Cu(OTf)2-catalyzed isomerization of 7-oxabicyclic alkenes: A practical route to the synthesis of 1-naphthol derivatives

Article abstract of DOI:10.1055/s-2008-1067268

Lewis acid catalyzed isomerization of 7-oxabicyclic alkenes into 1-naphthol derivatives in high yields (87-98%) under mild reaction conditions has been developed. The mechanism of this reaction is briefly postulated. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067268

PAPER
3043
Cu(OTf)2-Catalyzed Isomerization of 7-Oxabicyclic Alkenes:
A Practical Route to the Synthesis of 1-Naphthol Derivatives
A
P
ractica
l
Sy
a
nthesis of
1
n
-Naphthol
D
g
erivatives zhi Peng,1 Baomin Fan,1 Zhihui Shao,* Xuewei Pu, Penghui Li, Hongbin Zhang
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education,
School of Chemical Science and Technology, Yunnan University, Kunming 650091, P. R. of China
Fax +86(871)5033538; E-mail: zhihui_shao@hotmail.com
Received 19 May 2008; revised 19 June 2008
lysts for the isomerization of 7-oxabicyclic alkenes into 1-
naphthol derivatives, probably due to the reaction with the
bridging oxygen of 7-oxabicyclic alkenes, which reduces
the reactivity of Lewis acids. Metal triflates are unique
Lewis acids that are currently of great research inter-
est.12–17 Metal triflates are generally stable and still active
in the presence of many substrates containing heteroatoms
such as nitrogen, oxygen and sulfur. Due to these advan-
tages, they are widely used in organic synthesis.18 We en-
visioned that metal triflates with suitable cations and
anions might be effective catalysts for the isomerization
of 7-oxabicyclic alkenes into 1-naphthol derivatives. In
this paper, we report the first example of Cu(OTf)2-cata-
lyzed isomerization of 7-oxabicyclic alkenes into 1-naph-
thol derivatives under mild conditions.19
Abstract: Lewis acid catalyzed isomerization of 7-oxabicyclic alk-
enes into 1-naphthol derivatives in high yields (87–98%) under mild
reaction conditions has been developed. The mechanism of this re-
action is briefly postulated.
Keywords: catalysis, copper, isomerization, 1-naphthol derivative,
7-oxabicyclic alkenes
Brønsted acid catalyzed isomerization of 7-oxabicyclic
alkenes into 1-naphthol derivatives is one of the most fun-
damental reactions in organic synthesis.2–4 This process
has proven to be effective for incorporating the naphthol
fragment into complex molecules;5–8 however, the use of
strong protic acids has limited the utilization of this reac-
tion, especially in Brønsted acid sensitive substrates. Fur-
thermore, the use of strong protic acids leads to highly
acidic waste streams, which pose an environmental prob-
lem for industrial processes. For these reasons, several al-
ternative approaches to 1-naphthol derivatives that do not
require the presence of strong protic acids have been de-
veloped. Unfortunately, these methods suffer from draw-
backs such as the use of expensive palladium catalysts,
high reaction temperatures and limited substrate scope.
Miura et al.9 reported a palladium-catalyzed annulation of
o-bromobenzaldehydes with 2-substituted 2-alkenals,
however, high temperature (120 °C) is required in this re-
action. Furthermore, yields are generally moderate due to
the production of 1,3-disubstituted naphthalenes accom-
panied by decarbonylation. Recently, Martin et al.10 re-
ported an elegant palladium-catalyzed ring-opening of 7-
oxabicyclic alkenes with aryl and vinyl halides followed
by oxidation of the intermediate dihydronaphthols with 2-
iodoxybenzoic acid (IBX). This protocol provides 2-sub-
stituted 1-naphthol derivatives in good yields, however, it
suffers from drawbacks such as the use of expensive pal-
ladium catalyst and excess IBX (3 equiv). From a practi-
cal point of view, it is thus highly desirable to develop a
novel method for the preparation of 1-naphthol deriva-
tives.
This methodology has the following features: (i) it differs
from the isomerization catalyzed by Brønsted acids in
having a broad substrate scope; (ii) it can provide 2,4-di-
substituted 1-naphthol derivatives, which are potential 5-
lipoxygenase inhibitors and are difficult to synthesize via
Brønsted acid catalyzed isomerization; (iii) it uses less ex-
pensive copper catalyst; (iv) it offers high chemical yields
(87–98%).
