Studies in synthesis of new psoralenamines

Article abstract of DOI:10.1002/jhet.327

(Chemical Equation Presented) New amino psoralen derivatives have been synthesized via bromination. Bromination of 3,5-substituted psoralens has been studied. The second position of the furan ring is more susceptible to bromination than the α-position of

Full text of DOI:10.1002/jhet.327

March 2010
Studies in Synthesis of New Psoralenamines
379
Jagdish M. Patel and Shubhangi S. Soman*
Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda,
Vadodara 390 002, India
*E-mail: shubhangiss@rediffmail.com
Received July 22, 2009
DOI 10.1002/jhet.327
Published online 4 March 2010 in Wiley InterScience (www.interscience.wiley.com).
New amino psoralen derivatives have been synthesized via bromination. Bromination of 3,5-substi-
tuted psoralens has been studied. The second position of the furan ring is more susceptible to bromina-
tion than the a-position of the chromen-2-one ring in psoralens. Hence, the target psoralenamines were
synthesized starting with 3-bromo-7-hydroxy-4-methyl-chromen-2-one, which was condensed with dif-
ferent a-halo ketones and cyclized in ethanolic potassium hydroxide to get the desired 6-bromo psora-
lens, which were finally converted into psoralenamines.
J. Heterocyclic Chem., 47, 379 (2010).
INTRODUCTION
study was undertaken to synthesize some new amino
psoralen derivatives via bromination. Moreover, it was
of considerable interest to study the reactivity and orien-
tation of 3,5-substituted psoralens toward bromination.
Although it is evident that the third position of furan
ring in psoralens is the most reactive towards electro-
philic substitution, the behaviour of psoralens in which
the third position is blocked has not been reported for
bromination. The synthetic pathway followed by
MacLeod et al. [8] has been employed to prepare the
title compounds as outlined in Scheme 1.
Furocoumarins such as Psoralens (5-methoxy psoralen
or bergapton, 8-methoxy psoralen or xanthotoxin, 4,50,8-
trimethyl psoralen) are well known photosensitizing
drugs used in Psoralen Ultra Violet-A therapy for the
treatment of dermatological disorders, such as psoriasis,
vitiligo, mycosis, and atropic eczema [1]; as well as fun-
gal, viral, and bacterial infections [2]. Recently, Psoralen
derivatives have also been used in the treatment of cuta-
neous T-cell lymphoma [3], human immunodeficiency
diseases [4], and prevention of rejection of organ trans-
plants [5]. Introduction of aminomethyl group in furo-
coumarins enhances antibacterial activity [6]. Amino-
psoralens are used for nucleic acid probe preparations,
preparation of conjugates, inhibition of cell proliferation,
inactivation of virus for vaccine preparation, and in par-
ticular, for the inactivation of pathogens in blood prod-
ucts [7].
RESULTS AND DISCUSSION
b-Methyl umbelliferone (7-hydroxy-4-methyl-chro-
men-2-one) 1, [9] was condensed with different a-halo-
ketones, e.g., mono chloroacetone and phenacylbromide
to give the aryloxyketones 2 which when subjected to
cyclization in 0.1N ethanolic potassium hydroxide gave
the corresponding furocoumarin (psoralen) 3 as shown
Because of the wide spread and increasing interest in
aminopsoralens for their pharmacological action, this
C
V
2010 HeteroCorporation

380
J. M. Patel and S. S. Soman
Vol 47
Scheme 1
in Scheme 1. Furocoumarin 3 was brominated with bro-
mine in acetic acid to get the desired 6-bromo psoralen,
mine at CA6 position. Further doublets at d 7.50 ppm
(1H, J ¼ 1.6 Hz) for C2AH and d 2.31–2.32 ppm (3H,
J ¼ 1.6 Hz) for C3ACH3 corroborated the structure 7a.
The mass spectrum (LCMS) was obtained as m/z (rela-
tive intensity, 100%): 317 (8.88) Mþ23 (from Naþ),
295.1 (100) Mþ1, 292.9 (100) Mþ using mobile phase
Acetonitrile: Ammonium acetate 1 mM (90:10% v/v).
