Claisen rearrangement/Baylis-Hillman reaction/ring-closing metathesis as bases for the construction of substituted cyanonaphthalenes

Article abstract of DOI:10.1016/j.tet.2007.01.054

The present paper described how to establish a novel approach for various alkoxycyanonaphthalenes. It was started from isovanillin, and based on the Claisen rearrangement, O-alkylation, the Baylis-Hillman reaction, and ring-closing metathesis in sequence

Full text of DOI:10.1016/j.tet.2007.01.054

Tetrahedron 63 (2007) 2824–2828
Claisen rearrangement/Baylis–Hillman reaction/ring-closing
metathesis as bases for the construction of substituted
cyanonaphthalenes
Po-Yuan Chen,a Hsing-Ming Chen,b Liang-Yeu Chen,c Jing-Yu Tzeng,c Jui-Chi Tsai,c
Ping-Cheng Chi,a Sie-Rong Lic and Eng-Chi Wanga,
*
aFaculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
bBasic Medical Science Education Center, Fooyin University, Kaohsiung County 831, Taiwan
cInstitute of Pharmaceutical Sciences, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
Received 14 December 2006; revised 24 January 2007; accepted 25 January 2007
Available online 30 January 2007
Abstract—The present paper described how to establish a novel approach for various alkoxycyanonaphthalenes. It was started from isova-
nillin, and based on the Claisen rearrangement, O-alkylation, the Baylis–Hillman reaction, and ring-closing metathesis in sequence to produce
the title compounds in good yield.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
potential heterocyclic ring systems such as naphthotetr-
azoles,10 naphthotriazines,11 and so on. Until the present,
synthetic methods reported for the preparation of cyano-
arenes mainly included the reaction of aryl halides with
copper cyanide (Rosenmund–von Braun reaction),12 and
aryldiazonium salts with copper cyanide (Sandmeyer reac-
tion).13 Instead of copper, some transition metal-catalyzed
cyanations of aryl halides have been intensively studied.14
However, the toxic inorganic metal cyanides, which are
required for running those reactions, have disadvantages.
Therefore, to develop a unique route for new cyanonaphtha-
lenes with environment concerning is requisite and sig-
nificant. Herein, we extended our previous study15 and
disclosed a novel route by starting from isovanillin and based
on the Claisen rearrangement, Baylis–Hillman reaction, and
RCM in sequence to offer various cyanonaphthalenes, which
have paid no attention in the reported literatures (Scheme 1).
The discovery of the Claisen rearrangement almost a century
ago offered a brief and useful tool to give C-allyl functional-
ity from O-allylphenol.1 The Baylis–Hillman reaction which
offered a simple way to build up an allyl alcohol with a-elec-
tron withdrawing substituents has been used at various
aspects in organic synthesis.2 On the other hand, a molecule
with two olefinic functionalities can be ring-closed through
ring-closing metathesis (RCM), which becomes a powerful
and important tool to produce unsaturated cyclic com-
pounds,3 and also provides distinguished ways to generate
arenes with unique mechanisms.4 However, up to date, to
combine those reactions to construct the naphthalenes moi-
ety is still lacking. Naphthalenes, the sub-group of arenes,
have intensively attracted the attention of organic chemists
for many years due to their occurrence in synthetic and
nature products possessing valuable biological activities.5
The major synthetic naphthalenes, such as nabumetone6
and naproxen7 for anti-inflammation, and propranolol8 for
b-blocker to treat tachycardia and angina pectoris, are
currently used in medication. Recently, some cyanonaphtha-
lenes were synthesized and reported to exhibit as potential
tachykinin antagonists.9 Furthermore the nitrile can also
serve as useful functional group for some biologically
2. Results and discussion
2-Allyl-3-alkoxy-4-methoxybenzaldehydes (4a–e) prepared
from isovanillin (1) through three steps as our previous
report15 were allowed to react with acrylonitrile in the
presence of 1,4-diazabicylo[2.2.2]octane (DABCO) or 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) to undergo the
Baylis–Hillman reaction. Two solvent systems were taken
for this Baylis–Hillman reaction, when water/dioxane (1:1)
was used as solvent and DABCO as base, compound 5a
was obtained in the yield of 50% after stirring for 5 days.
Keywords: Claisen rearrangement; Ring-closing metathesis; Cyanonaphtha-
lenes.
