Methylenecyclopropane Ring Formation/Opening Cascade for the Synthesis of Indolizines

Article abstract of DOI:10.1021/acs.joc.7b01073

A unique strategy toward the synthesis of polysubstituted indolizines has been developed. When 2-pyridinyl-2-(2′-bromoallyl)-1-carboxylates were treated with Cs₂CO₃, the starting material went through a methylenecyclopropane ring formation/opening cascade, and the corresponding indolizines were obtained in moderate to good yield as a single regioisomer.

Full text of DOI:10.1021/acs.joc.7b01073

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Note
A Methylenecyclopropane Ring Formation/
Opening Cascade for the Synthesis of Indolizines
Congjun Zhu, Peng Zhao, Yan Qiao, Ke Xiao, Chuanjun Song, and Junbiao Chang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 01 Jun 2017
Downloaded from http://pubs.acs.org on June 1, 2017
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A Methylenecyclopropane Ring Formation/Opening Cascade for the Synthesis of Indolizines
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Congjun Zhu,a Peng Zhao,b Yan Qiao,c Ke Xiao,a Chuanjun Song,*a and Junbiao Chang*a,d
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a College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, P. R. of
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China
b Department of Chemistry, University of California, 1102 Natural Sciences II, Irvine, California 92697ꢀ
2025, United States
c
Pathophysiology Department, Basic Medical College of Zhengzhou University, 100 Science Avenue,
Zhengzhou 450001, P. R. of China
d
Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, 100
Science Avenue, 450001, P. R. of China
chjsong@zzu.edu.cn (C.S.); changjunbiao@zzu.edu.cn (J.C.)
Abstract: A unique strategy towards the synthesis of polysubstituted indolizines has been developed.
Treating 2ꢀpyridinylꢀ2ꢀ(2′ꢀbromoallyl)ꢀ1ꢀcarboxylates with Cs2CO3, the starting material went through a
methylenecyclopropane ring formation/opening cascade and the corresponding indolizines were obtained in
moderate to good yield as a single regioisomer.
N
ꢀfused heterocycles are one of the abundantly applicable motif in organic chemistry and they are
widely applied in medicinal and material chemistry. Countless pharmaceutical intermediates, dyes
and highꢀperformance materials are prepared.1 Among all the nitrogenꢀcontaining heterocycles,
indolizines are one important subclass due to their signigficant biological activities. Various
enzyme inhibitor, antimicrobial and anticancer agents are developed (Figure 1).2 Indolizines have
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received great attention from synthetic community and versatile strategies and methods have been
developed to access the scaffold and its derivatives.3 Most of the approaches towards indolizines
can be categorized into
4
type of reactions: cyclocondensations,4 cycloadditions,5
cyclization/elimination6 and cycloisomerizations.7 These methods, however, would require either
harsh reaction conditions or transition metals and ligands. We believe that there is still unexplored
territories in indolizines synthesis and a novel and environmentalꢀfriendly methodology is regarded
as a necessity.
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Figure 1. Representative biologically active indolizine derivatives.
Previously, we developed a novel strategy toward the synthesis of furanꢀ3ꢀcarboxylates from 3ꢀ
substituted 2ꢀ(2′ꢀbromoallyl)ꢀ3ꢀoxoꢀ1ꢀcarboxylate (Scheme 1).8 The reaction went through an
allenic intermediate and methylenecyclopropane ring formation/opening sequence. We further
envisioned that substrates bearing a pyridinyl functionality, in place of the carbonyl group, could be
used to achieve similar transformation to access indolizines by utilizing the nucleophilic character
of the nitrogen atom. To the best of our knowledge, this is the first example of preparing
polysubstituted indolizines from 2ꢀpyridinylꢀ2ꢀ(2′ꢀbromoallyl)ꢀ1ꢀcarboxylates.
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previous work
O
R2
CO2Et
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R1
Br
O
base
R1
CO2Et
R2
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present work
R1
CO2Et
R1
CO2Et
base
N
Br
N
R2
R2
Scheme 1. Previous and current work comparison.
