Synthesis of the melatonin receptor agonist Ramelteon using a tandem C-H activation-alkylation/Heck reaction and subsequent asymmetric Michael addition

Article abstract of DOI:10.1016/j.tetasy.2013.05.006

An asymmetric synthesis of the melatonin receptor agonist Ramelteon 1 has been achieved, which involved a tandem C-H activation-alkylation/Heck reaction and subsequent highly diastereoselective asymmetric Michael addition to generate the corresponding chiral intermediate, which was readily converted into Ramelteon 1 in 19% overall yield in 15 linear steps.

Full text of DOI:10.1016/j.tetasy.2013.05.006

Tetrahedron: Asymmetry 24 (2013) 827–832
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of the melatonin receptor agonist Ramelteon using
a tandem C–H activation–alkylation/Heck reaction and subsequent
asymmetric Michael addition
a,
XiaoDan Fu a, XingQun Guo a, XingWei Li a, LiDong He a, YuShe Yang b, , YouXi Chen
⇑
⇑
a Department of Medicinal Chemistry, Shanghai Sun-Sail Pharmaceutical Science & Technology Co., Ltd, No. 7, Building 1690, Cai-Lun Road, Zhangjiang Hi-Tech Park, Shanghai
201203, China
b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, State Key Laboratory of Drug Research, 555 Zu-Chong-Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203,
China
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric synthesis of the melatonin receptor agonist Ramelteon 1 has been achieved, which
involved a tandem C–H activation–alkylation/Heck reaction and subsequent highly diastereoselective
asymmetric Michael addition to generate the corresponding chiral intermediate, which was readily con-
verted into Ramelteon 1 in 19% overall yield in 15 linear steps.
Received 15 April 2013
Accepted 6 May 2013
Available online 2 July 2013
Ó 2013 Published by Elsevier Ltd.
1. Introduction
and subsequent highly diastereoselective asymmetric Michael
addition,12 which is then tested for industrial production. From a
Ramelteon 1 (Rozerem™, (S)-N-[2-(1,6,7,8-tetrahydro-2H-inde-
no[5,4-b]furan-8-yl)ethyl]-propionamide]), developed by Takeda
Pharmaceuticals North America, is the first selective agonist for
the melatonin MT1/MT2 receptors in the suprachiasmatic nucleus
(SCN)1 for the treatment of circadian rhythm sleep disorders.2 In
contrast to other FDA-approved drugs for this disease, it consti-
tutes as a new class of prescription drugs that do not cause the ad-
verse effects typically associated with the use of benzodiazepine
class of drugs, such as learning and memory impairment and drug
dependence since it has negligible affinity for the MT3 receptors.3
It is also the single prescription sleep medication that is not desig-
nated as a controlled substance by the US Drug Enforcement
Administration (DEA).4,5
medicinal chemistry point of view, a new synthetic approach of
Hamilton is presented herein based on our previous exploration
(Fig. 1).
2. Results and discussion
In recent decades, tandem reactions have been developed as an
efficient and straightforward one-step methodology for the con-
struction of fused heterocyclic compounds. Jafarpour11 reported
on a tandem palladium-catalyzed alkylation/alkenylation process
which forms at least three new C–C bonds in excellent yield, using
readily accessible starting materials, which inspired us to utilize
this method in our synthetic design.
Ramelteon has a simple but unique chemical scaffold contain-
ing a furan-fused tricycle ring and an asymmetric center at the
benzylic position. Currently, most of the reported total syntheses
of Ramelteon involve catalytic asymmetric hydrogenation6,7 or chi-
ral resolution8,9 of the corresponding racemic mixtures, which
have disadvantages such as low ee values or low yields. Zhang10 re-
ported a new approach to synthesize Ramelteon 1 from a commer-
cially unavailable starting material, however it is not suitable for
industrial production.
As shown in Scheme 1, commercially available compound 2 was
converted into compound 4 by employing Jafarpour’s11 method
after diazotization of the amino group, which was subjected to Fri-
edel–Crafts acylation and then recrystallized to afford compound 5
in good yield (47%). Protection of the carbonyl group in 5 was
HN
O
O
Herein, we have developed an efficient synthesis of a tricycle
intermediate 1,2,6,7-tetrahydro-8H-indeno[5, 4-b]furan-8-one
based on a tandem C–H activation–alkylation/Heck reaction11
(
)
S
⇑
Corresponding authors. Tel.: +86 21 50278490 8066; fax: +86 21 50278493.
E-mail addresses: ysyang@mail.shcnc.ac.cn (Y. Yang), cyxlzu@sina.com.cn
Ramelteon 1
Figure 1. Structure of Ramelteon 1.
(Y. Che).
0957-4166/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetasy.2013.05.006

828
XiaoDan Fu et al. / Tetrahedron: Asymmetry 24 (2013) 827–832
HO
NH2
HO
I
a
b
Br
O
I
2 3-aminophenol
3
4
O
O
d
c
O
Br
Br
O
I
O
I
5
7
Scheme 1. Reagents and conditions: (a) NaNO2, KI, CO(NH2)2, HCl (10%), rt, 90%; (b) K2CO3, 1,2-dibromoethane, acetone, 55 °C, 92%; (c) AlCl3, CH3COCl, CH2Cl2, 0 °C, 47%; (d)
PTS, ethylene glycol, toluene 140 °C, 95%.
achieved by treatment with ethylene glycol (PTS, toluene, 140 °C)
to obtain the key intermediate 7 in 95% yield, which was then sub-
jected to a tandem C–H activation–alkylation/Heck reaction pro-
cess to afford 9 as shown in Scheme 2. To achieve the optimal
yield with the lowest production cost, different reaction conditions
were carefully investigated as displayed in Schemes 3 and 4 and
Table 1. Initially, a direct alkylation/Heck reaction of compound 5
to obtain compound 9 was attempted; unfortunately, the yield
was below 20% (Scheme 3). Subsequently, the tandem reaction
was tried again after protecting the carbonyl with methanol, but
the result was not good (Scheme 4). Compound 5 was treated with
ethylene glycol (PTS, toluene, 140 °C) to protect the carbonyl; the
next step involving a tandem reaction was completed in a yield
of 61%. The base and the catalyst loading were also essential (en-
tries 1, 2, and 4 in Table 1). Finally, the optimal condition was
found in entry 4, which afforded compound 8 in high yield (85%).
Fustero12 reported a new intramolecular asymmetric Michael
reaction of tert-butanesulfinyl ketimines for the diastereoselective
synthesis of indanone derivatives with good yields and high diaste-
reoselectives. Based on the aforementioned result, compound 10
was obtained with high yield (81%) by treatment with (S)-N-
(tert-butylsulfinyl)amine (Ti(OEt)4, THF, 60 °C) after deprotection,
which was subjected to asymmetric Michael reaction to afford
compound 11 in an excellent yield of 98% and with an excellent
ee value of over 92% (determined by HPLC after conversion to com-
pound 12). Subsequently, hydrolysis of the chiral auxiliary in com-
pound 11 afforded chiral ester 12 (Scheme 2). Hydrogenation of
compound 12 gave the pure known compound 13, which was re-
duced with LiAlH4 (Scheme 5). Chiral amine 15 was obtained from
Gabriel reaction of compound 14 (three steps, total 90%). Finally,
Ramelteon 1 was obtained with an excellent ee value of over 92%
by acylation in the presence of propionyl chloride (Scheme 5).
3. Conclusion
In conclusion, we have reported a concise, asymmetric, and ste-
reocontrolled method for the synthesis of Ramelteon 1 via a tan-
dem C–H activation–alkylation/Heck reaction and subsequent
highly diastereoselective asymmetric Michael addition, using inex-
pensive commercially available 3-aminophenol 2 as a starting
material. Furthermore, the achieved methodology should be valu-
able for the medicinal modification of Ramelteon with high ee val-
ues in future drug discovery work.
4. Experimental
4.1. General
All reactions requiring anhydrous conditions were performed
under a positive pressure of argon using oven-dried glassware
(120 °C) which was cooled under argon. Next, THF was distilled
from sodium benzophenone ketyl, and DCM was distilled from
CaH2. Column chromatography was performed on Merck silica
gel Kieselgel 60 (230–400 mesh). Flash chromatography was car-
ried out using Merck Kieselgel 60 H silica or Matrex silica 60. Nu-
clear magnetic resonance (NMR) spectra were recorded on a
Bruker 400 MHz spectrometer in CDCl3 at 25 °C unless stated
otherwise and are reported in parts per million; J values are re-
corded in Hertz and multiplicities are expressed by the usual
conventions.
