Effect of solvent nature on the regioselectivity of the reactions of pyridinium ylides with E-1,2-di(alkylsulfonyl)-1,2-dichloroethene. from the reaction of 1,3-dipolar cycloaddition to the reaction of nucleophilic addition-elimination (AdN-E<s

Article abstract of DOI:10.1016/j.tet.2013.03.098

The effect of solvent nature on the reactions of pyridinium ylides with E-1,2-di(alkylsulfonyl)-1,2-dichloroethene was investigated for the first time. It was found, that in aprotic solvents (CHCl₃, DMF, CH₃CN) these reactions take p

Full text of DOI:10.1016/j.tet.2013.03.098

Tetrahedron 69 (2013) 5016e5021
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Effect of solvent nature on the regioselectivity of the reactions of
pyridinium ylides with E-1,2-di(alkylsulfonyl)-1,2-dichloroethene.
From the reaction of 1,3-dipolar cycloaddition to the reaction of
nucleophilic additioneelimination (AdNeE1,5)
,
b
,
y
,
,
z
Natalia E. Dontsova a , Vladimir N. Nesterov x, Anatoliy M. Shestopalov a
*
a N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., Moscow 119991, Russian Federation
b N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov str., Moscow 119991, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
The effect of solvent nature on the reactions of pyridinium ylides with E-1,2-di(alkylsulfonyl)-1,2-
dichloroethene was investigated for the first time. It was found, that in aprotic solvents (CHCl3, DMF,
CH3CN) these reactions take place as a 1,3-dipolar cycloaddition (1,3-DC) followed by double elimination
with the formation of substituted 1,2-di(alkylsulfonyl)indolizines. In a protic solvent (EtOH) in the
presence of excess Et3N and heating, the reactions of substituted pyridinium salts with E-1,2-
di(alkylsulfonyl)-1,2-dichloroethenes take place simultaneously as a 1,3-DC and as an additioneelimi-
nation (AdNeE1,5) and lead to the formation of 1,2-di(alkylsulfonyl)indolizines and 4,5-di(alkylsulfonyl)
furans.
Received 12 November 2012
Received in revised form 4 March 2013
Accepted 26 March 2013
Available online 6 April 2013
Keywords:
Nature of solvent
Pyridinium ylides
E-1,2-Di(alkylsulfonyl)-1,2-dichloroethene
1,3-Dipolar cycloaddition
1,2-Di(alkylsulfonyl)indolizines
Ó 2013 Elsevier Ltd. All rights reserved.
Additioneelimination (AdNeE1,5
)
4,5-Di(alkylsulfonyl)furans
1. Introduction
nitriles. For example, the reactions of unsaturated nitriles with 3-
cyanopyridinium ylides or isoquinolinium ylides form tetrahy-
1,3-Dipolar cycloaddition reactions of pyridinium ylides, quino-
linium ylides, and isoquinolinium ylides with unsaturated com-
pounds have been widely used in the preparative synthesis of
indolizines, imidazopyridines, and other cycloazines.1e5 The in-
fluence of the structures of the azinium ylides and of the un-
saturated compounds on the regio- and stereoselectivity of these
reactions is well known. Usually, for the synthesis of aromatic
indolizines, reactions of pyridinium ylides with acetylenes are
droindolizines or tetrahydrobenzoindolizines, respectively.11e13
In the presence of electrophilic groups, such as fluoride or
chloride in a
p-deficient ethylene, the 1,3-dipolar cycloaddition
reaction is followed by an elimination reaction to form aromatic
indolizines.14e17
Depending on the temperature conditions and the structures of
the pyridinium ylides, their reactions with unsaturated compounds
can proceed as double cycloadditions. For example, the reaction of
the acetylenedicarboxylic acid dimethyl ester with a pyridinium
ylide leads to a mixture of indolizine and quinazoline.3
Consequently, the dependence of regio- and stereoselectivity of
reactions of azinium ylides with unsaturated compounds on the
structure of the starting compounds and temperature is well
known. To date, the effect of the solvent nature on these reactions
remains virtually unexplored.1e5
used.1e5 As a rule, reactions of azinium ylides with
p-deficient
ethylenes proceed stereoselectively with the formation of hydro-
genated indolizines.6e8 The reactions of unsaturated nitriles with
pyridinium ylides lead to the formation of cyclopropanes.7,10 Re-
duction of the electron density in the aziniumylide leads to a change
in the direction of reactions of azinium ylides with unsaturated
* Corresponding author. Fax: þ7 (499) 135 53 28; e-mail address: gsv@ioc.ac.ru
(N.E. Dontsova).
2. Results and discussion
y
Current address: Department of Chemistry, University of North Texas, Denton,
TX 76203, USA.
z
Investigating the reactions of pyridinium ylides 2 with E-1,2-
di(alkylsulfonyl)-1,2-dichloroethenes 3, we first discovered that
Fax: þ7 (499) 135 53 28.
x
Fax: þ7 (495) 135 5085.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.098

N.E. Dontsova et al. / Tetrahedron 69 (2013) 5016e5021
5017
the solvent nature significantly affects the regioselectivity of such
reactions. Pyridinium salts 1 were treated with Et3N in a solvent,
generating pyridinium ylides 2, followed by the addition of ethenes
3. The reaction mixture was heated up to 50 ꢀC for 40 min. We
found that the reactions of pyridinium ylides 2aed with ethenes
3a,b in CHCl3 in the presence of Et3N proceed regioselectively with
the formation of a high yield of substituted 1,2-di(alkylsulfonyl)
indolizines 4aef (65e73%) (Scheme 1). In polar aprotic solvents
(CH3CN or DMF) the reactions of pyridinium ylide 2a with ethene
3a also occur with the formation of indolizine 4a (62 or 64%, re-
spectively). The formation of indolizines 4 can be represented with
a classical scheme of the 1,3-dipolar cycloaddition reaction through
the adduct 5. Subsequent double dehydrochlorination of 5 leads to
the aromatic indolizines 4.
