Friedel-crafts reaction of activated benzene rings with captodative and electron-deficient alkenes. A one-step synthesis of the natural product methyl 3-(2,4,5-trimethoxyphenyl)propionate

Article abstract of DOI:10.1081/SCC-200026193

Electrophilic aromatic substitution of activated benzenes with the captodative olefin 1-acetylvinyl-1-p-nitrobenzoate (9), and with the electron-deficient alkenes methyl acrylate (8a), methylvinylketone (8b), and acrolein (8c) were evaluated under Lewis a

Full text of DOI:10.1081/SCC-200026193

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Friedel–Crafts Reaction of
Activated Benzene Rings
with Captodative and
Electron‐Deficient Alkenes.
A One‐Step Synthesis of
the Natural Product Methyl
3‐(2,4,5‐Trimethoxyphenyl)propio
Raúl Aguilar a , Adriana Benavides a & Joaquín
Tamariz a
a Departamento de Química Orgánica, Escuela
Nacional de Ciencias Biológicas, Instituto
Politécnico Nacional, Prol. Carpio y Plan de Ayala,
11340, México, DF, Mexico
Published online: 30 Mar 2009.
To cite this article: Ral Aguilar , Adriana Benavides & Joaqun Tamariz (2004)
Friedel–Crafts Reaction of Activated Benzene Rings with Captodative and
Electron‐Deficient Alkenes. A One‐Step Synthesis of the Natural Product Methyl
3‐(2,4,5‐Trimethoxyphenyl)propionate, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:15, 2719-2735,
DOI: 10.1081/SCC-200026193
To link to this article: http://dx.doi.org/10.1081/SCC-200026193

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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 15, pp. 2719–2735, 2004
Friedel–Crafts Reaction of Activated
Benzene Rings with Captodative and
Electron-Deficient Alkenes. A One-Step
Synthesis of the Natural Product Methyl
3-(2,4,5-Trimethoxyphenyl)propionate
*
´ ´
Raul Aguilar, Adriana Benavides, and Joaquın Tamariz
´ ´
Departamento de Quımica Organica, Escuela Nacional de Ciencias
´ ´ ´
Biologicas, Instituto Politecnico Nacional, Mexico, DF, Mexico
ABSTRACT
Electrophilic aromatic substitution of activated benzenes with the
captodative olefin 1-acetylvinyl-1-p-nitrobenzoate (9), and with the
electron-deficient alkenes methyl acrylate (8a), methylvinylketone (8b),
and acrolein (8c) were evaluated under Lewis acid catalysis. Olefin 9
proved to be much more reactive than alkenes 8a–8c. We also
describe a one-step synthesis of the antifungal and larvicidal natural
*
´ ´ ´
Correspondence: Joaquın Tamariz, Departamento de Quımica Organica, Escuela
´ ´
Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Prol. Carpio y Plan
´
de Ayala, 11340, Mexico, DF, Mexico; Fax: þ5255-5396-3503; E-mail: jtamariz@
woodward.encb.ipn.mx.
2719
DOI: 10.1081/SCC-200026193
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2720
Aguilar, Benavides, and Tamariz
product methyl 3-(2,4,5-trimethoxyphenyl)propionate (6), by reaction of
1,2,4-trimethoxybenzene with 8a under microwave irradiation.
Key Words: Friedel–Crafts; Captodative olefins; Methyl 3-(2,4,5-tri-
methoxyphenyl)propionate.
INTRODUCTION
Antioxidant compounds of natural occurrence, containing the basic skel-
eton of cinnamic acid, have attracted wide interest because of their diverse
biological properties. In particular, ferulic acid (1),[1] caffeic acid (2),[2] and
analogs 3a–3c[3] along with some of their dimers 4a–4b,[4] are only a few
of a long list of phenolic derivatives exhibiting hypolipidemic, anticanceri-
genic, antiinflamatory, antimicrobial, and antineoplastic activities.[1b,3,5]
These compounds have been isolated from a variety of natural sources (for
recent examples, see Ref.[6]). Among the natural derivatives containing a satu-
rated side chain, one can find compounds 5a–5b and the a-hydroxylated 5c.[7]
Recently, methyl 3-(2,4,5-trimethoxyphenyl)propionate (6) was isolated from
the root bark of Cordia alliodora, showing high antifungal and larvicidal
activities in biological tests.[8]
Several strategies have been pursued for the synthesis of this kind of
structures. In most cases, they involve the combination of the preformed
aryl scaffold with the carboxylic synthon, in order to introduce the propionic

Friedel–Crafts Reaction of Activated Benzene Rings
2721
side chain. Common examples of this approach are the condensation between
substituted benzaldehydes with malonic acid or malonates,[9] the Heck reac-
tion starting from the aromatic ring and acrylates,[10] or conjugate addition
of organocuprates to alkenoic acids and esters.[11]
The introduction of side chains in aromatic rings has been usually carried
out by Friedel–Crafts acylation or alkylation with alkyl halides or alkenes.[12]
However, conjugate addition of aryl rings to Michael acceptors promoted by
Lewis acids, has been mostly limited due to several factors, among them: the
difficulty of properly activating the starting substrates, finding optimum reac-
tion conditions, or the formation of mixtures of isomers.[12,13]
As a continuation of our studies on the reactivity of the captodative olefins
1-acetylvinyl-1-arenecarboxylates,[14] and stimulated by the design and syn-
thesis of promising hypolypidemic agents analogous to a-asarone,[15] herein
we describe the Friedel–Crafts reactions of activated benzene rings with
our captodative oefin 9 and other electron-deficient alkenes (8a–8c). We
also report a straightforward synthesis, based in this methodology, of the
natural compound 6.
RESULTS AND DISCUSSION
Friedel–Crafts propionylation of anisole (7a) with either methyl acrylate
(8a) or methyl vinyl ketone (8b), under anhydrous aluminum chloride, was
unsuccessful. It is well known that phenols undergo alkylation satisfactorily
under these acidic conditions only when the ring is sufficiently activated,[16]
or with highly reactive Michael acceptors such as acrylonitrile.[17] In contrast,
the captodative olefin 1-acetylvinyl-1-p-nitrobenzoate (9) reacted with 7a,
Scheme 1.

