New approach for the construction of the coumarin frame and application in the total synthesis of natural products

Article abstract of DOI:10.1002/hlca.201000306

A new synthetic approach is described for building the coumarin scaffold through the Lewis acid-promoted cyclization of novel aryl 3-(dimethylamino)prop- 2-enoates 2a - 2f. The latter precursors were prepared via aminomethylenation of the corresponding aryl acetates 4a - 4f with the Bredereck reagent. This approach was used for the synthesis of biologically active natural compounds 1a - 1f, through a three-step procedure starting from the corresponding phenols.

Full text of DOI:10.1002/hlca.201000306

Helvetica Chimica Acta – Vol. 94 (2011)
185
New Approach for the Construction of the Coumarin Frame and Application
in the Total Synthesis of Natural Products
by Alberto Jerezanoa), Fabiola Jime´neza)b), Marꢀa del Carmen Cruzb), Luisa E. Montiela),
Francisco Delgadoa), and Joaquꢀn Tamariz*a)
a
´
´
´
) Departamento de Quꢀmica Organica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico
´
´
Nacional. Prol. Carpio y Plan de Ayala, 11340 Mexico, D.F., Mexico
(phone: þ5255-5729-6300/62411; fax: þ5255-5729-6300/46211;
e-mail: jtamariz@woodward.encb.ipn.mx; jtamarizm@gmail.com)
b
´
´
) Centro de Investigacion en Biotecnologꢀa Aplicada, Instituto Politecnico Nacional, Km 15 Carretera
´
Sta. Ines Tecuexcomac, Tepetitla 90700 Tlaxcala, Mexico
A new synthetic approach is described for building the coumarin scaffold through the Lewis acid-
promoted cyclization of novel aryl 3-(dimethylamino)prop-2-enoates 2a – 2f. The latter precursors were
prepared via aminomethylenation of the corresponding aryl acetates 4a – 4f with the Bredereck reagent.
This approach was used for the synthesis of biologically active natural compounds 1a – 1f, through a
three-step procedure starting from the corresponding phenols.
1. Introduction. – Coumarins (¼2H-1-benzopyran-2-ones) are some of the most
abundant metabolites found in extracts of many plant families, such as Orchidaceae,
Rutaceae, Euphorbiaceae, and Asteraceae, among others, and occur in several parts of
the plant [1]. The biogenetic route of coumarins follows the shikimate biosynthesis [2].
They have attracted widespread interest in view of their biological activity and
potential as pharmacological agents [3], since they have exhibited inhibitory properties
in platelet aggregation [4], as well as antibacterial action [5], and antifungal [6],
antitumor [7], and antiviral activities [8]. Accordingly, diverse synthetic strategies have
been reported to build their benzo-heterocyclic scaffold [9]. Among them, Pechmann
reaction is a common and useful method, starting from phenols and b-dicarbonyl
compounds, or the latter can be replaced by a propiolate or a 5-alkylidene Meldrumꢁs
acid [10]. Both methods involve a C(4)ꢀC(4a) bond-formation through the cyclization
step. Moreover, the coupling reactions, catalyzed by transition-metal complexes, the
Wittig reaction, and the ring-closing metathesis, among others, have resulted in very
efficient strategies to prepare functionalized coumarins [11].
Recently, we designed a new method for the preparation of benzofurans [12], which
was successfully extended to the synthesis of indoles [13]. This method was based on
the formation of the heterocycle by a Lewis acid-promoted cyclization of the properly
functionalized enaminones. With the aim of evaluating the versatility of this strategy in
the construction of the benzo-six-membered heterocyclic framework, we investigated
the preparation of coumarins, and their application in the total synthesis of naturally
occuring metabolites. Among these targets, we chose the biologically active coumarin
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢃrich

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scopoletin (1a), which has been isolated from different plants and fruits, such as the
leaves and root of Nicotiana tabacum [14] and Sapium sebiferum [15]. The latter is
called Wu-Jiu and used in the Chinese traditional medicine for the treatment of
squithosomiasis, or as a diuretic or cathartic [16]. Compound 1a is also isolated from
Morinda citrifolia [17], whose fruit is commonly known as Noni, which exhibits a wide
spectrum of folk medicine treatments, such as for arthritis, diabetes, hypertension,
menstrual disorders, AIDS, cancer, gastric ulcers, atherosclerosis, among others [18].
Compound 1a exhibits anticonvulsant [19] and hypotensive [20] activities, and it has
also been isolated from Mexican tarragon (Tagetes lucida Cv.), along with coumarins
such as isoscopoletin (1b), scoparone (1c), and herniarin (1d), which showed
antibacterial and fungicide activities [6][21]. Coumarins 1a – 1c were also extracted
from many plants [22], or from the fruit of Solanum dasyphyllum [23], exhibiting
anticonvulsant action in a murine model [24]. Ayapin (1e) and citropten (1f) are two
coumarins isolated from diverse natural sources, with potential antileukemia activity
[25].
2. Results and Discussion. – 2.1. Synthesis of Coumarins 1a – 1f. 2.1.1. Synthetic
Design. A retrosynthetic analysis of the preparation of coumarins 1a – 1f is depicted in
Scheme 1. The last step of the route involves the cyclization of the key enaminone
precursors 2a – 2f. Considering that the complex species 3 undergoes such a cyclization,
in accordance with Baldwinꢁs rules, this step would correspond to a favored 6-exo-trig
ring closure [26]. Actually, an additional challenge in this strategy is the formation of
enaminones 2, since the Ac group in their precursors, 4a – 4f, is probably not stable
Scheme 1. Proposed Synthetic Route

Helvetica Chimica Acta – Vol. 94 (2011)
187
enough under the reaction conditions of the condensation with dimethylformamide
dimethyl acetal (DMFDMA) [12][13]. Finally, acetates 4a – 4f would be prepared from
their properly functionalized phenols 5a – 5f.
2.1.2. Preparation of Enaminones 2a – 2e. Suitable phenolic substrates 5a and 5b, to
provide coumarins 1a and 1b, were prepared by conversion of the Bn-protected
aldehydes 7a and 7b in a three-step procedure in good yields (Scheme 2). The latter
were obtained by benzylation of isovanilline (6a) and vanilline (6b), respectively,
followed by Baeyer – Villiger rearrangement with m-chloroperbenzoic acid (MCPBA)
to yield formates 8a and 8b, which were hydrolyzed with K2CO3 in MeOH to give the
desired phenols 5a and 5b, respectively (Table 1). The latter were treated with Ac2O
under 4-(dimethylamino)pyridine (DMAP) catalysis (5.0 mol%) to provide the
respective acetates 4a and 4b in high yields (> 95%). A similar reaction sequence
was followed to obtain acetate 4c, starting from the methyl ether of vanilline, 7c, via
intermediates 8c and 5c (Scheme 2).
Scheme 2. Preparation of Enaminones 2a – 2e
Table 1. Reagents and Yields in the Preparation of Products 8a – 8c, 5a – 5c, 4a – 4f, and 2a – 2e
Sub- Reagents Product Sub- Reagents
Product Sub- Reagents
([%]) strate
Product
([%])
strate
([%])
strate
7a
7b
7c
8a
8b
8c
m-CPBA 8a (97) 5a
m-CPBA 8b (98) 5b
m-CPBA 8c (97) 5c
Ac2O/DMAP 4a (99) 4a
Ac2O/DMAP 4b (99) 4b
Ac2O/DMAP 4c (98) 4c
Ac2O/DMAP 4d (98) 4d
Ac2O/DMAP 4e (97) 4e
Ac2O/DMAP 4f (95)
(t-BuO)(Me2N)2CH 2a (75)
(t-BuO)(Me2N)2CH 2b (72)
(t-BuO)(Me2N)2CH 2c (78)
(t-BuO)(Me2N)2CH 2d (76)
(t-BuO)(Me2N)2CH 2e (74)
K2CO3
K2CO3
K2CO3
5a (99) 5d
5b (95) 5e
5c (99) 5f

