Mild and efficient synthesis of 1,8-naphthalide and 1,8- naphthalenedimethanol

Article abstract of DOI:10.1081/SCC-120038510

Mild and efficient procedures have been developed for synthesis of 1,8-naphthalide and 1,8-naphthalenedimethanol. In an ice-water bath, 1,8-naphthalide was prepared from 1,8-naphthlic anhydride using LiAlH ₄ as reducing agent. 1,8-Naphthalenedi

Full text of DOI:10.1081/SCC-120038510

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Mild and Efficient Synthesis of 1,8‐Naphthalide and
1
,8‐Naphthalenedimethanol
a a b b
a
b c
Huan Luo , Qingle Zeng
, Zhongrong Liu , Yongzhi Wei , Bogang Li
& Fengpeng
a
Wang
a
West China College of Pharmacy and College of Chemical Engineering, Sichuan
University, Chengdu, China
b
Institute of Pharmacy, Chengdu Diao Pharmaceutical Group, Chengdu, 610041, China
c
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
Published online: 17 Aug 2006.
To cite this article: Huan Luo , Qingle Zeng , Zhongrong Liu , Yongzhi Wei , Bogang Li & Fengpeng Wang (2004) Mild and
Efficient Synthesis of 1,8‐Naphthalide and 1,8‐Naphthalenedimethanol, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:12, 2269-2275, DOI: 10.1081/SCC-120038510
To link to this article: http://dx.doi.org/10.1081/SCC-120038510
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 12, pp. 2269–2275, 2004
Mild and Efficient Synthesis of
1,8-Naphthalide and
,8-Naphthalenedimethanol
1
1
Huan Luo, Qingle Zeng,
1,2,* 2
2,3,*
1
Zhongrong Liu, Yongzhi Wei,
1
and Fengpeng Wang
Bogang Li,
1
West China College of Pharmacy and College of Chemical Engineering,
Sichuan University, Chengdu, China
2
Institute of Pharmacy, Chengdu Diao Pharmaceutical Group,
Chengdu, China
3
Chengdu Institute of Biology, Chinese Academy of Sciences,
Chengdu, China
ABSTRACT
Mild and efficient procedures have been developed for synthesis of
1
1
,8-naphthalide and 1,8-naphthalenedimethanol. In an ice-water bath,
,8-naphthalide was prepared from 1,8-naphthlic anhydride using
LiAlH4 as reducing agent. 1,8-Naphthalenedimethanol was obtained
with good yield from reduction of 1,8-naphthalic anhydride by LiAlH
4
*
Correspondence: Qingle Zeng, West China College of Pharmacy and College of
Chemical Engineering, Sichuan University, Chengdu, China; Fax: 86-28-85225401;
E-mail: qinglezeng@yahoo.com. Bogang Li, Institute of Pharmacy, Chengdu Diao
Pharmaceutical Group, Chengdu 610041, China.
2
269
DOI: 10.1081/SCC-120038510
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
2
270
Luo et al.
and Lewis acids at room temperature. The effects of various factors on the
reduction of 1,8-naphthalic anhydride with LiAlH were investigated.
4
Key Words: Lewis acids; LiAlH ; 1,8-Naphthalic anhydride; 1,8-
4
Naphthalide; 1,8-Naphthalenedimethanol.
INTRODUCTION
1,8-Naphthalide and 1,8-naphthalenedimethanol are intermediates for
synthesis of pharmaceuticals and theoretical research. 1,8-Naphthalide
[
1]
[2]
[
3]
can be made by multiple-step reactions,
[
by oxidation of expensive
,8-naphthalenedimethanol, or by reduction of 1,8-naphthalic anhydride
4]
1
with NaBH4 (44% yield).
[
2a]
[5]
Besides synthesis by multiple steps,
,8-naphthalenedimethanol is usually prepared by reduction of naphthlic
1
anhydride with LiAlH under reflux (in THF for a long time in common),
[1b,2c,6]
4
[2b]
even so long as 6 days (in a mixture solvent of benzene and ether). However
long-time refluxing in THF (30 hr) led to a lot of by-products benzonorcara-
[
7]
diene. Besides, due to the high vapor pressure and flammability of THF,
long-time reflux in THF is latent danger for experiment room. We report
mild and efficient methods for synthesis of 1,8-naphthalide and 1,8-naphthalene-
dimethanol from 1,8-naphthalic anhydride (Sch. 1).
When we tried to prepare 1,8-naphthalenedimethanol, we added naphthlic
anhydride into a flask with a THF solution of LiAlH in an ice-water bath, and
4
then the mixture was heated to reflux for 2 hr. After workup and purification by
recrystallization from n-hexane and ethyl acetate, the product discovered
was unexpected not 1,8-naphthalenedimethanol but 1,8-naphthalide. In
another experiment, 1,8-naphthalic anhydride was reduced by LiAlH in an
4
ice–salt bath to give a crude product composing of 94.1% 1,8-naphthalide
Scheme 1. Synthesis of 1,8-naphthalide and 1,8-naphthalenedimethanol.

