An efficient synthesis of 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one

Full text of DOI:10.1080/00304940903078053

This article was downloaded by: [Pennsylvania State University]
On: 08 May 2012, At: 22:54
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
Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/uopp20
An Efficient Synthesis of 1,2,6,7-
Tetrahydro-8H-indeno[5,4-b]furan-8-one
Bo Wang a b , Lijuan Zhang a , Kaiyong Fu b , Yu Luo a , Wei Lu a & Jie
Tang a
a Department of Chemistry, East China Normal University, Shanghai,
P.R. China
b Shanghai Pu Yi Chem-Tech. Co., Ltd, Shanghai, P. R. China
Available online: 10 Jul 2009
To cite this article: Bo Wang, Lijuan Zhang, Kaiyong Fu, Yu Luo, Wei Lu & Jie Tang (2009): An
Efficient Synthesis of 1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one, Organic Preparations and
Procedures International: The New Journal for Organic Synthesis, 41:4, 309-314
To link to this article: http://dx.doi.org/10.1080/00304940903078053
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.

Organic Preparations and Procedures International, 41:309–314, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940903078053
An Efficient Synthesis
of 1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one
Bo Wang,1,2 Lijuan Zhang,1 Kaiyong Fu,2 Yu Luo,1 Wei Lu,1
and Jie Tang1
1Department of Chemistry, East China Normal University Shanghai, P.R. China
2Shanghai Pu Yi Chem-Tech. Co., Ltd Shanghai, P. R. China
Millions of people worldwide suffer from insomnia. Recently a new drug named Ramelteon
has been approved by FDA for the treatment of insomnia.1 In contrast to the present sleep
agents, Ramelteon works by a completely new mechanism, specifically targeting two recep-
tors in the brain, MT1 and MT2.2–5 Moreover, human studies have shown that Ramelteon
has no risk of drug dependence and abuse, which are often associated with other FDA-
approved drugs. However, the reported synthesis of Ramelteon involves rather inconvenient
procedures,3 especially for the preparation of the key intermediate 1,2,6,7-tetrahydro-8H-
indeno[5,4-b]furan-8-one (6). As a part of our exploration of a facile synthesis of Ramelteon,
we have developed an efficient preparation of compound 6 from commercially available
6-methoxyindan-1-one (7). Herein we report the detail of our investigations.
O
O
N
H
A
O
O
B
C
1,2,6,7-tetrahydro-8H-
indeno[5,4-b]furan-8-one (6)
Ramelteon
Figure 1
To the best of our knowledge, the only synthetic route to 1,2,6,7-tetrahydro-8H-
indeno[5,4-b]furan-8-one (6) involves nine steps from 2,3-dihydrobenzofuran (1).6–10 Thus,
a more convenient synthesis for ketone (6) was needed. Retrosynthetic analysis indicated
that this tricyclic compound might be synthesized via two strategies, namely construction
of the cyclopentanone moiety (C ring) or construction of tetrahydrofuran moiety (A ring).
Our first approach was to construct the cyclopentanone ring (C ring) from 2,3-
dihydrobenzofuran (1), as illustrated in Scheme 1. First, starting material 1 was transformed
Received February 2, 2009; in final form April 16, 2009.
Address correspondence to Yu Luo, Department of Chemistry, East China Normal University,
Shanghai 200062, P. R. China. E-mail: yluo@chem.ecnu.edu.cn
309

310
Luo et al.
into 2 according the reported procedure,10 which was treated with tert-butyl alcohol under
acidic conditions to give compound 3 in 85% yields. Subsequently, 3 was subjected to
Friedel-Crafts acylation to afford compound 5. The regioselectivity of acylation reaction
was probably dominated by the steric hindrance of the bulky tert-butyl group. Unfortu-
nately, removal of the tert-butyl group proved to be rather difficult. Indeed, under several
conditions, such as AlCl3, FeCl3 and AlCl3/dry HCl, the yield of the last step was still quite
low, with most of the compound 5 being recovered. The best yield was only 20%.