* Corresponding author. Tel.: +886 7 3121101; fax: +886 7 3125339;
e-mail: enchwa@kmu.edu.tw
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.054

P.-Y. Chen et al. / Tetrahedron 63 (2007) 2824–2828
2825
OR
OH
OR
OH
O
H3CO
H3CO
H3CO
H3CO
H3CO
ii
i
iii
iv
92%
80-98%
95%
53-67%
CHO
CHO
CHO
CN
CHO
OH
4
5
2
1
3
OR
H3CO
v
a. R = CH3; b. R = C2H5; c. R = (CH3)2CH;
d. R = n-C4H9; e. R = CH2C6H5; f. R=H
81-90%
CN
81%
vi
6
Scheme 1. Synthesis of substituted cyanonaphthalenes. Conditions: (i) allyl bromide K2CO3, acetone, reflux 8 h; (ii) 180 ꢁC, decalin, 5 h; (iii) (a) methyl iodide,
(b) ethyl iodide, (c) isopropyl bromide, (d) n-butyl bromide, and (e) benzyl bromide, K2CO3, acetone, reflux 8 h; (iv) acrylonitrile, DABCO, H2O, rt, 3–5 days;
(v) 5% second Grubbs’ catalyst, 0.05 M CH2Cl2, rt, 5–8 h; (vi) 20% Pd(OH)2/C, cyclohexene, ethanol, reflux 10 h.
In contrast, when water was used as sole solvent and
DABCO as base, the reaction time is shorter (3 days) and
the yield (60%) is higher than that of the mixed solvents.
The results giving the Baylis–Hillman adducts (5a–e) are
compiled in Table 1.
with H-7 in the structure of compound 6b can be clarified, re-
spectively. The signal of H-3 at d 7.39 linking with methoxyl
signal at d 4.02 and H-8 at d 8.20 linking with H-7 at d 7.56,
which has double doublet splits with coupling constant J¼8.8
and 1.4 Hz were observed. Besides, H-4 at d 7.66, which
linked with H-3, and H-5 at d 8.16, which havea meta-couple,
J¼1.8 Hz, linked with H-7 are also can be assigned. Further-
more, the ranking of chemical shift, H-3>H-7>H-4>
H-5>H-8, from upfield to downfield of those protons on
cyanonaphthalenes (6a–e) is certainly established. In addi-
tion, the structures of 6a–e were further confirmed by mass
spectra, HRMS, and elemental analysis. Furthermore, the
substitutedcyanonaphthol, 6f, wasproducedfromthedebenz-
ylation of 6e with Pd (OH)2/C and cyclohexene in refluxing
ethanol.
The spectral data of 5a–e, for example, the absorption at
3446–3469 and 2230–2253 cmꢀ1 in IR spectra was observed
indicating the presence of OH and CN functional group, re-
spectively. The signals at d 6.04–6.09 and 6.07–6.09 with
1
coupling constant J¼1.2–1.6 Hz in H NMR revealing the
existence of two geminal vinyl protons were also observed
in the structures 5a–e proving the work of the Baylis–Hill-
man reaction. In addition, the carbon signals in 13C NMR,
the molecular ion in EIMS, and exact mass in HRMS are
all match the structures 5a–e. Finally, the resulting adducts
(5a–e) were respectively subjected to RCM by Grubbs’ cat-
alyst (second generation) to undergo cyclization and elimina-
tion of water to give the desired cyanonaphthalenes (6a–e) in
the yield of 81–90%. The appearance of typical CN absorp-
tion at 2200–2230 cmꢀ1 in IR spectrum, no olefinic proton
at 1H NMR, and no sp3 carbon except for the alkoxy moiety
at 13C NMR spectra of giving 6a–e were observed indicating
the work of RCM. Moreover, in accordance with NOESY
technique, for example, the two key protons, H-3 which
neighbored with methoxyl group and H-8 which coupled
3. Conclusion
Based on the Claisen rearrangement, Baylis–Hillman reac-
tion, and RCM, we have successfully established a novel,
concise, and friendly to the earth way to construct new
substituted cyanonaphthalenes (6a–e). Moreover, compound
6e was debenzylated to give 1-hydroxy-6-cyano-2-methoxy-
naphthalene (6f) with polyfunctional groups, which can be
converted into corresponding compounds in diversity.
