TFA-Mediated DMSO-Participant Sequential Oxidation/1,3-Dipolar Cycloaddition Cascade of Pyridinium Ylides for the Assembly of Indolizines

Article abstract of DOI:10.1021/acs.joc.8b02755

A trifluoroacetic acid (TFA)-mediated cascade oxidation/1,3-dipolar cycloaddition reaction of stabilized pyridinium salts with dimethyl sulfoxide (DMSO) has been developed in the presence of K₂S₂O₈ and trimethylethylenedia

Full text of DOI:10.1021/acs.joc.8b02755

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pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
TFA-Mediated DMSO-Participant Sequential Oxidation/1,3-Dipolar
Cycloaddition Cascade of Pyridinium Ylides for the Assembly of
Indolizines
Wen-Ming Shu,*,† Jian-Xin He,† Xun-Fang Zhang,† Shuai Wang,† and An-Xin Wu*,‡
†College of Chemistry and Environmental Engineering, Yangtze University, Jingzhou 434023, People’s Republic of China
‡Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan 430079, People’s Republic of China
S
* Supporting Information
ABSTRACT: A trifluoroacetic acid (TFA)-mediated cascade
oxidation/1,3-dipolar cycloaddition reaction of stabilized
pyridinium salts with dimethyl sulfoxide (DMSO) has been
developed in the presence of K2S2O8 and trimethylethylenedi-
amine (TMEDA). In this transition-metal-free reaction,
DMSO acts as a one-carbon source, thus providing a
convenient method for the efficient and direct synthesis of
various indolizine derivatives.
ndolizines are an important class of aromatic heterocycles.
As a consequence of their unique electronic characteristics,
metal-free cascade oxidation/1,3-dipolar cycloaddition reaction
of pyridinium ylides with DMSO that leads to indolizine
derivatives (Scheme 1c).
I
they have found numerous applications in the fields of
materials chemistry and photochemistry.1 Indolizine deriva-
tives also possess a variety of biological activities, including
antibacterial, anticonvulsant, antitumor, and orexin receptor
antagonist activities (Figure 1).2 Therefore, the development
of efficient methods for the construction of functionalized
indolizines from simple and available substrates would be
highly valuable.
Initially, we explored N-phenacylpyridinium iodide 1a (0.2
mmol) as a model reactant. Heating reactant 1a with DMSO at
130 °C for 8 h in the presence of K2S2O8 and
trimethylethylenediamine (TMEDA) afforded the desired
indolizine 3a in 71% yield (Table 1, entry 1). Encouraged by
this result, we investigated other reaction conditions, including
the variation of additive, oxidant, and temperature. The results
are summarized in Table 1. First, the oxidants (K2S2O8,
Na2S2O8, (NH4)2S2O8, and Oxone) were added to the reaction
system (entries 1−4). K2S2O8 performed better than other
oxidants. However, when the reaction was carried out in the
absence of an oxidant, we did not detect the formation of
indolizine product 3a (entry 11). Subsequently, a screen of
various additives (TfOH, MsOH, TsOH·H2 O, HCl, H2SO4,
and TFA) revealed that TFA is the best choice for the reaction
(entries 5−10). Variation of the reaction temperature
confirmed that 130 °C was the optimal condition for this
protocol, with lower and higher temperatures affording
decreased yields (entries 12 and 13). Furthermore, a very
low yield was obtained in the absence of TMEDA (entry 14).
This result indicated that TMEDA plays an important role in
the reaction. The yield had no significant change when the
reaction carried out in an argon atmosphere (entry 15).
With optimized conditions in hand, we investigated the
scope of N-(acylmethyl)pyridinium iodides 1 (Scheme 2).
Notably, the electronic properties of the substituents on the
aromatic ring system had a little effect on the reaction. The
Because of its availability, low toxicity, and relative stability,
dimethyl sulfoxide (DMSO) is commonly used as a polar
solvent and mild oxidant in the synthesis of organic
molecules.3 However, DMSO is not often considered as an
important and versatile synthon in organic synthesis.4
Recently, the reactivity of DMSO has been explored in the
synthesis of complex organic compounds, including DMSO-
based methylthiomethylation (CH2SMe),5 methylation (Me),6
metheylenation (CH2),7 formylation (CHO),8 cyanation
(CN),9 thiomethylation (SMe),10 and methylsulfonylation
(SO2Me) reactions.11 Although DMSO has been used in
syntheses to introduce various functional groups, to the best of
our knowledge, there are fewer examples of its use in
complicated sequential annulation/aromatization reactions to
access heterocyclic aromatic rings.3,12 For example, Zhang and
co-workers reported an efficient copper-catalyzed annulation of
amidines with DMSO for the synthesis of quinazolines via C−
N bond forming reactions (Scheme 1a).13 Very recently,
Cheng et al. developed a palladium-catalyzed annulation of
ortho-vinylanilines with DMSO, leading to 4-aryl quinolines
(Scheme 1b).14 In these methods, DMSO generally provides a
CH fragment, leading to six-membered cyclics,7g,12d,e
rather than five-membered heterocycles. With our continued
interest in DMSO as synthons,15 we herein report a transition-
Received: October 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b02755
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Figure 1. Selected examples bearing an indolizine skeleton.