O
O
O
b
ref. 3
a
OH
OH
3
2
O
1
O
O
O
O
O
c
O
d
Cl
4
O
5
6
(a) H PO , t-BuOH, 90%; (b) (CO) Cl , DMF, CH Cl ; (c) AlCl , CH Cl , 70% from 13;
3
4
2
2
2
2
3
2
2
(d) AlCl , dry HCl, benzene, 20%
3
Scheme 1
These unsatisfactory results led us to devise new strategy. It was realized that the
construction of the tetrahydrofuran moiety (A ring) deserved careful investigation. Recently,
Marsaioli and coworkers11 reported that 6-allyloxyindan-1-one (8) could rearrange to give
6-hydroxy-7-allylindan-1-one (9) by heating in sealed ampoules. Although this protocol
could not be used in large-scale preparation, it inspired us to develop a novel synthetic
procedure of 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (6) (Scheme 2).
Commercially available 6-methoxyindan-1-one (7) was first converted to compound
8 in good yields according to the published procedures.11,12 Upon heating in N,N-
dimethylaniline, complete conversion of 8 into 9 was observed, without other regioisomers.
Subsequently, the intermediate 9 was treated with ozone and KBH4 to afford compound 10
in 85% yields. Esterification of compound 10 at low temperature (−10 ◦C) gave compound
11. In the final step, 11 was treated with triethylamine to give the tricyclic compound 6 in
65% yields. After crystallization, compound 6 was obtained in better than 99% purity. The
effectiveness and reliability of this procedure were undiminished on a preparative scale. At
present, the tricyclic compound 6 has been produced in kilogram without loss of purity or
yields.
In summary, we have developed a six-step synthesis of the tricyclic compound 6 in
41% overall yield from commercially available 6-methoxyindan-1-one (7). The advantages
of this procedure include short reaction steps, simple operation and good yields.

1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one
311
Me
OH
O
O
c
a
b
O
O
O
9
8
7
OMs
O
OH
OH
O
OH
e
d
O
O
10
11
6
(a) (i) AlCl3, toluene; (ii) K2CO3, acetone, allyl bromide, 85% (two steps);
(b) N,N-dimethylaniline, 1800C, 88%; (c) O3, KBH4, CH3OH, 85%;
(d) CH3SO2Cl, Py, CH2Cl2; (e) Et3N, EtOAc, 65% (two steps).
Scheme 2
Experimental Section
1H NMR spectra were recorded on a Bruker DRX-500 (500 MHz). 13C NMR spectra were
obtained on a JNM-EX400 (100 MHz). Mass spectra (MS) were determined on a Finnigan
MAT-95 mass spectrometer.
3-(7-tert-Butyl-2,3-dihydrobenzofuran-5-yl)propionic Acid (3)
To a solution of 2 (1.00 g, 5.21 mmol) in concentrated phosphoric acid (10 mL) was added
dropwise t-BuOH (0.424 g, 5.73 mmol). The mixture was heated at 80◦C for 4 h. After
cooling to room temperature, the mixture was poured into water (50 mL), and extracted
with CH2Cl2 (20.0 ml × 2). The organic phase was washed with brine (20 mL × 2), dried
with Na2SO4, and concentrated to give 3 (1.16 g, 90% yield) as a off-white solid, mp.
126–127◦C.
1H NMR (CDCl3): δ 1.33 (s, 9 H), 2.64 (t, J = 8.2 Hz, 2 H), 2.88 (t, J = 7.9 Hz,
2 H), 3.13 (t, J = 8.7 Hz, 2 H), 4.53 (t, J = 8.7 Hz, 2 H), 6.90 (d, J = 15.7 Hz, 2 H),
10.3 (br, 1 H). 13C NMR (100 MHz, CDCl3): δ 178.97, 156.53, 132.74, 131.68, 127.61,
124.64, 122.20, 70.48, 36.20, 34.00, 30.37, 29.69, 29.21. MS (EI): m/z 248 (M+, 37.80),
233 (100.00). HRMS (EI): m/z Calcd. for C15H20O3 [M+]: 248.1412. Found: 248.1413.
