Transformation of barakol into cassiarins A, B, and their derivatives

Article abstract of DOI:10.1016/j.tet.2010.07.053

Three semi-syntheses of cassiarins A and B from barakol are described. The route involving use of anhydrobarakol chloride as a key precursor showed most versatility because it does not require an expensive catalyst, protection of functional groups, or chromatographic purification, allowing the facile preparation of eight cassiarin derivatives. The photophysical properties of these compounds were characterized by UV-vis absorption, fluorescence emission, and quantum yield.

Full text of DOI:10.1016/j.tet.2010.07.053

Tetrahedron 66 (2010) 7539e7543
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Tetrahedron
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Transformation of barakol into cassiarins A, B, and their derivatives
*
Sarawut Kanputhorn, Amorn Petsom, Patchanita Thamyongkit
Research Center for Bioorganic Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Three semi-syntheses of cassiarins A and B from barakol are described. The route involving use of an-
hydrobarakol chloride as a key precursor showed most versatility because it does not require an ex-
pensive catalyst, protection of functional groups, or chromatographic purification, allowing the facile
preparation of eight cassiarin derivatives. The photophysical properties of these compounds were
characterized by UVevis absorption, fluorescence emission, and quantum yield.
Received 20 March 2010
Received in revised form 24 June 2010
Accepted 20 July 2010
Available online 24 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Barakol
Cassiarin A
Cassiarin B
Anhydrobarakol chloride
1. Introduction
reported the synthesis and bioactivity of cassiarin A and some de-
rivatives.10 Our work described here exploits the convenient access to
Cassia siamea is a common plant in Southeast Asia and
has been used extensively as a source of traditional medi-
cines. One of the most abundant chemical constituents of
C. siamea1e5 is barakol, being first extracted from fresh young
leaves and flowers.6 In 2007, Morita and co-workers dis-
covered two new alkaloids, cassiarins A and B in the plant.
These are much less abundant than barakol, but are interesting
for their potent antiplasmodial activity against Plasmodium
faciparum.7
gram quantities of barakol, and features conversion of its pyran-2-ol
moiety to pyridinium salts with the framework of cassiarins A and B.
2. Results and discussion
2.1. Syntheses of cassiarin A
Scheme 1 shows our three synthetic approaches to cassiarin
A. The first (Scheme 1a) begins with the reaction of barakol and
12
11
17
OCH3
13
15
16
O
10
5
N
N
O
14
OH
4
4a
6
3
2
7
HO
O
O
O
HO
O
8a
9
8
cassiarin A
cassiarin B
barakol
Two total syntheses of cassiarin A have been reported first by
Rudyantoandco-workers8 and subsequentlybyYaoandco-workers.9
Yao’s work also described the total synthesis of cassiarin B and three
new analogues of cassiarin A bearing different substituents at C-11.9
While the work described here was in progress, Morita also
triethylamine in aqueous methanol11 to obtain 5-acetonyl-7-
hydroxy-2-methyl chromone (1) in moderate yield. This com-
pound was also an intermediate in Morita’s recent synthesis.10
Attempt to simplify the published conditions for cassiarin A
formation by using shorter reaction time and no chromato-
graphic purification resulted in a lower yield of chromone 1 (58
vs 91%). Therefore, this approach is suggested when chromato-
graphy should be avoided.
* Corresponding author. Tel.: þ662 218 7587; fax: þ662 218 7598; e-mail
address: patchanita.v@chula.ac.th (P. Thamyongkit).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.053

7540
S. Kanputhorn et al. / Tetrahedron 66 (2010) 7539e7543
Scheme 2. Synthesis of cassiarin B and derivatives from 2.
The spectroscopic characterization of the products is illustrated
with the hydrochloride intermediate 3b. The presence of the
phenolic carbon (C-7) in the salt 3b was proven by HMBC correla-
tion spectroscopy: Protons H-6
(dH 6.38 ppm) and H-8 (dH
6.48 ppm) correlated with C-7 at dC 163.5 ppm (see Supplementary
data). In the free base cassiarin B, protons H-6 (dH 6.22 ppm) and
H-8 (dH 6.35 ppm) correlated with C-7 at dC 177.7 ppm, the latter
was therefore assigned as the conjugated carbonyl carbon.
Cl-
N+
H6
7
HO
O
H8
3b
Ring-opening of pyrylium ions and ring closure to form pyr-
idiniums,12 as depicted in Scheme 1c, enabled us to prepare several
N-substituted derivatives of the cassiarins featuring straight-chain
alkyl, bulky alkyl, aryl, or benzyl substituents. From the formation
of the corresponding salts 3cef, compounds 4e7 were obtained in
49e77% overall yield from 2. Within this series the yield of the
phenyl derivative 6 was diminished due to the reduced nucleo-
philicity of aniline13 relative to alkyl amines. The spectroscopic data
of 4 and 6 are consistent with those previously reported.10
Scheme 1. Three routes to cassiarin A from barakol.
