Divergent synthesis of linear and angular furocoumarin acetic acids from phloroglucinol

Article abstract of DOI:10.1055/s-2007-984536

Linear and angular furocoumarins can be obtained starting from phloroglucinol in a versatile, simple, direct, and efficient way, as demonstrated in the divergent syntheses described here. The key step is the alkali-mediated rearrangement of 4-halomethylcoumarins to benzofuran-3-acetic acids via α,β-unsaturated acids and the key intermediates are benzodipyrones, which, depending on their substitution, can either give or fail to give the ring-contraction reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984536

LETTER
1951
Divergent Synthesis of Linear and Angular Furocoumarin Acetic Acids from
Phloroglucinol
F
urocoumarinAc
e
i
tic
A
ci
o
dsfrom Phlo
v
roglucinol anna Delogu,*a Carmen Picciau,a Elias Quezada,a,b Lourdes Santana,b Eugenio Uriarteb
a
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy
Fax +39(070)6758553; E-mail: delogug@unica.it
b
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela,
Spain
Received 23 April 2007
pared in a similar way or by alternative methods,6 could be
used to obtain a wide variety of asymmetric dipyrones in
which the second pyrone nucleus would be 4-chloro-
methyl-substituted.
Abstract: Linear and angular furocoumarins can be obtained start-
ing from phloroglucinol in a versatile, simple, direct, and efficient
way, as demonstrated in the divergent syntheses described here. The
key step is the alkali-mediated rearrangement of 4-halomethylcou-
marins to benzofuran-3-acetic acids via a,b-unsaturated acids and
the key intermediates are benzodipyrones, which, depending on
their substitution, can either give or fail to give the ring-contraction
reaction.
O
O
O
O
O
O
Key words: Pechmann reaction, furocoumarin acetic acids, ring-
A
B
contraction reaction, divergent synthesis
Figure 1 Linear and angular furocoumarins. A) Psoralen: furo[3,2-
g]coumarin. B) Angelicin: furo[2,3-h]coumarin.
Furocoumarins are an important class of natural and
synthetic compounds and are widely studied for pharma-
cological and industrial applications.1 In particular, these
compounds are important as photochemotherapeutic
agents and are used to cure a variety of skin diseases. This
application is possible due to their ability to intercalate in
the double-stranded DNA and to undergo photoaddition
to thymine, thereby blocking cell growth and replication.2
In the present work, we describe an interesting example to
illustrate the application and synthetic possibilities of this
contraction reaction; namely the synthesis, starting from
phloroglucinol, of linear and angular (psoralens and an-
gelicins, respectively, Figure 1) furocoumarin acetic acids
(Scheme 1). The reaction between phloroglucinol (1) and
ethyl 4-chloroacetoacetate under Pechmann conditions
leads to 4-chloromethylcoumarin 45 and linear and angu-
lar dipyrones (compounds 2 and 3, respectively).7 The
angular dipyrone is obtained in much larger quantities in
relation to the linear dipyrone as position 8 is the preferred
position for the electrophilic substitution of coumarins
under these conditions.8 On the other hand, dichlorodipy-
rones are not obtained, but instead the phenolic hydroxyl
displaces the chloro substituent from the closest chlorom-
ethyl group, leading to the formation of the furan ring.
When compound 3 is treated under the appropriate alka-
line conditions (0.1 N NaOH) to give ring contraction of
the 4-chloromethyl-substituted pyrone ring, the ring con-
tracts and the other pyrone ring in the molecule is hydro-
lyzed to give with 78% yield the linear benzodifuran 5,9
which has a substitution pattern that has not previously
been reported in the literature. It would only be necessary
to replace the chloro substituent in the chloromethyl group
with, for example, a hydroxyl group (simply by an aque-
ous treatment with a yield of 72%) to make the pyrone
ring, now with a hydroxymethyl substituent (compound
6), resistant to ring contraction under the aforementioned
alkaline conditions. In this way, alkaline treatment of 6
only leads to hydrolysis of the second pyrone ring and
transposition of the double bond to give the furan ring of
psoralen 710 with 70.5% yield.
During the course of our research into the synthesis and
subsequent study of these heterocyclic compounds, we
previously focused our attention on a convenient contrac-
tion reaction of the coumarin pyrone ring to give a benzo-
furan when position 4 is occupied by a chloromethyl
chain. The reaction involves an alkali-mediated rear-
rangement of the coumarin via a,b-unsaturated acids.3
This behavior allowed us to obtain, in a very direct and ef-
ficient way, a wide range of furocoumarin derivatives that
are extremely difficult to prepare by other methods and,
for this reason, have not been studied in any detail in terms
of their pharmacological potential.4 The preparation of
these compounds involves the use of asymmetric dipy-
rones, one of the pyrone rings is 4-chloromethyl-substitut-
ed and the other cannot be transformed under the alkaline
conditions used.
The 4-chloromethyl substituted pyrone nucleus linked to
a benzene ring can often be obtained in one step by reac-
tion of the phenolic precursor and ethyl 4-chloroaceto-
acetate under Pechmann conditions.5 In an analogous way
a large number of hydroxycoumarins, which can be pre-
SYNLETT 2007, No. 12, pp 1951–1953
2
4
.0
7
.2
0
0
7
Advanced online publication: 27.06.2007
DOI: 10.1055/s-2007-984536; Art ID: G13107ST
© Georg Thieme Verlag Stuttgart · New York