R4O2S
Cl
Cl
R2
R1
R3
R2
R1
Br
R3
SO2R4
3 Et3N
N
N
Et3NH+Br
3a,b
50 oC, 40 min.
O
O
6
4
2a-d
1a-d
2a
2a
H
H
H
H
2,4-Me2-C6H3 3a Et
2,4-Me2-C6H3 3a n-Pr 6b 4b 36
6a 4a 38
14
17
9
44
18
2b Me Me 2,4-Me2-C6H3 3b n-Pr 6c 4c 50
R2
R1
R2
R3
R1
Me Me 4-F-C6H4
Me 2,4-Me2-C6H3
n-Pr
n-Pr
12
38
2c
2d
3b
3b
6d 4d
6e 4e
H
Cl
SO2R4
Cl
SO2R4
SO2R4
SO2R4
H
R3
O
N
N
2 Et3NH+Cl
+
4f
H
a Furans 6a-e were isolated as a mixture of substituted 1-[2-Phenyl-4,5-
bis(alkylsulfonyl)-3-furyl]pyridinium bromides and chlorides. Br¯ ions were
present in the reaction medium because pyridinium ylides 2 were generated in
situ, by treatment of phenacylpyridinium bromides with Et3N. The yields of
pyridinium bromides are shown. Resulting mixtures of pyridinium halides 6a-
e were converted into bromides by heating them with an excess of HBr.
O
4a-f
5
R1
R2
R3
R4
Solvent Pro- Yield
duct (%)
CHCl3
MeCN
DMF
H
H
H
H
H
H
H
H
2,4-Me2-C6H3
2,4-Me2-C6H3
2,4-Me2-C6H3
2,4-Me2-C6H3
Et
Et
Et
73
62
64
69
75
67
65
2a
2a
2a
2a
2b
2c
3a
3a
3a
3b
3b
3b
3b
4a
4a
4a
4b
4c
Scheme 2. The reactions of pyridinium ylides 2aed with ethenes 3a,b in EtOH.
n-Pr CHCl3
n-Pr CHCl3
n-Pr CHCl3
n-Pr CHCl3
Me Me 2,4-Me2-C6H3
Me Me 4-F-C6H4
4d
4e
+
CN
CN
Ar
H
Ar
2d Me
H
2,4-Me2-C6H3
NC
CN
Ar
CN
N
E1,3
N
AdN
4fa
+
O
EtOH
a
CN
DMSO
A mixture of substituted 6-methyl- 4e and 8-methylindolizines 4f was
isolated.
H2N
O
H2N
O
NH2
12
14
13
Scheme 1. The reactions of pyridinium ylides 2aed with ethenes 3a,b in aprotic
solvents.
Scheme 3. The reactions of pyridinium ylides and arylidenmalononitriles in alcohol.
In a protic solvent (EtOH) reactions of pyridinium ylides 2aed
with ethenes 3a,b proceed with the formation of a mixture of
substituted 1,2-di(alkylsulfonyl)furans 6aee and the corresponding
indolizines 4aef as minor components (Scheme 2). Formation of an
indolizine ring can probably occur not only simultaneously through
the adduct of 1,3-DC 5, but also stepwise. In this case, a Michael
adduct (reaction AdN) in the form of a zwitterion 7 is formed ini-
tially. Subsequent intramolecular closure of zwitterion 7 and dou-
ble elimination of HCl leads to the formation of indolizines 4.
However, the dominant direction of the reaction, presumably, be-
gins with the stage of protonation of the zwitterion 7 with ethanol
and the formation of adduct 8. The adduct 8 gets deprotonated with
EtOꢁ under the reaction conditions with the formation of enolate 9.
1,5-Elimination of HCl leads to the closure of the dihydrofuran ring
10, subsequent 1,2-elimination of HCl leads to substituted furan 6.
Furans 6 were isolated and characterized as salts.
Furans 6aee were isolated as a mixture of substituted 1-[2-
phenyl-4,5-bis(alkylsulfonyl)-3-furyl]pyridinium bromides and
chlorides in a ratio of approximately 8:1 (The ratios were calculated
based on the results of potentiometric titration of a mixture of
halides with 0.01 N solution of AgNO3). The resulting mixtures of
pyridinium halides 3aee were converted in to bromides by heating
them with an excess of HBr.
The structures of the synthesized compounds 4 and 6 were
confirmed by elemental analysis, 1H and 13C NMR spectroscopy, IR
spectroscopy, and mass spectrometry. The IR spectra of the com-
pounds 4 and 6 contain absorption bands corresponding to the
stretching vibrations of the sulfonyl group18 at 1332e1312 and
1148e1140 cmꢁ1. In addition, the spectra of indolizines 4 contain
characteristic bands for the carbonyl group absorption corre-
sponding to the stretching vibrations in the region
1672e1664 cmꢁ1. In the mass spectra of all synthesized indolizines
4aef the molecular ions Mþ were present. In the case of furans
6aee, signals corresponding to the mass of the cations [MꢁBr]þ
were present. In the 1H NMR spectra of furans 6 proton signals of
the pyridine fragment are found in the lower fields relative to the
signals of the corresponding protons in the indolizines 4. The sig-
nals of H(2) and H(6) in the furans 6 appear as two doublets in 6a,b,
Note, that similar zwitterions 11 were isolated from the re-
actions of pyridinium ylides 12 and arylidenmalononitriles 13 in
alcohol (Scheme 3).9,10 However, they underwent 1,3-elimination
in EtOH or DMSO with the formation of cyclopropanes.14 A cycli-
zation reaction to give the corresponding indolizine was not
observed.

