Synthesis of hexahydro[2]benzopyrano[4,3-c]pyridines as serotonin 5-HT 2C receptor agonists via intramolecular hetero Diels-Alder reactions

Article abstract of DOI:10.1016/j.tetlet.2011.03.054

Hexahydro[2]benzopyrano[4,3-c]pyridines were synthesized by an intramolecular hetero Diels-Alder reaction. The reaction was applicable to a range of substrates and the products could be easily converted into serotonin 5-HT_2C receptor agonists.

Full text of DOI:10.1016/j.tetlet.2011.03.054

Tetrahedron Letters 52 (2011) 3417–3420
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Tetrahedron Letters
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Synthesis of hexahydro[2]benzopyrano[4,3-c]pyridines as serotonin 5-HT2C
receptor agonists via intramolecular hetero Diels–Alder reactions
⇑
⇑
Yasuko Kiyoi , Steven Laats, Takao Kiyoi, Grant Wishart, Angus Brown, Peter Ray
Department of Chemistry, Merck Research Laboratories, MSD, Newhouse, Lanarkshire ML1 5SH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Hexahydro[2]benzopyrano[4,3-c]pyridines were synthesized by an intramolecular hetero Diels–Alder
reaction. The reaction was applicable to a range of substrates and the products could be easily converted
into serotonin 5-HT2C receptor agonists.
Received 28 October 2010
Revised 14 February 2011
Accepted 14 March 2011
Available online 21 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Intramolecular hetero Diels–Alder reaction
[2]Benzopyrano[4,3-c]pyridines
Serotonin 5-HT2C receptor agonists
Microwave-assisted synthesis
Agonists of the serotonin 5-HT2C receptor have become attrac-
tive drug targets because of their potential as therapeutic agents
for the treatment of obesity, diabetes, schizophrenia and urinary
incontinence.1 We have already reported on the synthesis of hexa-
hydro-2H-[2]benzopyrano[3,4-c]pyrroles 1, (Fig. 1) as 5-HT2C ago-
nists, following a lead optimization study.2 During this study, it
was envisaged that hexahydro-1H-[2]benzopyrano[4,3-c]pyridines
2 might also be potent 5-HT2C agonists.
Despite its pharmaceutically remarkable structure, there are
only a few reports on the synthesis of substituted hexahydro-1H-
[2]benzopyrano[4,3-c]pyridines 2 (Fig. 2). Santroch et al. reported
a synthesis via condensation of 3-phenyl-4-piperidinols and ke-
tones. However only 9-substituted compounds were obtained.3a
Nieforth et al. reported on a synthesis from indene without any
2
1
NH
H
R'
9
6
3
8
R
O
7
4
R''
5
1
2
PG
N
H
N
O
H
1
3
4
H
R'
9
10
7
R'
R
R
O
O
A
8
O
Santroch et al.
5
R1
R''
R''
6
R1
N
2
3
N
O
10
H
R4
9
H
+
R4
R3 R2
H
PG
N
H
O
O
8
PG
O
OH
7
R'
R3 R2
N
R'
5
6
7
R
R''
R
O
R''
Nieforth et al.
4
O
OH
N
O
10
7
H
Figure 1. The structures of 5-HT2C receptor agonists 1 and 2 and the retrosynthetic
route towards 2.
9
8
H
OH
O
⇑
Corresponding authors. Tel.: +44 (0)1698 736137; fax: +44 (0)1698 736187
O
(Y.K.); tel.: +44 (0)1698 736130; fax: +44 (0)1698 736187 (P.R.).
E-mail addresses: yasuko.i.kiyoi@gmail.com, yasuko.kiyoi@merck.com (Y. Kiyoi),
peter.ray@merck.com (P. Ray).
