Synthesis and cytotoxic evaluation of α-methylene-γ-butyrolactone bearing naphthalene and naphtho[2,1-b]furan derivatives

Article abstract of DOI:10.1016/S0223-5234(02)01354-5

Naphthalene α-methylene-γ-butyrolactones exhibits a unique cytotoxicity profile. They are highly cytostatic for leukaemia cancer cells but are not cytocidal. For almost all the solid tumours tested, they are both cytostatic and cytocidal. Substitution of a bromo atom on either naphthalene or both naphthalene and γ-phenyl moiety of the lactone enhanced potency while retaining the same cytotoxicity profile. The tricyclic naphtho[2,1-b]furan derivatives, prepared from 2-hydroxy-1-naphthaldehyde in an efficient pathway, also possess the same cytotoxicity profile.

Full text of DOI:10.1016/S0223-5234(02)01354-5

Eur. J. Med. Chem. 37 (2002) 333–338
www.elsevier.com/locate/ejmech
Laboratory note
Synthesis and cytotoxic evaluation of a-methylene-g-butyrolactone
bearing naphthalene and naphtho[2,1-b]furan derivatives
Kuan-Han Lee a,*, Bor-Ruey Huang b
a Department of Pharmacy, Tajen Institute of Technology, 20, Wei-Shih Rd, Shir-Ell Tsun, Pingtung, Taiwan
b School of Chemistry, Kaohsiung Medical Uni6ersity, Kaohsiung 807, Taiwan
Received 17 October 2001; accepted 25 February 2002
Abstract
Naphthalene a-methylene-g-butyrolactones exhibits a unique cytotoxicity profile. They are highly cytostatic for leukaemia
cancer cells but are not cytocidal. For almost all the solid tumours tested, they are both cytostatic and cytocidal. Substitution of
a bromo atom on either naphthalene or both naphthalene and g-phenyl moiety of the lactone enhanced potency while retaining
the same cytotoxicity profile. The tricyclic naphtho[2,1-b]furan derivatives, prepared from 2-hydroxy-1-naphthaldehyde in an
´
efficient pathway, also possess the same cytotoxicity profile. © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights
reserved.
Keywords: cytotoxicity; naphtho[2,1-b]furan; naphthalene; a-methylene-g-butyrolactone
naphthalene a-methylene-g-butyrolactone by substitu-
tion of a bromo atom on the g-phenyl moiety of the
lactone ring and/or naphthalene skeleton. Benzofuran
nucleus is found in various naturally occurring com-
pounds, and a number of their natural and synthetic
derivatives are known to exhibit interesting biological
properties [12]. Thus, the tricyclic naphtho[2,1-b]furan
derivatives, 9a and 9b, which containing the benzofuran
moiety were also synthesised from 2-hydroxy-1-naph-
thaldehyde (6) in an efficient pathway. Preparation and
cytotoxic evaluation of the title compounds are
described.
1. Introduction
The bicyclic naphthalene skeleton constitutes a large
number of clinical drugs, such as propranolol (I) [1],
naphazoline (II; a cardiovascular agent) [2], naproxen
(III) [3], nabumetone (IV; an anti-inflammatory agent)
[4] and methallenestril (V; a non-steroid oestrogen)
(Fig. 1). The a-methylene-g-butyrolactone moiety is a
characteristic component of a large number of natural
products which produce wide-ranging biological activi-
ties, including antitumour, bactericidal, fungicidal, an-
tibiotic, and anthelminthic properties [5–7]. Recently,
we have reported certain a-methylene-g-butyrolactone
bearing uracil (VI) [8,9], naphthalene (VII), quinoline
(VIII), and quinolin-2(1H)-one (IX) as potential antitu-
mour agents [10,11] (Fig. 2). Although quinolin-2(1H)-
one a-methylene-g-butyrolactones were the most
cytotoxic, naphthalene derivatives, 1 and 2 (Fig. 3), also
exhibited a distinct cytotoxicity profile. They are cyto-
static for leukaemia cancer cells but are both cytostatic
and cytocidal for most of the solid tumours tested. To
optimise the potency and retain their cytotoxicity
profile, structural modifications were carried out on
2. Chemistry
Synthesis of 2-[(1-bromonaphthalen-2-yloxy)methyl]-
2,3,4,5-tetrahydro-4-methylene-5-oxo-2-phenylfuran
(5a) and its derivatives, 5b and 5c, is illustrated in Fig.
