One-pot synthesis of polysubstituted indolizines by an addition/ cycloaromatization sequence

Article abstract of DOI:10.1021/jo400992n

Indolizines carrying various substituents in positions 5-8 were obtained from readily available 2-(1H-pyrrol-1-yl)nitriles and α,β-unsaturated ketones or aldehydes in a one-pot procedure. Michael addition of the deprotonated aminonitriles to the acceptors followed by acid-catalyzed electrophilic cyclization produces 5,6-dihydroindolizine-5-carbonitriles. From these stable intermediates, substituted indolizines were obtained via base-induced dehydrocyanation.

Full text of DOI:10.1021/jo400992n

Article
pubs.acs.org/joc
One-Pot Synthesis of Polysubstituted Indolizines by an Addition/
Cycloaromatization Sequence
Murat Kucukdisli and Till Opatz*
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10−14, D-55128 Mainz, Germany
S
* Supporting Information
ABSTRACT: Indolizines carrying various substituents in
positions 5−8 were obtained from readily available 2-(1H-
pyrrol-1-yl)nitriles and α,β-unsaturated ketones or aldehydes
in a one-pot procedure. Michael addition of the deprotonated
aminonitriles to the acceptors followed by acid-catalyzed
electrophilic cyclization produces 5,6-dihydroindolizine-5-
carbonitriles. From these stable intermediates, substituted
indolizines were obtained via base-induced dehydrocyanation.
Scheme 1. Synthesis of Indolizines from Pyrroles
INTRODUCTION
■
Similar to the indoles, their bioisosteric analogues, indolizines
are known to possess a variety of interesting biological activities
and have been classified as privileged scaffolds for the
construction of GPCR ligands.1 Other attractive bioactivities
of indolizines include antitubercular,2−4 phosphatase inhib-
itive,5−7 antioxidant,8 or anti-inflammatory.9 Consequently,
many synthetic methods have been developed for the
preparation of substituted indolizines.10,11 The majority of
them start from pyridine derivatives and complete the bicyclic
skeleton by construction of the pyrrole ring.12−22 In contrast,
the construction of the pyridine ring in indolizines is mostly
limited to the synthesis of benzo-fused products such as
pyrrolo[1,2-a]quinolines23−30 and pyrrolo[2,1-a]isoquino-
lines31−34 from 1- or 2-aryl-substituted pyrroles via the
formation of C8−C8a and N−C5 bonds, respectively. As a
notable exception, Kim and Lee recently reported on a
cycloaromatization approach to the synthesis of 6,8-disub-
stituted indolizines from 2-acetylpyrroles by formation of the
C6−C7 bond.35 Likewise, annulations of the pyrrole core were
achieved by formation of the C7−C8 bond in the indolizine
skeleton starting from functionalized pyrrole-2-carbaldehydes,
which gave indolizines devoid of a substituent in 8-position
(Scheme 1).36−41
ucts49−51 obtained by reaction of ammonia with the
corresponding aliphatic or aromatic aldehydes (Table 1).
As a model reaction, we investigated the conjugate addition
of deprotonated 2-(1H-pyrrol-1-yl)propanenitrile (1a) to
chalcone (2a). The action of KHMDS (1.1 equiv) at −78 °C
or KOtBu (1.1 equiv) at 0 °C on pronucleophile 1a in THF
followed by addition of electrophile 2a afforded after 2 h a
diastereomeric mixture (syn/anti 1:1) of the Michael adducts 3a
in 95% and 98% yield, respectively (Scheme 2).
In contrast, when 2-phenyl-2-(1H-pyrrol-1-yl)acetonitrile
(1d) was deprotonated with different bases (e.g., KHMDS,
KOtBu, LDA, NaH) and reacted with 2a at temperatures
ranging from −78 to 25 °C in DMF or THF, only low (<10%
yield) or no conversion was observed. When an excess of
iodomethane was added to the reaction mixture as a second
electrophile, 2-phenyl-2-(1H-pyrrol-1-yl)propanenitrile was
Here, we report a novel synthesis of indolizine with up to
four substituents on the pyridine ring by means of a one-pot
conjugate addition/cyclodehydration/dehydrocyanation se-
quence starting from 2-(1H-pyrrol-1-yl)nitriles and α,β-
unsaturated ketones or aldehydes. In contrast to other
methods,42−47 this strategy allows the facile decoration of the
pyridine unit up to persubstitution.
RESULTS AND DISCUSSION
■
2-(1H-Pyrrol-1-yl)nitriles 1a−e can be readily prepared in a
modified Clauson-Kaas procedure48 starting from commercially
available 2,5-dimethoxytetrahydrofuran and Strecker prod-
Received: May 6, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400992n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
equiv/BF3·OEt2, 3.0 equiv), and again base (DBU, 20 equiv).
The overall yields obtained were comparable to those of the
stepwise protocol. Table 2 summarizes the results obtained for
the reaction of nitriles 1a−e to various α,β-unsaturated
carbonyl compounds (2a−j). It turned out that the presence
of an electron-deficient α-substituent (R3) in the electrophile
required harsher conditions for the cyclodehydration. An
alternative procedure (Method B, Table 2) in which the
cheap AcOH/BF3·OEt2 system was replaced by triflic acid (1.5
equiv) had to be employed in this case. While the reaction of
the sterically hindered pyrrolonitrile 1c with chalcone (2a) gave
the indolizine 5c in low yield (Table 2, entry 3), the reaction of
pyrrolonitriles 1a, 1b, and 1e with the same electrophile
afforded indolizines 5a, 5b, and 5i in moderate to high yield
(Table 2, entries 1, 2, and 9). A similar observation was made
for the reaction of 1c with chalcone 2e (Table 2, entries 8 and
10 compared to entry 16). 5,6,7,8-Tetrasubstituted indolizines
5f and 5g were synthesized from ethyl 2-benzoyl-3-phenyl-
acrylate in 34% and 31% yield, respectively (Table 2, entries 6
and 7). The former example demonstrates that aromatic
substituents R1 can be introduced if additional enolate
stabilization is provided for the product of the vinylogous
addition step. Attempts to prepare the 5,6,7-trisubsubstituted
indolizine 5n from 2,3-bis(3,4-dimethoxyphenyl)acrylaldehyde
in the one-pot procedure failed in the dehydrocyanation step.
However, the desired product could be obtained in 39% yield
by a modified two-step procedure that includes a one-pot
conjugate addition/cyclodehydration sequence and dehydro-
cyanation of the crude dihydroindolizine 4n with KOtBu
instead of DBU (Table 2, entry 14).
Table 1. Preparation of Pyrrolonitriles 1a−e
a
entry
R1
Me
product
yield (%)
b
1
2
3
4
5
1a
1b
1c
1d
1e
90
PhCH2
iPr
76
b
92
Ph
76
63
Cy
a
b
Isolated yield. Aminonitrile hydrochloride was used.
Scheme 2. Conjugate Addition of Pyrrolonitriles 1a and 1d
formed almost quantitatively (GC−MS). This proved that the
deprotonation of the pronucleophile took place whereas the
conjugate addition to chalcone did not. Presumably, the anion
stabilizing capacity of the nitrile group and the phenyl ring in
conjunction with the electron-deficient pyrrole nitrogen
hampered the formation of a less stabilized ketone enolate.
Thus, the conjugate addition of 1d to 2a in an aprotic
environment should be reversible with the equilibrium being on
the side of the reactants unless a better stabilization for the
enolate is provided (vide infra).52
The product mixture 3a was further transformed into
dihydroindolizine 4a under acidic conditions. While even the
use of superstoichiometric amounts of acetic acid gave no
conversion, BF3·OEt2 (0.30 equiv) produced an appreciable
yield (76%) of the cyclodehydration product 4a (Scheme 3).
Furthermore, the one-pot sequence can be also applied to
exocyclic enone systems for preparing polycyclic nitrogen
heterocycles. For instance, pyrrolonitrile 1c could be reacted
with 2-(4-chlorobenzylidene)-6-methoxy-3,4-dihydronaphtha-
len-1(2H)-one (2k) and afforded tetracyclic compound 6 in
38% yield, demonstrating that no additional acceptor group in
the electrophile is required to obtain persubstituted products
(Scheme 4).
