A novel Fischer pseudo-benzylic decarboxylation approach to the 1,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl system

Article abstract of DOI:10.1016/j.tetlet.2014.11.101

A novel Fischer pseudo-benzylic decarboxylation approach to the 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl system was developed starting from geminally substituted cyclopentanone derivatives and appropriately substituted phenyl hydrazines. In addition, we demonstrate that substituents at the 3- and 7-positions can, for example, be useful synthetic handles for further functionalization.

Full text of DOI:10.1016/j.tetlet.2014.11.101

Accepted Manuscript
A novel Fischer pseudo-benzylic decarboxylation approach to the 1,2,3,4-tet-
rahydro-cyclopenta[b]indol-3-yl system
Antonio Garrido Montalban, You-An Ma, Steve Johannsen, Sagun Tandel,
Michael J. Martinelli
PII:
S0040-4039(14)02005-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.101
TETL 45485
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 September 2014
21 November 2014
22 November 2014
Please cite this article as: Garrido Montalban, A., Ma, Y-A., Johannsen, S., Tandel, S., Martinelli, M.J., A novel
Fischer pseudo-benzylic decarboxylation approach to the 1,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl system,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.11.101
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A novel Fischer pseudo-benzylic
decarboxylation approach to the 1,2,3,4-
tetrahydro-cyclopenta[b]indol-3-yl system
Antonio Garrido Montalban∗, You-An Ma, Steve Johannsen, Sagun Tandel and Michael J. Martinelli

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
A novel Fischer pseudo-benzylic decarboxylation approach to the 1,2,3,4-tetrahydro-
cyclopenta[b]indol-3-yl system
Antonio Garrido Montalban∗, You-An Ma, Steve Johannsen, Sagun Tandel and Michael J. Martinelli
Department of Chemical Research & Development, Arena Pharmaceuticals, Inc. 6154 Nancy Ridge Drive, San Diego, CA 92121, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
A
novel Fischer pseudo-benzylic decarboxylation approach to the 1,2,3,4-
tetrahydrocyclopenta[b]indol-3-yl system was developed starting from geminally substituted
cyclopentanone derivatives and appropriately substituted phenyl hydrazines. In addition, we
demonstrate that substituents at the 3- and 7-positions can, for example, be useful synthetic
handles for further functionalization.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Fischer synthesis
Decarboxylation
Tautomerization
Hydrolysis
Over ten thousand biologically active indole derivatives have
been identified to date. Of those, over 200 are currently marked
as drugs or undergoing clinical trials.1 As such, new or improved
methods for the construction of this heterocyclic system are
constantly needed. This is particularly true for the development
of safe and efficient large scale preparations, given the ubiquitous
characteristics of indoles among bioactive molecules and natural
products.2 As part of our pharmacological compound evaluation,
we were interested in synthesizing 7-alkoxy-1,2,3,4-tetrahydro-
cyclopenta[b]-indol-3-yl derivatives (see Fig. 1 for numbering of
the 1,2,3,4-tetrahydrocyclopenta[b]indole ring system). One of
candidate for the potential treatment of autoimmune diseases.
Although a variety of ring-substituted indoles are accessible
through classical methods such as the Fischer, Bischler,
Madelung, Reissert, Nenitzescu and Gassman procedures,4
limitations can arise from difficult to obtain precursors and/or
low reaction conversions.5 Our attempts to synthesize 7-oxo-
1,2,3,4-tetrahydrocyclopenta[b]-indol-3-yl derivatives using the
Nenitzescu reaction, for example, led only to multicomponent
mixtures.
cyclization
A
telescoped condensation intramolecular Heck
strategy (Scheme on the
1),6,8
Figure 1. 1,2,3,4-Tetrahydrocyclopenta[b]indole numbering system.
these compounds, APD3343,8 (Fig. 2), was selected as a clinical
Scheme 1. (i) Si(OEt)4, PPTS, DMF. (ii) Pd-catalyst, DIEA.
other hand, proved more successful but was still restrictive. As
expected, iodides (Table 1, Entries 1-3) were superior to
bromides (Table 1, Entries 4-6) in the cyclization step. The
benzyloxy derivative 4 (R = Bn), however, could not be obtained
Figure 2. APD334
———
∗ Corresponding author. Tel.: +1-858-453-7200; fax: +1-858-453-7210; e-mail: amontalban@arenapharm.com

2
Tetrahedron
under a variety of conditions and palladium catalysts (e.g.
removal at a later stage. Thus, 1011 was obtained quantitatively,
Pd(dppb)Cl2, Pd( dppp)Cl2, Table 1, Entries 7-12).7 Conversely,
the methoxy analogue 4 (R = Me) formed as the major product,
as determined by LC-MS, but due to 4 co-eluting with Si(OEt)4
or products derived therefrom, it could only be isolated in modest
yields after extensive column chromatography on silica (Table 1,
Entries 1-3). These results made us question the generality
Table 1. Formation of 4 under the conditions described in
Scheme 1 utilizing different Pd-catalysts
Scheme 2. (i) K2CO3, Acetone , reflux.