Table 1. The comparison of dioxane/H2O or H2O as solvents for aldehydes (4a–e) with selected bases (DABCO or DBU) to give the Baylis–Hillman adducts
(5a–e)
Compds
Solvents
Reaction timea (days)
Product and yieldsb (%)
R3N
4a
1,4-Dioxane:H2O (1:1)
H2O
1,4-Dioxane:H2O (1:1)
H2O
5
3
5
3
5a (57)
5a (61)
5a (35)
5a (42)
DABCO
DABCO
DBU
DBU
4b
1,4-Dioxane:H2O (1:1)
H2O
1,4-Dioxane:H2O (1:1)
H2O
5
3
5
3
5b (56)
5b (67)
5b (32)
5b (25)
DABCO
DABCO
DBU
DBU
4c
1,4-Dioxane:H2O (1:1)
H2O
5
3
5c (58)
5c (61)
DABCO
DABCO
4d
1,4-Dioxane:H2O (1:1)
H2O
5
3
5d (48)
5d (60)
DABCO
DABCO
4e
1,4-Dioxane:H2O (1:1)
H2O
5
3
5e (42)
5e (53)
DABCO
DABCO
a
The reaction time is determined by GC–MS until the desired product is no longer increased apparently.
Yield indicated the product which was isolated; the recovery starting material was not calculated.
b

2826
P.-Y. Chen et al. / Tetrahedron 63 (2007) 2824–2828
Besides, we have established all data for those cyanonaph-
thalenes (6a–f).
was obtained as a pale yellow liquid; Rf¼0.38 (ethyl ace-
tate/n-hexane¼1:2); IR (neat) cmꢀ1: 3458 cmꢀ1(OH),
2230 cmꢀ1 (CN); 1H NMR (CDCl3, 400 MHz) d 1.36 (t, J¼
7.2 Hz, 3H, OCH2CH3), 2.62 (br s, 1H, OH), 3.49 (ddt,
J¼16.4, 5.6, 2.0 Hz, 1H, ArCHaHbCH]CH2), 3.55 (ddt,
J¼16.4, 5.6, 1.6 Hz, 1H, ArCHaHbCH]CH2), 3.84 (s, 3H,
OCH3), 3.98 (m, 2H, OCH2CH3), 4.91 (ddt, J¼17.2, 1.6,
1.6 Hz, 1H, ArCH2CH]CHcHd), 5.05 (ddt, J¼10.0, 1.6,
1.6 Hz, 1H, ArCH2CHC]CHcHd), 5.44 (m, 1H, CHOH),
6.00 (ddt, J¼16.8, 10.0, 5.6 Hz, 1H, ArCH2CH]CH2),
6.07 (d, J¼1.6 Hz, 1H, CHeHf]C(CN)–), 6.09 (d,
J¼1.6 Hz, 1H, CHeHf]C(CN)–), 6.83 (d, J¼8.4 Hz, 1H,
ArH), 7.11 (d, J¼8.8 Hz, 1H, ArH); 13C NMR (CDCl3,
100 MHz) d 15.58, 29.75, 55.54, 68.99, 69.98, 110.55,
115.53, 117.26, 122.65, 125.76, 130.00, 130.36, 131.86,
137.20, 146.44, 153.09; EIMS (70 eV) m/z (rel intensity,
%) 273 (M+, 69), 244 (29), 221 (100), 193 (43), 185 (27),
184 (75), 143 (54), 115 (27); HRMS calcd for C16H19NO3:
273.1365, found: 273.1366.
4. Experimental
4.1. General
Melting points (Yanaco micro melting-point apparatus) were
uncorrected. 1H NMR and 13C NMR spectra were obtained
on a Varian Gemini-200 or Varian Unity plus 400 spectro-
meter. Chemical shifts were measured in parts per million
with respect to TMS. Elemental analyses were recorded on
a Heraeus CHNO rapid analyzer. Mass spectra were recorded
on a Chem/hp/middle spectrometer connected to a Hewlett
Packard series II model gas–liquid chromatograph. HRMS
spectra were performed on a JEOL JMS SX/SX 102A instru-
ment. Elemental analyses were run on Heraeus CHNO rapid
analyzer. Silica gel (230–400 mesh) for column chromato-
graphy and precoated silica gel plates (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.
