Synthesis of 3-aryl-8-oxo-5,6,7,8- tetrahydroindolizines via a palladium-catalyzed arylation and heteroarylation

Article abstract of DOI:10.1021/jo802768n

A selective palladium-catalyzed arylation and heteroarylation of 8-oxo-5,6,7,8-tetrahydroindolizines has been developed. Mechanistic studies assume an electrophilic substitution pathway for this transformation. This method provides an efficient one-step s

Full text of DOI:10.1021/jo802768n

novel cancer chemotherapeutics. Geldanamycin,6 as well as
aminoquinoline derivatives7 and purine analogues,8 have been
identified as inhibitors of Hsp-90.
Synthesis of 3-Aryl-8-oxo-5,6,7,8-
tetrahydroindolizines via a Palladium-Catalyzed
Arylation and Heteroarylation
Ste´phanie Gracia, Cle´ment Cazorla, Estelle Me´tay,
Ste´phane Pellet-Rostaing,* and Marc Lemaire*
Laboratoire de Catalyse et Synthe`se Organique, ICBMS,
Institut de Chimie et Biochimie Mole´culaires et
Supramole´culaires, CNRS, UMR 5246, UniVersite´ de Lyon,
69622 Villeurbanne, France
FIGURE 1. 8-Oxo-5,6,7,8-tetrahydroindolizine and Hsp-90 inhibitor.
pellet@uniV-lyon1.fr
To date, 3-aryl 8-oxo-5,6,7,8-tetrahydroindolizines has been
obtained by a-four step strategy involving a Suzuki-Miyaura9
coupling or a five-step procedure implementing a Mu¨ller-
Polleux10 preparation of pyrrole.
ReceiVed January 5, 2009
Herein, we disclose an alternative and pratical three-step
strategy for the preparation of 3-aryl 8-oxo-5,6,7,8-tetrahydroin-
dolizines 5 based on a direct arylation or heteroarylation of the
tetrahydroindolizine intermediate 4 (Scheme 1). Among the
different available methods for the formation of the tetrahy-
droindolizinone skeleton,1-4 condensation of γ-amino butyric
acid (GABA) with 2,3,4,5-tetrahydro-2,5-dimethoxytetrahydro-
furan,3 followed by the activation of the carboxylate group of
the resulting γ-pyrrolic acid 3 with PPA (polyphosphoric acid)
under modified Taylor conditions,1c was one of the most efficient
routes, affording the key intermediate 6,7-dihydro-8(5H)-
indolizinone 4 in an overall yield of 95%.
A selective palladium-catalyzed arylation and heteroarylation
of 8-oxo-5,6,7,8-tetrahydroindolizines has been developed.
Mechanistic studies assume an electrophilic substitution
pathway for this transformation. This method provides an
efficient one-step synthesis of 3-aryl-8-oxo-5,6,7,8-tetrahydro-
indolizines.
SCHEME 1. Preparation and Modification of 6,7-Dihydro-
8(5H) indolizinone
The 8-oxo-5,6,7,8-tetrahydroindolizine skeleton (Figure 1)
was reported as a key intermediate in the synthesis of indolizi-
dine building blocks1 and natural indolizidine alkaloids such
as the (+)-monomorine,1g indolizidine 209D,1,2 or polygonatines
A, B1f and kinganone.1,3 Recently, 3-aryl-8-oxo-5,6,7,8-tetrahy-
droindolizines4 were described as inhibitors of Hsp-90, an ATP-
dependent chaperone responsible for the regulation of stabili-
zation, activation, and degradation of a range of “client” proteins
involved in cell cycle regulation and signal conduction.5 Because
many oncogenic proteins are substrates for Hsp-mediated protein
folding processes, Hsp-90 has become an attractive target for
Selective coupling of aryl and heteroaryl motifs at the C-3
position of the tetrahydroindolizine ring allowed access to the
3-aryl-8-oxo-5,6,7,8-tetrahydroindolizines. Although similar
coupling reactions on various heterocyclic systems10 such as
furans,11 thiophenes,12 and indoles13 have been described in the
(1) (a) Bond, T. J.; Jenkins, R.; Ridley, A. C.; Taylor, P. C. J. Chem. Soc.,
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Patent WO 2008/024978.
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3160 J. Org. Chem. 2009, 74, 3160–3163
10.1021/jo802768n CCC: $40.75 2009 American Chemical Society
Published on Web 03/18/2009

TABLE 1. Arylation of 4 with Bromobenzene
conditions
PhBr
A
B
C
D
1.8 equiv
1.2 equiv
1.2 equiv
1.2 equiv
catalyst
KOAc
Pd(OAc)2 10%
2.3 equiv
PdCl2(PPh3)2 5%
2 equiv
PdCl2(PPh3)2 0.5%
2 equiv
PdCl2(PPh3)2 0.5%
2 equiv
H2O
2 equiv
0.2 equiv
0.2 equiv
additive
solvent
reaction time
conversion
PPh3 (0.02 equiv)
DMF (0.9 M)
101 h
NMP (0.5 M)
90 h
70%
DMF (1.8 M)
90 h
81%
NMP (1.8 M)
89 h
>95%
83%
literature, only few examples of the arylation of the pyrrole rings
were reported, and most of them described the intramolecular
aryl-pyrrolyl bond formation. However, some examples of
intermolecular aryl-pyrrolyl bond formation were reported
involving N-metalated pyrrole by Filippini14 and N-free or
N-methyl pyrrole by Ohta,15 nevertheless with low yields. The
first palladium-catalyzed selective arylation on 3-substituted
indolizines was finally reported in 2004 by Park.16
As already performed in our laboratory on benzo[b]-
thiophenes,17 arylation of 4 with bromobenzene was initially
examined using Pd(OAc)2 (10 mol %) with various bases
(K2CO3, Cs2CO3, Et3N, Ag2CO3, NaOAc, CsOAc, KOAc) and
additives including DCH18C6, NBu4Br, or Ph3P in DMF,
MeCN, DMSO, DMA, or dioxane at different temperature
varying from 80 to 130 °C. When the reaction was performed
in DMF at 100 °C with KOAc (2.3 equiv) and Ph3P (10 mol
%) (Table 1, column A), an 83% conversion of the correspond-
ing coupling adduct was observed.
Moreover, the pyrrole ring is predominantly arylated at the
3-position over the 2-position because attacking at the 3-position
gives rise to a more stable arenium ion as assumed by Li.19 Attacking
at the 2-position would fail to give such a stable arenium ion.
As additional argument that could also support the involve-
ment of electrophilic aromatic substitution, we attempted to
perform the arylation of the corresponding deoxygenated
tetrahydroindolizine obtained in 50% yield by the reductive
deoxygenation of the 6,7-dihydro-8(5H)-indolizinone using tert-
20
butylamine borane complex and AlCl3 (Scheme 2).
SCHEME 2. Preparation of 2-Phenyl-5,6,7,8-
tetrahydroindolizine
Conditions reported by Park16 on indolizines were also tested
(column B), but the conversion was lower. Experiments were
run with 0.5% of palladium complex and 0.2 equiv of water in
DMF (column C) or in NMP (column D). Finally, the arylation
of tetrahydroindolizinone proceeded more efficiently (>95%
conversion and 88% isolated yield) in the presence of catalytic
amounts of PdCl2(PPh3)2 (0.5%), KOAc (2 equiv) and H2O (0.2
equiv) in NMP (1.8 M) at 100 °C (column D).
The charge density calculation using semiempirical PM3
modeling showed that the 3-position of 11 is more electroneg-
ative than that observed with 4 (Figure 2).
Based on a molecular modeling using semiempirical PM3
that showed that the highest charge density of the unsubstituted
position of the pyrrole moiety was located at the 3-position
(Figure 2), we assumed that the mechanism of the arylation is
similar to that already proposed by Miura,18 Li,19 and Park.16
After oxidative addition of aryl bromide 6, the mechanism
involved an electrophilic attack by the resulting aryl-palladium
bromide species 7 to the 3-position of the pyrrole ring to form
the intermediate 8. Deprotonation of 8 followed by a reductive
elimination of aryl(tetrahydroindolizinone)palladium II 9 gave
the expected 3-aryl 8-oxo-5,6,7,8-tetrahydroindolizines 5 and
regenerated the palladium(0) catalyst.
(13) (a) Atika, Y.; Itagaki, Y.; Takizawa, S.; Ohta, A. Chem. Pharm. Bull.
1989, 37, 1477. (b) Itahara, T. Chem Commun. 1971, 254. (c) Akita, Y.; Inoue,
A.; Yamamoto, K.; Ohta, A. Heterocycles 1985, 23, 2327.
(14) Filippini, L.; Gusmeroli, M.; Riva, R. Tetrahedron Lett. 1992, 33, 1755.
(15) Aoyagi, Y.; Inoue, A.; Hashimoto, R.; Tokunaga, K.; Gohma, K.;
Komatsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J.; Homma, R.; Akita, Y.; Ohta,
A. Heterocycles 1992, 33, 257.
(16) Park, C. H.; Ryabova, V.; Seregin; Sromek, I. V.; Gevorgyan, A. W. V.
Org. Lett. 2004, 6, 1159.
(17) Fournier Dit Chabert, J.; Joucla, L.; David, E.; Lemaire, M. Tetrahedron
2004, 60, 3221.
(18) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull.
Chem. Soc. Jpn. 1998, 71, 467.
FIGURE 2. Calculated charge density.
J. Org. Chem. Vol. 74, No. 8, 2009 3161

TABLE 2. Arylation of 6,7-Dihydro-8(5H)-indolizinone
confirm that the mechanism of the arylation involved an
electrophilic substitution.
The scope of the reaction was finally explored by applying the
optimized reaction conditions to 6,7-dihydro-8(5H)-indolizinone
4 and various aryl bromides (Table 2). The effectiveness of the
coupling reaction is strongly influenced by the electronic effects
and the position of the aryl bromide substituents.
Electron-withdrawing groups at the ortho and para posi-
tions of the aryl bromide generally worked better (entries
2-7) than electron-donating groups in terms of the reaction
times and yields (entries 8-10), in accordance with the
Hammett coefficient.21 Excellent conversion and isolated
yields were also obtained with inductive electron-withdrawing
groups at the meta position (entries 11-13), and a moderate
conversion of 71% was reached with a methyl group (entry
14). Combining the effect of electron-withdrawing and
electron-donating groups at the para and ortho positions gave
5p in 56% yield (entry 16). On the other hand, poor
conversion and isolated yield were obtained with a ketone
substituent at the ortho position (entries 15), probably as a
result of the steric hindrance resulting from the bulky group.
Palladium-catalyzed heteroarylation of 4 with 3-bromopyri-
dine and quinoline (entries 17 and 18) as well as the
naphthalene coupling (entry 20) was more efficient than the
thiophene coupling due to the electron-donating property of
the sulfur atom. Consequently, electronic enrichment of the
arylpalladium bromide species dramatically penalized the
arylation conditions. This effect was less critical in the cases
of the imidazopyrimidines19 and indolizidines.16 The reduced
yields could be explained thanks to the charge density
evaluation using semiempirical PM3. The electronegativity
coefficient at the C-3 position of imidazopyrimidines of Li
(-0.356) and C-2 position of indolizines of Park (-0.290)
were higher than at the C-3 position of the tetrahydroin-
dolizinone (-0.257). Therefore, electrophilic attacks were
facilitated, and the enrichment of the arylpalladium halide
species was less important. In conclusion, a new three-step
highly divergent strategy was developed allowing the access
to 3-aryl 8-oxo-5,6,7,8-tetrahydroindolizines, known for their
inhibitive activity on the chaperone Hsp-90. From a pal-
ladium-catalyzed arylation and heteroarylation probably via
an electrophilic aromatic substitution mechanism, indoliz-
idines were obtained with global yields between 45% and
93%.
Experimental Section
Representative Procedure for Arylation of Compound 4.
8-Oxo-5,6,7,8-tetrahydroindolizine 4 (1 g, 7.35 mmol), KOAc
(1.44 g, 14.7 mmol), PdCl2(PPh3)2 (26 mg, 0.0367 mmol), and
arylbromide (8.8 mmol) followed by freshly distilled NMP (4
mL) were added to a Schlenk flask under argon atmosphere.
The mixture was stirred at 100 °C for 10 min. Then, water (23
µL, 1.3 mmol) was added to the solution. The reaction mixture
was stirred at 100 °C for the appropriate time, diluted with
dichloromethane (30 mL), and washed with water (3 × 10 mL).
The organic layer was dried (Na2SO4), and the solvent was
removed under reduced pressure. Purification by column chro-
a Determined by 1H NMR. b Degradation during purification was
observed.
(19) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Javadi, G. J.;
Cai, D.; Larsen, R. D. Org. Lett. 2003, 5, 4835.
(20) (a) Lau, C. K.; Tardif, S.; Dufresne, C.; Scheigetz, J. J. Org. Chem.
1989, 54, 491. (b) Gracia, S.; Schulz, J.; Pellet-Rostaing, S.; Lemaire, M. Synlett
2008, 1852.
The arylation of 10 afforded the compound 11 in 95%
conversion and 70% isolated yield in 18 h. This result could
(21) Brown, H. C.; McDaniel, D. J. Org. Chem. 1958, 23, 420.
3162 J. Org. Chem. Vol. 74, No. 8, 2009

matography (silica gel, cyclohexane/ethyl acetate 8/2) afforded
Acknowledgment. The authors thank the MRT for a grant
to S.G.
the desired compound 5a-t. 3-Phenyl-8-oxo-5,6,7,8-tetrahy-
1
droindolizine (5a): 88%; white solid; mp ) 121-122 °C; H
NMR (CDCl3, 300 MHz) δ 2.17 (m, 2H), 2.55 (t, 2H, J ) 6.2
Hz), 4.04 (t, 2H, J ) 6.2 Hz), 6.27 (d, 1H, J ) 4.1 Hz), 7.04 (d,
1H, J ) 4.1 Hz), 7.37 (m, 5 H); 13C NMR (CDCl3, 75 MHz) δ
23.9 (CH2), 36.3 (CH2), 44.5 (CH2), 111.9 (CH), 114.7 (CH),
122.4 (CH), 125.9 (2 CH), 129.2 (2 CH), 132.4 (Cq), 135.4 (Cq),
137.5 (Cq), 187.9 (CO); IR 3056, 3029, 2946, 2880, 1646, 1532,
1508, 1454, 1384, 1333 cm-1; HRMS[EI] calculated for
C14H13NO 211.0997, found 211.0998.
Supporting Information Available: Experimental proce-
dures, characterization data, and NMR spectra of all the new
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO802768N
J. Org. Chem. Vol. 74, No. 8, 2009 3163