Convenient synthesis and reactivity of ethyl 8-amino-6-methyl-2,3-dihydro- 4H-1-benzopyran-2-carboxylate

Article abstract of DOI:10.1081/SCC-200057984

We report and comprehensively describe the synthesis and reactivity of ethyl 8-amino-6-methyl-3,4-dihydro-2H-1-benzopyran-2-carboxylate. This peptidomimetic building block provides a constrained template that allows for the introduction of various functio

Full text of DOI:10.1081/SCC-200057984

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Convenient Synthesis
and Reactivity of Ethyl
8‐amino‐6‐methyl‐2,3‐dihydro‐4H‐1
Marko Anderluh a , Gašper Marc a & Marija Sollner
Dolenc a
a Faculty of Pharmacy, University of Ljubljana,
Aškerčeva, Ljubljana, Slovenia
Published online: 17 Dec 2010.
To cite this article: Marko Anderluh , Gašper Marc & Marija Sollner
Dolenc (2005): Convenient Synthesis and Reactivity of Ethyl
8‐amino‐6‐methyl‐2,3‐dihydro‐4H‐1‐benzopyran‐2‐carboxylate, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:11, 1461-1470
To link to this article: http://dx.doi.org/10.1081/SCC-200057984
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Synthetic Communicationsw, 35: 1461–1470, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200057984
Convenient Synthesis and Reactivity of
Ethyl 8-amino-6-methyl-2,3-dihydro-4H-1-
benzopyran-2-carboxylate
ˇ
Marko Anderluh, Gasper Marc and Marija Sollner Dolenc
ˇ ˇ
Faculty of Pharmacy, University of Ljubljana, Askerceva,
Ljubljana, Slovenia
Abstract: We report and comprehensively describe the synthesis and reactivity of
ethyl 8-amino-6-methyl-3,4-dihydro-2H-1-benzopyran-2-carboxylate. This peptidomi-
metic building block provides a constrained template that allows for the introduction of
various functionalities in a specific spatial orientation.
Keywords: Benzopyranes, 3,4-dihydro-2H-1-benzopyran derivatives, reduction, RGD
mimetic
INTRODUCTION
The past decade has witnessed major advances in the field of GPIIb/IIIa
(fibrinogen receptor) antagonists that are based predominantly on the
Arg-Gly-Asp (RGD) minimal amino acid sequence. A large number of non-
peptide RGD mimetics have been synthesized to obtain potent and orally deli-
verable compounds.[1] However, no such drug has yet passed clinical trials and
new compounds with high affinity for the fibrinogen receptor and potential
oral activity are still of interest.[2] A rigid scaffold that would bear the
aspartate and guanidine mimicking elements in their proper spatial orientation
is a promising key to molecules with high affinity for GP IIb/IIIa.[3] Numerous
bicyclic scaffolds have been used as peptidomimetic blocks for this
purpose. These include indole,[3] 3,4-dihydro-2H-benzopyran and
Received in Poland January 17, 2005
Address correspondence to Marija Sollner Dolenc, Faculty of Pharmacy, University
ˇ
ˇ
of Ljubljana, Askerceva 7, Ljubljana 1000, Slovenia. Tel. þ386 147 69 572;
Fax: þ 386 142 58 031; E-mail: marija.sollner@ffa.uni-lj.si
1461

1462
M. Anderluh, G. Marc, and M. Sollner Dolenc
tetrahydronaphthalene,[4] 3-oxo-1,4-benzodiazepine,[5] benzimidazole, ben-
zoxazole,[6] and pyrrolidone.[7]
We have designed and synthesized the hitherto unknown compound ethyl
8-amino-6-methyl-2,3-dihydro-4H-1-benzopyran-2-carboxylate. This hetero-
cycle constitutes a scaffold suitable for introducing various functionalities
to achieve the specific spatial orientation of the pharmacophoric groups
required for interaction with the receptor binding sites (Figure 1). The
