Synthesis of 2,3-dimethoxy-7-methyl-7,12-dihydro-6H-[1]-benzofuro-[2,3-c]- [1]-benzazepin-6,12-dione

Article abstract of DOI:10.3390/70300353

Treatment of 5,6-dimethoxy-2-(methylphenylcarbamoyl)-benzofuran-3- carboxylic acid with PPA yielded 2,3-dimethoxy-7-methyl-7,12-dihydro-6H-[1]- benzofuro-[2,3-c]-[1]-benzazepin-6,12-dione. The analogous 2-[(5,6- dimethoxybenzo-furan-2-carbonyl)methylamino]benzoic acid was resistant to cyclization, whereas 2-[(6-methoxybenzofuran-2-carbonyl)-amino]benzoic acid underwent cyclization to the corresponding 3,1-benzoxazin-4-one.

Full text of DOI:10.3390/70300353

Molecules 2002, 7, 353-362
molecules
ISSN 1420-3049
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Synthesis of 2,3-Dimethoxy-7-methyl-7,12-dihydro-6H-[1]-
benzofuro-[2,3-c]-[1]-benzazepin-6,12-dione.
Yvette A. Jackson* and Karla-Sue C. Marriott
Department of Chemistry, University of the West Indies, Mona, Kingston 7, Jamaica, West Indies
*Author to whom correspondence should be addressed; e-mail: yjackson@uwimona.edu.jm
Abstract: Treatment of 5,6-dimethoxy-2-(methylphenylcarbamoyl)-benzofuran-3-
carboxylic acid with PPA yielded 2,3-dimethoxy-7-methyl-7,12-dihydro-6H-[1]-
benzofuro-[2,3-c]-[1]-benzazepin-6,12-dione. The analogous 2-[(5,6-dimethoxybenzo-
furan-2-carbonyl)methylamino]benzoic acid was resistant to cyclization, whereas 2-[(6-
methoxybenzofuran-2-carbonyl)-amino]benzoic acid underwent cyclization to the
corresponding 3,1-benzoxazin-4-one.
Keywords: PPA, cyclization, benzoxazinone, benzofuro-[2,3-c]-[1]-benzazepin-6,12-
dione.
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Introduction
Rotenonoids, of general structure 1a, are 6-oxo analogues of the rotenoids, which are naturally
occurring insecticidal compounds with a range of other biological activity (antimicrobial, antiviral,
piscicidal etc.)[1-3]. Rearrangement of β-rotenonoids 2a to rotenonoids 1a under basic conditions is
well known [4, 5].
11
1
O
R'
R"
11
1
4
8
X
X
5
6
Y
7
O
4
O
O
1a X = Y = O
1b X = NH, Y = O
1c X =O, Y = NH
2a X = O; R', R" = O
2b X = NH; R', R" = O
2c X = O; R'=R"=H
2d X = NH; R'=R" = H

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Azarotenonoids (e.g. compounds 1b, 1c) – nitrogen analogues of rotenonoids – on the other hand,
are not widely known. The 5-azarotenonoid 1b has been prepared by photo-oxidative cyclization of
N-phenyl-4(H)-oxo-1-benzopyran-2-carboxamides [6]. To date, there are no references to
7-azarotenonoids (1c), or to nitrogen analogues of β-rotenonoids (e.g. 2b). We explored synthesis of
compounds of type 2b with a view to investigating their biological properties and carrying out
structure/activity relation studies. The de-oxo system 2d is known [7], and synthesis of the desired 2b
from this compound by oxidation seems a logical and straightforward path. Oxidation of 3-benzyl-
benzofurans to 3-aroylbenzofurans, and of [1]-benzofuran-[2,3-c]-[6H,12H-1]-benzoxepin-6-ones (2c)
to β-rotenonoids, have been reported as being anything but trivial [8, 5a]. Other approaches, therefore,
needed to be employed.
