Synthesis of certain benzoheterocyclic com pounds from 2- hydroxyacetophenone via cyclization and ring-closing metathesis

Article abstract of DOI:10.1002/jccs.200500025

Syn the sis of some benzoheterocyclic compounds like substituted benzofurans, 4-methyl-2H-chromenes and 3,4-dihydro-2H-benzo[e]oxepin-5-ones from 2-hydroxyacetophenone via base in duced cyclization and ring-closingme tath e sis (RCM) is described.

Full text of DOI:10.1002/jccs.200500025

Journal of the Chinese Chemical Society, 2005, 52, 159-167
159
Synthesis of Certain Benzoheterocyclic Compounds from
2-Hydroxyacetophenone via Cyclization and Ring-closing Metathesis
Keng-Shiang Huanga,b
Yu-Li Lina (
(
), Sie-Rong Lia (
), You-Feng Wanga (
), Tzu-Wei Tsaia,b
),
), Yung-Hua Chena (
(
),
Chih-Hui Yangc (
) and Eng-Chi Wanga* (
)
aFaculty of Medicinal and Applied Chemistry, Kaohsiung Medical University,
Kaohsiung City 807, Taiwan, R.O.C.
bGraduate Institute of Pharmaceutical Sciences, Kaohsiung Medical University,
Kaohsiung City 807, Taiwan, R.O.C.
cDepartment of Biological Science & Technology, I-Shou University, Kaohsiung County 840, Taiwan, R.O.C.
Synthesis of some benzoheterocyclic compounds like substituted benzofurans, 4-methyl-2H-chromenes
and 3,4-dihydro-2H-benzo[b]oxepin-5-ones from 2-hydroxyacetophenone via base induced cyclization and
ring-closing metathesis (RCM) is described.
Keywords: Benzofurans; 4-Methyl-2H-chromenes; 3,4-Dihydro-2H-benzo[b]oxepin-5-ones.
INTRODUCTION
Small heterocyclic molecules with bicyclic skeletons
reported methods for the construction of the skeleton of 2H-
chromenes include (i) the cross-coupling reaction of 4-tri-
fluoromethylsulfonyloxy-2H-chromenes with arylboronic
acids,8a (ii) the hydroformylation of 2-hydroxybenzophenone
with rhodium-catalyzed,8b (iii) the cyclization of 2-(1-phen-
ylallyl)phenol with potassium bicarbonate and Pd-cata-
lyzed,8c and (iv) the cyclization of propargylic aryl ethers
with Pt(IV)-catalyzed via intramolecular electrophilic hy-
droarylation.8d On the other hand, the synthesis of 3,4-di-
hydro-2H-benzo[b]oxepin-5-ones was prepared only by the
intramolecular dehydration of 4-phenoxybutyric acid with
polyphosphoric acid.9 Despite various synthetic methods for
the benzoheterocycles described above, there is still need for
new methods as the existing methods have various draw-
backs like non-availability of commercial starting materials,
difficulty in preparing the substituted congeners, tedious re-
action conditions, and lower yields. Thus, it is necessary to
develop a more efficient and straightforward method for the
construction of these heterocyclic compounds.
are ubiquitous in nature and often show interesting biological
activities.1 As a part of our previous studies, we have reported
certain substituted benzoheterocyclic and benzocarbocyclic
compounds such as a,b-unsaturated g-lactams,2a benzo[b]-
oxepines,2b benzo[c]oxocines,2c substituted naphthalenes,2d
substituted naphthols,2e substituted indenes2f and substituted
benzocycloheptenes.2g Our synthetic strategy was mainly
based on ring-closing metathesis using the powerful catalyst
developed by Grubbs.3 In continuation of our studies, we fo-
cus on other benzoheterocycles which have received little at-
tention and are difficult to prepare by the reported proce-
dures. 3-Methylbenzofuran and 7-acetylbenzo[b]furan are
attractive target molecules for their various biological activ-
ity/activities.4 The major synthetic strategies for the con-
struction of benzofurans include (i) coupling of conjugated
dienynes with Fisher carbene complexes,5a (ii) intramolecu-
lar cross-coupling of vinyl halides with phenols,5b (iii) reac-
tion of o-hydroxyphenyl ketones with 1-benzotriazol-1-yl-
alkyl chloride,5c and so on.6 Furthermore, 4-substituted 2H-
chromenes (2H-1-benzopyrans) act as the main skeleton for
naturally occurring neoflavenes,7 which are thought to be im-
portant intermediates in the biosynthetic transformation of
dalbergiquinols or dalbergiones into 4-arylcoumarins. The
In this continuing study, we would like to disclose a
new method for the preparation of substituted benzofurans
like (i) 3-methylbenzofuran (6) and 7-acetylbenzo[b]furan
(12); benzooxepinnones with 3,4-dihydro-2H-benzo[b]ox-
epin-5-one (4) and 9-propenyl-3,4-dihydro-2H-benzo[b]-
oxepin-5-one (11) (Scheme I) and substituted 2H-chromenes
like (ii) 4-methyl-2H-chromene (14) and 8-allyl-4-methyl-
* Corresponding author. E-mail: enchwa@kmu.edu.tw

160 J. Chin. Chem. Soc., Vol. 52, No. 1, 2005
Huang et al.
Scheme I
O
O
O
O
O
i
ii
CH3
CH3
CH3
iii
+
Cl
OH
O
O
CH2
4
CH3
1
2
3
iv
CH3
v
O
O
5
6
O
O
O
O
O
vi
viii
vii
CH3
CH3
CH3
OH
CH3
+
Cl
O
O
O
O
11
9
7
8
10
CH3
CH3
CH3
ix
O
Reaction conditions: i. excess ClCH2CH2Cl, H2O, NaOH, TBAB, 82%;
ii. t-BuOK/ THF, 40% (3) and 58% (4); iii. (Ph)3P+MeBr-, t-BuOK, 86%;
iv.1st generation Grubbs' cat., 95%; v. allyl bromide/acetone, K2CO3, 86%;
O
12
vi. reflux in neat, 4 h, 72%; vii. excess ClCH2CH2Cl, H2O, NaOH, TBAB, 78%;
viii. t-BuOK/THF, 18% (9) and 79% (10); ix. 1st generation Grubbs' cat., 95%.
