Synthesis and some transformations of new 9-furylnaphtho[2,3-b]furan derivatives

Article abstract of DOI:10.1016/j.tet.2006.06.027

The synthesis of a number of naphtho[2,3-b]furan derivatives, containing a furyl substituent in position 9 by intramolecular cyclization of 2-carboxy and 2-formylbis(5-alkylfur-2-yl)methanes is described. The reactivity of the title compounds in formylati

Full text of DOI:10.1016/j.tet.2006.06.027

Tetrahedron 62 (2006) 8045–8053
Synthesis and some transformations of new
9-furylnaphtho[2,3-b]furan derivatives
a
b
c
Alexander V. Butin,a, Vladimir V. Mel’chin, Vladimir T. Abaev, Wolfgang Bender,
*
Arkady S. Pilipenkoa and Gennady D. Krapivina
aResearch Institute of Heterocyclic Compounds Chemistry, Kuban State University of Technology, Moskovskaya st. 2,
Krasnodar 350072, Russia
bNorth-Ossetian State University, Vatutina 46, Vladikavkaz 362025, Russia
cBayer HealthCare AG, D-51368 Leverkusen, Germany
Received 8 February 2006; revised 29 May 2006; accepted 8 June 2006
Available online 27 June 2006
Abstract—The synthesis of a number of naphtho[2,3-b]furan derivatives, containing a furyl substituent in position 9 by intramolecular
cyclization of 2-carboxy and 2-formylbis(5-alkylfur-2-yl)methanes is described. The reactivity of the title compounds in formylation, acet-
ylation, nitration, and oxidation reactions has been investigated. It was shown that nitration of 2-methyl-9-(5-methyl-2-furyl)naphtho-
[2,3-b]furan-4-yl acetate leads to oxidative furan ring opening rather than to electrophilic substitution.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
naphthalene nucleus. For example, Narasimhan and Mali5a
have proposed a convenient method based on cyclization
of 2-methoxy-3-(2-methoxyvinyl)naphthalene, synthesized
from 2-methoxy-3-naphthaldehyde. It is also reported that
under the action of lithium iodide cyclobuta[a]naphthalene
derivatives undergo a transformation into naphthofurans.5b
The reaction of a-chloro-a-phenylthioketones with 2-naph-
thol, catalyzed by Lewis acids, also leads to the formation of
naphthofurans.5c Photolysis or thermolysis of cyclopro-
pa[b]naphthalene derivatives give naphthofurans with low
yields.5d In the paper of Royer et al.,5e a route to naphtho-
furan derivatives starting from methyl 3-hydroxy-2-naph-
thoate is disclosed.
Among natural compounds, representatives incorporating
the naphthofuran framework are quite common. Thus,
maturin and maturinin were isolated from the roots of
Cacalia decomposita.1a Later, another group of authors1b
isolated the natural analogs of the naphthofurans from the
roots of Senecio Canescens, namely 13-hydroxydehydroxy-
cacalohastine, 13-acetoxydehydrocacalohastine along with
the sesquiterpenoid naphthofuran derivative. In their recent
communication, some Japanese authors have reported1c
that a number of the above-mentioned naturally occurring
naphthofuran derivatives like maturin and 14-methoxydehy-
drocacalohastine were also isolated from Trichilia cuneata.
The synthesis of naphthofuran derivatives attracts our atten-
tion because of a fairly wide spectrum of biological activity.2
For example, nitro derivatives of naphthofurans possess pro-
nounced mutagenic activity,2b,c,f,g,m–o that is of interest for
medicinal chemistry. It should also be noted that furonaph-
thoquinones, a class of naturally occurring biologically
active compounds,3 can be synthesized directly from naph-
thofuran derivatives.4
However, the two most widespread and popular synthetic
approaches for the synthesis of the naphthofuran nucleus
are based on intramolecular cyclization of the corresponding
carboxy 2-benzylfurans (Scheme 1). Cyclization of the
OR
COOH
A
R
R
O
O
O
O
A number of methods for construction of the naphthofuran
framework are known. Thus, authors5 have demonstrated
some pathways to annulate furan ring directly onto the
OR
HOOC
B
R
R
Keywords: Furan; Cyclization; 9-Furylnaphtho[2,3-b]furan.
* Corresponding author. Tel.: +7 861 2559556; fax: +7 861 2596592;
e-mail: alexander_butin@mail.ru
Scheme 1.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.027

8046
A. V. Butin et al. / Tetrahedron 62 (2006) 8045–8053
ortho-carboxy group in the benzene part of the molecule
onto the b-position of the furan ring4 (path A) and b-carboxy-
furan cyclization onto the ortho-position of the aromatic
ring3b,6 (path B) eventually leads to the formation of the
naphthofuran framework. For our synthesis of new naphtho-
furan derivatives with potential biological activity, the reac-
tion in pathway A (Scheme 1) was employed.
derivatives of 2-formylbenzoic acid 1 and 2-alkylfuran 2 in
the presence of catalytic amounts of 70% perchloric acid
in dry 1,4-dioxane at 65–70 ꢀC (Scheme 2).9
Benzaldehydes 6, which served as precursors for the 4-un-
substituted 9-furylnaphthofurans 7, were obtained by reduc-
tion of benzoic acids 3 into alcohols 4 with subsequent mild
oxidation (Scheme 3). The last cyclization catalyzed by
hydrogen chloride in ethanol furnished the desired naphtho-
furans (Table 1).
2. Results and discussion
2.1. Synthesis of derivatives of 9-furylnaphtho-
[2,3-b]furan
The structure and spatial orientation of compound 7a was
unambiguously proved by X-ray crystallography (Fig. 1).
In a monocrystal of compound 7a, two independent mole-
In this article, we disclose our results on the synthesis and
transformations of the 9-furylsubstituted naphthofurans 4
and 7. Preliminary results were reported earlier.7 It is known
that the furan cycle can easily undergo different kinds of
transformations8 and therefore it is a very attractive substitu-
ent for the introduction into naphthofuran ring system.
Table 1. Naphthofuran synthesis via cyclization of compounds 3 and 6
4–7
R
R1
R2
Yield, %
4
5
6
7
a
b
c
d
e
f
H
H
H
H
H
H
Cl
Me
Me
Me
Et
t-Bu
Me
31
30.5
33
28
32
31
92
96
93
93
—
—
70
61
60
67
—
—
37
42
39
27
—
—
Cl
Br
Br
Br
H
The synthesis of 4-acetoxy-9-furylnaphthofurans 4 was ac-
complished according to the known procedure.4a,b As key
starting compounds, we used ortho-carboxybenzylfurans 3,
that are readily available via the reported condensation of
R
COOH
CHO
HClO4
+
R2
R1
1,4-dioxane
64-72%
O
1
2
OAc
COOH
R
R
R2
R2
R1
R1
O
O
ZnCl2
Ac2O, AcOH
28-33%
O
O
R2
R2
3
4
Scheme 2.
OH
R
COOH
R
R2
R2
LiAlH4
R1
PCC
O
R1
O
Et2O
CH2Cl2
60-70%
O
O
92-96%
R2
R2
3
5
R
CHO
R
R2
R2
R1
O
HCl
R1
O
EtOH
27-42%
O
O
R2
R2
6
7
Scheme 3.

A. V. Butin et al. / Tetrahedron 62 (2006) 8045–8053
8047
Figure 1. The X-ray crystal structure of two conformationally independent molecules of naphthofuran 7a.
cules were detected with different orientation of the furan
ring with regard to the naphthofuran framework.
an introduction of different reactive groups into compounds
4 and 7.
In both molecules, the naphthofuran fragment is planar
(plane 1). In molecule B, the furan cycle O2a–C14a–
C15a–C16a–C17a is rotated to 40.7ꢀ relative to the plane 1
with oxygen atoms faced as ‘one toward the other’. In
molecule A, furan O2–C14–C15–C16–C17 is rotated to
41.3ꢀ relative to the plane 1 with oxygen atoms ‘one against
the other’.