The UV spectrum in dichloromethane showed absorp-
tion at 282, 302, 323, 331, 342, 355, and 362 nm. Cycli-
zation of 3-bromo aryloxyketones 6 to 6-bromo psora-
lens 7 was the bottleneck of the process. Cyclization in
0.1N ethanolic potassium hydroxide at reflux tempera-
ture lowered the over all yield of the reaction drastically
due to the formation of mixture of products. One of the
product was identified as furocoumarilic acid formed
due to alkaline ring contraction [11], which has been
1
but from the H nuclear magnetic resonance (NMR) it
was revealed that the product formed was 2-bromo psor-
alen 4. This shows that the second position of the furan
ring is more reactive towards halogenation compared to
the a-position of the chromen-2-one ring in psoralens.
In the 1H-NMR of compound 2-bromo-3,5-dimethyl-
furo[3,2-g]chromen-7-one 4a, signal at d 6.27–6.28 ppm
corresponding to one proton for C6AH (or a-H of chro-
men-2-one) and the absence of signal at d 7.5 ppm for
C2AH proton alongwith C3ACH3 signal at d 2.24 ppm
confirmed the structure. The UV spectrum in dichloro-
methane showed absorption at 284, 302, 324, 333, 340,
and 347 nm. Consequently, the target amino psoralens
could not be prepared.
1
In a slightly modified methodology, b-methyl umbel-
liferone (7-hydroxy-4-methyl-chromen-2-one) 1 was first
brominated using bromine in acetic acid to give 3-
bromo-7-hydroxy-4-methyl-chromen-2-one 5 [10] in an
addition-elimination reaction, which was then condensed
with different a-halo ketones and cyclized to 6-bromo
psoralens 7 in a similar fashion as shown in Scheme 1.
In the 1H NMR of compound 6-bromo-3,5-dimethyl-
furo[3.2-g]chromen-7-one 7a, the absence of signal at d
6.28 ppm for C6AH proton and singlet for C5ACH3
signal at d 2.74 ppm confirmed the substitution of bro-
confirmed from the H NMR and infrared (IR) spectra
of 3-methyl-5-phenyl-benzo[1,2-b;5,4-b0]difuran-2-car-
boxylic acid 12 obtained during cyclization of 3-bromo-
4-methyl-7-(2-oxo-2-phenyl-ethoxy)-chromen-2-one 6b.
The furocoumarilic acid was obtained as white amor-
phous powder; mp 250ꢀC dec. and whose sodium and
potassium salts are hydrophobic. The other product
was identified as 6-ethoxy-5-methyl-3-phenyl-furo[3,2-
g]chromen-7-one 13 formed by nucleophilic attack of
1
ethanol, which also has been confirmed from H NMR.
The yield of 6-bromo psoralen was lowered due to these
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Studies in Synthesis of New Psoralenamines
381
gel G plates using UV/Iodine vapour as visualizing agent and
Acme’s silica gel (60–120 mesh) was used for column chro-
matographic purification. Elemental analyses were carried out
on Perkin-Elmer C, H, N, S analyzer (Model-2400). IR spectra
were recorded on Perkin-Elmer FTIR spectrometer (spectrum
RX1) using potassium bromide optics. UV spectra were
recorded on Perkin Elmer Lambda 35 UV/Vis spectrophotome-
ter. The mass spectrum was obtained on Perkin-Elmer Sciex
Triple Quadrupole LC/MS/MS Mass Spectrometer (Model-
016932) using Ion Spray source. NMR spectra were recorded
on Brucker 400 MHz. Spectrophotometer. Chemical shifts are
relative to tetramethylsilane on d-scale. Coupling constants are
given in Hz and relative peak areas were in agreement with all
assignments.
side reactions. Weaker bases like tri ethylamine and po-
tassium carbonate failed to give the expected results.
Cyclization in polyphosphoric acid and phosphorus (III)
oxychloride failed. Even the idea of first condensing 3-
bromo aryloxyketones 6 with amines, followed by
cyclization to yield amino psoralens failed, since the
cyclization reaction gave several decomposition prod-
ucts. Condensation of 3-bromo-4-methyl-7-(2-oxy-pro-
poxy)-chromen-2-one 6a with morpholine gave 4-mor-
pholin-4-ylmethyl-7-(2-oxo-propoxy)-chromen-2-one 11
1
as confirmed from H NMR, but could not be cyclized
as shown in Scheme 1. Consequently the concentration
of ethanolic potassium hydroxide was reduced from 0.1
to 0.025N and the cyclization of 3-bromo aryloxyke-
tones 6 to 6-bromo psoralens 7 was carried out at 65–
70ꢀC, which gave the desired results. Finally, 6-bromo
psoralens were condensed with different amines to give
General procedure for the preparation of 2a, 2b, 6a and
6b. To a stirred solution of 7-hydroxy-4-methyl-chromen-2-
one 1 (5 g, 0.028 moles), anhydrous potassium carbonate (4.90
g, 0.035 moles) and catalytic amount(0.05–0.1g) of potassium
iodide in (40 mL) of dry acetone was added dropwise a solu-
tion of mono chloroacetone (2.62 g, 0.028 moles) in (20 mL)
dry acetone at reflux temperature. It was refluxed for 12 h.
The reaction mixture was concentrated to dryness and then
poured into ice water and the solid collected by filtration. The
crude product was crystallized from ethanol to give white crys-
tals (3 g, 46%) of 4-methyl-7-(2-oxo-propoxy)-chromen-2-one
1
the corresponding amino methyl psoralens (8, 9, 10). H
NMR of compound 3-methyl-5-piperidin-1-ylmethyl-
furo[3,2-g]chromen-7-one 8a showed singlets at d 6.51
ppm corresponding to one proton for C6AH proton and
d
3.66 ppm corresponding to two protons for
2a, mp 154–156ꢀC lit. [12] 157ꢀC; IR (KBr): mmax, cmꢁ1
:
3061, 1705, 1609, 1591, 1454, 1384, 1360, 1288, 1220, 1166,
C5ACH2A, which confirmed the formation of 5-amino
methyl psoralens. In the 13C NMR, d values 99.59 ppm
for C6 and 59.91 ppm for C5ACH2A further confirmed
the structure. The UV spectrum in dichloromethane
showed absorption at 281, 301, 305, 329, 337 nm. The
mass spectrum (LCMS) for 3-methyl-5-morpholin-4-
ylmethyl-furo[3,2-g]chromen-7-one 9a. was obtained as
m/z (relative intensity, 100%): 338.1 (7.27) Mþ39 (from
Kþ), 322.2 (38.18) Mþ23 (from Naþ), 301.2 (70.90)
Mþ2, 299.9 (100) Mþ1 using mobile phase acetonitri-
le:ammonium acetate 1 mM (90:10% v/v).
1
958; H NMR (CDCl3, 400 MHz): d 2.32 (d, 3H, J ¼ 0.8 Hz,
C4ACH3), 2.42 (s, 3H, ACOCH3), 4.66 (s, 2H, AOCH2COA),
6.18 (d, 1H, J ¼ 0.8 Hz, C3AH), 6.77–6.78 (d, 1H, J ¼ 2.8
Hz, C8AH), 6.89–6.92 (dd, 1H, J ¼ 2.8 Hz and J ¼ 8.8 Hz,
C6AH), 7.54–7.56 (d, 1H, J ¼ 8.8 Hz, C5AH). Anal. calcd.
for C13H12O4 (232.23): C, 67.23; H, 5.20. Found: C, 67.02; H,
5.11. Potassium iodide is not required for the preparation of
compounds 6a and 6b.
4-Methyl-7-(2-oxo-2-phenyl-ethoxy)-chromen-2-one (2b). This
compound was obtained by column chromatographic purifica-
tion using petroleum ether (60–80ꢀC): ethyl acetate eluent, as
white crystals, 43% yield, mp 169–171ꢀC lit. [13] 173ꢀC; IR
(KBr): mmax, cmꢁ1: 3071, 1698, 1612, 1596, 1451, 1391, 1366,
1283, 1230, 1160, 968; 1H NMR (CDCl3, 400 MHz): d 2.34
(d, 3H, J ¼ 0.9 Hz, C4ACH3), 4.58 (s, 2H, AOCH2COA),
6.19 (d, 1H, J ¼ 0.9 Hz, C3AH), 6.79–6.80 (d, 1H, J ¼ 2.8
Hz, C8AH), 6.89–6.93 (dd, 1H, J ¼ 2.8 Hz and J ¼ 8.8 Hz,
C6AH), 7.52–7.68 (m, 6H, C5AH and C20-H to C60-H phenyl
protons). Anal. calcd. for C18H14O4 (294.30): C, 73.46; H,
4.79. Found: C, 72.99; H, 4.34.
The structures of all compounds have been estab-
lished on the basis of their elemental analyses and spec-
tral (IR, NMR) data.
