A convenient synthesis of furo[3,2-c]coumarins by a tandem alkylation/intramolecular aldolisation reaction

Article abstract of DOI:10.1016/S0040-4039(01)00490-7

A simple and efficient synthesis of furo[3,2-c]coumarin derivatives from 4-hydroxycoumarin and α-haloketones via a tandem O-alkylation/cyclisation protocol is described.

Full text of DOI:10.1016/S0040-4039(01)00490-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3503–3505
A convenient synthesis of furo[3,2-c]coumarins by a tandem
alkylation/intramolecular aldolisation reaction
Francesco Risitano,* Giovanni Grassi, Francesco Foti and Cristina Bilardo
Dipartimento di Chimica Organica e Biologica, Universit a` , Vill. S. Agata, I-98166 Messina, Italy
Received 12 January 2001; revised 12 March 2001; accepted 21 March 2001
Abstract—A simple and efficient synthesis of furo[3,2-c]coumarin derivatives from 4-hydroxycoumarin and a-haloketones via a
tandem O-alkylation/cyclisation protocol is described. © 2001 Elsevier Science Ltd. All rights reserved.
The 4-hydroxycoumarin fragment occurs in many syn-
thetic and natural products, which are used clinically as
the five-membered ring, starting from 4-hydroxycou-
marin 1. The reaction is also interesting because the
framework of these systems is entirely present in the
coumestans (6H-benzofuro[3,2-c]benzopyran-6-ones), a
class of physiologically active natural compounds such
as wedelolactone, medicagol, psoraldin, isopsoraldin,
1
2
drugs and pesticides as well as oral anticoagulants
3
and rodenticides. These important applications have
generated considerable interest in this ring system and
various 2,3- or 3,4-fused polycycles or open chain
derivatives have been synthesised. While many efforts
have been made to synthesise 3-alkyl-4-hydroxycou-
6
erosnin, and many others.
4
marin derivatives, only a few studies have focussed on
The idea arose from the observation that the highly
reactive enolic moiety of 1 can easily be utilised,
together with selected building blocks, in the construc-
tion of angular or linear polyheterocycles. With this in
mind, we chose the double electrophile a-haloketones 2
the synthesis of linearly or angularly fused tricyclic
complex systems. All the reported procedures referring
to this particular system require vigorous reaction con-
5
ditions and laborious preparation.
(
Scheme 1). In fact, for the entries (a–e), treatment of 1
This paper describes a simple and easy route to new
angular furocoumarins 3 differentially substituted on
with the ambident reagents 2 produced the expected
cycloadducts 3 in good yield (70–77%). The reaction
7
R
O
R'
OH
(
a-e)
X
R
O
O
O
O
O
AcOH/AcONH4
or piperidine
toluene
3
+
O
OH
O
R'
(g)
X= Cl, Br
1
2
COOEt
O
a
b
c
d
e
f
g
4
R
H
H
Ph
H
H
Me
Ph
Ph
Ph
H
CO2Et
R' Me
p-BrC6H4 p-OMeC6H4
Scheme 1.
*
Corresponding author. Tel.: +390906765512; fax: +39 90 393897; e-mail: frisitan@isengard.unime.it
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00490-7

3
504
F. Risitano et al. / Tetrahedron Letters 42 (2001) 3503–3505
was carried out in glacial AcOH/AcONH or piperidine
4.90 due to the generation of a new chiral carbon. An
4
in refluxing toluene/EtOH (4:1). In entry f, the desired
cycloaddition failed: desyl chloride 2f and 1 were recov-
ered unreacted. This failure can be attributed to the
presence of the bulky phenyl substituent in the a-posi-
tion. In entry g, however, the reaction of 1 with 2g
X-ray crystallographic analysis carried out on 3b also
10
confirmed the structure of compounds 3.
Formation of 3 can proceed following two different
pathways (Scheme 2). Firstly, (i), through dehydration
of 6 obtained by intramolecular CꢁC bond formation
of the initial adduct 5. Alternatively, (ii), by the tau-
tomeric form 7B of the aldol product 7A, which is
subjected to a 5-exo-trig cyclisation to give 6 through
intramolecular OꢁC bond formation and dehydration,
in a manner which follows the well-known Feist–
under similar conditions (AcOH/AcONH , refluxing
4
toluene/EtOH) gave the dihydrofuran derivative 4 in
7
high yield (90%). It must be noted that chemoselective
cyclisation is favoured at the carbonyl-C, rather than at
8
the ester-C, in accordance with accepted rules. The
stability of the a-hydroxyester 4 is remarkable and it
can be recrystallised and stored without any decompo-
sition. Moreover, it cannot be converted into the corre-
sponding derivative 3g. Treatment of the isolated 4 with
acids or bases did not promote any dehydration and, at
the end, compound 4 was unaltered.
11
Benary synthesis of 3-carbonyl substituted furans.
The latter reaction pathway also implies a partial
change in the direction of cyclisation. A similar process
should occur, at least partially, for the tautomeric form
7
C through the lactone carbonyl oxygen to give linear
policyclic fused heterocycles such as 8 or 9.
All the compounds synthesised were characterised by
1
13
their H and C NMR, and IR spectra, as well as by
9
The existence of the 4-hydroxycoumarin/2-hydroxy-
elemental analyses. IR spectra of compounds 3a–e and
12
−
1
chromone tautomerism has been demonstrated, for
instance, by the treatment of 4-hydroxycoumarin with
diazomethane, which afforded a mixture of 4-methoxy-
4
contain bands at 1735–1755 cm which are charac-
teristic of the stretching vibrations of the coumarin
carbonyl group. For compound 4 CꢀO and OH
ester
13
−
1
coumarin and 2-methoxychromone. Since products 8
and 9 were not observed, it can be assumed that 3 is
formed through pathway (i). In confirmation of this,
the X-ray of 3-phenylfuro[3,2-c]coumarin 3b showed
bands were also observed at 1702 cm and at 3331
−
1
1
cm , respectively. In the H NMR spectrum of the
dihydro derivative 4 the signal related to the OH
appears at l 6.54 and exchanges with D O; the methyl-
2
1
0
ene protons are split into an AB quartet centred at l
the phenyl substituent exclusively in the 3-position.
1
+ 2
R
O
X
R
(ii)
(i)
O
O
O
O
H
R'
R'
O
OH
O
5
7A
R
X
R
O
O
HO
O
OH
R'
R'
OH
3
-
H O
O
2
O
6
7B
O
O
O
HO
HO R'
OH
R'
R'
O
R
R
R
X
O
O
O
O
8
9
7C
Scheme 2.