5018
N.E. Dontsova et al. / Tetrahedron 69 (2013) 5016e5021
a singlet and a doublet in 6e, and a singlet in 6d,e in the area
9.25e9.55 ppm. The H(5) proton in the indolizines 4 shows as
a doublet in 4a,b and a singlet in 4c,d in the area 7.84e8.40 ppm. In
the reaction of ethene 1b with ylide 2d, an isomeric mixture of
substituted 6-methyl 4e and 8-methylindolizine 4f along with fu-
ran 6e was isolated. This mixture had a ratio between 4e and 4f of
1:2 based on an analysis of the 1H NMR spectrum. Previously, we
reported the formation of two isomeric indolizines in the reaction
to the formation of 1,2-di(alkylsulfonyl)indolizines and
4,5-di(alkylsulfonyl) furans.
4. Experimental section
4.1. General
All synthesized compounds were characterized by elemental
microanalysis, 1H, 13C NMR spectroscopy, IR spectroscopy, and mass
spectrometry. The progress of reactions and the compounds’ purity
were monitored by thin layer chromatography on silica gel-coated
aluminum plates with the use of a 2:1 hexane/acetone mixture as
an eluent and visualized under a UV lamp (254 nm). Melting points
were measured on a Kofler stage and are uncorrected. Elemental
microanalyses were obtained on a PerkineElmer 2400 CHNanalyzer.
The analytical results for C, H, and N were within ꢂ0.4 of the theo-
retical values. The IR spectra of the compounds were recorded on
PerkineElmer-577 Specord M-82 Fourier-spectrometer in KBr pel-
lets (1:200 mass), the frequencies are expressed in cmꢁ1. The 1H NMR
spectra were recorded on Bruker DRX-500 (500 MHz), Bruker AH-
300 (300 MHz), and Bruker WM-250 (250 MHz) and 13C NMR
spectra were recorded on Bruker AM-300 (75.47 MHz) instruments
for 5e12% solutions in DMSO-d6 with TMS as an internal standard
and CDCl3. Chemical shift values are listed in parts per million (ppm)
with reference to DMSO-d6 (1H, 2.50; 13C, 39.50) or CDCl3 (1H, 7.25,
13C, 77.0). Coupling constants (J) are given in Hertz. Hydrogen mul-
tiplicity (C, CH, CH2, CH3) information of 13C NMR spectra was ob-
tained from carbon JMOD-XH technique. The mass spectra of
indolizines 4aef and furans 6aee were obtained on a FINNIGAN MAT
INCOS 50 quadrupole mass spectrometer with ionization energy of
70 eV. High-resolution mass spectrometry data for pyridinium salts
1aed were acquired using a Q-TOF analyzer in CH3CN as solvent.
of E-1,2-di(alkylsulfonyl)-1,2-dichloroethene with
b-picolinium
ylide.16
The structure of furan 6c was investigated by X-ray analysis
(Fig.1). Geometric parameters of the cation have usual values.19 The
substituted furan heterocycle is strictly flat (deviation from the
ꢀ
mean plane of atoms does not exceed 0.002 A). Steric hindrance due
to the presence of many shortened intramolecular non-valence
contacts influences the geometry of the propylsulfonyl sub-
stituents and causes the turning of the 3,5-dimethylpyridine and
2,4-dimethylphenyl substituents relative to the plane of the het-
erocycle ring at 85.6ꢀ and 33.2ꢀ, respectively. The dihedral angle
between 3,5-dimethylpyridine and 2,4-dimethylphenyl sub-
stituents is equal to 88.9ꢀ. There are distortions from the tetrahe-
dral configuration oꢀbserved at sulfur atoms, such that angles range
between 103.2(3)
and 119.4(3)ꢀ at atom S(1) and between
104.4(3)ꢀ and 119.2(3)ꢀ at atom S(2). These values are usual for
substituted arylsulfones,20 and coincide with the values found in
earlier work in the substituted 1,2-di(ethylsulfonyl)indolizine.15
4.2. Pyridinium salts 1aed
Compounds 1aed were obtained from commercially available
pyridines by alkylation with the corresponding phenacyl bromides
at dry acetone on reflux.21
4.2.1. 1-[2-(2,4-Dimethylphenyl)-2-oxoethyl]pyridinium
1a. Yield¼92%,
white solid with mp 214e215 ꢀC (lit.
211.5e212.5 ꢀC).22 IR: 2923, 1680 cmꢁ1 1H NMR (DMSO-d6,
300 MHz) : 2.39 (s, 3H, 4-Me Ph), 2.46 (s, 3H, 2-Me Ph), 6.50 (s, 2H,
bromide
a
.
d
CH2CO), 7.26 (s,1H, 3-H Ph), 7.32 (d,1H, J 8.0 Hz, 5-H Ph), 8.00 (d,1H,
J 8.0 Hz, 6-H Ph), 8.29 (t, 2H, J 7.0 Hz, 3-H, 5-H Py), 8.77 (t, 1H, J
7.8 Hz, 4-H Py), 9.08 (d, 2H, J 6.1 Hz, 2-H, 6-H Py). 13C NMR (DMSO-
d6, 75.47 MHz) d: 21.0, 21.3, 67.2,126.7,127.7 (3C),130.1,130.2,132.9,
139.5, 143.7 (2C), 146.2, 192.0. Anal. Calcd for C15H16BrNO: C, 58.84;
H, 5.27; N, 4.57. Found: C, 59.05; H, 5.35, N, 4.50.