Having taken into account the free activated position 4 in
naphthofurans 7, we investigated some electrophilic reac-
tions of the title compounds. Formylation of compound 7b
using Vilsmeier reaction conditions selectively gave rise to
aldehyde 8 (73% yield). In turn, acylation of the same com-
pound with acetyl chloride in the presence of AlCl3 gave
monoacetylated 9 and bisacetylated products 10 in the ratio
of 1:2 and 39% overall yield (Scheme 4). The disappearance
of the signal at 6.3 ppm in 1H NMR spectrum of compound
10 was attributed to the presence of the acetyl group in the
4-position of the furan substituent.
2.2. Reactions of 9-furylnaphtho[2,3-b]furans
Literature reports on the reactivity of naphthofuran deriva-
tives are scarce. As mentioned above, naphthofuran deriva-
tives are rather widespread in nature and some natural and
synthetic naphthofurans possess biological activity. There-
fore, the search for new transformations of naphthofurans
and screening of the obtained compounds for biological
activity evaluation is of great importance. Aiming at further
functionalization of the naphthofuran nucleus, we attempted
Nitration of 9-furylnaphthofurans 7a,b with potassium ni-
trate in glacial acetic acid gave rise to new nitro derivatives
of naphthofurans 11a,b. As expected, nitration took place at
position 4 of the naphthofuran framework (Scheme 5).
Unexpectedly, the same nitro compound 11b was obtained
in the attempted nitrosation of compound 7b with sodium
H
O
Cl
O
I
O
Cl
73%
O
8
O
II
Ac
Ac
Cl
Cl
39%
7b
in ratio 1 : 2
+
O
O
O
O
I: DMF; POCl3
II: AcCl; AlCl3
Ac
9
10
Scheme 4.

8048
A. V. Butin et al. / Tetrahedron 62 (2006) 8045–8053
Cl
nitrite and acetic acid. To the best of our knowledge, the
nitration of the electron-rich aromatic and heterocyclic sys-
tems under similar conditions is well documented.10 It was
shown that this reaction starts with single electron transfer
from the substrate to the nitrogen oxides or nitrosonium cat-
ion with formation of the radical cation of the substrate. The
intermediate radical cation can react further with nitrite-
anion or nitrogen dioxide with the formation of the radical
or cationic complex with subsequent aromatization into
the nitro compound. The distinct reaction pathway depends
on the spin density distribution in the initially formed radical
cation and this study is under investigation.
Cl
PCC
O
O
CH2Cl2
35%
O
O
O
7b
13
Scheme 7.
3. Conclusion
The elaborated synthetic pathways allow broadening the
range of available naphthofuran derivatives. The structure
and spatial orientation of the molecules in the single crystal
of 2-methyl-9-(5-methyl-2-furyl)naphtho[2,3-b]furan (7a)
were studied by X-ray crystallography. Electrophilic substi-
tution reactions onto the 4-position of the naphthofuran
framework were studied as well as oxidative furan ring-
opening reactions. Further research on reactivity of the
obtained compounds is in progress.
NO2
R
R2
R
KNO3 or NaNO2
R2
R1
O
R1
O
AcOH
30-52%
O
O
R2
R2
7a,b
11a,b
a: R = H, R1 = H, R2 = Me
b: R = Cl, R1 = H, R2 = Me
4. Experimental
4.1. General
Scheme 5.
Nitration of 4-acetoxynaphthofuran 4a, in which the 4-posi-
tion susceptible to the electrophilic attack is already occu-
pied, with potassium nitrate in glacial acetic acid gave
compound 12 rather than any nitro compound (Scheme 6).
The structure of the compound was confirmed by the exis-
tence of 1H doublets at d 7.02 and 7.70 ppm in the NMR
spectrum with spin–spin splitting constant of J¼15.9 Hz,
which is typical for vicinal olefinic protons in trans orienta-
tion. Compound 12 resulting from the oxidative ring opening
of the furan ring in the 9-position of the naphthofuran was
also obtained from an alternative synthesis (Scheme 6).
For this purpose, the PCC or MMPP, common oxidants for
the synthesis of 1,4-unsaturated diketones from the furan
derivatives, were used.11
1
Melting points are uncorrected. H NMR spectra were re-
corded in CDCl3 on a Bruker AC 200 spectrometer at
200 MHz. Chemical shifts are reported in parts per million
relatively to the tetramethylsilane as an internal standard
and coupling constants (J) are given in absolute values in
Hertz to the nearest 0.1 Hz. 13C NMR spectra were recorded
on a Bruker AM300 (50.32 MHz) at ambient temperature in
CDC13. Mass spectra were recorded on a Kratos MS-30
instrument with 70 eV electron impact ionization at 200 ꢀC.
IR spectra were recorded on InfraLUM FT-02. Column
chromatography was carried out using silica gel KSK
(50–160 mkm) manufactured by LTD Sorbpolymer. Single
crystal suitable for X-ray crystallography was grown from
hexane.
OAc
4.1.1. General procedure for the preparation of naphtho-
furans 4. A mixture of 3 (1.0 mmol), acetic acid (2 mL),
acetic anhydride (2 mL), and ZnCl2 (2–4 mg) as catalyst
was refluxed until completion of the reaction (monitored
with TLC). The reaction mixture was poured into water
(10 mL), neutralized with NaHCO3, and extracted with
CH2Cl2 (3ꢁ10 mL). The organic layer was separated, dried
over Na2SO4, treated with active charcoal, and filtered off.
The solvent was removed in rotatory evaporator, and the
residue was purified on silica gel column with hexane–
CH2Cl2 (4:1) as an eluent. The solvent was removed in rota-
tory evaporator and the residue was recrystallized from
CH2Cl2–hexane.
OAc
a, b or c
O
O
34-50%
O
O
O
4a
12
a: KNO3 / AcOH
b: MMPP / benzene
c: PCC / CH2Cl2
Scheme 6.
4.1.1.1. 2-Methyl-9-(5-methyl-2-furyl)naphtho[2,3-b]-
furan-4-yl acetate (4a). Yield 100 mg, 31% as colorless
crystals; mp 145–147 ꢀC; IR (KBr): 1753, 1366, 1224,
The furan ring opening was also observed in the case of the
4-unsubstituted naphthofurans 7. It was shown that treat-
ment of compound 7b with pyridinium chlorochromate in
methylene chloride gave corresponding unsaturated di-
ketone 13 with 36% yield (Scheme 7).
1195, 1159, 1068, 1008, 948, 780, 753, 726 cmꢂ1 1H
;
NMR (CDCl3) d 2.50 (s, 3H, CH3), 2.52 (s, 3H, CH3),
2.54 (s, 3H, CH3), 6.27 (d, J¼3.1 Hz, 1H, 4-HFur), 6.40 (s,

A. V. Butin et al. / Tetrahedron 62 (2006) 8045–8053
8049
1H, 3-H), 6.88 (d, J¼3.1 Hz, 1H, 3-HFur), 7.47–7.54 (m, 2H,
6-H, 7-H), 7.95–8.00 (m, 1H, 5-H), 8.54–8.59 (m, 1H, 8-H);
13C NMR (CDCl3) d 13.9, 14.5, 20.8, 99.9, 107.5, 108.3,
113.0, 120.8, 122.5, 123.6, 124.5, 125.5, 126.3, 128.9,
136.5, 146.3, 151.5, 152.5, 158.5, 168.9. MS: m/z (%) 320
(M+, 10), 278 (100), 235 (19), 189 (14), 178 (20). Anal.
Calcd for C20H16O4: C, 74.99; H, 5.03. Found: C, 75.05;
H, 5.10.
