Expeditious synthesis of highly substituted indolizinones via a palladium-catalyzed domino sequence

Article abstract of DOI:10.1021/ol1006778

A direct one-pot approach to polysubstituted indolizinones from tertiary propargylic alcohols using a palladium-catalyzed domino process involving aminopalladation, reductive elimination, and 1,2-shift is described.

Full text of DOI:10.1021/ol1006778

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2500-2503
Expeditious Synthesis of Highly
Substituted Indolizinones via a
Palladium-Catalyzed Domino Sequence†
Ikyon Kim* and Kyungsun Kim
Medicinal Chemistry Research Center, Korea Research Institute of Chemical
Technology, Daejeon 305-600, Republic of Korea
ikyon@krict.re.kr
Received March 23, 2010
ABSTRACT
A direct one-pot approach to polysubstituted indolizinones from tertiary propargylic alcohols using a palladium-catalyzed domino process
involving aminopalladation, reductive elimination, and 1,2-shift is described.
In recent years, alkyne activation by electrophilic reagents
has represented a highly valuable means for many subsequent
Scheme 1. One-Pot Approach to Polysubstituted Indolizinones
synthetic transformations such as cyclization.1 For example,
intramolecular attack of activated alkyne(s) by internal
nucleophile(s) with a suitable length of tether allows access
to a wide variety of carbo- and heterocycles. Among many
alkynophilic reagents, palladium has been extensively em-
ployed as a reliable catalyst for a number of reactions
involving alkynes.2 In particular, exploitation of the orga-
nopalladium species formed before or after cyclization for
further elaboration in a one-pot fashion renders a domino
process possible.3
Although this procedure was easy to perform and provided
good overall yields, we decided to pursue a more direct
synthetic method of 3 from 1 without isolating 2. As shown
in Scheme 2, we reasoned that arylpalladium species formed
in situ by oxidative addition of Pd(0) to R3X could activate
As part of our medicinal research program, we recently
developed a facile combinatorial approach to an indolizinone4
core-based library with three diversity points (Scheme 1).5,6
† Dedicated to Professor George A. Kraus on the occasion of his 60th
birthday.
(4) Sarpong and Liu independently reported the synthesis of indoliz-
inones with no substituent at C2 position by using Pt(II) and Cu(I) catalysts,
respectively: (a) Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R.
Org. Lett. 2007, 9, 1169. (b) Yan, B.; Zhou, Y.; Zhang, H.; Chen, J.; Liu,
Y. J. Org. Chem. 2007, 72, 7783. For a catalyst-free approach to
indolizinones, see: (c) Kim, I.; Choi, J.; Lee, S.; Lee, G. H. Synlett 2008,
2334.
(1) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104,
3079. (b) Kirsch, S. F. Synthesis 2008, 3183. (c) Arcadi, A. Chem. ReV.
2008, 108, 3266. (d) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV.
2008, 108, 3351. (e) Lee, S. I.; Chatani, N. Chem. Commun. 2009, 371. (f)
Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin, T. Chem. Commun. 2009,
5075.
(5) Kim, K.; Kim, I. J. Comb. Chem. 2010, published ASAP March 31,
2010. DOI: 10.1021/cc100015k.
(2) (a) Negishi, E. Handbook of Organopalladium Chemistry for Organic
Synthesis; Wiley and Sons: New York, 2002; Vols. 1 and 2. (b) Palladium
Reagents and Catalysts: New PerspectiVes for the 21st Century; Tsuji, J.,
Ed.; John Wiley & Sons, Ltd.: Chichester, 2004. (c) Zeni, G.; Larock, R. C.
Chem. ReV. 2004, 104, 2285.
(6) For our contribution in the area of fused azacycles, see also: (a)
Kim, I.; Choi, J.; Won, H. K.; Lee, G. H. Tetrahedron Lett. 2007, 48, 6863.
(b) Kim, I.; Won, H. K.; Choi, J.; Lee, G. H. Tetrahedron 2007, 63, 12954.
(c) Kim, I.; Kim, S. G.; Kim, J. Y.; Lee, G. H. Tetrahedron Lett. 2007, 48,
8976. (d) Choi, J.; Lee, G. H.; Kim, I. Synlett 2008, 1243.
(3) Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106, 4644.
10.1021/ol1006778  2010 American Chemical Society
Published on Web 05/05/2010