4 . 2 . 2 . 1 - [ 2 - ( 2 , 4 - D i m e t h y l p h e n y l ) - 2 - o x o e t h y l ] - 3 , 5 -
dimethylpyridinium bromide 1b. Yield¼85%, a white solid with mp
219e220 ꢀC. IR: 2928, 1684 cmꢁ1. 1H NMR (DMSO-d6, 300 MHz)
d:
2.38 (s, 3H, 4-Me Ph), 2.46 (s, 3H, 2-Me Ph), 2.49 (s, 6H, 3-Me, 5-Me
Py), 6.35 (s, 2H, CH2CO), 7.20-7.38 (m, 2H, 5-H, 6-H Ph), 8.00 (s, 1H,
3-H Ph), 8.35 (s, 1H, 4-H Py), 8.85 (s, 2H, 2-H, 6-H Py). 13C NMR
Fig. 1. X-ray structure of compound 6c. Ellipsoids were drawn at the 50% level.
3. Conclusion
(DMSO-d6, 75.47 MHz) d: 17.7, 21.0, 21.3, 66.7, 126.7, 130.1, 130.3,
We were the first to observe the effect of the solvent nature
on the reaction of pyridinium ylides with E-1,2-di(alkylsulfonyl)-
1,2-dichloroethenes. It was found, that in aprotic solvents (CHCl3,
DMF, CH3CN) this reaction proceeds as a 1,3-dipolar cycloaddi-
tion (1,3-DC) followed by double elimination with the formation
of substituted 1,2-di(alkylsulfonyl)indolizines. In a protic solvent
(EtOH), the reaction of substituted pyridinium ylides with E-1,2-
di(alkylsulfonyl)-1,2-dichloroethenes occurs simultaneously as
a 1,3-DC and as an additioneelimination (AdNeE1,5) and leads
132.9, 137.3, 139.3, 143.0, 143.6, 146.9, 192.1. MS m/z 254.155
(MþꢁBr). Anal. Calcd for C17H20BrNO: C, 61.09; H, 6.03; N, 4.19.
Found: C, 61.33; H, 6.10; N, 4.27.
4.2.3. 1-[2-(3-Fluorophenyl)-2-oxoethyl]-3,5-dimethylpyridinium
bromide 1c. Yield¼83%, a white solid with mp 196e197 ꢀC. IR: 3013,
1696 cmꢁ1. 1H NMR (DMSO-d6, 300 MHz)
d: 2.50 (s, 6H, 3-Me, 5-Me
Py), 6.48 (s, 2H, CH2CO), 7.52 (t, 2H, J 8.8 Hz, 3-H, 5-H Ph), 8.14e8.21
(m. 2H, 2-H, 4-H Ph), 8.45 (s, 1H, 4-H Py), 8.80 (s, 2H, 2-H, 6-H Py). 13C

N.E. Dontsova et al. / Tetrahedron 69 (2013) 5016e5021
5019
NMR (DMSO-d6, 75.47 MHz)
d
: 17.7 (3-Me, 5-Me Py), 65.7,116.1,116.4,
with mp 175e176 ꢀC. IR: 1664, 1304, 1140 cmꢁ1. 1H NMR (DMSO-d6,
300 MHz) : 0.77 (t, 3H, J 7.4 Hz, CH3CH2), 1.04 (t, 3H, J 7.4 Hz,
CH3CH2), 1.33e1.60 (m, 2H, CH3CH2), 1.77e1.92 (m, 2H, CH3CH2),
2.20 (s, 3H, 6-Me Ind.), 2.34 (s, 3H, 4-Me Ph), 2.57 (s, 3H, 2-Me Ph),
2.72 (s, 3H, 8-Me Ind.), 3.30e3.42 (m, 2H, CH2SO2), 3.55e3.62 (m,
2H, CH2SO2), 7.07 (d, 1H, J 7.4 Hz, 5-H Ph), 7.14 (d, 1H, J 8.1 Hz, 6-H
Ph), 7.20 (s, 1H, 3-H Ph), 7.25 (s, 1H, C(7)H), 7.84 (s, 1H, C(5)H). 13C
130.3 (3-C, 5-C Py), 131.4, 131.5, 137.5, 143.0 (2C), 147.1, 164.0, 167.4,
189.5. MS m/z 244.114 (MþꢁBr). Anal. Calcd for C15H15BrFNO: C,
55.60; H, 4.67; N, 4.32. Found: C, 55.83; H, 4.76; N, 4.24.
d
4.2.4. 1-[2-(2,4-Dimethylphenyl)-2-oxoethyl]-3-methylpyridinium
bromide 1d. Yield¼91%, a white solid with mp 210e211 ꢀC. IR:
2925, 1681 cmꢁ1. 1H NMR (DMSO-d6, 300 MHz)
d
: 2.38 (s, 3H, 4-Me
NMR (DMSO-d6, 75.47 MHz) d: 12.6, 12.8, 15.0, 15.3, 17.1, 20.7, 21.0,
Ph), 2.47 (s, 3H, 2-Me Ph), 2.55 (s, 3H, 3-Me Py), 6.45 (s, 2H, CH2CO),
7.25 (s, 1H, 3-H Ph), 7.30 (d, 1H, J 8.1 Hz, 5-H Ph), 8.03 (d,1H, J 8.0 Hz,
6-H Ph), 8.18 (t, 1H, J 7.0 Hz, 5-H Py), 8.59 (d, 1H, J 7.8 Hz, 4-H Py),
8.93 (d, 1H, J 5.6 Hz, 6-H Py), 9.00 (s, 1H, 2-H Py). 13C NMR (DMSO-
22.1, 57.7, 69.3, 110.4, 120.6, 125.2, 126.4, 127.6, 128.5, 128.7, 131.5,
132.2, 132.7, 133.3, 134.3, 140.0, 143.6, 189.3. MS m/z 489 (Mþ, 19).
