Short synthesis of functionalized pentalongin derivatives using pyridinium ylid chemistry

Article abstract of DOI:10.1016/j.tet.2010.07.012

3-Substituted pentalongin derivatives possessing an acetal function at C-1 were synthesized by cyclization of acylmethylnaphthoquinones. The latter naphthoquinones were prepared starting from 2-dioxolanylnaphthoquinone by means of both a stoichiometric and a catalytic method deploying various pyridinium ylids.

Full text of DOI:10.1016/j.tet.2010.07.012

Tetrahedron 66 (2010) 7088e7096
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Short synthesis of functionalized pentalongin derivatives using
pyridinium ylid chemistry
*
Pieter Claes, Jan Jacobs, Sven Claessens, Norbert De Kimpe
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Substituted pentalongin derivatives possessing an acetal function at C-1 were synthesized by cycli-
zation of acylmethylnaphthoquinones. The latter naphthoquinones were prepared starting from 2-di-
oxolanylnaphthoquinone by means of both a stoichiometric and a catalytic method deploying various
pyridinium ylids.
Received 5 May 2010
Received in revised form 5 July 2010
Accepted 7 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pyranonaphthoquinones
Pentalongin
Pyridinium ylids
1. Introduction
Natural products are an important source of lead compounds
toward drug discovery. For instance, anticancer drugs, such as
daunorubicin, doxorubicin, mitomycin, mitoxantrones, and sain-
topin are all quinones derived from natural products or are natural
products themselves. Pentalongin 1 was isolated from the roots of
the Central East-African woody herb Pentas longiflora Oliv.1 The
roots of this herb are used in the Kenyan traditional medicine as
a cure against tapeworm, itchy rash, and acne. A decoction of the
roots is mixed with milk and used as a cure for malaria, but causes
acute diarrhea and acts as a purgative. In Rwanda the plant is
known as Isagara and it is mixed with butter as an ointment to treat
scabies and the skin disease Pityriasis versicolor.2 Multiple syn-
theses are known for this natural product applying a lot of different
strategies to construct the heterocyclic pyran ring.3 In previous
synthetic studies, Aldersley et al. and more recently Kobayashi et al.
synthesized 3-substituted pentalongin derivatives 2 by a pyr-
idinium ylid and an enamine strategy, respectively.4,5 An important
factor influencing drug distribution is the octanol/water partition
coefficient (log P). In order to have a broad range of compounds,
having different log P values, we envisaged the synthesis of
3-substituted benzo[g]chromenediones 3 bearing an acetal func-
tion at C-1 (Fig. 1). This acetal can serve as a point of attachment for
further functionalization, such as the addition of a sugar side chain
to alter the solubility. Table 1 gives an overview of the calculated
Figure 1. Proposed elaboration of the basic scaffold of pentalongin.
Table 1
Calculated log P values for the elaboration of the pentalongin basic skeleton using
ChemDraw Ultra 7.0 (
s
¼0.43e0.83 log P units)
R1
R2
OCH2CH2OH
OH
H
OMe
Me
H
i-Pr
t-Bu
ꢀ0.07
0.30
0.81
1.35
1.75
1.87
2.00
2.16
2.49
2.56
2.83
0.08
0.46
0.97
1.51
1.90
2.03
2.15
2.31
2.64
2.71
2.98
0.16
0.53
1.04
1.58
1.98
2.10
2.23
2.39
2.72
2.79
3.06
0.44
0.82
1.33
1.87
2.26
2.39
2.52
2.67
3.00
3.07
3.35
2,5-(MeO)2C6H3
4-MeOC6H4
C6H5
4-FC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
* Corresponding author. Tel.: þ32 9 264 59 51; fax: þ32 9 264 62 43; e-mail
address: norbert.dekimpe@UGent.be (N. De Kimpe).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.012

P. Claes et al. / Tetrahedron 66 (2010) 7088e7096
7089
log P values of our target compounds using ChemDraw Ultra 7.0
for over a month. The synthesis of 2-(1,3-dioxolan-2-yl)-1,4-
naphthoquinone 9 was achieved starting from the acetal formation
under DeaneStark conditions of the known 1,4-dimethoxy-2-for-
mylnaphthalene 10,14 resulting in 2-(1,3-dioxolan-2-yl)-1,4-dime-
thoxynaphthalene 11 in a 74% yield. Two reports on the oxidation of
2-(1,3-dioxolan-2-yl)-1,4-dimethoxynaphthalene 11 toward 2-(1,3-
dioxolan-2-yl)-1,4-naphthoquinone 9 with silver(II) dipicolinate,15
silver(I) oxide,16 cobalt(III) fluoride,16 and CAN16 as oxidants are
known in the literature. We herein report a procedure using CAN
minimizing the reaction time to two minutes in order to reduce
acetal hydrolysis to obtain 2-(1,3-dioxolan-2-yl)-1,4-naph-
thoquinone 9 in 86% yield (Scheme 1).
(
s
¼0.43e0.83 log P units). Pentalongin has a log P value of 0.53. The
hydroxyethoxy and the hydroxyl substituents at C-1 lower the log P,
while a methoxy group at C-1 increases the log P. Bulky sub-
stituents at C-3 increase the log P.
Moreover, these benzo[g]chromenediones with an acetal func-
tion at C-1 are also found in nature. 1-Hydroxydehydroherbarin 4
was isolated from a Corynespora species occurring in the cavern
beard lichen Usnea cavernosa.6 Ascomycone A 5 and B 6 were iso-
lated from an unidentified Ascomycete and exhibit activity against
the phytopathogens Magnaporthe grisea (rice blast fungus) and
Fusarium graminearum (wheat head blight fungus) (Fig. 2).7
Next, 2-(1,3-dioxolan-2-yl)-1,4-naphthoquinone 9 was reacted
with a wide variety of pyridinium ylids, which were generated in situ
by means of deprotonation of the corresponding pyridinium salts 12
with triethylamine. Interestingly, the addition of 1 equiv of triethyl-
amine to the reaction mixture led to the formation of acylmethyl
substituted quinones 13 together with trace amounts of 1-hydroxy-
ethoxy-pyranonaphthoquinones 14. Addition of 1.5 equiv of tri-
ethylamine led to full conversion of the acylmethyl substituted
naphthoquinones 13 to the 1-(hydroxyethoxy)pyranonaphtho-
quinones 14 in moderate to good yields (Scheme 2). In case of acyl-
methyl substituted naphthoquinones 13f and 13g, ring closure failed
under the given reaction conditions. However, using an excess of
Na2CO3 in CH3CN at 60 ꢁC, ring closure of acylmethyl substituted
naphthoquinones 13f and 13g could finally be performed (Scheme 2).
Since all 1-(hydroxyethoxy)pyranonaphthoquinones 14 showed
moderate sensitivity to light, all reactions were shielded from
daylight by means of aluminum foil. 1-Hydroxyethoxypyrano-
naphthoquinones 14 could be deprotected under acidic conditions
(aqueous HCl in HPLC grade solvent or acetic acid/H2O 1:1) to yield
the target 1-hydroxypyranonaphthoquinones 15. Nevertheless,
these compounds were highly unstable and decomposed readily
upon exposure to light. This decomposition involves more than
likely radicals, since it is known that quinones are prone to radical
OMe O
OH
OH
O
OMe
O
OH
O
OH
O
O
MeO
MeO
MeO
O
O
O
4 1-hydroxydehydroherbarin
5 ascomycone A
6 ascomycone B
Figure 2. Benzo[g]chomenedione natural products bearing an acetal function at C-1.
2. Results and discussion
Pyridinium ylids are versatile tools in organic synthesis, giving
rise to different heterocycles, for instance pyridines, furans, aze-
pines, etc.8 More specifically, in quinone chemistry, pyridinium
ylids proved to be very useful to introduce acetonyl side chains onto
quinone moieties.5 After introduction of the acetonyl side chain,
further elaboration toward the natural product isagarin,9 anthra-
quinones, pyranonaphthoquinones,5,10 2-azaanthraquinones,11 and
indolizines12 has been reported.
Initially, three quinones were considered as suitable Michael
acceptors for pyridinium ylid chemistry, namely 2-formyl-1,4-
naphthoquinone 7, 2-diethoxymethyl-1,4-naphthoquinone 8, and
2-(1,3-dioxolan-2-yl)-1,4-naphthoquinone 9 (Fig. 3). 2-Formyl-1,4-
naphthoquinone 7 was prepared by means of an oxidative deme-
thylation of 1,4-dimethoxy-2-formylnaphthalene 10 with cerium
(IV) ammonium nitrate (CAN). However, this aldehyde 7 was not
a suitable candidate for further elaboration since it decomposed
within minutes after synthesis. Reports in literature confirm this
observation and solve the instability issue by in situ generation of
2-formyl-1,4-naphthoquinone 7.13 However, this in situ protocol
did not produce satisfying results under the conditions presented
in this report. Therefore, 2-diethoxymethyl-1,4-naphthoquinone 8
was evaluated as a potential starting material, but this quinone 8
was an oily substance, very prone to hydrolysis. Finally, 2-(1,3-
dioxolan-2-yl)-1,4-naphthoquinone 9 was the quinone of choice
since it is a powder, which, upon storage under nitrogen, is stable
reactions.17,18 As
a result, only three 1-hydroxypyranonaph-
thoquinones 15 could be isolated in 48e91% yield (Scheme 2).
Therefore, it was decided to prepare the 1-methoxypyranonaph-
thoquinones 16 as an alternative, more stable target. These
derivatives were initially prepared by means of an acid catalyzed
acetalisation of 1-(hydroxyethoxy)pyranonaphthoquinones 14 in
methanol. However, this method only provided 1-methoxypyr-
anonaphthoquinones 16bee in 31e87% yield (Scheme 2). For all the
other derivatives, a boron(III) fluoride catalyzed acetalisation with
trimethyl orthoformate furnished the target compounds 16 in
moderate to good yields (Scheme 2). In contrast to 1-hydroxypyr-
anonaphthoquinones 15, the corresponding 1-methoxy analogues
proved to be easy to handle crystalline compounds, which were
only slightly sensitive to light. Therefore, these compounds are
ideal intermediates for further functionalisation at C-1.
Recently, a catalytic version of pyridinium ylid chemistry was
published by Yadav and Garima to synthesize aziridines.19 In this
paper, a one-pot reaction of phenacyl bromides and N-tosyl im-
ines catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO), yielding
the corresponding aziridines is described. Benefits of this method
are the catalytic use of organic base and the in situ preparation of
pyridinium salts as well as the corresponding ylids. However, in
our case, the use of DABCO as the catalytic tertiary amine under
Figure 3. Proposed starting materials for the synthesis of pentalongin derivatives 3.