pyridinium iodides bearing various electron-neutral (H) and
electron-donating (4-Me, 3-OMe, 4-OMe, 3,4-2OMe, 3,4-
OCH2 O) substituents on the benzene ring were smoothly
transformed into their corresponding products (3a−3f) in 65−
87% yields. To our delight, good to excellent yields were also
obtained for halo-substituted substrates (70−92%; 3g−3l and
3q). Heteroaryl (2-furyl and 2-thienyl) groups were also
investigated, and the yields were afforded in 75% and 82%,
respectively (3m and 3n). In addition, even when the substrate
contained sterically hindered 1-naphthyl and 2-naphthyl
groups, the corresponding products (3o and 3p) were
obtained in 86% and 78% yields, respectively. Finally, the
structure of 3b was determined by single-crystal X-ray
diffraction analysis (see Supporting Information).
Scheme 1. DMSO-Based Annulation/Aromatization
Reactions
Encouraged by these results, we further examined the scope
of the N-phenacylpyridinium salts 1 (Scheme 3). Pyridinium
salts bearing 3,5-dimethyl, 4-CO2Me, and 4-CN substituents
on the pyridinium gave the corresponding products in 58−71%
yields (4a, 4c, and 4d). Unfortunately, the desired products 4b
and 4e were not detected with 4-OMe or 4-I substituents on
the pyridinium group. The isoquinolinium salt was also a
suitable substrate for this transformation, leading to the
corresponding product 4f in 74% yield.
a
Table 1. Optimization of the Reaction Conditions
On the basis of our experimental results, a possible reaction
mechanism was proposed (Scheme 4, using 3a as an example).
Initially, DMSO (2) is activated by K2S2O8 to furnish thionium
ion 2′.16 This is attacked by the pyridinium ylide 1a′, derived
from N-phenacylpyridinium iodide 1a in the presence of
TMEDA, to furnish intermediate I. Next, intermediate I
undergoes rapid elimination of methanethiol to form the
methylene pyridinium salt II. This intermediate II participates
in a [3+2] cycloaddition reaction with pyridinium ylide 1a′,
converging on the tetrahydroindolizine III. Intermediate III is
oxidized to dihydroindolizine IV, which eliminates pyridine to
afford the desired product 3a. It is worth noting that the
potential intermediates 1a′, II, III, and IV were also detected
by ion trap mass spectrometry (ITMS) (see Supporting
Information).
In conclusion, we have developed a transition-metal-free
cascade oxidation/1,3-dipolar cycloaddition reaction for the
efficient and convenient synthesis of indolizine derivatives
from easily synthesized pyridinium salts and DMSO. DMSO
plays a vital role in this transformation, not only serving as a
solvent but also as a one-carbon source. Studies on the
application of this method to the synthesis of natural products
are underway in our laboratory.
b
entry
additive
oxidant
K2S2O8
Na2S2O8
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
130
130
130
71
66
59
60
78
45
17
26
30
83
0
(NH4)2S2O8
Oxone
130
TfOH
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
130
130
130
130
130
130
130
120
140
130
130
MsOH
TsOH·H2O
HCl
H2SO4
TFA
TFA
TFA
TFA
TFA
9
10
11
12
13
14
15
K2S2O8
K2S2O8
K2S2O8
K2S2O8
80
78
12
c
d
TFA
80
a
Reaction conditions: 1a (0.2 mmol, 2.0 equiv), additive (0.1 mmol,
1.0 equiv), oxidant (0.4 mmol, 4.0 equiv), TMEDA (0.1 mmol, 1.0
EXPERIMENTAL SECTION
b
c
■
equiv), and DMSO (3 mL) for 8 h. Isolated yields. Absence of
d
General Information. N-Phenacylpyridinium salts 1 were
prepared according to the literature procedure.17 Other substrates
and reagents were commercial grade and were used without further
TMEDA. Argon atmosphere.
B
DOI: 10.1021/acs.joc.8b02755
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Scheme 2. Scope of Pyridinium Ylides
a
Reaction conditions: pyridinium salts 1 (2.0 mmol, 2.0 equiv), TFA (1.0 mmol, 1.0 equiv), TMEDA (1.0 mmol, 1.0 equiv), and K2S2O8 (4.0
b
mmol, 4.0 equiv) was stirred in DMSO (5 mL) at 130 °C for 8 h. Isolated yields.
purification. TLC analysis was performed using precoated glass plates.
