Plladium-catalyzed arylation and heteroarylation of indolizines

Article abstract of DOI:10.1021/ol049866q

A highly effective protocol for palladium-catalyzed selective arylation and heteroarylation of indolizines at C-3 has been developed. Mechanistic studies unambiguously support an electrophilic substitution pathway for this transformation.

Full text of DOI:10.1021/ol049866q

ORGANIC
LETTERS
2004
Vol. 6, No. 7
1159-1162
Palladium-Catalyzed Arylation and
Heteroarylation of Indolizines
Choul-Hong Park, Victoria Ryabova, Ilya V. Seregin, Anna W. Sromek, and
Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago,
845 W. Taylor St., Chicago, Illinois 60607-7061
Vlad@uic.edu
Received January 22, 2004
ABSTRACT
A highly effective protocol for palladium-catalyzed selective arylation and heteroarylation of indolizines at C-3 has been developed. Mechanistic
studies unambiguously support an electrophilic substitution pathway for this transformation.
Indolizines substituted at C-3 are very attractive heterocyclic
units, as a number of representatives of this class1 and,
especially their partially or completely reduced analogues,
indolizidine alkaloids2 and related unnatural compounds,3
exhibit important biological properties. As a part of our
program on developing efficient methods toward differently
substituted indolizines, we were particularly interested in
elaborating efficient approaches toward C-3-arylated indoliz-
ines. To date, no general convenient methods for synthesis
of C-3-arylated indolizines exist.4 Scattered reports on
synthesis of C-3-arylated indolizines via various modes of
Chichibabin-type cyclocondensation5 are limited to particular
substitution patterns6 and generally provide low to moderate
yields of the products.7 Other methods such as dipolar
cycloaddition of pyridinium ylides with alkynes,8 cyclopro-
penones,9 or cyclopropenes10 are limited to use of symmetric
substrates, producing indolizines with two identical substit-
uents at the pyrrole ring. Finally, synthesis of indolizines
via cycloisomerization of alkynyl pyridines,11,12 a method
recently developed within our group, potentially can give
access to 3-arylindolizines; however, it would require
employment of rather expensive 3-aryl-1-propynes and, in
this case, is unlikely to be considered as synthetically useful.
Thus, we decided to explore the possibility of direct, last-
stage methods of arylation of the indolizine core. Although
analogous reactions on various heterocyclic systems such as
furans,13 thiophenes,13a,14 pyrroles,15 and indoles16 have long
(7) See, for example: Zhou, J.; Hu, Y. F.; Hu, H. W. Synthesis 1999,
166.
(8) See, for example: Katritzky, A. R.; Qui, G.; Yang, B.; He, H.-Y. J.
Org. Chem. 1999, 64, 7618.
(1) For recent examples, see: (a) Sawada, K.; Okada, S.; Kuroda, A.;
Watanabe, S.; Sawada, Y.; Tanaka, H. Chem. Pharm. Bull. 2001, 49, 799.
(b) Ostby, O. B.; Dalhus, B.; Gundersen, L.-L.; Rise, F.; Bast, A.; Haenen,
G. R. M. M. Eur. J. Org. Chem. 2000, 22, 3763.
(2) For recent reviews, see: (a) Michael, J. P. Alkaloids 2001, 55, 91.
(b) Michael, J. P. Nat. Prod. Rep. 2002, 19, 742.
(9) See, for example: (a) Wadsworth, D. H.; Bender, S. L.; Smith, D.
L.; Luss, H. R.; Weidner, C. H. J. Org. Chem. 1986, 51, 4639. (b)
Gundersen, L.-L.; Malterud, K. E.; Negussie, A. H.; Rise, F.; Teklu, S.;
Ostby, O. B. Bioorg. Med. Chem. 2003, 11, 5409.
(10) See, for example: Matsumoto, K.; Uchida, K. J. Chem. Soc., Perkin
Trans. 1 1981, 73.
(3) See, for example: (a) Halab, L.; Becker, J. A. J.; Darula, Z.; Tourwe,
D.; Kieffer, B. L.; Simonin, F.; Lubell, W. D. J. Med. Chem. 2002, 45,
5353. (b) Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 5546.
(4) For a review on syntheses and properties of indolizines, see:
Behnisch, A.; Behnisch, P.; Eggenweiler, M.; Wallenhorst, T. Indolizine.
In Houben-Weyl; 1994; Vol. E6b/1, 2a, pp 323-450.
(11) Kel’in, A. V.; Sromek, A. W.; and Gevorgyan, V. J. Am. Chem.
Soc. 2001, 123, 2074.
(12) Kim, J. T.; Gevorgyan, V. Org. Lett. 2002, 4, 4697.
(13) (a) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko,
M. Org. Lett. 2003, 5, 301. (b) McClure, M. S.; Glover, B.; McSorley, E.;
Millar, A.; Osterhout, M.; Roschangar, F. Org. Lett. 2001, 3, 1677.
(14) (a) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
Soc. 2002, 124, 5286. (b) Lavenot, L.; Gozzi, C.; Ilg, K.; Orlova, I.; Pealva,
V.; Lemaire, M. J. Organomet. Chem. 1998, 567, 49. (c) Gozzi, C.; Lavenot,
L.; Ilg, K.; Penalva, V.; Lemaire, M. Tetrahedron Lett. 1997, 38, 8867.
(15) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274.
(5) For original papers, see: (a) Chichibabin, A. E. Chem. Ber. 1927,
60B, 1607. (b) Chichibabin, A. E.; Stepanov, F. N. Chem. Ber. 1929, 62B,
1068.
(6) See, for example: Katritzky, A. R.; Caster, K. C.; Rubio, O.; Schwarz,
O. J. Heterocycl. Chem. 1986, 23, 1315.
10.1021/ol049866q CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/28/2004

