Total synthesis and antibacterial screening of (±)-7-butyl-6,8- dihydroxy-3-pentyl-3,4-dihydroisochromen-1-one

Article abstract of DOI:10.1080/10286020.2013.817993

A new total synthesis of (±)-7-butyl-6,8-dihydroxy-3-pentyl-3,4- dihydroisochromen-1-one, isolated as R-enantiomer from Geotrichum sp., has been described. Reaction of 4-butyl-3,5-dimethoxyhomophthalic anhydride with hexanoyl chloride in the presence of 1

Full text of DOI:10.1080/10286020.2013.817993

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Total synthesis and antibacterial
screening of ( ± )-7-butyl-6,8-
dihydroxy-3-pentyl-3,4-
dihydroisochromen-1-one
Aamer Saeed a , Hummera Rafique a & Muhammad Arshad b
a Department of Chemistry , Quaid-i-Azam University ,
Islamabad , 45320 , Pakistan
b Chemistry Division, Directorate of Science, PINSTECH , Nilore,
45320 , Islamabad , Pakistan
Published online: 22 Jul 2013.
To cite this article: Journal of Asian Natural Products Research (2013): Total synthesis and
antibacterial screening of ( ± )-7-butyl-6,8-dihydroxy-3-pentyl-3,4-dihydroisochromen-1-one,
Journal of Asian Natural Products Research, DOI: 10.1080/10286020.2013.817993
To link to this article: http://dx.doi.org/10.1080/10286020.2013.817993
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Journal of Asian Natural Products Research, 2013
http://dx.doi.org/10.1080/10286020.2013.817993
Total synthesis and antibacterial screening of (6)-7-butyl-6,8-
dihydroxy-3-pentyl-3,4-dihydroisochromen-1-one
Aamer Saeeda*, Hummera Rafiquea and Muhammad Arshadb
b
aDepartment of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan; Chemistry
Division, Directorate of Science, PINSTECH, Nilore, 45320 Islamabad, Pakistan
(Received 31 January 2013; final version received 18 June 2013)
A new total synthesis of (^)-7-butyl-6,8-dihydroxy-3-pentyl-3,4-dihydroisochromen-
1-one, isolated as R-enantiomer from Geotrichum sp., has been described. Reaction of
4-butyl-3,5-dimethoxyhomophthalic anhydride with hexanoyl chloride in the presence
of 1,1,3,3-tetramethyl guanidine and triethyl amine afforded 7-butyl-6,8-dimethoxy-3-
pentylisochromen-1-one, which was converted into corresponding 3,4-dihydroisochro-
men-1-one by successive ring opening and reduction. Final demethylation to furnish
the natural product was achieved using anhydrous aluminum chloride in ethanethiol.
The target compound and the intermediates were subjected to antibacterial evaluation
against 10 bacterial strains using levofloxacin as standard.
Keywords: isochromen-1-one; Geotrichum sp; 3,5-dimethoxy-4-butylhomophthalic
acid; antibacterial
1. Introduction
chromen-1-ones derivatives, with antima-
larial, antituberculous, antifungal, and
cytotoxic activities by bioassay-guided
fractionation from an endophytic fungus,
Geotrichum sp., collected from Crassoce-
phalum crepidioides [14]. The structures
were established as 7-butyl-6,8-dihydroxy-
3(R)-pent-11-enyl-3,4-dihydroisochro-
men-1-one, 7-but-15-enyl-6,8-dihydroxy-
3(R)-pent-11-enyl-3,4-dihydroiso chro-
men-1-one, and 7-butyl-6,8-dihydroxy-3
(R)-pentyl-3,4-dihydroisochromen-1-one
respectively,usingspectroscopictechniques
(Figure 1).
More than 300 isocoumarins (1H-2-benzo-
pyran-1-ones) have been isolated from a
wide range of natural sources (microbes,
plants, and insects) [1]. These compounds
have also been detected in pheromones of
termites and ants [2]. Several biological
activities have been reported for this class,
including cytotoxic, antimicrobial, antial-
lergic, algicidal, gastroprotective, protease
inhibitors, antifungal, and plant growth
regulators [3–6]. In addition, nephratoxic,
immunomodulatory, antiallergic, and anti-
malarial activities have also been ascribed
to this class of natural products [7–11].
Isocoumarins are isomeric to coumarins
with an inverted lactone ring, and most of
the natural isocoumarins possess a 3-alkyl
(C1–C17) or a 3-(un)substituted phenyl ring
and 6,8-dioxygenation due to their typical
biosynthetic origin [12,13].
An elegant total synthesis of 7-butyl-
6,8-dihydroxy-3(R)-pentyl-3,4-dihydroi-
socoumarin has been reported in 19%
overall yield [15]. Herein, we report a total
synthesis of title compound as a racemate.
The important feature of present synthesis
includes the accessibility of not only 7-
butyl-6,8-dihydroxy-3-pentyl-3,4-dihy-
droisocoumarin but also the corresponding
7-butyl-6,8-dimethoxy-3-pentylisocou-
Kongsaeree and coworkers reported
the isolation of three novel dihydroiso-
*Corresponding author. Email: aamersaeed@yahoo.com
q 2013 Taylor & Francis

2
A. Saeed et al.
(1) according to the route indicated in
HO
Scheme 1. Thus, the regioselective reduc-
tive electrophilic alkylation of dimethyl
acetal (1) using n-butyl bromide in dry
tetrahydrofuran (THF) at 08C, followed
by hydrolysis, afforded 4-butyl-3,5-
dimethoxybenzaldehyde (2) [19], which
was reduced to benzyl alcohol (3),
followed by conversion into corresponding
bromide (4) and nitrile (5). Hydrolysis
afforded 4-butyl-3,5-dimethoxyphenyla-
cetic acid (6). Methyl ester (7) of the
latter acid was subjected to Vilsmeier
Haack formylation to furnish methyl 4-
butyl-2-formyl-3,5-dimethoxyphenyl acet-
ate (8). The aldehyde exhibited peak for
O
OH
O
Figure 1. Thestructureof7-butyl-6,8-dihydroxy-
3(R)-pent-11-enyl-3,4-dihydroisocoumarin from
Geotrichum sp.
marin, together with the keto- and hydroxy
acid derivatives for comprehensive and
comparative bioevaluation studies. This
work is a continuation of our focusing on
the synthesis, characterization, crystal
structure, and biological evaluation of
this important class of secondary metab-
olites [16–18].
