A modular synthesis of polysubstituted indolizines

Article abstract of DOI:10.1002/ejoc.201200424

The N-alkylation of pyridines with cyanohydrin triflates or α-halonitriles furnishes 1-(1-cyanoalkyl)pyridinium salts that can react with nitroolefins under basic conditions to furnish polysubstituted indolizines. Overall, the indolizine core can be constructed from a pyridine, two aldehydes, and a nitroalkane, and no undesired functional groups remain in the products. When bromoacetonitrile was used for the N-alkylation, indolizine-3-carbonitriles were obtained instead. The pyridine component may be replaced by other azines, giving rise to related heterocyclic systems. Polysubstituted indolizines were synthesized through [3+2] cycloaddition of nitroalkenes with pyridinium ylides. In contrast to previous reports of 1,3-dipolar cycloadditions, in this work no electron-deficient groups remain in the products. Copyright

Full text of DOI:10.1002/ejoc.201200424

Job/Unit: O20424
/KAP1
Date: 03-07-12 15:57:32
Pages: 11
FULL PAPER
DOI: 10.1002/ejoc.201200424
A Modular Synthesis of Polysubstituted Indolizines
Murat Kucukdisli[a] and Till Opatz*[a]
Keywords: Cycloaddition / Nitrogen heterocycles / Sulfur heterocycles / Ylides
The N-alkylation of pyridines with cyanohydrin triflates or
α-halonitriles furnishes 1-(1-cyanoalkyl)pyridinium salts that
can react with nitroolefins under basic conditions to furnish
polysubstituted indolizines. Overall, the indolizine core can
be constructed from a pyridine, two aldehydes, and a nitro-
alkane, and no undesired functional groups remain in the
products. When bromoacetonitrile was used for the N-alkyl-
ation, indolizine-3-carbonitriles were obtained instead. The
pyridine component may be replaced by other azines, giving
rise to related heterocyclic systems.
the preparation of indolizidines by catalytic hydrogen-
ation.[9d,11c,14]
Introduction
Here, we present a short, convergent synthesis that allows
the modular assembly of tri- and tetrasubstituted indoliz-
ines from a pyridine, two aldehydes, and a primary nitro-
alkane as readily available starting materials, and leaves no
undesired functionalities in the products. Its key step is the
formal [3+2] cycloaddition of a 1-(1-cyanoalkyl)pyridinium
ylide[15] to an α,β-disubstituted nitroolefin.
Indolizines are an important class of N-heterocycles due
to their wide range of biological activities. For example,
they can function as potential calcium entry blockers,[1] cen-
tral nervous system depressants,[2] cardiovascular agents,[3]
and anti-tuberculosis agents.[4] Numerous synthetic ap-
proaches to the indolizine skeleton have been devised[5] in-
volving, for example, the Scholtz reaction of acetic acid[6]
or the 1,5-cyclization of unsaturated pyridinium ylides.[7]
A
frequently employed synthetic approach to the indolizine
skeleton is the 1,3-dipolar cycloaddition of pyridinium
ylides derived from α-halocarbonyl compounds with elec-
tron-deficient olefins or alkynes. In this case, however, at
least one acceptor group remains in the products.[8]
Results and Discussion
The synthesis of 1-(1-cyanoalkyl)pyridinium salts 2 can
start either from α-halonitriles or from cyanohydrin triflates
1, which, in turn, can be obtained from aldehyde cyanohyd-
rins and Tf2O.[16] Whereas the preparation of α-halonitriles
does not require the use of HCN,[17] the cyanohydrin
route[18] only uses a slight excess of this reagent. Pyridinium
salts 2 were obtained in moderate to very high yield and
could be purified by recrystallization from polar aprotic sol-
vents (Table 1).
Compared to the aforementioned procedures, a smaller
number of methods permit the construction of the aza-
bicyclic system without electron-withdrawing substitu-
ents.[9] A prominent example for the latter class of processes
is the Tschitschibabin reaction of 2-alkylpyridines with α-
haloketones which, under intermediate formation of the N-
alkylpyridinium salt, forms the C1–C2 bond of the indoliz-
ine in a cyclocondensation step.[10] However, the versatility
of the method is limited by the availability of various substi-
tuted 2-alkylpyridines. Another important method for the
preparation of electronically unbiased indolizines is the
transition-metal-catalyzed cycloisomerization of 2-alkynyl
or 2-propargyl-substituted N-heterocycles with formation
of the C3–N4 bond.[11] Indolizines devoid of acceptor
groups have been employed, for example, as histamine H3
receptor antagonists,[12] as inhibitors of phosphodiester-
ase 5A or phospholipase A2,[13] or as starting materials for
Table 1. Preparation of 1-(1-cyanoalkyl)pyridinium salts 2.
Entry
Product
R1
R2
X
Yield [%]
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
H
H
H
4-Ph
4-tBu
2-Me
H
Me
iPr
4-ClC6H4
Me
OTf
OTf
Cl
OTf
OTf
OTf
95
98
96
79
64
71
74
Me
Me
[a] Institute of Organic Chemistry, University of Mainz,
Duesbergweg 10-14, 55128 Mainz, Germany
Fax: +49-6131-39-22338
2g
CH2CH2Ph OTf
E-mail: opatz@uni-mainz.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200424.
For the optimization of the cycloaddition/elimination se-
quence to indolizines 4, pyridinium triflate 2a and 1-chloro-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Kucukdisli, T. Opatz
FULL PAPER
4-[(1E)-2-nitroprop-1-en-1-yl]benzene[19] (3a) were used as Table 3. Indolizines 4 prepared under the optimized conditions.
test compounds. Various bases, solvents, and temperature
ranges were screened (Table 2) and it turned out that the
best yields were obtained by using KOtBu as the base in
N,N-dimethylformamide (DMF) or tetrahydrofuran (THF)
at 0 °C (Table 2, entries 13 and 14); the use of Cs2CO3 in
hot DMF also proved effective (Table 2, entries 7 and 8).
Entry Product
R1
R2
R3
R4
Yield [%]
Table 2. Optimization of the cycloaddition to indolizines 4.
1
2
3
4a
4b
H
H
Me
Me
4-ClC6H4
2-naphth
4-
CNC6H4
4-FC6H4
–(CH2)4–
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
Me
Et
77
54
4c
H
Me
Et
62
4
5
6
7
8
9
4d
4e
4f
4g
4h
4i
H
H
H
7-tBu
7-Ph
H
H
5-Me
7-Ph
Me
Me
CH2CH2Ph
Me
Me
65
39
32
71
72
55
39
21
37
Me
Me
Me
Me
Me
Me
Me
Me
iPr
Entry
Base
Solvent
T
[°C]
Yield
[%]
10
11
12
4j
4k
4l
4-ClC6H4 4-ClC6H4
Me
Me
4-ClC6H4
1
2
3
4
5
6
7
8
K2CO3
Al2O3
Et3N
MeOH
none
reflux
250[a]
90
90
90
75
90
reflux
reflux
90
reflux
25
40
n.d.
57
59
45
49
60
65
n.d.
12
20
31
72
77
42
61
51
iPr
DMF
Cs2CO3
DMF[b]
DMF
[c]
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Li2CO3
turned out to give the highest yields. The results of the reac-
tion of various nitroolefins 3 with 1-(cyanomethyl)pyrid-
inium bromide (5) under these conditions are shown in
Table 4.
DMF
DMF
DMF
THF
pyridine
THF
THF
THF
DMF
9
10
11
12
13
14
15
16
17
pyridine
KOtBu
Table 4. Indolizine-3-carbonitriles 6 prepared under the optimized
conditions.
KOtBu
KOtBu[d]
KOtBu[d]
KOtBu
0
0
0
DMF/tBuOH
DMF/MeOH
MeOH
NaOMe[d]
NaOMe[e]
0Ǟ25
0Ǟ25
[a] Microwave heating. [b] Molecular sieves (3 Å) were added.
[c] Ag2O (1.0 mmol) was added. [d] 4.0 equiv. of base was used.
[e] 8.0 equiv. of base was used.
Entry
Product
R3
R4
Yield [%]
1
2
3
4
6a
6b
6c
6d
4-ClC6H4
2-naphth
4-CNC6H4
4-FC6H4
Me
Et
Et
81
82
70
81
The optimized conditions were then applied to the reac-
tion of pyridinium salts 2a–d with various nitroolefins
(Table 3). Whereas a 2-substituent in the parent pyridinium
salt (2f) led to diminished yield (product 4k), 4-substituents
did not affect the efficiency of indolizine formation.
Me
A possible explanation for the different behavior of α-
On the other hand, attempts to obtain 2,3-disubstituted substituted and α-unsubstituted 1-(cyanomethyl)pyridinium
indolizines from α-unsubstituted nitroolefins such as β-ni- salts may be the CH-acidity of intermediate 9 formed after
trostyrene were unsuccessful. In contrast to the Barton– concerted or stepwise addition of pyridinium ylide 7 to ni-
Zard synthesis, in which ethyl isocyanoacetate reacts with troolefin
3 and base-induced elimination of nitrite
nitroolefins with formation of pyrroles, neither 9-nitrophen- (Scheme 1). In the presence of an α-substituent (R2), dehy-
anthrene nor 5-nitro[1,10]phenanthroline gave indolizines drocyanation is the only option to produce an aromatic sys-
when reacted with 3a.[20] Presumably, the reactivity of the tem, whereas in the unsubstituted series, deprotonation fol-
intermediate pyridinium ylide in these cases is insufficient lowed by oxidation becomes the dominant process.
to compensate for the loss of aromaticity in the addition
step.
Whereas indolizines devoid of electron-withdrawing
groups (EWGs) such as compounds 4a–l can be sensitive
The presence of an α-substituent in the pyridinium salt towards aerial oxidation, indolizine-3-carbonitriles 6a–d are
appears to be required for the elimination of cyanide after much more stable and can be purified and stored without
ring closure because 1-(cyanomethyl)pyridinium bromide special precautions.[9f,21,22]
exclusively yielded indolizine-3-carbonitriles 6 instead of 3-
To determine the applicability of the indolizine synthesis
unsubstituted indolizines under all tested conditions.[21] Be- to parent systems other than pyridine, different N-heterocy-
cause this process involves an oxidative step, several oxi- cles were treated with a cyanohydrin triflate or bromoaceto-
dants were tested for their ability to improve the efficiency nitrile. The azinium ylides generated from the salts with
of formation of 6; silver(I) carbonate in THF at reflux KOtBu were treated with 1-chloro-4-[(1E)-2-nitroprop-1-
2
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A Modular Synthesis of Polysubstituted Indolizines
Table 5. Synthesis of pyrrolo-fused N-heterocycles.[a]
Scheme 1. Proposed mechanism for the syntheses of indolizines.
en-1-yl]benzene (3a) (method A) or diethyl azodicarboxyl-
ate (DEAD) (method B) as an even more reactive electro-
phile (Table 5).
In the case of isoquinoline and benzothiazole, the respec-
tive annulated products without an EWG could be obtained
in pure form and acceptable yield (Table 5, entries 1 and 4).
Whereas phthalazinium salt 12b reacted with both 3a and
DEAD (Table 5, entries 2 and 6), 1-methylimidazol-3-ium
salt 12c only reacted with the alkyne to yield pyrrolo[1,2-a]-
imidazole 13c in appreciable yield (Table 5, entry 3). As in
the case of pyridine, pyrrolo[2,1-a]isoquinoline-3-carbo-
nitrile (13e) was obtained in high yield (Table 5, entry 5)
from 12e using Ag2CO3. In contrast, the application of
method A to phenanthridine and 1-phenylpyrazole failed,
and the use of pyridazine only yielded an impure product.
Thus, the procedure works in both the six- and the five-
membered series but is not generally applicable.
Conclusions
A short and modular synthesis of highly substituted
indolizines and N-fused pyrrole-containing heterocycles
such as pyrroloisoquinoline, pyrrolophthalazine, pyrrolo-
imidazole, and pyrrolobenzothiazole has been developed
that generates the additional C1–C3 fragment from two al-
dehydes and a nitroalkane. In addition to this method,
indolizine-3-carbonitriles have been synthesized in high
yield via α-unsubstituted ylides with silver(I) carbonate.
The reaction conditions were also applied to different azin-
ium salts to compare the reactivity of ylides.
[a] Reaction conditions: KOtBu (4 equiv.), DMF, 0 °C. [b] Isolated
yield of azinium salt formation from the corresponding heterocycle.
[c] Isolated yield of the pyrrolo-fused compounds. [d] Ag2CO3
(2 equiv.) was used as base.
Experimental Section
General: All reactions were carried out in dried glassware under
an inert atmosphere (argon) in anhydrous solvents using standard
syringe and septa techniques. Anhydrous THF was distilled from
potassium/benzophenone under argon. Anhydrous dichlorometh-
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M. Kucukdisli, T. Opatz
FULL PAPER
ane was distilled from CaH2 under argon. The solvents used for
flash chromatography were distilled prior to use. Solvents were de-
gassed using an ultrasonic bath under an argon atmosphere. All
other solvents and reagents were purchased from commercial sup-
pliers and were used without further purification. TLC experiments
were carried out on aluminum sheets (Merck) coated with silica gel
60 F254 and spots were visualized with UV-light (254 nm, 366 nm)
and developed with phosphomolybdic acid reagent or ninhydrin.
Flash chromatography was carried out on silica gel (32–63 μm,
60 Å, 230–400 mesh, Acros). Melting points were determined with
a Dr. Tottoli apparatus and are uncorrected. NMR spectra were
recorded with a 300, 400, or 600 MHz spectrometer. The spectra
were measured in CDCl3, [D6]DMSO, CD3OD, or [D6]acetone and
the chemical shifts were referenced to the residual solvent signal
NMR (300 MHz, CDCl3): δ = 5.16 (d, J = 5.6 Hz, 1 H, CHCN),
2.35 (m, 1 H, CH), 1.19 (overlapping doublets, 6 H, 2 CH3) ppm.
General Procedure A
Synthesis of Ylide Precursors 2a–g: Cyanohydrin triflate or 2-
chloro-2-(4-chlorophenyl)acetonitrile (1.0 equiv.) and the corre-
sponding heterocyclic compound (1.0 equiv.) were dissolved in an-
hydrous diethyl ether (1 mL/1 mmol) and the reaction mixture was
stirred at room temperature for 2 h. The product was collected by
filtration and the salt was washed with diethyl ether. In some cases
for which the removal of the excess N-heterocycle was not compli-
cated, an excess amount of the azine was used.
1-(1-Cyanoethyl)pyridinium Triflate (2a): The title compound was
prepared according to general procedure A from pyridine (2.69 g,
34.0 mmol) and 1a (6.90 g, 34.0 mmol). The crude product was fur-
ther purified by recrystallization from EtOAc to yield 2a as a crys-
(CDCl3: δH = 7.26 ppm, δC = 77.16 ppm; [D6]DMSO: δH
2.50 ppm, δC = 39.52 ppm, CD3OD: δH = 3.31 ppm, δC
=
=
49.00 ppm, [D6]acetone: δH = 2.05 ppm, δC = 29.84 ppm).[23] IR
spectra were recorded on routine FTIR spectrometers using a dia-
mond ATR unit. MS spectra were recorded with double-focusing
spectrometers (FD-MS, FAB-MS, EI-MS) or with a linear ion trap
LC/MSD detector (ESI-MS). ESI-HRMS spectra were recorded
with a high-resolution Q-TOF spectrometer with a dual source and
a suitable external calibrant.
talline solid (9.11 g, 32.0 mmol, 95%); m.p. 65–67 °C. IR (neat): ν
˜
= 3136, 2970, 1255, 1149, 756 cm–1. 1H NMR (300 MHz, [D6]-
DMSO): δ = 9.30 (mc, 2 H, H2,6), 8.74 (tt, J = 7.8, 1.3 Hz, 1 H,
H4), 8.28 (mc, 2 H, H3,5), 6.31 (q, J = 7.1 Hz, 1 H, CHCN), 2.03
(d, J = 7.1 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 147.8 (C4), 144.1 (C2,6), 128.8 (C3,5), 120.7 (q, 1JC,F = 322 Hz,
CF3), 116.5 (CϵN), 56.3 (CH), 20.3 (CH3) ppm. C9H9F3N2O3S
(282.24): calcd. C 38.30, H 3.21, N 9.93, S 11.36; found C 38.09,
H 3.24, N 9.87, S 11.45. MS (ESI): m/z (%) = 133.1 (100) [M]+.
2-Hydroxypropanenitrile,[18a,24]
2-hydroxy-3-methylbutaneni-
trile,[25] and 2-hydroxy-4-phenylbutanenitrile[18b] were prepared
from the corresponding aldehydes using a slight excess of cyanide
source as described in the literature. 2-Chloro-2-(4-chlorophenyl)-
acetonitrile (1c)[26] and the nitroolefins 3a–d, 3f and 3g[19,21] were
synthesized from the corresponding aldehydes according to litera-
ture procedures. Nitroolefin 3e was obtained from commercial
sources, 1-(cyanomethyl)pyridinium bromide (5)[15b,27] and 2-
(cyanomethyl)isoquinolinium bromide (12e) were prepared accord-
ing to literature procedures.
1-(1-Cyano-2-methylpropyl)pyridinium Triflate (2b): The title com-
pound was prepared according to general procedure A from excess
pyridine (1.98 g, 25 mmol) and 1b (1.20 g, 5.19 mmol). The crude
product was recrystallized from EtOAc/diethyl ether to yield 2b
(1.54 g, 5.07 mmol, 98%) as a solid; m.p. 99–102 °C. IR (neat): ν
˜
1
= 2968, 1259, 1028, 741 cm–1. H NMR (300 MHz, [D6]DMSO): δ
= 9.24 (mc, 2 H, H2,6), 8.79 (t, J = 7.4 Hz, 1 H, H4), 8.31 (mc, 2
H, H3,5), 6.19 (d, J = 8.0 Hz, 1 H, H1Ј), 2.65 (m, 1 H, H2Ј), 1.10
(d, J = 6.5 Hz, 3 H, CH3), 0.89 (d, J = 6.6 Hz, 3 H, CH3) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 148.1 (C4), 144.2 (C2,6),
Preparation of Cyanohydrin Triflates:[8b] 1-Cyanoethyl trifluoro-
methanesulfonate and 1-cyano-2-methylpropyl trifluoromethane-
sulfonate were prepared from the corresponding cyanohydrin and
trifluoromethanesulfonic anhydride. To a solution of cyanohydrin
(1.0 equiv.) and distilled pyridine (1.2 equiv.) in anhydrous CH2Cl2
was slowly added trifluoromethanesulfonic anhydride (1.2 equiv.)
at 0 °C. After stirring for 15 min, the solvent was evaporated in
vacuo. The residue was dissolved in ether and filtered to remove
pyridinium triflate and the filtrate was evaporated to obtain the
crude cyanohydrin triflate.
1
129.0 (C3,5), 120.7 (q, JC,F = 322 Hz, CF3), 114.7 (CϵN), 65.8
(CHCN), 33.5 [CH(CH3)2], 17.7 (CH3), 17.6 (CH3) ppm.
C11H13F3N2O3S (310.29): calcd. C 42.54, H 4.22, N 9.03, S 10.33;
found C 42.39, H 3.98, N 9.07, S 11.40. MS (ESI): m/z (%) = 161.1
(100) [M]+.
1-[(4-Chlorophenyl)(cyano)methyl]pyridinium Chloride (2c): The title
compound was synthesized from 2-chloro-2-(4-chlorophenyl)aceto-
nitrile and pyridine. 2-Chloro-2-(4-chlorophenyl)acetonitrile (1c)
(1.24 g, 6.67 mmol) was added into freshly distilled pyridine
(4.91 g, 62.1 mmol) and the reaction mixture was stirred at r.t. for
2 d. Diethyl ether (20 mL) was added to the reaction vessel and
crude product was collected through filtration after washing several
times with diethyl ether, and then dried to yield 2c (1.70 g,
6.41 mmol, 96%) as a highly hygroscopic yellow solid. The melting
point range could not be determined due to the highly hygroscopic
1-Cyanoethyl Trifluoromethanesulfonate (1a): The title compound
was synthesized from acetaldehyde cyanohydrin (3.00 g,
42.2 mmol), Tf2O (14.11 g, 50.0 mmol) and pyridine (3.95 g,
50.0 mmol) in CH2Cl2 (200 mL). The crude product was further
purified by filtering through neutral Al2O3 to yield the triflate of
acetaldehyde cyanohydrin as a slightly pink oil (7.00 g, 82%). IR
(neat): ν = 2981, 1423, 1213, 1141 (s), 926 cm–1. 1H NMR
˜
nature of the material. IR (neat): ν = 2952, 1487, 1094, 799 cm–1.
(400 MHz, CDCl3): δ = 5.44 (q, J = 6.9 Hz, 1 H, CH), 1.83 (d, J
˜
1H NMR (300 MHz, [D6]DMSO): δ = 9.61 (mc, 2 H, H2,6), 8.77
(br. t, J = 7.8 Hz, 1 H, H4), 8.59 (s, 1 H, CH), 8.35–8.24 (m, 2 H,
H3, H5), 7.89 (AAЈ part of AAЈ–BBЈ system, 2 H, H3ЈЈ,5ЈЈ), 7.70–
7.64 (m, BBЈ part of AAЈ–BBЈ system, 2 H, H2ЈЈ,6ЈЈ) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 148.3 (C4), 144.2 (C2,6), 136.3
(C-Cl), 130.4 (2 CHAr), 129.9 (2 CHAr), 129.3 (2 CHAr), 126.8 (Cq),
114.6 (CϵN), 60.9 (CH) ppm. MS (ESI): m/z (%) = 229 (100) [M]+.
