New synthetic approach to [1]benzopyrano[4,3-b]pyridin-5-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.03.009

A new synthesis of [1]benzopyrano[4,3-b]pyridin-5-ones 4 was developed starting from 3-formyl-coumarin N-functionalized amidines 3. The reaction is based likely on the intramolecular cyclocondensation of the C-α amidinic carbanion in basic medium on the f

Full text of DOI:10.1016/j.tetlet.2004.03.009

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Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3447–3449
New synthetic approach to [1]benzopyrano[4,3-b]pyridin-5-one
derivatives
Egle M. Beccalli, Alessandro Contini and Pasqualina Trimarco*
Istituto di Chimica Organica ‘A. Marchesini’, Facoltꢀa di Farmacia e Centro Interuniversitario di Ricerca sulle Reazioni Pericicliche
e Sintesi di Sistemi Etero e Carbociclici, Universitꢀa degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
Received 15 December 2003; revised 23 February 2004; accepted 3 March 2004
Abstract—A new synthesis of [1]benzopyrano[4,3-b]pyridin-5-ones 4 was developed starting from 3-formyl-coumarin N-function-
alized amidines 3. The reaction is based likely on the intramolecular cyclocondensation of the C-a amidinic carbanion in basic
medium on the formyl group.
Ó 2004 Elsevier Ltd. All rights reserved.
The varied biological activities of the coumarins fused
with other heterocycles has encouraged researches with
regard to the procedures and substrates, improving the
feasibility of broad families of these compounds. Several
biological activities have been claimed for compounds
comprising both coumarins and coumarins fused to
pyridine ring. For instance, coumarin nucleus is present
in promising drug candidates as nonpeptidic HIV pro-
tease inhibitors,1 such as topoisomerase II2 and tyrosine
kinase3 inhibitors.
exploit the ability of these acetamidines to give intra-
molecular condensation reaction on 3-formyl group.
An inspection of the literature data related the existing
synthetic routes to benzopyranopyridin-5-ones can be
divided as a function of the starting materials. One of
these synthesis proceeds from 4-oxo-4H-1-benzopyran-
3-carbonitrile via Michael addition4 to the malonamide
in basic medium, opening of the pyrone ring and sub-
sequent rearrangement. Different syntheses proceed
from 4-aminocoumarin reacted with alkylvinylketones,6
or with keten S,S-acetals5 or with orthocarboxylic acid
amideacetals.11 The benzopyranopyridin-5-ones have
been prepared also from 4-amino-3-formyl-coumarin,12
which undergoes Knoevenagel condensation with
malonic or cyanoacetic esters in the presence of piper-
idine. A multi-step sequence from 4-chloro-3-formyl-
coumarin13 and Wittig phosphorane was also developed
to synthesize this tricyclic system.
Coumarins joined to pyridines have been reported to
posses antiallergic,4 anticoagulant,5 antidiabetic6 activi-
ties, and even analgesic7 properties, being characterized
by a phenantrene-like structure as found in tetrahydro-
cannabinol.
Previously we reported the synthesis of coumarin imid-
azole ring8 obtained from acetamidines substituted with
3-nitrocoumarin group on N-1. As a continuation of our
studies and as a part of a program directed toward the
synthesis of nitrogen heterocycles from substituted acet-
amidines9 we report here the reactivity of acetamidines
bearing 3-formyl-coumarin group on N-1 as starting
material to synthesize benzopyranopyridin-5-ones.
The novelty of our synthetic scheme is the use of tertiary
amidines bearing 3-formyl-coumarin group on N-1 to
achieve substituted benzopyranopyridin-5-ones by an
intramolecular cyclization reaction.
By reaction of an equimolar amount of 4-azido-3-form-
ylcoumarin14 1 and suitable enamines15 2a–f in methyl-
ene chloride solution at ꢀ40 °C the amidines 3a–f were
obtained in good yields and in a short reaction time.
We proposed to take advantage of nucleophilic char-
acter of the a-methylene group of amidines10 and to
Keywords: 3-Formylcoumarin amidines; Aldols; [1]Benzopyrano-
[4,3-b]pyridin-5-ones; Intramolecular cyclization.
The intermediate A was never isolated in all cases
(Scheme 1). The reaction time, yields and melting points
of compounds 3a–f are listed in Table 1.
* Corresponding author. Tel.: +39-2-50314483; fax: +39-2-50314476;
e-mail: trimarco@mailserver.unimi.it
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.009