4. 1-Bromo-2-naphthol (3) was treated with K2CO3 and
2-bromoacetophenone to give 2-(1-bromonaphthalen-2-
yloxy)-1-phenylethan-1-one (4a) in 72% yield. Accor-
dingly, 4b and 4c were prepared in a yield of 73 and
79%, respectively, from 3 and 4-substituted 2-bro-
moacetophenones. Reformatsky-type condensation of
4a–c to afford the target 5a–c proceeded smoothly in a
* Correspondence and reprints:.
E-mail address: khlee@ccsun.tajen.edu.tw (K.-H. Lee).
´
0223-5234/02/$ - see front matter © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S0223-5234(02)01354-5

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K.-H. Lee, B.-R. Huang / European Journal of Medicinal Chemistry 37 (2002) 333–338
Fig. 1. The bicyclic naphthalene skeleton containing propanolol (I), naphazoline (II), naproxen (III), nabumetone (IV), and methallenestril (V).
fairly good yield (83, 72 and 81%, respectively). Synthe-
sis of compounds 1 and 2 was previously reported [11].
Preparation of naphtho[2,1-b]furan a-methylene-g-
butyrolactones 9a and 9b is depicted in (Fig. 5). 2-Hy-
droxy-1-naphthaldehyde (6) was alkylated with
chloroacetone under basic condition to give 1-methyl-2-
(1-naphthaldehyde-2-yloxy)ethan-1-one (7) as an inter-
mediate which immediately cyclised through an
intramolecular Aldol-type condensation to afford 1-
(naphtho[2,1-b]furan-2-yl)ethan-1-one (8a) in a 76%
yield [13–16]. Compound 8a was previously synthesised
from the reaction of 2-naphthol and 3,4-dibromobutan-
2-one followed by oxidation with DDQ in an overall
yield of 54% [17]. Naphtho[2,1-b]furan-2-yl phenyl
methanone (8b), formerly synthesised by the condensa-
tion of 2-methoxy-1-naphthaldehyde and acetophenone
[18] followed by copper (II)-mediated photocyclisation
[19] in a 51% overall yield. This compound can be
easily obtained in 87% from 6 and 2-bromoacetophe-
none in one step. Reformatsky-type condensation of 8a
and 8b afforded the desired 9a and 9b, respectively.
Fig. 2. a-Methylene-g-butyrolactone bearing uracil (VI), naphthalene
(VII), quinoline (VIII), and quinolin-2(1H)-one (IX) derivatives.

K.-H. Lee, B.-R. Huang / European Journal of Medicinal Chemistry 37 (2002) 333–338
335
activity) compared with the control were calculated [20]
and summarised in Table 1. All these compounds
demonstrated potent growth inhibitory activities
against leukaemia cancer cells (log GI50B −5.0). a-
Methylene-g-butyrolactone
bearing
naphtho[2,1-
Fig. 3. The structure of the a-methylene-g-butyrolactone bearing
b]furans (9a and 9b) and naphthalenes (1 and 2) were
comparable in the inhibitory activity on human
leukaemia cancer cells. 1-Bromonaphthalene derivatives
5a–c exhibited a more potent growth inhibitory activity
(cytostatic) on leukaemia than the parent naphthalene
counterparts 1 and 2. The average log GI50 decreased in
an order 5c (−6.45)\5a (−6.37)\5b (−5.92)\1
(−5.81)\9a (−5.70)\2 (−5.64), 9b (−5.61). How-
ever, none of them were able to effectively cause cell
death of leukaemia (log LC50\ −4.0). For solid tu-
mours, the difference between GI50 and LC50 was rela-
tively small, indicating these a-methylene-g-butyro-
lactones were able to not only inhibit cell growth but
also kill the cells. The average log GI50 and the average
log LC50 decreased in an order 5c (−5.91; −5.33)\
naphthalene derivatives.
