Synthesis of dihydropyrano[3,2-e]indoles as rotationally restricted phenolic analogs of 5-hydroxyindole - Thermal Claisen approach versus gold catalysis

Article abstract of DOI:10.1016/j.tetlet.2010.12.084

The Claisen rearrangement/cyclization of 5-propargyloxyindoles (2) to afford dihydropyrano[3,2-e]indoles (3) as direct precursors to tetrahydropyrano[3,2-e]indoles (1, a rotationally restricted phenolic analog of 5-hydroxyindole) was examined using either

Full text of DOI:10.1016/j.tetlet.2010.12.084

Tetrahedron Letters 52 (2011) 1011–1013
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Tetrahedron Letters
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Synthesis of dihydropyrano[3,2-e]indoles as rotationally restricted phenolic
analogs of 5-hydroxyindole—thermal Claisen approach versus gold catalysis
⇑
George N. Karageorge, John E. Macor
Bristol-Myers Squibb R&D, Neuroscience Discovery Chemistry, 5 Research Parkway, Wallingford, CT 06492, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The Claisen rearrangement/cyclization of 5-propargyloxyindoles (2) to afford dihydropyrano[3,2-
e]indoles (3) as direct precursors to tetrahydropyrano[3,2-e]indoles (1, a rotationally restricted phenolic
analog of 5-hydroxyindole) was examined using either refluxing bromobenzene (156 °C) or Au+1 catalysis
in refluxing dioxane (101 °C). This transformation was best effected using Au+1 catalysis (i.e., tris[triphe-
nylphosphinegold(I)] oxonium tetrafluoroborate) because this method required a lower reaction temper-
ature and gave better yields when compared to the simple thermal reaction conditions (156 °C).
Ó 2010 Elsevier Ltd. All rights reserved.
Received 27 November 2010
Revised 10 December 2010
Accepted 19 December 2010
Available online 24 December 2010
Keywords:
Pyrano[3,2-e]indole
Serotonin
Indole
Claisen rearrangement
As a rotationally restricted phenolic analogs of 5-hydroxyin-
dole, tetrahydropyrano[3,2-e]indoles (1, Fig. 1) have been used as
analogs of the neurotransmitter serotonin (5-hydroxytryptamine,
5-HT) to make 5-HT2 receptor selective agents.1 These serotonin
mimics have been further refined as drug candidates for treating
eye diseases requiring reduced intraocular pressure (i.e., glau-
coma).2 Additional examples of tetrahydropyrano[3,2-e]indoles
can be found in the patent literature where they are claimed to
Using 5-propargyloxyindole derivatives (e.g., 2g, Scheme 1), we
could still utilize a Claisen rearrangement as the key carbon
framework transformation step, and this now led directly to the
dihydropyrano[3,2-e]indole heterocycle,6 which could easily be
converted to the tetrahydropyrano[3,2-e]indole via hydrogenation
(Scheme 1).6b Only two examples of this methodology have been
published, one of which directly utilized serotonin as the 5-propa-
rgyloxyindole source (Scheme 1).6b However, this method required
heating 5-propargyloxyindole derivatives (2) in refluxing bromo-
benzene (156 °C), which caused significant degradation of the 5-
proparglyoxyindole and/or the dihydropyrano[3,2-e]indole product
as indicated by the dark appearance of the completed reaction mix-
ture and the moderate yields of product 3.7,8 In fact, heating 5-prop-
argyloxyindole itself (2a, Table 1) at 156 °C yielded complete
decomposition of 2a and no identifiable product whatsoever.
Recently Au+1 catalysis (i.e., [(Ph3PAu)3O]BF4) has been used by
Toste and co-workers to facilitate Claisen-like rearrangements of
propargyloxy-alkenes.9 This methodology seemed to be potentially
transferable to cyclize 5-propargyloxyindoles 2. In this paper, we
report additional examples of thermal Claisen rearrangements of
5-proparyloxyindoles 2, examining the scope and limitations of
that reaction, and comparing that methodology versus utilizing
Au+1 catalysis to drive the Claisen rearrangement sequence.
5-Propargyloxyindole derivatives (2a–g) were prepared as
described in Scheme 2 using standard indole functionalization
chemistries. Typical procedures for the formation of dihydropyr-
ano[3,2-e]indoles (3a–g) were as follows and the comparison of
results is contained in Table 1.
be useful in treating sleep disorders, TNF
a mediated diseases, anx-
iety, obesity, depression, stress related diseases, and other dis-
eases.3 Recently,
a review of the biological activity of this
heterocycle has been published.4
Our original interest in tetrahydropyrano[3,2-e]indoles was as
rotationally restricted phenol bioisosteres for the 5-hydroxyindole
in serotonin (5-hydroxytryptamine, Fig. 1). Our initial approach to
the tetrahydropyrano[3,2-e]indole heterocycle utilized a Claisen
rearrangement of an appropriate disposed (2-propenyl)nitrotolu-
ene, followed by hydroboration, cyclization, and Leimgruber-Bat-
cho indole formation.5 This synthesis prepared the parent
heterocycle, but only after five steps in an overall low yield
(13%), and derivatization was needed to make analogs, such as
serotonin mimics (Fig. 1).5 However, these phenolic rotationally re-
stricted serotonin analogs had a unique effect on serotonin recep-
tor selectivity making them more selective for 5-HT2 receptors
versus 5-HT1 receptors.1 This result led us to develop an interest
in the tetrahydropyrano[3,2-e]indole heterocycle, and we have
looked into more efficient approaches for its preparation.
Thermal (156 °C): To deoxygenated bromobenzene (10 ml) was
added the 5-propargyloxyindole derivative (2, 1.00 g, Table 1),
⇑
Corresponding author. Tel.: +1 203 677 7092; fax: +1 203 677 7884.
E-mail address: john.macor@bms.com (J.E. Macor).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.084

