Catalyst-Free Annulation of 2-Pyridylacetates and Ynals with Molecular Oxygen: An Access to 3-Acylated Indolizines

Article abstract of DOI:10.1021/acs.joc.8b02883

A catalyst and additive-free annulation of 2-pyridylacetates and ynals under molecular oxygen was the first developed, affording 3-acylated indolizines in good to excellent yields. Molecular oxygen was used as the source of the carbonyl oxygen atom in indolizines. This approach was compatible with a wide range of functional groups, and especially it has been successfully extended to unsaturated double bonds and triple bonds, which were difficult to prepare by previous methods in a single step.

Full text of DOI:10.1021/acs.joc.8b02883

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Note
Catalyst-Free Annulation of 2-Pyridylacetates and Ynals
with Molecular Oxygen: an Access to 3-Acylated Indolizines
Zhengwang Chen, Pei Liang, Xiaoyue Ma, Hai-Qing Luo,
Guohai Xu, Tanggao Liu, Xiaowei Wen, Jing Zheng, and Hui Ye
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02883 • Publication Date (Web): 04 Jan 2019
Downloaded from http://pubs.acs.org on January 4, 2019
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Catalyst-Free Annulation of 2-Pyridylacetates and Ynals
with Molecular Oxygen: an Access to 3-Acylated
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9
Indolizines
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Zhengwang Chen,*,a,b Pei Liang,a Xiaoyue Ma,a Haiqing Luo,a Guohai Xu,a Tanggao Liu,a
Xiaowei Wen,a Jing Zheng,a Hui Ye*b
a
Key Laboratory of Organo-pharmaceutical Chemistry of Jiangxi province, Gannan Normal
University, Ganzhou, 341000, China.
b
Hubei Key Laboratory of Processing and Application of Catalytic Materials, Huanggang
Normal University, Huanggang, 438000, China.
O
OR2
R1
O
O2 (1 atm)
O
R1
H
N
toluene, 100 o
C
N
OR2
R3
R3
O
Catalyst and additive-free
43 examples
up to 91% yield
Oxygen-participated reaction
Readily available substrates
Double and triple bonds are compatible
ABSTRACT: A catalyst and additive-free annulation of 2-pyridylacetates and ynals
under molecular oxygen was the first developed, affording 3-acylated indolizines in
good to excellent yields. Molecular oxygen was used as the source of the carbonyl
oxygen atom in indolizines. This approach was compatible with a wide range of
functional groups, especially it has been successfully extended to unsaturated double
bonds and triple bonds, which were difficult to prepare by previous methods in a
single step.
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The indolizine core is one of the most significant nitrogen-fused heterocycles in
that it displays a broad array of biological and pharmacological activity.1
Additionally, indolizines are frequently used as organic semiconductors and
fluorescence dyes in materials science.2 As a result, it has attracted considerable
interest to develop efficient and versatile methods for their preparation. The main
approaches for indolizine synthesis included 1,3-dipolar cycloaddition,3 cyclization of
pyridine derivatives with alkenes,4 alkynes5 or carbonyl compounds,6 transannulations
of pyridotriazoles with alkynes,7 C-H functionalization reaction,8 cycloisomerization
of alkynylpyridine derivatives,9 multicomponent reactions,10 start from N-substituted
pyrrole rings.11 3-Acylated indolizines have found wide applications in
pharmaceuticals.12 Although some strategies such as 1,3-dipolar cycloaddition,13
iodine-mediated intramolecular cyclization14 and palladium-catalyzed C-3 acylation
of indolizines15 have been developed toward 3-acylated indolizines, these approaches
suffer from limitations such as the use of metal or nonmetal catalyst, stoichiometric
excess of oxidants, complex substrates, incompatibility with the sensitive functional
groups. In the interest of green chemistry and atom economy, further research into
catalyst-free methods to synthesize indolizines from readily accessible precursors is
still of great challenge.
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In the past decades, molecular oxygen has drawn much attention and widely
utilized in organic reactions. it is an ideal oxidant and reagent for organic
transformation because of its abundance, low cost and lack of environmentally
hazardous byproducts. Very recently, Cao group reported a novel acid-catalyzed
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three-component reaction of 2-pyridylacetates, aromatic ynals, and alcohols or thiols
to afford 3-(O/S)-substituted indolizines.16 Herein we described the first direct
synthesis of 3-acylated indolizines from 2-pyridylacetates, aromatic or aliphatic ynals
and molecular oxygen in catalyst-free conditions (Scheme 1). The reaction proceeded
smoothly with broad substrate scope and molecular oxygen was used as the source of
the acyl oxygen atom in indolizines.
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Scheme 1. Catalyst-Free Annulation of 2-Pyridylacetates and Ynals with
Molecular Oxygen toward 3-Acylated Indolizines
O
OR2
R1
O
O2 (1 atm)
O
R1
H
N
toluene, 100 o
C
N
OR2
R3
R3
O
As a starting point for the development of a catalyst-free method toward
3-acylated indolizines, the reaction of 2-pyridyl ethyl ester 1a and
phenylpropiolaldehyde 2a in oxygen atmosphere were evaluated to obtain the optimal
conditions. As shown in Table 1, a wide range of common solvents were examined at
100 °C or 80 °C, including aprotic polar solvents , aprotic nonpolar solvents and
protic polar solvents (Table 1, entries 1-8). The results revealed that the solvents are
important for the transformation. Among the solvents used, EtOH was proved
inappropriate, and the reaction can afford the corresponding product with 87% yield
in toluene solvent (Table 1, entry 5). Then the temperatures were tested and lower
temperature disfavored the reaction (Table 1, entries 9-11). Furthermore, it was
advantageous to react for 8 h (Table 1, entries 12 and 13). When oxygen was changed
to air, the yield decreased to 65% (Table 1, entry 14). In addition, in a control reaction
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with no oxygen, almost no product was obtained (Table 1, entry 15). These
experiments implied that molecular oxygen plays an important role in the reaction.
Table 1. Optimization of the Reaction Conditionsa
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O
OEt
O
O2 (1 atm)
O
H
N
N
OEt
solvent, temperature
Ph
Ph
O
3a
2a
1a
Entry
Solvent
Temperature
Time/h
Yield (%)
1
2
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7
8
9
10
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13
14b
15c
DMF
DMSO
dioxane
H2O
toluene
THF
100
100
100
100
100
80
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80
80
60
8
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8
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10
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75
72
60
55
87
40
69
n.p
77
61
MeCN
EtOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
rt
47
72
86
65
100
100
100
100
trace
a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol) with solvent (1.0 mL) in oxygen
b
c
atmosphere. Reacted in air atmosphere. Reacted in argon atmosphere. n.p = no
product.
Under the optimized reaction conditions (Table 1, entry 5), we probed the scope
and generality of this annulation approach to a set of ynals with 2-pyridyl ethyl ester
1a. As shown in Scheme 2, both aromatic and aliphatic ynals were favorable in the
transformation (3b-x). The substrates bearing either an electron-rich or an
electron-deficient group on the benzene ring were tolerated and delivered the
indolizine products in moderate to good yields (3b-u). The reaction was compatible
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with array of substituents, such as alkyl, aryl, alkyloxy, fluoro, chloro, bromo,
trifluoromethyl, acetyl, ester, cyano and nitro groups (3b-u). A sterically hindered
methyl group on the ortho-position furnished the product in lower yield (3d). The
di-substituted substrates formed the products in good yields (3g, 3m and 3n). It is
noteworthy that the substrates containing a bromo, acetyl, ester, cyano or nitro groups
could be further functionalized and have potential applications in pharmaceutical
chemistry. Aliphatic ynals led to lower yields compared to aromatic ynals (3v-x). To
our surprise, the reaction of 3-(trimethylsilyl)propiolaldehyde 2w and 1a gave the
corresponding product 3x in 32% yield and 3w in 38% yield. However, the substrates
containing a carboxy or a hydroxyl group did not lead to the corresponding products.