1
ZCHO at dH 10.41 and at dC 201.8 in H
NMR and 13C NMR spectra, respectively.
Oxidation of the aldehydic function was
achieved using sulfamic acid and sodium
chlorite in a mixture of water, THF, and
dimethyl sulfoxide (DMSO) to afford the
corresponding carboxyl ester (9). In IR
2. Results and discussion
4-Butyl-3,5-dimethoxy-homophthalic acid
was synthesized starting from 3,4,5-
trimethoxybenzaldehyde dimethyl acetal
O
O
n-Butyl bromide
H3CO
H3CO
Na Metal
O
H3CO
NaBH4 / THF
OH PBr3
H
MeOH
anhy. THF
H3CO
Dry benzene
stirring
C4H9
C4H9
stirring/ 24 hr
OCH3
(1)
OCH3
OCH3
(2)
(3)
H3CO
C4H9
H3CO
C4H9
OH
Br
H3CO
C4H9
KCN/H2O
KOH
CN
MeOH / H
reflux
Dioxane
reflux
O
H2O/ EtOH
reflux
OCH3
(4)
OCH3
(5)
OCH3
(6)
H3CO
C4H9
OCH3
OCH3
H3CO
C4H9
Sulfamic acid/
0˚C/ NaClO2
H3CO
C4H9
OCH3
Dry DMF
O
O
O
CHO
POCl3
55˚C
COOH
H2O/ THF/DMSO
OCH3
OCH3
MeOH/
NaOH
OCH3
(9)
reflux
(7)
(8)
H3CO
C4H9
OH
O
COOH
OCH3
(10)
Scheme 1. Synthesis of 3,5-dimethoxy-4-butylhomophthalic acid.

Journal of Asian Natural Products Research
3
O
H3CO
C4H9
H3CO
COOH
Ac2O
O
O
Dry Toluene
COOH
OCH3
C4H9
OCH3
(10')
O
(10)
TMG/ NEt3/
CH3CN
C5H11
Cl
C5H11
H3CO
C4H9
H3CO
C4H9
C5H11
C2H5OH
5% KOH
O
O
COOH
OCH3
(12)
(11)
O
OCH3
NaBH4
CH3OH
H
O
C5H11
H3CO
C4H9
H3CO
C5H11
Ac2O
reflux
OH
COOH
OCH3
C4H9
(14)
O
OCH3
(13)
H
O
C5H11
HO
C2H5SH/ 0–5 ˚C/ 1h
AlCl3 (anhyd)
C4H9
(15)
OH
O
Scheme 2. Synthesis of (^)-7-butyl-6,8-dihydroxy-3-pentyl-3,4-dihydroisocoumarin.
spectrum, the carbonyls of ester and
carboxyl groups were found at 1731 and
presence of 1,1,3,3-tetramethyl guanidine
(TMG) and triethyl amine furnished the 7-
butyl-6,8-dimethoxy-3-pentylisochromen-
1-one (11) in 74% yield [20]. The lactonic
carbonyl stretching in IR spectrum
appeared at 1725 cm21 and in mass
spectrum base peak was observed at m/z
234. The isochromen-1-one derivative
(11) exhibited the characteristic singlets
in 1H NMR spectrum for H-4 and H-5 at d
6.17 and d 6.64. In 13C NMR spectrum, the
carbonyl carbon (CvO) signal was
observed at d 162.6 and C-3 appeared at
d 158.5 (Scheme 2).
1
1716 cm21, respectively. H NMR spec-
trum indicated the singlets for ester
ZOCH3 at d 3.61 and benzylic-CH2 at d
4.32, respectively. The carbonyls of
carboxylic and ester appeared at d 175.2
and d 167.6 in 13C NMR spectrum.
Alkaline hydrolysis of the latter afforded
4-butyl-3,5-dimethoxyhomophthalic acid
(10) in good yield. In IR spectrum, the
carboxylic acid carbons (CvO) were
found at 1737 and 1718 cm21, respect-
ively, and the base peak observed at m/z
147 in the mass spectrum. 1H NMR
showed two characteristic singlets for
acidic ZOH protons at d 11.02 and d
10.91 ppm, whereas the carbonyl carbons
Alkaline hydrolysis of isochromen-1-
one (11) furnished the keto-acid (12). In IR
spectrum, the characteristic acidic and
ketonic carbonyl peak absorption of keto-
acid appeared at 1734 and 1712 cm21
,
appeared at d 175.6 and d 168.5 ppm in 13
C
respectively. In 1H NMR spectrum, the
singlet for benzylic protons appeared at d
2.83, and in 13C NMR spectrum, ketonic
and carboxylic carbonyls were observed at
NMR.
Cyclocondensation of 4-butyl-3,5-
dimethoxyhomophthalic acid (10) with
an excess of hexanoyl chloride in the

4
A. Saeed et al.
d 207.3 and d 168.5, respectively. The
keto-acid (12) was reduced to correspond-
ing hydroxy acid (13) using sodium
borohydride, followed by cyclodehydra-
tion with acetic anhydride to yield the
corresponding 3,4-dihydroisochromen-1-
one (14). In IR spectrum, the lactonic
carbonyl absorptions appeared at
1721 cm21, and 1H NMR spectrum
showed two double doublets of H-4
protons at d 3.31 and d 3.12. In 13C
NMR spectrum, the carbonyl and C-3 were
observed at d 168.4 and 78.5.
