Palladium-catalyzed intramolecular carbopalladation/cyclization cascade: Access to polycyclic N-fused heterocycles

Article abstract of DOI:10.1021/ol102447s

An efficient palladium-catalyzed intramolecular carbopalladation/ cyclization cascade toward tetra- and pentacyclic N-fused heterocycles has been developed. This transformation proceeds via the palladium-catalyzed coupling of aryl halides with internal propargylic esters or ethers followed by the 5-endo-dig cyclization leading to polycyclic pyrroloheterocycles in moderate to excellent yields.

Full text of DOI:10.1021/ol102447s

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5558-5560
Palladium-Catalyzed Intramolecular
Carbopalladation/Cyclization Cascade:
Access to Polycyclic N-Fused
Heterocycles
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 9, 2010
ABSTRACT
An efficient palladium-catalyzed intramolecular carbopalladation/cyclization cascade toward tetra- and pentacyclic N-fused heterocycles has
been developed. This transformation proceeds via the palladium-catalyzed coupling of aryl halides with internal propargylic esters or ethers
followed by the 5-endo-dig cyclization leading to polycyclic pyrroloheterocycles in moderate to excellent yields.
Nitrogen-containing heteroaromatic molecules and their
analogues are pharmaceutically significant scaffolds,
widely present in naturally occurring and synthetic
biologically active molecules.1 For example, molecules
containing an indolizine motif, such as Lamellarin D2 and
other closely related cores,3 exhibit a wide array of
biological activities, including human DNA topoisomerase
I inhibition,4 the ability to reverse multidrug resistance,5
and the ability to induce apoptosis through a mitochondria-
mediated pathway toward a broad range of cancer cell
lines.6 These significant biological activities brought
substantial attention to the synthesis of Lamellarins and
their analogues.7,8 Although several routes toward their core
exist, new methods allowing for the efficient construction
of heterocycles, particularly those with modified core and
different substitution patterns, are in high demand. We have
recently reported a two-component coupling methodology
toward fully substituted N-fused heterocycles.9,10 Although
quite general with respect to the heterocyclic core, this
(6) (a) Ballot, C.; Kluza, J.; Lancel, S.; Martoriati, A.; Hassoun, S. M.;
Mortier, L.; Vienne, J. C.; Briand, G.; Formstecher, P.; Bailly, C.; Neviere,
R.; Marchetti, P. Apoptosis 2010, 15, 769. (b) Ballot, C.; Kluza, J.;
Martoriati, A.; Nyman, U.; Formstecher, P.; Joseph, B.; Bailly, C.; Marchetti,
(1) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. ReV. 2008, 108,
264.
P. Mol. Cancer Ther. 2009, 8, 3307
.
(2) Facompre, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Perez, C.;
Manzanares, I.; Cuevas, C.; Bailly, C. Cancer Res. 2003, 63, 7392.
(3) (a) Bailly, C. Curr. Med. Chem. Anti-Cancer Agents 2004, 4, 363.
(b) Pla, D.; Francesch, A.; Calvo, P.; Cuevas, C.; Aligue, R.; Albericio, F.;
Alvarez, M. Bioconjugate Chem. 2009, 20, 1100.
(7) See for example: (a) Ohta, T.; Fukuda, T.; Ishibashi, F.; Iwao, M. J.
Org. Chem. 2009, 74, 8143. (c) Pla, D.; Marchal, A.; Olsen, C. A.; Albericio,
F.; Alvarez, M. J. Org. Chem. 2005, 70, 8231
.
(8) For recent synthetic approches toward novel hybrids, see: (a)
Ploypradith, P.; Petchmanee, T.; Sahakitpichan, P.; Litvinas, N. D.;
Ruchirawat, S. J. Org. Chem. 2006, 71, 9440. (b) Shen, L.; Yang, X.; Yang,
(4) Marco, E.; Laine, W.; Tardy, C.; Lansiaux, A.; Iwao, M.; Ishibashi,
F.; Bailly, C.; Gago, F. J. Med. Chem. 2005, 48, 3796.
(5) (a) Chittchang, M.; Batsomboon, P.; Ruchirawat, S.; Ploypradith,
P. ChemMedChem 2009, 4, 457. (b) Pla, D.; Marchal, A.; Olsen, C. A.;
Francesch, A.; Cuevas, C.; Albericio, F.; Alvarez, M. J. Med. Chem. 2006,
49, 3257.
B.; He, Q.; Hu, Y. Eur. J. Med. Chem. 2010, 45, 11
(9) For silyl ether tether approach in Pd-catalyzed biaryl coupling, see:
.
(a) Huang, C.; Gevorgyan, V. Am. Chem. Soc. 2009, 131, 10844. (b) Huang,
C.; Gevorgyan, V. Org. Lett. 2010, 12, 2442
.
(10) Chernyak, D.; Skontos, C.; Gevorgyan, V. Org. Lett. 2010, 12, 3242
.
10.1021/ol102447s  2010 American Chemical Society
Published on Web 11/08/2010