To optimize the reaction conditions, pyridine derivative 1a was tested under various conditions
(Table 1). Starting with the optimized conditions from our previous research,8a the reaction went
smoothly and 77% yield of 2a was obtained in the presence of 2 equivalents of Cs2CO3 and DMF
as solvent (entry 1). The spectroscopic data displayed by 2a were identical to those reported in the
literature.4c Extensive base screening showed that Cs2CO3 remained the best choice (entries 2ꢀ9)
and only K3PO4 gave comparable yield (entry 3), while no reaction occurred in the absence of base
(entry 10) Polar aprotic solvents as DMF and DMSO (entry 11) were preferred in this
transformation. No reactions were detected when halogenated solvents (entries 12ꢀ14) and toluene
(entry 17) were used as solvents. Other polar solvents like dioxane (entry 15), MeCN (entry 16) and
NMP (entry 18) didn’t lead to any acceptable yield probably because these are not ideal at solvate
the cesium cation. The amount of base required for this reaction was also examined (entries 1, 19ꢀ
21) and 2 equivalents of Cs2CO3 was found to give the highest yield. It was interesting to realize
that the methylenecyclopropane intermediate
3 could be isolated when the reaction was run at
o
o
lower temperature: 50% and 45% yield of intermediate
respectively (entries 22, 23). The isolated intermediate
3
were isolated at 60 C and 70 C,
3
is not stable while neat and it will
transform into indolizine 2a spontaneously at room temperature for overnight. Heating
3 could
accelerate the conversion rate to 2a. Isolation of the methylenecyclopropane intermediate
3
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supports our hypothesis of the reaction mechanism. Although elevated temperature favored the
o
formation of 2a, no improvement was observed at a temperature higher than 80 C (entries 24, 25
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8
vs 1).
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Table 1. Reaction of ethyl 4ꢀbromoꢀ2ꢀ(pyridinꢀ2ꢀyl)pentꢀ4ꢀenoate under various conditions.
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Entry
1
2
Base
Cs2CO3
NaH
K3PO4
CaOAc
NaHCO3
K2CO3
DIPEA
DBU
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DCM
DCE
CHCl3
dioxane
MeCN
toluene
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Temp. (oC)
80
2a Yield (%)a
3
Yield (%)a
77
13
72
20
ꢀ
4
ꢀ
ꢀ
ꢀ
ꢀ
71
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
50
45
ꢀ
80
80
80
80
80
80
80
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80
80
60
70
90
100
3
4
5b
6
7b
8b
9b
NMM
10b
11
12b
13b
14b
15b
16
17b
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20
21
22
23
24
25
ꢀ
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
ꢀ
trace
ꢀ
47
42
59
65
25
20
75
72
c
Cs2CO3d
Cs2CO3e
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
ꢀ
a Isolated yield. b No reaction. c 1.0 equiv. d 1.5 equiv. e 2.5 equiv.
The substrate scope was further explored and the results were collected in table 2. Reactions of
substrates with either an electronꢀdonating or electronꢀwithdrawing group substituted pyridine ring
proceeded smoothly to afford the desired product in moderate yield (2b
ꢀ
d
). When pyridines were
2f). This
replaced by more πꢀelectron delocalized quinolines, no reactivity drop was observed (2e
,
transformation was also compatible with various electronꢀwithdrawing groups other than esters on
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the benzylic position: methylketone, benzophenone and cyanide derivatives delivered the
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corresponding cycloadduct eventlessly (2g
disfavored 5ꢀmethyl (2j) and 5ꢀphenyl (2k) substituted alkenes, as well as strained cyclic alkene
2l), could all participate the reaction successfully. It should be noted that only 1,2ꢀdisubstituted
ꢀi). In regards to acceptors scope, the sterically
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(
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indolizines were isolated and no other isomers (i.e., 1,3ꢀdisubstituted derivatives or the
corresponding furan derivatives resulting from nucleophilic attack of the methylenecyclopropane
ring with the carbonyl oxygen atom) were observed. Increasing the bulkiness around the alkenes
(2jꢀ2l) didn’t alter the regiochemical outcome, which indicated that the indolizine formation is
highly regioselective.
Table 2. Substrate scope.
R1
R3
R3
R1
Cs2CO3
N
Br
DMF, 80 oC
N
R2
R2
1
2
CO2Et
CO2Et
CO2Et
CO2Et
N
N
N
N
O2N
Br
2a, 77%
CO2Et
2b, 46%
CO2Et
2c, 45%
2d, 30%
O
O
N
N
N
N
2g, 50%
2h, 43%
2f, 41%
2e, 60%
CN
O
O
O
N
N
N
N
2i, 48%
2j, 50%
2k, 46%
2l, 67%
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The limits of the substrates scope were revealed as we were testing the edge of this methodology.