Scheme 2
.
Proposed Mechanism
Table 1. Reaction Optimization
entry
X
Pd(0)
Pd(PPh3)4
base
Et3N
Na2CO3 CH3CN
K2CO3 CH3CN
Cs2CO3 CH3CN
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
solvent yield (%)e
1
2
3
4
5
6
7
8
I
CH3CN
69
50
96
56
99
80
85
98
52
91
trace
I
I
I
I
I
I
I
I
I
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
b
c
CH3CN
CH3CN
dioxane
THF
the alkyne moiety, inducing 5-endo-dig cyclization by the
neighboring pyridine group. The resulting indolizinium salt
4 would undergo reductive elimination to give 5.7,8 Finally,
1,2-migration9 would occur to furnish the desired indoliz-
inone 3.
9
10
11
DMF
d
Pd2(dba)3 + PPh3
CH3CN
CH3CN
Br Pd(PPh3)4
a A mixture of 1a (0.13 mmol), aryl halide (1.5 equiv), Pd(0) (10 mol
%), and base (2.5 equiv) in solvent (1 mL) was heated at 90 °C for 13 h
unless otherwise noted. b 5 mol % Pd(PPh3)4 was used. c 1 mol % Pd(PPh3)4
was used. d 5 mol % Pd2(dba)3 and 10 mol % PPh3 were used. e Isolated
yield.
With this hypothesis in mind, we planned to explore the
feasibility of this strategy.10,11 Herein we report a facile and
efficient approach to highly substituted indolizinones 3 using
a Pd-catalyzed cascade reaction of tertiary propargylic
alcohols 1. To find the optimal conditions, we screened
several reaction parameters with 1a and 1-iodo-4-nitroben-
zene as substrates. As shown in Table 1, K2CO3 was found
to give the best result among the bases examined (entries
1-4). The desired product was obtained in excellent yield
even with 5 mol % catalyst loading, although the yield was
diminished with 1 mol % of Pd(0) (entries 5 and 6). While
THF can be used as solvent, providing an excellent yield of
3a, dioxane or DMF gave inferior results (entries 7-9). Other
Pd(0) sources were tested to furnish the similar yield (entry
10). 1-Bromo-4-nitrobenzene, however, was not suitable for
this transformation, leaving room for further optimization
(entry 11). It should be mentioned that aryl halides were used
as precursor for introduction of the functional group at the
C2 position in this protocol, whereas our previous method
utilized R,ꢀ-unsaturated esters, terminal acetylenes, or bo-
ronic acids,5 which indicates both approaches are comple-
mentary.
With optimized conditions in hand, we first examined the
scope of aryl iodides with 1a (Table 2). Excellent yields of
the desired products were obtained with aryl iodides bearing
electron-withdrawing groups, whereas the reactions with aryl
iodides having electron-donating groups gave the corre-
sponding products in modest yields (entries 5-7 and 10).
Heterocycles were also incorporated successfully at the C2
position of indolizinones by using the corresponding iodides
(entries 8 and 12).
To expand the generality of this process, we also reacted
other tertiary propargylic alcohols bearing different substit-
uents at R1 and R2 sites with several aryl iodides under
identical reaction conditions (Table 3). To our delight, a
diverse array of densely functionalized indolizinones was
readily constructed in good to excellent yields. Due to the
difference in reactivity under these conditions, reactions of
1b and 1c with 2-bromo-5-iodopyridine only produced
2-bromopyridine-containing indolizinones 3o and 3t, provid-
ing a functional handle for further coupling reactions (entries
2 and 7).
In conclusion, we have shown that polysubstituted