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Once acetates 4a – 4c were prepared, they were reacted with DMFDMA under the
known reaction conditions (908 for 24 h) [12]. However, instead of the expected aryl 3-
(dimethylamino)prop-2-enoates, 2a – 2c, phenols 5a – 5c were isolated as the main
products. This reversal of reaction originated from the hydrolysis of the acetate group
in the presence of the MeOꢀ, which is produced by decomposition of DMFDMA in the
middle of the reaction, when the reactive species ((dimethylamino)(methoxy)methane
carbocation) is generated (Scheme 3). To avoid this undesired reaction, we investigated
the use of the Bredereck reagent {(tert-butoxy)[bis(dimethylamino)]methane} [27],
since the sterically hindered t-BuOꢀ ion should be a less nucleophilic species
(Scheme 4). Indeed, when acetates 4a – 4c were reacted with this reagent at 508 for
2 h under solvent-free conditions, aryl 3-(dimethylamino)propenoates 2a – 2c were
obtained in fairly good yields (Table 1).
Scheme 3
Scheme 4
Compounds 2d and 2e were also prepared in similar yields by reacting acetate 4d
and 4e with the Bredereck reagent (Table 1). These latter compounds were prepared in
almost quantitative yield by acetylation of 3-methoxyphenol (5d) and sesamol (5e),
respectively (Scheme 2).
In all cases, the propenoates 2a – 2e were obtained as a single stereoisomer, as
shown by NMR analysis of the crude mixture. The (E)-configuration of the C¼C bond
was indicated by the large coupling constant (J ¼ 12.9 Hz) between HꢀC(2) and
HꢀC(3) and confirmed by the NOE experiments. Thus, an enhancement of both
doublets of the vinylic H-atoms was observed, when the signal attributed to the Me2N
group was irradiated. The preference for the configuration of the (E)-stereoisomer
parallels with that observed in the preparation of analogous compounds [28]. This is
probably due to the higher stability achieved by the planar p-conjugated acrylate
system, when the bulky Me2N group is located at the opposite side of the C¼C bond.
The (E)-configuration of 2c was established by the X-ray crysrallography (Fig.). In the
crystal, this acrylate system adopts a planar s-cis conformation about the C(1)ꢀO(6)
bond, keeping the group distant from the PhO enamine moiety and in a non-planar
conformation with respect to the C¼O group.
2.1.3. Preparation of Coumarins 1a – 1e. Submitting aryl 3-(dimethylamino)prope-
noates 2a – 2e to Lewis-acid catalysis to carry out the cyclization to the corresponding
coumarins 1a – 1e was a more difficult process than that leading to the benzo-fused five-
membered heterocycles, i.e., benzofurans and indoles (Scheme 5). The formation of a
larger size heterocycle must have a more disfavorable entropic balance of the reaction,
retarding the conversion.

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Figure. X-Ray structure of 2c (ellipsoids with 30% probability level)
Scheme 5. Preparation of Coumarins 1a – 1e
Although many Lewis acids such as CuCl, TiCl4, BF3 · Et2O, AlCl3, and ZnCl2 were
tested, only the latter was able to catalyze the desired cyclization. The reaction
conditions had to be largely improved to enhance the yields (Table 2). For instance, a
variety of solvents (CH2Cl2, Cl2CHCHCl2, toluene, dioxane, DMF, and MeCN),
different temperatures, and reaction times, were tested, establishing the optimal and
reproducible conditions as follows: a stirring mixture of the enaminone 2 and activated
Table 2. Reagents and Yields in the Preparation of Coumarins 1a – 1g
Entry
Substrate
Reagents
Product ([%])
1
2
3
4
5
6
2a
2b
2c
2d
2e
4f
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
i) (t-BuO)(Me2N)2CH
ii) ZnCl2
1a (71)
1b (60)
1c (44)
1d/1g (9 : 1) (35)
1e (43)
1f (35)

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ZnCl2 (3.0 mol-equiv.) in dry dioxane was heated to 1008 for 8 days. It is worth noting
that, at the workup stage, the acid treatement (8% aq. soln. of HCl) of the residue was
necessary to obtain the best yields [11c][29]. The crude was recrystallized from MeOH
or purified by column chromatography to give the corresponding coumarins 1.
Interestingly, under these conditions, aryl 3-(dimethylamino)prop-2-enoates 2a – 2b
were directly converted into the natural coumarins 1a and 1b through a one-pot two-
step procedure, since the Bn-protected coumarin derivatives 9a and 9b were not
observed, and the yields were the best in the whole series (Table 2).
Unlike coumarins 1a – 1c and 1e, which were obtained as single regioisomers, the
cyclization of 2d led to the formation of the two possible regioisomers 1d/1g in a 9 :1
ratio (Table 2). This is in contrast with the highly regioselective cyclization for the
analoguous 3-methoxyphenyl enaminones to give the corresponding benzofuran and
indole [12][13]. It is likely that the drastic and long reaction time to give coumarins
decreases such selectivity, mainly when the aryl ring is substituted with only one
activating group.
2.2. Synthesis of Coumarins 1f and 1g. In the case of the synthesis of citroptene (1f),
we found that the aryl 3-(dimethylamino)prop-2-enoate 2f was very unstable upon
isolation and purification of the crude mixture after the reaction between acetate 4f
and the Bredereck reagent. Therefore, a better option was to carry out the trans-
formation without purification of 2f (Scheme 6). A mixture of 4f, which was prepared
by acetylation of 5f in the presence of Ac2O and DMAP, the Bredereck reagent in dry
dioxane, and the Lewis acid, was heated to reflux for 8 days, to give 1f in 35% yield as a
pale yellow powder.
Scheme 6. Preparation of Coumarins 1f and 1g
We also assessed the efficacy of this approach in the preparation of 3-substituted
coumarins. For this purpose, 5,7-dimethoxy-3-phenylcoumarin (1g) was prepared
following a similar synthetic route as shown for citroptene (1f; Scheme 6). Thus, phenol
5f was treated with 2-phenylacetic acid in the presence of dicyclohexylcarbodiimide
(DCC) to afford 4g in 80% yield. The latter was reacted with the Bredereck reagent
under analogous conditions as 4f, to obtain enaminone 2g, which was used without
purification as the substrate to carry out the cyclization in the presence of the Lewis
acid to furnish coumarin 1g in low yield (20%). All efforts to enhance the yield by
purification of the enaminone 2g or by modifying the reaction conditions or the catalyst
were unsuccessful.

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3. Conclusions. – We have described a new synthesis of naturally occurring
coumarins 1a – 1e in three steps, starting from the corresponding phenols, in moderate-
to-good overall yields. The approach included an intramolecular cyclization of
enaminones 2a – 2e as the final key step. For most of the cases, this reaction was
highly regioselective providing the desired heterocycles. Enaminones 2a – 2e were
successfully prepared by using the Bredereck reagent, avoiding hydrolysis of the acetate
precursors 4a – 4e. This pathway was also efficient for the preparation of citroptene (1f)
and the 3-substituted coumarin 1g, starting from the acetates 4f and 4g, respectively, in
a one-pot two-step reaction.
´
´
We are grateful to Dr. Hugo A. Jimenez-Vazquez for the X-ray diffraction analysis, and to Bruce
Allan Larsen for reviewing the English in the manuscript. J. T. gratefully acknowledges SIP-IPN (Grants
20070339, 20080527, 20090519, and 20100236) and CONACYT (Grants 43508-Q and 83446) for financial
support. A. J., F. J. , and L. E. M. thank CONACYT for graduate scholarships awarded, and SIP-IPN and
the Ludwig K. Hellweg Foundation for scholarship complements. C. C., F. D. , and J. T. are fellows of the
EDI-IPN and COFAA-IPN programs.
Experimental Part
General. All air-moisture-sensitive reactions were carried out under N2 using oven-dried glassware.
Dioxane and THF were freshly distilled on Na, and CH2Cl2 on CaH2, prior to use. ZnCl2 (5.0 g,
0.0366 mol) was activated in the presence of Zn (0.500 g, 0.076 mol) by refluxing in dry dioxane (40 ml)
at 1508 for 24 h; the Zn was removed by filtration, and the ZnCl2 was precipitated at r.t., filtered, and
dried in vacuum before being used [30]. All other reagents were used without further purification. Anal
TLC: E. Merck silica gel 60 F254-coated 0.25 plates were visualized by long- and short-wavelength UV
lamps. Column chromatography (CC): silica gel (SiO2; 230 – 400 mesh; Natland International Co.). M.p.:
Electrothermal cap. melting-point apparatus, uncorrected. IR Spectra: Perkin-Elmer (Spectrum 2000)
FT-IR spectrometer. 1H- (300 or 500 MHz) and 13C-NMR (75 or 125 MHz) spectra: Varian Mercury-300
or VNMR-500 instruments, with Me4Si as internal standard. EI-MS (70 eV): Thermo-Finnigan Polaris Q.
High-resolution mass spectra (HR-MS: in electron impact (EI; 70 eV) and FAB (mNBA) modes, on a
Jeol JSM-GCMateII and Jeol JMS-AX 505 HA spectrometers, resp. X-Ray crystal-structure determi-
nation: Oxford XcaliburS diffractometer.
3-(Benzyloxy)-4-methoxybenzaldehyde (7a). At r.t. and under N2, 6a (0.803 g, 5.28 mmol) was
added to a mixture of K2CO3 (0.728 g, 5.28 mmol) and NaOH (0.211 g, 5.28 mmol) in 50 ml of H2O. The
suspension was heated to reflux until the soln. became transparent, then BnBr (1.303 g, 7.62 mmol) was
slowly added, and the mixture was stirred at the same temp. for 1 h. The org. layer was separated, and the
aq. layer was washed with CH2Cl2 (2 ꢁ 45 ml). The combined org. layers were washed with brine until
neutral, dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by CC
(SiO2 (60 g); hexane/AcOEt 9 :1): to give 7a (1.25 g, 98%) as colorless crystals. Rf (hexane/AcOEt 9 :1)
0.27. M.p. 63 – 658 ([31]: 65 – 668).
4-(Benzyloxy)-3-methoxybenzaldehyde (7b). As described for 7a, 6b (4.56 g, 0.03 mmol), K2CO3
(4.14 g, 0.03 mmol), and BnBr (7.36 g, 0.043 mol) gave 7b (6.9 g, 95%). Pale yellow crystals. Rf (hexane/
AcOEt 9 :1) 0.26. M.p. 62 – 648 ([12b][32]: 62 – 648).
3,4-Dimethoxybenzaldehyde (7c). At r.t. and under N2, a mixture of 6b (2.0 g, 13.16 mmol) and
K2CO3 (2.72 g, 19.7 mmol) in 20 ml of dry THF was stirred and heated to reflux for 1 h. At 408, MeI
(3.74 g, 26.3 mmol) was slowly added, and the mixture was heated to reflux overnight. The mixture was
filtered, and the filtrate was washed with NaHCO3 until neutral. The org. layer was dried (Na2SO4), and
the solvent was removed under vacuum. The residue was purified by CC ((SiO2 (20 g); hexane/AcOEt
95 :5) to give 7c (1.77 g, 81%). White powder. Rf (hexane/AcOEt 9 :1) 0.16. M.p. 44 – 458 ([33][34]: 41 –
438).
3-(Benzyloxy)-4-methoxyphenyl Formate (8a). A mixture of 7a (0.50 g, 2.07 mmol) and m-CPBA
(1.39 g, 6.20 mmol) in 25 ml of CH2Cl2 was stirred at 208 overnight. The mixture was filtered, and the

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Helvetica Chimica Acta – Vol. 94 (2011)
filtrate was washed with NaHCO3 until neutral. The org. layer was dried (Na2SO4), and the solvent was
removed under vacuum. The residue was purified by CC (SiO2 (10 g); hexane/AcOEt 95 :5): to give 8a
(0.518 g, 97%). White powder. Rf (hexane/AcOEt 9 :1) 0.37. M.p. 68 – 708 ([12b]: 69 – 718).
4-(Benzyloxy)-3-methoxyphenyl Formate (8b). As described for 8a, a mixture of 7b (1.0 g,
4.12 mmol) and m-CPBA (5.56 g, 12.36 mmol) in 35 ml of CH2Cl2 was stirred at 208 overnight to give 8b
(1.04 g, 98%). White solid. Rf (hexane/AcOEt, 9 :1) 0.37. M.p. 70 – 728 ([8b]: 69 – 718).
3,4-Dimethoxyphenyl Formate (8c) [35]. As described for 8a, a mixture of 7c (0.50 g, 3.01 mmol) and
m-CPBA (1.39 g, 6.9 mmol) in 25 ml of CH2Cl2 was stirred at 208 overnight to give 8c (0.53 g, 97%).
White solid. Rf (hexane/AcOEt 9 :1) 0.40. M.p. 48 – 508.
Preparation of Phenols 5a – 5c. 3-(Benzyloxy)-4-methoxyphenol (5a) [36]. A mixture of 8a (0.50 g,
1.94 mmol) in MeOH (10 ml) and a 10% aq. soln. of K2CO3 (10 ml), at r.t. and under N2, was stirred for
30 min. The solvent was removed under vacuum. The residue was extracted with CH2Cl2 (2 ꢁ 20 ml), and
the soln. was washed with a 2% aq. soln. of HCl until neutral. The org. layer was washed with brine (2 ꢁ
25 ml), dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified by CC
(SiO2 (10 g); hexane/AcOEt 9 :1): to give 5a (0.44 g, 99%). White powder. Rf (hexane/AcOEt 8 :2) 0.20.
M.p. 83 – 858. IR (KBr): 3504, 1599, 1511, 1450, 1385, 1275, 1218, 1186, 1160, 1123, 1008, 967, 831, 758.
1H-NMR (300 MHz, CDCl3): 3.79 (s, MeO); 5.03 (s, PhCH2O); 5.34 (br. s, OH); 6.32 (dd, J ¼ 8.4, 3.0,
HꢀC(6)); 6.44 (d, J ¼ 3.0, HꢀC(2)); 6.72 (d, J ¼ 8.4, HꢀC(5)); 7.23 – 7.40 (m, 5 arom. H). 13C-NMR
(75 MHz, CDCl3): 56.8 (MeO); 70.8 (PhCH2O); 102.8 (C(2)); 106.5 (C(6)); 113.1 (C(5)); 127.2 (2 arom.
C); 127.9 (arom. C); 128.6 (2 arom. C); 136.8 (arom. C); 143.8 (C(4)); 149.0 (C(3)), 149.8 (C(1)). HR-EI-
MS: 230.0939 (Mþ, C14H14Oþ3 ; calc. 230.0943).
4-(Benzyloxy)-3-methoxyphenol (5b). As described for 5a, 8b (0.50 g, 1.94 mmol) gave 5b (0.42 g,
95%). White powder. Rf (hexane/AcOEt 8 :2) 0.20. M.p. 85 – 868 ([12b]: 85 – 868).
3,4-Dimethoxyphenol (5c). As described for 8a, 8c (0.50 g, 2.75 mmol) gave 5c (0.42 g, 99%). White
powder. Rf (hexane/AcOEt 8 :2) 0.26. M.p. 80 – 828 ([37a]: 78 – 808; [37b]: 80 – 828).
Preparation of Acetates 4a – 4e. 3-(Benzyloxy)-4-methoxyphenyl Acetate (4a). A mixture of 5a
(0.095 g, 0.413 mmol), Ac2O (0.541 g, 5.30 mmol), and DMAP (0.005 g, 0.041 mmol), under N2, was
stirred at 708 for 12 h. The mixture was extracted with CH2Cl2 (2 ꢁ 10 ml), and the soln. was washed with
a 10% aq. soln. of NaHCO3 until neutral. The org. layer was washed with brine (2 ꢁ 20 ml), dried
(Na2SO4), and the solvent was removed under vacuum. The residue was purified by CC (SiO2, (10 g);
hexane/AcOEt 85 :15): 4a (0.111 g, 99%). White powder. Rf (hexane/AcOEt 8 :2) 0.25. M.p. 76 – 778. IR
(KBr): 1761, 1595, 1510, 1390, 1368, 1259, 1203, 1177, 1150, 1121, 1009. 1H-NMR (300 MHz, CDCl3): 2.26
(s, MeCO2); 3.87 (s, MeO); 5.11 (s, PhCH2O); 6.62 – 6.68 (m, 2 HꢀC(2); HꢀC(6)); 6.86 (d, J ¼
8.7 HꢀC(5)); 7.28 – 7.48 (m, 5 arom. H). 13C-NMR (75 MHz, CDCl3): 21.0 (MeCO2); 56.3 (MeO); 71.1
(PhCH2O); 108.0 (C(2)); 111.8 (C(5)); 113.5 (C(6)); 127.3 (2 arom. C); 127.9 (arom. C); 128.6 (2 arom.
C); 136.6 (arom. C); 144.1 (C(1)); 147.5 (C(4)); 148.6 (C(3)); 169.8 (MeCO2). EI-MS (70 eV): 272 (14,
Mþ), 230 (70), 91 (100), 65 (16).
4-(Benzyloxy)-3-methoxyphenyl Acetate (4b). As described for 4a, a mixture of 5b (0.95 g,
4.13 mmol), Ac2O (5.41 g, 0.053 mol), and DMAP (0.051 g, 0.413 mmol) was stirred at 708 for 12 h to
give 4b (1.112 g, 99%). White powder. Rf (hexane/AcOEt 7:3) 0.40. M.p. 77 – 798. IR (KBr): 1763, 1600,
1510, 1454, 1386, 1366, 1269, 1203, 1182, 1128, 998, 751. 1H-NMR (300 MHz, CDCl3): 2.27 (s, MeCO2);
3.86 (s, MeO); 5.13 (s, PhCH2O); 6.56 (dd, J ¼ 8.8, 3.0, HꢀC(6)); 6.65 (d, J ¼ 3.0, HꢀC(2)); 6.85 (d, J ¼
8.8, HꢀC(5)), 7.26 – 7.45 (m, 5 arom. H). 13C-NMR (75 MHz, CDCl3): 20.9 (MeCO2); 55.8 (MeO); 71.2
(PhCH2O); 105.9 (C(2)); 112.7 (C(5)); 113.9 (C(6)); 127.2 (2 arom. C); 127.7 (arom. C); 128.4 (2 arom.
C); 136.8 (arom. C); 144.6 (C(1)); 145.8 (C(4)); 149.9 (C(3)); 169.7 (MeCO2). EI-MS (70 eV): 272 (35,
Mþ), 230 (100), 139 (76), 92 (60), 65 (30). HR-EI-MS: 272.1046 (Mþ, C16H16Oþ4 ; calc. 272.1049).
3,4-Dimethoxyphenyl Acetate (4c) [38]. As described for 4a, a mixture of 5c (0.90 g, 5.84 mmol),
Ac2O (7.15 g, 0.07 mol), and DMAP (0.072 g, 0.584 mmol) was stirred at 708 for 12 h to give 4c (1.12 g,
98%). White powder. Rf (hexane/AcOEt 8 :2) 0.30. M.p. 43 – 448. IR (KBr): 2960, 2834, 1760, 1603, 1510,
1461, 1264, 1236, 1206, 1186, 1146, 1126, 1025, 955, 894, 766. 1H-NMR (300 MHz, CDCl3): 2.29 (s,
MeCO2); 3.86 (s, MeO); 3.87 (s, MeO); 6.62 – 6.67 (m, 2 HꢀC(2), HꢀC(6)); 6.84 (d, J ¼ 8.3, HꢀC(5)).
13C-NMR (75 MHz, CDCl3): 21.0 (MeCO2); 55.9 (MeO); 56.1 (MeO); 105.6 (C(2)); 111.0 (C(5)); 112.7
(C(6)); 144.2 (C(1)); 146.7 (C(4)); 149.2 (C(3)); 169.9 (MeCO2). EI-MS (70 eV): 197 (45, [M þ 1]þ), 196

