Concise and efficient synthesis of linear furocoumarins: Psoralen and 4-methylpsoralen

Article abstract of DOI:10.1080/00397910600978093

A method for the rapid synthesis of psoralen and 4-methylpsoralen has been developed. The key intermediates, coumarinyloxyaldehydes, were obtained in only two steps from the easily available starting materials, 7-hydroxycoumarin derivatives, by an oxidative procedure. By using Swern oxidation, psoralen and 4-methylpsoralen were finally produced in the overall yields of 71% and 67%, respectively. Copyright Taylor & Francis Group, LLC.

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Concise and Efficient Synthesis of
Linear Furocoumarins: Psoralen and
4‐Methylpsoralen
Bang‐Le Zhang a b , Fang‐Dao Wang a & Jian‐Min Yue a
a State Key Laboratory of Drug Research, Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
Shanghai, China
b School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi,
China
Version of record first published: 25 Jul 2007.
To cite this article: Bang‐Le Zhang , Fang‐Dao Wang & Jian‐Min Yue (2007): Concise and Efficient Synthesis of
Linear Furocoumarins: Psoralen and 4‐Methylpsoralen, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 37:1, 63-70
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Synthetic Communicationsw, 37: 63–70, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600978093
Concise and Efficient Synthesis of
Linear Furocoumarins: Psoralen
and 4-Methylpsoralen
Bang-Le Zhang
State Key Laboratory of Drug Research, Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, Chinese Academy of
Sciences, Shanghai, China and School of Pharmacy, Fourth Military
Medical University, Xi’an, Shaanxi, China
Fang-Dao Wang and Jian-Min Yue
State Key Laboratory of Drug Research, Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, Chinese Academy of
Sciences, Shanghai, China
Abstract: A method for the rapid synthesis of psoralen and 4-methylpsoralen has been
developed. The key intermediates, coumarinyloxyaldehydes, were obtained in only two
steps from the easily available starting materials, 7-hydroxycoumarin derivatives, by an
oxidative procedure. By using Swern oxidation, psoralen and 4-methylpsoralen were
finally produced in the overall yields of 71% and 67%, respectively.
Keywords: linear furocoumarins, 4-methylpsoralen, psoralen, Swern oxidation
INTRODUCTION
Furocoumarins, such as psoralen (linear furocoumarins) and isopsoralen
(angular furocoumarins), are natural compounds that exhibit a variety of
biological activities.[1] Psoralen 1a is a typical representative of linear
Received in Japan March 16, 2006
Address correspondence to Jian-Min Yue, State Key Laboratory of Drug Research,
Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese
Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai
201203, China. E-mail: jmyue@mail.shcnc.ac.cn
63

64
B.-L. Zhang, F.-D. Wang, and J.-M. Yue
furocoumarins, and its derivatives are well-known photosensitizing drugs for
the treatment of some skin diseases (e.g., psoriasis, vitiligo, mycosis, and
eczema)[2] as well as fungus, viral, and bacterial infections.[3] Some its deriva-
tives are also used as biological probes to investigate of the structure and
function of nucleic acid in the field of molecular biology.[4] Recently, it was
reported that psoralen derivatives had applications in the treatment of
cutaneous T-cell lymphoma,[5] human immunodeficiency disease,[6] and pre-
vention of rejection of organ transplants.[7] Their action mechanism was
proposed to cause DNA damage and hinder cellular replication.[8]
Several synthetic methods have been developed to construct linear
furocoumarins since 1934.[9] These synthetic routes involve multiple steps to
construct the two heterocyclic rings from a central aromatic core and need pro-
tection and deprotection procedures to control regioselectivity, which mostly
results in low overall yields, especially in the syntheses of compounds 1 with
an unsubstituted furan ring.[10–15] To develop more efficient methods for the
syntheses of furocoumarins, Chimichi et al.[16] recently reported a base-
catalyzed cyclization reaction to construct the unsubstituted furan ring, and
this five-step method showed high regioselectivity and gave a good yield.
Some novel synthetic strategies were also developed, such as the intramolecu-
lar Diels–Alder reaction[17] and anionic [4 þ 2] cycloaddition method,[18]
aiming to build up the central aromatic part, but the overall yields were unsa-
tisfactory. We report herein a more efficient strategy for the syntheses of 1a
and 1b in three steps to give the overall yields of 71% and 67%, respectively.
RESULTS AND DISCUSSION
The strategy for the synthesis of psoralen and 4-methylpsoralen is outlined in
Scheme 1. Coumarinyloxyalcohols 3a and 3b were prepared in high yields of
96% and 94% by the alkylation of 7-hydroxycoumarin 2a and 7-hydroxy-4-
Scheme 1. Synthesis of psoralen (1a) and 4-methylpsoralen (1b). Reagents and con-
ditions: (i) 2-chloroethanol, K2CO3, cat, KI, DMF, 1108; (ii) oxidation; (iii) NaOH-
H2O, reflux.