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First, for substrates with
methylenecyclopropanes and
pyridine ring wouldn’t be the reason why no nucleophilic ring opening proceeds. Both electronꢀrich
and electronꢀpoor pyridines have been demonstrated to deliver the indolizine products (2b 2d). It is
a
3ꢀsubstituted pyridine ring, no indolizines but the
4
5 were isolated (Scheme 2, eq. 1). The electrostatic nature of the
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ꢀ
possible that the substitutions on the pyridine ring distort the conformation of the
methylenecyclopropane intermediate and makes the lone pair on nitrogen stay away from the
Bürgi–Dunitz angle of the cyclopropane ring. Calculations were conducted on the transition state of
the nucleophilic ring opening step and the high energy profiles obtained supported our rationale.
Second, reaction of the highly sterically hindered substrate 1o proceeded slowly while cleanly to
provide fused furan
6 instead of the desired indolizine (Scheme 2, eq. 2). The flanking phenyl
group may block the nucleophilic pyridine thus facilitate Oꢀattack over Nꢀattack.
Scheme 2. Substrate limitations.
Finally, we tested the possibility of indolizine formation of compound 1p (Scheme 3). However,
only alkyne was isolated. This result implied that an electronꢀwithdrawing group at the benzylic
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position of the pyridine ring (thus facilitating methylenecyclopropane ring formation) is essential to
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the reaction. More importantly, this evidence indicated that direct addition/elimination sequence
from nitrogen to vinyl bromide is not the preferred pathway.
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Scheme 3. Control experiment for determining reaction mechanism.
Based on the results above and our previous research outcome, a plausible mechanism involving
cyclopropane ring formation and nucleophilic cyclopropane ring opening was proposed in scheme
4. Enolization and elimination of HBr in the presence of base afforded intermediate
subsequent intramolecular enolate attack provided methylenecyclopropane . Pyridine nucleophilic
addition opened the cyclopropane ring from the less sterically hindered side to give II, which
underwent tautomerization to produce indolizine 2a
I and
3
.
Scheme 4. Proposed mechanism.
In summary, we have developed a novel Cs2CO3ꢀmediated protocol towards the synthesis of
indolizines. The reaction mechanism was believed to proceed via a methylenecyclopropane ring
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formation/opening sequence. This approach is environmentalꢀfriendly with a broad spectrum of
substrate scope.
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Experimental section
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Solvents were dried according to standard procedures9 where needed. Melting points were
determined on a hotꢀstage apparatus and were uncorrected. Infrared spectra were obtained using an
1
FTꢀIR spectrometer. H and 13C NMR spectra were obtained on a 400 MHz spectrometer. Mass
spectra were recorded on a QꢀTOF micro spectrometer. Flash column chromatography was
performed over silica gel 200‒300 mesh.
General procedure for the preparation of 2a-l, 4, 5, 6, 7. A sealed tube was charged with 1a-1p
(1.0 mmol), Cs2CO3 (2.0 mmol) and DMF (10 mL). The reaction system was recharged with
o
nitrogen for three times. The reaction mixture was allowed to stir at 80 C until completion of
reaction according to TLC. The cooled mixture was diluted with water (2 mL) and extracted with
ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine (3 x 10 mL), and
then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was
purified by silica gel column chromatography (petroleum ether/EtOAc) to afford the products.
Ethyl 2-methylindolizine-1-carboxylate (2a).
4c The title compound was prepared according to the
general procedure by stirring a mixture of ethyl 4ꢀbromoꢀ2ꢀ(pyridinꢀ2ꢀyl)pentꢀ4ꢀenoate 1a (56.6 mg,
0.2 mmol), Cs2CO3 (133.0 mg , 0.4 mmol) and DMF (2.0 mL) at 80 oC for 10 h. The crude product
was purified by silica gel column chromatography (10% EtOAc in petroleum ether) to afford 2a
1
(31.5 mg, 77% yield) as a colorless oil; H NMR (400 MHz, CDCl3):
δ
8.12 (1H, d,
J = 9.0 Hz),
7.87 (1H, d,
Hz), 4.36 (2H, q,
MHz, CDCl3):
J
= 6.8 Hz), 7.04 (1H, s), 6.97 (1H, ddd,
J
= 9.0, 6.7, 1.0 Hz), 6.62 (1H, td,
J
= 6.8, 1.1
J
= 7.1 Hz), 2.48 (3H, d, = 0.8 Hz), 1.41 (3H, t,
J
J
= 7.1 Hz); 13C NMR (100
δ
165.6, 136.5, 128.4, 125.2, 121.8, 119.6, 113.3, 111.9, 102.5, 59.1, 14.6, 12.9; IR
(neat): νmax/cmꢀ1 1680, 1506, 1427, 1259, 1214, 1080, 1028; HRMS (ESIꢀTOF) (m/z) [M+Na]+
calcd for C12H13NNaO2 226.0839 found 226.0848.