The structure of 3r was further confirmed by X-ray crystal diffraction
measurements.17
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Scheme 2. Substrate Scope of Ynalsa
O
OEt
O
O2 (1 atm)
O
H
N
toluene, 100 o
C
N
OEt
R
R
O
1a
2
3
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O
O
O
O
O
O
O
O
OEt
OEt
OEt
OEt
N
N
N
N
7
8
9
3b:
85%
3d:
65%
3c:
78%
3a:
87%
O
O
O
O
O
OEt
OEt
OEt
OEt
N
N
N
N
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O
O
O
Ph
3e:
3f:
3g:
3h:
80%
68%
OEt
78%
75%
O
O
O
O
OEt
OEt
OEt
N
N
N
F
N
O
O
O
OCH3
F
O
3i:
3j:
3k:
3l:
70%
84%
78%
OEt
71%
OEt
O
O
O
OEt
OEt
O
O
N
N
F
N
N
O
F
O
O
Br
Cl
F
F
3m:
3n:
3o:
3p:
74%
OEt
68%
OEt
80%
77%
OEt
O
O
O
O
O
OEt
N
N
N
N
CF3
O
O
O
O
CN
O
O
3q:
3r:
3s:
3t:
56%
80%
85%
OEt
79%
O
O
O
O
OEt
OEt
Si
OEt
and
N
N
N
N
H
O
NO2
O
O
O
3w:b
3v:
51%
3x:
32%
38%
3u:
67%
a
Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), and toluene (1.0 mL) at 100 °C
for 8 h in oxygen atmosphere. b The substrate was 3-(trimethylsilyl)propiolaldehyde.
Next, we investigated the scope of 2-pyridylacetates under the standard
conditions. Initially, different substituents on ester moiety were examined and the
results were summarized in Scheme 3. Fortunately, the ester groups bearing tertiary
carbon, trifluoroethyl or furylmethyl group were perfectly tolerated under the standard
conditions (4b-e). To our delight, some challenging substrates containing unsaturated
double bonds or triple bonds reacted efficiently with phenylpropiolaldehyde (4f-m).
Notably, Bîcu group recently reported the 3-acylated indolizines bearing propargylic
ester can improve human farnesyltransferase inhibition and the target compounds
were prepared in lower yields via multistep transformation.18 Pyridine ring bearing
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electron-rich (methyl group) and electron-poor substituents (bromo group) underwent
smoothly to generate the corresponding products in satisfactory yields, irrespective of
the ynals attached with electron-donating or electron-withdrawing groups on the
benzene ring (4o−t). It implied that this annulation reaction can be effective for the
3-acylated indolizine library.
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Scheme 3. Substrate Scope of 2-Pyridylacetates and Ynalsa
O
OR2
O
O2 (1 atm)
O
R1
R1
H
N
N
OR2
toluene, 100 o
C
R3
R3
O
1
2
4
CF3
O
O
O
O
O
O
O
O
O
N
N
N
N
O
O
O
4a:
4b:
4c:
4d:
91%
O
82%
O
78%
O
89%
O
O
O
O
O
O
N
N
N
N
O
O
O
O
4e:
4f:
4g:
4h:
62%
O
83%
O
82%
O
80%
O
O
O
O
O
N
N
N
N
O
O
O
O
4i:
4j:
4k:
4l:
84%
O
80%
O
85%
O
78%
O
O
O
O
O
N
N
Br
N
Br
N
O
O
O
O
4m
: 73%
4n:
4o
: 79%
4p
: 67%
47%
O
O
O
O
O
O
O
O
N
F
Br
N
N
N
CF3
O
O
O
O
Ph
F
4q
: 71%
4r
4s
: 66%
4t
: 62%
: 68%
a Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), and toluene (1.0 mL) at 100 °C for
8 h in oxygen atmosphere.
Scheme 4. Control Experiments
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O
O
OEt
O
O2 (1 atm)
O
(a)
H
N
N
OEt
TEMPO (1 equiv)
toluene, 100 o
Ph
C
Ph
1a
2a
2a
3a
, 83%
O2 (1 atm)
(b)
(c)
1a
3a
, 80%
BHT (1 equiv)
toluene, 100 o
C
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O
OEt
18O2 (1 atm)
1a
2a
N
toluene, 100 o
C
Ph
18O
3a-O18
, 75%
Some control experiments were conducted to elucidate the mechanism of the
reaction in Scheme 4. Radical-trapping experiments were carried out through the
addition of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or butylated
hydroxytoluene (BHT) to the reaction mixture in the standard conditions, the yields
only decreased slightly which can exclude the radical process (Scheme 4a and 4b).
18
The isotopic labeling study with O2 and the condition experiments (Table 1, entries
14 and 15) inferred that the oxygen atom of the product originated from molecular
oxygen (Scheme 4c).
On the basis of previous reports and our experimental results, a plausible
mechanism was proposed in Scheme 5. Initially, the Knoevenagel condensation of 1a
with 2a afforded the intermediate A under the promotion of pyridine moiety. It is
noteworthy that intermediate A can be detected with GC-MS and isolated as a mixture
with 3a. When this mixture was reacted under the standard conditions, intermediate A
can be transformed into 3a. Then intermediate B was formed via successive
nucleophilic attack and the activation of molecular oxygen. Finally, the 3a product
was furnished by elimination of hydroxyl group. According to the reaction
mechanism proposed, molecular oxygen acted as an electrophile. Although some
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electrophilic reagents were tried instead of oxygen to conduct the tandem reaction,
however, we failed to extend the reaction to other electrophiles at the present stage.
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Scheme 5. Possible Mechanism
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O
OEt
O
base
O
H
OEt
N
Ph
N
1a
2a
A
Ph
O
H
O
O
OEt
O
N
OEt
Ph
O
N
O
O
base
Ph
3a
B
In summary, we have explored a highly efficient and facile annulation reaction
for the synthesis of 3-acylated indolizines. A variety of 2-pyridylacetates and ynals
bearing various functional groups were tolerated under the standard conditions and
yielded the products in good yields. The merit of this transformation includes catalyst
and additive-free, oxygen participated reaction, simple operation, good functional
group tolerance, commercially or readily available substrates etc. Ongoing studies
regarding the mechanism and application are currently in our laboratory.
EXPERIMENTAL SECTION
General Information: 1H and 13C{1H} NMR spectra were obtained on a 400 and 100
MHz NMR spectrometer. The chemical shifts are referenced to signals at 7.26 and
77.0 ppm, respectively, chloroform is solvent with TMS as the internal standard
unless otherwise noted. Mass spectra were recorded on a GC-MS spectrometer at an
ionization voltage of 70 eV equipped with a DB-WAX capillary column (internal
diameter: 0.25 mm, length: 30 m). Elemental analyses were performed with a Vario
EL elemental analyzer. High resolution mass spectra (HRMS) (ion trap or TOF) were
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measured using an electrospray ionization (ESI) mass spectrometry. Silica gel
(300-400 mesh) was used for flash column chromatograph, eluting (unless otherwise
stated) with ethyl acetate/petroleum ether (PE) (60-90 oC) mixture.
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The 2-pyridylacetates 1a, 1b, 1o, and propargyl aldehydes 2a, 2v, 2w were
commercially available from Sigma-Aldrich China. Substituted 2-pyridylacetates
1c-1n have been prepared using the literature procedure,19 aryl substituted propargyl
aldehydes 2b-2u have been prepared using the literature procedure,20 and known
compounds data have been compared with the reported data.19,21 Characterization data
for new compounds is given below.
General Procedure for the Preparation of Substituted 2-Pyridylacetates
(1c-1n). To a suspended solution of 2-pyridylacetic acid hydrochloride (173 mg, 1.0
mmol) and alcohol (1.5 mmol) in 5 mL dichloromethane was added triethylamine
(0.27 mL, 2.0 mmol), 1,3-dicyclohexylcarbodiimide (DCC) (210 mg, 1.0 mmol) and a
catalytic amount of 4-(dimethylamino)pyridine (DMAP) (6.1 mg, 0.05 mmol) at 25
oC. The reaction mixture was stirred 12 h at 45 oC, the reaction mixture was filtered to
remove 1,3-dicyclohexylurea. The filtrate was washed with water (3×5 mL), dried
with MgSO4 and concentrated under reduced pressure, the crude product was purified
by column chromatography to give the pure sample.
tert-pentyl 2-(pyridin-2-yl)acetate (1d): yellow oil (157 mg, 76%); Rf = 0.55
(ethyl acetate / petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 8.54 (d, J =
4.4 Hz, 1H), 7.63 (td, J = 7.7, 1.7 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.16 (dd, J = 7.1,
5.3 Hz, 1H), 3.76 (s, 2H), 1.74 (q, J = 7.5 Hz, 2H), 1.40 (s, 6H), 0.81 (t, J = 7.5 Hz,
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3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 169.8, 154.9, 149.3, 136.4, 123.8, 121.8,
83.6, 45.1, 33.4, 25.4, 8.0. MS (EI) m/z: 207, 138, 120, 92, 71, 43. Anal. Calcd for
C12H17NO2: C, 69.54; H, 8.27; N, 6.76; Found: C, 69.15; H, 8.33; N, 6.70.