8
9
10
Figure 2. Previously reported synthetic routes to [2]benzopyrano[4,3-c]pyridines.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.054

3418
Y. Kiyoi et al. / Tetrahedron Letters 52 (2011) 3417–3420
Table 1
Cl
Cl
Cl
a
b
c
CO2H
CN
CO2H
CN
Intramolecular hetero Diels–Alder reactions of benzocyclobutene 4a
CHO
Bn
Bn
N
O
Cl
Cl
Cl
Cl
Bn
O
H
N
O
H
N
11
12
13
R2
Microwave
210 °C
+
H
H
CN
CO2H
Cl
O
O
d
e
Cl
O
Cl
Cl
trans-3a
R1
CN
4a
Entry Solvent
cis-3a
Cl
15
Cl
Time
(h)
Concentration
(mol/l)
Yielda
(%)
cis/
trans
1
2
14
16a
16b
16c
; R , R =H
f
1
2
; R =Br, R =H
1
2
3
4
Bromobenzene 0.5
0.50
0.18
0.24
0.35
<10
44
52
100:0
31:69
53:47
66:34
1
2
; R =H, R =Br
1,4-Dioxane
1,4-Dioxane
1,4-Dioxaneb
0.5
1.5
2
R2
Cl
R2
Cl
O
O
65
Bn
Bn
N
N
a
Isolated yield.
1,4-Dioxane/H2O = 10:1
h
g
b
R1
R1
17
O
HO
18a ; R1, R2=H
4a ; R1, R2=H
Benzocyclobutenes 4, the substrates for the hetero Diels–Alder
18b ; R1=Br, R2=H
18c ; R1=H, R2=Br
4b ; R1=Br, R2=H
4c ; R1=H, R2=Br
reactions, were synthesized from the corresponding halogenated
benzaldehydes in good yields.4 As a typical example, the synthesis
of compounds 4a–4d are illustrated in Scheme 1. Compound 16a
was prepared from 2,6-dichlorobenzaldehyde (11) using the same
procedure described in the preceding paper.2 Next, 16a was con-
verted into corresponding mono-bromo derivatives 16b and 16c
following treatment with N-bromosuccinimide (NBS), and separa-
tion by silica gel chromatography or recrystallization. Carboxylic
acid 16a was condensed with N-benzylhydroxypropylamine 17
to give amide 18a, which was oxidized to afford 4a. Benzocyclobut-
enes 4b–4d were synthesized in a similar manner.
The intramolecular hetero Diels–Alder reaction of 4a was ini-
tially performed using microwave heating at 210 °C with bromo-
benzene as the solvent (entry 1, Table 1). In the preceding
paper,2 bromobenzene was found to be the best solvent for the
hetero Diels–Alder reaction. However, for compound 4a, poor
yields of cis-3a were obtained. It was speculated that the reaction
required a higher temperature and thus 1,4-dioxane was chosen as
an alternative solvent. When the reaction was performed using
1,4-dioxane under microwave irradiation at 210 °C, the expected
product was obtained in a moderate yield, with a cis/trans ratio
of 31:69 (entry 2, Table 1). Changing the reaction time and concen-
tration affected both the yield and the cis/trans ratio (entries 2–4,
Table 1). Moreover, addition of 10% water as a co-solvent to assist
microwave heating was shown to improve the overall yield (entry
4, Table 1). The cis- and trans- isomers were readily separated by
O
Bn
Bn
N
N
H
OH
O
g
17
19
16a
19
Bn
Cl
O
N
H
4d
Scheme 1. Reagents and conditions for the synthesis of benzocyclobutenes 4a–4d:
(a) HO2CCH2CN, pyridine, NH4OAc, toluene, reflux using a Dean–Stark apparatus,
3 h, 98%; (b) NaBH4, NaHCO3, MeOH/H2O, rt, 0.5 h, 98%; (c) DMA, 150 °C, 2 h, quant.;
(d) NaNH2, liquid NH3, THF, À55 to À35 °C, 3 h, quant.; (e) KOH, EtOH/H2O, reflux,
2.5 h, 90%; (f) NBS, H2SO4, rt, 18 h, 16b (66%), 16c (29%) (isolated yields); (g) 17 or
19, 1-propanephosphonic acid anhydride, Et3N, CH2Cl2, rt, 18 h, 70–90%; (h) Dess–
Martin periodinane, CH2Cl2, rt, 3 h, 60–80%.
substituents on the aromatic rings.3b In our investigations, the
inclusion of substituents at C-7 was necessary. Therefore, we re-
quired an alternative synthetic procedure for preparing hexahy-
dro-1H-[2]benzopyrano[4,3-c]pyridines 2.