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Synthesis of 1,8-Naphthalide and 1,8-Naphthalenedimethanol
2271
1
and 5.9% 1,8-naphthalenedimethanol measured by H NMR, which was
recrystallized to give crystalline 1,8-naphthalide with 73.2% isolated yield.
As we know, combination of Lewis acids and metal hydride has produced
[8]
a number of efficient reducing agent. In order to find a mild condition for
preparing 1,8-naphthalenedimethanol, we resorted to combine LiAlH with
4
Lewis acids. 1,8-Naphthalic anhydride was reduced efficiently by LiAlH4
and Lewis acids. The results are listed in Table 1.
The mole ratios of reducing agent to substrate apparently affected yields.
Yields increased when the mole ratios of LiAlH to 1,8-naphthalic anhydride
4
varied from 1.2/1 to 3/1 (entries 1–3), and then slowed down while the mole
ratio up to 4/1 (entries 3 and 4). Therefore, 3/1 was adopted as the choice
mole ratio for other test. With the mole ratio of 3/1, good yields were achieved
when AlCl , ZnCl , and BF were used as Lewis acids.
3
2
3
The mole ratios of LiAlH to Lewis acids also had impact on results.
4
.
Except for BF3 Et O, excess Lewis acids resulted in formation of by-products,
2
Table 1. Synthesis of 1,8-naphthalenedimethanol by reduction of naphthalic
4
anhydride with LiAlH and Lewis acids.
Ratios of
reactants
Entries
Reactants and its adding order
Isolated yield (%)
1
2
3
4
5
6
7
8
9
LiAlH /AlCl /anhydride
1.2/0.4/1
2/0.67/1
3/1/1
4/1/1
1.2/0.6/1
3/1/1
3/1/3
2/1/1
3/1/1.5
3/1/1
3/1/3
60.2
70.5
78.3
79.1
67.2
84.1
4
4
4
3
3
3
LiAlH
LiAlH
/AlCl
/AlCl
/anhydride
/anhydride
LiAlH /AlCl /anhydride
4
4
4
3
LiAlH
LiAlH
/ZnCl
2
/anhydride
/anhydride/ZnCl
2
2
a
LiAlH /anhydride/ZnCl
(64.1/16.9/19.0)
63.7
4
.
LiAlH
LiAlH
4
/BF
3
Et
2
O/anhydride
a
.
4
/anhydride/BF
3
Et
2
O
80.6(92.9/7.1/0)
40.9
1
1
1
1
0
1
2
3
LiAlH /anhydride/SnCl
4
4
a
LiAlH
LiAlH
LiAlH
4
4
4
/anhydride/SnCl
/CaCl /anhydride
/anhydride
4
(70.6/19.1/10.3)
b
2
3/1/1
3/1
16.4 þ 36.1
c
69.5
a 1
Data in parentheses are measured by H NMR, and are corresponding to the mole
ratios of 1,8-naphthalenedimethanol/1,8-naphthalide/1,8-di(chloromethyl)naph-
thalene. Anhydride was added in a THF solution of LiAlH
2
4
in an ice-water bath for
hr, and then Lewis acids were added at room temperature for 3 hr.
b
Isolated yields of 1,8-naphthalenedimethanol (16.4%) and 1,8-naphthalide (36.1%),
respectively.
c
Refluxing for 15 hr.