4.1.1.3. 2-Cyano-3-(2-allyl-3-isopropyloxy-4-methoxy)-
phenyl-1-propen-3-ol (5c). Compound 5c (1.76 g, 61%)
was obtained as a pale yellow liquid; Rf ¼0.40 (ethyl ace-
tate/n-hexane¼1:2); IR (neat) cmꢀ1: 3469 mꢀ1 (OH),
2230 cmꢀ1 (CN); 1H NMR (CDCl3, 400 MHz) d 1.27 (d, J¼
6 Hz, 6H, CH(CH3)2), 2.59 (br s, 1H, OH), 3.48 (ddt, J¼16.4,
5.6, 1.6 Hz, 1H, ArCHaHbCH]CH2), 3.65 (ddt, J¼16.4, 5.6,
1.6 Hz, 1H, ArCHaHbCH]CH2), 3.83 (s, 3H, OCH3), 4.51
(sept, J¼6.0 Hz, 1H, CH(CH3)2), 4.92 (ddt, J¼17.2, 1.6,
1.6 Hz, 1H, ArCH2CH]CHcHd), 5.05 (ddt, J¼10.0, 1.6,
1.6 Hz, 1H, ArCH2CH]CHcHd), 5.48 (m, 1H, CHOH),
5.98 (ddt, J¼17.2, 10.0, 5.6 Hz, 1H, ArCH2CH]CH2),
6.05 (d, J¼1.6 Hz, 1H, CHeHf]C(CN)–), 6.07 (d, J¼
1.6 Hz, 1H, CHeHf]C(CN)–), 6.83 (d, J¼8.4 Hz, 1H,
ArH), 7.09 (d, J¼8.8 Hz, 1H, ArH); 13C NMR (CDCl3,
100 MHz) d 22.40, 30.00, 55.46, 69.85, 74.75, 110.49,
110.86, 115.56, 117.28, 122.22, 125.83, 129.86, 130.56,
132.05, 137.13, 144.93, 153.05; EIMS (70 eV) m/z (rel inten-
sity, %) 287 (M+, 25), 245 (64), 227 (21), 212 (21), 194 (45),
193 (100), 183 (26), 143 (33); HRMS calcd for C17H21NO3:
287.1521, found: 287.1522.
Isovanillin (1) was purchased from TCI, Japan. O-Allyliso-
vanillin (2), 2-allyl-3-hydroxy-4-methoxy-benzaldehydes
(3a–e), and 3-alkoxy-2-allyl-4-methoxybenzaldehydes
(4a–e) were prepared as described in the previous report.15
4.1.1. General procedure for the preparation of 2-cyano-
3-(2-allyl-3-alkoxy-4-methoxy)phenyl-1-propen-3-ol
(5a–e). A mixture of 4a–e (10.0 mmol) and acrylonitrile
(0.66 mL, 30 mmol) was added with DABCO (1.23 g,
11.0 mmol) in water (20 mL). The resulting mixture was
stirred at room temperature for 3 days. Then, the reaction
mixture was extracted with dichloromethane (3ꢂ50 mL).
The resulting extract was combined, washed with brine,
and dried over anhydrous MgSO4. After filtration, the filtrate
was concentrated in vacuo to give crude 5a–e, which was
respectively purified with chromatographic column (ethyl
acetate/n-hexane¼1:7).
4.1.1.1. 2-Cyano-3-(2-allyl-3,4-dimethoxy)phenyl-1-
propen-3-ol (5a). Compound 5a (1.58 g, 61%) was obtained
as a pale yellow liquid; Rf¼0.39 (ethyl acetate/n-hexane¼
1:2); IR (neat) cmꢀ1: 3466 cmꢀ1 (OH), 2254 cmꢀ1 (CN);
1H NMR (CDCl3, 400 MHz) d 3.02 (br s, 1H, OH), 3.46
(ddt, J¼16.4, 5.6, 2.0 Hz, 1H, ArCHaHbCH]CH2), 3.55
(ddt, J¼16.4, 5.6, 2.0 Hz, 1H, ArCHaHbCH]CH2), 3.78
(s, OCH3, 3H), 3.85 (s, OCH3, 3H), 4.89 (ddt, J¼17.2, 2.0,
2.0 Hz, 1H, ArCH2CH]CHcHd), 5.04 (ddt, J¼10.4, 2.0,
2.0 Hz, 1H, ArCH2CH]CHcHd), 5.41 (br s, 1H, CHOH),
5.98 (ddt, J¼17.2, 10.4, 5.6 Hz, 1H, ArCH2CH]CH2), 6.04
(d, J¼1.2 Hz, 1H, CHeHf]C(CN)–), 6.07 (d, J¼1.2 Hz, 1H,
CHeHf]C(CN)–), 6.83 (d, J¼8.4 Hz, 1H, ArH), 7.11 (d, J¼
8.4 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz) d 29.47,
55.44, 60.75, 69.76, 110.54, 115.49, 117.16, 122.79,
125.75, 129.96, 130.30, 131.62, 136.93, 147.00, 152.80;
EIMS (70 eV) m/z (rel intensity, %) 259 (M+, 67), 242 (32),
208 (34), 207 (100), 189 (43), 176 (28), 174 (34), 173 (31);
HRMS calcd for C15H17NO3: 259.1208, found: 259.1207.
