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

Article abstract of DOI:10.1016/j.tetlet.2011.03.055

[2]Benzopyrano[3,4-c]pyrroles were synthesized via an intramolecular hetero Diels-Alder reaction. The reaction was applicable to a wide 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.2011.03.055

Tetrahedron Letters 52 (2011) 3413–3416
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of hexahydro[2]benzopyrano[3,4-c]pyrroles as serotonin 5-HT2C
receptor agonists via intramolecular hetero Diels–Alder reactions
⇑
Takao Kiyoi , Mark Reid, Stuart Francis, Keneth Davies, Steven Laats, Duncan McArthur,
Anna-Marie Easson, Yasuko Kiyoi, Gary Tarver, Wilson Caulfield, Kirsty Gibson, Grant Wishart,
⇑
Angus J. Morrison, Julia M. Adam, 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:
[2]Benzopyrano[3,4-c]pyrroles were synthesized via an intramolecular hetero Diels–Alder reaction. The
reaction was applicable to a wide range of substrates and the products could be easily converted into
serotonin 5-HT2C receptor agonists.
Received 27 October 2010
Revised 9 February 2011
Accepted 14 March 2011
Available online 23 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Intramolecular hetero Diels–Alder reaction
[2]Benzopyrano[3,4-c]pyrroles
Serotonin 5-HT2C receptor agonists
Microwave-assisted synthesis
Agonists of the serotonin 5-HT2C receptor have become attractive
drug targets because of their potential as therapeutic agents for the
treatment of obesity, diabetes, schizophrenia, and urinary inconti-
nence.1 Hexahydro[2]benzopyrano[3,4-c]pyrroles (1, Fig. 1) were
identified as potent 5-HT2C agonists by high throughput screening
of our in-house compound library. For further optimization of this
series, it was desirable to introduce a range of electron-withdrawing
and -donating groups on the aromatic ring.
irradiation. The products were easily converted into the target
molecules for evaluation as potential 5-HT2C receptor agonists.
Benzocyclobutenes (3), the substrates for the hetero Diels–Al-
der reaction, were synthesized from the corresponding haloge-
nated benzaldehydes in good yields.3 As a typical example, the
synthesis of 3a is illustrated in Scheme 1. Thus, 2,6-dichlorobenz-
aldehyde (4) was reacted with cyanoacetic acid to give 5, followed
by a selective reduction of the carbon–carbon double bond, and
To date there are a very limited number of reports of the syn-
thesis of hexahydro[2]benzopyrano[3,4-c]pyrroles. Although
Oppolzer reported one example of an intramolecular hetero
Diels–Alder reaction to give 2 which had no substituents on the
aromatic ring (R = R0 = R00 = H, Fig. 1), however, the reaction yield
was very low (25%) despite a long reaction time (23 h) and high
dilution conditions.2 A similar reaction was reported by Loozen
et al. using mono- or di-benzyloxybenzocyclobutenes (3) (e.g.,
R = H, R0 = R00 = OBn) as starting materials. Higher yields were ob-
tained, probably due to the higher reactivity of the electron-rich
diene intermediates A, associated with the benzyloxy moieties.3
We herein report the synthesis of a variety of tetrahydro-2H-
[2]benzopyrano[3,4-c]pyrrol-1-ones (2), including examples pos-
sessing electron-withdrawing moieties on the aromatic ring, via
an intramolecular hetero Diels–Alder reaction using microwave
PG
R
2
NH
O
1
N
H
H
R'
9
6
3
R'
8
7
R
O4
O
5
R"
R"
1
2
PG
N
O
O
O
PG
R'
N
R'
O
R
R"
R
R"
3
A
⇑
Corresponding authors. Tel.: +44 (0)1698 736131; fax: +44 (0)1698 736187
(T.K.).
Figure 1. The structure of hexahydro[2]benzopyrano[3,4-c]pyrrole 5-HT2C receptor
agonists 1 and the proposed retrosynthetic route.
E-mail addresses: kiyoi@xc5.so-net.ne.jp, takao.kiyoi@merck.com (T. Kiyoi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.055

3414
T. Kiyoi et al. / Tetrahedron Letters 52 (2011) 3413–3416
Bn
N
Bn
Cl
Cl
Cl
O
a
NH
b
CO2H
CN
CO2H
CN
N
H
H
H
a
b
CHO
O
4
5
6
Cl
c
Cl
Cl
e
O
O
Cl
Cl
Cl
CN
cis-2a
cis-12a
cis-1a
Cl
d
CN
Bn
N
Bn
O
NH
7
8
Cl
Cl
N
H
H
H
a
b
O
O
O
O
O
Bn
Bn
CO2H
N
N
Cl
H
g
f
Cl
Cl
trans-2a
trans-12a
trans-1a
OH
O
Cl
Cl
Cl
9
11
3a
Bn
Bn
N
O
O
NH
N
Scheme 1. Reagents and conditions for the synthesis of benzocyclobutene 3a: (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, ꢀ55 to ꢀ35 °C, 3 h, quant.; (e) KOH, EtOH/H2O, reflux,
2.5 h, 90%; (f) HN(Bn)CH2CHOHCH3 (10), 1-propanephosphonic acid anhydride,
CH2Cl2, rt, 2 h, 96%; (g) Dess–Martin periodinane, CH2Cl2, rt, 3 h, 76%.
