Synthesis of 8-Oxo-3-acetylenic-5,6,7,8-tetrahydroindolizines via sonogashira coupling

Article abstract of DOI:10.1055/s-0029-1217953

A selective alkynylation of 3-bromoindolizinone, involving the first copper-free Sonogashira coupling on pyrrole ring, has been developed to afford 8-oxo-3-acetylenic-5,6,7,8-tetraihydroindolizinone.

Full text of DOI:10.1055/s-0029-1217953

LETTER
2617
Synthesis of 8-Oxo-3-acetylenic-5,6,7,8-tetrahydroindolizines via Sonogashira
Coupling
Synthesis of
8
t
-Oxo-3
é
-acetylenic
p
h
hydroindoliz
a
ines nie Gracia, Estelle Métay, Stéphane Pellet-Rostaing,* Marc Lemaire*
Laboratoire de Catalyse et Synthèse Organique, ICBMS, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, CNRS,
UMR 5246, Université de Lyon, 69622 Villeurbanne, France
Fax +33(4)72431408; E-mail: pellet@univ-lyon1.fr
Received 24 June 2009
Abstract: A selective alkynylation of 3-bromoindolizinone, in-
NBS, CH2Cl2
95%
O
O
volving the first copper-free Sonogashira coupling on pyrrole ring,
has been developed to afford 8-oxo-3-acetylenic-5,6,7,8-tetra-
hydroindolizinone.
Br
N
N
1
2
Key words: cross-coupling, pyrrole, palladium, alkynylation, alka-
loid
R
O
N
Sonogashira
coupling
R
The 8-oxo-5,6,7,8-tetrahydroindolizine skeleton was re-
ported 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 and B,1f and kinganone.1,3 Recently, 3-
substituted 8-oxo-5,6,7,8-tetrahydroindolizines have been
identified as inhibitors of Hsp-90, known for anticancer
properties.4 As part of our ongoing research toward 3-sub-
stituted 8-oxo-5,6,7,8-tetrahydroindolizines, we recently
reported an effective three-step synthesis of 3-aryl-8-oxo-
5,6,7,8-tetrahydroindolizines via a palladium-catalyzed
arylation or heteroarylation.5
3
Scheme 1 Modification of 3-bromoindolizinone
free Sonogashira coupling on a 3-haloindolizinone
(Scheme 1).
The synthesis of 3-haloindolizinone 2 relies on a proce-
dure based on the regioselective halogenation of the 6,7-
dihydro-8(5H)-indolizinone 1. N-Bromosuccinimide was
chosen as brominating agent. The use of 1.5 equivalents
of N-bromosuccinimide in dichloromethane gave a mix-
ture of 3-bromoindolizinone and 2,3-dibromoindolizino-
ne in the ratio 65:35. After optimization, halogenation of
the starting material gave the 3-bromoindolizinone 2 in
95% yield by using only 1 equivalent of N-bromosuccin-
imide in dichloromethane.11
Corresponding 3-alkynyl-8-oxo-5,6,7,8-tetrahydroindo-
lizines could be reached via a Sonogashira coupling on the
3-haloindolizinone. This useful method has been widely
applied as a key step in natural product and bioactive mol-
ecules synthesis. Traditionally, Sonogashira coupling is a
palladium-catalyzed cross coupling involving copper(I)
as cocatalyst with amine.6 During the last decades, efforts
focused on building such a C–C bond in the absence of
copper7 or palladium.8 Although Sonogashira coupling is
one of the leading ‘name’ reactions in organic synthesis to
introduce acetylenic moiety, only few examples of that
kind of coupling were reported on pyrrole ring. Most of
them describe the palladium-mediated coupling from io-
dopyrrole with Cu(I) as cocatalyst.9
The typical procedure for Sonogashira coupling was ini-
tially tested with palladium catalyst and CuI (entry 1,
Table 1) at room temperature to afford the corresponding
coupling adduct with more than 95% conversion in 86
hours.12 Palladium-free conditions (entry 2)13 as well as in
presence of palladium on charcoal (entry 3)14 did not give
any conversion. PdCl2 with Ph3P at room temperature (en-
try 4) or at 80 °C (entry 5)15 allowed increasing the con-
versions until 58%. When the PdCl2(PPh3)2 4 mol%
precatalyst was used (entry 6), a conversion of 70% was
reached. Finally, the Sonogashira coupling of phenylacet-
ylene on 3-bromoindolizinone with 10 mol% of
PdCl2(PPh3)2, 1.5 equiv of triethylamine in MeCN at
80 °C gave more than 95% conversion in two hours (entry 7).
This procedure represents the first copper-free Sonogashira
coupling on pyrrole ring.
Furthermore, to the best of our knowledge, only one
Sonogashira coupling at the C-2 position of the 2-iodo-
indolizine core was reported by Kim.10 To date, no cop-
per-free Sonogashira couplings were described on the
pyrrole ring or indolizine core.
Dichlorobis(triphenylphosphine)palladium(II) has been
already employed for the direct palladium-catalyzed alky-
nylation of N-fused heterocycles notably indolizine by
Gevorgyan.16
Herein, we report a practical access to 3-alkynyl-8-oxo-
5,6,7,8-tetrahydroindolizine scaffold via a direct copper-
SYNLETT 2009, No. 16, pp 2617–2620
Advanced online publication: 03.09.2009
DOI: 10.1055/s-0029-1217953; Art ID: G20806ST
x
x
.x
x
.2
0
0
9
When these conditions were performed on the indolizino-
ne with bromophenylacetylene, only 30% conversion was
© Georg Thieme Verlag Stuttgart · New York