Entry
1
R
X
I
Pd-catalyst
Pd(OAc)2
Yield %
32 (4a)
in g to kg scale, after commercially available ethyl 2-
oxocyclopentanecarboxylate (9) was alkylated with ethyl 2-
bromoacetate in the presence of potassium carbonate in acetone
(Scheme 2). Alkylation of 9 with other 2-bromo-esters and -
nitriles worked similarly well.
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
2
I
Pd(dppb)Cl2
Pd(dppp)Cl2
Pd(OAc)2
29 (4a)
3
I
44 (4a)
4
Br
Br
Br
I
5 (4a)
To test our hypothesis, 4-methoxyphenyl hydrazine (11a) and 10
were subjected to acid catalyzed Fischer indolization. To our
delight, the corresponding indole derivative formed under a
variety of conditions, and in the most promising iteration, merely
heating the two precursors in the presence of stoichiometric
amounts of acetic acid in ethanol gave the corresponding product
12a in high yield (Scheme 3).12 Under the established parameters,
this procedure was deemed safe and operationally simple enough
to be carried out in hundreds of grams. Interestingly, reaction of
4-benzyloxyphenyl hydrazine (11b) with 10 also resulted in the
successful formation of the indole derivative 12b. This was
particularly pleasing since, for unknown reasons to us, the
condensation intramolecular Heck cyclization strategy (vide
supra) of the respective benzyloxy aniline 1 failed, in our
laboratory, to yield the corresponding indole derivative 4
(Scheme 1, Table 1, Entries 7-12).
5
Pd(dppb)Cl2
Pd(dppp)Cl2
Pd(OAc)2
6 (4a)
6
6 (4a)
7
decomposition
decomposition
decomposition
no reaction
no reaction
no reaction
8
I
Pd(dppb)Cl2
Pd(dppp)Cl2
Pd(OAc)2
9
I
10
11
12
Br
Br
Br
Pd(dppb)Cl2
Pd(dppp)Cl2
and scalability of this approach and prompted us to explore other
routes. Thus, herein we now report a novel and more scalable
approach to the 7-oxo-1,2,3,4-tetrahydrocyclopenta[b]-indol-3-yl
system with broader application
CO2Et
RO
We first evaluated the condensation/cyclization reaction of 4-
CO2Et
NH
substituted
phenylhydrazines
5
with
ethyl
2-(2-
oxocylopentyl)acetate (2) (Figure 3). Although the correspon-
N
H
RO
10
i
NHNH2.HCl
11a R = Me
11b R = Bn
CO2Et
CO2Et
RO
N
N
H
Figure 3. Fischer Indolization of 2 with various 4-substituted phenyl
hydrazines.
RO
CO2Et
ding phenylhydrazones 6 formed successfully in-situ, subsequent
cyclization, independent of the electronic nature of the R-groups
investigated, invariably led to product mixtures in which the
desired indoles 8 were only minor components.9 Similar results
were obtained with the isolated phenylhydrazones 6 under a
variety of conditions. We reasoned that failure to mainly produce
the indoles (8) of interest was, in part, due to non-selective
tautomerization of the phenylhydrazones 6 to ene-hydrazines 7.10
Consequently, we decided to block one side of the cyclopentano-
ne derivative to tautomerization by introducing a second
functional group at the same carbon, with the potential for
N
EtO C
H
2
12a R = Me (94%)
12b R = Bn (71%)
Scheme 3. (i) 1 equiv AcOH, EtOH, 75 °C.
Next, we focused our attention to the removal of the ester
dummy group. We reasoned that, after hydrolysis,
decarboxylation should be feasible due to the 1,3 relationship of

3
the resulting pseudo-benzylic acid with the indole double bond.