CONCLUSION
■
In summary, a new method for the synthesis of indolizines has
been developed based on a one-pot sequential conjugate
addition/cyclodehydration/dehydrocyanation reaction of 2-
(1H-pyrrol-1-yl)nitriles with α,β-unsaturated carbonyl com-
pounds. We demonstrated that this sequence can be used for
the preparation of indolizines carrying up to four substituents in
the pyridine portion. No expensive reagents or catalysts are
required and the products were obtained in moderate to high
yields. The chromatographic purification of the final products is
simplified by their intense fluorescence.
Scheme 3. Stepwise Synthesis of Indolizine 5a
This yield could be increased to 82% by using In(OTf)3 (0.10
equiv) in CH2Cl2. However, the best result was obtained when
the reaction was performed with a mixture of ethanol (5 mL/
mmol pyrrolonitrile), acetic acid (7.0 equiv), and BF3·OEt2 (3.0
equiv) in THF during 18 h at room temperature (95% yield).
The base-induced dehydrocyanation of dihydroindolizine 4a
finally yielded the target indolizine 5a. While KOH (10.0
equiv) in ethanol−water afforded 5a in 65% yield after 3 h,
DBU (10.0 equiv) in THF gave 50% yield at room temperature
after 12 h. The latter figure could be improved to 87% when the
mixture was heated to reflux for 2 h.
EXPERIMENTAL SECTION
■
Compounds 2a, 1-phenylbut-2-en-1-one (2c), 3-(2-chlorophenyl)-1-
(4-fluorophenyl)prop-2-en-1-one (2e), and 3-(4-methoxyphenyl)-1-
(4-fluorophenyl)prop-2-en-1-one (2j) were obtained from commercial
suppliers. All other α,β-unsaturated aldehyde/ketones (2b, 2d, 2f−2i,
and 2k)53,49,54−58 and α-aminonitriles49−51 were prepared according to
literature procedures.
General Procedure for the Synthesis of Pyrrolonitrile (1a−
e).48 A solution of 2,5-dimethoxytetrahydrofuran in deionized water
(1.2 mL/mmol) was refluxed for 2 h. The mixture was allowed to cool
before addition of CH2Cl2 (2 mL/mmol), the corresponding α-
aminonitrile (1.0−1.2 equiv), and sodium acetate (2.4 equiv). The
reaction mixture was further stirred overnight at rt. It was made
We next explored the amalgamation of all three steps to a
one-pot sequence since all transformations involved can be
performed in THF in high yields. This was achieved by simply
adding consecutively base (KOtBu, 1.1 equiv), acid (AcOH, 7.0
B
dx.doi.org/10.1021/jo400992n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 2. One-Pot Synthesis of Polysubstituted Indolizines
b
entry
R1
R2
R3
R4
product
method
yield (%)
1
Me
Bn
iPr
Ph
Ph
Ph
Ph
Me
Ph
Ph
H
Ph
Ph
Ph
Me
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
A
A
A
A
A
B
B
A
B
A
A
A
A
A
A
A
85
54
41
31
10
31
34
59
69
67
71
80
22
39
36
16
2
H
3
H
4
Me
Me
Me
Ph
H
5
H
6
CO2Et
CO2Et
H
7
5g
5h
5i
8
Bn
Cy
Me
Me
Me
Me
Me
iPr
2-Cl-C6H4
Ph
4-F-C6H4
Ph
9
H
10
11
12
13
14
15
16
2-Cl-C6H4
3,4-(MeO)2C6H3
4-Cl-C6H4
2-thienyl
H
4-F-C6H4
2-furyl
tBu
5j
H
5k
5l
H
H
tBu
5m
5n
5o
5p
c
3,4-(MeO)2C6H3
4-MeO-C6H4
2-Cl-C6H4
3,4-(MeO)2C6H3
H
H
4-F-C6H4
iPr
H
4-F-C6H4
a
Method A: (i) KOtBu, 0 °C, THF (ii) AcOH, EtOH, BF3·OEt2, rt (iii) DBU, reflux. Method B: (i) KOtBu, 0 °C, DMF (ii) TfOH, rt (iii) DBU, 90
b
c
°C. Isolated yield. The reaction was performed in two steps and KOtBu at 25 °C was used for the dehydrocyanation instead of DBU.
57−59 °C; Rf 0.24 (ethyl acetate/petroleum ether 1:5); IR (ATR) ν =
Scheme 4. Synthesis of a Tetracyclic Nitrogen Heterocycle
1
3056, 3033, 2933, 2248, 1305, 1278, 1092, 727, 700 cm−1; H NMR,
COSY (400 MHz, CDCl3) δ 7.35−7.30 (m, 3H, H3″,5″, H4″), 7.11−
7.07 (m, 2H, H2″,6″), 6.70 (AA′ part of AA′BB′ system, 2H, H2′,5′),
6.23 (BB′ part of AA′BB′ system, 2H, H3′,4′), 5.03 (t, J = 7.3 Hz, 1H,
H2), 3.37 (dd, J = 13.8, 7.3 Hz, 1H, CH2‑a), 3.32 (dd, J = 13.8, 7.3 Hz,
1H, CH2‑b) ppm; 13C NMR, HSQC, HMBC (101 MHz, CDCl3) δ
133.9 (C1″), 129.3 (C2″,6″), 128.9 (C3″,5″), 128.0 (C4″), 119.7
(C2′,5′), 117.0 (CN), 110.1 (C3′,4′), 52.0 (C2), 42.1 (C3) ppm; ESI-
MS (m/z) 393.3 (100) [2 M + H]+, 235.1 (76) [M + K]+, 197.1 (90)
[M + H]+; HRMS (ESI) m/z [M + H]+ calcd for C13H13N2 197.1079,
found 197.1071.
3-Methyl-2-(1H-pyrrol-1-yl)butanenitrile (1c). Prepared ac-
cording to the general procedure described above from 2-amino-3-
methylbutanenitrile hydrochloride51 (2.67 g, 19.8 mmol) and 2,5-
dimethoxytetrahydrofuran (2.18 g, 16.5 mmol). The crude product
was further purified by column chromatography (ethyl acetate/
petroleum ether 1:5) to obtain 1c (2.26 g, 15.2 mmol, 92%) as a light
yellow liquid: Rf 0.34 (ethyl acetate/petroleum ether 1:5); IR (ATR) ν
alkaline with 2 M Na2CO3 solution, and the crude product was
extracted three times with CH2Cl2. The combined extracts were dried
over MgSO4, filtered, and then concentrated under reduced pressure.
Further purification was either performed by filtration through a pad of
silica or by vacuum distillation.
1
= 3107, 2969, 2248, 1487, 1278, 1089, 721 cm−1; H NMR, COSY
2-(1H-Pyrrol-1-yl)propanenitrile (1a).59,60 Prepared according
to the general procedure described above from 2-aminopropanenitrile
hydrochloride51 (5.33 g, 50.0 mmol) and 2,5-dimethoxytetrahydrofur-
an (5.49 g, 41.5 mmol). Distillation of the crude product yielded 1a
(4.47 g, 37.2 mmol, 90%) as a colorless liquid: bp 68−70 °C, 1 mmHg
(lit.60 bp 72−74 °C, 1.5 mmHg); Rf 0.21 (ethyl acetate/petroleum
ether 1:8); IR (ATR) ν = 3104, 2993, 2946, 2248, 1488, 1277, 1100,
1053, 723, 698 cm−1; 1H NMR,60 COSY (400 MHz, CDCl3) δ 6.79−
6.78 (AA′ part of AA′BB′ system, 2H, H2′,5′), 6.26−6.22 (BB′ part of
AA′BB′ system, 2H, H3′,4′), 5.03 (q, J = 7.2 Hz, 1H, H2), 1.86 (d, J =
7.2 Hz, 3H, H3) ppm; 13C NMR, HSQC, HMBC (101 MHz, CDCl3)
δ 119.2 (C2′,5′), 118.1 (CN), 110.3 (C3′,4′), 45.2 (C2), 21.4 (C3)
ppm; ESI-MS (m/z) 121.1 (100) [M + H]+; HRMS (ESI) m/z [M +
H]+ calcd for C7H9N2 121.0766, found 121.0763.
(300 MHz, CDCl3) δ 6.76 (AA′ part of AA′BB′ system, 2H, H2′,5′),
6.23 (BB′ part of AA′BB′ system, 2H, H3′,4′), 4.60 (d, J = 8.0 Hz, 1H,
H2), 2.40−2.23 (m, 1H, H3), 1.13 (d, J = 6.8 Hz, 3H, CH3), 0.95 (d, J
= 6.8 Hz, 3H, CH3) ppm; 13C NMR, HSQC, HMBC (75 MHz,
CDCl3) δ 120.0 (C2′,5′), 116.7 (CN), 109.8 (C3′,4′), 57.1 (C2), 34.6
(C3), 18.7 (CH3), 18.6 (CH3) ppm; ESI-MS (m/z) 189.1 (100) [M +
H]+; HRMS (ESI) m/z [M + H]+ calcd for C9H13N2 149.1079, found
149.1074.