Anal. Calcd for C25H31NO5S2: C, 61.32; H, 6.38; N, 2.86. Found: C,
61.59; H, 6.44; N, 2.85.
d6, 75.47 MHz) d: 17.8 (CH3), 21.0 (CH3), 21.2 (CH3), 66.9 (CH2), 126.7
(CH), 127.0 (CH), 130.0 (CH), 130.2 (C), 132.9 (CH), 138.1 (C), 139.4
(C), 143.5 (C), 143.7 (CH), 145.5 (CH), 146.5 (CH), 192.0 (C). MS m/z
240.138 (MþꢁBr). Anal. Calcd for C16H18BrNO: C, 60.04; H, 5.67; N,
4.37. Found: C, 60.28; H, 5.71; N, 4.30.
4.4.4. [6,8-Dimethyl-1,2-bis(propylsulfonyl)-3-indolizinyl](4-
fluorophenyl) methanone 4d. Yield¼0.32 g (67%), an yellow solid
with mp 155e156 ꢀC. IR: 1700, 1324, 1140 cmꢁ1. 1H NMR (DMSO-d6,
500 MHz) d: 0.86 (t, 3H, J 7.44 Hz, CH3CH2), 1.04 (t, 3H, J 7.44 Hz,
CH3CH2), 1.52e1.59 (m, 2H, CH3CH2), 1.82e1.90 (m, 2H, CH3CH2),
2.16 (s, 3H, 6-Me Ind.), 2.70 (s, 3H, 8-Me Ind.), 3.57e3.61 (m, 4H,
2CH2SO2), 7.20 (s, 1H. C(7)H), 7.37e7.41 (m, 2H, 3-H, 5-H Ph), 7.73 (s,
1H, C(5)H), 7.82e7.85 (m, 2H, 2-H, 6-H Ph). 13C NMR (DMSO-d6,
4.3. E-1,2-Di(alkylsulfonyl)-1,2-dichloroethenes 3a,b
Compounds 3a,b were synthesized according to a procedure
described earlier.18
75.47 MHz) d: 12.6 (CH3), 12.8 (CH3), 15.3 (CH2), 15.4 (CH2), 16.9
(CH3), 22.1 (CH3), 58.0 (CH2), 59.5 (CH2), 110.3 (C), 116.0 (CH), 116.3
(CH), 120.6 (CH), 125.3 (C), 126.8 (C), 128.6 (C), 131.9 (CH), 132.2
(CH), 132.3 (CH), 133.5 (C), 133.7 (C), 164.0 (C), 167.3 (C), 186.5 (C).
MS m/z 479 (Mþ, 21). Anal. Calcd for C23H26FNO5S2: C, 57.60; H,
5.46; N, 2.92. Found: C, 57.32; H, 5.51; N, 2.88.
4.4. Substituted 1,2-di(alkylsulfonyl)indolizines 4aef (general
procedure)
Triethylamine (3 mmol) was added to a stirred solution of pyr-
idinium salt 1 (1 mmol) in 8 ml of CHCl3 (CH3CN, DMSO) and then
a solution of sulfone 3 (1 mmol) was added dropwise. The reaction
mixture was heated at 50 ꢀC for 40 min (progress monitored by thin
layer chromatography), diluted with CHCl3, washed with water, and
dried with MgSO4. The solvent was evaporated and the solid resi-
due was recrystallized (Et2O/CHCl3¼1:2).
4.4.5. (2,4-Dimethylphenyl)[6-methyl-1,2-bis(propylsulfonyl)-3-
indolizinyl] methanone 4e and (2,4-dimethylphenyl)[8-methyl-1,2-
bis(propyl-sulfonyl)-3-indolizinyl]methanone 4f. Yield¼0.31 g (65%)
a white solid IR: 1664,1324,1140 cmꢁ1. 1H NMR (CDCl3, 250 MHz)
d:
0.87 (t, 3H, J¼7.3 Hz, CH3CH2 4e), 0.98e1.21 (m, CH3CH2 4e,
2CH3CH2 4f), 1.52e1.71 (m, 2H, CH3CH2 4e,f), 1.75e2.11 (m, 2H,
CH3CH2 4e,f), 2.26 (s, 6-Me Ind.4e), 2.37 (s, 3H, 4-Me Ph 4e,f), 2.66
(s, 3H, 2-Me Ph 4e,f), 2.80 (s, 8-Me Ind. 4f), 3.29e3.68 (m, 4H,
2CH2SO2 4e,f), 6.73e6.82 (m, C(6)H 4f), 6.96 (d, 1H, J 7.9 Hz, 5-H Ph
4e,f), 7.03 (d, 1H, J¼7.3 Hz, 6-H Ph 4e,f), 7.08e7.14 (m, C(7)H 4e, C(7)
H 4f), 7.18 (s, 1H, 3-H Ph 4e,f), 7.78 (s, C(5)H 4e), 7.84 (d, J¼6.10 Hz,
C(5)H 4f), 8.29 (d, J¼9.7 Hz, C(8)H 4e). 13C NMR (DMSO-d6,
4.4.1. [1,2-Bis(Ethylsulfonyl)-3-indolizinyl](2,4-dimethylphenyl)
methanone 4a. Yield¼0.32
153e154 ꢀC. IR: 1668,1312,1136 cmꢁ1.1H NMR (DMSO-d6, 300 MHz)
: 1.00 (t, 3H, J 7.3 Hz, CH3CH2), 1.20 (t, 3H, J 7.3 Hz, CH3CH2), 2.34 (s,
g (73%) a white solid with mp
d
3H, 4-CH3 Ph), 2.58 (s, 3H, 2-CH3 Ph), 3.42e3.56 (m, 4H, 2CH2SO2),
7.05e7.11 (m, 2H, C(7)H, 5-H Ph), 7.24e7.26 (m, 2H, C(6)H, 3-H Ph),
7.44e7.49 (m, 1H, C(8)H), 8.13 (d, 1H, J 7.3 Hz, 6-H Ph), 8.23 (d, 1H, J
75.47 MHz) d: 2.5 (CH3), 12.7 (CH3), 14.9 (CH2), 15.0 (CH2), 15.3
9.5 Hz, C(5)H).13C NMR (DMSO-d6, 75.47 MHz)
d: 6.0 (CH3), 7.0 (CH3),
(CH2), 15.9 (CH2), 17.4 (CH3), 20.6 (CH3), 20.9 (CH3), 22.3 (CH3), 57.4
(CH2), 57.7 (CH2), 58.4 (CH2), 59.3 (CH2), 110.8 (C), 115.6 (CH), 117.9
(CH), 122.2 (CH), 123.6 (CH), 125.9 (C), 126.4 (CH), 128.0 (C), 128.2
(CH), 128.6 (C), 129.1 (CH), 129.2 (C), 129.9 (CH), 131.5 (CH), 132.6
(CH), 134.0 (C), 134.3 (C), 134.5 (C), 139.9 (C), 140.0 (C), 143.7 (C),
188.3 (C). MS m/z 475 (Mþ, 21). Anal. Calcd for C24H29NO5S2: C,
60.61; H, 6.15; N, 2.94. Found: C, 60.78; H, 6.19; N, 2.90.
