Synthesis of 4-aza analog of ramelteon: A novel tricyclic 1,6,7,8-tetrahydro-2H-cyclopenta[d]furo[2,3-b]pyridine derivative as melatonin receptor ligand

Article abstract of DOI:10.1016/j.tetlet.2011.03.147

The 4-aza analog of ramelteon (-)-1, a novel tricyclic 1,6,7,8-tetrahydro- 2H-cyclopenta[d]furo[2,3-b]pyridine derivative, was synthesized via the intramolecular inverse electron demand Diels-Alder reaction followed by fluoride-induced desilylation-cyclization.

Full text of DOI:10.1016/j.tetlet.2011.03.147

Tetrahedron Letters 52 (2011) 3009–3011
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Synthesis of 4-aza analog of ramelteon: a novel tricyclic 1,6,7,8-tetrahydro-
2H-cyclopenta[d]furo[2,3-b]pyridine derivative as melatonin receptor ligand
⇑
Tatsuki Koike , Yasutaka Hoashi, Takafumi Takai, Osamu Uchikawa
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 17-85 Jusohonmachi, 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The 4-aza analog of ramelteon (ꢀ)-1, a novel tricyclic 1,6,7,8-tetrahydro-2H-cyclopenta[d]furo[2,3-b]pyr-
idine derivative, was synthesized via the intramolecular inverse electron demand Diels–Alder reaction
followed by fluoride-induced desilylation–cyclization.
Received 26 February 2011
Revised 28 March 2011
Accepted 31 March 2011
Available online 7 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ramelteon
Cyclopenta[d]furo[2,3-b]pyridine
Intramolecular Diels–Alder reaction
Desilylation–cyclization
Indeno[5,4-b]furan, the central core of ramelteon1 (Fig. 1), is a
novel angular tricyclic ring system that mimics the 5-methoxy in-
dole core of melatonin.2 Melatonin, a neurohormone secreted from
the pineal gland, exerts a sleep-promoting effect through the acti-
vation of melatonin receptors (MT1 and MT2). Ramelteon shows
more potent agonistic activity against these receptors than does
the natural ligand melatonin and has been marketed for the treat-
ment of insomnia.3 This type of angular tricyclic ring system ap-
pears not only in the melatonin receptor ligands but also in
many biologically active compounds such as serotonin (5-HT) li-
gands, including subtype selective ligands for 5-HT2c receptor.4
Therefore, this class of structure inspires the design and synthesis
of its structural analogs, which could be of value for SAR studies,
additional interaction for receptors, subtype selectivity, and the
identification of novel biological activity. In this regard, we dis-
placed the carbon atom at the 4-position of indeno[5,4-b]furan
with nitrogen, and novel tricyclic cyclopenta[d]furo[2,3-b]pyridine
derivative, 4-aza analog of ramelteon 1, was synthesized as a
melatonin receptor ligand (Fig. 1). A literature survey revealed that
there are no reports on such unique tricyclic cyclopenta[d]furo[2,3-
b]pyridines and their synthesis methods. Herein, we report an
efficient procedure for the synthesis of 1,6,7,8-tetrahydro-2H-
cyclopenta[d]furo[2,3-b]pyridine, which is converted to the 4-aza
analog of ramelteon 1.
O
O
N
H
N
H
MeO
O
N
H
4
melatonin
ramelteon
O
N
H
O
N
1
4-aza analog of ramelteon
Figure 1. Chemical structures of melatonin, ramelteon, and 4-aza analog of
ramelteon 1.
of ramelteon could be constructed by Friedel–Crafts cyclization;
however, the electron-deficient nature of the central pyridine ring
in 2 made the use of the aforementioned reaction difficult. Hence,
we attempted to synthesize the cyclopentane ring by fluoride-in-
duced desilylation–cyclization6 of propanal derivative 3. 4,5-
Difunctionalized 2,3-dihydrofuro[2,3-b]pyridine 4, which could
be obtained from pyrimidine 5 by the intramolecular inverse elec-
tron demand Diels–Alder reaction,7 was selected as the key
intermediate.
