On the synthesis of 9-furylnaphtho[2,3-b]furan derivatives

Article abstract of DOI:10.1002/jhet.5570420727

A simple synthetic pathway to the unknown 9-furyl-substituted naphthofuran derivatives has been developed involving intramolecular cyclization of 2-carboxyaryldifurylmethanes and 2-formylaryldifurylmethanes.

Full text of DOI:10.1002/jhet.5570420727

Nov-Dec 2005
1429
On the Synthesis of 9-Furylnaphtho[2,3-b]furan Derivatives
Vladimir V. Mel’chin [a], Vladimir T. Abaev [b], Alexander V. Butin* [a],
and Gennady D. Krapivin [a]
[a] Kuban State University of Technology, Moskovskaya 2, Krasnodar, 350072, Russia.
E-mail: alexander_butin@mail.ru
[b] North-Ossetian State University, Vatutina 46, Vladikavkaz, 362025, Russia.
Received April 14, 2005
A simple synthetic pathway to the unknown 9-furyl-substituted naphthofuran derivatives has been
developed involving intramolecular cyclization of 2-carboxyaryldifurylmethanes and 2-formylaryldifuryl-
methanes.
J. Heterocyclic Chem., 42, 1429 (2005).
Naphthofuran derivatives have been the subject of con-
To obtain 4-unsubstituted 9-furylnaphthofurans we used
the following approach: carboxy group in the compounds
stant interest due to a wide spectrum of physiological
activities [1]. Naphthofuran backbone is a part of some
natural compounds such as maturin [2], maturin acetate [3]
and 14-methoxydehydrocacalohastine [4], which were iso-
lated from Trichilia cuneata.
3 was reduced with LiAlH to give alcohols 5, which were
4
further oxidized into corresponding 2-formylaryldifuryl-
methanes 6. The latter gave 9-furylnaphthofurans 7 under
treatment with ethanolic HCl solution (Scheme 2).
It is well-known that furan ring can easily undergo a
number of modification reactions. That is why we have
intended to elaborate a convenient synthesis of 9-furyl-
naphtho[2,3-b]furan derivatives, which can serve, in our
opinion, as starting compounds for the synthesis of other
naphthofurans, promising as biologically active com-
pounds.
Scheme 2
Several synthetic approaches to the naphthofuran back-
bone are described. Most general of them involve the fol-
lowing steps: a) building up the furan ring at the naphtha-
lene core [5], b) construction of the central aromatic ring
through an intramolecular acylation reaction of the corre-
sponding 2-carboxybenzylfurans [6,7].
We chose the second approach for the synthesis of naph-
thofurans 4, as the starting 2-carboxybenzylfurans 3 [8]
had been readily available through the condensation of 2-
formylbenzoic acid 1 and 2-methylfuran (2) in the pres-
ence of HClO in 1,4-dioxane at 65-70 °C (Scheme 1). A
4
standard work-up [6] led to the corresponding 9-furyl-
naphthofurans 4.
EXPERIMENTAL
Scheme 1
1
Melting points are uncorrected. H NMR spectra were
recorded in CDCl on a Bruker AC 200 spectrometer at 200
3
MHz. Chemical shifts are reported in ppm relative to the tetram-
ethylsilane as an internal standard. IR spectra was recorded on
InfraLUM FT-02. Column chromatography was carried out using
silica gel KSK (50-160 mkm) manufactured by LTD
Sorbpolymer.
2-Bis(5-methyl-2-furyl)methylbenzoic acid (3a) was synthesized
and characterized earlier [8].
5-Chloro-2-bis(5-methyl-2-furyl)methylbenzoic Acid (3b).
The compound 3b was synthesized analogously to 3a starting
from 5-chloro-2-formylbenzoic acid (1b) in 70% yield. Colorless
-1
1
crystals with mp 222-223 °C; ir: COOH 1695 cm ; H nmr: δ
2.25 (s, 6H, CH ), 5.89 (s, 4H, H ), 6.60 (s, 1H, CH), 7.31 (d, J
3
Fur