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2,2,2-trifluoroethyl 2-(pyridin-2-yl)acetate (1e): yellow oil (179 mg, 82%); Rf =
0.45 (ethyl acetate / petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 8.57 (d,
J = 4.4 Hz, 1H), 7.68 (t, J = 7.1 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.25 – 7.18 (m,
13
1H), 4.52 (q, J = 8.4 Hz, 2H), 3.96 (s, 2H). C{1H} NMR (100 MHz, CDCl3): δ =
169.0, 153.2, 149.6, 136.8, 123.8, 122.8 (q, J = 275 Hz), 122.4, 60.6 (q, J = 36 Hz),
43.1. MS (EI) m/z: 219, 120, 92, 65, 39. Anal. Calcd for C9H8F3NO2: C, 49.32; H,
3.68; N, 6.39; Found: C, 49.01; H, 3.78; N, 6.46.
furan-3-ylmethyl 2-(pyridin-2-yl)acetate (1f): yellow oil (187 mg, 86%); Rf =
1
0.38 (ethyl acetate / petroleum ether = 1:3); H NMR (400 MHz, CDCl3): δ = 8.53 –
8.48 (m, 1H), 7.62 (td, J = 7.7, 1.8 Hz, 1H), 7.42 (dd, J = 1.4, 0.7 Hz, 1H), 7.35 (t, J =
1.6 Hz, 1H), 7.27 – 7.23 (m, 1H), 7.16 (ddd, J = 7.5, 4.9, 0.9 Hz, 1H), 6.37 (d, J = 1.2
13
Hz, 1H), 5.01 (s, 2H), 3.84 (s, 2H). C{1H} NMR (100 MHz, CDCl3): δ = 170.2,
153.8, 149.0, 143.0, 141.3, 136.5, 123.6, 121.9, 119.9, 110.2, 58.0, 43.3. MS (EI) m/z:
217, 173, 144, 120, 93, 81, 65, 53, 39. Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10;
N, 6.45; Found: C, 66.18; H, 5.18; N, 6.39.
hept-1-en-3-yl 2-(pyridin-2-yl)acetate (1h): yellow oil (193 mg, 83%); Rf = 0.62
(ethyl acetate / petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 8.53 (d, J =
4.4 Hz, 1H), 7.63 (td, J = 7.7, 1.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.16 (dd, J = 7.1,
5.3 Hz, 1H), 5.78 – 5.69 (m, 1H), 5.24 (q, J = 6.3 Hz, 1H), 5.16 (ddd, J = 23.1, 12.2,
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5.8 Hz, 2H), 3.84 (s, 2H), 1.66 – 1.52 (m, 2H), 1.28 – 1.19 (m, 4H), 0.84 (t, J = 6.9
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Hz, 3H). C{1H} NMR (100 MHz, CDCl3): δ = 169.8, 154.4, 149.3, 136.4, 136.2,
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123.7, 121.9, 116.6, 75.4, 44.15, 33.7, 27.0, 22.3, 13.8. MS (EI) m/z: 233, 178, 160,
134, 120, 92, 65, 41. Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00; Found:
C, 71.85; H, 8.29; N, 6.11.
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cyclohex-3-en-1-yl 2-(pyridin-2-yl)acetate (1i): yellow oil (185 mg, 80%); Rf =
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0.45 (ethyl acetate / petroleum ether = 1:3); H NMR (400 MHz, CDCl3): δ = 8.55 –
8.49 (m, 1H), 7.62 (td, J = 7.7, 1.8 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.15 (ddd, J = 7.5,
4.9, 1.0 Hz, 1H), 5.61 (ddt, J = 6.2, 4.4, 2.3 Hz, 2H), 3.99 (d, J = 6.7 Hz, 2H), 3.83 (s,
2H), 2.07 – 2.01 (m, 1H), 2.01 – 1.98 (m, 2H), 1.90 (tddd, J = 6.7, 5.1, 4.3, 2.5 Hz,
1H), 1.73 – 1.66 (m, 2H), 1.25 – 1.20 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ =
170.5, 154.3, 149.3, 136.5, 126.8, 125.3, 123.7, 121.9, 69.1, 43.7, 32.7, 27.9, 25.0,
24.2. MS (EI) m/z: 231, 217, 172, 138, 120, 92, 79, 65, 39. Anal. Calcd for
C14H17NO2: C, 72.70; H, 7.41; N, 6.06; Found: C, 72.46; H, 7.48; N, 6.13.
but-3-yn-1-yl 2-(pyridin-2-yl)acetate (1j): yellow oil (176 mg, 93%); Rf = 0.32
(ethyl acetate / petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 8.46 (d, J =
4.5 Hz, 1H), 7.57 (td, J = 7.7, 1.7 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.10 (dd, J = 7.4,
5.0 Hz, 1H), 4.15 (t, J = 6.9 Hz, 2H), 3.79 (s, 2H), 2.45 (td, J = 6.9, 2.6 Hz, 2H), 1.93
(t, J = 2.6 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ = 170.0, 153.9, 149.2, 136.4,
123.6, 121.9, 79.6, 69.8, 62.3, 43.4, 18.6. MS (EI) m/z: 189, 159, 144, 130, 120, 92,
65, 53, 39. Anal. Calcd for C11H11NO2: C, 69.83; H, 5.86; N, 7.40; Found: C, 69.62;
H, 5.95; N, 7.48.
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hex-3-yn-1-yl 2-(pyridin-2-yl)acetate (1k): yellow oil (191 mg, 88%); Rf = 0.41
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(ethyl acetate / petroleum ether = 1:3); H NMR (400 MHz, CDCl3): δ = 8.46 – 8.40
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(m, 1H), 7.55 (td, J = 7.7, 1.8 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.08 (ddd, J = 7.5,
4.9, 0.9 Hz, 1H), 4.08 (t, J = 7.0 Hz, 2H), 3.76 (s, 2H), 2.38 (tt, J = 7.0, 2.4 Hz, 2H),
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2.02 (qt, J = 7.5, 2.4 Hz, 2H), 0.98 (t, J = 7.5 Hz, 3H). C{1H} NMR (100 MHz,
CDCl3): δ = 170.0, 153.9, 149.1, 136.3, 123.61, 121.8, 83.1, 74.4, 63.0, 43.4, 18.8,
13.7, 12.0. MS (EI) m/z: 217, 202, 186, 172, 158, 144, 131, 120, 92, 65, 41. Anal.
Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45; Found: C, 71.64; H, 7.05; N, 6.55.
pent-4-yn-1-yl 2-(pyridin-2-yl)acetate (1l): yellow oil (185 mg, 91%); Rf = 0.30
(ethyl acetate / petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3): δ = 8.55 (dd, J =
4.9, 0.8 Hz, 1H), 7.65 (td, J = 7.7, 1.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.18 (ddd, J
= 7.5, 4.9, 1.0 Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 3.84 (s, 2H), 2.23 (td, J = 7.1, 2.7 Hz,
2H), 1.94 (t, J = 2.7 Hz, 1H), 1.88 – 1.81 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3):
δ = 170.5, 154.3, 149.4, 136.6, 123.8, 122.0, 82.9, 68.97, 63.4, 43.8, 27.3, 15.0. MS
(EI) m/z: 203, 186, 172, 158, 144, 131, 120, 92, 65, 41. Anal. Calcd for C12H13NO2:
C, 70.92; H, 6.45; N, 6.89; Found: C, 70.71; H, 6.56; N, 6.95.
General Procedure for the Preparation of Aryl Substituted Propiolaldehydes
(2b-2u). For the synthesis of E: To a stirred of substituted iodobenzene (1 mmol) in
triethylamine (5 mL) under argon were sequentially added Pd(PPh3)2Cl2 (14 mg, 2
mol%), and CuI (7.6 mg, 4 mol%) at room temperature. The mixture was allowed to
stirred for 10 min. Then propargyl alcohol (1.1 mmol) was added. The mixture was
allowed to stir overnight. After the reaction was finished, water (5 mL) was added and
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the solution was extracted with ethyl acetate (3×5 mL), the combined extract was
dried with anhydrous MgSO4. Solvent was removed, and the residue was separated by
column chromatography to give the aryl substituted propargyl alcohol E (The yields
were between 90% to 99%).
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For the synthesis of (2b-2u): MnO2 (652mg, 7.5 mmol) was added to a solution of
aryl substituted propargyl alcohol E (0.5 mmol) in dichloromethane (5 mL) at room
temperature. The mixture was allowed to stir overnight. Then the solid was filtered,
and the solvent were removed under reduced pressure. The residue was purified by
column chromatography to give the pure aryl substituted propiolaldehydes.