Initially, we focused on the retrosynthetic analysis of tricyclic
ketone 2, which could be readily converted to 1 via the synthesis
route reported for ramelteon1,5 (Scheme 1). The cyclopentane ring
⇑
Corresponding author. Tel.: +81 6 6300 6546; fax: +81 6 6300 6306.
E-mail address: Koike_Tatsuki@takeda.co.jp (T. Koike).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.147

3010
T. Koike et al. / Tetrahedron Letters 52 (2011) 3009–3011
Table 1
O
Fluoride-induced desilylation–cyclization reaction of 3. Method A: Heating of
a
suspension of 3 and TBAT at 70 °C; method B: Dropwise addition of a solution of 3 to a
pre-heated (70 °C) suspension of TBAT
O
N
H
O
O
O
N
N
OH
O
TMS
TBAT
O
1
3
2
4
N
H
solvent
70 oC
N
O
3
10
O
4
5
TMS
TMS
Br
Entry
Solvent
Method
Yield (%)
N
H
N
1
2
3
4
MeCN
Toluene
DME
A
A
A
B
39
Decomp.
56
O
DME
71
attempted the microwave irradiation, and microwave heating of
5 at 220 °C for 10 h afforded the target compound 7 in 67% yield
(at higher temperatures, degradation of 7 was observed). Subse-
quent regioselective bromination at the 5-position of 7 gave the
desired 4,5-difunctionalized 2,3-dihydrofuro[2,3-b]pyridine 4 in
80% yield. Propanal derivative 3 was synthesized by Stille cou-
pling8 of bromide 4 with allyltributyltin, followed by hydrobora-
tion with 9-BBN/BF3ꢁEt2O6 and subsequent oxidation with 2-
iodoxybenzoic acid (IBX).
O
N
TMS
N
5
Scheme 1. Retrosynthesis of the 4-aza analog of ramelteon 1.
Construction of the cyclopentane ring by fluoride-induced desi-
lylation–cyclization (Table 1) was investigated. This cyclization
method was reported by Beierle et al.6 for the synthesis of louisia-
nin C, which has a cyclopentapyridine ring as the core skeleton. As
per their procedure, 3 was heated up to 70 °C with tetrabutylam-
monium difluorotriphenylsilicate (TBAT)6 in acetonitrile. However,
the reaction gave the desired product only in moderate yield (39%,
entry 1) accompanied by a large amounts of byproducts. For the
improvement of the chemical yield, we optimized the reaction sol-
vent first. The use of toluene resulted in the decomposition of 3
(entry 2), while the use of 1,2-dimethoxyethane (DME), a polar sol-
vent, resulted in enhanced chemical yield (56%, entry 3). Then, we
fixed DME as the solvent and modified the reaction procedure to
suppress the intermolecular reaction, since the byproducts were
thought to be formed from the polymerization of 3. Dropwise addi-
tion of a solution of propanal 3 in DME to a pre-heated (70 °C) sus-
pension of TBAT in DME (method B) resulted in increased reaction
yield (71%, entry 4).
O
O
N
a
b or c
4
TMS
O
N
TMS
N
N
N
6
5
7
O
4
5
TMS
Br
O
d
e
TMS
TMS
f
N
N
4
8
O
O
TMS
g
N
OH
N
H
After successful preparation of the novel 1,6,7,8-tetrahydro-2H-
cyclopenta[d]furo[2,3-b]pyridine scaffold, compound 10 was then
converted to the 4-aza analog of ramelteon 1 (Scheme 3). Oxida-
tion of cyclopentanol derivative 10 by tetra-n-propylammonium
perruthenate (TPAP)/N-methylmorpholine N-oxide (NMO)9 affor-
ded the key intermediate 2 in 68% yield. Introduction of the amide
side chain in ketone 2 was achieved by following the synthesis pro-
cedure reported for ramelteon.1,5 Horner–Wadsworth–Emmons
reaction of 2 with diethylcyanophosphonate gave nitrile 11 as a
mixture of E/Z isomers. Hydrogenation of 11 over Raney cobalt
(ODHT-60), followed by acylation and hydrogenation over Pd/C,
afforded target compound 1 as a racemic mixture. The optically ac-
tive isomers (ꢀ)-1 and (+)-1 were obtained by chiral resolution
using preparative HPLC.10
O
9
3
Scheme 2. Synthesis of 2,3-dihydrofuro[2,3-b]pyridine. Reagents and conditions:
(a) LDA, TMSCl, THF, ꢀ78 °C, 91%; (b) nitrobenzene, microwave heating, 220 °C,
67%; (c) nitrobenzene, 200 °C, 14%; (d) Br2, NaHCO3, CH2Cl2, rt, 80%; (e) allyltribu-
tyltin, PdCl2(PPh3)2, DMF, 100 °C, 96%; (f) BF3ꢁEt2O, 9-BBN, 0 °C; then, N,N,N,N-
tetramethylethlenediamine, 30% H2O2 aq, 2.5 M NaOH aq., rt, 66%; (g) IBX, DMSO,
rt, 87%.
