Synthesis of pyrrolo[2,1,5-cd]indolizines through dehydrogenative heck annelation of indolizines with diaryl acetylenes using dioxygen as an oxidant

Article abstract of DOI:10.1021/ol503681n

A dehydrogenative Heck annelation reaction of indolizine with diaryl acetylene via dual C-H bond cleavage was developed. Oxygen gas was employed as a clean oxidant in this catalysis under base-free conditions. Diarylpyrrolo[2,1,5-cd]indolizines were synthesized with high atom economy. In addition, kinetic isotope experiments provided evidence for C-H bond metalation of the 5-position of the indolizine as the rate-limiting step.

Full text of DOI:10.1021/ol503681n

Letter
pubs.acs.org/OrgLett
Synthesis of Pyrrolo[2,1,5-cd]indolizines through Dehydrogenative
Heck Annelation of Indolizines with Diaryl Acetylenes Using
Dioxygen as an Oxidant
Huayou Hu,*,†,§ Guodong Li,† Weiming Hu,† Yun Liu,‡ Xiang Wang,† Yuhe Kan,*,† and Min Ji§
†Jiangsu Key Laboratory for Chemistry of Low-Dimensional Materials, School of Chemistry and Chemical Engineering, Huaiyin
Normal University, Huaian 223300, China
‡Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, School of Chemistry and Chemical Engineering,
Jiangsu Normal University, Xuzhou 221116, China
§State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing
210096, China
S
* Supporting Information
ABSTRACT: A dehydrogenative Heck annelation reaction of
indolizine with diaryl acetylene via dual C−H bond cleavage
was developed. Oxygen gas was employed as a clean oxidant in
this catalysis under base-free conditions. Diarylpyrrolo[2,1,5-
cd]indolizines were synthesized with high atom economy. In
addition, kinetic isotope experiments provided evidence for
C−H bond metalation of the 5-position of the indolizine as the rate-limiting step.
evelopment of efficient strategies for the construction of
considerable attention from organic chemists and stimulated
Dpolycyclic heterocycles with various properties is of great the development of new synthetic strategies to construct
pyrrolo[2,1,5-cd]indolizines.6
In the past several decades, the [8 + 2]-cycloaddition of
importance in modern organic chemistry. One of the most
powerful tools is the Heck annelation reaction.1 Over the past
indolizine with an electron-deficient alkyne has been frequently
used for the preparation of pyrrolo[2,1,5-cd]indolizines.7
However, only electron-deficient alkynes could be used in
this stage. Therefore, using an electron-rich alkyne to construct
pyrrolo[2,1,5-cd]indolizine remains a challenge in this field.
Recently, pyrrolo[2,1,5-cd]indolizines were synthesized via a
palladium-catalyzed decarboxylative coupling reaction between
indolizines and α,β-unsaturated carboxylic acids.8 As a follow-
up to our interest in indolizine derivatives,9 we considered the
synthesis of pyrrolo[2,1,5-cd]indolizine from indolizine with an
electron-rich internal alkyne through the dehydrogenative Heck
annelation reaction (Scheme 2).
few years, dehydrogenative Heck annelation reactions using
arenes as starting materials instead of aryl halides have been
developed.2 These methods succeed in losing only two
hydrogen atoms from the substrates, which is more compatible
with the atom economy principle (Scheme 1).3
Scheme 1. Differences between Heck Annelation and
Dehydrogenative Heck Annelation
In the preliminary study, N,N-dimethylindolizine-1-carbox-
amide 1a (0.20 mmol) and 1,2-diphenylethyne 2a (1.5 equiv)
with palladium acetate (10 mol %) as catalyst and DMSO
(dimethyl sulfoxide) as solvent were chosen as our model
system. As the results show (Table 1), the yield of the proposed
product 3aa reached 32% under oxygen atmosphere (balloon)
and base-free conditions with the dimer 9 as the main
byproduct (Table 1, entry 1). The structure of 3aa was
confirmed by CCDC (Figure 1).10 Based on the previously
reported results,9f,g,11 acetic acid or potassium acetate was
added to improve the reaction selectivity between dimerization
and Heck annelation. As shown in Table 1 (entries 2−4), acetic
Pyrrolo[2,1,5-cd]indolizine, commonly known as cycl[2,2,3]-
azine, is the most interesting member of the cyclazine family.