Results and Discussion
The pathway shown in Scheme 1 was first explored. Rotenoids are often oxygenated at positions 2
and 3 [9]. Use of 3-bromo-7-methoxycoumarin (3) would result in only the monomethoxy
rotenonoids, however this material was available in quantity and was seen as a useful prototype for our
studies.
Scheme 1. Synthetic plan
MeO
MeO
MeO
O
HO C
2
O
O
O
N
H
N
H
Br
O
O
O
4
5
We anticipated that Ullmann-type condensation [10,11] of 3 with anthranilic acid would afford
compound 4, which should undergo intramolecular cyclization to the desired azarotenonoid 5.
Reaction of 3 with anthranilic acid in the presence of copper, however, produced acid 6 (42%) after 4
hours, and upon treatment of 6 with polyphosphoric acid (PPA), 3,1-benzoxazin-4-one 7a was
obtained (70%, Scheme 2).
Scheme 2
1
N
H
MeO
HO
N
ii)
i)
3
HO C
2
O
O
4
MeO
O
O
MeO
3
O
O
O
N
H
O
6
7a
Reagents: i) antranilic acid, Cu, CuBr, K2CO3, DMF, 140ûC; ii) PPA

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Scheme 3
R
1
N
MeO
R
R
i)
COOH
HO C
2
O
O
4
O
MeO
ii)
MeO
3
O
O
NH
8a R = H
8b R = OMe
O
7a R = H
7b R = OMe
6 R = H
Reagents: i) PCl5; ii) antranilic acid
Strong IR absorptions at 1635 and 1773 cm-1, corresponding to the C=N and ester functionality,
were observed. Compounds of this type are known to undergo base hydrolysis to produce the
corresponding N-acyl anthranilic acids, which are then readily reconverted to benzoxazinones on
treatment with NaOAc/Ac2O [12]. Our reaction product exhibited this reactivity, forming compound
6 on treatment with KOH. Subsequent treatment of compound 6 with NaOAc/Ac2O, caused re-
formation of benzoxazinone 7a.
We also obtained benzoxazinone 7a in 40% yield by treatment of acid 8a with PCl5 and then
reacting the resultant acid chloride with anthranilic acid (Scheme 3). It is clear that under Ullmann
reaction conditions, 3-bromo-7-methoxycoumarin (3) underwent rearrangement to 6-methoxy-
benzofuran-2-carboxylic acid (8a). The rearrangement of such coumarins is known to occur in
alkaline media [13, 14]. We verified our observation by subjecting compound 3 to treatment with
potassium carbonate in DMF at 140°C for 4 hours – conditions as obtained for the attempted Ullmann
reaction but without copper and anthranilic acid. Quantitative conversion to compound 8a, identical in
all respects with an authentic sample [15], was achieved.
Compounds of type 6, then, would cyclize to yield 3,1-benzoxazin-4-ones more readily than they
would to give the desired benzazepines. (Compound 8b on treatment with PCl5 followed by
anthranilic acid gave 7b.) We considered that absence of the amide proton would disallow
benzoxazinone formation, and could augur well for occurrence of the desired cyclization. With this in
mind, compound 10a was prepared as shown in Scheme 4. Treatment of 10a with PPA, however,
yielded none of the required 11a and as predicted, none of the corresponding benzoxazinone was
formed. Even after heating 10a in PPA at 80-100°C for 24 hours, only starting material was
recovered. Compound 10a was also unreactive to Friedel-Crafts conditions. Treatment with PCl5
followed by SnCl4 for 23 hours at 95°C afforded only starting material. Our work with the analogous
2-carbophenoxy-5,6-dimethoxybenzofuran-2'-carboxylic acid (10b, X = O) also shows that it is inert
to Friedel-Crafts reaction conditions (using SnCl4 as Lewis acid) [16].

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Scheme 4
OMe
O
OMe
MeO
O
MeO
PPA MeO
i)
MeO C
ii)
2
HO C
8b
2
X
X
MeO
O
O
O
X
N
H
O
O
10a X = N-Me
10b X =O
11a X = N-Me
11b X =O
9
Reagents: I) methyl anthranilate, DCC, DMAP, CH2Cl2, rt; ii) NaH, MeI, THF
Synthesis of compound 11a was eventually achieved by the pathway shown in Scheme 5.