We began our investigations with 7-oxabenzonorborna-
diene (1a) in the presence of a range of 10 mol% metal
salts (Table 1). It was found that Zn(OTf)2 and AgOTf
were not useful for obtaining the desired 1-naphthol 2a
(entries 1 and 2). Given that copper Lewis acids have been
successfully applied in numerous reactions, we then
turned our attention to the use of copper salts as catalysts.
CuCl and CuBr did not promote the reaction (entries 3 and
4). Similarly, CuOTf proved to be a poor catalyst for the
reaction (entry 6). In contrast, CuBr2 did catalyze the de-
sired reaction, albeit in low efficiency (entry 5). When
Cu(OTf)2 was employed as a catalyst, the desired reaction
took place smoothly to give the product 2a in 96% yield
after 30 minutes at room temperature (entry 7). Moreover,
the catalyst loading could be decreased to 5 mol%, with-
out decreasing the yield (entry 8).
During the past decades, metal-based Lewis acids have
found many applications in organic synthesis.11 Neverthe-
less, they have largely been neglected as effective cata-
We then examined several solvents for the isomerization
of 7-oxabenzonorbornadiene (1a) into 1-naphthol (2a).
The results presented in Table 2 show that, of the solvents
investigated, 1,2-dichloroethane (DCE) was found to be
the best solvent (entry 5).
SYNTHESIS 2008, No. 19, pp 3043–3046
x
x.
x
x
.
2
0
0
8
In order to study the generality of this methodology, sev-
eral 7-oxabicyclic alkenes were reacted under the opti-
Advanced online publication: 05.09.2008
DOI: 10.1055/s-2008-1067268; Art ID: F11408SS
© Georg Thieme Verlag Stuttgart · New York

3044
F. Peng et al.
PAPER
Table 1 Isomerization of 7-Oxabenzonorbornadiene (1a) into 1-
Naphthol (2a) with Different Lewis Acidsa
dronaphthalenes also reacted under our current catalytic
system, providing the corresponding 2,4-disubstituted 1-
naphthol derivatives (entries 6–8), which are difficult to
synthesize via Brønsted acid catalyzed methods.4 This in-
dicated that the mechanism of Cu(OTf)2-catalyzed
OH
catalyst (10 mol%)
O
DCE, r.t.
1a
2a
Table 3 Cu(OTf)2-Catalyzed Isomerization of Various 7-Oxaben-
zonorbornadienes into 1-Naphthol Derivativesa
Entry
Metal catalyst
Zn(OTf)2
AgOTf
Time (h)
Yield (%)b
n.r.
R1
OH
R1
R5
R2
R3
R5
R2
R3
1
2
3
4
5
6
7
8
12
12
12
12
12
12
Cu(OTf)2 (5 mol%)
DCE, r.t.
O
n.r.
R4
R6
R4
R6
CuCl
n.r.
1
CuBr
n.r.
97–98% yield
CuBr2
45
Entry Alkene
Time
(min)
Product
Yield
(%)b
CuOTf
<5
OH
OH
Cu(OTf)2
Cu(OTf)2
0.5
96
1
60
98
O
1
98c
a Reagents and conditions: 7-oxabenzonorbornadiene (1a; 0.2 mmol),
metal salt (10 mol%), DCE (2 mL), r.t.
b Isolated yield.
MeO
MeO
MeO
2
30
97
O
c 5 mol% catalyst.
MeO
Table 2 Screening of the Solvents for the Isomerization of 7-Oxa-
benzonorbornadiene (1a) into 1-Naphthol (2a) Catalyzed by
Cu(OTf)2
OH
a
3
40
95
96
O
OH
Cu(OTf)2 (5 mol%)
O
OH
Br
Br
Br
solvent, r.t.
4
12 h
O
1a
2a
Br
Entry
Solvent
hexane
toluene
THF
Time (h)
Yield (%)b
OH
OH
OH
OH
1
2
3
4
5
1
1
1
1
1
n.r.
<5
<3
94
98
O
O
5
30
18
15
60
94
89
90
87
CH2Cl2
DCE
6
7
a Reagents and conditions: 7-oxabenzonorbornadiene (1a; 0.2 mmol),
Cu(OTf)2 (5 mol%), DCE (2 mL), r.t.
b Isolated yield.
O
mized conditions; the results are summarized in Table 3.