2-Phenyl-2-(1H-pyrrol-1-yl)acetonitrile (1d).61 Prepared ac-
cording to the general procedure described above from 2-amino-2-
phenylacetonitrile50 (1.15 g, 8.7 mmol) and 2,5-dimethoxytetrahy-
drofuran (1.15 g, 8.7 mmol). The crude product was further purified
by column chromatography (ethyl acetate/petroleum ether 1:5) to
obtain 1d (1.21 g, 6.7 mmol, 76%) an orange solid: mp 50−51 °C; Rf
0.29 (ethyl acetate/petroleum ether 1:5); IR (ATR) ν = 3105, 2917,
3-Phenyl-2-(1H-pyrrol-1-yl)propanenitrile (1b). Prepared ac-
cording to the general procedure described above from 2-amino-3-
phenylpropanenitrile50 (877 mg, 6.00 mmol) and 2,5-dimethoxyte-
trahydrofuran (661 mg, 5.00 mmol). The crude product was further
purified by column chromatography (ethyl acetate/petroleum ether
1:5) to obtain 1b (744 mg, 3.79 mmol, 76%) as a yellow solid: mp
1
2253, 1484, 1267, 1089, 772, 695 cm−1; H NMR, COSY (400 MHz,
CDCl3) δ 7.48−7.42 (m, 3H, H3″,5″, H4″), 7.42−7.32 (m, 2H,
H2″,6″), 6.80 (AA′ part of AA′BB′ system, 2H, H2′,5′), 6.30 (BB′ part
of AA′BB′ system, 2H, H3′,4′), 6.15 (s, 1H, H2) ppm; 13C NMR,
C
dx.doi.org/10.1021/jo400992n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
HSQC, HMBC (101 MHz, CDCl3) δ 133.2 (C1″), 129.8 (C4″),
129.4 (C3″,5″), 126.8 (C2″,6″), 120.3 (C2′,5′),116.5 (CN), 110.4
(C3′,4′), 53.5 (C2) ppm; ESI-MS (m/z) 365.2 (100) [2 M + H]+,
183.1 (7) [M + H]+; HRMS (ESI) m/z [M + H]+ calcd for C12H11N2
183.0922, found 183.0917.
(ethyl acetate/cyclohexane 1:5) to obtain 5b (195 mg, 0.54 mmol,
54%) as a yellow solid: mp 180−181 °C (dec); Rf 0.57 (ethyl acetate/
cyclohexane 1:5); IR (ATR) ν = 3141, 3058, 2930, 1493, 1265, 736,
1
699 cm−1; H NMR (400 MHz, DMSO-d6) δ 7.78−7.74 (m, 2H),
7.53−7.49 (m, 4H), 7.48−7.43 (m, 3H), 7.43−7.36 (m, 1H), 7.30−
7.25 (m, 3H), 7.22−7.15 (m, 3H), 6.82 (s, 1H, H7), 6.78 (dd, J = 4.0,
2.8 Hz, 1H, H2), 6.58 (dd, J = 4.0, 1.4 Hz, 1H, H1), 4.36 (s, 2H) ppm;
13C NMR (75 MHz, DMSO-d6) δ 139.4, 138.3, 136.7, 130.9, 130.2,
130.1, 129.3, 128.8, 128.8, 128.6, 128.2, 128.1, 127.6, 127.4, 126.6,
124.8, 119.5, 114.4, 112.9, 99.8, 34.5 (CH2) ppm; ESI-MS (m/z)
360.2 (100) [M + H]+, 359.2 (42) [M]+; HRMS (ESI) m/z [M + H]+
calcd for C27H22N 360.1752, found 360.1747.
5-Isopropyl-6,8-diphenylindolizine (5c). Prepared according to
method A from 1c (148 mg, 1.00 mmol) and 2a (208 mg, 1.00 mmol).
The crude product was purified by column chromatography (ethyl
acetate/cyclohexane 1:5) to obtain 5c (127 mg, 0.41 mmol, 41%) as a
white solid: mp 115−117 °C; Rf 0.80 (ethyl acetate/cyclohexane 1:5);
IR (ATR) ν = 3056, 2967, 2876, 1576, 1264, 760, 734, 698 cm−1; 1H
NMR, COSY (400 MHz, DMSO-d6) δ 7.80 (dd, J = 2.8, 1.4 Hz, 1H,
H3), 7.67 (m, 2H, 2HPh), 7.51−7.36 (m, 8H, 8HPh), 6.89 (dd, J = 4.0,
2.8 Hz, 1H, H2), 6.56 (m, 2H, H1, H7), 3.55 (sept, J = 7.0 Hz, 1H,
CH(CH3)2), 1.39 (d, J = 7.0 Hz, 6H, (CH3)2CH) ppm; 13C NMR,
HSQC, HMBC (101 MHz, DMSO-d6) δ 140.5, 138.3, 137.0 (C5),
131.6 (C8a), 129.4, 129.2 (C8), 128.7, 128.4, 128.1, 127.9, 127.2,
123.0 (C6), 120.3 (C7), 114.1 (C2), 113.8 (C3), 99.0 (C1), 29.2
(CH(CH3)2), 17.8 (CH3)2CH) ppm; ESI-MS (m/z) 312.2 (100) [M
+ H]+, 311.2 (13) [M+]; HRMS (ESI) m/z [M + H]+ calcd for
C23H22N 312.1752, found 312.1746.
5,8-Dimethyl-6-phenylindolizine (5d). Prepared according to
method A from 1a (120 mg, 1.00 mmol) and 4-phenylbut-3-en-2-
one54 (2b, 146 mg, 1.00 mmol). The crude product was purified by
column chromatography (ethyl acetate/cyclohexane 1:5) to obtain 5d
(69 mg, 0.31 mmol, 31%) as a brown oil: Rf 0.75 (ethyl acetate/
cyclohexane 1:5); IR (ATR) ν = 2928, 2857, 1493, 1394, 1280, 1025,
769, 703, 680 cm−1; 1H NMR, COSY (400 MHz, DMSO-d6) δ 7.49−
7.43 (m, 3H, H3, H3′,5′), 7.40−7.35 (m, 3H, H2′,6′, H4′), 6.85 (dd, J
= 3.9, 2.7 Hz, 1H, H2), 6.56 (s, 1H, H7), 6.51 (dd, J = 3.9, 1.5 Hz, 1H,
H1), 2.43 (s, 3H, 5-CH3), 2.40 (s, 3H, 8-CH3) ppm; 13C NMR,
HSQC, HMBC (101 MHz, DMSO-d6) δ 139.7 (C1′), 132.8 (C8a),
129.7 (C2′,6′), 128.3 (C3′,5′), 127.6 (C5), 126.9 (C4′), 124.6 (C8),
122.5 (C6), 119.3 (C7), 113.6 (C2), 111.5 (C3), 98.3 (C1), 17.5 (5-
CH3), 15.8 (8-CH3) ppm; ESI-MS (m/z) 222.1 (100) [M + H]+,
221.1 (73) [M]+; HRMS (ESI) m/z [M + H]+ calcd for C16H16N
222.1283, found 222.1278.
2-Cyclohexyl-2-(1H-pyrrol-1-yl)acetonitrile (1e). Prepared ac-
cording to the general procedure described above from 2-amino-2-
cyclohexylacetonitrile49 (829 mg, 6.00 mmol) and 2,5-dimethoxyte-
trahydrofuran (661 mg, 5.00 mmol). The crude product was further
purified by column chromatography (ethyl acetate/petroleum ether
1:10) to obtain 1e (591 mg, 3.14 mmol, 63%) as a white solid: mp
39−40 °C; Rf 0.35 (ethyl acetate/petroleum ether 1:10); IR (ATR) ν
= 2930, 2855, 2246, 1487, 1277, 1093, 720 cm−1; 1H NMR (300 MHz,
CDCl3) δ 6.73 (AA′ part of AA′BB′ system, 2H, H2′,5′), 6.21 (BB′
part of AA′BB′ system, 2H, H3′,4′), 4.59 (d, J = 8.1 Hz, 1H, H2),
2.01−1.90 (m, 2H), 1.86−1.66 (m, 3H), 1.50−1.44 (m, 1H), 1.31−
1.10 (m, 4H), 1.05−0.93 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3)
δ 120.1 (C2′,5′), 116.8 (CN), 109.7 (C3′,4′), 56.4 (C2), 43.4, 29.4,
29.2, 25.8, 25.5 ppm; ESI-MS (m/z) 399.2 (100) [2 M + Na]+, 377.2
(88) [2 M + H]+, 189.1 (28) [M + H]+; HRMS (ESI) m/z [M + H]+
calcd for C12H17N2 189.1392, found 189.1386.
