A convenient approach to the synthesis of dialkyl 5-oxo-1,2-dihydro-5H- chromeno [4,3-b]pyridine-2,3-dicarboxylates

Article abstract of DOI:10.1080/00397910801929465

Coumarin and its analogs are considered privileged scaffolds in the current synthetic and pharmacological research. The chemical behavior of enaminocarbaldehydes of the coumarin moiety under intramolecular Wittig reaction conditions in the presence of tri

Full text of DOI:10.1080/00397910801929465

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A Convenient Approach to the Synthesis
of Dialkyl 5‐Oxo‐1,2‐dihydro‐5H‐chromeno
[4,3‐b]pyridine‐2,3‐dicarboxylates
Toma N. Glasnov a & Ivo C. Ivanov a
a Faculty of Pharmacy, Department of Organic Chemistry, Medical University
of Sofia, Sofia, Bulgaria
Version of record first published: 24 Apr 2008
To cite this article: Toma N. Glasnov & Ivo C. Ivanov (2008): A Convenient Approach to the Synthesis of
Dialkyl 5‐Oxo‐1,2‐dihydro‐5H‐chromeno [4,3‐b]pyridine‐2,3‐dicarboxylates, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:10, 1579-1588
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Synthetic Communicationsw, 38: 1579–1588, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801929465
A Convenient Approach to the Synthesis of
Dialkyl 5-Oxo-1,2-dihydro-5H-chromeno
[4,3-b]pyridine-2,3-dicarboxylates
Toma N. Glasnov and Ivo C. Ivanov
Faculty of Pharmacy, Department of Organic Chemistry, Medical
University of Sofia, Sofia, Bulgaria
Abstract: Coumarin and its analogs are considered privileged scaffolds in the current
synthetic and pharmacological research. The chemical behavior of enaminocarbalde-
hydes of the coumarin moiety under intramolecular Wittig reaction conditions in the
presence of triphenylphosphine and dimethyl or diethyl acetylenedicarboxylates has
been studied, resulting in the isolation of a series of dimethyl and diethyl 5-oxo-1,2-
dihydro-5H-chromeno[4,3-b]pyridine-2,3-dicarboxylates in good to high yields.
Keywords: Annelated ring system, coumarin, enaminoaldehydes, Wittig reaction
INTRODUCTION
As well-established pharmacophores, coumarins or pyridine-benzopyran
fused systems are ubiquitous backbone subunits in many compounds of
natural or synthetic origin with remarkable pharmacological action such as
anticoagulant (warfarin-like), antibacterial, anti-allergic, wound-healing, or
broncho-dilatating activity.[1] Remarkably wide spectra of chromen-2-one
annelated ring systems of various types have been synthesized in the past
years as N-containing analogs of naturally occurring substances[2] or as fluor-
escent dyes.[3] The continuing studies on the biologically active ingredients of
Received October 25, 2007
Address correspondence to Toma N. Glasnov, Faculty of Pharmacy, Department of
Organic Chemistry, Medical University of Sofia, Dunav 2, BG-1000, Sofia, Bulgaria.
E-mail: tomaglasnov@yahoo.com
1579

1580
T. N. Glasnov and I. C. Ivanov
Scheme 1.
Cannabis sativa L., and in particular tetrahydrocannabinol, should also be
mentioned.[4]
Most of the known methods for insertion of N-atom into the phenantrene
¨
skeleton are based on well-established reactions, for example, Krohnke
pyridine synthesis, Pechmann condensation, Skraup synthesis, Diels–Alder,
or Vilsmeier–Haak.[5] One of them, the Wittig reaction, has turned into a
standard tool for the preparative synthesis.[5g] Its intramolecular variant has
been applied for the synthesis of numerous four- five- six- and seven-
membered carbo- and heterocycles. Another successful synthesis of bezopyr-
ano[4,3-b]pyridine-5-ones has also been realized through intermediate
coumarin-acetamidines containing a formyl group.[6]
We report here on the application of coumarinic enaminoaldehydes as
useful starting materials to produce hitherto unknown 5-oxo-1,2-dihydro-
5H-chromeno[4,3-b]pyridine-2,3-dicarboxylates in good to excellent yields
by using symmetrical acetylene dicarboxylates (Scheme 1). The enaminones
1a–g, utilized in this study, are readily available. Upon treating 4-hydroxy-
coumarin with various amines in acidic media, the corresponding 4-amino-
coumarines were formed, which were then formylated under Vilsmeier–
Haack reaction conditions to give the desired enaminoaldehydes 1a–g.[7]