Our second approach (Scheme 1b) features a one-pot conden-
sation of barakol with ammonium ions in refluxing methanol.
Cassiarin A precipitated in good yields and chromatographic puri-
fication was not required.
2.3. Comparative characterization of synthetic and natural
cassiarins
Scheme 1c shows our third method exploits the known11 con-
version of barakol to stable anhydrobarakol chloride 2. This com-
pound was reacted with an excess of ammonium hydroxide
solution followed by treatment with concentrated hydrochloric
acid to give cassiarin A hydrochloride 3a. The product was isolated
in almost quantitative yield by removal of the solvent and then
washing with THF. The free base was formed by treatment with 5%
w/v aqueous sodium carbonate solution and was isolated in 90%
yield without the need of chromatographic purification.
The formation of synthetic cassiarins A and B was confirmed by
1H and 13C NMR spectroscopy and mass spectrometry. Compared
with the previously reported data of the natural products,7 both
synthetic cassiarins obtained from this study gave consistent 1H
and 13C NMR results as summarized in Table 1.
However, to some extent, the melting points (decomposition
point) of the synthetic cassiarins were found to be higher than the
reported values and their color appeared to be different from the
natural products. Although the reason of the melting point differ-
ence is unclear, it is likely that the natural source contains a trace
amount of colored components, which might be difficult to be
completely removed by common purification techniques.
2.2. Synthesis of cassiarin B and derivatives
In a similar manner as described for the synthesis outlined in
Scheme 1c, cassiarin B and some N-substituted derivatives were
obtained (Scheme 2). For instance, reaction of the compound 2 with
methyl-4-aminobutyrate in methanol with triethylamine, followed
by formation of salt 3b, then liberation of the free base afforded Cas-
siarin B in 52%; again no chromatographic purification was required.
2.4. Photophysical properties of cassiarin derivatives
Amongst all the cassiarin compounds, cassiarin A showed
a distinct absorption maximum at 323 nm and its chloride salt at

S. Kanputhorn et al. / Tetrahedron 66 (2010) 7539e7543
7541
Table 1
1H and 13C NMR data of synthetic cassiarins A and B compared with those of natural cassiarins7 (shown in the square brackets)
Carbon
Cassiarin Aa
Cassiarin Ba
position
b
b
b
b
dH
dC
dH
dC
2
3
4
4a
5
6
7
8
8a
9
163.0 [161.5]
103.2 [103.7]
150.7 [150.6]
111.5 [111.5]
139.2 [138.8]
103.2 [102.9]
166.2 [164.6]
101.7 [100.7]
156.9 [156.4]
20.6 [20.1]
166.7 [168.0]
96.5 [97.3]
6.06 (s, 1H) [6.03 (s, 1H)]
6.70 (s, 1H) [6.74 (s, 1H)]
147.2 [148.6]
108.1 [109.3]
135.1 [136.5]
107.3 [107.9]
173.3 [174.6]
104.5 [105.1]
155.5 [156.7]
20.0 [21.0]
6.47 (s, 1H) [6.46 (s, 1H)]
6.49 (s, 1H) [6.48 (s, 1H)]
6.55 (s, 1H) [6.48 (s, 1H)]
6.69 (s, 1H) [6.60 (s, 1H)]
2.22 (s, 3H) [2.20 (s, 3H)]
6.70 (s, 1H) [6.70 (s, 1H)]
2.52 (s, 3H) [2.43 (s,3H)]
6.75 (s, 1H) [6.78 (s, 1H)]
10
11
12
13
114.3 [113.7]
148.4 [149.5]
22.5 [22.7]
116.1 [117.1]
139.8 [141.4]
20.9 [20.2]
2.34 (s, 3H) [2.34 (s,3H)]
2.57 (s, 3H) [2.50 (s,3H)]
4.16 (t, J¼8.4 Hz, 2H)
[4.10 (t, J¼8.5 Hz, 2H)]
2.00e2.12 (m, 2H)
47.2 [48.0]
14
15
23.1 [23.8]
29.7 [30.3]
[1.98 (m, 2H)]
2.68 (t, J¼6.3 Hz, 2H)
[2.57 (t, J¼6.3 Hz, 2H)]
16
17
173.2 [174.4]
52.0 [50.9]
3.85 (s, 3H) [3.72 (s, 3H)]
a
All spectra were recorded in CD3OD/CDCl3 (1:1).
