Stereoselective synthesis of tetrahydro-2H-[2]benzopyrano[3,4-c]pyrrol-3- ones and related compounds as precursors of serotonin 5-HT2C receptor agonists

Article abstract of DOI:10.1016/j.tetlet.2011.03.053

Tetrahydro-2H-[2]benzopyrano[3,4-c]pyrrol-3-ones and the related 3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole analogues were synthesised by an intramolecular Diels-Alder reaction. The observed stereoselectivity was dependent upon the nature of t

Full text of DOI:10.1016/j.tetlet.2011.03.053

Tetrahedron Letters 52 (2011) 3421–3425
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Tetrahedron Letters
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Stereoselective synthesis of tetrahydro-2H-[2]benzopyrano[3,4-c]pyrrol-3-ones
and related compounds as precursors of serotonin 5-HT2C receptor agonists
⇑
Stuart Francis , Takao Kiyoi, Mark Reid, Keneth Davies, Steven Laats, Duncan McArthur, Helen Feilden,
Anna Marie Easson, Yasuko Kiyoi, Grant Wishart, 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:
Available online 21 March 2011
Tetrahydro-2H-[2]benzopyrano[3,4-c]pyrrol-3-ones and the related 3a-methyl-2,3,3a,4,5,9b-hexahydro-
1H-benzo[e]isoindole analogues were synthesised by an intramolecular Diels–Alder reaction. The
observed stereoselectivity was dependent upon the nature of the tethered dienophile as well as the judi-
cious placement of the amide.
Ó 2011 Published by Elsevier Ltd.
The Diels–Alder reaction is a very efficient and powerful tool for
the synthesis of both carbocyclic and heterocyclic systems.1 One
method of harnessing the Diels–Alder reaction involves utilising
the benzocyclobutene motif as a latent diene equivalent. Benzocy-
clobutenes, following photo or thermal activation, undergo cyclo-
reversion to reactive o-quinodimethane species, which if tethered
to a dienophile, can rapidly react to construct elaborate polycyclic
systems with defined stereochemistry. The utility of this approach
was elegantly demonstrated by Oppolzer during his total synthesis
of the polycyclic natural product chelidonine.2 This has been fol-
lowed with several groups exploiting this strategy to assemble a
range of 6,6,5 tricycles.3 However, these reports concede several
deficits including long reaction times, high temperatures and the
need to utilise electron-rich precursors, which have generally given
poor yields. Furthermore, stereoselective hetero Diels–Alder reac-
tions to afford trans-tetrahydro-2H-[2]benzopyrano[3,4-c]pyrrol-
3-ones have not been reported so far.
Interestingly, recent literature has shown that microwave heat-
ing has broadened the utility of this reaction allowing electron
poor systems to undergo transformations in good yields.4 This
observation ties in well with our own recent experience, utilising
microwave heating to affect high yielding intramolecular hetero
Diels–Alder reactions from benzocyclobutene intermediates.5 We
had previously reported a series of tetrahydro-2H-[2]benzopyr-
ano[3,4-c]pyrrol-1-ones which had displayed interesting activity
at the 5-HT2C receptor.6 Using benzocylobutene 1 in an intramolec-
ular hetero Diels–Alder reaction, via an o-quinodimethane, a mix-
ture of cis/trans lactams 14a:14b was obtained, which, following
further derivatisation, gave a mixture of cis-5a and trans-bridge-
head 5b compounds (Fig. 1). These could be readily separated by
silica gel chromatography or, using more vigorous conditions,
could be driven to give cis-bridgehead compound 5a, exclusively.
Herein we further elaborate on several modifications of our pre-
viously reported synthesis: firstly transposing the amide from ben-
zocyclobutene 1 to that of benzocyclobutene 7 allowed exquisite
control in delivering solely trans-bridgehead 5b relative stereo-
chemistry. Secondly substituting the tethered dienophile by
replacing the ketone with various alkenes allowed access to the
carbocyclic 3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoin-
doles 6a and 6b and related derivatives.
Intermediate 9, a previously disclosed synthetically useful ben-
zocyclobutene carboxylic acid intermediate, was coupled with
benzylamine to give amide 10 (Scheme 1).5 Following reduction
with borane, the amine 11 could be coupled with a range of a-keto
acids. The coupling of amine 11 with pyruvic acid using 1-propyl-
phosphonic acid anhydride as the coupling reagent yielded amide
7 efficiently. Due to the high temperatures often required during
the Diels–Alder reaction, many literature methods employ
o-dichlorobenzene as a high boiling solvent, commonly refluxing
for many hours or even days.7 We found that toluene coupled with
microwave heating could still achieve the high temperatures re-
quired and so was an expedient surrogate, which greatly facilitated
product isolation due to the relative ease of solvent removal.
Microwave irradiation promoted an intramolecular Diels–Alder
reaction to yield the trans-lactam 12, exclusively. However, it
was necessary to use higher temperatures and longer reaction
times (220 °C for 2 h) than our previously reported conditions for
complete conversion of 1.5 A flexible synthesis for efficiently syn-
thesising both pairs of diastereomers, merely by placement of
the amide, was now in hand. Lactam 12 was reduced using bor-
ane-THF to give 13 which was subsequently converted into amine
5b via treatment with 1-chloroethyl chloroformate (ACE-Cl),
followed by methanol.8 It is noteworthy that the transformations
involved going from benzocyclobutene 7 through to 5b, universally
⇑
Corresponding author. Tel.: +44 (0)1698 736118; fax: +44 (0)1698 736187.
E-mail addresses: francis.stuart@ymail.com, stuart.francis@merck.com(S. Francis).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.03.053

