Gold-catalyzed multicomponent synthesis of aminoindolizines from aldehydes, amines, and alkynes under solvent-free conditions or in water

Article abstract of DOI:10.1021/ol701886e

A gold(III)-catalyzed multicomponent coupling/cycloisomerization reaction of heteroaryl aldehydes, amines, and alkynes under solvent-free conditions or in water has been developed. This methodology provides rapid access to substituted aminoindolizines wit

Full text of DOI:10.1021/ol701886e

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4323-4326
Gold-Catalyzed Multicomponent
Synthesis of Aminoindolizines from
Aldehydes, Amines, and Alkynes under
Solvent-Free Conditions or in Water
Bin Yan and Yuanhong Liu*
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 August 3, 2007
ABSTRACT
A gold(III)-catalyzed multicomponent coupling/cycloisomerization reaction of heteroaryl aldehydes, amines, and alkynes under solvent-free
conditions or in water has been developed. This methodology provides rapid access to substituted aminoindolizines with high atom economy
and high catalytic efficiency. Especially, the coupling of enantiomerically enriched amino acid derivatives produces the corresponding N-indolizine-
incorporated amino acid derivatives without loss of enantiomeric purity.
One-pot multicomponent coupling reactions (MCRs) have
attracted significant research interest in recent years.1 Espe-
cially, multicomponent reactions with atom economy and
the identification of catalytic procedures that can be run under
solvent-free conditions or in water are ideal protocols for
the development of environmentally friendly and economical
advantageous chemical processes.2 In the past decade,
transition-metal-catalyzed C-N bond-forming reactions have
become important methods for the preparation of nitrogen-
containing heterocycles in both academic and pharmaceutical
research areas.3 Indolizines, which exhibit intriguing mo-
lecular structures featured by an N-bridgehead bicyclic ring
system fused with both a π-excessive pyrrole and a π-de-
ficient pyridine, have received much attention in recent
years.4 Many of the synthetic and natural indolizines have
displayed important biological activities which can find a
variety of applications in pharmaceutical use.5 Among
various synthetic approaches for indolizines, metal-catalyzed
C-N bond-forming methodologies have proved to be
versatile in terms of efficiency and of having a wide scope
(3) For reviews, see (a) Ojima, I. In ComprehensiVe Organometallic
Chemistry III; Mingos, D. M., Crabtree, R. H., Eds.; Elsevier: Amsterdam,
2007; Vol. 10, pp 695-724. (b) Tsuji, J. Palladium Reagents and Catalysis;
John Wiley & Sons: Chichester, 2004. (c) Nakamura, I.; Yamamoto, Y.
Chem. ReV. 2004, 104, 2127. (d) Tsuji, J. Transition Metal Reagents and
Catalyst; John Wiley & Sons Ltd.: New York, 2000.
(4) 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, U.K., 1996;
Vol. 8, p 237.
(1) For reviews, see (a) Posner, G. H. Chem. ReV. 1986, 86, 831. (b)
Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating,
T. A. Acc. Chem. Res. 1996, 29, 123. (c) Bienayme´, H.; Hulme, C.; Oddon,
G.; Schmitt, P.; Chem.sEur. J. 2000, 6, 3321. (d) Multicomponent
Reactions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim, 2005.
(2) For reviews on reactions in water or under solvent-free conditions,
see (a) Li, C. J. Chem. ReV. 1993, 93, 2023. (b) Metzger, J. Angew. Chem.,
Int. Ed. 1998, 37, 2975. (c) Tanaka, K.; Toda, F. Chem. ReV. 2000, 100,
1025. (d) Li, C. J. Chem. ReV. 2005, 105, 3095. (e) Hobbs, H. R.; Thomas,
N. R. Chem. ReV. 2007, 107, 2786.
(5) For recent reviews, see (a) Micheal, J. P. Alkaloids 2001, 55, 91. (b)
Micheal, J. P. Nat. Prod. Rep. 2002, 19, 742.
10.1021/ol701886e CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/14/2007

of application.6 These include CuX-mediated cycloisomer-
ization of alkynyl pyridines,6a-d Au-catalyzed 1,2-migration/
cycloisomerization of propargylic substrates,6e and so forth.
However, there are few reports concerning multicomponent
synthesis of indolizines using transition metals.7 Recently,
we reported a Pd/Cu catalyzed one-pot synthesis of 3-ami-
noindolizines through the cascade coupling/cycloisomeriza-
tion reactions of propargyl amines or amides with heteroaryl
bromides.8a We have also described a Cu-catalyzed cyclo-
isomerization or cyclization/1,2-migration of OAc-substituted
propargylic pyridine or its derivatives to indolizines or
indolizinones.8b During further studies for the construction
of functionalized indolizines, we envisioned that 1-amino-
indolizines 1 might be formed by metal-catalyzed cyclization
of NR1R2-substituted propargylic pyridines, which could be
accessed in situ via three-component coupling of aldehydes,
alkynes, and amines by Mannich-Grignard type reactions
(Figure 1). Recent works by Li9 and others10 have demon-
pure R-amino acid derivatives with aldehydes and alkynes
produces the corresponding indolizines without loss of
enantiomeric purity.
To test the hypothesis, we first examined the coupling
reactions of pyridine-2-carboxaldehyde, piperidine, and phen-
ylacetylene in the presence of various metal catalysts (Table
1). We found that, in the presence of 1 mol % NaAuCl4‚
Table 1. Opitimization Studies for the Metal-Catalyzed
Three-Component Coupling Reactions
yield
entry
catalyst
solvent
temp/time
(%)a,b
1
2
3
4
5
6
7
8
2 mol % NaAuCl4·2H2O
2 mol % NaAuCl4·2H2O
1 mol % NaAuCl4·2H2O
2 mol % AuCl3
H2O
H2O
H2O
H2O
H2O
60 °C, 3 h
rt, 5 days
80
38
85c
86
60 °C, 3 h
60 °C, 3 h
60 °C, 12 h
60 °C, 1.5 h
60 °C, 1.5 h
rt, 72 h
60 °C, 1.5 h
60 °C, 12 h
60 °C, 1.5 h
2 mol % AuCl
20
d
2 mol % NaAuCl4·2H2O
1 mol % NaAuCl4·2H2O
1 mol % NaAuCl4·2H2O
5 mol % CuBr
5 mol % CuBr
10 mol % Cu(OTf)2
-
-
-
93c
95c
86c
d
d
e
9
10
11
H2O
-
7c
-
d
-
e
Figure 1. Multicomponent approach to aminoindolizines.
H2O
a Pyridine-2-carboxaldehyde (1.0 mmol), piperidine (1.1 mmol), and
phenylacetylene (1.5 mmol) were used. b Isolated yields based on aldehyde.
c Phenylacetylene (1.2 mmol) was used. d Solvent-free. e Complicated reac-
tion mixture was observed.
strated that several kinds of metal catalysts could be realized
for this type of coupling reaction. In this paper, we report a
gold-catalyzed one-step synthetic route to 1,3-disubstituted
indolizines under solvent-free conditions or in water, in
which a gold catalyst was utilized as a single-pot catalyst to
catalyze independent reactions in the same reaction vessel,
and there was no need to isolate the intermediate of
propargylic pyridines. Furthermore, the coupling of optically
2H2O, this three-component coupling/cycloisomerization
reaction proceeded smoothly in water to afford the desired
3-phenyl-1-(piperidin-1-yl)indolizine 1a in 85% yield after
11
3 h at 60 °C (Table 1, entry 3). AuCl3 also showed good
catalytic activity in water to afford 86% of 1a (Table 1, entry
4). However, AuCl was found to be less effective and only
20% of 1a was obtained (Table 1, entry 5). Interestingly,
95% of 1a was achieved using 1 mol % NaAuCl4‚2H2O
under solvent-free conditions at 60 °C within 1.5 h (Table
1, entry 7). In addition, the reactions could be performed at
room temperature; however, a longer reaction time was
required and lower product yields were observed (Table 1,
entries 2 and 8). On the other hand, the use of copper
catalysts could not give good results under the current
conditions (Table 1, entries 9-11).
As illustrated in Table 2, this multicomponent process can
be readily diversified through combinations of a range of
heteroaryl aldehydes, amines, and alkynes. With respect to
amines, cyclic amines afforded moderate to excellent yields
of indolizines (Table 2, entries 1-6 and 12). For example,
pyrrolidine and morpholine led to 1,3-disubstituted indoliz-
(6) (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. (e) Seregin, I.
V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128, 12050. (f) Smith, C. R.;
Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9, 1169.
(7) (a) Ohsawa, A.; Abe, Y.; Igeta, H. Bull. Chem. Soc. Jpn. 1980, 53,
3273. (b) For a coupling/1,3-dipolar cycloaddition sequence to indolizines,
see Rotaru, A. V.; Druta, I. D.; Oeser, T.; Mu¨ller, T. J. J. HelV. Chim. Acta
2005, 88, 1798.
(8) (a) Liu, Y. H.; Song, Z. Q.; Yan, B. Org. Lett. 2007, 9, 409. (b)
Yan, B.; Zhou, Y. B.; Zhang, H.; Chen, J. J.; Liu, Y, H. J. Org. Chem.,
published online Aug 25, http://dx.doi.org/10.1021/jo070983j.
(9) (a) Li, C. J.; Wei, C. M. Chem. Commun. 2002, 268. (b) Wei, C.
M.; Li, C. J. J. Am. Chem. Soc. 2002, 124, 5638. (c) Wei, C. M.; Li, C. J.
J. Am. Chem. Soc. 2003, 125, 9584. (d) Wei, C. M.; Li, Z. G.; Li, C. J.
Org. Lett. 2003, 5, 4473. (e) Huang, B. S.; Yao, X. Q.; Li, C. J. AdV. Synth.
Catal. 2006, 348, 1528.
(10) (a) Gommermann, N.; Koradin, C.; Polbom, K.; Knochel, P.; Angew.
Chem., Int. Ed. 2003, 42, 5763. (b) Lo, V. K.; Liu, Y. G.; Wong, M. K.;
Che, C. M. Org. Lett. 2006, 8, 1529. (c) Kantam, M. L.; Prakash, B. V.;
Reddy, C. R. V.; Sreedhar, B. Synlett 2005, 2329. (d) Shi, L.; Tu, Y. Q.;
Wang, M.; Zhang, F. M.; Fan, C. A. Org. Lett. 2004, 6, 1001. (e) Choudary,
B. M.; Sridhar, Ch.; Kantam, M. L.; Sreedhar, B. Tetrahedron Lett. 2004,
45, 7319.
(11) For AuCl3 catalyzed coupling of aldehydes, amines, and alkynes to
propargylamines, see ref 9c.
4324
Org. Lett., Vol. 9, No. 21, 2007

electron-donating groups, displayed high reactivities (Table
2, entries 1 and 2). Alkyl alkynes such as 1-octyne or
functionalized alkyne could also be successfully incorporated
into the indolizine products (Table 2, entries 3 and 4).
Employing 2-quinolinecarboxaldehyde proceeded well to
generate benz[e]indolizine 1l in 74% yield (Table 2, entry
11). The use of piperazine as an amine afforded bridged
indolizine 1m in 52% yield (Table 2, entry 12). We also
investigated the same reactions in water (the results are listed
in parentheses). These reactions revealed that the current
three-component reactions also occurred smoothly in water
at 60 °C; however, in most cases, the yields were lower than
those obtained under solvent-free conditions.
Table 2. Gold-Catalyzed Three-Component Coupling
Reactions to Aminoindolizines
Table 3. Au-Catalyzed Coupling Reactions of
Pyridine-2-Carboxaldehyde, Amino Acid Derivatives, and
Alkyne under Solvent-Free Conditions
a Unless noted, all the reactions were carried out at 60 °C for 1-4 h
using aldehyde (1.0 mmol), amine (1.1 mmol), alkyne (1.2 mmol), and 1
mol % NaAuCl4‚2H2O under solvent-free conditions. b Isolated yields based
on aldehyde. c The results of the same reaction (reaction time and yields)
carried out in water are listed in the parentheses. d 0.55 equiv of piperazine
was used.
a All of the chiral substrates are >99% ee as determined by chiral-column
HPLC. b Unless noted, all the reactions were carried out at 60 °C using
aldehyde (1.0 mmol), amine (1.1 mmol), alkyne (1.2 mmol), and 1 mol %
NaAuCl4‚2H2O. c Isolated yields based on aldehyde. d Determined by chiral-
column HPLC. e 70% of 3a was obtained under the conditions in water for
1.5 h. f 43% of 3d was obtained under the conditions in water for 25 h.
g 1.0 mmol amine was used. h 5 mol % NaAuCl4‚2H2O was used.
ines 1f and 1g in 68% and 96% yields, respectively (Table
2, entries 5 and 6). Diallylamine and dibenzylamine also gave
products 1h and 1i in excellent yields (91% for 1h and 98%
for 1i). However, the yields were low with allylphenylamine
and methylphenylamine (Table 2, entries 9 and 10). It should
be noted that while the current catalyst is quite effective for
some secondary amines, however, the substrates of primary
amines such as PhNH2 could not be used for this reaction.
In this case, only a complicated reaction mixture was
observed. Aryl alkynes, whenever with electron-deficient or
Arylation of complex amines, especially optically pure
amines, has drawn much attention in recent years.12 R-Amino
acids are useful building blocks in organic synthesis, and
Org. Lett., Vol. 9, No. 21, 2007
4325

chiral N-aryl-R-amino acids are common core structures for
a number of synthetically challenging and medicinally
important agents.13 The above methodology may provide a
new class of N-indolizine-incorporated R-amino acid deriva-
tives with high enantiomeric purity, which may find potential
utilities in pharmacological areas. We then applied the Au-
catalyzed protocol to the coupling of amino acid derivatives
with 2-pyridyl aldehyde and alkynes. First, we checked the
reaction of N-benzyl-glycine ethyl ester 2a under solvent-
free conditions. It was found that the desired indolizine 3a
was rapidly formed in 86% yield at 60 °C for 1.5 h (Table
3, entry 1). The use of N-benzyl-L-alanine methyl ester 2b
resulted in the formation of 3b in 85% yield without any
racemization, as determined by chiral-column HPLC analysis
(Table 3, entry 2). The coupling reactions were also tested
with other common amino acid derivatives (Table 3, entries
3-6). In all cases, the products were found to be >99%
enantiometric excess (ee) with a yield range from 52 to 85%.
Thus, we could conclude that the present conditions were
mild enough to avoid the racemization of either the starting
materials or the products. In addition, the functionalities of
esters and thioethers were well tolerated during the reactions.
The reactions could also be performed in water to generate
the corresponding products 3a and 3d in 70% and 43%
yields, respectively, as depicted in Table 3 (footnotes e and
f).
Scheme 1
electrophilicity of the alkyne, and the subsequent nucleophilic
attack of the nitrogen lone pair would produce the cation 5,
which undergoes deprotonation followed by demetalation to
afford indolizines.
In summary, we have developed a Au-catalyzed multi-
component coupling/cycloisomerization reaction of het-
eroaryl aldehydes, amines, and alkynes under solvent-free
conditions or in water. This methodology provides rapid
access to substituted aminoindolizines with high atom
economy and high catalytic efficiency. Especially, the
coupling of enantiomerically enriched amino acid derivatives
produces the corresponding N-indolizine-incorporated amino
acid derivatives without loss of enantiomeric purity. Further
studies to extend the scope and synthetic utility for this Au-
catalyzed cascade reaction and the employment of amino
acid derivatives as amine substrates for the multicomponent
reactions are in progress in our laboratory.
We propose the following mechanism for the formation
of aminoindolizines, which is analogous to Cu-catalyzed
cycloisomerization of OAc-substituted propargylic pyridines
(Scheme 1).8b First, a gold-catalyzed three-component cou-
pling of pyridine-2-carboxaldehyde, amine, and alkyne
occurred to afford NR1R2-substituted propargylic pyridine
4 via a Mannich-Grignard reaction.9c Coordination of the
triple bond in alkyne 4 to the gold catalyst enhances the
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (Grant Nos. 20121202, 20423001,
and 20732058), the Chinese Academy of Science, and the
Major State Basic Research Development Program (Grant
No. 2006CB806105) for financial support.
(12) (a) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 8451. (b) Ma, D. W.; Zhang, Y. D.; Yao, J. C.; Wu, S. H.; Tao,
F. G. J. Am. Chem. Soc. 1998, 120, 12459. (c) Nishiyama, M.; Yamamoto,
M.; Koie, Y. Tetrahedron Lett. 1998, 39, 617. (d) Ma, D. W.; Xia, C. F.
Org. Lett. 2001, 3, 2583.
(13) (a) Sardina, F. J.; Rapoport, H. Chem. ReV. 1996, 96, 1825. (b)
Endo, Y.; Shudo, K.; Furuhata, K.; Ogura, H.; Sakai, S.; Aimi, N.;
Hitotsuyanagi, Y.; Koyama, Y. Chem. Pharm. Bull. 1984, 32, 358. (c) Endo,
Y.; Ohno, M.; Hirano, M.; Itai, A.; Shudo, K. J. Am. Chem. Soc. 1996,
118, 1841. (d) Leeson, P. D.; Carling, R. W.; Smith, J. D.; Baker, R.; Foster,
A. C.; Kemp, J. A. Med. Chem. Res. 1991, 1, 64. (e) Nagata, R.; Ae, N.;
Tanno, N. Bioorg. Med. Chem. Lett. 1995, 5, 1527. (f) Hosokami, T.;
Kuretani, M.; Higashi, K.; Asano, M.; Ohya, K.; Takasugi, N.; Mafune,
E.; Miki, T. Chem. Pharm. Bull. 1992, 40, 2712.
Supporting Information Available: Experimental details
and spectroscopic characterization of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL701886E
4326
Org. Lett., Vol. 9, No. 21, 2007