J¼1.9, 9.3 Hz, 1H, 7-H), 8.09 (d, J¼1.9 Hz, 1H, 5-H),
8.60 (d, J¼9.3 Hz, 1H, 8-H); 13C NMR (CDCl3) d 20.9,
28.8 (3C), 29.3 (3C), 33.0, 33.4, 96.3, 104.0, 109.0, 112.8,
118.7, 123.0, 123.4, 124.9, 126.7, 128.3, 128.5, 129.7,
135.6, 146.0, 151.0, 164.6, 168.7. MS: m/z (%) 482/484
(M+, 11/10), 440/442 (67/62), 425/427 (100/98). Anal.
Calcd for C26H27BrO4: C, 64.93; H, 6.26. Found: C,
65.01; H, 6.20.
4.1.1.2. 6-Chloro-2-methyl-9-(5-methyl-2-furyl)naph-
tho[2,3-b]furan-4-yl acetate (4b). Yield 110 mg, 30.5%
as colorless crystals; mp 140–143 ꢀC; IR (KBr): 1751,
4.1.1.6. 7-Chloro-2-methyl-9-(5-methyl-2-furyl)naph-
tho[2,3-b]furan-4-yl acetate (4f). Yield 110 mg, 31% as
colorless crystals; mp 166–168 ꢀC; IR (KBr): 1751, 1616,
1541, 1396, 1356, 1342, 1220, 1186, 1118, 1067, 1008,
1
1195, 1008, 905, 860, 795, 775, 730, 563 cmꢂ1; H NMR
(CDCl3) d 2.50 (s, 3H, CH3), 2.52 (s, 3H, CH3), 2.55 (s,
3H, CH3), 6.27 (d, J¼3.1 Hz, 1H, 4-HFur), 6.38 (s, 1H,
3-H), 6.89 (d, J¼3.1 Hz, 1H, 3-HFur), 7.42 (dd, J¼2.1,
9.3 Hz, 1H, 7-H), 7.94 (d, J¼2.1 Hz, 1H, 5-H), 8.54 (d,
J¼9.3 Hz, 1H, 8-H); 13C NMR (CDCl3) d 13.9, 14.5, 20.8,
100.1, 107.6, 108.6, 113.5, 119.7, 123.5, 124.4, 126.2,
126.9, 128.3, 130.6, 135.5, 145.9, 151.3, 152.8, 159.1,
168.6. MS: m/z (%) 354/356 (M+, 10/3), 312/314 (100/33),
277 (44), 269 (15), 189 (10), 178 (14), 149 (13). Anal. Calcd
for C20H15ClO4: C, 67.71; H, 4.26. Found: C, 67.78; H, 4.20.
949, 977, 884, 813, 783, 739 cmꢂ1 1H NMR (CDCl3)
;
d 2.51 (s, 3H, CH3), 2.52 (s, 3H, CH3), 2.54 (s, 3H, CH3),
6.29 (d, J¼3.1 Hz, 1H, 4-HFur), 6.38 (s, 1H, 3-H), 6.91 (d,
J¼3.1 Hz, 1H, 3-HFur), 7.41 (dd, J¼1.9, 9.0 Hz, 1H, 6-H),
7.90 (d, J¼9.0 Hz, 1H, 5-H), 8.62 (d, J¼1.9 Hz, 1H, 8-H);
13C NMR (CDCl3) d 13.9, 14.5, 20.8, 100.0, 107.6, 107.9,
113.4, 122.1, 122.6, 122.8, 125.2, 125.4, 129.3, 131.5,
136.6, 145.7, 152.0, 152.8, 158.8, 168.5. MS: m/z (%) 354/
356 (M+, 8/3), 312/314 (100/31), 277 (15), 269 (18), 178
(19), 149 (11). Anal. Calcd for C20H15ClO4: C, 67.71; H,
4.26. Found: C, 67.75; H, 4.22.
4.1.1.3. 6-Bromo-2-methyl-9-(5-methyl-2-furyl)naph-
tho[2,3-b]furan-4-yl acetate (4c). Yield 130 mg, 33% as
colorless crystals; mp 148–150 ꢀC; IR (KBr): 1755, 1597,
1555, 1395, 1350, 1334, 1220, 1194, 1081, 1004, 902,
4.1.2. General procedure for the preparation of alcohols
5. To a stirred suspension of benzoic acid 3 (50.0 mmol) in
anhydrous Et2O (150 mL), LiAlH4 (100.0 mmol) was added
portionwise under cooling (ꢂ3 to 0 ꢀC). The reaction was
monitored by TLC analysis, and after 5 h the mixture was
carefully poured into ice water and neutralized with 6 M
hydrochloric acid. The product was extracted with Et2O
(3ꢁ100 mL), dried with Na2SO4, treated with active char-
coal, and filtered off. The solvent was removed in rotatory
evaporator and the residue was recrystallized from hexane.
792, 778, 563 cmꢂ1 1H NMR (CDCl3) d 2.49 (s, 3H,
;
CH3), 2.52 (s, 3H, CH3), 2.55 (s, 3H, CH3), 6.27 (d,
J¼3.1 Hz, 1H, 4-HFur), 6.38 (s, 1H, 3-H), 6.89 (d,
J¼3.1 Hz, 1H, 3-HFur), 7.54 (dd, J¼2.1, 9.3 Hz, 1H, 7-H),
8.11 (d, J¼2.1 Hz, 1H, 5-H), 8.47 (d, J¼9.3 Hz, 1H, 8-H);
13C NMR (CDCl3) d 14.0, 14.5, 20.9, 100.1, 107.7, 108.7,
113.5, 118.9, 123.0, 123.5, 124.9, 127.1, 128.4, 128.7,
135.4, 145.9, 151.3, 152.8, 159.2, 168.7. MS: m/z (%) 398/
400 (M+, 17/17), 356/358 (100/98), 277 (42), 234 (18),
219 (12), 178 (13), 149 (11). Anal. Calcd for C19H15BrO4:
C, 60.17; H, 3.79. Found: C, 60.20; H, 3.72.
4.1.2.1. 2-Di(5-methyl-2-furyl)methylphenylmethanol
(5a). Yield 13 g, 92% as colorless crystals; mp 65–67 ꢀC;
IR (KBr): 3296, 1612, 1562, 1450, 1218, 1022, 1002, 951,
778 cmꢂ1; 1H NMR (CDCl3) d 1.61 (br s, 1H, OH), 2.26 (s,
6H, CH3), 4.75 (s, 2H, CH2), 5.74 (s, 1H, CH), 5.85 (d,
J¼3.2 Hz, 2H, 3-HFur), 5.89 (d, J¼3.2 Hz, 2H, 4-HFur),
7.19–7.31 (m, 3H, HAr), 7.40–7.45 (m, 1H, HAr). Anal. Calcd
for C18H18O3: C, 76.57; H, 6.43. Found: C, 76.50; H, 6.49.
4.1.1.4. 6-Bromo-2-ethyl-9-(5-ethyl-2-furyl)naphtho-
[2,3-b]furan-4-yl acetate (4d). Yield 120 mg, 28%; mp
84–86 ꢀC; IR (KBr): 1756, 1587, 1545, 1389, 1344, 1354,
1193, 1100, 1035, 903, 758 cmꢂ1 1H NMR (CDCl3)
;
d 1.34–1.50 (m, 6H, CH2CH3), 2.56 (s, 3H, COCH3),
2.79–2.92 (m, 4H, CH2CH3), 6.27 (d, J¼3.1 Hz, 1H, 4-
HFur), 6.38 (s, 1H, 3-H), 6.92 (d, J¼3.1 Hz, 1H, 3-HFur),
7.54 (dd, J¼2.1, 9.3 Hz, 1H, 7-H), 8.11 (d, J¼2.1 Hz, 1H,
5-H), 8.51 (d, J¼9.3 Hz, 1H, 8-H); 13C NMR (CDCl3)
d 11.5, 12.35, 20.9, 21.7, 22.1, 98.4, 106.1, 108.8, 113.2,
118.8, 123.0, 123.3, 124.9, 127.0, 128.4, 128.6, 135.6,
145.9, 151.2, 158.3, 164.5, 168.6. MS: m/z (%) 426/428
(M+, 14/14), 384/386 (100/93), 370/372 (56/53), 290 (10),
233 (14), 189 (16), 149 (15). Anal. Calcd for C22H19BrO4:
C, 61.84; H, 4.48. Found: C, 61.89; H, 4.42.