3-(3,5-difluorophenyl)propiolaldehyde (2m): yellow solid (75 mg, 90%); mp:
o
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38-40 C; Rf = 0.57 (ethyl acetate / petroleum ether = 1:12); H NMR (400 MHz,
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CDCl3): δ = 9.39 (s, 1H), 7.12-7.06 (m, 2H), 6.97-6.91 (m, 1H). C{1H} NMR (100
MHz, CDCl3): δ = 176.1, 162.6 (dd, J = 250, 13 Hz), 121.9 (t, J = 12 Hz), 115.9 (dd, J
= 19, 8 Hz), 107.4 (t, J = 25 Hz), 90.9 (t, J = 4 Hz), 88.5. MS (EI) m/z: 166, 138, 118,
87, 61, 38. Anal. Calcd for C9H4F2O: C, 65.07; H, 2.43; Found: C, 64.92; H, 2.52.
3-(3,4-difluorophenyl)propiolaldehyde (2n): yellow oil (73 mg, 88%); Rf = 0.50
(ethyl acetate / petroleum ether = 1:12); 1H NMR (400 MHz, CDCl3): δ = 9.39 (s, 1H),
7.44-7.35 (m, 2H), 7.24-7.17 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ = 176.3,
152.3 (dd, J = 255, 13 Hz), 150.0 (dd, J = 250, 13 Hz), 130.3 (dd, J = 6, 3 Hz), 122.1
(d, J = 19 Hz), 118.1 (d, J = 18 Hz), 116.2 (dd, J = 8, 4 Hz), 92.0, 88.2. MS (EI) m/z:
166, 138, 118, 87, 61, 38. Anal. Calcd for C9H4F2O: C, 65.07; H, 2.43; Found: C,
64.83; H, 2.56.
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General Procedure for the Preparation of 3-Acylated Indolizines. A mixture of
2-pyridylacetates (0.2 mmol) and ynal (0.2 mmol) in toluene (1.0 mL) was heated at
100 °C for 8 h in a sealed tube under 1 atm of oxygen. After the reaction was finished,
water (5 mL) was added and the solution was extracted with ethyl acetate (3×5 mL),
the combined extract was dried with anhydrous MgSO4. Solvent was removed, and
the residue was separated by column chromatography to give the pure sample.
ethyl 3-benzoylindolizine-1-carboxylate (3a):14a yellow solid (51 mg, 87%); mp:
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81-83 C; Rf = 0.60 (ethyl acetate / petroleum ether = 1:5); H NMR (400 MHz,
CDCl3): δ = 9.98 (d, J = 7.1 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 7.84 – 7.79 (m, 3H),
7.61 – 7.55 (m, 1H), 7.52 (dd, J = 8.0, 6.6 Hz, 2H), 7.48 – 7.43 (m, 1H), 7.09 (td, J =
13
7.0, 1.2 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). C{1H} NMR
(100 MHz, CDCl3): δ = 185.5, 164.0, 139.9, 131.4, 129.2, 129.0, 128.9, 128.3, 127.6,
122.5, 119.5, 115.2, 106.2, 99.9, 60.0, 14.5. MS (EI) m/z: 293, 265, 248, 221, 188,
105, 77, 51.
ethyl 3-(4-methylbenzoyl)indolizine-1-carboxylate (3b):13a yellow solid (52 mg,
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85%); mp: 105-107 C; Rf = 0.60 (ethyl acetate / petroleum ether = 1:5); H NMR
(400 MHz, CDCl3): δ = 9.95 (d, J = 7.1 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 7.83 (s,
1H), 7.74 (d, J = 8.1 Hz, 2H), 7.44 (ddd, J = 8.9, 6.9, 1.0 Hz, 1H), 7.32 (d, J = 7.9 Hz,
2H), 7.07 (td, J = 6.9, 1.3 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H), 1.40 (t, J =
13
7.1 Hz, 3H). C{1H} NMR (100 MHz, CDCl3): δ = 185.4, 164.12, 142.0, 139.7,
137.1, 129.1, 129.1, 129.0, 128.7, 127.4, 122.6, 119.4, 115.1, 106.0, 60.0, 21.5, 14.52.
MS (EI) m/z: 307, 279, 262, 235, 207, 188, 144, 119, 91, 65, 57.
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ethyl 3-(3-methylbenzoyl)indolizine-1-carboxylate (3c): yellow solid (51 mg, 84%);
mp: 98-100 oC; Rf = 0.55 (ethyl acetate / petroleum ether = 1:6); 1H NMR (400 MHz,
CDCl3): δ = 9.96 (d, J = 7.0 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 7.82 (s, 1H), 7.63 –
7.56 (m, 2H), 7.45 (dd, J = 8.4, 7.4 Hz, 1H), 7.41 – 7.33 (m, 2H), 7.09 (td, J = 7.0, 1.1
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Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). C{1H}
NMR (100 MHz, CDCl3): δ = 185.8, 164.1, 139.9, 139.8, 138.2, 132.2, 129.3, 129.2,
129.0, 128.2, 127.6, 126.2, 122.6, 119.5, 115.2, 106.2, 60.1, 21.4, 14.5. MS (EI) m/z:
307, 279, 262, 235, 207, 188, 144, 119, 91, 65. HRMS (m/z) (ESI-ion trap): calcd. for
C19H18NO3 [M+H]+ 308.1281; found 308.1290.
ethyl 3-(2-methylbenzoyl)indolizine-1-carboxylate (3d): yellow solid (40 mg,
65%); mp: 86-88 oC; Rf = 0.60 (ethyl acetate / petroleum ether = 1:5); 1H NMR (400
MHz, CDCl3): δ = 10.07 (dt, J = 7.0, 1.1 Hz, 1H), 8.40 (dt, J = 9.0, 1.2 Hz, 1H), 7.54
(s, 1H), 7.48 (ddd, J = 8.9, 6.9, 1.1 Hz, 1H), 7.42 – 7.37 (m, 2H), 7.30 (dd, J = 7.2, 5.7
Hz, 2H), 7.12 (td, J = 7.0, 1.4 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.37 (t,
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J = 7.1 Hz, 3H). C{1H} NMR (100 MHz, CDCl3): δ = 187.5, 163.9, 140.0, 139.7,
136.0, 130.8, 129.7, 129.3, 129.3, 128.0, 127.8, 125.2, 123.3, 119.5, 115.4, 106.4,
60.0, 19.5, 14.5. Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56; Found: C,
74.01; H, 5.67; N, 4.63.
ethyl 3-(2-ethylbenzoyl)indolizine-1-carboxylate (3e): yellow liquid (44 mg,
68%); Rf = 0.64 (ethyl acetate / petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3):
δ = 10.08 (d, J = 7.0 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 7.53 (s, 1H), 7.50 – 7.41 (m,
2H), 7.36 (dd, J = 9.7, 8.4 Hz, 2H), 7.28 (d, J = 7.4 Hz, 1H), 7.11 (t, J = 6.9 Hz, 1H),
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4.35 (q, J = 7.1 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.20 (t, J =
7.6 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 187.6, 163.9, 142.4, 139.9, 139.3,
129.8, 129.3, 129.3, 129.2, 128.0, 127.8, 125.1, 123.4, 119.5, 115.4, 106.3, 60.0, 26.1,
15.9, 14.4. MS (EI) m/z: 321, 276, 248, 204, 132, 104, 78. HRMS (m/z) (ESI-ion
trap): calcd. for C20H20NO3 [M+H]+ 322.1438; found 322.1430.
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ethyl 3-(4-(tert-butyl)benzoyl)indolizine-1-carboxylate (3f): yellow solid (54 mg,
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78%); mp: 113-115 C; Rf = 0.64 (ethyl acetate / petroleum ether = 1:5); H NMR
(400 MHz, CDCl3): δ = 9.96 (dt, J = 7.1, 1.1 Hz, 1H), 8.39 (dt, J = 9.0, 1.2 Hz, 1H),
7.86 (s, 1H), 7.79 – 7.75 (m, 2H), 7.55 – 7.51 (m, 2H), 7.43 (ddd, J = 8.9, 6.8, 1.1 Hz,
1H), 7.07 (td, J = 7.0, 1.4 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H),
1.39 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ = 185.4, 164.1, 155.1, 139.7, 137.1,
129.1, 128.9, 128.7, 127.4, 125.3, 122.7, 119.4, 115.0, 106.1, 60.0, 35.0, 31.2, 14.5.
MS (EI) m/z: 349, 335, 306, 290, 262, 202, 174, 130, 124, 89, 78, 57. HRMS (m/z)
(ESI-ion trap): calcd. for C22H24NO3 [M+H]+ 350.1751; found 350.1744.
ethyl 3-(3,5-dimethylbenzoyl)indolizine-1-carboxylate (3g): yellow solid (48 mg,
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75%); mp: 129-131 C; Rf = 0.62 (ethyl acetate / petroleum ether = 1:5); H NMR
(400 MHz, CDCl3): δ = 9.96 (d, J = 7.1 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 7.82 (s,
1H), 7.47 – 7.42 (m, 1H), 7.40 (s, 2H), 7.21 (s, 1H), 7.08 (td, J = 7.0, 1.2 Hz, 1H),
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4.38 (q, J = 7.1 Hz, 2H), 2.41 (s, 6H), 1.40 (t, J = 7.1 Hz, 3H). C{1H} NMR (100
MHz, CDCl3): δ = 186.1, 164.1, 140.0, 139.8, 138.0, 133.0, 129.2, 128.9, 127.4,
126.6, 122.7, 119.4, 115.1, 106.1, 60.0, 21.2, 14.5. HRMS (m/z) (ESI-TOF): calcd.
for C20H20NO3 [M+H]+ 322.1438; found 322.1431.
