A novel synthesis of substituted naphthalenes via Claisen rearrangement and RCM reaction

Article abstract of DOI:10.1016/S0040-4039(01)01231-X

A novel synthesis of substituted naphthalenes was studied. Starting from isovanillin, basing on Claisen rearrangement and ring-closing metathesis (RCM), a series of 1-alkoxy-2-methoxynaphthalenes and 1-alkoxy-2-methoxy-8-methylnaphthalenes together with a

Full text of DOI:10.1016/S0040-4039(01)01231-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6155–6157
A novel synthesis of substituted naphthalenes via Claisen
rearrangement and RCM reaction
Keng-Shiang Huang and Eng-Chi Wang*
School of Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
Received 19 March 2001; revised 2 July 2001; accepted 6 July 2001
Abstract—A novel synthesis of substituted naphthalenes was studied. Starting from isovanillin, basing on Claisen rearrangement
and ring-closing metathesis (RCM), a series of 1-alkoxy-2-methoxynaphthalenes and 1-alkoxy-2-methoxy-8-methylnaphthalenes
together with a series of 2-alkoxy-3-methoxynaphthalenes were synthesized. © 2001 Elsevier Science Ltd. All rights reserved.
Naphthalenes, playing an important role as structural
units or key intermediates of naturally occurring alka-
loids attract the synthetic and natural product chemists
for their biological activities. Just as 1,8-dioxygenated
4-aryl-6-methylnaphthalene moiety is a structure unit of
anti-HIV agents michellamines A–C,1 and the related
naphthols.5 Recently, de Koning et al.5 reported by
heating O-allyl substituted acylbenzenes with potassium
tert-butoxide in DMF with simultaneous irradiation
from a high-pressure mercury lamp to afford substi-
tuted naphthalenes. However, those methods still have
some disadvantages including tedious reaction condi-
tions, low yield, and commercially unavailable key
intermediates which are difficult to prepare. Thus, it is
necessary to develop more practical and efficient meth-
ods for the preparation of multi-substituted naphthale-
nes. Since Grubbs et al.6 discovered a novel alkylidene
ruthenium complex as a catalyst for ring-closing
metathesis (RCM) in 1995, it has been widely applied in
organic synthesis for many aspects.7 Until present only
a little attention has been paid to apply this RCM
reaction to naphthalene chemistry.8 Herein we like to
report a novel strategy for the synthesis of appropriate
naphthalenes such as 1-alkoxy-2-methoxynaphthalenes,
naphthylisoquinoline
alkaloids;2
1-bromo-4,5-di-
methoxy-7-methyl- naphthalene is a key intermediate of
antimalarial alkaloids, korupensamine C and ancistro-
brevine B;3 and naphthol is a starting material for
propranolol, a b-blocking agent.4 However, the strate-
gies for the construction of substituted naphthalenes
are quite insufficient. In literatures few methods have
been described such as cyclization of 2-allyl-3-benzyl-
oxy-4,6-dimethoxyacetophenone with potassium tert-
butoxide gave 5-methylnaphthalene in 48% yield by a
reported procedure,5 cyclization of 2-(1-propenyl)-
benzamides with base resulted in the formation of
Conditions and % yields of Claisen rearrangement
OH
R
CH3O
Reaction
time (hr)
product (%yield)
( oC/solvent)
2a
2b
3b
Compds
CHO
O
R
2
92
3
CH3O
175-180/neat
180/decalin
1a
1a
1a
OH
5
1
95
95
CH3O
CHO
217/Diethylanilline
1
CHO
R
175-180/neat
1b
1b
1b
a. R=H
b. R=CH3
48
71
67
16
36
180/decalin
10
20
16
16
3
217/Diethylanilline
Scheme 1.