dH and dC are chemical shifts of 1H and 13C NMR, respectively, and reported in parts per million (ppm).
b
293, 338, and 363 nm. Cassiarin B derivatives exhibited absorption
at 316e317 and 369e372 nm, while their chloride salts exhibited
a slight absorption shift to 302e304 and 372e374 nm. For all
cassiarin compounds, absorption coefficients of the neutral forms
are higher than those of the corresponding chloride salts. Upon
excitation at the maximum absorption wavelength of each com-
pounds, cassiarin A and its salt showed an emission at 456 nm,
while cassiarin B derivatives and their salts exhibited emissions at
482e489 nm. Fluorescence quantum yields of all compounds
range from 0.05 to 0.10 in methanol. Quantum yields for the
compounds bearing bulky N-substituents, i.e., cyclohexyl and
phenyl, are slightly lower in the series. Cassiarin A and its corre-
sponding salt 3a give highest quantum yields of these compounds,
indicating the N-alkyl/aryl substituents provide pathways to ac-
celerate non-radiationless decay. In most cases, the neutral form
of cassiarin compounds had higher quantum yields than their
corresponding chloride salts.
were AR grade. 1H NMR, 13C NMR, and HMBC spectra were obtained
in CD3OD, unless noted otherwise, using Varian Mercury NMR
spectrometer at 400 MHz for 1H, and 100 MHz for 13C nuclei unless
stated otherwise. Chemical shifts (d) are reported in parts per
million (ppm) relative to the residual solvent peak. Coupling con-
stants (J) are reported in hertz (Hz). Mass spectra were recorded by
electrospray ionization mass spectrometry (ESI-MS) on a Bruker
Daltonics micro TOF Mass Spectrometer. Absorption spectra were
recorded in methanol at room temperature with a Varian Cary-3 G
UV/Vis spectrophotometer. Emission spectra were measured in
methanol at room temperature on a Horiba Fluorolog-3 spectro-
photometer. Absorption coefficients (e .
) are expressed in Mꢀ1 cmꢀ1
4.2. Experimental procedure
4.2.1. Extraction of barakol. Following a standard procedure14 with
slight modification, fresh young leaves and flowers of C. siamea (2 kg)
were boiled with 0.5% (v/v) aqueous sulfuric acid (2.5 L) for 30 min
and filtered. The filtrate was basified with a saturated sodium car-
bonate solution to pH 9e10. The resulting basic solution was divided
into four portions and each was extracted with dichloromethane
(200 mLꢁ4). The combined dichloromethane extracts were con-
centrated under reduced pressure until the volume of organic ex-
tract was one-fourth of the starting volume, and then equal volume
of distilled water was added. The mixture was shaken vigorously, to
give a yellow needle crystalline solid of barakol (9.7 g on average)
that was collected by filtration. The spectroscopic data are consistent
with those described in the literature.
3. Conclusions
This study describes the use of naturally abundant barakol to
prepare bioactive cassiarins A and B and their N-substituted de-
rivatives. The anhydrobarakol chloride 2 proved to be a useful in-
termediate for efficient synthesis of cassiarin derivatives bearing
different N-substituent providing simple routes, obviating expensive
catalysts, protection, and time consuming purification steps. The
distinct photophysical properties of cassiarin A and its salt from
other cassiarin derivatives indicated the significant effect of N-sub-
stituent on those properties. Cassiarins A, B, and their derivatives
tend to be fluorescent, and the correlation between N-substitution
and quantum yields was also observed.
4.2.2. 5-Acetonyl-7-hydroxy-2-methyl chromone (1). Following a pub-
lished procedure11 with slight modification, a mixture of barakol
(0.232 g, 1.00 mmol) and triethylamine (0.101 g, 1.00 mmol) in 5% v/v
aqueous methanol (5.0 mL) was reacted at room temperature for
12 h. The mixture was concentrated under reduced pressure. The
resulting residual crude was purified by a silica column using ethyl-
acetate as eluent to obtain chromone 1 (0.075 g, 32%). The spectro-
scopic data are consistent with those described in the literature.