Scheme II
CH2
CH3
CH3
O
i
ii
7
O
14
13
CH2
CH3
CH3
O
iii
iv
v
CH3
8
O
O
O
17
16
15
Reaction conditions: i. (Ph)3P+MeBr-, t-BuOK, 86%; ii.1st generation Grubbs' cat.,
92%; iii. allyl bromide/acetone, K2CO3, 86%; iv. (Ph)3P+MeBr-, t-BuOK, 75%; v.
1st generation Grubbs' cat., 92%.
2H-chromene (17) (Scheme II). A noteworthy point is that no
attention has been paid to apply the chemistry of ring-closing
metathesis to the synthesis of compounds 6, 12, 14, or 17.
of tetra-butylammonium bromide (TBAB) as phase transfer
catalyst to furnish 2-chloroethoxyacetophenone (2) in the
yields of 82%. The structure of compound 2 is supported by
its H-, 13C-NMR spectral data. For example, the H-NMR
spectra of compound 2 showed the disappearance of the phe-
nolic proton signal (5.88 ppm) of starting material, com-
pound 1. Moreover, the appearance of two new sets of triplet
signals of two protons with J = 6.2 Hz at 3.86 ppm and at 4.32
ppm was observed indicating the presence of 2-chloroethoxy
group in compound 2. Compound 2 was reacted with potas-
sium tert-butoxide at room temperature to give 2-vinylaceto-
phenone (3) in 40% yields together with 3,4-dihydro-2H-
1
1
RESULTS AND DISCUSSION
Synthesis of benzofurans, and 3,4-dihydro-2H-benzo[b]-
oxepin-5-ones (Scheme I)
As per the general procedure, 2-hydroxyacetophenone
(1) was allowed to react with a large excess amount of 1,2-di-
chloroethane and aqueous sodium hydroxide in the presence

Synthesis of Certain Benzoheterocyclic Compounds
J. Chin. Chem. Soc., Vol. 52, No. 1, 2005 161
benzo[b]oxepin-5-one (4) in the yields of 58%, respectively.
The effects of reaction temperature and different bases on
elimination or cyclization of compound 2 were investigated.
Also, it was allowed to react with (a) t-BuOK/THF, at room
temperature; other conditions such as (b) t-BuOK/THF, at 0
°C; (c) KOH/H2O, at room temperature; and (d) DBU/MeOH,
at room temperature were also examined. The yield of result-
ing products derived from elimination and cyclization by var-
ious conditions is compiled in Table 1. When DBU (1,8-di-
azabicyclo[5.4.0]undec-7-ene) was used as a reaction base,
no product was obtained by either E-2 elimination or cycliza-
tion, but the starting material was recovered (Entry 4). In the
case of using t-BuOK or KOH as reaction base, the yield of
products caused by elimination or cyclization has no obvious
difference (Entries 1 and 3). On the other hand, if the reaction
temperature is lowered, the product obtained by E-2 elimina-
tion was found of little benefit (Entries 1 and 2). The structure
of compound 3 can be confirmed basically by examining the
new formation of O-vinyl signals and the disappearance of
2-chloroethoxy signals in 1H-NMR spectrum compared with
starting material, compound 2. On the other hand, the 1H- and
13C-NMR spectra of compound 4 can also be well assigned
and utilized to confirm the structure. Subsequently, when
compound 3 was reacted with methyltriphenylphosphonium
bromide and potassium tert-butoxide in THF at 0 °C to un-
dergo the Wittig reaction, it gave 1-isopropenyl-2-vinyloxy-
benzene (5) as the precursor for ring-closing metathesis in
86% yields. The structure of compound 5 can be verified by
examining the new formation of isopropenyl signals and the
disappearance of acetyl signal in the spectra of 1H-NMR and
13C-NMR compared with compound 3. Finally, the precursor
5 was reacted with 5% mole Grubbs’ catalyst in 0.01 M anhy-
drous CH2Cl2 solution to undergo ring-closing metathesis to
successfully give 3-methylbenzofuran (6) in yields of 95%.
acted with allyl bromide in the presence of potassium carbon-
ate to undergo O-allylation to give 2-allyloxyacetophenone
(7) in the yields of 86%. Then, compound 7 was heated to the
reflux in neat to undergo Claisen rearrangement to furnish an
exclusively ortho product, 3-allyl-2-hydroxyacetophenone
(8) in the yields of 72%. The structure of compound 8 can be
identified by the coupling constants of the aromatic protons
in 1H-NMR spectrum. Followed by utilizing a phase transfer
catalyst, TBAB, and a large excess amount of dichloroethane
in aqueous NaOH (20%), compound 8 smoothly underwent
SN2 substitution to give exclusively monoalkylated products,
3-allyl-2-chloroethoxyacetophenone (9) in the yields of 78%.
As in the general procedure, by the treatment of compound 9
with potassium tert-butoxide at room temperature, it under-
went both E-2 elimination and concomitantly underwent the
double bond isomerization to give 3-propenyl-2-vinyloxy-
acetophenone (10) as the precursor for ring-closing metathe-
sis in the yields of 18%. Together with 9-propenyl-3,4-di-
hydro-2H-benzo[b]oxepin-5-one, (11) was obtained from
compound 9 due to competitive cyclization, in the yields of
79%. In our reaction conditions, the new double bond ob-
tained from the isomerization of allyl group was found to
conjugate with benzene ring and in trans-form because the
olefinic coupling constant, J = 15.8 Hz of a propenyl group
was observed. The structure of compounds 10 and 11, which
has the same molecular weight, m/z 202, can be easily distin-
guished from each other by their 1H-NMR spectra data. For
instance, the 1H-NMR spectra of compound 10 exhibited one
propenyl signal at d 1.91 (dd, J = 6.4, 1.6 Hz, CH=CHCH3),
6.27 (dq, J = 15.8, 6.4 Hz, CH=CHCH3) and 6.55 (dq, J =
15.8, 1.6 Hz, CH=CHCH3), and one O-vinyl signal at 4.21
(dd, J = 14.0, 2.4 Hz, 1H, OCH=CH2), 4.26 (dd, J = 6.4, 2.4
Hz, 1H, OCH=CH2), and 6.54 (dd, J = 14.0, 6.4 Hz, 1H,
OCH=CH2). On the other hand, the 1H-NMR spectra of com-
pound 11 exhibited no signals of O-vinyl protons, but has an
-OCH2CH2CH2- signal at d 2.18 (quint., J = 7.0 Hz, 2H,
-OCH2CH2CH2-), 2.87 (t, J = 7.0 Hz, 2H, -OCH2CH2CH2-),
and 4.24 (t, J = 7.0 Hz, 2H, -OCH2CH2CH2-) to prove the
1
The structure of benzofuran (6) was assigned by H-
NMR and 13C-NMR and was comparable with previous re-
ports.4-6 Thus, we have found a new route to 3-methylbenzo-
furan (6). Furthermore, 2-hydroxyacetophenone (1) was re-
Table 1. Yields of compound 3, 4 derived from compound 2 via E-2 elimination or
cyclization with various conditions
Reaction time
Products (% yields)
Entry
Conditions
(hr)
Compound (3)
Compound (4)
1
2
3
4
t-BuOK/THF, rt
t-BuOK/THF, 0 °C
KOH/H2O, rt
2
4
2
2
(40)
(48)
(37)
(--)
(58)
(45)
(57)
(--)
DBU/MeOH, rt

162 J. Chin. Chem. Soc., Vol. 52, No. 1, 2005
Huang et al.
