cis/trans-Isochromanones. DMAP induced cycloaddition of homophthalic anhydride and aldehydes

Article abstract of DOI:10.1016/j.tet.2004.01.040

Homophthalic anhydride (1) reacts with wide variety of aromatic aldehydes, in the presence of chloroform and DMAP (N,N-dimethyl-4-amino-pyridine) at room temperature, to give in high yields cis- and trans-1-oxo-isochroman-4- carboxylic acids. Under these

Full text of DOI:10.1016/j.tet.2004.01.040

Tetrahedron 60 (2004) 2525–2530
cis/trans-Isochromanones. DMAP induced cycloaddition
of homophthalic anhydride and aldehydes
*
Milen G. Bogdanov and Mariana D. Palamareva
Faculty of Chemistry, Sofia University, 1, J. Bouchier Ave., 1164 Sofia, Bulgaria
Received 28 October 2003; revised 16 December 2003; accepted 15 January 2004
Abstract—Homophthalic anhydride (1) reacts with wide variety of aromatic aldehydes, in the presence of chloroform and DMAP (N,N-
dimethyl-4-amino-pyridine) at room temperature, to give in high yields cis- and trans-1-oxo-isochroman-4-carboxylic acids. Under these
conditions, the trans-isomer is predominant and formation of Perkin-type products was not observed in contrast to the reaction carried out in
the presence of pyridine. The unexpected trans-6-oxo-11-thiophen-2-yl-11,12-dihydro-6H-dibenzo[c,h]chromene-12-carboxylic acid
methyl ester (8) was isolated when the reaction between 1 and thiophene-2-carbaldehyde was carried out in pyridine.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Table 1. Ratios among products in the reaction of homophthalic anhydride
(1) and benzaldehyde (2a) under different reaction conditions
Until now, the reaction between homophthalic anhydride (1)
and aldehydes has been performed under different reaction
conditions1–7 affording the corresponding thermodynamic-
ally controlled C-4 methylene condensed products of type
4 or the kinetically controlled cycloadducts trans-32
(Scheme 1). This reaction has been performed both in
basic and acidic media (Table 1). The best results for
benzaldehyde have been observed in the presence of strong
base at low temperature2 (entry 3). In contrast, under
the same catalyst, but at room temperature2 (entry 4), the
reaction is considered as thermodynamically controlled
yielding a mixture of acid trans-3a and the C-4 methylene
condensed product 4a, the latter being predominant.
When the reaction is carried out in the presence of a
Lewis acid (BF3·Et2O complex, entry 5),3 the reaction
gives the cycloadducts cis- and trans-3a and formation of
4a is not observed. It is clear that there is some contra-
diction as to which is the thermodynamically favored
diastereomer. In the analogous reaction between 1 and
Entry
Catalyst
Reaction
conditions
Ratios (%)
t (8C)
Time (h)
cis-3a
trans-3a
4a
1
1
2
3
4
5
Na/liq. NH3
2
rt
rt
0-rt
rt
rt
14
24
24
33
5
—
—
—
—
38
61
35a
83a
5a
—
Na2CO3
NaH2
43a
—
NaH2
82a
—
BF3·Et2O3
43
a
Isolated as a methyl esters after treatment of acidic residue with
diazomethane.
acyclic imines,8,9 the trans is the thermodynamically
preferred diastereomer.
4-Dimethylaminopyridine (DMAP) is known to be an
excellent catalyst for a variety of synthetic trans-
formations under mild conditions, such as alkylation,
acylation, silylation, esterification, polymerisation and
Scheme 1.
Keywords: Homophthalic anhydride; Aldehydes; Cycloaddition; DMAP; Pyridine; Isochroman-4-carboxylic acids.
*
Corresponding author. Tel.: þ359-2-8161-221; fax: þ359-2-962-54-38; e-mail address: mpalamareva@chem.uni-sofia.bg
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.040

2526
M. G. Bogdanov, M. D. Palamareva / Tetrahedron 60 (2004) 2525–2530
rearrangements.10 This paper presents a study on the
reaction of homophthalic anhydride (1) with different
aromatic or heteroaromatic aldehydes in the presence of
DMAP at mild conditions: room temperature and duration
of 1.5–2.5 h. Thus, we demonstrated that under these
conditions 1 reacted with benzaldehyde to give cyclo-
adducts cis-3a and trans-3a only. This procedure gives
excellent results and was extended to a wide variety of
aromatic aldehydes. A comparison with the reaction in the
presence of pyridine is done.
prepared in another way.11 It is clear that cycloaddition is
the preferred reaction when DMAP is used as a base. The
formation of the C-4 methylene condensed by-products 4
depends on the type of the aromatic or heteroaromatic
substituent on the aldehyde. Formation of 4 is avoided if
the substituent X does not deactivate or even activates the
aldehyde group to nucleophilic addition (entries a, b, g). It is
worth noting that the nitrogen atom in 9-methyl-carbazole-
3-carbaldehyde (2g) influences slightly the aldehyde group.