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ethyl 3-([1,1'-biphenyl]-4-carbonyl)indolizine-1-carboxylate (3h):1b yellow solid
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(59 mg, 80%); mp: 155-157 C; Rf = 0.55 (ethyl acetate / petroleum ether = 1:5); H
NMR (400 MHz, CDCl3): δ = 9.99 (d, J = 7.0 Hz, 1H), 8.44 – 8.39 (m, 1H), 7.93 –
7.88 (m, 3H), 7.76 – 7.72 (m, 2H), 7.68 (dd, J = 5.2, 3.3 Hz, 2H), 7.52 – 7.45 (m, 3H),
7.44 – 7.39 (m, 1H), 7.10 (td, J = 7.0, 1.3 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.41 (t, J
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= 7.1 Hz, 3H). C{1H} NMR (100 MHz, CDCl3): δ = 185.0, 164.0, 144.3, 140.0,
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139.8, 138.5, 129.5, 129.1, 128.9, 128.8, 127.9, 127.6, 127.2, 127.0, 122.5, 119.4,
115.2, 106.2, 60.0, 14.5.
ethyl 3-(1-naphthoyl)indolizine-1-carboxylate (3i): yellow liquid (48 mg, 70%);
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Rf = 0.56 (ethyl acetate / petroleum ether = 1:5); H NMR (400 MHz, CDCl3): δ =
10.19 (d, J = 6.9 Hz, 1H), 8.43 (d, J = 8.9 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.00 (d, J
= 8.2 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 6.9 Hz, 1H), 7.59 (s, 1H), 7.58 –
7.48 (m, 4H), 7.16 (t, J = 6.9 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 186.6, 163.9, 140.1, 137.4, 133.7, 130.7,
130.4, 129.5, 129.4, 128.3, 128.0, 126.9, 126.5, 126.3, 125.3, 124.4, 123.7, 119.5,
115.5, 106.4, 60.0, 14.4. Anal. Calcd for C22H17NO3: C, 76.95; H, 4.99; N, 4.08;
Found: C, 76.68; H, 5.10; N, 4.20.
ethyl 3-(4-methoxybenzoyl)indolizine-1-carboxylate (3j):13b yellow solid (54 mg,
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84%); mp: 107-109 C; Rf = 0.58 (ethyl acetate / petroleum ether = 1:6); H NMR
(400 MHz, CDCl3): δ = 9.88 (dt, J = 7.1, 1.0 Hz, 1H), 8.36 (dt, J = 9.0, 1.2 Hz, 1H),
7.85 – 7.80 (m, 3H), 7.40 (ddd, J = 8.9, 6.8, 1.1 Hz, 1H), 7.06 – 7.02 (m, 1H), 7.02 –
6.98 (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). 13C{1H}
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NMR (100 MHz, CDCl3): δ = 184.5, 164.1, 162.4, 139.6, 132.3, 131.1, 129.0, 128.2,
127.2, 122.5, 119.4, 114.9, 113.6, 105.8, 60.0, 55.4, 14.50.
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ethyl 3-(4-fluorobenzoyl)indolizine-1-carboxylate (3k):14c yellow solid (49 mg,
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78%); mp: 106-108 C; Rf = 0.55 (ethyl acetate / petroleum ether = 1:6); H NMR
(400 MHz, CDCl3): δ = 9.92 (d, J = 7.1 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 7.86 – 7.81
(m, 2H), 7.78 (s, 1H), 7.48 – 7.42 (m, 1H), 7.19 (t, J = 8.6 Hz, 2H), 7.11 – 7.06 (m,
1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). C{1H} NMR (100 MHz,
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CDCl3): δ = 184.0, 164.8 (d, J = 250 Hz), 163.9, 139.9, 136.0 (d, J = 3 Hz), 131.2 (d,
J = 9 Hz), 129.1, 128.6, 127.7, 122.3, 119.5, 115.4 (d, J = 22 Hz), 115.3, 106.4, 60.1,
14.5. MS (EI) m/z: 311, 283, 266, 239, 211, 188, 160, 144, 123, 95, 75, 51.
ethyl 3-(3-fluorobenzoyl)indolizine-1-carboxylate (3l): yellow solid (44 mg,
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71%); mp: 115-117 C; Rf = 0.56 (ethyl acetate / petroleum ether = 1:5); H NMR
(400 MHz, CDCl3): δ = 1H NMR (400 MHz, CDCl3) δ 9.95 (d, J = 7.0 Hz, 1H), 8.40
(d, J = 8.9 Hz, 1H), 7.81 (s, 1H), 7.59 (dd, J = 7.6, 1.1 Hz, 1H), 7.53 – 7.44 (m, 3H),
7.30 – 7.26 (m, 1H), 7.11 (td, J = 7.0, 1.3 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J
= 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 183.8, 163.9, 162.5 (d, J = 246
Hz), 141.9 (d, J = 7 Hz), 140.0, 130.0 (d, J = 8 Hz), 129.2, 129.0, 127.9, 124.6 (d, J =
3 Hz), 122.1, 119.5, 118.3 (d, J = 21 Hz), 115.8 (d, J = 22 Hz), 115.5, 106.6, 60.1,
14.5. MS (EI) m/z: 311, 283, 266, 239, 211, 188, 160, 144, 123, 95, 75, 51. HRMS
(m/z) (ESI-ion trap): calcd. for C18H15FNO3 [M+H]+ 312.1030; found 312.1020.
ethyl 3-(3,5-difluorobenzoyl)indolizine-1-carboxylate (3m): yellow solid (49
mg, 74%); mp: 137-139 oC; Rf = 0.62 (ethyl acetate / petroleum ether = 1:6); 1H NMR
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(400 MHz, CDCl3): δ = 1H NMR (400 MHz, CDCl3) δ = 9.92 (d, J = 7.0 Hz, 1H),
8.41 (d, J = 8.9 Hz, 1H), 7.80 (s, 1H), 7.52 – 7.46 (m, 1H), 7.35 – 7.28 (m, 2H), 7.13
(td, J = 6.9, 1.1 Hz, 1H), 7.02 (tt, J = 8.7, 2.3 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.41
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 182.1, 163.7, 162.7 (dd, J
= 250, 12 Hz), 142.8 (t, J = 3.2 Hz), 140.3, 129.2, 128.6 (d J = 67 Hz), 121.6, 119.6,
115.7, 115.7, 111.9 (d, J = 26 Hz), 106.9, 106.6 (t, J = 26 Hz), 60.2, 14.5. MS (EI)
m/z: 329, 301, 284, 257, 229, 188, 160, 141, 113, 89, 63, 51. HRMS (m/z) (ESI-TOF):
calcd. for C18H14F2NO3 [M+H]+ 330.0936; found 330.0931.
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ethyl 3-(3,4-difluorobenzoyl)indolizine-1-carboxylate (3n): yellow solid (45 mg,
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68%); mp: 107-109 C; Rf = 0.57 (ethyl acetate / petroleum ether = 1:5); H NMR
(400 MHz, CDCl3): δ = 1H NMR (400 MHz, CDCl3) δ = 9.89 (d, J = 7.0 Hz, 1H),
8.40 (d, J = 8.9 Hz, 1H), 7.78 (s, 1H), 7.69 – 7.63 (m, 1H), 7.61 – 7.57 (m, 1H), 7.50
– 7.44 (m, 1H), 7.34 – 7.26 (m, 1H), 7.11 (t, J = 6.6 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H),
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1.40 (t, J = 7.1 Hz, 3H). C{1H} NMR (100 MHz, CDCl3): δ = 182.4, 163.8, 152.6
(dd, J = 240, 15 Hz), 150.1 (dd, J = 234, 13 Hz), 140.1, 136.7 (t, J = 4 Hz), 129.1,
128.7, 128.0, 125.6 (dd, J = 7, 4 Hz), 121.8, 119.6, 118.3 (d, J = 18 Hz), 117.3 (d, J =
18 Hz), 106.7, 60.2, 14.4, 15.5. MS (EI) m/z: 329, 301, 284, 257, 229, 188, 160, 141,
113, 89, 63. HRMS (m/z) (ESI-ion trap): calcd. for C18H13F2NO3 [M+H]+ 330.0936;
found 330.0959.
ethyl 3-(4-chlorobenzoyl)indolizine-1-carboxylate (3o):14c yellow solid (52 mg,
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80%); mp: 101-103 C; Rf = 0.59 (ethyl acetate / petroleum ether = 1:5); H NMR
(400 MHz, CDCl3): δ = 9.93 (d, J = 7.1 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 7.79 – 7.74
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(m, 3H), 7.51 – 7.43 (m, 3H), 7.09 (td, J = 7.0, 1.3 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H),
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1.40 (t, J = 7.1 Hz, 3H). C{1H} NMR (100 MHz, CDCl3): δ = 184.0, 163.9, 140.0,
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138.1, 137.7, 130.3, 129.1, 128.7, 128.6, 127.8, 122.1, 119.5, 115.4, 106.5, 60.1, 14.5.