4.1.1.4.
2-Cyano-3-(2-allyl-3-butoxy-4-methoxy)-
phenyl-1-propen-3-ol (5d). Compound 5d (1.81 g, 60%)
was obtained as a pale yellow liquid; Rf ¼0.39 (ethyl
acetate/n-hexane¼1:2); IR (neat) cmꢀ1: 3458 cmꢀ1 (OH),
2230 cmꢀ1 (CN); 1H NMR (CDCl3, 400 MHz) d 0.97 (t, J¼
7.2 Hz, 3H, CH2CH2CH2CH3), 1.49 (m, 2H, CH2CH2-
CH2CH3), 1.75 (quint, J¼7.05 Hz, 2H, CH2CH2CH2CH3),
2.52 (d, J¼4.0 Hz, 1H, OH), 3.48 (ddt, J¼16.0, 5.6,
1.6 Hz, 1H, ArCHaHbCH]CH2), 3.59 (ddt, J¼16.0, 5.6,
1.6 Hz, 1H, ArCHaHbCH]CH2), 3.84 (s, 3H, OCH3), 3.91
(m, 2H, OCH2CH2CH2CH3), 4.90 (ddt, J¼17.2, 1.6,
1.6 Hz, 1H, ArCH2CH]CHcHd), 5.05 (ddt, J¼10.4, 1.6,
1.6 Hz, 1H, ArCH2CH]CHcHd), 5.44 (s, 1H, CHOH),
6.00 (ddt, J¼17.2, 10.8, 5.6 Hz, 1H, ArCH2CH]CH2), 6.07
(d, J¼1.6 Hz, 1H, CHeHf]C(CN)–), 6.09 (d, J¼1.6 Hz, 1H,
CHeHf]C(CN)–), 6.83 (d, J¼8.8 Hz, 1H, ArH), 7.10 (d,
J¼8.8 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz)
d 13.86, 19.08, 29.69, 32.27, 55.54, 69.98, 73.08, 110.61,
115.53, 117.25, 122.60, 125.76, 129.97, 130.39, 131.82,
137.25, 146.55, 153.13; EIMS (70 eV) m/z (rel intensity,
%) 301 (M+, 41), 227 (31), 194 (31), 193 (100), 184 (34),
4.1.1.2. 2-Cyano-3-(2-allyl-3-ethoxyl-4-methoxy)-
phenyl-1-propen-3-ol (5b). Compound 5b (1.83 g, 67%)

P.-Y. Chen et al. / Tetrahedron 63 (2007) 2824–2828
2827
143 (23), 142 (32), 115 (24); HRMS calcd for C18H23NO3:
301.1678, found: 301.1680.
(OCH2CH3), 107.19, 116.24, 119.61, 123.03, 124.79,
126.31, 127.98, 130.88, 134.05, 141.73, 150.95; EIMS
(70 eV) m/z (rel intensity, %) 227 (M+, 62), 199 (100), 185
(23), 184 (81), 170 (44), 156 (39), 128 (14), 115 (17);
HRMS calcd for C14H13NO2: 227.0946, found: 227.0948;
Anal. Calcd for C14H13NO2: C, 73.99%; H, 5.77%; N,
6.16%. Found: C, 74.03%; H, 5.75%; N, 6.20%.
