Efficient synthesis of trisubstituted [1]benzopyrano[4,3-b]pyrrol-4(1H)-one derivatives from 4-hydroxycoumarin

Article abstract of DOI:10.1016/S0040-4039(03)00012-1

Various trisubstituted [1]benzopyrano[4,3-b]pyrrol-4(1H)-one derivatives have been synthesized from 4-hydroxycoumarin with a 30-40% yield over six steps. The key step of the synthesis is a base-promoted intramolecular cyclization of enamines 5, followed by dehydration to generate the fused pyrrole ring.

Full text of DOI:10.1016/S0040-4039(03)00012-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1599–1602
Efficient synthesis of trisubstituted
[1]benzopyrano[4,3-b]pyrrol-4(1H)-one derivatives from
4-hydroxycoumarin
Yuan-Xiu Liao, Pei-Yu Kuo and Ding-Yah Yang*
Department of Chemistry, Tunghai University, 181, Taichung-Kang Rd. Sec.3, Taichung, Taiwan 407
Received 8 November 2002; revised 19 December 2002; accepted 27 December 2002
Abstract—Various trisubstituted [1]benzopyrano[4,3-b]pyrrol-4(1H)-one derivatives have been synthesized from 4-hydroxycou-
marin with a 30–40% yield over six steps. The key step of the synthesis is a base-promoted intramolecular cyclization of enamines
5, followed by dehydration to generate the fused pyrrole ring. © 2003 Elsevier Science Ltd. All rights reserved.
The varied biological activity of coumarins fused with a
pyrrole ring system1–5 has continued to stimulate a
great deal of interest in the development of new
methodologies for the synthesis of multi-substituted
[1]benzopyranopyrroles. In 1999, for instance, an inter-
esting procedure was reported for synthesis of
[1]benzopyrano[4,3-b]pyrrol-4(1H)-ones from N(a)-(2-
oxo-2H-1-benzopyran-4-yl) Weinreb a-aminoamides.6
However, this procedure employed the unstable N,O-
dimethylhydroxylamine7 as a protection group and 1,3-
dicyclohexylcarbodiimide (DCC) as an activating
group, which lowers the atom efficiency of the synthe-
sis. Furthermore, it suffered from the need for expen-
sive organometallic reagents (RLi or RMgBr, up to 3
equiv.) and low temperature (as low as −60°C).
Recently, 4-chloro-3-formylcoumarin and a-amino
derivatives have been used in the synthesis of 2-func-
tionalized [1]benzopyrano[4,3-b]pyrrol-4(1H)-one deriva-
tives via the Fischer–Fink reaction.8 Although this
new synthesis requires neither protection nor harsh
conditions, there are still several drawbacks with this
synthetic route. First, the competing Knorr-type trans-
formation might be observed if the a-amino derivatives
possess a low electrophilic group or very reactive alkyl
ketone. Second, since the 3-formyl group on coumarin
is highly susceptible to nucleophilic attack, a second
attack of an a-amino derivative may occur, complicat-
ing the products. Third, only 1,2-disubstituted, but not
1,2,3-trisubstituted [1]benzopyrano[4,3-b]pyrrol-4(1H)-
one derivatives can be prepared by this synthesis. Thus,
an efficient and protection-free synthesis of multi-func-
tionalized [1]benzopyrano[4,3-b]pyrrol-4(1H)-one deriva-
tives from inexpensive materials under mild con-
ditions remains to be discovered. Here, we report an
efficient procedure for preparation of trisubstituted
[1]benzopyrano[4,3-b]pyrrol-4(1H)-one derivatives by
reacting 2-acyl-4-methoxycoumarin with a-amino
derivatives (e.g. methyl glycinate and a-amino ketones)
followed
by
intramolecular
cyclization
and
dehydration.
The reactions, as shown in Scheme 1, were performed
by O-acylation of commercially available 4-hydroxy-
coumarin 1 with various acyl chlorides in the presence
of triethylamine in methylene chloride to give the corre-
sponding enol esters 2, which were further treated with
potassium cyanide without purification at ambient tem-
perature for two days to obtain a good yield of the
isomerized 2-acyl-4-hydroxycoumarins 3. Methylation
of the 4-hydroxy group of 3 with diazomethane (gener-
ated by Diazald) in ether in an ice-bath afforded the
corresponding methyl ethers 4 with a moderate yield.
Following purification of methyl ethers 4 by chro-
matography, a 1,4-addition and elimination reaction of
4 with the appropriate a-amino derivatives using tri-
ethylamine as a base in methanol gave the precipitated
enamines 5, which were further treated with sodium
methoxide without purification to yield the fused
pyrroles 6. In this multi-step reaction, sodium methox-
ide serves as a second stronger base to facilitate the
cyclization and subsequent dehydration of 5. The yields
of products 6a–e were, with one exception, uniformly
excellent; only analogues with R1=ethyl afforded the
Keywords: 4-hydroxycoumarin; fused pyrrole ring.
* Corresponding author. Tel.: +886-4-2359-7613; fax: +886-4-2359-
0426; e-mail: yang@mail.thu.edu.tw
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00012-1

