Simple and efficient synthesis of 4,7-dimethoxy-1(H)-indene

Article abstract of DOI:10.1080/00397910701319189

Stirring 4,7-dimethoxy-1-indanol in chloroform at room temperature in the presence of a catalytic amount of p-toluenesulfonic acid gave 4,7-dimethoxy-1(H)-indene in quantitative yield. Other solvents, including benzene, which was the most frequently used one for this reaction, gave mostly polymeric materials. The new method was also effective for dehydration of other electron-rich benzylic alcohols. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701319189

This article was downloaded by: [University of Delaware]
On: 22 April 2013, At: 12:07
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Simple and Efficient Synthesis of
4
,7‐Dimethoxy‐1(H)‐indene
a
a
a
Xiang Zhang , Muralidhara Thimmaiah & Shiyue Fang
a
Department of Chemistry, Michigan Technological University, Houghton,
Michigan, USA
Version of record first published: 30 Jun 2007.
To cite this article: Xiang Zhang , Muralidhara Thimmaiah & Shiyue Fang (2007): Simple and Efficient
Synthesis of 4,7‐Dimethoxy‐1(H)‐indene, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:11, 1873-1877
To link to this article: http://dx.doi.org/10.1080/00397910701319189
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

w
Synthetic Communications , 37: 1873–1877, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701319189
Simple and Efficient Synthesis of
,7-Dimethoxy-1(H)-indene
4
Xiang Zhang, Muralidhara Thimmaiah, and Shiyue Fang
Department of Chemistry, Michigan Technological University,
Houghton, Michigan, USA
Abstract: Stirring 4,7-dimethoxy-1-indanol in chloroform at room temperature in the
presence of a catalytic amount of p-toluenesulfonic acid gave 4,7-dimethoxy-1(H)-
indene in quantitative yield. Other solvents, including benzene, which was the most fre-
quently used one for this reaction, gave mostly polymeric materials. The new method
was also effective for dehydration of other electron-rich benzylic alcohols.
Keywords: dehydration, dimethoxyindene, indene, synthesis
Indene is a useful building block in materials science, organometallic
chemistry, medicine, and organic synthesis. Indene-based polymers and copo-
lymers have been shown to possess useful properties in photolithography
applications such as positive photoresists with high resolution, sensitivity,
[
1,2]
and good etching resistance.
ligands in organometallic chemistry: their transition-metal complexes can
Indene and its derivatives are interesting
1
be stable or in equilibrium among identities formed through h , h , and h
3
5
coordination fashions; the dynamic properties of these complexes offer oppor-
tunities in the design of stoichiometric and catalytic reactions for which acces-
[3,4]
sible open coordination sites are important.
Because of their structural
resemblance to indoles, indene derivatives have been employed as rigid
models for the receptor interactions of cannabimimetic indoles with the
Received in the USA October 19, 2006
Address correspondence to Shiyue Fang, Department of Chemistry, Michigan
Technological University, 1400 Townsend Drive, Houghton, MI 49931, USA.
E-mail: shifang@mtu.edu
1
873

1
874
X. Zhang, M. Thimmaiah, and S. Fang
[
5,6]
cannabinoid brain receptor.
Being bioisosteric moieties of the indole ring
in melatonin, indene was of interest for the development of synthetic
compounds possessing agonist or antagonist properties for melatonin
receptors; these compounds have been claimed to be useful for the
treatment of depression, sleep disorders, and disturbances of circadian
[
7]
rhythm. Indene is also documented as the important precursor for the
synthesis of cis-aminoindanol, a key chiral precursor to the HIV protease
[
8,9]
[10]
inhibitor Crixivan,
as well as for other biological applications.
Because fine-tuning the electronic and steric effects of the indenes are
highly desired in most of these applications, development of methodologies
for efficient preparation of indenes with various functional groups on their
aromatic ring is important.
The most convenient and frequently used method for the synthesis of
indenes is the dehydration of the corresponding indanol in benzene or
toluene in the presence of a catalytic amount of p-toluenesulfonic acid by
azeotropic removal of water. Using this method, many indene derivatives
[
11]
[12]
[13]
such as indene,
dimethyl-1(H)-indene,
methoxyindenes 4-methoxy-1(H)-indene,
6-nitro-1(H)-indene,
6-bromo-1(H)-indene,
[15]
4,7-
and the electron-rich
[
14]
4-isopropyl-1(H)-indene,
[16]
[17]
5-methoxy-1(H)-indene,
[
18]
and 6-methoxy-1(H)-indene
have been prepared. Recently, we needed to
prepare multigram quantities of the more electron-rich 4,7-dimethoxy-1(H)-
indene (1) for one of our projects. When the reaction conditions were
applied for dehydration of 4,7-dimethoxy-1-indanol (2) to give 1, troublesome
tarry materials were afforded. Although pure 1 was obtained after careful
workup and chromatography, the yield was much lower than reported in litera-
[
19]
ture
and was not practically useful for our applications. We reasoned that
the cationic intermediate formed by loss of water from 2 is too stable for rapid
conversion to the product 1; as a result, this intermediate has sufficient time to
react with the electron-rich aromatic ring of 1, 2, and/or the resulting products
through Friedel–Crafts reaction to give oligomers and polymers. Accord-
ingly, high-dilution conditions were tested to prevent these intermolecular
side reactions and favor the intramolecular elimination of a proton from
the intermediate to form the desired product; unfortunately, even when the
concentration of the substrate was lowered to 0.01 M, the yield of 1 was
only slightly improved.
Although disappointed with the low yield of 1 by dehydration of 2 using
benzene as solvent, we noticed that 2 in CDCl in an NMR tube was quanti-
3
tatively converted to 1 at room temperature within 1 week. Encouraged by this
observation, we tested preparation of 1 by stirring 2 in chloroform with a con-
centration of 0.02 M at room temperature; however, after 24 h, only about 5%
conversion was observed. Although the reaction was very clean, the low rate
prevents its practical synthetic applications. We then tested adding a catalytic
amount of p-toluenesulfonic acid (0.5 mol%) to this solution; gratifyingly, the
reaction was completed within 2.5 h, and quantitative yield of 1 was obtained
(
Scheme 1). More important, the product was very pure after aqueous workup