General Procedure for the One-Pot Synthesis of Indolizines
5a−p. Method A. To a solution of corresponding 2-(1H-pyrrol-1-
yl)nitrile 1a−e in dry THF (0.1 M) at 0 °C was added a solution of
KOtBu in dry THF (1.1 equiv, 1.0 M). The solution was stirred for 5
min, and a solution of corresponding α,β-unsaturated aldehyde/ketone
(1.0 equiv) in dry THF (0.2 M) was added. The reaction was
monitored by TLC analysis. When the conversion of the pyrrolonitrile
was complete (TLC monitoring, about 2 h), the reaction was
quenched with a solution of AcOH (7.0 equiv) in EtOH (1.4 M). The
reaction mixture was stirred for 15−18 h at ambient temperature after
BF3·OEt2 (3.0 equiv) was added. DBU (20 equiv) was slowly added to
an acidic solution (caution, exothermic reaction). After the mixture
was heated under reflux for about 2 h (TLC monitoring), it was
quenched with water (20 mL/mmol pyrrolonitrile). The product was
extracted four times with EtOAc (30 mL/mmol pyrrolonitrile). The
combined organic phases were washed with brine, dried over
magnesium sulfate, and concentrated in vacuo. The resulting crude
product was purified by column chromatography.
Method B. To a solution of corresponding 2-(1H-pyrrol-1-yl)nitrile
1a−e in dry DMF (0.1 M) at 0 °C was added a solution of KOtBu (1.1
equiv) in dry DMF (0.5 M). The solution was stirred for 5 min, and a
solution of the corresponding α,β-unsaturated aldehydes/ketone (1.0
equiv) in dry DMF (0.2 M) was added. When the conversion of
pyrrolonitrile was complete (TLC monitoring, about 2 h), triflic acid
(1.5 equiv) was added at 0 °C, and the mixture was stirred for 15−18
h at ambient temperature. DBU (20 equiv) was slowly added to an
acidic solution (caution, exothermic reaction). After the mixture was
heated to 90 °C for about 2 h (TLC monitoring), it was quenched
with water (20 mL/mmol pyrrolonitrile). The product was extracted
four times with EtOAc (30 mL/mmol pyrrolonitrile). The combined
organic phases were washed with brine, dried over magnesium sulfate,
and concentrated in vacuo. The resulting crude product was purified
by column chromatography.
5-Methyl-6,8-diphenylindolizine (5a). Prepared according to
method A from 1a (120 mg, 1.00 mmol) and 2a (208 mg, 1.00 mmol).
The crude product was purified by column chromatography
(petroleum ether) to obtain 5a (242 mg, 0.85 mmol, 85%) as a
yellow oil: Rf 0.14 (petroleum ether); IR (ATR) ν = 2976, 2861, 1443,
1376, 1110, 773, 759, 724, 698 cm−1; 1H NMR (300 MHz, CD3OD) δ
7.68−7.62 (m, 2H, HPh), 7.47−7.31 (m, 9H, 8HPh, H3), 6.89 (dd, J =
4.0, 2.8 Hz, 1H, H2), 6.68 (s, 1H, H7), 6.60 (dd, J = 4.0, 1.4 Hz, 1H,
H1), 2.48 (s, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 141.5, 140.7,
133.1, 131.4, 131.0, 130.2, 129.6, 129.43, 129.37, 128.7, 128.1, 124.9,
120.8, 115.2, 112.3, 100.9, 16.4 (CH3) ppm; ESI-MS (m/z) 284.2
(100) [M + H]+, 283.2 (18) [M]+; HRMS (ESI) m/z [M + H]+ calcd
for C21H18N 284.1439, found 284.1430.
5,6-Dimethyl-8-phenylindolizine (5e). Prepared according to
method A from 1a (120 mg, 1.00 mmol) and 2c (146 mg, 1.00 mmol).
The crude product was purified by column chromatography (ethyl
acetate/petroleum ether 1:5) to obtain 5e (21 mg, 0.10 mmol, 10%) as
a red oil: Rf 0.77 (ethyl acetate/petroleum ether 1:5); IR (ATR) ν =
1
2924, 2853, 1444, 1377, 1279, 774, 722, 700 cm−1; H NMR, COSY
(400 MHz, DMSO-d6) δ 7.67−7.64 (m, 2H, H2′,6′), 7.51−7.46 (m,
2H, H3′,5′), 7.43 (dd, J = 2.7, 1.5 Hz, 1H, H3), 7.42−7.38 (m, 1H,
H4′), 6.81 (dd, J = 4.0, 2.7 Hz, 1H, H2), 6.69 (s, 1H, H7), 6.49 (dd, J
= 4.0, 1.5 Hz, 1H, H1), 2.49 (s, 3H, 5-CH3), 2.31 (s, 3H, 6-CH3) ppm;
13C NMR, HSQC, HMBC (101 MHz, DMSO-d6) δ 138.8 (C1′),
130.7 (C8a), 128.8 (C5), 128.72 (C8), 128.70 (C3′,5′), 128.0
(C2′,6′), 127.6 (C4′), 120.8 (C7), 115.9 (C6), 113.6 (C2), 111.0
(C3), 99.0 (C1), 17.5 (6-CH3), 14.6 (5-CH3) ppm; ESI-MS (m/z)
223.1 (72) [M + H]+, 222.1 (100) [M]+; HRMS (ESI) m/z [M + H]+
calcd for C16H16N 222.1283, found 222.1277.
Ethyl 5-Methyl-6,8-diphenylindolizine-7-carboxylate (5f).
Prepared according to method B from 1a (120 mg, 1.00 mmol) and
ethyl 2-benzoyl-3-phenylacrylate55 (2d, 280 mg, 1.00 mmol). The
crude product was purified by column chromatography (ethyl acetate/
cyclohexane 1:5) to obtain 5f (109 mg, 0.31 mmol, 31%) as a light
yellow oil: Rf 0.62 (ethyl acetate/cyclohexane 1:5); IR (ATR) ν =
1
2925, 1723, 1446, 1291, 1189,1030, 726, 697 cm−1; H NMR, COSY
5-Benzyl-6,8-diphenylindolizine (5b). Prepared according to
method A from 1b (196 mg, 1.00 mmol) and 2a (208 mg, 1.00
mmol). The crude product was purified by column chromatography
(400 MHz, DMSO-d6) δ 7.61 (dd, J = 2.7, 1.4 Hz, 1H, H3), 7.50−7.35
(m, 8H, HPh), 7.33−7.27 (m, 2H, HPh), 6.94 (dd, J = 4.0, 2.7 Hz, 1H,
H2), 6.30 (dd, J = 4.0, 1.4 Hz, 1H, H1), 3.58 (q, J = 7.1 Hz, 2H,
D
dx.doi.org/10.1021/jo400992n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
OCH2), 2.36 (s, 3H, 5-CH3), 0.61 (t, J = 7.1 Hz, 3H, CH3CH2) ppm;
13C NMR, HSQC, HMBC (101 MHz, DMSO-d6) δ 167.4 (CO2Et),
137.2, 136.5, 130.7 (C8a), 130.2, 130.1 (C5), 128.8, 128.4, 128.1,
128.0, 127.5, 127.3, 123.6 (C7), 120.2 (C6), 115.2 (C2), 112.9 (C3),
102.4 (C1), 60.0 (OCH2), 16.2 (5-CH3), 13.2 (CH3CH2) ppm; ESI-
MS (m/z) 356.2 (100) [M + H]+; HRMS (ESI) m/z [M + H]+ calcd
for C24H22NO2 356.1651, found 356.1646.