Ethyl 2,7-dimethylindolizine-1-carboxylate (2b).4c The title compound was prepared according to
the general procedure by stirring a mixture of ethyl 4ꢀbromoꢀ2ꢀ(4ꢀmethylpyridinꢀ2ꢀyl)pentꢀ4ꢀenoate
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1b (59.4 mg, 0.2 mmol), Cs2CO3 (133.0 mg , 0.4 mmol) and DMF (2.0 mL) at 80 C for 10 h. The
5
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crude product was purified by silica gel column chromatography (7% EtOAc in petroleum ether) to
56 oC; 1H NMR (400 MHz, CDCl3):
= 6.9, 1.5 Hz), 4.36 (2H, q,
δ
7
8
9
afford 2b (20.0 mg, 46% yield) as a pale yellow solid; mp 54
7.92 (1H, s), 7.76 (1H, d, = 6.9 Hz), 6.95 (1H, s), 6.46 (1H, dd,
7.2 Hz), 2.45 (3H, d, = 0.6 Hz), 2.34 (3H, s), 1.41 (3H, t,
CDCl3): 165.8, 137.2, 132.7, 128.1, 124.7, 118.1, 114.5, 112.5, 101.1, 59.0, 21.4, 14.7, 13.0; IR
-
J
J
J
=
10
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J
J
= 7.1 Hz); 13C NMR (100 MHz,
δ
(neat): νmax/cmꢀ1 1660, 1513, 1416, 1266, 1235, 1081, 1038; HRMS (ESIꢀTOF) (m/z) [M+H]+ calcd
for C13H16NO2 218.1176 found 218.1172.
Ethyl 5-bromo-2-methylindolizine-1-carboxylate (2c). The title compound was prepared
according to the general procedure by stirring a mixture of ethyl 4ꢀbromoꢀ2ꢀ(6ꢀbromopyridinꢀ2ꢀ
yl)pentꢀ4ꢀenoate 1c (73.0 mg, 0.2 mmol), Cs2CO3 (133.0 mg , 0.4 mmol) and DMF (2.0 mL) at 80
oC for 10 h. The crude product was purified by silica gel column chromatography (2% EtOAc in
o
1
petroleum ether) to afford 2c (25.3 mg, 45% yield) as a white soild; mp 51-53 C; H NMR (400
MHz, CDCl3):
4.38 (2H, q,
δ
8.17 (1H, d, 8.8 Hz), 7.37 (1H, s), 6.92 (1H, d,
J = 7.0 Hz), 6.85 (1H, t, J = 7.5 Hz),
J
= 7.1 Hz), 2.52 (3H, s), 1.43 (3H, t,
J
= 7.1 Hz); 13C NMR (100 MHz, CDCl3):
δ
165.4, 138.0, 128.7, 121.7, 118.4, 115.9, 114.8, 114.2, 104.7, 59.4, 14.6, 13.1; IR (neat): νmax/cmꢀ1
1680, 1482, 1433, 1274, 1249, 1202, 1085; HRMS (ESIꢀTOF) (m/z) [M+H]+ calcd for
C12H13BrNO2 282.0124, found 282.0128.
Ethyl 2-methyl-6-nitroindolizine-1-carboxylat (2d) 4c
The title compound was prepared
.
according to the general procedure by stirring a mixture of ethyl 4ꢀbromoꢀ2ꢀ(5ꢀnitropyridinꢀ2ꢀ
yl)pentꢀ4ꢀenoate 1d (65.6 mg, 0.2 mmol), Cs2CO3 (133.0 mg , 0.4 mmol) and DMF (2.0 mL) at 80
for 15 h. The crude product was purified by silica gel column chromatography (7% EtOAc in
℃
o
1
petroleum ether) to afford 2d (15.0 mg, 30% yield) as a yellow soild; mp 118
(400 MHz, CDCl3): 9.03 (1H, dd, = 1.2, 0.6 Hz), 8.20 (1H, d, = 9.9 Hz), 7.71 (1H, dd,
= 7.1Hz), 2.52 (3H, d, = 0.9 Hz), 1.43 (3H, t, = 7.1
-121 C; H NMR
δ
J
J
J =
10.0, 2.0 Hz), 7.28 (1H, s), 4.40 (2H, q,
Hz); 13C NMR (100 MHz, CDCl3):
J
J
J
δ
164.7, 136.9, 136.0, 132.4, 125.5, 119.3, 115.7, 115.1, 106.3,
59.9, 14.5, 13.1; IR (neat): νmax/cmꢀ1 1681, 1634, 1543, 1500, 1321, 1281, 1190, 1072; HRMS (ESIꢀ
TOF) (m/z) [M+H]+ calcd for C12H13N2O4 249.0870 found 249.0875.