3-Bromo-4-methyl-7-(2-oxy-propoxy)-chromen-2-one (6a). This
compound was obtained as white crystals (DMF/ethanol), 68%
yield, mp 204–206ꢀC; IR (KBr): mmax, cmꢁ1: 3062, 2910,
1719, 1698, 1628, 1593, 1392, 1218; 1H NMR (CDCl3, 400
MHz): d 2.32 (s, 3H, C4ACH3), 2.62 (s, 3H, ACOCH3), 4.67
(s, 2H, AOCH2COA), 6.78–6.79 (d, 1H, J ¼ 2.4 Hz, C8AH),
6.92–6.95 (dd, 1H, J ¼ 2.4 Hz and J ¼ 9.2 Hz, C6AH), 7.60–
7.62 (d, 1H, J ¼ 9.2 Hz, C5AH). Anal. calcd. for C13H11O4Br
(311.12): C, 50.18; H, 3.56. Found: C, 50.06; H, 3.23.
3-Bromo-4-methyl-7-(2-oxo-2-phenyl-ethoxy)-chromen-2-
one (6b). This compound was obtained as white crystals (tolu-
ene), 63% yield, mp 181–182ꢀC; IR (KBr): mmax, cmꢁ1: 3060,
EXPERIMENTAL
1
Melting points (uncorrected) were determined using a scien-
tific capillary melting point apparatus. Purity of the compounds
was checked by thin layer chromatography on Acme’s silica
2907, 1717, 1698, 1623, 1598, 1384, 1210; H NMR (CDCl3,
400 MHz):
d 2.36 (s, 3H, C4ACH3), 4.61 (s, 2H,
AOCH2COA), 6.79–6.80 (d, 1H, J ¼ 2.4 Hz, C8AH), 6.93–
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J. M. Patel and S. S. Soman
Vol 47
6.95 (dd, 1H, J ¼ 2.4 Hz and J ¼ 9.2 Hz, C6AH), 7.50–7.66
(m, 6H, C5AH and C20-H to C60-H phenyl protons). Anal.
calcd. for C18H13O4Br (373.20): C, 57.93; H, 3.51. Found: C,
57.61; H, 3.31.
General procedure for the preparation of 3a, 3b, 7a and
7b. Compound 4-methyl-7-(2-oxo-propoxy)-chromen-2-one 2a
(1 g, 0.0043 moles) was dissolved in 0.1N ethanolic potassium
hydroxide (100 mL) and refluxed for 12 h. The excess ethanol
was removed by distillation in vacuo and the reaction mixture
was poured into ice-hydrochloric acid and the solid collected
by filtration. The crude product was crystallized from ethanol
to give white crystals (0.38 g, 41%) of 3,5-dimethyl-furo[3,2-
g]chromen-7-one 3a, mp 224–226ꢀC lit. [12] 220ꢀC; IR (KBr):
men-7-one 4a, mp 230–232ꢀC; IR (KBr): mmax, cmꢁ1: 3085,
1758, 1689, 1640, 1577, 1341, 1121; 1H NMR (CDCl3, 400
MHz): d 2.24 (s, 3H, C3ACH3), 2.52 (d, 3H, J ¼ 1.08 Hz,
C5ACH3), 6.27–6.28 (d, 1H, J ¼ 1.08 Hz, C6AH), 7.36 (s,
1H, C9AH), 7.58 (s, 1H, C4AH). Anal. calcd. for C13H9O3Br
(293.11): C, 53.27; H, 3.09. Found: C, 52.98; H, 3.11.
2-Bromo-5-methyl-3-phenyl-furo[3,2-g]chromen-7-one (4b). This
compound was obtained as yellow crystals (ethanol), 61%
yield, mp 238–239ꢀC; IR (KBr): mmax, cmꢁ1: 3084, 1750,
1
1686, 1636, 1578, 1347, 1110; H NMR (CDCl3, 400 MHz): d
2.46 (d, 3H, J ¼ 1.05 Hz, C5ACH3), 6.28 (d, 1H, J ¼ 1.05
Hz, C6AH), 7.47–7.64 (m, 6H, C3Aphenyl protons and
C9AH), 7.75 (s, 1H, C4AH). Anal. calcd. for C18H11O3Br
(355.18): C, 60.86; H, 3.12. Found: C, 60.82; H, 2.94.
m
max, cmꢁ1: 3090, 1728, 1639, 1610, 1580, 1388, 1144, 1082;
1H NMR (CDCl3, 400 MHz): d 2.21–2.22 (d, 3H, J ¼ 1.5 Hz,
C3ACH3), 2.51–2.52 (d, 3H, J ¼ 1.08 Hz, C5ACH3), 6.27–
6.28 (d, 1H, J ¼ 1.08 Hz, C6AH), 7.36 (s, 1H, C9AH), 7.52
(d, 1H, J ¼ 1.5 Hz, C2AH), 7.58 (s, 1H, C4AH). Anal. calcd.
for C13H10O3 (214.21): C, 72.88; H, 4.70. Found: C, 72.62; H,
4.51.