Complete demethylation of 3,4-dihy-
droisochromen-1-one (14) was achieved
using ethanethiol and anhydrous aluminum
chloride [21]. In IR spectrum, the charac-
teristic (OZH) stretching appeared at
3421 cm21 and in mass spectrum, the base
peak was observed at m/z 206. In 1H NMR
spectrum, besides the disappearance of C-6
and C-8 methoxy protons, a broad singlet
for ZOH proton appeared at d 11.43. The
multiplet for H-3 was noted at d 4.46–4.49
and double doublets for H-4 at d 3.56 and d
3.25. In 13C NMR spectrum, the carbonyl
carbon (CvO) was observed at d 169.5 and
C-3 appeared at d 79.3. Two downfield
carbon signals at d 161.7 and d 160.1 were
assigned to C-6 and C-8, respectively. The
spectroscopic data (1H and 13C NMR, mass
spectrum) of the synthetic compound were
in close agreement with those of the natural
product [14,15].
Micrococcus aureus, Staphylococcus
aureus, and Streptococcus specie. Anti-
bacterial assay was determined by agar
well diffusion assay technique by using the
Mueller Hinton Agar. The fresh inoculums
of these bacteria were prepared and diluted
by sterilized normal saline. The turbidity
of these cultures was adjusted by using 0.5
McFarland. A homogeneous bacterial
lawn was developed by sterile cotton
swabs. The inoculated plates were bored
by 6-mm-sized borer to make the wells.
The sample dilutions were prepared by
dissolving each sample (5.0 mg) in 1.0 ml
of DMSO used as negative control in this
bioassay. The equimolar concentration
of levofloxacin (5.0 mg/ml), a broad-
spectrum antibiotic (positive control),
was prepared. These plates were incubated
at 378C for 24 h. Antibacterial activity of
the synthesized compounds (10–15) was
determined by measuring the diameter of
zone of inhibition (mm, ^standard devi-
ation) and presented by subtracting the
activity of the negative control. The
experiments were repeated thrice to mini-
mize the errors; only the mean values are
reported in Table 1.
7-Butyl-6,8-dimethoxyhomophthalic
acid (10) showed antibacterial activity
against six different strains of gram-positive
and gram-negative bacteria, though it was
more effective against Micrococcus luteus.
7-Butyl-6,8-dimethoxy-3-pentylisocou-
marin (12) displayed significant activity
against seven different bacterial strains
but remarkable activity more than the
standard drug against Shigella specie and
S. paratyphi.
In vitro evaluation of antibacterial
activity of the key precursors homophtha-
lic acid (10), 7-butyl-6,8-dimethoxy-3-
pentylisochromen-1-one (11), keto-acid
(12), hydroxy acid (13) dihydroisocou-
marin (14), and the title 6,8-dihydroxy-
3,4-dihydroisochromen-1-one (15) was
performed under aseptic conditions
against 10 different bacterial strains [22].
These include the six Gram-negative
strains viz. Pseudomonas aeroginosa,
Escherichia coli, Salmonella typhi, Shi-
gella specie, Salmonella paratyphi, and
Proteus mirabilis and four were Gram-
positive strains viz Bacillus subtilus,
Keto-acid (13) exhibited minute
activity against seven strains of bacteria.
The hydroxy acid (14) showed good
activity comparable to the standard drug
against S. paratyphi and S. typhi, besides
the rest of six bacterial strains. 3,4-
Dihydroisocoumarin (15) was effective
against E. coli only, and the target 7-butyl-
6,8-dihydoxy-dihydroisocoumarin (16)

Journal of Asian Natural Products Research
Table 1. Antibacterial bioassay of compounds 10–15.
5
P.
E.
S.
P.
B.
M.
S.
Sh. S. para St.
aeroginosa coli typhi mirabilis subtilus luteus aureus specie typhi specie
Compound
10
11
12
13
14
15
–
–
9
11
–
–
25
9
–
–
4
8
2
13
18
11
19
–
–
16
–
11
16
–
17
15
12
15
–
13
21
12
–
–
–
32
–
16
–
–
–
–
27
–
19
–
4
15
10
8
–
7
24
20
14
15
–
11
29
9
–
34
10
38
–
14
13
21
Levofloxacin
33 24
Notes: Gram-positive bacteria: B. subtilus, M. aureus, S. aureus, St. specie, P. mirabilis.
Gram-negative bacteria: P. aeroginosa, E. coli, S. typhi, Sh. specie, S. paratyphi.
Key: –, no activity concentration ¼ 5.0 mg/ml; the bold values indicate good activity compared with the
standard.
showed little antibacterial activity against
six different bacterial strains (Table 1).
In conclusion, an efficient total syn-
thesis of the natural dihydroisochromen-1-
one (^)-7-butyl-6,8-dihydroxy-3-pentyl-
3,4-dihydroisochromen-1-one (15) has
been successfully achieved using 7-butyl-
6,8-dimethoxyhomophthalic acid as a key
precursor. 7-Butyl-6,8-dimethoxy-3-pen-
tylisochromen-1-one (11) and the hydroxy
acid (13) showed significant antibacterial
activity against different bacterial strains.
silica gel from Merck (Darmstadt,
Germany).
3.2 4-Butyl-3,5-
dimethoxybenzaldehyde (2)
Compound 2 was prepared according to
the synthetic procedure reported in the
literature [15]. Yield 82%; Rf 0.5;
amorphous solid; mp 47–488C; IR (KBr)
n
max: 2936 (CvCZH), 1734 (CvO ester),
;
1568 (CvC), 1056 (CZO) cm21 1H
NMR (CDCl3, d ppm): 9.83 (1H, s,
ZCHO), 6.97 (2H, s, Ar–H), 3.81 (6H, s,
ZOCH3), 2.63 (2H, t, J ¼ 6.3 Hz, H-10),
1.33–1.36 (2H, m, H-20), 1.27–1.31 (2H,
m, H-30), 0.89 (3H, t, J ¼ 6.6 Hz, H-40);
13C NMR (CDCl3, d ppm): 201.5 (alde-
hydic CvO), 158.4 (C-3,C-5), 135.1 (C-2,
C-6), 127.2 (C-4), 104.6 (C-1), 55.6 (2 £
ZOCH3), 38.7 (C-10), 23.1 (C-20), 22.6 (C-
30), 13.8 (C-40); Elemental analysis:
Found: C, 70.17%; H, 8.04%; calcd for
C13H18O3: C, 70.23%, H, 8.15%.