Thus, treatment of diester 12a with 50% aq NaOH in
ethanol/water gave the corresponding diacid 13a in 61% yield
(Scheme 4). As expected and in analogy to β-ketoacids, simply
in modest yield. 16 could also be conveniently obtained from
14a via a one pot de-methylation/re-esterification procedure
using excess BBr3 and quenching of the resulting reaction
mixture with ethanol.16
In summary, we have developed a new entry into the 1,2,3,4-
tetrahydrocyclopenta[b]-indol-3-yl core by utilizing a Fischer
indolization of geminally substituted cyclopentanone derivatives
followed by a pseudo-benzylic decarboxylation of the resulting
acids. Furthermore, we demonstrate that substituents at the 3- and
7-positions can, for example, be useful synthetic handles for
further functionalization. We are now evaluating the asymmetric
version of the pseudo-benzylic decarboxylation step and general
applicability of this methodology.
Acknowledgments
We would like to thank Arena Pharmaceuticals, Inc. for the
generous support of our studies.
References and notes
1. Bronner, S M.; Im, G.-Y. J.; Garg, N. K. Indoles and Indolizidines
In Heterocycles in Natural Product Synthesis; Majumdar, K. C.
and Chattopadhyay, S. K., Eds.; Wiley-VCH Verlag & Co. KGaA,
Weinheim, 2011; pp 221–265 and references therein.
2. Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195-7210
and references therein.
Scheme 4. (i) 50% aq NaOH, EtOH/H2O then 6 N HCl. (ii) AcOH,
60 °C.
3. Jones, R. XXIII International Symposium on Medicinal
Chemistry, Lisbon, Portugal – September 7-11, 2014.
heating 13a in acetic acid resulted in smooth decarboxylation to
the corresponding tricycle 14a.13 Similarly, 12b gave after
hydrolysis (13b) and decarboxylation the corresponding acid 14b
in 55% overall yield.
4. (a) Joule, J. A.; Mills, K.; Smith, G. F. In Heterocyclic Chemistry,;
Chapman & Hall , London, 1995; Third Ed., pp305-349. (b)
Gilchrist, G. L. In Heterocyclic Chemistry, Longman Scientific &
Technical, Essex, 1992; Second Ed., pp223-236. (c) Davies, D. T.
In Aromatic Heterocyclic Chemistry; Davies, S. G., Ed.; Oxford
University Press, Oxford, 1992; pp 53-60.
Fischer re-esterification of 14a,b and 15 to 4a,b and 16,
respectively, was easily achieved via refluxing the corresponding
acids in ethanol with a catalytic amount of sulfuric acid (Scheme
5). Acid catalyzed reaction with other alcohols also succeeded
5. Garrido Montalban, A.; Baum, S. M.; Cowell, J.; McKillop, A.
Tetrahedron Lett. 2012, 53, 4276-4279.
6. Sturino, C. F.; O’Neill, G.; Lachance, N.; Boyd, M.; Berthelette,
C.; Labelle, M.; Li, L.; Roy. B.; Scheigetz, J.; Tsou, N.; Aubin,
Y.; Bateman, K. P.; Chauret, N.; Day, S. H.; Lévesque, J.-F.; Seto,
C.; Silva, J. H.; Trimble, L. A.; Carriere, M.-C.; Denis, D.; Greig,
G.; Kargman, S.; Lamontagne, S.; Mathieu, M.-C.; Sawyer, N.;
Slipetz, D.; Abraham, W. M.; Jones, T.; McAuliffe, M.; Piechuta,
H.; Nicoll-Griffith, D. A.; Wang, Z.; Zamboni, R.; Young, R. N.;
Metters, K. M. J. Med. Chem. 2007, 50, 794-806 and references
therein.
7. Conde Ceide, S.; Garrido Montalban, A. Tetrahedron Lett. 2006,
47, 4415-4418.
8. Buzard, D. J.; Kim, S. H.; Lopez, L.; Kawasaki, A.; Zhu, X.;
Moody, J.; Thorensen, L.; Calderon, I.; Ullman, B.; Han, S.;
Lehmann, J.; Gharbaoui, T.; Sengupta, D.; Calvano, L.; Garrido
Montalban, A.; Ma, Y.-A.; Sage, C.; Gao, Y.; Semple, G.;
Edwards, J.; Barden, J.; Morgan, M.; Chen, W.; Usmani, K.;
Chen, C.; Sadeque, A.; Christopher, R. J.; Thatte, J.; Fu, L.;
Solomon, M.; Mills, D.; Whelan, K.; Al-Shamma, H.; Gatlin, J.;
Le, M.; Gaidarov, I.; Anthony, T.; Unett, D. J.; Blackburn, A.;
Rueter, J.; Stirn, S.; Behan, D. P.; Jones, R. M. Med. Chem. Lett.
