Palladium-catalyzed C-3 desulfitative arylation of indolizines with sodium arylsulfinates and arylsulfonyl hydrazides

Article abstract of DOI:10.1039/c5ra25504j

Derivatized indolizines were efficiently prepared by direct C-3 arylation of indolizines using sodium arylsulfinates and arylsulfonyl hydrazides. Pd-catalyzed desulfitative C-3 arylation with sodium arylsulfinates was achieved with the assistance of peroxides, and the catalytic efficiency was promoted by N-containing ligands. Arylsulfonyl hydrazides were also successfully applied in Pd-catalyzed desulfitative C-3 arylation with indolizines, and the side homocoupling reactions can be restrained in the component solvent under milder conditions. Various derivatives were synthesized in good yields by both methods, offering expedient protocols for the synthesis of C-3 functionalized indolizine molecules.

Full text of DOI:10.1039/c5ra25504j

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Palladium-catalyzed C-3 desulfitative arylation of
indolizines with sodium arylsulfinates and
arylsulfonyl hydrazides†
Cite this: RSC Adv., 2016, 6, 21814
a
a
a
a
b
*
*
Chunjie Wang, Huali Jia, Zhiwei Li, Hui Zhang and Baoli Zhao
Derivatized indolizines were efficiently prepared by direct C-3 arylation of indolizines using sodium
arylsulfinates and arylsulfonyl hydrazides. Pd-catalyzed desulfitative C-3 arylation with sodium
arylsulfinates was achieved with the assistance of peroxides, and the catalytic efficiency was promoted
by N-containing ligands. Arylsulfonyl hydrazides were also successfully applied in Pd-catalyzed
desulfitative C-3 arylation with indolizines, and the side homocoupling reactions can be restrained in the
component solvent under milder conditions. Various derivatives were synthesized in good yields by both
methods, offering expedient protocols for the synthesis of C-3 functionalized indolizine molecules.
Received 1st December 2015
Accepted 7th February 2016
DOI: 10.1039/c5ra25504j
www.rsc.org/advances
Consequently, many synthetic methodologies for functional-
ized indolizine have been reported.9 More effort has been paid
Introduction
Indolizine has a delocalized 10p-electron aromatic structure,1
and is of theoretical and practical interest in a wide variety of
natural products with useful biocidal activities.2 The indolizine
framework occupies a special place in heterocyclic systems due
to the presence of this structurally challenging nitrogen
heterocyclic moiety in a number of bioactive natural products3
(Fig. 1) with antimicrobial (1a–1d), uterotrophic (1e, for
estrogen binding affinity), anticancer (1f–1h), antidiabetic
(1i), anti-inammatory (1j and 1k), antihistaminic, anti-
acetylcholinic (1l–1n), antitubercular (1o) and antioxidant (1p
and 1q, for lipoxygenase) activities. Most of the work on indo-
lizine derivatives has been concerned with the search for
organic materials4 and potential candidates for pharmaceutical
research,5 such as phosphatase inhibitors (1r), phosphodies-
terase inhibitors (1s), PDE5A inhibitors (1t), L-type calcium
channel blockers (1u) and leukotriene synthesis inhibitors (1v).6
The medicinal and biological relevance of the indolizine
derivatives has created a need for the development of efficient
synthetic strategies for obtaining such derivatives.7 Tradition-
ally, substituted indolizines can be obtained by the reaction of
pyridinium ylides with ethylenic compounds to form dihy-
droindolizines which readily oxidize to the aromatic system.
The enormous advances in metal-catalyzed direct arylation with
C–H functionalization involved have envolved into the most
powerful synthetic tools for generation of biaryl compounds.8
to decorate the indolizine core and derivatized with interesting
method, such as olenation,10 alkynylation,11 benzylation,12
sulfenylation13 and dimerization.14
aCollege of Chemistry and Chemical Engineering, Zhoukou Normal University,
Zhoukou, Henan Province 466000, China. E-mail: wangcjzz@163.com
bInstitute of Applied Chemistry and Department of Chemistry, Shaoxing University,
Shaoxing, Zhejiang Province 312000, China. E-mail: babygareld@126.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra25504j
Fig. 1 Indolizine framework in bioactive natural products.
21814 | RSC Adv., 2016, 6, 21814–21821
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Previous studies also applied bromoarenes15 and chloroar-
RSC Advances
enes16 as arylation reagents to indolizines, arylation with rela-
tively unreactive organo species, such as arylboronic species17
and aryltriuoroborate salts,18 has also been reported. Owe to
the important application of 3-aryl-indolizine19 (such as full-
color tenability of emission wavelength of the indolizine core
C3-Indo-Fluor20), more effort for the synthesis of C-3 arylation
indolizine derivatives should be paid.
Along with the development of new electrophilic partners for
C–C bond formation, arenesulfonates and their analogues have
been regarded as good substrate, which are easily availability,
inexpensiveness, and high versatility. In our continuing interest
in the discovery of new arylating reagents based on desultative
coupling,21 we are very interested at arylsulnic acids and aryl-
sulfonyl hydrazides. Arylsulnic salts are stable and easy to
handle reagents, which show great potential as aryl sources for
the synthesis of various aromatic compounds. The density
functional theory (DFT) calculation showed that C–SO2R bond
dissociation enthalpies (BDEs) are much lower than corre-
sponding C–CO2R BDEs, which proved arylsulnic acids are
more reactive substrates than arylcarboxylic acids.22 Arylsulnic
acids have been widely used these years for Heck,23 Hiyama,21b
Suzuki cross-coupling reactions,21c C–H bond activation24 and
addition with triple bond25 in recent years.26
Arylsulfonyl hydrazides are readily accessible solids and
compatible with moisture, which can be prepared in one step
from readily available arylsulfonyl chlorides and hydrazine
hydrates. Arylsulfonyl hydrazides have been widely employed as
sulfone27 or thioether28 sources to construct organic sulfur
compounds through the cleavage of N–S and/or S–O bond.
Recently, arylsulfonyl hydrazides have been employed as novel
aryl sources by means of their C–S bonds, which would undergo
Fig. 3 Research outline for direct C-3 arylation of indolizines using
sodium arylsulfinates and arylsulfonyl hydrazides.
found to be very important cross-coupling partners. Arylsulfonyl
hydrazides have been used as aryl sources via desultation–
denitrogenation for Heck-type reaction29 Hiyama,30 Suzuki31 and
direct C–H bond arylations.32 We have reported a novel protocol
to construct C-3 indolizines using arylsulfonyl chloride as aryl
sources33 (Fig. 2). Despite this success, limitations of arylsul-
fonyl chloride have been noted such as moisture sensitivity and
long reaction time. Thus it is necessary to explore air-stable,
readily available, and inexpensive alternatives. Herein, we
disclose practical and convenient procedures to synthesize
various derivatized indolizines with arylsulnic salts and aryl-
sulfonyl hydrazides (Fig. 3).