The synthesis of 2,3-dihydrofuro[2,3-b]pyridine is described in
Scheme 2. For the direct access to the introduction of a substituent
at the 4-position of the ring, the intramolecular inverse electron
demand Diels–Alder reaction7 of 2-(3-butynyloxy)pyrimidine was
carried out. A trimethylsilyl (TMS) group was introduced at the ter-
minal position of the known alkyne 67, and the resulting tethered
alkyne 5 was subjected to the heating condition following the
experimental procedure described by Frissen et al.7 When 5 was
heated in nitrobenzene at 200 °C for 24 h, the desired 4-trimethyl-
silyl 2,3-dihydrofuro[2,3-b]pyridine 7 was obtained in very low
yield (14%), and most of the starting material was recovered. The
extremely slow reaction rate might due to steric repulsion of the
TMS group on the alkyne side chain. To activate the reaction, we
The (ꢀ)-1 isomer exhibited potent binding affinities11 for mela-
tonin receptors (MT1: Ki = 3.4 nM, MT2: Ki = 1.3 nM), while (+)-1
exhibited negligible affinities (MT1: Ki = >10,000 nM, MT2: Ki =
>10,000 nM). This result demonstrated that the 1,6,7,8-tetrahy-
dro-2H-cyclopenta[d]furo[2,3-b]pyridine scaffold is a potent mi-
mic of the 5-methoxyindole core of melatonin.
In conclusion, a method for synthesizing a novel 1,6,7,8-tetra-
hydro-2H-cyclopenta[d]furo[2,3-b]pyridine
was
successfully
developed; this synthesis involved intramolecular inverse electron

T. Koike et al. / Tetrahedron Letters 52 (2011) 3009–3011
3011
OH
References and notes
O
O
O
b
a
1. Uchikawa, O.; Fukatsu, K.; Tokunoh, R.; Kawada, M.; Matsumoto, K.; Imai, Y.;
Hinuma, S.; Kato, K.; Nishikawa, H.; Hirai, K.; Miyamoto, M.; Ohkawa, S. J. Med.
Chem. 2002, 45, 4222.
N
N
O
2. Reiter, R. J. Endocr. Rev. 1991, 12, 151.
10
11
2
3. (a) Kato, K.; Hirai, K.; Nishiyama, K.; Uchikawa, O.; Fukatsu, K.; Ohkawa, S.;
Kawamata, Y.; Hinuma, S.; Miyamoto, M. Neuropharmacology 2005, 48, 301; (b)
Miyamoto, M. CNS Neurosci. Ther. 2009, 15, 32.
O
CN
4. (a) Shimada, I.; Maeno, K.; Kazuta, K.; Kubota, H.; Kimizuka, T.; Kimura, Y.;
Hatanaka, K.; Naitou, Y.; Wanibuchi, F.; Sakamoto, S.; Tsukamoto, S. Bioorg.
Med. Chem. 2008, 16, 1966; (b) Bentley, J. M.; Adams, D. R.; Bebbington, D.;
Benwell, K. R.; Bickerdike, M. J.; Davidson, J. E.; Dawson, C. E.; Dourish, C. T.;
Duncton, M. A.; Gaur, S.; George, A. R.; Giles, P. R.; Hamlyn, R. J.; Kennett, G. A.;
Knight, A. R.; Malcolm, C. S.; Mansell, H. L.; Misra, A.; Monck, N. J.; Pratt, R. M.;
Quirk, K.; Roffey, J. R.; Vickers, S. P.; Cliffe, I. A. Bioorg. Med. Chem. Lett. 2004, 14,
2367.