2618
S. Gracia et al.
LETTER
Table 1 Alkynylation of 2 with Phenylacetylene
Ph
O
O
Br
N
N
Sonogashira
coupling
Ph
2
3a
Entry Catalyst (mol%)
Cocatalyst (mol%)
Additive (mol%) Base (equiv) Solvent Temp (°C) Time (h) Conversion (%)
1
2
3
4
5
6
7
PdCl2(PPh3)2 (10)
CuI (2)
CuI (5)
–
Et3N (1.5)
L-Pro (0.06)
K2CO3 (2)
Et3N (2)
DMF
r.t.
60
r.t.
r.t.
80
80
80
86
24
24
24
24
24
2
>95
–
–
–
–
–
–
–
–
DMF
Pd/C (1)
XPhos (1)
NMP
–
PdCl2 (4)
Ph3P (8)
MeCN
MeCN
MeCN
MeCN
54
58
71
>95
PdCl2 (4)
Ph3P (8)
Et3N (2)
PdCl2(PPh3)2 (4)
PdCl2(PPh3)2 (10)
–
–
Et3N (1.5)
Et3N (1.5)
a Determined by GC.
reached (Scheme 2). Thus, our method allowed obtaining The scope of the reaction was finally explored by apply-
the same product with much higher conversion.
ing the optimized reaction conditions17 to the 3-bromoin-
dolizinone with various terminal alkynes (Table 2).
Not surprisingly, electron-donating group on the acety-
lene moiety gave better conversions and isolated yields.
Nevertheless, in methylic ester case (entry 7), the cou-
pling is dramatically penalized. Based on this result,
Mårtensson’s conditions18 were tested but did not give
any coupling product. Whatever, the aryl-type substituent
(entries 1 and 2) or heteroaryl (entry 9), conversions high-
er than 95% were obtained with isolated yield upper than
80%. Finally, inductive electron-withdrawing groups on
terminal alkynes (entries 3 and 8) gave good conversions
but difficulties in purification occurred.
Ph
O
O
Br
N
N
PdCl2(PPh3)2 (10 mol%)
Et3N, MeCN
Ph
Ph
80 °C
conversion >95% in 2 h
O
O
Br
Ph
H
N
N
PdCl2(PPh3)2 (5 mol%)
AcOK, PhMe
80 °C
conversion 30% in 2 h
Scheme 2 Comparison of two alkynylation methods
Table 2 Pd-Catalyzed Alkynylation of 3-Bromoindolizinone
Entry
R
Product
Conversion (%)a Isolated yield (%)
O
N
1
Ph
3a
3b
>95
>95
82
90
N
Ph
O
2
F
F
O
b
3
4
CH2NMe2
3c
>95
>95
–
N
N
O
TMS
3d
86
N
TMS
Synlett 2009, No. 16, 2617–2620 © Thieme Stuttgart · New York