1012
G. N. Karageorge, J. E. Macor / Tetrahedron Letters 52 (2011) 1011–1013
NH2
NH2
1
R3
R3
O
HO
HO
O
R2
R2
N
H
N
H
N
H
N
H
Free Rotation of
Phenol Oxygen
Lone Pair
Restricted Rotation
of Phenol Oxygen
Lone Pair
Serotonin
Tetrahydroyrano[3,2-e]indole
Selective for 5-HT2 Receptors
(1,R2=H,R3=CH2CH2NH2)
Figure 1.
NH2
NH-Cbz
NH2
NH-Cbz
156 o
56%
C
HO
O
H2, Pd/C
100%
O
O
N
H
N
H
N
H
N
H
2g
3g
(1, R2 = H, R3 = CH2CH2NH2)
Scheme 1. Synthesis of a tetrahydropyrano[3,2-e]indole via a 5-propargyloxyindole.6b
NO2
CHO
O
O
d, e
b
N
H
N
H
HO
O
a
O
O
c
N
H
N
H
O
O
OCH3
f
N
H
O
OCH2Ph
N
H
Scheme 2. Synthesis of 5-proparyloxyindole derivatives. Reagents and conditions: (a) propargyl bromide (1.1 equiv), Cs2CO3 (1.1 equiv), acetone, rt (95%); (b) POCl3
(1.1 equiv), DMF, rt (98%); (c) oxalyl chloride (1.1 equiv), ether, followed by triethylamine/methanol (75%); (d) nitromethane [solvent], ammonium acetate (2.1 equiv),
sonication (81%); (e) NaBH4 (4 equiv), silica gel (4Â weight), isopropanol/chloroform (1:5) (61%); (f) EtMgBr (1.1 equiv) followed by benzyl chloroformate (1 equiv) (28%).
and the resulting solution/mixture was stirred at reflux for 18–
48 h. The reaction was monitored by TLC (50% EtOAc/hexane as
eluent), and the Rf of the product dihydropyrano[3,2-e]indole (3)
Table 1
Synthesis of dihydropyrano[3,2-e]indoles
was typically very close to the Rf of the starting 5-propargyloxyin-
dole (2). However, the dihydropyanoindole (3) stained dark red
R3
R3
using PMA (phosphomolybdic acid) staining and heating of the
TLC plate, while the 5-propargyloxyindole starting material (2)
stained blue in PMA with heating. When starting material was con-
sumed, the reaction solution was concentrated under reduced
pressure, and the residue purified by column chromatography
using silica gel with typically EtOAc/hexane (1:3) as the eluent.
Au+1 catalysis (101 °C): To a stirred solution of the 5-propa-
rgyloxyindole derivative (2, 1.00 g, Table 1) in deoxygenated diox-
ane (10 ml) was added, tris[triphenylphosphinegold(I)] oxonium
tetrafluoroborate (5 mol %). The resulting reaction solution was
stirred at reflux (101 °C) for 4–18 h. Reaction monitoring and puri-
fication of the dihydropyanoindole (3) were carried out as de-
scribed above.
O
O
(see table)
N
H
N
H
2
3
R3
Yield 3 (%) at 156 °C
Yield 3 (%) with
Au catalysis at 101 °C
a
b
d
e
f
–H
–CHO
0
50
80
50
67
84
25
39
58
566b
–CO2CH2Ph
–CH2CH2NO2
–(CO)CO2Me
Not done
56
g
–CH2CH2NHCbz6b