Synthesis of Linear Furocoumarins
65
methylcoumarin 2b, respectively, with 2-chloroethanol in dried DMF (1108C)
in the presence of anhydrous K2CO3 (1.5 eq) and a catalytic amount of KI.
Subsequently, compounds 3a and 3b were oxidized to the key intermediates
4a and 4b, respectively, by an optimized reaction condition in excellent
yields. With intermediates 4a and 4b in hand, the desired compounds 1a
and 1b were finally synthesized by a NaOH-catalyzed cyclization procedure
in the overall yields of 76% and 74%, respectively. To get a homogeneous
solution of aldehydes 4a,b for the easy addition, a mixture of solvents
(H2O–dioxane ¼ 1 : 1) was thus applied. The other reaction conditions were
similar to those of Chimichi’s method.[16]
The crucial step is the transformation of compounds 3a and 3b to the key
intermediates 4a and 4b, respectively, by an oxidative procedure. A number of
oxidants, such as PCC,[19] BaMnO4,[20] DMSO-trifluoroacetic anhydride
(TFAA), and DMSO-(COCl)2 (Swern oxidation)[21] were applied under
different oxidation conditions, aiming to improve the reaction yields of 4a
and 4b (Table 1). In this optimization process, the oxidant PCC was the
first choice, but it gave a mixture of 4a and 5 (Table 1, Entry 1) in
moderate yield at room temperature, and compound 5 was an undesired
product. By using a smaller amount of PCC and silica or alumina as
supported reagent, the popular regimes to improve the selectivity for such a
reaction, the products still afforded mixtures and the selectivity was only
slightly improved. The oxidation of 3a with PCC at a temperature of 08C
Table 1. Syntheses of 4 from 3 at different oxidation conditions
Oxidation
regimes
Yields
(%)a
Entry
1
Substrates
Products
3a
PCCb
4a
5
23
30
32
28
30
25
0
2
3
3a
3a
PCC-Silicab
4a
5
PCC-Aluminab
4a
5
4
5
6
7
8
9
3a
3a
3a
3b
3a
3b
BaMnO4
BaMnO4
NRe
4a
4a
4b
4a
4b
c
d
,5
52
54
97
96
DMSO-TFAA
DMSO-TFAA
DMSO-(COCl)2
DMSO-(COCl)2
aIsolated yields, except for entry 5.
bReactions were carried out in CH2Cl2 at 258C (1.5 eq PCC),
monitored by TLC until the starting material was fully reacted.
cRefluxing in CH2Cl2 for 24 h.
dRefluxing in toluene for 24 h.
eNo reaction observed as monitored by TLC.

66
B.-L. Zhang, F.-D. Wang, and J.-M. Yue
was also tried, but the reaction did not happened after 24 h. The oxidation of
3a with BaMO4 was conducted using a normal procedure; the starting material
was kept unreacted, and when refluxed in CH2Cl2 or toluene, only a small
amount of 3a were transformed to 4a (Table 1, Entry 5). Fortunately, with
the application of DMSO-based oxidation conditions as the alternatives, 3a
was smoothly transformed to 4a in good yield, especially under the Swern
oxidation condition using (COCl)2 to activate DMSO. Both the 3a and 3b
were smoothly oxidized to give 4a and 4b respectively in almost quantitative
yield (.95%, Table 1, entries 8 and 9). The physical and spectroscopic data of
all the products are in good agreement with those reported in the literature.
In summary, a concise synthetic approach to synthesize the biologically
active linear furocoumarins has been developed from the readily available
7-hydroxycoumarin derivatives involving the Swern oxidation as the key
step. This research work has afforded an efficient method for the syntheses
of 1a and 1b in three steps to give overall yields of 71% and 67%, respectively.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker AM-400 spectrometer using TMS
as internal standard. IR spectra were recorded on a Nicolet Magna 750 spec-
trometer, and only characteristic absorptions were reported. EI mass spectra
were performed on a Finnigan MAT-95 spectrometer. All the oxygen- or
moisture-sensitive reactions were carried out under a nitrogen atmosphere.
Dichloromethane, triethylamine, DMSO, and DMF were distilled from
calcium hydride immediately prior to use. 7-hydroxycoumarin 2a and
7-Hydroxycoumarin 2b were commercially available or prepared easily by
the literature method.[22]
General Procedure for the Preparation of Alcohols 3a and 3b
A mixture of hydroxycoumarins 2 (10 mmol), potassium carbonate (2.07 g,
15 mmol), 2-chloroethanol (1.62 g, 20 mmol), and KI (80 mg) in DMF
(50 mL) was heated to 1108C, stirred overnight under a nitrogen atmosphere,
and monitored by thin-layer chromatography (TLC) until the starting material
was fully reacted. After cooling to room temperature, 50 mL of water was
added and extracted with ethyl acetate (3 ꢀ 50 mL). The combined organic
phase was first washed with water (3 ꢀ 20 mL) and then brine (20 mL) and
dried over anhydrous Na2SO4. After removal of solvent, the crude product
was purified by a flash chromatography to give the desired alcohols 3.
Data
3a: white solid; 1.97 g (96%); mp 93–948C [lit.[23] 92.5–93.58C]; 1H
NMR (300 M, CDCl3) d 7.64 (d, J ¼ 9.7 Hz, 1H), 7.39 (d, J ¼ 8.7 Hz, 1H),