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Ethyl 2-methylpyrrolo[1,2-a]quinoline-3-carboxylate (2e) 4c
. The title compound was prepared
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8
according to the general procedure by stirring a mixture of ethyl 4ꢀbromoꢀ2ꢀ(quinolinꢀ2ꢀyl)pentꢀ4ꢀ
enoate 1e (66.6 mg, 0.2 mmol), Cs2CO3 (133.0 mg , 0.4 mmol), and DMF (2.0 mL) at 80 oC for 6 h.
The crude product was purified by silica gel column chromatography (10% EtOAc in petroleum
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45
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49
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53
54
55
56
57
58
59
60
o
1
ether) to afford 2e (30.4 mg, 60% yield) as a white solid; mp 120
-
122 C; H NMR (400 MHz,
= 8.4 Hz), 7.69 (1H, d, = 7.5 Hz), 7.57 (1H, S),
= 9.5 Hz), 4.40 (2H, q, = 7.1 Hz),
165.7, 134.6, 132.2, 128.7,
CDCl3):
7.54 (1H, t,
2.52 (3H, s), 1.43 (3H, t,
δ
8.13 (1H, d,
J
= 9.5 Hz), 7.84 (1H, d,
J
J
J
= 8.3 Hz), 7.37 (1H, t,
J
= 7.3 Hz), 7.28 (1H, d,
J
J
J
= 7.1 Hz); 13C NMR (100 MHz, CDCl3):
δ
128.5, 126.7, 124.1, 123.7, 122.9, 118.7, 114.5, 111.8, 106.2, 59.4, 14.6, 13.1; IR (neat): νmax/cmꢀ1
1669, 1549, 1448, 1263, 1213, 1074; HRMS (ESIꢀTOF) (m/z) [M+H]+ calcd for C16H16NO2
254.1176 found 254.1183.
Ethyl 2,7-dimethylpyrrolo[1,2-a]quinoline-3-carboxylate (2f). The title compound was prepared
according to the general procedure by stirring a mixture of ethyl 4ꢀbromoꢀ2ꢀ(6ꢀmethylquinolinꢀ2ꢀ
yl)pentꢀ4ꢀenoate 1f (69.4 mg, 0.2 mmol), Cs2CO3 (133.0 mg , 0.4 mmol) and DMF (2.0 mL) at 80
oC for 10 h. The crude product was purified by silica gel column chromatography (10% EtOAc in
petroleum ether) to afford 2f (22.0 mg, 41% yield) as a white solid; mp 118ꢀ120 C; 1H NMR (400
o
MHz, CDCl3):
(1H, dd,
δ
8.13 (1H, d,
J
= 9.4 Hz), 7.78 (1H, d,
J
= 8.5 Hz), 7.59 (1H, s), 7.52 (1H, s), 7.40
= 7.1 Hz), 2.54 (3H, d, = 0.7 Hz), 2.50 (3H,
165.8, 134.5, 133.7, 130.4, 129.8,
J
= 8.5, 1.5 Hz), 7.28 (1H, s), 4.42 (2H, q,
J
J
s), 1.46 (3H, t,
J
= 7.1 Hz); 13C NMR (100 MHz, CDCl3):
δ
128.4, 126.6, 123.7, 122.8, 118.6, 114.3, 111.7, 105.9, 59.3, 21.0, 14.6, 13.1; IR (neat): νmax/cmꢀ1
1669, 1549, 1433, 1272, 1197, 1079; HRMS (ESIꢀTOF) (m/z) [M+H]+ calcd for C17H18NO2
268.1332 found 268.1332.