General procedure for the preparation of 8a, 8b, 9a, 9b,
10a and 10b. A solution of 6-bromo-3,5-dimethyl-furo[3.2-
g]chromen-7-one 7a (0.5 g, 0.0017 moles) and piperidine (0.35
mL, 0.0035 moles) in dry DMF (10 mL) was heated at 95–
100ꢀC for 1 hour. The reaction mixture was poured into ice
water and the solid collected by filtration. The crude product
was crystallized from ethanol to give light brown crystals
(0.28 g, 55%) of 3-methyl-5-piperidin-1-ylmethyl-furo[3,2-
g]chromen-7-one 8a, mp 185ꢀC; IR (KBr): mmax, cmꢁ1: 3059,
2971, 1718, 1639, 1616, 1579, 1454, 1337, 1158, 1120, 1096;
1H NMR (CDCl3, 400 MHz): d 1.47–1.48 (t, 2H, C40ACH2-),
1.59–1.65 (m, 4H, C30ACH2- and C50ACH2A), 2.27–2.28 (d,
3H, J ¼ 1.2 Hz, C3ACH3), 2.51 (t, 4H, C20ACH2- and
C60ACH2A), 3.66 (s, 2H, C5ACH2A), 6.51 (s, 1H, C6AH),
7.35 (s, 1H, C9AH), 7.43–7.44 (d, 1H, J ¼ 1.2 Hz, C2AH),
7.92 (s, 1H, C4AH); 13C NMR (CDCl3, 100 MHz): d 7.84
(C2ACH3), 24.10 (C30 and C50), 26.07 (C40), 55.05 (C20 and
C60), 59.91 (C5ACH2A), 99.59 (C6), 112.51 (C9), 114.92–
115.73 (C4, C4a and C3), 126.23 (C3a), 143 (C2), 151.86
(C8a), 153.04 (C9a), 156.42 (C5), 161.57 (C7). Anal. calcd.
for C18H19O3N (297.35): C, 72.70; H, 6.44; N, 4.71. Found:
C, 72.56; H, 6.18; N, 4.44.
In the preparation of compounds 7a and 7b the concentra-
tion of ethanolic potassium hydroxide was reduced from 0.1 to
0.025N and the reaction was maintained at 65–70ꢀC for 12 h.
5-Methyl-3-phenyl-furo[3,2-g]chromen-7-one (3b). This
compound was obtained as white crystals (ethanol), 41% yield,
mp 181–182ꢀC lit. [13] 185ꢀC; IR (KBr): mmax, cmꢁ1: 3090,
1
1720, 1632, 1612, 1575, 1385, 1142, 1075; H NMR (CDCl3,
400 MHz): d 2.48–2.49 (d, 3H, J ¼ 1.1 Hz, C5ACH3), 6.29–
6.30 (d, 1H, J ¼ 1.1 Hz, C6AH), 7.48–7.49 (m, 1H, C40-H),
7.54–7.59 (m, 2H, C30-H and C50-H), 7.54 (s, 1H, C2AH),
7.65–7.67 (m, 2H, C20-H and C60-H), 7.86 (s, 1H, C9AH),
7.90 (s, 1H, C4AH). Anal. calcd. for C18H12O3 (276.28): C,
78.25; H, 4.37. Found: C, 77.85; H, 4.30.
6-Bromo-3,5-dimethyl-furo[3.2-g]chromen-7-one (7a). This
compound was obtained as yellow crystals (toluene), 30%
yield, mp 224–226ꢀC; IR (KBr): mmax, cmꢁ1: 3088, 2925,
1733, 1693, 1639, 1602, 1556, 1350, 1151, 1074; 1H NMR
(CDCl3, 400 MHz): d 2.31–2.32 (d, 3H, J ¼ 1.6 Hz,
C3ACH3), 2.74 (s, 3H, C5ACH3), 7.42 (s, 1H, C9AH), 7.50
(d, 1H, J ¼ 1.6 Hz, C2AH), 7.74 (s, 1H, C4AH); LCMS: m/z
(relative intensity, 100%): 317 (8.88) Mþ23 (from Naþ),
295.1 (100) Mþ1, 292.9 (100) Mþ. Anal. calcd. for
C13H9O3Br (293.11): C, 53.27; H, 3.09. Found: C, 52.98; H,
3.11.