4. Experimental
4.1. Materials and methods
All reagents were analytical grade, purchased from Fluka, or
Aldrich Chemicals Co., Ltd. and were used as received without
further purification. Melting points were uncorrected and recorded
under ambient condition, except Cassiarins A and B whose melting
points were measured under N2 atmosphere. Solvents for reactions
4.2.3. Anhydrobarakol chloride (2). Following a published pro-
cedure11 with slight modification, to a solution of barakol (0.232 g,
1.00 mmol) in methanol (2.0 mL), concentrated hydrochloric acid

7542
S. Kanputhorn et al. / Tetrahedron 66 (2010) 7539e7543
(0.5 mL) was slowly added at room temperature. The mixture was
stirred during the addition of the acid until greenish-yellow nee-
dles were obtained. The mixture was cooled to 0e5 ꢂC in an ice bath
and the stirring was continued at this temperature for additional
15 min. The residual mixture was precipitated by adding THF
(10.0 mL). The resulting solid was filtered and washed with THF to
give 2 (0.147 g, 58%). The spectroscopic data are consistent with
those described in the literature.
temperature for 2 h. The resulting mixture was further reacted with
concentrated hydrochloric acid (0.5 mL) at this temperature for
additional 12 h. Methanol was removed under reduced pressure,
and the residual solid was precipitated by adding THF (10.0 mL).
The product was filtered and washed with THF to obtain N-4-
methoxy-4-oxobutyl cassiarin A chloride (3b) as a light yellow solid
(0.152 g, 87%). Mp 243 ꢂC (dec); 1H NMR (D2O/DMSO-d6 (9.5:0.5))
d
1.83e1.91 (m, 2H), 2.28 (s, 3H), 2.36 (s, 3H), 2.47 (t, J¼6.6 Hz, 2H),
3.55 (s, 3H), 3.98 (t, J¼8.0 Hz, 2H), 6.38 (d, J¼1.6 Hz, 1H), 6.48 (d,
4.2.4. Cassiarin A. Method A: from chromone 1. A mixture of chro-
mone 1 (0.232 g, 1.00 mmol) and ammonium acetate (0.154 g,
2.00 mmol) were reacted in glacial acetic acid (5.0 mL) under reflux
for 4e5 h (TLC monitoring; MeOH/CH2Cl2 (1:4)). The reaction
mixture was diluted with distilled water (5.0 mL) and cooled to
0e5 ꢂC in an ice bath. The resulting mixture was basified with
a saturated sodium carbonate solution to pH 9e10 and the stirring
was continued until the precipitates were appeared. The resulting
solid was filtered off and washed with water to afford cassiarin A
(0.124 g, 58%). The spectroscopic data are consistent with those
described in Method C.
J¼2.0 Hz, 1H), 6.54 (s, 1H), 6.76 (s, 1H); 13C NMR (D2O/DMSO-d6
(9.5:0.5))
d 175.4, 169.1, 163.5, 155.0, 148.7, 142.6, 135.6, 116.7, 110.1,
103.8, 101.1, 97.1, 52.2, 47.7, 29.7, 22.1, 20.1, 19.2; ESI-MS m/z 314.1
([MꢀCl]þ); ESIHRMS obsd 314.1382 ([MꢀCl]þ), calcd 314.1387
([MꢀCl]þ), 349.1081 (Mþ; M¼C18H20ClNO4); labs nm
(e) 302
(10,612), 373 (6852); lem nm (lex¼373 nm) 488.
F
¼0.07.
To a solution of 3b (0.152 g, 0.435 mmol) in water (4.0 mL), was
added a 5% (w/v) aqueous sodium carbonate solution (1.0 mL). The
mixture was stirred at room temperature for 5 min. The aqueous
solution was extracted with chloroform (4ꢁ15.0 mL). The combined
chloroform extracts were concentrated under reduced pressure
until the volume of organic extract was reduced to approximately
1.0 mL. The resulting mixture was kept at the room temperature
until the precipitate was formed. After filtration and washing with
a small amount of chloroform, cassiarin B was obtained as a yellow
solid (0.081 g, 60%). Mp 116e118 ꢂC (dec); 1H NMR (CDCl3/CD3OD
4.2.5. Method B: from direct condensation of barakol with ammo-
nium salts. Barakol (0.232 g, 1.00 mmol) and ammonium acetate
(0.154 g, 2.00 mmol) or ammonium chloride (0.107 g, 2.00 mmol)
were mixed in methanol (10.0 mL). The mixture was stirred and
refluxed for 4e5 h (TLC monitoring; MeOH/CH2Cl2 (1:4)). The re-
action mixture was concentrated under reduced pressure, and the
residue was dissolved in distilled water (5.0 mL). The resulting
solution was cooled in an ice bath and basified with a saturated
sodium carbonate solution to pH 9e10, and the stirring was con-
tinued until the solid were appeared. The resulting solid was fil-
tered off and washed with water to afford cassiarin A (0.122, 57%
and 0.143 g, 67% when ammonium acetate and ammonium chlo-
ride was employed, respectively). The spectroscopic data are con-
sistent with those described in Method C.
1:1, 300 MHz)
J¼6.3 Hz, 2H), 3.85 (s, 3H), 4.16 (t, J¼8.4 Hz, 2H), 6.55 (s, 1H), 6.69 (s,
1H), 6.70 (s, 1H), 6.75 (s, 1H); 13C NMR (CDCl3/CD3OD 1:1)
20.0,
d 2.00e2.12 (m, 2H), 2.52 (s, 3H), 2.57 (s, 3H), 2.68 (t,
d
20.9, 23.1, 29.7, 47.2, 52.0, 96.5, 104.5, 107.3, 108.1, 116.1, 135.1, 139.8,
147.2, 155.5, 166.7, 173.2, 173.3; ESI-MS m/z 314.1 ([MþH]þ);
ESIHRMS obsd 314.1387 ([MþH]þ), calcd 314.1387 ([MþH]þ),
313.1314 (Mþ; M¼C18H19NO4); labs nm
(e) 316 (15,629), 370
¼0.08.
(11,107); lem nm (lex¼370 nm) 485.
F
4.3. A General procedure for synthesis of N-substituted
cassiarin A chlorides 3cef
4.2.6. Method C: from anhydrobarakol chloride (2). A solution of salt
2 (0.125 g, 0.501 mmol) in methanol (2.0 mL) was reacted with a 25%
w/v aqueous ammonium hydroxide solution (0.5 mL) at room tem-
perature for 2 h. The resulting mixture was further reacted with
concentrated hydrochloric acid (0.5 mL) and the stirring was con-
tinued at this temperature for 12 h. Methanol was removed under
reduced pressure, and THF (10.0 mL) was added to the residual solid.
The solid was filtered and washed with THF to afford a pure cassiarin
A chloride (3a) as a light green solid (0.124 g, 99%). Mp 327 ꢂC (dec);
A mixture of 2 (0.125 g, 0.501 mmol) and amine (1.00 mmol) in
methanol (2.0 mL) was stirred at room temperature for 2 h. The
resulting mixture was further reacted with concentrated hydro-
chloric acid (0.5 mL) at room temperature for additional 12 h. The
solvent was removed under reduced pressure and the residual solid
was then treated with THF (10.0 mL). The resulting solid was col-
lected by filtration and washed with THF to afford a light yellow
solid of N-substituted cassiarins A chlorides 3cef.
1H NMR
d
2.45 (s, 3H), 2.46 (s, 3H), 6.50 (s,1H), 6.85 (d, J¼1.6 Hz,1H),
6.89 (d, J¼1.6 Hz 1H), 7.06 (s, 1H); 13C NMR
d
17.5, 19.1, 98.0, 101.1,
4.3.1. 4-Butyl-8-hydroxy-2,5-dimethylpyrano[2,3,4-ij]isoquinolin-4-
104.4, 109.4, 114.2, 138.1, 140.6, 148.3, 156.4, 166.1, 168.1; ESI-MS m/z
214.1 ([MꢀCl]þ); ESIHRMS obsd 214.0882 ([MꢀCl]þ), calcd 214.0863
ium chloride (3c). Yield (0.135 g, 88%). Mp 245 ꢂC (dec); 1H NMR
d
1.04 (t, J¼7.4 Hz, 3H),1.44e1.53 (m, 2H), 1.67e1.75 (m, 2H), 2.53 (s,
3H), 2.62 (s, 3H), 4.27 (t, J¼8.2 Hz, 2H), 6.84 (s, 1H), 6.89 (s, 1H), 6.90
(s, 1H), 7.21 (s, 1H); 13C NMR
12.6, 18.9, 19.2, 19.5, 29.8, 48.5, 97.4,
([MꢀCl]þ), 249.0557 (Mþ; M¼C13H12ClNO2). labs nm (
e) 298 (6840),
338 (4945), 363 (6505); lem nm (lex¼363 nm) 456.
F¼0.10.
d
To a solution of 3a (0.125 g, 0.501 mmol) in water (5.0 mL), was
added a 5% w/v aqueous sodium carbonate solution (1.0 mL). The
resulting mixture was stirred for 20 min. The resulting precipitate
was filtered and washed with water to give cassiarin A as a light
greenish-yellow solid (0.096 g, 90%). Mp 316e318 ꢂC (dec); 1H NMR
101.4, 104.2, 110.7, 117.2, 136.4, 142.7, 149.2, 155.8, 165.4, 168.8; ESI-
MS m/z 270.1 ([MꢀCl]þ); ESIHRMS obsd 270.1531 ([MꢀCl]þ), calcd
270.1489 ([MꢀCl]þ), 305.1183 (Mþ; M¼C17H20ClNO2); labs nm (
e)
302 (9057), 372 (7697); lem nm (lex¼372 nm) 484.
F
¼0.07.