20.8 (CH3), 21.0 (CH3), 50.5 (CH2), 51.3 (CH2), 105.9 (C), 116.1 (CH),
118.6 (CH), 124.5 (C), 125.4 (CH), 126.5 (CH), 126.8 (CH), 128.8 (C),
131.9 (CH), 132.8 (CH), 133.8 (C), 135.9 (C), 140.1 (C), 144.0 (C), 188.2
(C). MS m/z 433 (Mþ, 23). Anal. Calcd for C21H23NO5S2: C, 58.18; H,
5.35; N, 3.23. Found: C, 58.37; H, 5.41; N, 3.30.
4.4.2. [1,2-Bis(Propylsulfonyl)-3-indolizinyl](2,4-dimethylphenyl)
methanone 4b. Yield¼0.32
g
(69%)
a
white solid with mp
4.5. Substituted [4,5-di(alkylsulfonyl)-3-furyl]-pyridinium
bromides 6aee (general procedure)
122e123 ꢀC. IR: 1664, 1304, 1144 cmꢁ1. 1H NMR (CDCl3, 250 MHz)
d:
0.88 (t, 3H, J 7.2 Hz, CH3CH2), 1.02 (t, 3H, J 7.2 Hz, CH3CH2), 1.57e1.70
(m, 2H, CH3CH2), 1.72e1.88 (m, 2H, CH3CH2), 2.37 (s, 3H, 4-CH3 Ph),
2.66 (s, 3H, 2-CH3 Ph), 3.30e3.60 (m, 4H, 2CH2SO2), 6.87e6.93 (m,
1H, C(7)H), 6.98 (d,1H, J 7.8 Hz, 5-H Ph), 7.06 (d,1H, J 7.8 Hz, 6-H Ph),
7.19 (s,1H, 3-H Ph), 7.23e7.30 (m,1H, C(6)H), 7.98 (d,1H, J 7.3 Hz, C(8)
Triethylamine (3 mmol) was added to a stirred solution of pyr-
idinium salt 1 (1 mmol) in EtOH (10 ml), and then a solution of
sulfone 3 (1 mmol) was added dropwise. The reaction mixture was
heated at 50 ꢀC for 40 min (progress monitored by thin layer
chromatography). The solvent was evaporated and the solid residue
was dissolved in CHCl3, washed with water, and dried with MgSO4.
Then the solution was concentrated and the solid residue was
washed with hot acetone and separated by decantation. The solid
residue was dissolved in a glacial acetic acid (10 ml), 5e6 fold ex-
cess of HBr (48%) and the calculated amount of acetic anhydride for
binding water were added. The reaction mixture was heated to
50e60 ꢀC and kept at this temperature for 40e50 min. The crystals
of compounds 6aee were precipitated out with diethyl ether. The
acetone solution was evaporated; the solid residue was washed
H), 8.40 (d, 1H, J 9.1 Hz, C(5)H). 13C NMR (DMSO-d6, 75.47 MHz)
d:
12.5 (CH3), 12.5 (CH3), 14.9 (CH2), 15.9 (CH2), 20.7 (CH3), 21.0 (CH3),
57.4 (CH2), 58.5 (CH2), 106.7 (C), 116.2 (CH), 118.6 (CH), 125.4 (CH),
126.4 (CH), 126.8 (CH), 128.4 (C), 131.7 (CH), 132.7 (2CH), 134.1 (C),
135.7 (C), 140.0 (C), 143.9 (C), 188.2 (C). MS m/z 461 (Mþ, 15). Anal.
Calcd for C23H27NO5S2: C, 59.85; H, 5.90; N, 3.03. Found: C, 60.12; H,
5.97; N, 2.96.
4.4.3. [6,8-Dimethyl-1,2-bis(propylsulfonyl)-3-indolizinyl](2,4-
dimethylphenyl) methanone 4c. Yield¼0.37 g (75%) a white solid

5020
N.E. Dontsova et al. / Tetrahedron 69 (2013) 5016e5021
with warm water (40 ꢀC), and separated by decantation. Final
Table 1
X-ray crystallographic data and processing parameters for 6c
products 4aef were crystallized and isolated.