parent bicycle has proven its versatility in the synthesis of novel dopamine
D2 partial agonists.[8] The similar basic structures were prepared as com-
ponents of receptor molecules.[9]
The synthesis of ethyl 8-amino-6-methyl-2,3-dihydro-4H-1-benzopyran-
2-carboxylate is outlined in Scheme 1. Treatment of the starting 20-hydroxy-
50-methylacetophenone (commercially available from Acros Organics) with
nitric acid in glacial acetic acid (1) gave the corresponding nitro compound
(2).[10] This was followed by Claisen condensation of acetophenone 2 with
diethyl oxalate to give 3. The later was subjected to intramolecular addition
with subsequent dehydration under acidic conditions. An similar condensation
route (steps 2 and 3, Scheme 1) was reported by Barker and Ellis,[11] whereas
Naylor et al. reported a condensation procedure with previous benzylation of
the phenol compound.[12] A one-step transformation of 4 to 6 was achieved by
catalytic hydrogenation. To the best of our knowledge, the detailed synthetic
procedure of this step has not been published yet. This prompted us to
intensely explore reaction conditions of this one-step multiple reduction. An
initial attempt, using palladium on activated charcoal (10%) as the catalyst
under normal conditions (1 bar, rt), resulted in reduction of the nitro group
(5). The hydrogenation reaction proceeded further under higher pressure
and temperature (7 bar, 508C), but after 5 h MS analysis still showed the
presence of peaks with m/z 235 (6) and 251 (presumably 7). The presence of
Figure 1. Ethyl 8-amino-6-methyl-3,4-dihydro-2H-1-benzopyran-2-carboxylate as a
scaffold suitable for introducing various functionalities at positions 2 and 8 by for-
mation of amide bonds. The constrained scaffold is supposed to mimic “cup-shaped”
conformation of the RGD tripeptide that could lead to more potent GPIIb/IIIa anta-
gonists (the term “cup-shaped” originally refers to the conformation of the RGD-
sequence peptide backbone in reported peptide antagonists).[1a,4]

Ethyl 8-amino-6-methyl-2,3-dihydro-4H-1-benzopyran-2-carboxylate
1463
Scheme 1.
the higher m/z peak suggested that the reduction proceeds in the following
order: the reduction of the nitro group to an amine, double bond hydrogenation,
and further reduction of the keto group to methylene via a hydroxy derivative
(1, Scheme 2), although the alternative pathway seems possible
(2, Scheme 2). The reaction went to completion under more rigorous conditions
(10 bar, 608C, 48 h).
The reactivity of the bicyclic product was studied by derivatization of 6 at
positions 2 and 8 (Scheme 3). At position 8, only coupling with strong electro-
philic species such as acyl halides or anhydrides was achieved. This is due to
extremely low nucleophilic character of the amino group at position 8. At
position 2, facile amide bond formation was observed after ethyl ester
alkali-mediated saponification.
Scheme 2.

1464
M. Anderluh, G. Marc, and M. Sollner Dolenc
Scheme 3.
CONCLUSIONS
In conclusion, we report an efficient and simple protocol for the synthesis of
ethyl 8-amino-6-methyl-2,3-dihydro-4H-1-benzopyran-2-carboxylate. This
bicyclic compound can be readily substituted at the amino group at position
8 and the carboxyl group at position 2. Thus it can be envisaged as a
template that allows introduction of various functionalities in specific
spatial orientations. Utilization of this template for the preparation of new
GPIIb/IIIa antagonists is under progress.