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3448
E. M. Beccalli et al. / Tetrahedron Letters 45 (2004) 3447–3449
OH O
H
1 H
R1
R
H
N
N3
O
R2N
O
N
CHO
O
H
N
H
R1
H
O
R2N
N
OHC
N
R1
+
CHO
O
-
3O
O
R2N
H
5a-f*
C
∆
,
H
2a-f
O
1
O
A
H3
R2N
C
3a-f
O
l2
°
OHC
C
R1
R2N
H2
C
O
C
O
H
N
NH2
O
0
4
-
R1
CHO
O
N
O
+
3a-f
R2N
6
Scheme 1.
4a-f
5a-d* not isolated aldols
Scheme 2.
Amidines 3a–d with a catalytic amount of sodium
methoxide in refluxing methanol afforded the expected
tricyclic compounds 4a–d (Scheme 2). In these reaction
conditions the aldol intermediate resulted likely from
nucleophilic attack of the C-a amidinic carbanion on
formyl group and the derivatives 4a–d were formed
through water elimination favored by aromatization of
the pyridine ring. Nevertheless other mechanistic
hypotheses cannot be excluded.
General procedure for the synthesis of amidine derivatives
3a–f: The suitable enamine 2a–f (10 mmol) was dissolved
in CH2Cl2 (20 mL). Checking strictly the inner temper-
ature (ꢀ40 °C, acetone–CO2 bath) an equimolar amount
of azide 1, dissolved in CH2Cl2 (30 mL), was slowly
dropped in, under stirring. The mixture was kept at
ꢀ30 °C for the time indicated in Table 1, until disap-
pearance of the starting azide. The mixture came back to
room temperature, the solvent was then evaporated and
the crude product purified by crystallization from iPr2O
to give pure 3a–f. Yields are reported in Table 1. All new
compounds gave satisfactory analytical and spectro-
scopic data.
In the case of amidines 3e–f, the isolation of the aldol
intermediates 5e–f (about 30% yield) validated the pro-
posed mechanism. In these cases the transformation
process resulted quite slow (about 2h compared with
30 min for the compounds 3a–d: see experimental), and
besides the expected benzopyranopyridinones 4e–f also
the 4-amino-3-formylcoumarin14 6 (about 35%) was
formed (Scheme 2). The isolation of 4-amino-3-formyl-
coumarin 6 is not surprising and arose from the known
hydrolytic reaction of amidine16 in basic medium.
Selected spectroscopic data: 3a, yellow crystals; IR
;
(Nujol) 1698 (C@O), 1656 (CHO) cmꢀ1 1H NMR
(CDCl3): 3.60–4.13 (10H, m, morpholine and CH2),
7.10–7.36 (5Hþ2H, m, ArH and H-6 and H-8 coum.),
7.56 (1H, td, J ¼ 8:4 and 1.8 Hz, H-7 coum.), 8.01 (1H,
dd, J ¼ 8:0 and 1.8 Hz, H-5 coum.), 10.14 (1H, s; CHO);
13C NMR (CDCl3): 37.5 (CH2), 46.8 (CH2NCH2), 66.0
(CH2OCH2), 100.9 (C-3 coum.), 117.1, 123.8, 126.7,
133.4 (CH coum.), 119.7 (C-4a coum.), 127.4, 128.3,
129.1 (ArCH), 134.2 (ArCqu), 154.2 (C-4 coum.), 158.0
(C-8a coum.), 164.6 (N@CAN), 164.9 (C@O), 189.1
(CHO).
It is reasonable to assume that benzopyranopyridinones
4 arise from carbanion intermediacy. In this case the
difficult formation of alkyl carbanion could explain
the low yields of benzopyranopyridinones 4e–f such
as the isolation of the aldols 5e–f and the hydrolysis
derivative 6.
In conclusion, a new approach to benzopyranopyridin-
5-ones 4 is reported, by way of an intramolecular
cyclization starting from easily accessible substituted
acetamidines of 3-formyl coumarin. This method can be
applied with good yields and short reaction time to get
benzopyranopyridin-5-one derivatives substituted on C-
3 with aromatic chain. It is in progress a different syn-
thetic strategy directed to implementation the yields of
compounds like 4e–f, bearing an alkyl chain on C-3.
General procedure for the synthesis of [1]benzopyr-
ano[4,3-b]pyridin-5-one derivatives 4a–f: A catalytic
amount of sodium methoxide (0.5 mL, 30% solution)
was added to a stirred suspension of the appropriate
3-formylamidine 3a–f (4 mmol) in methanol (100 mL).
The mixture was refluxed until the starting amidine
disappeared (reaction times indicated in Table 2). The
Table 1. Reaction time, yields and melting points of amidines 3
Entry
NR2
R1
Reaction time (h)
Yield (%)
Mp (°C)
a
b
c
d
e
f
Morpholine
Diethylamine
Morpholine
Morpholine
Morpholine
Morpholine
Phenyl
Phenyl
1.5
1.5
1
76
65
78
63
170
127
153
138
4-Bromophenyl
4-Methoxyphenyl
isoPropyl
3
270
269
134
108
Benzyl