4,7-Dimethoxy-1(H)-indene
1875
Scheme 1.
(10% K CO ); removing organic solvents gave product 1 as colorless crystals.
2 3
In addition, there was no need for distilling the solvent for the reaction; chloro-
form (ACS reagent) purchased from Aldrich can be used directly. Performing
the reaction at a higher concentration (0.05 M) in the presence of the same
amount of acid catalyst also gave a high yield of 1, but the product was con-
taminated with small amounts of oligomers and polymers. We were curious to
know if this reaction could be equally efficient in benzene at a concentration of
0.02 M in the presence of 0.5 mol% p-toluenesulfonic acid at room tempera-
ture; we found that the reaction could proceed, but the rate was much slower
(
6 h ꢀ60% conversion) and only low yield of 1 could be obtained (ꢀ25%);
Most of the starting material was again transformed to polymeric materials.
Other solvents such as CH Cl , Et O, and THF were also tested under
2
2
2
otherwise identical conditions, and all gave results much inferior to
chloroform.
To find out the generality of these new conditions for dehydration, the
1
-indanols 3a–c, 1-tetrahydronaphthols 4a–c, and benzylic alcohols 5a–e
were subjected to dehydration under similar conditions, and the results are
shown in Table 1. The electron-rich 1-indanols 3a and 3b and 1-tetrahydro-
naphthols 4a and 4b gave good to excellent yields of the corresponding dehy-
dration products with the same catalyst loading (0.5 mol%). The electron-rich
benzylic alcohols 5a–d reacted slower even with higher catalyst loading
(5 mol%) and gave lower yields. The less electron-rich 3c and 5e could not
be dehydrated under these conditions, but 4c, which has no electron-
donating group on its aromatic ring, was dehydrated in 45% yield under
these conditions in the presence of 5 mol% of catalyst.
In summary, by simply changing the solvent benzene or toluene to
chloroform in a known dehydration reaction and lowering the reaction
temperature, a practical method for the preparation of 4,7-dimethoxy-
1(H)-indene (1) has been developed. This reaction is easy to perform, the
product is clean, and the yield is high. Compound 1 appeared in a
number of publications; however, its preparation was either omitted or inef-
19–23]
[
ficient.
by treating 2 with PPh3 in CCl4 at reflux,
and only one reference detailed its preparation in high yield
but this method used a
[24]
toxic reagent and product purification was more complicated. As a result,
we believe that our method will be the first choice for the preparation of
1 by those who need substantial amounts of this electron-rich indene
derivative in material science, organometallic chemistry, medicine, and

1
876
X. Zhang, M. Thimmaiah, and S. Fang
Table 1. Dehydration of 1-indanols 3, 1-tetrahydronaphthols 4, and benzylic alcohols 5
Starting
alcohol
Catalyst amount
(mol%)
Reaction
time (h)
Isolated
yield (%)
1
2
R
R
3
3
3
4
4
4
5
5
5
5
5
a
b
c
4-OCH
5-OCH
3
5-OCH
6-OCH
H
3
3
0.5
0.5
5
1
1
90
69
3
4-OCH3
12
4
,10
78
a
b
c
5-OCH
6-OCH
H
3
8-OCH
H
3
0.5
0.5
5
3
1
83
45
H
12
6
a
b
c
2-OCH
3-OCH
3
6-OCH
4-OCH
3
3
0.5
5
33
58
3
8
3-OCH3
4-OCH3
H
6-OCH3
5
8
48
22
d
e
H
H
0.5
5
1
12
0
organic synthesis. In addition, this method was also found effective for
dehydration of other electron-rich 1-indanols, 1-tetrahydronaphthols, and
benzylic alcohols.
EXPERIMENTAL
Compound 4,7-dimethoxy-1-indanol (2) was prepared by reducing 4,7-
dimethoxy-1-indanone (Aldrich) with NaBH in refluxing 95% EtOH for
4
[
11]
30 min.
Alcohols 3–5 were either commercially available or prepared in
the same manner. Chloroform for the dehydration reaction was purchased
from Aldrich (ACS reagent) and used directly.
Standard Procedure for Dehydration
After drying under vacuum, compound 2 (1.94 g, 10 mmol), a white solid, was
dissolved in chloroform (500 ml). p-Toluenesulfonic acid monohydrate (9.5 mg,
0.05 mmol) was added, and the mixture was stirred under a nitrogen atmosphere.
The reaction was monitored by thin-layer chromatography (TLC, silica gel,
hexane/ether ¼ 1:1; Rf ¼ 0.8 for 1 and 0.2 for 2) and completed within
2.5 h. To the reaction mixture was added 50 ml K CO solution (10%), and
2 3
the mixture was transferred into a separation funnel. The aqueous phase was
removed, and the organic phase was further washed with K CO (10%, 50 ml)
2
3