Pyrrolo[2,1,5-cd]indolizine derivatives are of great importance
in the field of pharmaceuticals and are also versatile building
blocks for natural products, bioactive compounds, and drugs.4
Moreover, pyrrolo[2,1,5-cd]indolizines were observed to have
long wavelength absorption and fluorescence in the visible light
region and were used as fluorescent probes and organic
electroluminescent materials.5 Their importance has drawn
Received: December 22, 2014
© XXXX American Chemical Society
A
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Letter
conditions as follows: 10 mol % of palladium acetate, 10 mol %
of L, 3.0 mL of DMSO as solvent under O2 at 110 °C for 8 h
with 2.0 equiv of 2a (Table 1, entry 14). Importantly, no 3aa
was detected in the absence of palladium acetate (Table 1,
entry 15).
Scheme 2. Different Ways of Synthesizing Pyrrolo[2,1,5-
cd]indolizines from Indolizines and Alkynes
Regarding the substrate scope of indolizines, a series of
different indolizines coupled with 2a were studied under
standard conditions (Scheme 3). Indolizines bearing an
a
Scheme 3. Scope of Indolizines
a
Table 1. Optimization of Reaction Conditions
amount
(%)
yield of 3aa
b
entry
additive
solvent
(%)
c
1
2
3
4
5
6
NA
0
200
200
10
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
32
52
33
57
61
55
acetic acid
potassium acetate
acetic acid
trifluoroacetic acid
10
trifluoromethanesulfonic
acid
10
7
8
9
pivalic acid
10
10
10
10
10
10
10
10
10
DMSO
DMSO
DMSO
DMSO
NMP
35
59
67
71
18
15
27
76
0
benzoic acid
2-nitrobenzoic acid
10 2,6-difluorobenzoic acid
11 2,6-difluorobenzoic acid
12 2,6-difluorobenzoic acid
DMA
13 2,6-difluorobenzoic acid
DMF
d
14
2,6-difluorobenzoic acid
2,6-difluorobenzoic acid
DMSO
DMSO
e
15
a
Reaction conditions: 10 mol % of palladium acetate, 3.0 mL of
b
c
solvent under O2 (balloon) at 110 °C for 8 h. Isolated yield. No
addition. With 2.0 equiv of 2a. No palladium acetate.
d
e
a
Reaction conditions: 1 (0.20 mmol), 2a (0.40 mmol), 10 mol % of
palladium acetate, 10 mol % of L, 3.0 mL of DMSO, under O2
(balloon) at 110 °C.
electron-withdrawing group at the 1-position (1a−g) reacted
with 2a smoothly. Indolizines with a substituted group at the 2-
position were unreactive under standard conditions. However,
good yields were achieved under additive-free conditions (1h−
m), which was in accord with our previous results.9f,g At the
same time, indolizine without an electron-withdrawing group
(1n) was decomposed under standard reaction conditions,
while 3ka (20%) and 4ka (58%) were isolated by using methyl
2-phenylindolizine-1-carboxylate (1l) as the starting material.
Moreover, fused indolizine with two electron-withdrawing
groups at the 1- and 2-positions (1o) was unreactive even when
the reaction temperature was increased to 130 °C. Notably,
indolizine 1p did not give any six-membered ring product.
To study the substrate scope and regioselectivity of diaryl
acetylenes, different diaryl acetylenes were coupled with 1i
under standard conditions without any additive (Scheme 4).