Column chromatography was performed using silica gel (200−300
mesh). IR spectra were recorded on a PerkinElmer PE-983 infrared
spectrometer as KBr pellets with absorption in cm−1. 1H NMR spectra
were determined at 25 °C on a Varian Mercury 400 or 600 MHz
spectrometer. 13C NMR spectra were recorded in CDCl3 or DMSO-
d6 on a 100/150 MHz spectrometer. Chemical shifts are given in ppm
relative to the internal standard of tetramethylsilane (TMS). HRMS
was obtained on an Thermo Scientific LTQ Orbitrap XL equipped
with an atmospheric pressure chemical ionization (APCI) source or
electrospray ionization (ESI) source. Melting points were determined
using an XT-4 apparatus and not corrected. The X-ray crystal-
structure determinations were obtained on a Bruker APEX DUO
CCD system.
General Procedure for the Synthesis of 3a−3q and 4a−4f
(3a as an Example). The mixture of N-phenacylpyridinium iodide
1a (650.2 mg, 2.0 mmol), TFA (114.0 mg, 1.0 mmol), TMEDA
(116.2 mg, 1.0 mmol), and K2S2O8 (1.081 g, 4.0 mmol) was added in
DMSO (5 mL), and the resulting mixture was stirred at 130 °C for 8
h. After the reaction completed, 100 mL of water was then added to
the mixture. The residue was extracted with CH2Cl2 three times (3 ×
100 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy on silica gel (petroleum ether/CH2Cl2 = 1/15) to afford the
desired product 3a.
Indolizine-1,3-diylbis(phenylmethanone) (3a):.18,19 83% yield
1
(270.1 mg); yellow solid; mp 211−213 °C; H NMR (400 MHz,
CDCl3) δ (ppm) 10.01 (d, J = 6.8 Hz, 1H), 8.65 (d, J = 8.8 Hz, 1H),
7.85−7.75 (m, 4H), 7.62 (s, 1H), 7.56−7.50 (m, 3H), 7.48−7.44 (m,
4H), 7.17 (t, J = 7.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm) 190.3, 185.5, 140.7, 139.9, 139.7, 131.5, 131.5, 130.4, 129.0,
128.9, 128.9, 128.8, 128.3, 128.3, 122.4, 120.3, 116.3, 113.6; IR (KBr,
cm−1) 1636, 1608, 1573, 1506, 1444, 1422, 1360, 1344, 1273, 1224,
1145, 1060, 1021, 882, 870, 765, 754, 656; HRMS (ESI, LTQ-
Orbitrap) m/z [M + H]+ calcd for C22H16NO2 326.1176, found
326.1177.
Indolizine-1,3-diylbis(p-tolylmethanone) (3b):19 72% yield (257.9
1
mg); yellow solid; mp 208−210 °C; H NMR (400 MHz, CDCl3) δ
(ppm) 9.98 (d, J = 6.8 Hz, 1H), 8.63 (d, J = 9.2 Hz, 1H), 7.74−7.70
(m, 4H), 7.64 (s, 1H), 7.55−7.47 (m, 1H), 7.30−7.25 (m, 4H),
C
DOI: 10.1021/acs.joc.8b02755
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The Journal of Organic Chemistry
Note
Orbitrap) m/z [M + H]+ calcd for C24H20NO4 386.1387, found
386.1388.
a
Scheme 3. Scope of Pyridinium Salts
Indolizine-1,3-diylbis((4-methoxyphenyl)methanone) (3d): 65%
yield (250.5 mg); yellow solid; mp 179−181 °C; 1H NMR (400
MHz, CDCl3) δ (ppm) 9.93 (d, J = 6.8 Hz, 1H), 8.59 (d, J = 8.8 Hz,
1H), 7.89−7.74 (m, 4H), 7.63 (s, 1H), 7.53−7.41 (m, 1H), 7.14−
7.10 (m, 1H), 6.98−6.95 (m, 4H), 3.87 (s, 3H), 3.86 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 189.1, 184.5, 162.5,
162.4, 140.5, 132.5, 132.2, 131.1, 131.1, 129.4, 128.8, 128.2, 122.3,
120.2, 115.8, 113.6, 113.6, 55.4, 55.3; IR (KBr, cm−1):1629, 1606,
1567, 1509, 1495, 1475, 1421, 1333, 1309, 1228, 1170, 1149, 1058,
1023, 886, 875, 842, 783, 766, 607; HRMS (ESI, LTQ-Orbitrap) m/z
[M + H]+ calcd for C24H20NO4 386.1387, found 386.1386.
Indolizine-1,3-diylbis((3,4-dimethoxyphenyl)methanone) (3e):
76% yield (338.6 mg); yellow solid; mp 208−210 °C; 1H NMR
(400 MHz, CDCl3) δ (ppm) 9.92 (d, J = 7.2 Hz, 1H), 8.59 (d, J = 8.8
Hz, 1H), 7.70 (s, 1H), 7.54−7.51 (m, 1H), 7.49−7.42 (m, 4H),
7.17−7.14 (m, 1H), 6.93−6.89 (m, 2H), 3.96 (s, 6H), 3.95(2) (s,
3H), 3.95(0) (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm)
189.1, 184.4, 152.2, 152.1, 149.0, 148.9, 140.6, 132.6, 132.3, 129.5,
128.8, 128.3, 123.3, 123.2, 122.3, 120.2, 115.9, 113.6, 111.7, 111.7,
110.0, 110.0, 56.0, 56.0, 56.0; IR (KBr, cm−1) 1633, 1598, 1578, 1500,
1426, 1336, 1269, 1219, 1178, 1141, 1098, 1025, 874, 815, 806, 776,
758, 631, 622; HRMS (ESI, LTQ-Orbitrap) m/z [M + H]+ calcd for
C26H24NO6 446.1598, found 446.1599.