structure of 11, which was cyclized. Thus, we have success-
fully built up the precursor 10 for ring-closing metathesis, to-
gether with the cyclized product 11 in one pot. Finally, while
this precursor 10 was reacted with 5% mole Grubbs’ catalyst
in 0.01 M anhydrous CH2Cl2 to undergo ring-closing metath-
esis, successfully gave 7-acetylbenzo[b]furan (12) in excel-
lent yields of 95%. The structure of benzofuran 12 was con-
firmed by their 1H-NMR and 13C-NMR spectra. For instance,
the 1H-NMR spectra of benzofuran 12 exhibited a singlet at d
2.84 for three-protons indicating the presence of one acetyl
group. In addition, the signals at d 6.85, 7.74, each showed
one-proton with doublet having a coupling constant J = 2.4
Hz, indicating the H-3 and H-2 protons of the furan ring, to-
gether at d 7.30, 7.79, and 7.90 revealed three aromatic pro-
tons, respectively. In the 13C-NMR spectra, it showed ten car-
bons, matching the structure of 12. Furthermore, the molecu-
lar ion, m/z 160 was observed, which is coincident with the
calculated one for 12, C10H8O2.
dihydro-2H-benzo[b]oxepin-5-one were also synthesized.
EXPERIMENTAL
General remarks
1H- and 13C-NMR spectra were obtained on a Varian
Gemini-200, or Varian Unity plus 400. Chemical shifts were
measured in parts per million with respect to TMS. MS spec-
tra were recorded on a Chem/hp/middle instrument. HRMS
spectra were performed on a JEOL JMS SX/SX 102A instru-
ment. Elemental analyses were recorded on a Heraeus CHN-
O Rapid Analyzer. Silica gel (70-230 mesh) for column chro-
matography and the precoated silica gel plate (60 F-254) for
TLC were purchased from E. Merck Co. UV light (254 nm)
was used to detect spots on TLC plates after development.
Grubbs catalyst (first generation) was purchased from Fluca
Company.
Synthesis of 4-methyl-2H-chromenes (Scheme II)
Preparation of 2-chloroethoxyacetophenone (2)10a
Compound 7 was allowed to react with methyltriphen-
ylphosphonium bromide and potassium tert-butoxide in an-
hydrous THF to undergo Wittig reaction to afford 2-allyl-
oxy-1-isopropenylbenzene (13) as the precursor of ring-clos-
ing metathesis in yields of 86%. Subsequently, compound 13
treated with 5% mole Grubbs’ catalyst in 0.01 M anhydrous
CH2Cl2 to undergo RCM, successfully gave 4-methyl-2H-
chromene (14) in yields of 92%. The structure of compound
14, which was confirmed by 1H-NMR and 13C-NMR, was co-
incident with those of previous reports.7,8 On the other hand,
as in the general procedure, compound 8 was alkylated with
allyl bromide in anhydrous acetone in the presence of potas-
sium carbonate to give 3-allyl-2-allyloxyacetophenone 15 in
yields of 86%. Followed by the Wittig reaction of compound
15, it gave 3-allyl-2-allyloxy-1-isopropenylbenzene (16) in
yields of 75%. Finally compound 16, which was reacted with
5% mole Grubbs’ catalyst in 0.01 M anhydrous CH2Cl2 to un-
dergo ring-closing metathesis, successfully gave 8-allyl-4-
methyl-2H-chromene (17) in yields of 92%. The structure of
2-Hydroxyacetophenone (1) (2.72 g, 20 mmol) in di-
chloroethane (30 mL), NaOH (1.04 g, mmol) in H2O (35 mL),
and 10% mol TBAB (0.65 g, 2 mmol) were mixed and the
mixture was stirred at rt for 8 h. Then, the organic layer was
separated, washed with brine, dried over anhydrous MgSO4,
and filtered. The filtrate was concentrated to remove dichlo-
roethane in vacuo. The given residue was subjected to silical
gel column chromatography (ethyl acetate/n-hexane = 1/20)
to give pure compound 2 in good yields.
2-Chloroethoxyacetophenone (2) (3.2 g, 82%) was ob-
tained as colorless crystals, mp 28-29 °C (ethyl acetate + n-
Hexane), Rf = 0.13 (ethyl acetate/n-hexane = 1/18), 1H-NMR
(CDCl3, 400 MHz) d 2.66 (s, 3H, COCH3), 3.86 (t, J = 5.6 Hz,
2H, OCH2CH2Cl), 4.32 (t, J = 5.6 Hz, 2H, OCH2CH2Cl), 6.87
(dd, J = 8.0, 0.8 Hz, 1H, ArH), 7.01 (td, J = 8.8, 0.8 Hz, 1H,
ArH), 7.43 (td, J = 7.6, 1.6 Hz, 1H, ArH), 7.72 (dd, J = 7.6,
1.6 Hz, 1H, ArH); 13C-NMR (CDCl3, 100 MHz) d 32.10,
41.91, 68.37, 112.19, 121.22, 128.47, 130.50, 133.54, 157.28,
199.51; EI-MS (70 eV) m/z (rel. intensity, %) 201 (M+3, 25),
199 (M+1, 78), 183 (34), 163 (43), 147 (21), 145 (31), 121
(100), 119 (74), 91 (60); HRMS for C10H11ClO2: 198.0442.
Found: 198.0446. Anal. Calcd for C10H11O2Cl: C, 60.46; H,
5.58. Found: C, 60.50; H, 5.61.
1
chromene 17 was confirmed by its H-NMR and 13C-NMR
spectra.
In conclusion, in this report we have shown the ring-
closing metathesis chemistry can be applied to the versatile
synthesis of a number of benzoheterocyclic compounds like
3-methylbenzofuran, 7-acetylbenzo[b]furan, 4-methyl-2H-
chromene, and 8-allyl-4-methyl-2H-chromene. In addition,
some expected products derived from cyclization such as
3,4-dihydro-2H-benzo[b]oxepin-5-one and 9-propenyl-3,4-
Preparation of 2-vinyloxyacetophenone (3)10b and 3,4-
dihydro-2H-benzo[b]oxepin-5-one (4)9
A solution of 2-chloroethoxyacetophenone (2) (2.99 g,
15 mmol) in anhydrous THF (40 mL) was added with pot.

Synthesis of Certain Benzoheterocyclic Compounds
J. Chin. Chem. Soc., Vol. 52, No. 1, 2005 163
tert-butoxide (2.25 g, 20 mmol) in portion, and the given
mixture was stirred at rt for 2 h. After the end of reaction, the
reaction mixture was concentrated to remove THF in vacuo.
To the resulting residue was added water (100 mL) and then it
was extracted with ethyl acetate (20 mL ´ 5). The extracted
solution was dried over anhydrous magnesium sulfate. After
filtration, the given filtrate was concentrated in vacuo, and
the resulting residue was purified from column chromatogra-
phy on silica gel (n-hexane) to give pure compounds 3 and 4,
respectively.
the filtrate was concentrated in vacuo to give a pale yellow
residue. Finally, the given residue was subjected to column
chromatography (n-hexane) to afford pure compound 5.
1-Isopropenyl-2-vinyloxybenzene (5) (0.6 g, 86%) was
obtained as colorless liquids, Rf = 0.52 (n-hexane), 1H-NMR
(CDCl3, 400 MHz) d 2.11 (s, 3H, CH3), 4.37 (dd, J = 6.0, 1.6
Hz, 1H, OCH=CH2), 4.67 (dd, J = 13.6, 1.6 Hz, 1H, OCH=CH2),
5.08, 5.16 (each m, 1H, Ar(CH3)C=CH2), 6.58 (dd, J = 13.6,
6.0 Hz, 1H, OCH=CH2), 6.97 (dd, J = 7.6, 1.6 Hz, 1H, ArH),
7.06 (td, J = 7.6, 1.6 Hz, 1H, ArH), 7.24 (m, 2H, ArH);
13C-NMR (CDCl3, 100 MHz) d 23.23, 94.11, 115.80, 117.72,
123.51, 128.31, 129.66, 134.38, 142.96, 149.00, 153.58;
EI-MS (70 eV) m/z (rel. intensity, %) 161 (M+1, 22), 160 (M+,
44), 147 (38), 145 (52), 132 (100), 131 (31), 117 (19), 91
(10); HRMS for C11H12O: 160.0883. Found: 160.0885.
2-Vinyloxyacetophenone (3) (1.0 g, 40%) were ob-
1
tained as colorless liquids, Rf = 0.34 (n-hexane), H-NMR
(CDCl3, 400 MHz) d 2.63 (s, 3H, COCH3), 4.54 (dd, J = 6.0,
2.0 Hz, 1H, OCH=CH2), 4.81 (dd, J = 14.0, 2.0 Hz, 1H,
OCH=CH2), 6.64 (dd, J = 14.0, 6.0 Hz, 1H, OCH=CH2), 7.05
(d, J = 8.4, 1H, ArH), 7.14 (t, J = 7.8 Hz, 1H, ArH), 7.47 (td, J
= 7.6, 1.8 Hz, 1H, ArH), 7.77 (dd, J = 8.0, 1.8 Hz, 1H, ArH);
13C-NMR (CDCl3, 100 MHz) d 31.56, 96.41, 117.41, 123.33,
129.43, 130.30, 133.52, 147.59, 155.70, 198.76; EI-MS (70
eV) m/z (rel. intensity, %) 163 (M+1, 70), 147 (40), 145 (26),
121 (33), 119 (81), 117 (21), 91 (100); HRMS for C10H10O2:
162.0675. Found: 162.0676.
Preparation of 3-methylbenzofuran (6)4-6
1-Isopropenyl-2-vinyloxybenzene (5) (0.48 g, 3 mmol)
dissolved in anhydrous CH2Cl2 (30 mL) was stirred and
Grubbs’ catalyst (0.12 mg, 3 ´ 5% mmol) was added at rt un-
der nitrogen. The mixture was continually stirred for 8 h. Di-
chloromethane was removed from the reaction mixture in
vacuo, and the residue was purified by column chromatogra-
phy on silica gel (using n-hexane as mobile phase) to give
pure compound 6.
3,4-Dihydro-2H-benzo[b]oxepin-5-one (4) (1.4 g,
58%) were obtained as colorless liquids, Rf = 0.21 (n-hex-
ane), 1H-NMR (CDCl3, 400 MHz) d 2.15 (m, 2H, H-3), 2.87
(t, J = 7.0 Hz, 2H, H-4), 4.21 (t, J = 6.6 Hz, 2H, H-2), 7.07 (m,
2H, ArH), 7.40 (td, J = 7.8, 1.8 Hz, 1H, ArH), 7.75 (dd, J =
7.8, 1.8 Hz, 1H, ArH); 13C-NMR (CDCl3, 100 MHz) d 26.30,
40.56, 72.78, 120.74, 122.70, 129.04, 129.43, 133.68, 162.00,
200.61; EI-MS (70 eV) m/z (rel. intensity, %) 163 (M+1, 32),
162 (M+, 100), 132 (24), 131 (42), 120 (16), 105 (24), 104 (16),
92 (44); HRMS for C10H10O2: 162.0675. Found: 162.0678.