3. Experimental
3.1 General experimental procedures
Melting points were recorded using a
digital Gallenkamp (SANYO) model MPD
BM 3.5 apparatus (Loughborough, UK)
and are uncorrected. 1H NMR and 13C
NMR spectra were determined in CDCl3 at
300 and 75 MHz, respectively, using
Bruker AM-300 spectrophotometer (Bill-
erica, Middlesex, MA, USA). FT IR
spectra were recorded using Bio-Rad
Excalibur FTS 3000 MX spectropho-
tometer (Madison, WI, USA); Mass
spectra (EI, 70 eV) on a GC-MS instru-
ment (Agilent Technologies 1200 series
Santa Clara, CA, USA) and elemental
analyses with a LECO-183 CHNS analy-
zer (LECO Corporation, St Joseph, MI,
USA). All compounds were purified by
thin layer chromatography (TLC) using
3.3 4-Butyl-3,5-dimethoxybenzyl
alcohol (3)
4-Butyl-3,5-dimethoxybenzaldehyde (2)
(4.3g, 0.0193mmol) and sodium borohy-
dride (4.18 g, 116 mmol) were suspended in
freshly distilled THF (120ml). The reaction
mixture was stirred for 15–20min at 658C
and then added methanol (120ml) dropwise

6
A. Saeed et al.
during 30min. The mixture was refluxed
for 4 h, then cooled to room temperature
and treated with saturated ammonium
chloride solution (100ml). Stirring was
continued for 1 h, and then the mixture was
acidified with dilute hydrochloric acid and
extracted with ethyl acetate (3 £ 25ml).
The extract was dried and evaporated, to
yield 4-butyl-3,5-dimethoxybenzyl alcohol
(3); yield 74%; Rf 0.2; amorphous solid; mp
180–1828C; IR (KBr) nmax: 3342 (OZH),
2933 (CvCZH), 1575 (CvC), 1034
(C-10), 13.8 (C-40); Elemental analysis:
Found: C, 54.27%; H, 6.56%; calcd for
C13H19BrO2: C, 54.36%; H, 6.65%.
3.5 2-(4-Butyl-3,5-dimethoxyphenyl)
acetonitrile (5)
4-Butyl-3,5-dimethoxybenzyl bromide (4)
(4.0 g, 1.34 mmol) was dissolved in a
mixture of ethyl alcohol (100 ml) and
water (100ml). Potassium cyanide (1.3g,
1.91mmol) was then added to reaction flask
and the resulting mixture was refluxed for
4 h. Reaction mixture was poured onto ice
cold water and extracted with ethyl acetate
(3 £ 20ml). The extract was dried over
anhydrous Na2SO4, evaporated to afford the
2-(4-butyl-3,5-dimethoxyphenyl) aceto-
nitrile (5); yield 68%; Rf 0.25; amorphous
solid; mp 64–668C; IR (KBr) nmax: 2933
(CvCZH), 2268 (ZCN), 1576 (CvC),
1
(CZO)cm21; H NMR (CDCl3, d ppm):
6.36 (2H, s, Ar–H), 4.34 (2H, s, ZCH2),
4.07 (1H, s, ZOH), 3.80 (6H, s, ZOCH3),
2.64 (2H, t, J ¼ 6.2 Hz, H-10), 1.33–1.36
(2H, m, H-20), -1.28-1.32-134 (2H, m, H-
30), 0.89 (3H, t, J ¼ 6.5 Hz, H-40); 13C
NMR (CDCl3, d ppm): 158.2 (C-3,C-5),
137.1 (C-2,C-6), 117.8 (C-4), 104.7 (C-1),
55.6 (ZOCH3), 41.3 (ZCH2), 38.9 (C-10),
23.4 (C-20), 22.7 (C-30), 14.1 (C-40);
Elemental analysis: found: C, 69.47%; H,
8.84%; calcd for C13H20O3: C, 69.60%, H,
8.97%.
1028 (CZO) cm21 1H NMR (CDCl3, d
;
ppm): 6.27 (2H, s, Ar–H), 4.32 (6H, s,
ZOCH3), 2.57 (2H, t, J ¼ 7.1 Hz, H-10),
3.68 (2H, s, ZCH2), 1.32–1.62 (4H, m, H-
20,H-30), 0.93 (3H, t, J ¼ 6.8 Hz, H-40); 13C
NMR (75MHz, d CDCl3): 158.6 (C-3,C-5),
130.5 (C-1), 118.6 (ZCuN), 108.7 (C-4),
105.3 (C-2,C-6), 56.2 (ZOCH3), 38.7
(ZCH2), 34.3 (C-10), 23.5 (C-20), 22.4 (C-
30), 14.1 (C-40); Elemental analysis: Found:
C, 71.97%; H, 8.13%; N, 5.91%; calcd for
C14H19NO2: C, 72.06%; H, 8.20%; N,
5.98%.