O
O
O
O
O
O
a
b
c
O
Br
O
I
COOEt
COOEt
7
8
9
O
O
O
O
O
S
N
S
d
e
N
O
COOEt
COOEt
COOEt
11
12
10
Scheme 2. Reagents and conditions: (a) Norbornene, ethyl acrylate, Pd(OAc)2, PPh3, K2CO3, DME, 80 °C, 85%; (b) HCl (36%), THF:H2O (2:1), rt, 95%; (c) Ti(OEt)4, (S)-N-(tert-
butanesulfinyl)amine, THF, 60 °C, 81%; (d) TBAF (1 M THF), ꢀ78 °C, 98%; (e) 3 M HCl, CH3OH, rt, 88%.

XiaoDan Fu et al. / Tetrahedron: Asymmetry 24 (2013) 827–832
829
O
O
I
3eq. Cs2CO3
5eq.
+
EtOOC
0.2eq. PPh3, 0.1eq Pd(OAc)2
Br
O
O
2 equiv.
80°C, 12h
yield<20%
COOEt
5
9
Scheme 3. Conversion of compound 5 to compound 9 directly.
O
O
O
I
3eq. Cs2CO3
O
5eq.
O
+
EtOOC
0.2eq. PPh3, 0.1eq Pd(OAc)2
O
O
Br
O
2 equiv.
80°C, 12h
yield<20%
COOEt
COOEt
6
9
Scheme 4. Conversion of compound 6 (protected with methanol) to compound 9.
Table 1
Conversion of compound 7 to compound 8
O
O
O
O
O
+
EtOOC
n equiv.
Pd(OAc)2,
PPh3,base
O
Br
O
O
I
COOEt
COOEt
7
8
9
Entry
n (equiv)
Base
Temp
Catalyst (mol %)
Yielda (%)
1
2
3
4
2
2
5
5
Cs2CO3
K2CO3
K2CO3
K2CO3
80 °C, 12 h
80 °C, 12 h
80 °C, 12 h
80 °C, 12 h
10
10
10
3
61
60
70
85
a
Isolated yield.
COOEt
COOEt
HO
a
b
O
O
O
O
12
13
14
O
H2N
c
d
O
O
N
H
15
1
Scheme 5. Reagents and conditions: (a) Pd–C, H2, EA:AcOH (1:1), 40 °C, 98%; (b) LiAlH4, THF, rt, 97%; (c) (i) MsCl, Et3N, CH2Cl2, rt; (ii) phthalimide potassium salt, DNF, 100 °C;
(iii) hydrazine hydrate, EtOH, 80 °C, 90% (three steps); (d) CH3CH2COCl, Et3N, DCM, rt, 95%.
4.2. 3-Iodophenol 3
stirred at 0 °C for 30 min. To the mixture was added urea (440 g,
7.33 mol) slowly portionwise, and then stirred at 0 °C for 1 h, after
which in a separate flask, potassium iodide (3.04 kg, 18.33 mol)
suspended in water (1 L) and 1,2-dichloroethane (1 L) were added
to the suspension. This mixture was cooled to 0 °C, and then
To a suspension of 3-aminophenol (1 kg, 9.16 mol) in 10%
hydrochloric acid (600 mL) was added a solution of sodium nitrite
(948 g, 13.75 mol) in water (300 mL) at 0 °C dropwise and then

830
XiaoDan Fu et al. / Tetrahedron: Asymmetry 24 (2013) 827–832
poured slowly into the diazonium mixture. The reaction was stir-
red for 30 min at 0 °C, then allowed to warm to room temperature
and stirred for another 2 h. The reaction mixture was filtered
through Celite and the solid was rinsed with dichloromethane.
The organic phase was washed with water and dried over anhy-
drous Na2SO4, then concentrated in vacuo to provide the product
3-iodophenol.
phy on silica gel (15:1 petroleum ether/ethyl acetate) to furnish
6.8 g (85%) of 8 as a clear colorless solid. 1H NMR (400 MHz, CDCl3)
d 8.39 (d, J = 16.3 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 8.4 Hz,
1H), 6.05 (d, J = 16.3 Hz, 1H), 4.55 (t, J = 8.6 Hz, 2H), 4.26 (q,
J = 7.1 Hz, 2H), 4.00 (t, J = 6.9 Hz, 2H), 3.72 (t, J = 6.9 Hz, 2H), 3.29
(t, J = 8.6 Hz, 2H), 1.65 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR
(101 MHz, CDCl3) d 166.6, 159.9, 143.4, 134.2, 129.9, 126.70,
121.0, 109.3, 77.6, 76.5, 75.3, 71.1, 63.1, 60.0, 30.9, 27.3, 14.5.