Table 1. Arylation and Heteroarylation of Indolizines
Table 2. Relative Rates of Pd-Catalyzed Arylation and
Electrophilic Acylation of Selected Indolizines
relative rates
R1
method Aa
method Bb
H
Me
CO2Et
(e)
(d )
(a )
1.00
0.97
0.66
1.00
0.67
0.33
a Performed with 5% PdCl2(PPh3)2, 2 ) 0.75 equiv of p-NO2C6H4Br,
KOAc, H2O in NMP, 100 °C. b Performed with 1 equiv of AlCl3, 2 ) 0.75
equiv of AcCl, CH2Cl2, -78 °C.
been known, no reports on arylations involving indolizines
have been reported to date.17 Herein we report efficient
palladium-catalyzed arylation and heteroarylation of indoliz-
ines, which allows for selective incorporation of aromatic
or heteroaromatic substituent at the C-3 position of this
heterocycle.
Initial experiments revealed that indolizine 1a indeed
underwent arylation in the presence of different palladium
sources in DMSO; however, a 3-fold excess with respect to
arylbromide was required to attain high yields, and the
reaction was rather sluggish, as it took 2 days for completion.
Optimization experiments18 indicated that arylation of in-
dolizines proceeded much faster (1-3 h) in the presence of
catalytic amounts of PdCl2(PPh3)2, KOAc (2 equiv), and H2O
(2 equiv) in NMP at 100 °C. Under these reaction conditions,
a variety of differently substituted indolizines 1 underwent
smooth arylation with an equimolar amount of 2 to afford
C-3-arylated products 3 in good to excellent yields (Table
1). A variety of substituents are tolerated both on the
indolizine and aryl halide. Nitro phenyl bromide 2a reacted
efficiently with all indolizines tested (Table 1, entries 1, 3,
5, 6, and 9). Notably, electron-rich bromoanisole 2c under-
went cross-coupling with both 2-cyanoindolizine 1b and
2-methylindolizine 1d (entries 4 and 8). Most remarkably,
naphthyl bromide 2d and even bromothiophene 2e were able
to undergo cross-coupling with 1e to produce naphthyl- and
hetaryl-substituted indolizines 3ec and 3ed in reasonable
yields (entries 11 and 12).
Naturally, we were interested in elucidating the mechanism
for this arylation reaction. Different mechanisms, depending
on substitution patterns and reaction conditions, have been
proposed for analogous arylations of other heterocycles (vide
infra). We were particularly intrigued by Sharp’s recent report
on the regioselective Heck arylation of 3-ester-substituted
furans and thiophenes (Scheme 1).13a It occurred to us that
(16) (a) Akita, Y.; Itagaki, Y.; Takizawa, S.; Ohta, A. Chem. Pharm.
Bull. 1989, 37, 1477. (b) Itahara, T. Chem. Commun. 1981, 254. (c) Akita,
Y.; Inoue, A.; Yamamoto, K.; Ohta, A. Heterocycles 1985, 23, 2327.
(17) When our project was underway, a report on Pd-catalyzed arylation
of imidazopyrimidines appeared; see: Li, W.; Nelson, D. P.; Jensen, M. S.;
Hoerrner, S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5, 4835.
(18) See Supporting Information for details.
a Yields refer to pure isolated yields. b NMR yield. c Reactions were run
in NMP at 100 °C by using a 0.5 M solution of 1 with the following molar
ratio: 1:2:PdCl2(PPh3)2:H2O: KOAc ) 1:1.2:0.05:2:2.
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Org. Lett., Vol. 6, No. 7, 2004