Ethyl 5,6,8-Triphenylindolizine-7-carboxylate (5g). Prepared
according to method B from 1d (182 mg, 1.00 mmol) and 2d55 (280
mg, 1.00 mmol). The crude product was purified by column
chromatography (ethyl acetate/cyclohexane 1:10) to obtain 5g (142
mg, 0.34 mmol, 34%) as a yellow solid: mp 62−63 °C; Rf 0.36 (ethyl
acetate/cyclohexane 1:10); IR (ATR) ν = 3058, 2978, 1720, 1444,
1253, 1227, 1083, 1030, 721, 695 cm−1; 1H NMR (400 MHz, DMSO-
d6) δ 7.52−7.45 (m, 5H), 7.41−7.34 (m, 5H), 7.17−7.11 (m, 5H),
6.90 (dd, J = 2.8, 1.4 Hz, 1H, H3), 6.80 (dd, J = 4.0, 2.8 Hz, 1H, H2),
6.32 (dd, J = 4.0, 1.4 Hz, 1H, H1), 3.59 (q, J = 7.1 Hz, 2H, CH2), 0.61
(t, J = 7.1 Hz, 3H, CH3) ppm; 13C NMR (75 MHz, DMSO-d6) δ
167.2 (CO2Et), 136.6, 136.2, 133.7, 133.1, 131.4, 130.5, 130.3, 129.0,
128.94, 128.93, 128.7, 128.5, 128.4, 127.4, 126.9, 124.2, 121.3, 115.1
(C2), 113.6 (C3), 102.4 (C1), 60.2 (CH2), 13.2 (CH3) ppm; ESI-MS
(m/z) 440.2 (7) [M + Na]+, 418.2 (100) [M + H]+, 417.2 (2) [M]+;
HRMS (ESI) m/z [M + H]+ calcd for C29H24NO2 418.1807, found
418.1800.
2.33 (s, 3H, CH3) ppm; 13C NMR, HSQC, HMBC (101 MHz,
1
DMSO-d6) δ 161.8 (d, JCF = 244.8 Hz, C4″), 137.7 (C1′), 134.6 (d,
4JCF = 3.2 Hz, C1″), 133.2 (C2′), 132.4 (C6′), 130.8 (C8a), 130.2
3
(C6), 130.0 (d, JCF = 8.2 Hz, C2″,6″), 129.5, 129.4, 127.8 (C8),
2
127.3, 120.2 (C5), 119.2 (C7), 115.6 (d, JCF = 21.4 Hz, C3″,5″),
114.6 (C2), 112.1 (C3), 99.9 (C1), 15.9 (CH3) ppm; ESI-MS (m/z)
336.1 (100) [M + H]+, 335.1 (9) [M]+; HRMS (ESI) m/z [M + H]+
calcd for C21H16ClFN 336.0955, found 336.0949.
6-(3,4-Dimethoxyphenyl)-8-(furan-2-yl)-5-methylindolizine
(5k). Prepared according to method A from 1a (120 mg, 1.00 mmol)
and 3-(3,4-dimethoxyphenyl)-1-(furan-2-yl)prop-2-en-1-one56 (2f,
258 mg, 1.00 mmol). The crude product was purified by column
chromatography (ethyl acetate/petroleum ether 1:5) to obtain 5k
(237 mg, 0.71 mmol, 71%) as a light yellow solid: mp 140−142 °C
(dec); Rf 0.30 (ethyl acetate/petroleum ether 1:5); IR (ATR) ν =
1
3055, 2934, 2834, 1505, 1257, 1240, 1025, 855, 810, 733 cm−1; H
NMR, COSY (400 MHz, DMSO-d6) δ 7.83 (d, J = 1.7 Hz, 1H, H5″),
7.55 (dd, J = 2.8, 1.4 Hz, 1H, H3), 7.18 (s, 1H, H7), 7.11 (d, J = 3.4
Hz, 1H, H3″), 7.05 (d, J = 8.3 Hz, 1H, H5′), 7.02 (d, J = 2.0 Hz, 1H,
H2′), 6.99 (dd, J = 4.0, 1.4 Hz, 1H, H1), 6.96−6.93 (m, 2H, H2, H6′),
6.67 (dd, J = 3.4, 1.7 Hz, 1H, H4″), 3.81 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 2.52 (s, 3H, 5-CH3) ppm; 13C NMR, HSQC, HMBC (101
MHz, DMSO-d6) δ 150.8 (C2″), 148.5 (C3′), 148.0 (C4′), 142.8
(C5″), 131.8 (C1′), 129.7 (C5), 127.5 (C8a), 122.4 (C6), 122.0
(C6′), 118.0 (C8), 116.7 (C7), 114.5 (C2), 113.6 (C2′), 112.0 (2C
overlapped, C3, C4″), 111.7 (C5′), 108.1 (C3″), 100.3 (C1), 55.60
(OCH3), 55.56 (OCH3), 16.3 (5-CH3) ppm; ESI-MS (m/z) 334.2
(100) [M + H]+, 333.2 (15) [M]+; HRMS (ESI) m/z [M + H]+ calcd
for C21H20NO3 334.1443, found 334.1440.
5-Benzyl-6-(2-chlorophenyl)-8-(4-fluorophenyl)indolizine
(5h). Prepared according to method A from 1b (196 mg, 1.00 mmol)
and 2e (261 mg, 1.00 mmol). The crude product was purified by
column chromatography (ethyl acetate/cyclohexane 1:10) to obtain
5h (242 mg, 0.59 mmol, 59%) as a yellow solid: mp 71−72 °C; Rf 0.48
(ethyl acetate/cyclohexane 1:10); IR (ATR) ν = 3058, 3032, 1506,
8-tert-Butyl-6-(4-chlorophenyl)-5-methylindolizine (5l). Pre-
pared according to method A from 1a (120 mg, 1.00 mmol) and 1-(4-
chlorophenyl)-4,4-dimethylpent-1-en-3-one49 (2g, 223 mg, 1.00
mmol). The crude product was purified by column chromatography
(ethyl acetate/cyclohexane 1:50) to obtain 5l (238 mg, 0.80 mmol,
80%) as a white solid: mp 84−85 °C; Rf 0.41 (ethyl acetate/
cyclohexane 1:50); IR (ATR) ν = 2968, 2871, 1491, 1265, 1090, 834,
1
1265, 1223, 1158, 837, 736, 696 cm−1; H NMR, COSY (400 MHz,
DMSO-d6) δ 7.80−7.74 (m, 2H, H2″,6″), 7.64−7.60 (m, 1H, H3′),
7.60−7.55 (m, 1H, H6′), 7.48−7.40 (m, 2H, H4′, H5′), 7.36−7.29
(m, 3H, H3, H3″,5″), 7.27−7.14 (m, 5H, PhCH2), 6.79 (dd, J = 4.0,
2.8 Hz, 1H, H2), 6.70 (s, 1H, H7), 6.57 (dd, J = 4.0, 1.2 Hz, 1H, H1),
4.29 (d, J = 16.3 Hz, 1H, CH2‑a), 4.09 (d, J = 16.3 Hz, 1H, CH2‑b
)
ppm; 13C NMR, HSQC, HMBC (101 MHz, DMSO-d6) δ 161.9 (d,
1
732, 703 cm−1; H NMR, COSY (400 MHz, DMSO-d6) δ 7.54−7.50
4
1JCF = 244.9 Hz, C4‴), 137.5 (C1′), 136.1, 134.4 (d, JCF = 3.0 Hz,
(AA′ part of AA′BB′ system, 2H, H3′,5′), 7.46−7.41 (m, 3H, H3,
H2′,6′), 6.87 (dd, J = 4.1, 2.8 Hz, 1H, H2), 6.72 (dd, J = 4.1, 1.4 Hz,
1H, H1), 6.52 (s, 1H, H7), 2.42 (s, 3H, 5-CH3), 1.45 (s, 9H,
(CH3)3C) ppm; 13C NMR, HSQC, HMBC (101 MHz, DMSO-d6) δ
138.9 (C1′), 137.2 (C8), 131.7 (C4′), 131.6 (C2′,6′), 130.4 (C8a),
128.33 (C3′,5′), 128.29 (C5), 120.9 (C6), 115.7 (C7), 113.4 (C2),
110.9 (C3), 101.8 (C1), 34.6 (C(CH3)3), 29.6 ((CH3)3C), 16.0 (5-
CH3) ppm; ESI-MS (m/z) 298.2 (60) [M + H]+, 297.2 (100) [M]+;
HRMS (ESI) m/z [M + H]+ calcd for C19H21ClN 298.1363, found
298.1359.