3. Results and discussion
All compounds were evaluated in vitro against 60
human tumour cell lines derived from nine cancer cell
types (leukaemia, non-small cell lung cancer, colon
cancer, CNS cancer, melanoma, ovarian cancer, renal
cancer, prostate cancer, and breast cancer). For each
compound, dose–response curves for each cell line were
measured with five different drug concentrations, the
concentration causing 50% cell growth inhibition (GI50;
equating to cytostatic activity) and the concentration
causing 50% cell death (LC50; equating to cytocidal
Fig. 4. Sythesis of a-methylene-g-butyrolactone bearing 1-bromonaphthalene derivatives 5a–c.
Fig. 5. Synthesis of a-methylene-g-butyrolactone bearing naphthol[2,1-b]furans 9a–b.

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K.-H. Lee, B.-R. Huang / European Journal of Medicinal Chemistry 37 (2002) 333–338
Table 1
Inhibition of in vitro human cancer cells by a-methylene-g-butyrolactones [log GI50 (log LC50)(M)] a
Cell line
1
2
5a
5b
5c
9a
9b
Leukaemia
CCRF-CEM
HL-60(TB)
K-562
−5.81 (\−4.0) −5.77 (\−4.0) −6.46 (\−4.0) −6.33 (\−4.0) −6.62 (\−4.0) −5.81 (\−4.0) −5.92 (\−4.0)
−5.76 (\−4.0) −5.86 (\−4.0) −6.67 (\−4.0) −6.51 (\−4.0) −6.76 (\−4.0) Nd b (\−4.0) −5.64 (\−4.0)
−5.43 (\−4.0) −5.57 (\−4.0) −6.27 (\−4.0) −5.78 (\−4.0) −6.23 (\−4.0) −5.58 (\−4.0) −5.56 (\−4.0)
MOLT-4
RPMI-8226
SR
−5.55 (\−4.0) −5.50 (\−4.0) −6.53 (\−4.0) −5.66 (\−4.0) −6.65 (\−4.0) nd
−5.64 (\−4.0) −5.65 (\−4.0) −6.25 (\−4.0) −5.71 (\−4.0) −6.37 (\−4.0) nd
−6.64 (\−4.0) −5.48 (\−4.0) −6.04 (\−4.0) −5.51 (\−4.0) −6.09 (\−4.0) nd
−5.50 (\−4.0)
−5.67 (\−4.0)
−5.38 (\−4.0)
L-Average c
−5.81 (\−4.0) −5.64 (\−4.0) −6.37 (\−4.0) −5.92 (\−4.0) −6.45 (\−4.0) −5.70 (\−4.0) −5.61 (\−4.0)
Solid cancers
HOP-92
KM12
−5.78 (−5.06) −5.84 (−5.04) −5.98 (−5.10) −6.38 (nd) −5.97 (nd) −5.86 (−5.22) −5.63 (−4.71)
−5.44 (−4.44) −5.66 (−4.65) −5.67 (−4.95) −5.74 (−5.06) −5.80 (−5.18) −5.69 (−4.45) −5.00 (−4.16)
−5.45 (−4.43) −5.55 (−4.57) −5.75 (−5.22) −5.74 (−5.21) −5.84 (−5.20) −5.92 (−5.26) −5.74 (−5.21)
U-251
UACC-62
IGROV1
786-0
−5.52 (−4.45) −5.30 (−4.38) −5.77 (−5.15) −5.79 (−5.16) −5.86 (−5.26)
nd
−5.39 (−4.41)
−5.79 (−5.11) −5.81 (−4.84) −5.96 (−5.25) −5.80 (−5.11) −5.94 (−5.26) −5.78 (\−4.0) −5.53 (−4.14)
−5.84 (−5.26) −5.83 (−5.25) −5.85 (−5.27) −5.84 (−5.18) −6.02 (−5.17) −5.92 (−5.26) −5.76 (−5.08)
−5.39 (−4.38) −5.19 (−4.36) −5.64 (−4.49) −5.69 (−4.74) −5.90 (−5.30) −5.79 (−5.18) −5.00 (−4.33)
PC-3
BT-549
−5.99 (−5.28) −5.72 (−4.89) −6.14 (−5.20) −5.80 (−5.22) −5.97 (nd)
−5.75 (−4.62) −5.66 (−4.70)
S-Average d
Mean e
−5.65 (−4.80) −5.61 (−4.75) −5.85 (−5.08) −5.85 (−5.10) −5.91 (−5.33) −5.82 (−4.86) −5.46 (−4.59)
−5.50 (−4.59) −5.48 (−4.52) −5.76 (−4.63) −5.71 (−4.53) −5.92 (−4.85) −5.74 (−4.64) −5.35 (−4.32)
a Data obtained from NCIs in vitro disease-oriented tumour cell screen [20]. GI50: drug molar concentration causing 50% cell growth inhibition;
LC50: drug molar concentration causing 50% cell death.