H
H
c
a - b
H
O
H
H
O
O
Cl
Cl
Cl
trans-2e
cis-2e
cis-1e
Scheme 2. Reagents and conditions: (a) BH3ꢁMe2S, THF, reflux, 6 h, then 5 N HCl,
68–93%; (b) ACE-Cl, toluene, microwave, 160 °C, 15 min then MeOH, 46–78%; (c)
0.1 equiv DBN, toluene, reflux, 1.2 h, 88%.
Table 1
Intramolecular hetero Diels–Alder reaction of benzocyclobutene 3a
decarboxylation and sodium amide mediated cyclobutyl ring for-
mation to give 8. The nitrile group of 8 was hydrolyzed to give
the corresponding carboxylic acid and a subsequent condensation
reaction with 2-hydroxypropylamine derivative 10 gave amide 11.
The hydroxy group was then oxidized to afford 3a. Benzocyclobut-
enes 3b–3m were synthesized in a similar manner.
The intramolecular hetero Diels–Alder reaction of 3a was ini-
tially performed using conventional heating under reflux condi-
tions in bromobenzene (bp = 156 °C) as a solvent (Table 1, entry
1). The desired tricyclic product 2a was obtained in moderate yield
as a mixture of cis- and trans-isomers (cis:trans = 69:31). When the
reaction was performed under microwave irradiation conditions at
180 °C, the product was obtained in a similar yield, although the
trans-isomer was formed predominantly (Table 1, entry 2). Im-
proved results were obtained with microwave irradiation at
Bn
Bn
O
O
O
N
N
Bn
H
H
N
+
PhBr
O
O
O
Cl
Cl
Cl
3a
cis-2a
trans-2a
Entry
Reaction conditions
Reflux, 16 h
Yielda (%)
cis:trans
1
2
51
50
93
73
69:31
31:69
53:47
100:0
Microwave, 180 °C, 30 min
Microwave, 210 °C, 30 min
Microwave, 240 °C, 80 min
3
4b
a
Isolated yield.
o-Dichlorobenzene was used as solvent.
b
Table 2
Intramolecular hetero Diels–Alder reaction of a variety of benzocyclobutenes
Bn
R1
Bn
R1
O
R5
O
O
R5
R5
Bn
N
N
R4
H
H
N
R4
R3
R4
R3
Microwave
R1
+
R3
210 °C, 30 min.
O
O
PhBr
O
R2
R2
R2
trans-2a-m
3a-m
cis-2a-m
Substrate
R1
R2
Cl
OBn
Cl
H
Cl
CF3
H
H
Cl
Me
Cl
R3
R4
R5
Yielda (%)
cis:trans
3a
3b
3c
3d
3e
3f
3g
3h
3i
Me
Me
Me
Me
H
H
H
H
H
H
Et
CH2F
CF3
H
H
Br
H
H
H
OBn
H
Br
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
93
86
66
0
86
85
93
69
65
77
72
81
50
53:47
60:40
91:9
––
55:45
93:7
39:61
93:7
88:12
65:35
57:43
91:9
3j
3k
3l
OMe
H
H
Cl
Cl
H
H
3m
H
100:0
a
Isolated yield.