C1‴), 133.2 (C2′), 132.3 (C6′), 131.3 (C5), 130.9 (C8a), 130.1 (d,
3JCF = 8.1 Hz, C2‴,6‴), 129.8 (C4′), 129.7 (C3′), 128.73, 128.66,
2
127.7, 127.4 (C5′), 126.7, 122.0 (C6), 119.1 (C7), 115.6 (d, JCF
=
21.4 Hz, C3‴,5‴), 114.4 (C2), 113.1 (C3), 99.9 (C1), 34.6 (CH2)
ppm; ESI-MS (m/z) 412.2 (100) [M + H]+, 411.2 (64) [M]+; HRMS
(ESI) m/z [M + H]+ calcd for C27H20ClFN 412.1268, found 412.1265.
5-Cyclohexyl-6,8-diphenylindolizine (5i). Prepared according
to method B from 1e (188 mg, 1.00 mmol) and 2a (208 mg, 1.00
mmol). The crude product was purified by column chromatography
(ethyl acetate/cyclohexane 1:5) to obtain 5i (244 mg, 0.69 mmol,
69%) as a white solid: mp 174−175 °C; Rf 0.49 (ethyl acetate/
cyclohexane 1:5); IR (ATR) ν = 2928, 2853, 1445, 1261, 1028, 760,
699 cm−1; 1H NMR (600 MHz, DMSO-d6, 70 °C) δ 7.85 (s, 1H, H3),
7.68−7.65 (m, 2H), 7.49−7.44 (m, 4H), 7.42−7.36 (m, 4H), 6.88 (dd,
J = 3.7, 3.0 Hz, 1H, H2), 6.55−6.53 (m, 2H, H1, H7), 3.20−3.14 (m,
1H), 2.33−1.59 (m, 7H), 1.34−1.12 (m, 3H) ppm; 13C NMR (151
MHz, DMSO-d6, 70 °C) δ 140.4, 138.1, 136.3, 131.7, 129.1, 128.9,
128.3, 127.9, 127.7, 127.5, 126.8, 123.2, 120.2 (C7), 113.5 (C2), 113.3
(br, C3), 98.7 (C1), 40.6, 40.1, 26.0, 24.9 ppm; ESI-MS (m/z) 352.3
(100) [M + H]+, 351.3 (53) [M]+; HRMS (ESI) m/z [M + H]+ calcd
for C26H26N 352.2065, found 352.2059.
6-(2-Chlorophenyl)-8-(4-fluorophenyl)-5-methylindolizine
(5j). Prepared according to method A from 1a (120 mg, 1.00 mmol)
and 2e (261 mg, 1.00 mmol). The crude product was purified by
column chromatography (ethyl acetate/petroleum ether 1:10) to
obtain 5j (225 mg, 0.67 mmol, 67%) as a white solid: mp 124−125
°C; Rf 0.56 (ethyl acetate/petroleum ether 1:10); IR (ATR) ν = 3136,
3119, 3056, 2913, 1504, 1265, 1218, 1156, 837, 761, 736, 690 cm−1;
1H NMR, COSY (400 MHz, DMSO-d6) δ 7.75−7.69 (m, 2H,
8-tert-Butyl-5-methyl-6-(thiophen-2-yl)indolizine (5m). Pre-
pared according to method A from 1a (120 mg, 1.00 mmol) and 4,4-
dimethyl-1-(thiophen-2-yl)pent-1-en-3-one58 (2h, 149 mg, 1.00
mmol). The crude product was purified by column chromatography
(ethyl acetate/petroleum ether 1:5) to obtain 5m (58 mg, 0.22 mmol,
22%) as a yellow oil: Rf 0.73 (ethyl acetate/petroleum ether 1:5); IR
1
(ATR) ν = 2956, 1436, 1268, 823, 760, 693 cm−1; H NMR, COSY
(400 MHz, DMSO-d6) δ 7.60 (dd, J = 5.0, 1.3 Hz, 1H, H5′), 7.45 (dd,
J = 2.8, 1.3 Hz, 1H, H3), 7.16−7.12 (m, 2H, H3′, 4′), 6.87 (dd, J = 4.0,
2.8 Hz, 1H, H2), 6.72 (dd, J = 4.0, 1.3 Hz, 1H, H1), 6.61 (s, 1H, H7),
2.55 (s, 3H, 5-CH3), 1.43 (s, 9H, (CH3)3C) ppm; 13C NMR, HSQC,
HMBC (101 MHz, DMSO-d6) δ 141.3 (C2′), 137.1 (C8), 130.2
(C8a), 129.2 (C5), 127.4, 127.3, 126.1 (C5′), 116.2 (C7), 114.9 (C6),
113.6 (C2), 111.3 (C3), 102.1 (C1), 34.6 (C(CH3)3), 29.5 (CH3)3C),
16.1 (5-CH3) ppm; ESI-MS (m/z) 270.1 (100) [M + H]+, 269.1 (8)
[M]+; HRMS (ESI) m/z [M + H]+ calcd for C17H20NS 270.1317,
found 270.1313.
6,7-Bis(3,4-dimethoxyphenyl)-5-methylindolizine (5n). Pre-
pared according to modified method A. To a solution of 1a (60 mg,
0.50 mmol) in dry THF (5 mL) at 0 °C was added a solution of
KOtBu in dry THF (0.6 mL, 1.0 M). The solution was stirred for 5
min, and a solution of 2,3-bis(3,4-dimethoxyphenyl)acrylaldehyde53
(2i, 104 mg, 0.50 mmol) in dry THF (2.5 mL) was added. When the
H2″,6″), 7.61−7.58 (m, 1H, HAr′), 7.57 (dd, J = 2.8, 1.4 Hz, 1H, H3),
7.49−7.41 (m, 3H, 3HAr′), 7.33−7.26 (m, 2H, H3″,5″), 6.94 (dd, J =
4.0, 2.8 Hz, 1H, H2), 6.62 (s, 1H, H7), 6.61 (d, J = 1.4 Hz, 1H, H1),
E
dx.doi.org/10.1021/jo400992n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
conversion of the pyrrolonitrile was complete (TLC monitoring, about
2 h), the reaction was quenched with a solution of AcOH (0.2 mL) in
EtOH (2.5 mL). The reaction mixture was stirred for 15−18 h at
ambient temperature after BF3·OEt2 (0.2 mL) was added. The reaction
mixture was quenched with water (10 mL), and the dihydroindolizine
was extracted three times with EtOAc (20 mL each). The combined
organic phases were washed with brine, dried over magnesium sulfate,
and concentrated in vacuo. To a solution of the dihydroindolizine in
dry THF (5 mL) was added a solution of KOtBu in dry THF (1.0 mL,
1.0 M), and the reaction mixture was stirred for 2 h at rt (TLC
monitoring). It was quenched with water (10 mL). The product was
extracted four times with EtOAc (15 mL). The combined organic
phases were washed with brine, dried over magnesium sulfate, and
concentrated in vacuo. The resulting crude product was purified by
column chromatography (ethyl acetate/cyclohexane 1:3) to obtain 5n
(78 mg, 0.19 mmol, 39%) as a white solid: mp 179−180 °C; Rf 0.35
(ethyl acetate/cyclohexane 1:3); IR (ATR) ν = 2998, 2933, 2834,
6-(4-Chlorophenyl)-5-isopropyl-10-methoxy-7,8-dihydro-
benzo[h]pyrrolo[2,1-a]isoquinoline (6). Prepared according to
method B from 1c (148 mg, 1.00 mmol) and 2k57 (299 mg, 1.00
mmol). The crude product was purified by column chromatography
(ethyl acetate/cyclohexane 1:5) to obtain 6 (151 mg, 0.38 mmol,
38%) as a yellow solid: mp 158−159 °C; Rf 0.52 (ethyl acetate/
petroleum ether 1:5); IR (ATR) ν = 3052, 2963, 2935, 2835, 1606,
1
1486, 1282, 1263, 1087, 840, 734, 699 cm−1; H NMR, COSY (400
MHz, DMSO-d6) δ 8.04 (d, J = 8.6 Hz, 1H, H12), 7.70 (dd, J = 2.7,
1.2 Hz, 1H, H3), 7.54−7.48 (AA′ part of AA′−BB′ system, 2H,
H3′,5′), 7.31−7.26 (BB′ part of AA′−BB′ system, 2H, H2′,6′), 6.92
(dd, J = 8.6, 2.7 Hz, 1H, H11), 6.89−6.87 (m, 2H, H2, H9), 6.85 (dd,
J = 4.1, 1.2 Hz, 1H, H1), 3.79 (s, 3H, OCH3), 3.22 (br s, 1H,
CH(CH3)2), 2.62−2.53 (m, 2H, H8), 2.13−2.04 (m, 2H, H7), 1.32
(br s, 6H, (CH3)2CH) ppm; 13C NMR, HSQC, HMBC (101 MHz,
DMSO-d6) δ 158.2 (C10), 139.5 (C8a), 137.7 (C4′), 136.7 (C5),
132.2 (C1′), 131.7 (C2′,6′), 129.9 (C12c), 128.6 (C3′,5′), 126.5
(C12), 126.0 (C6a), 125.5 (C12a), 121.9 (C6), 121.8 (C12b), 113.9
(C2), 113.3 (C9), 112.9 (C3), 111.5 (C11), 98.4 (C1), 55.1 (CH3O),
30.1 (CH(CH3)2), 28.4 (C8), 26.0 (C7), 17.4 ((CH3)2CH) ppm; ESI-
MS (m/z) 404.1 (38), 403.1 (38), 402.2 (100) [M + H]+; HRMS
(ESI) m/z [M + H]+ calcd for C26H25ClNO 402.1625, found
402.1621.