Scheme 1. Proposed Heck Arylation of Heterocycles13a
Scheme 3. Possible Mechanisms for Pd-Catalyzed Arylation
of Indolizines
arylation of indolizines 1a-c, possessing EWG at C-2, and
thus resembling Sharp’s substrate 4, may potentially proceed
via a similar Heck-type process. Thus, we attempted a
cascade Heck reaction19 of 1f, aiming for spirocyclic
compound 5 (Scheme 2). If successful, this process would
not only bring firm support for the involvement of a Heck-
type mechanism but also allow for straightforward access
to polycyclic, indolizine-containing heteroaromatic com-
pounds. However, trials on this cascade transformation with
allyl ether 1f were unsuccessful, producing a mixture of
arylated indolizines 6 and 7 instead (Scheme 2). We also
Scheme 2. Attempts to Perform Heck Reaction on Indolizines
erocycles, which can be adopted for arylation of indolizines,
are depicted in Scheme 3. In addition to the Heck mechanism
(A)21 discussed above, several other pathways have been
suggested.
C-H activation motif B has been proposed by Miura for
the “coordination-assisted” C-3 arylation of 2-carbamoyl-
substituted thiophenes14a and also by Sames as a possible
route for arylation of unsubstituted indoles.15 To elucidate
possible involvement of C-H activation (path B) in the Pd-
catalyzed arylation of indolizines, a kinetic isotope effect
study was performed (Scheme 4). We subjected deuterium-
labeled 2-carboethoxyindolizine 1a to our arylation condi-
tions. If C-H activation path B is in operation, a substantial
isotope effect would be expected.22
Scheme 4. Isotope Effect Study
attempted to perform a reductive Heck reaction20 on 1a
toward dihydroindolizine derivative 8 (Scheme 2). However,
numerous efforts to perform this transformation under a
variety of reducing conditions failed. We also attempted the
arylation of 6-carboethoxyindolizine 1g, expecting to obtain
the product of the Heck reaction, indolizine 9 (Scheme 2).
To our surprise, however, 1g was selectively arylated at C-3
instead, producing 10 as a single regioisomer.
Experiments revealed, however, no isotope effect (kH/D
1), thus disfavoring possible involvement of pathway B.
Another related mechanism, cross-coupling pathway C,
has been proposed by Miura23 and Sames24 for the copper-
)
Failure to obtain any support for involvement of the Heck-
type protocol in the arylation of indolizines prompted us to
consider alternative mechanistic routes for this reaction.
Different pathways proposed for arylation of various het-
(20) Brase, S.; de Meijere, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; John Wiley and Sons:
New York, 2002; Vol. 1, pp 1405-1430.
(21) For Heck arylation of furans, see: ref 13a. For Heck arylation of
thiophenes, see: refs 13a and 14b,c.
(22) Jones, W. D. Acc. Chem. Res. 2003, 36, 140.
(23) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 467.
(19) Brase, S.; de Meijere, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis, Negishi, E., Ed.; John Wiley and Sons:
New York, 2002; Vol. 1, pp 1369-1404.
(24) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 10580.
Org. Lett., Vol. 6, No. 7, 2004
1161