Attempts at direct oxidation of 13 to 16a using KMnO4 were unsuccessful. Oxidation of 14 using
trimethylamine-N-oxide (TMANO), however, produced aldehyde 15 (50%), which on further
oxidation yielded 16a (90%) [17-19]. Heating 16a in PPA at 900C for 24 hours effected
intramolecular cyclization to 11a in 25% yield.
Scheme 5
OMe
O
OMe
OMe
MeO
MeO
MeO
iii)
i)
ii)
CH
CH
CH Br
3
3
2
O
O
CO H
N
2
N
CH
3
O
CH
O
3
12
13
14
OMe
OMe
O
OMe
O
MeO
MeO
MeO
O
v)
iv)
CHO
CO H
2
O
O
N
N
O
N
CH
CH
CH
3
3
O
3
16a X = N-Me
16b X = O
15
11a
Reagents: I) N-methylaniline, DCC, DMAP, CH2Cl2, rt; ii) NBS, CCl4, hυ;
iii) TMANO, DMSO, rt; iv) NBS, CCl4, hυ, then H2O; v) PPA

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The fact that we achieved hydrolysis of amide 13 in refluxing NaOH (40% aqueous) prompted us
to investigate the possibility of similar reaction with our compound 11a in hope of possible
rearrangement to the azarotenonoid. Compound 11a, however, proved resistant to treatment with
NaOH.
Conclusions
We have synthesized 2,3-dimethoxy-7-methyl-7, 12-dihydro-6H-[1]-benzofuro-[2,3-c]-[1]-benz-
azepin-6,12-dione (11a) via acid-catalysed cyclization of 16a. This pathway is not useful for
formation of β-rotenonoids, since under the reaction conditions the ester linkage of compounds such as
10b and 16b are quite labile.
Acknowledgements
This work was supported in part by a UWI/IDB research grant, which is gratefully acknowledged.
Experimental
General
All melting points are uncorrected. IR spectra (KBr disks) were obtained on a Perkin Elmer 735B
model or a Perkin Elmer 1600 FT-IR spectrometer. NMR spectra were recorded were determined in
CDCl3 solutions on a Bruker 200 MHz spectrometer. The resonances are reported in δ units downfield
1
from TMS; J values are given in Hz. For ease of reporting H-NMR data, the protons on the
benzofuran side of the molecule have been labelled as H and those on the phenyl ring as H'. Elemental
analyses were carried out by MEDAC Ltd., Egham, Surrey, UK.
2-[(6-Methoxybenzofuran-2-carbonyl)-amino]benzoic acid (6)
To a 25 mL round bottomed flask fitted with a reflux condenser and a calcium chloride guard tube,
were added 7-methoxy 3-bromocoumarin (3) (0.50 g, 1.97 mmol) and N, N-dimethylformamide (10
mL). Anthranilic acid (0.27 g, 1.97 mmol), potassium carbonate (0.875 g, 6.30 mmol), copper powder
(5.0 mg) and copper (I) bromide (8 mg) were added with stirring to this solution and the mixture was
heated at 140°C for 4 hours. The mixture was then allowed to cool, diluted with water (40 mL), and
treated with decolorizing carbon (0.12 g). After filtration the filtrate was acidified with hydrochloric
acid (3N) and the resulting precipitate was collected and washed with water (25 mL).