Helvetica Chimica Acta – Vol. 94 (2011)
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(50, Mþ), 154 (100), 139 (40), 111 (25), 93 (18), 65 (20). HR-EI-MS: 196.0739 (Mþ, C10H12Oþ4 ; calc.
196.0736).
3-Methoxyphenyl Acetate (4d) [39]. As described for 4a, a mixture of 5d (1.5 g, 12.1 mmol), Ac2O
(14.80 g, 0.145 mol), and DMAP (0.149 g, 1.21 mmol) was stirred at 708 for 12 h to give 4d (1.97 g, 98%).
Pale yellow oil. Rf (hexane/AcOEt 7:3) 0.52. IR (film): 1764, 1607, 1592, 1489, 1370, 1285, 1264, 1209,
1137, 1041, 951, 777. 1H-NMR (300 MHz, CDCl3): 2.27 (s, MeCO2); 3.78 (s, MeO); 6.64 (t, J ¼ 2.1,
HꢀC(2)); 6.68 (ddd, J ¼ 8.1, 2.1, 1.2, HꢀC(4) or HꢀC(6)); 6.77 (ddd, J ¼ 8.1, 2.1, 1.2, HꢀC(6) or HꢀC(4));
7.26 (t, J ¼ 8.1, HꢀC(5)). 13C-NMR (75 MHz, CDCl3): 20.8 (MeCO2); 55.1 (MeO); 107.4 (C(2)); 111.4
(C(5)); 113.6 (C(6)); 129.6 (C(4)); 151.5 (C(1)); 160.3 (C(3)); 169.1 (MeCO2). EI-MS (70 eV): 167 (45,
[M þ 1]þ), 166 (100, Mþ), 125 (28), 124 (70), 95 (10).
1,3-Benzodioxol-5-yl Acetate (4e). As described for 4a, a mixture of 5e (0.51 g, 3.70 mmol), Ac2O
(4.53 g, 0.044 mol), and DMAP (0.046 g, 0.37 mmol) was stirred at 708 for 12 h to give 4e (0.65 g, 97%).
Colorless oil. Rf (hexane/AcOEt 9 :1) 0.28. IR (film): 1761, 1614, 1503, 1484, 1444, 1370, 1248, 1212, 1171,
1120, 1037, 947, 895, 817. 1H-NMR (300 MHz, CDCl3): 2.22 (s, MeCO2); 5.92 (s, OCH2O); 6.49 (dd, J ¼
8.7, 2.4, HꢀC(6)); 6.59 (d, J ¼ 2.4, HꢀC(4)); 6.74 (d, J ¼ 8.7, HꢀC(7)). 13C-NMR (75 MHz, CDCl3): 20.6
(MeCO2); 101.5 (C(2)); 103.5 (C(4)); 107.7 (C(7)); 113.7 (C(6)); 144.7 (C(5)); 145.1 (C(7a)); 147.7
(C(3a)); 169.5 (MeCO2). EI-MS (70 eV): 180 (20, Mþ), 139 (10), 138 (100), 137 (84), 79 (8).
3,5-Dimethoxyphenyl Acetate (4f) [40]. As described for 4a, a mixture of 5f (1.19 g, 12.4 mmol),
Ac2O (15.01 g, 0.147 mol), and DMAP (0.153 g, 1.24 mmol) was stirred at 708 for 12 h to give 4f (2.30 g,
95%). Colorless oil. Rf 0.37 (hexane/AcOEt 9 :1). IR (film): 1766, 1613, 1477, 1430, 1369, 1207, 1155,
1
1130, 1052, 890, 829. H-NMR (300 MHz, CDCl3): 2.18 (s, MeCO2); 3.67 (s, 2 MeO); 6.18 (d, J ¼ 2.1,
2 HꢀC(2), HꢀC(6)); 6.25 (t, J ¼ 2.1, HꢀC(4)). 13C-NMR (75 MHz, CDCl3): 21.0 (MeCO2); 55.3 (MeO);
98.1 (C(4)); 100.1 (C(2), C(6)); 152.1 (C(1)); 161.0 (C(3), C(5)); 169.2 (MeCO2). EI-MS (70 eV): 197
(50, [M þ 1]þ), 196 (100, Mþ), 155 (8), 125 (20). HR-EI-MS: 196.0735 (Mþ, C10H13Oþ4 ; calc. 196.0736).
3,5-Dimethoxyphenyl 2-Phenylacetate (4g). A mixture of 10 (0.44 g, 3.25 mmol) and DCC (0.742 g,
3.60 mmol) in dry AcOEt (10 ml), under N2, was stirred at 208 for 10 min. Then, 5f (0.50 g, 3.25 mmol)
was added dropwise at the same temp., and the mixture was stirred overnight. The mixture was filtered,
and the filtrate washed with brine (2 ꢁ 15 ml). The org. layer was dried (Na2SO4), and the solvent was
removed under vacuum. The residue was purified by CC (SiO2 (20 g); hexane/AcOEt 95 :5): to give 4g
(0.706 g, 80%). Colorless oil. Rf (hexane/AcOEt 9 :1) 0.21. IR (film): 1757, 1614, 1477, 1455, 1429, 1346,
1327, 1234, 1205, 1129, 1061, 989, 832, 727. 1H-NMR (300 MHz, CDCl3): 3.71 (s, 2 MeO); 3.82 (s,
HꢀC(2)); 6.23 (d, J ¼ 2.4, 2 HꢀC(2’’), HꢀC(6’’)); 6.31 (t, J ¼ 2.4, HꢀC(4’’)); 7.24 – 7.38 (m, 5 arom. H).
13C-NMR (75 MHz, CDCl3): 41.0 (C(2)); 55.1 (MeO); 97.9 (C(4’’)); 99.8 (C(2’’), C(6’’)); 127.1 (C(4’));
128.5 (C(3’)); 129.1 (C(2’)); 133.2 (C(1’)); 152.0 (C(1’’)); 160.8 (C(3’’), C(5’’)); 169.6 (CO). HR-FAB-
MS: 272.1046 (Mþ, C16H16Oþ4 ; calc. 272.1049).
Preparation of Enaminones 2a – 2e. 3-(Benzyloxy)-4-methoxyphenyl (2E)-3-(Dimethylamino)prop-
2-enoate (2a). Under N2, a mixture of 4a (0.047 g, 0.173 mmol) and the Bredereck reagent (0.036 g,
0.207 mmol), in a threaded ACE glass pressure tube with a sealed Teflon screw cap, was heated to 508 for
1 h. The mixture was diluted with CH2Cl2 (5 ml), and 5 ml of cold H2O were added. The org. layer was
washed with brine (2 ꢁ 5 ml), dried (Na2SO4), and the solvent was removed under vacuum. The residue
was purified by CC (SiO2 (5 g); hexane/AcOEt 75 :25) to give 2a (0.042 g, 75%). White powder. Rf
(hexane/AcOEt 6 :4) 0.21. M.p. 121 – 1228. IR (KBr): 1698, 1638, 1509, 1347, 1264, 1213, 1187, 1151, 1123,
1009, 968. 1H-NMR (300 MHz, CDCl3): 2.88 (br., Me2N); 3.86 (s, MeO); 4.65 (d, J ¼ 12.9, HꢀC(2)); 5.10
(s, PhCH2O); 6.67 (dd, J ¼ 8.6, 2.7, HꢀC(6’)); 6.72 (d, J ¼ 2.7, HꢀC(2’)); 6.86 (d, J ¼ 8.6, HꢀC(5’)); 7.27 –
7.46 (m, 5 arom. H); 7.57 (d, J ¼ 12.9, HꢀC(3)). 13C-NMR (75 MHz, CDCl3): 45.5 (Me2N); 56.2 (MeO);
70.8 (PhCH2O); 82.9 (C(2)); 108.4 (C(2’)); 111.8 (C(5’)); 113.8 (C(6’)); 127.3 (2 arom. C); 127.7 (arom.
C); 128.4 (2 arom. C); 136.7 (arom. C); 145.0 (C(1’)); 146.6 (C(4’)); 148.3 (C(3’)); 154.1 (C(3)); 168.2
(CO). EI-MS (70 eV): 327 (4, Mþ), 279 (8), 207 (12), 167 (50), 149 (100). HR-EI-MS: 327.1478 (Mþ,
C19H21NOþ4 ; calc. 327.1471).
4-(Benzyloxy)-3-methoxyphenyl (2E)-3-(Dimethylamino)prop-2-enoate (2b). As described for 2a, a
mixture of 4b (0.052 g, 0.191 mmol) and the Bredereck reagent (0.040 g, 0.229 mmol) was heated to 508
for 1 h to give 2b (0.045 g, 72%). White powder. Rf (hexane/AcOEt 6 :4) 0.18. M.p. 114 – 1168. IR (KBr):
1
1697, 1639, 1616, 1509, 1346, 1264, 1213, 1188, 1124, 1091, 988, 969. H-NMR (300 MHz, CDCl3): 2.95