Results and discussion
Optimization of C-3 desultative arylation with sodium
arylsulnates
the loss of N2 and SO2 gas in situ. In the presence of palladium The reaction of indolizine-1-carbonitrile with sodium benze-
catalysts and carbonyl compounds, arylsulfonyl hydrazides can nesulnate was chosen as a model system for optimization
readily convert into very active diazo compounds which are studies (Table 1). Initially, the reaction was carried out in
CH3CN at 100 ꢀC for 6 h in the presence of palladium acetate (3
mol%) as a catalyst and Cu(OAc)2 (2 equiv.) as an oxidant only
gave tiny amounts of the desired arylation product, but instead
formed a large amount of unwanted sulfonyldibenzene by-
product (Table 1, entry 1).34 Although the addition of other
Cu-salts and Ag-salts as oxidants to the reaction system also
failed to occur desultative C-3 arylation (Table 1, entries 2–10),
the presence of Ag-salts was observed to diminish the homo-
coupling sulfonyldibenzene (Table 1, entries 7–10). When
simultaneously adding benzoyl peroxide (BPO) as oxidants, we
were pleased to nd that ethyl 3-phenylindolizine-1-carboxylate
was obtained in 56% yield without the detection of sulfonyldi-
benzene by-product (Table 1, entry 11). Other peroxides, such as
di-t-butyl peroxide (DTBP), tert-butyl peroxybenzoate (TBPB),
and tert-butyl peroxypivalate (TBPV) were signicantly more
effective, whereas di-tert amyl peroxide (DTAP) and tert-amyl
hydroperoxide (TAHP) gave comparable results (Table 1, entries
12–16). tert-Butyl cumyl peroxide (TBCP) and dicumyl peroxide
(DCP) were ineffective for the generation of 1a (Table 1, entries
17 and 18). However, no 1a was detected when the model
reaction was performed with tert-butyl hydroperoxide (TBHP)
Fig. 2 Different bond cleavage types of indolizines' C-3 arylation.
(Table 1, entry 19). Among the oxidants tested, tert-butyl
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Table 1 Oxidant selection for Pd-catalyzed C-3 arylation of indoli- Table 2 Catalyst selection for Pd-catalyzed C-3 arylation of indoli-
zines with sodium arylsulfinatesa,b zines with sodium arylsulfinatesa
Yield (%) Yield (%)
Yield (%)
Entry Oxidant of 1a
Entry
Catalyst
Ligand
Yieldb (%)
Entry Oxidant
of 1a
of 1b
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdI2
—
PPh3
BINAP
DBN
81
38
41
84
88
90
93
84
72
85
88
79
71
76
63
69
—
1
2
3
4
5
6
7
8
9
Cu(OAc)2
CuCl2
CuBr2
Cu(OTf)2 14
Cu(TFA)2 18
CuI
AgOAc
Ag2CO3
AgOTf
AgNO3
8
10
5
74
65
60
71
61
—
23
27
40
27
11
12
13
14
15
16
17
18
19
20
BPO
56
75
77
72
70
68
52
57
—
81
DTBP
TBPB
TBPV
DTAP
TAHP
TBCP
DCP
DBU
1,10-Phenanthroline
2,20-Bipyridine
TMEDA
—
29
26
39
33
9
DMAP
TBHP
TBPA
10
11
12
13
14
15
16
17
2,20-Bipyridine
2,20-Bipyridine
2,20-Bipyridine
2,20-Bipyridine
2,20-Bipyridine
2,20-Bipyridine
2,20-Bipyridine
2,20-Bipyridine
10
PdCl2
a
Reaction conditions: sodium benzenesulnate (0.6 mmol), indolizine-
1-carbonitrile (0.5 mmol), Pd(OAc)2 (3 mol%), oxidant (0.5 mmol),
CH3CN (1.0 ml) at 100 ꢀC for 6 hours under air unless otherwise
indicated. b Isolated C-3 arylation yield.
Pd(CH3CN)2Cl2
Pd(PPh3)4
Pd2(dba)3
PdCl2(dppf)
PdCl2(PPh3)3
—
peroxyacetate (TBPA) was preferentially chosen as the oxidant
with the highest yield (Table 1, entry 20).
a
Reaction conditions: sodium benzenesulnate (0.6 mmol), indolizine-
1-carbonitrile (0.5 mmol), catalyst (3 mol%), ligand (0.05 mmol),
oxidant (0.5 mmol),CH3CN (1.0 ml) at 100 ꢀC for 6 hours under air
unless otherwise indicated. b Isolated C-3 arylation yield.