HRMS (ESI): calcd. for [C13H10ClN2]+ 229.0533; found 229.0530.
= 6.9 Hz, 3 H, CH3) ppm. 13C NMR (101 MHz, CDCl3): δ = 118.3
1
(q, JC,F
= 320 Hz, CF3), 114.6 (CϵN), 68.8 (CH), 20.1
(CH3) ppm. C4H4F3NO3S (203.13): calcd. C 23.65, H 1.98, N 6.90,
S 15.76; found C 23.96, H 1.94, N 6.88. The compound decom-
posed during the ESI-MS measurement.
1-Cyano-2-methylpropyl Trifluoromethanesulfonate (1b):[8b] The title
compound was synthesized from 2-hydroxy-3-methylbutanenitrile
(1.98 g, 20.0 mmol), Tf2O (6.77 g, 24.0 mmol) and pyridine (1.90 g,
24.0 mmol) in CH2Cl2 (100 mL). The crude product was further
purified by filtering through neutral Al2O3 to yield 1-cyano-2-
1-(1-Cyanoethyl)-4-phenylpyridinium Triflate (2d): The title com-
pound was prepared according to general procedure A from 4-
phenylpyridine (1.15 g, 7.40 mmol) and 1a (1.50 g, 7.40 mmol). The
1
methylpropyl trifluoromethanesulfonate as an oil (3.4 g, 74%). H
4
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A Modular Synthesis of Polysubstituted Indolizines
crude product was recrystallized from CH2Cl2 to yield 2d (2.08 g,
sion was complete, the solvent was evaporated in vacuo. The resi-
due was dissolved in ethyl acetate and washed with water. The
5.85 mmol, 79%) as a solid; m.p. 135–137 °C. IR (neat): ν = 3051,
˜
1
1258, 1152, 994, 854 cm–1. H NMR (300 MHz, [D6]DMSO): δ = aqueous phase was extracted twice with ethyl acetate and the com-
9.31 (AAЈ part of AAЈ–BBЈ system, 2 H, H2,6), 8.64 (BBЈ part of bined organic layers were washed with brine, dried with MgSO4,
AAЈ–BBЈ system, 2 H, H3,5), 8.16–8.11 (m, 2 H), 7.75–7.62 (m, 3
H), 6.28 (q, J = 7.1 Hz, 1 H, CH), 2.05 (d, J = 7.1 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 156.7 (C4), 144.0
(C2,6), 133.2 (C1Ј),132.7 (C4Ј), 129.8 (2 CHAr), 125.0 (2 CHAr),
120.7 (2 CHAr), 116.6 (CϵN), 55.4 (CH), 20.0 (CH3) ppm.
C15H13F3N2O3S (358.33): calcd. C 50.28, H 3.66, N 7.82, S 8.95;
found C 50.34, H 3.73, N 7.78, S 8.95. MS (ESI): m/z (%) = 209.1
(100) [M]+.
and the solvent was removed in vacuo.
2-(4-Chlorophenyl)-1,3-dimethylindolizine (4a): The title compound
was prepared according to general procedure B from 2a (282 mg,
1.00 mmol) and (E)-1-chloro-4-(2-nitroprop-1-enyl)benzene (3a;
198 mg, 1.00 mmol). The crude product was purified by filtration
through silica (ethyl acetate/cyclohexane, 1:10) to obtain 4a
(196 mg, 0.77 mmol, 77%) as a yellow solid; m.p. 138–140 °C; Rf
= 0.74 (ethyl acetate/cyclohexane, 1:10). IR (neat): ν = 3076 (s),
˜
3041, 2924, 2856, 1454, 1317, 842, 721 cm–1. H NMR (400 MHz,
1
4-tert-Butyl-1-(1-cyanoethyl)pyridinium Triflate (2e): The title com-
pound was prepared according to general procedure A from 4-tert-
butylpyridine (676 mg, 5.00 mmol) and 1a (1.02 g, 5.00 mmol). The
crude product was recrystallized from EtOAc to yield 2e (1.08 g,
CDCl3, COSY, HSQC, HMBC): δ = 7.66 (dt, J = 7.1, 1.2 Hz, 1 H,
H5), 7.45–7.41 (AAЈ part of AAЈ–BBЈ system, 2 H, H3Ј,5Ј), 7.36
(dt, J = 9.0, 1.3 Hz, 1 H, H8), 7.32–7.27 (BBЈ part of AAЈ–BBЈ
system, 2 H, H2Ј,6Ј), 6.63 (ddd, J = 9.0, 6.4, 1.1 Hz, 1 H, H7), 6.53
(ddd, J = 7.1, 6.4, 1.3 Hz, 1 H, H6), 2.42 (s, 3 H, 3-CH3), 2.32 (s,
3 H, 1-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 134.6 (C4Ј),
132.3 (C1Ј), 131.8 (2 C, C2Ј,6Ј), 129.3 (C8a), 128.5 (2 C, C3Ј,5Ј),
126.3 (C2), 121.6 (C5), 117.5 (C8), 116.3 (C3), 114.6 (C7), 110.2
(C6), 105.6 (C1), 10.2 (3-CH3), 9.4 (1-CH3) ppm. MS (ESI): m/z
(%) = 288.0 (9) [M + 2O + H]+, 271.9 (22) [M + OH]+, 256.0 (100)
[M + H]+. HRMS (ESI): calcd. for [C16H14ClN]+ 255.0815; found
255.0819.
3.2 mmol, 64%) as a solid; m.p. 137–140 °C. IR (neat): ν = 3081,
˜
3056, 2968, 1463, 1253, 1029 cm–1. 1H NMR (300 MHz, [D6]-
DMSO): δ = 9.19 (AAЈ part of AAЈ -BBЈ system, 2 H, H2,6), 8.30
(BBЈ part of AAЈ -BBЈ system, 2 H, H3,5), 6.26 (q, J = 7.1 Hz, 1
H, CH), 2.01 (d, J = 7.1 Hz, 3 H, CH3), 1.38 [s, 9 H, C(CH3)
3] ppm. 13C NMR (100.6 MHz, [D6]DMSO): δ = 172.4 (C4), 143.4
(C2,6), 125.8 (C3,5), 120.7 (q, 1JC,F = 322 Hz, CF3), 116.6 (CϵN),
55.4 (CH), 36.6 [C(CH3)3], 29.4 [C(CH3)3], 20.1 (CH3) ppm.
C13H17F3N2O3S (338.34): calcd. C 46.15, H 5.06, N 8.28, S 9.48;
found C 46.00, H 4.97, N 8.27, S 9.46. MS (ESI): m/z (%) = 189.1
(100) [M]+.
1-Ethyl-3-methyl-2-(2-naphthyl)indolizine (4b): The title compound
was prepared according to general procedure B from 2a (282 mg,
1.00 mmol) and (E)-2-(2-nitrobut-1-enyl)naphthalene (3b; 227 mg,
1.00 mmol). The crude product was purified by filtration through
silica (ethyl acetate/cyclohexane, 1:10) to obtain 4b (154 mg,
0.54 mmol, 54%) as a yellow oil. Rf = 0.67 (ethyl acetate/cyclohex-
1-(1-Cyanoethyl)-2-methylpyridinium Triflate (2f): The title com-
pound was prepared according to general procedure A from α-pic-
oline (466 mg, 5.00 mmol) and 1a (1.02 g, 5.00 mmol). The solid
was recrystallized from chloroform to yield crystalline 2f (1.05 g,
3.55 mmol, 71%); m.p. 150–151 °C. IR (neat): ν = 2957, 2925,
˜
ane, 1:10). IR (neat): ν = 3053, 2965, 1460, 1016, 947, 860, 820,
˜
1
1261, 1150, 994 cm–1. H NMR (300 MHz, [D6]DMSO): δ = 9.31
736 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.96–7.88 (m, 3 H,
Hnaphth), 7.83 (d, J = 1.6 Hz, 1 H, Hnaphth), 7.70 (dt, J = 7.0, 1.0 Hz,
1 H, H5), 7.58–7.50 (m, 3 H, Hnaphth), 7.45 (dt, J = 9.0, 1.2 Hz, 1
H, H8), 6.66 (ddd, J = 8.9, 6.4, 1.4 Hz, 1 H, H7), 6.56 (ddd, J =
6.9, 6.4, 1.4 Hz, 1 H, H6), 2.87 (q, J = 7.5 Hz, 2 H, CH2), 2.45 (s,
3 H, 3-CH3), 1.16 (t, J = 7.5 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 133.9 (Cq,naphth), 133.6 (Cq,naphth), 132.2
(Cq,naphth), 129.1 (CHnaphth), 129.0 (CHnaphth), 128.7 (C8a), 128.0
(CHnaphth), 127.8 (CHnaphth), 127.7 (CHnaphth), 127.0 (C2), 126.1
(CHnaphth), 125.7 (CHnaphth), 121.7 (C5), 117.6 (C8), 116.6 (C3),
114.5 (C7), 113.4 (C1), 110.2 (C6), 17.6 (CH2), 16.6 (CH3), 10.2
(CH3) ppm. MS (ESI): m/z (%) = 318.1 (30) [M + 2O + H]+, 302.1
(47) [M + OH]+, 286.1 (100) [M + H]+, 285.0 (33) [M]+. HRMS
(ESI): calcd. for [C21H19N]+ 285.1517; found 285.1515.
(dd, J = 6.4, 1.4 Hz, 1 H, H6), 8.59 (td, J = 7.9, 1.4 Hz, 1 H, H4),
8.16–8.07 (m, 2 H, H3,5), 6.37 (q, J = 7.0 Hz, 1 H, CH), 2.90 (s, 3
H, 2-CH3), 1.97 (d, J = 7.0 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 156.1 (C2), 147.0 (C4), 142.9 (C6),130.6
1
(C3), 126.6 (C5), 120.7 (q, JC,F = 322 Hz, CF3), 116.7 (CϵN),
52.2 (CH), 20.2 (CH3), 19.7 (CH3) ppm. C10H11F3N2O3S (296.26):
calcd. C 40.54, H 3.74, N 9.46, S 11.32; found C 40.45, H 3.40, N
9.49, S 10.64. MS (ESI): m/z (%) = 147.1 (100) [M]+.