To our delight, the ring-opening of all 7-oxabicyclic alk-
enes proceeded smoothly to give the corresponding 1-
naphthol derivatives in high yields (entries 1–8). Various
substituents including electron-withdrawing (entries 4
and 8) electron-donating (entries 2, 3 and 7) and neutral
groups (entries 1, 5 and 6) in the aromatic ring of the 7-
oxabicyclic alkenes were well tolerated. Furthermore, 4-
monosubstituted l,4-epoxy-l,4-dihydronaphthalene af-
forded the desired product in 94% yield (entry 5). It is
noteworthy that 1,4-disubstituted l,4-epoxy-1,4-dihy-
Br
Br
Br
8
O
Br
a Reagents and conditions: 7-oxabenzonorbornadiene (0.2 mmol),
Cu(OTf)2 (5 mol%), DCE (2 mL), r.t.
b Isolated yield.
Synthesis 2008, No. 19, 3043–3046 © Thieme Stuttgart · New York

PAPER
A Practical Synthesis of 1-Naphthol Derivatives
3045
1H and 13C NMR spectra were recorded at r.t. on a Bruker Avance
DPX 400 NMR spectrometer (400 and 100 MHz, respectively);
chemical shifts (d) are expressed in ppm, and J values are given in
Hz. All chemicals and solvents were used as received without fur-
ther purification unless otherwise stated. Flash column chromatog-
raphy was performed on silica gel (230–400 mesh).
isomerization might be different to that of Brønsted acid
catalyzed isomerization.
This methodology provides an alternative method for the
preparation of 2,4-disubstituted 1-naphthols,20 offering a
simple route to potential 5-lipoxygenase inhibitors21 as
well as aromatic sesquiterpenes isolated from the Het-
erotheca species.22–25
1-Naphthol Derivatives 2a–h; Typical Procedure
To a solution of Cu(OTf)2 (3.6 mg, 0.01 mmol) in anhydrous DCE
(1 mL), 7-oxabicyclic alkenes1 (0.2 mmol) in DCE (1 mL) was add-
ed under a nitrogen atmosphere. The resulting mixture was stirred
at r.t. until the reaction was complete (TLC monitoring). The mix-
ture was then quenched by the addition of H2O (2 mL), extracted
with CH2Cl2 (10 mL) and dried over Na2SO4. The crude product
was purified by flash silica gel column chromatography (n-hexane–
EtOAc) to yield the corresponding 1-naphthol derivatives 2a–h.
In addition, Cu(OTf)2-catalyzed ring-opening usually
provided the 1-naphthol derivatives in higher yields com-
pared with Brønsted acid catalyzed isomerization and oth-
er methods. For instance, treatment of 6,7-dimethyl-1,4-
epoxy-l,4-dihydronaphthalene with Cu(OTf)2 gave 6,7-
dimethyl-l-naphthol in 95% yield (entry 3) compared to
71% using a Brønsted acid.4 Ring-opening of 1,4-dimeth-
yl-l,4-epoxy-l,4-dihydronaphthale in the presence of
Cu(OTf)2 provided 2,4-dimethyl-1-naphthols in 89%
yield (entry 6), while the palladium-catalyzed annulation
reaction of o-bromobenzaldehydes with methyl-2-pent-
enal afforded 2,4-dimethyl-1-naphthols in 52% yield.9
Naphthalen-1-ol (2a)2
1H NMR (400 MHz, CDCl3): d = 8.15–8.07 (m, 1 H), 7.79–7.77 (m,
1 H), 7.47–7.41 (m, 3 H), 7.29–7.24 (m, 1 H), 6.76–6.73 (m, 1 H),
5.44 (br s, 1 H).
13C NMR (125 MHz, CDCl3): d = 151.3, 134.8, 127.7, 126.5, 125.9,
125.3, 124.4, 121.6, 120.8, 108.7.
On the basis of the results presented above, a tentative
mechanism for the ring opening of 7-oxabicyclic alkenes
was proposed (Scheme 1), in which the Lewis acid first
coordinates to the bridging oxygen, and cleavage of the
activated C–O bond occurs concomitantly to give the al-
5,8-Dimethoxynaphthalen-1-ol (2b)
1H NMR (400 MHz, CDCl3): d = 9.49 (s, 1 H), 7.75 (d, J = 7.3 Hz,
1 H), 7.40 (t, J = 8.0 Hz, 1 H), 6.96 (d, J = 7.6 Hz, 1 H), 6.62 (s,
2 H), 3.97 (s, 3 H), 3.94 (s, 3 H).
lylic cation A. Then the R group migrates from the 1-po- 13C NMR (125 MHz, CDCl3): d = 154.4, 150.2, 150.0, 128.4, 127.3,
115.6, 113.0, 111.3, 103.3, 103.0, 56.2, 55.7.
sition to the 2-position, giving the species C.