Recrystallization from ethanol gave 6 (0.26 g, 42%); mp 209-212°C; IR cm-1: 1624, 1675, 3350 (br);
1H-NMR δH: 3.92 (3H, s, -OCH3), 5.95 (1H, br, -N-H), 6.85 (1H, dd, J = 2, 8, H-5), 7.15 (2H, m, H-7,
4'), 7.50 (3H, m, H-3, 4, 5'), 8.15 (1H, dd, J = 1, 8, H-6'), 8.80 (1H, dd, J = 1, 8, H-3'), 12.5 (1H, s,

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COOH); 13C-NMR δC: 55.6, 95.8, 111.1, 113.4, 116.0, 120.1, 120.7, 122.7, 122.7, 131.5, 134.1, 141.1,
148.2, 156.2, 157.1, 159.9,170.3; MS m/e (relative intensity) 311.03 (M+, 82), 293.02 (14), 192.03
(22), 175.04 (100), 119.06 (46). HRMS calcd. for C17H13NO5: 311.0794. Found: 311.0794.
2-(6’-Methoxybenzofuran)-3,1-benzoxazin-4-one (7a)
a) Compound 6 (2.0 g, 6.43 mmol) was added to well-stirred PPA (20 mL) which had been preheated
to 90°C. This mixture was stirred at 110°C for 2 h, then poured onto ice (200 g), neutralized with 6N
ammonia, and the resultant precipitate filtered and washed with saturated sodium bicarbonate. The
solid was air-dried and purified by chromatography (neutral alumina, 4:1 hexane-EtOAc) to give 7a
(1.3 g, 70%), mp 210-212°C (MeOH); IR cm-1: 1773, 1635, 1599; 1H-NMR δH: 3.90 (3H, s, -O-CH3 ),
6.95-7.00 (1H, dd, J = 2, 8, 5'-H), 7.15 (1H, d, J = 2, H-7'), 7.50-7.65 (3H, m, H-6, H-8, H-3'), 7.65-
7.95 (2H, m, H-7, H-4'), 8.20-8.26 (1H, dd, J = 1, 8, H-5); 13C-NMR δC: 55.5, 95.6, 113.5, 113.9,
116.7, 120.4, 122.8, 127.0, 128.3, 128.6, 136.7, 144.3, 146.4, 157.5, 160.5. Anal. Calcd. for
C17H11NO4: C, 69.61; H, 3.78; N, 4.78; Found: C, 69.46. H, 3.74; N, 4.76%.
b) PCl5 (0.63 g, 3.04 mmol) was added, with stirring, to a mixture of 6-methoxybenzofuran-2-
carboxylic acid (8a, 0.38 g, 1.99 mmol) [13] in benzene (5mL). This was heated at reflux for 2 h, after
which time it was cooled to room temperature and then in an ice-bath. Anthranilic acid (0.28 g, 2.01
mmol was dissolved in pyridine (1 mL) and this solution was added dropwise to the reaction mixture
with cooling and stirring. Upon completion of addition the ice-bath was removed and the reaction
mixture was stirred at room temperature for 3 h. Benzene was then evaporated in vacuo and water
added to the resultant crude brown precipitate. This was then collected by filtration and air dried.
Recrystallisation from methanol yielded 7a as pale yellow crystals (0.235 g, 40%).
Alkaline hydrolysis of compound 7a.
Compound 7a (51.6 mg, 0.18 mmol) was added to ethanol (2 mL) with stirring. To this mixture
potassium hydroxide (50 mg, 0.89 mmol) was added and the mixture heated at reflux for 2 h. The
reaction mixture was then concentrated in vacuo and the crude product dissolved in the minimum
amount of water and acidified with conc. HCl. The product was collected by filtration, washed with
cold water and dried at the pump, to yield 6 as a white powder (51.4 mg, 94%), mp 209-212ºC.
Conversion of 6 to 7a using sodium acetate and acetic anhydride.
A mixture of 6 (38.7 mg, 0.12 mmol), acetic anhydride (0.65 mL) and sodium acetate (204 mg) was
heated to 140ºC with stirring for 1 h. The reaction mixture was then cooled in an ice-bath and
immediately solidified to give a pale yellow precipitate. Water (5 mL) was added to this precipitate
and the solution extracted with dichloromethane. The organic extract was then concentrated in vacuo

Molecules 2002, 7
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and the crude product recrystallised from methanol to yield 7a as a pale yellow powder (20.3 mg,
56%), mp 210-213ºC.