5. Yamano, T.; Yamashita, M.; Adachi, M.; Tanaka, M.; Matsumoto, K.; Kawada,
M.; Uchikawa, O.; Fukatsu, K.; Ohkawa, S. Tetrahedron: Asymmetry 2006, 17,
184.
6. (a) Beierle, J. M.; Osimboni, E. B.; Metallinos, C.; Zhao, Y.; Kelly, T. R. J. Org.
Chem. 2003, 68, 4970; (b) Pilcher, A. S.; DeShong, P. J. Org. Chem. 1996, 61, 6901.
7. Frissen, A. E.; Marcelis, A. T. M.; van der Plas, H. C. Tetrahedron 1989, 45, 803.
8. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
N
H
c
O
N
N
d
(-) -1
1
1
(+)-
Scheme 3. Synthesis of 4-aza analog of ramelteon 1. Reagents and conditions: (a)
TPAP, NMO, molecular sieves 4 Å, MeCN, rt, 68%; (b) NaH, (EtO)2POCH2CN, THF, 0 °C,
91%; (c) (1) H2, Raney cobalt (ODHT-60), NH3, EtOH, rt; (2) EtCOCl, Et3N, CH2Cl2,
0 °C; (3) 10% Pd/C, H2, EtOH, rt, 56%. (d) HPLC resolution (CHIRALPAK AS).
demand Diels–Alder reaction followed by fluoride-induced desily-
lation–cyclization. 4-Aza analog of ramelteon (ꢀ)-1 was synthe-
sized and demonstrated that this scaffold is a potent mimic of
the 5-methoxy indole core of melatonin. The method described
herein can be extended to the synthesis of many valuable analogs
that can be used for the identification of a wide variety of biologi-
cally active compounds as well as melatonin receptor ligands.
9. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639.
10. The racemic 1 (515 mg) was subjected to the chiral resolution using HPLC
(CHIRALPAK AS™, hexane/ethanol = 84:16, containing 0.1% diethylamine) to
afford (ꢀ)-1 (short retention time, 237 mg, >99% ee) and (+)-1 (long retention
time, 241 mg, >99% ee). (ꢀ)-1: ½a D20
ꢂ
= ꢀ72.8 (c = 0.59, MeOH); 1H NMR (CDCl3)
d 1.16 (3H, t, J = 7.4 Hz), 1.56–1.71 (1H, m), 1.74–1.90 (1H, m), 1.99–2.13 (1H,
m), 2.20 (2H, q, J = 7.4 Hz), 2.25–2.40 (1H, m), 2.69–2.94 (2H, m), 3.07–3.41
(5H, m), 4.46–4.72 (2H, m), 5.50 (1H, br s), 7.80 (1H, s). (+)-1: ½a D20
ꢂ
= +75.6
(c = 0.59, MeOH); 1H NMR (CDCl3) d 1.16 (3H, t, J = 7.7 Hz), 1.57–1.70 (1H, m),
1.75–1.90 (1H, m), 2.00–2.13 (1H, m), 2.20 (2H, q, J = 7.7 Hz), 2.25–2.38 (1H,
m), 2.69–2.94 (2H, m), 3.08–3.39 (5H, m), 4.50–4.67 (2H, m), 5.49 (1H, br s),
7.80 (1H, s).
Acknowledgments
11. The binding affinities of (ꢀ)-1 and (+)-1 were evaluated based on the method
of Kato et al.3 using 2-[125I]-iodomelatonin as radioligand in CHO cells
expressing human melatonin receptor (MT1 or MT2). The dissociation
constant of the compound for the receptor (Ki) was calculated using the
The authors thank Dr. Shigenori Ohkawa and Dr. Yuji Ishihara
for their helpful discussions.
following equation: Ki = IC50/(1 + L/Kd), where
L and Kd represent the
concentration and the affinity constant of 2-[125I]melatonin in the binding
assay, respectively.
Supplementary data
Supplementary data (experimental procedures and supporting
data for all compounds) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.03.147.