2722
Aguilar, Benavides, and Tamariz

Friedel–Crafts Reaction of Activated Benzene Rings
2723
.
catalyzed by BF3 Et2O at room temperature, to give only the para isomer 10a
(Sch. 1) in 75% yield (Table 1). This behavior is different from that of capto-
dative 2-chloroacrylonitrile, which affords
a mixture of alkylation
products: the para (major product) and ortho isomers and the bis adduct.[18]
The reactivity of 9 was assessed with less activated benzenes such as
benzene itself, toluene, acetanilide, and iodobenzene, under similar conditions
as before, but no condensation products were detected. It is known that only
extremely reactive Michael acceptors such as vinylidene cyanide react with
aromatic hydrocarbons similar to the above.[19]
As expected, olefin 9 reacted with veratrol (7b) even at a lower reaction
temperature (108C) than that used for 7a, providing the corresponding adduct
10b in high yield (Table 1, entry 2). However, olefins 8a and 8b did not react
with 7b even in the presence of a large excess of other catalysts (ZnCl2, TiCl4,
ZnI2, and AlCl3), different solvents (CHCl2CHCl2), temperatures (408C and
1408C), or energy sources (microwaves), and most of the starting materials
were recovered. Under any of these conditions, acrolein (8c) polymerizes
rapidly.
When compounds 10a and 10b were treated with K2CO3 in a mixture of
THF/MeOH (8 : 1), alcohols 11a and 11b were obtained in 95% and 68%
yield, respectively (Sch. 1). These alcohols were stable at room temperature
and they were purified via standard column chromatography on silica gel.
It is likely that the reactivity of benzenes activated with methoxy groups,
in the presence of Lewis acids, was low due to coordination of the catalyst
with these substituents.[13a] This hypothesis is supported by the fact that at
room temperature, compound 10b was obtained as a single product in the
presence of a large excess of catalyst (10 mol equiv.), while an insepa-
rable mixture of 10b and a second product (12) was observed when only
Scheme 2.

2724
Aguilar, Benavides, and Tamariz
Scheme 3.
2 mol equiv. of catalyst were added (Sch. 1). When this mixture was hydro-
lyzed, compound 13 was isolated by column chromatography. The latter
could arise from 10b through a two-step process: (a) cyclization of 10b to
intermediate 14 due to the activated benzene ring and the electrophilicity of
the carbonyl group;[20] (b) alkylation at the position of the tertiary benzylic
alcohol of 14 by a second molecule of 7b promoted by the catalyst (Sch. 2).
Resorcinol dimethyl ether (7c) would be expected to be more reactive in
Friedel-Crafts reactions due to the synergistic electron-donor effect of the two
methoxy groups. Indeed, when the reaction is carried out with methyl acrylate
(8a), catalyzed by pyrophosphoric acid or AlCl3, it proceeds in good yield to
give mono- or bis-propionate condensation products.[21] We investigated the
reaction of 7c with the captodative alkene 9 in the presence of aluminum
Scheme 4.

Friedel–Crafts Reaction of Activated Benzene Rings
2725
chloride (Sch. 3), observing a faster condensation with respect to the exper-
iments carried out with 7a and 7b, and furnishing the mono-adduct 15 as a
single product (Table 1, entry 3); no traces of the bis adduct 16 were detected.
The significant biological activity of a- and b-asarones,[22] and of com-
pound 6,[8] which possess the 1,2,4-trimethoxyphenyl moiety, prompted us
to evaluate the reactivity of 1,2,4-trimethoxybenzene (7d) with different
Michael acceptors. Table 1 summarizes the results obtained in the conden-
sation of 7d with 8a–8c and 9 catalyzed by anhydrous AlCl3. Thus, when
8b and 8c reacted at room temperature in methylene chloride for more than
24 hr, products 17a and 17b were obtained in good yield (Sch. 4). Captodative
olefin 9 proved again to be the most reactive electrophile, since it underwent
very fast addition (30 min) (Table 1, entry 8) to give 17c in high yield (Sch. 4).
Even though methyl acrylate (8a) failed to give the expected product 6 under
these conditions, the use of sym-tetrachloroethane[17] as solvent at 808C for 1
week provided 6 in 37% yield. The reaction time was shortened and the yield
improved by microwave irradiation (200 W) of the same mixture in a Teflon
screw-capped glass tube at 808C for 8 hr, giving 6 in 66% yield (Table 1, entry
5). The preparation of 6 represents, at present, the shortest synthesis of this
biologically active natural product, since the previously reported syntheses,
starting from b-asarone or asaraldehyde, furnished 6 in three steps.[23]
The higher reactivity of olefin 9, when compared with that of 8a–8c, in
electrophilic aromatic substitution, may be explained on the basis of FMO
arguments.[24] The energetically more favorable interaction is expected to
be that between LUMOalkenes and HOMObenzenes. Calculation (HF/6-
31Gꢀ) of the FMO energies of compounds 8b, ethyl acrylate (8d), and 9
show that the LUMO energy of 9 is 0.4634 eV and 0.7350 eV lower than
the LUMO energies of 8b and 8d, respectively.[25]
In summary, we have shown that captodative olefin 9 is a very reactive
electrophile in Friedel-Crafts reactions catalyzed by Lewis acids, with
activated benzene substrates containing 1–3 methoxy groups. 1,2,4-Tri-
methoxybenzene (7d) undergoes electrophilic aromatic substitution with
monosubstituted electron-deficient olefins to give the mono-adduct as the
main product. An efficient and total synthesis of the natural fungicide and
antilarvarian compound 6 was accomplished in one step.
EXPERIMENTAL
General
Melting points (uncorrected) were determined with an Electrothermal
capillary melting point apparatus. IR spectra were recorded on a

2726
Aguilar, Benavides, and Tamariz
1
Perkin-Elmer 1600 spectrophotometer. H (300 MHz) and 13C (75.4 MHz)
NMR spectra were recorded on a Varian Gemini-300 instrument, in CDCl3
as solvent and TMS as internal standard. Mass spectra (MS) and high-resol-
ution mass spectra (HRMS) were obtained, in electron impact (EI) (70 eV)
and FAB modes, on a Hewlett-Packard 5971A and on a Jeol JMS-SX 102
spectrometers, respectively. Microanalyses were performed by M-H-W Lab-
´
oratories (Phoenix, AZ), and Centro de Investigaciones Quımicas, Universi-
´
dad Autonoma de Hidalgo (Pachuca, Hgo., Mexico). Analytical thin-layer
chromatography was carried out using E. Merck silica gel 60 F254
(0.25 mm) plates, visualizing by long- and short-wavelength UV lamps.
Microwave (MW) irradiation was performed on a SEV/MIC-1 MW reactor.
All air and moisture sensitive reactions were carried out under nitrogen
using oven-dried glassware. Methylene chloride and sym-tetrachloroethane
were freshly distilled over calcium hydride, prior to use. All other reagents
were used without further purification. Olefin 9 was prepared as reported.[14]
4-(p-Anisyl)-3-(p-nitrobenzoyloxy)-2-butanone (10a). To a solution of
0.20 g (0.85 mmol) of 9 in dry CH2Cl2 (8 mL), at 08C, 0.24 g (1.70 mmol) of
.
BF2 Et2O and 0.92 g (8.52 mmol) of 7a were successively added. The mixture
was stirred at room temperature under nitrogen for 48 hr. EtOAc (75 mL) was
added, and the mixture was washed with water (2 ꢁ 10 mL), saturated
aqueous solution of NaHCO3 (3 ꢁ 15 mL), and water until neutral. The
organic layer was dried (Na2SO4) and the solvent was removed under
vacuum. The residue was purified by column chromatography on silica gel
(6 g, hexane/EtOAc, 9 : 1) to give 0.22 g (75%) of 10a as a yellow powder:
Rf 0.7 (hexane/EtOAc, 7 : 3); mp 81–838C; IR (CH2Cl2) 1726, 1611, 1525,
1345, 1280, 1108 cm21 1H NMR (300 MHz, CDCl3) d 2.16 (s, 3H,
;
CH3CO), 3.14 (dd, J ¼ 13.7, 7.5 Hz, 1H, ArCH2CH), 3.24 (dd, J ¼ 13.7,
4.9 Hz, 1H, ArCH2CH), 3.78 (s, 3H, OMe), 5.44 (dd, J ¼ 7.5, 4.9 Hz, 1H,
ArCH2CH), 6.82–6.88 (m, 2H, ArH), 7.16–7.22 (m, 2H, ArH), 8.16–8.21
(m, 2H, ArH), 8.27–8.32 (m, 2H, ArH); 13C NMR (75.4 MHz, CDCl3) d
27.1 (CH3CO), 35.9 (ArCH2CH), 55.2 (MeO), 80.4 (ArCH2CH), 114.1
(ArH), 123.6 (ArH), 127.2 (Ar), 130.3 (ArH), 130.9 (ArH), 134.6 (Ar),
150.8 (Ar), 158.8 (Ar), 164.1 (CO2Me), 204.3 (COCH3); MS (70 eV) m/z
150 (Mþ 2 193, 100), 134 (5), 120 (9), 104 (36), 92 (19), 76 (27). Anal.
calcd for C18H17NO6: C, 62.97; H, 4.99; N, 4.07. Found: C, 62.81; H, 4.78;
N, 4.14.
4-(3,4-Dimethoxyphenyl)-3-(p-nitrobenzoyloxy)-2-butanone (10b). Fol-
lowing the method of preparation of 10a, with 0.10 g (0.42 mmol) of 9 in dry
.
CH2Cl2 (5 mL), 0.58 g (4.10 mmol) of BF3 Et2O and 0.29 g (2.10 mmol) of
7b, and stirred at 108C for 48 hr, gave 0.135 g (85%) of 10b as a pale
yellow powder: Rf 0.3 (hexane/EtOAc, 7 : 3); mp 101–1038C; IR (CH2Cl2)
1
1719, 1524, 1352, 1273, 1108 cm-1; H NMR (300 MHz, CDCl3) d 2.17

Friedel–Crafts Reaction of Activated Benzene Rings
2727
(s, 3H, CH3CO), 3.15 (dd, J ¼ 14.4, 7.9 Hz, 1H, ArCH2CH), 3.24 (dd,
J ¼ 14.4, 5.3 Hz, 1H, ArCH2CH), 3.84 (s, 3H, OMe), 3.85 (s, 3H, OMe),
5.47 (dd, J ¼ 7.9, 5.2 Hz, 1H, ArCH2CH), 6.70–6.92 (m, 3H, ArH), 8.16–
8.38 (m, 4H, ArH); 13C NMR (75.4 MHz, CDCl3) d 27.1 (CH3CO), 36.4
(ArCH2CH), 55.80 (MeO), 55.85 (Me), 80.2 (ArCH2CH), 111.2 (ArH),
112.3 (ArH), 121.4 (ArH), 123.6 (ArH), 127.6 (Ar), 130.8 (ArH), 134.6
(Ar), 148.2 (Ar), 148.9 (Ar), 150.7 (Ar), 164.0 (CO2Me), 204.3 (COCH3);
MS (70 eV) m/z 175 (Mþ 2 197, 51), 161 (56), 150 (37), 121 (100), 104
(27), 92 (10), 76 (17). Anal. calcd for C19H19NO7: C, 61.12; H, 5.13; N,
3.75. Found: C, 61.20; H, 5.20; N, 3.62.
4-(p-Anisyl)-3-hydroxy-2-butanone (11a). To a solution of 0.10 g
(0.27 mmol) of 10a in dry THF (8 mL), at 08C, 0.91 g (6.6 mmol) of K2CO3
in dry MeOH (1 mL) were added. The mixture was stirred at room temperature
under nitrogen for 15 min. EtOAc (60 mL) was added and the mixture was
washed with water until neutral. The organic layer was dried (Na2SO4) and
the solvent was removed under vacuum. The residue was purified by
column chromatography on silica gel (3 g, hexane/EtOAc, 8 : 2) to give
0.054 g (95%) of 11a as a pale yellow oil: Rf 0.62 (hexane/EtOAc, 7 : 3);
IR (film) 3465, 1714, 1611, 1513, 1357, 1300, 1247, 1178, 1111, 1086,
1
1032 cm21; H NMR (300 MHz, CDCl3) d 2.20 (s, 3H, CH3CO), 2.84 (dd,
J ¼ 14.3, 7.1 Hz, 1H, ArCH2CH), 3.09 (dd, J ¼ 14.3, 4.7 Hz, 1H,
ArCH2CH), 3.38 (br s, 1H, OH), 3.78 (s, 3H, OMe), 4.36–4.39 (m, 1H,
ArCH2CH), 6.81–6.86 (m, 2H, ArH), 7.10–7.26 (m, 2H, ArH); 13C NMR
(75.4 MHz, CDCl3) d 25.8 (CH3CO), 39.1 (ArCH2CH), 55.2 (MeO), 77.8
(ArCH2CH), 114.0 (ArH), 128.4 (Ar), 130.2 (ArH), 158.6 (Ar), 209.2
(COCH3); MS (70 eV) m/z 194 (Mþ, 10), 176 (1), 121 (100), 107 (4), 91
(15), 77 (13). HRMS (FABþ) [Mþ] (mNBA) calcd for C11H14O3: 194.0943.
Found: 194.0948.
4-(3,4-Dimethoxyphenyl)-3-hydroxy-2-butanone (11b). Following the
method of preparation of 11a, with 0.11 g (0.29 mmol) of 10b, and 0.91 g
(6.6 mmol) of K2CO3, and stirring at room temperature for 24 hr, gave
0.045 g (68%) of 11b as a yellow oil: Rf 0.18 (hexane/EtOAc, 7 : 3); IR
1
(CH2Cl2) 3498, 1708, 1512, 1261, 1136, 1027 cm21; H NMR (300 MHz,
CDCl3) d 2.21 (s, 3H, CH3CO), 2.84 (dd, J ¼ 14.3, 7.1 Hz, 1H, ArCH2CH),
3.10 (dd, J ¼ 14.3, 4.7 Hz, 1H, ArCH2CH), 3.41 (br s, 1H, OH), 3.86 (s, 3H,
OMe), 3.87 (s, 3H, OMe), 4.36–4.43 (m, 1H, ArCH2CH), 6.72–6.82 (m,
3H, ArH); 13C NMR (75.4 MHz, CDCl3)
d 25.8 (CH3CO), 39.5
(ArCH2CH), 55.88 (MeO), 55.89 (MeO), 77.7 (ArCH2CH), 111.4 (ArH),
112.7 (ArH), 121.2 (ArH), 129.0 (Ar), 148.2 (Ar), 149.1 (Ar), 209.1
(COCH3); MS (70 eV) m/z 224 (Mþ, 5), 151 (100), 137 (5), 121 (4), 107
(8), 91 (4), 77 (5). HRMS (FABþ) [Mþ] (mNBA) calcd for C12H16O4:
224.1049. Found: 224.1045.