Thus, aldehyde 2g behaves in a similar manner to 2a in the
reaction studied. The presence of electron-donating group in
2c–f deactivates the aldehyde group and always leads to
formation of 4 along with adducts 3.
2. Results and discussion
2.2. Large scale preparation of acids 3a–g
2.1. Small scale syntheses of 3-aryl-1-oxo-isochroman-4-
carboxylic acids 3a–g
For the isolation and characterization of acids 3a–g, we
carried out the reactions between 1 and 2a–g, on 2.7–
3.9 mmol of substrate, in the presence of DMAP–chloro-
form. In all cases, both diastereomeric cycloadducts were
formed. The diastereomers of 3a,b were separated by
fractional crystallization. In case 2d, column chromatog-
raphy lead to isolation of 4d only, while cis- and trans-3d
crystallized as a diastereomeric mixture. 3c,e,f and g were
isolated as trans-isomers only, since the quantity of the
relevant cis-isomers was small. All isolated compounds
Scheme 1 shows that the reaction between 1 and aldehydes
2a–g, including benzaldehyde (2a), lead always to
cycloadducts 3, while the C-4 methylene condensed
by-products 4 are obtained in cases c–f only. To establish
the ratios among cis-3, trans-3 and 4 in the presence of
DMAP, the reaction between 1 and aldehydes 2a–g was
performed on a small scale (by 0.54–0.77 mmol of 1) under
mild conditions (Table 2). The aprotic solvent used was
chloroform. Such studies on the reaction of 1 with aldehydes
are not known. The reaction is stereoselective towards the
trans-isomer. The ratios among cis-3, trans-3 and 4 were
determined by 1H NMR spectroscopy from the integrals of
relevant protons. The signals for the protons at C-3 and C-4
were used1–6 for any isomer of type 3. In the case of
products 4c–f, the olefinic proton was taken into account.
1
gave the expected spectroscopic data (IR, H NMR) and
microanalyses.
2.2.1. Preparation of acid trans-3e and the methyl esters
6, 7 and 8. Comparison between two basic catalysts. The
reaction between 1 and thiophene-2-carbaldehyde 2e was
performed also on larger scales (18–36 mmol of substrate)
both in DMAP–chloroform and in pyridine. These
experiments aimed to compare of DMAP with another
basic catalyst. Significant differences were established, as
shown in Scheme 2. When the reaction was carried out in
pyridine, the unsaturated anhydride 5 was isolated in 27%
yield. Compound 5 is known11 but is prepared in another
way. Having isolated 5, the acidic residue was treated with
diazomethane giving a mixture of compounds 6, 7 and 8
(TLC) separated by column chromatography of the crude
reaction mixture. The presence of 6 and 7 is well under-
stood, but the presence of 8 is unexpected. There is no
literature procedure for the preparation of compounds of this
type in a reaction between 1 and carbonyl compounds. The
structure of compound 8 was confirmed by spectral data
The results are summarized in Table 2. The configuration of
1–6
each isomer was determined on the basis of J3,4
.
trans
Configuration was as to the isomer with greater J3,4
(J3,4.5.6 Hz) and cis configuration as to the isomer with
smaller J3,4 (J3,4,4 Hz). It is clear that the quantities of 3
(both isomers) vary from 70 to 100% when 1 is not present
at the end of the reaction (TLC). When benzaldehyde or
substituted benzaldehydes are used, the total yield of
cycloadducts 3a–d,g (both isomers) is 95%. In the cases
when the aldehyde is substituted with a heterocyclic ring,
such as furan-2-yl and thiophen-2-yl (2e,f), the C-4
methylene condensed products 4e,f were detected in
quantities 9–30%. It is known that the reaction of 1 with
furfural in the presence of sodium carbonate6 gives the C-4
methylene condensed product 4f only. 4e is known, but is
Table 2. Ratios among products in the reaction of homophthalic anhydride and aromatic aldehydes in the presence of DMAP at room temperature
2
X–CHO
Reaction time (h)a
Total yield (%)b
Ratio (%)c
3-cis
3-trans
4
2a
2b
2c
2d
2e
2f
Benzaldehyde
4-Nitro-benzaldehyde
2
2
2.5
2
1.5
1.5
2
100
98
98
100
100
100
80
30
23
16
16
9
70
77
80
79
82
62
91
—
—
4
5
9
4-Methoxy-benzaldehyde
Benzo[1,3]dioxole-5-carbaldehyded
Thiophene-2-carbaldehyde
Furan-2-carbaldehyde
8
9
30
—
2g
9-Methyl-9H-carbazole-3-carbaldehyde
a
The complete consumption of 1 was determined by TLC.
Yields of the obtained acidic residue before recrystallization.
b
c
d
The ratio was determined by 1H NMR integrals of the obtained acidic residue (see text).
Pipperonal.

M. G. Bogdanov, M. D. Palamareva / Tetrahedron 60 (2004) 2525–2530
2527
Scheme 2.
(1H, 13C NMR, MS, IR) and microanalysis. In general, the
lower value of J9,10 (J¼1.3 Hz) in 1H NMR spectrum
suggests the cis-configuration of 8 and a conformation with
equatorial thiophenyl and axial methoxycarbonyl group,1
but X-ray crystallography of 812 showed the configuration to
be trans and that the substituents at C-9 and C-10 are
diaxial. The torsion angle H9–C9–C10–H10 is 788.
(Fig. 1). This angle agrees with the smaller value of the
coupling constant J9,10. The presence of the parent acid of
8 can be rationalized by lactam ring opening in trans-3e
and subsequent interaction with an equimolar quantity of
homophthalic anhydride.
cyclo-addition reaction of homophthalic anhydride with
aldehydes, catalyzed by DMAP. The reaction occurs under
mild conditions and has been extended to a wide variety of
aldehydes. The reaction is highly stereoselective towards
the trans-cycloadducts in cases 3a–g. This method has been
compared with the analogous reaction in pyridine and has
proved to be preferable.
4. Experimental
Melting points were determined on a Kofler hot stage
apparatus and are uncorrected. The IR spectra were
recorded on a Specord 75. Nujol was used for all acidic
1
products and chloroform for all other compounds. The H
NMR spectra were obtained on a Bruker AM300 NMR
spectrometer at 300.13 MHz and Bruker Avance DRX-250
spectrometer at 250.13 MHz. The 13C NMR spectra were
obtained on a Bruker AM300 NMR spectrometer at 75 MHz
in CDCl3. The chemical shift is given in ppm (d) relative to
tetramethylsilane as internal standard. The integrals in the
1H NMR spectra show that any compound was isolated in
purity more than 98%. Mass spectra were recorded on a
Hewlett Packard MS 5973 using electron impact of 30 eV.
The microanalyses were done in the relevant laboratories at
the Faculty of Chemistry, University of Sofia. TLC was
done on precoated 0.2 mm Merck silica gel 60F254 plates.
Merck silica gel 60 (0.040–0.063 mm) was used for
chromatographic filtration and column chromatography.
Figure 1. Configuration and conformation of trans-8.
The reaction between 1 and thiophene-2-carbaldehyde 2e in
the presence of DMAP on larger scale proceeded similarly
to the smaller-scale cases and by-products 5 (Perkin-type)
and 8 were not observed. Under these conditions, we were
able to isolate also acid cis-3e. The conversion of trans-3e to
the methyl ester was accomplished by treatment with
diazomethane in diethylether solution. The direct esterifica-
tion of acid 3e or its treatment with iodomethane in the
presence of potassium carbonate leads to a,b-unsaturated
product 7.
4.1. General procedure for determination of the ratios of
the products obtained from 1 and aldehydes 2a–g in the
small scale experiments
To a mixture of 1 (0.54–0.77 mmol) and 1.1 equiv. of
corresponding aldehyde (see Table 2) in dry chloroform
(1 ml), DMAP (1 equiv.) was added. The reaction mixture
was stirred at room temperature for 1.5–2.5 h. At the end of
the reaction, presence of 1 was not established (TLC). The
obtained carboxylic acids were extracted with 10% sodium
hydrogen carbonate and the aqueous layer was acidified
(pH¼3) with 10% hydrochloric acid and extracted with
ethyl acetate. The organic layer was dried (sodium sulfate),
filtered and the solvent was then evaporated. The ratios of
3. Conclusions
We have presented an optimized method for synthesis of
1-oxo-isochroman-4-carboxylic acid derivatives by the

2528
M. G. Bogdanov, M. D. Palamareva / Tetrahedron 60 (2004) 2525–2530
all products (cis-3/trans-3/4) were determined, as described
above, by 1H NMR (300 MHz) integrations. The data
obtained are summarized in Table 2.
dimethyl sulfoxide-d6): d¼4.35 (1H, d, J¼7.5 Hz, H-4),
6.06 (1H, d, J¼7.5 Hz, H-3), 7.38 (1H, d, J¼7.8 Hz, phenyl
proton), 7.50 (1H, t, J¼7.5 Hz, phenyl proton), 7.61–7.69
(3H, m, phenyl protons), 8.11 (1H, dd, J¼1.3, 7.8 Hz,
phenyl proton), 8.19–8.23 (2H, m, phenyl protons), 13.21
(1H, s, COOH). Anal. Calcd for C16H11NO6: C, 61.35%; H,
3.54%; Found: C, 61.51%; H, 3.54%.
4.2. General procedure for synthesis of 1-oxo-
isochroman-4-carboxylic acids on large scales
To a mixture of 1 (2.69–3.87 mmol) and 1.1 equiv. of cor-
responding aldehyde 2 in dry chloroform (5 ml) DMAP
(1 equiv.) was added. The reaction mixture was stirred at
room temperature for 1.5–2.5 h. At the end of the reaction,
when 1 was shown to have been consumed (TLC), the
obtained carboxylic acids were extracted with 10% sodium
hydrogen carbonate. The aqueous layer was acidified
(pH¼3) with 10% hydrochloric acid and extracted with
ethyl acetate. The organic layer was dried (sodium sulfate),
filtered and the solvent was then evaporated under reduced
pressure. The products were obtained by precipitation or
fractional crystallization of the residue.
4.2.3. 3-(4-Methoxy-phenyl)-1-oxo-isochroman-4-carb-
oxylic acid (3c). trans-Diastereomer. The residue crystal-
lized as white crystals (from ethyl acetate). Yield: 0.60 g
(60%), mp 149–151 8C; IR (Nujol): (CO) 1740, 1715 cm21
;
1H NMR (250 MHz, dimethyl sulfoxide-d6): d¼3.73 (3H, s,
OCH3), 4.61 (1H, d, J¼7.2 Hz, H-4), 5.86 (1H, d, J¼7.2 Hz,
H-3), 6.89–6.95 (2H, m, phenyl protons), 7.32–7.39 (3H,
m, phenyl protons), 7.51 (1H, dt, J¼1.0, 7.5 Hz, phenyl
proton), 7.69 (1H, dt, J¼1.5, 7.5 Hz, phenyl proton), 7.97
(1H, dd, J¼1.3, 7.8 Hz, phenyl proton), 13.22 (1H, s,
COOH). Anal. Calcd for C17H14O5: C, 68.45%; H, 4.73%;
Found: C, 68.68%; H, 4.68%.
4.2.1. 3-Phenyl-1-oxo-isochroman-4-carboxylic acids
(3a). cis-Diastereomer. The residue was treated with
dichloromethane until precipitation. Yield: 0.14 g (14%),
mp 179–180 8C, (lit.3 mp 189–190 8C); IR (Nujol): (CO)
1735, 1710 cm21; 1H NMR (250 MHz, dimethyl sulfoxide-
d6): d¼4.14 (1H, d, J¼3.5 Hz, H-4), 5.80 (1H, d, J¼3.5 Hz,
H-3), 7.38–7.46 (4H, m, phenyl protons), 7.53–7.59 (3H,
m, phenyl protons), 7.65 (1H, dt, J¼1.5, 7.5 Hz, phenyl
proton), 8.18 (1H, dd, J¼1.4, 7.8 Hz, phenyl proton), 13.01
(1H, s, COOH). Anal. Calcd for C16H12O4: C, 71.64%; H,
4.51%; Found: C, 71.36%; H, 4.32%.
4.2.4. 3-Benzo[1,3]dioxol-5-yl-1-oxo-isochroman-4-carb-
oxylic acids (3d) and 2-(2-benzo[1,3]dioxol-5-yl-1-carb-
oxyvinyl)-benzoic acid (4d). A precipitate being a mixture
of cis- and trans-diastereomers 3d (from ethyl acetate, after
column chromatography) was obtained. Yield: 0.76 g (76%),
1
mp 139–141 8C; IR (Nujol): (CO) 1740, 1700 cm21; H
NMR (250 MHz, dimethyl sulfoxide-d6).
cis-Diastereomer. d¼4.08 (1H, d, J¼3.6 Hz, H-4), 5.69
(1H, d, J¼3.6 Hz, H-3).
trans-Diastereomer. The dichloromethane filtrate was
distilled under reduced pressure and the product was
recrystallized from ethyl acetate giving colorless prisms.
Yield: 0.61 g (61%), mp 169–170 8C, (lit.3 mp 180–
trans-Diastereomer. d¼4.30 (1H, d, J¼8.0 Hz, H-4), 5.77
(1H, d, J¼8.0 Hz, H-3), other signals for both dia-
stereomers: d¼5.95 (2H, s, –OCH2O–), 6.73 (1H, d,
J¼8.0 Hz, phenyl proton), 6.80–6.89 (2H, m, phenyl
protons), 7.29 (1H, d, J¼8 Hz, phenyl proton), 7.45 (1H,
t, J¼7.4 Hz, phenyl proton), 7.61 (1H, dt, J¼1.5, 7.6 Hz,
phenyl proton), 8.17 (1H, dd, J¼1.3, 7.6 Hz, phenyl proton).
Anal. Calcd for C17H12O6: C, 65.39%; H, 3.87%; Found: C,
64.98%; H, 4.05%.
181 8C); IR (Nujol): (CO) 1735, 1715 cm21 1H NMR
;
(250 MHz, dimethyl sulfoxide-d6): d¼4.36 (1H, d, J¼
7.5 Hz, H-4), 5.92 (1H, d, J¼7.5 Hz, H-3), 7.29–7.39 (6H,
m, phenyl protons), 7.50 (1H, t, J¼7.5 Hz, phenyl proton),
7.62 (1H, dt, J¼1.5, 7.5 Hz, phenyl proton), 8.18 (1H, dd,
J¼1.5, 7.8 Hz, phenyl proton), 12.75 (1H, s, COOH). Anal.
Calcd for C16H12O4: C, 71.64%; H, 4.51%; Found: C,
71.88%; H, 4.11%.
By-product 4d was obtained from the filtrate of 3d as
colorless prisms (from ethyl acetate, after column chroma-
tography). Yield: 0.04 g (4%), mp 177–179 8C; IR (Nujol):
;
(CO) 1745, 1715 cm21 1H NMR (250 MHz, dimethyl
sulfoxide-d6): d¼5.94 (2H, s, –OCH2O–), 6.24 (1H, d,
J¼1.5 Hz, phenyl proton), 6.69 (1H, dd, J¼1.8, 8.3 Hz,
phenyl proton), 6.79 (1H, d, J¼8.0 Hz, phenyl proton), 7.09
(1H, dd, J¼1.8, 7.0 Hz, phenyl proton), 7.45–7.57 (2H, m,
phenyl protons), 7.56 (1H, s, H-olefinic), 8.01 (1H, dd,
J¼2.0, 7.0 Hz, phenyl proton), 12.57 (2H, s, COOH).
4.2.2. 3-(4-Nitro-phenyl)-1-oxo-isochroman-4-carboxylic
acids (3b). cis-Diastereomer. The residue was treated with
dichloromethane until precipitation. Yield: 0.18 g (18%),
1
mp 199–201 8C; IR (Nujol): (CO) 1740, 1710 cm21; H
NMR (250 MHz, dimethyl sulfoxide-d6): d¼4.48 (1H, d,
J¼3.5 Hz, H-4), 6.19 (1H, d, J¼3.5 Hz, H-3), 7.53–7.62
(2H, m, phenyl protons), 7.74 (1H, dt, J¼1.5, 7.5 Hz, phenyl
proton), 7.83 (2H, d, J¼8.5 Hz, phenyl protons), 8.06 (1H,
dd, J¼1.3, 7.8 Hz, phenyl proton), 8.32–8.36 (2H, m,
phenyl protons), 12.86 (1H, s, COOH). Anal. Calcd for
C16H11NO6: C, 61.35%; H, 3.54%; Found: C, 61.41%; H,
3.44%.
4.2.5. 3-Thiophen-2-yl-1-oxo-isochroman-4-carboxylic
acid (3e). trans-Diastereomer. This compound was
obtained as colorless prisms (from ethyl acetate). Yield:
0.75 g (75%), mp 122–124 8C; IR (Nujol): (CO) 1740,
1685 cm21 1H NMR (250 MHz, dimethyl sulfoxide-d6)
;
trans-Diastereomer. After isolation of the cis-isomer, the
solvent was removed under reduced pressure and the
product was crystallized from ethanol–water (1:1) as
colorless prisms. Yield: 0.70 g (70%), mp 163–165 8C; IR
d¼4.28 (1H, d, J¼5.7 Hz, H-4), 6.23 (1H, d, J¼5.7 Hz,
H-3), 6.92 (1H, dd, J¼3.6, 5.0 Hz, thienyl proton),
7.03–7.09 (1H, m, thienyl proton), 7.25 (1H, dd, J¼3.6,
5.0 Hz, thienyl proton), 7.40–7.45 (1H, m, phenyl proton),
7.48–7.52 (1H, m, phenyl proton), 7.63 (1H, dt, J¼1.6,
(Nujol): (CO) 1740, 1715 cm21 1H NMR (250 MHz,
;

M. G. Bogdanov, M. D. Palamareva / Tetrahedron 60 (2004) 2525–2530
2529
7.7 Hz, phenyl proton), 8.12 (1H, dd, J¼1.5, 7.8 Hz, H-8).
Anal. Calcd for C14H10O4S: C, 61.30%; H, 3.67%; Found:
C, 61.50%; H, 3.51%.
dt, J¼1.5, 7.5 Hz, phenyl proton), 8.03 (1H, dd, J¼1.5,
7.7 Hz, phenyl proton), 12.95 (1H, s, COOH). Anal. Calcd
for C14H10O4S: C, 61.30%; H, 3.67%; Found: C, 61.28%;
H, 3.67%.
4.2.6. 3-Furan-2-yl-1-oxo-isochroman-4-carboxylic acid
(3f). trans-Diastereomer. This compound was obtained as
white crystals (from ethyl acetate). Yield: 0.54 g (54%), mp
152–154 8C; IR (Nujol): (CO) 1730, 1710 cm21; 1H NMR
(250 MHz, dimethyl sulfoxide-d6): d¼4.59 (1H, d, J¼
4.8 Hz, H-4), 6.07 (1H, d, J¼4.8 Hz, H-3), 6.31 (1H, d,
J¼3.3 Hz, furyl proton), 6.40 (1H, dd, J¼2.0, 3.5 Hz, furyl
proton), 7.49–7.55 (2H, m, phenyl protons), 7.64 (1H, dd,
J¼0.8, 2.0 Hz, furyl proton), 7.72 (1H, dt, J¼1.5, 7.8 Hz,
phenyl proton), 7.95 (1H, d, J¼7.8 Hz, phenyl proton),
13.40 (1H, s, COOH). Anal. Calcd for C14H10O5: C,
65.12%; H, 3.90%; Found: C, 64.97%; H, 3.88%.
4.3.2. Reaction in pyridine. 4-Thiophen-2-yl-methylene-
isochroman-1,3-dione (5), trans-1-oxo-3-thiophen-2-yl-iso-
chroman-4-carboxylic acid methyl ester (6), 2-(1-methoxy-
carbonyl-2-thiophen-2-yl-vinyl)-benzoic acid methyl ester
(7) and trans-6-oxo-11-thiophen-2-yl-11,12-dihydro-6H-
dibenzo [c,h]chromene-12-carboxylic acid methyl ester (8)
To a mixture of 5.91 g (36.5 mmol) homophthalic anhy-
dride and 5 ml (57.74 mmol) 2-thiophene carbaldehyde,
35 ml pyridine was added. After stirring for 5 h. at room
temperature, the reaction mixture was filtered to give orange
crystals of 5 (2.67 g) in 27% yield. The filtrate was diluted
with water and extracted with chloroform. The chloroform
layer was washed with diluted hydrochloric acid once and
extracted with 10% sodium hydrogen carbonate. The
hydrogen carbonate extract was washed once with ethyl
acetate, acidified (pH¼3) with 10% hydrochloric acid and
extracted three times with ethyl acetate (100 ml). The
organic layers were washed with water, dried (sodium
sulfate) and the solvent was removed under reduced
pressure to give 6.74 g an oil. The residue, containing
acidic compounds was diluted with chloroform and treated
with diazomethane. The mixture was stirred at room
temperature for 2 h. The excess diazomethane and chloro-
form was removed under reduced pressure giving an oil
(6.80 g). The residue was purified by column chroma-
tography on silica gel to give the esterified products trans-6
(2.34 g, 34%), trans-8 (1.00 g, 15%) along with 1.70 g
(25%) of 7.
4.2.7. 3-(9-Methyl-9H-carbazol-3-yl)-1-oxo-isochroman-
4-carboxylic acid (3g). trans-Diastereomer. This com-
pound was precipitated in water, purified by recrystalliza-
tion and isolated as white crystals (from DMF). Yield:
0.78 g (78%), mp 206–208 8C; IR (Nujol): (CO) 1740,
1
1715 cm21; H NMR (250 MHz, dimethyl sulfoxide-d6):
d¼3.87 (3H, s, –NCH3), 4.79 (1H, d, J¼8.0 Hz, H-4), 6.07
(1H, d, J¼8.0 Hz, H-3), 7.22 (1H, t, J¼7 Hz, phenyl
proton), 7.39–7.62 (6H, m, phenyl protons), 7.71 (1H, dt,
J¼1.5, 7.8 Hz, phenyl proton), 8.03 (1H, dd, J¼1.0, 7.5 Hz,
phenyl proton), 8.13 (1H, d, J¼7.8 Hz, phenyl proton), 8.26
(1H, s, phenyl proton), 13.26 (1H, s, COOH). Anal. Calcd
for C23H17NO4: C, 74.38%; H, 4.61%; Found: C, 73.99%;
H, 4.52%.
4.3. Reaction between homophthalic anhydride and
thiophene-2-carbaldehide (2e) performed on larger
scales and subsequent transformations
Compound 5 was obtained as orange needles (from
pyridine). Yield: 2.67 g (27%). After recrystallization
from DMF: mp 232 8C, (lit.11 mp 232 8C); IR: (CO–O–
CO) 1755, 1715 cm21; 1H NMR (250 MHz, TFA): d¼7.25
(1H, t, J¼4 Hz, thienyl proton), 7.53 (1H, t, J¼7.5 Hz,
phenyl proton), 7.80–7.96 (4H, m, thienyl and phenyl
protons), 8.27 (1H, d, J¼8 Hz, phenyl proton), 8.60 (1H, s,
H-olefinic). Anal. Calcd for C14H8O3S: C, 65.61%; H,
3.15%; Found: C, 65.59%; H, 3.15%.