Then we attempted to append the ligands to enhance the
reaction activity. However, decreased yields of products were
obtained with the introduction of phosphine ligands (Table 2,
entries 2 and 3). To our delight, N-contained ligands were
crucial for the transformation. Among the N-ligand examined,
such as DBN (1,5-diazabicyclo[4.3.0]non-5-ene), DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene), 1,10-phenanthroline, 2,20-
bipyridine, TMEDA (N,N,N0,N0-tetramethyl-ethane-1,2-diamine)
and DMAP (4-dimethylaminopyridine), 2,20-bipyridine was
shown the best (Table 2, entries 4–9). During the screening of
palladium catalysts, such as PdI2, PdCl2, PdCl2(CH3CN)2,
provided the products in 85%, 88%, 79% yield, respectively
(Table 2, entries 10–12). Transformations with Pd(0) catalysts
obtained moderate yields (Table 2, entries 13 and 14), and the
formation of arylation product was about 63–69% using P-
contained palladium catalyst (Table 2, entries 15 and 16). No
product was formed in the absence of Pd (Table 2, entry 17).
in Table 3, we found the Cu salts were crucial for this trans-
formation. Among the oxidant examined, such as AgOAc, BPO,
DDQ and Oxone, no products were detected (Table 3, entries
2–5). We have reported that Cu(II) salts mediated homo-
coupling with arylsulfonyl hydrazides to afford biarylsulfone
under 100 ꢀC, and this transformation could be obviously
restrain under lower temperature.35 Intriguingly, when the
reaction was performed under 70 ꢀC, it gave 64% yield of
desired arylation products, whereas gave less than 10% of the
by-product (sulfonyldibenzene and biphenyl) (Table 3, entry 6).
Other Cu(II) salts such as Cu(OTf)2, CuBr2 and Cu(NO3)2 have
shown comparable activities to the transformation (Table 3,
entries 7–9). On the contrary, one-valence copper such as CuBr
did not coped with this reaction (Table 3, entry 10). Indeed, the
yield increased to 80% when CuCl2 was employed as the oxidant
without the detection of desultative homocoupling by-
Optimization of C-3 desultative arylation with arylsulfonyl
hydrazides
We initiated our investigation of phenylsulfonyl hydrazide and products (Table 3, entry 11).
indolizine-1-carbonitrile to optimize the reaction parameters.
The following optimization is about solvents applied in this
To our delight, the occurred in the presence of Pd(OAc)2 (2 reaction. The effects of solvents were investigated and the by-
mol%) and Cu(OAc)2 (1 mmol) in NMP (1-methyl-2-pyrrolidone) products sulfonyldibenzene have also been detected (Table 3,
under 100 ꢀC, and 23% of the desired products was detected entries 12–16). Among solvents explored, DMSO, DMF and DMA
(Table 3, entry 1). However, 22% yield of sulfonyldibenzene and afforded the desired arylation products with 82%, 77% and 71%
7% yield of biphenyl has also been detected by GC-MS. The side- yields (Table 3, entries 12–14). The reaction did not occur at all
reaction would consume the phenylsulfonyl hydrazide and when carried out in toluene or xylene (Table 3, entries 15 and
restrict the C-3 arylation. The effects of catalysts, oxidants, 16). Furthermore, the side reaction did not occur at all when
solvents and reaction temperature were investigated. As shown carried out in CH3CN, indicating that it may be a better choice
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Table 3 Oxidant and solvent selection for Pd-catalyzed C-3 arylation Table 4 Catalyst selection on the reactiona
of indolizines with sodium arylsulfinatesa,b
Yield (%) Yield (%) Yield (%)
Entry
Catalyst
Yield (%)
Entry
Catalyst
Yield (%)
Entry Oxidant
Solvent
of 3a
of 3b
of 3c
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Ni(OAc)2
Co(OAc)2
AuCl3
RuCl3
RhCl3
FeCl2
PdCl2
PdBr2
PdI2
80
—
—
—
—
—
—
82
84
77
11
12
13
14
15
16
17
18
19
20
PdCl2(PPh3)3
Pd(dppf)Cl2
Pd(PhCN)2Cl2
Pd(CH3CN)2Cl2
Pd(OTs)2
73
77
81
79
89
92
—
—
—
—
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Cu(OAc)2 NMP
23
—
—
—
—
64
76
73
70
—
80
82
77
71
—
—
70
82
85
88
22
—
—
—
—
5
4
5
8
—
7
AgOAc
BPO
DDQ
NMP
NMP
NMP
NMP
—
—
—
—
4
Oxone
Pd(TFA)2
Cu(OAc)2 NMP
Pd(PPh3)4
Pd2(dba)3
Pd(dba)2
CuBr2
Cu(OTf)2
NMP
NMP
—
10
—
—
—
—
—
—
—
—
—
—
—
—
—
Cu(NO3)2 NMP
10
—
CuBr
NMP
a
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
NMP
DMSO
DMF
4
Reaction
conditions:
indolizine-1-carbonitrile
(0.5
mmol),
21
29
38
—
—
—
4
6
2
—
phenylsulfonyl hydrazides (0.6 mmol), catalyst (3 mol%), CuCl2
(1 mmol), MTBE/CH3CN (1.0 ml, v/v ¼ 1 : 1) at 70 ꢀC for 6 hours
unless otherwise indicated.