LETTER
Synthesis of 8-Oxo-3-acetylenic-5,6,7,8-tetrahydroindolizines
2619
Table 2 Pd-Catalyzed Alkynylation of 3-Bromoindolizinone (continued)
Entry
5
R
Product
Conversion (%)a Isolated yield (%)
O
3e
3f
94
55
62
–
N
O
6
7
8
(CH2)2Me
CO2Me
94
N
O
3g
3h
(–)c
>95
N
MeO2C
O
60
N
HO
HO
O
9
3i
3j
>95
85
83
78
N
N
N
O
10
N
MeO
MeO
a Determined by GC.
b Degradation during purification was observed.
c Conversion obtained with conditions ref. 18.
J. M. Tetrahedron Lett. 2000, 41, 3035. (f) Michael, J. P.
Nat. Prod. Rep. 2007, 24, 191. (g) Toyooka, N.; Zhou, D.;
Nemoto, H. J. Org. Chem. 2008, 73, 4575.
In conclusion, a four-step highly divergent strategy from
g-aminobutyric acid and dimethoxytetrahydrofurane was
developed allowing the access to 3-acetylenic-8-oxo-
5,6,7,8-tetrahydroindolizines which potentially have in-
hibitive activity on the chaperone Hsp-90. Based on the
first copper-free Sonogashira coupling described on pyr-
role ring, indolizidines were obtained with global yields
between 50% and 81%.
(2) Amos, R. I. J.; Gourlay, B. S.; Molesworth, P. P.; Smith,
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Acknowledgment
The authors thank the MRT for a grant attributed to S.G.
References and Notes
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Synlett 2009, No. 16, 2617–2620 © Thieme Stuttgart · New York

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LETTER
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113.2 (CH), 114.7 (CH), 131.9 (Cq), 131.8 (Cq), 186.5 (CO).
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(17) General Procedure for Copper-Free Sonogashira
Coupling (See Supporting Information)
To a solution of 2 and PdCl2 (PPh3)2 (10 mol%) in dry MeCN
(0.5 M) under argon were added Et3N (1.5 equiv) then
acetylene (1.2 equiv). The resulting mixture was heated at
80 °C in a sealed tube for the required time (as monitored by
GC). The mixture was cooled at r.t. then diluted with
CH2Cl2. The organic layer was washed with H2O, brine,
dried over Na2SO4, concentrated, and finally purified on
column chromatography (cyclohexane and cyclohexane–
EtOAc = 9:1).
3-(Phenylethynyl)-8-oxo-5,6,7,8-tetrahydro-indolizine
(3a)
(11) Synthesis of 3-Bromo-8-oxo-5,6,7,8-tetrahydro-
indolizine (2)
Yield 82%; yellow powder. 1H NMR (300 MHz, CDCl3): d
= 2.32 (m, 2 H), 2.62 (dd, 2 H, J = 6.21, 7.53 Hz), 4.22 (dd,
2 H, J = 5.64, 7.14 Hz), 6.53 (d, 1 H, J = 4.32 Hz), 7.00 (d,
1 H, J = 4.14 Hz), 7.37 (m, 3 H), 7.52 (m, 2 H). 13C NMR (75
MHz, CDCl3): d = 23.6 (CH2), 36.4 (CH2), 43.7 (CH2), 80.1
(Cq), 95.6 (Cq), 114.1 (CH), 116.1 (CH), 120.1 (Cq), 122.6
(Cq), 128.8 (CH), 129.2 (CH), 131.8 (Cq), 131.8 (CH), 187.2
(CO). HRMS (EI): m/z calcd for C16H13NO: 235.0997;
found: 235.0995.
To a solution of 8-oxo-5,6,7,8-tetrahydroindolizine in
CH2Cl2 (0.12 M) was added NBS (1 equiv) portionwise.
The resulting mixture was stirred for 10 min (as monitored
by TLC). After removal of the solvent in vacuum, the
crude product was purified by column chromatography
(cyclohexane–EtOAc, 9:1). A white powder is obtained with
95% yield. 1H NMR (300 MHz, CDCl3): d = 2.26 (m, 2 H),
2.54 (m, 2 H), 4.02 (t, 2 H, J = 5.85 Hz), 6.26 (d, 1 H,
J = 4.32 Hz), 6.96 (d, 1 H, J = 4.14 Hz). 13C NMR (75 MHz,
CDCl3): d = 23.2 (CH2), 35.7 (CH2), 44.4 (CH2), 109 (Cq),
(18) Ljungdahl, T.; Bennur, T.; Dallas, A.; Emtenäs, H.;
Mårtensson, J. Organometallics 2008, 27, 2490.
Synlett 2009, No. 16, 2617–2620 © Thieme Stuttgart · New York