ring does not qualitatively change the HOMO/LUMO
distribution, which perfectly explains arylation of 1g at the
pyrrole ring to give 10 (Scheme 2).
Finally, to gain further support for electrophilic mechanism
D, we performed kinetic studies. It was expected that
electron-donating substituents at C-2 of indolizine would
accelerate arylation at C-3, whereas electron-withdrawing
groups should suppress the reaction. To test this hypothesis,
competition experiments were run between indolizine (1e),
2-methylindolizine (1d), and 2-carboethoxyindolizine (1a).
The relative rates of Pd-catalyzed arylation (method A) of
1e:1d:1a were found to be: 1.00:0.97:0.66. The EWG-
substituted indolizine 1a underwent the slowest arylation,
as expected; however, 2-methylindolizine 1d was arylated
slightly more slowly than parent indolizine 1e. Potentially,
this could be attributed to the steric bulk of the methyl group.
To get a direct comparison of relative rates of Pd-catalyzed
arylation with traditional Friedel-Crafts-type reactions, we
set up electrophilic acylation of the same substrates with acyl
chloride in the presence of AlCl3 (method B). Experiment
revealed relative rates of C-3 acylation of 1e:1d:1a equal to
1:00:0.67:0.33. Although the values are not identical, the
trend in rates for Friedel-Crafts acylation of indolizines
reflects the trend in rates found for the Pd-catalyzed arylation
reaction. We believe that these kinetic results, in combination
with all experimental and computational data presented
above, strongly support the electrophilic mechanism for the
Pd-catalyzed arylation of indolizines.
Figure 1. HOMO and LUMO Densities of 1e.
assisted C-2 arylation of azoles. Thus, we looked at cross-
coupling (path C) as a possible route for our arylation
reaction. Since it has been reported that arylation of acidic
sites of the heterocycles is promoted by the addition of Cu
salts,23,24 we attempted arylation of 1a in the presence of
CuI. Contrary to our expectations, the presence of CuI greatly
lengthened reaction times and reduced yields, thus disfavor-
ing the involvement of mechanism C.
The fourth possible mechanism (D), electrophilic aromatic
substitution, was initially proposed by Miura23 and since then
has often been considered as the most probable mechanism
for arylation of heterocycles.13a,15,17,25 Accordingly, we drew
our attention to mechanism D. Importantly, the absence of
an isotope effect in the arylation of 1a, mentioned above
(Scheme 4), does not contradict with electrophilic mechanism
D. In this case, C-H cleavage is a fast step,26 and thus no
isotope effect could be expected. Furthermore, it is generally
believed that the pyrrole ring of indolizines is rather electron-
rich, as it easily undergoes electrophilic substitution reac-
tions.4 Our DFT calculations (B3LYP/6-31G*) perfectly
confirmed this point, revealing that the pyrrole ring has an
extended HOMO, whereas the LUMO mostly resides at the
pyridine ring (Figure 1). Thus, it is quite reasonable that Pd-
catalyzed electrophilic arylation selectively occurs at the
electron-rich pyrrole ring. Similar arguments were provided
by Li for the selective arylation of the imidazole ring in
imidazopyrimidines.17 It is noteworthy that our calculations
revealed that introduction of an EWG at C-6 of the pyridine
In conclusion, the direct, efficient, regioselective C-3 aryl-
and heteroarylation of indolizines has been developed. A
variety of substituents on both the indolizine and aryl
bromide are tolerated, providing rapid access to substituted
indolizines in good to very high yields. Electrophilic
substitution has been strongly supported as the mechanism
through a combination of experimental and computational
data.
Acknowledgment. We gratefully acknowledge the fi-
nancial support of the National Institutes of Health (GM-
64444).
Supporting Information Available: Detailed experi-
mental procedures for preparation of and spectroscopic data
for compounds 3aa-ed and 10. This material is available
free of charge via the Internet at http://pubs.acs.org.
(25) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41, 1569.
Erratum: Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41,
2227.
(26) Taylor, R. Electrophilic Aromatic Substitution, John Wiley and
Sons: Chichester, UK, 1990; pp 25-57.
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