1
1509, 1248, 1135, 1024, 862, 765 cm−1; H NMR, COSY (400 MHz,
DMSO-d6) δ 7.42 (br s, 1H, H3), 7.40 (s, 1H, H7), 6.90−6.86 (m, 2H,
H2, H5′), 6.80 (d, J = 8.2 Hz, 1H, H5″), 6.73 (dd, J = 8.2, 1.8 Hz, 1H,
H6″), 6.67−6.64 (m, 2H, H2′, H6′), 6.53 (dd, J = 3.8, 1.1 Hz, 1H,
H1), 6.48 (d, J = 1.8 Hz, 1H, H2″), 3.73 (s, 3H, OCH3), 3.69 (s, 3H,
OCH3), 3.55 (s, 3H, OCH3), 3.44 (s, 3H, OCH3), 2.39 (s, 3H, 5-CH3)
ppm; 13C NMR, HSQC, HMBC (101 MHz, DMSO-d6) δ 148.0
(C3′), 147.4 (2C overlapped, C4′, C3″), 147.1 (C4″), 133.6 (C1″),
131.7 (C8a), 131.6 (C7), 130.8 (C1′), 130.6 (C5), 123.4, 122.3, 121.0
(C6″), 115.9 (C8), 115.3, 114.4 (C2), 113.3 (C2″), 111.14, 111.08,
110.5 (C3), 99.8 (C1), 55.4 (2 C overlapped), 55.3, 55.0, 16.7 (5-
CH3) ppm; ESI-MS (m/z) 436.2 (12) [M + Na]+, 404.2 (100) [M +
H]+, 403.2 (5) [M]+; HRMS (ESI) m/z [M + H]+ calcd for
C25H26NO4 404.1862, found 404.1859.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds 1a−e, 5a−p, and 6.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: opatz@uni-mainz.de.
■
8-(4-Fluorophenyl)-5-isopropyl-6-(4-methoxyphenyl)-
indolizine (5o). Prepared according to method A from 1c (148 mg,
1.00 mmol) and 2j (256 mg, 1.00 mmol). The crude product was
purified by column chromatography (ethyl acetate/petroleum ether
1:20) to obtain 5o (130 mg, 0.36 mmol, 36%) as a yellow solid: mp
62−64 °C; Rf 0.12 (ethyl acetate/petroleum ether 1:20); IR (ATR) ν
Notes
The authors declare no competing financial interest.
1
= 2963, 2836, 1609, 1518, 1244, 1222, 1016, 832, 737, 701 cm−1; H
ACKNOWLEDGMENTS
■
NMR (400 MHz, CD3CN) δ 7.73−7.66 (m, 3H, H3, H2″,6″), 7.32−
7.27 (AA′ part of AA′BB′ system, 2H, H2′,6′), 7.23−7.16 (m, 2H,
H3″,5″), 7.02−6.96 (BB′ part of AA′BB′ system, 2H, H3′,5′), 6.86
(dd, J = 4.0, 2.9 Hz, 1H, H2), 6.58 (s, 1H, H7), 6.54 (dd, J = 4.0, 1.4
Hz, 1H, H1), 3.83 (s, 3H, OCH3), 3.60 (sept, J = 7.3 Hz, 1H,
CH(CH3)2), 1.41 (d, J = 7.3 Hz, 6H, (CH3)2CH) ppm; 13C NMR (75
We thank Dr. J. C. Liermann (Mainz) for NMR spectroscopy
and Prof. Dr. T. Hoffmann (Mainz) and his co-workers for
mass spectrometry.
REFERENCES
■
1
MHz, CD3CN) δ 163.3 (d, JCF = 244.7 Hz), 159.9, 138.6, 136.2,
(1) Beghyn, T.; Deprez-Poulain, R.; Willand, N.; Folleas, B.; Deprez,
B. Chem. Biol. Drug Des. 2008, 72, 3−15.
3
136.1, 134.0, 133.2, 131.7, 131.2 (d, JCF = 8.2 Hz), 129.4, 124.1,
2
122.0, 116.3 (d, JCF = 21.5 Hz), 114.7, 114.6, 99.9 (C1), 56.0
(2) Muthusaravanan, S.; Perumal, S.; Yogeeswari, P.; Sriram, D.
Tetrahedron Lett. 2010, 51, 6439−6443.
(OCH3), 30.4 (CH(CH3)2), 18.2 ((CH3)2CH) ppm; ESI-MS (m/z)
360.2 (100) [M + H]+, 359.2 (98) [M]+; HRMS (ESI) m/z [M + H]+
calcd for C24H23FNO 360.1764, found 360.1760.
(3) Gundersen, L.-L.; Charnock, C.; Negussie, A. H.; Rise, F.; Teklu,
S. Eur. J. Pharm. Sci. 2007, 30, 26−35.
6-(2-Chlorophenyl)-8-(4-fluorophenyl)-5-isopropylindolizine
(5p). Prepared according to method A from 1c (148 mg, 1.00 mmol)
and 2e (261 mg, 1.00 mmol). The crude product was purified by
column chromatography (ethyl acetate/petroleum ether 1:5) to obtain
5p (58 mg, 0.16 mmol, 16%) as a yellow oil: Rf 0.71 (ethyl acetate/
petroleum ether 1:5); IR (ATR) ν = 2963, 2878, 1608, 1504, 1244,
1175, 1032, 832, 736, 701 cm−1; 1H NMR, COSY (400 MHz, DMSO-
d6) δ 7.81 (dd, J = 2.8, 1.2 Hz, 1H, H3), 7.72−7.66 (m, 2H, H2″,6″),
7.62−7.58 (m, 1H, HAr′), 7.47−7.41 (m, 3H, HAr′), 7.33−7.26 (m, 2H,
H3″,5″), 6.91 (dd, J = 4.0, 2.8 Hz, 1H, H2), 6.56 (dd, J = 4.0, 1.2 Hz,
1H, H1), 6.43 (s, 1H, H7), 3.23 (br s, 1H, CH(CH3)2), 1.39 (d, J =
7.1 Hz, 3H, CH3‑a), 1.30 (br s, 3H, CH3‑b) ppm; 13C NMR, HSQC,
(4) Gundersen, L.-L.; Negussie, A. H.; Rise, F.; Østby, O. B. Arch.
Pharm. 2003, 336, 191−195.
(5) Chen, S.; Xia, Z.; Nagai, M.; Lu, R.; Kostik, E.; Przewloka, T.;
Song, M.; Chimmanamada, D.; James, D.; Zhang, S.; Jiang, J.; Ono,
M.; Koya, K.; Sun, L. Med. Chem. Commun. 2011, 2, 176−180.
(6) Donnell, A. F.; Dollings, P. J.; Butera, J. A.; Dietrich, A. J.;
Lipinski, K. K.; Ghavami, A.; Hirst, W. D. Bioorg. Med. Chem. Lett.
2010, 20, 2163−2167.
(7) Weide, T.; Arve, L.; Prinz, H.; Waldmann, H.; Kessler, H. Bioorg.
Med. Chem. Lett. 2006, 16, 59−63.
(8) Østby, O. B.; Dalhus, B.; Gundersen, L.-L.; Rise, F.; Bast, A.;
Haenen, G. R. M. M. Eur. J. Org. Chem. 2000, 3763−3770.
(9) Dawood, K. M.; Abdel-Gawad, H.; Ellithey, M.; Mohamed, H. A.;
Hegazi, B. Arch. Pharm. 2006, 339, 133−140.