MS (EI) m/z: 327, 299, 282, 255, 227, 188, 160, 139, 111, 89, 75, 51.
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ethyl 3-(4-bromobenzoyl)indolizine-1-carboxylate (3p):13b yellow solid (57 mg,
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77%); mp: 122-124 C; Rf = 0.60 (ethyl acetate / petroleum ether = 1:5); H NMR
(400 MHz, CDCl3): δ = 9.93 (d, J = 7.1 Hz, 1H), 8.40 (dt, J = 8.9, 1.1 Hz, 1H), 7.77
(s, 1H), 7.70 – 7.63 (m, 4H), 7.46 (ddd, J = 8.9, 6.9, 1.1 Hz, 1H), 7.10 (td, J = 7.0, 1.3
Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ = 184.1, 163.9, 140.0, 138.6, 131.6, 130.4, 129.1, 128.8, 127.9, 126.2,
122.1, 119.5, 115.4, 106.5, 60.1, 14.5.
ethyl 3-(3-(trifluoromethyl)benzoyl)indolizine-1-carboxylate (3q): yellow solid
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(58 mg, 80%); mp: 78-80 C; Rf = 0.48 (ethyl acetate / petroleum ether = 1:6); H
NMR (400 MHz, CDCl3): δ = 9.97 (dt, J = 7.0, 1.1 Hz, 1H), 8.42 (dt, J = 9.0, 1.2 Hz,
1H), 8.07 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.66
(t, J = 7.8 Hz, 1H), 7.50 (ddd, J = 8.9, 6.9, 1.1 Hz, 1H), 7.14 (td, J = 7.0, 1.3 Hz, 1H),
4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ = 183.7, 163.8, 140.6, 140.2, 132.0 (q, J = 5 Hz), 130.1 (q, J = 23 Hz), 129.2, 129.0,
128.9, 128.1, 127.9 (q, J = 4 Hz), 125.7 (q, J = 4 Hz), 123.6 (q, J = 271 Hz), 122.0,
119.6, 115.6, 106.9, 60.2, 14.4. MS (EI) m/z: 361, 333, 289, 261, 188, 173, 145, 115,
89, 78, 51. HRMS (m/z) (ESI-ion trap): calcd. for C19H15F3NO3 [M+H]+ 362.0999;
found 362.0990.
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ethyl 3-(4-acetylbenzoyl)indolizine-1-carboxylate (3r):14b yellow solid (57 mg,
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85%); mp: 138-140 C; Rf = 0.38 (ethyl acetate / petroleum ether = 1:5); H NMR
(400 MHz, CDCl3): δ = 9.98 (d, J = 7.0 Hz, 1H), 8.41 (dd, J = 8.9, 1.1 Hz, 1H), 8.11 –
8.07 (m, 2H), 7.89 – 7.86 (m, 2H), 7.76 (s, 1H), 7.48 (ddd, J = 8.9, 6.9, 1.1 Hz, 1H),
7.12 (td, J = 7.0, 1.3 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.67 (s, 3H), 1.39 (t, J = 7.1
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Hz, 3H). C{1H} NMR (100 MHz, CDCl3): δ = 197.5, 184.3, 163.8, 143.7, 140.1,
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138.9, 129.2, 129.1, 129.0, 128.2, 128.1, 122.2, 119.5, 115.6, 106.7, 60.1, 26.8, 14.4.
MS (EI) m/z: 335, 307, 290, 263, 235, 220, 188, 160, 147, 119, 91, 77, 43.
ethyl 3-(4-(methoxycarbonyl)benzoyl)indolizine-1-carboxylate (3s):14b yellow
solid (55 mg, 79%); mp: 119-121 oC; Rf = 0.41 (ethyl acetate / petroleum ether = 1:5);
1H NMR (400 MHz, CDCl3): δ = 9.97 (d, J = 7.0 Hz, 1H), 8.42 – 8.38 (m, 1H), 8.19 –
8.15 (m, 2H), 7.86 – 7.83 (m, 2H), 7.75 (s, 1H), 7.48 (ddd, J = 8.9, 6.9, 1.1 Hz, 1H),
7.12 (td, J = 7.0, 1.3 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 1.38 (t, J = 7.1
Hz, 3H). C{1H} NMR (100 MHz, CDCl3): δ = 184.4, 166.3, 163.8, 143.7, 140.1,
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132.4, 129.5, 129.2, 129.1, 128.7, 128.0, 122.2, 119.5, 115.5, 106.7, 60.1, 52.3, 14.4.
ethyl 3-(4-cyanobenzoyl)indolizine-1-carboxylate (3t):14b yellow solid (36 mg,
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56%); mp: 135-137 C; Rf = 0.34 (ethyl acetate / petroleum ether = 1:5); H NMR
(400 MHz, CDCl3): δ = 9.97 (d, J = 7.0 Hz, 1H), 8.43 (d, J = 8.9 Hz, 1H), 7.91 – 7.87
(m, 2H), 7.85 – 7.80 (m, 2H), 7.73 (s, 1H), 7.55 – 7.50 (m, 1H), 7.16 (td, J = 7.0, 1.3
Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ = 183.2, 163.7, 143.7, 140.3, 132.3, 129.3, 129.1, 128.5, 121.9, 119.7,
118.1, 115.9, 114.9, 107.1, 60.3, 14.5. MS (EI) m/z: 318, 290, 273, 246, 218, 188, 160,
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ethyl 3-(4-nitrobenzoyl)indolizine-1-carboxylate (3u):13b yellow solid (45 mg,
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67%); mp: 138-140 C; Rf = 0.41 (ethyl acetate / petroleum ether = 1:5); H NMR
(400 MHz, CDCl3): δ = 9.98 (d, J = 7.0 Hz, 1H), 8.43 (d, J = 8.9 Hz, 1H), 8.39 – 8.35
(m, 2H), 7.97 – 7.93 (m, 2H), 7.73 (s, 1H), 7.53 (ddd, J = 8.8, 6.9, 1.0 Hz, 1H), 7.17
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(td, J = 7.0, 1.3 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). C{1H}
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NMR (100 MHz, CDCl3): δ = 182.8, 163.66, 149.4, 145.3, 140.3, 129.7, 129.3, 129.1,
128.5, 123.6, 121.8, 119.7, 115.9, 107.2, 60.3, 14.4.
ethyl 3-hexanoylindolizine-1-carboxylate (3v):14c yellow solid (29 mg, 51%); mp:
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82-84 C; Rf = 0.53 (ethyl acetate / petroleum ether = 1:5); H NMR (400 MHz,
CDCl3): δ = 9.94 (d, J = 7.1 Hz, 1H), 8.35 (d, J = 9.0 Hz, 1H), 8.01 (s, 1H), 7.41 –
7.37 (m, 1H), 7.02 (td, J = 7.0, 1.3 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.94 – 2.89 (m,
2H), 1.82 – 1.75 (m, 2H), 1.45 (d, J = 7.1 Hz, 3H), 1.41 – 1.36 (m, 4H), 0.91 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 191.1, 164.1, 139.3, 129.1, 127.0,
125.5, 122.7, 119.4, 115.0, 105.6, 60.0, 39.4, 31.6, 25.2, 22.5, 14.5, 13.9. MS (EI) m/z:
256, 243, 214, 198, 141, 130, 104, 78, 41.
ethyl 3-formylindolizine-1-carboxylate (3w):14a yellow solid (16 mg, 38%); Rf =
0.60 (ethyl acetate / petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3): δ = 9.76 (s,
1H), 9.72 (d, J = 6.9 Hz, 1H), 8.37 (d, J = 9.0 Hz, 1H), 7.93 (s, 1H), 7.49 – 7.44 (m,
1H), 7.07 (td, J = 6.9, 1.2 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ = 178.5, 163.7, 140.0, 129.4, 128.8, 128.3,
123.8, 119.6, 115.5, 107.4, 60.1, 14.5. MS (EI) m/z: 272, 244, 230, 201, 186, 170, 106,
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ethyl 3-((trimethylsilyl)carbonyl)indolizine-1-carboxylate (3x): liquid (18 mg,
32%); Rf = 0.60 (ethyl acetate / petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3):
δ = 8.57 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.65 (td, J = 7.8, 1.8 Hz, 1H), 7.44 – 7.41 (m,
1H), 7.21 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 6.91 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 1.40
(t, J = 7.1 Hz, 3H), 0.22 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ = 166.8, 152.1,
149.5, 143.5, 136.6, 123.3, 121.5, 115.2, 106.6, 101.1, 61.4, 14.1, 0.3. MS (EI) m/z:
217, 189, 172, 145, 116, 89, 63, 39. Anal. Calcd for C15H19NO3Si: C, 62.25; H, 6.62;
N, 4.84; Found: C, 61.97; H, 6.75; N, 4.96.