2728
Aguilar, Benavides, and Tamariz
1-(3,4-Dimethoxyphenyl)-5,6-dimethoxy-1-methyl-2-indanol (13). Fol-
lowing the method of preparation of 10a, with 0.10 g (0.42 mmol) of 9 in dry
.
CH2Cl2 (5 mL), 0.12 g (0.84 mmol) of BF3 Et2O, and 0.29 g (2.1 mmol) of 7b,
and stirring the mixture for 24 hr, gave a crude which was purified by column
chromatography on silica gel (10 g, hexane/EtOAc, 8 : 2). Hydrolysis of the
resultant product following the method of preparation of 11a, yielded 0.04 g
(27%) of 13 as a white powder: Rf 0.22 (hexane/EtOAc, 6 : 4); mp 65–
678C; IR (film) 3502, 1606, 1505, 1463, 1407, 1297, 1252, 1208, 1143,
1
1080, 1027 cm21; H NMR (300 MHz, CDCl3) d 1.55 (s, 3H, CH3), 1.87
(br s, 1H, OH), 2.79 (dd, J ¼ 15.4, 6.3 Hz, 1H, H-3), 3.12 (dd, J ¼ 15.4,
6.3 Hz, 1H, H-3), 3.77 (s, 3H, OMe), 3.79 (s, 3H, OMe), 3.86 (s, 3H, OMe),
3.90 (s, 3H, OMe), 4.44 (t, J ¼ 6.3 Hz, 1H, H-2), 6.53 (s, 1H, ArH), 6.69–
6.80 (m, 3H, ArH), 6.82 (s, 1H, ArH); 13C NMR (75.4 MHz, CDCl3) d 19.8
(CH3), 38.3 (C-3), 55.4 (C-1), 55.8 (2MeO), 55.9 (MeO), 56.1 (MeO), 83.8
(C-2), 107.7 (ArH), 108.0 (ArH), 110.6 (2Ar), 119.1 (ArH), 131.1 (Ar),
139.6 (Ar), 140.6 (Ar), 147.5 (Ar), 148.5 (Ar), 148.60 (Ar), 148.62 (Ar);
MS (70 eV) m/z 344 (Mþ, 35), 329 (8), 301 (14), 191 (100), 165 (20), 163
(22), 151 (20), 115 (7), 91 (6), 77 (6). HRMS (FABþ) [Mþ] (mNBA) calcd
for C20H24O5: 344.1624. Found: 344.1622.
4-(2,4-Dimethoxyphenyl)-3-(p-nitrobenzoyloxy)-2-butanone (15). Fol-
lowing the method of preparation of 10a, with 0.102 g (0.43 mmol) of 9 in dry
CH2Cl2 (5 mL), 0.058 g (0.43 mmol) of AlCl3 and 0.06 g (0.43 mmol) of 7c,
gave 0.12 g (75%) of 15 as a pale yellow powder: Rf 0.76 (hexane/EtOAc,
7 : 3); mp 67–698C; IR (CH2Cl2) 1719, 1610, 1587, 1526, 1464, 1345,
1208, 1115, 1102, 1034, 837, 719 cm21 1H NMR (300 MHz, CDCl3) d
;
2.23 (s, 3H, CH3CO), 3.04 (dd, J ¼ 14.1, 8.1 Hz, 1H, ArCH2CH), 3.30 (dd,
J ¼ 14.1, 5.2 Hz, 1H, ArCH2CH), 3.78 (s, 3H, OMe), 3.80 (s, 3H, OMe),
5.48 (dd, J ¼ 8.1, 5.2 Hz, 1H, ArCH2CH), 6.40–6.43 (m, 3H, ArH), 7.10
(d, J ¼ 8.1 Hz, 1H, ArH), 8.14–8.28 (m, 4H, ArH); 13C NMR (75.4 MHz,
CDCl3) d 26.8 (CH3CO), 31.0 (ArCH2CH), 55.2 (MeO), 55.3 (MeO), 79.2
(ArCH2CH), 98.4 (ArH), 104.0 (ArH), 115.9 (Ar), 123.5 (ArH), 130.8
(ArH), 131.5 (ArH), 134.9 (Ar), 150.5 (Ar), 158.2 (Ar), 160.3 (Ar), 164.0
(CO2Me), 204.1 (COCH3); MS (70 eV) m/z 373 (Mþ, 3), 206 (30), 191
(23), 175 (43), 151 (100), 121 (24), 104 (16), 76 (10). HRMS (FABþ) [Mþ]
(mNBA) calcd for C19H19NO7: 373.1162. Found: 373.1162.
4-(2,4,5-Trimethoxyphenyl)-2-butanone (17a).[26] To a solution of
0.25 g (1.49 mmol) of 7d in dry CH2Cl2 (5 mL), at 08C under nitrogen,
0.20 g (1.49 mmol) of AlCl3 and 1.043 g (14.9 mmol) of 8b were successively
added. The mixture was stirred at room temperature for 30 hr. EtOAc (75 mL)
was added, and the mixture was washed with water (2 ꢁ 10 mL), saturated
aqueous solution of NaHCO3 (3 ꢁ 15 mL), and water until neutral. The
organic layer was dried (Na2SO4) and the solvent was removed under