(10) Singh, G. S.; Mmatli, E. E. Eur. J. Med. Chem. 2011, 46, 5237−
5257.
(11) Uchida, T.; Matsumoto, K. Synthesis 1976, 209−236.
(12) Aggarwal, T.; Kumar, S.; Dhaked, D. K.; Tiwari, R. K.;
Bharatam, P. V.; Verma, A. K. J. Org. Chem. 2012, 77, 8562−8573.
1
HMBC (101 MHz, DMSO-d6) δ 161.8 (d, JCF = 244.8 Hz, C4″),
4
138.6, 137.5, 134.5 (d, JCF = 3.1 Hz, C1″), 133.1, 131.9, 131.7, 130.1
3
(d, JCF = 8.2 Hz, C2″,6″), 129.6, 129.4, 128.2, 127.3, 120.1, 119.5
(C7), 115.6 (d, 2JCF = 21.4 Hz, C3″,5″), 114.2 (C2), 113.9 (C3), 99.3
(C1), 29.9 (CH(CH3)2), 17.4 (CH3) ppm; ESI-MS (m/z) 364.2
(100) [M + H]+, 363.2 (55) [M]+; HRMS (ESI) m/z [M + H]+ calcd
for C23H20ClFN 364.1268, found 364.1263.
F
dx.doi.org/10.1021/jo400992n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(13) Kucukdisli, M.; Opatz, T. Eur. J. Org. Chem. 2012, 4555−4564.
(14) Hazra, A.; Mondal, S.; Maity, A.; Naskar, S.; Saha, P.; Paira, R.;
Sahu, K. B.; Paira, P.; Ghosh, S.; Sinha, C.; Samanta, A.; Banerjee, S.;
Mondal, N. B. Eur. J. Med. Chem. 2011, 46, 2132−2140.
(15) Bai, Y.; Zeng, J.; Ma, J.; Gorityala, B. K.; Liu, X.-W. J. Comb.
Chem. 2010, 12, 696−699.
(50) Lagriffoul, P.-H.; Tadros, Z.; Taillades, J.; Commeyras, A. J.
Chem. Soc., Perkin Trans. 2 1992, 1279−1285.
(51) Paventi, M.; Edward, J. T. Can. J. Chem. 1987, 65, 282−289.
(52) Kaplan, L. A.; Glover, D. J. J. Am. Chem. Soc. 1966, 88, 84−95.
(53) Chuang, T.-H.; Chang, W.-Y.; Li, C.-F.; Wen, Y.-C.; Tsai, C.-C.
J. Org. Chem. 2011, 76, 9678−9686.
(54) Therkelsen, F. D.; Hansen, A.-L. L.; Pedersen, E. B.; Nielsen, C.
Org. Biomol. Chem. 2003, 1, 2908−2918.
(16) Chernyak, D.; Skontos, C.; Gevorgyan, V. Org. Lett. 2010, 12,
3242−3245.
(55) Antonioletti, R.; Bovicelli, P.; Malancona, S. Tetrahedron 2002,
58, 589−596.
(56) Greiner-Bechert, L.; Otto, H.-H. Arch. Pharm. 1991, 324, 563−
572.
(17) Kaloko, J.; Hayford, A. Org. Lett. 2005, 7, 4305−4308.
(18) Basavaiah, D.; Jaganmohan Rao, A. Chem. Commun. 2003, 604−
605.
(19) Boultadakis, E.; Chung, B.; Elsegood, M. R. J.; Weaver, G. W.
(57) Aizenshtat, Z.; Hausmann, M.; Pickholtz, Y.; Tal, D.; Blum, J. J.
Org. Chem. 1977, 42, 2386−2394.
Synlett 2002, 1547−1549.
(20) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc.
2001, 123, 2074−2075.
(58) Savin, V. I.; Flegontov, S. A.; Kitaev, Y. P. Chem. Heterocycl.
Compd. 1972, 8, 1204−1207.
(21) Katritzky, A. R.; Qiu, G.; Yang, B.; He, H.-Y. J. Org. Chem. 1999,
64, 7618−7621.
(59) Flament, I.; Sonnay, P.; Ohloff, G. Helv. Chim. Acta 1977, 60,
1872−1883.
(22) Wei, X.; Hu, Y.; Li, T.; Hu, H. J. Chem. Soc., Perkin Trans. 1
1993, 2487−2489.
(60) Herz, W.; Raden, D. S.; Murty, D. R. K. J. Org. Chem. 1956, 21,
896−898.
̌
(23) Petuskova, J.; Bruns, H.; Alcarazo, M. Angew. Chem., Int. Ed.
(61) Bernhart, C.; Gagnol, J. P.; Gautier, P. N-Pyrroleacetic acid
amides and their therapeutic use. US4329343A, 1982.
2011, 50, 3799−3802.
(24) Verma, A. K.; Shukla, S. P.; Singh, J.; Rustagi, V. J. Org. Chem.
2011, 76, 5670−5684.
(25) Chai, D. I.; Lautens, M. J. Org. Chem. 2009, 74, 3054−3061.
(26) Yamashita, M.; Horiguchi, H.; Hirano, K.; Satoh, T.; Miura, M.
J. Org. Chem. 2009, 74, 7481−7488.
(27) Hulcoop, D. G.; Lautens, M. Org. Lett. 2007, 9, 1761−1764.
(28) Kanno, K.; Liu, Y.; Iesato, A.; Nakajima, K.; Takahashi, T. Org.
Lett. 2005, 7, 5453−5456.
(29) Mamane, V.; Hannen, P.; Furstner, A. Chem.Eur. J. 2004, 10,
̈
4556−4575.
(30) Furstner, A.; Mamane, V. J. Org. Chem. 2002, 67, 6264−6267.
(31) Ackermann, L.; Wang, L.; Lygin, A. V. Chem. Sci. 2012, 3, 177−
̈
180.
(32) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010,
12, 2068−2071.
(33) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock, R.
C. Angew. Chem., Int. Ed. 2009, 48, 1138−1143.
(34) de Koning, C. B.; Michael, J. P.; Pathak, R.; van Otterlo, W. A.
L. Tetrahedron Lett. 2004, 45, 1117−1119.
(35) Lee, J. H.; Kim, I. J. Org. Chem. 2013, 78, 1283−1288.
(36) Nagaraj, M.; Boominathan, M.; Muthusubramanian, S.;
Bhuvanesh, N. Synlett 2012, 23, 1353−1357.
(37) Zhu, H.; Stockigt, J.; Yu, Y.; Zou, H. Org. Lett. 2011, 13, 2792−
̈
2794.
(38) Ge, Y.-Q.; Jia, J.; Yang, H.; Zhao, G.-L.; Zhan, F.-X.; Wang, J.
Heterocycles 2009, 78, 725−736.
(39) Virieux, D.; Guillouzic, A.-F.; Cristau, H.-J. Tetrahedron 2006,
62, 3710−3720.
(40) Ohier, P.; Daïch, A.; Decroix, B. Tetrahedron 1996, 52, 13547−
13556.
(41) Cheeseman, G. W. H.; Eccleshall, S. A.; Thornton, T. J.
Heterocycl. Chem. 1985, 22, 809−811.
(42) Phun, L. H.; Aponte-Guzman, J.; France, S. Angew. Chem., Int.
Ed. 2012, 51, 3198−3202.
(43) Kim, M.; Vedejs, E. J. Org. Chem. 2004, 69, 6945−6948.
(44) Settambolo, R.; Caiazzo, A.; Lazzaroni, R. Tetrahedron Lett.
2001, 42, 4045−4048.
́ ́
(45) Barluenga, J.; Tomas, M.; Rubio, E.; Lopez-Pelegrín, J. A.;
García-Granda, S.; Priede, M. P. J. Am. Chem. Soc. 1999, 121, 3065−
3071.
(46) Smith, J. O.; Mandal, B. K. J. Heterocycl. Chem. 1997, 34, 1441−
1446.
(47) Yerxa, B. R.; Moore, H. W. Tetrahedron Lett. 1992, 33, 7811−
7814.
(48) Gourlay, B. S.; Molesworth, P. P.; Ryan, J. H.; Smith, J. A.
Tetrahedron Lett. 2006, 47, 799−801.
(49) Schafer, I.; Opatz, T. Synthesis 2011, 1691−1704.
̈
G
dx.doi.org/10.1021/jo400992n | J. Org. Chem. XXXX, XXX, XXX−XXX