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methyl 3-benzoylindolizine-1-carboxylate (4a):22 yellow solid (51 mg, 91%); mp:
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153-155 C; Rf = 0.52 (ethyl acetate / petroleum ether = 1:5); H NMR (400 MHz,
CDCl3): δ = 9.96 (dt, J = 7.0, 1.0 Hz, 1H), 8.38 (dt, J = 9.0, 1.1 Hz, 1H), 7.82 – 7.79
(m, 3H), 7.59 – 7.54 (m, 1H), 7.52 – 7.48 (m, 2H), 7.44 (ddd, J = 8.9, 6.9, 1.1 Hz,
1H), 7.08 (td, J = 7.0, 1.3 Hz, 1H), 3.89 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
= 185.5, 164.3, 139.8, 139.8, 131.4, 129.1, 128.9, 128.8, 128.3, 127.7, 122.5, 119.3,
115.2, 105.8, 51.2. MS (EI) m/z: 279, 248, 220, 202, 193, 174, 144, 116, 105, 77, 51.
tert-butyl 3-benzoylindolizine-1-carboxylate (4b):13b yellow solid (53 mg, 82%);
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mp: 125-126 C; Rf = 0.63 (ethyl acetate / petroleum ether = 1:5); H NMR (400
MHz, CDCl3): δ = 9.97 (dt, J = 7.1, 1.0 Hz, 1H), 8.34 (dt, J = 9.0, 1.2 Hz, 1H), 7.83 –
7.80 (m, 2H), 7.78 (s, 1H), 7.57 (ddd, J = 6.4, 3.8, 1.4 Hz, 1H), 7.53 – 7.48 (m, 2H),
7.42 (ddd, J = 8.9, 6.9, 1.1 Hz, 1H), 7.07 (td, J = 7.0, 1.4 Hz, 1H), 1.62 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3): δ = 185.5, 163.5, 139.9, 139.5, 131.3, 129.2,
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265, 248, 220, 188, 160, 105, 77, 41.
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9.97 (d, J = 7.1 Hz, 1H), 8.34 (d, J = 9.0 Hz, 1H), 7.83 – 7.77 (m, 3H), 7.60 – 7.54 (m,
1H), 7.52 – 7.47 (m, 2H), 7.45 – 7.39 (m, 1H), 7.06 (td, J = 7.0, 1.2 Hz, 1H), 1.95 (q,
J = 7.5 Hz, 2H), 1.58 (s, 6H), 0.95 (t, J = 7.5 Hz, 3H). C{1H} NMR (100 MHz,
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CDCl3): δ = 185.4, 163.4, 139.9, 139.5, 131.3, 129.2, 129.1, 128.9, 128.2, 127.3,
122.2, 119.4, 115.0, 107.9, 83.1, 33.5, 25.9, 8.3. MS (EI) m/z: 335, 265, 248, 220,
188, 160, 144, 115, 105, 77, 43. Anal. Calcd for C21H21NO3: C, 75.20; H, 6.31; N,
4.18; Found: C, 74.95; H, 6.40; N, 4.27.
2,2,2-trifluoroethyl 3-benzoylindolizine-1-carboxylate (4d): yellow solid (62 mg,
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89%); mp: 130-132 C; Rf = 0.54 (ethyl acetate / petroleum ether = 1:5); H NMR
(400 MHz, CDCl3): δ = 9.98 (dt, J = 7.1, 1.1 Hz, 1H), 8.34 (dt, J = 9.0, 1.2 Hz, 1H),
7.87 – 7.80 (m, 3H), 7.62 – 7.57 (m, 1H), 7.55 – 7.48 (m, 3H), 7.13 (td, J = 7.0, 1.3
Hz, 1H), 4.71 (q, J = 8.5 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ = 185.6, 161.9,
140.1, 139.5, 131.7, 129.4, 129.1, 128.9, 128.4, 127.4, 123.2 (q, J = 276 Hz), 119.2,
115.6, 103.7, 59.8 (q, J = 36 Hz). HRMS (m/z) (ESI-ion trap): calcd. for
C18H13F3NO3 [M+H]+ 348.0842; found 348.0830.
furan-3-ylmethyl 3-benzoylindolizine-1-carboxylate (4e): yellow liquid (43 mg,
62%); Rf = 0.38 (ethyl acetate / petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3):
δ = 9.97 (d, J = 7.0 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 7.81 (dd, J = 9.0, 1.9 Hz, 3H),
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7.61 – 7.41 (m, 6H), 7.10 (dd, J = 6.9, 5.8 Hz, 1H), 6.51 (s, 1H), 5.24 (s, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ = 185.6, 163.8, 143.4, 141.6, 139.9, 139.7, 131.5, 129.2,
129.0, 128.9, 128.4, 127.8, 122.6, 120.8, 119.4, 115.3, 110.7, 105.7, 57.3. MS (EI)
m/z: 345, 248, 220, 191, 144, 105, 81, 77, 53. Anal. Calcd for C21H15NO4: C, 73.03;
H, 4.38; N, 4.06; Found: C, 72.81; H, 4.49; N, 4.13.
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allyl 3-benzoylindolizine-1-carboxylate (4f): yellow solid (51 mg, 83%); mp:
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98-100 C; Rf = 0.54 (ethyl acetate / petroleum ether = 1:5); H NMR (400 MHz,
CDCl3): δ = 9.97 (d, J = 7.1 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 7.85 – 7.79 (m, 3H),
7.60 – 7.55 (m, 1H), 7.54 – 7.49 (m, 2H), 7.46 (dd, J = 8.4, 7.4 Hz, 1H), 7.12 – 7.07
(m, 1H), 6.05 (ddt, J = 17.1, 10.5, 5.7 Hz, 1H), 5.39 (dq, J = 17.2, 1.5 Hz, 1H), 5.27
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(ddd, J = 10.4, 2.5, 1.2 Hz, 1H), 4.83 (dt, J = 5.7, 1.4 Hz, 2H). C{1H} NMR (100
MHz, CDCl3): δ = 185.5, 163.6, 139.9, 139.8, 132.6, 131.4, 129.2, 129.0, 128.9,
128.3, 127.7, 122.5, 119.4, 118.1, 115.3, 105.8, 64.7. HRMS(m/z) (ESI-ion trap):
calcd. for C19H16NO3 [M+H]+ 306.1125; found 306.1116.
hept-1-en-3-yl 3-benzoylindolizine-1-carboxylate (4g): yellow liquid (59 mg,
82%); Rf = 0.64 (ethyl acetate / petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3):
δ = 9.98 (dt, J = 7.0, 1.0 Hz, 1H), 8.41 (dt, J = 9.0, 1.1 Hz, 1H), 7.85 – 7.80 (m, 3H),
7.61 – 7.56 (m, 1H), 7.54 – 7.49 (m, 2H), 7.46 (ddd, J = 8.9, 6.9, 1.1 Hz, 1H), 7.10
(td, J = 7.0, 1.3 Hz, 1H), 5.91 (ddd, J = 17.0, 10.5, 6.3 Hz, 1H), 5.52 (dd, J = 13.4, 6.2
Hz, 1H), 5.32 (dt, J = 17.2, 1.3 Hz, 1H), 5.20 (dt, J = 10.5, 1.2 Hz, 1H), 1.84 – 1.67
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(m, 2H), 1.42 – 1.33 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H). C{1H} NMR (100 MHz,
CDCl3): δ = 185.5, 163.4, 139.9, 139.9, 137.0, 131.4, 129.2, 129.0, 128.9, 128.3,
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127.6, 122.5, 119.5, 116.4, 115.2, 106.3, 74.5, 34.1, 27.3, 22.4, 13.9. MS (EI) m/z:
361, 265, 248, 220, 188, 160, 105, 77, 41. Anal. Calcd for C23H23NO3: C, 76.43; H,
6.41; N, 3.88; Found: C, 76.20; H, 6.48; N, 3.95.