3.4 4-Butyl-3,5-dimethoxybenzyl
bromide (4)
4-Butyl-3,5-dimethoxybenzyl alcohol (3)
(4.1 g, 180 mmol) was dissolved in dry
benzene (30–35 ml). The solution was
treated with phosphorous tribromide
(6.7 ml, 360 mmol) and the resulting
mixture was stirred for 4 h. Then, the
reaction mixture was poured on to ice cold
water, and the organic layer was separated
and evaporated to afford crude 4-butyl-
3,5-dimethoxybenzyl bromide (4); yield:
70%; Rf 0.6; oil; IR (KBr): 2931
(CvCZH), 1581 (CvC), 1026 (CZO)
cm21; 1H NMR (CDCl3, d ppm): 6.32 (2H,
s, Ar–H), 4.57 (2H, s, ZCH2), 3.76 (6H, s,
ZOCH3), 2.61 (2H, t, J ¼ 5.8 Hz, H-10),
1.28–1.34 (4H, m, H-20,H-30), 0.94 (3H, t,
J ¼ 6.1 Hz, H-40); 13C NMR (CDCl3, d
ppm): 158.1 (C-3,C-5), 138.4 (C-2,C-6),
117.5 (C-4), 134.5 (C-1), 55.4 (ZOCH3),
39.5 (ZCH2), 23.1 (C-20), 22.4 (C-30), 16.1
3.6 2-(4-Butyl-3,5-dimethoxyphenyl)
acetic acid (6)
2-(4-Butyl-3,5-dimethoxyphenyl) aceto-
nitrile (5) (3.8 g, 19.8 mmol) was dissolved
in a mixture of water (15 ml) and dioxane
(15 ml). Then, potassium hydroxide
(12.81g in 12ml of H2O, 228 mmol) was
added, and the mixture was refluxed for
11–12h. The reaction mixture was poured
onto ice cold water and extracted with ethyl
acetate (25ml). The extract was discarded
and the aqueous layer was acidified with
dilute HCl. Precipitates were filtered out to

Journal of Asian Natural Products Research
7
afford 2-(4-butyl-3,5-dimethoxyphenyl)
acetic acid (6); yield 73%; Rf 0.4;
amorphous solid; mp 123–1258C; IR
found: C, 67.57%; H, 7.96%; calcd for
C15H22O4: C, 67.64%; H, 8.32%.
(KBr) nmax
(CvCZH), 1711 (CvO acidic), 1575
(CvC), 1046 (CZO) cm21 1H NMR
:
3284 (OZH), 2924
3.8 Methyl 4-butyl-2-formyl-3,5-
dimethoxyphenyl acetate (8)
;
(CDCl3, d ppm): 11.13 (1H, s, ZCOOH),
6.26 (2H, s, Ar), 4.26 (2H, s, ZCH2), 3.73
(6H, s, ZOCH3), 2.64 (2H, t, J ¼ 7.1 Hz,
H-10), 1.30–1.61 (4H, m, H-20,H-30), 0.92
(3H, t, J ¼ 6.8 Hz, H-40); 13C NMR
Phosphorous
oxychloride
(1.24 ml,
11.3mmol) was added dropwise into a
stirred solution of methyl 2-(4-butyl-3,5-
dimethoxyphenyl) acetate (7) (3.0 g,
11.3mmol) in dry DMF (15 ml) at 558C.
The reaction mixture was heated at about
1008C for 2 h and stirred overnight at room
temperature. Then, the reaction mixture was
poured into aqueous solution of sodium
acetate (10%, 10ml) and shaken vigorously.
Methyl 4-butyl-2-formyl-3,5-dimethoxy-
phenyl acetate (8) was precipitated out;
yield 75%; Rf 0.3; semi-solid; IR (KBr)
(CDCl3,
d ppm): 176.3 (carboxylic
CvO), 159.2 (C-3,C-5), 134.4 (C-1),
108.5 (C-4), 106.3 (C-2,C-6), 56.5
(ZOCH3), 48.7 (ZCH2), 34.6 (C-10), 23.7
(C-20), 22.3 (C-30), 14.1 (C-40); Elemental
analysis: found: C, 66.56%; H, 7.86%;
calcd for C14H20O4: C, 66.64%; H, 7.97%.
nmax: 2932 (CvCZH), 1724 (ester CvO),
1686 (aldehyde CvO), 1577 (CvC), 1052
3.7 Methyl 2-(4-Butyl-3,5-
dimethoxyphenyl) acetate (7)
1
(CZO) cm21; H NMR (CDCl3, d ppm):
A stirred solution of 2-(4-butyl-3,5-
dimethoxyphenyl) acetic acid (6) (3.5 g,
13.8 mmol) in dry methanol (20 ml) was
treated dropwise with conc. H2SO4 (3 ml).
The mixture was refluxed for 7–8 h. The
reaction was monitored by TLC. After the
completion of reaction, the mixture was
concentrated to 55 ml and extracted with
ethyl acetate (3 £ 30 ml). The extract was
washed with saturated brine, dried, and
concentrated to give crude oil which was
distilled to afford methyl 2-(4-butyl-3,5-
dimethoxyphenyl) acetate (7); yield 81%;
10.41 (1H, s, ZCHO), 6.37 (1H, s, Ar–H),
4.31 (2H, s, ZCH2), 3.73 (3H, s, ZOCH3),
3.71 (3H, s, ZOCH3), 3.26 (3H, s, ester
ZOCH3), 2.68 (2H, t, J ¼ 7.1 Hz, H-10),
1.26Z1.61 (4H, m, H-20,H-30), 0.92 (3H, t,
J ¼ 6.8 Hz, H-40); 13C NMR (CDCl3, d
ppm): 201.8 (aldehyde CvO), 169.4 (ester
CvO), 163.4 (C-5), 161.3 (C-3), 135.8 (C-
2), 125.2 (C-6), 121.4 (C-4), 116.5 (C-1),
56.3 (Ar–OCH3), 52.4 (ester ZOCH3), 42.2
(ZCH2), 34.3 (C-10), 23.4 (C-20), 22.5
(C-30), 14.1 (C-4?); Elemental analysis:
found: C, 65.17%; H, 7.46%; calcd for
C16H22O5: C, 65.28%; H, 7.52%.