HRMS (EI-quadrupole) m/z: [M]+ Calcd for C17H20O5 304.1311;
Found 304.1310.
4.3. 1-(2-Bromoethoxy)-3-iodobenzene 4
The preparation of 1-(2-bromoethoxy)-3-iodobenzene was car-
ried out according to the literature.11
4.7. (E)-Ethyl 3-(5-acetyl-2,3-dihydrobenzofuran-4-yl)acrylate 9
4.4. 1-(4-(2-Bromoethoxy)-2-iodophenyl)ethanone 5
To a solution of 8 (8.2 g, 27 mmol, 1 equiv) in THF (40 mL) and
water (20 mL) was added dropwise 36% HCl (3.4 mL, 40.5 mmol,
1.5 equiv) at 0 °C, and the mixture was stirred at ambient temper-
ature for 2 h, which was then neutralized by adding saturated
aqueous NaHCO3, then extracted with ethyl acetate (3 ꢁ 40 mL).
The organic layer was washed with saturated NaHCO3 (50 mL)
and brine (50 mL). The organic layer was dried over anhydrous
Na2SO4 and concentrated to obtain crude 9, which was recrystal-
lized by a mixture solvent of petroleum ether and ethyl acetate
(3:1) furnished 6.66 g of 9 (95%) as white crystals. 1H NMR
(400 MHz, CDCl3) d 8.08 (d, J = 16.3 Hz, 1H), 7.70 (d, J = 8.4 Hz,
1H), 6.81 (d, J = 8.4 Hz, 1H), 6.16–5.92 (m, 1H), 4.65 (t, J = 8.7 Hz,
2H), 4.27 (q, J = 7.2 Hz, 2H), 3.31 (t, J = 8.7 Hz, 2H), 2.53 (s, 3H),
1.31 (t, J = 8.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 198.7, 166.3,
163.1, 144.1, 133.5, 132.0, 130.2, 127.0, 121.7, 109.3, 71.8, 60.5,
29.4, 28.3, 13.8. HRMS (EI-quadrupole) m/z: [M]+ Calcd for
To a solution of 4 (100 g, 306 mmol, 1 equiv) in anhydrous DCM
(200 mL) was added acetyl chloride (28.8 g, 367 mmol, 1.2 equiv)
at 0 °C. Then AlCl3 (53 g, 398 mmol, 1.3 equiv) was added portion-
wise to this stirred mixture over a period of 30 min, and the mix-
ture was stirred at ambient temperature for 2 h. After the
reaction was completed, the mixture was poured slowly into ice-
water and extracted with DCM (3 ꢁ 100 mL). The organic layer
was washed with 1 M NaOH (50 mL), water (50 mL), and brine
(50 mL). The organic layer was dried over anhydrous Na2SO4 and
concentrated to obtain crude 5, which was recrystallized by a
mixed solvent of petroleum ether/ethyl acetate (5:1) to provide
64 g of 5 (47%) as white crystals. 1H NMR (400 MHz, CDCl3) d
7.47 (d, J = 8.1 Hz, 1H), 7.39 (dd, J = 8.2, 1.5 Hz, 1H), 7.24 (d,
J = 1.3 Hz, 1H), 4.5–4.28 (m, 2H), 3.71 (dd, J = 6.0, 5.3 Hz, 2H),
2.66 (s, 3H). 13C NMR (101 MHz, CDCl3) d 198.8, 159.8, 134.9,
130.8, 127.6, 113.9, 92.8, 68.0, 28.8, 28.4. HRMS (EI-quadrupole)
m/z: [M]+ Calcd for C10H10O2BrI 367.8909; Found 367.8907.
C15H16O4 260.1049; Found 260.1051.