Scheme 1.

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P. Claes et al. / Tetrahedron 66 (2010) 7088e7096
Scheme 2.
the described conditions with 1-bromo-3-methylbutan-2-one 17i
and 2-(1,3-dioxolan-2-yl)-1,4-naphthoquinone 9 gave no reaction,
most probably due to the formation of a charge transfer complex
of the quinone moiety with DABCO. Repeating the same reaction
with a catalytic amount of pyridine instead of DABCO yielded
1-(2-hydroxyethoxy)-3-isopropyl-1H-benzo[g]isochromene-5,10-
dione 14i in 31% yield. In the optimal reaction conditions, 1.5 equiv
2-yl)-1,4-naphthoquinone 9, and 0.2 equiv pyridine were reacted
overnight at room temperature to form the acylmethyl substituted
quinone 13 and subsequently heated at 60 ꢁC for 20 h to induce
cyclization toward 1-(hydroxyethoxy)pyranonaphthoquinones 14
(Scheme 3). The catalytic version of the reaction proved to give
similar results in the synthesis of 1-(hydroxyethoxy)pyr-
anonaphthoquinones 14 in comparison to the equimolar method
(Table 2).
Na2CO3, 1 equiv a-halogenated ketone 17, 1 equiv 2-(1,3-dioxolan-
Scheme 3. Catalytic version of the synthesis of 1-(hydroxyethoxy)pyranonaphthoquinones 14.

P. Claes et al. / Tetrahedron 66 (2010) 7088e7096
7091
Table 2
3. Conclusion
Comparison between the equimolar and catalytical synthesis of 1-(hydroxyethoxy)
pyranonaphthoquinones 14
A new methodology toward the synthesis of substituted pen-
talongin derivatives bearing an acetal function at C-1 is described.
This methodology is based on the addition of pyridinium ylids to
introduce the necessary acylmethyl side chain. Both a catalytic and
a stoichiometric version of this reaction were investigated. 1-
(Hydroxyethoxy)pyranonaphthoquinones 14 proved to be key in-
termediates for the synthesis of 1-hydroxypyranonaphthoquinones
15 and 1-methoxypyranonaphthoquinones 16.
Compound
R
Equimolar method (%) Catalytic method (%)
Crudec Isolated Yield Crudec Isolated yield
14a
14b
14c
14d
14e
14f
14g
14h
14i
C6H5
57
47
55
44
68
70b
52
43
52
41
65
69
48
42
27
74
24
72
53
77
57
52
57
70a
60
42a
d
d
32
d
d
d
d
d
31
18
4-MeOC6H4
4-BrC6H4
4-FC6H4
4-ClC6H4
4-MeC6H4
2,5-(MeO)2C6H3 72b
4. Experimental section
Me
i-Pr
t-Bu
64
51
81
14j
4.1. General experimental methods
a
Notes: for X¼Cl, the reaction only occurred upon the addition of 10 mol % of KI
Spectroscopic data were recorded as follows: 1H NMR spectra
were recorded at300 MHz,13C NMR spectrawere recorded at75 MHz
and 19F NMR spectra were recorded at 282 MHz. Peak assignments
were performed with the aid of 2D-COSY and HSQC spectra. Mass
spectra were recorded using a direct inlet system (70 eV) with a VL
detector (ES, 4000 V). Elemental analyses were executed with a Per-
kineElmer Series II CHNS/O Analyzer 2400. The reported melting
points are not corrected. Flash chromatography was carried out using
a glass column with silica gel (particle size 0.035e0.07 mm, pore di-
ameter ca. 6 nm). Solvent systems were determined via initial TLC
analysis (silica gel). Reaction progress was monitored by means of LC-
analysis. All solvents used were HPLC grade, all chemicals were used
without further purification with the exception of trimethyl ortho-
formate, which was purified by means of a vacuum distillation. All
pyridinium salts were prepared by dropwise addition of pyridine
(1 equiv) to a solution of commercially available halomethylketones
in anhydrous ethyl acetate. After overnight reaction the salts were
filtered off, dried under high vacuum, and stored under nitrogen. 1-
Bromo-3-methyl-2-butanone 17i was not commerciallyavailable and
was prepared according to a literature procedure.20
and heating for 2 days at 60 ꢁC.
b
Reaction under the given reaction conditions yielded a mixture of 13 and 14 and
the reaction mixture was heated at 50 ꢁC for 12 h in the presence of 5 equiv Na2CO3
to obtain complete conversion.
c
Occurrence in the reaction crude after workup as determined by means of LC.
During the synthesis of 1-(hydroxyethoxy)pyranonaph-
thoquinones 14, some remarkable side reactions were observed.
Attempts to ring close acylmethyl substituted naphthoquinones 13f
and 13g using HCl (6 M)/THF, yielded 1-(4-hydroxybutoxy)pyr-
anonaphthoquinones 21 due to ring opening of THF in acidic
medium. Upon the use of HCl (6 M)/dioxane or CH2Cl2, attempts to
ring close acylmethyl substituted naphthoquinones 13f and 13g
yielded 1-ethoxypyranonaphthoquinones 22, ascribed to the
presence of minor solvent impurities of ethanol in reagent grade
dichloromethane and dioxane (Scheme 4). Moreover, upon
deprotection of 1-hydroxyethoxypyranonaphthoquinone 14a by
means of HCl (6 M)/THF, both phenomenons were observed
(Scheme 4) and, as a consequence, only HPLC grade solvents were
used to avoid such artifacts.
4.2. Synthesis of 2-(1,3-dioxolan-2-yl)-1,4-
dimethoxynaphthalene 11
To a solution of 2-formyl-1,4-dimethoxynaphthalene 10 (5 g,
23.12 mmol) in toluene (50 ml), ethylene glycol (5.74 g,
92.49 mmol, 4 equiv) and para-toluenesulphonic acid (0.044 g;
0.23 mmol; 0.01 equiv) were added. The reaction was heated under
reflux for 4 h using a DeaneStark apparatus. Subsequently, the
reaction mixture was washed once with aq satd NaHCO3 (30 ml)
and twice with brine (2ꢂ20 ml). Drying over MgSO4 and evapora-
tion of the solvent in vacuo yielded 2-(1,3-dioxolan-2-yl)-1,4-
dimethoxynaphthalene 11, which was sufficiently pure (97%,
LC-MS) to be used in the next step without further purification.
4.2.1. 2-(1,3-Dioxolan-2-yl)-1,4-dimethoxynaphthalene
74%, mp 109.2 ꢁC, brown crystals. 1H NMR (CDCl3):
11. Yield
3.97 (3H, s,
d
OCH3), 4.01 (3H, s, OCH3), 4.10e4.11 (2H, m, OCH2CH2O), 4.24e4.26
(2H, m, OCH2CH2O), 6.29 (1H, s, CH(OCH2CH2O)), 6.91 (1H, s, CH-3),
7.45e7.59 (2H, m, CH-6, and CH-7), 8.07e8.09 (1H, m, CHAr),
8.07e8.09 (1H, m, CHAr). 13C NMR (CDCl3):
d 55.64 (OCH3), 63.40
(OCH3), 65.48 (OCH2CH2O), 99.33 (CH(OCH2CH2O)), 100.62 (CH-3),
122.11 (CH-6 or CH-7), 122.45 (CH-6 of CH-7), 125.16 (Cquat), 126.24
(CH-5 of CH-8), 126.75 (CH-5 or CH-8), 127.38 (Cquat), 128.51 (Cquat),
148.97 (COCH3), 152.14 (COCH3). IR (cmꢀ1): nmax 1371. MS (ESþ) m/z
(%): 261 (MþHþ, 100).
4.3. Synthesis of 2-(1,3-dioxolan-2-yl)-1,4-naphthoquinone 9
2-(1,3-Dioxolan-2-yl)-1,4-dimethoxynaphthalene 11 (1.47 g,
Scheme 4.
5.63 mmol) was dissolved in CH3CN (20 ml), and a solution of CAN

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P. Claes et al. / Tetrahedron 66 (2010) 7088e7096
(9.26 g, 16.89 mmol, 3 equiv) in water (20 ml) was added in one
portion. The reaction mixture was stirred for 2 min at room tem-
perature and subsequently poured in a mixture of 20 ml of ethyl
acetate and 20 ml of brine. The organic layer was washed with
brine (20 ml) and the solvent was evaporated in vacuo, yielding the
crude 2-(1,3-dioxolane-2-yl)-1,4-naphthoquinone 9, which was
sufficiently pure to be used without further purification (98%,
LC-MS).
(MꢀOCH2CH2OH, 100). Anal. Calcd for C21H16O5: C, 72.41, H, 4.63,
obtained: C, 72.26, H, 4.29.
4.4.4. 1-(2-Hydroxyethoxy)-3-(4-methoxyphenyl)-1H-benzo[g]iso-
chromene-5,10-dione 14b. Yield 43%, mp 223.7 ꢁC, Rf 0.10 (petro-
leum ether/ethyl acetate 4/1), red crystals. 1H NMR (CDCl3):
d
3.78e3.84 (2H, m, CH2O), 3.88 (3H, s, OCH3), 4.01e4.08 (1H, m,
CHaHbO), 4.13e4.20 (1H, m, CHaHbO), 6.72 (1H, s, CH-1), 6.83 (1H, s,
CH-4), 6.99 (2H, d, J¼8.8 Hz, 2ꢂCHAr), 7.70e7.86 (2H, m, CH-7, and
CH-8), 7.86 (2H, d, J¼8,8 Hz, 2ꢂCHAr), 8.05e8.19 (2H, m, CH-6, and
4.3.1. 2-(1,3-Dioxolan-2-yl)-1,4-naphthoquinone 9. Yield 86%, mp
120.0 ꢁC, yellow powder, spectral data in accordance with the lit-
CH-9). 13C NMR (CDCl3):
d
55.85 (OCH3); 70.65 (2ꢂCH2), 91.57 (CH-
erature.16 1H NMR (CDCl3):
d
4.08 (4H, s, OCH2CH2O), 6.08 (1H, s, CH
(OCH2CH2O)), 7.11 (1H, s, CH-3), 7.75e7.78 (2H, m, CH-6, and CH-7),
8.16e8.22 (2H, m, CH-5, and CH-8). 13C NMR (CDCl3):
65.62
4), 95.37 (CH-1), 114.37 (2ꢂCHAr), 120.90 (Cquat), 125.68 (Cquat),
126.31 (CH-6 or CH-9), 126.81 (CH-6 of CH-9), 128.12 (2ꢂCHAr),
131.96 (Cquat), 132.90 (Cquat), 133.51 (CH-7 or CH-8), 134.40 (CH-7 or
CH-8), 137.56 (Cquat), 159.52 (Cquat), 162.19 (Cquat), 182.69 (C]O),
183.24 (C]O). IR (cmꢀ1): nOH¼3746, nC]O¼1671, 1647, nCHAr¼1507.