Herein we report on the synthesis of a variety of hexahydro-1H-
[2]benzopyrano[4,3-c]pyridines 2, which contain substituents on
the aromatic ring, via an intramolecular hetero Diels–Alder reac-
tion using microwave irradiation according to the retrosynthetic
route shown in Figure 1.
Table 2
Intramolecular hetero Diels–Alder reaction of benzocyclobutenes 4a–4d
Bn
N
Bn
N
R5
O
O
H
O
H
Microwave
Bn
R5
R5
R2
R4
N
R4
R3
R4
R3
210 °C
R1
R1
+
R3
O
O
1,4-dioxane:H2O=10:1
R1
R2
R2
cis-3a-d
O
4a-d
trans-3a-d
Substrate
Concentration (mol/l)
Time (h)
R1
R2
R3
R4
R5
Yielda (%)
cis/trans
4a
4b
4b
4b
4c
4d
0.35
0.34
0.14
0.12
0.09
0.20
2
2
1
1
3
1.5
H
H
H
H
H
Me
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
H
H
H
H
H
H
H
H
H
H
H
Br
H
65
48
50
58
17
26
66:34
82:18
71:29
65:35
100:0
68:32
H
a
Isolated yield.

Y. Kiyoi et al. / Tetrahedron Letters 52 (2011) 3417–3420
3419
analogues.5 The results are listed in Table 2. Analogue 4b gave
the desired products cis-3b and trans-3b, and lower concentrations
afforded better yields. However, derivative 4c gave exclusively cis-
3c in low yield, presumably due to the steric repulsion between the
bromine atom and the amide side chain. For the ketone derivative
4d, the corresponding cis-3d and trans-3d, products were obtained
in a poor overall yield.
Bn
N
Bn
N
H
N
O
H
H
H
a
b
H
H
H
O
O
O
Cl
Cl
Cl
cis-20a
Bn
cis-3a
cis-2a
As shown in Scheme 2, the tricyclic products obtained could be
easily converted into the 5-HT2C agonists 2. The amide of cis-3a
was reduced to the corresponding amine using BH3ÁTHF or
BH3ÁMe2S. Cleavage of the benzyl group was achieved by reaction
Bn
N
H
N
O
H
N
H
H
a
b
H
H
H
O
a
-chloroethyl chloroformate (ACE-Cl) to afford cis-2a.6 The
O
O
with
Cl
trans-2a
corresponding trans-isomer of 2a was obtained in a similar man-
ner. Deprotection of cis-20d did not afford the desired cis-2d, and
instead gave 21 albeit in low yield. However, trans-20d could be
converted into trans-2d in 9% yield.
As for the previously reported hexahydro-2H-[2]benzopyr-
ano[3,4-c]pyrroles, the bromine atom on the aromatic ring could
be readily converted into a variety of functional groups. For exam-
ple, the bromine atom of cis-3b was converted into chloro com-
pounds 22 and 23,7 or alkyl compounds 24 and 25 as shown in
Scheme 3. The corresponding trans-isomer underwent similar
transformations (Scheme 3).