Empirical formula
Formula weight
Wavelength (A)
C25H32BrNO5S2
4.5.1. 1-[2-(2,4-Dimethylphenyl)-4,5-bis(ethylsulfonyl)-3-furyl]-pyr-
idinium bromide 6a. Yield¼0.20 g (38%) a white solid with mp
228e229 ꢀC, IR: 1636,1322,1148 cmꢁ1.1H NMR (DMSO-d6, 300 MHz)
570.55
0.71073
153(2)
Monoclinic
Colorless, Prism
P21/c
11.737(4)
17.831(6)
12.957(5)
96.16(3)
ꢀ
Temperature (K)
Crystal system
Color and shape
Space group
d: 1.28 (t, 3H, J 7.4 Hz, CH3CH2), 1.37 (t, 3H, J 7.4 Hz, CH3CH2), 2.27 (s,
3H, 4-Me Ph), 2.34 (s, 3H, 2-Me Ph), 3.71e3.77 (m, 4H, 2CH2SO2), 7.02
(d, 1H, J 8.4 Hz, 5-H Ph), 7.08 (d, 1H, J 7.9 Hz, 6-H Ph), 7.23 (s, 1H, 3-H
Ph), 8.37e8.42 (m, 2H, 3-H, 5-H Py), 8.88e8.94 (m, 1H, 4-H Py), 9.51
ꢀ
a/A
ꢀ
b/A
ꢀ
(d, 2H, J 5.7 Hz, 2-H, 6-H Py). 13C NMR (DMSO-d6, 75.5 MHz)
d: 5.6
c/A
ꢀ
b
/
(CH3), 6.8 (CH3), 19.5 (CH3), 20.8 (CH3), 50.5 (CH2), 51.7 (CH2), 119.9
(C),125.1 (C),126.9 (C),126.9 (CH),128.4 (2CH),129.5 (CH),132.1 (CH),
138.5 (C),142.2 (C),147.4 (C),147.8(CH),149.7(2CH),153.4(C). MSm/z
434 (MþꢁHal,14). Anal. CalcdforC21H24BrNO5S2: C, 49.03;H, 4.70; N,
2.72. Found: C, 48.83; H, 4.64; N, 2.75.
3
ꢀ
Volume (A )
Z
2696(2)
4
1.406
1.714
Dcalcd (Mg/m3)
m
(mmꢁ1
)
F(000)
1184
Crystal size/mm
Limiting indices
0.30ꢃ0.23ꢃ0.20
0ꢄhꢄ13, 0ꢄkꢄ21, ꢁ15ꢄlꢄ15
1.75e25.05
Psi-scan
0.0961
4585/0/307
1.072
range (ꢀ)
4.5.2. 1-[2-(2,4-Dimethylphenyl)-4,5-bis(propylsulfonyl)-3-furyl]-
q
Absorption correction
Psi-scan
pyridinium bromide 6b. Yield¼0.20 g (36%) a white solid with mp
224e225 ꢀC, IR: 1636,1324,1148 cmꢁ1.1H NMR (CDCl3, 250 MHz):
d:
Data/restraints/parameters
0.99 (t, 3H, J 7.3 Hz, CH3CH2), 1.05 (t, 3H, J 7.3 Hz, CH3CH2), 1.76e1.92
(m, 2H, CH3CH2), 1.95e2.10 (m, 2H, CH3CH2), 2.27 (s, 3H, 4-Me Ph),
2.38 (s, 3H, 2-Me Ph), 3.61e3.68 (m, 2H, CH2SO2), 3.99e4.05 (m, 2H,
CH2SO2), 6.88 (d,1H, J 7.9 Hz, 5-H Ph), 7.05 (s,1H, 3-H Ph), 7.25 (d,1H,
J 8.0 Hz, 6-H Ph), 8.14e8.20 (m, 2H, 3-H, 5-H Py), 8.60e8.66 (m,1H, 4-
GOF on (F2)
R1, wR2
0.0720, 0.1255
1.447 and ꢁ1.170
ꢀꢁ3
Largest different peak and hole (e A
)
4.5.4. 1-[2-(4-Fluorophenyl)-4,5-bis(propylsulfonyl)-3-furyl]-3,5-
H Py), 9.88e9.90 (m, 2H, 2-H, 6-H Py).13C NMR (CDCl3, 75.47 MHz)
d:
dimethylpyridinium bromide 6d. Yield¼0.07 g (12%) a white solid
13.0, 13.1, 14.8, 15.8, 20.5, 21.4, 58.4, 59.2, 119.9, 125.1, 127.4, 127.9,
128.2 (2CH), 130.4, 132.4, 139.0, 142.9, 148.1, 148.9, 149.0 (2CH),
154.4. MS m/z 462 (MþꢁHal, 12). Anal. Calcd for C23H28BrNO5S2: C,
50.92; H, 5.20; N, 2.58. Found: C, 50.73; H, 5.15; N, 2.56.
with mp>230 ꢀC. IR: 1636, 1324, 1144 cmꢁ1 1H NMR (DMSO-d6,
.
500 MHz) d: 0.96 (t, 3H, J 7.42 Hz, CH3CH2), 1.05 (t, 3H, J 7.42 Hz,
CH3CH2), 1.68e1.73 (m, 2H, CH3CH2), 1.79e1.85 (m, 2H, CH3CH2),
2.52 (s, 3H, 3-Me, Py), 2.55 (s, 3H, 5-Me Py), 3.65e3.69 (m, 2H,
CH2SO2), 3.74e3.78 (m, 2H, CH2SO2), 7.35e7.39 (m, 4H, 2-H, 3-H, 5-
H, 6-H Ph), 8.73 (s, 1H, 4-H Py), 9.25 (s, 2H, 2-H, 6-H Py). 13C NMR
4.5.3. 1-[2-(2,4-Dimethylphenyl)-4,5-bis(propylsulfonyl)-3-furyl]-
3,5-dimethylpyridinium bromide 6c. Yield¼0.29 g (50%) awhite solid
with mp 207e208 ꢀC. IR: 1636, 1322, 1144 cmꢁ1. 1H NMR (DMSO-d6,
(DMSO-d6, 75.47 Hz) d: 12.4, 12.5, 14.9, 15.6, 17.8 (2CH3), 57.1, 58.3,
116.9, 117.2, 120.8, 120.9, 122.7, 127.4, 129.4. 129.5, 139.0, 144.3,
147.5, 150.7, 150.9, 162.1, 165.4. MS m/z 480 (MþꢁHal, 14). Anal.
