence
or absence of a methoxy substituent at C5 cannot be derived
from the results of NOE experiments.
0.035–0.070 mm, pore diameter ca. 6 nm) using a glass
column.
4.2. Synthetic procedures
4.2.1. 2-Hydroxy-4,5-methylenedioxybenzaldehyde 6.
Gattermann procedure. Dry hydrogen chloride was bubbled
through a stirred suspension of sesamol 5 (4.14 g;
30 mmol), zinc(II) cyanide (5.28 g, 45 mmol), zinc(II)
chloride (1.02 g; 7.5 mmol) and a trace of sodium chloride
in 100 ml of diethyl ether. To prevent the in situ formed
hydrogen cyanide from escaping, the flask was connected to
a condenser, cooled with ice water. After the formation of a
green precipitate the solution is additionally treated with dry
hydrogen chloride gas for 30 min. The ether was decanted
and the precipitate was rinsed thoroughly with ether. The
formed iminium salt was dissolved in 75 ml of water. A few
drops of concentrated sulfuric acid were added and
the resulting mixture was heated to 100 8C for 30 min.
The reaction mixture was cooled to room temperature and
the formed crystals were filtered off. The crystals were
dissolved in dichloromethane and the solution was dried
over magnesium sulfate. After filtration and evaporation of
the solvent 3.76 g (76%) of pure 2-hydroxy-4,5-methyl-
enedioxybenzaldehyde 6 was obtained.
Based on the spectroscopic evidence the structure of the
natural coumarin from M. flavida has to be revised to 5,8-
1
dimethoxy-6,7-methylenedioxycoumarin 4. The H NMR
data for both the synthesized 5,8-dimethoxy-6,7-methyl-
enedioxycoumarin 4 and the natural coumarin from
M. flavida are given in table 2. These data show clearly
that the natural product from M. flavida is identical to 5,8-
dimethoxy-6,7-methylenedioxycoumarin 4.
3. Conclusion
Four natural coumarins were synthesized (of which three for
the first time) from the corresponding o-hydroxybenzalde-
hydes using the Wittig reaction. Comparison of the
spectroscopic data of the synthetic coumarins with literature
data led to the structural revision of a tetraoxygenated
coumarin from M. flavida and unequivocally proved the
structure of a trioxygenated coumarin from A. trymalioides.
Vilsmeier procedure. Sesamol (4.14 g, 30 mmol) was
dissolved in N,N-dimethylformamide (24 ml). At 0 8C
16 ml of phosphoroxytrichloride was added. The resulting
mixture was stirred for 1 h at 100 8C. After cooling, the
reaction mixture was poured into 250 ml of a saturated
sodium acetate solution and heated for 45 min at 100 8C.
The reaction mixture was cooled down again and the
precipitate was filtered off. The precipitate was recrystal-
lized from ethanol, giving 3.02 g (61%) of pure 2-hydroxy-
4,5-methylenedioxybenzaldehyde 6 as white needles.
4. Experimental
4.1. General
1H NMR spectra (270 or 300 MHz) and 13C NMR spectra
(68 or 75 MHz) were recorded on a Joel JNM-EX 270 NMR
spectrometer or a Joel Eclipse FT 300 NMR spectrometer,
respectively. IR spectra were recorded on a Perkin–Elmer
Spectrum One spectrophotometer. Mass spectra were
recorded on an Agilent 1100 Series VL mass spectrometer
(ES 70 eV) or on a Varian MAT 112 mass spectrometer (EI
70 eV). Melting points were measured with a Bu¨chi B-450
apparatus. Elemental analyses were measured with a
Perkin–Elmer 2400 Elemental Analyzer. Flash chromato-
graphy was performed with ACROS silica gel (particle size
Mp (8C): 127 (lit. 125–12618). IR (KBr, cmK1): 3500
(broad, OH); 1605 (broad, C]O). 1H NMR (270 MHz,
CDCl3): d 6.02 (2H, s, OCH2O); 6.46 (1H, s, 3-CH); 6.85
(1H, s, 6-CH); 9.62 (1H, s, CHO); 11.78 (OH). 13C NMR
(68 MHz, CDCl3): d 98.33 (3-CH); 102.19 (OCH2O);
109.34 (6-CH); 113.64 (1-Cq); 141.33 (5-Cq); 155.18 (2-
or 4-Cq); 161.51 ((2- or 4-Cq); 193.71 (CHO). MS (70 eV,

D. Maes et al. / Tetrahedron 61 (2005) 2505–2511
2509
EI, m/z (%)): 166 (MC, 100); 165 (90); 107 (15); 79 (11); 69
(11); 53 (24); 52 (14); 51 (13). Anal. Calcd for C8H6O4: C,
57.84%; H, 3.64%. Found: C, 57.99%; H, 3.49%.