4.3.1. Reaction in DMAP–chloroform. 1-Oxo-3-thio-
phen-2-yl-isochroman-4-carboxylic acid (3e). To a stirring
mixture of 3.00 g (18.52 mmol) homophthalic anhydride
and 1.7 ml (18.25 mmol) 2-thiophene carbaldehyde in dry
chloroform (20 ml) was added DMAP 3.34 g (27.37 mmol).
After stirring for 1.5 h. at room temperature, TLC analysis
showed the absence of homophthalic anhydride. The
reaction mixture was then extracted with 10% sodium
hydrogen carbonate three times. The hydrogen carbonate
layers were washed once with ethyl acetate, acidified with
10% hydrochloric acid and extracted with ethyl acetate. The
organic layer was washed with water and dried (sodium
sulfate). The solvent was removed under reduced pressure.
Crystallization of the residue gave:
Compound 6 was obtained as colorless prisms after column
chromatography (from hexane–ethyl acetate). Yield: 2.34 g
1
(34%), mp 126–128 8C; IR: (CO) 1750, 1730 cm21; H
NMR (300 MHz, deuteriochloroform): d¼3.75 (3H, s,
OCH3), 4.34 (1H, d, J¼6.3 Hz, H-4), 6.18 (1H, d, J¼
6.3 Hz, H-3), 6.23 (1H, dd, J¼3.6, 5.0 Hz, thienyl proton),
7.04–7.07 (1H, m, thienyl proton), 7.26 (1H, dd, J¼1.5,
5.1 Hz, thienyl proton), 7.29 (1H, dm, J¼7.6 Hz, phenyl
proton), 7.49 (1H, t, J¼7.6 Hz, phenyl proton), 7.63 (1H, dt,
J¼1.5, 7.6 Hz, phenyl proton), 8.15 (1H, dd, J¼1.5, 7.8 Hz,
phenyl proton); 13C NMR (75 MHz): d¼169.71, 163.28,
139.62, 135.45, 134.40, 130.65, 129.07, 127.67, 127.20,
126.79, 126.66, 124.74, 76.32, 52.93, 50.41; MS m/z: 288
(molecular ion), 229 (M2COOCH3)þ. Anal. Calcd for
C15H12O4S: C, 62.49%; H, 4.20%; Found: C, 62.18%; H,
3.80%.
trans-Diastereomer. This compound was obtained as color-
less prisms (from hexane–ethyl acetate). Yield: 3.74 g
(74%), mp 122–124 8C (see Section 4.2.5).
cis-Diastereomer. This compound was obtained as colorless
needless (from ethyl acetate) after isolation of the trans-
diastereomer. Yield: 0.35 g (7%), mp 160–162 8C; IR
;
(Nujol): (CO) 1740, 1690 cm21 1H NMR (300 MHz,
dimethyl sulfoxide-d6): d¼4.37 (1H, d, J¼3.5 Hz, H-4),
6.23 (1H, d, J¼3.5 Hz, H-3), 7.09 (1H, dd, J¼3.5, 5.0 Hz,
thienyl proton), 7.24 (1H, d, J¼3.5 Hz, thienyl proton),
7.52–7.60 (3H, m, thienyl and phenyl protons), 7.72 (1H,
Compound 7 was obtained as colorless prisms after column

2530
M. G. Bogdanov, M. D. Palamareva / Tetrahedron 60 (2004) 2525–2530
chromatography (from hexane–ethyl acetate). Yield: 1.70 g
(25%), mp 90–92 8C, (lit.11 mp 90 8C); IR: (CO) 1730,
wise. The reaction mixture was stirred for 3 h. added to
water and extracted with ethyl acetate. The organic layer
was washed with water, dried (sodium sulfate) and
evaporated giving an oil. The later afforded 7 as colorless
crystals (from ethyl acetate) in yield 76% (0.38 g), mp
90–92 8C.
1710 cm21 1H NMR (300 MHz, deuteriochloroform):
;
d¼3.75 (3H, s, -OCH3), 3.78 (3H, s, -OCH3), 6.88 (1H,
dd, J¼3.6, 8.8 Hz, thienyl proton), 7.06–7.08 (1H, m,
thienyl proton), 7.15–7.19 (1H, m, phenyl proton), 7.30
(1H, dd, J¼1.4, 8.8 Hz, thienyl proton), 7.51–7.62 (2H, m,
phenyl protons), 7.98 (1H, s, H-olefinic), 8.16 (1H, dd,
J¼1.5, 7.7 Hz, phenyl proton); 13C NMR (75 MHz):
d¼167.59, 166.55, 138.61, 137.05, 133.16, 132.87,
131.98, 131.33, 131.31, 130.38, 130.06, 129.95, 128.81,
126.76, 52.21, 52.03; MS m/z: 302 (molecular ion), 243
(M2COOCH3)þ. Anal. Calcd for C16H14O4S: C, 63.56%;
H, 4.67%; Found: C, 63.27%; H, 4.93%.
