Palladium-catalyzed carbonylative cyclization/arylation cascade for 2-aroylindolizine synthesis

Article abstract of DOI:10.1021/ol302947r

An efficient synthesis of densely substituted 2-aroylindolizines via the palladium-catalyzed carbonylative cyclization/arylation is reported. This transformation proceeds via the 5-endo-dig cyclization of 2-propargylpyridine triggered by an aroyl Pd complex. It produced diversely substituted 2-aroylindolizines in good to excellent yields.

Full text of DOI:10.1021/ol302947r

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Palladium-Catalyzed Carbonylative
Cyclization/Arylation Cascade for
2‑Aroylindolizine Synthesis
Zhou Li, Dmitri Chernyak, and Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061, United States
vlad@uic.edu
Received October 25, 2012
ABSTRACT
An efficient synthesis of densely substituted 2-aroylindolizines via the palladium-catalyzed carbonylative cyclization/arylation is reported. This
transformation proceeds via the 5-endo-dig cyclization of 2-propargylpyridine triggered by an aroyl Pd complex. It produced diversely substituted
2-aroylindolizines in good to excellent yields.
Indolizines have attracted noteworthy attention in recent
years because of their profound biological effects.1 Both
naturally occurring and synthetic indolizines have shown
great potential in pharmaceutical research as cytotoxins,2
anti-inflammatory agents,3 and 5-HT3 receptor antago-
nists.4 In this regard, transformations that utilize readily
available substrates to provide access to diversely sub-
stituted indolizines, especially those bearing an electron-
withdrawing group at the C-2 postion,5 are in high demand.
The classic Tschichibabin reaction provides straightforward
access to C-2-substituted indolizines via the condensation of
picolines and R-bromoacetophenone derivatives. However,
the limited availability of starting materials restricts the
substitution pattern of the product.6 The [3 þ 2] cycload-
dition of pyridinium ylides with alkynes provides another
viable route to the indolizine core. However, the regios-
electivity issue, as well as the moderate yields caused by
necessary oxidation of the formed intermediate, limit its
synthetic application.7 The MoritaꢀBaylisꢀHillman reac-
tion can also be utilized for the preparation of indolizin-2-yl
ketone from an appropriate Michael acceptor. However,
it suffers from the narrow range of starting materials that
can be used and the usually low reactivity of the sub-
strates.8 In addition to the traditional condensation methods,
transition-metal catalysis has been widely used for the
(1) (a) Flitsch, W. Comprehensive Heterocyclic Chemistry, II; Perga-
mon Press: Oxford, 1984; Vol. 8, 237ꢀ 248. (b) Fan, H.; Peng, J.; Hamann,
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(5) For biological activity of indolizines bearing an electron-with-
drawing group at the C-2 position, see: (a) Shen, Y.-M.; Lv, P.-C.; Chen,
W.; Liu, P.-G.; Zhu, H.-L.; Zhang, M.-Z. Eur. J. Med. Chem. 2010, 45,
3184–3190. (b) Wu, X.-W.; Wu, Z.-P.; Chen, J.-W.; Zhang, W.; Gu,
L.-Q.; Huang, Z.-S.; An, L.-K.; Wang, L.-X.; Zhang, H.-B. Eur. J. Med.
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A. R.; Sarpong, R. Org. Lett. 2007, 9, 4547. (f) Barluenga, J.; Lonzi, G.;
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Riesgo, L.; Lopez, L. A.; Tomas, M. J. Am. Chem. Soc. 2010, 132,
13200and refs 11 and 15.
r
10.1021/ol302947r
XXXX American Chemical Society