* Corresponding author. Fax: 886-7-3125339; e-mail: enchwa@cc.kmu.edu.tw
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01231-X

6156
K.-S. Huang, E.-C. Wang / Tetrahedron Letters 42 (2001) 6155–6157
1-alkoxy-2-methoxy-8-methylnaphthalenes,
together
aldehydes with vinyl magnesium bromide, it gave corre-
sponding 1-(2-allyl-3-alkoxy-4-methoxyphenyl)-2-pro-
pen-1-ols (6a–c), 1-[3-alkoxy-4-methoxy-2-(1-methyl-
allyl)phenyl]-2-propen-1-ols (6d–f), and 1-[5-alkoxy-2-
(2-butenyl)-4-methoxyphenyl]-2-propen-1-ols (7d-f) in
good yields. Finally by treating these propen-1-ols with
Grubbs’ catalyst to undergo RCM reaction, and fol-
lowed by dehydration in situ in the presence of silica
gel, it afforded a series of substituted naphthalenes
8a–f, and 9g–i in good yields. The results of percentage
yield were compiled in Table 1.
with a series of 2-alkoxy-3-methoxynaphthalenes start-
ing from isovanillin via Claisen rearrangement (Scheme
1) and RCM reaction (Scheme 2).
Claisen rearrangement with three different reaction
conditions: gently boiling and with strongly stirring in
neat, in decalin, and in N,N-diethylanilline were,
respectively investigated. When 1a was treated in all
three different conditions, it gave almost ortho product,
2a in 92–95% yields. But, when 1b was treated with the
same conditions, it not only gave ortho product, 2b but
also para product, 3b in various ratios (see Scheme 1).
When 2a, 2b, and 3b were, respectively treated with
some various alkyl halides, it afforded corresponding
2-allyl-3-alkoxy-4-methoxybenzaldehydes (4a–c), 3-
alkoxy-4-methoxy-2-(1-methylallyl)benzaldehydes (4d–
f), and 2-(2-butenyl)-5-alkoxy-4-methoxybenzaldehydes
(5d–f) in excellent yields. Followed by treating these
In conclusion with our synthetic strategy starting from
isovanillin, basing on Claisen rearrangement and RCM
reaction, a novel route to prepare appropriately substi-
tuted naphthalenes such as 1-alkoxy-2-methoxynaph-
thalenes and 1-alkoxy-2-methoxy-8-methylnaphthalenes
together with a series of 2-alkoxy-3-methoxynaphthale-
nes has been established. The synthesis of other substi-
OR1
OR1 R
R
OH
OR1
CH3O
R
R
CH3O
CH3O
Grubbs cat.
CH3O
R1Br(Cl)
K2CO3
MgBr
CHO
CHO
OH
6
2
8
4
a. R=H, R1=CH3 ; b. R=H, R1=C2H5 ;
PCy3
Ru
Cl
Ph
a. R=H
b. R=CH3
c. R=H, R1=CH2C6H5 ; d. R= R1=CH3 ;
Grubbs cat.=
H
Cl
e. R=CH3, R1=C2H5 ; f. R=CH3, R1=CH2C6H5
PCy3
OR1
OR1
OH
CH3O
CH3O
CH3O
OR1
R1Br(Cl)
K2CO3
MgBr
Grubbs cat.
OH
CHO
CHO
OCH3
5
7
9
3b
CH3
CH3
CH3
g. R1=CH3
h. R1=C2H5
i. R1=CH2C6H5
d. R1=CH3
e. R1=C2H5
f. R1=CH2C6H5
Scheme 2.
Table 1. Yields (%) for compounds 4, 5, 6, 7, 8 and 9 in Scheme 2
Substituents
Aldehydes 4
Aldehydes 5
Propen-1-ols 6
Propen-1-ols 7
Naphthalenes 8a Naphthalenes 9a
a
b
c
R=H, R1=CH3
R=H, R1=C2H5
R=H,
88
80
98
96
86
89
83
919
95
R1=CH2C6H5
R=R1=CH3
R=CH3,
d
e
92
80
83
84
78
82
83
84
89
89
R1=C2H5
f
R=CH3,
97
87
80
92
80
R2=CH2C6H5
R1=CH3
R1=C2H5
g
h
i
82
84
89
R1=CH2C6H5
a All naphthalenes are new compounds except 8a,10 8d,11 9g,8 and 9i.12 The structural elucidation of these intermediates and all substituted
naphthalenes was confirmed by spectral data such as 1H NMR, 13C NMR, MS and HRMS.