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S. Francis et al. / Tetrahedron Letters 52 (2011) 3421–3425
Initial heating gives a mixtures of cis/trans
isomers. Prolonged heating at high
temperature gives exclusively cis
O
N
O
X
steps
N
X
Cl
Cl
2
1
NH
3
NH
1 X=O
2 X=CH2
3 X=O
4 X=CH2
9a
H
H
3a
8
7
9b
X4
X
6
Cl
5
Cl
5b (trans) X=O
5a (cis) X=O
6b (trans) X=CH2
6a (cis) X=CH2
N
O
O
N
O
steps
O
exclusively trans
Cl
Cl
7
8
Figure 1. Benzocyclobutene intermediates undergo intramolecular (hetero) Diels–Alder reaction proceeding via an o-quinodimethane intermediate giving varying ratios of
cis/trans products depending on the amide position and the tethered dienophile.
O
O
N
N
H
H
OH
c
a,b
Cl
Cl
Cl
d
11
10
9
R
N
H
N
e
N
O
H
f
O
O
O
O
Cl
Cl
Cl
13 R = Bn
5b R = H
12
7
g
Scheme 1. Reagents and conditions: (a) (COCl)2, CH2Cl2 0 °C, 16 h, 100%; (b) benzylamine, Et3N, CH2Cl2, 0 °C, 99%; (c) BH3ÁDMS, CH2Cl2, reflux, 4 h, then 2 N HCl, 55%; (d)
pyruvic acid, 1-propylphosphonic acid anhydride, DIPEA, CH2Cl2, 16 h, 69%; (e) toluene, microwave irradiation, 220 °C, 100%; (f) BH3ÁTHF, THF, reflux, 4 h, then 2 N HCl, 69%;
(g) 1-chloroethyl chloroformate, toluene, reflux, 16 h, then MeOH, 78%.
required either more forcing conditions or gave lower yields. It is
suspected that the inherent ring strain of the trans-system is
responsible for this, where the five-membered ring could be espe-
cially susceptible to alternative reaction pathways such as ring-
opening.
During the course of this work it became increasingly clear that
there was an intrinsic instability within the trans-6,6,5 fused
system. This observation was supported with several pieces of
evidence, which we believe illustrates the inherent strain within
these systems: prolonged heating at temperatures of 210 °C and
above gradually converted any initial trans-lactam 14b completely
into cis-14a (Scheme 2). This epimerisation could also be per-
formed at lower temperature with the addition of a catalytic base
such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).9 It has also been
possible to epimerise non-lactam systems similar to trans-
compound 13 into their corresponding cis-equivalent 15. However,
without the carbonyl conferring high acidity to the benzylic
position a stronger base such as sodium hydride is required along
with a higher temperature.10
To access the analogous 3a-methyl-2,3,3a,4,5,9b-hexahydro-
1H-benzo[e]isoindoles 6a and 6b and their derivatives, we chose
to utilise the previously described chemistry with the slight