precipitate was dissolved in ether (20 ml), poured into 20 ml
of a 2 N hydrogen chloride solution and extracted with
diethyl ether (3!20 ml). The combined organic layers were
washed with a 2 N hydrogen chloride solution (10 ml) and
water (10 ml). The organic layer was dried over magnesium
sulfate. After filtration and evaporation of the solvent the
residue was chromatographed over silica gel (20% ethyl
acetate/80% hexane), giving 136 mg (69%) of pure
2-hydroxy-3-methoxy-4,5-methylenedioxybenzaldehyde 9.
4.2.2. 3-Bromo-2-hydroxy-4,5-methylenedioxybenzalde-
hyde 7. To a solution of 2-hydroxy-4,5-methylenedioxy-
benzaldehyde 6 (0.83 g; 5 mmol) and aluminium(III)
chloride (0.27 g; 2 mmol) in dichloromethane (50 ml),
bromine (0.88 g; 5.5 mmol) was added dropwise. After
6 h of stirring at room temperature the reaction mixture was
poured into a saturated aqueous sodium metabisulfite
solution (50 ml) and extracted three times with dichloro-
methane (50 ml). The combined organic layers were washed
with 50 ml of a saturated sodium bicarbonate solution and
50 ml of water. The organic layer was dried over
magnesium sulfate. After filtration and evaporation of the
solvent 1.2 g (98%) of 3-bromo-2-hydroxy-4,5-methylene-
dioxybenzaldehyde 7 was obtained.
Mp (8C): 97.9–98.2 (white powder). IR (KBr, cmK1): 3420
(broad, OH); 1620 (C]O). 1H NMR (270 MHz, CDCl3): d
4.05 (3H, s, OCH3); 6.02 (2H, s, OCH2O); 6.65 (1H, s,
6-CH); 9.65 (1H, s, CHO); 11.73 (1H, s, OH). 13C NMR
(68 MHz, CDCl3): d 60.50 (OCH3); 102.32 (OCH2O);
103.72 (6-CH); 114.03 (1-Cq); 141.92 (Cq); 144.63 (Cq);
144.96 (Cq); 153.55 (Cq); 194.16 (CHO). MS (70 eV, EI,
m/z (%)): 196 (MC, 100); 195 (19); 181 (11); 165 (16); 150
(16); 123 (10); 120 (13); 95 (13); 69 (13); 66 (11); 55 (24);
53 (21); 44 (10). Anal. Calcd for C9H8O5: C, 55.11%; H,
4.11%. Found: C, 55.32%; H, 3.98%.
Mp (8C): 141 (light yellow solid). IR (KBr, cmK1): 3440
(broad, OH); 1632 (C]O). 1H NMR (270 MHz, CDCl3): d
6.12 (2H, s, OCH2O); 6.87 (1H, s, 6-CH); 9.61 (1H, s,
CHO); 12.36 (OH). 13C NMR (75 MHz, CDCl3): d 91.22
(CBr); 102.67 (OCH2O); 108.59 (6-CH); 113.80 (1-Cq);
141.08 (5-Cq); 153.34 (2- or 4-Cq); 157.99 (2- or 4-Cq);
193.58 (CHO). MS (70 eV, EI, m/z (%)): 244/6 (MC, 100);
243/5 (70); 131/3 (17); 79 (20); 77 (20); 55 (16); 53 (54); 51
(38); 50 (31); 49 (15); 44 (10). Anal. Calcd for C8H5O4Br:
C, 39.21%; H, 2.06%. Found: C, 39.37%; H, 2.15%.
