Two-component approach toward a fully substituted N-fused pyrrole ring

Article abstract of DOI:10.1021/ol1011949

(Figure Presented) An efficient two-component palladium-catalyzed arylation/cyclization cascade approach toward a variety of N-fused pyrroloheterocycles has been developed. This transformation proceeds via the palladium-catalyzed coupling of aryl halides

Full text of DOI:10.1021/ol1011949

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3242-3245
Two-Component Approach Toward a
Fully Substituted N-Fused Pyrrole Ring
Dmitri Chernyak, Cathy Skontos, and Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
Vlad@uic.edu
Received May 24, 2010
ABSTRACT
An efficient two-component palladium-catalyzed arylation/cyclization cascade approach toward a variety of N-fused pyrroloheterocycles has
been developed. This transformation proceeds via the palladium-catalyzed coupling of aryl halides with propargylic esters or ethers followed
by the 5-endo-dig cyclization leading to highly functionalized pyrroloheterocycles in good to excellent yield.
Nitrogen-containing heteroaromatic molecules and their
analogues are pharmaceutically important scaffolds, broadly
Scheme 1
.
Approaches Toward Indolizines with Different
Substitution Patterns
present in naturally occurring and synthetic biologically
active molecules.1 For example, molecules containing in-
dolizine and other closely related cores exhibit a wide array
of biological activities, including cytotoxicity,2 multidrug
resistance (MDR) reversal in some cancer cell lines,3 and
immunomodulation.4
In this regard, transformations that utilize readily available
substrates to provide access to densely substituted pyrrolo-
heterocycles are in high demand.5 Previously, our group
reported silver-catalyzed cycloisomerization of propargyl
heterocycles as a route to 1,3-disubstituted N-fused hetero-
cycles (Scheme 1, eq 1).6 An alternative protocol is based
on the gold-catalyzed migratory cycloisomerization of pro-
(1) (a) Bailly, C. Curr. Med. Chem. Anti-Cancer Agents 2004, 4, 363.
(b) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. ReV. 2008, 108,
264.
(2) (a) Ishibashi, F.; Tanabe, S.; Oda, T.; Iwao, M. J. Nat. Prod. 2002,
65, 500. (b) Liu, R.; Liu, Y.; Zhou, Y.-D.; Nagle, D. G. J. Nat. Prod. 2007,
70, 1741.
pargyl ethers into various types of 1,2-disubstituted N-fused
heterocycles (eq 2).7 Although these methods are general
with respect to the heterocyclic core, these approaches are
limited to the synthesis of 1,3- or 1,2-disubstituted indoliz-
ines, while either the C-2 or C-3 position remains unfunc-
tionalized. This problem was recently mitigated by employ-
ing stoichiometric amounts of iodine,5f-h followed by cross-
(3) (a) Pla, D.; Marchal, A.; Olsen, C. A.; Francesch, A.; Cuevas, C.;
Albericio, F.; Alvarez, M. J. Med. Chem. 2006, 49, 3257. (b) Chittchang,
M.; Batsomboon, P.; Ruchirawat, S.; Ploypradith, P. ChemMedChem 2009,
4, 457.
(4) (a) Facompre, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Perez,
C.; Manzanares, I.; Cuevas, C.; Bailly, C. Cancer Res. 2003, 63, 7392. (b)
Marco, E.; Laine, W.; Tardy, C.; Lansiaux, A.; Iwao, M.; Ishibashi, F.;
Bailly, C.; Gago, F. J. Med. Chem. 2005, 48, 3796.
10.1021/ol1011949  2010 American Chemical Society
Published on Web 06/14/2010

coupling steps. Herein, we report a Pd-catalyzed two-
component arylation/cyclization cascade approach toward
1,2,3-trisubstituted N-fused heterocycles in good to excellent
yields (eq 3).8
Table 1. Optimization of Cascade Approach
We hypothesized that Ar-Pd-X species would undergo
carbopalladation of the propargylic moiety of 1 with
subsequent 5-endo-dig cyclization to produce 2 (eq 3).
entry
X
Pd
base solvent additive yield, %b
To test this idea, the easily accessible propargyl-containing
pyridine 19 was first subjected to the palladium-catalyzed
arylation/cyclization reaction. Employing iodobenzene as the
electrophilic component led to formation of the desired
indolizine 2a in 49% yield (Table 1, entry 1). Attempts to
substitute DMF with other solvents were not particularly
successful (entries 2-4). Utilizing different lithium and
ammonium salts led to a significant improvement in the
reaction yields (entries 5-8). Switching the base from NEt3
to K2CO3 was also beneficial (entry 9).
1
I
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
DMF
DMA
NMP
MeCN
DMF
DMF
DMF
DMF
-
49
46
47
34c
54
57
60
62
69
72
26
2
I
I
I
I
I
I
I
I
I
-
3
-
4
-
5
LiCl
TBAC
TBAB
TBAI
TBAI
TBAId
TBAId
6
7
8
9
K2CO3 DMF
10
11
PdCl2(PPh3)2 K2CO3 DMF
K2CO3 DMF
Br PdCl2(PPh3)2
a Reactions were run in the precence of 5 mol % of catalyst in appropriate
solvent (0.33 M) at 120 °C for 4 h. b GC/MS yields. c Reaction was
performed at 90 °C. d Reaction was run with additional 40 mol % of PPh3.
Table 2. Arylation/Cyclization Cascade Reactions of Propargylic Esters 1a
a All reactions were performed on 0.5 mmol scale in DMF (0.33 M) at 120 °C. b Yield of the isolated product after flash chromatography on silica gel.
Org. Lett., Vol. 12, No. 14, 2010
3243