G. N. Karageorge, J. E. Macor / Tetrahedron Letters 52 (2011) 1011–1013
1013
Claisen rearrangement/cyclizations of 5-propargyloxyindoles
(2) occurred under both via thermal (156 °C) and Au+1 catalyzed
conditions (101 °C) to provide dihydropyrano[3,2-e]indoles (3) in
reasonable yields in one step (Table 1). Yields were generally
slightly better using the Au+1 catalysis, and furthermore, the reac-
tion times were shorter and the temperature required for the
transformation was significantly lower using the Au+1 assist. The
lower reaction temperatures and gave better yields when com-
pared to the simple thermal reaction conditions (bromobenzene
reflux, 156 °C). Further examination of the scope of this Au+1 cata-
lyzed transformation is in progress and those results will be re-
ported in due course.
References and notes
tris[triphenylphosphinegold(I)]
oxonium
tetrafluoroborate
1. Macor, J. E.; Fox, C. B.; Johnson, C. J.; Koe, B. K.; Lebel, L. A.; Zorn, S. H. J. Med.
Chem. 1992, 35, 3625.
2. May, J. A.; Chen, H.-H.; Rusinko, A.; Lynch, V. M.; Sharif, N. A.; McLaughlin, M. A.
J. Med. Chem. 2003, 46, 4188–4195.
3. (a) WO 2007109141.; (b) WO 2005009370.; (c) WO 2002004457.; (d) US
5288748.
4. Sinicropi, M. S.; Caruso, A.; Conforti, F.; Marrelli, M.; El Kashef, H.; Lancelot, J.-C.;
Rault, S.; Statti, G. A.; Menichini, F. J. Enzyme Inhib. Med. Chem. 2009, 24, 1148.
5. Macor, J. E.; Ryan, K.; Newman, M. E. Tetrahedron 1992, 48, 1039.
6. (a) Macor, J. E.; Blank, D. H.; Post, R. J. Tetrahedron Lett. 1994, 35, 45; (b) Macor, J.
E. Tetrahedron Lett. 1995, 36, 7019; (c) Macor, J. E.; Langer, O. D.; Gougoutas, J. Z.;
Malley, M. F.; Cornelius, L. A. M. Tetrahedron Lett. 2000, 41, 3541.
7. The two examples published were colored-black reaction mixtures with charred
material before purification.
(5 mol %) effected a lower transition temperature for the desired
transformation. It should be noted that the parent 5-propa-
rgyloxyindole 2a which was decomposed under the higher temper-
ature conditions, was converted under Au+1 catalysis to its
dihydropyrano[3,2-e]indole derivative 3a in 50% yield, showing
the benefit of the milder conditions.
While not studied here in detail, but precedented in the litera-
ture,6b simple hydrogenation (H2, Pd/C) of dihydropyrano[3,2-e]in-
doles (3) affords tetrahydropyrano[3,2-e]indoles (1) in high yield.
In conclusion, the Claisen rearrangement/cyclization of 5-prop-
argyloxyindoles (2) to afford dihydropyrano[3,2-e]indoles (3) as di-
rect precursors to tetrahydropyrano[3,2-e]indoles (1, a rotationally
restricted hydrogen-bonding phenolic analog of 5-hydroxyindole)
8. The mechanism of the rearrangement of 5-propargyloxyindoles to
dihydropyrano[3,2-e]indoles has been examined in Refs. 6b,c and is consistent
with the sequence shown below:
NH-CBZ
NH-CBZ
NH-CBZ
NH-CBZ
Claisen
O
O
Rearrangement
O
O
[1,2] shift
[3,3] Shift
N
N
H
N
N
PhBr, Δ (156° C)
H
H
H
was best effected using Au+1 catalysis (i.e., tris[triphenylphos-
phinegold(I)] oxonium tetrafluoroborate) as this method required
9. Sherry, B. D.; Maus, L.; Laforteza, B. N.; Toste, F. D. J. Am. Chem. Soc. 2006, 128,
8132.