F. Risitano et al. / Tetrahedron Letters 42 (2001) 3503–3505
3505
On the basis of the above results, the reaction leading
to 3 is unhindered when the nearby a-carbon of 2 is not
particularly bulky. This can prevent the O-alkylation
process and/or the following 5-exo-trig cyclisation.
When this condition is satisfied, the resulting hydroxyl
group on the tertiary carbon atom or in the benzylic
position is easily expelled as water, under the conditions
used, to give 3. The unsuccessful dehydration of 4 to
give 3g, however, reflects the well-known difficulties
that a-hydroxy-acids or -esters have in losing water
intramolecularly.
ml) and the precipitate was filtered off, washed with
water (50 ml) and recrystallised from EtOH to give 3a–e
or 4.
8. (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976,
734736; (b) Baldwin, J. E.; Cutting, J.; Dupont, W.;
Kruse, L.; Silbermann, L.; Thomas, R. C. J. Chem. Soc.,
Chem. Commun. 1976, 736–738; (c) Baldwin, J. E.; Reiss,
J. A. J. Chem. Soc., Chem. Commun. 1977, 77.
−
1
9. Selected data: 3a: mp 135°C; IR (Nujol): w=1747 cm ;
1
H NMR (CDCl , 300 Mz, rt): l=2.30 (s, 3H, CH ),
3
3
13
7.24–7.82 (m, 5H); C NMR (CDCl , 75 Mz, rt): l=8.2,
3
1
1
02.1, 112.5, 116.8, 119.6, 120.5, 124.6, 130.1, 142.5,
51.8, 156.9, 158.2. Anal. C H O requires (%) C, 72.88;
12
8
3
References
H, 4.03. Found (%) C, 73.08; H, 4.12. Compound 3b: mp
−
1 1
1
77°C; IR (Nujol): w=1739 cm ; H NMR (CDCl , 300
3
13
1
2
. (a) Feuer, G. Prog. Med. Chem. 1973, 10, 85–93; (b)
Obaseki, O.; Porter, W. R. J. Heterocyclic Chem. 1982,
9, 385–390; (c) Das Gupta, K.; Chatterjee, R. M.; Das,
K. R. Indian J. Chem. Sect. B 1981, 20, 511–515.
Mz, rt): l=7.35−7.89 (m, 10H); C NMR (CDCl , 75
3
Mz, rt): l=107.8, 110.6, 112.1, 120.1, 124.8, 125.3, 128.0,
128.3, 128.5, 129.0, 131.3, 143.3, 151.9, 157.0, 158.1.
Anal. C H O requires (%) C, 77.85; H, 3.84. Found
1
17
10
3
. (a) Kazmier, F. J. Mayo Clin. Proceed. 1974, 49, 918–925;
(%) C, 77.98; H, 3.92. Compound 3c: mp 198°C; IR
−
1
1
(b) Kralt, T.; Classen, V. In Drug Design; Ariens, E. J.,
(Nujol): w=1747 cm ; H NMR (CDCl , 300 Mz, rt):
3
13
Ed.; Academic Press: New York, 1972; Vol. 3, pp. 189–
l=7.33–7.91 (m, 9H); C NMR (CDCl , 75 Mz, rt):
3
2
2
30; (c) O’Reilly, R. A. Ann. Rev. Med. 1976, 27, 245–
62.
107.7, 112.0, 116.1, 120.8, 121.3, 121.5, 124.2, 124.9,
128.4, 130.5, 131.4, 143.4, 152.0, 157.2, 158.2. Anal.
C H BrO requires (%) C, 59.85; H, 2.66. Found (%) C,
3
4
. Hermodson, M. A.; Barker, W. M.; Link, K. P. J. Med.
17
9
3
Chem. 1971, 14, 167–173.
. Appendino, G.; Cravotto, G.; Tagliapietra, S.; Ferraro,
S.; Nano, G. M.; Palmisano, G. Helv. Chim. Acta 1991,
60.08; H, 2.82. Compound 3d: mp 166°C; IR (Nujol):
−
1 1
w=1740 cm ; H NMR (CDCl , 300 Mz, rt): l=3.88 (s,
3
13
3H, OCH ), 6.98–7.87 (m, 9H); C NMR (CDCl , 75