4.1.2.2. 5-Chloro-2-di(5-methyl-2-furyl)methylphenyl-
methanol (5b). Yield 15.5 g, 98% as colorless crystals; mp
71–72 ꢀC; IR (KBr): 3252, 1616, 1561, 1477, 1407, 1216,
1087, 1049, 1020, 880, 778 cmꢂ1; 1H NMR (CDCl3) d 1.70
(br s, 1H, OH), 2.25 (s, 6H, CH3), 4.72 (s, 2H, CH2), 5.62
(s, 1H, CH), 5.84 (d, J¼3.2 Hz, 2H, 3-HFur), 5.89 (d,
J¼3.2 Hz, 2H, 4-HFur), 7.10 (d, J¼8.3 Hz, 1H, HAr), 7.25
(dd, J¼1.8, 8.3 Hz, 1H, HAr), 7.46 (d, J¼1.8 Hz, 1H, HAr).
Anal. Calcd for C18H17ClO3: C, 68.25; H, 5.41. Found: C,
68.31; H, 5.39.
4.1.1.5.
6-Bromo-2-(tert-butyl)-9-[5-(tert-butyl)-2-
4.1.2.3. 5-Bromo-2-di(5-methyl-2-furyl)methylphenyl-
methanol (5c). Yield 16.8 g, 93% as colorless crystals; mp
75–76 ꢀC; IR (KBr): 3252, 1717, 1589, 1558, 1473, 1451,
furyl]naphtho[2,3-b]furan-4-yl acetate (4e). Yield
155 mg, 32% as colorless crystals; mp 101–103 ꢀC; IR
(KBr): 1759, 1586, 1365, 1194, 1161, 1117, 1025, 906,
1
1047, 1020, 864, 777 cmꢂ1; H NMR (CDCl3) d 1.66 (br
810, 793 cmꢂ1; H NMR (CDCl3) d 1.43 (s, 18H, CH3),
s, 1H, OH), 2.25 (s, 6H, CH3), 4.72 (s, 2H, CH2), 5.61
(s, 1H, CH), 5.85 (d, J¼3.2 Hz, 2H, 3-HFur), 5.88 (d,
J¼3.2 Hz, 2H, 4-HFur), 7.05 (d, J¼8.3 Hz, 1H, HAr), 7.39
1
2.57 (s, 3H, COCH3), 6.25 (d, J¼3.2 Hz, 1H, 4-HFur), 6.35
(s, 1H, 3-H), 6.91 (d, J¼3.2 Hz, 1H, 3-HFur), 7.53 (dd,

8050
A. V. Butin et al. / Tetrahedron 62 (2006) 8045–8053
(dd, J¼2.1, 8.3 Hz, 1H, HAr), 7.60 (d, J¼2.1 Hz, 1H, HAr).
Anal. Calcd for C18H17BrO3: C, 59.85; H, 4.74. Found: C,
59.91; H, 4.69.
Anal. Calcd for C18H15BrO3: C, 62.03; H, 4.94. Found: C,
62.08; H, 4.89.
4.1.4. General procedure for the preparation of naphtho-
furans 7. A solution of 6 (1 g) in EtOH (12 mL) was treated
with ethanolic HCl solution (2 mL) prepared by saturation of
200 g of ethanol with 100 g of gaseous HCl. The mixture
was kept at 50 ꢀC for 1 h (TLC monitoring). The reaction
mixture was poured into water (100 mL), neutralized with
NaHCO3, and extracted with CH2Cl2 (3ꢁ50 mL). The or-
ganic layer was separated, dried with Na2SO4, treated with
active charcoal, and filtered off. The solvent was removed
under reduced pressure, and the oily residue was purified
on silica gel column eluting with hexane–benzene (3:1).
The residue was recrystallized from hexane–benzene.
4.1.2.4. 5-Bromo-2-di(5-ethyl-2-furyl)methylphenyl-
methanol (5d). Yield 18 g, 93% as colorless crystals; mp
85–87 ꢀC; IR (KBr): 3266, 1556, 1473, 1401, 1365, 1181,
1
1047, 1011, 863, 775 cmꢂ1; H NMR (CDCl3) d 1.19 (t,
J¼7.6 Hz, 6H, CH2CH3), 1.68 (br s, 1H, OH), 2.58 (q,
J¼7.6 Hz, 2H, CH2CH3), 4.71 (s, 2H, CH2), 5.61 (s, 1H,
CH), 5.85 (d, J¼3.1 Hz, 2H, 3-HFur), 5.89 (d, J¼3.1 Hz,
1H, 4-HFur), 7.00 (d, J¼8.3 Hz, 1H, HAr), 7.38 (dd, J¼1.9,
8.3 Hz, 1H, HAr), 7.60 (d, J¼1.9 Hz, 1H, HAr). Anal. Calcd
for C20H21BrO3: C, 61.71; H, 5.44. Found: C, 61.78; H, 5.39.
4.1.3. General procedure for the preparation of benz-
aldehydes 6. A solution of alcohol 5 (35.5 mmol) in dry
CH2Cl2 (100 mL) was added dropwise to the suspension
of pyridinium chlorochromate (70.0 mmol) in dry CH2Cl2
(100 mL). The mixture was stirred for 6 h at rt. At the end
of the reaction (TLC monitoring), the precipitate was filtered
off and washed with hot CH2Cl2 (3ꢁ100 mL). The filtrate
was concentrated in rotatory evaporator, and the oily residue
was purified chromatographically on silica gel column with
hexane–CH2Cl2 (10:1) mixture as eluent. The fraction
containing desired benzaldehyde was concentrated to the
volume of 20 mL and left to crystallize overnight.
WARNING: Care should be taken when handling benzene as
a solvent due to its carcinogenic properties.
4.1.4.1. 2-Methyl-9-(5-methyl-2-furyl)naphtho[2,3-b]-
furan (7a). Yield 350 mg, 37% as colorless crystals; mp
59–61 ꢀC; IR (KBr): 1619, 1604, 1540, 1399, 1331, 1250,
1216, 1152, 1094, 1022, 943, 894, 879, 793, 752 cmꢂ1; 1H
NMR (CDCl3) d 2.52 (s, 3H, CH3), 2.54 (s, 3H, CH3),
6.28 (d, J¼3.1 Hz, 1H, 4-HFur), 6.50 (s, 1H, 3-H), 6.93 (d,
J¼3.1 Hz, 1H, 3-HFur), 7.39–7.52 (m, 2H, 6-H, 7-H), 7.89
(s, 1H, 4-H), 7.90–7.95 (m, 1H, 5-H), 8.57–8.61 (m, 1H,
8-H); 13C NMR (CDCl3) d 14.0, 14.5, 102.4, 107.5, 109.4,
113.0, 118.0, 123.9, 125.0, 126.1, 128.4 (2C), 130.1,
131.0, 146.9, 151.3, 152.4, 158.3. MS: m/z (%) 262 (M+,
100), 219 (66), 191 (12), 190 (23), 189 (33), 149 (19).
Anal. Calcd for C18H14O2: C, 82.42; H, 5.38. Found: C,
82.49; H, 5.43.