approach is limited to the synthesis of bicyclic and tricyclic
heteroaromatic molecules only (eq 1). Herein, we report a
novel Pd-catalyzed arylation cyclization cascade that allows
for easy assembly of various tetra- and penta-cyclic isoch-
romanone-annelated and other heterocycles.
Table 2. Carbopalladation/Cyclization Reaction of Propargylic
Esters 1a
We envisioned, that internal Ar-Pd-X species would
undergo carbopalladation of the propargylic moiety of 1 with
subsequent 5-endodig cyclization to produce 2 (Table 1). This
Table 1. Optimization of Reaction Conditionsa
entry
X
Pd
base
solvent yield, %b
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Br
Br
Br
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(MeCN)2 Cs2CO3 NMP
PdCl2(MeCN)2 K3PO4
PdCl2(MeCN)2 K2CO3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cs2CO3 NMP
-
-
traces
-
-
traces
25
32
K3PO4
K2CO3
NMP
NMP
NMP
NMP
Cs2CO3 NMP
K3PO4
K2CO3
DMF
NMP
NMP
72c,d
9
37
10
11c
12
13
Pd(OAc)2 K2CO3
Br
Br
I
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2CO3
K2CO3
K2CO3
NMP
DMA
DMA
68c,d
80c,d
21c,d
a Reactions were run in the presence of 5 mol % of Pd-catalyst in
appropriate solvent (0.5M) at 130 °C for 8 h unless otherwise noted.
b GC/MS yields. c Reactions was performed in appropriate solvent (0.33M)
at 130 °C for 8 h. d Isolated yield.
idea was tested on cyclization of easily available propargyl-
containing pyridine 111 in the presence of PdCl2(PPh3)2
catalyst. However, only trace amounts of desired product 2
were observed (Table 1, entries 1-3). Switching to
PdCl2(MeCN)2 catalyst did not provide any improvement of
reaction outcome (entries 4-6). However, employment of
the ligand-free catalyst Pd(OAc)2 led to considerable en-
hancement of the reaction yields (entries 7-9). Solvent and
concentration screening revealed the optimal conditions
(entry 12).
(11) For transition-metal catalyzed cycloisomerization approaches toward
N-fused pyrroloheterocycles, see: (a) Seregin, I. V.; Gevorgyan, V. J. Am.
Chem. Soc. 2006, 128, 12050. (b) Seregin, I. V.; Schammel, A. W.;
Gevorgyan, V. Org. Lett. 2007, 9, 3433. (c) Smith, C. R.; Bunnelle, E. M.;
Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9, 1169. (d) Hardin, A. R.;
Sarpong, R. Org. Lett. 2007, 9, 4547. (e) Yan, B.; Zhou, Y.; Zhang, H.;
Chen, J.; Liu, Y. J. Org. Chem. 2007, 72, 7783.
a All reactions were performed on 0.15 mmol scale in DMA (0.33 M)
at 100 to 130 °C for time specified in the Supporting Information. b Yield
of the isolated product after flash chromatography on silica gel.
Org. Lett., Vol. 12, No. 23, 2010
5559

With these optimized conditions in hand, the scope of
this cascade cyclization was examined (Table 2). Hence,
benzyloxy-propargylic esters 1, possessing different alkyl
(entries 1-3), alkenyl (entry 4), aryl (entries 5-7)
substituents at the triple bond underwent smooth conver-
sion to give the corresponding polycyclic heterocycles
2a-g in good yields. The generality of this transformation
was further extended by employment of a number of
functionalized benzyloxy-propargylic esters that smoothly
were converted into the corresponding polycyclic N-fused
heterocycles 2 h-k (entries 8-11). Importantly, this
transformation performed with comparable efficiency with
other heterocyclic cores; isoquinoline and quinoline pro-
pargylic ester were effectively transformed to the penta-
cyclic N-fused heterocycles 2l and 2m, respectively
(entries 12, 13).
Table 3. Carbopalladation/Cyclization Reaction of Propargylic
Ethers 3a
Furthermore, we found that propargylic ethers 312 could
also be utilized in this transformation providing access to
another polycyclic scaffold, employing slightly modified
reaction conditions13 (Table 3). Interestingly, this reaction
proved even more general with respect to the functional
group compatibility (Table 3, entries 1-6). Pentacyclic
heterocycle 4g was also efficiently obtained using this
methodology.
Notably, this transformation could also be successfully
performed on the carbocyclic analog, giving access to the
fused indenofuran derivative 4h (entry 8). Propargylic silyl
ethers 3i-m also proved efficient to undergo the carbo-
palladation/cyclization sequence, thus affording access
toward novel silacyclic scaffolds (entries 8-13).9
In summary, we have developed a new synthetic
protocol for rapid and efficient assembly of three distinct
tetra- and pentacyclic cores from easily accessible starting
materials. This cascade carbopalladation/cyclization ap-
proach is complementary to the previously developed
methods10,11,14 toward multisubstituted N-fused hetero-
cycles.
Acknowledgment. We gratefully acknowledge the fi-
nancial support of the National Institutes of Health (GM-
64444).
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.
OL102447S
(12) See Supporting Information for the detailed preparative procedures.
(13) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667.
a All reactions were performed on 0.15 mmol scale in appropriate solvent
(0.33 M) at 120 to 135 °C for time specified in the Supporting Information.
b Isolated yield. c Reaction conditions A: Pd(OAc)2 (5 mol %), K2CO3 (2.0
equiv), n-Bu4NCl (1.0 equiv), DMF, 120 °C. d Reaction conditions B: Pd(OAc)2
(5 mol %), K2CO3 (2.0 equiv), LiCl (1.0 equiv), p-xylene, 135 °C.
(14) (a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem.
Soc. 2001, 123, 2074. (b) Schwier, T.; Sromek, A. W.; Yap, D. M. L.;
Chernyak, D.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 9868. (c)
Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Tetrahedron 2008, 64,
6876. For a catalyst-free approach toward indolizines, see: (d) Chernyak,
D.; Gadamsetty, S. B.; Gevorgyan, V. Org. Lett. 2008, 10, 2307
.
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Org. Lett., Vol. 12, No. 23, 2010