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Y.-X. Liao et al. / Tetrahedron Letters 44 (2003) 1599–1602
Scheme 1.
based-promoted intramolecular cyclization reaction,
followed by dehydration to generate the pyrrole ring as
a stable end product. The pyrrole ring was identified
corresponding cyclized derivatives with less than 80%
yield. Final N-alkylation of 6 with various alkyl halides
using potassium carbonate as a base in dry acetone at
room temperature led to the trisubstituted
[1]benzopyranopyrroles 7 in a near quantitative yield.
1
from H NMR spectra on the basis of a typical NꢀH
shift at 8.8–8.4 ppm. The molecular structure of 7 was
established by X-ray10 crystallographic analysis of 7j
(Fig. 1), and the analogous structures of other products
The key feature of this synthesis was the methylation of
planar 2-acylcoumarin 3 with diazomethane to increase
their electrophilicity. The resulting dipolar repulsions
between the C-2 carbonyl group and the other two
oxygen atoms on the ring system of methyl ethers 4
cause deformation of the triketones from planarity9 and
result in their high susceptibility to nucleophilic attack
on the C-4 position by a primary amine to regenerate
the relatively stable intramolecular hydrogen bond, as
indicated in enamines 5. The mechanism for the
intramolecular cyclizaiton reaction of enamines 5 to
pyrroles 6 was confirmed by the isolation and identifi-
cation of the intermediate alcohol 8, as outlined in
Scheme 2. Clearly, the process involves an expected
1
were determined by H and 13C NMR spectroscopy.
Twenty examples of the conversion of 4-hydroxycou-
marin to various substituted fused pyrrole systems are
listed in Table 1.11 The results indicate that the present
pyrrole synthesis has considerable versatility, since a
variety of substituted fused pyrrole systems have been
obtained from readily available starting materials, e.g.
acyl chlorides, a-amino derivatives, and alkyl halides.
Moreover, the overall yields of the substituted
[1]benzopyranopyrroles in Table 1 ranged from 23 to
54%, which increases the attractiveness of the
approach. Finally, no protections, deprotections or
Scheme 2.

Y.-X. Liao et al. / Tetrahedron Letters 44 (2003) 1599–1602
1601
Figure 1. X-Ray crystal structure of 7j.
Table 1. List of various prepared [1]benzopyrano[4,3-b]pyrrol-4(1H)-one derivatives
Entry
Compd
R1
R2
R3
Formula
Mp (°C)
Yielda (%)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
Me
Me
Et
OMe
p-C6H4Br
OMe
OMe
p-C6H4Br
OMe
OMe
OMe
p-C6H4Br
p-C6H4Br
p-C6H4Br
OMe
H
H
H
H
H
Me
Et
Bn
Me
Et
Bn
Me
Et
Bn
Me
Et
Bn
Me
Et
C14H11NO4
C19H12BrNO3
295–296
363–364 (dec.)
201–203
250–252
351–353 (dec.)
192–193
186–187
250–252
249–250
221–223
252–253
185–187
131–133
118–120
217–219
201–202
163–164
262–263
214–215
233–234
28
28
27
54
49
25
24
25
25
24
25
26
25
23
49
47
49
45
44
45
C
C
15H13NO4
19H13NO4
Ph
Ph
Me
Me
Me
Me
Me
Me
Et
C23H14BrNO3
C15H13NO4
C16H15NO4
C21H17NO4
9
C20H14BrNO3
C21H16BrNO3
C26H18BrNO3
10
11
12
13
14
15
16
17
18
19
20
C
16H15NO4
C17H17NO4
22H19NO4
Et
Et
OMe
OMe
OMe
OMe
C
Ph
Ph
Ph
Ph
Ph
Ph
C20H15NO4
C21H17NO4
C26H19NO4
C24H16BrNO3
C25H18BrNO3
C30H20BrNO3
OMe
7m
7n
7o
p-C6H4Br
p-C6H4Br
p-C6H4Br
Bn
a Overall yield from 4-hydroxycoumarin to the final product.
Acknowledgements
harsh conditions are involved in the synthesis and the
overall route offers the advantage of being relatively
short. All reactions are carried out at room temperature
and only one column chromatography is required in all
six steps. These considerations suggest that the present
synthetic method may offer certain advantages when
substituted [1]benzopyranopyrroles are desired.
The financial assistance provided by National Science
Council of Republic of China is thankfully
acknowledged.
References
To summarize, we describe here an efficient route for
the preparation of [1]benzopyrano[4,3-b]pyrrol-4(1H)-
one derivatives from 4-hydroxycoumarin via readily
accessible 2-acyl-4-methoxycoumarins. These com-
pounds may facilitate the discovery of potential benzo-
diazepine receptor ligands.
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1602
Y.-X. Liao et al. / Tetrahedron Letters 44 (2003) 1599–1602
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scopic data for the indicated structures. Representative
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was stirred for another 8 h at room temperature. After
concentrated in vacuo, the residue was then extracted
with ethyl acetate twice. The combined organic extracts
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Data Centre as supplementary publication number
CCDC-194324. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (0) 1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
1
74% overall yield. Mp 217–219°C. H NMR (CDCl3, 300
MHz) l 8.12 (d, J=6.9 Hz, 1H, Ar H), 7.50–7.34 (m, 8H,
Ar H’s), 4.39 (s, 3H, NCH3), 3.60 (s, 3H, OCH3). 13C
NMR (CDCl3, 75 MHz) l 161.9, 157.2, 152.9, 137.7,
132.8, 132.0, 129.9, 129.8, 127.6, 127.3, 125.7, 123.9,
122.2, 118.3, 113.9, 108.0, 51.6, 36.2. IR (KBr) w 3006,
1732, 1695, 1506, 1458, 1431, 1213, 1127, 788, 756 cm−1
.
HRMS (EI) calcd for C20H15NO4 (M+), 333.0997, found
333.0999.
11. All new compounds exhibited satisfactory 1H and 13C
NMR, IR, and low and high resolution mass spectro-