Desulfitative palladium-catalyzed direct C-3 arylation of indolizines with arylsulfonyl chlorides

Article abstract of DOI:10.1002/aoc.3326

An efficient Pd-catalyzed desulfitative approach to C-3 arylation of indolizine derivatives has been developed, and the protocol uses readily available arylsulfonyl chlorides as the arylation reagent under nitrogen. This transformation was performed in a mixed solvent of 1-methyl-2-pyrrolidone and dimethoxyethane using simple triphenylphosphine as a ligand, which provides a new method for the C-3 arylation of indolizines. An efficient Pd-catalyzed desulfitative approach to C-3 arylation of indolizine derivatives has been developed, the protocol using readily available arylsulfonyl chlorides as the arylation reagent under nitrogen. This transformation proceeds in a mixed solvent of NMP and DME using simple triphenylphosphine a ligand, and provides a new method for the C-3 arylation of indolizines.

Full text of DOI:10.1002/aoc.3326

Full paper
Received: 18 February 2015
Revised: 15 March 2015
Accepted: 2 April 2015
Published online in Wiley Online Library: 18 May 2015
(wileyonlinelibrary.com) DOI 10.1002/aoc.3326
Desulfitative palladium-catalyzed direct C-3
arylation of indolizines with arylsulfonyl
chlorides
Wei Zhanga, Fang Liub and Baoli Zhaoc*
An efficient Pd-catalyzed desulfitative approach to C-3 arylation of indolizine derivatives has been developed, and the protocol
uses readily available arylsulfonyl chlorides as the arylation reagent under nitrogen. This transformation was performed in a
mixed solvent of 1-methyl-2-pyrrolidone and dimethoxyethane using simple triphenylphosphine as a ligand, which provides a
new method for the C-3 arylation of indolizines. Copyright © 2015 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site
Keywords: desulfitative arylation; indolizines; arylsulfonyl chlorides
Introduction
Results and discussion
Nowadays, indolizines have emerged as important N-based hetero-
cycles, which are commonly present in pharmaceutical building
blocks.[1–8] Consequently, many synthetic methodologies for
functionalized indolizines have been reported.[9–11] Many efforts
have aimed to decorate the indolizine core and produce
derivatives.[12–27] C-3 arylation methods for indolizine have been
developed in the last ten years. In 2004, Gevorgyan and co-workers
reported the first Pd-catalyzed C-3 arylation reaction with aryl bro-
mides, and then Fagnou and co-workers reported a similar catalytic
system.[28–30] Aryl chloride is a more challenging substrate in
Pd-catalyzed chemistry for its poor reactivity and the strength of
the aryl–Cl bond which is difficult to oxidize with Pd species. You
and co-workers[31,32] applied aryl chlorides as arylation partners to
achieve this target successfully. Arylboronic acid derivatives are
regarded as important reagents. In 2009, Xia and You reported an
approach to achieve indolizine C-3 arylation with arylboronic acids
using C-3 chlorination and Suzuki–Miyarua cross-coupling.[31]
Direct arylation of indolizines with arylboronic acids was reported
recently by Hu and co-workers, which can be successfully achieved
via a Pd(OAc)/O2 system using picolinic acid as a ligand.[23] In 2012,
we reported an indolizine C-3 arylation with ArBF3K to afford corre-
sponding products.[33]
We initiated our investigation using the model reaction of methyl
2-methylindolizine-1-carboxylate with phenylsulfonyl chloride to
optimize the reaction conditions. The results of optimization of
the reaction conditions are summarized in Table 1. The desulfitative
arylation occurs with Pd(PPh3)4 (5mol%) in the presence of
NaHCO3 in DMF under nitrogen, providing methyl 2-methyl-3-
phenylindolizine-1-carboxylate in 51% yield (Table 1, entry 1). We
investigated the effect of solvents which influence the reaction
activities. The optimization results are summarized in Table 1. The
yields obtained in other polar aprotic solvents such as N,N-
Dimethylacetamide (DMA), DMSO and 1-methyl-2-pyrrolidone
(NMP) are in the range 60–72% (Table 1, entries 2–4). Other organic
solvents have been tested; however, no better results are obtained
(Table 1, entries 5–8). Subsequently, we further considered the
application of a mixed solvent to enhance the efficiency. We chose
NMP (which showed the best results in the initial solvent testing) to
mix with other solvents. To our delight, the yields of the reaction
increase with mixtures of various solvents (53–79%; Table 1, entries
9–11). The reaction proceeds smoothly in a solvent comprised of
NMP and dimethoxyethane (DME) (Table 1, entry 12). Finally, we
adjusted the proportions of NMP and DME (Table 1, entries
13–20), and in general, increasing NMP favors the formation
Transition metal-catalyzed desulfitative arylation of heteroarenes
with sodium arylsulfinates and/or arylsulfonyl chlorides, arylsulfonyl
hydrazides and arylsulfinic acids has emerged as a novel arylation
approach.[34–44] Arylsulfonyl chlorides are inexpensive and readily
available reagents, which have been demonstrated as a class of
coupling partners in Pd-catalyzed desulfitative C–C cross-coupling
reactions.[45–58] Prompted by our continuing interest in metal-
catalyzed cross-coupling reactions with ArSO2R derivatives such
as ArSO2Na or ArSO2Cl,[58–62] herein, we describe a new application
of arylsulfonyl chloride in arylation reactions with indolizines to
afford C-3 arylation products using a more convenient Pd-catalyzed
desulfitative reaction (Scheme 1).
*
Correspondence to: Baoli Zhao, Institute of Applied Chemistry and Department
of Chemistry, Shaoxing University, Shaoxing, Zhejiang Province 312000, China.
E-mail: babygarfield@126.com
a Department of Chemistry and Chemical Engineering, Xinxiang University,
Xinxiang, Henan Province 453003, China
b Life Science Research Center, Hebei North University, Zhangjiakou, Hebei Province
075000, China
c
Institute of Applied Chemistry and Department of Chemistry, Shaoxing University,
Shaoxing, Zhejiang Province 312000, China
Appl. Organometal. Chem. 2015, 29, 524–527
Copyright © 2015 John Wiley & Sons, Ltd.

Desulfitative arylation of indolizines with arylsulfonyl chlorides
Table 2. Screening of various catalysts and bases for Pd-catalyzed
arylationa
Entry
Catalyst
PdCl2
Base
Yield(%)b
1
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
K3PO4
47
45
56
72
80
95
92
88
—
81
15
10
75
80
86
—
62c
2
PdI2
3
PdCl2(CH3CN)2
PdCl2(dppf)
PdCl2(PPh3)3
Pd(PPh3)4
Pd2(dba)3
Pd(dba)2
—
4
5
6
7
Scheme 1. Methods for indolizine C-3 arylation.
8
9
10
11
12
13
14
15
16
17
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
NaOH
Table 1. Solvent selection for desulfitative Pd-catalyzed C-3 arylationa
Et3N
KOAc
K2CO3
Na2CO3
—
NaHCO3
aReaction conditions: 2-methylindolizine-1-carboxylate (0.5 mmol),
phenylsulfonyl chloride (0.6 mmol), catalyst (5 mol%), base (0.5 mmol),
DMSO–DME (2.0 ml; 9:1 v/v) at 80 °C for 3 h unless otherwise indicated.
Entry
Solventb
Yield(%)c Entry
Solventb
Yield(%)c
bIsolated arylation yield under nitrogen.
cIsolated arylation yield under air.
1
2
3
4
5
6
7
8
9
10
DMF
DMA
51
60
66
72
52
10
22
49
79
71
11 NMP–toluene (1:1)
12 NMP–DME (1:1)
13 NMP–DME (9:1)
14 NMP–DME (4:1)
15 NMP–DME (3:1)
16 NMP–DME (2:1)
17 NMP–DME (1:2)
18 NMP–DME (1:3)
19 NMP–DME (1:4)
20 NMP–DME (1:9)
53
85
90
95
86
80
70
74
77
69
DMSO
NMP
CH3CN
product, whereas the use of NaOH and Et3N gives yields less than
15% (Table 2, entries 10–12). KOAc, K2CO3 and Na2CO3 were tested,
and, to our delight, Na2CO3 give a better result (86%; Table 2, en-
tries 13–15). Furthermore, the reaction does not occur at all when
carried out without bases, indicating that base may be an important
factor for this reaction (Table 2, entry 16). Notably, only 62% yield of
arylation product is isolated under air (Table 2, entry 17). Finally, the
desulfitative arylation proceeds well with a catalytic system com-
posed of Pd(PPh3)4 (5mol%) and NaHCO3 (1 equiv.) in NMP–DME
(4:1) at 80 °C under nitrogen for 3 h.
With the optimized conditions in hand, we next set out to ex-
plore the scope of the method with respect to this Pd-catalyzed
desulfitative arylation of indolizines with arylsulfonyl chlorides. To
expand the scope of substrates, several indolizines were surveyed
under the present reaction conditions, as shown in Fig. 1. It should
be noted that the yield of desired product is slightly decreased
along with increasing carbon chain of ester (3a to 3b to 3c to 3d).
When 2-methylindolizine-1-carbonitrile and 2-methylindolizin-1-yl
acetate react with phenylsulfonyl chloride, the desired products
are obtained in 89 and 91% yields, respectively (Fig. 1, 3e and 3f).
The reaction also proceeds well when the methyl substituent is re-
moved from the C-2 position of indolizine. Different functionalities
on the C-3 position of the indolizine ring, whether electron-
withdrawing or electron-donating groups, are compatible. As
shown in Fig. 1, this reaction is compatible with ester, keto, cyano,
carbamyl and acetoxyl substituents, and furnishes the desired prod-
uct in good yields (Fig. 1, 3 g–3 k). Gratifyingly, a variety of substit-
uents on other positions of the indolizine successfully couple with
Toluene
1,4-Dioxane
DME
NMP–dioxane (1:1)
NMP–CH3CN (1:1)
aReaction conditions: 2-methylindolizine-1-carboxylate (0.5 mmol),
phenylsulfonyl chloride (0.6 mmol), Pd(OAc)2 (5 mol%), NaHCO3
(0.5 mmol), solvent (2.0 ml) at 80 °C under nitrogen for 3 h unless
otherwise indicated.
bSolvent proportion by volume in parentheses.
cIsolated yield.
of C-3 arylation product. A volume ratio of NMP to DME of 4:1
shows the best efficiency (Table 1, entry 14).
The effects of catalysts and bases were also investigated. As
evident from Table 2, we initially tested various palladium catalysts
for this desulfitative coupling reaction using NMP–DME (4:1) as the
solvent. Among the Pd catalysts explored, PdCl2, PdI2 and
PdCl2(CH3CN)2 afford the desired product with 47, 45 and 56%
yields. Increased yields are obtained with the introduction of phos-
phine ligands (Table 2, entries 4 and 5). Transformation using Pd(0)
catalysts leads to good yields (Table 2, entries 6–8). No product is
formed in the absence of Pd catalyst (Table 2, entry 9). Thus,
Pd(PPh3)4 was selected for further optimization. In this reaction var-
ious bases seem to play key roles in promoting efficacy. Intriguingly,
when K3PO4 is used as the base, it gives an 81% yield of arylation
Appl. Organometal. Chem. 2015, 29, 524–527
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