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Helvetica Chimica Acta – Vol. 94 (2011)
(br., Me2N); 3.86 (s, MeO); 4.67 (d, J ¼ 12.9, HꢀC(2)); 5.12 (s, PhCH2O); 6.57 (dd, J ¼ 8.5, 2.4, HꢀC(6’));
6.69 (d, J ¼ 2.4, HꢀC(2’)); 6.84 (d, J ¼ 8.5, HꢀC(5’)); 6.95 – 7.46 (m, 5 arom. H); 7.58 (d, J ¼ 12.9,
HꢀC(3)). 13C-NMR (75 MHz, CDCl3): 45.5 (Me2N); 55.9 (MeO); 71.5 (PhCH2O); 83.0 (C(2)); 106.6
(C(2’)); 113.2 (C(6’)); 114.2 (C(5’)); 127.3 (2 arom. C); 127.7 (arom. C); 128.5 (2 arom. C); 137.2 (arom.
C); 145.2 (C(4’)); 145.7 (C(1’)); 149.9 (C(3’)); 154.2 (C(3)); 168.2 (CO). EI-MS (70 eV): 327 (3, Mþ), 143
(10), 98 (100), 92 (8). HR-EI-MS: 327.1471 (Mþ, C19H21NO4þ ; calc. 327.1471).
3,4-Dimethoxyphenyl (2E)-3-(Dimethylamino)prop-2-enoate (2c). As described for 2a, a mixture of
4c (0.50 g, 2.55 mmol) and the Bredereck reagent (0.533 g, 3.06 mmol) was heated to 508 for 1 h to give 2c
(0.499 g, 78%). Pale yellow crystals (hexane/AcOEt 1:9). Rf (hexane/AcOEt 6 :4) 0.12. M.p. 96 – 988. IR
(KBr): 1700, 1608, 1511, 1436, 1348, 1265, 1234, 1195, 1137, 1088, 1026, 984, 865, 786. 1H-NMR (300 MHz,
CDCl3): 2.88 (br., Me2N); 3.86 (s, MeO); 3.87 (s, MeO); 4.68 (d, J ¼ 12.9, HꢀC(2)); 6.63 – 6.70 (m,
2 HꢀC(2’), HꢀC(6’)); 6.84 (d, J ¼ 8.4, HꢀC(5’)); 7.59 (d, J ¼ 12.9, HꢀC(3)). 13C-NMR (75 MHz, CDCl3):
44.4 (Me2N); 55.7 (MeO); 56.0 (MeO); 82.9 (C(2)); 106.1 (C(2’)); 111.0 (C(5’)); 113.1 (C(6’)); 145.1
(C(1’)); 146.0 (C(4’)); 149.0 (C(3’)); 154.1 (C(3)); 168.2 (CO). EI-MS (70 eV): 251 (5, Mþ), 154 (10), 99
(14), 98 (100), 83 (20). HR-FAB-MS: 252.1234 ([M þ H]þ, C13H18NO4þ ; calc. 252.1236).
3-Methoxyphenyl (2E)-3-(Dimethylamino)prop-2-enoate (2d). As described for 2a, a mixture of 4d
(0.50 g, 3.01 mmol) and the Bredereck reagent (0.63 g, 3.61 mmol) was heated to 508 for 1 h to give 2d
(0.506 g, 76%). Pale red oil. Rf (hexane/AcOEt 6 :4) 0.33. IR (film): 1705, 1615, 1489, 1436, 1347, 1225,
1136, 1090, 979. 1H-NMR (300 MHz, CDCl3): 2.90 (br., Me2N); 3.77 (s, MeO); 4.66 (d, J ¼ 12.9,
HꢀC(2)); 6.65 – 6.75 (m, 3 HꢀC(2’), HꢀC(4’), HꢀC(6’)); 7.24 (t, J ¼ 8.1, HꢀC(5’); 7.58 (d, J ¼ 12.9,
HꢀC(3)). 13C-NMR (75 MHz, CDCl3): 36.6 (MeN); 44.4 (MeN); 55.1 (MeO); 82.7 (C(2)); 107.7 (C(2’));
110.6 (C(4’) or C(6’)); 114.1 (C(6’) or C(4’)); 129.3 (C(5’)); 152.4 (C(1’)); 154.2 (C(3)); 160.1 (C(3’));
167.8 (CO). EI-MS (70 eV): 222 (4, [M þ 1]þ), 124 (14), 99 (6), 98 (100), 70 (9), 55 (8). HR-EI-MS:
221.1050 (Mþ, C12H15NOþ3 ; calc. 221.1052).
1,3-Benzodioxol-5-yl (2E)-3-(Dimethylamino)prop-2-enoate (2e). As described for 2a, a mixture of
4e (0.50 g, 2.78 mmol) and the Bredereck reagent (0.58 g, 3.33 mmol) was heated to 508 for 1 h to give 2e
(0.483 g, 74%). White powder. Rf (hexane/AcOEt 7:3) 0.17. M.p. 112 – 1138. IR (KBr): 1705, 1613, 1473,
1434, 1349, 1225, 1204, 1153, 1131, 1091, 1052, 988. 1H-NMR (300 MHz, CDCl3): 2.90 (br., Me2N); 4.65
(d, J ¼ 12.9, HꢀC(2)); 5.95 (s, OCH2O); 6.53 (dd, J ¼ 8.2, 2.1, HꢀC(6’)); 6.63 (d, J ¼ 2.1, HꢀC(4’)); 6.75 (d,
J ¼ 8.2, HꢀC(7’)); 7.57 (d, J ¼ 12.9, HꢀC(3)). 13C-NMR (75 MHz, CDCl3): 36.9 (MeN); 44.6 (MeN); 82.8
(C(2)); 101.3 (C(2’)); 104.3 (C(4’)); 107.7 (C(7’)); 114.2 (C(6’)); 144.5 (C(7a’)); 145.8 (C(5’)); 147.7
(C(3a’)); 154.2 (C(3)); 168.2 (CO). EI-MS (70 eV): 235 (4, [M þ 1]þ), 137 (4), 98 (100), 70 (10), 55 (8).
HR-EI-MS: 235.0844 (Mþ, C12H13NO4þ ; calc. 235.0845).
Preparation of Coumarins 1a – 1g. 7-Hydroxy-6-methoxy-2H-1-benzopyran-2-one (¼ Scopoletin; 1a).
Under N2, a mixture of 2a (0.120 g, 0.37 mmol) and activated ZnCl2 (0.151 g, 1.11 mmol) in dry dioxane
(10 ml) was stirred at 1008 for 8 days. The solvent was removed under vacuum, and an 8% aq. soln. of HCl
(20 ml) was added. Then, it was extracted with CH2Cl2 (2 ꢁ 20 ml), and the org. layer was washed with
brine (2 ꢁ 10 ml), dried (Na2SO4), and the solvent was removed under vacuum. The residue was purified
by recrystallization from MeOH to give 1a (0.05 g, 71%). Pale brown solid. Rf (hexane/AcOEt 1:1) 0.26.
M.p. 200 – 2028 ([41a]: 205 – 2068; [41b]: 201 – 2028). IR (KBr): 3341, 1703, 1608, 1562, 1510, 1436, 1290,
1139, 922. 1H-NMR (500 MHz, CDCl3/(D6)DMSO 99 :1): 3.92 (s, MeO), 6.21 (d, J ¼ 9.5, HꢀC(3)); 6.86
(s, HꢀC(5)); 6.90 (s, HꢀC(8)); 7.62 (d, J ¼ 9.5, HꢀC(4)); 8.80 (br. s, OH). 13C-NMR (125 MHz, CDCl3/
(D6)DMSO 99 :1): 59.1 (MeO); 103.2 (C(8)); 108.0 (C(5)); 110.8 (C(4a)); 112.2 (C(3)); 143.5 (C(4));
145.0 (C(6)); 149.9 (C(8a)); 150.7 (C(7)); 161.5 (C(2)). EI-MS (70 eV): 192 (4, Mþ), 150 (6), 108 (100),
107 (74), 79 (28), 77 (34). HR-EI-MS: 192.0422 (Mþ, C10H8O4þ ; calc. 192.0423).
6-Hydroxy-7-methoxy-2H-1-benzopyran-2-one (¼ Isoscopoletin; 1b). As described for 1a, a mixture
of 2b (0.12 g, 0.37 mmol) and activated ZnCl2 (0.151 g, 1.11 mmol) was stirred at 1008 for 8 d; then, the
residue was purified by CC (SiO2 (15 g); CH2Cl2/MeOH 99.5 :0.5): to give 1b (0.039 g, 60%). White
powder. Rf (hexane/AcOEt 1:1) 0.26. M.p. 138 – 1408 ([42]: 1478). IR (KBr): 3339, 1704, 1608, 1564,
1510, 1435, 1291, 1263, 1219, 1190, 1140, 1019, 922, 861. 1H-NMR (500 MHz, CDCl3): 3.96 (s, MeO); 6.15
(br. s, OH); 6.27 (d, J ¼ 9.5, HꢀC(3)); 6.85 (s, HꢀC(5)); 6.92 (s, HꢀC(8)); 7.59 (d, J ¼ 9.5, HꢀC(4)).
13C-NMR (125 MHz, CDCl3): 56.4 (MeO); 103.2 (C(8)); 107.5 (C(5)); 111.5 (C(4a)); 113.4 (C(3)); 143.3