1430
V. V. Mel’chin, V. T. Abaev, A. V. Butin, and G. D. Krapivin
Vol. 42
= 8.3 Hz, 1H, H ), 7.48 (dd, J = 2.3, 8.3 Hz, 1H, H ), 8.04 (d, J
Anal. Calcd for C H ClO : C, 68.25; H, 5.41. Found: C,
18 17 3
Ar
Ar
= 2.3 Hz, 1H, H
)
68.31; H, 5.39.
Ar
Anal. Calcd for C
65.42; H, 4.52.
H ClO : C, 65.36; H, 4.57. Found: C,
18 15 4
2-Bis(5-methyl-2-furyl)methylbenzaldehyde (6a).
A solution of 2-bis(5-methyl-2-furyl)methylphenylmethanol
2-Methyl-9-(5-methyl-2-furyl)naphtho[2,3-b]furan-4-yl Acetate
(4a).
(5a) (10 g, 35.5 mmol) in dry CH Cl (100 mL) was added
2
2
dropwise to the suspension of pyridinium chlorochromate (15
g, 70.0 mmol) in dry CH Cl (100 mL). The mixture was
A mixture of 2-bis(5-methyl-2-furyl)methylbenzoic acid (3a)
2
2
(4.0 g; 13.5 mmol), acetic acid (10 mL), acetic anhydride (10
stirred for 6 hours at rt. At the end of the reaction (TLC con-
trol) the precipitate was collected by filtration and washed with
mL) and ZnCl as catalyst was stirred under reflux for 3 hours.
2
The reaction was monitored with TLC, and, after completion, the
mixture was poured into water (100 mL), neutralized with
hot CH Cl (3 x 100 mL). The filtrate was concentrated in
2 2
vacuo, and the oily residue was purified chromatographically
on silica gel eluting with hexane - CH Cl (10:1). The eluate
NaHCO , and extracted with CH Cl (3 x 80 mL). The organic
3
2
2
2
2
layer was separated, dried with Na SO , and treated with active
was concentrated to the volume of 50 mL and left to crystallize
2
4
charcoal. The solvent was removed under reduced pressure, and
the residue purified on silica gel with hexane – CH Cl (4:1) as
overnight. The compound 6a (7 g, 70% yield) was isolated as
-1
1
colorless crystals with mp 63-65 °C; ir: CHO 1695 cm ;
H
2
2
an eluent to give 1.34 g (31% yield) of the title compound as col-
orless crystals. Mp 145-147 °C (CH Cl /hexane); ir: CH COO
nmr: δ 2.25 (s, 6H, CH ), 5.87 (s, 4H, H ), 6.46 (s, 1H, CH),
3
Fur
7.31-7.33 (m, 1H, H ), 7.42-7.54 (m, 1H, H ), 7.85-7.88 (m,
2
2
3
Ar
Ar
-1
1
1753 cm ; H nmr: δ 2.50 (s, 3H, CH ), 2.52 (s, 3H, CH ), 2.54
1H, H ), 10.27 (s, 1H, CHO).
3
3
Ar
(s, 3H, CH ), 6.27 (d, J = 3.1 Hz, 1H, 4-H ), 6.40 (s, 1H, 3-H),
Anal. Calcd. for C H O : C, 77.13; H, 5.75. Found: C,
3
Fur
18 16 3
6.88 (d, J = 3.1 Hz, 1H, 3-H ), 7.47-7.54 (m, 2H, 6-H, 7-H),
77.20; H, 5.58.
Fur
7.95-8.00 (m, 1H, 5-H), 8.54-8,59 (m, 1H, 8-H).
5-Chloro-2-bis(5-methyl-2-furyl)methylbenzaldehyde (6b).
Anal. Calcd. for C
H O : C, 74.99; H, 5.03. Found: C,
20 16 4
Aldehyde 6b; was synthesized analogously to 6a starting from
the alcohol 5b in 60.4% yield as colorless crystals with mp 75-77
75.10; H, 5.10.
6-Chloro-2-methyl-9-(5-methyl-2-furyl)naphtho[2,3-b]furan-4-
yl Acetate (4b).
-1
1
°C; ir: CHO 1693 cm ; H nmr: δ 2.25 (s, 6H, CH ), 5.89 (s, 4H,
3
H
), 6.34 (s, 1H, CH), 7.26 (d, J = 8.3 Hz, 1H, H ), 7.84 (dd, J
Fur
Ar
Compound 4b; was synthesized analogously to 4a starting
from compound 3b in 30.5% yield as colorless crystals with mp
= 2.1, 8.3 Hz, 1H, H ), 7.84 (d, J = 2.1 Hz, 1H, H ), 10.23 (s,
1H, CHO).
Ar
Ar
-1
1
140-143 °C; ir: CH COO 1751 cm ; H nmr: δ 2.50 (s, 3H,
Anal. Calcd for C
H
ClO : C, 68.68; H, 4.80. Found: C,
3
18 15
3
CH ), 2,52 (s, 3H, CH ), 2,55 (s, 3H, CH ), 6.27 (d, J = 3.1 Hz,
68.73; H, 4.85.
3
3
3
1H, 4- H ), 6.38 (s, 1H, 3-H), 6.89 (d, J = 3.1 Hz, 1H, 3-H ),
7.42 (dd, J = 2.1, 9.3 Hz, 1H, 7-H), 7.94 (d, J = 2.1 Hz, 1H, 5-H),