4.8. (E)-Ethyl 3-(5-(1-(S)-((tert-butylsulfinyl)imino)ethyl)-2,3-
dihydrobenzofuran-4-yl) acrylate 10
4.5. 2-(4-(2-Bromoethoxy)-2-iodophenyl)-2-methyl-1,3-
dioxolane 7
A solution of 9 (4 g, 15.4 mmol, 1 equiv) and 66% Ti(OEt)4
(21.3 g, 61.5 mmol, 4 equiv) in anhydrous THF (40 mL) was stirred
for 10 min at 0 °C. To the resulting solution was added (S)-N-(tert-
butylsulfinyl)amine (2.05 g, 16.9 mmol, 1.1 equiv) and stirred at
60 °C for 24 h. Next, saturated aqueous NaHCO3 was added at
0 °C until white titanium salts precipitated. The suspension was fil-
tered through a short pad of Celite washing with small portions of
ethyl acetate. The filtrate was extracted with ethyl acetate and the
combined organic layers were washed with brine, dried over anhy-
drous Na2SO4, and concentrated to give crude 10, which was puri-
fied by flash chromatography on silica gel (3:1 petroleum ether/
ethyl acetate) to give 4.5 g (81%) of 10 as a brown oil. 1H NMR
(400 MHz, CDCl3) d 7.91–7.84 (m, 1H), 7.36 (d, J = 8.3 Hz, 1H),
6.82 (d, J = 8.4 Hz, 1H), 6.06 (dd, J = 16.3, 9.5 Hz, 1H), 4.73–4.53
(m, 2H), 4.24 (t, J = 7.2 Hz, 2H), 3.45–3.22 (m, 2H), 2.71 (s, 3H),
1.30 (q, 3H), 1.25 (s, 9H). 13C NMR (101 MHz, CDCl3) d 179.4,
166.2, 162.0, 143.6, 133.9, 131.1, 129.6, 127.0, 121.6, 109.3, 71.8,
To a mixture of 5 (66 g, 179 mmol, 1 equiv) and toluene
(240 mL) were added ethane-1,2-diol (55.5 g, 894 mmol, 5 equiv)
and p-toluenesulfonic acid (3.12 g, 17.9 mmol, 0.1 equiv). Next,
the reaction mixture was stirred at 140 °C to remove the water
by a Dean–Stark Trap. After the reaction was completed, it was
quenched by adding 10% NaHCO3, then concentrated under re-
duced pressure to remove the solvent, after which the residue
was dissolved in ethyl acetate (100 mL). The organic layer was sep-
arated, washed with water (50 mL) followed by brine (50 mL),
dried, concentrated, and purified by flash chromatography (10:1
petroleum ether/ethyl acetate) to provide 70 g (95%) of 7 as a clear
colorless solid. 1H NMR (400 MHz, CDCl3) d 7.55 (d, J = 8.7 Hz, 1H),
7.49 (d, J = 2.6 Hz, 1H), 6.87 (dd, J = 8.7, 2.6 Hz, 1H), 4.26 (t,
J = 6.1 Hz, 2H), 4.03 (td, J = 6.1, 4.4 Hz, 2H), 3.69 (dt, J = 9.2,
4.0 Hz, 2H), 3.62 (t, J = 6.1 Hz, 2H), 1.76 (s, 3H). 13C NMR
(101 MHz, CDCl3) d 157.5, 136.8, 128.0, 128.0, 113.9, 108.4, 92.8,
67.9, 64.5, 63.8, 28.8, 25.5. HRMS (EI-quadrupole) m/z|: [M]+ Calcd
for C12H14O3BrI 411.9171; Found 411.9168.
60.7, 56.5, 30.2, 29.3, 22.3, 14.2. ½a D25
¼ ꢀ4:1 (c 1.0, CHCl3). HRMS
ꢂ
(EI-quadrupole) m/z: [M]+ Calcd for C19H25NO4S 363.1504; Found
363.1502.
4.6. (E)-Ethyl 3-(5-(2-methyl-1,3-dioxolan-2-yl)-2,3-
4.9. Ethyl 2-((8S)-6-(((S)-tert-butylsulfinyl)imino)-2,6,7,8-
dihydrobenzofuran-4-yl) acrylate 8
tetrahydro-1H-indeno[5,4-b]furan-8-yl)acetate 11
Compound
7
(11 g, 26.63 mmol, 1 equiv), ethyl acrylate
To a solution of 10 (5.5 g, 15.1 mmol, 1 equiv) in anhydrous THF
(80 mL) was added TBAF (1 M in THF, 18 mL, 18.1 mmol, 1.2 equiv)
at ꢀ78 °C, and the reaction temperature was allowed to rise until
TLC revealed the disappearance of 10. Next, the reaction mixture
was quenched with saturated NH4Cl and extracted with ethyl ace-
tate (3 ꢁ 25 mL). The organic layer was washed with brine (30 mL).