a
Isolated yields
Indolizine-1,3-diylbis(benzo[d][1,3]dioxol-5-ylmethanone) (3f):
87% yield (359.7 mg); yellow solid; mp 222−224 °C; 1H NMR
(400 MHz, CDCl3) δ (ppm) 9.92 (d, J = 6.8 Hz, 1H), 8.60 (d, J = 8.8
Hz, 1H), 7.64 (s, 1H), 7.57−7.49 (m, 1H), 7.42−7.39 (m, 2H),
7.36−7.34 (m, 2H), 7.19−7.15 (m, 1H), 6.91−6.89 (m, 2H), 6.08 (s,
2H), 6.07 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm)
188.8, 184.1, 150.8, 150.7, 147.9, 147.9, 140.7, 134.2, 133.9, 129.5,
128.9, 128.5, 124.8, 124.8, 122.2, 120.3, 116.0, 113.5, 109.2, 109.2,
107.9, 107.8, 101.7, 101.66; IR (KBr, cm−1) 1622, 1591, 1496, 1436,
1348, 1255, 1210, 1161, 1102, 1037, 921, 842, 824, 781, 765, 754,
664; HRMS (ESI, LTQ-Orbitrap) m/z [M + H]+ calcd for
C24H16NO6 414.0972, found 414.0978.
Indolizine-1,3-diylbis((2-chlorophenyl)methanone) (3g): 70%
yield (276.0 mg); yellow solid; mp 211−212 °C; 1H NMR (400
MHz, CDCl3) δ (ppm) 9.99 (d, J = 6.8 Hz, 1H), 8.65 (d, J = 8.8 Hz,
1H), 7.74 (d, J = 8.0 Hz, 4H), 7.60 (t, J = 8.0 Hz, 1H), 7.53 (s, 1H),
7.50−7.45 (m, 4H), 7.22 (t, J = 6.6 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 189.0, 184.2, 141.0, 138.1, 138.1, 138.0,
130.3, 130.2, 129.8, 129.4, 129.2, 128.8, 128.8, 122.3, 120.4, 116.6,
7.17−7.13 (m, 1H), 2.42 (s, 3H), 2.41 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 190.1, 185.4, 142.1, 142.0, 140.7, 137.2,
137.0, 130.1, 129.1, 129.0, 128.9, 128.6, 122.4, 120.3, 116.1, 113.6,
21.5, 21.5; IR (KBr, cm−1) 1617, 1502, 1417, 1345, 1226, 1177, 1154,
1056, 1015, 890, 876, 829, 777, 765, 714, 619, 600; HRMS (ESI,
LTQ-Orbitrap) m/z [M + H]+ calcd for C24H20NO2 354.1489, found
354.1490.
Indolizine-1,3-diylbis((3-methoxyphenyl)methanone) (3c): 82%
yield (316.0 mg); yellow solid; mp 121−122 °C; 1H NMR (400
MHz, CDCl3) δ (ppm) 9.96 (d, J = 6.8 Hz, 1H), 8.63 (d, J = 8.8 Hz,
1H), 7.68 (s, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.39−7.35 (m, 3H),
7.35−7.31 (m, 3H), 7.15 (t, J = 7.2 Hz, 1H), 7.10−7.01 (m, 2H),
3.84 (s, 3H), 3.83 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm) 189.7, 185.0, 159.4, 159.3, 141.0, 140.8, 140.6, 130.3, 129.2,
129.1, 128.9, 128.8, 122.1, 121.2, 120.1, 117.7, 117.6, 116.2, 113.5,
113.4, 55.2, 55.2; IR (KBr, cm−1) 1633, 1578, 1501, 1481, 1432,
1338, 1250, 1209, 1150, 1035, 808, 788, 755, 654; HRMS (ESI, LTQ-
Scheme 4. Possible Mechanism
D
DOI: 10.1021/acs.joc.8b02755
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The Journal of Organic Chemistry
Note
113.5; IR (KBr, cm−1) 1618, 1589, 1510, 1485, 1418, 1357, 1345,
1222, 1157, 1088, 1056, 1013, 879, 838, 779, 758, 702, 688; HRMS
(ESI, LTQ-Orbitrap) m/z [M + H]+ calcd for C22H14Cl2 NO2
394.0396, found 394.0398.