construction of diversely functionalized, especially het-
eroatom-substituted indolizines, under mild conditions.9
Nonetheless, the selective introduction of functionality at
the C-2 position is still a challenging task.10 Along this
line, our group has recently reported a synthesis of 2-aryl
indolizines via the palladium catalyzed arylative 5-endo-dig
cyclization of 2-propargylpyridine (Scheme 1, eq 1).11
Herein, we report a Pd-catalyzed cascade carbonylative
cyclization/arylation approach to densely substituted
2-aroylindolizines that proceeds in good to excellent
yields (Scheme 1, eq 2).
the expected carbonylative cyclization/arylation cascade
to obtain 2.
To test this idea, we examined the carbonylative cycliza-
tion of pivaloate 1a and different aryl halides under con-
tinuous 10 psi CO supply. Initially, we found that the
carbonylative cyclization of 1a and iodobenzene in the
presence of Pd(PPh3)Cl2 catalyst yielded 2a in quantitative
yield (Table 1, entry 1). However, aryl halides bearing
electron-withdrawing groups, such as methyl p-iodo-
benzoate, were not competent reactants under these
conditions (entry 2).14 On the contrary, the combina-
tion of Pd(OAc)2 catalyst, PCy3 ligand, and triethyla-
mine base afforded benzoate 2f in 90% yield (entry 3).
Under the same conditions, the yield of 2a was only
19% along with a substantial amount of palladium
black produced, which implied decomposition of an
excessively reactive catalyst (entry 4). The yield of 2a
was improved to 51% by switching ligand to PPh3
(entry 5). The reaction that was performed in a sealed
Schlenk tube, which simplified the reaction setup and
allowed a higher pressure (20 psi and above), provided
2a in 86% yield at 20 psi CO pressure (entry 6). Finally,
the screening of different solvents under a reduced
temperature revealed that acetonitrile was the optimal
choice over DMF and toluene (entries 7ꢀ9).
Scheme 1. Indolizine Synthesis via Palladium-Catalyzed
Cyclization
Continuing with our efforts in the synthesis of
diversely functionalized indolizines, we thought that
the employment of benzoyl chloride instead of an aryl
halide as electrophile in this cascade cyclization would
provide 2-benzoylindolizine.12 However, the reaction
of pivaloate 1a with benzoyl chloride in the presence of
a Pd catalyst failed to produce even a trace amount of
2a (eq 3).
Thus, we thought of alternative methods to introduce
the benzoyl function at the C-2 position of indolizine.
Since (1) an acylpalladium species can be formed via a
migratory insertion of carbon monoxide into an arylꢀ
palladium bond and (2) there have been reported
examples on synthesis of diaryl ketones via the palla-
dium-catalyzed carbonylative cyclization/arylation cas-
cades,13 we anticipated that under a CO atmosphere
the in situ formed acyl palladium species might trigger
Table 1. Optimization of Conditions
temp
yield
(%)b
entry
ligand
base solvent (°C) COa
2a, >99c
2f decc
2f, 90
(10) For the regioselectivity of the direct CꢀH functionalization of
indolizine, see: (a) Renard, M.; Gubin, J. Tetrahedron Lett. 1992, 33,
4433. (b) Shipman, M. Science of Synthesis 2000, 10, 777. (c) Park, C.-H.;
Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett.
2004, 6, 1159. (d) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am.
Chem. Soc. 2007, 129, 7742. (e) Petit, A.; Flygare, J.; Miller, A. T.;
Winkel, G.; Ess, D. H. Org. Lett. 2012, 14, 3680.
(11) (a) Chernyak, D.; Skontos, C.; Gevorgyan, V. Org. Lett. 2010,
12, 3242. (b) Chernyak, D.; Gevorgyan, V. Org. Lett. 2010, 12, 5558.
(12) For palladium-catalyzed acylation reactions using acyl chlorides
as the electrophile, see: (a) Tohda, Y.; Sonogashira, K.; Hagihara, N.
Synthsis 1977, 777. (b) Negishi, E.-i.; Bagheri, V.; Chatterjee, S.; Luo,
F.-T.; Miller, J. A.; Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181.