b Not determined.
c Average log GI50 and log LC50 values for six leukaemia cancer cells.
d Average log GI50 and log LC50 values for eight solid cancer cells.
e Mean values over all cell lines tested. Theses cell lines are: leukaemia (CCRF-CEM, HL-60 (TB), K-562, MOLT-4, PRMI-8226, and SR);
non-small cell lung cancer (A549/ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, and NCI-H522); colon cancer (COLC
205, HCC-2998, HCT-116, HCT-15, HT29, KM12, and SW-620); CNS cancer (SF-268, SF-295, SF-539, SNB-19, SNB-75, and U251); melanoma
(LOX IMVI, MALME-3M, M14, SK-MEL-2, SK-MEL-28, SK-MEL-5, and UACC-257); ovarian cancer (IGROV1, OVCAR-3, OVCAR-4,
OVCAR-5, OVCAR-8, and SK-OV-3); renal cancer (786-0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, and UO-31); prostate cancer (PC-3
and DU-145); and breast cancer (MCF7, MCF7/ADR-RES, MDA-MB-231/ ATCC, HS 578T, MDA-MB-435, MDA-N and T-47D).
5a (−5.85; −5.08), 5b (−5.85; −5.10)\9a (−5.82;
−4.86)\1 (−5.65; −4.80)\2 (−5.61; −4.75)\9b
(−5.46; −4.59). Among them, 2-[(1-bromonaph-
thalen-2-yloxy)methyl]-2-(4-bromophenyl)-2,3,4,5-tetra-
hydro-4-methylene-5-oxofuran (5c) is the most cyto-
toxic with a mean log GI50 value of −5.92.
of eight solid cancer cells, and a mean log GI50 value of
−5.92 against all 60 cancer cell tested.
5. Experimental protocols
5.1. Chemistry
Melting points were determined on
a Yanaco
4. Conclusion
micromelting point apparatus and are uncorrected. The
ultraviolet (UV) absorption spectra were obtained on a
Beckman UV–Visible spectrophotometer. Nuclear
magnetic resonance (NMR) (1H and 13C) spectra were
recorded on a Varian Gemini-200 spectrometer. Chemi-
cal shifts were expressed in parts per million (l) with
tetramethylsilane (TMS) as an internal standard. Thin-
layer chromatography (TLC) was run on precoated (0.2
mm) Silica gel 60 F-254 plates manufactured by EM
Laboratories, Inc., and short-wave UV light (254 nm)
was used to detect the UV-absorbing spots. Elemental
analyses were carried out in the Instrument Center of
National Science Council at National Cheng-Kung
a-Methylene-g-butyrolactone bearing naphthalene, 1-
bromonaphthalene, and naphtho[2,1-b]furan exhibited
a unique cytotoxicity profile. They are highly cytostatic
for leukaemia cancer cells but are not cytocidal. How-
ever, they are both cytostatic and cytocidal for almost
all the solid tumours tested. Among them, 2-[(1-
bromonaphthalen-2-yloxy)methyl]-2-(4-bromophenyl)-
2,3,4,5-tetrahydro-4-methylene-5-oxofuran (5c) is the
most cytotoxic with an average log GI50 value of
−6.45 against the growth of six leukaemia cancer cells,
an average log GI50 value of −5.91 against the growth

K.-H. Lee, B.-R. Huang / European Journal of Medicinal Chemistry 37 (2002) 333–338
337
University using Heraeus CHN-O-Rapid elemental
analyser, and all values are within 90.4% of the
theoretical compositions.