Scheme 2. Arylation/Cyclization Cascade Reactions of Propargylic Ethers 3
a Reaction was performed under optimized conditions reported in Table 2.
Furthermore, using triphenylphosphine as an additive led
to the formation of 2a in 78% yield (entry 10). Employment
of bromo-benzene under these conditions proved to be less
efficient producing indolizine 2a in 29% yield only (entry
11).
Next, under the optimized conditions, the scope of this
cascade cyclization was examined (Table 2). Thus, acetyloxy
and pivalyloxy-propargylic esters possessing alkyl (entries
1-7), aryl (entries 8 and 9), or alkenyl (entry 10) substituents
at the triple bond underwent smooth conversion to give the
corresponding heterocycles 2a-j in good to excellent yields.
To provide a handle for further functonalization, pivalates
were chosen over acetates due to their greater potential to
participate in Suzuki-Miyaura10 and Kumada5e coupling
reactions.
bromobenzenes performed equally well in this process
(4a-c). Similarly, the cascade cyclization of propargylic
silylether 3 gave the corresponding indolizine 4e in 73%
yield.
Presumably, this palladium-catalyzed arylation/cycliza-
tion reaction proceeds through a coordination of the triple
bond of an alkyne 1 with ArPdX, triggering the 5-endo-
dig cyclization by the nucleophilic attack of the pyridyl
nitrogen, leading to the formation of zwitterionic adduct
5 (Scheme 3). The latter, upon deprotonation/tautomer-
Scheme 3. Proposed Mechanism
The generality of this process was expanded by utiliza-
tion of a variety of functionalized iodobenzenes which
uneventfully cyclized into the corresponding indolizines
2k-p (entries 11-16). Notably, this reaction proceeded
equally efficiently with other heterocyclic cores; quinoline
and isoquinoline propargylic esters were successfully
utilized in this transformation providing access to tricyclic
cores 2q-t in a highly efficient manner (entries 17-20).
It was also found that propargylic phenylethers 3 could
be employed in this transformation (Scheme 2). Interestingly,
(5) (a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc.
2001, 123, 2074. (b) Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong,
R. Org. Lett. 2007, 9, 1169. (c) Hardin, A. R.; Sarpong, R. Org. Lett. 2007,
9, 4547. (d) Yan, B.; Zhou, Y.; Zhang, H.; Chen, J.; Liu, Y. J. Org. Chem.
2007, 72, 7783. (e) Schwier, T.; Sromek, A. W.; Yap, D. M. L.; Chernyak,
D.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 9868. For a catalyst-free
approach toward indolizines, see: (f) Chernyak, D.; Gadamsetty, S. B.;
Gevorgyan, V. Org. Lett. 2008, 10, 2307. (g) Kim, I.; Choi, J.; Won, H. K.;
Lee, G. H. Tetrahedron Lett. 2007, 48, 6863. (h) Kim, I.; Won, H. K.;
Choi, J.; Lee, G. H. Tetrahedron 2007, 63, 12954. (i) Kim, I.; Kim, S. G.;
Kim, J. Y.; Lee, G. H. Tetrahedron Lett. 2007, 48, 8976.
(6) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Org. Lett. 2007, 9,
3433.
ization and subsequent reductive elimination,11 would give
product 2.
In summary, we have developed a practical and efficient
two-component coupling method toward fully substituted
fused pyrroloheterocycles, including indolizines, pyrrolo-
quinolines, and pyrroloisoquinolines. This method is comple-
(7) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128, 12050.
(8) When this manuscript was in preparation, a related report on synthesis
of the indolizinone core appeared: Kim, I.; Kim, K. Org. Lett. 2010, 12,
2500.
(9) See Supporting Informationfor a detailed preparative procedure.
(10) Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008,
130, 14422.
(11) (a) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285. (b) Cacchi,
S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873. (c) Zeni, G.; Larock, R. C.
Chem. ReV. 2006, 106, 4644.
3244
Org. Lett., Vol. 12, No. 14, 2010

mentary to the previously developed approaches6,7,12 toward
mono- and disubstituted N-fused pyrroloheterocycles.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge the finan-
cial support of the National Institutes of Health (GM-64444
and 1P50 GM-086145).
(12) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Tetrahedron 2008,
64, 6876
.
OL1011949
Org. Lett., Vol. 12, No. 14, 2010
3245