(CDCl3/CD3OD 1:1, 300 MHz)
d
2.22 (s, 3H), 2.34 (s, 3H), 6.06 (s, 1H),
4.3.2. 4-Cyclohexyl-8-hydroxy-2,5-dimethylpyrano[2,3,4-ij]iso-
6.47 (s, 1H), 6.49 (s, 1H), 6.70 (s, 1H); 13C NMR (CDCl3/CD3OD 1:1)
quinolin-4-ium chloride (3d). Yield (0.145 g, 87%). Mp 338 ꢂC
d
20.6, 22.4, 101.7, 103.2, 111.5, 114.3, 139.2, 148.4, 150.7, 156.9, 163.1,
(dec); 1H NMR (CD3OD/CDCl3 (1:4))
d 1.35e1.41 (m, 1H),
166.2; ESI-MS m/z 214.1 ([MþH]þ); ESIHRMS obsd 214.0870
1.46e1.56 (m, 2H), 1.82 (d, J¼13.2 Hz, 1H), 1.96 (d, J¼11.6 Hz, 2H),
2.05 (d, J¼13.2 Hz, 2H), 2.33e2.41 (m, 2H), 2.54 (s, 3H), 2.63 (s,
3H), 4.61 (t, J¼12.0 Hz, 1H), 6.83 (s, 1H), 6.87 (s, 1H), 6.93 (s, 1H),
([MþH]þ), calcd 214.0868 ([MþH]þ), 213.0790 (Mþ; M¼C13H11NO2);
labs nm (
e) 323 (7043); lem nm (lex¼323 nm) 456. ¼0.10.
F
Cassiarin B. Following a procedure described for cassiarin A
(Method C), a mixture of 2 (0.125 g, 0.501 mmol), methyl-4-ami-
nobutyrate hydrochloride (0.154 g, 1.00 mmol), and triethylamine
(0.101 g, 1.00 mmol) in methanol (2.0 mL) was reacted at room
7.14 (s, 1H); 13C NMR (CD3OD/CDCl3 (1:4))
d 20.9, 21.5, 24.4,
25.98, 25.98, 28.71, 28.71, 63.3, 99.3, 102.6, 105.0, 111.9, 118.9,
136.0, 142.2, 149.4, 155.7, 165.9, 166.9; ESI-MS m/z 296.2
([MꢀCl]þ); ESIHRMS obsd 296.1674 ([MꢀCl]þ), calcd 296.1645

S. Kanputhorn et al. / Tetrahedron 66 (2010) 7539e7543
7543
([MꢀCl]þ), 331.1339 (Mþ; M¼C19H22ClNO2); labs nm
(
e
)
302
calcd 296.1645 ([MþH]þ), 295.1572 (Mþ; M¼C19H21NO2); labs nm (
e)
(10,517), 376 (5568); lem nm (lex¼376 nm) 489.
F
¼0.08.
316 (12,139), 372(8925); lem nm (lex¼372 nm) 483. ¼0.09.
F
4.3.3. 8-Hydroxy-2,5-dimethyl-4-phenylpyrano[2,3,4-ij]isoquinolin-
4.4.3. 2,5-Dimethyl-4-phenylpyrano[2,3,4-ij]isoquinolin-8(4H)-one
(6). Yield (0.056 g, 65%). Mp 132 ꢂC (dec); 1H NMR
2.01 (s, 3H),
2.21 (s, 3H), 5.45 (s, 1H), 6.43 (d, J¼1.2 Hz,1H), 6.49 (d, J¼1.2 Hz 1H),
6.86 (s, 1H), 7.45e7.47 (m, 2H), 7.68e7.72 (m, 3H); 13C NMR
19.1,
4-ium chloride (3e). Yield (0.123 g, 76%). Mp 258 ꢂC (dec); 1H NMR
d
d
2.15 (s, 3H), 2.35 (s, 3H), 5.81 (s,1H), 6.99 (d, J¼1.6 Hz,1H,), 7.01 (d,
J¼1.6 Hz, 1H), 7.33 (s, 1H), 7.50e7.51 (m, 2H), 7.75e7.77 (m, 3H); 13C
d
NMR
d
19.3, 19.7, 98.3, 101.5, 104.8, 110.0, 116.0, 127.10, 127.10,
19.5, 96.6, 104.9, 106.3, 108.6, 114.1, 127.74, 127.74, 130.4, 130.62,
130.62, 135.8, 137.3, 140.3, 147.8, 156.5, 166.2, 178.4; ESI-MS m/z
290.1 ([MþH]þ); ESIHRMS obsd 290.1137 ([MþH]þ), calcd 290.1176
130.97, 130.97, 130.97, 136.8, 136.9, 142.8, 150.5, 156.4, 166.3, 169.1;
ESI-MS m/z 290.1 ([MꢀCl]þ); ESIHRMS obsd 290.1110 ([MꢀCl]þ),
calcd 290.1176 ([MꢀCl]þ), 325.0870 (Mþ; M¼C19H16ClNO2); labs nm
([MþH]þ), 289.1103 (Mþ; M¼C19H15NO2); labs nm (
e) 317 (13,350),
(e
) 304 (7803), 372 (5943); lem nm (lex¼372 nm) 482.