EXPERIMENTAL
General
Chemicals from Aldrich Chemical Co., Fluka, and Acros Organics were used
without further purification. Anhydrous solvents were prepared according to
standard procedures.[13] Analytical TLC was performed on Merck silica-gel
(60 GF 254) plates (0.25 mm) and components were visualized with ultraviolet
light (254-nm wavelength). Column chromatography was carried out on silica
gel 60 (particle size 240–400 mesh). Melting points were determined on a
1
Reichert hot stage microscope and are uncorrected. H NMR spectra were
recorded on Bruker AVANCE DPX300 spectrometer in CDCl3 or DMSO-d6

Ethyl 8-amino-6-methyl-2,3-dihydro-4H-1-benzopyran-2-carboxylate
1465
solution with TMS as the internal standard. IR spectra were obtained on a
Perkin-Elmer 1600 FT-IR spectrometer. Microanalyses were performed on
a Perkin-Elmer C, H, N analyzer 240 C. Mass spectra were obtained using
a VG-Analytical Autospec Q mass spectrometer. All yields relate to
purified products.
1-(2-Hydroxy-5-methyl-3-nitrophenyl)-1-etanone 2. To a cooled
(158C) solution of 20-hydroxy-50-methylacetophenone (1, 15.20 g, 101 mmol)
in 90 mL of glacial acetic acid the nitric acid (65%, 5.0 mL, 110 mmol) was
added stepwise and the mixture stirred for 4 h. The temperature was
allowed to rise to rt and stirring continued overnight. The pale yellowish
crystals, which precipitated from the reaction mixture, were filtered off and
recrystallized from ethanol. Yield: 12.3 g (63%). Mp 129–1318C. (KBr,
cm21): 3460, 3077, 1654, 1578, 1526, 1458, 1362, 1344, 1267, 1181, 1107,
1
979, 876, 802, 759, 661, 586. H NMR (CDCl3, 300 MHz): d 2.40 (s, 3H,
CH3), 2.71 (s, 3H, CH3), 7.86 (d, 1H, J ¼ 2.0 Hz, Ar-H), 8.09 (d, 1H,
J ¼ 2.0 Hz, Ar-H), 12.87 (s, 1H, OH) ppm. MS (EI) ¼ 195 (Mþ). Anal.
calcd. for C9H9N1O4: C, 55.38; H, 4.65; N, 7.18. Found: C, 55.12; H, 4.33;
N, 6.95.
Ethyl 4-(2-hydroxy-5-methyl-3-nitrophenyl)-2,4-dioxobutanoate 3.
To a solution of sodium (4.60 g, 200 mmol) in anhydrous ethanol (100 mL)
20-hydroxy-50-methyl-30-nitroacetophenone (2, 9.76 g, 50.0 mmol) was added
during vigorous stirring. After 30 min of stirring, diethyl oxalate (20.4 mL,
150 mmol) was added and the reaction mixture heated under reflux for a
further 2 h. The reaction mixture was allowed to cool to rt and was poured
over the mixture of 60 mL of 4 M HCl and 90 g of ice. The precipitated
crystals were filtered off, dried at high temperature (608C), and ccompound
recrystallized from ethanol. Yield: 12.7 g (86%). Mp 146–1498C. IR (KBr,
1
cm21): 3444, 1731, 1628, 1530, 1458, 1269, 1075, 979, 832, 790, 747. H
NMR (DMSO-d6, 300 MHz): d 1.21 (t, 3H, J ¼ 7.1 Hz, CH2CH3), 2.37
(s, 3H, Ar-CH3), 3.06 (d, 1H, J ¼ 16.5 Hz, COCH2CO), 3.44 (d, 1H,
J ¼ 16.5 Hz, COCH2CO), 4.22 (q, 2H, J ¼ 7.1 Hz CH2CH3), 7.86 (d, 1H,
J ¼ 2.0 Hz, Ar-H), 8.06 (d, 1H, J ¼ 2.0 Hz, Ar-H), 8.69 (s, 1H, OH) ppm.
MS (FAB) ¼ 296 (MHþ). Anal. calcd. for C13H13N1O7: C, 52.88; H, 4.44;
N, 4.74. Found: C, 52.62; H, 4.21; N, 4.54.