RESULTS AND DISCUSSION
In a recent work,[8] we demonstrated 4-aminocoumarin-3-carbaldehydes 1a–g
to be handy intermediates for the synthesis of 2H-chromeno[4,3-b]pyridine-
2,5(1H)-diones. Earlier studies in our labaratory have shown that these amino-
ladehydes react in the presence of triphenylphosphine in terms of the Wittig
reaction, resulting in the isolation of some 1-alkyl-1H-chromeno[4,3-
b]pyridine-2,5-diones.[5f] A recent report extended the application of the
intramolecular Wittig reaction to the heterocyclization of 4-hydroxycoumarin-
3-carbaldehyde or indole-7-carbaldehyde with different symmetrical acetylene
dicarboxylic esters.[9] Hence, we initially attempted the synthesis of 5-
oxo-1,2-dihydro-5H-chromeno[4,3-b]pyridine-2,3-dicarboxylates by reacting
equimolar amounts of 4-aminocoumarin-3-carbaldehyde (1a), triphenyl
phosphine, and dimethyl acetylendicarboxylate 2a (CH2Cl2 as solvent) at

Convenient Approach to the Synthesis
1581
room temperature for 12 hours. This trial was unsuccessful because of incomplete
conversion of the starting material into the product even after prolonging the
reaction time by 6 hours. However, optimizing the reaction conditions by using
dimethylformamide (DMF) as reaction medium of higher polarity, increasing
the reaction temperature up to 50 8C, and adding 0.5 equivalents of both Ph3P
and dimethylacetylendicarboxylate 2a in one portion after 1 h, proved to be
crucial for the completion of the reaction in 2 h. Upon conjugate addition of
Ph3P to the activated acetylene 2a, consequent formation of phosphonium salt
and phosphorane, and following intermolecular Wittig transformation, the
desired product 3a was formed (Scheme 1) and isolated in 71% yield by
removal of the solvent under vacuum and successive flash chromatography of
the solid residue. A similar type of intermolecular processes have already been
observed and discussed by authors working on various other systems.[9]
Further experiments proved that the described procedure is applicable to
a variety of similar enaminones. All of the utilized starting compounds
were readily converted into the corresponding dialkyl 5-oxo-1,2-dihydro-
5H-chromeno[4,3-b]pyridine-2,3-dicarboxylates (3a–m) (Table 1). As
expected, increasing the bulkiness of the N-substituent (R1) in the series
(e.g., Table 1, entries 3e–g and 3k–m) resulted in longer reaction times.
The structure of the synthesized diaklyl 1-alkyl-5-oxo-1,2-dihydro-5H-
chromeno[4,3-b]pyridine-1,2-dicarboxylates (3a–m) was successfully and
1
unambiguously assigned on the basis of H and 13C NMR spectral data. The
signals of the characteristic methine protons at C-2 and C-4 positions
Table 1. Substitution pattern, reaction times, and isolated yields for the newly
synthesized compounds 3a–m
Reaction
time (h)
Product
R1
R2
Yield (%)a
3a
3b
3c
3d
3e
3f
H
CH3
CH3
CH3
2
3
71
87
93
90
61
92
86
84
85
91
90
88
85
C2H5
C3H7
C4H9
CH3
CH3
6
7
CH3
CH3
12
10
9
CH2C6H5
CH2CH55CH2
H
3g
3h
3i
CH3
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
2.5
3
CH3
C2H5
3j
5
3k
3l
C3H7
CH2C6H5
CH2CH55CH2
10
12
10
3m
aYields of isolated products after flash chromatography (see the Experimental
section).

1582
T. N. Glasnov and I. C. Ivanov
appeared at d ¼ 5.18–5.34 and d ¼ 7.56–7.84, respectively, in the 1H NMR
spectrum of compounds 3a–m. Supplemental mass spectra (MS) spectra and
elemental microanalyses are in good agreement with the expected values.
In summary, we have demonstrated a useful approach to the synthesis of
1,2-dihydro-chromeno[4,3-b]pyridine-2,3-dicarboxylates in good to high
yields by a type of intramolecular Wittig reaction starting from easily obtain-
able N-substituted 4-aminocoumarins.
EXPERIMENTAL
The thin-layer chromatography (TLC) was performed on pre coated silica-gel
1
Merck 60 F254 plates. H NMR and 13C NMR spectra were recorded on a
360-MHz Bruker AMX instrument at 360 and 90 MHz, respectively.
Low-resolution mass spectra (LRMS) were obtained on an HP 1100 LC/
MS instrument using atmospheric pressure chemical ionisation (APCI)
technique (positive or negative mode). Column chromatography was
performed on silica gel (Merck 60H), using the dry-flash method.