1-(1-Cyano-3-phenylpropyl)pyridinium Triflate (2g): The title com-
pound was prepared according to general procedure A from pyr-
idine (79 mg, 1.00 mmol) and 2-hydroxy-4-phenylbutanenitrile (1d;
293 mg, 1.00 mmol). The crude product was recrystallized from
CH2Cl2/diethyl ether mixture to yield 2g (276 g, 0.74 mmol, 74%)
as a solid; m.p. 82–84 °C. IR (neat): ν = 3062, 2950, 1255, 1157,
˜
1029 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 9.30 (mc, 2 H,
H2,6), 8.74 (tt, J = 7.8, 1.2 Hz, 1 H, H4), 8.28 (mc, 2 H, H3,5),
7.33–7.27 (m, 2 H, H-Ph), 7.25–7.18 (m, 3 H, H-Ph), 6.32 (t, J =
7.1 Hz, 1 H, H1Ј), 2.87–2.61 (m, 4 H, H2Ј, H3Ј) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 147.9, 144.3, 138.7, 128.9, 128.6, 128.3,
126.6, 115.5 (CN), 60.2 (CH), 34.9 (CH2), 30.6 (CH2) ppm.
C16H15F3N2O3S (372.36): calcd. C 51.61, H 4.06, N 7.52, S 8.61;
found C 51.77, H 3.83, N 7.38, S 8.72. MS (ESI): m/z (%) = 223.1
(100) [M]+.
2-(4-Cyanophenyl)-1-ethyl-3-methylindolizine (4c): The title com-
pound was prepared according to general procedure B from 2a
(282 mg, 1.00 mmol) and (E)-4-(2-nitrobut-1-enyl)benzonitrile (3c;
202 mg, 1.00 mmol). The crude product was purified by filtration
through silica (ethyl acetate/cyclohexane, 1:10) to obtain 4c
(161 mg, 0.62 mmol, 62%) as a yellow solid; m.p. 98–100 °C; Rf =
0.65 (ethyl acetate/cyclohexane, 1:10). IR (neat): ν = 3067, 2970,
˜
2931, 2227, 1360, 855, 795 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.76–7.70 (AAЈ part of AAЈ–BBЈ system, 2 H, H3Ј,5Ј), 7.67 (dt, J
= 7.0, 1.3 Hz, 1 H, H5), 7.49–7.43 (BBЈ part of AAЈ–BBЈ system,
2 H, H2Ј,6Ј), 7.40 (dt, J = 9.0, 1.3 Hz, 1 H, H8), 6.65 (ddd, J =
9.0, 6.4, 1.2 Hz, 1 H, H7), 6.56 (td, J = 6.7, 1.3 Hz, 1 H, H6), 2.78
(q, J = 7.5 Hz, 3 H, CH2), 2.39 (s, 3 H, 3-CH3), 1.11 (t, J = 7.5 Hz,
3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.7, 132.1,
131.0, 129.0, 125.3, 121.7, 119.4, 117.7, 116.4, 115.1, 112.9, 110.7,
110.0, 29.8, 27.0, 17.4, 16.5, 10.1 ppm. MS (ESI): m/z (%) = 293.1
General Procedure B
Synthesis of Indolizines 4a–l: A solution of KOtBu (4 mmol) in an-
hydrous DMF (5.0 mL) was slowly added to a stirred solution of
pyridinium salt (1 mmol) and nitroolefin (1 mmol) in anhydrous
DMF (10 mL) at 0 °C under argon. The mixture was stirred at
0 °C, and the reaction was monitored by TLC. When the conver-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20424
/KAP1
Date: 03-07-12 15:57:32
Pages: 11
M. Kucukdisli, T. Opatz
FULL PAPER
(36) [M + 2O + H]+, 277.0 (100) [M + OH]+, 261.0 (87) 2869, 1592, 1488, 1090, 811, 740 cm–1. 1H NMR (300 MHz,
[M + H]+, 260.1 (95) [M]+. HRMS (ESI): calcd. for [C18H16N2]+
260.1313; found 260.1303.
CDCl3): δ = 7.62 (br d, J = 7.4 Hz, 1 H, H5), 7.45–7.39 (AAЈ part
of AAЈ–BBЈ system, 2 H, H3Ј,5Ј), 7.32–7.26 (BBЈ part of AAЈ–BBЈ
system, 2 H, H2Ј,6Ј), 7.21 (d, J = 1.0 Hz, 1 H, H8), 6.61 (dd, J =
7.4, 2.0 Hz, 1 H, H6), 2.40 (s, 3 H, 3-CH3), 2.31 (s, 3 H, 1-CH3),
1.35 [s, 9 H, C(CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ = 138.0
(C7), 134.9 (C4Ј), 132.2 (C1Ј), 131.8 (C2Ј,6Ј), 130.6 (C8a), 128.4
(C3Ј,5Ј), 126.3 (C2), 121.3 (C5), 115.3 (C3), 111.2 (C8), 109.7 (C6),
104.7 (C1), 34.4 [C(CH3)3], 30.7 [(CH3)3C], 10.1 (3-CH3), 9.4 (1-
CH3) ppm. MS (ESI): m/z (%) = 344.2 (28) [M + 2O + H]+, 328.3
(100) [M + OH]+, 312.3 (28) [M + H]+, 311.3 (32) [M]+. HRMS
(ESI): calcd. for [C20H22NCl]+ 311.1441; found 311.1452.
2-(4-Fluorophenyl)-1,3-dimethylindolizine (4d): The title compound
was prepared according to general procedure B from 2a (282 mg,
1.00 mmol) and (E)-1-fluoro-4-(2-nitroprop-1-enyl)benzene (3d;
181 mg, 1.00 mmol). The crude product was purified by filtration
through silica (ethyl acetate/cyclohexane, 1:10) to obtain 4d
(165 mg, 0.65 mmol, 65%) as a yellow solid; m.p. 118–119 °C; Rf
= 0.76 (ethyl acetate/cyclohexane, 1:10). IR (neat): ν = 3067, 2992,
˜
1
1505, 1470, 843, 784 cm–1. H NMR (300 MHz, CDCl3): δ = 7.65
(br. d, J = 7.0 Hz, 1 H, H5), 7.36–7.27 (m, 3 H, H3Ј,5Ј, H8), 7.18–
7.07 (mc, 2 H, H2Ј,6Ј), 6.61 (br. dd, J = 8.9, 6.4 Hz, 1 H, H7), 6.51
(ddd, J = 7.2, 6.4, 1.4 Hz, 1 H, H6), 2.39 (s, 3 H, 3-CH3), 2.29
(s, 3 H, 1-CH3) ppm. 13C NMR (101 MHz, [D6]DMSO, HSQC,
7-Phenyl-2-(4-chlorophenyl)-1,3-dimethylindolizine (4h): The title
compound was prepared according to general procedure B from 2d
(358 mg, 1.00 mmol) and (E)-1-chloro-4-(2-nitroprop-1-enyl)benz-
ene (3a; 198 mg, 1.00 mmol). The crude product was purified by
filtration through silica (ethyl acetate/cyclohexane, 1:10) to obtain
4h (240 mg, 0.72 mmol, 72%) as a green solid; m.p. 194–195 °C; Rf
1
3
HMBC): δ = 161.0 (d, JC,F = 243.1 Hz, C4Ј), 131.8 (d, JC,F
=
4
8.0 Hz, 2 C, C2Ј,6Ј), 131.7 (d, JC,F = 3.1 Hz, C1Ј), 128.5 (C8a),
125.5 (C2), 122.2 (C5), 117.1 (C8), 116.0 (C3), 115.2 (d, JC,F
2
=
21.1 Hz, 2 C, C3Ј,5Ј), 114.5 (C7), 109.9 (C6), 104.6 (C1), 9.8 (3-
CH3), 9.2 (1-CH3) ppm. MS (ESI): m/z (%) = 272.1 (52) [M + 2O
+ H]+, 256.1 (63) [M + OH]+, 240.1 (100) [M + H]+, 239.2 (73) [M]
+. HRMS (ESI): calcd. for [C16H14FN]+ 239.1110; found 239.1119.
= 0.74 (ethyl acetate/cyclohexane, 1:10). IR (neat): ν = 3025, 2924,
˜
1489, 1091, 832, 796, 728 cm–1. 1H NMR (300 MHz, CDCl3,
COSY, HSQC, HMBC): δ = 7.72 (dd, J = 7.4, 1.0 Hz, 1 H, H5),
7.69–7.65 (m, 2 H, H2ЈЈ,6ЈЈ), 7.59 (dd, J = 1.9, 1.0 Hz, 1 H, H8),
7.48–7.41 (m, 4 H, H3ЈЈ,5ЈЈ, H3Ј,5Ј), 7.35–7.27 (m, 3 H, H2Ј,6Ј,
H4ЈЈ), 6.86 (dd, J = 7.3, 1.9 Hz, 1 H, H6), 2.44 (s, 3 H, 3-CH3),
2.35 (s, 3 H, 1-CH3) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
138.9 (C1ЈЈ), 134.2 (C4Ј), 131.7 (C2Ј,6Ј), 131.2 (C1Ј), 128.9 (3 C,
C8a,3ЈЈ,5ЈЈ), 128.4 (C3Ј,5Ј), 126.8 (C4ЈЈ), 126.1 (C2), 126.0 (C7),
125.6 (C2ЈЈ,6ЈЈ), 122.6 (C5), 116.6 (C3), 113.7 (C8), 109.1 (C6),
106.3 (C1), 9.9 (C3-CH3), 9.3 (C1-CH3) ppm. MS (ESI): m/z (%)
= 364.0 (33) [M + 2O + H]+, 348.1 (100) [M + OH]+, 332.1 (17)
[M + H]+, 331.1 (31) [M]+. HRMS (ESI): calcd. for [C22H18NCl]+
331.1128; found 311.1118.
6-Methyl-7,8,9,10-tetrahydropyrido[2,1-a]isoindole (4e): The title
compound was prepared according to general procedure B from 2a
(282 mg, 1.00 mmol) and 1-nitrocyclohex-1-ene (3e; 127 mg,
113 μL, 1.00 mmol). The crude product was purified by filtration
through silica (ethyl acetate/cyclohexane, 1:10) to obtain 4e (72 mg,
0.39 mmol, 39%) as a slightly yellowish oil. Rf = 0.72 (ethyl acetate/
cyclohexane, 1:10). IR (neat): ν = 2923, 1590, 1465 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 7.59 (d, J = 7.0 Hz, 1 H, H5), 7.24 (dd, J
= 8.7, 1.2 Hz, 1 H, H1), 6.56–6.50 (m, 1 H, H2), 6.45 (td, J = 6.7,
1.2 Hz, 1 H, H3), 2.86–2.77 (m, 2 H, CH2), 2.77–2.68 (m, 2 H,
CH2), 2.35 (s, 3 H, CH3), 1.90–1.84 (m, 4 H, H8, H9) ppm. 13C
NMR (75 MHz, CDCl3): δ = 127.6 (C10b), 122.7 (C6a), 121.0 (C4),
116.6 (C1), 114.4 (C10a), 113.3 (C2), 109.5 (C3), 108.4 (C6), 24.2
(CH2), 24.0 (CH2), 22.1 (CH2), 21.2 (CH2), 9.2 (CH3) ppm. MS
(ESI): m/z (%) = 218.1 (14) [M + 2O + H]+, 202.1 (100) [M +
OH]+, 186.1 (2) [M + H]+. HRMS (ESI): calcd. for [C13H15N]+
185.1214; found 185.1204.
