Furan ring opening-isochromene ring closure: A new approach to isochromene ring synthesis

Article abstract of DOI:10.1016/j.tetlet.2005.09.056

A new approach toward the synthesis of 1H-isochromenes based on the recyclization of the furan ring in the corresponding ortho- hydroxymethylbenzylfurans is described.

Full text of DOI:10.1016/j.tetlet.2005.09.056

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8439–8441
Furan ring opening–isochromene ring closure: a new approach
to isochromene ring synthesis
Alexander V. Butin,a,* Vladimir T. Abaev,b Vladimir V. MelÕchina and Artem S. Dmitrieva
aKuban State University of Technology, Moskovskaya st. 2, Krasnodar 350072, Russia
bNorth-Ossetian State University, Vatutina st. 46, Vladikavkaz 362025, Russia
Received 15 June 2005;revised 30 August 2005;accepted 9 September 2005
Available online 17 October 2005
Abstract—A new approach toward the synthesis of 1H-isochromenes based on the recyclization of the furan ring in the correspond-
ing ortho-hydroxymethylbenzylfurans is described.
Ó 2005 Elsevier Ltd. All rights reserved.
The isochromene framework is a frequent structural
motif in naturally occurring molecules. For example,
flaccidin isolated from the orchids Dendrobium amoenum
and Coelogyne flaccida includes an isochromene frame-
work.1a A number of compounds isolated from Canna-
bis sativa also can be viewed as isochromene
derivatives.1b The roots and the stem of a tree Ulmus
davidiana (widespread in Korea) are used in oriental
medicines for the treatment of inflammations, edema,
and stomach cancer. Natural sesquiterpenoids isolated
from U. davidiana also incorporate an isochromene
fragment in their structure.1c Hence there is a continuing
interest in the elaboration of new routes to the iso-
chromene ring as well as to new interesting derivatives
of this heterocyclic system.
1H-chromene. In essence, this method is based on the
intramolecular cyclization of a 2-methylenehydroxyben-
zyl carbonyl compound formed in situ.
We are involved in the development of a general access
to the synthesis of benzannelated heterocycles based on
the recyclization of ortho-substituted benzylfurans.7
Furan ring opening under protolytic conditions, when
the furan ring acts as a 1,4-dicarbonyl equivalent is well
known.8 We have found that the presence of suitable
nucleophiles at ortho-positions of the benzene ring of
benzylfurans dramatically facilitates furan ring cleavage.
By varying the ortho-substituent in the benzylfuran,
we succeeded in obtaining derivatives of benzofuran,9
indole,10 isochromenone11 and isoquinolone12 (Scheme
1). It is worth mentioning that the recyclization step in
ortho-substituted phenyldifuryl methanes is often
accompanied by secondary cyclization of the resulting
butan-3-one fragment onto the b-position of the second
furan ring, thus leading to the formation of condensed
tetracyclic molecules.7,11,12
Few approaches exist for the construction of the iso-
chromene ring. For example, a rather simple method
starting from homophthalic acid was reported.2 Mono-
phosphonium salts derived from a,a0-dibromoxylene
were reacted with sodium carboxylates giving rise to
chromene derivatives.3 Recently, palladium catalyzed
intramolecular cyclization of 2-alkynylbenzyl alcohols,4a
2-allylbenzyl alcohols,4b or allyl-2-bromobenzyl alco-
hols4c was reported. The synthesis of the isochromene
ring is also possible via cyclization of cis-acyl-ortho-
quinodimethanes.5 Chatterjea6 proposed the synthesis
of 1H-isochromene by reduction of 1H-1-isochrome-
none via its open form with subsequent cyclization to
Pursuing our methodology for the synthesis of the
benzannelated heterocycles, we studied the behavior of
XH
X
HCl/EtOH
O
O
R
R
Keywords: Furan;Recyclization;1 H-Isochromene.
X = O, NTs, COO, CON
*
Corresponding author.
alexander_butin@mail.ru
Tel.:
+7
(861)
2559556;e-mail:
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.056