Indolizine-1,3-diylbis(thiophen-2-ylmethanone) (3n): 75% yield
(252.9 mg); yellow solid; mp 169−170 °C; H NMR (400 MHz,
1
CDCl3) δ (ppm) 9.85 (d, J = 7.2 Hz, 1H), 8.60 (d, J = 8.8 Hz, 1H),
8.24 (s, 1H), 7.81−7.79 (m, 2H), 7.65−7.64 (m, 2H), 7.52−7.46 (m,
1H), 7.20−7.17 (m, 2H), 7.14−7.10 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 180.7, 176.2, 144.7, 143.9, 140.7, 132.1,
132.1, 131.9, 131.8, 128.8, 128.7, 127.8, 127.8, 127.3, 122.1, 120.3,
116.2, 113.5; IR (KBr, cm−1) 1631, 1593, 1511, 1482, 1413, 1357,
1333, 1272, 1234, 1192, 1156, 1058, 1038, 868, 846, 811, 773, 757,
721, 633; HRMS (ESI, LTQ-Orbitrap) m/z [M + H]+ calcd for
C18H12NO2S2 338.0304, found 338.0301.
Indolizine-1,3-diylbis((4-chlorophenyl)methanone) (3h): 91%
yield (358.8 mg); yellow solid; mp 188−190 °C; 1H NMR (400
MHz, CDCl3) δ (ppm) 9.98 (d, J = 6.8 Hz, 1H), 8.65 (d, J = 8.4 Hz,
1H), 7.74 (d, J = 8.0 Hz, 4H), 7.62−7.58 (m, 1H), 7.53 (s, 1H),
7.48−7.44 (m, 4H), 7.22 (t, J = 7.2 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 189.0, 184.2, 140.9, 138.1, 138.0, 137.9,
137.9, 130.3, 130.2, 129.9, 129.4, 129.2, 128.8, 128.7, 122.2, 120.4,
116.7, 113.4; IR (KBr, cm−1) 1638, 1616, 1589, 1508, 1484, 1441,
1423, 1357, 1342, 1271, 1222, 1177, 1156, 1131, 1086, 1057, 1011,
886, 874, 844, 837, 774, 759, 746, 703; HRMS (ESI, LTQ-Orbitrap)
m/z [M + H]+ calcd for C22H14Cl2NO2 394.0396, found 394.0398.
Indolizine-1,3-diylbis((2,4-dichlorophenyl)methanone) (3i): 92%
yield (424.1 mg); yellow solid; mp 153−155 °C; 1H NMR (400
MHz, CDCl3) δ (ppm) 10.07 (d, J = 7.2 Hz, 1H), 8.67 (d, J = 8.8 Hz,
1H), 7.70−7.65 (m, 1H), 7.51−7.46 (m, 2H), 7.37−7.35 (m, 1H),
7.34−7.32 (m, 3H), 7.31−7.27 (m, 1H), 7.05 (s, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ (ppm) 187.6, 182.6, 140.7, 137.9, 137.1, 136.5,
136.3, 132.4, 132.0, 130.8, 130.5, 130.3, 130.2, 130.0, 129.9, 129.6,
127.2, 127.1, 122.9, 120.5, 117.3, 114.5; IR (KBr, cm−1) 1626, 1682,
1511, 1489, 1444, 1421, 1363, 1348, 1219, 1135, 1102, 1077, 1037,
890, 876, 827, 783, 773, 719, 528; HRMS (ESI, LTQ-Orbitrap) m/z
[M + H]+ calcd for C22H12Cl4NO2 461.9617, found 461.9622.
Indolizine-1,3-diylbis((3,4-dichlorophenyl)methanone) (3j): 83%
yield (382.6 mg); yellow solid; mp 217−219 °C; 1H NMR (400
MHz, CDCl3) δ (ppm) 9.95 (d, J = 7.2 Hz, 1H), 8.63 (d, J = 8.8 Hz,
1H), 7.93−7.87 (m, 2H), 7.65−7.60 (m, 3H), 7.58−7.54 (m, 2H),
7.52 (s, 1H), 7.27−7.23 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ (ppm) 187.4, 182.6, 141.0, 139.3, 139.1, 136.3, 136.2, 133.1, 133.1,
130.9, 130.6, 130.6, 129.9, 129.8, 129.2, 127.9, 127.9, 122.0, 120.4,
117.0, 113.2; IR (KBr, cm−1) 1635, 1606, 1502, 1483, 1441, 1422,
1339, 1217, 1166, 1133, 1069, 1027, 923, 781, 761, 717, 520; HRMS
(ESI, LTQ-Orbitrap) m/z [M + H]+ calcd for C22H12Cl4NO2
461.9617, found 461.9620.