Friedel–Crafts Reaction of Activated Benzene Rings
2729
vacuum. The residue was purified by column chromatography on silica gel
(10 g, hexane/EtOAc, 9 : 1) to give 0.276 g (78%) of 17a as a yellow
powder: Rf 0.74 (hexane/EtOAc, 7 : 3); mp 52–548C; IR (CH2Cl2) 1708,
1609, 1512, 1459, 1399, 1359, 1315, 1273, 1201, 1120, 1031, 853,
1
821 cm21; H NMR (300 MHz, CDCl3) d 2.14 (s, 3H, CH3CO), 2.66–2.74
(m, 2H, ArCH2CH2CO), 2.77–2.85 (m, 2H, ArCH2CH2CO), 3.80 (s, 3H,
OMe), 3.83 (s, 3H, OMe), 3.88 (s, 3H, OMe), 6.51 (s, 1H, ArH), 6.71
(s, 1H, ArH); 13C NMR (75.4 MHz, CDCl3) d 24.5 (ArCH2CH2CO), 29.9
(CH3CO), 44.1 (ArCH2CH2CO), 56.11 (MeO), 56.15 (MeO), 56.5 (MeO),
97.5 (ArH), 114.2 (ArH), 120.6 (Ar), 142.6 (Ar), 147.8 (Ar), 151.4 (Ar),
208.8 (COCH3); MS (70 eV) m/z 238 (Mþ, 59), 223 (6), 196 (7), 181
(100), 151 (28), 136 (6), 121 (4), 91 (4), 77 (5). Anal. calcd for C13H18O4:
C, 65.53; H, 7.61. Found: C, 65.55; H, 7.41.
3-(2,4,5-Trimethoxyphenyl)propionaldehyde (17b).[27] Following the
method of preparation of 17a, with 0.834 g (14.9 mmol) of 8c, and stirring
for 24 hr, gave 0.25 g (75%) of 17b as a pale yellow oil: Rf 0.72 (hexane/
EtOAc, 7 : 3); IR (CH2Cl2) 1717, 1608, 1511, 1459, 1397, 1316, 1202,
1119, 1030, 859 cm21
;
1H NMR (300 MHz, CDCl3) d 2.70 (br t,
J ¼ 7.3 Hz, 2H, ArCH2CH2CO), 2.88 (t, J ¼ 7.3 Hz, 2H, ArCH2CH2CO),
3.80 (s, 3H, OMe), 3.83 (s, 3H, OMe), 3.88 (s, 3H, OMe), 6.51 (s, 1H,
ArH), 6.71 (s, 1H, ArH), 9.80 (s, 1H, CHO); 13C NMR (75.4 MHz, CDCl3)
d 23.0 (ArCH2CH2CO), 44.2 (ArCH2CH2CO), 56.0 (MeO), 56.1 (MeO),
56.6 (MeO), 97.4 (ArH), 114.1 (ArH), 119.8 (Ar), 142.6 (Ar), 148.0 (Ar),
151.3 (Ar), 202.6 (CHO); MS (70 eV) m/z 224 (Mþ, 59), 209 (4), 181
(100), 168 (35), 151 (34), 136 (11), 121 (9), 91 (9), 77 (14). Anal. calcd for
C12H16O4: C, 64.27; H, 7.19. Found: C, 64.18; H, 6.95.
3-( p-Nitrobenzoyloxy)-4-(2,4,5-trimethoxyphenyl)-2-butanone (17c). Fol-
lowing the method of preparation of 17a, with 0.348 g (1.49 mmol) of 9, and
stirring for 30 min, gave 0.486 g (81%) of 17c as a yellow powder: Rf 0.71
(hexane/EtOAc, 7 : 3); mp 77–798C; IR (CH2Cl2) 1719, 1608, 1522, 1464,
1
1439, 1401, 1344, 1279, 1214, 1224, 1118, 1102, 1014, 853, 718 cm21; H
NMR (300 MHz, CDCl3) d 2.22 (s, 3H, CH3CO), 3.06 (dd, J ¼ 14.1,
8.1 Hz, 1H, ArCH2CH), 3.31 (dd, J ¼ 14.1, 5.1 Hz, 1H, ArCH2CH), 3.80
(s, 3H, OMe), 3.81 (s, 3H, OMe), 3.88 (s, 3H, OMe), 5.49 (dd, J ¼ 8.1,
5.1 Hz, 1H, ArCH2CH), 6.51 (s, 1H, ArH), 6.74 (s, 1H, ArH), 8.15–8.19
(m, 2H, ArH), 8.26–8.30 (m, 2H, ArH); 13C NMR (75.4 MHz, CDCl3) d
26.9 (CH3CO), 31.1 (ArCH2CH), 55.9 (MeO), 56.1 (Me), 56.6 (MeO), 79.3
(ArCH2CH), 96.9 (ArH), 114.6 (ArH), 115.2 (Ar), 123.5 (ArH), 130.8
(ArH), 134.9 (Ar), 142.6 (Ar), 149.0 (Ar), 150.6 (Ar), 151.7 (Ar), 164.0
(CO2Me), 204.1 (COCH3); MS (70 eV) m/z 403 (Mþ, 9), 236 (8), 205 (54),
181 (100), 151 (21), 150 (20), 136 (7), 104 (12), 76 (6). HRMS (FABþ)
[Mþ] (mNBA) calcd for C20H21NO8: 403.1267. Found: 403.1270.