Synthesis of Linear Furocoumarins
67
6.90–6.84 (m, 2H), 6.27 (d, J ¼ 9.7 Hz, 1H), 4.15 (t, J ¼ 8.7 Hz, 2H), 4.09
(m, 2H), 2.12 (t, J ¼ 12.3 Hz, 1H); EI-MS m/z (%) 206 (Mþ, 85), 162 (80),
134 (100), 105 (10), 89 (15); IR (KBr): 3554, 3407, 3076, 2945, 1693, 1612,
845 cm21. Anal. calcd. for C11H10O4: C, 64.08; H, 4.89. Found: C, 64.24;
H, 4.83.
3b: white needles; 2.06 g (94%); mp 146–1478C; 1H NMR (300 M, CDCl3) d
7.51 (d, J ¼ 9.0 Hz, 1H), 6.91–6.83 (m, 2H), 6.15 (q, J ¼ 3.6 Hz, 1H), 4.15
(m, 2H), 4.01 (m, 2H), 2.40 (dd, J ¼ 3.6 Hz, J ¼ 1.8 Hz, 3H); 2.07
(t, J ¼ 12.0 Hz, 1H); EI-MS m/z (%) 220 (Mþ, 70), 176 (55), 148 (100),
103 (10); IR (KBr): 3442, 3070, 2956, 1709, 1620, 847 cm21. Anal. calcd.
for C12H12O4: C, 65.45; H, 5.49. Found: C, 65.28; H, 5.42.
General Procedure for the Preparation of Aldehydes 4a and 4b
A solution of oxalyl chloride (0.252 g, 2 mmol) in anhydrous CH2Cl2 (5 mL)
was cooled to 2788C under a nitrogen atmosphere, and a solution of DMSO
(0.156 g, 2 mmol) in CH2Cl2 (2 mL) was added dropwise (the temperature
was kept below 2658C), and stirred for 10 min. A solution of alcohols 3
(1 mmol) in CH2Cl2 (15 mL) was added dropwise at a temperature below
2658C and stirred for another 30 min. Triethylamine (0.505 g, 5 mmol) was
then added dropwise. The reaction mixture was stirred for 15 min at a temp-
erature below 2658C and allowed to warm up to room temperature. The
reaction mixture was diluted with CH2Cl2 and filtered through a pad of
silica gel. Removal of the solvent under vacuum afforded the aldehydes 4a
and 4b.
Data
[16b]
4a: white solid; 0.197 g (97%); mp 124–1268C [lit.
1H NMR (400 M, DMSO-d6)
125–1278C];
d
9.64 (t, J ¼ 1.2 Hz, 1H), 7.98
(d, J ¼ 9.6 Hz, 1H), 7.62 (d, J ¼ 8.4 Hz, 1H), 7.01–6.94 (m, 2H), 6.29
(d, J ¼ 9.2 Hz, 1H), 5.02 (s, br, 2H); EI-MS m/z (%) 204 (Mþ, 100), 175
(70), 162 (30), 145 (65), 89 (40); IR (KBr): 3439, 2854, 1751, 1731, 1602,
837 cm21
.
4b: white solid; 0.21 g (96%); mp 143–1448C [lit.[16b] 144–1468C]; 1H NMR
(400 M, CDCl3) d 9.88 (s, 1H), 7.56 (d, J ¼ 8.8 Hz, 1H), 6.92 (dd, J ¼ 8.8 Hz,
J ¼ 2.4 Hz, 1H), 6.81 (d, J ¼ 2.4 Hz, 1H), 6.19 (d, J ¼ 0.8 Hz, 1H), 4.69
(s, 2H), 2.42 (d, J ¼ 0.8 Hz, 3H); EI-MS m/z (%) 218 (Mþ, 100), 189 (45),
176 (45), 159 (50), 147 (60), 103(40); IR (KBr): 3430, 2922, 2854, 1720,
1618, 1392, 847 cm21
.