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272
Luo et al.
mainly 1,8-di(chloromethyl)naphthalene (entries 7 and 11). Because BF is
3
covalent compound, and others are ionic compounds (entry 9).
.
For Lewis acids, AlCl , ZnCl , and BF Et O, their yields were compar-
3
2
3
2
able as a whole under similar conditions (entries 3, 6, and 9). The reason prob-
ably is the same active reducing agent AlH was produced in situ when LiAlH
3
4
[8a]
and Lewis acids were mixed.
The results demonstrate that the reducing
behavior of AlH to 1,8-naphthalic anhydride are distinctly different from
3
B H , the former gives 1,8-naphthalenedimethanol and the latter affords
2
6
[
9]
2
,1,3-peri-naphthopyran.
When SnCl was used in the reduction, the yield of 1,8-naphthalene-
4
dimethanol was lower than those with Lewis acids above (entry 10). The
4
consumption of partial LiAlH by reducible Sn leaded to the lower yield.
þ
4
1
,8-Naphthalic anhydride was reduced into a mixture of 16.4%
,8-naphthalenedimethanol and 36.1% 1,8-naphthalide when anhydrous
CaCl was added into the reduction system (entry 12). The result is alike to
1
2
[10]
that of only LiAlH used (27% and 39%, respectively). The ionicity of
þ
Li and Ca are analogous, so no AlH was produced when CaCl met
4
2þ
3
2
with LiAlH4.
,8-Naphthalenedimethanol was achieved with 69.5% yield by refluxing
in THF for 15 hr (entry 13), whose yield was lower than that obtained by
1
reduction with LiAlH and Lewis acids.
4
CONCLUSION
In an ice-water bath, 1,8-naphthalic anhydride was reduced with LiAlH4
to give 1,8-naphthalide with good isolated yield. With AlH formed in situ by
3
LiAlH and Lewis acids, 1,8-naphthalic anhydride was reduced under room
4
temperature to give 1,8-naphthalenedimethanol with high yield. The effects
of various Lewis acids, the mole ratios of LiAlH to 1,8-naphthalic anhydride
4
and of LiAlH to Lewis acids on the reduction of 1,8-naphthalic anhydride
4
with LiAlH were investigated.
4
EXPERIMENTAL
Melting points (uncorrected) were measured on an Electro-thermal digital
melting point apparatus. Electrospray ionization mass spectra (ESI-MS, posi-
DECA
tive and negative mode) were recorded using a Finnigan LCQ
1
mass spec-
trometer. H NMR spectra were recorded in CDCl or CD COCD on a
3
3
3
Bruker Avance 600 MHz spectrometer. Infrared spectra were recorded on a
PerkinElmer Spectrum One FT-IR spectrometer (KBr discs). 1,8-Naphthalic

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Synthesis of 1,8-Naphthalide and 1,8-Naphthalenedimethanol
2273
anhydride, lithium aluminum hydride, anhydrous ferrous chloride, anhydrous
tin tetrachloride, and boron trifluoride ethyl ether were purchased from Acros
Chemical Co. and were used without further purification. Anhydrous zinc
chloride (analytic purity) was melted to remove water for 15 min over electric
oven. THF was distilled from sodium benzophenone ketyl.
Typical Procedure for Reduction of 1,8-Naphthalic Anhydride
to 1,8-Naphthalide by LiAlH4
LiAlH (15 mmol), and dry THF (20 mL) were placed in a 100 mL flask
4
fitted with a CaCl guard tube. The flask was cooled to about 08C with an ice
2
bath and mounted over a magnetic stirrer. 1,8-Naphthalic anhydride (0.99 g,
5
mmol) was added into the flask slowly. After 3 hr, the excess LiAlH was
4
destroyed by addition of 5 mL water, and the mixture was adjusted with 1 N
HCl to weak acidity. The resultant two-phase solution was extracted with
three portions of ethyl acetate, followed by washing with brine. After the
solvent was evaporated, the crude product was recrystallized from ethanol
[
3]
to give yellow sheet crystals 0.624 g (73.2% yield). M.p.: 157–1598C (lit.
þ
1
56–1578C) ESI-MS (positive mode, m/z): 185 (M þ H) ; (negative mode,
2
m/z): 169 (M 2 H 2 H O) , 183 (M 2 H) ; IR (cm ): 1719, 1626,1585,
2
21
2
1
516, 1456, 1350, 1244, 1085, 1052, 777; H NMR (600 MHz, CDCl ), d
1
5
3
.85 (s, 2H), 7.40 (d, 1H, J ¼ 7.2 Hz), 7.57 (t, 1H, J ¼ 7.8 Hz), 7.68 (t, 1H,
J ¼ 7.8 Hz), 7.87 (d, 1H, J ¼ 8.4 Hz), 8.13 (d, 1H, J ¼ 8.4 Hz), 8.42 (d, 1H,
J ¼ 7.2 Hz)
Typical Procedure for Preparation of 1,8-
Naphthalenedimethanol with LiAlH and Lewis Acids
4
Dry THF (20 mL), LiAlH (6 mmol) and anhydrous ZnCl (3 mmol) were
4
2
added in a 100 mL round-bottom flask fitted with a CaCl guard tube and
2
mounted over a magnetic stirrer. 1,8-Naphthalic anhydride (0.99 g, 5 mmol)
was added into the flask slowly at room temperature. After 6 hr, the excess
LiAlH was destroyed by addition of 5 mL water, and the mixture was
4
adjusted with 1 N HCl to weak acidity. The resultant two-phase solution
was extracted with ethyl acetate (3 ꢀ 15 mL), washed with brine and then
dried over anhydrous MgSO . After the solvent was evaporated, the crude pro-
4
duct was recrystallized with benzene and methanol (1/1) to give white crystals
[
2c]
0
1
1
.790 g (84.1% yield). M.p.: 161–1638C (lit. 157–1588C); ESI-MS (m/z):
þ
þ
21
71 (M þ H 2 H O) , 189 (M) ; IR (cm ): 3345, 3241, 1601, 1510,1425,
2
1
366, 1320, 1058, 1035, 1013, 998, 826, 774.724; H NMR (600 MHz,