The combined organic layer was dried over anhydrous Na2SO4 and
concentrated to obtain crude 11, which was purified by flash
(13.33 g, 133 mmol, 5 equiv), norbornene (12.54 g, 133 mmol,
5 equiv), K2CO3 (11 g, 80 mmol, 3 equiv), Pd(OAc)2 (179 mg,
799 lmol, 3% equiv), and PPh3 (699 mg, 2.66 mmol, 10% equiv)
were dissolved in 80 mL of degassed dry DME. The mixture was
flushed with Ar and heated at 80 °C for 16 h. After cooling at rt,
the mixture was diluted with diethyl ether, washed with water,
dried over anhydrous Na2SO4, and purified by flash chromatogra-

XiaoDan Fu et al. / Tetrahedron: Asymmetry 24 (2013) 827–832
831
chromatography on silica gel (3:1 petroleum ether/ethyl acetate)
to give 5.4 g (98%) of 11 as a brown oil. 1H NMR (400 MHz, CDCl3)
d 7.64 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.67 (dd, J = 15.5,
14.1 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.69 (d, J = 18.8 Hz, 2H),
3.33–3.12 (m, 2H), 2.99–2.73 (m, 2H), 2.48–2.36 (m, 1H), 1.28 (s,
9H), 1.20 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 181.1,
171.2, 165.3, 148.9, 132.2, 124.7, 122.2, 110.0, 72.4, 60.4, 57.1,
J = 7.9 Hz, 1H), 4.66–4.42 (m, 2H), 3.90–3.65 (m, 2H), 3.26 (dt,
J = 15.0, 9.7 Hz, 2H), 3.19–3.05 (m, 1H), 2.99–2.82 (m, 1H), 2.83–
2.67 (m, 1H), 2.27 (dtd, J = 12.6, 8.3, 6.4 Hz, 1H), 2.11 (dtd,
J = 13.5, 7.5, 4.1 Hz, 1H), 1.92–1.74 (m, 1H), 1.68 (dddd, J = 13.4,
10.1, 6.8, 5.4 Hz, 1H). ½a D25
¼ ꢀ81:4 (c 1.0, CHCl3).
ꢂ
4.13. (S)-2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl) eth-
anamine 15
39.4, 38.2, 37.1, 27.7, 22.4, 14.0. ½a D25
ꢂ
¼ þ96:9 (c 1.0, CHCl3). HRMS
(EI-quadrupole) m/z: [M]+ Calcd for C19H25NO4S 363.1504; Found
363.1505.
To a solution of 14 (2.8 g, 13.7 mmol, 1 equiv) were added me-
syl chloride (1.7 g, 15.1 mmol, 1.1 equiv) and Et3N (2.8 g,
27.4 mmol, 2 equiv) at room temperature. After being stirred for
1 h, the reaction mixture was quenched with a saturated sodium
bicarbonate solution (10 mL), extracted with DCM, washed with
brine, dried over anhydrous Na2SO4, and concentrated under re-
duced pressure to furnish a yellow liquid, which was dissolved in
DMF (20 mL). Next, phthalimide potassium salt (2.8 g, 15.1 mmol,
1.1 equiv) was added to the solution, and the mixture was heated
at 100 °C for 1 h. After the reaction was completed, it was poured
into ice-water, extracted with DCM, washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure to
furnish a yellow solid, which was dissolved in EtOH (20 mL).
Hydrazine hydrate (1.7 g, 15.1 mmol, 1.1 equiv) was added to the
solution, and refluxed for 3 h. The suspension was filtered through
Celite and washed with DCM. The filtrate was extracted with DCM
and the combined organic layers were washed with water and
brine, dried over anhydrous Na2SO4, and concentrated to give
crude 15 2.76 g (90%, three steps), which was used without further
purification. 1H NMR (400 MHz, CDCl3) d 8.41 (s, 2H), 6.93 (d,
J = 7.8 Hz, 1H), 6.61 (d, J = 7.8 Hz, 1H), 4.60–4.47 (m, 2H), 3.40–
3.11 ((m, 5H), 2.87–2.75 (m, 2H), 2.35–1.95 (s, 2H), 1.89–1.65 (m,
4.10. (S)-Ethyl 2-(6-oxo-2,6,7,8-tetrahydro-1H-indeno[5,4-b] fur-
an-8-yl)acetate 12
To a solution of 11 (5.4 g, 14.9 mmol, 1 equiv) in anhydrous
MeOH (40 mL) was added 3 M HCl (12 mL, 22.4 mmol, 1.5 equiv)
at 0 °C, and then stirred at room temperature for 4 h, after which
TLC revealed the disappearance of 11. The reaction mixture was then
quenched with saturated brine, and extracted with ethyl acetate
(3 ꢁ 30 mL). The organic layer was washed with brine (30 mL).