MS (ESꢀ) m/z (%): 333 (MꢀHþ, 100). Anal. Calcd for C22H18O6: C,
69.83, H, 4.79, obtained: C, 70.04, H, 4.91.
d
(OCH2CH2O), 98.23 (CH(OCH2CH2O)), 126.31 (CHAr), 126.64 (CHAr),
132.03 (Cquat), 134.09 (2ꢂCHAr), 134.17 (CH-3), 138.78 (Cquat), 144.98
(Cquat), 184.48 (C]O), 185.52 (C]O). IR (cmꢀ1): nmax 1662. MS (ESþ)
m/z (%): 231 (MþHþ, 100).
4.4.5. 3-(4-Bromophenyl)-1-(2-hydroxyethoxy)-1H-benzo[g]iso-
4.4. Synthesis of 3-substituted 1-(2-hydroxyethoxy)-1H-
benzo[g]isochromene-5,10-diones 14
chromene-5,10-dione 14c. Yield 52%, mp 187.5 ꢁC, Rf 0.10 (petro-
leum ether/ethyl acetate 7:3), red crystals. 1H NMR (CDCl3):
d 3.09
(1H, br s, CH2OH), 3.67e3.81 (2H, m, CH2O), 3.99e4.06 (1H, m,
CHaCHbO), 4.10e4.17 (1H, m, CHaCHbO), 6.68 (1H, s, CH-1), 6.89 (1H,
s, CH-4), 7.59 (2H, d, J¼8.3 Hz, 2ꢂCHAr), 7.71 (2H, d, J¼8.3 Hz,
4.4.1. Method A. Et3N was added dropwise (1.31 mmol, 0.183 ml,
1.5 equiv) to
a solution of 2-(1,3-dioxolan-2-yl)-1,4-naphtho-
quinone 9 (0.2 g, 0.873 mmol) and the desired pyridinium salt 12
(0.873 mmol; 1 equiv) in CH3CN (2 ml). The reaction mixture was
stirred for 14 h, shielded from light by means of aluminum foil, and
subsequently poured in brine (8 ml). The aqueous phase was
extracted with chloroform (3ꢂ4 ml). Evaporation of the solvent in
vacuo yielded the product, which was further purified by means of
column chromatography on silica gel (petroleum ether/ethyl ace-
tate). 3-Acylmethyl-2-(1,3-dioxolan-2-yl)-1,4-naphthoquinones 13f
and 13g did not cyclize spontaneously and were stirred in CH3CN in
the presence of 5 equiv of Na2CO3 for 12 h at 60 ꢁC. Filtration of the
solids followed by evaporation of the solvent in vacuo yielded
the crude 1-(2-hydroxyethoxy)-1H-benzo[g]isochromene-5,10-
diones 14f and 14g, which were further purified by means of column
chromatography on silica gel (petroleum ether/ethyl acetate).
2ꢂCHAr), 7.71e7.83 (2H, m, 2ꢂCHAr), 8.10e8.18 (2H, m, 2ꢂCHAr). 13
C
NMR (CDCl3):
d 62.20 (CH2O), 70.85 (CH2O), 93. 31 (CH-4), 95.25
(CH-1), 122.26 (Cquat), 125.68 (Cquat), 126.38 (CHAr), 126.89 (CHAr),
127.64 (2ꢂCHAr), 131.82 (Cquat), 132.02 (Cquat), 132.15 (2ꢂCHAr),
132.69 (Cquat), 133.77 (CHAr), 134.49 (CHAr), 136.90 (Cquat), 157.97
(Cquat), 182.81 (2ꢂC]O). IR (cmꢀ1): nOH¼3472, nC]O¼1673, 1649,
nCHAr¼1543, 1484, nCeO¼1270, 1306. MS (ESꢀ) m/z (%): 425/427
(MꢀHþ, 100/98). Anal. Calcd for C21H15BrO5: C, 59.04, H, 3.54,
obtained: C, 59.35, H, 3.26.
4.4.6. 3-(4-Fluorophenyl)-1-(2-hydroxyethoxy)-1H-benzo[g]iso-
chromene-5,10-dione 14d. Yield 41%, mp 136.1 ꢁC, Rf 0.16 (petro-
leum ether/ethyl acetate 7/3), red crystals. 1H NMR (CDCl3):
d
3.78e3.84 (2H, m, CH2OH), 4.01e4.06 (1H, m, CHaHbCH2OH),
4.12e4.20 (1H, m, CHaHbCH2OH), 6.72 (1H, s, CH-1), 6.87 (1H, s, CH-
4), 7.16 (2H, m, 2ꢂCHAr), 7.70e7.78 (2H, m, CH-7, and CH-8),
4.4.2. Method B. Pyridine (0.174 mmol, 19 ml, 0.2 equiv) was added
dropwise to a solution of 2-(1,3-dioxolan-2-yl)-1,4-naphthoquinone
9 (0.2 g, 0.873 mmol), the desired halomethylketone 17 (0.873 mmol,
1.0 equiv), and Na2CO3 (1.31 mmol, 129 mg, 1.5 equiv) in CH3CN
(3.5 ml). The reaction mixture was stirred at room temperature for
22 h and subsequently heated at 60 ꢁC for 22 h. Extraction and pu-
rification were executed as described under method A. For chlor-
omethylketones 17h and 17j, KI (0.087 mmol,14.4 mg, 0.1 equiv) was
added and the reaction mixture was heated for two days at 60 ꢁC.
The yields, which are reported below, are the ones obtained
with method A.
7.82e7.93 (2H, m, 2ꢂCHAr), 8.12e8.21 (2H, m, CH-6, and CH-9). 13
C
NMR (CDCl3): 62.23 (CH2OH), 70.79 (CH2CH2OH), 92.73 (CH-4),
95.33 (CH-1), 116.12 (2ꢂCHAr, JCeF¼21.9 Hz), 121.85 (Cquat), 126.38
(CH-6 or CH-9), 126.89 (CH-6 or CH-9), 128.43 (2ꢂCHAr
,
JCeF¼9.2 Hz), 129.38 (Cquat, JCeF¼3.5 Hz), 131.86 (Cquat), 132.73
(Cquat), 133.74 (CH-7 or CH-8), 134.49 (CH-7 or CH-8), 137.13 (Cquat),
158.25 (C-3), 164.51 (Cquat, JCeF¼251.5 Hz), 182.95 (2ꢂC]O). 19F
NMR (CDCl3): ꢀ107.98 to ꢀ108.09 (1F, m, F). IR (cmꢀ1): nOH¼3073,
nC]O¼1672, 1650, nCHAr¼1505. MS (ESþ) m/z (%): 305
(MꢀOCH2CH2OH, 100). Anal. Calcd for C21H15FO5: C, 68.85, H, 4.13,
obtained: C, 68.54, H, 4.24.
4.4.3. 1-(2-Hydroxyethoxy)-3-phenyl-1H-benzo[g]isochromene-5,10-
dione 14a. Yield 52%, mp 161.1 ꢁC, Rf 0.13 (petroleum ether/ethyl
4.4.7. 3-(4-Chlorophenyl)-1-(2-hydroxyethoxy)-1H-benzo[g]iso-
acetate 7/3), orange crystals. 1H NMR (CDCl3):
d
3.06 (1H, t,
chromene-5,10-dione 14e. Yield 65%, mp 166.9 ꢁC, Rf 0.10 (petroleum
J¼6.6 Hz, OH), 3.78e3.84 (2H, m, CH2OH), 4.01e4.08 (1H, m,
CHaHbO), 4.13e4.20 (1H, ddd, J¼3.9 Hz, 6.6 Hz, 11.1 Hz, CHaHbO),
6.74 (1H, s, CH-1), 6.94 (1H, s, CH-4), 7.45e7.51 (3H, m, 3ꢂCHAr),
7.74e7.80 (2H, m, CH-7, and CH-8), 7.86e7.92 (2H, m, 2ꢂCHAr),
ether/ethyl acetate 7/3), red crystals. 1H NMR (CDCl3):
d 3.08 (1H, br
s, OH), 3.78e3.84 (2H, m, CH2O), 4.01e4.06 (1H, m, CHaHbO),
4.12e4.20 (1H, m, CHaHbO), 6.71 (1H, s, CH-1), 6.90 (1H, s, CH-4), 7.43
(2H, d, J¼8.8 Hz, 2ꢂCHAr), 7.70e7.86 (2H, m, CH-7, and CH-8), 7.83
8.13e8.20 (2H, m, CH-6, and CH-9). 13C NMR (CDCl3):
d
62.24
(2H, d, J¼8.8 Hz, 2ꢂCHAr), 8.10e8.21 (2H, m, CH-6, and CH-9). 13
C
(CH2O), 70.76 (CH2O), 93.02 (CH-4), 95.24 (CH-1), 121.91 (Cquat),
126.29 (2ꢂCHAr), 126.35 (CH-6 of CH-9), 126.86 (CH-6 or CH-9),
128.92 (2ꢂCHAr), 131.16 (CHAr), 131.91 (Cquat), 132.77 (Cquat), 133.13
(Cquat), 133.70 (CH-7 or CH-8), 134.44 (CH-7 or CH-8), 137.21 (Cquat),
159.26 (Cquat), 182.89 (C]O), 183.01 (C]O). IR (cmꢀ1): nOH¼3483,
nC]O¼1671, 1650, nCHAr¼1545. MS (ESþ) m/z (%): 287
NMR (CDCl3): d 62.20 (CH2OH), 70.84 (CH2CH2OH), 93.27 (CH-4),
95.25 (CH-1), 122.18 (Cquat), 126.38 (CH-6 or CH-9), 126.87 (CH-6 or
CH-9), 127.47 (2ꢂCHAr), 129.19 (2ꢂCHAr), 131.57 (Cquat), 131.82
(Cquat), 132.69 (Cquat), 133.76 (CH-7 or CH-8), 134.49 (CH-7 or CH-8),
136.92 (Cquat), 137.22 (Cquat), 157.93 (C-3), 182.81 (2ꢂC]O). IR
(cmꢀ1): nOH¼3446, nC]O¼1654, nCHAr¼1490. MS (ESþ) m/z (%): 321/

P. Claes et al. / Tetrahedron 66 (2010) 7088e7096
7093
323 (MꢀOCH2CH2OH, 100/32). Anal. Calcd for C21H15ClO5: C, 65.89,
(CDCl3): d 21.05 (CH3), 62.13 (CH2O), 70.65 (CH2O), 94.10 (CH-4),
H, 3.95, obtained: C, 65.63, H, 3.67.