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2
274
Luo et al.
CD COCD ), d4.54 (s, 2H), 5.27 (s, 4H), 7.44 (t, 2H, J ¼ 7.5 Hz), 7.64 (d, 2H,
3
3
J ¼ 7.2 Hz), 7.87 (d, 2H, J ¼ 7.8 Hz).
REFERENCES
1
. (a) Johnson, R.; Smith, H. Phosphonic Acid Derivatives Useful as Anti-
inflammatory Agents. PCT Patent WO92/10,504, June, 25, 1992;
b) Portoghese, P.S.; Ohkawa, S. Spiroindane Opiate Analogs. US Patent
,298,622, Mar, 29, 1994.
(
5
2. (a) Clayden, J.; Frampton, C.S; McCarthy, C; Westlund, N. Perilithiation
and the synthesis of 8-substituted-1-naphthamides. Tetrahedron 1999, 55,
14161; (b) Kamada, T.; Wasada, N.; Yamamoto, O. Studies on 8,9,10,11-
tetrahydro-7H-cycloocta[de]naphthalenes. I. Conformations of 8,8,10,10-
tetrasubstituted derivatives of 8,9,10,11-tetrahydro-7H-cycloocta[de]-
naphthalene. Bull. Chem. Soc. Jap. 1976, 49, 275; (c) Boekelheide, B.;
Vick, G.K. A synthesis of pleiadiene and acepleiadylene. J. Am. Chem.
Soc. 1956, 78, 653.
3
4
. Fuson, R.C.; Munn, G. 1,8-Naphthalide. J. Am. Chem. Soc. 1949, 71,
1870.
. (a) Murahashi, S.; Naota, T.; Ito, K.; Maeda, Y.; Taki, H. Ruthenium-
catalyzed oxidative transformation of alcohols and aldehydes to esters
and lactones. J. Org. Chem. 1987, 52, 4319; (b) Ishii, Y.; Yoshida, T.;
Yamawaki, K.; Ogawa, M. Lactone synthesis of a,v-diols with hydrogen
peroxide catalyzed by heteropoly acids combined with cetylpyridinium
chloride. J. Org. Chem. 1988, 53, 5549.
5
. Weinheimer, A.J.; Kantor, S.W.; Hauser, C.R. Rearrangement of diphe-
nan to 9,10-dihydro-9-phenanthrol by potassium amide and dehydration
to phenanthrene. Results with 1,8-naphthalan, phthalan, and 2,5-dihydro-
furan. J. Org. Chem. 1953, 18, 801.
6
7
8
. Beyler, R.E.; Sarett, L.H. Approaches to total synthesis of adrenal ster-
oids. IV. The stereochemistry of 5-methyl-1,2,3,4,4aa,5,6,7,8,8aa-deca-
hydronaphthalene-1b,4b-diol-6-one. J. Am. Chem. Soc. 1952, 74, 1406.
. Popovici-Muller, J.V.; Spencer, T.A. The singular reduction of 1,8-bis-
hydroxymethylnaphthalene to a benzonorcaradiene by LiAlH . Tetra-
4
hedron Lett. 1997, 38, 8161.
. (a) Brown, H.C.; Yoon, N.M. Selective reductions. X. Reaction of alumi-
num hydride with selected organic compounds containing representative
functional groups. Comparison of the reducing characteristics of lithium
aluminum hydride and its derivatives. J. Am. Chem. Soc. 1966, 88, 1464;
(b) Zweifel, G.; Brown, H.C. Hydration of olefins, dienes, and acetylenes
via hydroboration. Org. React. 1963, 13, 1; (c) Gensler, W.J.; Johnson, F.;

ORDER
REPRINTS
Synthesis of 1,8-Naphthalide and 1,8-Naphthalenedimethanol
2275
Sloan, A.D. J. Am. Chem. Soc. 1960, 82, 6074; (d) Khurana, J.M.;
Chanuhan, S. A practical large scale synthesis of 9-(hydroxymethyl)-
fluorene-4-carboxylic acid (HOFmCO H). Synth. Commun. 2001, 31,
2
3485.
9. Cason, J.; Lynch, D.K.; Weiss, A. Hydride reductions of napthalic
anhydrides. J. Org. Chem. 1973, 38, 1944.
Received in Japan December 15, 2003

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