4.2.5. 2-Hydroxy-3,6-dimethoxy-4,5-methylenedioxy-
benzaldehyde 10. 3,6-Dibromo-2-hydroxy-4,5-methylene-
dioxybenzaldehyde 8 (0.97 g; 3 mmol) and copper(II)
chloride (0.16 g; 1.2 mmol) were dissolved in a mixture of
12 ml of methanol and 12 ml of N,N-dimethylformamide.
To this solution 24 ml of 2 N sodium methoxide in methanol
was added dropwise. The reaction mixture was stirred for
32 h at 100 8C. The solvent was evaporated and the residue
was dissolved in diethyl ether (120 ml), poured into 120 ml
of 2 N hydrogen chloride solution and extracted with diethyl
ether (3!100 ml). The combined extracts were washed
with 2 N hydrogen chloride solution (60 ml) and water
(60 ml). The organic layers were dried on magnesium
sulfate. After filtration and evaporation of the solvent the
residue was separated by chromatography over silica (20%
ethyl acetate, 80% hexane). This procedure yielded 508 mg
(52%) of 2-hydroxy-3,6-dimethoxy-4,5-methylenedioxy-
benzaldehyde 10, 106 mg (18%) of 2-hydroxy-3-methoxy-
4,5-methylenedioxybenzaldehyde 9, 18 mg (3%) of
2-hydroxy-6-methoxy-4,5-methylenedioxybenzaldehyde
11, and 15 mg (3%) of 2-hydroxy-4,5-methylenedioxy-
benzaldehyde 6.
4.2.3. 3,6-Dibromo-2-hydroxy-4,5-methylenedioxy-
benzaldehyde 8. To a solution of 2-hydroxy-4,5-methyl-
enedioxybenzaldehyde
6
(0.83 g; 5 mmol) and
aluminium(III) chloride (0.27 g; 2 mmol) in dichloro-
methane (50 ml) bromine (4 g; 25 mmol) was added
dropwise. After 32 h of stirring at room temperature the
reaction mixture was poured into a saturated sodium
metabisulfite solution (50 ml) and extracted three times
with dichloromethane (50 ml). The combined organic layers
were washed with 50 ml of a saturated sodium bicarbonate
solution and 50 ml of water. The organic layer was dried
over magnesium sulfate. After filtration and evaporation of
the solvent 1.51 g (93%) of 3,6-dibromo-2-hydroxy-4,5-
methylenedioxybenzaldehyde 8 was obtained.
Mp (8C): 198 (light yellow solid). IR (KBr, cmK1): 3446
(broad, OH); 1627 (C]O). 1H NMR (270 MHz, CDCl3): d
2-Hydroxy-3,6-dimethoxy-4,5-methylenedioxybenzaldehyde
10. Mp (8C): 121.4 (white powder). IR (KBr, cmK1): 3447
(broad, OH); 1625 (C]O). 1H NMR (270 MHz, CDCl3): d
3.94 (3H, s, 6-OCH3); 4.07 (3H, s, 3-OCH3); 5.97 (2H, s,
OCH2O); 10.04 (1H, s, CHO); 12.59 (1H, s, OH). 13C NMR
(68 MHz, CDCl3): d 60.22 (OCH3); 60.90 (OCH3); 102.01
(OCH2O); 107.46 (1-Cq); 126.72 (3-Cq or 5-Cq); 128.07
(3-Cq or 5-Cq); 139.53 (6-Cq); 147.78 (2-Cq or 4-Cq); 154.59
(2-Cq or 4-Cq); 192.52 (CHO). MS (70 eV, ESC, m/z (%)):
227 (MCHC). Anal. Calcd for C10H10O6: C, 53.10%; H,
4.46%. Found: C, 52.91%; H, 4.33%.