3-Methylbenzofuran (6) (0.3 g, 95%) were obtained as
colorless liquids, Rf = 0.52 (n-hexane), 1H-NMR (CDCl3, 400
MHz) d 2.01 (d, J = 1.0 Hz, 3H, CH3), 7.23 (td, J = 7.6, 1.2
Hz, 1H, H-5), 7.28 (td, J = 7.6, 1.2 Hz, 1H, H-6), 7.40 (q, J =
1.0 Hz, 1H, H-2), 7.45 (dd, J = 7.6, 1.2 Hz, 1H, H-7), 7.52
(dd, J = 7.6, 1.2 Hz, 1H, H-4); 13C-NMR (CDCl3, 100 MHz) d
7.81, 111.21, 115.52, 119.30, 122.11, 123.96, 128.93, 141.26,
155.16; EI-MS (70 eV) m/z (rel. intensity, %) 133 (M+1, 10),
132 (M+, 100), 131 (92), 103 (13); HRMS for C9H8O:
132.0570. Found: 132.0571.
Preparation of 1-isopropenyl-2-vinyloxybenzene (5)
Under dried nitrogen, to a stirred suspension of methyl-
triphenylphosphonium bromide (3.58 g, 10 mmol) in dry
THF (20 mL) at 0 °C, was added potassium tert-butoxide
(1.13 g, 10 mmol) in several portions over 10 min. Then, a
yellowish white suspension was formed, and to which subse-
quently was added 2-vinyloxyacetophenone (3) (0.81 g, 5
mmol) in THF (15 mL), in drops. The resulting suspension
was continually stirred for 2-3 h until compound 3 was con-
sumed completely from the monitoring of TLC (n-hexane)
monitoring. At the end of reaction, the resulting mixture was
concentrated in vacuo. To the residue was added water (100
mL) and then it was extracted with ethyl acetate (20 mL ´ 5).
The resulting organic layer was combined and washed with
brine, and then dried over anhydrous MgSO4. After filtration,
Preparation of 2-allyloxyacetophenone (7)10c-e
As in the general procedure, 2-hydroxyacetophenone
(1) (13.62 g, 100 mmol) dissolved in anhydrous acetone (100
mL) was stirred and then allyl bromide (14.52 g, 120 mmol)
and anhydrous K2CO3 (16.59 g, 120 mmol) were added. The
resulting mixture was continually stirred and refluxed for 8 h,
then cooled to rt, and filtered. The filtrate was concentrated in
vacuo to give crude 2-allyloxyacetophenone (7). After purifi-
cation with column chromatography (silica gel, ethyl ace-
tate/n-hexane = 1/20), pure compound 7 was afforded.
2-Allyloxyacetophenone (7) (15.0 g, 86%) were ob-
tained as colorless liquids, Rf = 0.31 (ethyl acetate/n-hexane

164 J. Chin. Chem. Soc., Vol. 52, No. 1, 2005
Huang et al.
= 1/18), 1H-NMR (CDCl3, 400 MHz) d 2.64 (s, 3H, COCH3),
4.64 (dt, J = 5.2, 1.2 Hz, 2H, OCH2CH=CH2), 5.32 (ddt, J =
10.4, 1.2, 1.2 Hz, 1H, OCH2CH=CH2), 5.44 (ddt, J = 17.2,
1.2, 1.2 Hz, 1H, OCH2CH=CH2), 6.08 (ddt, J = 17.2, 10.4, 5.2
Hz, 1H, CH=CH2), 6.94 (d, J = 8.0 Hz, 1H, ArH), 6.99 (td, J =
8.8, 0.8 Hz, 1H, ArH), 7.43 (td, J = 7.6, 1.6 Hz, 1H, ArH),
7.73 (dd, J = 7.6, 1.6 Hz, 1H, ArH); 13C-NMR (CDCl3, 100
MHz) d 31.90, 69.34, 112.74, 118.11, 120.72, 128.63, 130.34,
132.59, 133.45, 157.85, 199.85; EI-MS (70 eV) m/z (rel. in-
tensity, %) 177 (M+1, 18), 176 (M+, 2), 161 (50), 148 (22),
133 (78), 132 (24), 121 (100), 115 (23), 105 (60), 92 (23), 91
(29); HRMS for C11H12O2: 176.0832. Found: 176.0834.
OCH2CH2Cl), 5.08, 5.11 (each m, 1H, OCH2CH=CH2), 5.98
(m, 1H, CH=CH2), 7.14 (dd, J = 7.8, 7.6 Hz, 1H, H-5), 7.35
(dd, J = 7.6, 1.6 Hz, 1H, H-4), 7.43 (dd, J = 7.8, 1.6 Hz, 1H,
H-6); 13C-NMR (CDCl3, 100 MHz) d 30.41, 33.47, 42.61,
74.86, 116.43, 124.43, 127.77, 133.91, 134.10, 134.25, 136.53,
154.71, 201.06; EI-MS (70 eV) m/z (rel. intensity, %) 241
(M+3, 13), 239 (M+1, 42), 174 (62), 161 (40), 159 (100), 149
(23), 133 (49), 131 (49), 115 (21), 105 (31), 91 (21); HRMS
for C13H15ClO2: 238.0755. Found: 238.0757.
Preparation of 3-propenyl-2-vinyloxyacetophenone (10)
and 9-propenyl-3,4-dihydro-9-propenyl-2H-benzo[b]-
oxepin-5-one (11)
Preparation of 3-allyl-2-hydroxyacetophenone (8)10f-g
Under the protection of dry argon, 2-allyloxyacetophe-
none (7) (13.20 g, 75 mmol) was strongly stirred and heated
to boil gently in neat. After the end of reaction (4 h), which
was monitored by TLC, the resulting residue was subjected to
chromatographic column (ethyl acetate/n-hexane = 1/20) to
give pure compound 8.
A solution of 3-allyl-2-chloroethoxyacetophenone (9)
(3.59 g, 15 mmol) in anhydrous THF (40 mL) was stirred and
pot. tert-butoxide (2.25 g, 20 mmol) was added at rt for 2 h.
Then, THF was removed from the reaction mixture in vacuo.
To the residue was added water (50 mL) and then it was ex-
tracted with ethyl acetate (20 mL ´ 5). The extracted solution
was washed with brine and dried over anhydrous magnesium
sulfate. After filtration, the filtrate was concentrated in
vacuo, and the given residue was purified from column chro-
matography on silica gel (n-hexane) to give pure compound
10 and 11.