S. Francis et al. / Tetrahedron Letters 52 (2011) 3421–3425
3423
R
N
O
O
O
N
N
H
H
H
d
N
a
+
O
O
O
O
Cl
Cl
Cl
Cl
14a (cis)
14b (trans)
1
15 (cis) R = Bn
5a (cis) R = H
e
b or c
Scheme 2. Reagents and conditions: (a) toluene, microwave irradiation, 210 °C, 100%; (b) toluene, microwave irradiation, 220 °C, 100%; (c) DBN, toluene 110 °C, 80%; (d)
BH3ÁTHF, THF, reflux, 4 h, then 2 N HCl, 69%; (e) 1-chloroethyl chloroformate, toluene, reflux, 16 h, then MeOH, 78%.
O
O
N
O
H
b
a
OH
N
R
N
H
R
Cl
Cl
R
Cl
16 R = H
17 R = Me
18 R = H, 97%
10
R = H, 20a (cis), 32% + 20b
19 R = Me, 34%
(
trans), 68%
R = Me, 21a (cis), 29% + 21b
(
trans), 69%
NH
R
N
H
H
c
d
R
Cl
Cl
R = H, 22 (cis), 79%
R = H, 24 (cis), 66%
R = Me, 25a (cis), 66% + 25b (trans), 22%
R = Me, 23a (cis), 54% + 23b (trans), 24%
Scheme 3. Reagents and conditions: (a) 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide, Et3N, rt, 16 h; (b) bromobenzene, 190 °C, microwave irradiation,
1 h; (c) (i) BH3ÁTHF, THF, reflux, 4 h, (ii) 2 N HCl; (d) 1-chloroethyl chloroformate, toluene, 160 °C, microwave irradiation, 15 min, then MeOH.
modification of attaching the appropriately decorated alkene
(Scheme 3). The aforementioned acid 9 was again the key precur-
sor which was coupled readily with benzylamine 16 to yield amide
18 in almost quantitative yield. Likewise amine 17, synthesised in
30% yield by reductive amination of benzylamine with trans-2-
methyl-2-butenal, could be coupled with 9 to give amide 19. Fol-
lowing heating at 190 °C for 30 min in a microwave, both systems
underwent the Diels–Alder reaction in high overall yields. Interest-
ingly the trans/cis ratio was almost identical in both cases and
perhaps even more intriguing was the very similar ratio obtained
with the comparable ketone system 1, albeit with significantly
improved overall conversion.5 Furthermore, amide 18 showed
the same predilection for complete conversion into the cis-diaste-
reomer 20a as ketone analogue 1, when heated under more vigor-
ous conditions (220 °C for 1 h in the microwave).
To access C-4 epimers 29a and 29b, amine 11 was coupled with
angelic acid in moderate yield, and subsequently the Diels–Alder
reaction transferred the trans-relationship of the methyl groups
of angelic acid into the desired anti-relationship with respect to
the 3a and 4-positions of the newly formed ring (Scheme 4). In this
instance however, despite the complete conversion, the products
were obtained as an inseparable mixture of cis/trans-lactams 27a
R
N
N
H
H
N
c
O
b
a
11
O
Cl
Cl
Cl
26
27a (cis) + 27b (trans)
28a (cis
29a (cis
)
)
+
+
28b (trans) R = Bn
29b (trans) R = H
d
Scheme 4. Reagents and conditions: (a) angelic acid, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide, Et3N, rt, 16 h, 48%; (b) bromobenzene, 190 °C,
microwave irradiation, 1 h, 100%; (c) (i) BH3ÁTHF, THF, reflux, 4 h, (ii) 2 N HCl, 28a (21%), 28b (58%); (d) 1-chloroethyl chloroformate, toluene, 160 °C, microwave irradiation,
15 min, then MeOH, 29a (12%), 29b (50%).

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S. Francis et al. / Tetrahedron Letters 52 (2011) 3421–3425
and 27b.11 This problem was easily circumvented by carrying out
the borane reduction on the crude amide, which delivered a
separable mixture (by silica gel chromatography) with a 3:1 ratio
in favour of trans-product 28b. This result proved to be consistent
with several closely related publications. These show that similar
benzocyclobutene systems undergoing a Diels–Alder reaction with
a tethered alkene have great difficulty in delivering high levels of
diastereocontrol.3 However, in direct contrast, we have clearly
O
N
H
disfavoured pathway
N
O
O
H
x
Cl
Cl
14a
(cis)
O
2-endo arrangment
HO
N
O
O
N
Cl
epimerisation
O
Cl
1
O
N
H
O
N
H
Cl
O
O
Cl
favoured pathway
2 -exo arrangment
14b (trans)
Figure 2. Proposed arrangement of the o-quinodimethane prior to the Diels–Alder reaction giving cis/trans mixtures.
disfavoured pathway
N
H
x
O
Cl
O
N
H
-endo arrangement
8
O
N
O
O
O
12
Cl
Cl
7
N
H
O
Cl
O
favoured pathway
-exo arrangement
8
Figure 3. Proposed arrangement of the o-quinodimethane prior to the Diels–Alder reaction leading to the trans-product.