8440
A. V. Butin et al. / Tetrahedron Letters 46 (2005) 8439–8441
R1
COOH
R1
COOH
CHO
R3
R3
O
2
R
HClO4
+
O
2
R
1,4-dioxane
O
2
1
R3
3a-g
OH
R1
R3
2
R
LiAlH4
Et2O
O
O
R3
4a-g
Scheme 2.
Table 1. Isochromene synthesis via recyclization of compounds 4
ortho-hydroxymethylbenzylfurans with the standard
recyclization conditions, namely reflux in ethanol satu-
rated with hydrogen chloride.
3, 4, 6
R1
R2
R3
Yield (%)
3
4
6
a
b
c
d
e
f
H
Br
Cl
H
H
OCH3
Br
H
H
H
Br
Cl
H
H
Me
Me
Me
Me
Me
Me
Et
68
70
72
75
78
65
67
91
93
96
72
69
85
93
63
61
66
57
55
70
59
2-Carboxybenzylfurans13 3 were obtained by condensa-
tion of 2-formylbenzoic acid derivatives 1 with 2-
alkylfurans 2 in dry 1,4-dioxane at 65–70 °C in the pres-
ence of a catalytic amount of 70% perchloric acid
(Scheme 2). Reduction of the carboxy group of com-
pounds 3 with lithium aluminum hydride gave the corre-
sponding benzyl alcohols 4.14
g
Treatment of compounds 4 with a saturated solution of
hydrogen chloride in ethanol afforded tetracyclic iso-
chromene derivatives 6.15 Like the analogous recycliza-
tions to isocoumarin and isoquinolone derivatives,11,12
no intermediate ketones 5 were isolated (Scheme 3,
Table 1).
a wide number of 1H-isochromene derivatives is possi-
ble by varying the R1–R3substituents.
Acknowledgements
Financial support was provided by Bayer HealthCare
AG and the Russian Foundation of Basic Research
(Grant 03-03-32759).
In conclusion, we note that the method described in this
letter is potentially very general because the synthesis of
OH
OH
R1
R1
R1
H
R3
O
+
O
R3
2
R
2
R
2
R
O
H
O
R3
O
O
O
R3
R3
R3
4a-g
R1
R1
R1
O
O
O
O
O
R3
OH
2
R
H+
R3
2
R
2
R
- H2O
O
O
R3
R3
R3
R3
5a-g
6a-g
Scheme 3.

A. V. Butin et al. / Tetrahedron Letters 46 (2005) 8439–8441
8441
pletion of the reaction (TLC monitoring). The mixture
was poured into water, and the resulting precipitate was
filtered off, washed with a little methylene chloride, and
recrystallized from acetone–ethanol to give 3b. Yield
(5.8 g, 70%), white crystals. Mp = 226–227 °C;Anal.
found: C, 57.58;H, 4.10. C 18H15BrO4 requires: C, 57.62;
H, 4.03; mmax (KBr): 1699 cmꢀ1; dH (200 MHz, CDCl3):
2.25 (6H, s, CH3), 5.88 (4H, s, HFur), 6.58 (1H, s, CH),
7.24 (1H, d, J = 8.3 Hz, HAr), 7.63 (1H, dd, J = 2.0,
8.3 Hz, HAr), 8.19 (1H, d, J = 2.0 Hz, HAr).
References and notes
1. (a) Majumder, P. L.;Guha, S.;Sen, S. Phytochemistry
1999, 52, 1365–1369;(b) Papadakis, D. P.;Salemink, C.
A.;Alikaridis, F. J.;Kephalas, T. A. Tetrahedron 1983, 39,
2223–2225;(c) Kim, J.-P.;Kim, W.-G.;Koshino, H.;
Jung, J.;Yoo, I.-D. Phytochemistry 1996, 43, 425–430.
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498.
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1979, 20, 2149–2150.
14. A typical procedure is as follows: To a cooled suspension
(ꢀ3 to 0 °C) of 3b (15 g, 40.0 mmol) in 225 ml of
anhydrous diethyl ether, LiAlH4 (3.19 g, 80.0 mmol) was
added slowly with vigorous stirring. After the reaction was
complete (TLC monitoring), the resulting suspension was
poured into water, acidified with HCl to pH 6–7 and
extracted with ethyl acetate. The combined extracts were
dried over anhydrous Na2SO4, purified with active char-
coal and the solvent was evaporated under reduced
pressure. The residue was recrystallized from hexane.
Yield of 4b 13.4 g, (93%), colorless crystals. Mp 75–77 °C;
Anal. found: C, 59.98;H, 4.61. C 18H17BrO3 requires: C,
59.85;H, 4.74; mmax (KBr): 3261 cmꢀ1; dH (200 MHz,
CDCl3): 1.66 (1H, br s, OH), 2.25 (6H, s, CH3), 4.72 (2H,
s, CH2), 5.61 (1H, s, CH), 5.85 (2H, d, J = 3.2 Hz, 3-HFur),
5.88 (2H, d, J = 3.2 Hz, 4-HFur), 7.05 (1H, d, J = 8.3 Hz,
4. (a) Gabriele, B.;Salerno, G.;Fazio, A.;Pittelli, R.
Tetrahedron 2003, 59, 6251–6259;(b) Giles, R. G. F.;
Green, I. R.;Taylor, C. P. Tetrahedron Lett. 1999, 40,
4871–4872;(c) Shi, L.;Narula, C. K.;Mak, K. T.;Kao,
L.;Xu, Y.;Heck, R. F. J. Org. Chem. 1983, 48, 3894–
3900.
5. Hug, R.;Hansen, H.-J.;Schmid, H.
Helv. Chim. Acta
1972, 55, 10–15.
6. (a) Chatterjea, J. N. Chem. Ber. 1958, 91, 2636–2638;(b)
Chatterjea, J. N.;Banerjee, B. K.;Jha, H. C. Chem. Ber.
1965, 98, 3279–3285.
7. See the following review: Butin, A. V.;Abaev, V. T. Izvest.
AN. Seriya Khim. 2001, 1436–1443.
8. See the following reviews: (a) Dean, F. M. Adv. Hetero-
cycl. Chem. 1982, 30, 167–238;(b) Dean, F. M. Adv.
Heterocycl. Chem. 1982, 31, 237–344;(c) Piancatelli, G.;
DÕAuria, M.;D ÕOnofrio, F. Synthesis 1994, 867–889.
9. (a) Butin, A. V.;Krapivin, G. D.;Zavodnik, V. E.;
KulÕnevich, V. G. Khim. Geterotsikl. Soedin. 1993, 616–
626;(b) Abaev, V. T.;Gutnov, A. V.;Butin, A. V. Khim.
Geterotsikl. Soedin. 1998, 603–607;(c) Gutnov, A. V.;
Butin, A. V.;Abaev, V. T.;Krapivin, G. D.;Zavodnik, V.
E. Molecules 1999, 4, 204–218;see the following review:
(d) Butin, A. V.;Gutnov, A. V.;Abaev, V. T.;Krapivin,
G. D. Molecules 1999, 4, 52–61.
H
Ar), 7.39 (1H, dd, J = 2.1, 8.3 Hz, HAr), 7.60 (1H, d,
J = 2.1 Hz, HAr).
15. A typical procedure is as follows: A mixture of 4b (12 g,
33.0 mmol), 48 ml of ethanol saturated with hydrogen
chloride (100 g HCl in 200 g ethanol) and 150 ml of the
ethanol was refluxed for 20 min. After completion of the
reaction (TLC monitoring), the reaction mixture was
poured into water, neutralized with sodium carbonate,
and extracted with ethyl acetate. The extract was dried
over Na2SO4, and the solvent was evaporated to dryness.
The resulting oil was dissolved in 100–150 ml of hexane
under reflux with addition of activated charcoal and then
filtered through a pad of silica gel. The solution was then
left in a refrigerator overnight and the resulting precipitate
filtered off. Yield of 6b 6.9 g (61%) colorless crystals. Mp
110–112 °C;Anal. found: C, 62.82;H, 4.48. C 18H15BrO2
requires: C, 62.99;H, 4.41; dH (200 MHz, CDCl3): 2.05
(3H, s, CH3), 2.44 (3H, s, CH3), 2.66 (2H, d, J = 6.7 Hz,
CH2), 4.97 (2H, s, CH2), 5.28 (1H, t, J = 6.7 Hz, @CH),
6.22 (1H, s, HFur), 7.21 (1H, d, J = 2.1 Hz, HAr), 7.43 (1H,
dd, J = 2.1, 8.4 Hz, HAr), 7.87 (1H, d, J = 8.4 Hz, HAr).
10. Butin, A. V.;Stroganova, T. A.;Lodina, I. V.;Krapivin,
G. D. Tetrahedron Lett. 2001, 42, 2031–2033.
11. Gutnov, A. V.;Abaev, V. T.;Butin, A. V.;Dmitriev, A. S.
J. Org. Chem. 2001, 66, 8685–8686.
12. Abaev, V. T.;Osipova, A. A.;Butin, A. V.
Khim.
Geterotsikl. Soedin. 2001, 849–850.
13. A typical procedure is as follows: To a solution of 5-
bromo-2-formylbenzoic acid (5 g, 22.0 mmol) in 35 ml of
1,4-dioxane, 0.065 ml of 70% HClO4 and 5.90 ml
(66.0 mmol) of 2-methylfuran were added. The reaction
mixture was maintained at 70 °C for 15 min until com-