indolizinones could be constructed from readily available
tertiary propargylic alcohols in a one-pot manner employ-
ing a Pd-catalyzed domino procedure where aminopalla-
dation and reductive elimination were successfully coupled
with 1,2-rearrangement for the first time. Mild reaction
conditions, ease of operation, high yields, and a wide
(7) For reviews, see: (a) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J.
Org. Chem. 2002, 2671. (b) Balme, G.; Bouyssi, D.; Lomberget, T.;
Monteiro, N. Synthesis 2003, 2115. (c) Cacchi, S.; Fabrizi, G. Chem. ReV.
2005, 105, 2873. (d) Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106, 4644
.
(8) (a) Tsuda, T.; Ohashi, Y.; Nagahama, N.; Sumiya, R.; Saegusa, T.
J. Org. Chem. 1988, 53, 2650. (b) Arcadi, A.; Cacchi, S.; Del Rosario, M.;
Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996, 61, 9280. (c) Rossi, R.;
Bellina, F.; Biagetti, M.; Mannina, L. Tetrahedron Lett. 1998, 39, 7599.
(d) Jacobi, P. A.; Liu, H. Org. Lett. 1999, 1, 341. (e) Flynn, B. L.; Hamel,
E.; Yung, M. K. J. Med. Chem. 2002, 45, 2670. (f) Dai, G.; Larock, R. C.
J. Org. Chem. 2003, 68, 920. (g) Bossharth, E.; Desbordes, P.; Monteiro,
N.; Balme, G. Org. Lett. 2003, 5, 2441. (h) Hu, Y.; Nawoschik, K. J.; Liao,
Y.; Ma, J.; Fathi, R.; Yang, Z. J. Org. Chem. 2004, 69, 2235. (i) Cacchi,
S.; Fabrizi, G.; Goggiamani, A. AdV. Synth. Catal. 2006, 348, 1301
.
(9) (a) Paquette, L. A.; Lanter, J. C.; Johnston, J. N. J. Org. Chem.
1997, 62, 1702. (b) Paquette, L. A.; Kinney, M. J.; Dullweber, U. J. Org.
Chem. 1997, 62, 1713. (c) Fenster, M. D. B.; Patrick, B. O.; Dake, G. R.
Org. Lett. 2001, 3, 2109. (d) Overman, L. E.; Pennington, L. D. J. Org.
Chem. 2003, 68, 7143. (e) Kirsch, S. F.; Binder, J. T.; Lie´bert, C.; Menz,
H. Angew. Chem., Int. Ed. 2006, 45, 5878.
(10) To the best of our knowledge, strategic applications of this
combination (aminopalladation, reductive elimination, and 1,2-migration)
in a cascade manner have never been reported in the literature.
(11) Pd-catalyzed ring expansion of 1-(1-alkynyl)cycloalkanols is a
related process. (a) Larock, R. C.; Reddy, C. K. Org. Lett. 2000, 2, 3325.
(b) Larock, R. C.; Reddy, C. K. J. Org. Chem. 2002, 67, 2027. (c) Wei,
L.-M.; Wei, L.-L.; Pan, W.-B.; Wu, M.-J. Tetrahedron Lett. 2003, 44, 595
.
Org. Lett., Vol. 12, No. 11, 2010
2501

Table 2. Synthesis of Indolizinones from the Reaction of 1a
with Various (Hetero)aryl Iodides
Table 3. Synthesis of Indolizinones from the Reaction of
Diverse Propargylic Alcohols with Various (Hetero)aryl Iodides
a Isolated yield (%).
a Isolated yield (%).
2502
Org. Lett., Vol. 12, No. 11, 2010

functional-group tolerance are several merits of this highly
efficient protocol. Given the importance of this scaffold
as a pharmacophore, the chemistry described here should
be useful for the rapid assembly of diverse indolizinone
derivatives. Further investigation to extend the scope of
this reaction as well as biological evaluation of these
compounds is currently underway and will be reported in
the near future.
Acknowledgment. The authors thank Korea Research
Institute of Chemical Technology for financial support.
Supporting Information Available: Experimental pro-
cedure, characterization data, and copies of 1H and 13C NMR
spectra of 3. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL1006778
Org. Lett., Vol. 12, No. 11, 2010
2503