Helvetica Chimica Acta – Vol. 94 (2011)
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(C(4)); 144.0 (C(7)); 149.7 (C(6)); 150.3 (C(8a)); 161.4 (C(2)). MS (70 eV): 192 (100, Mþ), 177 (60), 164
(58), 149 (92), 121 (68), 79 (15), 69 (23). HR-EI-MS: 192.0425 (Mþ, C10H8O4þ ; calc. 192.0423).
6,7-Dimethoxy-2H-1-benzopyran-2-one (¼ Scoparone; 1c). As described for 1a, a mixture of 2c
(0.20 g, 0.80 mmol) and activated ZnCl2 (0.33 g, 2.43 mmol) was stirred at 1008 for 8 d; then, the residue
was purified by recrystallization (EtOH) to give 1c (0.072 g, 44%). Pale brown powder. Rf (hexane/
AcOEt 1:1) 0.34. M.p. 138 – 1408 ([10 h]: 144 – 1468). IR (film): 1727, 1616, 1514, 1452, 1424, 1384, 1279,
1248, 1206, 1171, 1141, 1006. 1H-NMR (500 MHz, CDCl3): 3.92 (s, MeO); 3.95 (s, MeO); 6.28 (d, J ¼ 9.5,
HꢀC(3)); 6.84 (s, HꢀC(8)); 6.87 (s, HꢀC(5)); 7.63 (d, J ¼ 9.5, HꢀC(4)). 13C-NMR (125 MHz, CDCl3):
56.3 (MeO); 56.4 (MeO); 99.9 (C(8)); 108.0 (C(5)); 111.4 (C(4a)); 113.5 (C(3)); 143.3 (C(4)); 146.3
(C(6)); 150.0 (C(8a)); 152.8 (C(7)); 161.4 (C(2)). EI-MS (70 eV): 206 (100, Mþ), 191 (42), 178 (49), 163
(55), 135 (50), 107 (50), 79 (30), 77 (32). HR-EI-MS: 206.0577 (Mþ, C11H10O4þ ; calc. 206.0579).
7-Methoxy-2H-1-benzopyran-2-one (¼ Herniarin; 1d). 5-Methoxy-2H-1-benzopyran-2-one (1g) [43].
As described for 1a, a mixture of 2d (0.10 g, 0.45 mmol) and activated ZnCl2 (0.185 g, 1.36 mmol) was
stirred at 1008 for 8 d; then, the residue was purified by CC (SiO2 (15 g); hexane/AcOEt 9 :1): 1d/1g 9 :1
(0.028 g, 35%). Pale yellow powder.
Data of 1d. Rf (hexane/AcOEt 1:1) 0.60. M.p. 110 – 1128 ([11c]: 117 – 1188; [43]: 119 – 1208; [44]:
117 – 1198). IR (film): 1706, 1611, 1507, 1464, 1399, 1351, 1282, 1232, 1205, 1123, 1024, 980, 829. 1H-NMR
(500 MHz, CDCl3): 3.88 (s, MeO); 6.25 (d, J ¼ 9.5, HꢀC(3)); 6.81 (d, J ¼ 2.7, HꢀC(8)); 6.84 (dd, J ¼ 8.4,
2.7, HꢀC(6)); 7.38 (d, J ¼ 8.4, HꢀC(5)); 7.65 (d, J ¼ 9.5, HꢀC(4)); signals attributed to the minor isomer:
3.94 (s, MeO); 6.34 (d, J ¼ 9.6, HꢀC(3)); 6.72 (br. d, J ¼ 8.5, HꢀC(6)); 6.92 (br. d, J ¼ 8.5, HꢀC(8)); 7.44
(t, J ¼ 8.5, HꢀC(7)); 8.10 (d, J ¼ 9.6, HꢀC(4)). 13C-NMR (125 MHz, CDCl3): 55.7 (MeO); 100.8 (C(8));
112.5 (C(4a)); 112.5 (C(6)); 113.0 (C(3)); 128.7 (C(5)); 143.4 (C(4)); 155.9 (C(8a)); 161.2 (C(2)); 162.8
(C(7)); signals attributed to the minor isomer: 56.0 (MeO); 105.1 (C(8)); 109.1 (C(6)); 109.6 (C(4a)),
114.5 (C(3)); 132.3 (C(7)); 138.5 (C(4)); 155.1 (C(8a)); 156.1 (C(5)); 160.9 (C(2)). MS (70 eV): 176 (62,
Mþ), 148 (98), 133 (100), 105 (20), 77 (26). HR-EI-MS: 176.0473 (Mþ, C10H8Oþ3 ; calc. 176.0474).
6H-[1,3]Dioxolo[4,5-g]-1-benzopyran-6-one (¼Ayapin; 1e). As described for 1a, a mixture of 2e
(0.10 g, 0.43 mmol) and activated ZnCl2 (0.174 g, 1.28 mmol) was stirred at 1008 for 8 d; then, the residue
was purified by recrystallization (PrOH) to give 1e (0.034 g, 43%). Pale brown powder. Rf (hexane/
AcOEt 1:1) 0.54. M.p. 220 – 2228 ([10h]: 222 – 2238; [11a][11c]: 225 – 2278; [43]: 225 – 2268; [11f][11g]:
229 – 2308). IR (KBr): 1707, 1628, 1579, 1491, 1452, 1256, 1120, 1040, 940, 833. 1H-NMR (500 MHz,
CDCl3): 6.07 (s, 2 HꢀC(2)); 6.28 (d, J ¼ 9.5, HꢀC(7)); 6.82 (s, HꢀC(4)); 6.83 (s, HꢀC(9)); 7.58 (d, J ¼ 9.5,
HꢀC(8)). 13C-NMR (125 MHz, CDCl3): 98.4 (C(4)); 102.3 (OCH2O); 105.0 (C(9)); 112.7 (C(8a)); 113.4
(C(7)); 143.5 (C(8)); 144.9 (C(9a)); 151.2 (C(3a)); 151.3 (C(4a)); 161.2 (C(6)). MS (70 eV): 190 (77,
Mþ), 163 (11), 162 (95), 161 (100), 76 (14). HR-EI-MS: 190.0264 (Mþ, C10H6Oþ4 ; calc. 190.0266).
5,7-Dimethoxy-2H-1-benzopyran-2-one (¼Citropten; 1f). As described for 2a, a mixture of 4f
(0.28 g, 1.43 mmol) and the Bredereck reagent (0.373 g, 2.14 mmol) was heated to 508 for 1 h to give 2f
(0.25 g) as a crude material, which was used without purification in the next reaction. Thus, as described
for 1a, the crude 2f and activated ZnCl2 (0.572 g, 4.21 mmol) were reacted, and the residue obtained was
purified by recrystallization from EtOH to give 1f (0.103 g, 35%). Pale yellow powder: Rf (hexane/
AcOEt 1:1) 0.58. M.p. 146 – 1478 ([10h]: 143 – 1448; [11c]: 147.5 – 1498; [43]: 143 – 1448). IR (KBr): 1711,
1611, 1468, 1456, 1363, 1222, 1206, 1153, 1117, 817. 1H-NMR (500 MHz, CDCl3): 3.85 (s, MeO), 3.88 (s,
MeO), 6.14 (d, J ¼ 10.0, HꢀC(3)); 6.29 (d, J ¼ 2.4, HꢀC(6)); 6.42 (br. d, J ¼ 2.4, HꢀC(8)); 7.95 (dd, J ¼
10.0, 0.5, HꢀC(4)). 13C-NMR (125 MHz, CDCl3): 55.8 (MeO); 55.9 (MeO); 92.8 (C(8)); 94.8 (C(6));
104.0 (C(4a)); 110.9 (C(3)); 138.7 (C(4)); 156.8 (C(8a)); 157.0 (C(5)); 161.5 (C(2)); 163.7 (C(7)). EI-MS
(70 eV): 206 (72, Mþ), 178 (100), 163 (59), 149 (19), 135 (51), 77 (18). HR-EI-MS: 206.0580 (Mþ,
C11H10Oþ4 ; calc. 206.0579).
5,7-Dimethoxy-3-phenyl-2H-chromen-2-one (1g). As described for 1f, a mixture of 4g (0.25 g,
0.92 mmol) and the Bredereck reagent (0.24 g, 1.38 mmol) was heated to 508 for 1 h to give 2g (0.20 g) as
a crude material, which was used without purification in the next reaction. Thus, the crude 2g and
activated ZnCl2 (0.816 g, 6.00 mmol) were reacted, and the residue obtained was purified by
recrystallization from EtOH to give 1g (0.051 g, 20%) as a pale yellow powder. Rf (hexane/AcOEt
1:1) 0.70. M.p. 168 – 1708 ([45]: 1788). IR (KBr): 1715, 1619, 1501, 1477, 1453, 1432, 1350, 1318, 1291, 1217,
1
1153, 1108, 1041, 821, 782. H-NMR (500 MHz, CDCl3): 3.87 (s, MeO); 3.91 (s, MeO); 6.30 (d, J ¼ 2.5,