2-(4-Chlorophenyl)-1-isopropyl-3-methylindolizine (4i): The title
compound was prepared according to general procedure B from 2b
(310 mg, 1.00 mmol) and (E)-1-chloro-4-(2-nitroprop-1-enyl)benz-
ene (3a; 198 mg, 1.00 mmol). The crude product was purified by
filtration through silica (ethyl acetate/cyclohexane, 1:10) to obtain
4i (157 mg, 0.55 mmol, 55%) as a yellow solid; m.p. 140–142 °C;
R = 0.78 (ethyl acetate/cyclohexane, 1:10). IR (neat): ν = 3073,
˜
f
2965, 1480, 1092, 843, 731, 703 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 7.88 (dt, J = 7.2, 1.0 Hz, 1 H, H5), 7.42–7.36 (AAЈ part of
AAЈ–BBЈ system, 2 H, H3Ј,5Ј), 7.33 (dt, J = 9.0, 1.2 Hz, 1 H, H8),
7.26–7.20 (BBЈ part of AAЈ–BBЈ system, 2 H, H2Ј,6Ј), 6.59 (ddd,
J = 9.0, 6.4, 1.0 Hz, 1 H, H7), 6.46 (ddd, J = 7.2, 6.4, 1.2 Hz, 1 H,
H6), 3.38 (sept, J = 7.2 Hz, 1 H, 1-CH), 2.17 (s, 3 H, 1-CH3), 1.31
[d, J = 7.3 Hz, 6 H, (CH3)2CH] ppm. 13C NMR (75 MHz, CDCl3):
δ = 135.5 (C4Ј), 132.6 (C1Ј), 132.1 (C2Ј,6Ј), 129.2 (C8a), 128.2
(C3Ј,5Ј), 125.9 (C2), 125.6 (C3), 122.8 (C5), 117.9 (C8), 114.5 (C7),
109.9 (C6), 106.5 (C1), 25.8 (1-CH), 20.4 [(CH3)2CH], 9.13 (1-
CH3) ppm. MS (ESI): m/z (%) = 316 (10) [M + 2O + H]+, 300.0
(6) [M + OH]+, 284.0 (100) [M + H]+. HRMS (ESI): calcd. for
[C18H18NCl + H]+ 284.1206; found 284.1219.
1-Methyl-2-phenyl-3-(2-phenylethyl)indolizine (4f): The title com-
pound was prepared according to general procedure B from 2g
(186 mg, 0.50 mmol) and (E)-(2-nitroprop-1-enyl)benzene (3f;
82 mg, 0.50 mmol). The crude product was purified by filtration
through silica (ethyl acetate/cyclohexane, 1:10) to obtain 4f (50 mg,
0.16 mmol, 32%) as a yellow oil. Rf = 0.78 (ethyl acetate/cyclohex-
1
ane, 1:10). IR (neat): ν = 3063, 2923, 1453, 762, 731, 700 cm–1. H
˜
NMR (300 MHz, [D6]acetone): δ = 8.04 (d, J = 7.0 Hz, 1 H, H5),
7.47–7.09 (m, 11 H, PhH, H8), 6.64 (ddd, J = 8.8, 6.3, 0.8 Hz, 1
H, H7), 6.57–6.51 (m, 1 H, H6), 3.20–3.12 (m, 2 H CH2), 2.94–
2.87 (m, 2 H, CH2), 2.23 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
[D6]acetone): δ = 142.2, 137.6, 136.8, 130.9, 129.6, 129.1, 129.0,
128.8, 127.0, 126.7, 122.7, 120.6, 118.1, 115.2, 110.6, 106.2, 34.6,
27.2, 9.2 ppm. MS (ESI): m/z (%) = 384.2 (77) [M + 2O + H]+,
328.3 (100) [M + O + H]+, 312.2 (12) [M + H]+. HRMS (ESI):
calcd. for [C23H21N + H]+ 312.1752; found 312.1762.
2,3-Bis(4-chlorophenyl)-1-methylindolizine (4j): The title compound
was prepared according to general procedure B from 2c (265 mg,
1.00 mmol) and (E)-1-chloro-4-(2-nitroprop-1-enyl)benzene (3a;
198 mg, 1.00 mmol). The crude product was purified by filtration
through silica (ethyl acetate/cyclohexane, 1:10) to obtain 4j
(110 mg, 0.39 mmol, 39%) as a yellow solid; m.p. 169–171 °C; Rf
7-tert-Butyl-2-(4-chlorophenyl)-1,3-dimethylindolizine (4g): The title
compound was prepared according to general procedure B from 2e
(338 mg, 1.00 mmol) and (E)-1-chloro-4-(2-nitroprop-1-enyl)benz-
ene (3a; 198 mg, 1.00 mmol). The crude product was purified by
filtration through silica (ethyl acetate/cyclohexane, 1:10) to obtain
4g (221 mg, 0.71 mmol, 71%) as a yellow solid; m.p. 136–138 °C;
= 0.68 (ethyl acetate/cyclohexane, 1:10). IR (neat): ν = 3070, 3051,
˜
2922, 1396, 1091, 833, 826, 737 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 7.99 (br d, J = 7.1 Hz, 1 H, H5), 7.39 (dt, J = 9.0, 1.2 Hz, 1
H, H8), 7.36–7.30 (m, 2 H, CHAr), 7.29–7.17 (m, 2 H, CHAr), 7.14–
R = 0.84 (ethyl acetate/cyclohexane, 1:10). IR (neat): ν = 2964,
˜
f
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20424
/KAP1
Date: 03-07-12 15:57:32
Pages: 11
A Modular Synthesis of Polysubstituted Indolizines
7.08 (m, 2 H, CHAr), 6.74–6.64 (m, 1 H, H7), 6.45 (t, J = 7.0 Hz, raphy (ethyl acetate/cyclohexane, 1:5) to obtain 6a (216 mg, 81%)
1 H, H6), 2.33 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ as a solid; m.p. 156–159 °C; Rf = 0.44 (ethyl acetate/cyclohexane,
= 133.9 (Cq), 133.2 (Cq), 132.4 (Cq), 132.0 (CHAr), 131.7 (CHAr),
1:5). IR (neat): ν = 3094, 2922, 2195, 1382, 1096, 828, 740,
˜
1
130.8 (Cq), 129.9 (Cq), 129.3 (CHAr), 128.5 (CHAr), 127.1 (Cq), 725 cm–1. H NMR (400 MHz, CDCl3, COSY, HSQC, HMBC): δ
121.9 (C5), 120.3 (C3), 117.8 (C8), 116.6 (C7), 111.0 (C6), 107.3 = 8.22 (dt, J = 6.8, 0.9 Hz, 1 H, H5), 7.50–7.44 (m, 5 H, H8, 4ϫ
(C1), 9.4 (CH3) ppm. MS (ESI): m/z (%) = 384.1 (46) [M + 2O +
CHAr), 7.01 (ddd, J = 9.0, 6.8, 0.9 Hz, 1 H, H7), 6.80 (td, J = 6.8,
H]+, 368.2 (67) [M + OH]+, 352.2 (36) [M + H]+, 351.2 (100) [M]+. 1.2 Hz, 1 H, H6), 2.33 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
HRMS (ESI): calcd. for [C21H15NCl2]+ 351.0582; found 351.0582.
CDCl3): δ = 135.3 (C2), 135.2 (C8a), 134.2 (Cq), 131.0 (Cq), 130.8
(CHAr), 129.1 (CHAr), 125.3 (C5), 121.6 (C7), 118.0 (C8), 114.7
(CN), 113.3 (C6), 108.4 (C1), 93.1 (C3), 9.3 (CH3) ppm.
C16H11ClN2 (266.73): calcd. C 72.05, H 4.16, N 10.50; found C
71.94, H 4.26, N 10.51. MS (ESI): m/z (%) = 288.9 (34) [M +
2-(4-Chlorophenyl)-1,3,5-trimethylindolizine (4k): The title com-
pound was prepared according to general procedure B from 2f
(296 mg, 1.00 mmol) and (E)-1-chloro-4-(2-nitroprop-1-enyl)benz-
ene (3a; 198 mg, 1.00 mmol). The crude product was purified by
filtration through silica (ethyl acetate/cyclohexane, 1:10) to obtain
4k (56 mg, 0.21 mmol, 21%) as a yellow solid; m.p. 105–107 °C; Rf
Na]+, 266.9 (100) [M
+
H]+. HRMS (ESI): calcd. for
[C16H11NCl]+ 266.0611; found 266.0621.
= 0.75 (ethyl acetate/cyclohexane, 1:10). IR (neat): ν = 2923, 1488,
˜
1-Ethyl-2-(naphthalen-2-yl)indolizine-3-carbonitrile (6b): The title
compound was prepared according to general procedure C from 5
(100 mg, 0.50 mmol) and (E)-2-(2-nitrobut-1-enyl)naphthalene (3b;
114 mg, 0.50 mmol). The crude product was purified by column
chromatography (ethyl acetate/cyclohexane, 1:5) to obtain 6b
(121 mg, 0.41 mmol, 82%) as a yellow solid; m.p. 113–116 °C; Rf
1
1376, 1090, 830, 795, 725 cm–1. H NMR (300 MHz, CDCl3): δ =
7.42–7.37 (AAЈ part of AAЈ–BBЈ system, 2 H, H3Ј,5Ј), 7.24–7.19
(BBЈ part of AAЈ–BBЈ system, 2 H, H2Ј,6Ј), 7.15 (ddd, J = 9.0,
1.3, 0.6 Hz, 1 H, H8), 6.44 (dd, J = 9.0, 6.4 Hz, 1 H, H7), 6.13–
6.10 (m, 1 H, H6), 2.83 (s, 3 H, 5-CH3), 2.73 (s, 3 H, 3-CH3), 2.18
(s, 3 H, 1-CH3) ppm. 13C NMR (101 MHz, [D6]DMSO): δ = 134.7
(C4Ј), 134.4 (C5), 132.2 (2 C, C2Ј,6Ј), 131.2 (C1Ј), 130.6 (C8a),
128.2 (2 C, C3Ј,5Ј), 127.2 (C2), 118.2 (C3), 115.6 (C8), 115.1 (C7),
111.4 (C6), 105.1 (C1), 21.3 (5-CH3), 14.1 (3-CH3), 9.2 (1-
CH3) ppm. MS (ESI): m/z (%) = 286.0 (60) [M + OH]+, 270.0 (100)
[M + H]+. HRMS (ESI): calcd. for [C17H16NCl + H]+ 270.1050;
found 270.1037.