2-(5',6'-Dimethoxybenzofuran)-3,1-benzoxazin-4-one (7b).
PCl5 (0.76 g, 3.63 mmol) was added, with stirring, to a mixture of 5,6-dimethoxybenzofuran-2-
carboxylic acid (8b, 0.50 g, 2.26 mmol) [20] in benzene (8 mL). This was heated at reflux for 2 h, then
cooled to room temperature and then in an ice-bath. A solution of anthranilic acid (0.33 g, 2.41 mmol)
in pyridine (1 mL) was added dropwise to the reaction mixture with cooling and stirring. Upon
completion of addition the ice-bath was removed and the reaction mixture was stirred at room
temperature for 3 h. Benzene was then evaporated in vacuo and water added to the resultant crude
precipitate which was collected by filtration and air dried. The crude was purified by chromatography
(SiO2, dichloromethane) to yield 7b as yellow crystals (0.28 g, 39%), mp 231-232°C (MeOH); IR cm-1
1
1751, 1632, 1598; H-NMR δH 3.90 (3H, s, O-CH3), 4.00 (3H, s, -O-CH3), 7.00 (1H, s, H-3'), 7.12
(1H, s, H-7'), 7.40-7.55 (1H, m, H-7), 7.60 (1H, s, H-4'), 7.70-7.90 (2H, m, H-6, H-8), 8.20-8.30 (1H,
dd, J = 2, 8, H-5); 13C-NMR δC 56.2, 56.3, 95.2, 95.2, 102.4, 113.8, 119.4,127.2, 128.2, 128.7, 128.7,
136.7, 144.4, 146.7, 147.7, 151.1, 151.9, 158.6. Anal. Calcd. for C18H13NO5: C, 66.86; H, 4.06; N,
4.33 %; Found: C, 66.60; H, 4.03; N, 4.31.
2-[(5,6-Dimethoxybenzofuran-2-carbonyl)-amino]benzoic acid methyl ester (9).
5,6-Dimethoxybenzofuran-2-carboxylic acid [20] (0.513 g, 2.437 mmol) was added, with stirring
to a solution of methyl anthranilate (0.303 g, 2.00 mmol) in dichloromethane (10 mL). To this mixture
was added 4-(N,N-dimethylamino)pyridine (DMAP) (0.036 g, 0.294 mmol) and 1,3-dicyclo-
hexylcarbodiimide (DCC) (0.506 g, 2.45 mmol) and the whole left to stir at room temperature for 24 h.
The reaction mixture was then filtered under vacuum and the filtrate concentrated in vacuo. The crude
product was recrystallised from CH2Cl2/MeOH to yield compound 9 as feathery brown crystals (0.530
g, 77%), mp 210-211°C; IR cm-1: 1695, 1670, 1568; 1H-NMR δH: 3.90 (3H, s, -O-CH3), 4.00 (3H, s, -
O-CH3), 4.10 (3H, s, -CO2-CH3), 7.10-7.20 (3H, m, H-4, H-7, H-4'), 7.50-7.65 (2H, m, H-3, H-5'),
8.10 (1H, d, J = 8, H-6'), 8.90 (1H, d, J = 8, H-3'); 13C-NMR δC: 52.4, 56.2, 56.2, 95.3, 102.5, 111.8,
115.2, 119.5, 120.5, 122.7, 130.9, 134.6, 141.1, 147.3, 148.1, 150.3, 150.5, 157.2, 168.6. Anal. Calcd.
for C19H17NO6: C, 64.22; H, 4.82; N, 3.94. Found: C, 63.91; H, 4.87; N, 4.11%.
2-[(5,6-Dimethoxybenzofuran-2-carbonyl)-methylamino]benzoic acid (10a).