4.1.1.5. 2-Cyano-3-(2-allyl-3-benzyloxy-4-methoxy)-
phenyl-1-propen-3-ol (5e). Compound 5e (1.77 g, 53%)
was obtained as a pale yellow liquid; Rf ¼0.37 (ethyl
acetate/n-hexane¼1:2); IR (neat) cmꢀ1: 3446 cmꢀ1 (OH),
1
2230 cmꢀ1 (CN); H NMR (CDCl3, 400 MHz) d 2.17 (d,
J¼4.4 Hz, 1H, OH), 3.45 (ddt, J¼16.0, 5.2, 1.6 Hz, 1H,
ArCHaHbCH]CH2), 3.59 (ddt, J¼16.0, 5.2, 1.6 Hz, 1H,
ArCHaHbCH]CH2), 3.90 (s, 3H, OCH3), 4.90 (ddt,
J¼17.2, 1.6, 1.6 Hz, 1H, ArCH2CH]CHcHd), 4.99 (d, J¼
5.6 Hz, 2H, OCH2Ph), 5.05 (dd, J¼10, 1.6, 1.6 Hz, 1H,
ArCH2CH]CHcHd), 5.44 (dt, J¼4.4, 0.8 Hz, 1H, CHOH),
5.98 (ddt, J¼17.2, 5.2, 1.6 Hz, 1H, ArCH2CH]CH2),
6.09 (d, J¼1.6 Hz, 2H, CH2]C(CN)–), 6.91 (d, J¼8.8 Hz,
1H, ArH), 7.17 (d, J¼8.8 Hz, 1H, ArH), 7.32–7.40 (m,
3H, OCH2PhH), 7.44–7.46 (m, 2H, OCH2PhH); 13C NMR
(CDCl3, 100 MHz) d 29.88, 55.70, 70.17, 74.83, 110.81,
115.72, 117.25, 123.04, 125.69, 127.93, 128.06, 128.25,
128.39, 129.97, 130.07, 130.46, 132.15, 137.30, 137.63,
146.19, 153.28; EIMS (70 eV) m/z (rel intensity, %) 335
(M+, 23), 244 (10), 226 (12), 194 (13), 191 (11), 185 (13),
92 (26), 91 (100); HRMS calcd for C21H21NO3: 335.1521,
found: 335.1513.
4.1.2.3. 1-Isopropoxy-2-methoxy-6-cyanonaphthalene
(6c). Compound 6c (0.15 g, 85%) was obtained as a colorless
crystal; mp 80–81 ꢁC, Rf ¼0.42 (ethyl acetate/n-
1
hexane¼1:5); IR (KBr) cmꢀ1: 2223 cmꢀ1 (CN); H NMR
(CDCl3, 200 MHz) d 1.35 (d, J¼6.0 Hz, 6H, OCH(CH3)2),
4.00 (s, 3H, OCH3), 4.67 (sept., J¼6.0 Hz, 1H, OCH(CH3)2),
7.39 (d, J¼8.8 Hz, 1H, H-3), 7.53 (dd, J¼1.4, 8.8 Hz, 1H, H-
7), 7.63 (d, J¼8.8 Hz, 1H, H-4), 8.13 (d, J¼1.4 Hz, 1H, H-5),
8.22 (d, J¼8.8 Hz, 1H, H-8); 13C NMR (CDCl3, 50 MHz)
d 22.64 (OCH(CH3)2), 56.55 (OCH3), 75.60 (OCH(CH3)2),
107.10, 116.28, 119.52, 123.52, 124.39, 125.96, 127.99,
131.64, 133.85, 140.69,150.94; EIMS (70 eV) m/z (rel inten-
sity, %) 241 (M+, 26), 199 (100), 186 (21), 185 (82), 156 (31);
HRMS calcd for C15H15NO2: 241.1103, found: 241.1101;
Anal. Calcd for C15H15NO2: C, 74.67%; H, 6.27%; N,
5.81%. Found: C, 74.69%; H, 6.30%; N, 5.79%.
4.1.2.4. 1-n-Butoxy-2-methoxy-6-cyanonaphthalene
(6d). Compound 6d (0.2 g, 81%) was obtained as a colorless
crystal; mp 45–46 ꢁC, Rf ¼0.39 (ethyl acetate/n-hexane¼
4.1.2. General procedure for the preparation of 6-cyano-
1-alkoxy-2-methoxynaphthalenes (6a–e). A solution of
5a–e (0.20 g, 0.77 mmol) in dichloromethane (60 mL) was
added with Grubbs’ catalyst (second generation) (0.03 g,
0.04 mmol) under the protection of dried nitrogen at room
temperature. The resulting mixture was stirred for 5 h from
the monitoring of TLC, and then concentrated in vacuo.