T. Kiyoi et al. / Tetrahedron Letters 52 (2011) 3413–3416
3415
NH
NH
H
H
H
O
O
17
Bn
Boc
O
15
O
H
Boc
N
N
e
N
H
c
H
H
a
b
NH
Boc
O
N
O
O
d
O
14
OBn
OH
OBn
e
13
cis-2b
O
18
16
OTf
N
O
g
NH
f
H
NH
H
O
O
N
S
20
19
Scheme 3. Reagents and conditions: (a) (i) BH3ꢁTHF, THF, reflux, 9 h, then 5 N HCl, 90%, (ii) ACE-Cl, toluene, microwave 160 °C, 30 min, then MeOH, (iii) Boc2O, DMAP, Et3N,
CH2Cl2, rt, 16 h, 40%; (b) Pd–C, H2, MeOH, rt, 16 h, quant.; (c) (i) EtI, NaH, DMF, rt, 76%, (ii) 5 N HCl, 1,4-dioxane, MeOH, 70 °C, 1 h, 97%; (d) PhNTf2, NaH, THF, rt, 2 h, 60%; (e) (i)
trimethylboroxine or 3,5-dimethylisoxazol-4-yl boronic acid, Pd(PPh3)4, K2CO3, 1,4-dioxane, H2O, microwave, 130 °C, 20 min, 53–95%, (ii) 5 N HCl, 1,4-dioxane, MeOH, 100 °C,
30 min, 20–77%; (f) (i) Pd(OAc)2, BINAP, NaSMe, toluene, microwave, 120 °C, 30 min, 51%, (ii) 5 N HCl, 1,4-dioxane, MeOH, 70 °C, 1 h, 52%; (g) (i) Pd2(dba)3, BINAP, pyrrolidine,
t-BuONa, toluene, microwave, 135 °C, 15 min, 25%, (ii) 5 N HCl, 1,4-dioxane, MeOH, 70 °C, 1 h, 45%.
210 °C to give 2a in 93% yield in a cis:trans ratio of 53:47 (Table 1,
entry 3). It is noteworthy that when the microwave reaction was
performed at 240 °C for 80 min using o-dichlorobenzenzene as
the solvent, the cis-isomer was formed stereoselectively, probably
due to an in situ isomerisation reaction to form the thermodynam-
ically more stable cis-isomer (Table 1, entry 4). The reason for the
decreased yield compared to the lower temperature conditions
(Table 1, entry 3) may be a result of decomposition of 3a during
the reaction.
Encouraged by these results, we next applied the optimum con-
ditions (210 °C, 30 min using microwave irradiation) to a variety of
benzocyclobutenes to explore the scope of this reaction in making
diverse analogs of 5-HT2C agonists.4 The results are listed in Table
2. As can be seen from Table 2, this intramolecular hetero Diels–Al-
der reaction tolerates a variety of functional groups. Benzyloxy
derivative 3b afforded the corresponding product in good yield,
and di-halogenated analogue 3c also gave the desired products
2c. However, the 9-chloro derivative 2d was not obtained, proba-
bly because of the steric repulsion between the chlorine atom
and the amide side chain. A variety of aldehydes (R1 = H, 3e–3j)
afforded the corresponding products 2e–2j in good yields as mix-
tures of cis- and trans-isomers. When an electron-withdrawing
group such as CH2F or CF3, was at R1, the reaction proceeded in a
more cis-selective manner (2l and 2m).
moieties as shown in Scheme 4. Further functionalization, such
as stereoselective alkylation on the 5-position of the tricyclic
system, has been achieved by benzylic oxidation of 24 using Jones’
Bn
O
NH
N
H
H
b
H
H
O
O
Cl
Bn
H
O
Cl
N
a
Cl
22
Cl
21
H
NH
H
NH
H
H
H
O
b
Br
c
Cl
O
cis-2i
O
Br
Cl
cis-1i
Cl
23
Scheme 4. Reagents and conditions: (a) NiCl2, N-methyl-2-pyrrolidone, microwave
180 °C, 10 min, then 210 °C, 60 min, 62%; (b) (i) BH3ꢁMe2S, THF, reflux, 3 h, then 5 N
HCl, 56–84%, (ii) ACE-Cl, toluene, microwave 160 °C, 15–20 min then MeOH, 77%;
(c) trimethylboroxine, Pd(PPh3)4, K2CO3, 1,4-dioxane, microwave, 100 °C, 15 min,
then 120 °C, 15 min, 33%.
O
N
O
N
NH
OEt
OEt
H
H
H
The hetero Diels–Alder products, cis-2 and trans-2 could be eas-
ily separated by silica gel column chromatography and converted
into the corresponding pyrrolidines, cis-1 and trans-1. As shown
in Scheme 2, the amide groups of cis-2a and trans-2a were reduced
to the corresponding amines using BH3ꢁMe2S, followed by depro-
a
b
O
O
O
Cl
Cl
Cl
O
cis-1a
24
25
tection of the benzyl group by reaction with a-chloroethyl chloro-
formate (ACE-Cl) to afford cis-1a and trans-1a.5 The trans-isomer of
2e could also be converted into the cis-isomer by treatment with a
catalytic amount of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) under
reflux in toluene.3 Furthermore, the cis-isomer 2e could be easily
converted into cis-1e as described above.
