Furan ring opening - Isocoumarine ring closure: A recyclization reaction of 2-carboxyaryldifurylmethanes

Article abstract of DOI:10.1002/jhet.5570430510

A general method for the synthesis of isocoumarine derivatives has been developed. Bis(5-R-2-furyl)methylbenzoic acids (R = methyl, ethyl) underwent recyclization and subsequent cyclization into tetracyclic isochromene-1-one derivatives under treatment with hydrogen chloride in methanol. It has been shown that intermediate 4-(5-R-furan-2-yl)-3-(3-oxo-3-R-propyl)-isochromene-1- ones can be obtained selectively by varying a concentration of the hydrogen chloride and reaction times. In the case of R = tert-butyl only corresponding 4-[5-(tert-butyl)-2-furyl]-3-(4,4-dimethyl-3-oxopentyl)-1-isochromenones were isolated regardless of the reaction conditions.

Full text of DOI:10.1002/jhet.5570430510

Sep-Oct 2006
1195
Furan Ring Opening – Isocoumarine Ring Closure:
A Recyclization Reaction of 2-Carboxyaryldifurylmethanes
Vladimir T. Abaev [a], Artem S. Dmitriev [b], Andrey V. Gutnov [c],
Sergey A. Podelyakin [b] and Alexander V. Butin* [b]
[a] North-Ossetian State University, Vatutina 46, Vladikavkaz, 362025, Russia
[b] Kuban State University of Technology, Moskovskaya 2, Krasnodar, 350072, Russia
E-mail: alexander_butin@mail.ru
[c] Leibniz-Institut für Organische Katalyse an der Universität Rostock e.V.,
Albert-Einstein-Str. 29a 18059 Rostock, Germany
Received November 20, 2005
O
O
O
1
1
1
R3
OH
O
R
R
R
+
+
O
O
H
H
R3
2
2
2
R
R
R
O
O
O
O
R3
3
R3
R3
R
R3 = Me, Et, tBu
R3 = Me, Et, tBu
R3 = Me, Et
A general method for the synthesis of isocoumarine derivatives has been developed. Bis(5-R-2-
furyl)methylbenzoic acids (R = methyl, ethyl) underwent recyclization and subsequent cyclization into
tetracyclic isochromene-1-one derivatives under treatment with hydrogen chloride in methanol. It has been
shown that intermediate 4-(5-R-furan-2-yl)-3-(3-oxo-3-R-propyl)-isochromene-1-ones can be obtained
selectively by varying a concentration of the hydrogen chloride and reaction times. In the case of R = tert-
butyl only corresponding 4-[5-(tert-butyl)-2-furyl]-3-(4,4-dimethyl-3-oxopentyl)-1-isochromenones were
isolated regardless of the reaction conditions.
J. Heterocyclic Chem., 43, 1195 (2006).
Introduction.
formation of the required configuration for carbonyl and
carboxyl substituents [10]. The second way provides the
introduction of a carboxy group into the ortho-position of
benzylcarbonyl compounds [11]. The third approach,
most popular, results from the attachment the of
methylenecarbonyl group to the ortho-position of benzoic
acids, and the function can exist both in explicit [2b,7,12]
and in latent form (acetylenes [13], vinyl bromides [14],
preoxidized ethylenes [5,15], enol ethers [16] etc.).
Isocoumarine derivatives are an important class of
natural lactones possessing many kinds of biological
activity [1]. A whole number of synthetic isocoumarines
are of great interest as pharmaceuticals with antifungal
[2], antibacterial [2b], anticoagulant activity [3], human
leukocyte elastase inhibitors [4].
The highly reactive heterocyclic ring of isocoumarine
makes it an attractive synthon for the synthesis of other
types of hetero- and carbocyclic compounds. For
example, total syntheses of some natural products like
nitidine [5], tetracycline antibiotic pretetramide [6],
antraquinone anticancer agents of angucyclines (±)-PD
116740 series [7], natural antibiotics (±)-Cervinomycins
A1 and A2 [8], and cannabinoids [9] include isocoumarine
ring transformation as an intermediate step.
Scheme 1
O
O
OH
O
X
R
X
Altogether it stimulates the development of new
syntheses of isocoumarine core and their applications for
practical needs. Although many synthetic approaches
have been elaborated, the intramolecular cyclization of
ortho-(ethan-2-one)benzoic acids remains the main
among them (Scheme 1). There are at least three known
ways to synthesize these compounds. The first one is
based on building up the phenyl ring with simultaneous
R
O
It is well-known that alkylfurans can easily undergo
protolytic furan ring cleavage to form 1,4-dicarbonyl
compounds, and this property is often used in practice
[17]. Therefore the furan could be considered as a masked
equivalent of a carbonyl group (Scheme 2). From this

1196
V. Abaev, A. Dmitriev, A. Gutnov, S. Podelyakin, and A. Butin
Vol 43
ortho-functionalized benzylfurans is the acid-catalyzed
condensation of alkylfurans with corresponding ortho-
substituted benzaldehydes [19, 20].
point of view, ortho-substituted benzylfurans are in fact
latent equivalents of ortho-substituted benzylcarbonyl
compounds.
Thus, the first step in the reaction sequence involved
the synthesis of 2-formylbenzoic acid derivatives, which
Such recyclization of ortho-substituted benzylfurans is
prerequisite to our new successful method of building up
numerous benzannelated heterocycles [18]. In the
preliminary communication on two examples it was
reported that the treatment of 2-carboxyaryldifuryl-
methanes with boiling methanol saturated with hydrogen
chloride don’t stop on the stage of furan ring recyclization
but accompanies with secondary cyclization into
tetracyclic isocoumarine derivatives [19]. In the present
work we showed applicability of this reaction for the
synthesis of wide range of these compounds. Moreover
the reaction conditions were found for the selective
synthesis of the isocoumarine ketones which were
postulated as intermediates in the preliminary
communication [19].
is
a well developed area [21]. We used radical
bromination of phthalides 1 with subsequent hydrolysis of
3-bromophthalides [22] to obtain a number of 2-
formylbenzoic acids 2 (Scheme 4, Table 1).
Scheme 4
O
R1
R1
COOH
A
O
2
2
R
CHO
R
2
1
A: 1) Br2, hv, 2) H2O
Results and Discussion.
The synthesis of 2-carboxyaryldifurylmethanes 4 was
carried out by keeping dioxane solutions of 2-
formylbenzoic acids 2 and 2-alkylfurans 3 at 60 °C in the
presence of HClO4 (Scheme 5, Table 2). The elevated
To realize the methodology of isocoumarine synthesis
we had to prepare benzylfurans with carboxy group in
ortho-position (Scheme 3). The easiest way to prepare
Scheme 2
H+
R
R'
R
R'
R
R'
O
O
O
O
O
YH
R
YH
R
Y
O
R''
R'
O
R''
X
X
X
R
Scheme 3
HO
O
O
O
OH
O
R'
R
O
R"
X
X
X
R
R
R"
O
O
COOH
CHO
O
X
X

Sep-Oct 2006
Synthesis of 2,4-dimethylfuro[2',3':3,4]cyclohepta[1,2-c]isochromen-8(6H)-one
1197
isocoumarines 7a-j with only traces of the opened
ketone 6 under TLC control (Scheme 6, Table 3). We
observed similar secondary cyclizations in the
reactions of N-benzyl-2-bis(5-methyl-2-furyl)-methyl-
benzamide [18f], 2-bis(5-methyl-2-furyl)-methyl-
phenylmethanols [18g] and N-tosyl-2-bis(5-methyl-2-
furyl)-methylanilines [23], where the reaction also did
not come to stop on the stage of ketones. The facile
intramolecular cyclization of such ketones was first
demonstrated for 3-(5-methyl-2-furyl)-3-(3-oxobutyl)-
benzo[b]furans [24], initial products of 2-bis(5-methyl-
2-furyl)-methylphenols recyclization.
Table 1
Yields of 2-formylbenzoic acids 2a-i
Entry
R1
H
NO2
Cl
Br
H
H
R2
H
Product
2a
2b
2c
2d
2e
2f
2g
Yield (%)
a
b
c
d
e
f
g
h
i
70
73
70
72
72
70
75
78
73
H
H
H
Br
Cl
H
OMe
H
OMe
OMe
I
2h
2i
After some experimentation we were pleased to find
that ketones 6 could be selectively obtained by treatment
of 2-carboxyaryldifurylmethanes with more diluted
methanolic HCl solution (8 % weight) for 40 minutes with
55-75% yield. Tetracyclic products 7 were also observed
but in minor quantities (< 10%).
temperature allowed to reduce the reaction time to 20-30
minutes and to enhance the yields in comparison with the
earlier reported procedure [19]. Noteworthy, the reaction
with 2-tert-butylfuran was complicated by formation of
reasonable amounts of 3-furylphthalides 5 as byproduct,
and even longer reaction times did not change the
products ratio but led to decomposition of participating
compounds.
A completely different picture emerged after going
from methyl and ethyl substituted benzylfurans 4a-j to
those with tert-butyl substituent in the position 5 of
furans. Treatment of these compounds with highly
concentrated HCl/MeOH solution for 5 minutes led
Keeping 2-carboxyaryldifurylmethanes 4a-j under
reflux in methanolic HCl solution (30 weight % of
HCl) for 30 minutes led to formation of tetracyclic
Scheme 5
O
R3
COOH
R1
R1
O
R1
COOH
O
O
2
R3
2
A
R
R
+
+
2
CHO
R
O
O
R3
R3
2
3
4
5
A: HClO4, 1,4-dioxane
Table 2
Yields of 2-Carboxyaryldifurylmethanes 4a-o and 2-Furylphthalides 5k-o
Entry
R1
H
NO2
Cl
Br
H
H
OMe
OMe
H
NO2
H
NO2
Cl
Br
I
R2
R3
Product
Yield (%)
Product
Yield (%)
a
b
c
d
e
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
68
72
64
67
69
70
60
62
68
70
14
16
18
19
22
H
Br
Cl
H
OMe
H
H
H
H
H
f
g
h
i
j
k
l
m
n
o
Et
tBu
tBu
tBu
tBu
tBu
5k
5l
5m
5n
5o
21
29
31
32
36
H
H

1198
V. Abaev, A. Dmitriev, A. Gutnov, S. Podelyakin, and A. Butin
Vol 43
Scheme 6
O
O
O
1
R3
1
1
R
OH
O
R
R
HCl
O
O
H
4a-o
R3
+
+
2
2
2
MeOH
R3
-H
R
R
R
O
O
O
H
O
O
R3
R3
R3
O
O
O
1
1
1
R
R
R
O
O
O
R3
2
-H2O
2
2
R
R
R
O
O
O
O
OH
R3
3
3
3
R
R
R3
R
7
6
Table 3
Yields of Isocoumarine Derivatives 6 and 7
Entry
R1
R2
R3
Product
Yield (%)
Product
Yield (%)
a
b
c
d
e
H
NO2
Cl
Br
H
H
MeO
MeO
H
NO2
H
NO2
Cl
Br
I
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Et
6a
6b
6c
6d
6e
55
72
68
70
75
7a
7b
7c
7d
7e
7f
7g
7h
7i
66
70
72
75
65
63
68
65
69
71
H
Br
Cl
H
MeO
H
H
H
H
H
f
g
h
i
j
k
l
m
n
o
Et
7j
tBu
tBu
tBu
tBu
tBu
6k
6l
6m
6n
6o
80
75
82
81
79
H
H
EXPERIMENTAL
1H nmr spectra were recorded on
exclusively to ketones 6k-o. Even longer reaction times
did not help in the formation of tetracyclic isocoumarines,
as only strong decomposition was observed in this case.
Such inability for secondary cyclizations can be attributed
to lowered activity of the carbonyl group of ketones 6k-o
due to sterical hindrance caused by bulky tert-butyl
substituent.
a
Bruker AC200
spectrometer (200 MHz) and Bruker AM300 spectrometer (300
MHz) at ambient temperature in CDC13, DMSO-d6 using
CHC13, (ꢀ = 7.26) or tetramethylsilane (ꢀ = 0.00) as internal
standards. Chemical shifts (ꢀ) are quoted in ppm and coupling
constants (J) are given in absolute values in Hz to the nearest 0.1
Hz. 13C nmr spectra were recorded with a Bruker AM300 (75.5
MHz) at ambient temperature in CDC13 with ꢀ (CDC13) = 77.0
as internal standard. Infrared spectra were recorded with an
InfraLUM FT-02 spectrometer. Mass spectra were recorded on a
Kratos MS-30 instrument with 70 eV electron impact ionization
at 200 ºC. All solvents were distilled prior to use. Melting points
are uncorrected.
In conclusion,
a general and easy method for
preparation of biologically relevant isocoumarine
derivatives was developed. Highly complex tetracyclic
heterocyclic molecules were constructed in only two steps
starting from as simple substances as 2-formylbenzoic
acids 2 and 2-alkylfurans 3.

Sep-Oct 2006
Synthesis of 2,4-dimethylfuro[2',3':3,4]cyclohepta[1,2-c]isochromen-8(6H)-one
1199
6-Nitro-3H-isobenzofuran-1-one 1b was synthesized by
nitration of phthalide 1a [25] under known conditions (KNO3
/H2SO4) [26].
6-Halogenated isobenzofuran-1-ones 1c, 1d, 1i were obtained
by Sandmeyer reaction [27] from 6-amino-3H-isobenzofuran-1-
one (see below).
5-Chloro-2-bis(5-methyl-2-furyl)methylbenzoic acid (4c).
This compound was obtained according to the general method
in 64% yield as colorless prisms (ethanol-acetone), mp 222-
223°; ir (Nujol): 1686 (O=C-O) cm-1; 1H nmr (200 MHz,
CDCl3): ꢀ 2.25 (s, 6H, CH3), 5.89 (s, 4H, HFur), 6.60 (s, 1H, CH),
7.31 (d, 3J = 8.3 Hz, 1H, HAr), 7.48 (dd, 4J = 2.3, 3J = 8.3 Hz, 1H,
HAr), 8.04 (d, 4J = 2.3 Hz, 1H, HAr).
6-Amino-3H-isobenzofuran-1-one.
Anal. Calcd. for C18H15ClO4: C, 65.36; H, 4.57. Found: C,
65.25; H, 4.61.
A mixture of phthalide 1b 70 g (0.391 mol), 60 g of Fe
powder, 70 mL of acetic acid, 210 mL of ethyl acetate and 210
mL of water was stirred under reflux for 1 hour. The mixture
was cooled, carefully treated with 100 g of solid NaHCO3, and
additionally refluxed for 10 minutes. The suspension was
extracted three times with 300 mL of boiling dioxane. Combined
organic extracts were treated with active charcoal, filtered and
evaporated. The residue was recrystallized from EtOH/acetone
to give 50 g (86%) of the title compound with mp 186-187°C.
5-Halogenated isobenzofuran-1-ones 1e and 1f were obtained
by Sandmeyer reaction [28] from 5-amino-3H-isobenzofuran-1-
one [29].
5-Bromo-2-bis(5-methyl-2-furyl)methylbenzoic acid (4d).
This compound was obtained according to the general method
in 67% yield as colorless prisms (dichloromethane-hexane), mp
1
226-227°; ir (Nujol): 1685 (O=C-O) cm-1; H nmr (200 MHz,
CDCl3): ꢀ 2.25 (s, 6H, CH3), 5.88 (s, 4H, HFur), 6.58 (s, 1H, CH),
7.24 (d, 3J = 8.3 Hz, 1H, HAr), 7.63 (dd, 4J = 2.0, 3J = 8.3 Hz, 1H,
HAr), 8.19 (d, 4J = 2.0 Hz, 1H, HAr).
Anal. Calcd. for C18H15BrO4: C, 57.62; H, 4.03. Found: C,
57.70; H, 4.09.
6-Methoxy-3H-isobenzofuran-1-one 1g [30] and 5,6-
dimethoxy-3H-isobenzofuran-1-one 1h [31] were obtained by
ortho-chloromethylation of corresponding methoxybenzoic
acids.
2-Formylbenzoic acids 2a-i were synthesized from
isobenzofuran-1-one 1a-i through the bromination followed by
hydrolysis under slightly modified conditions [22c].
4-Bromo-2-bis(5-methyl-2-furyl)methylbenzoic acid (4e).
This compound was obtained according to the general method
in 69% yield as colorless prisms (dichloromethane-hexane), mp
1
153-154°; ir (Nujol): 1688 (O=C-O) cm-1; H nmr (200 MHz,
CDCl3): ꢀ 2.26 (s, 6H, CH3), 5.90 (s, 4H, HFur), 6.66 (s, 1H, CH),
7.48 (dd, 4J = 2.1, 3J = 8.9 Hz, 1H, HAr), 7.52 (d, 4J = 2.1 Hz, 1H,
HAr), 7.93 (d, 3J = 8.9 Hz, 1H, HAr).
General Procedure for the Preparation of 2-Formylbenzoic acids
2a-i.
Anal. Calcd. for C18H15BrO4: C, 57.62; H, 4.03. Found: C,
57.53; H, 3.96.
A mixture of isobenzofuran-1-ones 1a-i (0.14 mol) and Br2
(0.14 mol) in 500 mL of CCl4 was stirred under reflux and
irradiation with a 200 W lamp. After the reaction is completed
(TLC control), the solvent was evaporated, and the oily residue
was dissolved in hot water. The solution was treated with active
charcoal, filtered and left to crystallize.
4-Chloro-2-bis(5-methyl-2-furyl)methylbenzoic acid (4f).
This compound was obtained according to the general method
in 70% yield as colorless prisms (dichloromethane-hexane), mp
1
166-165°; ir (Nujol): 1684 (O=C-O) cm-1; H nmr (200 MHz,
CDCl3): ꢀ 2.26 (s, 6H, CH3), 5.90 (s, 4H, HFur), 6.68 (s, 1H, CH),
7.33 (dd, 4J = 2.1, 3J = 9.0 Hz, 1H, HAr), 7.35 (d, 4J = 2.1 Hz, 1H,
HAr), 8.03 (d, 3J = 9.0 Hz, 1H, HAr).
Anal. Calcd. for C18H15ClO4: C, 65.36; H, 4.57. Found: C,
65.23; H, 4.50.
General Procedure for the Preparation of 2-Carboxybenzylfurans
4a-o and 3-Furylphthalides 5k-o.
To a solution of 2-formylbenzoic acid (0.1 mol) and
alkylfuran (0.4 mol) in 200 mL of dioxane 3 mL of HClO4
(conc. 70%) was added in one portion. The mixture was
thermostated at 60 ºC for 25 minutes, and then poured into
water. The precipitated solid was collected by filtration and
recrystallized.
In the case of 2-tert-butylfuran the mixture of compounds 4k-
o and phthalides 5k-o was separated by column chromatography
on silica gel (Sorbpolymer, 50-160 mkm) using hexane –
CH2Cl2 (2:1) as an eluent.
2-Bis(5-methyl-2-furyl)methyl-5-methoxybenzoic acid (4g).
This compound was obtained according to the general method
in 60% yield as colorless prisms (dichloromethane-hexane), mp
1
191-192°; ir (Nujol): 1668 (O=C-O) cm-1; H nmr (200 MHz,
4
DMSO-d6): ꢀ 2.19 (s, 6H, CH3), 3.79 (s, 3H, OCH3), 5.80 (d, J
4
= 3.2 Hz, 2H, 3-HFur), 5.96 (d, J = 3.2 Hz, 2H, 4-HFur), 6.49 (s,
4
3
3
1H, CH), 7.09 (dd, J = 2.6, J = 8.6 Hz, 1H, HAr), 7.17 (d, J =
4
8.6 Hz, 1H, HAr), 7.35 (d, J = 2.6 Hz, 1H, HAr), 13.09 (bs, 1H,
OH).
Compounds 4a, 4i was described [19].
Anal. Calcd. for C19H18O5: C, 69.93; H, 5.56. Found: C,
69.99; H, 5.51.
2-Bis(5-methyl-2-furyl)methyl-5-nitrobenzoic acid (4b).
This compound was obtained according to the general method
in 72% yield as pale yellow prisms (dichloromethane-hexane),
mp 189-190°; ir (Nujol): 1682 (O=C-O) cm-1; 1H nmr (300
2-Bis(5-methyl-2-furyl)methyl-4,5-dimethoxybenzoic acid
(4h).
3
MHz, CDCl3): ꢀ 2.24 (s, 6H, CH3), 5.89 (d, J = 3.2 Hz, 2H, 4-
This compound was obtained according to the general method
in 62% yield as colorless prisms (dichloromethane-hexane), mp
HFur), 5.97 (d, 3J = 3.2 Hz, 2H, 3-HFur), 6.72 (s, 1H, CH), 7.58 (d,
4
3
3J = 8.2 Hz, 1H, HAr), 8.32 (dd, J = 2.0, J = 8.2 Hz, 1 H, HAr),
1
138-139°; ir (Nujol): 1670 (O=C-O) cm-1; H nmr (200 MHz,
8.91 (d, 4J = 2.0 Hz, 1 H, HAr).
CDCl3): ꢀ 2.56 (s, 6H, CH3), 3.83 (s, 3H, OCH3), 3.94 (s, 3H,
OCH3), 5.88 (s, 4H, HFur), 6.77 (s, 1H, CH), 6.89 (s, 1H, HAr),
7.64 (s, 1H, HAr).
Anal. Calcd. for C18H15NO6: C, 63.34, H, 4.43. Found: C,
63.22, H, 4.40.

1200
V. Abaev, A. Dmitriev, A. Gutnov, S. Podelyakin, and A. Butin
Vol 43
Anal. Calcd. for C20H20O6: C, 67.41; H, 5.66. Found: C, 67.50;
Anal. Calcd. for C24H27IO4: C, 56.93; H, 5.37. Found: C,
H, 5.72.
56.99; H, 5.34.
2-Bis(5-ethyl-2-furyl)methyl-5-nitrobenzoic acid (4j).
3-[5-(tert-Butyl)-2-furyl]-1,3-dihydro-1-isobenzofuranone (5k).
This compound was obtained according to the general method in
70% yield as pale yellow prisms (dichloromethane-hexane), mp
131-132°; ir (Nujol): 1685 (O=C-O) cm-1; 1H nmr (300 MHz,
This compound was obtained according to the general method
in 21% yield as colorless prisms (dichloromethane-hexane), mp
73-74°; ir (Nujol): 1768 (O=C-O) cm-1; 1H nmr (200 MHz,
3
CDCl3): ꢀ 1.19 (t, J = 7.5 Hz, 6H, CH2CH3), 2.58 (q, 3J = 7.5 Hz,
3
CDCl3): ꢀ 1.26 (s, 9 H, tBu), 5.94 (d, J = 3.2 Hz, 1H, 4-HFur),
4H, CH2CH3), 5.89 (d, 3J = 3.2 Hz, 2H, 4-HFur), 5.97 (d, 3J = 3.2 Hz,
6.16 (d, 3J = 3.2 Hz, 1H, 3-HFur), 6.45 (s, 1H, CH), 7.47-7.72 (m,
3H, HAr), 7.95-7.99 (m, 1H, HAr).
3
2H, 3-HFur), 6.73 (s, 1H, CH), 7.58 (d, J = 8.2 Hz, 1H, HAr), 8.33
(dd, 4J = 2.0, 3J = 8.2 Hz, 1H, HAr), 8.92 (d, 4J = 2.0 Hz, 1H, HAr).
Anal. Calcd. for C20H21NO4: C, 70.78; H, 6.24. Found: C,
70.88; H, 6.29.
Anal. Calcd. for C16H16O3: C, 74.98; H, 6.29. Found: C,
74.89; H, 6.23.
3-[5-(tert-Butyl)-2-furyl]-6-nitro-1,3-dihydro-1-isobenzo-
furanone (5l).
2-Bis[5-(tert-butyl)-2-furyl]methylbenzoic acid (4k).
This compound was obtained according to the general method
in 14% yield as colorless prisms (dichloromethane-hexane), mp
This compound was obtained according to the general method
in 29% yield as pale yellow prisms (dichloromethane-hexane),
mp 117-118°; ir (Nujol): 1766 (O=C-O) cm-1; 1H nmr (200
1
118-119°; ir (Nujol): 1684 (O=C-O) cm-1; H nmr (200 MHz,
3
3
CDCl3): ꢀ 1.24 (s, 18 H, tBu), 5.82 (d, J = 3.1 Hz, 2H, 4-HFur),
MHz, CDCl3): ꢀ 1.24 (s, 9 H, tBu), 5.99 (d, J = 3.2 Hz, 1H, 4-
5.86 (d, 3J = 3.1 Hz, 2H, 3-HFur), 6.66 (s, 1H, CH), 7.28-7.36 (m,
2H, HAr), 7.45-7.52 (m, 1H, HAr), 8.04-8.07 (m, 1H, HAr).
Anal. Calcd. for C24H28O4: C, 75.76; H, 7.42. Found: C, 75.88;
H, 7.38.
HFur), 6.28 (d, 3J = 3.2 Hz, 1H, 3-HFur), 6.55 (s, 1H, CH), 7.68 (d,
4
3
3J = 8.4 Hz, 1H, HAr), 8.57 (d.d, J = 1.9, J = 8.4 Hz, 1H, HAr),
8.79 (d, 4J = 1.9 Hz, 1H, HAr).
Anal. Calcd. for C16H15NO5: C, 63.78; H, 5.02. Found: C,
63.89; H, 5.06.
2-Bis[5-(tert-butyl)-2-furyl]methyl-5-nitrobenzoic acid (4l).
3-[5-(tert-Butyl)-2-furyl]-6-chloro-1,3-dihydro-1-
isobenzofuranone (5m).
