Synthesis of Indolizine Derivatives by Pd-Catalyzed Oxidative Carbonylation

Article abstract of DOI:10.1021/acs.orglett.5b02220

An efficient synthesis of indolizine derivatives by palladium-catalyzed oxidative carbonylation of propargylic pyridines has been developed. The reaction can be conducted at room temperature and under 3 bar of CO in the presence of Pd₂(dba)

Full text of DOI:10.1021/acs.orglett.5b02220

Letter
pubs.acs.org/OrgLett
Synthesis of Indolizine Derivatives by Pd-Catalyzed Oxidative
Carbonylation
Tongyu Xu and Howard Alper*
Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie
Curie, Ottawa, Ontario, Canada, K1N 6N5
S
* Supporting Information
ABSTRACT: An efficient synthesis of indolizine derivatives
by palladium-catalyzed oxidative carbonylation of propargylic
pyridines has been developed. The reaction can be conducted
at room temperature and under 3 bar of CO in the presence of
Pd2(dba)3 or Pd/C. The catalyst Pd/C could be easily
removed from the reaction and recycled.
he construction of diverse functionalized N-heterocycles is
are also prepared from 2-pyridyl alkynyl carbinols, catalyzed by
1
Tan important goal in synthetic organic chemistry. For Ru and Ag, or cyclized by heating in a polar protic solvent
(Scheme 1d).4b,7
example, indolizines are found in a number of natural products
and biologically active compounds.2 Among the strategies to
Transition-metal-catalyzed carbonylation has been widely
used to synthesize many valuable compounds, including esters,
amides, aldehydes, ketones, alcohols, etc.9 In recent years,
oxidative carbonylation has attracted considerable atten-
tion.10,11 Pd-catalyzed oxidative carbonylation could proceed
under mild conditions, which avoids the difficult oxidative
addition of metal with aryl halide at high temperature and could
provide diverse reaction pathways to form potentially useful
compounds. To the best of our knowledge, there is only one
example using the nitrogen in a pyridyl ring as the
intramolecular nucleophile in oxidative carbonylation reactions,
affording 11H-pyrido[2,1-b]quinazolin-11-ones from N-aryl-2-
aminopyridines using K2S2O8 as the oxidant in TFA.12 Herein
we report an efficient palladium-catalyzed oxidative alkox-
ycarbonylation of propargylic pyridines to synthesize indolizine
derivatives under mild conditions.
prepare N-heterocycles, the synthesis of functionalized
compounds with the same core structure from the same or
similar starting materials has potential benefit, easily building a
library to screen and optimize the lead compound.3 For
example, the synthesis of indolizines from propargylic pyridines
is an attractive approach.4−8 Indolizines could be formed by the
cycloisomerization or cyclization of propargylic pyridines in the
presence of metal catalysts such as Pt, Cu, Ag, Au, and In and
by heating in a polar protic solvent such as water and alcohol
(Scheme 1a).4 Iodine could promote the cyclization of
propargylic pyridines to form iodoindolizines (Scheme 1b).5
Palladium-catalyzed (carbonylative)cyclization/arylation has
also been used to synthesize indolizines from propargylic
pyridines and aryl halides (Scheme 1c).6 Indolizine derivatives
Initially, substrate 1a was used to study the conditions for the
reaction (Table 1). In the presence of 5 mol % Pd(PPh3)2Cl2,
methoxycarbonylation product 1-pivaloxy-2-methoxylcarbonyl-
3-phenyl-indolizine (2a) was obtained in 66% yield using 1,4-
benzoquinone (BQ) as the oxidant at 60 °C (entry 1). The
yield did not change when the reaction was effected at room
temperature (entry 2). Then different catalyst precursors were
studied. When Pd(0) type catalysts Pd(PPh3)4 and Pd2(dba)3
were used, 2a was obtained in 60% and 85% yields, respectively
(entries 3 and 4). When the heterogeneous catalyst Pd/C was
used, 2a was obtained in 80% yield (entry 5). The commonly
used palladium catalyst precursor Pd(OAc)2 gave 2a in only
49% yield (entry 6). The results indicate that phosphine ligand
is not necessary. The yield of 2a decreased when the amount of
catalyst was reduced (entries 7−9). Then we examined the
effect of CO on the reaction. When the pressure was reduced to
Scheme 1. Synthesis of Indolizines from Propargylic
Pyridines
Received: July 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02220