Sodium hydride (0.093 g, 3.87 mmol) was stirred with pre-dried THF (6 mL) in an atmosphere of
nitrogen. Compound 9 (0.20 g, 0.58 mmol) was added and the mixture was stirred at room
temperature for 30 minutes. Iodomethane (0.11 mL, 1.72 mmol) was added and the reaction mixture
was then heated at reflux for 6 h. After this time, ethanol was added to the reaction mixture, solvent

Molecules 2002, 7
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was removed in vacuo and water (20 mL) added to the resultant precipitate. The solution formed was
then extracted exhaustively with CH2Cl2, the extract concentrated in vacuo, and the crude product
recrystallised from hexane to yield 10a as light brown shiny crystals (0.102 g, 70%), mp 194-196°C;
1
IR cm-1: 1727, 1678, 1621; H-NMR δH: 3.45 (3H, s, -NH-CH3), 3.85 (3H, s, -O-CH3), 3.90 (3H, s, -
O-CH3), 6.05 (1H, s, H-7), 6.80-6.90 (2H, m, H-4, H-4'), 7.29-7.38 (1H, dd, J = 1, 8, H-5'), 7.50-7.70
(2H, m, H-3, H-6'), 8.09-8.18 (1H, dd, J = 1, 8, H-3'); 13C-NMR δC: 39.2, 55.7, 55.7, 94.5, 102.1,
111.6, 118.4, 128.0, 129.1, 129.4, 131.7, 132.8, 143.3, 146.5, 147.0, 149.2, 149.5, 159.1, 166.4; MS
m/e (relative intensity) 355 (M+, 46), 310 (12), 205 (100), 149 (40). HRMS calcd. for C19H17NO6:
355.1056. Found: 355.1071.
5,6-Dimethoxy-3-methylbenzofuran-2-carboxylic acid methyl phenyl amide (13).
To a mixture of N-methylaniline (0.462 g, 4.31 mmol) in CH2Cl2 (25 mL), 3-methyl-5,6-
dimethoxybenzofuran-2-carboxylic acid [21] (1.01 g, 4.27 mmol) was added with stirring. DMAP
(0.090 g, 0.44 mmol) was then added, followed by DCC (0.934 g, 4.53 mmol). The reaction mixture
was left to stir at room temperature for 23 h. After this time the mixture was filtered and the filtrate
was washed successively with water (2 x 10 mL), 5% acetic acid (2 x 10 mL) and again with water (2 x
10 mL). The organic solution was then dried (Na2SO4) and concentrated in vacuo. The crude product
was recrystallised from hexane to yield 13 as brown diamond shaped crystals (0.852 g, 62%), mp 102-
103°C; IR cm-1: 1653, 1620, 1597; 1H-NMR δH: 2.40 (3H, s, Ar-CH3), 3.50 (3H, s, -N-CH3), 3.80 (3H,
13
s, -O-CH3), 3.85 (3H, s, -O-CH3), 6.56 (1H, s, H-7), 6.85 (1H, s, H-4), 7.10-7.35 (5H, m, -N-Ar); C-
NMR δC: 9.2, 39.2, 56.2, 56.2, 94.7, 100.8, 120.7, 122.6, 126.0, 126.3, 128.9, 143.3, 144.5, 146.7,
148.4, 149.8, 161.6. Anal. Calcd. for C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C, 69.81; H,
6.04; N, 4.58%.
3-Bromomethyl-5,6-dimethoxybenzofuran-2-carboxylic acid methyl phenyl amide (14).
To a mixture of the amide 13 (1.66 g, 5.10 mmol) in CCl4 (100 mL), N-bromosuccinimide (NBS)
(1.11 g, 6.24 mmol) was added with stirring. The reaction was then enclosed in a dark box and
irradiated with a 100 W light bulb which allowed gentle reflux. After 24 h the mixture was filtered, the
filtrate was concentrated in vacuo, and the resulting crude product was triturated with hot hexane to
yield 14 as a tan powder (1.50 g, 73%), mp 113-115°C; IR cm-1: 1702, 1602, 1595; 1H-NMR δH: 3.50
(3H, s, -N-CH3), 3.80 (3H, s, -O-CH3), 3.90 (3H, s, -O-CH3), 5.00 (2H, s, -CH2-Br), 6.50 (1H, s, H-7),
13
7.05 (1H, s, H-4), 7.15-7.36 (5H, m, -N-Ar); C-NMR δC: 22.2, 39.3, 56.3, 56.3, 94.6, 100.8, 118.5,
123.24, 126.0, 126.1, 126.8, 128.9, 129.1, 143.9, 144.0, 147.1, 148.5, 150.3, 160.4. Anal. Calcd. for
C19H18BrNO4: C, 56.45; H, 4.49; N, 3.46. Found: C, 56.19; H, 4.57; N, 3.86. %.