Rf 0.5; oil; IR (KBr) nmax
(CvCZH), 1732 (CvO ester), 1587
(CvC), 1053 (CZO) cm21 1H NMR
: 2926
;
3.9 Methyl 4-butyl 2-carboxy-3,5-
dimethoxyphenyl acetate (9)
(CDCl3, d ppm): 6.36 (2H, s, Ar–H), 4.28
(2H, s, ZCH2), 3.73 (6H, s, ZOCH3), 3.63
(3H, s, ester ZOCH3). 2.65 (2H, t,
J ¼ 7.1 Hz, H-10), 1.29–1.63 (4H, m, H-
20,H-30), 0.93 (3H, t, J ¼ 6.8 Hz, H-40); 13C
NMR (CDCl3, d ppm): 168.6 (ester
CvO), 158.7 (C-3,C-5), 134.2 (C-1),
108.7 (C-4), 106.6 (C-2,C-6), 56.4
(ZOCH3), 52.7 (ester ZOCH3), 46.5
(ZCH2), 34.7 (C-10), 23.3 (C-20), 22.4
(C-30), 14.1 (C-40); Elemental analysis:
Methyl 4-butyl-2-formyl-3,5-dimethoxy-
phenyl acetate (8) (2 g, 6.802 mmol) and
sulfamic acid (2.24 g, 23.13 mmol) in
30 ml H2O:THF:DMSO (20:10:1) at 08C
were treated with NaClO2 (1.99 g,
22.01 mmol) in 5 ml H2O. The reaction
mixture was stirred for 20 min at 08C and
then diluted with ethyl acetate (100 ml),
washed with saturated aqueous ammonium

8
A. Saeed et al.
chloride (2 £ 30 ml) and saturated aqueous
sodium chloride (30 ml). Organic layer
was dried over anhydrous sodium sulfate
and evaporated to afford methyl 4-butyl 2-
carboxy-3,5-dimethoxyphenyl acetate (9);
(carboxylic ZCvO), 168.5 (carboxylic
ZCH2ZCvO), 161.7 (C-5), 160.5 (C-3),
136.2 (C-2), 124.3 (C-1), 118.4 (C-4),
105.7 (C-6), 55.8 (ZOCH3), 55.6
(ZOCH3), 42.5 (ZCH2), 34.7 (C-10),
23.4 (C-20), 22.5 (C-30), 14.1 (C-40); MS
(70 eV) m/z (%): 296 [M]þz (57), 251 (34),
177 (16), 147 (100%), 91 (28); Elemental
analysis: Found: C, 60.63%; H, 6.65%;
calcd for C15H20O6: C, 60.80%, H, 6.78%.
yield 67%; Rf 0.35; oil; IR (KBr) nmax
:
3276 (OZH), 2935 (CvCZH), 1731
(ester CvO), 1716 (carboxylic CvO),
1564 (CvC), 1046 (C-O) cm21; 1H NMR
(CDCl3, d ppm): 8.76 (1H, s, ZCOOH),
7.56 (1H, s, H-6), 4.32 (2H, s, ZCH2), 3.72
(3H, s, ZOCH3), 3.69 (3H, s, ZOCH3),
3.61 (3H, s, ester ZOCH3), 2.63 (2H, t,
J ¼ 7.1 Hz, H-10), 1.31–1.63 (4H, m, H-20,
H-30), 0.90 (3H, t, J ¼ 6.8 Hz, H-40); 13C
NMR (CDCl3, d ppm): 175.2 (carboxylic
CvO), 167.6 (ester CvO), 161.2 (C-3),
160.4 (C-5), 136.8 (C-2), 127.3 (C-6),
121.6 (C-4), 117.4 (C-1), 62.4 (ester
ZOCH3), 55.7 (ZOCH3), 55.4 (ZOCH3),
42.6 (ZCH2), 34.5 (C-10), 23.5 (C-20), 22.6
(C-30), 14.1 (C-40); Elemental analysis:
Found: C, 61.83%; H, 7.07%; calcd for
C16H22O6: C, 61.91%; H, 7.13%.
3.11 7-Butyl-6,8-dimethoxy-3-
pentylisochromen-1-one (11)
4-Butyl-3,5-dimethoxyhomophthalic acid
(10) was converted into corresponding
anhydride (100) by refluxing it with acetic
anhydride in the presence of dry toluene as
solvent and used as such in next step.
The anhydride (100) (0.5 g, 1.96 mmol)
was condensed with hexanoyl chloride
(1.14 ml, 8.29 mmol) in the presence
of TMG and triethyl amine afforded the
7-butyl-6,8-dimethoxy-3-pentylisochro-
men-1-one. After completion, the reaction
mixture was concentrated and then
extracted with ethyl acetate. The two
phases were separated, and the organic
layer was washed with saturated sodium
chloride solution and then dried over
anhydrous (Na2SO4) to get 7-butyl-6,8-
dimethoxy-3-pentylisochromen-1-one (11),
which was then purified by preparative
TLC using (petroleum ether and ethyl
acetate, 7:3) as eluent; yield 74%; Rf 0.7;
amorphous solid; mp 195–1968C; IR (KBr)
3.10 4-Butyl-3,5-
dimethoxyhomophthalic acid (10)
Methyl 4-butyl-2-carboxy-3,5-dimethoxy-
phenyl acetate (9) (1.5 g, 4.84 mmol) was
dissolved in ethanol (15 ml) and treated
with KOH (5%, 10 ml). The reaction
mixture was refluxed for 1–2 h and the
ethanol was rotary evaporated. The aqu-
eous layer was acidified with dilute
hydrochloric acid to afford 4-butyl-3,5-
dimethoxyhomophthalic acid (10); yield
77%; Rf 0.3; semi-solid; mp 123–1258C;
IR (KBr) nmax: 3226 (OZH), 2937
(CvCZH), 1737 (carboxylic CvO),
1718 (carboxylic CH2ZCvO), 1586
n
max: 3027 (CvCZH), 2956 (CZH), 1725
1
(CvO lactonic), 1577 (CvC) cm21; H
NMR (CDCl3, d ppm): 6.64 (1H, s, H-5),
6.17 (1H, s, H-4), 3.76 (3H, s, ZOCH3),
3.72 (3H, s, ZOCH3), 2.63 (2H, t,
J ¼ 7.4 Hz, H-10), 2.53–2.56 (2H, m, H-
100), 1.34–1.85 (10H, m, H-20,H-30,H-40,H-
200,H-300), 0.93 (3H, t, J ¼ 7.2 Hz, H-400),
0.89 (3H, t, J ¼ 6.8 Hz, H-50); 13C NMR
(CDCl3, d ppm): 162.6 (CvO), 161.4 (C-
6), 160.7 (C-8), 158.5 (C-3), 138.4 (C-10),
127.8 (C-4), 118.5 (C-7), 106.3 (C-5),
103.6 (C-9), 56.7 (ZOCH3), 56.4
(CvC), 1044 (CZO) cm21 1H NMR
;
(CDCl3, d ppm): 11.02 (1H, s, ZCOOH),
10.91 (1H, s, ZCH2ZCOOH), 6.34 (1H,
s, H-6), 3.73 (3H, s, ZOCH3), 3.71 (3H,
s, ZOCH3), 2.87 (2H, s, ZCH2), 2.64
(2H, t, J ¼ 7.1 Hz, H-10), 1.32Z1.67 (4H,
m, H-20,H-30), 0.91 (3H, t, J ¼ 6.8 Hz, H-
40); 13C NMR (CDCl3, d ppm): 175.6

Journal of Asian Natural Products Research
9
(ZOCH3), 34.7 (C-10), 34.1 (C-100), 31.5
3.13 3-Butyl-6-(2-hydroxyheptyl)-2,4-
dimethoxybenzoic acid (13)
(C-20), 24.8 (C-200), 24.3 (C-30), 22.9 (C-40),
22.4 (C-300), 14.2 (C-400); 14.1 (C-50); MS
(70eV) m/z (%): 332 [M]þz (37), 261 (62),
234 (100), 157 (26); Elemental analysis:
Found: C, 72.14%; H, 8.36%; calcd for
C20H28O4: C, 72.28%; H, 8.43%.