S. Francis et al. / Tetrahedron Letters 52 (2011) 3421–3425
3425
demonstrated that with the ketone-derived tetrahydro-2H-[2]
benzopyrano[3,4-c]pyrrol-3-ones, complete diasteroselectivity
can be obtained. This evidence led us to believe that the intramo-
lecular Diels–Alder reaction on the o-quinodimethane 2 derived
from ring opening of 1 proceeds via an exo transition state giving
the trans-lactam 14b as the kinetic product ( Fig. 2). However,
excessive heating or addition of base readily leads to epimerisation
Grove and Dr Angus Morrison for their support and help through-
out this process.
References and notes
1. For selected reviews, see: (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassiligiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698; (b) Jorgensen,
K. A. Angew. Chem., Int. Ed. 2000, 39, 3558–3588.
of the benzylic
more stable cis-bridgehead compound 14a.
a-amide proton giving the thermodynamically
2. Oppolzer, W.; Keller, K. J. Am. Chem. Soc. 1971, 93, 3836–3837.
3. (a) Basha, F. Z.; McClellan, W. J.; DeBernardis, J. F. J. Heterocycl. Chem. 1987, 24,
789–791; (b) Basha, F. Z.; McClellan, W. J.; DeBernardis, J. F. Tetrahedron Lett.
1991, 32, 5469–5472; (c) Trehan, I. R.; Singh, N. P.; Jain, V. K. Indian J. Chem.,
Sect. B 1995, 34, 484–486.
4. Ibrahim-Ouali, M.; Santelli, M.; Oumzil, K. Synlett 2005, 1695–1698.
5. Kiyoi, T.; Reid, M.; Francis, S. J.; 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. C. Tetrahedron Lett. 2011, 52. accepted.
6. Grove, S. J.; Kiyoi, T.; Mistry, A. D.; Ray, P. C.; Wishart, G. WO 2009/037220;
Chem. Abstr. 2009, 150, 374510.
7. Baudoin, O.; Retailleau, P.; Chaumontet, M. J. Org. Chem. 2009, 74, 1774–
1776.
When the amide is transposed as in compound 7, trans-lactam
12 was obtained exclusively (Fig. 3). We believe that the reaction
must again proceed via a lower energy exo transition state. How-
ever, in this instance, despite the highly strained nature of trans-
lactam 12, transposition of the amide carbonyl now renders the
benzylic proton significantly less acidic and so epimerisation does
not occur under the reaction conditions. Thus epimerisation to the
cis-derivative can only be achieved with the addition of a strong
base and hence we ultimately achieve high yields of solely trans-
product 12.
In summary, we have disclosed a versatile synthesis which
harnesses the intramolecular Diels–Alder reaction. Judicious
placement of the amide carbonyl, coupled with microwave
heating, eliminated the need for either electron-rich aromatic
substituents or excessively long reactions at high temperatures
as previously required within similar systems. This has allowed
us to synthesise both tetrahydro-2H-[2]benzopyrano[3,4-c]
pyrrol-3-ones with exquisite cis or trans selectivity and 3a-
methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole analogues
exhibiting complex stereochemistry as precursors of biologically
interesting 5-HT2C agonists.
8. Arvela, R. K.; Leadbeater, N. E. Synlett 2003, 1145.
9. Loozen, H. J. J.; Brands, F. T. L.; Winter, M. S. Recl. Trav. Chim. 1982, 101, 298.
10. Typical conditions used to achieve epimerisation of a range of trans-amine 10
derivatives were NaH, DMF at 240 °C, in the microwave reactor for 10 min.
11. Typical procedure for the intramolecular Diels–Alder reaction: a solution of
N-benzyl-3-chloro-N-(2-methylbut-2-enyl)-1,2-dihydrocyclobutabenzene-1-
carboxamide (26) (0.97 mmol, 330 mg) in bromobenzene (6 ml) was subjected
to microwave irradiation using a microwave synthesiser (Initiator™ Eight,
Biotage) at 190 °C for 1 h. The reaction mixture was purified directly using a
silica gel column (eluting with heptane then 5–20% EtOAc in heptane) to afford
an inseparable mixture of cis-27a (96 mg, 0.3 mmol, 29%) and trans-27b
(229 mg, 0.67 mmol, 70%). cis-27a: 1H NMR (400 MHz, CDCl3): d 8.36 (1H, d,
ArH), 7.45–7.13 (7 H, m, 7 Â ArH), 4.55 (1H, d, CHHPh), 4.47 (1H, d, CHHPh),
3.40 (1H, s, CH), 3.07–2.94 (3H, m, 3 Â CH), 2.40 (1H, dd, CH), 2.21–2.10 (1H, m,
CH2), 0.99 (3H, d, CH3), 0.68 (3H, s, CH3); trans-27b: 1H NMR (400 MHz, CDCl3)
d 7.42 (1H, d, ArH), 7.33–7.22 (7H, m, ArH), 4.57 (1H, d, CHHPh), 4.34 (1H, d,
CHHPh), 3.34 (1H, s, CH), 3.24 (1H, d, CH), 3.01 (1H, d, CH), 2.90 (1H, dd, CH),
2.38 (1H, dd, CH), 1.77 (1H, m, CH), 1.04 (3H, s, CH3), 0.91 (3H, d, CH3).
Acknowledgements
The author would like to offer his greatest thanks to the many
colleagues who worked on the project, especially to Dr Simon