K.-S. Huang, E.-C. Wang / Tetrahedron Letters 42 (2001) 6155–6157
6157
tuted naphthalenes and naphthols via RCM reaction
References
are currently in progress in our laboratory. Further-
more the investigation of the effect of various allyloxy
groups on isovanillin to undergo Claisen rearrangement
is also currently in progress.
1. Boyd, M. R.; Hallock, Y. F.; Cardellina, II, J. H.;
Manfredi, K. P.; Blunt, J. W.; McMahon, J. B.; Buckheit,
Jr., R. W.; Bringmann, G.; Schaffer, M.; Cragg, G. M.;
Thomas, D. W.; Jato, J. G. J. Med.Chem. 1994, 37,
1740–1745.
General procedure for the preparation of naphthalenes
2. Hallock, Y. F.; Manfredi, K. P.; Blunt, J. W.; Cardellina,
II, J. H.; Schaffer, M.; Gluden, K. P.; Bringmann, G.;
Lee, A. Y.; Clardy, J.; Francois, G.; Boyd, M. R. J. Org.
Chem. 1994, 59, 6349–6355.
3. (a) Hoye, T. R.; Mi, L. Tetrahedron Lett. 1996, 37,
3097–3098; (b) Hoye, T. R.; Mi, L. J. Org. Chem. 1997,
62, 8586–8588.
4. (a) Kunz, W.; Jacobi, H.; Koch, K. Patent Sanol
Arzneim. DE 1236523, 1967; Chem. Abstr. 1967, 67,
64046k; (b) Crowther, A. F.; Smith, L. H. Patent Impe-
rial Chem. Ind. BE 640312. 1964; Chem. Abstr. 1965, 63,
6933.
5. de Koning, C. B.; Michael, J. P.; Rousseau, A. L. J.
Chem. Soc., Perkin Trans. 1 2000, 787–797 and references
cited therein.
6. Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2039–2041.
7. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413–4450; (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18–29; (c) Wang, E. C.; Huang, K. S.; Lin,
G. W.; Lin, J. R.; Hsu, M. K. J. Chin. Chem. Soc. 2001,
48, 83–90.
8. Evans, P.; Grigg, R.; Ramzan, M. I.; Sridharan, V.;
York, M. Tetrahedron Lett. 1999, 40, 3021–3024.
9. Data for 6b: colorless liquid, 1H NMR (CDCl3, 600
(8a–f) and (9g–i)
Compound 6a–f or 7d–f (1 mmol) dissolved in anhy-
drous CH2Cl2 (15 mL), was added with Grubbs catalyst
(0.05 mmol). The mixture was stirred for 2 h at ambient
temperature under dry argon. And then the solution
was added with silica gel (0.25 g) and continually
stirred for overnight at room temperature. Finally the
solvent was removed under reduced pressure, and the
residue was subjected to a silica gel column (1:1 hexane/
MTBE) or to distill under vacuum to give 8a–f and
9g–i, respectively. The selected spectral data was given
as follows: Compound 8f was obtained as colorless
crystals, mp 67–68°C; bp 120–121°C (3 mmHg); 1H
NMR (CDCl3, 600 MHz) l: 2.89 (s, 3H, CH3
6 ), 3.99 (s,