W. Zhang et al.
Scheme 2. Possible mechanism.
(Fig. 1, 3w). Finally, methyl pyrrolo[2,1-a]isoquinoline-1-carboxylate
is also desulfitatively arylated in reasonable yield (Fig. 1, 3x).
Mechanism
On the basis of previous work and the results of our study,[23,28–33]
a
plausible Pd(0)/Pd(II) mechanism for the desulfitative arylation as
shown in Scheme 2 is proposed. First is the oxidative addition of
Pd(0) with phenylsulfonyl chloride to form intermediate A. Accom-
panied with the release of sulfur dioxide, electrophilic palladation
occurs at the preferential C-3 position of indolizine with intermedi-
ate B to form intermediate C, with base being necessary for the
removal of HCl. The subsequent reductive elimination of intermedi-
ate C generates the arylation products, and then the formed Pd(0) is
regenerated to complete the cycle (Scheme 2).
Experimental: typical procedure
A mixture of indolizine (0.5mmol), arylsulfonyl chloride (0.6mmol),
Pd(PPh3)4 (5mol%) and NaHCO3 (0.5 mmol) was stirred in DMSO–
DME (2.0ml; 9:1v/v) at 80 °C under nitrogen for 3 h. Afterwards,
2 ml of water was added to the reaction solution which was then fil-
tered through a filter paper and the solution was extracted three
times with Et2O (2ml). The organic phase was combined and evap-
orated under reduced pressure. The residue was purified with a
SiO2 column (ethyl acetate–hexane) to afford the desired product.
Figure 1. Desulfitative Pd-catalyzed C-3 arylation of indolizines with
arylsulfonyl chlorides. Reaction conditions: indolizines (0.5 mmol),
arylsulfonyl chlorides (0.6 mmol), Pd(OAc)2 (5 mol%), NaHCO3 (0.5 mmol),
DMSO–DME (2.0 ml; 9:1 v/v) at 80 °C under nitrogen for 3 h. The yields
indicated for each product are isolated arylation yields.
Conclusions
phenylsulfonyl chloride, such as methyl 7-methylindolizine-1-
carboxylate, methyl 5-chloroindolizine-1-carboxylate and dimethyl
indolizine-1,6-dicarboxylate (Fig. 1, 3 l–3n). Subsequently, we ap-
plied our method to other arylsulfonyl chlorides to prepare an array
of methyl 3-arylindolizine-1-carboxylates with either electron-
withdrawing groups or electron-donating groups successfully en-
gaged in this reaction (Fig. 1, 3o–3 t). Notably, bromo, chloro and
fluoro substituents on the sulfonyl chloride moiety do not affect
the yields of the desired arylation products, and offers the potential
for highly chemoselective transformations (Fig. 1, 3q–3 s). An ortho-
or meta-substituent group on the aromatic ring of the arylsulfonyl
chloride does dramatically decrease the reaction yield (Fig. 1, 3u
and 3v). Heteroaromatic sulfonyl chlorides, such as thiophene-2-
sulfonyl chloride, are tolerated, albeit with a slightly decreased yield
A novel method for desulfitative C-3 arylation was developed
through the reaction of indolizines with arylsulfonyl chlorides cata-
lyzed by 5 mol% Pd(PPh3)4. The reaction proceeded under mild
conditions in air without external oxidants and ligands. This meth-
odology provides an effective and cheap way for the synthesis of
indolizine derivatives. The transformation was promoted by a
mixed solvent and carried through via the release of SO2.
Acknowledgements
This study was supported by the National Natural Science Founda-
tion of China (no. 21402123), the Zhejiang Provincial Natural Sci-
ence Foundation of China (no. LQ14B020001) and the Education
Department of Zhejiang Province (no. Y201328443).
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Appl. Organometal. Chem. 2015, 29, 524–527

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