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cyclohex-3-en-1-ylmethyl 3-benzoylindolizine-1-carboxylate (4h): yellow liquid
(57 mg, 80%); Rf = 0.59 (ethyl acetate / petroleum ether = 1:5); 1H NMR (400 MHz,
CDCl3): δ = 9.98 (dt, J = 7.0, 1.0 Hz, 1H), 8.38 (dt, J = 8.9, 1.2 Hz, 1H), 7.86 – 7.80
(m, 3H), 7.62 – 7.56 (m, 1H), 7.56 – 7.50 (m, 2H), 7.46 (ddd, J = 8.9, 6.9, 1.1 Hz,
1H), 7.10 (td, J = 7.0, 1.3 Hz, 1H), 5.76 – 5.64 (m, 2H), 4.24 (d, J = 6.3 Hz, 2H), 2.20
(dd, J = 16.9, 3.6 Hz, 1H), 2.12 (ddd, J = 8.0, 6.0, 3.9 Hz, 3H), 1.90 – 1.82 (m, 2H),
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1.44 – 1.34 (m, 1H). C{1H} NMR (100 MHz, CDCl3): δ = 185.5, 164.1, 139.8,
139.8, 131.4, 129.2, 128.9, 128.3, 127.7, 127.0, 125.5, 122.5, 119.4, 115.2, 106.2,
68.4, 33.3, 28.4, 25.4, 24.4. MS (EI) m/z: 359, 265, 248, 220, 188, 105, 77, 41. Anal.
Calcd for C23H21NO3: C, 76.86; H, 5.89; N, 3.90; Found: C, 76.58; H, 5.96; N, 3.82.
but-3-yn-1-yl 3-benzoylindolizine-1-carboxylate (4i):18 yellow solid (53 mg,
84%); Rf = 0.46 (ethyl acetate / petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3):
δ = 9.98 (d, J = 7.1 Hz, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.82 (dd, J = 11.3, 4.3 Hz, 3H),
7.58 (ddd, J = 6.4, 3.7, 1.3 Hz, 1H), 7.55 – 7.44 (m, 3H), 7.11 (td, J = 7.0, 1.2 Hz,
1H), 4.44 (t, J = 6.8 Hz, 2H), 2.68 (td, J = 6.8, 2.7 Hz, 2H), 2.03 (t, J = 2.6 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ = 185.6, 163.6, 139.8, 139.7, 131.5, 129.2,
129.1, 128.96, 128.3, 127.8, 122.6, 119.5, 115.3, 105.6, 80.2, 69.9, 61.8, 19.2. MS
(EI) m/z: 317, 265, 248, 220, 188, 168, 144, 115, 105, 77, 51.
hex-3-yn-1-yl 3-benzoylindolizine-1-carboxylate (4j): yellow liquid (55 mg,
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80%); Rf = 0.56 (ethyl acetate / petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3):
δ = 9.96 (d, J = 7.0 Hz, 1H), 8.42 (d, J = 8.9 Hz, 1H), 7.84 – 7.78 (m, 3H), 7.59 – 7.54
(m, 1H), 7.52 – 7.47 (m, 2H), 7.44 (ddd, J = 8.8, 6.9, 1.0 Hz, 1H), 7.08 (td, J = 7.0,
1.2 Hz, 1H), 4.38 (t, J = 6.9 Hz, 2H), 2.61 (tt, J = 6.9, 2.3 Hz, 2H), 2.18 – 2.12 (m,
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2H), 1.09 (t, J = 7.5 Hz, 3H). C{1H} NMR (100 MHz, CDCl3): δ = 185.5, 163.6,
139.8, 139.7, 131.4, 129.1, 129.1, 128.8, 128.3, 127.6, 122.5, 119.5, 115.2, 105.9,
83.4, 75.1, 62.4, 19.4, 14.0, 12.3. HRMS (m/z) (ESI-ion trap): calcd. For C22H20NO3
[M+H]+ 346.1438; found 346.1429.
pent-4-yn-1-yl 3-benzoylindolizine-1-carboxylate (4k): yellow liquid (56 mg,
85%); Rf = 0.50 (ethyl acetate / petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3):
δ = 9.97 (d, J = 7.1 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 7.81 (dd, J = 5.3, 3.2 Hz, 3H),
7.61 – 7.56 (m, 1H), 7.54 – 7.49 (m, 2H), 7.48 – 7.43 (m, 1H), 7.10 (td, J = 7.0, 1.2
Hz, 1H), 4.43 (t, J = 6.3 Hz, 2H), 2.36 (td, J = 7.0, 2.6 Hz, 2H), 2.01 (dd, J = 13.3, 6.7
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Hz, 2H), 1.96 (t, J = 2.7 Hz, 1H). C{1H} NMR (100 MHz, CDCl3): δ = 185.5,
163.9, 139.8, 139.8, 131.4, 129.2, 128.9, 128.9, 128.3, 127.7, 122.5, 119.4, 115.3,
105.9, 83.1, 69.0, 62.7, 27.8, 15.4. MS (EI) m/z: 331, 289, 265, 248, 220, 188, 160,
144, 115, 105, 77, 39. Anal. Calcd for C21H17NO3: C, 76.12; H, 5.17; N, 4.23; Found:
C, 75.93; H, 5.23; N, 4.35.
but-3-yn-2-yl 3-benzoylindolizine-1-carboxylate (4l): yellow liquid (49 mg,
78%); Rf = 0.49 (ethyl acetate / petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3):
δ = 9.97 (d, J = 7.1 Hz, 1H), 8.42 (d, J = 8.9 Hz, 1H), 7.85 – 7.79 (m, 3H), 7.62 – 7.56
(m, 1H), 7.55 – 7.45 (m, 3H), 7.11 (td, J = 7.0, 1.3 Hz, 1H), 5.71 (qd, J = 6.7, 2.1 Hz,
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1H), 2.49 (d, J = 2.1 Hz, 1H), 1.64 (d, J = 6.7 Hz, 3H). C{1H} NMR (100 MHz,
CDCl3): δ = 185.6, 162.7, 140.0, 139.7, 131.5, 129.2, 129.0, 128.9, 128.4, 127.9,
122.6, 119.5, 115.4, 105.3, 82.5, 72.8, 59.6, 21.4. MS (EI) m/z: 317, 265, 248, 220,
188, 160, 144, 115, 105, 77, 51. Anal. Calcd for C20H15NO3: C, 75.70; H, 4.76; N,
4.41; Found: C, 75.43; H, 4.85; N, 4.52.
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2-methylbut-3-yn-2-yl 3-benzoylindolizine-1-carboxylate (4m): yellow solid (48
mg, 73%); mp: 111-113 oC; Rf = 0.52 (ethyl acetate / petroleum ether = 1:5); 1H NMR
(400 MHz, CDCl3): δ = 9.97 (dt, J = 7.1, 1.1 Hz, 1H), 8.40 (dt, J = 9.0, 1.2 Hz, 1H),
7.84 – 7.77 (m, 3H), 7.61 – 7.55 (m, 1H), 7.54 – 7.49 (m, 2H), 7.45 (ddd, J = 8.9, 6.9,
1.1 Hz, 1H), 7.10 (td, J = 7.0, 1.4 Hz, 1H), 2.60 (s, 1H), 1.83 (s, 6H). 13C{1H} NMR
(100 MHz, CDCl3): δ = 185.5, 162.4, 139.9, 139.9, 131.4, 129.2, 129.1, 128.9, 128.3,
127.7, 122.5, 119.5, 115.3, 106.5, 85.1, 72.3, 71.7, 29.3. Anal. Calcd for C21H17NO3:
C, 76.12; H, 5.17; N, 4.23; Found: C, 75.86; H, 5.25; N, 4.34.
methyl 3-hexanoylindolizine-1-carboxylate (4n): yellow solid (25 mg, 47%); Rf
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(d, J = 7.1 Hz, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.02 (s, 1H), 7.44 – 7.37 (m, 1H), 7.03
(td, J = 7.0, 1.3 Hz, 1H), 3.93 (s, 3H), 2.94 – 2.88 (m, 2H), 1.82 – 1.74 (m, 2H), 1.42
– 1.35 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ = 191.1,
164.5, 139.3, 129.1, 127.1, 125.5, 122.7, 119.3, 115.1, 105.2, 51.2, 39.4, 31.6, 25.2,
22.5, 13.9. MS (EI) m/z: 273, 242, 230, 27, 214, 220, 198, 188, 175, 144, 116, 89, 77,
41. Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12; Found: C, 70.05; H, 7.13;
N, 5.24.
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