(3×75 mL). The CH2Cl2 extracts were combined,
washed with H2O, dried (Na2SO4), and evaporated to
give a residual solid which was crystallised from
CH2Cl2 and Et2O (1:5) to afford 5a (0.68 g, 83%). m.p.:
1
5.1.1. 2-(1-Bromonaphthalen-2-yloxy)-1-phenylethan-
1-one (4a)
160–161 °C; H-NMR (CDCl3-d): l 3.27 (dt, 1H, J=
17.0, 2.6 Hz, C-3%-H), 3.91 (dt, 1H, J=17.0, 2.6 Hz,
C-3%-H), 4.22 and 4.37 (AB type, 2H, J=10.2 Hz,
OCH2), 5.74 (t, 1H, J=2.6 Hz, CH2=C-4%), 6.34 (t,
1H, J=2.6 Hz, CH2=C-4%), 7.12–8.23 (m, 11H, Ar).
13C-NMR (CDCl3-d): l 37.30 (C-3%), 75.91 (OCH2),
84.21 (C-2%), 110.14, 115.21, 122.34, 124.84 (CH2=C-
4%), 125.22, 126.35, 127.84, 128.05, 128.55, 129.02,
130.33, 133.09, 140.39, 152.45, 169.30 (CꢀO). Anal.
Found: C, 64.23; H, 4.24. Calc. for C22H17BrO3: C,
64.57; H, 4.19%.
1-Bromo-2-naphthol (3, 2.23 g, 10 mmol), K2CO3
(1.52 g, 11 mmol) and dry DMF (20 mL) were stirred
at r.t. for 30 min. To this solution was added 2-bro-
moacetophenone (2.19 g, 11 mmol) in dry DMF (10
mL) in one portion. The resulting mixture was stirred
at r.t. for 48 h (TLC monitoring), then poured into
ice-water (100 mL), and extracted with CH2Cl2 (3×20
mL). The organic phase was washed with H2O, dried
(Na2SO4), and evaporated. The solid residue was crys-
tallised from CH2Cl2 and Et2O (1:10) to afford 4a (2.46
1
g, 72%). m.p.: 114–115 °C; H-NMR (CDCl3-d): l 5.48
5.1.5. 2-[(1-Bromonaphthalen-2-yloxy)methyl]-2,3,4,5-
tetrahydro-4-methylene-2-(1,1%-biphenyl-4-yl)-5-
oxofuran (5b)
(s, 2H, OCH2), 7.16–8.27 (m, 11H, Ar); 13C-NMR
(CDCl3-d): l 72.74 (OCH2), 110.16, 115.34, 124.84,
126.38, 127.80, 128.03, 128.26, 128.83, 128.95, 130.37,
133.15, 133.96, 134.36, 152.61, 194.19 (CꢀO). Anal.
Found: C, 63.14; H, 3.80. Calc. for C18H13BrO2: C,
63.36; H, 3.84%.
From 4b, as described for 5a: Yield 72%. m.p.:
1
108–109 °C. H-NMR (CDCl3-d): l 3.32 (dt, 1H, J=
16.9, 2.6 Hz, C-3%-H), 3.95 (dt, 1H, J=16.9, 2.6 Hz,
C-3%-H), 4.22 and 4.37 (AB type, 2H, J=10.2 Hz,
OCH2), 5.76 (t, 1H, J=2.6 Hz, CH2=C-4%), 6.36 (t,
1H, J=2.6 Hz, CH2ꢀC-4%), 7.15–8.24 (m, 15H, Ar).
13C-NMR (CDCl3-d): l 37.31 (C-3%), 75.85 (OCH2),
84.14 (C-2%), 110.15, 115.21, 122.46, 124.85 (CH2ꢀC-4%),
125.71, 126.35, 127.11, 127.44, 127.68, 127.84, 128.05,
128.87, 129.03, 130.34, 133.09, 134.56 (C-4%), 139.30,
140.22, 141.54, 152.45, 169.26 (CꢀO). Anal. Found: C,
69.30; H, 4.47. Calc. for C28H21BrO3: C, 69.29; H,
4.36%.