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Helvetica Chimica Acta – Vol. 94 (2011)
HꢀC(6)); 6.46 (dd, J ¼ 2.5, 0.5, HꢀC(8)); 7.33 – 7.38 (m, HꢀC(4’)); 7.40 – 7.45 (m, 2 HꢀC(3’)); 7.70 – 7.72
(m, 2 HꢀC(2’)); 8.12 (d, J ¼ 0.5, HꢀC(4)). 13C-NMR (125 MHz, CDCl3): 55.8 (MeO); 56.0 (MeO); 92.4
(C(8)); 94.9 (C(6)); 104.8 (C(4a)); 122.7 (C(3)); 128.1 (C(4’)); 128.3 (C(3’)); 128.4 (C(2’)); 135.3 (C(1’));
135.4 (C(4)); 156.1 (C(8a)); 157.1 (C(5)); 161.1 (C(2)); 163.4 (C(7)). EI-MS (70 eV): 282 (74, Mþ), 255
(36), 254 (43), 239 (80), 199 (93), 155 (55), 153 (54), 127 (45), 125 (94), 101 (52), 99 (80), 85 (84), 45
(100), 41 (53). HR-EI-MS: 282.0893 (Mþ, C17H14O4þ ; calc. 282.0892).
Single-Crystal X-Ray Crystallography. Single-crystals of 2c were obtained by recrystallization from
AcOEt/hexane 9 :1 as pale yellow crystals. These were mounted in glass fibers. Crystallographic
measurements were performed using MoKa radiation (graphite crystal monochromator, l ¼ 71073 ꢄ), at
r.t. Intensities were corrected for Lorentz and polarization effects. No absorption correction was applied.
Anisotropic temp. factors were introduced for all non-H-atoms. The H-atoms were placed in idealized
positions, and their atomic coordinates were refined. Unit weights were used in the refinement. The
structure was solved using the SIR92 [46] program as implemented in the WinGX suite [47], and refined
using SHELX97 within WinGX, on a personal computer. ORTEP Diagrams were made with PLATON
[48].
Data for 2c. Formula C13H17NO4; Mr, 251.28; crystal size, 0.42 ꢁ 0.39 ꢁ 0.29 mm; crystal system,
monoclinic; space group, P1 21/c1; unit cell parameters, a ¼ 14.9384 (3), b ¼ 8.55750 (10), c ¼ 10.6619
(3) ꢄ, a ¼ 90, b ¼ 104.044 (2)8, g ¼ 908, V¼ 1322.23 (5) ꢄ3; temp., 294(2) K; Z ¼ 4; Dx ¼ 1.262 Mg/m3;
absorption coefficient, 0.094 mmꢀ1; q scan range, 2.76 – 32.478; reflections collected, 13849; independent
reflections, 4323; reflections observed, 2775; R ¼ 0.0504; wR ¼ 0.1324; goodness-of-fit 1.054.
CCDC-770542 contains the supplementary crystallographic data for the structure of 2c. These data
can be obtained, free of charge, via www.ccdc.cam.ac.uk/data_request/cif.
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Received August 13, 2010