Functionalization at C-10 of the tricyclic system was achieved
by direct bromination using N-bromosuccinimide. Initially bro-
mination of cis-20a was attempted, however, this resulted in a
poor yield of a complex mixture. Deprotection of N-benzyl cis-
20a afforded cis-2a, which could be brominated to afford the cor-
responding para-bromo compound cis-2c. para-Bromo cis-2c was
readily converted into chloro 30 or alkyl 31 derivatives as illus-
trated in Scheme 4. The corresponding trans-isomer also under-
went similar transformations (Scheme 4).
Cl
trans-3a
Cl
trans-20a
Bn
Bn
H
N
H
N
O
H
N
N
H
H
a
b
O
O
O
Cl
OH
21
Cl
Cl
Cl
cis-20d
cis-3d
cis-2d
Bn
N
Bn
H
N
O
H
N
H
H
a
b
O
O
O
Cl
trans-2d
Cl
trans-3d
Cl
trans-20d
Scheme 2. Reagents and conditions: (a) BH3ÁMe2S or BH3ÁTHF, THF, reflux, 6 h, then
5 N HCl, reflux, 1 h, 68–93%; (b) ACE-Cl, toluene, microwave, 160 °C, 15 min, then
MeOH, microwave, 160 °C, 5 min, 9–78%.
In summary, a series of hexahydro-1H-[2]benzopyrano[4,3-c]
pyridines were synthesized by intramolecular hetero Diels–Alder
reaction under microwave irradiation conditions and the reaction
was applied to a range of substrates. Although the Diels–Alder
reaction afforded a mixture of cis- and trans-products, both could
be easily separated by silica gel column chromatography and con-
verted into the corresponding 5-HT2C receptor agonists.
silica gel column chromatography and used in further steps toward
the target 5-HT2C agonists.
Encouraged by these results, we next applied the optimized
conditions (entry 4, Table 1) to benzocyclobutenes 4b–4d to
explore the scope of this reaction for the preparation of diverse
Bn
Bn
O
H
N
O
H
N
H
H
O
O
Br
Br
Cl
Cl
cis-3b
trans-3b
a
a
Bn
N
Bn
N
Bn
N
Bn
N
H
N
H
N
H
H
H
H
H
H
c
c
b
c
b
H
H
H
H
H
H
O
O
O
O
O
O
Cl
Cl
Br
Cl
Br
Cl
Cl
Cl
Cl
cis-20b
Cl
Cl
Cl
22
23
trans-20b
26
27
d
d
c
Bn
N
Bn
N
H
N
H
H
N
H
N
N
H
H
H
H
H
H
d
c
H
H
H
H
H
H
O
O
O
O
O
O
Br
Br
Cl
cis-2b
Cl
Cl
Cl
Cl
Cl
24
25
trans-2b
28
29
Scheme 3. Reagents and conditions: (a) BH3ÁTHF, THF, reflux, 4 h, then 5 N HCl, reflux, 1 h, 63–66%; (b) NiCl2, NMP, microwave, 210 °C, 0.5 h, both 71%; (c) ACE-Cl, toluene,
microwave, 160 °C, 30 min, then MeOH, microwave, 160 °C, 5 min, 50–70%; (d) trimethylboroxine, Pd(PPh3)4, K2CO3, 1,4-dioxane, microwave, 130 °C, 20 min, 22–92%.

3420
Y. Kiyoi et al. / Tetrahedron Letters 52 (2011) 3417–3420
Bn
N
Bn
N
Bn
N
Bn
N
Br
Cl
Br
Cl
H
H
H
H
a
a
H
H
H
H
O
O
O
O
Cl
Cl
H
N
H
N
cis-20a
cis-20c
trans-20a
trans-20c
Cl
Cl
Cl
Cl
H
H
b
b
H
H
H
H
O
O
c
c
H
H
H
N
H
N
N
N
Br
Cl
Br
H
H
H
H
a
30
a
32
H
N
H
N
H
H
H
H
O
O
O
O
d
d
H
H
Cl
Cl
Cl
O
O
cis-2c
trans-2c
cis-2a
trans-2a
Cl
Cl
31
33
Scheme 4. Reagents and conditions: (a) NBS, H2SO4, rt, 18 h, 3–52%; (b) ACE-Cl, toluene, microwave, 160 °C, 30 min, then MeOH, microwave, 160 °C, 5 min, 95–100%; (c)
NiCl2, NMP, microwave, 210 °C, 30 min, 26–32%; (d) trimethylboroxine, Pd(PPh3)4, K2CO3, 1,4-dioxane, microwave, 130 °C, 30 min, 4–15%.