General Procedure for the Synthesis of Dialkyl 1-Alkyl-5-oxo-1,2-
dihydro-5H-chromeno[4,3-b]pyridine-2,3-dicarboxylates (3a–m)
The corresponding 4-aminocoumarin-3-carbaldehyde 1a–f (1 mmol),
triphenyl phosphine (262 mg, 1.0 mmol), and 10 mL of DMF were stirred at
room temperature for 10 min in a 10-mL round-bottom flask. Dimethyl
acetylene dicarboxylate 2a (1.0 mmol) (or diethyl ester 2b) was added
dropwise for another 10 min, and the dark-orange colored solution thus
obtained was heated at 50 8C. A second portion of 0.5 eq. of PPh3 was added
after 1 h, instantly followed by an additional 0.5 eq. of acetylene dicarboxylate
2a or 2b. The reaction continued until no starting material could be detected
by TLC. After removing the reaction medium under reduced pressure, the
products 3a–k were isolated by dry flash chromatography on silica gel
(eluted by petroleum ether–ethylacetate 1:1).
Dimethyl 5-Oxo-1,2-dihydro-5H-chromeno[4,3-b]pyridine-2,3-
dicarboxylate (3a)
Reaction time 2 h, yield 71%, bright yellow crystals, mp 258–260 8C
(2-propanol). 1H NMR (DMSO-d6): d ¼ 3.64 (s, 3H), 3.74 (s, 3H), 5.31
(s, 1H), 7.37 (d, J ¼ 8.31, 1H), 7.42 (t, J ¼ 7.65, 1H), 7.56 (s, 1H), 7.69
(t, J ¼ 7.76, 1H), 8.11 (d, J ¼ 7.92, 1H), 9.38 (br s, 1H); 13C NMR (DMSO-
d6): d 51.7 (2 C), 52.52, 92.96, 111.75, 112.36, 117.18, 123.02, 124.1, 131.3,
133.57, 150.4, 152.88, 158.8, 164.43, 170.23; MS (pos. APCI) m/z (%) 316

Convenient Approach to the Synthesis
1583
(15, M þ 1), 315 (100, M), 255 (15, M 2 1). Anal. calcd. for C16H13NO6: C,
60.95%; H, 4.16%; N, 4.44%. Found: C, 60.85%; H, 4.05%; N, 4.37%.
Dimethyl 1-Methyl-5-oxo-1,2-dihydro-5H-chromeno[4,3-
b]pyridine-2,3-dicarboxylate (3b)
Reaction time 3 h, yield 87%, bright yellow crystals, mp 204–206 8C
(ethanol). 1H NMR (DMSO-d6): d ¼ 3.68 (s, 3H), 3.72 (s, 3H), 3.84
(s, 3H), 5.19 (s, 3H), 7.26–7.35 (m, 2H), 7.54 (t, J ¼ 7.22, 1H), 7.62
(t, J ¼ 7.24, 1H), 7.85 (s, 1H), 8.03 (d, J ¼ 7.51, 1H), 8.13 (d, J ¼ 7.51,
1H); 13C NMR (DMSO-d6): d 45.23, 52.08, 52.85, 62.01, 101.44, 112.56,
114.93, 118.37, 123.72, 126.31, 130.87, 132.71, 152.57, 154.18, 159.98,
165.53, 170.44; MS (pos. APCI) m/z (%) 330 (20, M þ 1), 329 (100, M),
314 (10, M 2 16). Anal. calcd. for C17H15NO6: C, 62.00%; H, 4.59%; N,
4.25%. Found: C, 62.05%; H, 4.55%; N, 4.22%.
Dimethyl 1-Ethyl-5-oxo-1,2-dihydro-5H-chromeno[4,3-b]pyridine-
2,3-dicarboxylate (3c)
Reaction time 6 h, yield 93%, bright yellow crystals, mp 197–200 8C
1
(2-propanol). H NMR (DMSO-d6): d ¼ 1.46 (t, J ¼ 7.06, 3H), 3.66 (s, 3H),
3.74–3.85 (m, 4H), 3.99 (m, J ¼ 7.06, 1H), 5.32 (s, 1H), 7.27–7.39 (m, 2H),
7.54 (t, J ¼ 7.24, 1H), 7.84 (s, 1H), 7.89 (d, J ¼ 8.15, 1H); 13C NMR
(CDCl3): d 14.91, 49.90, 52.14, 52.82, 57.48, 103.93, 113.74, 115.13, 118.32,
123.96, 125.63, 130.72, 132.61, 152.89, 154.03, 160.02, 165.59, 170.69; MS
(pos. APCI) m/z (%) 343 (100, M). Anal. calcd. for C18H17NO6: C, 62.97%;
H, 4.99%; N, 4.08%. Found: C, 63.01%; H, 4.96%; N, 4.12%.
Dimethyl 5-Oxo-1-propyl-1,2-dihydro-5H-chromeno[4,3-
b]pyridine-2,3-dicarboxylate (3d)
Reaction time 7 h, yield 90%, bright yellow crystals, mp 194–196 8C
(2-propanol). 1H NMR (CDCl3): d 0.87 (t, J ¼ 7.36, 3H), 1.72–1.94
(m, 2H), 3.65 (s, 3H), 3.81 (t, J ¼ 7.62, 2H), 3.85 (s, 3H), 5.34 (s, 1H),
7.27–7.34 (m, 2H), 7.51–7.56 (t, J ¼ 7.79, 1H), 7.83 (s, 1H), 7.89
(d, J ¼ 8.16, 1H); 13C NMR (CDCl3): d 10.86, 23.05, 52.15, 52.82, 57.05,
57.49, 103.74, 113.70, 115.12, 118.32, 123.94, 125.83, 130.64, 132.59,
153.06, 154.06, 160.08, 165.59, 170.69; MS (neg. APCI) m/z (%) 357 (100,
M), 314 (55, M 2 43), 284 (10, M 2 73). Anal. calcd. for C19H19NO6: C,
63.86%; H, 5.36%; N, 3.92%. Found: C, 63.78%; H, 5.33%; N, 3.88%.

1584
T. N. Glasnov and I. C. Ivanov
Dimethyl 1-Butyl-5-oxo-1,2-dihydro-5H-chromeno[4,3-b]pyridine-
2,3-dicarboxylate (3e)
Reaction time 12 h, yield 61%, bright yellow crystals, mp 166–168 8C
1
(methanol). H NMR (CDCl3): d 0.91 (t, J ¼ 7.35, 3H), 1.26–1.32 (m, 2H),
1.73–1.89 (m, 2H), 3.67 (s, 3H), 3.84–3.90 (m, 5H), 5.39 (s,1H), 7.27–
7.35 (m, 2H), 7.54 (t, J ¼ 7.76, 1H), 7.84 (s, 1H), 7.91 (d, J ¼ 8.17, 1H);
13C NMR (CDCl3): d 13.59, 19.70, 31.63, 52.12, 52.83, 55.13, 57.55,
103.70, 113.62, 115.12, 118.33, 123.91, 125.81, 130.66, 132.60, 153.04,
154.04, 160.08, 165.59, 170.71; MS (neg. APCI) m/z (%) 371 (100, M),
314 (39, M 2 57). Anal. calcd. for C20H21NO6: C, 64.68%; H, 5.70%; N,
3.77%. Found: C, 64.55%; H, 5.48%; N, 3.69%.
Dimethyl 1-Allyl-5-oxo-1,2-dihydro-5H-chromeno[4,3-b]pyridine-
2,3-dicarboxylate (3g)
Reaction time 9 h, yield 86%, bright yellow crystals, mp 129–131 8C
(2-propanol). H NMR (CDCl3): d 3.66 (s, 3H), 3.85 (s, 3H), 4.33–4.39
1
(m, 1H), 4.48–4.54 (m, 1H), 5.33 (s, 1H), 5.44 (d, J ¼ 10.22, 1H), 5.68
(d, J ¼ 17.11, 1H), 5.89–6.00 (m, 1H), 7.27–7.35 (m, 2H), 7.55
(t, J ¼ 7.76, 1H), 7.84 (s, 1H), 7.93 (d, J ¼ 8.07, 1H); 13C NMR (90 MHz,
DMSO-d6): d 52.14, 52.77, 57.18, 57.54, 104.41, 114.22, 115.10, 118.23,
120.75, 124.07, 125.72, 130.55, 132.45, 132.74, 153.16, 154.02, 160.00,
165.40, 170.58; MS (pos. APCI) m/z (%): 355 (100, M). Anal. calcd. for
C19H17NO6: C, 64.22; H, 4.82; N, 3.94. Found: C, 64.19; H, 4.76; N, 3.98.
Dimethyl 1-Benzyl-5-oxo-1,2-dihydro-5H-chromeno[4,3-
b]pyridine-2,3-dicarboxylate (3f)
Reaction time 10 h, yield 92%, bright yellow crystals, mp 178–180 8C
(methanol). 1H NMR (CDCl3): d 3.66 (s, 3H), 3.74 (s, 3H), 4.98
(d, J ¼ 15.43, 1H), 5.13 (d, J ¼ 15.45, 1H), 5.22 (s, 1H), 7.23 (t, J ¼ 7.65,
1H), 7.34–7.45 (m, 5H), 7.56 (t, J ¼ 7.78, 1H), 7.82 (s, 1H), 8.00
(d, J ¼ 8.05, 1H); 13C NMR (CDCl3): d 52.01, 52.78, 57.35, 58.56, 104.85,
114.84, 115.25, 118. 28, 124.16, 125.61, 127.01, 127.59, 128.55, 129.14,
129.41, 130.35, 132.77, 135.77, 153.56, 154.10, 160.04, 164.99, 170.55;
MS (pos. APCI) m/z (%) 406 (20, M þ 1), 405 (100, M). Anal. calcd. for
C23H19NO6: C, 68.14%; H, 4.72%; N, 3.45%. Found: C, 68.23%; H, 4.76%;
N, 3.52%.

Convenient Approach to the Synthesis
1585
Diethyl 5-Oxo-1,2-dihydro-5H-chromeno[4,3-b]pyridine-2,3-
dicarboxylate (3h)
Reaction time 2.5 h, yield 84%, bright yellow crystals, mp 245–246 8C
1
(ethanol). H NMR (DMSO-d6): d 1.13 (t, J ¼ 7.07, 3H), 1.26 (t, J ¼ 7.07,
3H), 4.07 (m, J ¼ 7.07, 2H), 4.17–4.26 (m, 2H), 5.28 (d, J ¼ 3.53, 1H),
7.38 (d, J ¼ 8.32, 1H), 7.46, (t, J ¼ 7.59, 1H), 7.55 (s, 1H), 7.74
(t, J ¼ 7.82, 1H), 8.12 (d, J ¼ 7.98, 1H), 9.33 (d, J ¼ 3.48 H); 13C NMR
(DMSO-d6): d 14.37, 14.65, 52.61, 60.86, 61.88, 93.56, 113.12, 117.89,
123.71, 124.80, 131.59, 134.23, 151.10, 153.61, 159.51, 164.70, 170.40;
MS (pos. APCI) m/z (%) 344 (25, M þ 1), 343 (100, M), 270 (36,
M 2 74). Anal. calcd. for C18H17NO6: C, 62.97%; H, 4.99%; N, 4.08%.
Found: C, 63.01%; H, 4.85%; N, 4.16%.
Diethyl 1-Methyl-5-oxo-1,2-dihydro-5H-chromeno[4,3-b]pyridine-
2,3-dicarboxylate (3i)
Reaction time 3 h, yield 88%, bright yellow crystals, mp 186–188 8C
1
(ethanol). H NMR (CDCl3): d 1.20 (t, J ¼ 7.12, 3H), 1.35 (t, J ¼ 7.12,
3H), 3.73 (s, 3H), 4.13 (m, J ¼ 7.06, 2H), 4.30 (q, J ¼ 7.12, 2H), 5.18
(s, 1H), 7.27–7.35 (m, 2H), 7.55 (t, J ¼ 7.77, 1H), 7.86 (s, 1H), 8.04
(d, J ¼ 8.23, 1H); 13C NMR (CDCl3): d 14.01, 14.34, 45.26, 61.00, 62.91,
62.11, 101.36, 113.39, 115.01, 118.36, 123.68, 126.26, 130.27, 132.61,
152.50, 154.16, 160.11, 165.17, 169.94; MS (pos. APCI) m/z (%) 358 (21,
M þ 1), 357 (100, M), 283 (11, M 2 74). Anal. calcd. for C19H19NO6: C,
63.86%; H, 5.36%; N, 3.92%. Found: C, 63.75%; H, 5.41%; N, 4.06%.
Diethyl 1-Ethyl-5-oxo-1,2-dihydro-5H-chromeno[4,3-b]pyridine-
2,3-dicarboxylate (3j)
Reaction time 5 h, yield 91%, bright yellow crystals, mp 148–150 8C
1
(ethanol). H NMR (CDCl3): d 1.18 (t, J ¼ 7.11, 3H), 1.35 (t, J ¼ 7.12,
3H), 1.46 (t, J ¼ 7.08, 3H), 3.78 (m, 1H), 4.00 (m, 1H), 4.10 (quartet,
J ¼ 7.10, 2H), 4.27–4.35 (m, 2H), 5.30 (s, 1H), 7.27–7.35 (m, 2H), 7.54
(t, J ¼ 7.22, 1H), 7.83 (s, 1H), 7.89 (d, J ¼ 8.13, 1H); 13C NMR (CDCl3): d
13.95, 14.32, 14.92, 49.91, 57.60, 61.02, 61.80, 103.80, 114.57, 115.20,
118.28, 123.92, 125.58, 130.10, 132.50, 152.81, 153.98, 160.16, 165.22,
170.18; MS (pos. APCI) m/z (%) 372 (19, M þ 1), 371 (100, M), 325 (10,
M 2 46), 297 (15, M 2 74). Anal. calcd. for C19H19NO6: C, 64.68%; H,
5.70%; N, 3.77%. Found: C, 64.59%; H, 5.65%; N, 3.68%.

1586
T. N. Glasnov and I. C. Ivanov
Diethyl 5-Oxo-1-propyl-1,2-dihydro-5H-chromeno[4,3-b]pyridine-
2,3-dicarboxylate (3k)
Reaction time 12 h, yield 90%, bright yellow crystals, mp 104–106 8C
1
(ethanol). H NMR (CDCl3): d 0.87 (t, J ¼ 7.34, 3H), 1.71 (t, J ¼ 7.10,
3H), 1.34 (t, J ¼ 7.12, 3H), 1.71–1.96 (m, 2H), 3.81 (t, J ¼ 7.55, 2H), 4.09
(t, J ¼ 7.07, 2H), 4.26–4.35 (m, 2H), 5.32 (s, 1H), 7.27–7.34 (m, 2H),
7.53 (t, J ¼ 7.55, 1H), 7.82 (s, 1H), 7.89 (d, J ¼ 8.04, 1H); 13C NMR
(CDCl3): d 10.86, 13.97, 14.32, 23.03, 57.06, 57.63, 61.02, 61.79, 103.68,
114.57, 115.21, 118.29, 123.88, 125.77, 130.00, 132.47, 152.97, 154.03,
160.18, 165.22, 170.17; MS (neg. APCI) m/z (%) 386 (29, M þ 1), 385
(100, M), 342 (54, M 2 43). Anal. calcd. for C21H23NO6: C, 65.44%; H,
6.02%; N, 3.63%. Found: C, 65.35%; H, 5.97%; N, 3.71%.
Diethyl 1-Benzyl-5-oxo-1,2-dihydro-5H-chromeno[4,3-b]pyridine-
2,3-dicarboxylate (3l)
Reaction time 12 h, yield 89%, bright yellow crystals, mp 121–123 8C
1
(ethanol). H NMR (CDCl3): d 1.17 (t, J ¼ 7.12, 3H), 1.26 (t, J ¼ 7.11,
3H), 4.10 (quartet, J ¼ 7.10, 2H), 4.19–4.23 (m, 2H), 4.97 (d, J ¼ 15.38,
1H), 5.14 (d, J ¼ 15.40, 1H), 5.19 (s, 1H), 7.27 (t, J ¼ 7.67, 1H), 7.33–
7.37 (m, 6H), 7.55, (t, J ¼ 7.34, 1H), 7.81 (s, 1H), 7.99 (d, J ¼ 7.69, 1H);
13C NMR (CDCl3): d 13.93, 14.23, 57.47, 58.64, 60.84, 61.77, 104.78,
115.34, 115.71, 118.25, 124.09, 125.59, 127.61 (2 C), 128.50, 129.09 (2 C),
129.72, 132.65, 135.92, 153.46, 154.07, 160.13, 164.59, 170.05; MS (neg.
APCI) m/z (%) 434 (20, M þ 1), 433 (100, M), 342 (37, M 2 91). Anal.
calcd. for C21H23NO6: C, 69.27%; H, 5.35%; N, 3.23%. Found: C, 69.38%;
H, 5.43%; N, 3.32%.
Diethyl 1-Allyl-5-Oxo-1,2-dihydro-5H-chromeno[4,3-b]pyridine-
2,3-dicarboxylate (3m)
Reaction time 10 h, yield 85%, bright yellow crystals, mp 110–112 8C (2-
propanol).1H-NMR (360-MHz, CDCl3): d 1.18 (t, J ¼ 7.12 Hz, 3H), 1.35
(t, J ¼ 7.13 Hz, 3H), 4.10 (q, J ¼ 7.11 Hz, 2H), 4.24–4.35 (m, 2H), 4.37
1
(d, J ¼ 5.13 Hz, 1H), 4.48–4.54 (m, 1H), 5.31 (s, 1H), 5.44 (dd, J ¼ 0.94,
1
2
2J ¼ 10.27, 1H), 5.57 (dd, J ¼ 0.91, J ¼ 17.10, 1H), 5.90–6.01 (m, 1H),
1
7.27–7.36 (m, 2H), 7.52–7.57 (m, 1H), 7.83 (s, 1H), 7.93 (dd, J ¼ 1.18,
2J ¼ 8.17, 1H); 13C NMR (90-MHz, DMSO-d6): d 13.94, 14.30, 57.34,
57.58, 61.02, 61.79, 104.35, 115.06, 115.19, 118.21, 120.62, 124.03,
125.68, 129.91, 132.58, 132.63, 153.09, 153.99, 160.13, 165.05, 170.08;
MS (pos. APCI) m/z (%): 383 (100, M). Anal. Calcd. for C21H21NO6: C,
65.79; H, 5.52; N, 3.65. Found: C, 65.80; H, 5.53; N, 3.60.

Convenient Approach to the Synthesis
REFERENCES
1587
1. (a) Ukawa, K.; Ishiguro, T.; Wada, Y.; Nohara, A. Synthesis of 5-oxo-5H-[1]ben-
zopyrano[4,3-b]pyridine derivatives. Heterocycles 1986, 24, 1931–1941;
(b) Sun, W.; Cama, L. D.; Birzin, E. T.; Warrier, S.; Locco, L.; Mosley, R.;
Hammond, M. L.; Rohrer, S. P. 6H-Benzo[c]chromene-6-one derivatives as
selective ERb agonists. Bioorg. Med. Chem. Lett. 2006, 16, 1468–1472;
(c) Pave, G.; Charald, P.; Viauld-Massuard, M.-C.; Troin, Y.; Guillaumet, G.