6-Bromo-5-methyl-3-phenyl-furo[3,2-g]chromen-7-one
(7b). This compound was obtained as yellow crystals (etha-
nol), 24% yield, mp 208–210ꢀC; IR (KBr): mmax, cmꢁ1: 3085,
2925, 1734, 1687, 1631, 1605, 1559, 1345, 1154, 1070; 1H
NMR (CDCl3, 400 MHz): d 2.69 (s, 3H, C5ACH3), 7.47–7.49
(m, 1H, C40-H), 7.54–7.58 (m, 2H, C30-H and C50-H), 7.56 (s,
1H, C2AH), 7.64–7.66 (m, 2H, C20-H and C60-H), 7.87 (s,
1H, C9AH), 8.02 (s, 1H, C4AH). Anal. calcd. for C18H11O3Br
(355.18): C, 60.86; H, 3.12. Found: C, 60.50; H, 3.07.
General procedure for the preparation of 4a and
4b. Compound 3,5-dimethyl-furo[3,2-g]chromen-7-one 3a
(1 g, 0.0046 moles) was dissolved in acetic acid (40 mL) by
warming and to this stirred solution, a solution of bromine
(0.24 mL, 0.0046 moles) in acetic acid (10 mL) was added
gradually. It was stirred for 3 h at room temperature and then
poured into ice water and the solid collected by filtration. The
crude product was crystallized from ethanol to give yellow
crystals (0.9 g, 66%) of 2-bromo-3,5-dimethyl-furo[3,2-g]chro-
3-Phenyl-5-piperidin-1-ylmethyl-furo[3,2-g]chromen-7-one
(8b). This compound was obtained by column chromato-
graphic purification using petroleum ether (60–80ꢀC): ethyl ac-
etate eluent, as light brown crystals, 52% yield, mp 158–
160ꢀC; IR (KBr): mmax, cmꢁ1: 3051, 2971, 1710, 1633, 1611,
1571, 1450, 1333, 1158, 1122, 1091; 1H NMR (CDCl3, 400
MHz):
d
1.51 (t, 2H, C40ACH2A), 1.64–1.66 (t, 4H,
C30ACH2A and C50ACH2-), 2.52 (t, 4H, C20ACH2- and
C60ACH2A), 3.67 (s, 2H, C5ACH2A), 6.52 (s, 1H, C6AH),
7.43–7.70 (m, 5H, C3Aphenyl protons), 7.55 (s, 1H, C2AH),
7.86 (s, 1H, C9AH), 8.50 (s, 1H, C4AH).
Anal. calcd. for C23H21O3N (359.42): C, 76.86; H, 5.88; N,
3.89. Found: C, 76.52; H, 5.61; N, 3.67.
3-Methyl-5-morpholin-4-ylmethyl-furo[3,2-g]chromen-
7-one (9a). This compound was obtained as light brown crys-
tals (DMF/ethanol), 60% yield, mp 236–238ꢀC; IR (KBr): mmax
,
cmꢁ1: 3060, 2969, 1719, 1632, 1611, 1577, 1455, 1337, 1153,
1115, 1094; 1H NMR (CDCl3, 400 MHz): d 2.30 (d, 3H, J ¼ 1.2
Hz, C3ACH3), 2.62–2.63 (t, 4H, C30ACH2A and C50ACH2A),
3.75–3.79 (m, 6H, C20ACH2A C60ACH2A & C5ACH2-), 6.56
(s, 1H, C6AH), 7.41 (s, 1H, C9AH), 7.48 (d, 1H, J ¼ 1.2 Hz,
C2AH), 7.92 (s, 1H, C4AH); lcms: m/z (relative intensity,
100%): 338.1 (7.27) Mþ39 (from Kþ), 322.2 (38.18) Mþ23
(from Naþ), 301.2 (70.90) Mþ2, 299.9 (100) Mþ1.
Anal. calcd. for C17H17O4N (299.32): C, 68.21; H, 5.72; N,
4.67. Found: C, 67.91; H, 5.56; N, 4.33.
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Studies in Synthesis of New Psoralenamines
383
(m, 2H, C20-H and C60-H), 7.63–7.66 (m, 3H, C6AH, C30-H
and C50-H), 7.93 (s, 1H, C4AH), 7.96 (s, 1H, C8AH).