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E. M. Beccalli et al. / Tetrahedron Letters 45 (2004) 3447–3449
Table 2. Reaction time, yields and melting points of benzopyranopyridin-5-ones 4a–f
3449
Entry
NR2
R1
Reaction time (h)
Yield (%)
Mp (°C)
a
b
c
d
e
f
Morpholine
Diethylamine
Morpholine
Morpholine
Morpholine
Morpholine
Phenyl
Phenyl
1
46
58
182
123
141
165
175
174
1
4-Bromophenyl
4-Methoxyphenyl
isoPropyl
0.5
0.5
7
94
85
36a
38a
Benzyl
7
a Total yield: see experimental.
solvent was evaporated under reduced pressure and the
crude residue was crystallized from iPr2O to afford
compounds 4a–d. The crude reaction mixture of ami-
dines 3e–f was chromatographed on a silica gel column
(EtOAc/cyclohexane, 1:4) affording a first fraction con-
taining 4e–f, a second fraction of 4-amino-3-formyl-
coumarin14 6 and finally the aldols 5e–f, respectively. A
catalytic amount of sodium methoxide (0.3 mL, 30%
solution) was added to the previously obtained aldols
5e–f. The mixture was refluxed for an additional time
(5 h) yielding a second batch of benzopyranopyridin-5-
one 4e–f then crystallized from iPr2O. Yields are
reported in Table 2. All new compounds gave satisfac-
tory analytical and spectroscopic data.
References and notes
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Selected spectroscopic data: 4a, cream crystals; IR
(Nujol) 1715 (C@O) cmꢀ1; 1H NMR (CDCl3): 3.42–3.58
(4H, m, CH2NCH2), 3.63–3.78 (4H, m, CH2OCH2),
7.23–7.60 (5Hþ3H, m, ArH and H-7,8,9 coum.), 8.28
(1H, s, H-4), 8.46 (1H, dd, J ¼ 8:0 and 1.8 Hz, H-10
coum.); 13C NMR (CDCl3): 30.1 (CH2), 49.1
(CH2NCH2), 66.8 (CH2OCH2), 110.2(C-4a), 117.4,
124.7, 124.9, 132.0 (CH coum.), 119.8 (C-10a), 126.7 (C-
3), 127.8, 128.5, 129.5 (ArCH), 139.3 (ArCqu), 141.4
(CH-4), 150.3 (C-6a), 153.5 (C-10b), 161.8 (C-2), 162.3
(C@O).
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148 °C (from iPr2O); IR (Nujol) 3450 (OH), 1663 (C@O)
cmꢀ1; 1H NMR (CDCl3): 0.95 (3H, d, J ¼ 6:7 Hz, CH3),
1.03 (3H, d, J ¼ 6:7 Hz, CH3), 1.58–1.65 (1H, m, CH3–
CH–CH3), 2.20 (1H, br s, exchangeable, OH), 2.89 (1H,
d, J ¼ 7:7 Hz, CH-3), 3.60–3.75, 4.00–4.08 and 4.40–
4.48 (3H, 3 m, CHNCH2), 3.75–3.85 (4Hþ1H, m,
CH2OCH2 and CHNCH2), 5.02(1H, s, CH-4), 7.23–
7.35 (2H, m, H-6 and H-8 coum.), 7.47–7.59 (1H, m, H-
7 coum.), 8.19 (1H, dd, J ¼ 7:4 and 1.3 Hz, H-5 coum.);
13C NMR (CDCl3): 20.6 (CH3), 21.7 (CH3), 29.7 (CH),
46.2(CH-3), 45.2and 47.8 (CH 2NCH2), 63.7 (CH-4),
67.3 (CH2OCH2), 100.5 (C-4a), 117.0, 123.8, 125.7,
131.9 (CH coum.), 119.8 (C-10a), 154.5 (C-6a), 155.0 (C-
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