Sodium borohydride (0.13 g, 3.43mmol)
was added portionwise to a stirred solution
of 3-butyl-2,4-dimethoxy-6-(2-oxoheptyl)
benzoic acid (12) (0.2g, 0.573 mmol) in
absolute ethanol (15 ml). The reaction
mixture was stirred for 2 h at room
temperature, diluted with water (50 ml),
acidified with conc. HCl, and stirred for a
further 2 h. It was then saturated with
ammonium sulfate, and extracted with ethyl
acetate (3 £ 30ml). The organic layer was
dried over anhydrous magnesium sulfate
and concentrated to afford 3-butyl-6-(2-
hydroxyheptyl)-2,4-dimethoxy benzoic
acid (13); yield 76%; Rf 0.4; semi-solid;
IR (KBr) nmax: 3453 (OZH), 3026
(CvCZH), 2914 (CZH), 1726 (carboxylic
3.12 3-Butyl-2,4-dimethoxy-6-(2-
oxoheptyl) benzoic acid (12)
A
stirred solution of 7-butyl-6,8-
dimethoxy-3-pentylisochromen-1-one (11)
(0.35 g, 1.05mmol) in ethanol (7–8 ml)
was treated with 5% KOH (15ml), and the
mixture was refluxed for 4 h. After cooling
the reaction mixture, most of the ethanol
was evaporated under reduced pressure.
Cold water (20 ml) was added and the
mixture was acidified with dilute hydro-
chloric acid when solid was precipitated.
Filtration followed by drying under vacuum
afforded 3-butyl-2,4-dimethoxy-6-(2-oxo-
heptyl) benzoic acid (12); yield 72%; Rf
0.45; sticky solid; IR (KBr) nmax: 3342
(OZH), 3023 (CvCZH), 2952 (CZH),
1734 (carboxylic CvO), 1712 (ketonic
CvO), 1581 (CvC) cm21
;
1H NMR
(CDCl3, d ppm): 10.9 (1H, s, ZCOOH),
6.42 (1H, s, H-5), 4.43 (1H, s, ZOH), 3.78
(3H, s, ZOCH3), 3.76 (3H, s, ZOCH3),
2.81–2.84 (2H, m, ZCH2), 2.62 (2H, t,
J ¼ 7.4 Hz, H-10), 2.55–2.58 (2H, m, H-
100), 1.34–1.85 (10H, m, H-20,H-30,H-40,H-
200,H-300), 0.94 (3H, t, J ¼ 7.1 Hz, H-400),
0.89 (3H, t, J ¼ 6.7 Hz, H-50); 13C NMR
(CDCl3, d ppm): 207.3 (ketonic CvO),
168.7 (carboxylic CvO), 162.8 (C-5),
160.7 (C-3), 136.7 (C-1), 118.5 (C-4),
105.6 (C-2), 102.7 (C-6), 78.5 (C-20), 56.7
(ZOCH3), 56.4 (ZOCH3), 40.7 (C-10), 37.5
(C-30), 34.6 (Ar–CH3), 31.5 (C-100), 24.6
(C-40), 23.8 (C-200), 22.9 (C-50), 22.5 (C-300),
22.1 (C-60), 14.2 (C-400), 14.1 (C-70); MS
(70eV) m/z (%): 352 [M]þz (25), 307 (32),
291 (100), 251 (22), 193 (13); Elemental
analysis: Found: C, 68.10%; H, 9.08%;
calcd for C20H32O5: C, 68.15%; H, 9.16%.
CvO), 1584 (CvC) cm21
;
1H NMR
(CDCl3, d ppm): 10.7 (1H, s, ZCOOH),
6.36 (1H, s, H-5), 3.77 (3H, s, ZOCH3),
3.74 (3H, s, ZOCH3), 2.83 (2H, s,
ZCH2benzylic), 2.64 (2H, t, J ¼ 7.2 Hz,
H-100), 2.54–2.57 (2H, m, H-10), 1.33–
1.83 (10H, m, H-20,H-30,H-40,H-200,H-300),
0.92 (3H, t, J ¼ 7.2 Hz, H-400), 0.89 (3H, t,
J ¼ 6.7 Hz, H-50); 13C NMR (CDCl3, d
ppm): 207.3 (ketonic C ¼ O), 168.5
(carboxylic CvO), 162.4 (C-5), 160.8 (C-
3), 136.4 (C-1), 108.5 (C-4), 105.6 (C-2),
102.7 (C-6), 56.5 (ZOCH3), 56.3
(ZOCH3), 46.7 (C-10), 43.5 (C-30), 34.4
(Ar–CH3), 31.3 (C-100), 24.7 (C-40), 23.6
(C-200), 23.1 (C-50), 22.7 (C-300), 22.3 (C-60),
14.2 (C-400), 14.0 (C-70); MS (70 eV) m/z
3.14 (6)-7-Butyl-6,8-dimethoxy-3-
pentyl-3,4-dihydroisochromen-1-one (14)
3-Butyl-6-(2-hydroxyheptyl)-2,4-dimethox-
ybenzoic acid (13) (0.14 g, 0.41 mmol) was
dissolved in acetic anhydride (4 ml) and
refluxed for 3 h. The reaction mixture was
then poured into chilled water, and it was
þz
(%): 350 [M] (31), 279 (42), 251 (56),
191 (100), 91 (25); Elemental analysis:
Found: C, 68.47%; H, 8.41%; calcd for
C20H30O5: C, 68.57%; H, 8.57%.