95.04 (CH-1), 120.83 (Cquat), 126.16 (CH-6 or CH-9), 126.62 (CH-6 or
CH-9), 131.69 (Cquat), 132.48 (Cquat), 133.52 (CH-7 or CH-8), 134.22
(CH-7 or CH-8), 136.90 (Cquat), 162.60 (Cquat); 182.91 (C]O), 182.96
(C]O). IR (cmꢀ1): nOH¼3461, nC]O¼1671, 1656, nCHAr¼1556. MS
(ESþ) m/z (%): 309 (MþNaþ, 100). Anal. Calcd for C16H14O5: C, 67.13,
H, 4.93, obtained: C, 67.38, H, 5.03.
4.4.8. 2-[2-(2,5-Dimethoxyphenyl)-2-oxoethyl]-3-(1,3-dioxolan-2-
yl)-1,4-naphthoquinone 13f. Yield 95%, mp 153.3 ꢁC, Rf 0.17 (petro-
leum ether/ethyl acetate 7/3), purple crystals. 1H NMR (CDCl3):
d
3.79 (3H, s, OCH3), 3.89e4.08 (3 and 4H, s and m, OCH3, and
OCH2CH2O), 4.63 (2H, s, CH2C]O), 6.16 (1H, s, CH(OCH2CH2O)),
6.95 (1H, d, J¼9.1 Hz, CH-30), 7.08 (1H, dd, J¼9.1 Hz, 3.3 Hz, CH-40),
7.37 (1H, d, J¼3.3 Hz, CH-60), 7.70e7.78 (2H, m, CH-6, and CH-7),
4.4.13. 1-(2-Hydroxyethoxy)-3-isopropyl-1H-benzo[g]isochromene-
5,10-dione 14i. Yield 31%, mp 89.6 ꢁC, Rf 0.13 (petroleum ether/
8.04e8.14 (2H, m, CH-5, and CH-8). 13C NMR (CDCl3):
d
41.22
ethyl acetate 7/3), brown crystals. 1H NMR (CDCl3):
d 1.24 (6H, d,
(CH2C]O), 55.89 (OCH3), 56.24 (OCH3), 65.31 (2ꢂOCH2), 98.23
(OeCHeO), 113.30 (CH-30), 114.11 (CH-60), 121.09 (CH-40), 126.47
(CH-5 or CH-8), 126.75 (CH-5 or CH-8), 127.27 (Cquat), 131.80 (Cquat),
132.06 (Cquat), 133.80 (CH-6 or CH-7), 134.02 (CH-6 or CH-7), 139.48
(Cquat), 146.57 (Cquat), 153.56 (Cquat), 153.65 (Cquat), 184.13 (C]O),
J¼7.2 Hz, CH(CH3)2), 2.67 (1H, septet, J¼7.2 Hz, CH(CH3)2), 3.10 (1H,
m, CH2OH), 3.80 (2H, m, CH2O), 3.92e3.99 (1H, m, CHaCHbO),
4.02e4.14 (1H, m, CHaCHbO), 6.17 (1H, s, CH-4), 6.53 (1H, s, CH-1),
7.70e7.89 (2H, m, 2ꢂCHAr), 8.10e8.14 (2H, m, 2ꢂCHAr). 13C NMR
(CDCl3):
d 19.96 (CH(CH3)2), 20.21 (CH(CH3)2), 33.71 (CH(CH3)2),
184.83 (C]O), 196.48 (C]O). IR (cmꢀ1):
(%): 409 (MþHþ, 100).
n
C]O¼1654. MS (ESþ) m/z
62.17 (CH2O), 70.61 (CH2O), 91.40 (CH-4), 94.82 (CH-1), 121.22 (Cq),
126.20 (CHAr), 126.69 (CHAr), 131.82 (Cq), 132.55 (Cq), 133.56 (CHAr),
134.26 (CHAr), 137.13 (Cq), 170.65 (Cq), 183.01 (C]O), 183.15 (C]O).
IR (cmꢀ1): nOH¼3542, nC]O¼1669, 1652, nCHAr¼1582, 1560,
nCeO¼1297. MS (ESꢀ) m/z (%): 313 (MꢀHþ, 100). Anal. Calcd for
C18H18O5: C, 68.78; H, 5.77, obtained: C, 68.49, H, 5.51.
4.4.9. 3-(2,5-Dimethoxyphenyl)-1-(2-hydroxyethoxy)-1H-benzo[g]
isochromene-5,10-dione 14f. Yield 69% (from 9), mp 152.2 ꢁC, Rf 0.25
(petroleum ether/ethyl acetate 1/1), dark red crystals. 1H NMR
(CDCl3):
d
3.15 (1H, t, J¼6.9 Hz, CH2OH), 3.80 (2Hþ3H, mþs, CH2Oþ
CH3O), 3.93 (3H, s, CH3O), 3.95e4.07 (1H, m, CHaCHbO), 4.10e4.17 (1H,
m, CHaCHbO), 6.67 (1H, s, CH-1), 6.93 (1H, d, J¼9.4 Hz, CH-30), 6.98 (dd,
J¼9.4, 2.8 Hz, CH-40), 7.35 (1H, s, CH-4), 7.41 (1H, d, J¼2.8 Hz, CH-60),
7.70e7.80 (2H, m, 2ꢂCHAr), 8.12e8.16 (2H, m, 2ꢂCHAr). 13C NMR
4.4.14. 3-tert-Butyl-1-(2-hydroxyethoxy)-1H-benzo[g]isochromene-
5,10-dione 14j. Yield 74%, mp 83.9, Rf 0.39 (petroleum ether/ethyl
acetate 4/1), orange crystals. 1H NMR (CDCl3):
d 1.27 (9H, s, C
(CH3)3), 4.00e4.03 (2H, m, CH2OH), 4.11e4.13 (2H, m, CH2CH2OH),
6.26 (1H, s, CH- 4), 6.74 (1H, s, CH-1), 7.72e7.74 (2H, m, CH-7, and
(CDCl3):
d 55.91 (CH3O), 56.23 (CH3O), 62.27 (CH2O), 70.72 (CH2O),
94.81 (CH-1), 98.47 (CH-4), 112.76 (CH-30), 114.02 (CH-60), 117.18 (CH-
40), 121.78 (Cquat), 122.58 (Cquat), 126.25 (CHAr), 126.78 (CHAr), 132.03
(Cquat), 132.81 (Cquat), 133.59 (CHAr), 134.28 (CHAr), 137.32 (Cquat),
152.92 (Cquat), 153.45 (Cquat), 156.11 (Cquat), 182.92 (C]O), 183.18 (C]
O). IR (cmꢀ1): nOH¼3423, nC]O¼1670, 1643, nCHAr¼1531, 1497,
nCeO¼1298. MS (ESꢀ) m/z (%): 407 (MꢀHþ, 100). Anal. Calcd for
C23H20O7: C, 67.64, H, 4.94, obtained: C, 67.41, H, 4.78.
CH-8), 8.10e8.13 (2H, m, CH-6, and CH-9). 13C NMR (CDCl3):
d 27.86
(C(CH3)3), 36.91 (C(CH3)3), 62.23 (CH2O), 70.61 (CH2O), 90.47 (CH-
4), 94.79 (CH-1), 121.22 (Cquat), 126.23 (CHAr), 126.75 (CHAr), 131.91
(Cquat), 132.58 (Cquat), 133.61 (CHAr), 134.28 (CHAr), 137.24 (Cquat),
172.68 (Cquat), 183.12 (C]O), 183.27 (C]O). IR (cmꢀ1): nOH¼3466,
nC]O¼1666, 1651, nCHAr¼1582, 1552, nCeO¼1267. MS (ESꢀ) m/z (%):
327 (MꢀHþ, 100). Anal. Calcd for C19H20O5: C, 69.50; H, 6.14,
obtained: C, 69.16, H, 5.78.
4.4.10. 3-(1,3-Dioxolan-2-yl)-2-(2-oxo-2-(4-methylphenyl)ethyl)-
1,4-naphthoquinone 13g. Since this compound could not be puri-
fied by recrystallization or column chromatography, it was used as
4.5. Synthesis of 3-aryl-1-hydroxy-1H-benzo[g]isochromene-
5,10-diones 15a, 15d, and 15e
such in the next step. 1H NMR (CDCl3):
d 2.42 (3H, s, CH3), 3.92 (4H,
m, OCH2CH2O), 4.60 (2H, s, CH2C]O), 6.14 (1H, s, CH(OCH2CH2O)),
7.30 (2H, d, J¼8.3 Hz, 2ꢂCHAr), 7.72e7.78 (2H, m, CH-6, and CH-7),
7.93 (2H, d, J¼8.3 Hz, 2ꢂCHAr), 8.08e8.17 (2H, m, CH-5, and CH-8).
3-(4-Halophenyl)-1-(2-hydroxyethoxy)-1H-benzo[g]isochromene-
5,10-diones14a, 14d, and 14e (2.18 mmol) were dissolved in THF
(5 ml), to which aqueous HCl (6 M, 5 ml) was cautiously added.
The reaction mixture was stirred for 20 h at room temperature,
shielded from light by means of aluminum foil, and poured in
brine (10 ml), after which it was extracted with chloroform
(3ꢂ5 ml). Drying over MgSO4 and evaporation of the solvent in
vacuo yielded the crude 3-(4-halophenyl)-1-hydroxy-1H-benzo
[g]isochromene-5,10-diones 15d and 15e. These compounds
were further purified by means of trituration with diethyl ether.
For 1-hydroxy-3-phenyl-1H-benzo[g]isochromene-5,10-dione 15a
the reaction was stirred for three days and a mixture was obtained
in which 1-hydroxy-3-phenyl-1H-benzo[g]isochromene-5,10-dione
15a wasthemajorcompound together with1-(4-hydroxy-butoxy)-3-
phenyl-1H-benzo[g]isochromene-5,10-dione 21a 1-ethoxy-3-phe-
nyl-1H-benzo[g]isochromene-5,10-dione 22a. 1-Hydroxy-3-phenyl-
1H-benzo[g]isochromene-5,10-dione 15a was isolated by means of
preparative TLC on silica gel (petroleum ether/ethyl acetate 7/3). Due
to the unstable nature of hydroxypyranonapthoquinones 15, ele-
mentary analysis could not be performed.