The residue was purified from silica-gel chromatographic
column (ethyl acetate/n-hexane¼1:15) to give pure 6a–e.
1
1:5); IR (KBr) cmꢀ1: 2223 cmꢀ1 (CN); H NMR (CDCl3,
200 MHz) d 1.01 (t, J¼7.0 Hz, 3H, –CH2CH2CH2CH3), 1.58
(m, 2H, –CH2CH2CH2CH3), 1.86 (quint, J¼7.0 Hz, 2H,
CH2CH2CH2CH3), 4.01 (s, 1H, OCH3), 4.12 (t, J¼7.0 Hz,
2H, OCH2CH2), 7.39 (d, J¼9.2 Hz, 1H, H-3), 7.55 (dd,
J¼1.4, 8.8 Hz, 1H, H-7), 7.64 (d, J¼9.2 Hz, 1H, H-4), 8.15
(d, J¼1.4 Hz, 1H, H-5), 8.19 (d, J¼8.8 Hz, 1H, H-8); 13C
NMR (CDCl3, 50 MHz) d 14.02, 19.43, 32.53, 56.80,
73.76, 107.31, 116.58, 119.65, 123.03, 124.70, 126.31,
128.15, 130.85, 134.08, 142.17, 150.95; EIMS (70 eV) m/z
(rel intensity, %) 255 (M+, 31), 199 (100), 185 (30), 184
(39), 156 (14); HRMS calcd for C16H17NO2: 255.1259,
found: 255.1263; Anal. Calcd for C16H17NO2: C, 75.27%;
H, 6.71%; N, 5.49%. Found: C, 75.30%; H, 5.73%; N, 5.52%.
4.1.2.1. 6-Cyano-1,2-dimethoxynaphthalene (6a).
Compound 6a (0.14 g, 85%) was obtained as a colorless crys-
tal; mp 98–99 ꢁC, Rf ¼0.34 (ethyl acetate/n-hexane¼1:5); IR
(KBr) cmꢀ1: 2219 cmꢀ1 (CN); 1H NMR (CDCl3, 400 MHz)
d 4.00 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 7.41 (d, J¼9.0 Hz,
1H, H-3), 7.57 (dd, J¼1.4, 8.8 Hz, 1H, H-7), 7.67 (d,
J¼9.0 Hz, 1H, H-4), 8.16 (d, J¼1.4 Hz, 1H, H-5), 8.09 (d,
J¼8.8 Hz, 1H, H-8), 13C NMR (CDCl3, 100 MHz) d 56.53
(OCH3), 61.15 (OCH3), 107.12, 116.18, 119.47, 122.64,
124.89, 126.30, 127.87, 130.26, 133.98, 142.53, 150.78;
EIMS (70 eV) m/z (rel intensity, %) 213 (M+, 71), 198 (61),
191 (71), 170 (94), 167 (28), 152 (22), 150 (25), 149 (100),
147 (29), 127 (22), 91 (38), 71 (27), 55 (37); HRMS calcd
for C13H11NO2: 213.0790, found: 213.0790; Anal. Calcd
for C13H11NO2: C, 73.23%; H, 5.20%; N, 6.57%. Found:
C, 73.26%; H, 5.19%; N, 6.59%.