3
3
7
4, 1451–1458 and references cited therein.
. (a) Saidi, M. R.; Bigdeli, K. J. Chem. Res. (S) 1998,
00–801 and references cited therein; (b) Majumdar, K.
Mz, rt): l=54.7, 107.1, 112.3, 114.7, 121.3, 121.6, 124.3,
125.0, 128.4, 130.6, 131.3, 143.3, 152.0, 157.5, 158.2,
160.9. Anal. C H O requires (%) C, 73.97; H, 4.14.
5
8
18
12
4
C.; De, R. N.; Khan, A. T.; Chattopdhyay, S. K; Dey,
K.; Patra, A. J. Chem. Soc., Chem. Commun. 1988,
Found (%) C, 74.08; H, 4.21. Compound 3e: mp 150°C;
−
1 1
IR (Nujol): w=1735 cm ; H NMR (CDCl , 300 Mz, rt):
3
13
7
77–779; (c) Yakout, E. M. A.; Ibrahim, N. M.;
Ghoneim, K. M.; Mahran, M. R. H. J. Chem. Research
S) 1999, 652–653; (d) Appendino, G.; Cravotto, G.;
Palmisano, G.; Annunziata, R. Synth. Commun. 1996, 26,
359–3371; (e) Appendino, G.; Cravotto, G.; Toma, L.;
Annunziata, R.; Palmisano, G. J. Org. Chem. 1994, 59,
556–5564; (f) Girreser, U.; Heber, D.; Schutt, M. J.
l=2.50 (s, 3H, CH ), 7.30–7.85 (m, 9H); C NMR
3
(CDCl , 75 Mz, rt): l=12.8, 107.8, 112.4, 116.5, 120.4,
3
(
124.5, 127.8, 128.4, 129.5, 130.8, 143.8, 149.4, 152.0,
153.2, 157.0, 158.1. Anal. C H O requires (%) C, 78.25;
12
8
3
3
H, 4.38. Found (%) C, 78.48; H, 4.50. Compound 4: mp
−
1
1
134°C; IR (Nujol): w=1755, 1702 cm ; H NMR
5
(DMSO , 300 Mz, rt): l=1.11 (t, 3H, CH , J=7.1 Hz),
d6
3
Heterocycl. Chem. 1998, 35, 1455–1460; (g) Kappe, T.;
Mayer, C. Synthesis 1981, 524–526.
4.20 (q, 2H, OCH , J=7.1 Hz), 4.90 (ABq, 2H, CH
J=10.7 Hz), 6.54 (s, 1H, OH), 7.41–7.81 (m, 4H);
,
C
2
2ring
13
6. (a) Wong, E. Fortschr. Chem. Org. Naturst. 1970, 28,
NMR (DMSO , 75 Mz, rt): l=14.8, 61.9, 79.8, 86.1,
d6
1
–152; (b) Bickoff, E. M.; Livingston, A. L.; Booth, A.
106.5, 111.74, 117.1, 123.4, 124.9, 134.7, 155.0, 157.6,
167.9, 170.7. Anal. C H O requires (%) C, 60.87; H,
4.38. Found (%) C, 61.08; H, 4.52.
10. Bruno, G.; Nicol o` , F.; Rotondo, A.; Risitano, F.; Grassi,
G.; Foti, F.; Bilardo, C. Acta Crystallogr., Sect. C, in
press.
N.; Thompson, C. R.; Hollwell, E. A.; Beinhart, E. G. J.
Anim. Sci. 1960, 19, 4–12; (c) Darbarwar, M.; Sundara-
murthy, V.; Subba Rao, N. V. Indian J. Chem. 1973, 11,
14
12
6
1
15–118.
7
. A typical experimental procedure for the preparation of 3
and 4. A toluene solution of the appropriate a-haloketone
2
11. (a) Feist, F. Chem. Ber. 1902, 35, 1545; (b) Benary, E.
Chem. Ber. 1911, 44, 493–499.
(4 mmol) was added to a solution of 4-hydroxycou-
marin 1 (0.65 g, 4 mmol) and AcOH/AcONH (20 mmol)
12. Porter, W. R.; Trager, W. F. J. Heterocyclic Chem. 1982,
19, 475–480 and references cited therein.
13. Arndt, F.; Loewe, L.; Un, R.; Ayca, E. Chem. Ber. 1951,
84, 319–325.
4
in toluene/EtOH abs. (50 ml; 40:10). The mixture was
stirred for 1 h and the solvent evaporated under reduced
pressure. The oily residue was treated with cold water (30
.
.