DMA
Toluene
Xylene
CH3CN
THF
1,4-Dioxane
MTBE
Pd(OTs)2, invariably worked well (Table 4, entries 8–15), but the
performance of Pd(TFA)2 was maximum, providing the C3-aryl
product 1a in 92% yield at 70 ꢀC (Table 4, entry 16). As
evident, the yield of 1a was not obtained at all when Pd(0)
catalysts was used (Table 4, entries 17–19). The experiment
under identical conditions without the aid of a palladium salt
ended with no conversion (Table 4, entry 20).
DME/CH3CN 86
a
Reaction
conditions:
indolizine-1-carbonitrile
(0.5
mmol),
phenylsulfonyl hydrazides (0.6 mmol), Pd(OAc)2 (3 mol%), oxidant
(1 mmol), solvent (1.0 ml, the v/v ratio of solvents was 1 : 1) at 70 ꢀC
b
for 6 hours unless otherwise indicated. GC-MS yield using hexane as
internal standard. c The reaction was performed under 100 ꢀC.
Substrate scope of the C-3 desultative arylation of
indolizines with sodium arylsulnates and arylsulfonyl
hydrazides
for this reaction (Table 3, entry 17). Although THF and 1,4-
dioxane afforded the same or a higher yield of the desired With the optimized reaction conditions in hand, we investi-
product, the competing homo-coupling product, sulfonyldi- gated the effect of electronic and structural variations of the
benzene, was the minor product in these cases(Table 3, entries arylsulfonyl hydrazides (column A) and sodium arylsulnates
18 and 19). Intriguingly, when MTBE (methyl tert-butyl ether) (column B). The scope of both reaction-types are presented in
was used as the solvent, it gave a 88% yield of desultative C-3 Table 5, for the comparison of two coupling reagents. As ex-
arylation product, whereas gave less than 5% of the by-product pected, a series of electron-donating functional groups on the
(Table 3, entry 20). Subsequently, we further considered the phenyl ring of phenylsulfonyl hydrazides, such as methoxy,
application of component solvent. It proceeded smoothly in methyl and tert-butyl were compatible under this procedure,
solvent comprised of DME and CH3CN (volume ratio 1 : 1) with and the products were isolated in good to excellent yields (Table
a yield of 86% (Table 3, entry 21). To our delight, the application 5, column A, entries 1–3). The halogen functional groups are
of MTBE and CH3CN could obviously reduce the formation of tolerant to the palladium-catalyzed C-3 arylation of arylsulfonyl
by-products. The isolation yield was up to 80% (Table 4, entry 1). hydrazides (Table 5, column A, entries 4 and 5). Encouraged by
At the outset, different transition metal catalysts, viz. these promising results, we further applied the optimized
Pd(OAc)2, Ni(OAc)2, Co(OAc)2, AuCl3, RuCl3, RhCl3 and FeCl2, reaction conditions to examine the substrate scope of arylsul-
were screened using CuCl2 as an oxidant in MTBE/CH3CN to fonyl hydrazides having electron-withdrawing substituents.