2730
Aguilar, Benavides, and Tamariz
Methyl 3-(2,4,5-trimethoxyphenyl)propionate (6).[8] Method A: Fol-
lowing the method of preparation of 17a, with 1.28 g (14.9 mmol) of 8a
(adding in 1 mol equiv. each portion every 3 hr) in sym-tetrachloroethane as
solvent (7 mL), and stirring for 1 week, gave 0.14 g (37%) of 6 as a white
gum. Method B: Following method A, stirring under MW irradiation
(200 W) to 808C for 8 hr in a Teflon screw-capped ACE pressure tube, gave
0.249 g (66%) of 6 as a white gum. Rf 0.69 (hexane/EtOAc, 7 : 3); mp 50–
528C; IR (CH2Cl2) 1733, 1609, 1513, 1444, 1399, 1312, 1290, 1204, 1123,
1
1034, 850 cm21; H NMR (300 MHz, CDCl3) d 2.56 (t, J ¼ 7.8 Hz, 2H,
ArCH2CH2CO), 2.85 (t, J ¼ 7.8 Hz, 2H, ArCH2CH2CO), 3.64 (s, 3H,
CO2Me), 3.78 (s, 3H, OMe), 3.80 (s, 3H, OMe), 3.85 (s, 3H, OMe), 6.48
(s, 1H, ArH), 6.69 (s, 1H, ArH); 13C NMR (75.4 MHz, CDCl3) d 25.6 (ArCH2-
CH2CO), 34.4 (ArCH2CH2CO), 51.4 (CO2CH3), 56.05 (MeO), 56.10 (MeO),
56.5 (MeO), 97.4 (ArH), 114.1 (ArH), 120.1 (Ar), 142.6 (Ar), 147.9 (Ar),
151.4 (Ar), 173.7 (CO2CH3); MS (70 eV) m/z 254 (Mþ, 41), 239 (10), 211
(6), 181 (100), 151 (29), 121 (4), 91 (3), 77 (5). HRMS (FABþ) [Mþ]
(mNBA) calcd for C13H18O5: 254.1154. Found: 254.1161.
ACKNOWLEDGMENTS
´
´
We thank Dr. Hugo A. Jimenez-Vazquez for reviewing the manuscript,
and Fernando Labarrios for his help in spectrometric measurements. J. T.
acknowledges CGPI/IPN (Grants 200410, 20040123, and 200140) for finan-
cial support. R. A. and A. B. thank CONACYT for graduate scholarships. J. T.
is a fellow of the EDI/IPN and COFAA/IPN programs.
REFERENCES
1. (a) Knaggs, A.R. The biosynthesis of shikimate metabolites. Nat. Prod.
Rep. 2003, 20, 119–136; (b) Nenadis, N.; Zhang, H.-Y.;
Tsimidou, M.Z.J. Structure-antioxidant activity relationship of ferulic
acid derivatives: effect of carbon side chain characteristic groups.
J. Agric. Food Chem. 2003, 51, 1874–1879.
2. (a) Petersen, M.; Simmonds, M.S.J. Rosmarinic acid. Phytochemistry
2003, 62, 121–125; (b) Okuda, T. Novel aspects of tannins — renewed
concepts and structure-activity relationships. Curr. Org. Chem. 1999, 3,
609–622.
3. (a) Liu, I.-M.; Chi, T.-C.; Hsu, F.-L.; Chen, C.-F.; Cheng, J.-T. Isoferulic
acid as active principle from the rhizoma of Cimicifuga dahurica to lower
plasma glucose in diabetic rats. Planta Med. 1999, 65, 712–714;

Friedel–Crafts Reaction of Activated Benzene Rings
2731
(b) Zou, Y.; Kim, A.R.; Kim, J.E.; Choi, J.S.; Chung, H.Y. Peroxynitrite
scavenging activity of sinapic acid (3,5-dimethoxy-4-hydroxycinnamic
acid) isolated from Brassica juncea. J. Agric. Food Chem. 2002, 50,
5884–5890; (c) Yeh, C.-T.; Yen, G.-C. Effects of phenolic acids on
human phenol sulfotransferases in relation to their antioxidant activity.
J. Agric. Food Chem. 2003, 51, 1474–1479.
4. (a) Wende, G.; Waldron, K.W.; Smith, A.C.; Brett, C.T. Developmental
changes in cell-wall ferulate and dehydrodiferulates in sugar beet. Phyto-
chemistry 1999, 52, 819–827; (b) Exarchou, V.; Nenadis, N.;
Tsimidou, M.; Gerothanassis, I.P.; Troganis, A.; Boskou, D. Antioxidant
activities and phenolic composition of extracts from Greek oregano,
Greek sage, and summer savory. J. Agric. Food Chem. 2002, 50,
5294–5299; (c) Andreasen, M.F.; Landbo, A.-K.; Christensen, L.P.;
Hansen, A.; Meyer, A.S. Antioxidant effects of phenolic rye (Secale
cereale L.) extracts, monomeric hydroxycinnamates, and ferulic acid
dehydrodimers on human low-density lipoproteins. J. Agric. Food
Chem. 2001, 49, 4090–4096; (d) Grabber, J.H.; Ralph, J.; Hatfield, R.D.
Model studies of ferulate-coniferyl alcohol cross-product formation in
primary maize walls: implications for lignification in grasses. J. Agric.
Food Chem. 2002, 50, 6008–6016.
5. (a) Cheng, Z.; Ren, J.; Li, Y.; Chang, W.; Chen, Z. Study on the multiple
mechanisms underlying the reaction between hydroxyl radical and pheno-
lic compounds by qualitative structure and activity relationship. Bioorg.
Med. Chem. 2002, 10, 4067–4073; (b) Erazo, S.; Negrete, R.;
Zaldivar, M.; Backhouse, N.; Delponte, C.; Silva, I.; Belmonte, E.;
´
´
Lopez-Perez, J.L.; San Feliciano, A. Methyl psilalate: a new antimicrobial
metabolite from Psila boliviensis. Planta Med. 2002, 68, 66–67;
(c) Lee, H.-S. Tyrosinase inhibitors of Pulsatilla cernva root-derived
materials. J. Agric. Food Chem. 2002, 50, 1400–1403, and references
cited therein; (d) Etzenhouser, B.; Hansch, C.; Kapur, S.; Selassie, C.D.
Mechanism of toxicity of esters of caffeic and dihydrocaffeic acids.
Bioorg. Med. Chem. 2001, 9, 199–209; (e) Kawamatsu, Y.;
Asakawa, H.; Saraie, T.; Imamiya, E.; Nishikawa, K.; Hamuro, Y.
Studies on antihyperlipidemic agents. II. Synthesis and biological activi-
ties of 2-chloro-3-arylpropionic acids. Arzneim.-Forsch. 1980, 30,
585–589; (f) Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.;
´
Vlietinck, A.; Lemiere, G. Synthesis and biological evaluation of dihydro-
benzofuran lignans and related compounds as potential antitumor agents
that inhibit Tubulin polymerization. J. Med. Chem. 1999, 42, 5475–5481;
(g) Kikuzaki, H.; Hisamoto, M.; Hirose, K.; Akiyama, K.; Taniguchi, H.
Antioxidant properties of ferulic acid and its related compounds. J. Agric.
Food Chem. 2002, 50, 2161–2168.