= 0.50 (ethyl acetate/cyclohexane, 1:5). IR (neat): ν = 3054, 2964,
˜
2928, 2194, 1427, 1216, 1130, 859, 814, 751, 728 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 8.28 (dt, J = 6.9, 1.0 Hz, 1 H, H5), 8.00
(br. s, 1 H, H1Ј), 7.99–7.88 (m, 3 H, 3CHnaphth), 7.66 (dt, J = 8.4,
1.7 Hz, 1 H, H8), 7.59–7.48 (m, 3 H, 3ϫ CHnaphth), 7.01 (ddd, J
= 9.0, 6.7, 1.0 Hz, 1 H, H7), 6.81 (td, J = 6.9, 1.2 Hz, 1 H, H6),
2.88 (q, J = 7.5 Hz, 2 H, CH2), 1.21 (q, J = 7.5 Hz, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 136.3 (Cq), 134.7 (Cq), 133.5 (Cq),
133.0 (Cq), 130.1 (Cq), 128.7 (CHnaphth), 128.5 (CHnaphth), 128.4
(CHnaphth), 127.9 (CHnaphth), 127.2 (CHnaphth), 126.5 (CHnaphth),
126.5 (CHnaphth), 125.4 (C5), 121.5 (C7), 118.0 (C8), 115.7 (Cq),
114.8 (Cq), 113.1 (C6), 93.7 (C3), 17.3 (CH2), 15.9 (CH3) ppm. MS
(ESI): m/z (%) = 319.2 (21) [M + Na]+, 297.2 (100) [M + H]+.
HRMS (ESI): calcd. for [C21H16N2 + Na]+ 319.1211; found
319.1211.
2-Isopropyl-1,3-dimethyl-7-phenylindolizine (4l): The title com-
pound was prepared according to general procedure B from 2d
(358 mg, 1.00 mmol) and (E)-4-methyl-2-nitropent-2-ene (3g;
129 mg, 1.00 mmol). The crude product was purified by filtration
through silica (ethyl acetate/cyclohexane, 1:10) to obtain 4l (97 mg,
0.37 mmol, 37%) as a yellow solid; m.p. 84–85 °C; Rf = 0.79 (ethyl
acetate/cyclohexane, 1:10). IR (neat): ν = 2959, 2925, 1390, 1362,
˜
1259, 750 cm–1. 1H NMR (300 MHz, CD3OD, COSY, HSQC,
HMBC): δ = 7.75 (d, J = 7.3 Hz, 1 H, H5), 7.64 (mc, 2 H, H2Ј,6Ј),
7.51 (br s 1 H, H8), 7.42–7.37 (mc, 2 H, H3Ј,5Ј), 7.25 (t, J = 7.4 Hz,
1 H, H4Ј), 6.79 (dd, J = 7.3, 1.7 Hz, 1 H, H6), 3.18 (sept, J =
7.1 Hz, 1 H, CH), 2.42 (s, 3 H, 3-CH3), 2.37 (s, 3 H, 1-CH3), 1.36
[d, J = 7.1 Hz, 6 H, (CH3)2CH] ppm. 13C NMR (100.6 MHz,
CD3OD): δ = 141.6 (C1Ј), 132.5 (C2), 130.7 (C8a), 129.8 (C3Ј,5Ј),
127.4 (C4Ј), 127.2 (C7), 126.8 (C2Ј,6Ј), 122.4 (C5), 116.1 (C3),
114.1 (C8), 109.5 (C6), 107.1 (C1), 27.3 (CH), 23.3 [(CH3)2CH],
10.0 (CH3), 9.9 (CH3) ppm. MS (ESI): m/z (%) = 296.1 (17) [M +
2O + H]+, 280.1 (16) [M + OH]+, 264.1 (100) [M + H]+, 263.1 (21)
[M]+. HRMS (ESI): calcd. for [C19H21N + H]+ 264.1752; found
264.1750.
2-(4-Cyanophenyl)-1-ethylindolizine-3-carbonitrile (6c): The title
compound was prepared according to general procedure C from 5
(100 mg, 0.50 mmol) and (E)-4-(2-nitrobut-1-enyl)benzonitrile (3c;
101 mg, 0.50 mmol). The crude product was purified by column
chromatography (ethyl acetate/cyclohexane, 1:5) to obtain 6c
(95 mg, 0.35 mmol, 70%) as a solid; m.p. 147–149 °C; Rf = 0.32
(ethyl acetate/cyclohexane, 1:5). IR (neat): ν = 2965, 2926, 2227,
˜
2196, 1534, 1453, 1356, 1224, 859, 754, 732 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 8.27 (dt, J = 6.9, 1.0 Hz, 1 H, H5), 7.82–
7.76 (AAЈ part of AAЈ–BBЈ system, 2 H, H3Ј,5Ј), 7.67–7.61 (BBЈ
part of AAЈ–BBЈ system, 2 H, H2Ј,6Ј), 7.54 (dt, J = 9.0, 1.1 Hz, 1
H, H8), 7.06 (ddd, J = 9.0, 6.7, 1.0 Hz, 1 H, H7), 6.87 (td, J = 6.8,
1.2 Hz, 1 H, H6), 2.80 (q, J = 7.6 Hz, 2 H, CH2), 1.18 (q, J =
7.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 137.6
(C4Ј), 134.7 (C2), 134.0 (C8a), 132.7 (C2Ј,6Ј), 130.1 (C3Ј,5Ј), 125.5
(C5), 122.0 (C7), 118.8 (Cq), 118.2 (C8), 115.7 (Cq), 114.2 (CN),
113.9 (C6), 111.9 (C1), 93.3 (C3), 17.2 (CH2), 15.9 (CH3) ppm.
C18H13N3 (271.32): calcd. C 79.68, H 4.83, N 15.49; found C 79.28,
H 4.77, N 15.75. MS (ESI): m/z (%) = 294.0 (94) [M + Na]+, 288.0
(37) [M + OH]+, 272.0 (100) [M + H]+. HRMS (ESI): calcd. for
[C18H13N3]+ 271.1109; found 271.1109.
General Procedure C
Synthesis of 3-Cyanoindolizines: 1-(Cyanomethyl)pyridinium brom-
ide (5; 1.0 equiv.) and the nitroolefin 3a–d (1.0 equiv.) were dis-
solved in freshly distilled THF (20 mL/mmol nitroolefin) at room
temperature. Ag2CO3 (2.0 equiv.) was added in one portion and the
reaction mixture was heated to reflux under an argon atmosphere
for 2 h. The solvent was removed in vacuo and the remaining solid
was extracted with ethyl acetate. The solution was decanted and
washed with water. The aqueous layer was extracted with ethyl
acetate and the combined organic layers were dried with MgSO4
and the solvent was removed in vacuo.
2-(4-Fluorophenyl)-1-methylindolizine-3-carbonitrile (6d): The title
compound was prepared according to general procedure C from 5
2-(4-Chlorophenyl)-1-methylindolizine-3-carbonitrile (6a): The title (100 mg, 0.50 mmol) and (E)-1-fluoro-4-(2-nitroprop-1-enyl)benz-
compound was prepared according to general procedure C from
5 (1.00 mmol) and (E)-1-chloro-4-(2-nitroprop-1-enyl)benzene (3a;
1.00 mmol). The crude product was purified by column chromatog-
ene (3d; 91 mg, 0.50 mmol). The crude product was purified by
column chromatography (ethyl acetate/cyclohexane, 1:5) to obtain
6d (102 mg, 0.41 mmol, 81%) as a solid; m.p. 162–164 °C; Rf =
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20424
/KAP1
Date: 03-07-12 15:57:32
Pages: 11
M. Kucukdisli, T. Opatz
FULL PAPER
0.44 (ethyl acetate/cyclohexane, 1:5). IR (neat): ν = 3070, 2914,
3-(1-Cyanoethyl)-1,3-benzothiazol-3-ium Triflate (12d): The title
compound was prepared according to general procedure A from
˜
2191, 1536, 1384, 1156, 859, 736, 726 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.24 (dt, J = 6.8, 1.1 Hz, 1 H, H5), 7.55–7.49 (mc, 2 benzothiazole (541 mg, 4.00 mmol) and 1a (1.22 g, 6.00 mmol).
H, H3Ј,5Ј), 7.47 (dt, J = 9.0, 1.1 Hz, 1 H, H8), 7.24–7.14 (mc, 2 H,
H2Ј,6Ј), 7.01 (ddd, J = 9.0, 6.7, 1.1 Hz, 1 H, H7), 6.81 (td, J = 6.8,
The white solid was filtered, washed with diethyl ether and recrys-
tallized from CH2Cl2 to yield 12d (1.12 g, 3.31 mmol, 83%); m.p.
1.2 Hz, 1 H, H6), 2.34 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
94–96 °C. IR (neat): ν = 3081, 1582, 1504, 1255, 1160, 1125 cm–1.
˜
1
CDCl3): δ = 162.2 (d, JC,F = 247.8 Hz, C-F), 135.6 (C2), 135.1 1H NMR (300 MHz, [D6]DMSO): δ = 10.75 (s, 1 H, H2), 8.58 (d,
3
4
(C8a), 131.2 (d, JC,F = 8.1 Hz, C2Ј,6Ј), 128.5 (d, JC,F = 3.6 Hz, J = 8.2 Hz, 1 H), 8.48 (d, J = 8.4 Hz, 1 H), 8.03 (pseudo t, J =
2
C1Ј), 125.3 (C5), 121.5 (C7), 117.9 (C8), 116.0 (d, JC,F = 21.6 Hz,
C3Ј,5Ј), 114.8 (CN), 113.2 (C6), 108.3 (C1), 93.2 (C3), 9.3
(CH3) ppm. MS (ESI): m/z (%) = 273.1 (3) [M + Na]+, 251.1 (100)
[M + H]+. HRMS (ESI): calcd. for [C16H11N2F + H]+ 251.0985;
found 251.0993.
7.9 Hz, 1 H), 7.92 (pseudo t, J = 7.7 Hz, 1 H), 6.72 (q, J = 7.0 Hz,
1 H, CH), 2.14 (d, J = 7.1 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 168.4 (C2), 164.4 (CH), 140.4 (C3a), 131.0 (C7a),
1
130.0 (CH), 128.8 (CH), 125.6 (CH), 120.7 (q, JC,F = 322 Hz,
CF3), 116.6 (CϵN), 60.7 (CH), 17.2 (CH3) ppm. C11H9F3N2O3S2
(338.32): calcd. C 39.05, H 2.68, N 8.28, S 18.96; found C 39.17,
H 2.72, N 8.27, S 19.07. MS (ESI): m/z (%) = 207.0 (100) [M +
H2O]+, 189.0 (64) [M]+, 164.1 (39).
2-(1-Cyanoethyl)isoquinolinium Triflate (12a): The title compound
was prepared according to general procedure A from isoquinoline
(646 mg, 5.00 mmol) and 1-cyanoethyl trifluoromethanesulfonate
(1.22 g, 6.00 mmol). The white solid was filtered, washed with cold
diethyl ether and recrystallized from diethyl ether to yield com-
pound 12a (1.55 g, 4.66 mmol, 93%) as a solid; m.p. 155–156 °C.
Synthesis of N-Fused-Pyrrole-Containing Heterocycles
Method A: To a solution of azinium salt (1 equiv.) and nitroolefin
(1 equiv.) in anhydrous DMF (10 mL/mmol azine) was slowly
added a solution of KOtBu (4 equiv.) in anhydrous DMF (5.0 mL/
mmol azine) at 0 °C. The mixture was stirred at this temperature
and monitored by TLC. When the reaction was complete, the sol-
vent was evaporated in vacuo. The residue was dissolved in ethyl
acetate, washed with water and the aqueous phase was extracted
twice with ethyl acetate. The combined organic layers were washed
with brine, dried with MgSO4 and the solvent was removed in
vacuo. In one case (Table 5, entry 5), Ag2CO3 (2 equiv.) was used
instead of KOtBu.
IR (neat): ν = 3066, 1644, 1403, 1264, 1167 cm–1. 1H NMR
˜
(300 MHz,
[D6]-
DMSO): δ = 10.26 (s, 1 H, H1), 9.03 (d, J = 6.8 Hz, 1 H, H3), 8.72
(d, J = 6.9 Hz, 1 H, H4), 8.60 (d, J = 8.0 Hz, 1 H, H8), 8.38 (m, 2
H, H6, H7), 8.15 (d, J = 8.0 Hz, 1 H, H5), 6.41 (q, J = 7.0 Hz, 1
H, CH), 2.11 (d, J = 7.0 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 150.5 (C1), 138.1 (C6), 137.7 (C4a), 133.0 (C3),
131.7 (C7), 131.2 (C8), 127.4 (C5), 127.2 (C8a), 126.7 (C4), 120.7
1
(q, JC,F
= 322 Hz, CF3), 116.6 (CϵN), 56.1 (CH), 20.1
(CH3) ppm. C13H11F3N2O3S (332.30): calcd. C 46.99, H 3.34, N
8.43, S 9.65; found C 46.84, H 3.18, N 8.10, S 9.73. MS (ESI): m/z
(%) = 183.1 (100) [M]+, 158.1 (22).
Method B: A solution of KOtBu (4 equiv.) in anhydrous DMF
(5.0 mL/mmol azine) was slowly added to a stirred solution of azin-
ium salt (1 equiv.) and DEAD (1 equiv.) in anhydrous DMF
(10 mL/mmol azine) at 0 °C. The mixture was stirred at 0 °C, and
the reaction was monitored by TLC. When the conversion was
complete, the solvent was evaporated in vacuo. The residue was
dissolved in ethyl acetate and washed with water. The aqueous
phase was extracted twice with ethyl acetate. The combined organic
layers were washed with brine, dried with MgSO4, and the solvent
was removed in vacuo.
2-(1-Cyano-2-methylpropyl)phthalazin-2-ium Triflate (12b): The title
compound was prepared according to general procedure A from
phthalazine (1.30 g, 10.0 mmol) and 1b (2.31 g, 10.0 mmol). The
white solid was filtered, washed with diethyl ether and recrys-
tallized from EtOAc to yield 12b (2.79 g, 7.7 mmol, 77%); m.p.
122–123 °C. IR (neat): ν = 3010, 2976, 1484, 1225, 1153, 1027 cm–1.
˜
1H NMR (300 MHz, [D6]DMSO): δ = 10.72 (s, 1 H, H1), 10.21 (s,
1 H, H4), 8.75 (d, J = 8.0 Hz, 1 H, H8), 8.68–8.59 (m, 2 H, H5,
H7), 8.49 (ddd, J = 8.3, 6.4, 2.1 Hz, H6), 6.41 (d, J = 7.1 Hz, 1 H,
H1Ј), 2.83–2.65 (m, 1 H, H2Ј), 1.18 (d, J = 6.7 Hz, 3 H, CH3), 1.04
(d, J = 6.7 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 155.4 (CH), 153.3 (CH), 140.4 (CH), 136.7 (CH), 131.4 (CH),
128.7 (CH), 128.1 (Cq), 127.6 (Cq), 120.6 (q, 1JC,F = 322 Hz, CF3),
114.4 (CN), 68.2 (C1Ј), 33.3 (C2Ј), 18.2 (CH3), 17.7 (CH3) ppm.
C14H14F3N3O3S (361.34): calcd. C 46.54, H 3.91, N 11.63, S 8.87;
found C 46.60, H 3.90, N 11.81, S 8.92. MS (ESI): m/z (%) = 212.1
(100) [M + H]+.
2-(4-Chlorophenyl)-1,3-dimethylpyrrolo[2,1-a]isoquinoline (13a): The
title compound was prepared according to method A from 12a
(332 mg, 1.00 mmol) and (E)-1-chloro-4-(2-nitroprop-1-enyl)benz-
ene (3a; 198 mg, 1.00 mmol). The crude product was purified by
column chromatography over silica (ethyl acetate/cyclohexane,
1:10) to obtain 13a (150 mg, 0.49 mmol, 49%) as a yellow solid;
m.p. 148–149 °C; Rf = 0.54 (ethyl acetate/cyclohexane, 1:10). IR
(neat): ν = 2960, 2923, 1547, 1480, 1359, 1087, 848, 779, 757 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 8.23 (d, J = 8.1 Hz, 1 H, H5),
7.59 (pseudo t, J = 8.1 Hz, 2 H, H9, H10), 7.52–7.42 [m, 3 H,
H8(7), H3Ј,5Ј], 7.37–7.26 [m, 3 H, H7(8), H2Ј,6Ј], 6.75 (d, J =
7.4 Hz, 1 H, H6), 2.57 (s, 3 H, CH3), 2.42 (s, 3 H, CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 134.3, 132.4, 132.3, 131.7, 128.5,
128.0, 127.24, 127.20, 126.9, 125.9, 124.5, 122.5, 121.5, 118.5,
110.7, 110.4, 13.1, 10.3 ppm. MS (ESI): m/z (%) = 338.2 (92) [M +
2O + H]+, 322.2 (100) [M + OH]+, 306.2 (56) [M + H]+, 305.2
(65) [M]+. HRMS (ESI): calcd. for [C20H16NCl]+ 305.0971; found
305.0980.
3-(1-Cyanoethyl)-1-methyl-1H-imidazol-3-ium Triflate (12c): Pre-
pared according to general procedure A from 1-methyl-imidazole
(328 mg, 4.00 mmol) and 1a (813 mg, 4.00 mmol). The white solid
was filtered, washed with diethyl ether and recrystallized from
CH2Cl2 to yield 12c (938 mg, 3.29 mmol, 82%); m.p. 52–54 °C. IR
(neat): ν = 3155, 3110, 2962, 1583, 1557, 1250, 1157, 1028,
˜
1
733 cm–1. H NMR (300 MHz, [D6]DMSO): δ = 9.35 (s,1 H, H2),
8.07 (d, J = 1.4 Hz, 1 H, H4), 7.82 (d, J = 1.4 Hz, 1 H, H5), 5.98
(q, J = 7.1 Hz, 1 H, H1Ј), 3.88 (s, 3 H, NCH3), 1.88 (d, J = 7.1 Hz, 2-(4-Chlorophenyl)-1-methyl-3-(propan-2-yl)pyrrolo[2,1-a]phthal-
3 H, H2Ј) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 137.0 (C2), azine (13b): The title compound was prepared according to method
124.6 (C5), 120.9 (C4), 117.1 (CN), 45.3 (CH), 36.2 (NCH3), 19.0 B from 12b (361 mg, 1.00 mmol) and 3a (198 mg, 1.00 mmol). The
(CH3) ppm. C8H10F3N3O3S (285.24): calcd. C 33.69, H 3.53, N crude product was purified by filtration through silica (ethyl acet-
14.73, S 11.24; found C 33.50, H 3.56, N 14.85, S 11.31. MS (ESI):
ate/cyclohexane, 1:10) to obtain 13b (114 mg, 0.34 mmol, 34%) as
a yellow solid; m.p. 136–138 °C; Rf = 0.50 (ethyl acetate/cyclohex-
m/z (%) = 136.2 (100) [M + H]+.
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20424
/KAP1
Date: 03-07-12 15:57:32
Pages: 11
A Modular Synthesis of Polysubstituted Indolizines
ane, 1:5). IR (neat): ν = 2962, 2932, 1357, 1202, 1016, 840, NMR (400 MHz, [D6]DMSO): δ = 8.39 (d, J = 8.1 Hz, 1 H, H10),
˜
752 cm–1 1H NMR (600 MHz, [D6]acetone, COSY, HSQC, 8.24 (d, J = 7.3 Hz, 1 H, H5), 7.89 (dd, J = 7.7, 0.9 Hz, 1 H, H7),
.
HMBC): δ = 8.47 (s, 1 H, H6), 8.15 (dd, J = 8.2, 1.1 Hz, 1 H,
H10), 7.87 (dd, J = 7.9, 1.4 Hz, 1 H, H7), 7.75 (ddd, J = 8.1, 7.3,
1.0 Hz, 1 H, H9), 7.52–7.50 (AAЈ part of AAЈ–BBЈ system, 2 H,
H3Ј,5Ј), 7.46 (ddd, J = 7.9, 7.5, 0.7 Hz, 1 H, H8), 7.37–7.34 (BBЈ
part of AAЈ–BBЈ system, 2 H, H2Ј,6Ј), 3.48 (sept, J = 7.2 Hz, 1 H,
CHiPr), 2.41 (s, 3 H, 1-CH3), 1.38 [d, J = 7.1 Hz, 6 H, (CH3)2-
CH] ppm. 13C NMR (151 MHz, [D6]acetone): δ = 143.2 (C6), 135.6
7.71–7.67 (m, 1 H, H9), 7.67–7.64 (AAЈ part of AAЈ-BBЈ system,
2 H, H3Ј,5Ј), 7.64–7.59 (m, 1 H, H8), 7.59–7.53 (BBЈ part of AAЈ-
BBЈ system, 2 H, H2Ј,6Ј), 7.30 (d, J = 7.3 Hz, 1 H, H6), 2.58 (s, 3
H, CH3) ppm. 13C NMR (101 MHz, [D6]DMSO): δ = 135.1 (C2),
133.2 (C1Ј), 131.5 (2 C, C2Ј,6Ј), 130.5 (C4Ј), 129.8 (C10b), 129.0
(2 C, C3Ј,5Ј), 128.5 (C9), 128.4 (C10a), 127.7 (C7), 127.6 (C8),
125.6 (C6a), 123.5 (C10), 123.1 (C5), 113.9 (C6), 113.6 (CN), 112.1
(C4Ј), 133.5 (2 C, C2Ј,6Ј), 133.1 (C1Ј), 133.0 (C9), 131.8 (C3), 130.2 (C1), 94.7 (C3), 12.5 (CH3) ppm. MS (ESI): m/z (%) = 339.4 (100)
(C6a), 129.0 (2 C, C3Ј,5Ј), 128.8 (C7), 125.8 (C8), 123.7 (C2), 122.2
(C10), 120.5 (C10a), 118.5 (C10b), 109.9 (C1), 26.8 (CHiPr), 20.9
[2 C, (CH3)2CH], 12.3 (1-CH3) ppm. MS (ESI): m/z (%) = 367.3
(39) [M + 2O + H]+, 351.4(100) [M + O + H]+, 335.5 (34) [M +
H]+. HRMS (ESI): calcd. for [C21H19N2C l + H]+ 335.1315; found
335.1312.
[M + Na]+, 317.5 (22) [M + H]+. C20H13ClN2 (316.79): calcd. C
75.83, H 4.14, N 8.84; found C 75.46, H 3.87, N 8.74.
Diethyl 3-(Propan-2-yl)pyrrolo[2,1-a]phthalazine-1,2-dicarboxylate
(13f): The title compound was prepared according to method B
from 12b (361 mg, 1.00 mmol) and DEAD (170 mg, 1.00 mmol).
The crude product was purified by flash chromatography over silica
(ethyl acetate/cyclohexane, 1:5) to obtain 13f (180 mg, 0.508 mmol,
51%) as a solid; m.p. 68–69 °C; Rf = 0.31 (ethyl acetate/cyclohex-
Diethyl 1,5-Dimethyl-1H-pyrrolo[1,2-a]imidazole-6,7-dicarboxylate
(13c): The title compound was prepared according to method B
from 12c (157 mg, 0.55 mmol) and DEAD (94 mg, 0.55 mmol).
The crude product was purified by flash chromatography over silica
(ethyl acetate/cyclohexane, 1:3) to obtain 13c (89 mg, 0.32 mmol,
58%) as a yellow solid; m.p. 118–120 °C; Rf = 0.22 (ethyl acetate/
ane, 1:5). IR (neat): ν = 2979, 2937, 1704, 1621, 1456, 1173,
˜
1
757 cm–1. H NMR (400 MHz, CDCl3, COSY, HSQC, HMBC): δ
= 8.88 (br. d, J = 8.7 Hz, 1 H, H10), 8.44 (s, 1 H, H6), 7.75–7.68
(m, 2 H, H7, H9), 7.54 (td, J = 7.5, 1.0 Hz, 1 H, H8), 4.42 (q, J =
7.2 Hz, 2 H, H2Ј), 4.37 (q, J = 7.2 Hz, 2 H, H2ЈЈ), 4.01 (sept, J =
7.1 Hz, 1 H, H1ЈЈЈ), 1.46 {d, J = 7.1 Hz, 6 H, [(CH3)2CH]}, 1.40
(t, J = 7.2 Hz, 3 H, H3Ј), 1.39 (t, J = 7.2 Hz, 3 H, H3ЈЈ) ppm. 13C
NMR (101 MHz, CDCl3): δ = 166.3 (C1ЈЈ), 166.1 (C1Ј), 145.1 (C6),
137.3 (C3), 132.7 (C7), 127.9 (C8), 127.8 (C9), 127.5 (C10a), 124.5
(C10), 122.9 (C10b), 120.8 (C6a), 114.9 (C2), 106.6 (C1), 61.2
(C2Ј), 61.1 (C2ЈЈ), 25.6 (C1ЈЈЈ), 20.1 [(CH3)2CH], 14.4 (C3ЈЈ), 14.3
(C3Ј) ppm. MS (ESI): m/z (%) = 377.2 (100) [M + Na]+, 355.3(30)
[M + H]+, 309.3 (71) [M – OC2H5]+. HRMS (ESI): calcd. for
[C20H22N2O4 + Na]+ 377.1477; found 377.1477.
cyclohexane, 1:3). IR (neat): ν = 2980, 1670, 1589, 1454, 1189,
˜
1083, 1048 cm–1 1H NMR (400 MHz, CDCl3, COSY, HSQC,
.
HMBC): δ = 6.80 (d, J = 2.2 Hz, 1 H, H3), 6.67 (d, J = 2.2 Hz, 1
H, H2), 4.31 (q, J = 7.1 Hz, 2 H, C2Ј), 4.21 (q, J = 7.1 Hz, 2 H,
C2ЈЈ), 3.96 (s, 3 H, NCH3), 2.33 (s, 3 H, 5-CH3), 1.35 (t, J = 7.1 Hz,
3 H, H3Ј), 1.29 (t, J = 7.1 Hz, 3 H, H3ЈЈ) ppm. 13C NMR
(101 MHz, CDCl3): δ = 166.7 (C1Ј), 163.8 (C1ЈЈ), 139.0 (C7a),
123.8 (C2), 117.9 (C6), 115.5 (C5), 104.1 (C3), 85.1 (C7), 60.7 (C2Ј),
59.3 (C2ЈЈ), 35.8 (NCH3), 14.6 (C3ЈЈ), 14.4 (C3Ј), 10.3 (5-
CH3) ppm. MS (ESI): m/z (%) = 301.3 (100) [M + Na]+, 279.3
(51) [M + H]+, 233.2 (49) [M – OC2H5]+. HRMS (ESI): calcd. for
[C14H18N2O4 + H]+ 279.1345; found 279.1346.
Diethyl 3-Methylindolizine-1,2-dicarboxylate (13g): The title com-
pound was prepared according to method B from 2a (282 mg,
1.00 mmol) and DEAD (170 mg, 1.00 mmol). The crude product
was purified by flash chromatography over silica (ethyl acetate/cy-
clohexane, 1:10) to obtain 13g (210 mg, 0.76 mmol, 76%) as a yel-
low waxy oil. Rf = 0.18 (ethyl acetate/cyclohexane, 1:4). IR (neat):
2-(4-Chlorophenyl)-1,3-dimethylpyrrolo[2,1-b][1,3]benzothiazole
(13d): The title compound was prepared according to method A
from 12d (338 mg, 1.00 mmol) and 3a (198 mg, 1.00 mmol). The
crude product was purified by chromatography over silica (ethyl
acetate/cyclohexane, 1:10) to obtain 13d (80 mg, 0.26 mmol, 26%)
as slightly brown solid; m.p. 134–137 °C; Rf = 0.60 (ethyl acetate/
ν = 2982, 1734, 1689, 1527, 1236, 1200, 1088, 1041, 782, 739 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 8.15 (dd, J = 9.2, 0.9 Hz, 1 H,
H5), 7.78 (dd, J = 7.1, 0.9 Hz, 1 H, H8), 7.06 (ddd, J = 9.0, 6.6,
1.0 Hz, 1 H), 6.79 (td, J = 6.8, 1.3 Hz), 4.40 (q, J = 7.2 Hz, 2 H,
OCH2), 4.34 (q, J = 7.2 Hz, 2 H, OCH2), 2.50 (s, 3 H, 3-CH3), 1.40
(t, J = 7.2 Hz, 3 H, CH3), 1.35 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 166.7 (CO2Et), 164.1 (CO2Et), 135.1
(Cq), 122.8, 122.5, 122.1 (Cq), 120.6 (Cq), 120.4, 113.4 (CN), 101.7
(Cq), 61.3 (OCH2), 59.9 (OCH2), 14.6 (CH3), 14.4 (CH3), 10.1
(CH3) ppm. MS (ESI): m/z (%) = 298.2 (100) [M + Na]+, 276.2
(29) [M + H]+, 230.1 (28) [M – OC2H5]+. HRMS (ESI): calcd. for
[C15H17NO4 + Na]+ 298.1055; found 298.1056.
cyclohexane, 1:10). IR (neat): ν = 3058, 3033, 2920, 1476, 1028,
˜
763, 742 cm–1 1H NMR (400 MHz, CDCl3, COSY,HSQC,
.
HMBC): δ = 7.75 (dd, J = 8.2, 0.6 Hz, 1 H, H5), 7.61 (dd, J = 7.9,
1.0 Hz, 1 H, H8), 7.44–7.39 (AAЈ part of AAЈ–BBЈ system, 2 H,
H3Ј,5Ј), 7.31 (td, J = 7.9, 1.2 Hz, 1 H, H6), 7.28–7.24 (BBЈ part of
AAЈ–BBЈ system, 2 H, H2Ј,6Ј), 7.19 (ddd overlapped, J = 7.8, 7.6,
1.0 Hz, 1 H, H7), 2.67 (s, 3 H, C1-CH3), 2.12 (s, 3 H, C3-
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 136.4 (C8a), 134.2
(C4Ј), 132.2 (C1Ј), 131.7 (C4a), 131.6 (C2Ј,6Ј), 128.5 (C3Ј,5Ј), 127.2
(C2), 125.3 (C6), 124.0 (C8), 123.4 (C3a), 123.0 (C7), 120.1 (C1),
112.8 (C5), 106.3 (C3), 12.7 (C1-CH3), 10.8 (C3-CH3) ppm. MS
(ESI): m/z (%) = 344.2 (23) [M + 2O + H]+, 328.2 (100) [M +
OH]+, 312.2 (28) [M + H]+, 311.2 (46) [M]+. HRMS (ESI): calcd.
for [C18H14NClS]+ 311.0535; found 311.0545.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H NMR and 13C NMR spectra for all new
compounds.
2-(4-Chlorophenyl)-1-methylpyrrolo[2,1-a]isoquinoline-3-carbonitrile
(13e): The title compound was prepared according to method A
from 2-(cyanomethyl)isoquinolinium bromide (12e; 249 mg,
1.00 mmol) and 3a (198 mg, 1.00 mmol). The crude product was
purified by chromatography over silica (ethyl acetate/cyclohexane,
1:10) to obtain 13e (150 mg, 0.49 mmol, 49%) as a yellow solid;
Acknowledgments
This work was supported by the Deutsche Forschungsgemein-
schaft. We thank Dr. N. Hanold for mass spectrometry and Dr.
J. C. Liermann for NMR spectroscopy.
m.p. 198–200 °C; Rf = 0.48 (ethyl acetate/cyclohexane, 1:10). IR
1
(neat): ν = 3090, 2917, 2196, 1516, 1366, 1224, 1095, 820 cm–1. H
˜
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
Date: 03-07-12 15:57:32
Pages: 11
M. Kucukdisli, T. Opatz
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Received: April 2, 2012
Published Online: ᭿
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20424
/KAP1
Date: 03-07-12 15:57:32
Pages: 11
A Modular Synthesis of Polysubstituted Indolizines
Heterocyclic Chemistry
Polysubstituted indolizines were synthe-
sized through [3+2] cycloaddition of nitro-
alkenes with pyridinium ylides. In contrast
to previous reports of 1,3-dipolar cyclo-
additions, in this work no electron-deficient
groups remain in the products.
M. Kucukdisli, T. Opatz* ................ 1–11
A Modular Synthesis of Polysubstituted
Indolizines
Keywords: Cycloaddition / Nitrogen hetero-
cycles / Sulfur heterocycles / Ylides
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11