20014, in press.
9. Sturino, C. F.; Lachance, N.; Boyd, M.; Berthelette, C.; Labelle,
M.; Li, L.; Roy, B.; Scheigetz, J.; Tsou, N.; Brideau, C.; Cauchon,
E.; Carriere, M.-C.; Denis, D.; Greig, G.; Kargman, S.;
Lamontagne, S.; Mathieu, M.-C.; Sawyer, N.; Slipetz, D.; O’Neill,
G.; Wang, Z.; Zamboni, R.; Metters, K. M.; Young, R. N. Bioorg.
Med. Chem. Lett. 2006, 16, 3043-3048.
Scheme 5. (i) EtOH, H2SO4 (0.6 equiv), reflux. (ii) 3 equiv BBr3,
+
-
CH2Cl2, -5 to 0 °C or EtOH/H2O, NH4 HCO2 , 10% Pd/C, 40 °C.
(iii) 3 equiv BBr3, CH2Cl2, -5 to 0 °C then EtOH, 40 °C.
10. Hughes, D. L.; Zhao, D. J. Org. Chem. 1993, 58, 228-233.
11. Kadas, I.; Morvai, V.; Arvai, G.; Toke, L.; Szollosy, A.; Toth, G.;
Bihari, M. Monatshefte fuer Chemie 1995, 126, 107-117.
12. Procedure for the preparation of indole derivative 12a: To a
suspension of (4-methoxyphenyl)hydrazine hydrochloride (379.5
g, 2.17 mol) and ethyl 1-(2-ethoxy-2-oxoethyl)-2-oxocyclopenta-
necarboxylate (526 g, 2.17 mol) in EtOH (2.0 L) AcOH (131 g,
124 mL, 2.17 mol) was added and the mixture stirred at 75 °C for
18 h under N2. The fine dark brown suspension was allowed to
cool and neutralized with saturated aqueous NaHCO3. The solvent
was evaporated under reduced pressure, the brown oily residue
neat or by using solvents such as chloroform or toluene. De-
methylation of 14a, on the other hand, was best achieved with
BBr3 whereas transfer hydrogenation14 of 14b using ammonium
formate in the presence of palladium-on-carbon (10% Pd/C) gave
the same product 15 without significant reduction of the indole to
the indoline.15 De-methylation of 4a or de-benzylation of 4b
using the respective conditions described above, gave indole 16

4
Tetrahedron
taken up in EtOAc (2 L), filtered and the organics washed with
water (3 x 500 mL) and brine (2 x 500 mL). The combined
aqueous layers were re-extracted with EtOAc. The combined
organics were dried (MgSO4) and the solvent was evaporated
under reduced pressure to afford ethyl 3-(2-ethoxy-2-oxoethyl)-7-
methoxy-1,2,3,4-tetrahydrocyclopenta[β]indole-3-carboxylate
(
703.4 g, 94%) as a thick dark brown oil. 1H NMR (400 MHz,
DMSO-d6) δ ppm 10.57 (s, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.85 (d,
J = 2.4 Hz, 1H), 6.67 (dd, J = 8.8, 2.5 Hz, 1H), 4.12 – 4.00 (m,
4H), 3.73 (s, 3H), 3.18 (d, J = 16.6 Hz, 1H), 3.05 – 2.99 (m, 1H),
2.81 (d, J = 16.6 Hz, 1H), 2.82 – 2.70 (m, 2H), 2.48 – 2.42 (m,
1H), 1.17 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H). LCMS m/z
= 346.2 [M + H]+.
13. Procedure for the preparation of indole derivative 14a: A solution
of 13a (191 g, 0.66 mol) in AcOH (1.0 L) was stirred at 60 °C for
4.5 h under N2. The dark brown solution was concentrated, the
precipitate collected under suction, washed with H2O (3 x 500
mL) and dried at 40 °C under vacuum overnight to afford 2-(7-
methoxy-1,2,3,4-tetrahydrocyclopenta[β]indol-3-yl)acetic
acid
(126.4 g, 78%) as a brown solid. 1H NMR (400 MHz, DMSO-d6)
δ ppm 12.16 (s, 1H), 10.42 (s, 1H), 7.18 (d, J = 8.7 Hz, 1H), 6.81
(d, J = 2.3 Hz, 1H), 6.62 (dd, J = 8.8, 2.5 Hz, 1H), 3.72 (s, 3H),
3.50 – 3.43 (m, 1H), 2.77 – 2.60 (m, 4H), 2.35 (dd, J = 16.0, 9.1
Hz, 1H), 2.12 – 2.04 (m, 1H). LCMS m/z = 246.1 [M + H]+.