Indolizine-1,3-diylbis(naphthalen-1-ylmethanone) (3o): 86%
yield (365.9 mg); yellow solid; mp 151−152 °C; 1H NMR (400
MHz, CDCl3) δ (ppm) 10.22 (d, J = 6.8 Hz, 1H), 8.73 (d, J = 8.8 Hz,
1H), 8.20−8.14 (m, 2H), 7.83−7.77 (m, 4H), 7.57−7.52 (m, 3H),
7.46−7.43 (m, 4H), 7.32 (t, J = 8.0 Hz, 2H), 7.23 (s, 1H), 7.19 (m,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 191.5, 186.5, 140.7,
137.6, 136.9, 133.6, 133.6, 131.4, 130.6, 130.6, 130.5, 130.4, 129.5,
129.4, 128.2, 128.1, 126.9, 126.8, 126.8, 126.5, 126.2, 126.1, 125.5,
125.3, 124.3, 124.2, 123.8, 120.4, 116.6, 115.3; IR (KBr, cm−1) 1638,
1610, 1499, 1452, 1433, 1349, 1281, 1243, 1212, 1154, 1141, 1135,
1051, 894, 832, 823, 810, 789, 769, 643; HRMS (ESI, LTQ-Orbitrap)
m/z [M + H]+ calcd for C30H20NO2 426.1489, found 426.1487.
Indolizine-1,3-diylbis(naphthalen-2-ylmethanone) (3p): 78%
yield (331.9 mg); yellow solid; mp 234−235 °C; 1H NMR (400
MHz, CDCl3) δ (ppm) 10.09 (d, J = 7.2 Hz, 1H), 8.73 (d, J = 8.8 Hz,
1H), 8.35 (s, 2H), 8.01−7.91 (m, 6H), 7.88 (d, J = 6.8 Hz, 2H), 7.80
(s, 1H), 7.66−7.48 (m, 5H), 7.28−7.21 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ (ppm) 190.3, 185.5, 140.8, 137.2, 137.0, 134.8,
132.4, 132.4, 130.5, 130.0, 130.0, 129.1, 129.1, 128.9, 128.3, 128.3,
127.8, 127.7, 126.7, 126.6, 125.4, 125.3, 122.7, 120.4, 116.3, 114.0; IR
(KBr, cm−1) 1636, 1606, 1498, 1448, 1422, 1348, 1280, 1248, 1217,
1164, 1149, 1137, 1053, 890, 832, 823, 783, 774, 752, 725, 633, 586,
478; HRMS (ESI, LTQ-Orbitrap) m/z [M + H]+ calcd for
C30H20NO2 426.1489, found 426.1492.
Indolizine-1,3-diylbis((4-fluorophenyl)methanone) (3q): 85%
yield (307.2 mg); yellow solid; mp 107−109 °C; 1H NMR (600
MHz, CDCl3) δ (ppm) 9.97 (d, J = 6.6 Hz, 1H), 8.63 (d, J = 8.4 Hz,
1H), 7.83 (s, 4H), 7.67−7.56 (m, 1H), 7.55 (s, 1H), 7.25−7.19 (m,
1H), 7.17 (m, 4H); 13C{1H} NMR (150 MHz, CDCl3) δ (ppm)
188.8, 184.0, 165.6, 163.9, 140.8, 135.9, 135.7, 131.3, 131.2, 129.9,
129.2, 122.1, 120.3, 116.5, 115.6, 115.5, 115.5, 115.4, 113.4; IR (KBr,
cm−1) 1610, 1492, 1447, 1424, 1342, 1229, 1128, 1055, 879, 846,
769, 597; HRMS (ESI, LTQ-Orbitrap) m/z [M + H]+ calcd for
C22H14F2NO2 362.0988, found 362.0986.
Indolizine-1,3-diylbis((3-bromophenyl)methanone) (3k): 81%
yield (391.4 mg); yellow solid; mp 179−182 °C; 1H NMR (400
MHz, CDCl3) δ (ppm) 9.98 (d, J = 7.2 Hz, 1H), 8.65 (d, J = 8.8 Hz,
1H), 7.96−7.93 (m, 2H), 7.72−7.69 (m, 2H), 7.68−7.65 (m, 2H),
7.63−7.59 (m, 1H), 7.56 (s, 1H), 7.39−7.34 (m, 2H), 7.25−7.21 (m,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 188.4, 183.7, 141.6,
141.4, 140.9, 134.6, 134.5, 131.9, 130.4, 130.0, 129.6, 129.2, 127.4,
127.4, 122.7, 122.7, 122.1, 120.4, 116.8, 113.3; IR (KBr, cm−1) 1631,
1615, 1558, 1503, 1482, 1441, 1418, 1337, 1218, 1157, 1055, 877,
765, 728, 682, 649; HRMS (ESI, LTQ-Orbitrap) m/z [M + H]+ calcd
for C22H14Br2NO2 481.9386, found 481.9391.
(6,8-Dimethylindolizine-1,3-diyl)bis(phenylmethanone) (4a):
71% yield (250.9 mg); yellow solid; mp 177−178 °C; 1H NMR
(400 MHz, CDCl3) δ (ppm) 9.82 (s, 1H), 7.91−7.89 (m, 2H), 7.76−
7.73 (m, 2H), 7.57−7.51 (m, 1H), 7.50−7.41 (m, 5H), 7.40 (s, 1H),
7.14 (s, 1H), 2.56 (s, 3H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ (ppm) 190.4, 185.1, 140.2, 139.3, 138.0, 132.4, 132.1,
131.2, 130.9, 130.1, 129.4, 128.9, 128.2, 125.6, 125.01, 121., 116.0,
21.1, 18.3; IR (KBr, cm−1) 1643, 1604, 1573, 1509, 1479, 1439, 1410,
1349, 1247, 1285, 1247, 1175, 1147, 983, 944, 874, 853, 832, 763,
720, 705, 676, 666; HRMS (ESI, LTQ-Orbitrap) m/z [M + H]+ calcd
for C24H20NO2 354.1489, found 354.1488.
Indolizine-1,3-diylbis((4-bromophenyl)methanone) (3l):19 76%
yield (367.2 mg); yellow solid; mp 218−220 °C; 1H NMR (400
MHz, CDCl3) δ (ppm) 9.98 (d, J = 7.2 Hz, 1H), 8.65 (d, J = 8.4 Hz,
1H), 7.67−7.64 (m, 4H), 7.63−7.62 (m, 3H), 7.61−7.58 (m, 2H),
7.52 (s, 1H), 7.22 (t, J = 7.2 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ (ppm) 189.1, 184.3, 140.9, 138.5, 138.3, 131.8, 131.7,
130.4, 130.4, 129.9, 129.5, 129.2, 126.6, 126.5, 122.2, 120.4, 116.7,
113.4; IR (KBr, cm−1) 1617, 1585, 1505, 1480, 1413, 1357, 1344,
1273, 1221, 1156, 1131, 1066, 1054, 1009, 877, 834, 778, 766, 749,
681, 617, 503, 459; HRMS (ESI, LTQ-Orbitrap) m/z [M + H]+ calcd
for C22H14Br2NO2 481.9386, found 481.9389.
Methyl 1,3-Dibenzoylindolizine-7-carboxylate (4c): 58% yield
1
(222.4 mg); yellow solid; mp 221−224 °C; H NMR (400 MHz,
CDCl3) δ (ppm) 9.97 (d, J = 7.2 Hz, 1H), 9.25 (s, 1H), 7.88−7.77
(m, 4H), 7.72−7.68 (m, 1H), 7.67 (s, 1H), 7.60−7.53 (m, 2H),
7.51−7.46 (m, 4H), 4.00 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ (ppm) 190.1, 185.8, 165.1, 139.4, 139.2, 139.2, 132.0, 131.9, 130.2,
129.1, 129.0, 129.0, 128.5, 128.4, 128.4, 123.4, 122.4, 116.0, 115.2,
52.7; IR (KBr, cm−1) 1729, 1625, 1610, 1572, 1525, 1500, 1468,
1446, 1411, 1338, 1292, 1225, 1155, 1134, 1049, 967, 908, 881, 721,
673, 665; HRMS (ESI, LTQ-Orbitrap) m/z [M + H]+ calcd for
C24H18NO4 384.1230, found 384.1233.
Indolizine-1,3-diylbis(furan-2-ylmethanone) (3m): 82% yield
1
(250.3 mg); yellow solid; mp 186−187 °C; H NMR (400 MHz,
CDCl3) δ (ppm) 10.02 (d, J = 6.8 Hz, 1H), 8.88 (s, 1H), 8.73 (d, J =
8.4 Hz, 1H), 7.70 (d, J = 4.2 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.36
(s, 2H), 7.13 (t, J = 6.8 Hz, 1H), 6.62 (s, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 175.7, 171.0, 154.1, 153.2, 145.7, 145.5,
141.0, 129.2, 129.0, 128.2, 121.8, 120.4, 117.6, 117.3, 116.3, 112.9,
112.2, 112.1; IR (KBr, cm−1) 1631, 1600, 1566, 1512, 1472, 1441,
1388, 1360, 1279, 1241, 1170, 1062, 1012, 937, 886, 832, 774, 752,
595; HRMS (ESI, LTQ-Orbitrap) m/z [M + H]+ calcd for
C18H12NO4 306.0761, found 306.0761.
1,3-Dibenzoylindolizine-7-carbonitrile (4d): 60% yield (210.2
1
mg); yellow solid; mp 202−204 °C; H NMR (400 MHz, CDCl3)
δ (ppm) 10.00 (d, J = 7.2 Hz, 1H), 9.00 (s, 1H), 7.82−7.80 (m, 4H),
E
DOI: 10.1021/acs.joc.8b02755
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The Journal of Organic Chemistry
Note
7.71 (s, 1H), 7.62−7.57 (m, 2H), 7.53−7.48 (m, 4H), 7.27−7.23 (m,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 190.0, 186.0, 138.9,
138.8, 137.9, 132.4, 132.2, 129.9, 129.1, 129.0, 128.9, 128.6, 128.6,
126.3, 123.8, 117.1, 115.9, 115.8, 110.7; IR (KBr, cm−1) 1622, 1597,
1577, 1512, 1469, 1409, 1351, 1342, 1230, 1168, 1046, 880, 814, 721,
706, 697, 661; HRMS (ESI, LTQ-Orbitrap) m/z [M + H]+ calcd for
C23H15N2O2 351.1128, found 351.1127.
W.; He, Y.; Wang, C. Application of primary halogenated hydro-
carbons for the synthesis of 3-aryl and 3-alkyl indolizines. Org. Biomol.
Chem. 2017, 15, 5016. (e) Li, X.; Zhao, J.; Xie, X.; Liu, Y. Synthesis of
functionalized indolizines via gold(i)-catalyzed intramolecular hydro-
arylation/aromatization of pyrrole-ynes. Org. Biomol. Chem. 2017, 15,
8119.
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Dimethyl Sulfoxide Involved One-Pot Synthesis of Quinoxaline
Derivatives. J. Org. Chem. 2017, 82, 3491. (b) Zhu, X.; Li, W.; Luo,
X.; Deng, G.; Liang, Y.; Liu, J. Catalyst-free and Additive-free Method
for the Synthesis of Benzothiazolethiones from o-Iodoanilines, DMSO
and Potassium Sulfide. Green Chem. 2018, 20, 1970.
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as a Synthon in Organic Chemistry. Synthesis 2016, 48, 1421. (b) Wu,
X. F.; Natte, K. The Applications of Dimethyl Sulfoxide as Reagent in
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Pyrrolo[2,1-a]isoquinoline-1,3-diylbis(phenylmethanone) (4f):18
74% yield (277.8 mg); yellow solid; mp 139−142 °C; 1H NMR (400
MHz, CDCl3) δ (ppm) 9.65 (d, J = 7.2 Hz, 1H), 8.99 (d, J = 8.4 Hz,
1H), 7.94−7.92 (m, 2H), 7.82−7.79 (m, 2H), 7.72 (d, J = 7.6 Hz,
1H), 7.58 (t, J = 7.6 Hz, 1H), 7.55−7.47 (m, 3H), 7.44 (t, J = 7.6 Hz,
4H), 7.41 (s, 1H), 7.27 (d, J = 7.6 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 192.1, 185.6, 139.6, 139.3, 136.5, 132.5,
131.6, 130.3, 130.2, 129.9, 129.3, 129.0, 128.2, 128.2, 127.6, 126.8,
126.7, 125.7, 124.9, 124.3, 123.0, 117.7, 115.7; IR (KBr, cm−1) 1614,
1573, 1514, 1451, 1419, 1384, 1336, 1268,1207, 963, 872, 802, 713,
652; HRMS (ESI, LTQ-Orbitrap) m/z [M + H]+ calcd for
C26H18NO2 376.1332, found 376.1335.
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General Method for N Methylation of Amines and Nitro Compounds
with Dimethylsulfoxide. Chem. - Eur. J. 2014, 20, 58. (b) Jia, J.; Jiang,
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Catalyzed O-Methylation of Carboxylic Acids Using DMSO as a
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Ren, Y.; Bian, M.; Yang, X.; Yang, B.; Yan, Q.; Zhao, J. An Iron(II)
Chloride Promoted Radical Cascade Methylation or α-Chloro-β-
methylation of N-Arylacrylamides with Dimethyl Sulfoxide. Adv.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b02755.
1
Copies of H and 13C NMR spectra of compounds 3a−
3q and 4a−4f and MS spectra of intermediates (PDF)
Crystal data for compound 3b (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: shuwm@yangtzeu.edu.cn.
*E-mail: chwuax@mail.ccnu.edu.cn.
■
(7) (a) Patel, O. P. S.; Anand, D.; Maurya, R. K.; Yadav, P. P. H2
O2/DMSO-Promoted Regioselective Synthesis of 3,3′-Bisimidazopyr-
idinylmethanes via Intermolecular Oxidative C(sp2)-H Bond
Activation of Imidazoheterocycles. J. Org. Chem. 2016, 81, 7626.
(b) Xue, L.; Cheng, G.; Zhu, R.; Cui, X. Acid-promoted oxidative
methylenation of 1,3-dicarbonyl compounds with DMSO: application
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Y. Q.; Liu, Q.; Luo, W. P.; Guo, C. C. Transition Metal-Free alpha-
Csp3-H Methylenation of Ketones to Form C horizontal lineC Bond
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Metal-Free In Situ Generation of Terminal Alkenes: Synthesis of
Multisubstituted Acrylamidines via Tandem sp3 C−H Olefination/sp2
C−H Arylation Reactions. ACS Catal. 2017, 7, 7783. (g) Phanin-
drudu, M.; Wakade, S. B.; Tiwari, D. K.; Likhar, P. R.; Tiwari, D. K.
Transition-Metal-Free Approach for the Synthesis of 4-Aryl-quino-
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ORCID
An-Xin Wu: 0000-0001-7673-210X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21472056, 21772051, and 21801022) for financial
support. This work was also supported by the Yangtze Youth
Talents Fund (2016cqn25) and the Doctoral Scientific
Research Startup Foundation of Yangtze University
(801090010135).
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