determine their catalytic efficacy (Table 4, entries 1–6). We were Gratifyingly, nitro and triuoromethyl functionalities on the
astonished to see that only the palladium salt could bring about phenyl ring of sulfonyl hydrazides, also afforded the desired
the desired conversion (Table 4, entry 1), and therefore the products in good yields (Table 5, column A, entries 6 and 7).
studies were directed to look at the prospective of other palla- These results implied that the electronic effect is not critical for
dium salts too. All the palladium(II) salts tried, viz. PdX2, this transformation. In comparison, different functionalities on
PdCl2(PPh3)3, Pd(dppf)Cl2, Pd(PhCN)2Cl2, Pd(CH3CN)2Cl2, and the phenyl ring of sodium arylsulnates, whether they were
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Table 5 The reaction of indolizine-1-carbonitrile with various aryl- Table
6
The reaction of various indolizines with phenylsulfonyl
sulfonyl hydrazides and sodium arylsulfinates
hydrazides and sodium phenylsulfinates
Entry
1
Indolizine
Yielda (%)
92
Yieldb (%)
93
Entry
R
Yielda (%)
Yieldb (%)
1
2
3
4
5
6
7
8
4-OCH3–C6H5
4-CH3–C6H5
4-t-Bu–C6H5
4-F–C6H5
4-Cl–C6H5
4-NO2–C6H5
4-CF3–C6H5
3-CH3–C6H5
3-F–C6H5
3-Cl–C6H5
3-Br–C6H5
3-CF3–C6H5
3-CHO–C6H5
2-CH3–C6H5
2-Br–C6H5
2-C10H7
94
91
87
90
84
86
85
83
91
88
90
83
76
81
77
82
71
90
92
85
82
88
81
78
87
91
86
85
81
77
88
84
86
77
2
3
88
91
90
87
9
10
11
12
13
14
15
16
17
4
5
6
7
8
84
77
82
87
89
89
83
86
81
91
1-C10H7
a
Reaction conditions of method A: indolizine-1-carbonitrile
(0.5 mmol), arylsulfonyl hydrazides (0.6 mmol), Pd(TFA)2 (3 mol%),
CuCl2 (1 mmol), MTBE/CH3CN (1.0 ml, v/v ¼ 1 : 1) at 70 ꢀC for 6
b
hours unless otherwise indicated. Reaction conditions of method B:
indolizines (0.5 mmol), sodium arylsulnate (0.6 mmol), Pd(OAc)2
(3 mol%), bipyridine (10 mol%), TBPA (0.6 mmol), CH3CN (1.0 ml) at
100 ꢀC for 6 hours unless otherwise indicated.
electron-withdrawing or electron-donating groups, are
compatible (Table 5, column B, entries 1–7). Although electron-
withdrawing substituted sodium arylsulnates showed slightly
decrease reactivity to electron-donating ones. The excellent
reactivity and high selectivity with bromo and chloro functional
groups, suggesting that both arylsulfonyl hydrazides and
sodium arylsulnates may have higher coupling reactivities
than the related aromatic halides, which revealed excellent
chemoselectivity of this method (Table 5, entries 5, 10 and 11).
Functional groups, such as triuoromethyl, uoro, and alde-
hyde, which are useful in further synthetic transformations,
were tolerated under the current conditions (Table 5, entries 9,
12 and 13). The ortho-substituted sodium arylsulnates, such as
ortho-methyl and ortho-bromo, can also afford a good product
yield, thus showing steric hindrance has little effect on this
reaction (Table 5, column A, entries 14 and 15). On the other
side, the hindrance of the phenyl ring of arylsulfonyl hydrazides
had slight effect on the efficiency (Table 5, column B, entries 14
and 15). It was interesting that polycyclic aromatic hydrocar-
bons (PAHs) substrates are still work under both two procedure
(Table 5, entries 16 and 17).