3-Allyl-2-hydroxyacetophenone (8) (9.5 g, 72%) were
obtained as colorless liquids, Rf = 0.49 (ethyl acetate/n-hex-
1
ane = 1/18), H-NMR (CDCl3, 400 MHz) d 2.16 (br s, 1H,
OH), 2.61 (s, 3H, COCH3), 3.42 (d, J = 6.6 Hz, 2H,
OCH2CH=CH2), 5.07 (m, 2H, OCH2CH=CH2), 6.00 (m, 1H,
CH=CH2), 6.83 (dd, J = 7.8, 7.6 Hz, 1H, H-5), 7.34 (dd, J =
7.6, 1.6 Hz, 1H, H-4), 7.61 (dd, J = 7.8, 1.6 Hz, 1H, H-6);
13C-NMR (CDCl3, 100 MHz) d 26.66, 33.33, 115.88, 118.32,
119.15, 128.70, 129.28, 136.00, 136.33, 160.29, 204.59; EI-
MS (70 eV) m/z (rel. intensity, %) 177 (M+1, 27), 176 (M+,
97), 161 (100), 158 (17), 143 (35), 133 (96), 105 (31), 79 (18),
77 (21); HRMS for C11H12O2: 176.0832. Found: 176.0833.
3-Propenyl-2-vinyloxyacetophenone (10) (0.6 g, 18%)
was obtained as colorless liquids, Rf = 0.36 (n-hexane),
1H-NMR (CDCl3, 400 MHz) d 1.91 (dd, J = 6.4, 1.6 Hz, 3H,
CH=CHCH3), 2.62 (s, 3H, COCH3), 4.21 (dd, J = 14.0, 2.4
Hz, 1H, OCH=CH2), 4.26 (dd, J = 6.4, 2.4 Hz, 1H, OCH=CH2),
6.27 (dq, J = 15.8, 6.4 Hz, 1H, CH3CH=CH), 6.54 (dd, J =
14.0, 6.4 Hz, 1H, OCH=CH2), 6.55 (dq, J = 15.8, 1.6 Hz, 1H,
CH3CH=CH), 7.20 (dd, J = 7.8, 7.6 Hz, 1H, H-5), 7.55 (dd, J
= 7.6, 1.6 Hz, 1H, H-4), 7.65 (dd, J = 7.8, 1.6 Hz, 1H, H-6);
13C-NMR (CDCl3, 100 MHz) d 18.85, 30.80, 91.83, 124.35,
125.33, 128.28, 128.79, 130.22, 132.15, 133.50, 150.22,
151.09, 199.73; EI-MS (70 eV) m/z (rel. intensity, %) 203
(M+1, 100), 202 (M+, 58), 187 (52), 160 (42), 159 (51), 145
(52), 131 (57); HRMS for C13H14O2: 202.0988. Found:
202.0983.
Preparation of 3-allyl-2-chloroethoxyacetophenone (9)
3-Allyl-2-hydroxyacetophenone (8) (4.4 g, 25 mmol)
in dichloroethane (40 mL), NaOH (1.12 g, 28 mmol) in H2O
(40 mL), and 10% mol TBAB (0.81 g, 2.5 mmol) was mixed
and stirred at rt for 8 h. Then the organic layer was separated,
washed with brine, dried over anhydrous MgSO4, and fil-
tered. The filtrate was concentrated to remove dichloroethane
in vacuo. The residue was purified from silical gel column
chromatography (ethyl acetate/n-hexane = 1/20) to give pure
compound 9.
9-Propenyl-3,4-dihydro-2H-benzo[b]oxepin-5-one
(11) (1.8 g, 79%) was obtained as colorless liquids, Rf = 0.16
(n-hexane), 1H-NMR (CDCl3, 400 MHz) d 1.92 (dd, J = 6.4,
1.6 Hz, 3H, CH=CHCH3), 2.18 (quint., J = 7.0 Hz, 2H, H-3),
2.87 (t, J = 7.0 Hz, 2H, H-4), 4.24 (t, J = 7.0 Hz, 2H, H-2),
6.24 (dq, J = 15.8, 6.4 Hz, 1H, CH3CH=CH), 6.55 (d, J = 15.8
Hz, 1H, CH3CH=CH), 6.83 (dd, J = 7.8, 7.6 Hz, 1H, H-7),
7.34 (dd, J = 7.6, 1.6 Hz, 1H, H-6), 7.61 (dd, J = 7.8, 1.6 Hz,
1H, H-8); 13C-NMR (CDCl3, 100 MHz) d 18.77, 25.96,
3-Allyl-2-chloroethoxyacetophenone (9) (4.6 g, 78%)
were obtained as colorless liquids, Rf = 0.24 (ethyl acetate/n-
1
hexane = 1/18), H-NMR (CDCl3, 400 MHz) d 2.62 (s, 3H,
COCH3), 3.50 (d, J = 6.8 Hz, 2H, CH2CH=CH2), 3.80 (t, J =
5.4 Hz, 2H, OCH2CH2Cl), 4.07 (t, J = 5.4 Hz, 2H,

Synthesis of Certain Benzoheterocyclic Compounds
J. Chin. Chem. Soc., Vol. 52, No. 1, 2005 165
40.25, 72.44, 122.63, 124.59, 127.65, 127.80, 129.80,
130.16, 134.18, 158.04, 201.07; EI-MS (70 eV) m/z (rel. in-
tensity, %) 203 (M+1, 24), 202 (M+, 100), 146 (28), 145 (32),
132 (32), 131 (51), 129 (24); HRMS for C13H14O2: 202.0988.
Found: 202.0989.
OCH2CH=CH2), 5.40 (ddt, J = 17.2, 1.2, 1.2 Hz, 1H,
OCH2CH=CH2), 6.05 (ddt, J = 17.2, 10.4, 5.2 Hz, 1H,
OCH2CH=CH2), 6.86 (d, J = 7.8 Hz, 1H, ArH), 6.91 (td, J =
7.6, 1.6 Hz, 1H, ArH), 7.22 (m, 2H, ArH); 13C-NMR (CDCl3,
100 MHz) d 23.17, 69.07, 112.35, 115.06, 117.10, 120.74,
128.18, 129.48, 133.17, 133.42, 144.22, 155.59; EI-MS (70
eV) m/z (rel. intensity, %) 175 (M+1, 100), 174 (M+, 17), 161
(53), 159 (20), 145 (64), 133 (56), 131 (39), 105 (41), 83 (20);
HRMS for C12H14O: 174.1039. Found: 174.1040.