Figure 1. ORTEP of 3aa.
acid was efficient, and 10 mol % of acetic acid as an additive was
superior to 2 equiv of acetic acid. Then, a series of acids were
tested for our model reaction. 2,6-Difluorobenzoic acid (L) was
found to be the most efficient (details about the role of additive
are in Supporting Information). Further investigation of
reaction solvents led us to establish the optimized reaction
B
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a
with higher electron density would react with indolizine slower
and can also explain the reason for regioselectivity of the
unsymmetrical alkynes and low reactivity of 2h with indolizine.
Isotope experiments were conducted to understand the
reaction mechanism. As the first step, D4-1i was synthesized
from pyridine-d5.13 Then 1i and D4-1i reacted with 2a in one
tube or in two parallel tubes under standard reaction conditions
for 30 min. The ratios of 3ia/D3-3ia were 2.3 and 3.2,
respectively, as detected by 1H NMR (Scheme 6). These results
were consistent with a primary kinetic isotope effect and
indicated the C−H bond metalation at the 5-position of
indolizine as the rate-limiting step.
Scheme 4. Scope and Regioselectivity of Diaryl Acetylenes
Scheme 6. Isotope Experiments
Based on our previously reported results9f and the present
study, a plausible reaction mechanism was proposed in Scheme
7. First, palladium diacetate reacted with 1 through C−H
Scheme 7. Proposed Mechanism
a
Reaction conditions: 1i (0.20 mmol), 2 (0.40 mmol), 10 mol % of
palladium acetate, 3.0 mL of DMSO, under O2 (balloon) at 110 °C.
Symmetrical acetylenes produced products in a smooth manner
(Scheme 4, 2b−d). However, 1,2-di(thiophen-2-yl)ethyne (2h)
only gave a trimer (5h). Unsymmetrical acetylenes gave two
isomers. The major products are always the isomers in which
the phenyl-ring-bearing electron-withdrawing group is near the
six-membered ring of indolizine (Scheme 4, 2e−g). Notably,
1,4-diphenylbuta-1,3-diyne (2i) gave two isomers in a 1:1 ratio.
These structures were confirmed by CCDC analysis.12
Unfortunately, alkynes that only bear one aryl group (2j−l)
were inefficient in this transformation.
activation to form intermediate 6, and then 6 coordinated with
2 and further transformed to 7 through insertion. Then 8 was
formed from 7 through a second C−H activation as the next
step (the rate-limiting step of this reaction), followed by
product 3 and Pd(0) generated from 8 through reductive
elimination. Finally, palladium acetate was regenerated from
Pd(0) under oxygen to complete the catalytic cycle.
To demonstrate the synthetic utility of this method, the
reaction was conducted on 4.0 mmol scale, producing 3ia in
98% yield (1.61 g, Scheme 8).
To understand the regioselectivity of the unsymmetrical
alkynes, a control experiment was also conducted. Indolizine 1i
reacted with an excess amount of 2a and 2b in one tube for 30
min (Scheme 5). The ratio of 3ia/3ib was 1.3, which was
1
measured by H NMR. This result indicates that the alkyne
Scheme 5. Control Experiments for Understanding the
Regioselectivity of Unsymmetrical Alkynes
In summary, a palladium-catalyzed dehydrogenative Heck
annelation of indolizine with diaryl acetylene was developed.
Oxygen gas was used as the only oxidant under base-free
conditions. For 2-unsubstituted indolizines, the catalytic
amount of 2,6-difluorobenzoic acid used as an additive was
crucial for the success of this transformation. A wide range of
C
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Scheme 8. Gram Scale Experiment
functional groups were tolerated both in indolizines and diaryl
acetylenes. The versatility of the pyrrolo[2,1,5-cd]indolizine
moiety should render this protocol highly attractive for both
material and medicinal chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, spectral data for all new compounds, and
fluorescence spectra of 3aa and 3ma. This material is available
free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: njuhhy@hotmail.com.
*E-mail: kyh@hytc.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the funding of NSFC (No. 21202058),
Education Department of Jiangsu Province (No.
13KJA150001), CPSF (Nos. 2012M511645, 2013T60483),
JSKLCLDM (No. SKC11093), and NBRPC (No.
2011CB933503).
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■
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