This compound was obtained according to the general method
in 16% yield as oil; ir (Nujol): 1687 (O=C-O) cm-1; 1H nmr (200
MHz, CDCl3): ꢀ 1.18 (s, 18 H, tBu), 5.81 (d, 3J = 3.1 Hz, 2H, 3-
HFur), 5.87 (d, 3J = 3.1 Hz, 2H, 4-HFur), 6.77 (s, 1H, CH), 7.49 (d,
This compound was obtained according to the general method
in 31% yield as colorless prisms (dichloromethane-hexane), mp
4
3
3J = 8.6 Hz, 1H, HAr), 8.22 (dd, J = 2.0, J = 8.6 Hz, 1H, HAr),
1
109-110°; ir (Nujol): 1766 (O=C-O) cm-1; H nmr (200 MHz,
8.79 (d, 4J = 2.0 Hz, 1H, HAr).
Anal. Calcd. for C24H27NO6: C, 67.75; H, 6.40. Found: C,
67.69; H, 6.43.
3
CDCl3): ꢀ 1.25 (s, 9 H, tBu), 5.95 (d, J = 3.2 Hz, 1H, 4-HFur),
3
3
6.19 (d, J = 3.2 Hz, 1H, 3-HFur), 6.43 (s, 1H, CH), 7.43 (d, J =
4
3
8.2 Hz, 1H, HAr), 7.67 (d.d, J = 1.4, J = 8.2 Hz, 1H, HAr), 7.93
(d, 4J = 1.4 Hz, 1H, HAr).
5-Chloro-2-bis[5-(tert-butyl)-2-furyl]methylbenzoic acid (4m).
Anal. Calcd. for C16H15ClO3: C, 66.10; H, 5.20. Found: C,
66.18; H, 5.18.
This compound was obtained according to the general method
in 18% yield as colorless prisms (hexane), mp 144-145°; ir
1
(Nujol): 1682 (O=C-O) cm-1; H nmr (200 MHz, CDCl3): ꢀ 1.24
6-Bromo-3-[5-(tert-butyl)-2-furyl]-1,3-dihydro-1-isobenzofu-
ranone (5n).
(s, 18 H, tBu), 5.86 (s, 4H, HFur), 6.60 (s, 1H, CH), 7.26 (d, 3J =
4
3
8.0 Hz, 1H, HAr), 7.46 (dd, J = 2.2, J = 8.0 Hz, 1H, HAr), 8.04
(d, 4J = 2.2 Hz, 1H, HAr).
This compound was obtained according to the general method
in 32% yield as colorless prisms, mp 112-113° (dichloro-
Anal. Calcd. for C24H27ClO4: C, 69.47; H, 6.56. Found: C,
69.38; H, 6.59.
1
methane-hexane); ir (Nujol): 1765 (O=C-O) cm-1; H nmr (200
3
MHz, CDCl3): ꢀ 1.25 (s, 9 H, tBu), 5.95 (d, J = 3.2 Hz, 1H, 4-
HFur), 6.19 (d, 3J = 3.2 Hz, 1H, 3-HFur), 6.40 (s, 1H, CH), 7.38 (d,
5-Bromo-2-bis[5-(tert-butyl)-2-furyl]methylbenzoic acid (4n).
4
3
3J = 8.1 Hz, 1H, HAr), 7.82 (d.d, J = 1.4, J = 8.1 Hz, 1H, HAr),
This compound was obtained according to the general method
in 19% yield as colorless prisms (benzene), mp 59-60°; ir
8.09 (d, 4J = 1.4 Hz, 1H, HAr).
1
(Nujol): 1681 (O=C-O) cm-1; H nmr (200 MHz, CDCl3): ꢀ 1.19
Anal. Calcd. for C16H15BrO3: C, 57.33; H, 4.51. Found: C,
57.41; H, 4.55.
(s, 18 H, tBu), 5.80 (s, 4H, HFur), 6.59 (s, 1H, CH), 7.15 (d, 3J =
4
3
8.3 Hz, 1H, HAr), 7.53 (dd, J = 2.0, J = 8.3 Hz, 1H, HAr), 8.10
(d, 4J = 2.0 Hz, 1H, HAr).
3-[5-(tert-Butyl)-2-furyl]-6-iodo-1,3-dihydro-1-isobenzo-
furanone (5o).
Anal. Calcd. for C24H27BrO4: C, 62.75; H, 5.92. Found: C,
62.65; H, 5.93.
This compound was obtained according to the general method
in 36% yield as colorless prisms (dichloromethane-hexane), mp
111-112°; ir (Nujol): 1769 (O=C-O) cm-1; H nmr (200 MHz,
2-Bis[5-(tert-butyl)-2-furyl]methyl-5-iodobenzoic acid (4o).
1
3
CDCl3): ꢀ 1.25 (s, 9 H, tBu), 5.95 (d, J = 3.2 Hz, 1H, 4-HFur),
This compound was obtained according to the general method
in 22% yield as colorless prisms (hexane), mp 114-116°; ir
3
3
6.19 (d, J = 3.2 Hz, 1H, 3-HFur), 6.39 (s, 1H, CH), 7.25 (d, J =
4
3
1
(Nujol): 1687 (O=C-O) cm-1; H nmr (200 MHz, CDCl3): ꢀ 1.19
8.0 Hz, 1H, HAr), 8.01 (d.d, J = 1.4, J = 8.0 Hz, 1H, HAr), 8.30
(d, 4J = 1.4 Hz, 1H, HAr).
(s, 18 H, tBu), 5.79 (s, 4H, HFur), 6.57 (s, 1H, CH), 7.02 (d, 3J =
4
3
Anal. Calcd. for C16H15IO3: C, 50.28; H, 3.96. Found: C,
50.14; H, 3.91.
8.3 Hz, 1H, HAr), 7.73 (dd, J = 2.0, J = 8.3 Hz, 1H, HAr), 8.29
(d, 4J = 2.0 Hz, 1H, HAr).

Sep-Oct 2006
Synthesis of 2,4-dimethylfuro[2',3':3,4]cyclohepta[1,2-c]isochromen-8(6H)-one
1201
General Procedure for the Preparation of 3-(3-Oxobutyl)-1-
isochromenones (6a-e).
7-Bromo-4-(5-methyl-2-furyl)-3-(3-oxobutyl)-1-isochromenone
(6d).
This compound was obtained according to the general method
in 70% yield as colorless prisms (hexane), mp 88-90°; ir (Nujol):
2-Carboxybenzylfurans 4a-e (0.025 mol) were stirred under
reflux in 130 mL of HCl/methanol solution (8 weight % HCl)
for 40 minutes, and then poured into cold water. The mixture
was extracted with CH2Cl2, washed with water. The organic
layer was diluted with hexane and filtered through a short pad of
silica gel. The solvent was evaporated, and the solid residue was
recrystallized.
1
1747 (O=C-O), 1703 (C=O) cm-1; H nmr (200 MHz, CDCl3): ꢀ
2.18 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.82-2.87 (m, 4H,
3
3
CH2CH2), 6.14 (d, J = 3.1 Hz, 1H, 4-HFur), 6.37 (d, J = 3.1 Hz,
3
4
3
1H, 3-HFur), 7.18 (d, J = 8.6 Hz, 1H, HAr), 7.75 (d.d, J = 2.1, J
= 8.6 Hz, 1H, HAr), 8.43 (d, 4J = 2.1 Hz, 1H, HAr); 13C nmr (75.5
MHz, CDCl3): ꢀ 13.68, 26.03, 29.80, 40.57, 107.09, 107.70,
112.90, 121.21, 121.48, 126.39, 131.84, 136.67, 137.88, 143.72,
153.19, 157.14, 160.44, 206.05; ms: m/z 377/375 (19/21) [M+ +
1], 376/374 (99/100) [M+], 333/331 (46/48), 289 (11), 277 (34),
275 (33), 139 (15), 43 (42).
4-(5-Methyl-2-furyl)-3-(3-oxobutyl)-1-isochromenone (6a).
This compound was obtained according to the general method
in 55% yield as colorless prisms (dichloromethane-hexane), mp
1
77-78°; ir (Nujol): 1747 (O=C-O), 1703 (C=O) cm-1; H nmr
Anal. Calcd. for C18H15BrO4: C, 57.62; H, 4.03. Found: C,
57.71; H, 3.99.
(300 MHz, CDCl3): ꢀ 2.17 (s, 3H, CH3), 2.37 (s, 3H, CH3),
3
2.81–2.89 (m, 4H, CH2CH2), 6.13 (d, J = 3.1 Hz, 1H, 4-HFur),
3
6.37 (d, J = 3.1 Hz, 1H, 3-HFur), 7.28-7.31 (m, 1H, HAr), 7.45-
6-Bromo-4-(5-methyl-2-furyl)-3-(3-oxobutyl)-1-isochromenone
(6e).
7.50 (m, 1H, HAr), 7.64-7.69 (m, 1H, HAr), 8.28-8.30 (m, 1H,
HAr); 13C nmr (75.5 MHz, CDCl3): ꢀ 13.68, 26.04, 29.80, 40.79,
106.00, 108.09, 112.65, 119.76, 124.51, 127.85, 129.39, 134.83,
137.89, 144.28, 152.95, 156.65, 161.75, 206.25; ms: m/z 297
(19) [M+ + 1], 296 (100) [M+], 254 (12), 253 (61), 235 (12), 211
(16), 197 (36), 43 (18).
This compound was obtained according to the general method
in 75% yield as colorless prisms (hexane), mp 113-115°; ir
1
(Nujol): 1747 (O=C-O), 1700 (C=O) cm-1; H nmr (200 MHz,
CDCl3): ꢀ 2.18 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.79-2.90 (m,
4H, CH2CH2), 6.16 (d, 3J = 3.1 Hz, 1H, 4-HFur), 6.39 (d, 3J = 3.1
Anal. Calcd. for C18H16O4: C, 72.96, H; 5.44. Found: C,
72.87; H, 5.50.
4
4
Hz, 1H, 3-HFur), 7.45 (d, J = 1.8 Hz, 1H, HAr), 7.60 (d.d, J =
1.8, 3J = 8.4 Hz, 1H, HAr), 8.13 (d, 3J = 8.4 Hz, 1H, HAr); 13C nmr
(75.5 MHz, CDCl3): ꢀ 13.71, 26.12, 29.80, 40.58, 107.17,
113.02, 118.43, 127.31, 130.63, 131.01, 131.12, 131.24, 139.33,
143.47, 153.29, 158.13, 161.06, 206.02; ms: m/z 377/375
(20/21) [M+ + 1], 376/374 (99/100) [M+], 334/332 (13/14),
333/331 (65/66), 291 (13), 289 (15), 277 (26), 275 (24), 139
(16), 43 (27).
4-(5-Methyl-2-furyl)-7-nitro-3-(3-oxobutyl)-1-isochromenone
(6b).
This compound was obtained according to the general method
in 72% yield as pale yellow prisms, mp 128-130° (dichloro-
methane-hexane); ir (Nujol): 1744 (O=C-O), 1705 (C=O) cm-1;
1H nmr (200 MHz, CDCl3): ꢀ 2.19 (s, 3H, CH3), 2.39 (s, 3H,
Anal. Calcd. for C18H15BrO4: C, 57.62; H, 4.03. Found: C,
57.70; H, 4.11.
3
CH3), 2.89 (s, 4H, CH2CH2), 6.17 (d, J = 3.1 Hz, 1H, 4-HFur),
3
3
6.44 (d, J = 3.1 Hz, 1H, 3-HFur), 7.46 (d, J = 8.9 Hz, 1H, HAr),
4
3
4
8.44 (d.d, J = 2.4, J = 8.9 Hz, 1H, HAr), 9.12 (d, J = 2.4 Hz,
1H, HAr); 13C nmr (75.5 MHz, CDCl3): ꢀ 13.68, 26.26, 29.78,
40.23, 107.28, 107.73, 113.41, 120.13, 125.29, 126.24, 128.78,
142.78, 142.92, 146.68, 153.68, 159.86, 160.68, 205.80; ms: m/z
342 (19) [M+ + 1], 341 (100) [M+], 326 (17), 298 (32), 280 (13),
252 (11), 196 (12), 43 (37), 28 (15).
General Procedure for the Preparation of 3-(4,4-Dimethyl-3-
oxopentyl)-1-isochromenones (6k-o).
2-Carboxybenzylfurans 4k-o (0.025 mol) were stirred under
reflux in 130 mL of HCl/methanol solution (30 weight % HCl)
for 5 minutes, and then poured into cold water. The mixture was
extracted with CH2Cl2, washed with water. The organic layer
was diluted with hexane and filtered through a short pad of silica
gel. The solvent was evaporated, and the solid residue was
recrystallized.
Anal. Calcd. for C18H15NO6: C, 63.34; H, 4.43. Found: C,
63.40; H, 4.38.
7-Chloro-4-(5-methyl-2-furyl)-3-(3-oxobutyl)-1-isochromenone
(6c).
4-[5-(tert-Butyl)-2-furyl]-3-(4,4-dimethyl-3-oxopentyl)-1-iso-
chromenone (6k).
This compound was obtained according to the general method
in 68% yield as colorless prisms (hexane), mp 82-83°; ir (Nujol):
This compound was obtained according to the general method
in 80% yield as oil; ir (Nujol): 1746 (O=C-O), 1701 (C=O) cm-1;
1H nmr (200 MHz, CDCl3): ꢀ 1.16 (s, 9 H, tBu), 1.33 (s, 9 H,
tBu), 2.76-2.85 (m, 2H, CH2), 2.92-3.00 (m, 2H, CH2), 6.12 (d,
1
1748 (O=C-O), 1699 (C=O) cm-1; H nmr (200 MHz, CDCl3): ꢀ
2.17 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.85 (s, 4H, CH2CH2), 6.14
3
3
(d, J = 3.1 Hz, 1H, 4-HFur), 6.37 (d, J = 3.1 Hz, 1H, 3-HFur),
3
4
3
3
3J = 3.2 Hz, 1H, 4-HFur), 6.37 (d, J = 3.2 Hz, 1H, 3-HFur), 7.31-
7.25 (d, J = 8.6 Hz, 1H, HAr), 7.60 (d.d, J = 2.0, J = 8.6 Hz,
1H, HAr), 8.25 (d, J = 2.0 Hz, 1H, HAr); 13C nmr (75.5 MHz,
4
7.35 (m, 1H, HAr), 7.46-7.53 (m, 1H, HAr), 7.65-7.72 (m, 1H,
HAr), 8.29-8.33 (m, 1H, HAr); 13C nmr (75.5 MHz, CDCl3): ꢀ
26.54(4C), 29.06(3C), 32.76, 34.56, 44.08, 103.37, 108.19,
112.01, 119.85, 124.46, 127.83, 128.34, 129.49, 134.89, 137.93,
144.13, 157.21, 164.96, 213.80; ms: m/z 381 (6) [M+ + 1], 380
(23) [M+], 324 (21), 323 (100), 57 (66), 55 (21), 43 (43).
Anal. Calcd. for C24H28O4: C, 75.76; H, 7.42. Found: C,
75.88; H, 7.37.
CDCl3): ꢀ 13.66, 25.96, 29.79, 40.60, 107.12, 107.64, 112.89,
120.99, 126.32, 128.73, 133.75, 135.10, 136.30, 143.78, 153.22,
157.00, 160.61, 206.16; ms: m/z 333/331 (7/20) [M+ + 1],
332/330 (34/100) [M+], 317/315 (5/14), 289/287 (19/54), 269
(13), 245 (15), 233 (17), 231 (42), 139 (11), 43 (21).
Anal. Calcd. for C18H15ClO4: C, 65.36; H, 4.57. Found: C,
65.41; H, 4.50.

1202
V. Abaev, A. Dmitriev, A. Gutnov, S. Podelyakin, and A. Butin
Vol 43
4-[5-(tert-Butyl)-2-furyl]-3-(4,4-dimethyl-3-oxopentyl)-7-nitro-
1-isochromenone (6l).
121.31, 126.21, 137.16, 137.97, 143.49, 157.84, 160.30, 165.13,
165.21, 213.41; ms: m/z 507 (10) [M+ + 1], 506 (37) [M+], 450
(23), 449 (100), 57 (14).
Anal. Calcd. for C24H27IO4: C, 56.93; H, 5.37. Found: C,
56.83; H, 5.32.
This compound was obtained according to the general method
in 75% yield as colorless prisms (hexane), mp 115-116°; ir
1
(Nujol): 1749 (O=C-O), 1708 (C=O) cm-1; H nmr (200 MHz,
CDCl3): ꢀ 1.17 (s, 9 H, tBu), 1.33 (s, 9 H, tBu), 2.81-2.89 (m,
General Procedure for the Preparation of Tetracyclic
Isochromenones (7a-j).
3
2H, CH2), 2.93-3.01 (m, 2H, CH2), 6.16 (d, J = 3.2 Hz, 1H, 4-
3
HFur), 6.44 (d, J = 3.2 Hz, 1H, 3-HFur), 7.48 (d, 3J = 8.9 Hz, 1H,
2-Carboxybenzylfurans 4a-j (0.025 mol) were stirred under
reflux in 130 mL of HCl/methanol solution (30 weight % HCl)
for 30 minutes, and then poured into cold water. The mixture
was extracted with CH2Cl2, washed with water. The organic
layer was diluted with hexane and filtered through a short pad of
silica gel. The solvent was evaporated, and the solid residue was
recrystallized.
4
3
4
HAr), 8.45 (d.d, J = 2.4, J = 8.9 Hz, 1H, HAr), 9.13 (d, J = 2.4
Hz, 1H, HAr); 13C nmr (75.5 MHz, CDCl3): ꢀ 26.50(3C), 26.77,
29.01(3C), 32.83, 34.00, 44.07, 103.63, 107.79, 112.75, 120.20,
125.35, 126.07, 128.76, 142.71, 142.78, 146.63, 159.97, 161.14,
165.61, 213.25; ms: m/z 426 (5) [M+ + 1], 425 (18) [M+], 369
(21), 368 (100), 57 (12).
Anal. Calcd. for C24H27NO6: C, 67.75; H, 6.40. Found: C,
67.83; H, 6.45.
Compounds 7a and 7i was described [19].
2,4-Dimethyl-10-nitrofuro[2',3':3,4]cyclohepta[1,2-c]isochromen-
8(6H)-one (7b).
4-[5-(tert-Butyl)-2-furyl]-7-chloro-3-(4,4-dimethyl-3-oxopentyl)-
1-isochromenone (6m).
This compound was obtained according to the general method
in 70% yield as yellow prisms (ethanol), mp 237-238°; ir
This compound was obtained according to the general method
in 82% yield as colorless prisms (hexane), mp 94-95°; ir (Nujol):
1
1
(Nujol): 1741 (O=C-O) cm-1; H nmr (300 MHz, CDCl3): ꢀ 2.04
1745 (O=C-O), 1702 (C=O) cm-1; H nmr (200 MHz, CDCl3): ꢀ
3
(s, 3H, CH3), 2.50 (s, 3H, CH3), 3.02 (d, J = 6.7 Hz, 2H, CH2),
1.15 (s, 9 H, tBu), 1.32 (s, 9 H, tBu), 2.72-2.84 (m, 2H, CH2),
3
3
5.40 (t, J = 6.7 Hz, 1H, =CH), 6.32 (s, 1H, HFur), 8.53 (s, 2H,
2.90-3.02 (m, 2H, CH2), 6.11 (d, J = 3.2 Hz, 1H, 4-HFur), 6.37
3
HAr), 9.17 (s, 1H, HAr); 13C nmr (75.5 MHz, CDCl3): ꢀ 13.85,
20.31, 32.01, 105.08, 106.07, 115.31, 120.43, 125.76, 126.25,
127.99, 128.80, 132.29, 140.58, 144.35, 146.38, 149.94, 152.11,
160.53; ms: m/z 324 (21) [M+ + 1], 323 (100) [M+], 309 (12),
308 (59), 262 (17).
(d, J = 3.2 Hz, 1H, 3-HFur), 7.28 (d, J = 8.6 Hz, 1H, HAr), 7.61
4
3
4
(d.d, J = 2.2, J = 8.6 Hz, 1H, HAr), 8.26 (d, J = 2.2 Hz, 1H,
HAr); 13C nmr (75.5 MHz, CDCl3): ꢀ 26.51(4C), 29.02(3C),
32.77, 34.31, 44.06, 103.42, 107.67, 112.20, 121.05, 126.16,
128.75, 133.64, 135.05, 136.32, 143.58, 157.45, 160.70, 165.12,
213.44; ms: m/z 416/414 (8/23) [M+], 359/357 (33/100), 57 (18).
Anal. Calcd. for C24H27ClO4: C, 69.47; H, 6.56. Found: C,
69.38; H, 6.49.
Anal. Calcd. for C18H13NO5: C, 66.87; H, 4.05. Found: C,
66.78; H, 4.10.
10-Chloro-2,4-dimethylfuro[2',3':3,4]cyclohepta[1,2-c]iso-
chromen-8(6H)-one (7c).
7-Bromo-4-[5-(tert-butyl)-2-furyl]-3-(4,4-dimethyl-3-oxo-
pentyl)-1-isochromenone (6n).
This compound was obtained according to the general method
in 72% yield as colorless powder (ethanol), mp 185-186°; ir
This compound was obtained according to the general method
in 81% yield as colorless prisms (hexane), mp 87-88°; ir (Nujol):
1
(Nujol): 1733 (O=C-O) cm-1; H nmr (200 MHz, CDCl3): ꢀ 2.04
3
1
1749 (O=C-O), 1699 (C=O) cm-1; H nmr (300 MHz, CDCl3): ꢀ
(s, 3H, CH3), 2.49 (s, 3H, CH3), 2.97 (d, J = 6.6 Hz, 2H, CH2),
5.38 (t, 3J = 6.6 Hz, 1H, =CH), 6.30 (s, 1H, HFur), 7.70 (d.d, 4J =
2.2, 3J = 8.8 Hz, 1H, HAr), 8.30 (d, 3J = 2.2 Hz, 1H, HAr), 8.32 (d,
4J = 8.8 Hz, 1H, HAr); 13C nmr (75.5 MHz, CDCl3): ꢀ 13.81,
20.32, 31.66, 104.99, 105.89, 115.483, 121.20, 126.27, 127.33,
129.14, 131.73, 133.27, 133.93, 134.99, 145.10, 146.90, 151.54,
161.09; ms: m/z 314/312 (34/100) [M+], 313 (27), 311 (24),
299/297 (28/83).
1.16 (s, 9 H, tBu), 1.32 (s, 9 H, tBu), 2.77-2.83 (m, 2H, CH2),
3
2.90-2.96 (m, 2H, CH2), 6.11 (d, J = 3.2 Hz, 1H, 4-HFur), 6.37
3
3
(d, J = 3.2 Hz, 1H, 3-HFur), 7.20 (d, J = 8.6 Hz, 1H, HAr), 7.75
4
3
4
(d.d, J = 2.0, J = 8.6 Hz, 1H, HAr), 8.43 (d, J = 2.0 Hz, 1H,
HAr); 13C nmr (75.5 MHz, CDCl3): ꢀ 26.51(3C), 26.57,
29.04(3C), 32.77, 34.28, 44.07, 103.42, 107.74, 112.21, 121.27,
121.36, 126.29, 131.85, 136.70, 137.85, 143.54, 157.61, 160.56,
165.15, 213.45; ms: m/z 460/458 (26/26) [M+], 404/402 (22/22),
403/401 (100/97), 57 (28).
Anal. Calcd. for C18H13ClO3: C, 69.13; H, 4.19. Found: C,
69.22; H, 4.11.
Anal. Calcd. for C24H27BrO4: C, 62.75; H, 5.92. Found: C,
62.67; H, 5.88.
10-Bromo-2,4-dimethylfuro[2',3':3,4]cyclohepta[1,2-c]isochromen-
8(6H)-one (7d).
4-[5-(tert-Butyl)-2-furyl]-3-(4,4-dimethyl-3-oxopentyl)-7-iodo-
1-isochromenone (6o).
This compound was obtained according to the general method
in 75% yield as colorless powder (ethanol), mp 176-177°; ir
1
(Nujol): 1734 (O=C-O) cm-1; H nmr (200 MHz, CDCl3): ꢀ 2.04
This compound was obtained according to the general method
in 79% yield as colorless prisms (hexane), mp 104-105°; ir
3
(s, 3H, CH3), 2.49 (s, 3H, CH3), 2.97 (d, J = 6.7 Hz, 2H, CH2),
5.38 (t, 3J = 6.7 Hz, 1H, =CH), 6.30 (s, 1H, HFur), 7.84 (d.d, 4J =
2.2, 3J = 8.6 Hz, 1H, HAr), 8.24 (d, 3J = 8.6 Hz, 1H, HAr), 8.47 (d,
4J = 2.2 Hz, 1H, HAr); 13C nmr (75.5 MHz, CDCl3): ꢀ 13.83,
20.33, 31.73, 105.07, 105.89, 115.47, 121.01, 121.42, 126.39,
127.37, 131.76, 132.27, 134.33, 137.82, 145.10, 147.08, 151.54,
160.96; ms: m/z 359 (20) [M+ + 1], 358/356 (100/100) [M+], 357
(41), 355 (22), 344/342 (15/15), 343/341 (73/74), 178 (13).
1
(Nujol): 1750 (O=C-O), 1703 (C=O) cm-1; H nmr (300 MHz,
CDCl3): ꢀ 1.15 (s, 9 H, tBu), 1.31 (s, 9 H, tBu), 2.77-2.82 (m,
3
2H, CH2), 2.90-2.95 (m, 2H, CH2), 6.11 (d, J = 3.2 Hz, 1H, 4-
3
HFur), 6.36 (d, J = 3.2 Hz, 1H, 3-HFur), 7.05 (d, 3J = 8.6 Hz, 1H,
4
3
4
HAr), 7.94 (d.d, J = 1.8, J = 8.6 Hz, 1H, HAr), 8.63 (d, J = 1.8
Hz, 1H, HAr); 13C nmr (75.5 MHz, CDCl3): ꢀ 26.51(3C), 26.62,
29.05(3C), 32.77, 34.26, 44.07, 92.13, 103.42, 107.81, 112.20,

Sep-Oct 2006
Synthesis of 2,4-dimethylfuro[2',3':3,4]cyclohepta[1,2-c]isochromen-8(6H)-one
1203
Anal. Calcd. for C18H13BrO3: C, 60.53; H, 3.67. Found: C,
60.43; H, 3.60.
131.32, 145.82 146.10, 148.91, 150.89, 154.88, 162.10; ms: m/z
339 (22) [M+ + 1], 338 (100) [M+], 337 (16), 224 (14), 223 (67).
Anal. Calcd. for C20H18O5: C, 71.00; H, 5.36. Found: C, 71.09;
H, 5.30.
11-Bromo-2,4-dimethylfuro[2',3':3,4]cyclohepta[1,2-c]isochro-
men-8(6H)-one (7e).
2,4-Diethyl-10-nitrofuro[2',3':3,4]cyclohepta[1,2-c]isochromen-
8(6H)-one (7j).
This compound was obtained according to the general method
in 65% yield as colorless powder (ethanol), mp 188-189°; ir
1
(Nujol): 1742 (O=C-O) cm-1; H nmr (200 MHz, CDCl3): ꢀ 2.05
This compound was obtained according to the general method
in 71% yield as yellow powder (ethanol), mp 193-194°; ir
3
(s, 3H, CH3), 2.51 (s, 3H, CH3), 2.97 (d, J = 6.6 Hz, 2H, CH2),
1
5.38 (t, 3J = 6.6 Hz, 1H, =CH), 6.31 (s, 1H, HFur), 7.61 (d.d, 4J =
1.8, 3J = 8.5 Hz, 1H, HAr), 8.18 (d, 3J = 8.5 Hz, 1H, HAr), 8.53 (d,
4J = 1.8 Hz, 1H, HAr); 13C nmr (75.5 MHz, CDCl3): ꢀ 13.99,
20.43, 31.88, 104.68, 105.94, 115.61, 118.63, 127.44, 127.58,
130.72, 130.92, 131.54, 131.87, 137.06, 145.01, 151.76, 161.85;
ms: m/z 359 (19) [M+ + 1], 358/356 (99/100) [M+], 357 (41), 355
(22), 344/342 (14/15), 343/341 (75/75), 178 (13).
(Nujol): 1739 (O=C-O) cm-1; H nmr (300 MHz, CDCl3): ꢀ 1.08
(t, 3J = 7.5 Hz, 3H, CH2CH3), 1.39 (t, 3J = 7.5 Hz, 3H, CH2CH3),
3
3
2.42 (q, J = 7.5 Hz, 2H, CH2CH3), 2.84 (q, J = 7.5 Hz, 2H,
3
3
CH2CH3), 3.03 (d, J = 6.7 Hz, 2H, CH2), 5.40 (t, J = 6.7 Hz,
1H, =CH), 6.32 (s, 1H, HFur), 8.52 (s, 2H, HAr), 9.17 (s, 1H, HAr);
13C nmr (75.5 MHz, CDCl3): ꢀ 12.11, 13.27, 21.58, 27.25, 31.89,
104.18, 105.10, 113.77, 120.43, 125.71, 126.18, 127.16, 128.75,
138.29, 140.64, 144.62, 146.32, 150.28, 157.56, 160.47; ms: m/z
352 (14) [M+ + 1], 351 (64) [M+], 336 (26), 323 (21), 322 (100),
276 (17).
Anal. Calcd. for C18H13BrO3: C, 60.53; H, 3.67. Found: C,
60.61; H, 3.61.
11-Chloro-2,4-dimethylfuro[2',3':3,4]cyclohepta[1,2-c]iso-
chromen-8(6H)-one (7f).
Anal. Calcd. for C20H17NO5: C, 68.37; H, 4.88. Found: C,
68.32; H, 4.82.
This compound was obtained according to the general method
in 63% yield as colorless powder (ethanol), mp 177-178°; ir
Acknowledgements.
1
(Nujol): 1735 (O=C-O) cm-1; H nmr (200 MHz, CDCl3): ꢀ 2.05
Financial support was provided by Bayer HealthCare AG and
the Russian Foundation of Basic Research (grant 03-03-32759).
3
(s, 3H, CH3), 2.51 (s, 3H, CH3), 2.98 (d, J = 6.6 Hz, 2H, CH2),
5.39 (t, 3J = 6.6 Hz, 1H, =CH), 6.31 (s, 1H, HFur), 7.45 (d.d, 4J =
1.7, 3J = 8.5 Hz, 1H, HAr), 8.26 (d, 3J = 8.5 Hz, 1H, HAr), 8.35 (d,
4J = 1.7 Hz, 1H, HAr); 13C nmr (75.5 MHz, CDCl3): ꢀ 13.83,
20.30, 31.79, 104.72, 105.85, 115.50, 118.21, 124.37, 127.35,
127.90, 131.46, 131.79, 136.90, 141.67, 145.00, 147.96, 151.66,
161.46; ms: m/z 314/312 (33/100) [M+], 313 (29), 311 (27),
299/297 (31/89), 298 (18).
REFERENCES
[1a] T. Ueno, H. Takahashi, M. Oda, M. Mizunuma, A.
Yokoyama, Y. Goto, Y. Mizushina, K. Sakaguchi and H. Hayashi,
Biochemistry, 39, 5995 (2000); [b] A. Trani, C. Dallanoce, G. Panzone,
R. Gianbattisita, F. Ripamonti, B. P. Goldstein and R. Ciabatti, J. Med.
Chem., 40, 967 (1997); [c] M. Chino, K. Nishikawa, M. Umekita, C.
Hayashi, T. Yamazaki, T. Tsuchida, T. Sawa, M. Hamada and T.
Takeuchi, J. Antibiot., 49, 752 (1996); [d] M. Chino, K. Nishikawa, T.
Tsuchida, R. Sawa, H. Nakamura, K. Nakamura, Y. Muraoka, D. Ikeda,
H. Naganawa, T. Sawa and T. Takeuchi, J. Antibiot., 50, 143 (1997); [e]
M. Chino, K. Nishikawa, A. Yamada, M. Ohsono, T. Sawa, F. Hanaoka,
M. Ishizuka and T. Takeuchi, J. Antibiot., 51, 480 (1998); [f] M.
Yoshikawa, E. Harada, N. Yagi, Y. Okuno, O. Muraoka, H. Aoyama and
N. Murakami, Chem. Pharm. Bull., 42, 721 (1994); [g] S. Kim, G. Fan,
J. Lee, J. J. Lee and D. Kim, J. Org. Chem., 67, 3127 (2002).
[2a] K. Nozawa, M. Yamada, Y. Tsuda, K. Kawai and S.
Nakajima, Chem. Pharm. Bull., 29, 3486 (1981); [b] M. T. Hussain, N.
H. Rama and A. Malik, Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem., 40B, 372 (2001).
Anal. Calcd. for C18H13ClO3: C, 69.13; H, 4.19. Found: C,
69.21; H, 4.12.
10-Methoxy-2,4-dimethylfuro[2',3':3,4]cyclohepta[1,2-c]-
isochromen-8(6H)-one (7g).
This compound was obtained according to the general method
in 68% yield as colorless powder (ethanol), mp 205-206°; ir
1
(Nujol): 1731 (O=C-O) cm-1; H nmr (200 MHz, DMSO-d6): ꢀ
3
2.00 (s, 3H, CH3), 2.46 (s, 3H, CH3), 2.90 (d, J = 6.6 Hz, 2H,
3
CH2), 3.89 (s, 3H, OCH3), 5.44 (t, J = 6.6 Hz, 1H, =CH), 6.51
(s, 1H, HFur), 7.50 (d.d, 4J = 2.8, 3J = 8.3 Hz, 1H, HAr), 7.63 (d, 4J
= 2.8 Hz, 1H, HAr), 8.26 (d, 3J = 8.3 Hz, 1H, HAr); 13C nmr (75.5
MHz, CDCl3): ꢀ 13.80, 20.34, 31.47, 55.65, 105.44, 105.80,
110.36, 115.76, 121.13, 124.31, 126.24, 126.93, 129.22, 131.44,
144.99, 145.77, 151.23, 158.79, 162.46; ms: m/z 309 (21) [M+ +
1], 308 (100) [M+], 307 (22), 294 (18), 293 (86).
[3] J. E. Kerrigan, J. Oleksyszyn, C. M. Kam, J. Selzler and J. C.
Powers, J. Med. Chem., 38, 544 (1995).
[4] C. M. Kam, J. E. Kerrigan, R. R. Plaskon, E. J. Duffy, P.
Lollar, F. L. Suddath and J. C. Powers, J. Med. Chem., 37, 1298 (1994).
[5] T. Minami, A. Nishimoto and M. Hanaoka, Tetrahedron
Lett., 36, 9505 (1995).
Anal. Calcd. for C19H16O4: C, 74.01; H, 5.23. Found: C, 74.11;
H, 5.18.
[6] T. M. Harris, C. M. Harris, T. A. Oster, L. E. Brown, Jr. Lee
and J. Y. C. Lee, J. Am. Chem. Soc., 110, 6180 (1988).
[7] F. M. Hauser, W. A. Dorsch and D. Mal, Org. Lett., 4, 2237
(2002).
[8] T. R. Kelly, C. T. Jagoe and Q. Li, J. Am. Chem. Soc., 111,
4522 (1989).
[9] J. Novák and C. A. Salemink, J. Chem. Soc., Perkin Trans. 1,
729 (1984).
10,11-Dimethoxy-2,4-dimethylfuro[2',3':3,4]cyclohepta[1,2-c]-
isochromen-8(6H)-one (7h).
This compound was obtained according to the general method
in 65% yield as colorless powder (ethanol)s, mp 230-231°; ir
1
(Nujol): 1732 (O=C-O) cm-1; H nmr (200 MHz, CDCl3): ꢀ 2.04
3
(s, 3H, CH3), 2.47 (s, 3H, CH3), 2.97 (d, J = 6.6 Hz, 2H, CH2),
3.99 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 5.38 (t, 3J = 6.6 Hz, 1H,
[10a] J. A. Elix and V. K. Jayanthi, Aust. J. Chem., 40, 1851
(1987); [b] M. Aicart and L. Mavoungou-Gomés, J. Heterocyclic Chem.,
22, 921 (1985).
=CH), 6.31 (s, 1H, HFur), 7.70 (s, 1H, HAr), 7.85 (s, 1H, HAr); 13
C
nmr (75.5 MHz, CDCl3): ꢀ 13.74, 20.30, 31.60, 55.86, 56.10,
105.29, 105.66, 105.88, 109.76, 113.13, 115.70, 126.88, 131.12,
[11a] E. Negishi, C. Copéret, T. Sugihara, I. Shimoyama, Y. Zhang,

1204
V. Abaev, A. Dmitriev, A. Gutnov, S. Podelyakin, and A. Butin
Vol 43
G. Wu and J. M. Tour, Tetrahedron, 50, 425 (1994); [b] E. Napolitano, A.
Ramacciotti and R. Fiaschi, Gazz. Chim. Ital., 118, 101 (1988); [c] E.
Napolitano, E. Giannone, R. Fiaschi and A. Marsili, J. Org. Chem., 48,
3653 (1983); [d] L. Colombo, C. Gennari, M. Santandrea, E. Narisano and
C. Scolastico, J. Chem. Soc., Perkin Trans. 1, 136 (1980).
Geterotsikl. Soedin., 849 (2001); [g] A. V. Butin, V. T. Abaev, V. V.
Mel’chin and A. S. Dmitriev, Tetrahedron Lett., 46, 8439 (2005).
[19] A. V. Gutnov, V. T. Abaev, A. V. Butin and A. S. Dmitriev,
J. Org. Chem., 66, 8685 (2001).
[20a] A. V. Gutnov, V. T. Abaev, A. V. Butin and V. E. Zavodnik,
Khim. Geterotsikl. Soedin., 162 (1996); [b] T. A. Stroganova, V. T.
Abaev, A. V. Butin and V. E. Zavodnik, Khim. Geterotsikl. Soedin., 168
(1996).
[21a] G. L. Grunewald, D. J. Sall and J. A. Monn, J. Med. Chem.,
31, 824 (1988); [b] T. Sugiura, T. Matsui, H. Nakai, M. Okamoto, S.
Hashimoto, Y. Iguchi, H. Wakatsuka and M. Kawamura, Synlett, 531
(1992); [c] J. N. Freskos, G. W. Morrow and J. S. Swenton, J. Org.
Chem., 50, 805 (1985).
[22a] D. C. Remy, S. W. King and D. Cochran, J. Org. Chem., 50,
4120 (1985); [b] B. M. Trost, G. T. Rivers and J. M. Gold, J. Org.
Chem., 45, 1835 (1980); [c] Organic Syntheses. An Annual Publication
of Satisfactory Methods for the Preparation of Organic Chemicals, J.
Wiley & Sons, 1943, pp 74-77.
[12a] K. Zamani, N. H. Rama and R. Iqbal, J. Heterocyclic Chem.,
37, 1651 (2000); [b] T. A. Carpenter, G. E. Evans, F. J. Leeper, J. Staunton
and M. R. Wilkinson, J. Chem. Soc., Perkin Trans. 1, 1043 (1984); [c] J.
A. Barber, J. Staunton and M. R. Wilkinson, J. Chem. Soc., Perkin Trans.
1, 2101 (1986); [d] S. E. Boiadjiev and D. A. Lightner, Tetrahedron, 58,
7411 (2002); [e] K. D. Sarma and U. Maitra, Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem., 40B, 1148 (2001); [f] S. F. Dyke, J. F.
Thorns, S. H. Hedges and D. W. Wiggins, Tetrahedron, 35, 1861 (1979).
[13a] H. Sashida and A. Kawamukai, Synthesis, 1145 (1999); [b]
J.-X. Wang, Z. Liu, Y. Hu, B. Wei and L. Kang, Synth. Commun., 32,
1937 (2002); [c] D. Bouyssi and G. Balme, Synlett, 1191 (2001); [d] T.
Sakamoto, M. An-naka, Y. Kondo and H. Yamanaka, Chem. Pharm.
Bull., 34, 2754 (1986).
[14] L. Wang and W. Shen, Tetrahedron Lett., 39, 7625 (1998).
[15a] T. Ezumi and N. Morishita, J. Heterocyclic Chem., 31, 145
(1994); [b] D. E. Korte, L. S. Hegedus and R. K. Wirth, J. Org. Chem.,
42, 1329 (1977).
[16a] S. P. Waters and M. C. Kozlowski, Tetrahedron Lett., 42,
3567 (2001); [b] M. Brasholz and H.-U. Reissig, Synlett, 2736 (2004); c)
F. Johnson and E. R. Marinelli, J. Org. Chem., 51, 3911 (1986).
[17] G. Piancatelli, M. D’Auria and F. D’Onofrio, Synthesis, 867
(1994).
[18a] A. V. Butin and V. T. Abaev, Izv. Akad. Nauk SSSR, Ser.
Khim., 1436 (2001); [b] A. V. Butin, G. D. Krapivin, V. E. Zavodnik
and V. G. Kul'nevich, Khim. Geterotsikl. Soedin., 616 (1993); [c] V. T.
Abaev, A. V. Gutnov and A. V. Butin, Khim. Geterotsikl. Soedin., 603
(1998); [d] A. V. Gutnov, A. V. Butin, V. T. Abaev, G. D. Krapivin and
V. E. Zavodnik, Molecules, 4, 204 (1999); [e] A. V. Butin, T. A.
Stroganova, I. V. Lodina and G. D. Krapivin, Tetrahedron Lett., 42,
2031 (2001); [f] V. T. Abaev, A. A. Osipova and A. V. Butin, Khim.
[23a] S. K. Smirnov, A. V. Butin, T. A. Stroganova and A. V.
Didenko, Khim. Geterotsikl. Soedin., 1098 (2005); [b] A. V. Butin, S. K.
Smirnov and T. A. Stroganova, , J. Heterocyclic Chem., 43, 623 (2006).
[24] A. V. Butin, A. V. Gutnov, V. T. Abaev and G. D. Krapivin,
Khim. Geterotsikl. Soedin., 833 (1998).
[25] Organic Syntheses. An Annual Publication of Satisfactory
Methods for the Preparation of Organic Chemicals, J. Wiley & Sons,
1936, pp 71-72.
[26] J. Tirouflet, Bull. Soc. Sci. Bretagne, Spec. No. 26, 7 (1951).
[27] J. Tirouflet, Bull. Soc. Sci. Bretagne, Spec. No. 26, 45 (1951).
[28] L. F. Levy and H. Stephen, J. Chem. Soc., 867 (1931).
[29] J. Tirouflet, Bull. Soc. Sci. Bretagne, Spec. No. 26, 35 (1951).
[30] M. Napoletano, G. Norcini, F. Pellacini, F. Marchini, G.
Morazzoni, P. Ferlenga and L. Pradella, Bioorg. Med. Chem. Lett., 11,
33 (2001).
[31] M. Barfield, R. J. Spear and S. Sternhell, J. Am. Chem. Soc.,
97, 5160 (1975).