Anal. Calcd. for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.43; H, 8.01.
3-(7-tert-Butyl-2,3-dihydrobenzofuran-5-yl)propionyl Chloride (4)
A solution of 3 (1.16 g, 4.67 mmol) and DMF (0.47 mmol) in dry CH2Cl2 (20 mL) was
cooled to 0–5◦C. To this solution was added dropwise oxalyl chloride (1.20 g, 9.34 mmol).
Then the mixture was stirred for 2 h at room temperature, and evaporated to dryness to give
crude 4 (1.20 g) as a yellow oil, which was used in the next step without purification.

312
Luo et al.
4-tert-Butyl-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (5)
A mixture of crude 4 (1.20 g) and AlCl3 (1.20 g, 9.00 mmol) in CH2Cl2 (20 mL) was
stirred room temperature for 4 h. After 4 disappeared, the mixture was quenched with water
(40 mL), and extracted with CH2Cl2 (20 mL × 2). The organic layer was washed with brine
(20 mL × 2), dried with Na2SO4 and concentrated to give a residue, which was purified by
column chromatography with ethyl acetate/hexane (1:3) to yield 5 (0.75 g, 70% yield from
3) as a pale yellow solid, mp. 130–132◦C.
1H NMR (CDCl3): δ 1.35 (s, 9 H), 2.65 (m, 2 H), 3.15 (d, J = 6 Hz, 2 H), 3.45 (t, J =
8.5 Hz, 2 H), 4.65 (m, 2 H), 7.15 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ 207.25, 158.29,
147.60, 140.52, 131.50, 123.97, 122.17, 71.65, 37.17, 34.87, 28.96, 28.16, 25.58. MS (EI):
m/z 230 (M+, 50.22), 231 (9.20), 216 (15.60), 215 (100.00). HRMS (EI): m/z Calcd. for
C15H18O2 [M+]: 230.1307. Found: 230.1310.
Anal. Calcd. for C15H18O2: C, 78.23; H, 7.88. Found: C, 78.02; H, 7.81.
6-Allyloxyindan-1-one (8)
A solution of 6-methoxyindan-1-one (7) (20 g, 0.123 mol) and AlCl3 (41.2 g, 0.308 mol)
in dry toluene (200 mL) was refluxed for 3 h. After cooling to room temperature, water
(200 mL) was added, and the organic layer was separated. The water phase was extracted
with ethyl acetate (200 mL × 2). The organic phase was combined, washed with brine
(100 mL × 2), dried over Na2SO4 and evaporated under reduced pressure to give 17 g of
6-hydroxyindan-1-one (93% yield). Subsequently, to a mixture of 6-hydroxyindan-1-one
(17 g, 0.115 mol) and K2CO3 (47.6 g, 0.345 mol) in acetone (300 mL), was added allyl
bromide (27.8 g, 0.23 mol). After refluxing for 7 h, the mixture was cooled to room
temperature and filtered to remove inorganic solid. The filtrate was evaporated under
reduced pressure to give 19.5 g of 8 (91% yield) as a pale yellow solid, mp. 50–51◦C, after
trituration with petroleum ether.
1H NMR (CDCl3): δ 2.70 (t, J = 6 Hz, 2 H), 3.05 (t, J = 6 Hz, 2 H), 4.56 (d, J = 4 Hz,
2 H), 5.29 (d, J = 11 Hz, 1 H), 5.41 (d, J = 17 Hz, 1 H), 6.05 (m, 1 H), 7.20 (m, 2 H), 7.36
(d, J = 8 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ206.90, 158.23, 148.03, 138.15, 132.69,
127.37, 124.43, 117.93, 105.99, 69.00, 36.95, 25.06. MS (EI): m/z 188 (M+, 74.16).