9
79
91
82
88
10
a
Reaction conditions of method A: indolizines (0.5 mmol),
phenylsulfonyl hydrazides (0.6 mmol), Pd(TFA)2 (3 mol%), CuCl2 (1
mmol), MTBE/CH3CN (1.0 ml, v/v ¼ 1 : 1) at 70 ꢀC for 6 hours unless
b
otherwise indicated. Reaction conditions of method B: indolizines
(0.5 mmol), sodium benzenesulnate (0.6 mmol), Pd(OAc)2 (3 mol%),
bipyridine (10 mol%), TBPA (0.6 mmol), CH3CN (1.0 ml) at 100 ꢀC for
6 hours unless otherwise indicated.
We next investigated the scope of the reaction with a series of
indolizines and phenylsulfonyl hydrazides or sodium
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hydrazides. These method have given straightforward access to
valuable C-3 substituted indolizine derivatives. Desultative C-3
arylation with sodium arylsulnates was achieved by the assis-
tance of peroxide for the restrain of unwanted sulfonyldi-
benzene by-product, and the catalytic efficiency was promoted
by N-contained ligand. Desultative C-3 arylation with arylsul-
fonyl hydrazides were also successful, and the side homocou-
pling reactions can be restrained in component solvent under
milder conditions. Further substrate scope and mechanistic
studies are ongoing in our laboratory.
Fig. 4 Mechanism proposed.
Acknowledgements
This study was supported by the National Natural Science
Foundation of China (no. 21402123), the Zhejiang Provincial
Natural Science Foundation of China (no. LQ14B020001), and
the Education Department of Zhejiang Province (no.
Y201328443).
phenylsulnates. To further explore the application of this
method, we tried many C-1 functional groups. Cyano and ester
groups all demonstrated reactivity and the products were iso-
lated in good yield, thus extending the potential applications of
the method (Table 6, entries 1–4). Other substituents in C-1
have also been investigated, such as nitro, acetyl, chloro and
bromo were successfully tolerance under reported conditions
(Table 6, entries 5–8). Meanwhile, 2-methylindolizine-1-
carbonitrile, bearing a sterically hindered group at its C2-
positions, also underwent the reaction with phenylsulfonyl
hydrazides or sodium phenylsulnate smoothly, providing the
corresponding products in slightly lower yields (79–82%) (Table
6, entry 9). C6-substituted methyl group also worked well and
the desired product was produced in an excellent yield (Table 6,
entry 10).
Notes and references
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Mechanism
On the basis of the previous chemistry and the results of our
study, a plausible Pd(0)/Pd(II) mechanism for the desultative
arylation as shown in Fig. 4 was proposed. First, arylsulfonyl
hydrazides was oxidized by Cu(II) to afford aryl(arylsulfonyl)
copper, which could occurred ligand exchange with Pd(OAc)2 to
form arylpalladium intermediate A. The electrophilic pallada-
tion occurs at the preferential C3-position of indolizine to form
intermediate B, following the removal of HOAc. The subsequent
reductive elimination generates the arylation products, then the
formed Pd(0) is oxidized to Pd(II) by Cu(II) to furnish the cycle. In
addition, the reductive elimination of phenyl(phenylsulfonyl)
copper might cause the formation of by-product such as sulfo-
nyldibenzene and biphenyl. A plausible mechanism to ratio-
nalize the transformation with arylsulnic acid sodium salt is
also illustrated in Fig. 3. First, the Pd(II) catalyst reacts with the
sulnic acid to form an intermediate C, which is subsequently
undergoes desulnation to generate the aryl-palladium
complex D. This intermediate species displaced by indolizine
to form intermediate B. A reductive elimination of C affords the
desired product and the Pd(0) catalyst is reoxidized to Pd(II) by
TBPA, thus closing the catalytic cycle.
Conclusions
In summary, we have developed the Pd-catalyzed desultative C-
3
arylation with sodium arylsulnates and arylsulfonyl
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