4.1.2.5. 1-Benzyloxy-6-cyano-2-methoxynaphthalene
(6e). Compound 6e (0.07 g, 81%) was obtained as a colorless
crystal; mp 39–40 ꢁC, Rf ¼0.38 (ethyl acetate/n-hexane¼
1
1:5); IR (KBr) cmꢀ1: 2219 cmꢀ1 (CN); H NMR (CDCl3,
400 MHz) d 4.01 (s, 3H, OCH3), 5.15 (s, 2H, OCH2Ph),
7.32–7.40 (m, 3H, OCH2PhH), 7.38 (d, J¼8.8 Hz, 1H,
H-3), 7.45 (dd, J¼8.8, 1.4 Hz, 1H, H-7), 7.48–7.50 (m, 2H,
OCH2PhH), 7.61 (d, J¼8.8 Hz, 1H, H-4), 8.08 (d, J¼
1.4 Hz, 1H, H-5), 8.10 (d, J¼8.8 Hz, 1H, H-8); 13C NMR
(CDCl3, 100 MHz) d 56.47, 75.27, 107.00, 116.04, 119.43,
122.85, 124.93, 126.13, 127.74, 128.09, 128.22, 128.37,
130.52, 133.83, 137.14, 141.27, 150.80; EIMS (70 eV) m/z
(rel intensity, %) 289 (M+, 100), 274 (11), 258 (23), 256
(47), 246 (13), 228 (23), 227 (16); HRMS calcd for
C19H15NO2: 289.1103, found: 289.1103; Anal. Calcd for
C19H15NO2: C, 78.87%; H, 5.23%; N, 4.84%. Found: C,
78.90%; H, 5.21%; N, 4.86%.
4.1.2.2. 6-Cyano-1-ethoxy-2-methoxynaphthalene
(6b). Compound 6b (0.15 g, 90%) was obtained as a color-
less crystal; mp 78–79 ꢁC, Rf ¼0.41 (ethyl acetate/n-
1
hexane¼1:5); IR (KBr) cmꢀ1: 2219 cmꢀ1 (CN); H NMR
(CDCl3, 400 MHz) d 1.47 (t, J¼7.0 Hz, 3H, OCH2CH3),
4.02 (s, 3H, OCH3), 4.21 (t, J¼7.0 Hz, 2H, OCH2CH3),
7.40 (d, J¼9.0 Hz, 1H, H-3), 7.56 (dd, J¼1.8, 8.8 Hz, 1H,
H-7), 7.66 (d, J¼9.0 Hz, 1H, H-4), 8.16 (d, J¼1.8 Hz, 1H,
H-5), 8.20 (d, J¼8.8 Hz, 1H, H-8), 13C NMR (CDCl3,
100 MHz) d 15.76 (OCH2CH3), 56.62 (OCH3), 69.47
4.1.3. Preparation of 1-hydroxy-6-cyano-2-methoxy-
naphthalene (6f). A mixture of compound 6e (0.09 g,

2828
P.-Y. Chen et al. / Tetrahedron 63 (2007) 2824–2828
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0.31 mmol), Pd(OH)2/C (20%, 0.05 g, 0.34 mmol), cyclo-
hexene (5.4 mL), and ethanol (30 mL) was refluxed for
10 h. The resulting mixture was concentrated in vacuo to
give the residue, which was purified from silica-gel chroma-
tographic column to yield pure 6f.
4.1.3.1. 1-Hydroxy-6-cyano-2-methoxynaphthalene
(6f). Compound 6f (0.05 g, 81%) was obtained as a colorless
crystal; mp 72–73 ꢁC, Rf ¼0.40 (ethyl acetate/n-hexane¼
1:5); IR (KBr) cmꢀ1: 3380 cmꢀ1 (OH), 2230 cmꢀ1 (CN);
1H NMR (CDCl3, 400 MHz) d 4.04 (s, 3H, OCH3), 6.12
(br s, 1H, OH), 7.36 (d, J¼8.6 Hz, 1H, H-3), 7.47 (d,
J¼8.6 Hz, 1H, H-4), 7.53 (dd, J¼1.8, 8.7 Hz, 1H, H-7),
8.13 (d, J¼1.8 Hz, 1H, H-5), 8.21 (d, J¼8.8 Hz, 1H, H-8);
13C NMR (CDCl3, 100 MHz) d 56.81, 107.37, 114.18,
119.61, 120.46, 122.65, 125.45, 127.79, 128.49, 134.05,
139.59, 143.65; EIMS (70 eV) m/z (rel intensity, %) 199
(M+, 77) 184 (100), 157 (14), 156 (99), 128 (54), 101 (33),
77 (15), 75 (25); HRMS calcd for C12H9NO2: 199.0633,
found: 199.0634; Anal. Calcd for C12H9NO2: C, 72.35%;
H, 4.55%; N, 7.03%. Found: C, 72.38%; H, 4.53%; N, 7.01%.
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Acknowledgements
We are grateful to NSC (NSC-95-2113-M-037-012), Taiwan
for financial support and to Professor Hiroki Takahata, To-
hoku Pharmaceutical University, Japan for encouragement.
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