MS (ESI): m/z (%) = 227.00 (42) [M+ + Na], 204.97 (100) [M+ + H].
HRMS (ESI): m/z [M+ + Na] calcd for C12H12O3Na: 227.0684;
Subsequently, the intermediate D forms and regenerates
the catalyst. Finally, compound D isomerizes to form the
1-naphthol derivative. In the case where R = H, a proton
rearrangement gives the 1-naphthol derivatives and re-
generates the catalyst.
found: 227.0697.
6,7-Dimethylnaphthalen-1-ol (2c)4
1H NMR (400 MHz, CDCl3): d = 7.87 (br s, 1 H), 7.53 (br s, 1 H),
7.30 (d, J = 8.2 Hz, 1 H), 7.19 (m, 1 H), 6.69 (d, J = 7.4 Hz, 1 H),
5.22 (br s, 1 H), 2.42 (s, 3 H), 2.40 (s, 3 H).
OLA
OLA
+
13C NMR (125 MHz, CDCl3): d = 150.8, 136.1, 135.0, 133.8, 127.3,
124.9, 123.0, 120.9, 119.8, 107.9, 20.3, 20.1.
R
R
MS (ESI): m/z (%) = 194.96 (68) [M+ + Na], 172.99 (62) [M+ + H],
148.93 (77).
B
A
R
R
R
O
6,7-Dibromonaphthalen-1-ol (2d)26
OLA
1H NMR (400 MHz, CDCl3): d = 8.45 (s, 1 H), 8.04 (s, 1 H), 7.30–
7.21 (m, 2 H), 6.77 (d, J = 6.7 Hz, 1 H), 5.32 (s, 1 H).
R
R
LA
13C NMR (125 MHz, CDCl3): d = 150.6, 134.4, 131.9, 127.4, 126.9,
124.2, 122.9, 121.3, 119.5, 109.6.
C
O
R
OH
R
R
MS (EI): m/z (%) = 301.8 (20), 192.9 (100).
R
R
4-Methylnaphthalen-1-ol (2e)4
1H NMR (400 MHz, CDCl3): d = 8.27 (d, J = 7.8 Hz, 1 H), 7.98 (d,
J = 7.8 Hz, 1 H), 7.61–7.52 (m, 2 H), 7.16 (d, J = 7.4 Hz, 1 H), 6.73
(d, J = 7.5 Hz, 1 H), 5.55 (br s, 1 H), 2.65 (s, 3 H).
D
Scheme 1 Proposed mechanism for Lewis acid catalyzed isomeri-
13C NMR (125 MHz, CDCl3): d = 149.9, 133.5, 126.6, 126.3, 126.1,
125.0, 124.6, 124.2, 122.1, 108.2, 18.9.
zation of 7-oxabicyclic alkenes
In summary, we have developed the first Cu(OTf)2-cata-
lyzed isomerization of 7-oxabicyclic alkenes to 1-naph-
thol derivatives in high yields under mild conditions. This
approach might make a valuable contribution to existing
methodology for the synthesis of complex molecules con-
taining the 1-naphthol fragment.
MS (EI): m/z (%) = 158.1 (100), 128.1 (31).
2,4-Dimethylnaphthalen-1-ol (2f)9
1H NMR (400 MHz, CDCl3): d = 8.14 (m, 1 H), 7.89 (m, 1 H), 7.48–
7.45 (m, 2 H), 7.06 (s, 1 H), 4.92 (s, 1 H), 2.58 (s, 3 H), 2.34 (s,
3 H).
Synthesis 2008, No. 19, 3043–3046 © Thieme Stuttgart · New York

3046
F. Peng et al.
PAPER
(5) Kaelin, D. E.; Lopez, O.; Martin, S. F. J. Am. Chem. Soc.
13C NMR (125 MHz, CDCl3): d = 146.9, 132.1, 129.5, 126.2, 125.1,
125.0, 124.6, 124.2, 121.4, 115.8, 18.6, 15.5.
2001, 123, 6937.
(6) Apsel, B.; Bender, J. A.; Escobar, M.; Kaelin, D. E.; Lopez,
O. D.; Martin, S. F. Tetrahedron Lett. 2003, 44, 1075.
(7) Kaelin, D. E.; Sparks, S. M.; Plake, H. R.; Martin, S. F.
J. Am. Chem. Soc. 2003, 125, 12994.
(8) Biland-Thommen, A. S.; Raju, G. S.; Blagg, J.; White, A. J.
F.; Barrett, A. G. M. Tetrahedron Lett. 2004, 45, 3181.
(9) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron
2000, 56, 1315.
MS (EI): m/z (%) = 272.1 (100), 157.0 (46).
2,4,6,7-Tetramethylnaphthalen-1-ol (2g)
1H NMR (400 MHz, CDCl3): d = 7.84 (s, 1 H), 7.60 (s, 1 H), 6.94
(s, 1 H), 4.84 (s, 1 H), 2.52 (s, 3 H), 2.41 (s, 6 H), 2.31 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 146.6, 134.8, 131.2, 128.8, 125.5,
124.2, 123.5, 121.1, 115.0, 20.6, 20.5, 18.9, 15.7.
(10) Chen, C. L.; Martin, S. F. J. Org. Chem. 2006, 71, 4810.
(11) Yamamoto, H. Lewis Acids in Organic Synthesis; Wiley-
VCH: Weinheim, 2000.
(12) Kobayashi, S.; Ogino, T.; Shimizu, H.; Ishikawa, S.;
Hamada, T.; Manabe, K. Org. Lett. 2005, 7, 4729.
(13) Curini, M.; Epifano, F.; Genovese, S.; Marcotullio, M. C.;
Rosati, O. Org. Lett. 2005, 7, 1331.
MS (EI): m/z (%) = 200.1 (100), 185.1 (40).
HRMS (ESI): m/z [M+ – H] calcd for C14H15O: 199.1128; found:
199.1060.
6,7-Dibromo-2,4-dimethylnaphthalen-1-ol (2h)
1H NMR (400 MHz, CDCl3): d = 8.38 (s, 1 H), 8.06 (s, 1 H), 7.00
(s, 1 H), 4.80 (s, 1 H), 2.44 (s, 3 H), 2.27 (s, 3 H).
(14) Deng, X. M.; Sun, X. L.; Tang, Y. J. J. Org. Chem. 2005, 70,
13C NMR (125 MHz, CDCl3): d = 146.2, 132.0, 130.9, 128.9, 126.8,
125.3, 124.5, 121.6, 121.1, 117.0, 18.4, 15.5.
6537.
(15) Lacey, J. R.; Anzalone, P. W.; Duncan, C. M.; Hackert, M.
J.; Mohan, R. S. Tetrahedron Lett. 2005, 46, 8507.
(16) Ollevier, T.; Nadeau, E. Synlett 2006, 219.
(17) Kang, Y. B.; Tang, Y.; Sun, X. L. Org. Biomol. Chem. 2006,
4, 299.
MS (EI): m/z (%) = 329.9 (96), 207 (100).
HRMS (ESI): m/z [M+ – H] calcd for C12H9Br2O: 328.9006; found:
328.8885.
(18) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. L.
Chem. Rev. 2002, 102, 2227.
(19) Villeneuve, K.; Tam, W. J. Am. Chem. Soc. 2006, 128, 3514.
(20) Dodge, J. A.; Chamberlin, A. R. Tetrahedron Lett. 1988, 29,
4827.
Acknowledgment
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (20702044).
(21) Baa, D. G. Eur. Pat. Appl. EP 2011071, 1987.
(22) Bohhnann, F.; Zdero, C. Chem. Ber. 1976, 109, 2021.
(23) Bohhnann, F.; Mailahn, W. Chem. Ber. 1981, 114, 1091.
(24) Adachi, K.; Taniguchi, N. Bull. Chem. Soc. Jpn. 1982, 55,
1655.
(25) Adachi, K.; Masahito, M. Bull. Chem. Soc. Jpn. 1983, 56,
651.
(26) Zhang, T. K.; Yuan, K.; Hou, X. L. J. Organomet. Chem.
2007, 692, 1912.
References
(1) Fangzhi Peng and Baomin Fan contributed equally to this
study
(2) Wittig, G.; Pohmer, L. Chem. Ber. 1956, 89, 1349.
(3) Batt, D. G.; Jones, D. G.; Greca, S. L. J. Org. Chem. 1991,
56, 6704.
(4) Olthuisb, E.; Ossenbroegko, Y.; Ewall, R.; Eels, E. D.;
Leegwat, A. J. Org. Chem. 1963, 28, 148.
Synthesis 2008, No. 19, 3043–3046 © Thieme Stuttgart · New York