10
A. Saeed et al.
extracted with ethyl acetate (2 £ 20 ml).
Organic layer was washed with 1%
NaHCO3 and water. The organic layer
was dried with Na2SO4 and concentrated
to get (^)-7-butyl-6,8-dimethoxy-3-pen-
tyl-3,4-dihydroisochromen-1-one (14);
yield 66%; Rf 0.65; yellow oil; IR (KBr)
concentrated to give (^)-7-butyl-6,8-dihy-
droxy-3-pentyl-3,4-dihydroisochromen-1-
one (15); yield 62%; Rf 0.3; oil; IR (KBr)
n
max: 3421 (OZH), 3046 (CvCZH), 2954
(CZH), 1724 (CvO), 1587 (CvC) cm21
;
1H NMR (CDCl3, d ppm): 11.43 (2H, s,
ZOH), 6.20 (1H, s, H-5), 4.46–4.49 (1H,
m, H-3), 3.56 (1H, dd, Jgem ¼ 12.4Hz,
Jtrans ¼ 14.2 Hz, H-4), 3.25 (1H, dd,
Jgem ¼ 12.4Hz, Jcis ¼ 6.2 Hz, H-4), 2.80–
2.83 (2H, m, ZCH2), 2.64 (2H, t,
J ¼ 7.5 Hz, H-10), 2.51–2.54 (2H, m, H-
100), 1.34–1.87 (10H, m, H-20,H-30,H-40,H-
200,H-300), 0.94 (3H, t, J ¼ 7.2 Hz, H-400),
0.91 (3H, t, J ¼ 6.8 Hz, H-50); 13C NMR
(CDCl3, d ppm): 169.5 (CvO), 161.7 (C-
8), 160.1 (C-6), 138.4 (C-10), 114.7 (C-7),
106.1 (C-5), 101.8 (C-9), 79.3 (C-3), 34.6
(C-10), 33.1 (C-4), 32.8 (C-100), 31.4 (C-20),
24.5 (C-200), 22.8 (C-30), 22.5 (C-40), 22.1
(C-300), 14.1 (C-400), 14.0 (C-50); MS
(70 eV) m/z (%): 306 [M]þz (47), 278
(35), 235 (67), 206 (100), 189 (43), 146
(34); Elemental analysis: Found: C,
70.43%; H, 8.47%; calcd for C18H26O4:
C, 70.55%; H, 8.54% (Petroleum ether:
ethyl acetate, 8:2).
n
max: 3037 (CvCZH), 2943 (CZH), 1721
;
(CvO), 1586 (CvC) cm21 1H NMR
(CDCl3, d ppm): 6.31 (1H, s, H-5), 4.42–
4.46 (1H, m, H-3), 3.84 (3H, s, ZOCH3),
3.81 (3H, s, ZOCH3), 3.51 (1H, dd,
Jgem ¼ 12.4 Hz, Jtrans ¼ 14.2 Hz, H-4),
3.22 (1H, dd, Jgem ¼ 12.4 Hz, Jcis ¼ 6.2 -
Hz, H-4), 2.77–2.81 (2H, m, ZCH2), 2.61
(2H, t, J ¼ 7.4 Hz, H-10), 2.52–2.56 (2H,
m, H-100), 1.35–1.87 (10H, m, H-20,H-30,
H-40,H-200,H-300), 0.93 (3H, t, J ¼ 7.2 Hz,
H-400), 0.89 (3H, t, J ¼ 6.7 Hz, H-50); 13C
NMR (CDCl3, d ppm): 168.4 (CvO),
161.7 (C-6), 158.8 (C-8), 138.4 (C-10),
114.2 (C-7), 106.3 (C-5), 102.6 (C-9), 79.1
(C-3), 56.7 (ZOCH3), 56.2 (ZOCH3),
41.8 (C-4), 34.3 (C-10), 33.2 (C-100), 31.2
(C-20), 30.7 (C-200), 24.4 (C-30), 22.7 (C-
40), 22.2 (C-300), 14.1 (C-400), 14.0 (C-50);
MS (70eV) m/z (%): 334 [M]þz (37), 306
(53), 263 (28), 234 (100), 206 (36), 165
(21); Elemental analysis: Found: C,
71.73%; H, 8.97%; calcd for C20H30O4:
C, 71.85%; H, 9.04%.
Acknowledgment
The authors are grateful to the Pakistan Science
Foundation (PSF) for a research grant under
Project No. PSF/Res/C-QU/CHEM (395).
3.15 (6)-7-Butyl-6,8-dihydroxy-3-
pentyl-3,4-dihydroisochromen-1-one (15)
(^)-7-Butyl-6,8-dimethoxy-3-pentyl-3,4-
dihydroisochromen-1-one (14) (1.25 mmol)
was dissolved in ethanethiol (3.5ml) and
the solution was cooled on ice. Aluminium
chloride (3.8mmol) was added as three
portions with an interval of 30min. After all
the aluminium chloride was added, the
reaction mixture was stirred on ice for 1 h.
The reaction was quenched with water,
alkalinized (10% NaHCO3), and extracted
with ethyl acetate. Sodium chloride was
added to enhance layer separation. The
combined organic layers were washed once
with brine, dried over sodium sulfate, and
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