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Screening of the Reaction Conditions
Scheme 2. Synthesis of Indolizines from Propargylic
Pyridines
a
b
entry
cat. (mol %)
oxidant (equiv) PCO (bar) yield of 2a (%)
c
1
Pd(PPh3)2Cl2/5
Pd(PPh3)2Cl2/5
Pd(PPh3)4/5
Pd2(dba)3/2.5
Pd/C/5
BQ/2
20
20
20
20
20
20
20
20
20
2
66
65
60
85
80
49
69
73
64
75
2
BQ/2
3
BQ/2
4
BQ/2
d
5
BQ/2
6
Pd(OAc)2/5
Pd2(dba)3/0.5
Pd2(dba)3/1
Pd/C/1
BQ/2
7
BQ/2
8
BQ/2
9
BQ/2
10
11
12
13
14
15
16
17
Pd2(dba)3/2.5
Pd2(dba)3/2.5
Pd2(dba)3/2.5
Pd/C/5
BQ/2
BQ/2
3
81
81
83
BQ/2
5
d
BQ/2
3
Pd2(dba)3/2.5
Pd2(dba)3/2.5
Pd2(dba)3/2.5
Pd2(dba)3/2.5
Cu(OAc)2/2
AgOAc/2
BzOOBz/2
3
<5 (2aa: 85)
3
43
<5
11
3
e
BQ/0.2
3
a
Conditions: 0.2 mmol of 1a, 2 mL of MeOH, room temperature, 12−
b
c
d
e
15 h. Isolated yield. 60 °C. 6 h. 1 bar air/3 bar CO.
3 bar and the palladium catalyst precursor was Pd2(dba)3 or
Pd/C, compound 2a was obtained in 81% and 83% yield,
respectively (entries 10 and 13, respectively). There was little
change in yield by increasing the pressure of CO to 5 bar.
When the oxidant Cu(OAc)2 was used instead of BQ,
cycloisomerization product 1-pivaloxy-3-phenyl-indolizine
(2aa) was obtained in 85% yield together with <5% 2a
(entry 14). Oxidant AgOAc gave 2a in 43% yield (entry 15).
When BzOOBz was used as the oxidant, most of 1a remained
(entry 16). Only an 11% yield of 2a was obtained by using 0.2
equiv of BQ at 1 bar air/3 bar of CO (entry 17).
The scope of the reaction was studied in the presence of
Pd2(dba)3 or Pd/C (Scheme 2). When the pivaloyl group of
the substrate was replaced by the acetyl group, Pd2(dba)3 gave
the corresponding product 2b in 60% yield but Pd/C was far
less effective. The substrate with a TBS group gave 2c in 63%
and 55% yields, using Pd2(dba)3 and Pd/C as the catalyst,
respectively. The yields of indolizines changed when the
substituent on the alkynyl moiety was replaced. Substrate 1d
with a cyclohexenyl substituent gave the corresponding product
2d in 51% and 62% yields using Pd2(dba)3 and Pd/C as the
catalyst, respectively. Product 2i was obtained in just 24% yield
using 1i with a butyl group. Then substrates with different
carboxylates were investigated. Both aromatic carboxylates and
aliphatic carboxylates could be successfully converted to
indolizine derivatives. Benzoxylate with the para-chlorine
substituent, 1e, gave 2e in 37% yield using Pd2(dba)3 as the
catalyst and 74% yield using Pd/C as the catalyst. Benzoxylate
with a para-methoxy substituent afforded 2f in 65% yield, using
Pd2(dba)3 as the catalyst, while only traces of product resulted
using Pd/C as the catalyst. Substrates 1g with para-
methylbenzoxylate and 1h with 2-naphthalate afforded the
corresponding products in 55−70% yield. When the carbox-
ylate was changed to cyclopropanecarboxylate or 1-
adamantanecarboxylate, the corresponding indolizines were
a
Conditions: 0.2 mmol of 1, 5 mol % of Pd, 0.4 mmol of BQ, 2 mL of
MeOH, room temperature, 12−15 h for Pd2(dba)3, 6 h for Pd/C.
isolated in 52−73% yields. A bromine substituent on the
pyridine ring had little effect on the yields (2f−2h, 2l).
Substrate 1m with a 4-pentyl phenyl substituent reacted to
form 2m in 54% and 56% yields using Pd2(dba)3 and Pd/C as
the catalyst, respectively. The reaction works well with other
alkenyl or alkynyl substituents in the substrates (62−65% yields
for 2n and 2o), and this could enable further transformations.
Other alcohols (ethanol, i-propanol, and n-propanol) were also
applied for the oxidative carbonylation, affording the
corresponding indolizines 2p−2r in 25−70% yields. i-Propanol
gave 2r in 25% yield possibly because of steric hindrance. To
broaden the potential application of the method, compound 2c
can be deprotected by TBAF and the C−Br bond in 2g can be
converted to C−C bond by Sonogashira coupling, affording
compounds 3 and 4 in 41% and 82% yields, respectively eqs 1
and 2.
B
DOI: 10.1021/acs.orglett.5b02220
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 3. Synthesis of Indolizines from Propargylic
Pyridines
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02220.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: howard.alper@uottawa.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the Natural Sciences and Engineering
Research Council of Canada for support of this research.
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