Calcd for C23H27BrFNO5S2: C, 49.28; H, 4.86; N, 2.50. Found: C,
49.47; H, 4.93; N, 2.58.
500 MHz) d: 0.99 (t, 3H, J 7.4 Hz, CH3CH2),1.05(t, 3H, J 7.4Hz, CH3CH2),
1.71e1.77 (m, 2H, CH3CH2),1.79e1.85 (m, 2H, CH3CH2), 2.29 (s, 3H, 4-
Me Ph), 2.36 (s, 3H, 2-Me Ph), 2.55 (s, 6H, 3-Me, 5-Me Py), 3.72e3.77
(m, 4H, 2CH2SO2), 7.05 (d,1H, J 7.9 Hz, 5-H Ph), 7.18 (d,1H, J 7.9 Hz, 6-H
Ph), 7.34 (s, 1H, 3-H Ph), 8.60 (s,1H, 4-H Py), 9.35 (s, 2H, 2-H, 6-H Py).
4.5.5. 1-[2-(2,4-Dimethylphenyl)-4,5-bis(propylsulfonyl)-3-furyl]-3-
methylpyridinium bromide 6e. Yield¼0.21 g (38%) a white solid
with mp 214e215 ꢀC. IR: 1636, 1332, 1140 cmꢁ1. 1H NMR (DMSO-d6,
13C NMR (DMSO-d6, 75.5 MHz)
d: 12.4 (CH3), 12.5 (CH3), 14.8 (CH2),
15.7 (CH2), 17.6 (2CH3), 19.5 (CH3), 20.8 (CH3), 57.1 (CH2), 58.4 (CH2),
119.9 (C),124.7 (C),126.9 (C),127.1 (CH), 129.6 (CH),132.2 (CH), 138.3
(2C), 138.5 (C), 142.3 (C), 144.4 (2CH), 147.8 (C), 150.6 (CH), 153.3 (C).
MS m/z 490 (Mþ¼Hal,17). Anal. Calcd for C25H32BrNO5S2: C, 52.62; H,
5.65; N, 2.45. Found: C, 52.41; H, 5.59; N, 2.40.
500 MHz) d: 0.99 (t, 3H, J 7.6 Hz, CH3CH2), 1.08 (t, 3H, J 7.6 Hz,
CH3CH2), 1.70e1.89 (m, 4H, 2CH3CH2), 2.28 (s, 3H, 4-Me Ph), 2.35 (s,
3H, 2-Me Ph), 2.55 (s, 3H, 3-Me Py), 3.68e3.82 (m, 4H, 2CH2SO2),
7.03 (d, 1H, J 7.6 Hz, 5-H Ph), 7.15 (d, 1H, J 7.6 Hz, 6-H Ph), 7.23 (s, 1H,
3-H Ph), 8.29 (t, 1H, J 6.9 Hz, 5-H Py), 8.75 (d, 1H, J 8.2 Hz, 4-H Py),
9.43 (d, 1H, J 5.7 Hz, 6-H Py), 9.55 (s, 1H, 2-H Py). 13C NMR (DMSO-
4.5.3.1. X-ray crystallography. Colorless crystals of compound 6c
were obtained by slow crystallization from ethanol for 3 days at room
d6, 75.47 MHz) d: 12.3 (CH3), 12.5 (CH3), 14.7 (CH2), 15.6 (CH2), 17.7
temperature. Crystaldatafor6c: C25H32BrNO5S2, Mw¼570.55gmolꢁ1
,
(CH3), 19.4 (CH3), 20.8 (CH3), 57.1 (CH2), 58.4 (CH2), 119.9 (C), 124.8
(C), 126.9 (CH), 127.6 (CH), 129.6 (CH), 132.0 (CH), 138.5 (C), 139.1
(C),142.2 (2C),145.2 (CH),146.8 (CH), 147.7 (C),150.0 (CH),153.2 (C).
MS m/z 476 (MþꢁHal, 8). Anal. Calcd for C24H30BrNO5S2: C, 51.79; H,
5.43; N, 2.52. Found: C, 51.95; H, 5.50; N, 2.55.
T¼153 K, monoclinic, space group P2(1)/c. Unit cell dimensions:
ꢀ
ꢀ
ꢀ
a¼11.737(4) A, b¼17.831(6) A, c¼12.957(5) A,
b
¼96.16(3)ꢀ,
V¼2696(2) A , Z¼4, rcalcd¼1.406 g/cm3,
m
¼1.71 mmꢁ1. The unit cell
3
ꢀ
parameters and intensities of 4585 reflections were collected on
a diffractometer Siemens P3/PC (lMo Ka, graphite monochromator, q/
2q
-scan mode to qmax¼25ꢀ). The structure was solved by direct
Supplementary data
method and refined by full-matrix least-squares. Non-hydrogen
atoms were refined anisotropically. All hydrogen atoms in the struc-
ture were positioned geometrically and were refined as riding atoms.
The final R factors were R1¼0.072 (2373 independent reflections) and
wR2¼0.1225. All calculations were performed using the SHELXL97
programs. Crystallographic data and processing parameters are given
in Table 1. The crystallographic coordinates have been deposited to
the Cambridge Crystallographic Data Centre, deposition number
CCDC-816039. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre, 12 Union Rd., Cambridge
CB2 1EZ, UK or via www.ccdc.cam.ac.uk/conts/retrieving.html.
Copies of 1H and 13C NMR spectra of all new compounds. Sup-
plementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2013.03.098. These
data include MOL files and InChiKeys of the most important com-
pounds described in this article.
References and notes
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5021
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