Ethyl6-methyl-8-nitro-4-oxo-4H-chromene-2-carboxylate4.Compound
3 (8.86 g, 30.0 mmol) was dissolved in 75 mL of glacial acetic acid and 5 mL
of conc. HCl. The reaction mixture was heated at 808C for 2 h, allowed to cool
to rt, and poured onto 30 g of ice. The precipitated product was filtered off and
purified with column chromatography using CHCl3 as an eluent. Yield: 6.70 g
(81%). Mp 148–1518C. IR (KBr, cm21): 3478, 3076, 2986, 1750, 1663, 1625,
1
1540, 1474, 1355, 1268, 1243, 1187, 1096, 1020, 872, 835, 781. H NMR
(DMSO-d6, 300 MHz): d1.46 (t, 3H, J ¼ 7.0 Hz, CH2CH3), 2.57 (s, 3H, Ar-
CH3), 4.48 (q, 2H, J ¼ 7.0, Hz CH2CH3), 7.17 (s, 1H, CO–CH ¼ ), 8.22
(s, 1H, Ar-H), 8.26 (s, 1H, Ar-H) ppm. MS (EI) ¼ 277 (Mþ). Anal. calcd.
for C13H11N1O6: C, 56.32; H, 4.00; N, 5.05. Found: C, 55.90; H, 3.65; N, 4.72.

1466
M. Anderluh, G. Marc, and M. Sollner Dolenc
Ethyl 8-amino-6-methyl-4-oxo-4H-chromene-2-carboxylate 5. Argon
was bubbled into a solution of 4 (0.277 g, 1.00 mmol) in glacial acetic acid
(12 mL) and palladium (10% by weight, 10% on active charcoal) was added
stepwise. Hydrogen was bubbled into the suspension and stirring continued
under 1 atm of hydrogen at rt until no nitro compound was detected with
TLC. After the catalyst was filtered off, 30 mL of water was added and crude
Na2CO3 used to adjust the pH to ꢀ8. Water phase was extracted with
3 ꢀ 30 mL of ethyl acetate and the organic phase was collected, dried over
Na2SO4, and evaporated under vacuum to give crude product. The pure
crude product was obtained using column chromatography with CHCl3 as
an eluent. Yield: 0.179 g (73%). Mp 127–1328C. IR (KBr, cm21): 3447,
3342, 1741, 1638, 1485, 1365, 1278, 1250, 1100, 1019, 837, 782, 628, 548.
1H NMR (CDCl3, 300 MHz): d1.42 (t, 3H, J ¼ 7.1 Hz, CH2CH3), 2.34
(s, 3H, Ar-CH3), 4.35 (s, 2H, NH2), 4.44 (q, 2H, J ¼ 7.1 Hz CH2CH3), 6.87
(s, 1H, CO–CH ¼ ), 7.04 (s, 1H, Ar-H), 7.28 (s, 1H, Ar-H) ppm. MS
(EI) ¼ 247 (Mþ). HRMS calcd. for C13H13N1O4: 247.085050. Found:
247.084458.
Ethyl 8-amino-6-methyl-2-chromanecarboxylate 6. Argon was bubbled
into a solution of 4 (1.00 g, 4.04 mmol) and conc. HCl (0.20 mL) in
anhydrous ethanol (120 mL) and palladium (10% by weight, 10% on
active charcoal) was added stepwise. The reaction mixture was placed in
the Parr high-pressure apparatus. Hydrogen was bubbled into the suspension
and stirring continued under 7 bar of hydrogen at 508C for the period of
5 h. A small amount of reaction mixture was filtered and the solvent evap-
orated under vacuum. The oily residue was analysed with mass spec-
trometry to confirm the formation of desired product. The rest of the
reaction mixture was continued stirring under 10 bar of hydrogen at 608C
until the completion of the reaction was detected with TLC (another
48 h). The catalyst was filtered off and the solvent evaporated under
vacuum. The residue was dissolved in 30 mL of water and crude Na2CO3
was added to adjust the pH (ꢀ8). Water phase was extracted with
3 ꢀ 30 mL of ethyl acetate and the organic phase collected, dried over
Na2SO4, and evaporated under vacuum to give a dark brown oily
product. Yield: 0.761 g (80%). IR (KBr, cm21): 2930, 1731, 1494, 1378,
1
1215, 1093, 857. H NMR (CDCl3, 300 MHz): d1.31 (t, 3H, J ¼ 6.6 Hz,
CH2CH3), 2.19 (s, 3H, Ar-CH3), 2.24 (m, 2H, CH2CH2CH), 2.74 (m, 2H,
CH2CH2CH), 3.76 (s, 2H, NH2), 4.26 (q, 2H, J ¼ 6.6 Hz CH2CH3), 4.71
(m, 1H, CH2CH2CH), 6.28 (s, 1H, Ar-H), 6.41 (s, 1H, Ar-H) ppm. MS
(EI) ¼ 236 (Mþ). Anal. calcd. for C13H17N1O3 ꢀ 0.25 H2O: C, 65.25; H,
7.37; N, 5.85. Found: C, 65.47; H, 7.59; N, 5.69.
Ethyl 8-[(4-cyanobenzoyl)amino]-6-methyl-2-chromanecarboxylate 8.
To a cooled (2108C) solution of amine (0.500 g, 2.13 mmol) and triethylamine
(0.30 mL, 2.13 mmol) in distilled dichloromethane (20 mL), 4-cyanobenzoyl
chloride (0.353 g, 2.13 mmol) was added stepwise and the mixture stirred for
6 h. During stirring, the temperature was allowed to rise to rt. The reaction

Ethyl 8-amino-6-methyl-2,3-dihydro-4H-1-benzopyran-2-carboxylate
1467
mixture was washed with water (20 mL), 10% aqueous citric acid
(2 ꢀ 20 mL), saturated aqueous NaHCO3 (2 ꢀ 20 mL), and brine (20 mL).
The organic phase was dried over Na2SO4, filtered, and evaporated under
vacuum. The crude residue was recrystallized from ethanol to give white
crystals. Yield: 0.528 g (68%). Mp 169–1728C. IR (KBr, cm21): 3327,
1
2229, 1730, 1655, 1550, 1466, 1222, 1028, 857, 668. H NMR (CDCl3,
300 MHz): d1.33 (t, 3H, J ¼ 7.0 Hz, CH2CH3), 2.18 (m, 1H, CH2CH2CH),
2.33 (s, 3H, Ar-CH3), 2.37 (m, 1H, CH2CH2CH), 2.80 (m, 2H, CH2CH2CH),
4.29 (q, 2H, J ¼ 7.0 Hz, CH2CH3), 4.79 (m, 1H, CH2CH2CH), 6.69 (s, 1H,
Ar-H), 7.81 (d, 2H, J ¼ 8.7 Hz, AB-Ar), 8.04 (d, 2H, J ¼ 8.7 Hz, A0B0-Ar)
8.19 (s, 1H, Ar-H), 8.66 (s, 1H, Ar-NHCO) ppm. MS (EI) ¼ 365 (Mþ).
Anal. calcd. for C21H20N2O4 ꢀ 0.75 H2O: C, 66.75; H, 5.73; N, 7.41.
Found: C, 66.50; H, 5.99; N, 7.80.
Ethyl 8-(f2-[(tert-butyloxycarbonyl)amino]acetylgamino)-6-methyl-2-
chromanecarboxylate 9. To a cooled (08C) solution of Boc-Glycine (0.410 g,
2.34 mmol) and triethylamine (0.384 mL, 2.76 mmol) in distilled dichloro-
methane (30 mL), ethyl chloroformate (0.22 mL, 2.34 mmol) was added
stepwise. After 15 min of stirring, the compound 6 (0.500 g, 2.125 mmol),
dissolved in 10 mL of distilled dichloromethane, was added. The stirring
was continued overnight and the temperature was allowed to rise to rt. The
reaction mixture was washed with water (30 mL), 0.01 M HCl (2 ꢀ 30 mL),
saturated aqueous NaHCO3 (2 ꢀ 30 mL), and brine (30 mL). The organic
phase was dried over Na2SO4, filtered, and evaporated under vacuum to
give pale brown oily compound. Yield 0.737 g (88%). IR (KBr, cm21):
3392, 2981, 1718, 1542, 1458, 1368, 1250, 1201, 1168, 1096, 1026, 856,
1
778. H NMR (DMSO-d6, 300 MHz): d1.31 (t, 3H, J ¼ 7.1 Hz, CH2CH3),
1.48 (s, 9H, 3 ꢀ CH3), 2.19 (m, 2H, CH2CH2CH), 2.37 (s, 3H, Ar-CH3),
2.75 (m, 2H, CH2CH2CH), 3.98 (d, 2H, J ¼ 4.9 Hz, CH2NHCO), 4.26
(q, 2H, J ¼ 7.1 Hz CH2CH3), 4.75 (m, 1H, CH2CH2CH), 5.23 (s, 1H,
CH2NHCO), 6.61 (s, 1H, Ar-H), 8.03 (s, 1H, Ar-H), 8.27 (s, 1H, Ar-NHCO)
ppm. MS (EI) ¼ 392 (Mþ). HRMS calcd. for C20H28N2O6: 392.195650.
Found: 392.194737.
Ethyl 6-methyl-8-f[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzoyl]
aminog-2-chromanecarboxylate 10. To a suspension of hydroxylammonium
chloride (0.765g, 11.0mmol) in anhydrous ethanol (20 mL), triethylamine
(1.53mL, 11.0mmol) was added and the resulting solution stirred for 20min,
after which a solution of 8 (1.380g, 3.78mmol) in anhydrous ethanol
(10mL) was added and the mixture was heated at 508C overnight. The
product was precipitated by cooling in the refrigerator and filtered off. The
crude product was used without further purification in the next step; in 1.0 g
of the latter (2.52 mmol) in freshly distilled pyridine (15 mL), argon was
bubbled for 5 min. Afterward, ethyl chloroformate (0.26 mL, 2.77mmol) was
added dropwise, stirred for 45min in an ice bath and then 30min at rt.
Again, the argon was bubbled in and the mixture heated under reflux
(ꢀ1208C) overnight. The solvent was evaporated under vacuum and the

1468
M. Anderluh, G. Marc, and M. Sollner Dolenc
water (30 mL) was poured onto crude residue. The water phase was acidified
with 1 M HCl (pH ffi 2) and extracted with ethyl acetate (3 ꢀ 30mL).