3H, OCH3), 5.07 (2H, OCH2C6H5), 7.20 (d, J=7.2 Hz,
6
6
1H), 7.21 (t, J=7.2 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H),
7.35 (t, J=7.2 Hz, 1H), 7.42 (t, J=7.2 Hz, 1H), 7.57 (d,
J=7.2 Hz, 2H), 7.61 (d, J=7.2 Hz, 1H), 7.62 (d, J=8.4
Hz, 1H); 13C NMR (CDCl3, 100 MHz) l: 24.05 (C
56.85 (OC6 H3), 75.56 (OC6 H2C6H5), 114.61, 123.64,
6
H3),
125.26, 126.49, 127.71, 127.93, 128.36, 128.65, 129.10,
130.92, 133.35, 137.92, 144.12, 149.81. EI–MS (70 eV)
m/z 278 (M+, 100), 263 (23.67), 245 (21.23), 235 (12.02),
202 (28.02), 145 (25.08), 129 (14.52), 115 (22.90), 91
(20.30); HRMS: calcd. for C19H18O2: 278.1307. Found:
278.1307. Compound 9h was obtained as colorless crys-
MHz) l: 1.36 (t, J=7.2 Hz, 3H, OCH2CH3
1H, OH, D2O exchangeable), 3.50 (ddt, J=15.6 Hz,
J=5.4 Hz, J=1.8 Hz, 1H, CH2=CH CH2), 3.60 (ddt,
J=15.6 Hz, J=5.4 Hz, J=1.8 Hz, 1H, CH2=CH CH2),
3.82 (s, 3H, OCH3), 3.98 (q, J=7.2 Hz, 2H, OCH2CH3),
6 ), 2.11 (br s.
1
6
tals, mp 77–78°C; H NMR (CDCl3, 600 MHz) l: 1.54
6
(t, J=6.8 Hz, 3H, OCH2CH3
6 ), 3.98 (s, 3H, OCH6 3), 4.21
6
(q, J=6.8 Hz, 2H, OCH2CH3), 7.11 (s, 2H, H-1 and
6
4.91 (dd, J=16.8 Hz, 1.8 Hz, 1H), 5.01 (dd, J=9.9 Hz,
1.8 Hz, 1H), 5.17 (dt, J=10.2 Hz, 1.2 Hz, 1H), 5.31 (dt,
J=16.8 Hz, 1.2 Hz, 1H), 5.35 (br. s, 1H), 6.02 (m, 2H),
6.80, 7.13 (each d, J=8.4 Hz, 2H, H-5 and H-6); 13C
H-4), 7.33 (dt, J=9.6 Hz, J=3.6 Hz, 2H, H-6, H-7),
7.68 (ddd, J=9.6 Hz, J=5.7 Hz, J=3.6 Hz, 2H, H-5,
H-8); 13C NMR (CDCl3, 100 MHz) l: 14.61 (C
6
H3),
55.80 (OC6 H3), 64.09 (OC6 H2CH3), 106.36, 107.27,
NMR (CDCl3, 100 MHz) l: 15.43 (OCH2C
(CH2=CHCH2), 55.35 (OCH3), 68.58 (OCH2CH3), 70.58
(CHOH), 110.23, 114.07, 122.17, 131.23, 137.43, 139.95,
6 H3), 29.69
124.04, 126.20, 129.07, 129.19, 148.72, 149.65; EI-MS
(70 eV) m/z 202 (M+, 79.17), 174 (100), 159 (58.71), 131
(91.91), 115 (31.07), 102 (33.21), 77 (13.06); HRMS:
calcd for C13H14O2: 202.0994. Found: 202.0992.
6
6
6
6
146.05, 151.97; HRMS, calcd for C15H20O3: 248.1412.
Found: 248.1414.
10. Bisanz, T. Rocz. Chem. 1956, 30, 111–118; Chem. Abstr.
1957, 51, 323i.
11. (a) Carvalho, C. F.; Russo, A. V.; Sargent, M. V. Aust. J.
Chem. 1985, 38, 777–792; (b) Loozen, H. J. J. J. Org.
Chem. 1975, 40, 520–521.
Acknowledgements
We wish to thank Professor Takahada Hiroki, Hokaido
Pharmaceutical University for valuable discussion, and
to thank NSC, Taiwan for financial support.
12. Narasimhan, N. S.; Mukhopadhyay, T.; Kusurkar, S. S.
Indian J. Chem. Sect. B. 1981, 20, 546–548.
.