Synthesis of novel tricyclic 2H,7H-furo[3',4':6,7]cyclohepta-[1,2-b]pyran system

Article abstract of DOI:10.1007/s10593-009-0199-5

The reaction of 8-hydroxy-1,3-dimethyl-4H-cyclohepta[c]furan-4-one with the ethoxymethylene derivatives of malononitrile or ethyl cyanoacetate in the presence of KOH gave noncyclic cyanovinyl derivatives as their potassium salts rather than the expected α-pyrone derivatives. They are smoothly cyclized to the target α-pyrones by refluxing with acid. The corresponding 3-benzamido-2H-pyran-2-ones can be obtained in a single vessel from the 2-aryl-4-ethoxymethylene-4H-1,3-oxazol-5-ones using the same scheme.

Full text of DOI:10.1007/s10593-009-0199-5

Chemistry of Heterocyclic Compounds, Vol. 44, No. 11, 2008
SYNTHESIS OF NOVEL TRICYCLIC
2H,7H-FURO[3',4':6,7]CYCLOHEPTA-
[1,2-b]PYRAN SYSTEM
M. Yu. Arsenyeva and V. G. Arsenyev
The reaction of 8-hydroxy-1,3-dimethyl-4H-cyclohepta[c]furan-4-one with the ethoxymethylene
derivatives of malononitrile or ethyl cyanoacetate in the presence of KOH gave noncyclic cyanovinyl
derivatives as their potassium salts rather than the expected α-pyrone derivatives. They are smoothly
cyclized to the target α-pyrones by refluxing with acid. The corresponding 3-benzamido-2H-pyran-
2-ones can be obtained in a single vessel from the 2-aryl-4-ethoxymethylene-4H-1,3-oxazol-5-ones
using the same scheme.
Keywords: hydroxytropone, enol, 2H-pyran-2-one, α-pyrone, tropolone, tropone, ethoxymethylene-
malononitrile, 4-ethoxymethylene-4H-1,3-oxazol-5-one, Michael addition.
Hydroxytropones are an important and interesting class of nonbenzenoid aromatic compounds which are
active nucleophiles with many properties resembling phenols [1].
We have studied the recently available 8-hydroxy-1,3-dimethyl-4H-cyclohepta[c]furan-4-one (1) which
can be regarded as a condensed analog of 4-hydroxytropone (γ-tropolone). For us the greatest interest is its
reactions with C-electrophiles and principally where this is accompanied by the annelation of a heterocycle to an
existing cyclohepta[c]furan system. Similar reactions have not been studied either for 4-hydroxytropone and
9-hydroxybenzocyclohepten-5-one closely related to 1 and are virtually unknown for the most investigated
hydroxytropone, i.e. tropolone.
In previous work we have found that the hydroxytropone 1 shows typical enol properties in reactions
with ylidenemalononitriles to give the novel condensed 4H,7H-furo[3',4':6,7]cyclohepta[1,2-b]pyran systems
[2].
The aim of this work was to study the reactions of the hydroxytropone 1 with some electrophilic alkenes
containing a good leaving group in the β-position of the double bond, e.g. with ethoxymethylene-malononitrile
or its analogs. Similar reactions of other enols generally give 2H-pyran-2-one derivatives (α-pyrones) [3-5]. In
this case the formation of condensed α-pyrones – novel 2H,7H-furo[3',4':6,7]cyclohepta-[1,2-b]pyran system
derivatives was expected. These products may possess useful physiological activity (antibacterial, antitumor,
etc.). Such activity is seen both in various natural and synthetic condensed α-pyrones [6-9] and in many natural
and synthetic heteroannelated tropones [10].
__________________________________________________________________________________________
Southern Federal University, Rostov-on-Don 344006, Russia; e-mail: arsenev.vg@gmail.com.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1632-1638, November, 2008. Original
article submitted June 14, 2007.