6.18 (2H, s, OCH2O); 10.00 (1H, s, CHO); 13.42 (OH). 13
C
NMR (68 MHz, CDCl3): d 90.49 (3-CBr); 101.58 (6-CBr);
102.82 (OCH2O); 110.83 (1-Cq); 139.85 (5-Cq); 152.83 (2-
or 4-Cq); 160.27 (2- or 4-Cq); 194.37 (CHO). MS (70 eV,
ESK, m/z (%)): 321/323/325 (MKHC). Anal. Calcd for
C8H4O4Br2: C, 29.66%; H, 1.24%. Found: C, 29.79%; H,
1.32%.
4.2.4. 2-Hydroxy-3-methoxy-4,5-methylenedioxybenzal-
dehyde 9. 3-Bromo-2-hydroxy-4,5-methylenedioxybenzal-
dehyde 7 (245 mg; 1 mmol) and copper(II) chloride (27 mg;
0.2 mmol) were dissolved in a mixture of 2 ml of methanol
and 2 ml of N,N-dimethylformamide. To this solution 4 ml
of a 2 N sodium methoxide solution in methanol was slowly
added. The reaction mixture was stirred for 32 h at 100 8C.
The solvent was removed under reduced pressure. The
2-Hydroxy-6-methoxy-4,5-methylenedioxybenzaldehyde 11.
Mp (8C): 121 (white powder). IR (KBr, cmK1): 3435 (broad,
OH); 1633 (C]O). H NMR (270 MHz, CDCl3): d 4.12
1
(3H, s, OCH3); 5.93 (2H, s, OCH2O); 6.12 (1H, s, 3-CH);
10.03 (1H, s, CHO); 12.56 (1H, s, OH). 13C NMR (68 MHz,
CDCl3): d 60.03 (OCH3); 92.14 (3-CH); 101.60 (OCH2O);

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D. Maes et al. / Tetrahedron 61 (2005) 2505–2511
107.24 (1-Cq); 127.41 (Cq); 143.79 (Cq); 157.27 (Cq);
162.49 (Cq); 191.99 (CHO). MS (70 eV, ESC, m/z (%)): 197
(MCHC). Anal. Calcd for C9H8O5: C, 55.11%; H, 4.11%.
Found: C, 55.37%; H, 4.19%.
4-CH). 13C NMR (68 MHz, CDCl3): d 59.99 (CH3O); 92.50
(8-CH); 101.83 (OCH2O); 106.63 (4a-Cq); 111.74 (3-CH);
131.76 (6-Cq); 138.05 (5-Cq); 138.84 (4-CH); 151.56 (7- or
8a-Cq); 152.67 (7- or 8a-Cq); 161.33 (C]O). MS (70 eV,
ESC, m/z (%)): 221 (MCHC). Anal. Calcd for C11H8O5: C,
60.01%; H, 3.66%. Found: C, 60.23%; H, 3.51%.
4.2.6. Ayapin (6,7-methylenedioxycoumarin) 1. 6H-
[1,3]Dioxolo[4,5-g]chromen-6-one.
2-Hydroxy-4,5-
methylenedioxybenzaldehyde 6 (166 mg; 1 mmol) and
methoxycarbonyltriphenylphosphorane (401 mg; 1.2 mmol)
were dissolved in 5 ml of N,N-diethylaniline. The reaction
mixture was stirred for 4 h at 220 8C under nitrogen
atmosphere. The reaction mixture was cooled down to
room temperature. The solvent was removed by vacuum
distillation (0.01 mmHg/40–50 8C). After chromatography
(50% diethyl ether, 50% hexane), 148 mg (78%) of pure
ayapin 1 was obtained (white solid).
4.2.9. 5,8-Dimethoxy-6,7-methylenedioxycoumarin 4.
4,9-Dimethoxy-6H-[1,3]dioxolo[4,5-g]chromen-6-one. The
synthesis of 5,8-dimethoxy-6,7-methylenedioxycoumarin 4
(41 mg; 0.16 mmol) out of 2-hydroxy-3,5-dimethoxy-4,5-
methylenedioxybenzaldehyde 9 (45.2 mg; 0.2 mmol) was
analogous to the synthesis of ayapin 1. Yield: 82% (yellow
solid).