F
¼0.07.
372 (10,350); lem nm (lex¼372 nm) 484.
F
¼0.07.
4.3.4. 4-Benzyl-8-hydroxy-2,5-dimethylpyrano[2,3,4-ij]isoquinolin-
4.4.4. 4-Benzyl-2,5-dimethylpyrano[2,3,4-ij]isoquinolin-8(4H)-one
(7). Yield (0.079 g, 87%). Mp 192 ꢂC (dec); 1H NMR
2.27 (s, 3H),
4-ium chloride (3f). Yield (0.152 g, 89%). Mp 291 ꢂC (dec); 1H NMR
d
d
2.43 (s, 3H), 2.54 (s, 3H), 5.64 (s, 2H), 6.80 (s, 1H), 6.96 (d, J¼1.6 Hz,
2.37 (s, 3H), 5.38 (s, 2H), 6.31 (s, 1H), 6.38 (d, J¼2.0 Hz, 1H), 6.47 (d,
1H), 7.00 (d, J¼2.0 Hz,1H), 7.15 (d, J¼7.2 Hz, 2H), 7.32 (s, 1H), 7.36 (d,
J¼1.6 Hz, 1H), 6.82 (s, 1H), 7.10 (d, J¼7.6 Hz, 2H), 7.30e7.33 (m, 1H),
J¼7.2 Hz, 1H), 7.39e7.43 (m, 2H); 13C NMR
d
18.9, 19.4, 51.4, 97.6,
7.36e7.40 (m, 2H); 13C NMR
d 18.7, 19.2, 50.3, 95.9, 105.1, 106.9,
101.6, 104.6, 110.7, 117.2, 125.26, 125.26, 128.0, 129.13, 129.13, 133.3,
136.7, 143.1, 150.5, 156.2, 166.0, 169.4; ESI-MS m/z 304.1 ([MꢀCl]þ);
ESIHRMS obsd 304.1365 ([MꢀCl]þ), calcd 304.1332 ([MꢀCl]þ),
108.3, 115.2, 125.14, 125.14, 127.7, 128.99, 128.99, 134.3, 135.6, 140.7,
147.8, 156.1, 166.4, 178.3; ESI-MS m/z 304.1 ([MþH]þ); ESIHRMS
obsd 304.1365 ([MþH]þ), calcd 304.1332 ([MþH]þ), 303.1259 (Mþ;
339.1026 (Mþ; M¼C20H18ClNO2); labs nm (
e
) 304 (8713), 374
M¼C20H17NO2); labs nm (
e) 317 (14,361), 372 (10,412); lem nm
lex¼372 nm) 488. ¼0.09.
(6533); lem nm (lex¼374 nm) 486.
F
¼0.08.
(
F
Acknowledgements
4.4. A general procedure for synthesis of N-substituted
cassiarin derivatives 4e7
We are thankful to Science and Technology Innovation Support
Grant, Faculty of Science, Chulalongkorn University for partial
financial support in this research.
To
a solution of N-substituted cassiarin A chloride 3cef
(0.30 mmol) in water (5.0 mL), was added triethylamine (0.061 g,
0.60 mmol). The mixture was stirred at room temperature for
5 min. The resulting solution was then extracted with chloroform
(15 mLꢁ4) or, in the case of 7, the resulting solid was filter off. For
4e6, the combined chloroform extracts were concentrated under
reduced pressure until the volume of organic extract was reduced
to 1.0 mL. The crude extract was kept at room temperature until the
yellow precipitate was obtained. The solid product was filtered off
and then dried under vacuum to give the N-substituted cassiarin B
derivative 4e7.
Supplementary data
Spectral data, including 1H NMR, 13C NMR, and high resolu-
tion mass spectra for new compounds. Supplementary data as-
sociated with this article can be found in online version at
doi:10.1016/j.tet.2010.07.053. These data include MOL files and
InChIKeys of the most important compounds described in this
article.
References and notes
4.4.1. 4-Butyl-2,5-dimethylpyrano[2,3,4-ij]isoquinolin-8-(4H)-one
(4). Yield (0.054 g, 67%). Mp 167 ꢂC (dec); 1H NMR
d 1.02 (t,
1. Singh, V.; Singh, J.; Sharma, J. P. Phytochemistry 1992, 31, 2176e2177.
2. Koyama, J.; Morita, I.; Tagahara, K.; Aqil, M. Phytochemistry 2001, 56, 849e851.
3. El-Sayyad, S. M.; Ross, S. A.; Sayed, H. M. J. Nat. Prod. 1984, 47, 708e719.
4. Arora, S.; Deymann, H.; Tiwari, R. D.; Winterfeldt, E. Tetrahedron 1971, 27,
981e984.
J¼7.4 Hz, 3H), 1.43e1.53 (m, 2H), 1.61e1.68 (m, 2H), 2.35 (s, 3H),
2.41 (s, 3H), 3.96 (t, J¼8.2 Hz, 2H), 6.21 (s, 1H), 6.33 (s, 1H), 6.34 (s,
1H), 6.63 (s, 1H); 13C NMR
d 12.6, 18.7, 19.2, 19.2, 30.2, 47.2, 95.6,
104.9, 106.9, 107.7, 115.2, 135.4, 140.1, 146.6, 155.7, 165.9, 177.7; ESI-
5. Biwas, K. M.; Mallik, H. Phytochemistry 1986, 25, 1727e1730.
6. Hassanali, A.; King, T. J.; Wallwork, S. C. J. Chem. Soc., Chem. Commun. 1969, 678.
7. Morita, H.; Oshimi, S.; Hirasawa, Y.; Koyama, K.; Honda, T.; Ekasari, W.; In-
drayanto, G.; Zaini, N. C. Org. Lett. 2007, 9, 3691e3693.
8. Rudyanto, M.; Tomizawa, Y.; Morita, H.; Honda, T. Org. Lett. 2008, 10,
1921e1922.
MS m/z 270.2 ([MþH]þ); ESIHRMS obsd 270.1538 ([MþH]þ), calcd
270.1489 ([MþH]þ), 269.1416 (Mþ; M¼C17H19NO2); labs nm (
e) 316
(13,193), 369 (9016); lem nm (lex¼369 nm) 484.
F
¼0.09.
9. Yao, Y.-S.; Yao, Z.-J. J. Org. Chem. 2008, 73, 5221e5225.
10. Morita, H.; Tomizawa, Y.; Deguchi, J.; Ishikawa, T.; Arai, H.; Zaima, K.; Hosoya,
T.; Hirasawa, Y.; Matsumoto, T.; Kamata, K.; Ekasari, W.; Widyawaruyanti, A.;
Wahyuni, T. S.; Zaini, N. C.; Honda, T. Bioorg. Med. Chem. 2009, 17, 8234e8242.
11. Bycroft, B. W.; Hassaniali-Walji, A.; Johnson, A. W.; King, T. J. J. Chem. Soc. C 1970,
12, 1686e1689.
12. Tolkunov, S. V.; Kryuchkov, M. A.; Tolkunov, V. S.; Dulenko, V. I. Chem. Heter-
ocycl. Compd. 2004, 40, 1082e1086.
13. Kibalny, A. V.; Afonin, A. A.; Dulenko, V. I. Chem. Heterocycl. Compd. 2004, 40,
1131e1136.
4.4.2. 4-Cyclohexyl-2,5-dimethylpyrano[2,3,4-ij]isoquinolin-8(4H)-
one (5). Yield (0.059 g, 67%). Mp 136 ꢂC (dec); 1H NMR (CD3OD/
CDCl3 (1:4))
d 1.21e1.31 (m, 1H), 1.39e1.48 (m, 2H), 1.80 (d,
J¼12.8 Hz, 1H), 1.90 (d, J¼12.4 Hz, 2H), 2.00 (d, J¼13.2 Hz, 2H),
2.22e2.26 (m, 2H), 2.43 (d, J¼5.6 Hz, 3H), 2.43 (s, 3H), 4.32e4.39 (m,
1H), 6.32 (s, 1H), 6.39 (s, 1H), 6.49 (s, 1H), 6.63 (s, 1H); 13C NMR
(CD3OD/CDCl3 (1:4)) d 20.8, 21.4, 24.7, 26.14, 26.14, 29.34, 29.34, 61.5,
97.7, 106.2, 108.5, 108.7, 116.9, 135.0, 139.4, 146.9, 155.9, 163.6, 178.4;
14. Deachapunya, C.; Poonyachoti, S.; Thongsaard, W.; Krishanamra, N. J. Pharma-
col. Exp. Ther. 2005, 314, 732e737.
ESI-MS m/z 296.2 ([MþH]þ); ESIHRMS obsd 296.1676 ([MþH]þ),