New efficient synthesis of pyrido[2,3-c] and pyrido[3,2-c]coumarin derivatives.
Synlett 2003, 987–990; (d) Lewis, W. H.; Stonard, R. J.; Porras-Reyes, A. T.;
Mustoe, T. A.; Thoms, A. Wound-healing composition. US Patent 5156847,
1992; Chem. Abstr. 1992, 117, 245630t; (e) Connor, D. T.; Unangst, P. C.;
Schwender, C. F.; Sorensen, R. J.; Carethers, M. E.; Puchalski, C.;
Brown, R. E.; Finkel, M. P. 3-(Aminoalkyl)-1,2,3,4-tetrahydro-5H-[1]benzopyr-
ano[3,4-c] pyridine-5-ones as potential anticholinergic bronchodilators. J. Med.
Chem. 1989, 32, 683–688.
2. (a) Heber, D. 5H-[1]benzopyrano[4,3-b]pyridine by condensation of 3-acylchro-
mones with enamines. Synthesis 1978, 691–692; (b) Heber, D. Reactions of het-
erocycles containing the 2-acyl-2-propenone structure, II: Pyrido[2,3-
d]pyrimidines from 4-oxo-4H-chromene-3-carbaldehydes and 4-aminouracils.
Arch. Pharm. 1983, 316, 55–62; (c) Heber, D. Reactions of heterocycles contain-
ing the 2-acyl-2-propenone structure, III: Pyrido[3,2-c]-coumarins from 3-substi-
tuted 1-benzopyrans and enamines. Arch. Pharm. 1987, 320, 402–406;
(d) Heber, D. Reactions of heterocycles containing the 2-acyl-2-propenone
structure, V: [1]Benzopyrano[4,3-b]pyridine-2,5-(2H,5H)-diones by cyclisation
of 3-substituted 4-aminocoumarins. Arch. Pharm. 1987, 320, 577–581;
(e) Heber, D. Reactions of heterocycles containing the 2-acyl-2-propenone
structure, VI: Novel preparation of 6-oxo-6H-[1]benzopyrano[4,3-b]quinoline
derivatives. Arch. Pharm. 1987, 320, 595–599; (f) Heber, D.; Berghaus, T.
Synthesis of 5H-[1]benzopyrano[4,3-b]pyridine-5-ones containing an azacannabi-
noidal structure. J. Het. Chem. 1994, 31, 1353–1359; (g) Winn, M.; Arendsen, D.;
Dodge, P.; Dren, A.; Dunningan, D.; Hallas, R.; Hwang, K.; Kyncl, J.; Lee, Y.-H.;
Plotnikoff, N.; Young, P.; Zaugg, H. Drugs derived from cannabinoids, 5: D6a,10a
-
Tetrahydrocannabinol and heterocyclic analogs containing side chains. J. Med.
Chem. 1976, 19, 461–471.
3. Wolfbeis, O. S. Luminescent heterocycles, part 8: Synthesis and properties of new
hydoxy-substituted coumarin-derived laser dyes. Monats. Chem. 1978, 109,
1413–1421.
4. Razdan, R. J. The total synthesis of cannabinoids. In The Total Synthesis of Natural
Products; ApSimon, J., Ed.; John Wiley and Sons: New York; 1981, Vol. 4,
pp. 186–262.
5. (a) Majumdar, K. C.; Bhattacharyya, T. Synthesis of bioactive heterocycles:
Amino Claisen rearrangement of 4-N-(4-aryloxybut-2ynyl)-N-methylaminocou-
marins. Tetrahedron Lett. 2001, 42, 4231–4233; (b) Chatterjea, J. N.;
Shaw, S. C.; Singh, J. N.; Singh, S. N. Synthesis of condensed pyridines, part I:
Pyrido[3,2-c]coumarins. Ind. J. Chem. Sec.
B
1977, 15, 430–431;
(c) Darbarwar, M.; Sundaramurthy, V. Synthesis of coumarines with 3:4-fused
ring systems and their physiological activity. Synthesis 1982, 337–388, and refer-
ences therein; (d) O’Callaghan, C. N. Synthesis of dialkyl 2-(2-hydroxyphenyl)-
4,6-dimethyl-1,2-dihydropyridine-3,5-dicrboxylates and alkyl 2,4-dimethyl-
5-oxo-5H-[1]benzopyrano[4,3-b]pyridine-3-carboxylates.
Synthesis
1987,

1588
T. N. Glasnov and I. C. Ivanov
499–503; (e) Heber, D.; Ivanov, I. C.; Karagiosov, S. K. The Vilsmeier reaction in
the synthesis of 3-substituted [1]benzopyrano[4,3-b]pyridine-5-ones. J. Het.