68
B.-L. Zhang, F.-D. Wang, and J.-M. Yue
5: white solid; mp 194–1958C; 1H NMR (400 M, CDCl3) d 7.66
(d, J ¼ 9.6 Hz, 1H), 7.63 (d, J ¼ 9.6 Hz, 1H), 7.42 (d, J ¼ 8.0 Hz, 1H),
7.40 (d, J ¼ 8.0 Hz, 1H), 6.92–6.76 (m, 2H), 6.77 (s, 1H) 6.76 (s, 1H), 6.29
(d, J ¼ 9.6 Hz, 1H), 6.26 (d, J ¼ 9.6 Hz, 1H), 4.77 (s, 2H), 4.64
(t, J ¼ 9.2 Hz, 2H), 4.26 (t, J ¼ 9.2 Hz, 2H); EI-MS m/z (%) 408 (Mþ, 40),
247 (100), 175 (40), 86 (20); IR (KBr): 3086, 1740, 1728, 1614, 847 cm21
Anal. calcd. for C22H16O8: C, 64.71; H, 3.95. Found: C, 64.87; H, 3.92.
.
General Procedure for the Cyclization Reactions
A solution of aldehydes 4a or 4b (0.5 mmol) in H2O-dioxane (1:1, 3 mL) was
added dropwise to a refluxing aqueous solution of NaOH (1.0 M, 10 mL)
under stirring for more than 30 minutes. The resulted mixture was stirred at
reflux for an additional 4 h and then cooled down to room temperature. The
solution was acidified to pH , 3 with 85% phosphoric acid and left
overnight. The resultant mixture was extracted with EtOAc (3 ꢀ 50 mL).
The organic phase was then washed with brine (3 ꢀ 20 mL) and dried over
anhydrous Na2SO4. After removal of the solvents, the residue was purified
by flash chromatography on silica gel eluted with petroleum ether–acetone
(4 : 1) to afford the compound 1a or 1b.
Data
1a: white solid; 71 mg (76%); mp 162–1638C [lit.[16a] 161–1628C]; 1H NMR
(400 M, CDCl3) d 7.81 (d, J ¼ 9.6 Hz, 1H), 7.70 (d, J ¼ 1.2 Hz, 1H), 7.69
(s, 1H), 7.49 (s, 1H), 6.84 (d, J ¼ 1.2 Hz, 1H), 6.39 (d, J ¼ 9.6 Hz, 1H); EI-
MS m/z (%) 186 (Mþ, 100), 158 (90), 130 (30), 102 (40); IR (KBr): 3157,
1720, 1633, 1286, 1136, 750 cm21
.
1b: white needles; 74 mg (74%); mp 187–1888C (crystallization in acetone)
1
[lit.[16a] 177–1788C, lit.[24] 185–1868C]; H NMR (400 M, CDCl3) d 7.82
(s, 1H), 7.69 (d, J ¼ 2.4 Hz, 1H), 7.48 (d, J ¼ 0.4 Hz, 1H), 6.86 (dd,
J ¼ 2.4 Hz, J ¼ 0.4 Hz, 1H), 6.27 (d, J ¼ 1.2 Hz, 1H), 2.51 (d, J ¼ 1.2 Hz,
3H); EI-MS m/z (%) 200 (Mþ, 100), 172 (70), 171 (75), 144 (10), 115
(25); IR (KBr): 3161, 1724, 1631, 1385, 746 cm21
.
ACKNOWLEDGMENT
National Natural Science Foundation of China (No. 30025044), Foundation
from the Ministry of Science and Technology of China (No. 2002CB512807),
and Shanghai Municipal Scientific Foundation (Nos. 03DZ19529 and
04XD14019) are gratefully acknowledged.

Synthesis of Linear Furocoumarins
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