6-Hydroxy-7-allylindan-1-one (9)
A solution of 8 (10.0 g, 53.2 mmol) in N,N-dimethylaniline (40 mL) was heated at 180◦C
for 10 h under nitrogen. After the rearrangement was completed, N,N-dimethylaniline was
evaporated under reduced pressure to give crude 18, which was recrystallized from ethyl
acetate to give 8.80 (88%) g of 9 as a yellow solid, mp. 124–125◦C.
1H NMR (CDCl3): δ 2.70 (t, J = 6 Hz, 2 H), 3.00 (t, J = 6 Hz, 2 H), 4.01 (d, J =
6 Hz, 2 H), 5.12 (m, 2 H), 5.27 (s, 1 H), 6.00 (m, 1 H), 7.06 (d, J =
8 Hz, 1 H), 7.25 (d, J = 8 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ 208.44, 154.03,
148.68, 135.83, 134.66, 125.28, 124.07, 122.98, 116.04, 37.69, 28.05, 24.37. MS (EI): m/z
188 (M+, 49.80), 173 (100.00). HRMS (EI): m/z Calcd. for C12H12O2 [M+]: 188.0837.
Found: 188.0839.
Anal. Calcd. for C12H12O2: C, 76.57; H, 6.43. Found: C, 76.42; H, 6.34.

1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one
6-Hydroxy-7-(2-hydroxyethyl)indan-1-one (10)
313
A stream of ozone was bubbled through a solution of 9 (8.80 g, 46.8 mmol) in methanol
(45 mL) at –40◦C until compound 9 disappeared. The excess ozone was removed by
purging with nitrogen. Potassium borohydride (2.53 g, 46.8 mmol) was added to decompose
ozonide, and the mixture was allowed to warm to room temperature with stirring for 1 h.
Then, the mixture was made slight acidic (pH 4–5) by the careful addition of a few drops
of 5% HCl. The mixture was extracted into ethyl acetate (20 mL × 3), washed with brine,
dried with Na2SO4, and concentrated to yield 7.64 g of 10 (85% yield) as a off-white solid,
mp. 135–136◦C, after trituration with petroleum ether.
1H NMR (DMSO-d6): δ 2.59 (t, J = 6 Hz, 2 H), 2.90 (t, J = 5.5 Hz, 2 H), 3.18 (t, J =
7.5 Hz, 2 H), 3.44 (m, 2 H), 4.68 (t, J = 5.5 Hz, 1 H), 7.08 (d, J = 8 Hz, 1 H), 7.19 (d, J =
8.5 Hz, 1 H), 9.5 (s, 1 H). 13C NMR (100 MHz, DMSO-d6): δ 207.37, 154.68, 146.62,
134.88, 124.72, 123.50, 121.90, 60.54, 37.20, 27.48, 23.86. MS (EI): m/z 192 (M+, 28.08),
174 (86.22), 173 (100.00). HRMS (EI): m/z Calcd. for C11H12O3 [M+]: 192.0786. Found:
192.0788.
Anal. Calcd. for C11H12O3: C, 68.74; H, 6.29. Found: C, 68.58; H, 6.11.
6-Hydroxy-7-(2-mesyloxyethyl)indan-1-one (11)
Methanesulfonyl chloride (4.74 g, 41.6 mmol) was added dropwise to a stirred solution of
10 (7.64 g, 39.6 mmol) and pyridine (6.32 g, 80.0 mmol) in CH2Cl2 (30 mL) at −10◦C.
After stirring for 10 h, a solution of 10% HCl (20 mL) was added to the mixture. The organic
layer was washed saturated NaHCO3 (20 mL × 2), dried with Na2SO4, and concentrated
to give crude 11 (10.5 g) as a pale yellow solid, after trituration with petroleum ether; it
was used directly in the next step.
1H NMR (CDCl3): δ 2.70 (m, 2 H), 3.00 (s, 3 H), 3.03 (t, J = 5.6 Hz, 2 H), 3.56 (t,
J = 6.6 Hz, 2 H), 4.51 (t, J = 6.6 Hz, 2 H), 7.12 (d, J = 8.2 Hz, 1 H), 7.26 (d, J = 8.1
Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ 208.31, 154.01, 149.00, 135.28, 126.12, 123.36,
121.14, 69.85, 37.57, 37.47, 24.58, 24.41. MS (EI): m/z 270 (M+, 2.98), 204 (100.00).
HRMS (EI): m/z Calcd. for C12H14O5S [M+]: 270.0562. Found: 270.0561.
Anal. Calcd. for C12H14O5S: C, 53.32; H, 5.22; S, 11.86. Found: C, 53.11; H, 5.13; S,
11.72.
1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one (6)
A solution of crude 11 (10.5 g) and triethylamine (7.86 g, 77.8 mmol) in ethyl acetate
(50 mL) was refluxed for 3 h, and cooled to room temperature. The mixture was washed
with 5% HCl (30 mL × 2), brine (20 mL × 2) and dried with Na2SO4. The organic layer
was evaporated to give crude product, which was recrystallized from ethyl acetate to afford
4.47 g of 2 (65% yield from 10) as a off white solid, mp. 132–133◦C; lit.10 mp. 133–134◦C.
1H NMR (CDCl3): δ 2.68 (t, J = 6 Hz, 2 H), 3.07 (t, J = 5.5 Hz, 2 H), 3.47 (t, J =
8.8 Hz, 2 H), 4.65 (t, J = 9 Hz, 2 H), 7.01 (d, J = 8 Hz, 1 H), 7.19 (d, J = 9 Hz, 1 H). 13C
NMR (100 MHz, CDCl3): δ 207.41, 160.22, 147.09, 133.65, 125.59, 123.90, 115.60, 72.32,
37.13, 28.38, 25.37. MS (EI): m/z = 174 (M+, 90.55), 173 (100.00).

314
Luo et al.
Acknowledgement
We gratefully acknowledge the financial support for New Century Excellent Talents in
university (NCET). And we also thank Lab of Organic Functional Molecules, the Sino-
French Institute of ECNU for support.
References
1. S. Hegde and M. Schmidt, Ann. Report Med. Chem., 41, 439 (2006).
2. K. Kato, K. Hirai, K. Nishiyama, O. Uchikawa, K. Fukatsu, S. Ohkawa, Y. Kawamata, S. Hinuma
and M. Miyamoto, Neuropharmacology, 48, 301 (2005).
3. R. T. Owen, Drugs of Today, 42, 255 (2006).
4. W. Richard, Exp. Rev. Neurother., 6, 957 (2006).
5. A. Karlm, D. Tolbert and C. Cao, J. Clin. Pharmacol., 46, 140 (2006).
6. S. Ohkawa, O. Uchikawa, K. Fukatsu and M. Miyamoto, US 6034239 (1997); Chem. Abstr., 127,
278142 (1997).
7. S. Urayama, E. Mutou, A. Inagaki, T. Okada and S. Sugisaki, WO 2006030739 (2006); Chem.
Abstr., 144, 331252 (2006).
8. V. K. Kansal, D. N. Mistry and S. L. Vasoya, WO 2008106179 (2008); Chem. Abstr., 149, 332191
(2008).
9. S. Ramdharane, T. C. Shah, J. M. Pandya, M. K. Singh and V. K. Agrawal, WO 2008062468
(2008); Chem. Abstr., 149, 9877 (2008).
10. O. Uchikawa, K. Fukatsu, R. Tokunoh, M. Kawada, K. Matsumoto, Y. Imai, S. Hinuma, K. Kato,
H. Nishikawa, K. Hirai, M. Miyamoto and S. Ohkawa, J. Med. Chem., 45, 4222 (2002).
11. D. C. Rodrigues, S. A. Fernandes and A. Marsaioli, Magn. Reson. Chem., 38, 970 (2000).
12. L. W. L. Woo, N. M. Howarth, A. Purohit, H. A. M. Hejaz, M. J. Reed and B. V. L. Potter,
J. Med. Chem., 41, 1068 (1998).