to microwave irradiation using
a microwave synthesizer (Initiator™ Eight,
References and notes
Biotage) at 210 °C for 2 h. The reaction mixture was concentrated and purified
using silica gel column chromatography eluting with heptane followed by EtOAc
(10–25%) in heptane to afford trans-3a (387 mg, 1.18 mmol, 22%) followed by
cis-3a (745 mg, 2.27 mmol, 43%). trans-3a: 1H NMR (400 MHz, CDCl3) d 1.9–2.1
(m, 1H), 2.3–2.4 (m, 1H), 3.25–3.35 (m, 1H), 3.4–3.5 (m, 1H), 3.61 (d, J = 8 Hz,
1H), 3.80 (dt, J = 8, 4 Hz, 1H), 4.57 (d, J = 16 Hz, 1H), 4.66 (d, J = 16 Hz, 1H), 4.78
(dd, J = 16, 4 Hz, 1H), 4.99 (d, J = 16 Hz, 1H), 7.15–7.40 (m, 7H), 8.33 (dd, J = 6,
2 Hz, 1H). cis-3a: 1H NMR (400 MHz, CDCl3) d 2.0–2.1 (m, 1H), 2.15–2.25 (m,
1H), 3.2–3.3 (m, 1H), 3.47 (d, J = 2 Hz, 1H), 3.6-3.7 (m, 1H), 4.13 (dd, J = 6, 2 Hz,
1H), 4.30 (d, J = 12 Hz, 1H), 4.72 (d, J = 16 Hz, 1H), 4.91 (d, J = 12 Hz, 1H), 5.01
(d, J = 16 Hz, 1H), 7.20–7.40 (m, 7H), 7.59 (dd, J = 6, 2 Hz, 1H).
1. For recent reviews on 5-HT2C agonists, see: Monck, N. J. T.; Kennett, G. A. In
Progress in Medicinal Chemistry; Lawton, G., Witty, D. R., Eds.; Elsevier:
Amsterdam, 2008;
p 281. Vol. 46; (b) Marston, O. J.; Heisler, L. K.
Neuropsychopharmacology 2009, 34, 252.
2. Kiyoi, T.; Reid, M.; Francis, S.; Davies, K.; Laats, S.; McArthur, D.; Easson, A.-M.;
Kiyoi, Y.; Tarver, G.; Caulfield, W.; Gibson, K.; Wishart, G.; Morrison, A. J.; Adam,
J. M.; Ray, P. Tetrahedron Lett. 2011, 52 (preceding paper)..
3. (a) Santroch, G.; Humber, L. G. U.S. Patent 4,132,709, 1979; Chem. Abstr. 1979,
90, 121571; (b) Nieforth, K. A.; Hite, G. J.; Lazer, E. S. J. Med. Chem. 1979, 22, 845.
4. Loozen, H. J. J.; Brands, F. T. L.; de Winter, M. S. Recl. Trav. Chim. 1982, 101, 298.
5. Typical procedure for the intramolecular Diels–Alder reaction: a solution of N-
benzyl-3-chloro-N-(3-oxopropyl)-1,2-dihydrocyclobutabenzene-1-carboxamide
(4a), (1.93 g, 5.30 mmol) in 1,4-dioxane (15 ml) and H2O (1.5 ml) was subjected
6. Yang, B. V.; O’Rourke, D.; Li, J. Synlett 1993, 195.
7. Arvela, R. K.; Leadbeater, N. E. Synlett 2003, 1145.