Mp (8C): 131–133 (lit. mp not reported32). IR (KBr, cmK1):
1724 (C]O), 1620, 1590. H NMR (270 MHz, CDCl3): d
1
Mp (8C): 229–230 (lit. 231–23226). IR (KBr, cmK1): 1705
(C]O), 1620, 1575. H NMR (270 MHz, CDCl3): d 6.07
4.02 (3H, s, 5-OCH3); 4.06 (3H, s, 8-OCH3) 6.03 (2H, s,
OCH2O); 6.22 (1H, d, JZ9.7 Hz, 3-CH); 7.93 (1H, d, JZ
9.7 Hz, 4-CH). 13C NMR (68 MHz, CDCl3): d 60.22
(8-OCH3); 61.25 (5-OCH3); 102.21 (OCH2O); 107.10
(4a-Cq); 112.24 (3-CH); 127.04 (Cq); 132.92 (Cq); 133.48
(Cq); 138.92 (4-CH); 143.07 (7- or 8a-Cq); 143.83 (7- or
8a-Cq); 160.59 (C]O). MS (70 eV, ESC, m/z (%)): 251
(MCHC). Anal. Calcd for C12H10O6: C, 57.60%; H, 4.03%.
Found: C, 57.50%; H, 4.20%.
1
(2H, s, OCH2O); 6.28 (1H, d, JZ9.6 Hz, 3-CH); 6.82 and
6.83 (each 1H, each s, 5-CH and 8-CH); 7.58 (1H, d, JZ
9.6 Hz, 4-CH). 13C NMR (68 MHz, CDCl3): d 98.42
(8-CH); 102.35 (OCH2O); 105.03 (5-CH); 112.68 (4a-Cq);
113.40 (3-CH);143.50 (4-CH); 144.92 (6-Cq); 151.25 (7- or
8a-Cq); 151.28 (7- or 8a-Cq); 161.26 (C]O). MS (70 eV,
EI, m/z (%)): 191 (MC1, 14); 190 (MC, 100); 162 (60); 161
(37); 81 (12); 79 (12); 76 (17); 53 (12); 51 (14). Anal. Calcd
for C10H6O4: C, 63.16%; H, 3.18%. Found: C, 63.36%; H,
3.28%.
Acknowledgements
4.2.7. 8-Methoxy-6,7-methylenedioxycoumarin 2.
4-Methoxy-6H-[1,3]dioxolo[4,5-g]chromen-6-one. The
synthesis of 8-methoxy-6,7-methylenedioxycoumarin 2
(169 mg; 0.77 mmol) from 2-hydroxy-3-methoxy-4,5-
methylenedioxybenzaldehyde 9 (196 mg; 1.00 mmol) was
analogous to the synthesis of ayapin 1. Yield: 77% (white
solid).
This work was financially supported by the Special
Research Fund (BOF) of Ghent University, the Fund for
Scientific Research-Flanders (FWO) and SECyT
(Argentina).
Mp (8C): 148–150 8C (lit. mp not reported5). IR (KBr, cmK1):
1705 (C]O), 1585. H NMR (270 MHz, CDCl3): d 4.12
1
References and notes
(3H, s, OCH3); 6.05 (2H, s, OCH2O); 6.29 (1H, d, JZ
9.6 Hz, 3-CH); 6.57 (1H, s, 5-CH); 7.56 (1H, d, JZ9.6 Hz,
4-CH). 13C NMR (68 MHz, CDCl3): d 60.70 (OCH3); 99.33
(5-CH); 102.30 (OCH2O); 113.30 (4a-Cq); 113.89 (3-CH);
131.91 (7- or 8a-Cq); 140.63 (7- or 8a-Cq); 143.47 (8-CH);
143.66 (4-CH); 145.60 (6-Cq); 160.59 (C]O). MS (70 eV,
EI, m/z (%)): 220 (MC, 100); 192 (51); 190 (32); 162 (22);
147 (22); 79 (26); 63 (21); 53 (19); 51 (29); 44 (27). Anal.
Calcd for C11H8O5: C, 60.01%; H, 3.66%. Found: C,
59.95%; H, 3.48%.
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