Chem. 1995, 505–509; (f) Ghosh, C. K.; Ray, A.; Patra, A. Benzopyrans, part
42[1]: Reactions of 4-oxo-4H-1-benzopyran-3-carbaldehyde with some active
methylene compounds in the presence of ammonia. J. Het. Chem. 2001,
1459–1463; (g) Murphy, P. J.; Brennan, J. The Wittig olefination reaction with
carbonyl compounds other than aldehydes and ketones. Chem. Soc. Rew. 1988,
17, 1–30; (h) Pars, H. G.; Granchelli, F. E.; Razdan, R. K.; Keller, J. K. Drugs
derived from cannabinoids, 1: Nitrogen analogs, benzopyranopyridines and benzo-
pyranopyrroles. J. Med Chem. 1976, 19, 445–454; (i) Pars, H. G.;
Granchelli, F. E.; Keller, J. K.; Razdan, R. K. Physiologically active nitrogen
analogs of tetrahydrocannabinols: Tetrahydrobenzopyrano[3,4-d]pyridines.
J. Am. Chem. Soc. 1966, 88, 3664–3665; (j) Palacios, F.; Alonso, C.;
Amezua, P.; Rubiales, G. Synthesis of aza polycyclic compounds derived from
pyrrolidine, indolizidine and indole via intramolecular Diels–Alder cycloadditions
of neutral 2-azadienes. J. Org. Chem. 2002, 67, 1941–1946; (k) Pandya, S. U.;
Pandya, U. R.; Hirani, B. R.; Brahmbhatt, D. I. One pot synthesis of diarylpyr-
ido[3,2-c]coumarins. J. Heterocycl. Chem. 2006, 43, 795–798.
6. (a) Becalli, E. M.; Contini, A. C.; Trimarco, P. New synthetic approach to [1]ben-
zopyrano[4,3-b]pyridin-5-one derivatives. Tetrahedron Lett. 2004, 45,
3447–3449; (b) Becalli, E. M.; Contini, A. C.; Trimarco, P. Substituted
coumarin amidines: Useful building blocks for the preparation of [1]benzopyr-
ano[4,3-b]pyridine-5-one and [1]benzopyrano[4,3-d]pyrimidine-5-one deriva-
tives. Tetrahedron 2005, 61, 4957–4964.
7. (a) Ivanov, I. C.; Karagiozov, S. K.; Manolov, I. Synthesis of 4-(monoalkylamino)-
coumarins. Arch. Pharm. 1991, 324, 61–62; (b) Ivanov, I. C.; Karagiozov, S. K.;
Simeonov, M. F. A facile synthesis of [1]benzopyrano[4,3-b]pyridine-5-ones.
Liebigs Ann. Chem. 1992, 203–207. For additional information on Vilsmeier–
Haak formylation of 4-aminocoumarins, see also Ref. 2d.
8. Ivanov, I. C.; Glasnov, T. N.; Heber, D. Synthesis of 2H-chromeno[4,3-b]pyridine-
2,5(1H)-diones and related heterocycles via the Erlenmeyer–Ploechl reaction.
J. Heterocycl. Chem. 2005, 42, 857–861.
9. (a) Rad-Moghadam, K.; Mohseni, M. A route to the synthesis of novel coumarins.
Monats. Chem. 2004, 135, 817–821; (b) Adib, M.; Sayahi, M. H. An efficient one-
pot synthesis of 4H-pyrrolo[3,2,1-ij]quinolines. Monatsh. Chem. 2006, 137,
207–211; (c) Yavari, I.; Adib, M.; Hojabri, L. Vinyltriphenylphosphonium salt
mediated synthesis of functionalized coumarines. Tetrahedron 2001, 57,
7537–7540; (d) Heys, L.; Murphy, P. J.; Coles, S. J.; Gelbirch, T.;
Hursthouse, M. B. Intramolecular Wittig reactions with lactones utilizing triphe-
nylphosphine and dimethyl acetylenedicarboxylate. Tetrahedron 1999, 40,
7151–7152; (e) Azizian, J.; Karimi, A. R.; Arefrad, H.; Mohammadi, A. A.;
Mohammadizadeh, M. R. Synthesis of some novel g-spirolactones. Monatsch.
Chem. 2004, 135, 729–733; (f) Yavari, I.; Samzadeh-Kermani, A. R. Vinylpho-
sphonium salt mediated steroselective synthesis of cyclobutene derivatives. A
facile route to highly electron-deficient 1,3-dienes 1998, 39, 6343–6344;
(g) Evans, L. A.; Griffiths, K. E.; Guthmann, H.; Muphy, P. J. Intramolecular
Wittig reactions with esters utilizing triphenylphosphine and dimethyl acetylene-
dicarboxylate. Tetrahedron Lett. 2002, 43, 299–301.