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5,6-Dimethoxy-3-formylbenzofuran-2-carboxylic acid methyl phenyl amide (15).
To 14 (1.41 g, 3.50 mmol) was added a solution of TMANO (0.40 g, 5.31 mmol) in DMSO (15
mL) and the mixture was stirred at room temperature for 1h, then poured into 5% saline solution (200
mL) with swirling. The resultant yellow precipitate was collected by filtration. Recrystallisation from
hexane/ethyl acetate yielded 15 as pale yellow crystals (0.60 g, 50%), mp 124-125°C; IR cm-1: 1673,
1
1639, 1619, 1594; H-NMR δH: 3.50 (3H, s, -N-CH3), 3.80 (3H, s, -O-CH3), 3.90 (3H, s, -O-CH3),
13
6.60 (1H, s, H-7), 7.10-7.45 (5H, m, -N-Ar), 7.60 (1H, s, H-4), 10.65 (1H, s, -CHO); C-NMR δC:
38.0, 55.8, 55.8, 93.8, 102.5, 115.1, 123.2, 125.7, 127.0, 128.9, 142.8, 148.0, 148.2, 150.0, 153.3,
158.8, 187.6. Anal. Calcd. for C19H17NO5 : C, 67.25; H, 5.05; N, 4.13. Found : C, 67.03; H, 5.06; N,
4.28%.
5,6-Dimethoxy-2-(methyl phenylcarbamoyl)-benzofuran-3-carboxylic acid (16a).
Compound 15 (0.39 g, 1.15 mmol) was dissolved in CCl4 (47 mL) and NBS (0.26 g, 1.46 mmol)
was added with stirring. The reaction was enclosed in a dark box and irradiated with a 100 W light
bulb for 24 h. The reaction mixture was then filtered and the filtrate concentrated in vacuo. To this
brown residue, water (20 mL) was added and the mixture was left to stand overnight. The water was
decanted and the resultant brown solid was dissolved in ethyl acetate. The solution was dried
(Na2SO4) and concentrated in vacuo . The crude product was recrystallised from ethanol to yield 16a
1
as a tan powder (0.37g, 90%); mp 170-172°C; IR cm-1: 1705, 1638, 1619, 1549; H-NMR δH: 3.55
(3H, s, -N-CH3), 3.80 (3H, s, -O-CH3), 3.95 (3H, s, -O-CH3) 7.20-7.55 (6H, m, -N-Ar, H-7), 7.70 (1H,
13
s, H-4); C-NMR δC: 39.2, 56.1, 56.1, 93.4, 103.1, 117.9, 125.9, 127.8, 129.1, 142.7, 148.0, 148.3,
150.7, 161.0, 162.6; MS m/e (relative intensity) 355 (M+, 14), 337 (24), 311 (100), 249 (67). HRMS
calcd. for C19H17NO6: 355.1056. Found: 355.1054.
2,3-Dimethoxy-7-methyl-7, 12-dihydro-6H-[1]-benzofuro-[2,3-c]-[1]-benzazepin-6,12-dione (11a).