Anal. calcd. for C18H12O4 (292.28): C, 73. 96; H, 4.13.
Found: C, 73.84; H, 4.03.
6-Ethoxy-5-methyl-3-phenyl-furo[3,2-g]chromen-7-one
(13). This compound was obtained by column chromato-
graphic purification using petroleum ether (60–80ꢀC): ethyl ac-
etate eluent, as white crystals, 55% yield, mp 169–171ꢀC; 1H
NMR (CDCl3, 400 MHz): d 1.46–1.50 (t, 3H, C6AOCH2CH3),
2.66 (s, 3H, C5ACH3), 4.46–4.51 (q, 2H, C6AOCH2CH3),
7.42–7.46 (m, 1H, C40-H), 7.52–7.56 (m, 2H, C20-H and C60-
H), 7.68–7.70 (m, 3H, C2AH, C30-H and C50-H), 7.81 (s, 1H,
C4AH), 7.94 (s, 1H, C9AH).
5-Morpholin-4-ylmethyl-3-phenyl-furo[3,2-g]chromen-7-
one (9b). This compound was obtained by column chromato-
graphic purification using petroleum ether (60–80ꢀC): ethyl
acetate eluent, as light brown crystals, 57%, mp 185–187ꢀC;
IR (KBr): mmax, cmꢁ1: 3057, 2966, 1712, 1632, 1606, 1573,
1
1454, 1330, 1152, 1115, 1091; H NMR (CDCl3, 400 MHz): d
2.64–2.66 (t, 4H, C30ACH2A and C50ACH2A), 3.76–3.79 (m,
6H, C20ACH2A C60ACH2- and C5ACH2A), 6.59 (s, 1H,
C6AH), 7.45–7.76 (m, 6H, C2AH and C3Aphenyl protons),
7.80 (s, 1H, C9AH), 8.13 (s, 1H, C4AH).
Anal. calcd. for C22H19O4N (361.39): C, 73.11; H, 5.29; N,
3.87. Found: C, 72.88; H, 5.10; N, 3.77.
3-Methyl-5-(4-phenyl-piperazin-1-ylmethyl)-furo[3,2-g]chromen-
7-one (10a). This compound was obtained as light brown crys-
Anal. calcd. for C20H16O4 (320.34): C, 74.98; H, 5.03.
Found: C, 74.73; H, 4.98.
tals (ethanol), 64% yield, mp 214–216ꢀC; IR (KBr): mmax
,
cmꢁ1: 3064, 2963, 1720, 1637, 1619, 1579, 1460, 1340, 1158,
1
1119, 1084; H NMR (CDCl3, 400 MHz): d 2.31 (d, 3H, J ¼
Acknowledgments. The authors are thankful to the Department
of Chemistry, The Maharaja Sayajirao University of Baroda for
providing the necessary facilities. One of the authors (JMP) is
thankful to UGC (Major project) and AICTE (National Doctoral
Fellowship), New Delhi for providing the financial assistance.
1.2 Hz, C3ACH3), 2.80 (t, 4H, C30ACH2- and C50ACH2ꢁ),
3.27–3.30 (t, 4H, C20ACH2- and C60ACH2A), 3.83 (s, 2H,
C5ACH2A), 6.60 (s, 1H, C6AH), 6.89–7.32 (m, 5H, N40-phe-
nyl protons), 7.45 (s, 1H, C9AH), 7.49 (d, 1H, J ¼ 1.2 Hz,
C2AH), 7.98 (s, 1H, C4AH).
Anal. calcd. for C23H22O3N2 (374.43): C, 73.77; H, 5.92; N,
7.48. Found: C, 73.51; H, 5.77; N, 7.09.
REFERENCES AND NOTES
3-Phenyl-5-(4-phenyl-piperazin-1-ylmethyl)-furo[3,2-
g]chromen-7-one (10b). This compound was obtained as
light brown crystals (ethanol/toluene), 62% yield, mp 180ꢀC
dec.; IR (KBr): mmax, cmꢁ1: 3061, 2963, 1713, 1631, 1611,
1578, 1450, 1337, 1157, 1108, 1088; 1H NMR (CDCl3, 400
MHz): d 2.79 (t, 4H, C30ACH2A and C50ACH2A), 3.3 (t, 4H,
C20ACH2A and C60ACH2A), 3.80 (s, 2H, C5ACH2A), 6.57
(s, 1H, C6AH), 6.92–7.68 (m, 10H, C3Aphenyl protons and
N40-phenyl protons), 7.55 (s, 1H, C2AH), 7.86 (s, 1H, C9AH),
8.45 (s, 1H, C4AH).