4.1.3.1. 2-Di(5-methyl-2-furyl)methylbenzaldehyde
(6a). Yield 7 g, 70% as colorless crystals; mp 63–65 ꢀC;
IR (KBr): 1695, 1572, 1213, 1019, 949, 871, 780, 753,
1
717, 678 cmꢂ1; H NMR (CDCl3) d 2.25 (s, 6H, CH3),
5.87 (s, 4H, HFur), 6.46 (s, 1H, CH), 7.31–7.33 (m, 1H,
HAr), 7.42–7.54 (m, 1H, HAr), 7.85–7.88 (m, 1H, HAr),
10.27 (s, 1H, CHO). Anal. Calcd for C18H16O3: C, 77.13;
H, 5.75. Found: C, 77.20; H, 5.58.
4.1.4.2. Crystal data of compound 7a. C18H14O2,
˚
monoclinic, space group P2(1)/ꢀc; a¼9.569(2) A, b¼
34.400(7) A, c¼8.457(2) A, a¼90 b¼95.90(3)ꢀ g¼90ꢀ,
˚
˚
3
V¼2769.1(10) A , Z¼8, Dcalcd¼1.258 mg/m3, F(000)¼
˚
4.1.3.2. 5-Chloro-2-di(5-methyl-2-furyl)methylbenz-
aldehyde (6b). Yield 6.8 g, 61% as colorless crystals; mp
75–77 ꢀC; IR (KBr): 1693, 1563, 1475, 1404, 1227, 1191,
1104; 5138 reflections collected, 4842 unique (Rint¼
0.0325); final R indices (4842 observed collections I>2sI):
R1¼0.0366, wR2¼0.0976; final R indices (all data): R1¼
0.1419, wR2¼0.1132. Crystallographic data (excluding
structure factors) for the structure in this article have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 295796. Cop-
ies of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uc].
Each request should be accompanied by the complete cita-
tion of this paper.
1
1109, 1022, 967, 900, 785, 721 cmꢂ1; H NMR (CDCl3)
d 2.25 (s, 6H, CH3), 5.89 (s, 4H, HFur), 6.34 (s, 1H, CH),
7.26 (d, J¼8.3 Hz, 1H, HAr), 7.49 (dd, J¼2.1, 8.3 Hz, 1H,
HAr), 7.84 (d, J¼2.1 Hz, 1H, HAr), 10.23 (s, 1H, CHO).
Anal. Calcd for C18H15ClO3: C, 68.69; H, 4.80. Found: C,
68.73; H, 4.85.
4.1.3.3. 5-Bromo-2-di(5-methyl-2-furyl)methylbenz-
aldehyde (6c). Yield 7.6 g, 60% as colorless crystals; mp
85–87 ꢀC; IR (KBr): 1699, 1562, 1476, 1278, 1232, 1187,
1020, 881, 782, 713 cmꢂ1; 1H NMR (CDCl3) d 2.25 (s, 6H,
CH3), 5.89 (s, 4H, HFur), 6.32 (s, 1H, CH), 7.19 (d, J¼
8.3 Hz, 1H, HAr), 7.64 (dd, J¼2.1, 8.3 Hz, 1H, HAr), 7.98
(d, J¼2.1 Hz, 1H, HAr), 10.22 (s, 1H, CHO). Anal. Calcd
for C18H15BrO3: C, 60.19; H, 4.21. Found: C, 60.25; H, 4.18.
4.1.4.3. 6-Chloro-2-methyl-9-(5-methyl-2-furyl)naph-
tho[2,3-b]furan (7b). Yield 400 mg, 42% as colorless crys-
tals; mp 94–96 ꢀC; IR (KBr): 1600, 1539, 1396, 1241, 1153,
1024, 943, 919, 880, 784 cmꢂ1; 1H NMR (CDCl3) d 2.51 (s,
3H, CH3), 2.54 (s, 3H, CH3), 6.29 (d, J¼3.1 Hz, 1H, 4-HFur),
6.50 (s, 1H, 3-H), 6.95 (d, J¼3.1 Hz, 1H, 3-HFur), 7.40 (dd,
J¼2.1, 9.3 Hz, 1H, 7-H), 7.78 (s, 1H, 4-H), 7.89 (d,
J¼2.1 Hz, 1H, 5-H), 8.55 (d, J¼9.3 Hz, 1H, 8-H); 13C
NMR (CDCl3) d 14.1, 14.5, 102.4, 107.6, 109.7, 113.3,
116.9, 125.6, 126.3, 126.6, 127.9, 129.6, 131.0, 131.7,
146.5, 151.0, 152.6, 158.9. MS: m/z (%) 296/298 (M+,
100/35), 253/255 (49/19), 219 (21), 218 (38), 190 (28),
4.1.3.4. 5-Bromo-2-di(5-ethyl-2-furyl)methylbenz-
aldehyde (6d). Yield 9.2 g, 67% as colorless oil; IR (KBr):
1693, 1605, 1560, 1462, 1377, 1183, 1014, 883, 789 cmꢂ1
;
1H NMR (CDCl3) d 1.17–1.22 (m, 6H, CH2CH3), 2.56–2.63
(m, 4H, CH2CH3), 5.90 (s, 4H, HFur), 6.32 (s, 1H, CH),
7.16 (d, J¼8.3 Hz, 1H, HAr), 7.63 (dd, J¼2.1, 8.3 Hz, 1H,
HAr), 7.99 (d, J¼2.1 Hz, 1H, HAr), 10.22 (s, 1H, CHO).

A. V. Butin et al. / Tetrahedron 62 (2006) 8045–8053
8051
189 (61), 149 (10). Anal. Calcd for C18H13ClO2: C, 72.85;
H, 4.42. Found: C, 72.80; H, 4.48.
the solution of acetyl chloride (400 mg, 50.5 mmol) in dry
CH2Cl2 was added and kept for 20 min. Then solution of
7b (500 mg, 1.7 mmol) in dry CH2Cl2 was added. The
mixture was stirred for 2 h at rt. At the end of the reaction
(TLC monitoring), the mixture was poured into water and
neutralized with NaHCO3. The emulsion was extracted
with CH2Cl2, combined organic layers were treated with
Na2SO4 and charcoal. The solvent was evaporated under
reduced pressure. The residue was separated by column
chromatography using silica gel (5–40 mkm) and benzene–
hexane¼2:1 as eluent to give products 9 (75 mg) and 10
(170 mg) in ratio 1:2 in total 39% yield.
4.1.4.4. 6-Bromo-2-methyl-9-(5-methyl-2-furyl)naph-
tho[2,3-b]furan (7c). Yield 370 mg, 39% as colorless crys-
tals; mp 119–121 ꢀC; IR (KBr): 1622, 1593, 1396, 1241,
1150, 1018, 960, 909, 868, 806, 775 cmꢂ1 1H NMR
;
(CDCl3) d 2.50 (s, 3H, CH3), 2.54 (s, 3H, CH3), 6.28 (d, J¼
3.1 Hz, 1H, 4-HFur), 6.50 (s, 1H, 3-H), 6.95 (d, J¼3.1 Hz,
1H, 3-HFur), 7.50 (dd, J¼2.1, 9.3 Hz, 1H, 7-H), 7.77 (s, 1H,
4-H), 8.06 (d, J¼2.1 Hz, 1H, 5-H), 8.48 (d, J¼9.3 Hz, 1H,
8-H); 13C NMR (CDCl3) d 14.0, 14.6, 102.5, 107.7, 109.7,
113.4, 116.9, 117.8, 126.5, 128.1 (2C), 130.0, 131.0, 132.2,
146.5, 150.0, 152.6, 158.9. MS: m/z (%) 340/342 (M+, 94/
100), 297/299 (45/28), 262 (14), 233 (14), 219 (27), 218
(35), 190 (32), 189 (56), 149 (28). Anal. Calcd for
C18H13BrO2: C, 63.36; H, 3.84. Found: C, 63.42; H, 3.80.
WARNING: Care should be taken when handling benzene as
a solvent due to its carcinogenic properties.
Compound 9 was isolated as yellow crystals with mp 122–
124 ꢀC; IR (KBr): 1668, 1596, 1529, 1424, 1384, 1357,
4.1.4.5. 6-Bromo-2-methyl-9-(5-ethyl-2-furyl)naphtho-
[2,3-b]furan (7d). Yield 260 mg, 27% as colorless crystals;
mp 58–60 ꢀC; IR (KBr): 1613, 1592, 1526, 1442, 1396,
1248, 1143, 1034, 933, 791 cmꢂ1 1H NMR (CDCl3)
;
d 2.51 (s, 3H, CH3), 2.55 (s, 3H, CH3), 2.78 (s, 3H, CH3),
6.29 (d, J¼3.1 Hz, 1H, 4-HFur), 6.63 (s, 1H, 3-H), 7.00 (d,
J¼3.1 Hz, 1H, 3-HFur), 7.43 (dd, J¼1.8, 9.2 Hz, 1H, 7-H),
8.28 (d, J¼1.8 Hz, 1H, 5-H), 8.60 (d, J¼9.2 Hz, 1H, 8-H);
13C NMR (CDCl3) 14.0, 14.6, 32.3, 102.5, 107.9, 112.9,
115.0, 124.0, 126.0, 126.5, 126.9, 128.3, 128.4, 130.0,
131.8, 145.6, 150.1, 153.5, 160.7, 202.1. MS: m/z (%) 338/
340 (M+, 52/27), 323/325 (100/42), 296/298 (39/19), 261
(23), 205 (13), 203 (10), 190 (26). Anal. Calcd for
C20H15ClO3: C, 70.91; H, 4.46. Found: C, 70.95; H, 4.41.
1212, 1139, 1037, 915, 894, 808, 775 cmꢂ1 1H NMR
;
(CDCl3) d 1.35–1.42 (m, 6H, CH2CH3), 2.81–2.92 (m, 4H,
CH2CH3), 6.28 (d, J¼3.2 Hz, 1H, 4-HFur), 6.50 (s, 1H, 3-
H), 6.98 (d, J¼3.2 Hz, 1H, 3-HFur), 7.52 (dd, J¼1.9,
9.3 Hz, 1H, 7-H), 7.77 (s, 1H, 4-H), 8.06 (d, J¼1.9 Hz,
1H, 5-H), 8.54 (d, J¼9.3 Hz, 1H, 8-H);13C NMR d 11.6,
12.4, 21.8, 22.1, 100.8, 106.1, 109.9, 113.2, 116.9, 117.8,
126.4, 128.0, 128.1, 130.0, 130.8, 132.2, 146.5, 150.9,
158.1, 164.3. MS: m/z (%) 368/370 (M+, 67/69), 353/355
(100/96), 297/299 (15/18), 290 (13), 262 (13), 246 (17),
231 (25), 218 (31), 203 (17), 202 (23), 190 (14), 189 (39),
176 (12), 170 (16). Anal. Calcd for C20H17BrO2: C, 65.06;
H, 4.64. Found: C, 65.02; H, 4.68.
Compound 10 was isolated as colorless crystals with mp
188–190 ꢀC; IR (KBr): 1672, 1573, 1556, 1406, 1374,
1
1154, 943, 926, 811, 687, 640 cmꢂ1; H NMR (CDCl3)
d 1.97 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.70 (s, 3H, CH3),
6.64 (s, 1H, 3-H), 7.42 (dd, J¼2.0, 9.0 Hz, 1H, 7-H), 7.70
(d, J¼9.2 Hz, 1H, 5-H), 8.01 (d, J¼2.0 Hz, 1H, 8-H), 8.50
(s, 1H, HFur); 13C NMR d 13.7, 15.9, 28.4, 31.2, 106.9,
109.3, 117.3, 121.7, 121.7, 126.7, 127.4, 127.5, 128.4,
130.8, 131.8, 148.0, 151.1, 153.8, 166.2, 193.2, 193.4.
MS: m/z (%) 380/382 (M+, 98/33), 365/367 (100/35), 337/
339 (14/3), 320 (10). Anal. Calcd for C22H17ClO4: C,
69.39; H, 4.50. Found: C, 69.45; H, 4.42.
4.1.5. Formylation and acylation of naphthofuran 7b.
4.1.5.1. 6-Chloro-2-methyl-9-(5-methyl-2-furyl)naph-
tho[2,3-b]furan-4-carbaldehyde (8). To a cooled (ꢂ1 to
0 ꢀC) solution of 7b (500 mg, 1.7 mmol) in DMF (8 mL),
POCl3 (8 mL) was added dropwise. The mixture was stirred
for 5 h at rt. At the end of the reaction (TLC monitoring), the
mixture was carefully poured into crash ice. The precipitate
obtained was filtered off, washed with water, and air-dried.
The recrystallization from diethyl ether with charcoal
afforded compound 8 as yellow crystals (400 mg, 73%).
Mp¼179–181 ꢀC; IR (KBr): 1668, 1572, 1513, 1429,
4.1.6. Nitrosation and nitration of naphthofurans 7.
4.1.6.1. 2-Methyl-9-(5-methyl-2-furyl)-4-nitronaphtho-
[2,3-b]furan (11a). To a stirred suspension of KNO3
(580 mg, 5.7 mmol) in glacial acetic acid (10 mL), a solution
of 7a (1 g, 3.8 mmol) in 20 mL acetic acid was added. The
mixture was kept at 50 ꢀC for 0.5 h (TLC monitoring). The
mixture was poured into water (100 mL), neutralized with
NaHCO3 and precipitate filtered off and recrystallized
from ethanol. Compound 11a (350 mg, 30%) was obtained
as yellow crystals with mp 157–159 ꢀC; IR (KBr): 1539,
1
1242, 1048, 1032, 893, 809, 785 cmꢂ1; H NMR (CDCl3)
d 2.51 (s, 3H, CH3), 2.52 (s, 3H, CH3), 6.28 (d, J¼3.1 Hz,
1H, 4-HFur), 7.04 (s, 1H, 3-H), 7.07 (d, J¼3.1 Hz, 1H,
3-HFur), 7.36 (dd, J¼1.6, 9.2 Hz, 1H, 7-H), 8.57 (d,
J¼9.2 Hz, 1H, 8-H), 8.98 (d, J¼1.6 Hz, 1H, 5-H), 10.68
(s, 1H, CHO); 13C NMR d 14.0, 14.6, 101.8, 108.3, 115.9,
116.7, 117.8, 122.2, 125.5, 125.9, 128.5, 130.7, 133.2,
135.5, 145.6, 149.7, 154.1, 162.6, 188.6. MS: m/z (%) 324/
326 (M+, 100/33), 295/297 (17/7), 253/255 (22/10), 218
(10), 202 (11), 189 (27). Anal. Calcd for C19H13ClO3: C,
70.27; H, 4.03. Found: C, 70.32; H, 4.08.
1
1508, 891, 786, 760, 687, 575 cmꢂ1; H NMR (CDCl3)
d 2.53 (s, 3H, CH3), 2.61 (s, 3H, CH3), 6.33 (d, J¼3.1 Hz,
1H, 4-HFur), 7.05 (s, 1H, 3-H), 7.10 (d, J¼3.1 Hz, 1H,
3-HFur), 7.56–7.60 (m, 1H, HAr), 7.66–7.70 (m, 1H, HAr),
8.71–8.79 (m, 2H, HAr); 13C NMR d 14.1, 14.7, 103.3,
108.3, 116.2, 116.5, 123.1, 124.2, 126.0 (2C), 127.0 (2C),
127.8, 127.9, 128.3, 145.1, 154.4, 162.8. MS: m/z (%) 307
(M+, 54), 278 (27), 277 (100), 235 (14), 234 (56), 203
(15), 189 (35), 178 (16), 149 (30). Anal. Calcd for
C18H13NO4: C, 70.35; H, 4.26. Found: C, 70.40; H, 4.21.
4.1.5.2. 1-[6-Chloro-2-methyl-9-(5-methyl-2-furyl)-
naphtho[2,3-b]furan-4-yl]-1-ethanone (9), 1-[5-(4-acetyl-
6-chloro-2-methylnaphtho[2,3-b]furan-9-yl)-2-methyl-3-
furyl]-1-ethanone (10). To the cooled (ꢂ7 to 0 ꢀC) stirred
suspension of AlCl3 (670 mg, 50.5 mmol) in dry CH2Cl2

8052
A. V. Butin et al. / Tetrahedron 62 (2006) 8045–8053
4.1.6.2.
6-Chloro-2-methyl-9-(5-methyl-2-furyl)-4-
overnight. Compound 12 (520 mg, 50%) was obtained as
yellow crystals.
nitronaphtho[2,3-b]furan (11b). Nitronaphthofuran 11b
was synthesized similar to 11a starting from naphthofuran
7b (yield: 430 mg, 33%) as yellow crystals with mp 211–
213 ꢀC; IR (KBr): 1596, 1539, 1494, 1319, 1233, 898,
WARNING: Care should be taken when handling benzene as
a solvent due to its carcinogenic properties.
791 cmꢂ1; H NMR (CDCl3) d 2.53 (s, 3H, CH3), 2.59 (s,
1
3H, CH3), 6.33 (d, J¼3.1 Hz, 1H, 4-HFur), 7.04 (s, 1H, 3-
H), 7.11 (d, J¼3.1 Hz, 1H, 3-HFur), 7.47 (dd, J¼2.1,
9.2 Hz, 1H, 7-HAr), 8.66 (d, J¼9.2 Hz, 1H, 5-HAr), 8.82
(d, J¼2.1 Hz, 1H, 8-HAr); 13C NMR d 14.0, 14.7, 103.6,
108.5, 116.5, 117.1, 122.2, 125.1, 126.1, 126.8, 128.7
(2C), 129.3 (2C), 134.6, 144.9, 154.8, 163.5. MS: m/z (%)
341/343 (M+, 100/36), 311/313 (75/36), 295/297 (25/11),
189 (14). Anal. Calcd for C18H12ClNO4: C, 63.26; H,
3.54. Found: C, 63.31; H, 3.50.
4.1.7.3. 2-Methyl-9-[(E)-4-oxo-2-pentenoyl]naphtho-
[2,3-b]furan-4-yl acetate (12) oxidation by MMPP. To
a solution of naphthofuran 4a (1 g, 3.1 mmol) in dry benzene
(50 mL), MMPP (15.3 g, 31.0 mmol) was added. The
mixture refluxed for 5 h. At the end of the reaction (TLC
monitoring), the phthalic acid was filtered off and washed
with hot benzene. The benzene extracts were combined
and washed with hot water. Then benzene solution concen-
trated in vacuum. The product was recrystallized from the
hexane–benzene mixture. Compound 12 (360 mg, 34%)
was obtained as yellow crystals.
4.1.6.3. 6-Chloro-2-methyl-9-(5-methyl-2-furyl)-4-nitro-
naphtho[2,3-b]furan (11b) by nitration with NaNO2. To
a stirred solution of 7b (500 mg, 1.7 mmol) in glacial acetic
acid (10 mL), NaNO2 (160 mg, 2.3 mmol) was added. The
mixture was kept at rt for 0.5 h (TLC monitoring). The reac-
tion mixture was poured into water (100 mL), neutralized
with NaHCO3, and filtered off. The residue was recrystal-
lized from acetone. Compound 11b (300 mg, 52%) was
obtained as yellow crystals with mp 211–213 ꢀC.
WARNING: Care should be taken when handling benzene as
a solvent due to its carcinogenic properties.
4.1.7.4.
(E)-1-(6-Chloro-2-methylnaphtho[2,3-b]-
furan-9-yl)-2-pentene-1,4-dione (13). A solution of naph-
thofuran 7b (1 g, 3.4 mmol) in dry CH2Cl2 (20 mL) was
added dropwise to the suspension of pyridinium chloro-
chromate (3.6 g, 16.8 mmol) in dry CH2Cl2 (20 mL). The
mixture was stirred for 60 h at rt. At the end of the reaction
(TLC monitoring), the precipitate was filtered off and
washed with hot CH2Cl2 (3ꢁ50 mL). The filtrate was con-
centrated in vacuum, and the oily residue was purified chro-
matographically on silica gel eluting with hexane–benzene
(3:1). The eluate was concentrated to the volume of 10 mL
and left to crystallize overnight. Compound 13 (370 mg,
35%) was obtained as yellow crystals with mp 124–
126 ꢀC; IR (KBr): 1694, 1661, 1492, 1400, 1337, 1285,
4.1.7. Oxidation of naphthofurans.
4.1.7.1. 2-Methyl-9-[(E)-4-oxo-2-pentenoyl]naphtho-
[2,3-b]furan-4-yl acetate (12) (oxidation with nitric
acid). To
a stirred suspension of KNO3 (470 mg,
4.7 mmol) in glacial acetic acid (10 mL), the solution of
4a (1 g, 3.1 mmol) in 20 mL acetic acid was added. The
mixture was kept at 50 ꢀC for 1 h (TLC monitoring). The
mixture was poured into water (100 mL), neutralized with
NaHCO3, and the precipitate was filtered off. The residue
was recrystallized from ethanol. Compound 12 (520 mg,
50%) was obtained as yellow crystals with mp 188–
190 ꢀC; IR (KBr): 1764, 1683, 1659, 1582, 1508, 1375,
1247, 1170, 1122, 1006, 971, 868, 807, 769, 728,
1
1241, 1094, 918, 886, 791 cmꢂ1; H NMR (CDCl3) d 2.44
(s, 3H, CH3), 2.54 (s, 3H, CH3), 6.54 (s, 1H, 3-H), 6.98 (d,
J¼15.9 Hz, 1H, HC]CH), 7.45 (dd, J¼2.0, 9.2 Hz, 1H,
7-H), 7.69 (d, J¼15.9 Hz, 1H, HC]CH), 7.90 (d,
J¼2.0 Hz, 1H, 5-H), 7.97 (s, 1H, 4-H), 9.37 (d, J¼9.2 Hz,
1H, 8-H); 13C NMR (CDCl3) d 14.5, 28.5, 102.4, 115.8,
122.1, 126.4, 126.8, 126.9, 127.7, 130.5, 131.2, 131.3,
138.0, 139.0, 153.2, 159.5, 191.5, 198.5. MS: m/z (%)
312/314 (M+, 67/25), 269/271 (76/25), 243/245 (100/27),
187/189 (40/13), 152 (74). Anal. Calcd for C18H13ClO3:
C, 69.13; H, 4.19. Found: C, 69.20; H, 4.15.
1
563 cmꢂ1; H NMR (CDCl3) d 2.43 (s, 3H, CH3), 2.52 (s,
3H, CH3), 2.56 (s, 3H, CH3), 6.43 (s, 1H, 3-H), 7.02 (d,
J¼15.9 Hz, 1H, HC]CH), 7.50–7.61 (m, 2H, 6-H, 7-H),
7.70 (d, J¼15.9 Hz, 1H, HC]CH), 8.00–8.03 (m, 1H,
5-H), 8.46–8.49 (m, 1H, 8-H); 13C NMR (CDCl3) d 14.4,
20.8, 28.4, 100.1, 114.6, 121.2, 122.5, 123.7, 125.2, 125.3,
127.5, 129.1, 137.9, 139.1, 140.5, 153.9, 158.8, 168.2,
191.0, 198.4. MS: m/z (%) 336 (M+, 26), 295 (38), 294
(100), 252 (17), 251 (85), 225 (72), 197 (20), 169 (27).
Anal. Calcd for C20H16O5: C, 71.42; H, 4.79. Found: C,
71.48; H, 4.83.
WARNING: Care should be taken when handling benzene as
a solvent due to its carcinogenic properties.
4.1.7.2. 2-Methyl-9-[(E)-4-oxo-2-pentenoyl]naphtho-
[2,3-b]furan-4-yl acetate (12) (oxidation with PCC). A
solution of naphthofuran 4a (1 g, 3.1 mmol) in dry CH2Cl2
(20 mL) was added dropwise to the suspension of pyri-
dinium chlorochromate (4 g, 18.8 mmol) in dry CH2Cl2
(20 mL). The mixture was stirred for 60 h at rt. At the
end of the reaction (TLC monitoring), the precipitate was
filtered off and washed with hot CH2Cl2 (3ꢁ50 mL). The
filtrate was concentrated in rotatory evaporator, and the
oily residue was purified chromatographically on silica gel
eluting with hexane–benzene (3:1). The eluate was
concentrated to the volume of 10 mL and left to crystallize
Acknowledgements
Financial support was provided by Bayer HealthCare AG
and the Russian Foundation of Basic Research (grant 03-
03-32759). We also thank Dr. Valery E. Zavodnik for
X-ray analysis.
References and notes
1. (a) Correa, J.; Romo, J. Tetrahedron 1966, 22, 685–691;
(b) Abdo, S.; Bernardi, M.; Marinoni, G.; Mellerio, G.;

A. V. Butin et al. / Tetrahedron 62 (2006) 8045–8053
8053
Samaniego, S.; Vidari, G.; Finzi, P. V. Phytochemistry 1992, 31,
3937–3941; (c) Doe, M.; Hirai, Y.; Kinoshita, T.; Shibata, K.;
Haraguchi, H.; Morimoto, Y. Chem. Lett. 2004, 33, 714–715.
2. (a) Cavier, R.; Buisson, J.-P.; Lemoine, J.; Royer, R. Eur. J.
Med. Chem. 1981, 16, 73–76; (b) Weill-Thevenet, N.;
Buisson, J.-P.; Royer, R.; Hofnung, M. Mutat. Res. 1981, 88,
355–362; (c) Nocentini, S.; Coppey, J.; Buisson, J.-P.; Royer,
R. Mutat. Res. 1981, 90, 125–135; (d) Gruest, J.; Montagnier,
L.; Buisson, J.-P.; Royer, R. Bull. Cancer 1981, 68, 328–331;
(e) Cavier, R.; Buisson, J.-P.; Royer, R. Eur. J. Med. Chem.
1982, 17, 91–92; (f) Weill-Thevenet, N.; Buisson, J.-P.;
Royer, R.; Hofnung, M. Mutat. Res. 1982, 104, 1–8; (g)
Averbeck, D.; Moradi, M.; Buisson, J.-P.; Royer, R. C. R.
Acad. Sci., Ser. C 1982, 295, 181–184; (h) Golde, A.;
Rouillard, D.; Buisson, J.-P.; Royer, R. Antimicrob. Agents
Chemother. 1983, 23, 328–331; (i) Amgar, A.; Cavier, R.;
Buisson, J.-P.; Royer, R. Ann. Pharm. Fr. 1983, 41, 283–285;
(j) Einhorn, J.; Lamotte, G.; Buisson, J.-P.; Demerseman, P.;
Royer, R.; Cavier, R. Eur. J. Med. Chem. 1984, 19, 143–147;
(k) Buisson, J.-P.; Royer, R.; Gayral, P. Eur. J. Med. Chem.
1984, 19, 249–253; (l) Venegas, M.; Sala, M.; Buisson, J.-P.;
Royer, R.; Chouroulinkov, I. Cancer Res. 1984, 44, 1969–
1975; (m) Su, Z. Z.; Cornelis, J. J.; Rommelaere, J.
Carcinogenesis 1981, 2, 1039–1043; (n) Quillardet, P.;
Huisman, O.; d’Ari, R.; Hofnung, M. Biochimie 1982, 64,
797–801; (o) Quillardet, P.; Huisman, O.; d’Ari, R.; Hofnung,
M. Proc. Natl. Acad. Sci. U.S.A. 1982, 79, 5971–5975; (p)
Le Francois-Chabas, D.; Montagnier, L. C. R. Acad. Sci.,
Ser. C 1983, 296, 283–286.
Snieckus, V.; Zani, C. L.; Romanha, A. J. Bioorg. Med.
Chem. Lett. 1995, 5, 1509–1512.
4. (a) Zani, C. L.; Oliveria, A. B.; Snieckus, V. Tetrahedron Lett.
1987, 28, 6561–6564; (b) Starling, S. M.; Raslan, D. S.;
Oliveira, A. B.; Zani, C. L. Synth. Commun. 1998, 28, 3567–
3578; (c) Starling, S. M.; Raslan, D. S.; Oliveira, A. B. Synth.
Commun. 1998, 28, 1013–1030; (d) Lopes, C. C.; Lopes,
R. S. C.; Pinto, A. V.; Costa, P. R. R. J. Heterocycl. Chem.
1984, 21, 621–622.
5. (a) Narasimhan, N. S.; Mali, R. S. Tetrahedron 1975, 31, 1005–
1009; (b) Ghera, E.; Maurya, R. Tetrahedron Lett. 1987, 28,
709–712; (c) Lee, T. V.; Galan, A. A.; Chapleo, C. B.
Tetrahedron Lett. 1987, 28, 2301–2302; (d) Halton, B.; Jones,
C. S.; Margetic, D. Tetrahedron 2001, 57, 3529–3536; (e)
Einhorn, J.; Demerseman, P.; Royer, R. J. Heterocycl. Chem.
1985, 22, 1243–1247.
6. (a) Ohta, Y.; Doe, M.; Morimoto, Y.; Kinoshiya, T. J. Hetero-
cycl. Chem. 2000, 37, 731–734; (b) Perry, P. J.; Pavlidis,
V. H.; Hadfield, J. A. Tetrahedron 1997, 53, 3195–3204.
7. Mel’chin, V. V.; Abaev, V. T.; Butin, A. V.; Krapivin, G. D.
J. Heterocycl. Chem. 2005, 42, 1429–1431.
8. See the following reviews: (a) Dean, F. M. Adv. Heterocycl.
Chem. 1982, 30, 167–238; (b) Dean, F. M. Adv. Heterocycl.
Chem. 1982, 31, 237–344; (c) Piancatelli, G.; D’Auria, M.;
D’Onofrio, F. Synthesis 1994, 867–889.
9. Gutnov, A. V.; Abaev, V. T.; Butin, A. V.; Dmitriev, A. S. J. Org.
Chem. 2001, 66, 8685–8686.
10. See the following review: Morkovnik, A. S. Usp. Khim. 1988,
57, 254–280; [Russ. Chem. Rev. (Engl. Transl.) 1988, 57,
144–160].
11. (a) Piancatelli, G.; Scettry, A.; D’Auria, M.; D’Onofrio, F.
Synthesis 1982, 245–258; (b) Piancatelli, G.; Scettry, A.;
D’Auria, M.; D’Onofrio, F. Tetrahedron 1980, 36, 661–663.
3. (a) Rao, M. M.; Kingston, D. G. J. Nat. Prod. 1982, 45, 600–
604; (b) Perry, P. J.; Pavlidis, V. H.; Hadfield, J. A.; Coutts,
I. G. C. J. Chem. Soc., Perkin Trans. 1 1995, 1085–1087; (c)
Ribeiro-Rodrigues, R.; Santos, W. G.; Oliveira, A. B.;