The combined organic layer was dried over anhydrous Na2SO4 and
concentrated to obtain crude 12, which was purified by flash chro-
matography on silica gel (4:1 petroleum ether/ethyl acetate) to give
3.4 g (88%) of 12 as a white solid. 1H NMR (400 MHz, CDCl3) d 7.61 (d,
J = 8.3 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.85–4.60 (m, 2H), 4.14 (q,
J = 7.2 Hz, 2H), 3.74 (td, J = 7.5, 3.9 Hz, 1H), 3.39–3.18 (m, 2H),
3.05–2.84 (m, 2H), 2.61–2.36 (m, 2H), 1.23 (t, J = 8.0 Hz, 3H). 13C
NMR (101 MHz, CDCl3) d 204.8, 171.6, 166.6, 153.4, 130.3, 125.0,
122.5, 110.4, 72.6, 60.1, 43.4, 38.4, 33.7, 27.0, 14.2. ½a D25
¼ ꢀ73:5 (c
ꢂ
1.0, CHCl3). Chiral HPLC (96:4, tR minor = 14.0 min, tR major = 17.4 min).
HRMS (EI-quadrupole) m/z: [M] Calcd for C15H16O4 260.1049;
+
Found 260.1046. The enantiomeric excess was determined as de-
scribed in theprocedure: Column:AD-H. Solvent:Mobile phase. Mo-
bile phase: Hexane:IPA = 70:30. Concentration: 0.5 mg/mL.
2H). ½a 2D5
¼ ꢀ69:2 (c 1.0, CHCl3).
ꢂ
4.14. Ramelteon 1
Injection volume: 10 lL. Flow rate: 0.5 mL/min. Detection: UV oper-
ated at 234 nm. Temp: 30 °C.
The preparation of Ramelteon 1 was carried out according to
the literature.10 1H NMR (400 MHz, CDCl3) d 6.96 (d, J = 8.0 Hz,
1H), 6.60 (t, J = 8.0 Hz, 1H), 5.51 (br, 1H), 4.65–4.42 (m, 2H),
3.41–3.28 (m, 2H), 3.29–3.01 (m, 4H), 2.95–2.84 (m, 1H),
2.82–2.70 (m, 1H), 2.34–2.21 (m, 1H), 2.17 (q, J = 7.6 Hz, 2H),
2.08–1.91 (m, 1H), 1.89–1.75 (m, 1H), 1.70–1.56 (m, 1H),
4.11. (S)-Ethyl 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-
yl)acetate 13
To a solution of 12 (3 g, 11.53 mmol, 1 equiv) in ethyl acetate
(10 mL) and AcOH (10 mL) was added in portions 10% Pd/C
(0.6 g, 0.58 mmol, 0.05 equiv), and the mixture was hydrogenated
under 40 psi of H2 and at 45 °C for 24 h. The reaction mixture
was filtered through Celite and concentrated under reduced pres-
sure to furnish 2.8 g (98%) crude 13 as a white solid. 1H NMR
(400 MHz, CDCl3) d 6.96 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H),
4.63–4.48 (m, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.63–3.53 (m, 1H),
3.25–3.05 (m, 2H), 2.94–2.84 (m, 1H), 2.82–2.70 (m, 2H), 2.42–
2.28 (m, 2H), 1.85 (ddt, J = 13.8, 8.3, 5.6 Hz, 1H), 1.27 (t,
1.14 (t, J = 8.2 Hz, 3H).
½
a 2D5
ꢂ
¼ ꢀ54:8 (c 1.0, CHCl3). LC–MS:
260.20[M+H]+.
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ꢂ
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NMR (400 MHz, CDCl3)
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