1952
G. Delogu et al.
LETTER
If we synthesize the second ring of the 4-chloromethyl- on only one of the two pyrone rings to give in 78% yield,
substituted pyrone on a previously formed coumarin that the angelicin (10).11
is unsubstituted or substituted with a different group in
This means that the key step, the contraction of the 4-chlo-
this position, then the furan contraction only occurs in one
romethyl-substituted pyrane nucleus to the 4-carboxy-
case. This approach was used in the transformation of
methyl-substituted furan ring, can be carried out through
coumarin 4. Treatment with water replaces the chloro sub-
a very easy, general, and efficient procedure. The applica-
tion of this synthetic method will enable the preparation of
a large series of these types of compounds, which were
stituent with a hydroxy group to give the hydroxymethyl-
coumarin 8.
Treatment of this compound with ethyl chloroacetoace- designed in order to evaluate their properties as photo-
tate under Pechmannn conditions led with a 84.5% yield chemotherapeutic agents.
to the asymmetric dipyrone 9. This dipyrone enabled a se-
lective contraction to be performed in an alkaline medium
Acknowledgment
We thank the Xunta de Galicia (PXIB20304PR and BTF20302PR),
Ministerio de Sanidad y Consumo (PI061457), Ministero dell’Uni-
OH
versità e della Ricerca MUR-Prin 2005, and Progetto di Ricerca
Scientifica 2005-Università di Cagliari for financial support.
HO
OH
1
References and Notes
(1) Santana, L.; Uriarte, E.; Roleira, F.; Milhazes, N.; Borges, F.
Curr. Med. Chem. 2004, 11, 3239.
a
(2) Dalla Via, L.; Marciani-Magno, S. Curr. Med. Chem. 2001,
8, 1405.
(3) (a) Fall, Y.; Santana, L.; Teijeira, M.; Uriarte, E.
Heterocycles 1995, 41, 647. (b) Santana, L.; Teijeira, M.;
Uriarte, E.; Teran, C.; Linares, B.; Villar, R.; Laguna, R.;
Cano, E. Eur. J. Pharm. Sci. 1999, 7, 161.
O
Cl
O
Cl
OH
O
O
O
O
O
O
O
HO
O
4
O
O
(4) (a) Willis, I.; Menter, J. M. J. Nat. Cancer Inst. 1984, 66,
143. (b) Greenman, W. M.; Grass, J. A.; Talib, S.;
Stassinopoulos, A.; Hei, D. J.; Hearst, J. E. WO 9903976 A2
19990128, 1999; Chem. Abstr. 1999, 130, 152548.
(c) Cook, D.; Merritt, J.; Nerio, A.; Rapoport, H.;
Stassinopoulos, A.; Wollowitz, S.; Matejovic, J. WO
9830545 A1 19980716, 1998; Chem. Abstr. 1998, 129,
136107. (d) Kontogiorgis, C.; Hadjipavlou-Litina, D.
J. Enzyme Inhib. Med. Chem. 2003, 18, 63.
(5) (a) Zagotto, G.; Gia, O.; Baccichetti, F.; Uriarte, E.;
Palumbo, M. Photochem. Photobiol. 1993, 58, 486.
(b) Smitha, G.; Sanjeeva Reddy, Cc. Synth. Commun. 2004,
34, 3997. (c) Valizadeh, H.; Shockravi, A. Tetrahedron Lett.
2005, 46, 3501. (d) Sharma, G. V. M.; Reddy, J. J.;
Lakshmi, P. S.; Krishna, P. R. Tetrahedron Lett. 2005, 46,
6119.
Cl
2
3
c
b
b
O
O
CO2H
OH
OH
OH
O
O
c
O
O
HO
O
O
O
OH
6
5
8
HOOC
a
OH
OH
(6) Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E.
Curr. Med. Chem. 2005, 12, 887.
O
COOH
O
(7) A solution of 1 (300 mg, 2.4 mmol) in H2SO4 was stirred at
r.t. for 20 min. Then, ethyl 4-chloroacetoacetate (1.60 mL,
1.95 g, 11.89 mmol) was added dropwise and the reaction
was stirred at r.t. overnight. Ice (50 mL) was added, the
solution was filtered, and the precipitate was washed with
cold H2O until the washings were pH 7. The residue was
purified by silica gel column chromatography (hexane–
EtOAc, 4:1 to 3:2) to afford 2 (16 mg, 2.5% yield), 3 (104
mg, 15.0% yield), and 4 (220 mg, 41.0% yield), all as pure
white solids.
O
c
O
O
OH
O
O
Cl
OH
9
7
OH
OH
10-Chloromethyl-8H-8-oxofuro[4,3,2-e]pyran[3,2-
g]coumarin(2): mp 243–244 °C. IR (KBr): 2960, 1684,
1639, 1590, 1390, 1208, 1109, 1074, 856 cm–1. 1H NMR
(500 MHz, DMSO-d6): d = 4.93 (s, 2 H, CH2Cl), 5.90 (d,
J = 2.1 Hz, 2 H, H-2), 6.20 (t, J = 2.1 Hz, 1 H, H-3), 6.56 (s,
1 H, H-9), 7.03 (s, 1 H, H-6). MS: m/z (%) = 292 (2) [M +
2]+, 290 (15) [M+], 178 (86), 163 (69), 135 (10).
10-Chloromethyl-8H-8-oxofuro[4,3,2-d,e]pyran[3,2-
h]coumarin(3): mp 266–267 °C. IR (KBr): 2960, 1684,
O
O
O
10
HOOC
Scheme 1 Reagents and conditions: (a) ethyl 4-chloroacetate,
H2SO4, r.t., 12 h; (b) H2O, reflux, 48 h; (c) 0.1 N NaOH, 0 °C, 30 min.
Synlett 2007, No. 12, 1951–1953 © Thieme Stuttgart · New York