8,54 (d, J = 9.3 Hz, 1H, 8-H).
Fur
Fur
2-Methyl-9-(5-methyl-2-furyl)naphtho[2,3-b]furan (7a).
A solution of 6a (2 g, 7.14 mmol) in EtOH (10 mL) was treated
with ethanolic HCl solution (100 g HCl (gas) in 200 g ethanol, 5
mL). The mixture was kept at 50 °C for 1 hour. At the end of the
reaction (TLC control) the mixture was poured into water (100
Anal. Calcd. for C
H ClO : C, 67.71; H, 4.26. Found: C,
20 15 4
67.78; H, 4.20.
2-Bis(5-methyl-2-furyl)methylphenylmethanol (5a).
mL), neutralized with NaHCO , and extracted with CH Cl (3 x
3
2
2
80 mL). The organic layer was separated, dried with Na SO ,
To stirred suspension of 2-bis(5-methyl-2-furyl)methylbenzoic
2
4
treated with active charcoal. The solvent was removed under
reduced pressure, and the oily residue purified on silica gel elut-
ing with hexane – benzene (3:1) to give 0.7 g (37.4% yield) of the
acid (3a) (15 g, 50.7 mmol) in anhydrous Et O (150 mL) LiAlH
2
4
(3.9 g, 101.4 mmol) was added portionwise under cooling (-3 – 0
°C). The reaction was controlled with TLC, and after 5 hours the
mixture was poured into ice water and carefully neutralized with 6
compound
7a as colorless crystals with mp 59-61 °C (hexane);
1
M hydrochloric acid. The product was extracted with Et O (3 x
H nmr: δ 2.52 (s, 3H, CH ), 2,54 (s, 3H, CH ), 6.28 (d, J = 3.1
2
3 3
200 mL), dried with Na SO , treated with active charcoal. The
Hz, 1H, 4-H ), 6.50 (s, 1H, 3-H), 6.93 (d, J = 3.1 Hz, 1H, 3-
Fur
2
4
H
), 7.39-7.52 (m, 2H, 6-H, 7-H), 7.89 (s, 1H, 4-H), 7.90-7.95
solvent was removed in vacuo, the residue was recrystallized from
hexane to give 13.1 g (92% yield) of the title compound as color-
Fur
(m, 1H, 5-H), 8.57-8,61 (m, 1H, 8-H).
-1
1
less crystals with mp 65-67 °C; ir: OH br 3296 cm ; H nmr: δ
Anal. Calcd. for C H O : C, 82.42; H, 5.38. Found: C,
18 14 2
1.61 (br s, 1H, OH), 2.26 (s, 6H, CH ), 4.75 (s, 2H, CH ), 5.74 (s,
82.49; H, 5.43.
3
2
1H, CH), 5.85 (d, J = 3.2 Hz, 1H, 3- H ), 5.89 (d, J = 3.2 Hz, 1H,
Fur
6-Chloro-2-methyl-9-(5-methyl-2-furyl)naphtho[2,3-b]furan
(7b).
4- H ), 7.19-7.31 (m, 3H, H ), 7.40-7.45 (m, 1H, H ).
Fur
Ar
Ar
Anal. Calcd. for C
H O : C, 76.57; H, 6.43. Found: C,
18 18 3
Naphthofuran 7b; was synthesized analogously to 7a start-
ing from the aldehyde 6b in 37% yield as colorless crystals
76.50; H, 6.19.
5-Chloro-2-bis(5-methyl-2-furyl)methylphenylmethanol (5b).
1
with mp 94-96 °C; H nmr: δ 2.51 (s, 3H, CH ), 2,54 (s, 3H,
3
Compound 5b; was synthesized analogously to 5a starting from
compound 3b in 98% yield as colorless crystals with mp 71-73 °C; ir:
CH ), 6.29 (d, J = 3.1 Hz, 1H, 4-H ), 6.50 (s, 1H, 3-H), 6.95
3 Fur
(d, J = 3.1 Hz, 1H, 3-H ), 7.40 (dd, J = 2.1, 9.3 Hz, 1H, 7-H),
Fur
-1 1
OH br 3252 cm ; H nmr: δ 1.70 (br s, 1H, OH), 2.25 (s, 6H, CH ),
7.78 (s, 1H, 4-H), 7.89 (d, J = 2.1 Hz, 1H, 5-H), 8,55 (d, J =
9.3 Hz, 1H, 8-H).
3
4.72 (s, 2H, CH ), 5.62 (s, 1H, CH), 5.84 (d, J = 3.2 Hz, 2H, 3-H ),
2
Fur
5.89 (d, J = 3.2 Hz, 2H, 4-H ), 7.10 (d, J = 8.3 Hz, 1H, H ), 7.25
Anal. Calcd for C H ClO : C, 72.85; H, 4.42. Found: C,
Fur
Ar
18 13 2
(dd, J = 1.8, 8.3 Hz, 1H, H ), 7.46 (d, J = 1.8 Hz, 1H, H ).
72.80; H, 4.48.
Ar
Ar

Nov-Dec 2005
On the Synthesis of 9-Furylnaphtho[2,3-b]furan Derivatives
1431
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Acknowledgements.
Financial support was provided by Bayer HealthCare AG and
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