(c) Renaldo, A. F.; Labadie, J. W.; Stille, J. K. Org. Synth. 1989, 67,
86. (d) Kabalka, G. W.; Malladi, R. R.; Tejedor, D.; Kelley, S. Tetra-
hedron Lett. 2000, 41, 999.
1
2
3
4
5
6
7
8
9
Pd(PPh3)2Cl2/PPh3 K2CO3 DMF
Pd(PPh3)2Cl2/PPh3 K2CO3 DMF
100
100
80
A
A
A
A
A
B
B
B
B
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
NEt3 DMF
NEt3 DMF
NEt3 DMF
NEt3 DMF
NEt3 DMF
NEt3 toluene
NEt3 MeCN
80
2a, 19
2a, 51
2a, 86
2a, 65
2a, 45
2a, 95
80
80
70
70
70
a (A) Reactions were conducted in flask with continuous 10 psi CO
supply. (B) Reactions were conducted in a sealed Schlenk tube with 20
psi CO. b Isolated yields of 0.5 mmol reactions. c 1 equiv of TBAI was
added.
(13) For selected reports on the palladium-catalyzed carbonylative
cyclization/arylation cascade, see: (a) Arcadi, A.; Cacchi, S.; Carnicelli,
V.; Marinelli, F. Tetrahedron 1994, 50, 437. (b) Dai, G.; Larock, R. C.
Org. Lett. 2001, 4, 193. (c) Hu, Y.; Zhang, Y.; Yang, Z.; Fathi, R. J. Org.
Chem. 2002, 67, 2365. (d) Dai, D.; Larock, R. C. Org. Lett. 2002, 4, 193.
(14) See the Supporting Information for details.
With the optimized conditions in hand, the scope of
reaction was examined. It was found that a series of
iodoarenes bearing different substituents at various
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Reaction Scope of Carbonylative Cyclization
a Conditions: Pd(OAc)2 (5 mol %), PPh3 (10 mol %), ArꢀI (1.5 equiv), triethylamine (2 equiv), MeCN (0.2 M), 70 °C, CO 20 psi in a sealed Schlenk
tube, 12 h. b Isolated yields of 0.5 mmol reactions.
positions smoothly underwent this carbonylative cycliza-
tion with 1a, yielding indolizines 2a to 2i in moderate to
excellent yields (Table 2, entries 1ꢀ9). The cyclization of
3-n-hexyl-, n-butyl-, and cyclohexenyl-substituted pivalo-
ates also provided the expected products in good yield
(entries 10ꢀ15). Substrates possessing a functionalized
pyridine ring at C-5 produced indolizines 2p and 2q and
pyrrolo[1,2-a]quinoline 2r in moderate to good yields
(entries 16ꢀ18). On the contrary, cyclization of 3-methyl-
substituted pyridine provided 8-methyl 2s in a relative low
yield (entry 19). In addition to various pivaloates, a
TBDMS ether was equally effective in this reaction, yield-
ing 2t in 80% yield (entry 20). More interestingly, the
cyclization of 1-(1-pyridin-2-ylpropargyl)morpholine
resulted in the 1-morpholin-1-ylindolizine 2u in 71%
yield, which provided a convenient access to the C-2
substituted 1-aminoindolizines.15
Presumably, this palladium-catalyzed carbonylative
cyclization starts with the formation of the aroylpalla-
dium species 3 (Scheme 2) via a migratory insertion of
CO into the arylꢀpalladium bond, followed by its
coordination of the triple bond of 1 to the palladium
center. The 5-endo-dig cyclization leads to the forma-
tion of indolizinium intermediate 4, which after a
proton lossꢀaromatization sequence produces hetero-
aryl palladium species 5. The reductive elimination of 5
releases the product 2-benzoylindolizine 2 to regener-
ate the Pd catalyst.
In summary, a Pd-catalyzed carbonylative cyclization/
arylation approach to 2-aroylindolizines has been devel-
oped. Thisnewmethodallowsfor theefficient and selective
synthesis of important5 2-aroylindolizines from readily
(15) For synthesis of 2-nonsubstituted 1-aminoindolizine via the A3
coupling reaction, see: (a) Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323.
(b) Bai, Y.; Zeng, J.; Ma, J.; Gorityala, B. K.; Liu, X.-W. J. Comb. Chem.
2010, 12, 696.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Proposed Mechanism
available propargylpyridines and iodoarenes under a car-
bon monoxide atmosphere.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. The support of the National Insti-
tutes of Health (GM-64444 and 1P50 GM-086145) is
gratefully acknowledged.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX