Bis(5-alkyl-2-furyl)(2-carboxyphenyl)-methanes for the synthesis of tetracyclic isochromone derivatives

Full text of DOI:10.1021/jo016030h

J . Org. Chem. 2001, 66, 8685-8686
8685
Sch em e 1
Bis(5-a lk yl-2-fu r yl)(2-ca r boxyp h en yl)-
m eth a n es for th e Syn th esis of Tetr a cyclic
Isoch r om on e Der iva tives
Andrey V. Gutnov,† Vladimir T. Abaev,†
Alexander V. Butin,*,‡ and Artem S. Dmitriev‡
North-Ossetian State University, Vatutina 46,
Vladikavkaz, 362025, Russian Federation, and Kuban State
Technological University, Moskovskaya 2,
Sch em e 2
Krasnodar, 350072, Russian Federation
alexander_butin@mail.ru
Received August 15, 2001
In tr od u ction
Isochromone (isocoumarin) derivatives constitute a
class of heterocyclic compounds that is widespread in
nature, and there are plenty of examples for biological
activity of different kinds.1 The main synthetic approach
toward isochromone still involves utilizing the cyclization
of 2-(2-oxoethyl)benzoic acids (Scheme 1), the carbonyl
group of which can be both in apparent2 and in latent
form (acetylenes,3 preoxidized ethylenes,4 enol ethers,5
vinyl bromides6).
It is a well-known fact that alkylfurans in acidic media
are able to act as a source of 1,4-dicarbonyl compounds,
and this property of furan derivatives is extensively used
in organic synthesis.7 Our previous investigations have
shown that a number of ortho-substituted benzylfurans
in acidic media undergo the recyclization reaction of
furan ring with formation of new heterocycles such as
benzo[b]furans,8 indoles,9 and isoquinolones.10 Herein, we
report a new approach to the synthesis of isochromone
(isocoumarin) derivatives, and in this case, the furan
cycle also provides a carbonyl function for heterorecy-
clization.
Resu lts a n d Discu ssion
First of all, bis(5-alkyl-2-furyl)(2-carboxyphenyl)meth-
anes 1a ,b have been obtained by condensation of 2-alkyl-
furans and 2-formylbenzoic acid in dioxane in the pres-
ence of HClO4 (Scheme 2).
The following treatment of the benzoic acids 1a ,b with
anhydrous methanolic HCl solution affords the isoch-
romones 2a ,b with high yields (Scheme 3).
Apparently the reaction begins with the protonation
of one of two furan rings, followed by the intramolecular
attack of the hydroxy group of 2-carboxyphenyl residue
on the furanyl cation. The intermediate spiro compound
then transforms into 4-(5-alkyl-2-furyl)-3-(3-oxobutyl)-
1H-1-isochromenone 3. Unfortunately, all attempts have
failed to isolate this compound because it easily under-
goes intramolecular cyclization of the carbonyl group to
the 3-position of the furyl moiety affording the tetracyclic
isochromones 2a ,b. This result is consistent with those
obtained previously, as 3-(5-methyl-2-furyl)-3-(3-oxobu-
tyl)benzo[b]furans also easily underwent intramolecular
cyclization into tetracyclic benzofuran derivatives,8b and
also the recyclization of N-benzyl-2-bis(5-methyl-2-furyl)-
methylbenzamide into isoquinolone derivative was ac-
companied with secondary cyclization into similar tet-
racyclic compound.10
* To whom correspondence should be addressed.
† North-Ossetian State University.
‡ Kuban State Technological University.
(1) (a) Barry, R. D. Chem. Rev. 1964, 64, 229. (b) Houser, F. M.;
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K. N. J . Org. Chem. 1998, 63, 2488 and references therein.
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(5) (a) Sakamato, T.; Kondo, Y.; Yasuhara, A.; Yamanaka, H.
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(8) (a) Butin, A. V.; Krapivin, G. D.; Zavodnik, V. E.; Kul’nevich, V.
G. Khim. Geterotsikl. Soedin. 1993, 616; Chem. Heterocycl. Compd.
(Engl. Transl.) 1993, 29, 524. (b) Abaev, V. T.; Gutnov, A. V.; Butin,
A. V. Khim. Geterotsikl. Soedin. 1998, 603; Chem. Heterocycl. Compd
(Engl. Transl.) 1998, 34, 529. (c) Gutnov, A. V.; Butin, A. V.; Abaev,
V. T.; Krapivin, G. D.; Zavodnik, V. E. Molecules 1999, 4, 204.
(9) Butin, A. V.; Stroganova, T. A.; Lodina, I. V.; Krapivin, G. D.
Tetrahedron Lett. 2001, 42, 2031.
It has been also found possible to obtain the tetracycles
2a ,b directly from 2-alkylfurans and 2-formylbenzoic acid
by a one-pot procedure with moderate yields.
In conclusion, a simple and convenient synthesis of
novel tetracyclic system of 1,11-dialkyl-3,5-dihydrofuro-
[2′,3′:3,4]cyclohepta[c]isochromen-5-one has been devel-
oped starting from easily available materials.
Exp er im en ta l Section
Gen er a l Meth od s. All 1H and 13C NMR spectra were
recorded at 200 and 50 MHz, respectively, using CDCl3 as a
solvent; chemical shifts are in ppm downfield from tetrameth-
ylsilane as internal standard; IR spectra were taken in Nujol,
and the most intense or representative bands are reported
(10) Abaev, V. T.; Osipova A. A.; Butin, A. V. Khim. Geterotsikl.
Soedin. 2001, 849; Chem. Heterocycl. Compd. (Engl. Transl.) 2001, 37,
785.
10.1021/jo016030h CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/10/2001

8686 J . Org. Chem., Vol. 66, No. 25, 2001
Notes
Sch em e 3
(in cm-1). Melting points are uncorrected. 2-Formylbenzoic acid
obtained from Aldrich; freshly distilled 2-methylfuran and
2-ethylfuran were taken for each synthesis.
Gen er a l P r oced u r e for th e Syn th esis of Bis(5-a lk yl-2-
fu r yl)(2-car boxyph en yl)m eth an es. To the solution of 2-formyl-
benzoic acid (1.5 g, 0.01 mol) and 2-alkylfuran (0.022 mol) in 5
mL of dioxane 0.2 mL of 70% HClO4 was added, and the mixture
left overnight at room temperature. It was then poured into 30
mL of water, and the precipitated solid was filtered 3 h later.
Bis(5-m eth yl-2-fu r yl)(2-car boxyph en yl)m eth an e 1a: yield
55%; mp 145-146 °C (benzene); 1H NMR (CDCl3) δ 2.22 (s, 6H,
CH3), 5.86 (d, J ) 3.2 Hz, 2H, 3-HFur), 5.89 (d, J ) 3.2 Hz, 2H,
4-HFur), 6.68 (s, 1H, CH), 7.30-7.39 (m, 2H, HAr), 7.47-7.58 (m,
1H, HAr), 8.03-8.12 (m, 1H, HAr); 13C NMR (CDCl3) δ 13.6 (2C),
40.6, 106.1 (2C), 108.6 (2C), 127.0, 127.9, 130.2, 131.7, 133.1,
142.2, 151.4, 152.7, 173.4; IR (Nujol) 2900, 1690 cm-1; m/z 296
(M+). Anal. Calcd for C18H16O4: C, 72.96; H, 5.44. Found: C,
73.03; H, 5.41.
1,11-Meth yl-3,5-d ih yd r ofu r o[2′,3′:3,4]cycloh ep ta [c]isoch -
r om en -5-on e 2a : yield 86%; mp 146-147 °C (ethanol); 1H NMR
(CDCl3) δ 2.03 (d, J ) 1.2 Hz, 3H, CH3), 2.48 (d, J ) 1.0 Hz, 3H,
CH3), 2.98 (d, J ) 6.8 Hz, 2H, CH2), 5.37 (t.q, J ) 1.2, 6.8 Hz,
1H, dCH), 6.29 (q, J ) 1.0 Hz, 1H, HFur), 7.45-7.54 (m, 1H,
HAr), 7.72-7.81 (m, 1H, HAr), 8.31-8.40 (m, 2H, HAr); 13C NMR
(CDCl3) δ 13.8, 20.3, 31.6, 105.4, 105.7, 115.5, 119.7, 124.4, 127.0,
127.4, 129.8, 137.6, 134.8, 135.4, 145.5,146.8, 151.3, 162.3; IR
(Nujol) 1740 cm-1; m/z 278 (M+). Anal. Calcd for C18H14O3: C,
77.68; H, 5.07. Found: C, 77.24; H, 5.05.
1,11-Eth yl-3,5-d ih yd r ofu r o[2′,3′:3,4]cycloh ep ta [c]isoch -
r om en -5-on e 2b: yield 89%; mp 168-169 °C (ethanol); 1H NMR
(CDCl3) δ 1.05 (t, J ) 7.5 Hz, 3H, CH2CH3), 1.48 (t, J ) 7.5 Hz,
3H, CH2CH3), 2.40 (q. d, J ) 1.2, 7.5 Hz, 2H, CH2CH3), 2.83 (q.
d, J ) 1.0, 7.5 Hz, 2H, CH2CH3), 2.99 (d, J ) 6.8 Hz, 2H, CH2),
5.38 (t.t, J ) 1.2, 6.8 Hz, 1H, dCH), 6.29 (t, J ) 1.0 Hz, 1H,
HFur), 7.45-7.56 (m, 1H, HAr), 7.72-7.81 (m, 1H, HAr), 8.31-
8.41 (m, 2H, HAr); 13C NMR (CDCl3) δ 12.1, 13.2, 21.5, 27.2, 31.5,
103.8, 105.4, 114.0, 119.8, 124.4, 126.2, 127.4, 129.8, 134.8, 135.6,
137.6, 145.8, 147.2, 156.8, 162.3; IR (Nujol) 1740 cm-1; m/z 306
(M+). Anal. Calcd for C20H18O3: C, 78.41; H, 5.92. Found: C,
78.27; H, 5.69.
On e-P ot P r oced u r e for th e Syn th esis of 1,11-Alk yl-3,5-
d ih yd r ofu r o[2′,3′:3,4]cycloh ep ta [c]isoch r om en -5-on es 2a ,b.
To the solution of 2-formylbenzoic acid (1.5 g, 0.01 mol) and
2-alkylfuran (0.022 mol) in 10 mL of methanol was added 2 mL
of dry saturated methanolic HCl solution in one portion, and
the reaction mixture was stirred for 5 min. Then 8 mL of CH3-
OH/HCl was added, and the darkened mixture was stirred under
reflux within 30 min. Then it was cooled and diluted with 100
mL of H2O. The liberated thick dark oil was washed by
decantation, dissolved in 20 mL of ethanol, and left overnight.
Double recrystallization of the precipitated crystalline solid from
ethanol gave 37% and 41% yields of 2a and 2b. Main analytical
data are the same as for those mentioned above.
Bis(5-eth yl-2-fu r yl)(2-ca r boxyp h en yl)m eth a n e 1b: yield
67%; mp 114-115 °C (benzene); 1H NMR (CDCl3) δ 1.17 (t, J )
7.5 Hz, 6H, CH2CH3), 2.59 (q, J ) 7.5 Hz, 4H, CH2CH3), 5.85
(d, J ) 3.2 Hz, 2H, 3-HFur), 5.88 (d, J ) 3.2 Hz, 2H, 4-HFur), 6.68
(s, 1H, CH), 7.28-7.39 (m, 2H, HAr), 7.45-7.56 (m, 1H, HAr),
8.04-8.11 (m, 1H, HAr); 13C NMR (CDCl3) δ 12.2 (2C), 21.4 (2C),
40.8, 104.4 (2C), 108.4 (2C), 126.9, 128.0, 130.2, 131.7, 133.0,
142.4, 152.6 (2C), 157.2 (2C), 173.3; IR (Nujol) 2900, 1690 cm-1
;
m/z 324 (M+). Anal. Calcd for C20H20O4: C, 74.06; H, 6.21.
Found: C, 73.81; H, 6.35.
Gen er a l P r oced u r e for th e Syn th esis of 1,11-Alk yl-3,5-
d ih yd r ofu r o[2′,3′:3,4]cycloh ep ta [c]isoch r om en -5-on es. To
a solution of compound 1a ,b (0.01 mol) in 10 mL of methanol
10 mL of dry saturated methanolic HCl solution was added in
one portion, and the reaction mixture stirred under reflux for
30 min. Then it was cooled and diluted with 100 mL of H2O.
The liberated thick oil was washed by decantation, dissolved in
20 mL of ethanol, and left overnight to crystallize.
J O016030H