General and direct synthesis of 3-aminoindolizines and their analogues via Pd/Cu-catalyzed sequential cross-coupling/cycloisomerization reactions

Article abstract of DOI:10.1021/ol062766v

An efficient and one-step synthesis of 3-aminoindolizines or benz[e]indolizines from the reactions of propargyl amines or amides with heteroaryl bromides was developed. This methodology is realized by a tandem reaction using Pd/Cu catalysts, which could c

Full text of DOI:10.1021/ol062766v

ORGANIC
LETTERS
2007
Vol. 9, No. 3
409-412
General and Direct Synthesis of
3-Aminoindolizines and Their Analogues
via Pd/Cu-Catalyzed Sequential
Cross-Coupling/Cycloisomerization
Reactions
Yuanhong Liu,* Zhiquan Song, and Bin Yan
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032,
People’s Republic of China
yhliu@mail.sioc.ac.cn
Received November 14, 2006
ABSTRACT
An efficient and one-step synthesis of 3-aminoindolizines or benz[e]indolizines from the reactions of propargyl amines or amides with heteroaryl
bromides was developed. This methodology is realized by a tandem reaction using Pd/Cu catalysts, which could catalyze coupling and
cycloisomerization reactions in the same vessel.
Indolizines, which exhibit intriguing molecular structures
featured by an N-bridgehead bicyclic ring system fused with
both a π-excessive pyrrole and a π-deficient pyridine, have
received much attention in recent years.1 Many of the
synthetic and natural indolizines have displayed important
biological activities which can find a variety of applications
in pharmaceutical use.2 For example, they have been
employed as antibacterial, antiviral, antiinflammatory,3a,b and
cardiovascular agents,3c as testosterone 3R-reductase inhibi-
tors,3d as 5-HT4 receptor antagonists,3e and as CNS depres-
sion agents.3f As a consequence, there is a growing interest
in the synthesis of indolizine derivatives. The synthetic
approaches for indolizines4-12 mainly include: reactions of
2-alkylpyridine with acid anhydrides (Scholtz reaction)5 or
R-halo ketones (Tschitschibabin reaction);6 1,3-dipolar cy-
cloadditions of pyridinium and related heteroaromatic ylides
(3) (a) Nash, R. J.; Fellows, L. E.; Dring, J. V.; Striton, C. H.; Carter,
D.; Hegarty, M. P.; Bell, E. A. Phytochemistry 1988, 27, 1403. (b)
Molyneux, R. J.; James, L. F. Science 1982, 216, 190. (c) Gubin, J.;
Descamps, M.; Chatelain, P.; Nisato, D. Eur. Pat. Appl. EP 235111, 1987;
Chem. Abstr. 1988, 109, 6405b. (d) Okada, S.; Sawada, K.; Kuroda, A.;
Watanabe, S.; Tanaka, H. Eur. Pat. Appl. EP 519353, 1992; Chem. Abstr.
1993, 118, 212886y. (e) King, F. D.; Gaster, L. M.; Joiner, G. F. PCT Int.
Appl. WO 9308187, 1993; Chem. Abstr. 1993, 119, 160281. (f) Harrell,
W. B. J. Pharm. Sci. 1970, 59, 275.
(4) For reviews, see: (a) Uchida, T.; Matsumoto, K. Synthesis 1976,
209. (b) Behnisch, A.; Behnisch, P.; Eggenweiler, M.; Wallenhorst, T.
Indolizine. In Houben-Weyl; Thieme: Stuttgart, 1994; Vol. E6b/1, 2a, pp
323-450.
(5) (a) Scholtz, M. Ber. Dtsch. Chem. Ges. 1912, 45, 734. (b) Boekel-
heide, V.; Windgassen, R. J., Jr. J. Am. Chem. Soc. 1959, 81, 1456.
(6) (a) Tschitschibabin, A. E. Ber. Dtsch. Chem. Ges. 1927, 60, 1607.
(b) Hurst, J.; Melton, T.; Wibberley, D. G. J. Chem. Soc. 1965, 2948. For
a one-pot reaction, see: (c) Bora, U.; Saikia, A.; Boruah, R. C. Org. Lett.
2003, 5, 435.
(1) For reviews, see: (a) The Structure, Reactions, Synthesis, and Uses
of Heterocyclic Compounds. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vols.
1-8. (b) Flitsch, W. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, UK, 1996;
Vol. 8, p 237.
(2) For recent reviews, see: (a) Micheal, J. P. Alkaloids 2001, 55, 91.
(b) Micheal, J. P. Nat. Prod. Rep. 2002, 19, 742.
10.1021/ol062766v CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/12/2007

with electron-deficient alkynes or alkenes;7 1,5-dipolar
cyclizations of N-allylpyridinium salts;8 reactions of 2-halo-
pyridinium salts with â-dicarbonyl compounds;9 iron-
catalyzed carbocyclization of N-substituted pyrrolotrienes;10
and cyclization of the silicon-capped (Z)-2-pyridine vinyl-
acetylene with basic alcohol solutions.11 However, these
strategies have some limitations, more or less, such as being
restricted to specific substituted substrates or involvement
of multistage synthesis. Recently, Gevorgyan et al. reported
an efficient synthesis of 3-indolizines12 via CuX-mediated
cycloisomerization of alkynyl pyridines. In this reaction, a
high catalyst loading (0.5-1 equiv) and high reaction
temperature (130-150 °C) were required, and only 3-alkyl-
substituted indolizines were constructed according to the
report.12 Nevertheless, a general synthetic method for func-
tionalized indolizines such as 3-aminoindolizines has not
been established.13 In our ongoing efforts to investigate the
coordination behavior of (2-pyridyl)alkynes with early transi-
tion metals, we have developed a zirconium-mediated
cyclodimerization of these heteroaryl-substituted alkynes.14
Within this program, pyridyl alkynes tethered with an amino
group were needed as substrates.14b When we applied
Sonogashira coupling15 of the corresponding heteroaryl
bromides with propargylic amines to form the requisite N-(2-
alkynyl)amines, we noted that, in some cases, a small amount
of byproduct with strong fluorescence was always formed
during the reaction. The byproduct was identified as 3-ami-
noindolizines. For example, the reaction of 2-bromopyridine
1a with N,N-diphenyl(prop-2-ynyl)amine 2a in Et2NH using
1 mol % of PdCl2(PPh3)2 and 2 mol % of CuI as catalysts
afforded the (2-pyridyl)alkyne 3a in 89% yield along with
2% of indolizine 4a (see Table 1, entry 1). Inspired by the
results outlined above, we became interested in developing
a direct route to indolizines from readily available precursors
of heteroaryl bromides and propargyl amines via a domino
process because a domino or cascade reaction would greatly
enhance the efficiency of the synthesis and minimize the
Table 1. Optimization Studies for the Pd/Cu-Catalyzed
Coupling/Cycloisomerization Reactions
yield yield
(%) (%)
of 3ab of 4ab
Pd
temp/
time
entry cat.a
CuX
base
solvent
1
2
3
4
5
6
7
8
9
1% 2% CuI
2% 30% CuCl Et2NHd
2% 10% CuI 1.5 K2CO3 DMA
-
Et2NH 50 °C, 12 h
89c
31
88
3
2
7
2c
8
4
DMA
50 °C, 16 h
50 °C, 12 h
50 °C, 12 h
50 °C, 12 h
50 °C, 12 h
50 °C, 12 h
50 °C, 12 h
80 °C, 2 h
2% 10% CuCl 4.0 DBU
2% 10% CuCl 2.0 DBU
1% 4% CuCl 4.0 DBU
DMA
DMA
DMA
DMA
THF
89
61
76
92
18
96
85
9
2% 10% CuI
2% 10% CuI
2% 10% CuI
2% 10% CuI
2% 10% CuI
4.0 DBU
4.0 DBU
3.0 DBU
3.0 DBU
7
70
<1
7
DMA
10
11
toluene 80 °C, 20 h
DMA
3.0
piperidine
80 °C, 20 h
76
12
13
14
15
16
2% 10% CuI
2% 10% CuI
2% 10% CuI
2%f 10% CuI
1% 10% CuI
3.0 Cs2CO3 DMA
80 °C, 9 h
80 °C, 2 h
80 °C, 18 h
80 °C, 2 h
80 °C, 4 h
<1
<1
86
5
75
96
7
91
96
3.0 DBU
DMA
DMA
DMA
DMA
e
NEt3
3.0 DBU
3.0 DBU
<1
a Unless otherwise noted, all the Pd catalysts were PdCl2(PPh3)2. bUnless
otherwise noted, all the yields were GC yields. cIsolated yields. dEt2NH
e
was used as cosolvent, and the ratio of Et2NH/DMA was 4:1. Et3N was
f
used as cosolvent, and the ratio of Et3N/DMA was 1:7. Pd(PPh3)4 was
used as a catalyst.
amount of the required reagents.16 Herein, we report a one-
step synthetic route to 3-substituted indolizines, in which a
Pd/Cu catalyst was utilized as a single-pot catalyst to catalyze
independent reactions in the same reaction vessel, and there
is no need to isolate the intermediate of pyridyl alkynes. The
yields of this process range from 41% to 96%, and the
procedure readily accommodates considerable functionalities.
The above-mentioned reaction of 2-bromopyridine 1a and
propargyl amine 2a was chosen for optimization of the
coupling/cycloisomerization process. The representative re-
sults are shown in Table 1. We first examined the reaction
using 2 mol % of PdCl2(PPh3)2 and 30 mol % of CuCl in
Et2NH-DMA; however, the yield of the coupling product
3a was decreased to 31%, and the desired indolizine 4a was
formed in 8% yield after stirring at 50 °C for 16 h (Table 1,
entry 2). Switching the base to a carbonate base such as K2-
CO3 only increased the yield of 3a to 88% (Table 1, entry
3). After many efforts, we were delighted to find that
cyclization proceeded smoothly and provided a 89% GC
yield of the indolizine 4a in DMA at 50 °C for 12 h with 4
equiv of DBU as a base (Table 1, entry 4). The structure of
4a was unambiguously confirmed by X-ray crystallographic
analysis, which clearly showed N-bridgehead heterocycles.17
Decreasing the amount of DBU to 2 equiv resulted in a lower
yield of 4a (61%, Table 1, entry 5). When the reaction was
carried out in THF (Table 1, entry 8), the coupling product
of 3a was formed in 70% yield, whereas only 18% of 4a
was produced. Interestingly, the reaction time was dramati-
(7) (a) Miki, Y.; Hachiken, H.; Takemura, S.; Ikeda, M. Heterocycles
1994, 22, 701. (b) Poissonnet, G.; Theret-Bettiol, M.-H.; Dodd, R. H. J.
Org. Chem. 1996, 61, 2273. (c) Katritzky, A. R.; Qiu, G.; Yang, B.; He,
H.-Y. J. Org. Chem. 1999, 64, 7618. (d) Fang, X.; Wu, Y. M.; Deng, J.;
Wang, S. W. Tetrahedron 2004, 60, 5487.
(8) (a) Sasaki, T.; Kanematsu, K.; Kakehi, A.; Ito, G. Tetrahedron 1972,
28, 4947. (b) Pohjala, E. Tetrahedron Lett. 1972, 13, 2585.
(9) Nugent, R. A.; Murphy, M. J. Org. Chem. 1987, 52, 2206.
(10) Takacs, J. M.; Weidner, J. J.; Takacs, B. E. Tetrahedron Lett. 1993,
34, 6219.
(11) Kaloko, J., Jr.; Hayford, A. Org. Lett. 2005, 7, 4305.
(12) (a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem.
Soc. 2001, 123, 2074. (b) Kim, J. T.; Gevorgyan, V. Org. Lett. 2002, 4,
4697. (c) Kim, J. T.; Butt, J.; Gevorgyan, V. J. Org. Chem. 2004, 69, 5638.
(d) Kim, J. T.; Gevorgyan, V. J. Org. Chem. 2005, 70, 2054.
(13) A one-pot procedure for the synthesis of 3-(dialkylamino)indolizines
has been reported by the Pd-catalyzed reaction of 2-bromopyridine,
propargyl alcohol, and secondary amine; however, the reaction usually
afforded low yields of the products (<49%). See: (a) Ohsawa, A.; Abe,
Y.; Igeta, H. Bull. Chem. Soc. Jpn. 1980, 53, 3273. For the use of
3-aminoindolizines in the treatment of cancer, see: (b) Koya, K.; Sun, L.;
Ono, M.; Ying, W.; Li, H. PCT Int. Appl. WO 03022846, 2003.
(14) (a) Liu, Y.; Liu, M.; Song, Z. J. Am. Chem. Soc. 2005, 127, 3662.
(b) Song, Z.; Li, Y.; Liu, M.; Cong, L.; Liu, Y. Organometallics 2006, 25,
5035.
(15) (a) Lautens, M.; Yoshida, M. J. Org. Chem. 2003, 68, 762. (b) Van
den Hoven, B. G.; Alper, H. J. Am. Chem. Soc. 2001, 123, 1017. (c) Roesch,
K. R.; Larock, R. C. J. Org. Chem. 2001, 66, 412.
(16) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(b) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(17) See Supporting Information.
410
Org. Lett., Vol. 9, No. 3, 2007

cally reduced to 2 h by increasing the reaction temperature
to 80 °C. In this case, only a trace amount of 3a was observed
(Table 1, entry 9). The use of mixed solvents of NEt3-DMA
only resulted in the formation of 3a as a major product after
18 h at 80 °C (Table 1, entry 14). Pd(PPh3)4 also served as
a suitable palladium source for this reaction to give 4a in
91% yield (Table 1, entry 15).
On the basis of the above optimization results, we chose
the following reaction conditions: 2 mol % of PdCl2(PPh3)2,
10 mol % of CuI, and 3 equiv of DBU in DMA stirred at 80
°C for an appropriate time. The present method could be
applied successfully to a variety of heteroaryl bromides and
propargyl amines bearing various types of functionalities.
The results are summarized in Table 2. In most cases, the
smoothly and afforded 4c in 88% yield (Table 2, entry 2).
Substitution on the aromatic ring with a methoxy or chloride
group afforded the corresponding indolizines 4d and 4e in
76% and 74% yields, respectively (Table 2, entries 3 and
4). The reaction also proceeded well with alkyne 2e bearing
an allylic group, which was well tolerated during the Pd/
Cu-catalyzed process, affording 4f in 82% yield (Table 2,
entry 5). Introducing dialkyl or dibenzyl groups on the
nitrogen of the amine resulted in a low yield reaction at 80
°C; however, the results improved considerably at 130 °C
to give 3-(dialkylamino)indolizine 4g and 4h in 48 and 66%
yields, respectively (Table 2, entries 6 and 7). The use of
(1-prop-2-ynyl)piperidine 2h afforded 3-(1-piperidyl)indoli-
zine 4i in 46% yield at 130 °C (Table 2, entry 8). When
2-bromopyrimidine was subjected to the reaction, the cor-
responding product 4j was obtained in 47% yield (Table 2,
entry 9). Employing 2-bromoquinoline also proceeded well
to give benz[e]indolizine 4k and 4l in 92% and 93% yields,
respectively (Table 2, entries 10 and 11). These results
indicated that the nature of the substituent on nitrogen had
a strong influence on the cyclization reactions. The reaction
worked well with aryl/methyl, aryl/allyl, or diaryl-substituted
propargyl amines, giving generally good yields of the
corresponding products. Conversely, the dialkyl substitutions
on nitrogen gave lower chemical yields and a higher reaction
temperature of 130 °C was needed. This might be because
the initial propargyl-allenyl isomerization required for cyclo-
isomerization in the coupling intermediate of alkynyl
pyridines12a became more difficult.
Table 2. One-Step Synthesis of 3-Aminoindolizines from the
Reaction of Heteroaryl Bromides With Propargyl Amines
Propargyl amides possess acidic propargylic hydrogens
that allow facile base-induced isomerization to an allenic
intermediate,18 thus it was expected to be also a good
substrate for indolizine formation. We next investigated Pd/
Cu-catalyzed reactions of 2-bromopyridine with various
propargyl amides (Table 3, entries 1-4). As we expected,
all the reactions proceeded very well to afford the corre-
sponding indolizines in 63-83% yields within 1.5-6 h at
80 °C. A heterocyclic group could be easily introduced to
the product by employing an R-thienyl-substituted N-
propargylamide 2k (Table 3, entry 3). The reaction with a
cyclic amide such as (1-prop-2-ynyl)azepan-2-one 2l afforded
5d in 79% yield (Table 3, entry 4). The N-Boc-protected
propargylic amides 2m-o cyclized smoothly to generate the
corresponding compounds 5e-g in 72-80% yields (Table
3, entries 5-7). The reaction has also been accomplished
starting from an alkyne tethered with a heterocycle group
such as the carbazolyl group, furnishing 5h in 59% yield
(Table 3, entry 8).
Di- or triarylamines are important in the fields of both
chemistry and material science. They have been used as
oxidative catalysts in electronic chemistry,19a hole-transport
materials in OLEDs,19b organic electrooptic materials,19c and
organic ferromagnets,19d etc.19 The above methodology
provided a new class of indolizine-incorporated di- or
triarylamines which may find potential utilities in these areas.
a Isolated yields. All the reactions were carried out using 2 mol % of
PdCl2(PPh3)2, 10 mol % of CuI, and 3 equiv of DBU in DMA.
intermediates of the coupling product 3 were completely
consumed, and the corresponding 3-aminoindolizines were
formed in 46-93% yields. 5-Methylpyridyl-substituted
substrate afforded the corresponding indolizine 4b in 83%
yield (Table 2, entry 1). Alkyne 2a, with a phenyl and a
methyl group on the nitrogen, underwent coupling/cyclization
(18) (a) Nilsson, B. M.; Hacksell, U. J. Heterocycl. Chem. 1989, 26,
269. (b) Nilsson, B. M.; Vargas, H. M.; Ringdahl, B.; Hacksell, U. J. Med.
Chem. 1992, 35, 285.
Org. Lett., Vol. 9, No. 3, 2007
411

Scheme 1
Table 3. One-Step Synthesis of 3-Indolizines from
2-Bromopyridines with Various Alkynes
conditions12a for the synthesis of 3-alkylindolizines (50 mol
% of CuCl in Et3N/DMA ) 1:7, 130 °C for 7 h), only 16%
of 4a was formed, along with several undefined products.
These results indicated that only CuI is effective for the
second step of cycloisomerization, and the use of DBU as a
base is superior to other bases. DBU may facilitate a
propargyl-allenyl isomerization to an allenic intermediate
or serve as a good ligand to stabilize the copper intermedi-
ates.
Scheme 2
a Isolated yields. All the reactions were carried out using 2 mol % of
PdCl2(PPh3)2, 10 mol % of CuI, and 3 equiv of DBU in DMA.
In summary, we have developed a Pd/Cu-catalyzed
coupling/cycloisomerization of propargyl amines or amides
with various haloheteroaromatic substrates under mild reac-
tion conditions, which provided an efficient and one-step
route to 3-aminoindolizines or benz[e]indolizines with a wide
range of substituents. These compounds are potentially useful
in pharmaceutical and material science. This work also
represents a valuable complement relative to existing pro-
cedures for the synthesis of 3-indolizines. Further studies to
extend the scope of synthetic utility for this Pd/Cu-catalyzed
cascade reaction are in progress in our laboratory.
Interestingly, a triarylamine with two indolizine units could
be constructed by this one-step procedure. For example, the
reaction of N,N-dipropargyl arylamine 6 with excess amounts
of 2-bromopyridine (3 equiv) employing 4 mol % of PdCl2-
(PPh3)2, 2 equiv of CuCl, and 8 equiv of DBU gave the
triarylamines 7a-c in 41-43% yields (Scheme 1). Addition-
ally, clean formation of a phenyl-bridged diaryl amine 9 was
achieved in 72% yield by using 1,4-diaminobenzene 8 as
substrate (Scheme 1).
To elucidate the reaction mechanism, we investigated the
indolizine formation from the coupling product of N-(2-
alkynyl)amine 3a (Scheme 2). The cycloisomerization oc-
curred efficiently with a CuI/DBU/DMA system without
using a palladium catalyst. However, under literature
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (Grant No. 20402019, 20121202,
20423001), Chinese Academy of Science, for financial
support.
Supporting Information Available: Experimental details
and spectroscopic characterization of all new compounds and
CIF file giving crystallographic data of 4a. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) (a) Wain, A. J.; Streeter, I.; Thompson, M.; Fietkau, N.; Drouin,
L.; Fairbanks, A. J.; Compton, R. G. J. Phys. Chem. B 2006, 110, 2681.
(b) Loy, D. E.; Koene, B. E.; Thompson, M. E. AdV. Funct. Mater. 2002,
12, 245. (c) Spraul, B. K.; Suresh, S.; Sassa, T.; Herranz, M. AÄ .; Echegoyen,
L.; Wada, T.; Perahia, D.; Smith, D. W., Jr. Tetrahedron Lett. 2004, 45,
3253. (d) Wienk, M. M.; Janssen, R. A. J. J. Am. Chem. Soc. 1997, 119,
4492.
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