(3) A stirring solution of trans-3e (1.00 g, 3.65 mmol) in
5 ml chloroform was treated with diazomethane. The
mixture was stirred at room temperature for 2 h. The excess
diazomethane and chloroform was removed under
reduced pressure giving an oil. The later afforded trans-6
as colorless crystals (from ethyl acetate) in yield 85%
(0.85 g), mp 126–128 8C.
Compound 8 was obtained as colorless prisms after column
chromatography (from hexane–ethyl acetate). Yield: 1.00 g
1
(15%), mp 220–222 8C; IR: (CO) 1740, 1730 cm21; H
Acknowledgements
NMR (300 MHz, deuteriochloroform) d¼3.61 (3H, s,
OCH3), 4.12 (1H, d, J¼1.3 Hz, H-4), 5.33 (1H, d, J¼
1.3 Hz, H-3), 6.73–6.79 (2H, m, thienyl protons), 7.01 (1H,
dd, J¼1.5, 4.8 Hz, thienyl proton), 7.29 (1H, dd, J¼1.7,
7.4 Hz, thienyl proton), 7.35 (1H, dt, J¼1.3, 7.4 Hz, phenyl
proton), 7.41–7.51 (2H, m, phenyl protons), 7.65–7.75 (2H,
m, phenyl protons), 7.99 (1H, dd, J¼1.3, 7.6 Hz, phenyl
proton), 8.36 (1H, dm, J¼7.6 Hz, phenyl proton); 13C NMR
(75 MHz): d¼171.59, 161.64, 147.78, 143.32, 136.33,
135.10, 130.97, 130.74, 130.36, 129.93, 128.73, 128.09,
127.83, 126.85, 125.19, 124.47, 123.31, 122.57, 121.37,
111.31, 52.80, 52.18, 35.86; MS m/z: 388 (molecular ion),
329 (M2COOCH3)þ. Anal. Calcd for C23H16O4S: C,
71.12%; H, 4.15%; Found: C, 71.02%; H, 4.07%.
The authors thank Mr. Boian Iliev for some NMR
spectroscopy.
References and notes
1. Haimova, M.; Stanoeva, E.; Ivanova, S.; Palamareva, M.;
Spassov, S. Commun. Dept. Chem., Bulg. Acad. Sci. 1977, 10,
489–509.
2. Okunaka, R.; Honda, T.; Kondo, M.; Tamura, Y.; Kita, Y.
Chem. Pharm. Bull. 1991, 39, 1298–1301.
3. Niefang, Y.; Poulain, R.; Tartar, A.; Gesquire, J. Tetrahedron
1999, 55, 13735–13740.
4.4. Methyl ester 6 of acid trans-3e
4. Girota, N.; Wendler, N. J. Org. Chem. 1969, 34, 3192–3194.
5. Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K. Chem.
Pharm. Bull. 1981, 29, 3486–3493.
The reaction was attempted in three modes.
6. Kaji, H.; Yamada, M.; Nozawa, K.; Kawai, K.; Nakajima, S.
Org. Prep. Proced. Int. 1986, 18, 253.
(1) To a stirring solution of trans-3e (0.71 g, 2.59 mmol) in
3.5 ml methanol, H2SO4 (0.2 ml, 3.8 mmol) was added
dropwise. The reaction mixture was refluxed for 3 h. and
left over night. The colorless crystals were filtered and
washed with water/methanol yielding 0.55 g (74%) of 7, mp
90–92 8C.
7. Jones, J.; Pinder, A. J. Chem. Soc. 1958, 2621.
8. Kozekov, I. D.; Koleva, R. I.; Palamareva, M. D. J. Heterocycl.
Chem. 2002, 39, 229–235.
9. Stoyanova, M. P.; Kozekov, I. D.; Palamareva, M. D.
J. Heterocycl. Chem. 2003, 40, 795–803.
10. Scriven, E. F. V. J. Chem. Soc., Rev. 1983, 12, 129.
11. El-Rayyes, N. R.; Ali, A. H. A. J. Heterocycl. Chem. 1976, 13,
83–88.
(2) To a mixture of potassium carbonate (0.24 g,
1.74 mmol) and acid trans-3e (0.48 g, 1.74 mmol) in DMF
(3 ml), iodomethane (0.2 ml, 3.47 mmol) was added drop-
12. Bogdanov, M.; Todorov, I. To be published.