O
N
OEt
NH
H
H
c
d
O
O
Cl
The benzyloxy group or bromine atom on the aromatic ring
(e.g., cis-2b or cis-2i) could be readily converted into a variety of
functional groups. For example, the benzyl group of 13 was cleaved
by hydrogenation and the phenol was further transformed into alk-
oxy, alkyl, aryl, mercapto, and amino moieties (Scheme 3). The bro-
mine atom of cis-2i could be converted into chloro6 or alkyl
Cl
26
27
Scheme 5. Reagents and conditions: (a) ClCO2Et, NaHCO3, THF, H2O, rt, 16 h,
quant.; (b) Jones’ reagent, rt, 2 h, 62%; (c) (i) MeLi, THF, ꢀ78 °C, 2 h, then AcOH, (ii)
Et3SiH, TFA, CH2Cl2, ꢀ78 °C to rt, 2 h, 70%; (d) KOH, MeOH, H2O, microwave 150 °C,
30 min, 52%.

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T. Kiyoi et al. / Tetrahedron Letters 52 (2011) 3413–3416
reagent to afford lactone 25. Alkylation and triethylsilane-
mediated reduction7 afforded 26, which was deprotected to give
27 (Scheme 5).
References and notes
1. For recent reviews on 5-HT2C agonists, see (a) Monck, N. J. T.; Kennett, G. A. In
Progress in Medicinal Chemistry; Lawton, G., Witty, D. R., Eds.; Elsevier:
In summary, a series of [2]benzopyrano[3,4-c]pyrroles was syn-
thesized by intramolecular hetero Diels–Alder reaction under
microwave irradiation conditions. The reaction was applied to a
wide range of substrates bearing a variety of dienes and dieno-
philes with electron-donating or -withdrawing properties.
Although the hetero Diels–Alder reaction afforded a mixture of
cis- and trans-isomers, both of these could be readily separated
by silica gel column chromatography and converted into the corre-
sponding pyrrolidine 5-HT2C receptor agonists. The cis-isomers
(e.g., cis-2a or cis-2e) could be obtained stereoselectively using
higher temperature conditions or by treatment of the trans-isomer
with DBN. Benzyloxy or bromo atoms have been shown to be effec-
tive functional handles to introduce diversity on to the aryl ring.
Moreover, oxidation and stereoselective alkylation of the 5-posi-
tion were achieved. The stereoselective synthesis of the trans-iso-
mers is currently under investigation and will be reported in the
near future.
Amsterdam, 2008; Vol.46,
Neuropsychopharmacology 2009, 34, 252.
2. Oppolzer, W. Angew. Chem., Int. Ed. 1972, 11, 1031.
3. Loozen, H. J. J.; Brands, F. T. L.; de Winter, M. S. Recl. Trav. Chim. 1982, 101,
298.
4. Typical procedure of the intramolecular Diels–Alder reaction: a solution of N-
benzyl-3-chloro-N-(2-oxopropyl)-1,2-dihydrocyclobutabenzene-1-carboxamide
(3a, 936 mg, 2.86 mmol) in bromobenzene (30 ml) was subjected to microwave
irradiation in two microwave vials using a microwave synthesizer (Initiator™
Eight, Biotage) at 210 °C for 30 min. The reaction mixture was purified directly
using a silica gel column chromatography eluting with heptane followed by
ethyl acetate (10–50%) in heptane to afford trans-2a (409 mg, 1.25 mmol, 44%)
followed by cis-2a (461 mg, 1.41 mmol, 49%). trans-2a; 1H NMR (CDCl3) d 1.01 (s,
3H), 3.10 (d, 1H), 3.37 (d, 1H), 3.70 (s, 1H), 4.46 (d, 1H), 4.55 (d, 1H), 4.93 (d, 1H),
p 281; (b) Marston, O. J.; Heisler, L. K.
4.94 (d, 1H), 7.20–7.35 (m, 7H), 8.11 (d, 1H), EI-MS: m/e 328.3 (M+H)+. cis-2a; 1
NMR (CDCl3) d 1.42 (s, 3H), 3.30–3.40 (m, 3H), 4.44 (d, 1H), 4.54 (d, 1H), 4.67 (d,
1H), 4.80 (d, 1H), 7.20–7.35 (m, 7H), 7.48 (t, 1H). EI-MS: m/e 328.2 (M+H)+.
5. Yang, B. V.; O’Rourke, D.; Li, J. Synlett 1993, 195.
6. Arvela, R. K.; Leadbeater, N. E. Synlett 2003, 1145.
7. Ohta, H.; Ishizaka, T.; Tatsuzuki, M.; Yoshinaga, M.; Iida, I.; Yamaguchi, T.;
Tomishima, Y.; Futaki, N.; Toda, Y.; Saito, S. Bioorg. Med. Chem. 2008, 16, 1111.
H