Collected organic phase was washed with 1 M HCl (2 ꢀ 30mL), saturated
aqueous NaHCO3 (2 ꢀ 30mL), and brine (30 mL). The organic phase was
dried over Na2SO4, filtered, and evaporated under vacuum. Yield: 0.69g
(67%). Mp 255–2608C. IR (KBr, cm21): 3384, 3196, 2977, 1737, 1650,
1
1546, 1462, 1220, 866, 670. H NMR (DMSO-d6, 300 MHz): d1.20 (t, 3H,
J ¼ 7.2 Hz, CH2CH3), 2.05 (m, 1H, CH2CH2CH), 2.23 (s, 3H, Ar-CH3), 2.27
(m, 1H, CH2CH2CH), 2.64 (m, 1H, CH2CH2CH), 2.81 (m, 1H, CH2CH2CH),
4.16 (q, 2H, J ¼ 7.2 Hz CH2CH3), 4.92 (m, 1H, CH2CH2CH), 6.75 (d, 1H,
J ¼ 1.5 Hz, Ar-H), 7.53 (d, 1H, J ¼ 1.5 Hz, Ar-H), 7.96 (d, 2H, J ¼ 8.7 Hz,
AB-Ar), 8.10 (d, 2H, J ¼ 8.7 Hz, A0B0-Ar), 9.43 (s, 1H, Ar-NHCO) ppm. MS
(FAB) ¼ 424 (MHþ). Anal. calcd. for C22H21N3O6: C, 62.41; H, 5.00; N,
9.92. Found: C, 62.14; H, 5.18; N, 9.65.
Ethyl
3-f[(6-methyl-8-f[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)
benzoyl]aminog-3,4-dihydro-2H-chromen-2-yl)carbonyl]aminogpropanoate
11. To a dispersion of 10 (0.660 g, 1.56 mmol) in 96% ethanol (30 mL), 1 M
NaOH (4.70 mL, 4.70 mmol) was added and stirred at rt until no starting
compound was detected by TLC. The solvent was evaporated under
vacuum and residue dissolved in water (10 mL). The water phase was
acidified with 1 M HCl (pH ffi 2) and the precipitated product was filtered
off and dried at 608C (M ¼ 0.502 g, 81%). The crude product was used
without further purification in the next step; to a cooled (2108C)
solution of carboxylic acid (0.180 g, 0.46 mmol) and ethyl b-alanine
(0.078 g, 0.50 mmol) in anhydrous N,N-dimethylformamide (15 mL),
1-hydroxybenzotriazole (HOBt) monohydrate (0.084 g, 0.55 mmol) and N-
methylmorpholine (0.15 mL, 1.4 mmol) were added. The pH of the
mixture was checked with wet pH-indicator strip (ꢀ8) and N-ethyl-N0-
(dimethylaminopropyl)carbodiimide hydrochloride (EDC ꢀ HCl) (0.115 g,
0.59 mmol) was added. The temperature was allowed to rise to rt and the
mixture was stirred until complete conversion to the final product was
detected with TLC. The solvent was evaporated and the residue was
dissolved in ethyl acetate (20 mL), washed with aqueous citric acid (10%,
2 ꢀ 20 mL) and brine (20 mL), and dried over Na2SO4. The solvent was evap-
orated under vacuum to yield crude amorphus product. Yield: 0.221 g (79%).
Mp 198–2058C. IR (KBr, cm21): 3360, 3090, 1797, 1727, 1652, 1548, 1466,
1220, 1077, 939, 858, 735, 674. 1H NMR (DMSO-d6, 300 MHz): d1.10 (t, 3H,
J ¼ 7.2 Hz, CH2CH3), 2.07 (m, 2H, CH2CH2CH), 2.23 (s, 3H, Ar-CH3), 2.28
(t, 2H, J ¼ 3.8 Hz, CONHCH2CH2CO), 2.73 (m, 2H, CH2CH2CH), 3.42
(m, 2H, CONHCH2CO), 3.95 (q, 2H, J ¼ 7.2 Hz CH2CH3), 4.67 (m, 1H,
CH2CH2CH), 6.79 (s, 1H, Ar-H), 7.27 (s, 1H, Ar-H), 7.98 (d, 2H,
J ¼ 8.5 Hz, AB-Ar), 8.14 (d, 2H, J ¼ 8.5 Hz, A0B0-Ar), 8.54 (t, 1H,
J ¼ 5.1 Hz, CH2NHCO), 10.00 (s, 1H, Ar-NHCO) ppm. MS (FAB) ¼ 495
(MHþ). Anal. calcd. for C25H26N4O7 ꢀ 0.5 H2O: C, 59.84; H, 5.41; N,
11.13. Found: C, 60.13; H, 5.41; N, 10.99.

Ethyl 8-amino-6-methyl-2,3-dihydro-4H-1-benzopyran-2-carboxylate
1469
ACKNOWLEDGMENTS
We thank Roger Pain for his careful reading of the manuscript and many
useful suggestions.
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(4), 337–360;
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