1328
0009-3122/08/4411-1328©2008 Springer Science+Business Media, Inc.

In fact, it was found that the hydroxytropone 1 reacts readily with ethoxymethylenemalononitrile or
ethoxymethylenecyanoacetate but to give not the expected 2H-pyran-2-ones but the noncyclic vinyl derivatives
3a,b as their potassium salts. The reaction occurs by short refluxing of the starting materials with an equimolar
amount of potassium hydroxide in ethanol in 45-60% yield. Evidently the electrophilic alkene attacks position 7
in the starting hydroxytropone to form the Michael type adduct 2 with subsequent loss of ethanol to give the
conjugated product as its salt.
K+
R
C
R
O
O
O
NC
CN
R
NC
KOH
EtOH
Me
Me
+
Me
EtO
–EtOH
EtO
O
O
K+
–
HO
O
O
O
Me
Me
Me
3a,b
1
2
3 a R = CN, b R = CO2Et
Even when heated in DMSO at 190ºC compounds 3a,b do not undergo cyclization to the expected
pyrone or its imine. The high stability of compounds 3a,b is evidently due to the high degree of delocalization
of the negative charge and lowering of the electrophilicity of the nitrile groups of the cyanovinyl substituent.
Compounds 3a,b are brown, crystalline materials insoluble in chloroform, readily soluble in DMF and
DMSO, and soluble in water.
1
The H NMR spectra of compounds 3a,b show signals for the furan ring methyl groups as two three –
proton singlets at 2.60 ppm, two one-proton methine doublet signals in the seven-membered ring at 5.50-5.60
and 7.60-7.90 ppm, and a singlet signal for the vinyl substituent at 7.90 (3a) and 8.60 ppm (3b). The IR
spectrum of compound 3a showed sharp, partially overlapping bands for the stretching vibrations of the nitrile
groups at 2200 and 2186 cm-1. The broad, strong multiplet band at 1600-1526 cm-1 evidently corresponds to
C=O and C=C stretching vibrations of the ionized oxodienol fragment in the seven-membered ring. The
lowering of the carbonyl stretching frequency is due to the high degree of conjugation and delocalization of the
negative charge in this fragment [11].
However, cyclization of compounds 3a,b can be achieved under acid catalyzed conditions by refluxing
with excess 46% HBr in alcohol to give the pyrones 5a,b. The nitrile group takes part in the cyclization and the
intermediate pyroneimine 4 undergoes hydrolysis to pyrone 5. In the case of compound 3a the reaction is
accompanied by hydrolysis of the second CN group to an amide. A similar acid catalyzed reaction has been
reported before [12].
O
O
HBr, H2O
Me
Me
HBr
3a,b
R
EtOH
R
O
O
O
O
Me
5a,b
O
Me
HN
4
5 a R = CONH2, b R = CO2Et
The synthesis of pyrones 5a,b can be carried out in one vessel from the hydroxytropone 1 without
separation of the compounds 3a,b.
Compounds 5a,b are yellow, crystalline materials; compound 5a is soluble in DMF and 5b readily
soluble in chloroform.
1329

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
H
N
3a
3b
5a
5b
9a
9b
9c
C15H9KN2O3
C17H14KNO5
C15H11NO5
С17H14O6
59.07
59.20
57.95
58.11
63.23
63.16
65.01
64.97
69.77
69.80
63.82
63.73
66.57
66.49
3.07
2.98
4.27
4.02
3.77
3.89
4.27
4.49
4.33
4.18
3.61
3.57
3.91
3.72
8.97
9.20
3.70
3.99
4.71
4.91
—
>300 (dec.)
>300 (dec.)
>300 (dec.)
190-200
60
45
64
85
55
51
45
C21H15NO5
C21H14ClNO5
C21H14FNO5
3.52
3.88
3.21
3.54
3.31
3.69
229-230
220-221
231-232
1
The H NMR spectra of compounds 5a,b show singlet signals for the furan ring methyl groups at
2.70-2.90, seven-membered ring methine proton doublets at 6.30-7.30, and a pyran proton singlet at 8.20-8.50
ppm. The spectrum of 5a also shows the presence of a broad two- proton singlet for the amide group at 7.85
ppm and the spectrum of 5b a triplet (1.40 ppm) and quartet (4.40 ppm) for the ethyl group protons.
The IR spectrum of pyrone 5b has bands for the lactone carbonyl of the pyrone ring (1766 cm-1) [13], an
ester carbonyl (1700 cm-1), conjugated seven-membered ring carbonyl (1633 cm-1), and a system of conjugated
C=C bonds at 1586 cm-1.
Ar
N
O
O
O
Ar
N
KOH
EtOH
1
+
Me
O
O
EtO
O
K+
O
O
6a–c
Me
7
EtOK
EtOH
HBr
H2O
Me
H
Ar
HN
N
EtOH
O
O
O
Ar
Me
O
O
O
O
Me
9a–c
EtO
K+
O
O
Me
8
6-9 a Ar = Ph, b Ar = 2-ClC6H4, c Ar = 4-FC6H4
In order to synthesize 3-benzamido-2H-pyran-2-ones the hydroxytropone 1 was treated with the 2-aryl-
4-ethoxymethylene-4H-1,3-oxazol-5-ones 6a-c. The reactions were performed in the presence of KOH in alcohol
as before. The potassium salt of the vinyl derivative 7 or 8 formed underwent cyclization without separation using
46% HBr in alcohol. Hence a one vessel synthesis gave the target 3-benzamido-2H-pyran-2-ones 9a-c.
1330

TABLE 2. Spectroscopic Characteristics of the Compounds Synthesized
Com-
pound
IR spectrum, ν, cm−1
1Н NMR spectrum, δ , ppm (J, Hz)*
2200, 2186, 1600, 1573, 1526
2.56 (3Н, s); 2.62 (3Н, s); 5.56 (1Н, d, J = 13);
7.64 (1Н, d, J = 13); 7.87 (1Н, s)
3a
2180, 1666, 1600, 1580, 1526,
1206
1.20 (3Н, t, J = 8); 2.57 (3Н, s); 2.60 (3H, s);
4.14 (2Н, q, J = 8); 4.20 (1Н, s); 5.49 (1Н, d, J = 13);
7.88 (1Н, d, J = 13); 8.62 (1H, s)
3b
3446, 3326, 1733, 1680, 1633,
1613, 1586, 1540, 1213
2.64 (3Н, s); 2.78 (3Н, s); 6.17 (1Н, d, J = 13);
7.22 (1Н, d, J = 13); 7.86 (2H, br. s); 8.54 (1Н, s)
5a
5b
1766, 1700, 1633, 1613, 1586,
1540, 1226
1.37 (3H, t, J = 8); 2.71 (3H, s); 2.88 (3H, s);
4.37 (2H, q, J = 8); 6.29 (1H, d, J = 13);
6.77 (1H, d, J = 13); 8.22 (1H, s)
3446, 1713, 1666, 1633, 1606,
1206
2.75 (3H, s); 2.85 (3H, s); 6.38 (1H, d, J = 13);
6.84 (1H, d, J = 13); 7.50-7.65 (3H, m);
7.91 (2H, d, J = 8); 8.62 (2H, br. s)
9a
9b
9c
3345, 1726, 1673, 1640, 1626,
1540, 1226
2.76 (3Н, s); 2.84 (3Н, s); 6.39 (1Н, d, J = 13);
6.85 (1Н, d, J = 13); 7.36-7.54 (3Н, m);
7.80 (1Н, d, J = 8); 8.62 (1H, s); 8.78 (1H, br. s)
3393, 1713, 1666, 1640, 1620,
1540, 1233
2.77 (3Н, s); 2.86 (3H, s); 6.39 (1Н, d, J = 13);
6.82 (1Н, d, J = 13); 7.22 (2H, dd, J = 9);
7.92 (2Н, dd, J = 9, J = 4)
_______
* The 1H NMR spectra of compounds 3a,b, 5a were recorded in DMSO-d6
and compounds 5b, 9a-c in CDCl3.
Compounds 9a-c are yellow-greenish, crystalline materials soluble in DMF, chloroform, and acetonitrile.
The 1H NMR spectra of pyranones 9a-c show furan ring three-proton methyl group singlets at 2.86 and
2.83 ppm, seven-membered ring one methine protons doublets at 6.40-6.82, aryl group protons signals at
7.20-7.90, a pyran ring proton singlet at 8.60, and a broad N–H proton singlet at 8.55-8.77 ppm.
The IR spectrum of compound 9a shows absorption bands for the N–H stretching vibrations at
3446 cm-1, a pyrone ring lactone carbonyl (1713), amide carbonyl (1666), seven-membered ring carbonyl
(1633), C=C bond system (1606), and C–O fragment (1240 cm-1).
Hence 8-hydroxy-1,3-dimethyl-4H-cyclohepta[c]furan-4-one in the presence of KOH shows a high
nucleophilic reactivity when treated with the electrophilic alkenes ethoxymethylene malononitrile,
ethylcyanoacetate, and 2-aryloxazol-5-ones. For the first two reagents pure cyanovinyl derivatives can be
isolated as their potassium salts. The later readily cyclize to the novel target condensed 2H,7H-furo-
[3',4':6,7]cyclohepta[1,2-b]pyran system under acid catalyzed conditions. A one vessel reaction of
hydroxytropone 1 with the 2-aryl-4-ethoxymethylene-4H-1,3-oxazol-5-ones occurs in two stages, initially base
catalyzed and then using acid to give the corresponding 3-benzamido-2H-pyran-2-ones.
EXPERIMENTAL
The IR spectra of the samples prepared were recorded on a Specord IR-71 instrument using vaseline oil.
1H NMR spectra were taken on Bruker DPX-250 (250 MHz) and Varian VXR-300 (300 MHz) spectrometers
using CDCl3 as deuterated solvent. 13C NMR spectra were taken on a Varian VXR-300 (75 MHz) Unity
spectrometer using CDCl3. Internal TMS was used as a standard for both.
8-Hydroxy-1,3-dimethyl-4H-cyclohepta[c]furan-4-one was prepared by a method developed before
[14]. Ethoxymethylenemalononitrile, ethoxymethylenecyanoacetate, and ethoxymethyleneoxazones were
prepared by the reaction of the corresponding active methylene compound with triethylorthoformate and acetic
anhydride by a known method.
1331

Potassium Salt of [(8-Hydroxy-1,3-dimethyl-4-oxo-4H-cyclohepta[c]furan-7-yl)methylene]malono-
nitrile (3a). A solution of KOH (0.14 g) in ethanol (5 ml) was added to a suspension of the 8-hydroxytropone 1
(0.48 g, 2.5 mmol) and ethoxymethylenemalononitrile (0.31 g, 2.5 mmol) in ethanol (5 ml) and refluxed with
stirring for 5 min. Precipitation of the product began after 1-2 min. The reaction mixture was left overnight at
room temperature. The product was filtered off and washed with ethanol to give pure material. The purity of the
product fell with attempts to recrystallized it.
Potassium Salt of Ethyl 2-Cyano-3-(8-hydroxy-1,3-dimethyl-4-oxo-4H-cyclohepta[c]furan-7-yl)-
acrylate (3b). Obtained similarly to compound 3a from the 8-hydroxytropone 1 (0.48 g, 2.5 mmol) and
ethoxymethylenecyanoacetate (0.42 g, 2.5 mmol). The product was also pure without recrystallization.
8,10-Dimethyl-2,7-dioxo-2H,7H-furo[3',4':6,7]cyclohepta[1,2-b]pyran-3-carboxamide (5a). HBr
(46%, 1 ml) was added to a suspension of compound 3a (0.76 g, 2.5 mmol) in ethanol (10 ml). The solution was
refluxed for 5 min and water (50 ml) was added portionwise. The reaction mixture was left overnight at room
temperature. The product was filtered off, washed with water, dried, and purified by crystallization from MeNO2
to give greenish crystals.
Ethyl 8,10-Dimethyl-2,7-dioxo-2H,7H-furo[3',4':6,7]cyclohepta[1,2-b]pyran-3-carboxylate (5b)
was prepared similarly to compound 5a from compound 3b (0.88 g, 2.5 mmol) and 46% HBr (1 ml) in ethanol
10 ml). Yellow-greenish crystals (MeCN). 13C NMR spectrum, δ, ppm: 14.1, 14.6, 16.6, 61.8, 110.5, 112.1,
112.9, 119.0, 130.3, 134.2, 153.7, 154.8, 157.5, 159.1, 161.9, 162.6, 183.7.
8,10-Dimethyl-2,7-dioxo-2H,7H-furo[3',4':6,7]cyclohepta[1,2-b]pyran-3-carboxamide (5a) (one
vessel reaction). KOH (0.14 g) in ethanol (5 ml) was added to a suspension of 8-hydroxytropone 1 (0.48 g,
2.5 mmol) and ethoxymethylenemalononitrile (0.31 g, 2.5 mmol ) in ethanol (5 ml) and refluxed for 5 min with
stirring. 46% HBr (1 ml) was then added. The solution was refluxed for 5 min and water (50 ml) was added
portionwise. The reaction mixture was left overnight at room temperature. The product was filtered off, washed
with water, dried, and purified by recrystallization from MeNO2. One vessel product yield 41%.
Ethyl 8,10-Dimethyl-2,7-dioxo-2H,7H-furo[3',4':6,7]cyclohepta[1,2-b]pyran-3-carboxylate (5b)
was prepared in a single vessel similarly to compound 5a. The precipitate was recrystallized from MeCN. Final
product yield 60%.
N-(8,10-Dimethyl-2,7-dioxo-2H,7H-furo[3',4':6,7]cyclohepta[1,2-b]pyran-3-yl)benzamide (9a) was
prepared in one vessel similarly to compound 5a from the 8-hydroxytropone 1 (0.48 g, 2.5 mmol) and 4-
ethoxymethylene-2-phenyl-4H-1,3-oxazol-5-one (6a) (0.54 g, 2.5 mmol). Yellow-greenish crystals (MeCN). 13C
NMR spectrum, δ, ppm: 15.1, 16.6, 112.1, 112.5, 119.6, 122.9, 127.5 (2C), 128.9, 129.4 (2C), 131.5, 133.0,
133.7, 135.7, 151.9, 153.6, 157.6, 158.9, 166.4, 184.5.
3-(2-Chlorophenylcarboxamido)-8,10-dimethyl-2,7-dioxo--2H,7H-furo[3',4':6,7]cyclohepta[b]pyran
(9b) was prepared similarly to compound 9a from compound 1 (0.48 g, 2.5 mmol) and 2-(2-chlorophenyl)-
4-ethoxymethylene-4H-1,3-oxazol-5-one (6b) (0.99 g , 2.5 mmol). Yellow-green crystals (MeCN).
8,10-Dimethyl-2,7-dioxo-3-(4-fluorophenylcarboxamido)-2H,7H-furo[3',4':6,7]cyclohepta[b]pyran
(9c) was prepared similarly to compound 9a from tropone 1 (0.48 g, 2.5 mmol) and 4-ethoxy-methylene-2-(4-
fluorophenyl)-4H-1,3-oxazol-5-one (6c) (0.95 g, 2.5 mmol). Yellow-green crystals (MeCN–H2O, 2:1).
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