To PPA (2 mL) which had been pre-heated to 900C, compound 16a (0.100 g, 0.28 mmol) was
added with stirring over 15 min. The reaction mixture was then heated at 90°C for 24 h, poured into
water/crushed ice (100mL) and was extracted exhaustively with ethyl acetate. The organic extract was
dried (Na2SO4) and concentrated in vacuo and the crude product was chromatographed (SiO2, 2:1
dichloromethane-ethyl acetate) to yield 11a as bright yellow needles (0.024 g, 25%); mp 227-229°C;
IR cm-1: 1637, 1617, 1563; 1H-NMR δH: 3.70 (3H, s, -N-CH3), 3.95 (3H, s, -O-CH3), 4.00 (3H, s, -O-
CH3), 7.19 (1H, s, H-4), 7.35-7.50 (2H, m, H-1, H-10), 7.60-7.70 (2H, m, H-9, H-8), 8.15 (1H, dd, J =
1, 8, H-11); 13C-NMR δC: 39.0, 56.3, 56.3, 94.8, 103.0, 116.3, 122.0, 125.2, 125.7, 130.2, 132.8,
132.9, 140.0, 147.5, 148.7, 150.7, 151.7, 157.7, 184.6. Anal. Calcd. for C19H15NO5: C, 67.65; H, 4.48;
N, 4.15. Found: C, 67.15; H, 4.51; N, 4.35%.

Molecules 2002, 7
362
References
1. Crombie, L.; Josephs, J. L.; Larkin, J.; Weston, J. B. J. Chem. Soc., Chem. Commun., 1990, 14,
972.
2. Gabbutt, C. D.; Hepworth, J. D.; Heron, B. M. J. Chem. Soc., Perkin Trans. 1, 1992, 3015.
3. Ashack, R. J.; McCarty, L. P.; Malek, R. S.; Goodman, F. R.; Peet, N. J. Med. Chem., 1980, 23,
1022.
4. Takei, M. O. Chem. Ber., 1932, 65, 1041.
5. a) Marriott, K-S. C.; Anderson, M.; Jackson, Y. A. Heterocycles, 2001, 55, 91; b) Sakakibara, J.;
Nagai, S.; Akiyama, T.; Ueda, T.; Oda, N.; Kidouchi, K. Heterocycles, 1988, 27, 423.
6. Srimannarayana G.; Akshaya Kumar, K. Ind. J. Chem., Sect. B., 1981, 20B, 604.
7. Chatterjea, J. N. J. Indian Chem. Soc., 1957, 34, 347.
8. Whalley, W. B.; Lloyd, G. J. Chem. Soc., 1956, 3213.
9. Carlson, D. G.; Weisleder, D.; Tallent, W. H. Tetrahedron, 1973, 29, 2731.
10. Goshaev, M.; Otroshchenko, O. S.; Sadykov, A. S. Russ. Chem. Rev., 1972, 12, 1046.
11. Fanta, P. E. Chem. Rev., 1964, 64, 613.
12. a) Zentmeyer D. T.; Wagner, E. C. J. Org. Chem., 1949, 14, 967; b) Errede, L. A. J. Org. Chem.,
1976, 41, 1763.
13. Fuson, R. C.; Kneisley, J. W.; Kaiser, E. W. Organic Syntheses, Coll. Vol. III, 1955, 209.
14. Jackson, Y. A.; Williams, M. F. Heterocycles, 1997, 45, 787.
15. Ramachandran, P.; Tefteller, A.; Paulson, G.; Cheng, T.; Lin, C.; Horton, W. J. Org. Chem., 1963,
28, 398.
16. Jackson, Y. A.; Marriott, K-S. C. unpublished results.
17. Suzuki, S.; Onishi, T.; Fujita, Y.; Misawa, H.; Otera, J. Bull. Chem. Soc. Jpn., 1986, 59, 3287.
18. Franzen, V.; Otto, S. Chem. Ber., 1961, 94, 1360.
19. Cheung, Y. Tetrahedron Lett., 1979, 40, 3809.
20. Singh, G.; Nair, G. V.: Aggarwal, K. P. J. Sci. Ind. Res., 1956, 15B, 190.
21. Patel, M. G.; Sethna, S. J. Indian Chem. Soc., 1960, 37, 227.
Sample Availability: Samples of compounds 7, 9, 12 and 14 are available from the authors.
© 2002 by MDPI (http://www.mdpi.org). Reproduction is permitted for non commercial purposes.