Preparation of 7-acetylbenzo[b]furan (12)4-6
A solution of 3-propenyl-2-vinyloxyacetophenone (10)
(0.61 g, 3 mmol) in dichloromethane (30 mL) was stirred and
Grubbs’ catalyst (0.12 mg, 3 ´ 5% mmol) was added. The
mixture was continually stirred at rt for 8 h. Dichloromethane
was removed from the reaction mixture in vacuo, and the
given residue was purified by column chromatography on sil-
ica gel (using n-hexane as mobile phase) to give pure com-
pound 12.
Preparation of 4-methyl-2H-chromene (14)7,8
A solution of 2-allyloxy-1-isopropenylbenzene (13)
(0.52 g, 3 mmol) in dichloromethane (30 mL) was stirred and
Grubbs’ catalyst (0.12 mg, 3 ´ 5% mmol) was added at rt un-
der dry argon. The reaction mixture was continually stirred
for 8 h. Then, dichloromethane was removed from the reac-
tion mixture in vacuo, and the given residue was purified
from column chromatography on silica gel (using n-hexane
as mobile phase) to give pure compound 14.
7-Acetylbenzo[b]furan (12) (0.3 g, 95%) were obtained
as colorless liquids, Rf = 0.50 (ethyl acetate/n-hexane = 1/9),
1H-NMR (CDCl3, 400 MHz) d 2.84 (s, 3H, CH3), 6.85, 7.74
(each d, J = 2.4 Hz, 1H, H-3 and H-2), 7.30 (t, J = 8.0 Hz, 1H,
H-5), 7.79, 7.90 (each dd, J = 8.0, 1.2 Hz, 1H, H-4 and H-6);
13C-NMR (CDCl3, 100 MHz) d 30.56, 106.53, 122.19,
122.65, 125.17, 126.37, 128.88, 145.34, 153.06, 196.11; EI-
MS (70 eV) m/z (rel. intensity, %) 161 (M+1, 6), 160 (M+, 56),
146 (10), 145 (100), 117 (32), 89 (24); HRMS for C10H8O2:
160.0519. Found: 160.0521.
4-Methyl-2H-chromene (14) (0.41 g, 92%) were ob-
1
tained as colorless liquids, Rf = 0.29 (n-hexane), H-NMR
(CDCl3, 400 MHz) d 2.01 (q, J = 2.0 Hz, 3H, CH3), 4.74 (dq, J
= 2.0, 2.0 Hz, 2H, H-2), 5.56 (sixt., J = 2.0 Hz, 1H, H-3), 6.79
(dd, J = 7.6, 1.6 Hz, 1H, ArH), 6.89 (td, J = 7.6, 1.6 Hz, 1H,
ArH), 7.13 (m, 2H, ArH); 13C-NMR (CDCl3, 100 MHz) d
17.92, 65.42, 115.71, 118.37, 121.09, 123.49, 124.30,
128.94, 130.20, 154.18; EI-MS (70 eV) m/z (rel. intensity, %)
147 (M+1, 9), 146, (M+, 84), 145 (100), 132 (18), 131 (93),
116 (7), 115 (20), 103 (9); HRMS for C10H10O: 146.0726.
Found: 146.0728.
Preparation of 2-allyloxy-1-isopropenylbenzene (13)
Under dried nitrogen, a suspension of methyltriphenyl-
phosphonium bromide (3.58 g, 10 mmol) in dry THF (20 mL)
at 0 °C was added with potassium tert-butoxide (1.13 g, 10
mmol) in several portions over 10 minutes. After 10 min. of
addition, a yellowish white suspension was formed, and sub-
sequently 2-allyloxyacetophenone (7) (0.88 g, 5 mmol) in
THF (15 mL) was added in drops. The given suspension was
continually stirred for 2-3 h until the acetophenone was con-
sumed completely from the monitoring of TLC (n-hexane).
Then, the suspension was concentrated in vacuo. To the resi-
due was added water (50 mL) and then it was extracted with
ethyl acetate (20 mL ´ 5). The organic layer was washed with
brine, dried over anhydrous MgSO4, and then filtered. The
filtrate was concentrated in vacuo to give a pale yellow resi-
due. Finally the given residue was subjected to column chro-
matography (n-hexane) to afford pure compound 13.
Preparation of 3-allyl-2-allyloxyacetophenone (15)
As in the general procedure, to 3-allyl-2-hydroxyaceto-
phenone (8) (4.4 g, 25 mmol) dissolved in anhydrous acetone
(30 mL) was added allyl bromide (3.39 g, 28 mmol) and an-
hydrous K2CO3 (3.87 g, 28 mmol). The resulting mixture was
stirred and refluxed for 8 h, then cooled to room temperature,
and filtered. The filtrate was concentrated in vacuo to give
crude 3-allyl-2-allyloxyacetophenone (15). After purifica-
tion with column chromatography (silica gel, ethyl acetate/
n-hexane = 1/20) it gave pure compound 15.
3-Allyl-2-allyloxyacetophenone (15) (4.6 g, 86%)
were obtained as colorless liquids, Rf = 0.34 (ethyl acetate/n-
1
2-Allyloxy-1-isopropenylbenzene (13) (3.0 g, 86%)
were obtained as colorless liquids, Rf = 0.36 (n-hexane),
1H-NMR (CDCl3, 400 MHz) d 2.14 (s, 3H, CH3), 4.55 (dt, J =
5.2, 1.2 Hz, 2H, OCH2CH=CH2), 5.07, 5.13 (each m, 1H,
Ar(CH3)C=CH2), 5.25 (ddt, J = 10.4, 1.2, 1.2 Hz, 1H,
hexane = 1/18), H-NMR (CDCl3, 400 MHz) d 2.62 (s, 3H,
COCH3), 3.46 (dt, J = 6.8, 1.6 Hz, 2H, ArCH2CH=CH2), 4.32
(dt, J = 5.2, 1.2 Hz, 2H, OCH2CH=CH2), 5.08 (ddt, J = 17.2,
1.6, 1.6 Hz, 1H, ArCH2CH=CH2), 5.10 (ddt, J = 10.4, 1.6, 1.6
Hz, 1H, ArCH2CH=CH2), 5.27 (ddt, J = 10.4, 1.2, 1.2 Hz, 1H,

166 J. Chin. Chem. Soc., Vol. 52, No. 1, 2005
Huang et al.