4.4.11. 1-(2-Hydroxyethoxy)-3-(4-methylphenyl)-1H-benzo[g]iso-
chromene-5,10-dione 14g. Yield 48% (from 9), mp 153.5 ꢁC, Rf 0.28
(petroleum ether/ethyl acetate 4/1), red crystals. 1H NMR (CDCl3):
d
2.46 (3H, s, CH3), 3.10 (1H, t, J¼7.0 Hz, CH2OH), 3.68e3.81 (2H, m,
CH2O), 3.99e4.06 (1H, m, CHaCHbO), 4.10e4.17 (1H, m, CHaCHbO),
6.71 (1H, s, CH-1), 6.89 (1H, s, CH-4), 7.27 (2H, d, J¼8.3 Hz, 2ꢂCHAr),
7.71e7.81 (2H, m, 2ꢂCHAr), 7.77 (2H, d, J¼8.3 Hz, 2ꢂCHAr),
8.10e8.18 (2H, m, 2ꢂCHAr). 13C NMR (CDCl3):
d 21.64 (CH3), 62.20
(CH2O), 70.67 (CH2O), 92.37 (CH-4), 95.21 (CH-1), 121.45 (Cquat),
126.26 (3ꢂCHAr), 126.78 (CHAr), 129.64 (2ꢂCHAr), 130.34 (Cquat),
131.88 (Cquat), 132.78 (Cquat), 133.53 (CHAr), 134.34 (CHAr), 137.30
(Cquat), 141.76 (Cquat), 182.69 (C]O), 183.03 (C]O). IR (cmꢀ1):
nOH¼3447, nC]O¼1674, 1646, nCHAr¼1540, 1507, nCeO¼1270. MS
(ESþ) m/z (%): 301 (MꢀHOCH2CH2O, 100). Anal. Calcd for C22H18O5:
C, 72.92, H, 5.01, obtained: C, 72.66, H, 4.80.
4.4.12. 1-(2-Hydroxyethoxy)-3-methyl-1H-benzo[g]isochromene-
5,10-dione 14h. Yield 42%, mp 108.6 ꢁC, Rf 0.10 (petroleum ether/
4.5.1. 1-Hydroxy-3-phenyl-1H-benzo[g]isochromene-5,10-dione
ethyl acetate 7/3), brown crystals. 1H NMR (CDCl3):
d
2.17 (3H, s,
15a. Yield 40%, mp 154.0 ꢁC, Rf 0.26 (petroleum ether/ethyl acetate 7/
CH3), 3.17 (1H, br s, OH), 3.68e3.83 (2H, m, CH2OH), 3.93e4.06 (2H,
m, CH2CH2OH), 6.13 (1H, s, CH-1), 6.50 (1H, s, CH-4), 7.68e7.77 (2H,
m, CH-7, and CH-8), 8.07e8.11 (2H, m, CH-6, and CH-9). 13C NMR
3), orange red crystals.1H NMR (CDCl3):
d 3.99 (1H, br s, OH), 6.92 (1H, s,
CH-1), 6.93 (1H, s, CH-4), 7.43e7.50 (m, 3ꢂCHAr), 7.69e7.79 (2H, m, CH-
7, and CH-8), 7.87e7.91 (2H, m, 2ꢂCHAr), 8.12e8.15 (2H, m, CH-6, and

7094
P. Claes et al. / Tetrahedron 66 (2010) 7088e7096
CH-9). 13C NMR (CDCl3):
d
88.72 (CH-1), 92.72 (CH-4), 122.56 (Cquat),
[g]isochromene-5,10-diones 16bee, which were further purified by
126.22 (CH-6 or CH-9),126.33 (2ꢂCHAr),126.68 (CH-6 or CH-9),128.73
(2ꢂCHAr), 131.03 (CHAr), 131.81 (Cquat), 132.70 (Cquat), 133.05 (Cquat),
133.44 (CH-7 or CH-8),134.31 (CH-7 or CH-8),136.50 (Cquat),158.94 (C-
3),182.15 (C]O),183.14 (C]O). IR (cmꢀ1): nOH¼3331. nC]O¼1670, 1640.
nCHAr¼1535. MS (ESꢀ) m/z (%): 303 (MꢀHþ. 100).
means of recrystallization from methanol.
4.7.1. 1-Methoxy-3-(4-methoxyphenyl)-1H-benzo[g]isochromene-
5,10-dione 16b. Yield 87%, mp 173.6 ꢁC, Rf 0.33 (petroleum ether/
ethyl acetate 7/3), purple crystals. 1H NMR (CDCl3):
d 3.68 (3H, s,
OCH3), 3.88 (3H, s, OCH3), 6.50 (1H, s, CH-1), 6.84 (1H, s, CH-4), 6.97
4.5.2. 3-(4-Fluorophenyl)-1-hydroxy-1H-benzo[g]isochromene-5,10-
(2H, d, J¼8.8 Hz, 2ꢂCHAr), 7.69e7.82 (2H, m, CH-7, and CH-8), 7.86
dione 15d. Yield 48%, mp 221.2 ꢁC, Rf 0.21 (petroleum ether/ethyl
(2H, d, J¼8.8 Hz, 2ꢂCHAr), 8.11e8.16 (2H, m, CH-6, and CH-9). 13
C
acetate 4/1), red crystals. 1H NMR (CDCl3):
d
3.80 (1H, br s, OH), 6.82
NMR (CDCl3): d 55.57 (OCH3), 56.00 (OCH3), 91.90 (CH-4), 95.80
(1H, s, CH-1), 6.87 (1H, s, CH-4), 7.11e7.17 (2H, m, 2ꢂCHAr),
(CH-1), 114.32 (2ꢂCHAr), 121.05 (Cquat), 125.74 (Cquat), 126.18 (CH-6
or CH-9), 126.69 (CH-6 or CH-9), 128.06 (2ꢂCHAr), 131.96 (Cquat),
132.93 (Cquat), 133.30 (CH-7 or CH-8), 134.29 (CH-7 or CH-8), 137.25
(Cquat), 159.16 (Cquat), 162.05 (Cquat), 181.94 (C]O), 183.41 (C]O). IR
7.70e7.75 (2H, m, CH-7, and CH-8), 7.86e7.91 (2H, m, 2ꢂCHAr),
8.05e8.15 (2H, m, CH-6, and CH-9). 13C NMR (DMSO-d6):
d 88.82
(CH-1), 92.84 (CH-4), 116.57 (2ꢂCHAr, JCeF¼21.9 Hz), 123.80 (Cquat),
126.18 (CHAr), 126.81 (CHAr), 129.09 (2ꢂCHAr, JCeF¼8.1 Hz), 130.28
(Cquat, JCeF¼3.5 Hz), 131.90 (Cquat), 132.73 (Cquat), 133.51 (CHAr),
(cmꢀ1):
n
C]O¼1672, 1645. nCHAr¼1538, 1506. MS (ESþ) m/z (%): 317
(MꢀCH3O, 100). Anal. Calcd for C21H16O5: C, 72.41, H, 4.63,
134.41 (CHAr), 135.27 (Cquat), 136.12 (Cquat), 164.14 (Cquat
,
obtained: C, 72.03, H, 4.47.
JCeF¼249.2 Hz), 182.11 (C]O), 183.35 (C]O). 19F NMR (DMSO-d6):
ꢀ109.14 to ꢀ109.19 (1F, m, F). IR (cmꢀ1): nOH¼3287, nC]O¼1672,
1646. nCHAr¼1502. MS (ESꢀ) m/z (%): 321 (MꢀHþ, 100).
4.7.2. 3-(4-Bromophenyl)-1-methoxy-1H-benzo[g]isochromene-
5,10-dione 16c. Yield 71%, mp 172.1e178.1 ꢁC, Rf 0.17 (petroleum
ether/ethyl acetate 19/1), red crystals. 1H NMR (CDCl3):
d 3.68 (3H,
4.5.3. 3-(4-Chlorophenyl)-1-hydroxy-1H-benzo[g]isochromene-5,10-
s, CH3), 6.51 (1H, s, CH-1), 6.93 (1H, s, CH-4), 7.59 (2H, d, J¼8.3 Hz,
dione 15e. Yield 90%, mp 236.4 ꢁC, Rf 0.23 (petroleum ether/ethyl
2ꢂCHAr), 7.71 (2H, d, J¼8.3 Hz, 2ꢂCHAr), 7.71e7.83 (2H, m, 2ꢂCHAr),
acetate 4/1), red crystals. 1H NMR (DMSO-d6):
d
6.60 (1H, d,
8.10e8.18 (2H, m, 2ꢂCHAr). 13C NMR (CDCl3):
d 56.23 (CH3O), 93.65
J¼5.0 Hz, CH-1), 6.88 (1H, s, CH-4), 7.58 (2H, d, J¼8.8 Hz, 2ꢂCHAr),
7.83e7.95 (2H, m, CH-7, and CH-8), 7.83e7.95 (2H, d, J¼8.8 Hz,
2ꢂCHAr), 8.01e8.09 (2H, m, CH-6, and CH-9). 13C NMR (DMSO-d6):
(CH-1), 95.76 (CH-4), 122.38 (Cquat), 125.47 (Cquat), 126.25 (CHAr),
126.75 (CHAr), 127.56 (2ꢂCHAr), 131.82 (Cquat), 132.11 (2ꢂCHAr),
132.72 (Cquat), 133.51 (CHAr), 134.37 (CHAr), 136.57 (Cquat), 157.62
(Cquat), 182.04 (C]O), 182.92. IR (cmꢀ1): nC]O¼1671, 1656,
nCHAr¼1586, 1566, 1551, 1487 nCeO¼1305, 1269. MS (ESþ) m/z (%):
365.0/367.0 (MꢀCH3O, 100). Anal. Calcd for C2OH13BrO4: C, 60.47, H,
3.30, obtained: C, 60.12, H, 3.14.
d
88.78 (CH-1), 93.40 (CH-4), 124.15 (Cquat), 126.18 (CH-6 or CH-9),
126.81 (CH-6 or CH-9), 128.29 (2ꢂCHAr), 129.56 (2ꢂCHAr), 131.85
(Cquat), 132.51 (Cquat), 132.70 (Cquat), 133.44 (CH-7 or CH-8), 135.25
(CH-7 and CH-8), 135.94 (Cquat), 136.06 (Cquat), 157.16 (C-3), 182.11
(C]O), 183.23 (C]O). IR (cmꢀ1): nOH¼3278, nC]O¼1673, 1640.
nCHAr¼1529. MS (ESꢀ) m/z (%) 337/339 (MꢀHþ, 100/32).
4.7.3. 3-(4-Fluorophenyl)-1-methoxy-1H-benzo[g]isochromene-5,10-
dione 16d. Yield 34%, mp 162.8 ꢁC, Rf 0.45 (petroleum ether/ethyl
acetate 4/1), red crystals. 1H NMR (CDCl3):
d 3.66 (3H, s, OCH3), 6.50
4.6. Synthesis of 1-hydroxy-3-(4-methoxyphenyl)-1H-benzo
[g]isochromene-5,10-dione 15b
(1H, s, CH-1), 6.89 (1H, s, CH-4), 7.10e7.17 (2H, m, 2ꢂCHAr),
7.70e7.75 (2H, m, CH-7, and CH-8), 7.86e7.91 (2H, m, 2ꢂCHAr),
8.05e8.15 (2H, m, CH-6, and CH-9). 13C NMR (CDCl3):
d 56.23
1-(2-Hydroxyethoxy)-3-(4-methoxyphenyl)-1H-benzo[g]isoch-
romene-5,10-dione 14b (825 mg, 2.18 mmol) was dissolved in THF
(5 ml) to which aqueous HCl (2 M, 5 ml) was added and the reaction
mixture was stirred for 20 h at room temperature, shielded from light
by means of aluminum foil. The reaction mixture was poured in brine
(10 ml) and extracted with chloroform (3ꢂ5 ml). Drying over MgSO4
and evaporation of the solvent in vacuo yielded the crude 1-hydroxy-3-
(4-methoxyphenyl)-1H-benzo[g]isochromene-5,10-dione 15b. This
compound was found to be too unstable to record a 13C NMR spectrum.
(OCH3), 93.09 (CH-4), 95.82 (CH-1), 116.08 (2ꢂCHAr, JCeF¼21.9 Hz),
121.10 (Cquat), 126.26 (CH-6 or CH-9), 126.77 (CH-6 or CH-9), 128.35
(2ꢂCHAr, JCeF¼9.2 Hz), 129.44 (Cquat, JCeF¼3.5 Hz), 131.88 (Cquat),
132.78 (Cquat), 133.51 (CH-7 or CH-8), 134.40 (CH-7 or CH-8), 136.81
(Cquat), 157.91 (C-3), 164.43 (Cquat, JCeF¼251.5 Hz), 182.11 (C]O),
183.13 (C]O). IR (cmꢀ1):
n
C]O¼1676, 1652, nCHAr¼1551, 1503. MS
(ESþ) m/z (%) 305 (MꢀCH3O. 100). Anal. Calcd for C2OH13FO4: C,
71.43, H, 3.90, obtained: C, 71.67, H, 4.06.
4.7.4. 3-(4-Chlorophenyl)-1-methoxy-1H-benzo[g]isochromene-
4.6.1. 1-Hydroxy-3-(4-methoxyphenyl)-1H-benzo[g]isochromene-
5,10-dione 16e. Yield 82%, mp 164.3 ꢁC, Rf 0.40 (petroleum ether/
5,10-dione 15b. Yield 91%, mp 223.7 ꢁC, purple crystals. 1H NMR
ethyl acetate 4/1), red crystals. 1H NMR (CDCl3):
d 3.68 (3H, s,
(acetone-d6):
d 3.87 (3H, s, CH3O), 6.83 (1H, s, CH-1), 6.88 (1H, s,
OCH3), 6.49 (1H, s, CH-1), 6.92 (1H, s, CH-4), 7.43 (2H, d, J¼8.8 Hz,
2ꢂCHAr), 7.69e7.82 (2H, m, CH-7, and CH-8), 7.43 (2H, d, J¼8.8 Hz.
2ꢂCHAr), 8.05e8.15 (2H, m, CH-6, and CH-9). 13C NMR (CDCl3):
CH-4), 7.07 (d, J¼8.8 Hz, 2ꢂCHAr), 7.83e7.95 (2H, m, CH-6, and CH-
7), 7.90 (d, J¼8.8 Hz, 2ꢂCHAr), 8.10e8.21 (2H, m, CH-5, and CH-8).
IR (cmꢀ1): nOH¼3382, nC]O¼1669, 1640, nCHAr¼1535, 1501. MS (ESꢀ)
m/z (%): 333 (MꢀHþ, 100).
d
56.24 (OCH3), 93.62 (CH-4), 95.76 (CH-1), 122.32 (Cquat), 126.28
(CH-6 or CH-9), 126.78 (CH-6 or CH-9), 127.42 (2ꢂCHAr), 129.18
(2ꢂCHAr), 131.66 (Cquat), 131.85 (Cquat), 132.75 (Cquat), 133.54 (CH-7
or CH-8),134.40 (CH-7 or CH-8),136.64 (Cquat), 137.06 (Cquat), 157.64
(C-3), 182.08 (C]O), 183.01 (C]O). IR (cmꢀ1): nC]O¼1670, 1654.
nCHAr¼1542. MS (ESþ) m/z (%) 321/323 (MꢀCH3O, 100/32). Anal.
Calcd for C20H13ClO4: C: 68.09, H: 3.71, obtained: C: 67.92, H: 3.46.
4.7. Synthesis of 1-methoxy-1H-benzo[g]isochromene-5,10-
diones 16bee
3-Aryl-1-(2-hydroxyethoxy)-1H-benzo[g]isochromene-5,10-di-
ones 14bee (0.27 mmol) were dissolved in methanol (2 ml), to
which one drop of concentrated sulfuric acid was added. The re-
action mixture was stirred for 24 h at 60 ꢁC, shielded from light by
means of aluminum foil, and poured in brine (10 ml). Extraction
with chloroform (3ꢂ5 ml), drying over MgSO4, and evaporation of
the solvent in vacuo yielded the crude 3-aryl-1-methoxy-1H-benzo
4.8. Synthesis of 1-methoxy-1H-benzo[g]isochromene-5,10-
diones 16a and 16fej
General procedure. The 1-(2-hydroxyethoxy)-1H-benzo[g]iso-
chromene-5,10-dione 14 (0.27 mmol) of choice and trimethyl

P. Claes et al. / Tetrahedron 66 (2010) 7088e7096
7095
orthoformate (59 mg, 0.58 mmol, 2.05 equiv) were dissolved in dry
dichloromethane (5 ml). Subsequently BF3$OEt2 (0.01 ml, 0.03 mmol,
0.1 equiv) was added dropwise under a nitrogen atmosphere at 0 ꢁC.
The reaction mixture, shielded from light by means of aluminum foil,
reacted for 3 h at 0 ꢁC and was subsequently quenched with satd aq
NaHCO3 (10 ml) and extracted with chloroform (3ꢂ5 ml). Evapora-
tionof thesolventinvacuoyieldedthecrude1-methoxy-1H-benzo[g]
isochromene-5,10-diones 16, which were further purified by means
of preparative TLC on silica gel (petroleum ether/ethyl acetate 9/1).
1), orange crystals.1H NMR (CDCl3):
d
1.25 (6H, d, J¼7.2 Hz, CH(CH3)2),
2.68 (1H, septet, J¼7.2 Hz, CH(CH3)2), 3.62 (CH3O), 6.18 (1H, s, CH-4),
6.31 (1H, s, CH-1), 7.67e7.76 (2H, m, 2ꢂCHAr), 8.08e8.12 (2H, m,
2ꢂCHAr). 13C NMR (CDCl3):
d 20.16 (CH(CH3)2), 20.27 (CH(CH3)2),
33.71 (CH(CH3)2), 56.20 (CH3O), 91.76 (CH-4), 95.39 (CH-1), 121.25
(Cquat), 126.12 (CHAr), 126.61 (CHAr), 131.88 (Cquat), 132.66 (Cquat),
133.35 (CHAr), 134.19 (CHAr),136.87 (Cquat),170.36 (Cquat),182.33 (C]
O), 183.41 (C]O). IR (cmꢀ1): nC]O¼1668, 1653, nCHAr¼1582, 1552,
nCeO¼1299. MS (ESþ) m/z (%): 253 (MꢀCH3O, 100). Anal. Calcd for
C17H16O4: C, 71.82, H, 5.67, obtained: C, 72.16, H, 5.85.
4.8.1. 3-Phenyl-1-methoxy-1H-benzo[g]isochromene-5,10-dione
16a. Yield 58%, mp 141.4 ꢁC, Rf 0.18 (petroleum ether/ethyl acetate 9/
4.8.6. 3-tert-Butyl-1-methoxy-1H-benzo[g]isochromene-5,10-dione
1), orange crystals. 1H NMR (CDCl3):
d
3.65 (3H, s, OCH3), 6.51 (1H, s,
16j. Yield 48%, mp 64.2 ꢁC, Rf 0.56 (petroleum ether/ethyl acetate
CH-1), 6.96 (1H, s, CH-4), 7.46e7.48 (3H, m, 3ꢂCHAr), 7.70e7.77 (2H,
7/3), brown crystals. 1H NMR (CDCl3):
d 1.28 (9H, s, C(CH3)3), 3.63
m, CH-7, and CH-8), 7.88e7.93 (2H, m, 2ꢂCHAr), 8.13e8.18 (2H, m, CH-
(3H, s, OCH3), 6.24 (1H, s, CH-1), 6.32 (1H, s, CH-4), 7.66e7.76 (2H,
6, and CH-9). 13C NMR (CDCl3):
d 56.15 (OCH3), 93.37 (CH-4), 95.71
m, CH-7, and CH-8), 8.07e8.12 (2H, m, CH-6, and CH-9). 13C NMR
(CH-1),122.03 (Cquat),126.25 (2ꢂCHAr and CH-6 or CH-9),126.75 (CH-
6 or CH-9), 128.89 (2ꢂCHAr), 131.02 (CHAr), 131.93 (Cquat), 132.83
(Cquat), 133.18 (Cquat), 133.45 (CH-7 or CH-8), 134.34 (CH-7 or CH-8),
136.90 (Cquat), 158.92 (Cquat), 182.13 (C]O), 183.20 (C]O). IR (cmꢀ1):
nC]O¼1674,1650. nCHAr¼1540. MS (ESþ) m/z (%): 287 (MꢀCH3O,100).
Anal. Calcd for C2OH14O4: C, 75.46, H, 4.43, obtained: C, 75.15, H, 4.22.
(CDCl3):
d
28.00 (3ꢂCH3), 36.90 (C(CH3)3), 56.36 (OCH3), 90.75 (CH-
4), 95.40 (CH-1), 121.17 (Cquat), 126.09 (CH-6 or CH-9), 126.60 (CH-6
or CH-9), 131.88 (Cquat), 132.86 (Cquat),133.35 (CH-7 or CH-8), 134.19
(CH-7 or CH-8), 136.90 (Cquat), 172.39 (Cquat), 182.30 (C]O), 183.46
(C]O). IR (cmꢀ1):
n
C]O¼1655, 1672. nCHAr¼1557. MS (ESþ) m/z (%):
267 (MꢀCH3O. 100). Anal. Calcd for C18H18O4: C, 72.47, H, 6.08,
obtained: C, 72.27, H, 5.92.
4.8.2. 3-(2,5-Dimethoxyphenyl)-1-methoxy-1H-benzo[g]iso-
chromene-5,10-dione 16f. Yield 86%, mp 153.2 ꢁC, Rf 0.26 (petroleum
4.9. Synthesis of 3-aryl-1-(4-hydroxybutoxy)-1H-benzo[g]
isochromene-5,10-diones 21f and 21g
ether/ethyl acetate 4/1), purple crystals. 1H NMR (CDCl3):
d
3.68 (3H, s,
OCH3), 3.83 (3H, s, OCH3), 3.94 (3H, s, OCH3), 6.46 (1H, s, CH-1),
6.94e6.98 (2H, m, 2ꢂCHAr), 7.39 (1H, s, CH-4), 7.44 (1H, d, J¼3.3 Hz,
CH-30), 7.69e7.78 (2H, m, CH-7, and CH-8), 8.12e8.16(2H, m, CH-6, and
2-Acylmethyl-3-(1,3-dioxolan-2-yl)-1,4-naphthoquinones 13f
and 13g (2.18 mmol) were dissolved in THF (5 ml), to which aque-
ous HCl (6 M, 5 ml) was added cautiously. The reaction mixture was
stirred for three days at room temperature, shielded from light by
means of aluminum foil, poured in brine (10 ml) and extracted with
chloroform (3ꢂ5 ml). Drying over MgSO4 and evaporation of the
solvent in vacuo yielded the crude 3-aryl-1-(4-hydroxybutoxy)-1H-
benzo[g]isochromene-5,10-diones 21f and 21g, which were further
purified by means of column chromatography or preparative TLC
on silica gel (petroleum ether/ethyl acetate 4/1).
CH-9). 13C NMR (CDCl3):
d 55.84 (OCH3), 56.02 (OCH3), 56.11 (OCH3),
95.18 (CH-1), 98.78 (CH-4), 112.65 (CH-30), 113.85 (CH-60), 116.92 (CH-
40), 121.78 (Cquat),122.53 (Cquat),126.07 (CH-6 or CH-9),126.75 (CH-6 or
CH-9), 131.96 (Cquat), 132.77 (Cquat), 133.28 (CH-7 or CH-8), 134.10
(CH-7 or CH-8),137.00 (Cquat), 152.58 (COCH3), 153.35 (COCH3), 155.67
(Cquat), 182.10 (C]O), 183.29 (C]O). IR (cmꢀ1):
n
C]O¼1666 en 1655.
nCHAr¼1542. MS (ESþ) m/z (%): 347 (MꢀCH3O, 100). Anal. Calcd for
C22H18O6: C, 69.83, H, 4.79, obtained: C, 69.95, H, 5.03.
4.8.3. 1-Methoxy-3-(4-methylphenyl)-1H-benzo[g]isochromene-
4.9.1. 1-(4-Hydroxybutoxy)-3-(4-methylphenyl)-1H-benzo[g]iso-
5,10-dione 16g. Yield 62%, mp 165.2 ꢁC; Rf 0.08 (petroleum ether/
chromene-5,10-dione 21f. Yield 85%, mp 125.9 ꢁC, Rf 0.26 (petroleum
ethyl acetate 19/1); red crystals. 1H NMR (CDCl3):
d
2.39 (3H, s, CH3),
ether/ethyl acetate 7/3), red crystals. 1H NMR (CDCl3):
d 1.75e1.82
3.67 (3H, s, CH3O), 6.47 (1H, s, CH-1), 6.88 (1H, s, CH-4), 7.25 (2H, d,
(4H, m, 2ꢂCH2), 2.42 (3H, s, CH3), 3.46e3.52(2H, m, CH2O), 3.91e3.95
(1H, m, CHaHbO), 4.05e4.14 (1H, m, CHaHbO), 6.57 (1H, s, CH-1), 6.91
(1H, s, CH-4), 7.28 (2H, d, J¼8.3 Hz, 2ꢂCHAr), 7.70e7.76 (2H, m, CH-7,
and CH-8), 7.79 (2H, d, J¼8.3 Hz, 2ꢂCHAr), 8.12e8.17 (2H, m, CH-6, and
J¼8.3 Hz, 2ꢂCHAr), 7.71e7.81 (2H, m, 2ꢂCHAr), 7.77 (2H, d, J¼8.3 Hz,
2ꢂCHAr), 8.10e8.18 (2H, m, 2ꢂCHAr). 13C NMR (CDCl3):
d 21.63
(CH3), 56.03 (CH3O), 92.72 (CH-4), 95.69 (CH-1), 121.60 (Cquat),
126.18 (CHAr), 126.23 (2ꢂCHAr), 129.62 (2ꢂCHAr), 130.41 (Cquat),
131.93 (Cquat), 132.86 (Cquat), 133.35 (CHAr), 134.28 (CHAr), 137.06
(Cquat), 141.59 (Cquat), 159.19 (Cquat), 182.01 (C]O), 183.24 (C]O). IR
(cmꢀ1): nC]O¼1671, 1649, nCHAr¼1593, 1539, 1507, nCeO¼1029. MS
(ESþ) m/z (%): 301 (MꢀCH3O, 100). Anal. Calcd for C21H16O4: C,
75.89, H, 4.85, obtained: C, 75.58, H, 4.66.
CH-9).13C NMR (CDCl3):
d 21.53 (CH3), 26.87 (CH2), 28.98 (CH2), 44.74
(CH2O), 68.03 (CH2O), 92.52 (CH-4), 94.54 (CH-1), 121.50 (Cquat),
126.05 (2ꢂCHAr), 126.57 (CH-6 and CH-9), 129.52 (2ꢂCHAr), 130.33
(Cquat),131.84 (Cquat),132.73(Cquat),133.23(CH-7orCH-8),134.13(CH-
7 or CH-8), 136.89 (Cquat), 141.47 (Cquat), 158.99 (Cquat), 181.86 (C]O),
183.16 (C]O). IR (cmꢀ1): nOH¼2930. nC]O¼1675, 1649, nCHAr¼1544.
MS (ESþ) m/z (%): 301 (MꢀO(CH2)4OH,100). Anal. Calcd for C24H22O5:
C, 73.83, H, 5.68, obtained: C, 74.05, H, 5.88.
4.8.4. 1-Methoxy-3-methyl-1H-benzo[g]isochromene-5,10-dione
16h. Yield 65%, mp 123.6 ꢁC, Rf 0.09 (petroleum ether/ethyl acetate
19/1), orange crystals. 1H NMR (CDCl3):
d
2.19 (3H, s, CH3), 3.61
4.9.2. 3-(2,5-Dimethoxyphenyl)-1-(4-hydroxybutoxy)-1H-benzo[g]
isochromene-5,10-dione 21g. Yield 60%, Rf 0.26 (petroleum ether/
ethyl acetate 7/3), purple amorphous crystals. 1H NMR (CDCl3):
(CH3O), 6.18 (1H, s, CH-4), 6.30 (1H, s, CH-1), 7.68e7.77 (2H, m,
2ꢂCHAr), 8.10e8.15 (2H, m, 2ꢂCHAr). 13C NMR (CDCl3):
d 20.98
(CH3), 55.98 (CH3O), 94.52 (CH-4), 95.60 (CH-1), 121.04 (Cquat),
126.12 (CHAr), 126.58 (CHAr), 131.80 (Cquat), 132.63 (Cquat), 133.36
(CHAr), 134.20 (CHAr), 136.64 (Cquat), 162.26 (Cquat), 182.30 (C]O),
183.18 (C]O). IR (cmꢀ1): nC]O¼1669, 1658, nCHAr¼1592, 1582, 1557,
nCeO¼1302. MS (ESþ) m/z (%): 225 (MꢀCH3O, 100). Anal. Calcd for
C15H12O4: C, 70.31, H, 4.72, obtained: C, 70.48, H, 4.93.
d
1.78e1.83 (4H, m, 2ꢂCH2), 3.36e3.49 (2H, m, CH2O), 3.84 (1H, s,
OCH3), 3.86e3.91 (1H, m, CHaHbO), 3,94 (1H, s, OCH3), 3.96e4.08
(1H, m, CHaHbO), 6.53 (1H, s, CH-1), 6.92e6.96 (2H, m, 2ꢂCHAr),
7.39 (1H, s, CH-4), 7.42e7.45 (1H, m, CHAr), 7.72e7.79 (2H, m, CH-7,
and CH-8), 8.12e8.17 (2H, m, CH-6, and CH-9). 13C NMR (CDCl3):
d
15.34 (CH2), 29.14 (CH2), 44.87 (CH2O), 55.92 (OCH3), 56.19
(OCH3), 68.12 (CH2O), 94.17 (CH-1), 98.87 (CH-4), 112.73 (CHAr),
113.86 (CHAr), 116.90 (CHAr), 121.88 (Cquat), 122.60 (Cquat), 126.11
(CH-6 or CH-9), 126.66 (CH-6 or CH-9), 132.06 (Cquat), 132.83 (Cquat),
4.8.5. 3-Isopropyl-1-methoxy-1H-benzo[g]isochromene-5,10-dione
16i. Yield 75%, mp 84.5 ꢁC, Rf 0.24 (petroleum ether/ethyl acetate 19/

7096
P. Claes et al. / Tetrahedron 66 (2010) 7088e7096
133.36 (CH-7 or CH-8), 134.15 (CH-7 or CH-8), 137.03 (Cquat), 152.89
(Cquat), 153.41 (Cquat), 155.56 (Cquat), 182.13 (C]O), 183.38 (C]O). IR
(cmꢀ1): nOH¼2946, nC]O¼1672, 1649, nCHAr¼1533. MS (ESþ) m/z (%):
347 (MꢀO(CH2)4OH, 100). Anal. Calcd for C25H24O7: C, 68.80, H,
5.54, obtained: C, 69.06, H, 5.68.
acetate 7/3), orange crystals. 1H NMR (CDCl3):
d
1.26 (3H, t, J¼7.2 Hz,
OCH2CH3), 2.42 (3H, s, CH3), 3.94 (1H, dq, J¼9.6, 7.2 Hz, OCHaHb),
4.09 (1H, dq, J¼9.6 Hz, 7.2 Hz, OCHaHb), 6.60 (1H, s, CH-1), 6.91 (1H,
s, CH-4), 7.27 (2H, d, J¼8.3 Hz, 2ꢂCHAr), 7.79 (2H, d, J¼8.3 Hz,
2ꢂCHAr), 7.69e7.78 (2H, m, CH-7, and CH-8), 8.12e8.17 (2H, m, CH-
6, and CH-9). 13C NMR (CDCl3):
d 15.36 (CH3), 21.63 (CH3), 64.75
4.10. Synthesis of 3-aryl-1-ethoxy-1H-benzo[g]isochromene-
5,10-diones 22a, f, g
(OCH2), 92.67 (CH-1), 94.44 (CH-4), 121.70 (Cquat), 126.14 (CH-6 of
CH-9), 126.23 (2ꢂCHAr), 126.64 (CH-6 of CH-9), 129.59 (2ꢂCHAr),
130.57 (Cquat), 131.96 (Cquat), 132.89 (Cquat), 133.30 (CH-7 of CH-8),
134.22 (CH-7 of CH-8), 137.03 (Cquat), 141.50 (C-3), 182.02 (C]O),
2-Acylmethyl-3-(1,3-dioxolan-2-yl)-1,4-naphthoquinones 13f and
13g or 3-phenyl-1-(2-hydroxyethoxy)-1H-benzo[g]isochromene-
5,10-dione 14a (1.22 mmol) were dissolved in reagent grade CH2Cl2
(5 ml), to which HCl (6 M, 5 ml) was added. The reaction mixture,
shielded from light by means of aluminum foil, was vigorously stirred
for 3 days at room temperature, poured in brine (10 ml) and extracted
withchloroform (3ꢂ5 ml). Evaporation of the solvent invacuoyielded
the crude 3-aryl-1-ethoxy-1H-benzo[g]isochromene-5,10-diones
22a, f, and g. 1-Ethoxy-3-(4-methylphenyl)-1H-benzo[g]isochro-
mene-5,10-dione 22g was recrystallizedfromethanol, while3-aryl-1-
ethoxy-1H-benzo[g]isochromene-5,10-diones 22a and 22f were
purified by means of column chromatographyon silica gel (petroleum
ether/ethyl acetate 4/1).
183.32 (C]O). IR (cmꢀ1):
n
C]O¼1673 en 1641. nCHAr¼1538, 1530,
1504. MS (ESþ) m/z (%): 301 (MꢀCH2CH3O, 100). Anal. Calcd for
C21H16O4: C: 75.89, H: 4.85, obtained: C: 75.65, H: 4.55.
Acknowledgements
The authors are indebted to the ‘Research FoundationeFlanders
(FWO-Vlaanderen)’ for financial support of this research.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.07.012.
4.10.1. 1-Ethoxy-3-phenyl-1H-benzo[g]isochromene-5,10-dione
22a. Yield 98%, mp 144.6 ꢁC, Rf 0.14 (petroleum ether/ethyl acetate
References and notes
4/1), orange crystals. 1H NMR (CDCl3):
d
1.26 (3H, t, J¼7.2 Hz,
1. De Kimpe, N.; Van Puyvelde, L.; Schripsema, J.; Erkelens, J.; Verpoortere, R.
Magn. Reson. Chem. 1993, 31, 329e330.
2. Medicinal Plants of East-Africa; Kowaro, J. O., Ed.; East Afrikan Literature Bureau:
OCH2CH3), 3.93 (1H, dq, J¼9.6 Hz, 7.2 Hz, OCHaHb), 4.10 (1H, dq,
J¼9.6, 7.2 Hz, OCHaHb), 6.57 (1H, s, CH-1), 6.91 (1H, s, CH-4),
7.29e7.43 (3H, m, 3ꢂCHAr), 7.69e7.74 (2H, m, CH-7, and CH-8),
Dar Es Salaam, 1976; p 190.
7.83e7.90 (2H, m, 2ꢂCHAr), 8.08e8.13 (2H, m, CH-6, and CH-9). 13
C
3. (a) For a review on the synthesis of pentalongin, see Claessens, S.; Verniest, G.;
Jacobs, J.; Van Hende, E.; Habonimana, P.; Nguyen Van, T.; Van Puyvelde, L.;
DeKimpe, N. Synlett 2007, 829e850; (b) Kesteleyn, B.; De Kimpe, N.; Van Puyvelde,
L.Synthesis1999,1881e1883;(c)Kesteleyn, B.;DeKimpe, N.;VanPuyvelde, L.J. Org.
Chem. 1999, 64, 1173e1179; (d) Claessens, S.; Naidoo, D.; Mulholland, D.; Ver-
schaeve, L.; Van Staden, J.; De Kimpe, N. Synlett 2006, 621e623.
4. Koyama, J.; Morita, I.; Kobayashi, N.; Osakai, T.; Usuki, Y.; Taniguchi, M. Bioorg.
Med. Chem. Lett. 2005, 15, 1079e1082.
5. Aldersley, M. F.; Chishti, S. H.; Dean, F. M.; Douglas, M. E.; Ennis, D. S. J. Chem.
NMR (CDCl3): d 15.34 (CH3), 64.85 (OCH2), 93.30 (CH-4), 94.46 (CH-
1), 122.12 (Cquat), 126.17 (CHAr), 126.22 (2ꢂCHAr), 126.67 (Cquat),
128.84 (2ꢂCHAr), 130.90 (CHAr), 131.94 (Cquat), 132.84 (Cquat), 133.33
(CHAr), 133.36 (CHAr), 134.23 (CHAr), 136.81 (C-3), 182.07 (C]O),
183.17 (C]O). IR (cmꢀ1): nC]O¼1673, 1652. nCHAr¼1548. MS (ESþ)
m/z (%) 287 (MꢀCH2CH3O, 100). Anal. Calcd for C21H16O4: C: 75.89,
H: 4.85, obtained: C: 75.58, H: 4.72.
Soc., Perkin Trans. 1 1990, 2163e2174.
6. Paranagama, P. A.; Wijeratne, E. M. K.; Burns, A. M.; Marron, M. T.; Gunatilaka,
M. K.; Arnold, A. E.; Gunatilaka, A. A. L. J. Nat. Prod. 2007, 70, 1700e1705.
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8. (a) Johnson, A. W. Ylid Chemistry; Department of Chemistry, University of
Saskatchewan, Regina, Saskatchewan, Canada, Academic: New York, NY, 1966;
4.10.2. 3-(2,5-Dimethoxyphenyl)-1-ethoxy-1H-benzo[g]iso-
chromene-5,10-dione 22f. Yield 67%, decomposition at 181.6 ꢁC, Rf
0.30 (petroleum ether/ethyl acetate 7/3), purple crystals. 1H NMR
€
p 388; (b) Krohnke, F. Synthesis 1976, 1e24.
(CDCl3):
d
1.26 (3H, t, J¼7.2 Hz, OCH2CH3), 3.83 (3H, s, OCH3), 3.94
9. Kesteleyn, B.; Van Puyvelde, L.; De Kimpe, N. J. Org. Chem. 1999, 64, 438e440.
10. (a) King, L. C.; Ostrum, G. K. J. Org. Chem. 1964, 29, 3459e3461; (b) Aldersley, M.
F.; Dean, F. M.; Hamzah, A. S. Tetrahedron Lett. 1986, 27, 255e258.
11. (a) Kesteleyn, B.; Nguyen Van, T.; De Kimpe, N. Tetrahedron 1999, 55,
2091e2102; (b) Nguyen Van, T.; Verniest, G.; Claessens, S.; De Kimpe, N. Tet-
rahedron 2005, 61, 2295e2300; (c) Jacobs, J.; Claessens, S.; Mbala, B. M.; Huy-
gen, K.; De Kimpe, N. Tetrahedron 2009, 65, 1193e1199.
12. (a) Zhao, S.; Neves, M. G. P. M. S.; Tome, A. C.; Silva, A. M. S.; Cavaleiro, J. A. S. Tet-
rahedron Lett. 2005, 46, 5487e5490; (b) Liu, Y.; Hu, H.-Y.; Liu, Q.-J.; Hu, H.-W.;
Xu, J.-H. Tetrahedron 2007, 63, 2024e2033.
13. (a) Kobayashi, K.; Yoneda, K.; Uchida, M.; Matsuoka, H.; Morikawa, O.; Konishi, H.
Heterocycles 2001, 55, 2423e2429; (b) Brimble, M. A.; Elliott, R. J. R. Tetrahedron
1997, 53, 7715e7730.
14. Tanoue, Y.; Terada, A.; Matsumoto, Y. Bull. Chem. Soc. Jpn. 1989, 62, 2736e2738.
15. Tomatsu, A.; Takemura, S.; Hashimoto, K.; Nakata, M. Synlett 1999, 1474e1476.
16. Kloc, K.; Mlochowski, J.; Syper, L. Chem. Lett. 1980, 9, 725e728.
17. Claessens, S.; Verniest, G.; El Hady, S.; Nguyen Van, T.; Kesteleyn, B.;
Van Puyvelde, L.; De Kimpe, N. Tetrahedron 2006, 62, 5152e5158.
18. Blankespoor, R. L.; Boldenhow, P. J.; Hansen, E. C.; Kallemeyn, J. M.; Lohse, A. G.;
Rubush, D. M.; Vrieze, D. J. Org. Chem. 2009, 74, 3933e3935.
(3H, s, OCH3), 3.94 (1H, dq, J¼9.6, 7.2 Hz, OCHaHb), 4.09 (1H, dq,
J¼9.6, 7.2 Hz, OCHaHb), 6.56 (1H, s, CH-1), 6.93 (1H, d, J¼9.2 Hz, CH-
30), 6.97 (1H, dd, J¼9.2, 2.8 Hz, CH-40), 7.39 (1H, s, CH-4), 7.44 (1H, d,
J¼2.8 Hz, CH-60), 7.69e7.78 (2H, m, CH-7, and CH-8), 8.12e8.16 (2H,
m, CH-6, and CH-9). 13C NMR (CDCl3):
d 15.32 (CH3), 55.94 (OCH3),
56.23 (OCH3), 64.73 (OCH2), 93.98 (CH-1), 98.87 (CH-4), 112.76 (CH-
30), 114.03 (CH-60), 116.92 (CH-40), 121.78 (Cquat), 122.02 (Cquat),
122.83 (Cquat), 126.12 (CH-6 of CH-9), 126.64 (CH-6 of CH-9), 132.12
(Cquat), 132.93 (Cquat), 133.33 (CH-7 of CH-8), 134.14 (CH-7 of CH-8),
137.07 (Cquat), 152.97 (COCH3). 153.44 (COCH3), 155.71 (C-3), 182.23
(C]O), 183.49 (C]O). IR (cmꢀ1): nC]O¼1666, 1648, nCHAr¼1528,
1498. MS (ESþ) m/z (%): 347 (MꢀCH2CH3O, 100). Anal. Calcd for
C23H20O6: C: 70.40, H: 5.14, obtained: C: 70.15, H: 4.82.
4.10.3. 1-Ethoxy-1H-3-(4-methylphenyl)-benzo[g]isochromene-5,10-
dione 22g. Yield 86%, mp 159.6 ꢁC, Rf 0.30 (petroleum ether/ethyl
19. Yadav, L. D. S.; Garima, R. K. Synlett 2009, 3123e3126.
20. Gaudry, M.; Marquet, A. Org. Synth. 1988, 6, 193e195.