2732
Aguilar, Benavides, and Tamariz
6. (a) Grabber, J.H.; Ralph, J.; Hatfield, R.D. Cross-linking of maize walls
by ferulate dimerization and incorporation into lignin. J. Agric. Food
Chem. 2000, 48, 6106–6113; (b) Ford, J.D.; Huang, K.-S.;
Wang, H.-B.; Davin, L.B.; Lewis, N.G. Biosynthetic pathway to the
cancer chemopreventive secoisolariciresinol diglucoside-hydroxymethyl
glutaryl ester-linked lignan oligomers in flax (Linum usitatissimum)
seed. J. Nat. Prod. 2001, 64, 1388–1397; (c) Bryngelsson, S.;
Dimberg, L.H.; Kamal-Eldin, A. Effects of commercial processing on
levels of antioxidants in oats (Avena sativa L.). J. Agric. Food Chem.
2002, 50, 1890–1896; (d) Lee, E.J.; Kim, S.R.; Kim, J.; Kim, Y.C. Hepa-
toprotective phenylpropanoids from Scrophularia buergeriana roots
against CCl4-induced toxicity: action mechanism and structure-activity
relationship. Planta Med. 2002, 68, 407–411; (e) Alvarez, L.;
Delgado, G. C- and O-glycosyl-a-hydrodihydrochalcones from Eysen-
hardtia polistachya. Phytochemistry 1999, 50, 681–687; (f) Cai, R.;
Hettiarachchy, N.S.; Jalaluddin, M. High-performance liquid chromato-
graphy determination of phenolic constituents in 17 varieties of
cowpeas. J. Agric. Food Chem. 2003, 51, 1623–1627.
7. (a) Shimoji, Y.; Tamura, Y.; Nakamura, Y.; Nanda, K.; Nishidai, S.;
Nishikawa, Y.; Ishihara, N.; Uenakai, K.; Ohigashi, H. Isolation and
identification of DPPH radical scavenging compounds in kurosu (Japa-
nese unpolished rice vinegar). J. Agric. Food Chem. 2002, 50,
6501–6503; (b) Baderschneider, B.; Winterhalter, P. Isolation and
characterization of novel benzoates, cinnamates, flavonoids, and lignans
from Riesling wine and screening for antioxidant activity. J. Agric.
Food Chem. 2001, 49, 2788–2798; (c) Silva, F.A.M.; Borges, F.;
Ferreira, M.A. Effects of phenolic propyl esters on the oxidative stability
of refined sunflower oil. J. Agric. Food Chem. 2001, 49, 3936–3941.
8. Ioset, J.-R.; Marston, A.; Gupta, M.P.; Hostettmann, K. Antifungal and
larvicidal compounds from the root bark of Cordia alliodora. J. Nat.
Prod. 2000, 63, 424–426.
9. (a) Jones, G. The Knoevenagel condensation. Org. React. 1967, 15,
204–599; (b) Piccolrovazzi, N.; Pino, P.; Consiglio, G.; Sironi, A.;
Moret, M. Electronic effects in homogeneous indenylzirconium
Ziegler–Natta catalysts. Organometallics 1990, 9, 3098–3105;
(c) Delgado, F.; Tamariz, J.; Zepeda, G.; Landa, M.; Miranda, R.;
´
Garcıa, J. Knoevenagel condensation catalyzed by a Mexican bentonite
using infrared irradiation. Synth. Commun. 1995, 25, 753–759;
(d) Hatsuda, M.; Kuroda, T.; Seki, M. An improved synthesis of (E)-cin-
namic acid derivatives via the Claisen–Schmidt condensation. Synth.
Commun. 2003, 33, 427–434.

Friedel–Crafts Reaction of Activated Benzene Rings
2733
10. (a) Williams, D.B.G.; Lombard, H.; Holzapfel, C.W. A comparative
study of some Pd-catalysed Heck reactions in polar- and aqueous bi-
phasic media. Synth. Commun. 2001, 31, 2077–2081; (b) Qandil, A.M.;
Miller, D.W.; Nichols, D.E. A practical and cost-effective synthesis
of 6,7-dimethoxy-2-tetralone. Synthesis 1999, 2033–2035; (c)
Vallin, K.S.A.; Emilsson, P.; Larhed, M.; Hallberg, A. High-speed
Heck reactions in ionic liquid with controlled microwave heating.
J. Org. Chem. 2002, 67, 6243–6246; (d) Heck, R.F. Palladium-catalyzed
vinylation of organic halides. Org. React. 1982, 27, 345–390.
11. (a) Permutter, P. Conjugate Addition Reactions in Organic Synthesis; Per-
gamon Press: Oxford, 1992; 199–282; (b) Malmberg, H.; Nilsson, M.;
Ullenius, C. Stereoselectivity in the transfer of the 2-(1-dimethylami-
ꢀ
noethyl)phenyl group, Rꢀ, from LiR2 Cu and LiRꢀ(2-thienyl)Cu to
enones. Tetrahedron Lett. 1982, 23, 3823–3826; (c) Lipshutz, B.H.;
Sengupta, S. Organocopper reagents: substitution, conjugate addition,
carbo/metallocupration, and other reactions. Org. React. 1992, 41,
135–631.
12. (a) Olah, G.A.; Krishnamurti, R.; Prakash, G.K.S. Friedel–Crafts alky-
lations. In Comprehensive Organic Synthesis; Trost, B.M., Fleming, I.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 3, 293–339;
(b) Mahindaratne, M.P.D.; Wimalasena, K. Detailed characterization of
p-toluenesulfonic acid monohydrate as a convenient, recoverable, safe,
and selective catalyst for alkylation of the aromatic nucleus. J. Org.
Chem. 1998, 63, 2858–2866.
13. (a) Shen, Y.-s.S.; Liu, H.-x.; Chen, Y.-q. The first Friedel-Crafts reaction
of nitrobenzene. J. Org. Chem. 1990, 55, 3961–3962; (b) Bunce, R.A.;
Reeves, H.D. Amberlyst-15 catalyzed addition of phenols to a,b-unsatu-
rated ketones. Synth. Commun. 1989, 19, 1109–1117; (c) Yadav, J.S.;
Abraham, S.; Reddy, B.V.S.; Sabitha, G. InCl3-catalysed conjugate
addition of indoles with electron-deficient olefins. Synthesis 2001,
2165–2169; (d) Jensen, K.B.; Thorhauge, J.; Hazell, R.G.;
Jørgensen, K.A. Catalytic asymmetric Friedel-Crafts alkylation of b,g-
unsaturated a-ketoesters: enantioselective addition of aromatic C–H
bonds to alkenes. Angew. Chem., Int. Ed. 2001, 40, 160–163;
(e) Tateiwa, J.-l.; Horiuchi, H.; Hashimoto, K.; Yamauchi, T.;
Uemura, S. Cation-exchanged montmorillonite-catalyzed facile Friedel-
Crafts alkylation of hydroxy and methoxy aromatics with 4-hydroxybu-
tan-2-ones to produce rasberry ketone and some pharmaceutically
active compounds. J. Org. Chem. 1994, 59, 5901–5904.
14. (a) Reyes, A.; Aguilar, R.; Mun˜oz, A.H.; Zwick, J.-C.; Rubio, M.;
Escobar, J.-L.; Soriano, M.; Toscano, R.; Tamariz, J. Highly selective
Diels-Alder cycloadditions of captodative dienophiles 1-acetylvinyl