4,7-Dimethoxy-1(H)-indene
1877
and water (50 ml) and then dried over anhydrous Na SO . Removal of solvent
2
4
under reduced pressure gave 1 as a crystalline solid (1.67 g, 95%). Analytical
1
data of 1 (mp, H and C NMR, and MS) were consistent with reported ones
13
[
19,24]
in literature.
manner, and if the reaction was too slow, higher catalyst loading was used
see Table 1). After aqueous workup, a short silica-gel column was needed to
purify the products. All the starting alcohols and their dehydration products
Dehydration of other alcohols was performed in the same
(
1
13
are known and were identified by H NMR, C NMR, and MS.
REFERENCES
1. Hatakeyama, J.; Kaneo, T.; Hasegawa, K.; Watanabe, T.; Watanabe, O.;
Takeda, T. Jpn. Kokai Tokkyo Koho JP2004149756, 2004, Filing date, March 7,
2003.
2
3
4
5
6
7
. Neiser, J.; Gottweis, J. Spisy Pedagogicke Fakulty v Ostrave 1969.
. O’Connor, J. M.; Casey, C. P. Chem. Rev. 1987, 87, 307–318.
. Stradiotto, M.; McGlinchey, M. J. Coord. Chem. Rev. 2001, 219, 311–378.
. Huffman, J. W.; Padgett, L. W. Curr. Med. Chem. 2005, 12, 1395–1411.
. Huffman, J. W. Curr. Med. Chem. 1999, 6, 705–720.
. Mathje-Allainmat, M.; Andrieux, J.; Langlois, M. Expert Opin. Ther. Patents
1997, 7, 1447–1458.
8
9
. O’Brien, X. M.; Parker, J. A.; Lessard, P. A.; Sinskey, A. J. Appl. Microbiol. Bio-
technol. 2002, 59, 389–399.
. Stafford, D. E.; Yanagimachi, K. S.; Stephanopoulos, G. Adv. Biochem. Eng./Bio-
technol. 2001, 73, 85–101.
0. Ganellin, C. R. Adv. Drug Res. 1967, 4, 163–249.
1
1
1
1
1. Hauser, F. M.; Prasanna, S. Synthesis 1980, 621–623.
2. Miller, R. B.; Frincke, J. M. J. Org. Chem. 1980, 45, 5312–5315.
3. Methcohn, O.; Moore, C.; Vanrooyen, P. H. J. Chem. Soc., Perkin Trans. 1985, 1,
1
793–1801.
4. Frim, R.; Rabinovitz, M.; Bodwell, G.; Raulfs, F. W.; Hopf, H. Chem. Ber. 1989,
22, 737–744.
5. Kobayashi, T.; Tanaka, K.; Miwa, J.; Katsumura, S. Tetrahedron: Asymmetry
004, 15, 185–188.
1
1
1
2
1
1
6. Nguy, N. M.; Chiu, I. C.; Kohn, H. J. Org. Chem. 1987, 52, 1649–1655.
7. Marino, S. T.; Stachurska-Buczek, D.; Huggins, D. A.; Krywult, B. M.;
Sheehan, C. S.; Nguyen, T.; Choi, N.; Parsons, J. G.; Griffiths, P. G.;
James, I. W.; Bray, A. M.; White, J. M.; Boyce, R. S. Molecules 2004, 9, 405–426.
8. Winter, J. C.; Godse, D. D.; Gessner, P. K. J. Org. Chem. 1965, 30, 3231–3233.
9. Piccolrovazzi, N.; Pino, P.; Consiglio, G.; Sironi, A.; Moret, M. Organometallics
1
1
1
990, 9, 3098–3105.
0. De Armas, J.; Kolis, S. P.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122,
977–5983.
2
5
2
2
1. Foster, P.; Rausch, M. D.; Chien, J. C. W. J. Organomet. Chem. 1997, 527, 71–74.
2. Demarinis, R. M.; Bryan, W. M.; Shah, D. H.; Hieble, J. P.; Pendleton, R. G.
J. Med. Chem. 1981, 24, 1432–1437.
2
2
3. Marechal, E. J. Macromol. Sci., Chem. 1973, 7, 433–460.
4. Qazi, T. U. Libyan J. Sci. 1980, 39–44.