LETTER
1639, 1590, 1390, 1208, 1109, 1074, 856 cm–1. 1H NMR
Furocoumarin Acetic Acids from Phloroglucinol
1953
6.73 (s, 1 H, H-8), 7.67 and 7.69 (2 s, 1 + 1 H, H-2 and H-6),
9.99 (br s, 1 H, OH), 12.31 (br s, 2 H, 2 COOH). MS: m/z
(%) = 290 (0.2) [M+], 261 (12), 247 (58), 231 (12), 203
(100), 201 (15), 164 (5).
(500 MHz, DMSO-d6): d = 5.11 (s, 2 H, CH2Cl), 5.82 (d,
J = 2.0 Hz, 2 H, H-4), 6.31 (t, J = 2.0 Hz, 1 H, H-3), 6.58 (s,
1 H, H-9), 7.03 (s, 1 H, H-6). MS: m/z (%) = 292 (0.5) [M +
2]+, 290 (3) [M+] , 220 (1.6), 142 (1.7), 104 (3), 79 (25), 54
(51), 46 (80), 33 (100).
(10) 6-Carboxymethyl-5-hydroxy-4-hydroxymethylfuro[3,2-
g]coumarin (7): mp 290 °C (dec.). IR (KBr): 3550, 2930,
2800, 1715, 1595, 1430, 1100, 1080, 835 cm–1. 1H NMR
(250 MHz, DMSO-d6): d = 3.84 (s, 2 H, CH2CO), 4.76 (s, 2
H, CH2OH), 6.05 (s, 1 H, H-3), 6.88 (s, 1 H, H-9), 7.96 (s, 1
H, H-7), 9.45 (br s, 1 H, OH), 11.05 (br s, 2 H, 2 OH). MS:
m/z (%) = 291 (9) [M + 1]+, 290 (100) [M+], 272 (15), 246
(20), 205 (10).
(11) 9-Carboxymethyl-5-hydroxy-4-hydroxymethylfuro[2,3-
h]coumarin (10): mp 285 °C (dec.). IR (KBr): 2949, 2840,
1716, 1599, 1432, 1108, 1088, 832 cm–1. 1H NMR (250
MHz, DMSO-d6): d = 3.80 (s, 2 H, CH2CO), 4.72 (s, 2 H,
CH2OH), 6.08 (s, 1 H, H-3), 6.79 (s, 1 H, H-6), 7.58 (s, 1 H,
H-8), 10.80 (br s, 3 H, 3 OH). MS: m/z (%) = 291 (8) [M +
1]+, 290 (100) [M+], 272 (18), 246 (9), 228 (15).
(8) (a) Kravtchenko, D. V.; Chibisova, T. A.; Traven, V. F.
Russ. J. Org. Chem. 1999, 35, 899. (b) González-Gómez, J.
C.; Santana, L.; Uriarte, E. Tetrahedron 2003, 59, 8171.
(9) Synthesis of 3,5-Bis(carboxymethyl)-4-hydroxyfuro[3,2-
f]benzofuran (5)
A mixture of 3 (100 mg, 0.344 mmol) in 0.1 N NaOH (10
mL) was stirred at 0 °C for 30 min. Then, 3 N HCl was added
to give pH 6.0 at the same temperature. The resulting brown
precipitate was filtered off and washed with cold H2O until
the washings were pH 7. The residue was purified by silica
gel column chromatography (CH2Cl2–MeOH, 9:1 to 4:1) to
give 5 (77 mg, 78.0%); mp 147 °C (dec.). IR (KBr): 3520,
2949, 2840, 1746, 1620, 1599, 1422, 1128, 1080, 830 cm–1.
1H NMR (DMSO-d6): d = 3.74 and 3.77 (2 s, 2 + 2 H, 2 CH2),
Synlett 2007, No. 12, 1951–1953 © Thieme Stuttgart · New York

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