2734
Aguilar, Benavides, and Tamariz
arenecarboxylates to unsymmetrically substituted butadienes. J. Org.
Chem. 1990, 55, 1024–1034; (b) Peralta, J.; Bullock, J.P.; Bates, R.W.;
Bott, S.; Zepeda, G.; Tamariz, J. Stereoselective synthesis, NMR confor-
mational study and Diels-Alder reaction of b-functionalized 1-acetylvinyl
arenecarboxylates. Tetrahedron 1995, 51, 3979–3996; (c) Ochoa, M.E.;
Arias, A.S.; Aguilar, R.; Delgado, F.; Tamariz, J. Captodative olefin
3-p-nitrobenzoyloxy-3-buten-2-one as a Diels-Alder ketene equivalent
for the synthesis of g-hydroxycyclohexenones. Tetrahedron 1999, 55,
14535–14546; (d) Herrera, R.; Nagarajan, A.; Morales, M.A.;
´
´
´
Mendez, F.; Jimenez-Vazquez, H.A.; Zepeda, G.; Tamariz, J. Regio-
and stereoselectivity of captodative olefins in 1,3-dipolar cycloadditions.
A DFT/HSAB theory rationale for the observed regiochemistry of
nitrones. J. Org. Chem. 2001, 66, 1252–1263.
´
15. (a) Dıaz, F.; Mun˜oz, H.; Labarrios, F.; Chamorro, G.; Salazar, M.;
Morelos, M.E.; Tamariz, J. Synthesis and hypolipidemic activity of
some a-asarone analogs. Med. Chem. Res. 1993, 3, 101–109;
´
(b) Labarrios, F.; Gardun˜o, L.; Vidal, M.R.; Garcıa, R.; Salazar, M.;
´
´
Martınez, E.; Dıaz, F.; Chamorro, G.; Tamariz, J. Synthesis and hypolipi-
daemic evaluation of a series of a-asarone analogues related to clofibrate
in mice. J. Pharm. Pharmacol. 1999, 51, 1–7; (c) Cruz, A.; Gardun˜o, L.;
´
´
´
´
Salazar, M.; Martınez, E.; Jimenez-Vazquez, H.A.; Dıaz, F.;
Chamorro, G.; Tamariz, J. Synthesis and hypolipidemic activity of modi-
fied side chain a-asarone homologues. Arzneim.-Forsch. 2001, 51,
535–544.
16. Johnston, H.W.; Gross, F.J. Cyanoethylation of phenol; isolation of an
ortho-addition product. J. Org. Chem. 1957, 22, 1264–1265.
17. Chatterjee, A.; Hazra, B.G. Carbon–carbon cyanoethylation of anisole
and its derivatives. Tetrahedron 1977, 33, 1983–1987.
18. Hazra, B.G.; Pore, V.S.; Basu, S. Titanium tetrachloride-mediated
carbon–carbon chlorocyanoethylation of anisole: synthesis of tyrosine
derivatives. Synthetic Commun. 1995, 25, 2847–2855.
19. Westfahl, L.; Gresham, T.L. Vinylidene cyanide. V. The aluminum chlor-
ide catalyzed reaction of vinylidene cyanide and aromatic compounds.
J. Am. Chem. Soc. 1954, 76, 1076–1080.
´
´
´
20. Martınez, R.; Jimenez-Vazquez, H.A.; Tamariz, J. Regioselective syn-
thesis of N-substituted 4-methylene-2-oxazolidinones and 4-oxazolin-2-
ones. Study of reactivity in thermal Michael conjugate additions. Tetrahe-
dron 2000, 56, 3857–3866.
21. Narayana, M.; Dash, J.F.; Gardner, P.D. Phosphorus acids in organic
systems. III. Specific pyrophosphoric acid catalysis in the conversion of
resorcinol dimethyl ether to coumarins. J. Org. Chem. 1962, 27,
4704–4705.

Friedel–Crafts Reaction of Activated Benzene Rings
2735
´
22. (a) Chamorro, G.; Salazar, M.; Salazar, S.; Mendoza, T. Farmacologıa y
´
toxicologıa de Guatteria gaumeri y a-asarona. Rev. Inv. Clin. 1993, 45,
¨
597–604, and references cited therein; (b) Goggelmann, W.;
Schimmer, O. Mutagenicity testing of b-asarone and commercial
calamus drugs with Salmonella typhimurium. Mutation Res. 1983, 121,
¨
191–194; (c) Abel, G. Chromosomenschadigende wirkung von
b-asaron in menschlichen lymphocyten. Planta Med. 1987, 53, 251–253.
23. (a) Sinha, A.K.; Dogra, R.; Joshi, B.P. A concise conversion of b-asarone
to 1-(2-carbomethoxyethyl)-2,4,5-trimethoxybenzene occurring in
Cordia alliodora. Ind. J. Chem. 2002, 41B, 635–638; Section B;
(b) Vanisree, M.; Kavitha, J.; Subbaraju, G.V. Synthesis of methyl
3-(2,4,5-trimethoxyphenyl)propionate, an antifungal and larvicidal con-
stituent of Cordia alliodora. Asian J. Chem. 2002, 14, 534–536.
24. Fleming, I. Frontier Orbitals and Organic Chemical Reactions; John
Wiley & Sons: Chichester, 1976.
´
´
25. (a) Jimenez-Vazquez, H.A.; Ochoa, M.E.; Zepeda, G.; Modelli, A.;
Jones, D.; Mendoza, J.A.; Tamariz, J. Structural, spectroscopic, and theor-
etical study of 1-acetylvinyl p-nitrobenzoate, a highly reactive and selec-
tive captodative olefin in cycloaddition reactions. J. Phys. Chem. A 1997,
´ ´
101, 10082–10089; (b) Herrera, R.; Jimenez-Vazquez, H.A.; Modelli, A.;
¨
Jones, D.; Soderberg, B.C.; Tamariz, J. Synthesis of new captodative
alkenes: alkyl 2-aroyloxy acrylates — structure, and reactivity in Diels-
Alder cycloadditions. Eur. J. Org. Chem. 2001, 4657–4669.
26. Aldous, F.A.B.; Barrass, B.C.; Brewster, K.; Buxton, D.A.; Green, D.M.;
Pinder, R.M.; Rich, P.; Skeels, M.; Tutt, K.J. Structure-activity relation-
ships in psychotomimetic phenylalkylamines. J. Med. Chem. 1974, 17,
1100–1111.
27. De Lombaert, S.; Blanchard, L.; Stamford, L.B.; Tan, J.; Wallace, E.M.;
Satoh, Y.; Fitt, J.; Hoyer, D.; Simonsbergen, D.; Moliterni, J.;
Marcopoulos, N.; Savage, P.; Chou, M.; Trapani, A.J.; Jeng, A.Y.
Potent and selective non-peptidic inhibitors of endothelin-converting
enzyme-1 with sustained duration of action. J. Med. Chem. 2000, 43,
488–504.
Received in the USA March 31, 2004