5.1.2. 2-(1-Bromonaphthalen-2-yloxy)-1-(1,1%-
biphenyl-4-yl)ethan-1-one (4b)
From 3 and 2-bromo-4%-phenylacetophenone as de-
1
scribed for 4a: 73% yield. m.p.: 144–145 °C; H-NMR
(CDCl3-d): l 5.51 (s, 2H, OCH2), 7.19–8.28 (m, 15H,
Ar); 13C-NMR (CDCl3-d): l 72.85 (OCH2), 110.15,
115.34, 124.83, 126.39, 127.26, 127.41, 127.81, 128.04,
128.41, 128.92, 128.97, 130.39, 133.04, 133.17, 139.64,
146.62, 152.63, 193.86 (CꢀO). Anal. Found: C, 68.85;
H, 4.31. Calc. for C24H17BrO2: C, 69.08; H, 4.11%.
5.1.6. 2-[(1-Bromonaphthalen-2-yloxy)methyl]-2-(4-
bromophenyl)-2,3,4,5-tetrahydro-4-methylene-5-
oxofuran (5c)
5.1.3. 2-(1-Bromonaphthalen-2-yloxy)-1-(4-
bromophenyl)ethan-1-one (4c)
From 4c, as described for 5a: Yield 81%. m.p.:
1
From 3 and 2-bromo-4%-bromoacetophenone as de-
138–139 °C. H-NMR (CDCl3-d): l 3.22 (dt, 1H, J=
1
scribed for 4a: 79% yield. m.p.: 129–130 °C; H-NMR
16.9, 2.6 Hz, C-3%-H), 3.89 (dt, 1H, J=16.9, 2.6 Hz,
C-3%-H), 4.22 and 4.37 (AB type, 2H, J=10.2 Hz,
OCH2), 5.75 (t, 1H, J=2.6 Hz, CH2=C-4%), 6.35 (t,
1H, J=2.6 Hz, CH2=C-4%), 7.11–8.23 (m, 10H, Ar).
13C-NMR (CDCl3-d): l 37.26 (C-3%), 75.54 (OCH2),
83.67 (C-2%), 110.14, 115.10, 122.75, 122.85, 124.93
(CH2ꢀC-4%), 126.33, 127.05, 127.90, 128.06, 129.09,
130.37, 131.90, 133.05, 134.10 (C-4%), 139.45, 152.27,
168.93 (CꢀO). Anal. Found: C, 53.95; H, 3.38. Calc. for
C22H16Br2O3: C, 54.13; H, 3.30%.
(CDCl3-d): l 5.39 (s, 2H, OCH2), 7.16–8.27 (m, 10H,
Ar); 13C-NMR (CDCl3-d): l 72.82 (OCH2), 110.16,
115.14, 124.95, 126.37, 127.90, 128.04, 129.04, 129.28,
129.93, 130.40, 132.14, 133.05, 133.12, 152.37, 193.60
(CꢀO). Anal. Found: C, 51.70; H, 2.95. Calc. for
C18H12Br2O2: C, 51.46; H, 2.88%.
5.1.4. 2-[(1-Bromonaphthalen-2-yloxy)methyl]-2,3,4,5-
tetrahydro-4-methylene-5-oxo-2-phenylfuran (5a)
To a solution of 2-(1-bromonaphthalen-2-yloxy)-1-
phenylethan-1-one (4a, 0.68 g, 2 mmol) in dry THF (60
mL) were added activated zinc powder (0.17 g, 2.6
mmol), hydroquinone (4 mg), and ethyl 2-(bro-
momethyl)acrylate (0.52 g, 2.6 mmol). The mixture was
refluxed under nitrogen atmosphere for 6 h (TLC moni-
toring). After cooling, it was poured into an ice-cold
5% HCl solution (200 mL), and extracted with CH2Cl2
5.1.7. 1-(Naphtho[2,1-b]furan-2-yl)ethan-1-one (8a)
2-Hydroxy-1-naphthaldehyde (6, 1.72 g, 10 mmol),
K2CO3 (3.04 g, 22 mmol) and dry DMF (20 mL) were
stirred at r.t. for 30 min. To this solution was added
dropwise chloroacetone (1.38 g, 15 mmol) in dry DMF
(10 mL). The resulting mixture was stirred at r.t. for 48
h. (TLC monitoring), then poured into ice-water (100

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K.-H. Lee, B.-R. Huang / European Journal of Medicinal Chemistry 37 (2002) 333–338
mL), and extracted with CH2Cl2 (3×20 mL). The
organic phase was washed with brine, dried (Na2SO4),
and evaporated. The solid residue was crystallised from
EtOAc to give 1.60 g of 8a, m.p. 132–133 °C [17] in
76% yield.
Acknowledgements
Financial support of this work by the National
Science Council of the Republic of China and Tajen
Institute of Technology is gratefully acknowledged. We
also thank National Cancer Institute (NCI) of the USA
for the anticancer screenings and the National Center
for High-Performance Computing for providing com-
puter resources and chemical database services.
5.1.8. Naphtho[2,1-b]furan-2-yl phenyl methanone (8b)
From 6 and 2-bromoacetophenone as described for
8a [18,19]: 87% yield.
5.1.9. 2,3,4,5-Tetrahydro-2-methyl-4-methylene-2-
(naphtho[2,1-b]furan-2-yl)-5-oxofuran (9a)
References
To a solution of 8a (0.42 g, 2 mmol) in dry THF (30
mL) were added activated zinc powder (0.17 g, 2.6
mmol), hydroquinone (4 mg), and ethyl 2-(bro-
momethyl)acrylate (0.52 g, 2.6 mmol). The mixture was
refluxed under nitrogen atmosphere for 10 h (TLC
monitoring). After cooling, it was poured into an ice-
cold 5% HCl solution (200 mL), and extracted with
CH2Cl2 (3×75 mL). The CH2Cl2 extracts were com-
bined, washed with brine, dried (Na2SO4), and evapo-
rated to give a residual solid which was crystallised
from EtOAc to give 9a (0.44 g, 80%). m.p. 123–124 °C.
1H-NMR (CDCl3-d): l 1.57 (s, 3H, CH3), 3.06 (dt, 1H,
J=16.7, 2.6 Hz, C-3%-H), 3.52 (dt, 1H, J=16.7, 2.6
Hz, C-3%-H), 5.73 (t, 1H, J=2.6 Hz, CH2=C-4%), 6.35
(t, 1H, J=2.6 Hz, CH2=C-4%), 7.20 (s, 1H, CH),
7.26–8.11 (m, 6H, Ar). 13C-NMR (CDCl3-d): l 26.09
(CH3), 39.66 (C-3%), 79.54 (C-2%), 102.49 (CH), 112.41,
123.01, 123.14, 123.39, 124.87 (CH2ꢀC-4%), 126.03,
126.71, 127.85, 128.94, 130.51, 134.73 (C-4%), 152.85,
156.68, 169.58 (CꢀO). Anal. Found: C, 77.55; H, 5.41.
Calc. for C18H14O3: C, 77.68; H, 5.07%.
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5.1.10. 2,3,4,5-Tetrahydro-4-methylene-2-(naphtho-
[2,1-b]furan-2-yl)-5-oxo-2-phenylfuran (9b)
Yield: 79%. m.p. 179–180 °C. 1H-NMR (CDCl3-d): l
3.50 (dt, 1H, J=16.8, 2.6 Hz, C-3%-H), 4.01 (dt, 1H,
J=16.8, 2.6 Hz, C-3%-H), 5.76 (t, 1H, J=2.6 Hz,
CH2=C-4%), 6.37 (t, 1H, J=2.6 Hz, CH2=C-4%), 6.96
(s, 1H, CH), 7.26–7.99 (m, 12H, Ar). 13C-NMR
(CDCl3-d): l 40.48 (C-3%), 82.54 (C-2%), 105.14 (CH),
112.44, 112.50, 122.92, 123.17, 123.41, 124.90 (CH2ꢀC-
4%), 125.74, 126.27, 126.71, 127.84, 128.82, 128.91,
130.49, 134.10 (C-4%), 140.94, 153.20, 156.28, 169.29
(CꢀO). Anal. Found: C, 81.44; H, 5.13. Calc. for
C23H16O3: C, 81.16; H, 4.74%.