14. Rajagopal, S.; Spatola, A. F. J. Org. Chem. 1995, 60, 1347-1355.
15. Procedure for the preparation of indole derivative 15 via
debenzylation: To a solution of 14b (1.02 g, 3.17 mmol) in EtOH
(10 mL) and water (0.5 mL), ammonium formate (1.20 g, 19.04
mmol) and wet palladium-on-carbon (10%wt, 0.10 g, 0.094 mmol)
were added under N2. The dark purple reaction mixture was heated
to 40 °C. Conversion by HPLC after stirring for 4.5 h at 40 °C was
determined to be 75%. Additional ammonium formate (1.20 g,
19.04 mmol) and wet palladium-on-carbon (10%wt, 0.10 g, 0.094
mmol) were added. Reaction completion was achieved after
stirring under N2 at 40 °C for further 5 h. The reaction mixture
was allowed to cool, filtered through celite and the filter cake
washed with EtOH (3 X 3 mL). The combined filtrates were
concentrated, the greenish residue taken up in H2O and the pH
adjusted to ~2 with 6 N HCl. The aqueous mixture was extracted
with EtOAc (10 mL), the layers separated and the aqueous layer
back extracted with EtOAc (2 x 5 mL). The combined organic
layers were dried (Na2SO4), filtered and concentrated to give the
title compound (0.40 g, 55%) as a purple solid. 1H NMR (400
MHz, DMSO-d6) δ ppm 12.15 (s, 1H), 10.26 (s, 1H), 8.48 (s, 1H),
7.08 (d, J = 8.6 Hz, 1H), 6.63 (d, J = 2.3 Hz, 1H), 6.49 (dd, J =
8.6, 2.4 Hz, 1H), 3.49 – 3.39 (m, 1H), 2.72 (dd, J = 15.9, 5.3 Hz,
1H), 2.69 – 2.56 (m, 3H), 2.34 (dd, J = 15.9, 9.2 Hz, 1H), 2.11 –
2.02 (m, 1H). LCMS m/z = 232.0 [M + H]+.
16. Telescoped procedure for the preparation of indole devirative 16:
To a solution of BBr3 (115 g, 43.3 mL, 458 mmol, 3 equiv) in
CH2Cl2 (70 mL)
a
suspension of 2-(7-methoxy-1,2,3,4-
tetrahydrocyclopenta[b]indol-3-yl)acetic acid (14a, 37.44 g, 153
mmol) in CH2Cl2 (300 mL) was added slowly while maintaining
the reaction temperature between -5 to 0 °C. The resulting dark
brown suspension was stirred at -5 to 0 °C for an additional 1 h.
EtOH (187 mL) was added dropwise to the reaction mixture while
maintaining the temperature between 0 - 10 °C. The resulting
solution was heated at 40 °C for 30 min. The solution was cooled
and the pH adjusted to 8 by adding 10 N NaOH (142.9 mL, 1.43
mol) slowly while maintaining the temperature between 0 - 3 °C.
The solvent was removed under reduced pressure until about 200
mL of concentrate remained. The pH was adjusted to about 7 with
concentrated HCl, the suspension filtered, the solids washed with
H2O (3 x 200 mL) and dried under vacuum at ambient temperature
overnight. The light brown material was dissolved in EtOAc (200
mL), and filtered washing the solids with EtOAc. The combined
organics were washed with saturated aqueous NaHCO3.(2 x 200
mL), brine (200 mL), dried (Na2SO4) and the solvent rotary
evaporated
to
afford
ethyl
2-(7-hydroxy-1,2,3,4-
tetrahydrocyclopenta[β]indol-3-yl)acetate (35.2 g, 88.9 %) as a
light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.25 (s,
1H), 8.47 (s, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.62 (d, J = 2.1 Hz,
1H), 6.49 (dd, J = 8.6, 2.3 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.49
– 3.42 (m, 1H), 2.76 (dd, J = 15.7, 5.5 Hz, 1H), 2.71 – 2.55 (m,
3H), 2.42 (dd, J = 15.7, 8.9 Hz, 1H), 2.11 – 2.03 (m, 1H), 1.20 (t,
J = 7.1 Hz, 3H). LCMS m/z = 260.1 [M + H]+.