[1] Grundmann, K. M.; Ludwig, R.; Zollner, T. M.; Ochsen-
dorf, F.; Thaci, D.; Boehncke, W. H.; Krutmann, J.; Kaufmann, R.;
Podda, M. J Am Acad Dermatol 2004, 50, 734; Park, J. H.; Lee, M.
H. Int J Dermatol 2004, 43, 138; Petering, H.; Breuer, C.; Herbst, R.;
Kapp, A.; Werfel, T. J Am Acad Dermatol 2004, 50, 68.
[2] Diederen, P. V. M. M.; Weelden, H.; Sanders, C. J. G.;
Toonstra, J.; Vloten, W. A. J Am Acad Dermatol 2003, 48, 215;
Miolo, G.; Tomanin, R.; Rossi, A. D.; Dall’Acqua, F.; Zacchello, F.;
Scarpa, M. J Photochem Photobiol B. 1994, 26, 241; Lage, C.;
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Anal. calcd. for C28H24O3N2 (436.50): C, 77.04; H, 5.54; N,
6.41. Found: C, 76.72; H, 5.41; N, 6.22.
4-Morpholin-4-ylmethyl-7-(2-oxo-propoxy)-chromen-2-one
(11). This product was obtained by column chromatographic
purification using petroleum ether (60–80ꢀC): ethyl acetate elu-
ent, as white crystals, 50% yield, mp 138–140ꢀC; 1H NMR
(CDCl3, 400 MHz): d 2.30 (s, 3H, ACOCH3), 2.53–2.55 (t,
4H, C30ACH2A and C50ACH2A), 3.59 (s, 2H, C4ACH2A),
3.72–3.74 (t, 4H, C20ACH2A and C60ACH2A), 4.64 (s, 2H,
C7AOCH2COA), 6.40 (s, 1H, C3AH), 6.75–6.76 (d, 1H, J ¼
2.56 Hz, C8AH), 6.86–6.89 (dd, 1H, J ¼ 2.6 Hz and J ¼ 8.88
Hz, C6AH), 7.78–7.80 (d, 1H, J ¼ 8.88 Hz, C5AH).
Anal. calcd. for C17H11O5N (309.27): C, 66.02; H, 3.58; N,
4.52. Found: C, 66.01; H, 3.33; N, 4.41.
[4] Goupil, J. J. Fr. Add 2,698,270, 1994; Goaster, J. L. Fr.
Add 2,691,629, 1993.
[5] Legitimo, A.; Consolini, R.; DiStefano, R.; Bencivelli, W.;
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[6] Nagesam, M.; Mohan Raju K.; Subramanyam Raju M. J.
Indian Chem Soc 1988, 65, 380.
[7] Wollowitz, S.; Isaacs, S. T.; Rapoport, H.; Spielmann, H.
P.; Nerio, A. US Pat. 5,593,823 (1994); Wollowitz, S. I.; Nerio A. US
Pat. 6,455,286 B1 (2000).
[8] MacLeod, J. K.; Worth, B. R. Tetrahedron Lett 1972, 237.
[9] Pechmann, H. V.; Duisberg, C. Ber. 1883, 16, 2122.
[10] Nofal, Z. M.; El-Masry, A. H.; Fahmy, H. H.; Sarhan, A. I.
Egypt J Pharm Sci 1997, 38, 1.
3-Methyl-5-phenyl-benzo[1,2-b;5,4-b0]difuran-2-carboxylic
acid (12). This compound was obtained as white amorphous
[11] Bray, W.; Mayer, R. Z. Chem 1963, 3, 150.
powder (ethanol), 52% yield, mp 250ꢀC dec.; IR (KBr): mmax
,
[12] Ray, J. N.; Silooja, S. S.; Vaid, V. R. J Chem Soc 1935,
813.
cmꢁ1: 3433, 3107, 3030, 2922, 1682, 1627, 1598, 1440, 1366,
1332, 1318, 1165, 1119; 1H NMR ((CD3)2SO, 400 MHz): d
2.58 (s, 3H, C3ACH3), 7.32–7.36 (m, 1H, C40-H), 7.44–7.47
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet