An efficient preparation of indolizines through a tandem palladium-catalyzed cross-coupling reaction and cycloisomerization

Article abstract of DOI:10.1039/c0cc01945c

An efficient synthetic method for producing indolizines through a tandem Pd-catalyzed selective allenyl cross-coupling reaction using organoindium reagents and cycloisomerization was developed in a one-pot process.

Full text of DOI:10.1039/c0cc01945c

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An efficient preparation of indolizines through a tandem
palladium-catalyzed cross-coupling reaction and cycloisomerizationw
Hyunseok Kim,a Kwangmoo Lee,a Sunggak Kim*b and Phil Ho Lee*a
Received 18th June 2010, Accepted 8th July 2010
DOI: 10.1039/c0cc01945c
An efficient synthetic method for producing indolizines through a
tandem Pd-catalyzed selective allenyl cross-coupling reac-
tion using organoindium reagents and cycloisomerization was
developed in a one-pot process.
Since indolizine is an important structural motif frequently
found in natural products and has been used as an essential
skeleton in pharmaceutics, efficient and versatile synthetic
methods for producing indolizine derivatives have been actively
investigated1 and many synthetic strategies for producing
indolizine have been described in the literature:2 Pt-catalyzed
cycloisomerization or a tandem cyclization/1,2-migration of
pyridine propargylic alcohols,2h Au-catalyzed cycloisomeriza-
tion of propargyl alkynyl imines,2i and Cu-catalyzed cyclo-
isomerization of N-containing heterocycles into various types
of N-fused pyrroloheterocycles.2j However, an efficient synthetic
method for producing indolizines has been continuously
needed to overcome difficult introduction of specific substi-
tuents or requirements of multistep synthesis. Furthermore,
many synthetic methods required preorganized pyridine
derivatives possessing functionalized alkynyl or homoalkynyl
groups on the 2-position. Therefore, an alternate method
having various functional group variations on the indolizine
nucleus is highly desirable to study structural and biological
activity. Especially, a direct preparation of indolizines from
pyridine derivatives and nucleophilic coupling partners
through a tandem cross-coupling reaction and cycloisomeriza-
tion in a one-pot process is more challenging.
Scheme 1 Preparation of indolizines through tandem cross-coupling
and cycloisomerization.
in situ from ethyl 4-bromo-2-alkynoates and indium and
cycloisomerization in a one-pot process (Scheme 1).
First, we tried to introduce allenyl groups on the 2-position
of pyridine. When sulfonate ester 1a4 was treated with
organoindium reagent generated in situ from ethyl 4-bromo-
2-pentynoate (2a)5 and indium in the presence of palladium
catalyst, the expected products, 2-(1-ethoxycarbonyl-1-butyn-3-yl)-
pyridine (4) and 2-(1-ethoxycarbonyl-1,2-butadien-1-yl)pyridine
(5), were not detected, whereas 1-ethoxycarbonyl-3-methylin-
dolizine (3a) was surprisingly produced in 37% yield. Evidently,
indolizine 3a was produced via tandem Pd-catalyzed allenyl
cross-coupling reaction and cycloisomerization.
Encouraged by this preliminary result, several experiments
were carried out to optimize reaction conditions (Table 1).
First, the catalytic activity of several palladium complexes and
Table 1 Reaction optimizationa
Previously, we found that organoindium reagents generated
in situ from indium and propargyl bromides can be employed
effectively in Pd-catalyzed cross-coupling reactions, and then
producing regio- and stereoselectively substituted allenes.3 In
the pursuit of an ongoing medicinal chemistry program, we
have been recently interested in introducing a wide range of
substituents on the 1- and 3-positions, especially ethoxycarbonyl
group on 1-position, of indolizines. In this respect, we envisioned
that indolizine might be formed through tandem Pd-catalyzed
cross-coupling reaction and cycloisomerization in a one-pot
process. In this communication, we report the direct formation
of indolizines through tandem Pd-catalyzed allenyl cross-
coupling reaction using organoindium reagents generated
Yield
(%)
Entry
Cat.
Met
t/h
1
2
3
4
5
6
7
8
Pd(dppf)2/(p-CF3-C6H4)3P
Pd2dba3CHCl3/Ph3P
In
In
In
In
In
In
In
In
In
In
In
Mg
Zn
18
18
18
18
18
24
24
20
18
20
1.5
1.5
1.5
0b
37c
23d
40c
36d
57c
70e
45f
40f
54b
75g
0h
Pd2dba3CHCl3/Xantphos
Pd2dba3CHCl3/(2-Furyl)3P
Pd2dba3CHCl3/DPEphos
Pd2dba3CHCl3/(p-CF3-C6H4)3P
Pd2dba3CHCl3/(p-CF3-C6H4)3P
Pd(OAc)2/Ph3P
Pd(OAc)2/(p-CF3-C6H4)3P
Pd(OAc)2/Xantphos
Pd(OAc)2/Xantphos
9
10
11
12
13
a Department of Chemistry and Institute for Molecular Science and
Fusion Technology, Kangwon National University,
Chuncheon 200-701, Republic of Korea.
Pd(OAc)2/Xantphos
Pd(OAc)2/Xantphos
0h
E-mail: phlee@kangwon.ac.kr; Fax: +82 33 253 7582;
Tel: +82 33 250 8493
a
Reactions were carried out with 1a (1 equiv.), 2a (3 equiv.), In
b
(2 equiv.) and NaI (3 equiv.) unless otherwise noted. 4 mol% Pd/8 mol%
b Division of Chemistry and Biological Chemistry, School of Physical
& Mathematical Sciences, Nanyang Technological University,
Singapore 637371
ligand (L). c 2 mol% Pd/16 mol% L. 2 mol% Pd/8 mol% L. 4 mol%
Pd/32 mol% L. f 4 mol% Pd/16 mol% L. g 8 mol% Pd/16 mol% L. 2a
(2 equiv.) and Mg or Zn (2.5 equiv.) were used.
d
e
h
w Electronic supplementary information (ESI) available: Experimental
details and spectra. See DOI: 10.1039/c0cc01945c
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ligands was examined. Among the catalysts examined, combi-
nation of Pd(OAc)2/Xantphos6 showed high catalytic activity,
producing indolizine 3a in 75% yield (entry 11). Other palladium
complexes such as Pd2dba3CHCl3 and Pd(dppf)2 and ligands
such as Ph3P, (2-furyl)3P, DPEphos and (p-CF3–C6H4)3P were
less effective.7 THF was the best solvent among several reac-
tion media examined (THF, DMF, and dioxane). Among the
additives (NaI, NaBr, LiI, LiBr, and LiCl) examined, the use
of sodium iodide is essential for satisfactory results (entry 11).
Although the role of NaI was not completely established at
present, it can be reasoned that addition of NaI facilitates
formation of the organoindium reagent through substitu-
tion. Under the optimum conditions, 1-bromo-2-butyne and
3-bromo-1-phenyl-1-butyne did not produce the corresponding
indolizine,8 indicating that ethoxycarbonyl group might be
essential in cyclization reaction. Moreover, subjecting 1a to 2a
and Mg or Zn in refluxing THF did not give 3a (entries 12
and 13). Ethyl 4-iodo-2-pentynoate was detected in part in
1H NMR upon treatment of 2a with NaI in THF-d8, indicating
that iodide anion substituted bromide in 2a, and then, the
corresponding iodide smoothly reacted with indium to produce
an organoindium reagent.
To demonstrate the efficiency and scope of the present
method, we applied this catalytic system to a range of 2-pyridyl
triflates 1 and ethyl 4-bromo-2-alkynoates 2. The results are
summarized in Table 2. For the 2-pyridyl triflates as electro-
philic coupling partners, various substituents such as methyl,
nitro, and chloro groups on the pyridine ring did not influence
the efficiency of the reactions. Especially, 2-pyridyl triflates
having 4-methyl (entries 9 and 10), 5-methyl (entries 13
and 14), or 6-methyl groups (entries 15 and 16) resulted in
the selective formation of a variety of indolizines in moderate
to good yields. The yields of the cross-coupling products were
slightly decreased for 2-pyridyl triflate 1g possessing nitro
group, indicating that cycloisomerization is less favorable
owing to electron withdrawing group (entries 17 and 18).
Table 2 Tandem Pd-catalyzed cross-coupling reaction and cycloisomerizationa
1
3
Entry
X
2
t/h
Yield (%)
1
2
3
4
5
6
7
8
OTf
OTf
OTf
OTf
I
I
I
I
2a
2b
2c
2d
2a
2b
2c
2d
1.5
2
1.5
4
2.5
1.5
1.5
1.5
3a
3b
3c
3d
3a
3b
3c
3d
75
75
80
81
75
76
81
79
1a
1b
9
OTf
OTf
I
2a
2c
2a
2d
2.5
2
2
3e
3f
3e
3g
78
83
81
70
1c
1d
10
11
12
I
2
13
14
OTf
OTf
2a
2c
3
3h
3i
74
76
1e
1f
1.5
15
16
OTf
OTf
2a
2b
12
4
3j
75
76
3k
17
18
OTf
OTf
2a
2d
14
16
3l
60
57
1g
3m
19
20
21
22
OTf
OTf
I
2a
2b
2a
2b
7
2.5
2
3n
3o
3n
3o
73
81
79
69
1h
1i
I
2
23
24
OTf
OTf
2a
2d
2
2
3p
3q
70
73
1j
a
8 mol% Pd(OAc)2 and 16 mol% Xantphos were used in refluxing THF. NaI (3 equiv.) as an additive was used.
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Exposure of 5-chloro-2-pyridyl triflate (1h) to ethyl 4-bromo-
6-hexynoate (2b) afforded selectively the corresponding
indolizine 3o in 81% yield (entry 20). It was gratifying to
obtain 1,5-dimethyl-3-ethoxycarbonyl pyrrolo[1,2-a]quinoline
3p in 70% yield by the treatment of 1j with 2a and indium
(entry 23). In the case of 2d, the desired 3q were obtained in
73% yield (entry 24). For the ethyl 4-bromo-2-alkynoates as
nucleophilic coupling partners, the presence of various alkyl
substituents such as methyl, ethyl, n-propyl, and phenethyl
groups on propargylic carbon exhibited little effect on either
the reaction rate or product yield. Pd-catalyzed cross-coupling
reaction of 2-pyridyl triflate (1a) with organoindium reagent
generated in situ from 2c and 2d in the presence of indium
produced 3c and 3d in 80% and 81% yields, respectively
(entries 3 and 4).
Finally, nitrogen atom on pyridine derivative 9 would attack
the activated double bond in allene by 5-endo mode, affording
vinylpalladium 10, which subsequently undergoes proton
transfer followed by resonance to provide indolizine 3. Since
our attempts to isolate allenylpyridine 8 were unsuccessful,
cycloisomerization might be occurring thermally. Ethyl 4-bromo-
2-butynoate did not produce 1-ethoxycarbonylindolizine,8
indicating that stability of the intermediate allene 8 might be
very important in cycloisomerization. The elucidation of the
detailed reaction mechanism awaits further studies.
In summary, we developed the direct formation of
indolizines through tandem Pd-catalyzed cross-coupling reac-
tion using organoindium reagents generated in situ from ethyl
4-bromo-2-alkynoate and indium and cycloisomerization in a
one-pot process. This method would pave a new way to
synthetically valuable processes of a wide range of indolizine
derivatives.
Our next interest was given to the direct preparation
of 1-ethoxycarbonyl-3-alkyl indolizine (3) via a tandem
Pd-catalyzed cross-coupling reaction of aryl iodides 1 with
ethyl 4-bromo-alkynoate 2 and cycloisomerization. Treatment
of 2-iodopyridine (1b) with 2a, 2b, 2c, and 2d having methyl,
ethyl, n-propyl, and phenethyl on propargylic carbon provided
the corresponding indolizine in moderate to good yields
(entries 5–8). The present method worked equally well with
2-iodo-4-methylpyridine (1d) and 5-chloro-2-iodopyridine (1i),
leading to selective formation of 1-ethoxycarbonyl indolizines
(entries 11, 12 and 21, 22).
This work was supported by the NRL Program funded by
the National Research Foundation of Korea (NRF) and
by NRF grant funded by the Korea government (MEST)
(2009-0087013). This work was supported by the second phase
of the Brain Korea 21 Program in 2009 and by the Korea
Sanhak Foundation. Dr Sung Hong Kim at the KBSI (Daegu)
is thanked for obtaining the MS data. The NMR data were
obtained from the central instrumental facility in Kangwon
National University.
Although the mechanism of the present reaction has not
been established, a plausible reaction mechanism for a tandem
Pd-catalyzed cross-coupling reaction and cycloisomerization is
shown in Scheme 2. The 2-pyridyl palladium(II) complex 6,
initially formed from 2-pyridyl triflate or 2-iodopyridine
derivatives (1) and Pd(0) catalyst, undergoes transmetallation
with organoindium reagent generated in situ from 2 and
indium followed by reductive elimination, producing 8.
Notes and references
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6 Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
7 dba: dibenzylideneacetone. dppf: 1,10-bis(diphenylphosphino)-
ferrocene. DPEphos: bis(2-diphenylphosphinophenyl)ether.
8 These reactions gave messy TLC. The corresponding allenes were
not obtained.
Scheme 2 Plausible reaction mechanism.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6341–6343 | 6343