OCH2CH=CH2), 5.41 (ddt, J = 17.2, 1.2, 1.2 Hz, 1H,
OCH2CH=CH2), 5.97 (ddt, J = 17.2, 10.4, 5.2 Hz, 1H,
OCH2CH=CH2), 6.05 (ddt, J = 17.2, 10.4, 6.8 Hz, 1H,
ArCH2CH=CH2), 7.12 (dd, J = 7.8, 7.6 Hz, 1H, H-5), 7.35
(dd, J = 7.6, 1.6 Hz, 1H, H-4), 7.44 (dd, J = 7.8, 1.6 Hz, 1H,
H-6); 13C-NMR (CDCl3, 100 MHz) d 30.43, 33.61, 76.28,
116.28, 117.87, 124.17, 127.75, 130.15, 133.08, 133.99,
134.23, 136.59, 155.59, 201.37; EI-MS (70 eV) m/z (rel. in-
tensity, %) 217 (M+1, 66), 161 (100), 159 (58), 149 (52), 133
(58), 131 (55); HRMS for C14H16O2: 216.1145. Found:
216.1146.
131 (97), 129 (59), 128 (51), 115 (50); HRMS for C15H18O:
214.1352. Found: 214.1352.
Preparation of 8-allyl-4-methyl-2H-chromene (17)7,8
To a solution of 3-allyl-2-allyloxy-1-isopropenylben-
zene (16) (1.07 g, 5 mmol) in CH2Cl2 (50 mL) was added
Grubbs’ catalyst (0.12 mg, 3 ´ 5% mmol) at rt under argon.
The reaction mixture was continually stirred for 8 h. Then, di-
chloromethane was removed from the reaction mixture in
vacuo, and the given residue was purified from column chro-
matography on silica gel (using n-hexane as mobile phase) to
give pure compound 17.
Preparation of 3-allyl-2-allyloxy-1-isopropenylbenzene
(16)
8-Allyl-4-methyl-2H-chromene (17) (0.9 g, 92%) were
obtained as colorless liquids, Rf = 0.46 (n-hexane), 1H-NMR
(CDCl3, 400 MHz) d 2.01 (d, J = 2.0 Hz, 3H, CH3), 3.34 (dt, J
= 6.8, 1.6 Hz, 2H, ArCH2CH=CH2), 4.86 (d, J = 2.0 Hz, 2H,
H-2), 5.02 (ddt, J = 17.2, 1.6, 1.6 Hz, 1H, ArCH2CH=CH2),
5.06 (ddt, J = 10.4, 1.6, 1.6 Hz, 1H, ArCH2CH=CH2), 5.58
(sixt, J = 2.0 Hz, 1H, H-3), 5.98 (ddt, J = 17.2, 10.4, 6.8 Hz,
1H, ArCH2CH=CH2), 6.85 (dd, J = 7.8, 7.6 Hz, 1H, H-5),
7.00 (dd, J = 7.6, 1.6 Hz, 1H, H-4), 7.04 (dd, J = 7.8, 1.6 Hz,
1H, H-6); 13C-NMR (CDCl3, 100 MHz) d 18.12, 33.92,
65.24, 115.24, 118.26, 120.59, 121.66, 124.23, 127.12,
129.61, 130.58, 136.96, 151.72; EI-MS (70 eV) m/z (rel. in-
tensity, %) 186 (M+, 58), 185 (51), 172 (17), 171 (100), 145
(13), 129 (17), 128 (25), 115 (19); HRMS for C13H14O:
186.1039. Found: 186.1040.
To a suspension of methyl triphenylphosphonium bro-
mide (3.58 g, 10 mmol) in dry THF (20 mL) at 0 °C, was
added potassium tert-butoxide (1.13 g, 10 mmol) under dried
nitrogen, in several portions over 10 minutes. After 10 min.
of addition, a yellowish white suspension was formed, and
subsequently 3-allyl-2-allyloxyacetophenone (15) (1.08 g, 5
mmol) was added in THF (15 mL) in drops. The suspension
was continually stirred for 2-3 h until the acetophenone was
consumed completely from the monitoring of TLC (n-hex-
ane). Then, the reaction mixture was concentrated in vacuo.
To the given residue was added water (50 mL) and then it was
extracted with ethyl acetate (20 mL ´ 5). The organic layer
was washed with brine, dried over anhydrous MgSO4, and
then filtered. The filtrate was concentrated in vacuo to give a
pale yellow residue. Finally the given residue was purified
from column chromatography (n-hexane) to afford pure com-
pound 16.
ACKNOWLEDGEMENTS
3-Allyl-2-allyloxy-1-isopropenylbenzene (16) (1.6 g,
75%) was obtained as colorless liquids, Rf = 0.52 (n-hexane),
1H-NMR (CDCl3, 400 MHz) d 2.14 (s, 3H, CH3), 3.43 (dt, J =
6.8, 1.6 Hz, 2H, ArCH2CH=CH2), 4.30 (dt, J = 5.2, 1.2 Hz, 2H,
OCH2CH=CH2), 5.05, 5.14 (each m, 1H, Ar(CH3)C=CH2),
5.10 (ddt, J = 17.2, 1.6, 1.6 Hz, 1H, ArCH2CH=CH2), 5.14
(ddt, J = 10.4, 1.6, 1.6 Hz, 1H, ArCH2CH=CH2), 5.20 (ddt, J
= 10.4, 1.2, 1.2 Hz, 1H, OCH2CH=CH2), 5.35 (ddt, J = 17.2,
1.2, 1.2 Hz, 1H, OCH2CH=CH2), 5.99 (ddt, J = 17.2, 10.4, 5.2
Hz, 1H, OCH2CH=CH2), 6.05 (ddt, J = 17.2, 10.4, 6.8 Hz,
1H, ArCH2CH=CH2), 7.01 (dd, J = 7.8, 7.6 Hz, 1H, H-5),
7.07 (dd, J = 7.6, 1.6 Hz, 1H, H-4), 7.10 (dd, J = 7.8, 1.6 Hz,
1H, H-6); 13C-NMR (CDCl3, 100 MHz) d 23.00, 34.12, 73.79,
115.32, 115.67, 116.90, 123.85, 127.91, 129.20, 133.46,
134.22, 137.19, 137.38, 144.38, 154.05; EI-MS (70 eV) m/z
(rel. intensity, %) 214 (M+, 3), 199 (39), 185 (39), 183 (41),
173 (45), 171 (64), 158 (61), 145 (100), 143 (55), 132 (82),
We are grateful to the NSC (NSC 93-2113-M-037-009),
Taiwan, for financial support.
Received May 31, 2004.
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