1-(2-Methylindolizin-1-yl)ethanone (2g) 10
The title compound was prepared according to the
.
general procedure by stirring a mixture of 5ꢀbromoꢀ3ꢀ(pyridinꢀ2ꢀyl)hexꢀ5ꢀenꢀ2ꢀone 1g (51.0 mg,
0.2 mmol), Cs2CO3 (133.0 mg , 0.4 mmol) and DMF (2.0 mL) at 80 oC for 10 h. The crude product
was purified by silica gel column chromatography (7% EtOAc in petroleum ether) to afford 2g
(17.5 mg, 50% yield) as a light yellow needle like solid; mp 69ꢀ72 oC; 1H NMR (400 MHz, CDCl3):
δ
8.31 (1H, d, J = 9.1 Hz), 7.90 (1H, d, J = 6.8 Hz), 7.09‒7.04 (2H, m), 6.70 (1H, td, J = 6.8, 1.1
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Hz), 2.55 (3H,s), 2.50 (3H, d,
J δ 193.3, 136.7, 127.0,
= 0.8 Hz); 13C NMR (100 MHz, CDCl3):
125.1, 123.4, 120.2, 114.1, 113.1, 112.7, 30.8, 14.2; IR (neat): νmax/cmꢀ1 1633, 1604, 1489, 1406,
1228, 1140, 1020; HRMS (ESIꢀTOF) (m/z) [M+H]+ calcd for C11H12NO 174.0913 found 174.0912.
(2-Methylindolizin-1-yl)(phenyl)methanone (2h) 11
The title compound was prepared according
.
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11
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13
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16
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60
to the general procedure by stirring a mixture of 4ꢀbromoꢀ1ꢀphenylꢀ2ꢀ(pyridinꢀ2ꢀyl)pentꢀ4ꢀenꢀ1ꢀone
1h (63 mg, 0.2 mmol), Cs2CO3 (133.0 mg , 0.4 mmol) and DMF (2.0 mL) at 80 oC for 10 h. The
crude product was purified by silica gel column chromatography (5% EtOAc in petroleum ether) to
afford 2h (20.0 mg, 43% yield) as a yellow oil; 1H NMR (400 MHz, CDCl3):
δ 7.91 (1H, d, J = 6.8
Hz), 7.67 (2H, t,
s), 6.88 (1H, ddd,
MHz, CDCl3):
J
= 6.9, 1.5 Hz), 7.51 (1H, ttt,
J
= 8.4, 7.4, 1.2 Hz), 7.47‒7.41 (3H, m), 7.10 (1H,
J
= 7.7, 6.7, 0.9 Hz), 6.64 (1H, td, J
= 6.8, 1.0 Hz), 2.24 (3H, s); 13C NMR (100
δ
192.1, 142.1, 137.0, 130.8, 128.5, 128.3, 128.2, 125.3, 122.4, 119.4, 114.3, 112.7,
12.9; IR (neat): νmax/cmꢀ1 1605, 1493, 1415, 1299, 1239, 1137; HRMS (ESIꢀTOF) (m/z) [M+H]+
calcd for C16H14NO 236.1070 found 236.1079.
2-Methylindolizine-1-carbonitrile (2i) 12
The title compound was prepared according to the
.
general procedure by stirring a mixture of 4ꢀbromoꢀ2ꢀ(pyridinꢀ2ꢀyl)pentꢀ4ꢀenenitrile 1i (47.2 mg,
0.2 mmol), Cs2CO3 (133.0 mg , 0.4 mmol) and DMF (2.0 mL) at 80 oC for 10 h. The crude product
was purified by silica gel column chromatography (10% EtOAc in petroleum ether) to afford 2i
o
1
(15.0 mg, 48% yield) as a white needle like solid; mp 99ꢀ101 C; H NMR (400 MHz, CDCl3):
δ
7.91 (1H, d,
J
= 6.9 Hz), 7.51 (1H, d,
J
= 9.0 Hz), 7.05 (1H, s), 7.98 (1H, ddd,
J
= 8.8, 6.7, 0.8 Hz),
6.67 (1H, td,
J
= 6.8, 0.9 Hz), 2.38 (3H, s); 13C NMR (100 MHz, CDCl3):
δ 137.7, 128.5, 125.8,
122.0, 117.2, 116.7, 112.4, 112.3, 82.8, 11.1; IR (neat): νmax/cmꢀ1 2201, 1635, 1519, 1298, 1249,
1137; HRMS (ESIꢀTOF) (m/z) [M+H]+ calcd for C10H9N2 157.0760 found 157.0761.
1-(2-Ethylindolizin-1-yl)ethanone (2j).The title compound was prepared according to the general
procedure by stirring a mixture of 5ꢀbromoꢀ3ꢀ(pyridinꢀ2ꢀyl)heptꢀ5ꢀenꢀ2ꢀone 1j (53.4 mg, 0.2 mmol),
o
Cs2CO3 (133.0 mg , 0.4 mmol) and DMF (2.0 mL) at 80 C for 20 h. The crude product was
purified by silica gel column chromatography (17% EtOAc in petroleum ether) to afford 2j (19.0
1
mg, 50% yield) as a pale yellow needle like solid; mp 87ꢀ89 oC; H NMR (400 MHz, CDCl3):
δ
8.23 (1H, d,
J = 9.1 Hz), 7.93 (1H, d, J = 6.8 Hz), 7.08‒7.04 (2H, m), 6.69 (1H, td, J = 6.8, 1.1 Hz),
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2.96 (2H, qd,
J
= 7.4, 0.6 Hz), 2.56 (3H, s), 1.32 (3H, t,
J
= 7.4 Hz); 13C NMR (100 MHz, CDCl3):
δ
193.2, 136. 8, 134.1, 125.5, 123.3, 120.1, 112.8, 112.6, 112.6, 31.0, 21.3, 14.2; IR (neat): νmax/cmꢀ
1
1881, 1760, 1680, 1540, 1375, 1270, 1108; HRMS (ESIꢀTOF) (m/z) [M+H]+ calcd for C12H14NO
9
188.1070 found 188.1070.
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59
60
1-(2-Phenylindolizin-1-yl)ethanone (2k).The title compound was prepared according to the
general procedure by stirring a mixture of 5ꢀbromoꢀ6ꢀphenylꢀ3ꢀ(pyridinꢀ2ꢀyl)hexꢀ5ꢀenꢀ2ꢀone 1k
(65.8 mg, 0.2 mmol), Cs2CO3 (133.0 mg , 0.4 mmol) and DMF (2.0 mL) at 80 oC for 16 h. The
crude product was purified by silica gel column chromatography (10% EtOAc in petroleum ether)
1
to afford 2k (23.0 mg, 46% yield) as a brown oil; H NMR (400 MHz, CDCl3):
δ
8.40 (1H, d,
= 7.0), 7.04
= 6.9, 1.2 Hz), 4.14 (2H, s), 2.43 (3H, s);
191.8, 135.7, 134.7, 127.8, 127.3, 125.9, 122. 5, 122.2, 121.9,
J =
9.0 Hz), 7.66 (1H, d,
J = 7.0 Hz), 7.25‒7.22 (2H, m), 7.19‒7.16 (1H, m), 7.10 (2H, d, J
(1H, ddd,
J = 8.9, 6.7, 0.9 Hz), 6.89 (1H, s), 6.65 (1H, td, J
13C NMR (100 MHz, CDCl3):
δ
119.8, 115.3, 112.3, 111.6, 31.4, 26.9; IR (neat): νmax/cmꢀ1 1830, 1750, 1685, 1500,1450, 1275,
1150; HRMS (ESIꢀTOF) (m/z) [M+H]+ calcd for C17H16NO 250.1226 found 250.1230.
1-(1,2,3,4-Tetrahydropyrido[1,2-a]indol-10-yl)ethanone (2l) 13
. The title compound was prepared
according to the general procedure by stirring a mixture of 1ꢀ(2ꢀbromocyclohexꢀ2ꢀenꢀ1ꢀyl)ꢀ1ꢀ
(pyridinꢀ2ꢀyl)propanꢀ2ꢀone 1l (58.6 mg, 0.2 mmol), Cs2CO3 (133.0 mg , 0.4 mmol) and DMF (2.0
mL) at 80 oC for 16 h. The crude product was purified by silica gel column chromatography (5%
EtOAc in petroleum ether) to afford 2l (28.6 mg, 67% yield) as a yellow needle like solid; mp 153ꢀ
156 oC; 1H NMR (400 MHz, CDCl3):
δ 8.36 (1H, d, J = 9.0 Hz), 7.71 (1H, d, J = 6.8 Hz), 7.07 (1H,
ddd,
J = 8.9, 6.7, 0.9 Hz), 6.76 (1H, td, J = 6.8, 1.2 Hz), 2.98 (2H, t, J = 6.1 Hz), 2.67 (2H, t, J =
6.1 Hz), 2.51 (3H, s), 1.98‒1.93 (2H, m), 1.91‒1.85 (2H, m); 13C NMR (100 MHz, CDCl3):
δ
193.0,
135.6, 125.6, 122.7, 121.9, 121.7, 120.1, 112.6, 111.6, 30.8, 25.0, 23.6, 22.2, 21.3. IR (neat):
νmax/cmꢀ1 1800, 1575, 1430, 1350, 1200, 1120, 1075; HRMS (ESIꢀTOF) (m/z) [M+H]+ calcd for
C14H16NO 214.1226 found 214.1230.
Ethyl 1-(3-bromopyridin-2-yl)-2-methylenecyclopropanecarboxylate (4). The title compound
was prepared according to the general procedure by stirring a mixture of ethyl 4ꢀbromoꢀ2ꢀ(3ꢀ
bromopyridinꢀ2ꢀyl)pentꢀ4ꢀenoate 1m (72.6 mg, 0.2 mmol), Cs2CO3 (133.0 mg , 0.4 mmol) and
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DMF (2.0 mL) at 80 C for 15 h. The crude product was purified by silica gel column
5
6
7
8
chromatography (7% EtOAc in petroleum ether) to afford (50.0 mg, 89% yield) as a pale yellow
4
liquid; 1H NMR (400 MHz, CDCl3):
δ
8.47 (1H, dd, J = 4.7, 1.4 Hz), 7.87 (1H, dd, J = 8.0, 1.5 Hz),
9
7.10 (1H, dd,
2.41 (1H, dt,
J
= 8.0, 4.7 Hz), 5.98 (1H, t,
= 9.5, 2.6 Hz), 2.23 (1H, dt,
J
= 2.9 Hz), 5.57 (1H, t,
J
= 2.3 Hz), 4.21‒4.10 (2H, m),
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51
52
53
54
55
56
57
58
59
60
J
J = 9.5, 2.6 Hz), 1.18 (3H, t, J
= 7.1 Hz); 13C NMR (100
MHz, CDCl3):
δ 170.6, 154.9, 147.3, 140.3, 133.7, 124.0, 123.7, 104.9, 61.4, 35.1, 18.8, 14.1; IR
(neat): νmax/cmꢀ1 1719, 1571, 1443, 1246, 1087, 1017; HRMS (ESIꢀTOF) (m/z) [M+H]+ calcd for
C12H13BrNO2 282.0124 found 282.0129.
Ethyl 1-(3-methoxypyridin-2-yl)-2-methylenecyclopropanecarboxylate (5). The title compound
was prepared according to the general procedure by stirring a mixture of ethyl 4ꢀbromoꢀ2ꢀ(3ꢀ
methoxypyridinꢀ2ꢀyl)pentꢀ4ꢀenoate 1n (62.6 mg, 0.2mmol), Cs2CO3 (133.0 mg , 0.4 mmol) and
o
DMF (2.0 mL) at 80 C for 48 h. The crude product was purified by silica gel column
chromatography (17% EtOAc in petroleum ether) to afford
5
(44.3 mg, 95% yield) as a pale yellow
= 8.2, 4.5 Hz),
= 2.2 Hz), 4.18‒4.05 (2H, m),
= 9.4, 2.5 Hz), 1.15 (3H, t, = 7.1 Hz);
170.5, 154.4, 145.3, 139.3, 132.9, 122.4, 116.3, 103.2, 59.9, 54.42,
1
oil; H NMR (400 MHz, CDCl3):
δ
8.11 (1H, dd,
= 8.2, 4.5 Hz), 5.75 (1H, t, = 2.8 Hz), 5.53 (1H, t,
= 9.4, 2.5 Hz), 2.18 (1H, dt,
J = 4.5, 1.6 Hz), 7.19 (1H, dd, J
7.15 (1H, dd,
J
J
J
3.86 (3H, s), 2.35 (1H, dt,
J
J
J
13C NMR (100 MHz, CDCl3):
δ
30.5, 16. 9, 13.1; IR (neat): νmax/cmꢀ1 1720, 1560, 1465, 1258, 1090, 1024; HRMS (ESIꢀTOF) (m/z
)
[M+H]+ calcd for C13H16NO3 234.1125 found 234.1141.
2-(2-Phenyl-4,5,6,7-tetrahydrobenzofuran-3-yl)pyridine (6) 14
. The title compound was prepared
according to the general procedure by stirring a mixture of 2ꢀ(2ꢀbromocyclohexꢀ2ꢀenꢀ1ꢀyl)ꢀ1ꢀ
phenylꢀ2ꢀ(pyridinꢀ2ꢀyl)ethanone 1o (71.0 mg, 0.2 mmol), Cs2CO3 (133.0 mg , 0.4 mmol) and DMF
(2.0 mL) at 80 oC for 40 h. The crude product was purified by silica gel column chromatography
(10% EtOAc in petroleum ether) to afford
recovered.
6 (44.0 mg, 40% yield) together with 35.5 mg of 1o
Compound
0.9 Hz), 7.63 (1H, td,
m), 7.24‒7.19 (2H, m), 2.72 (2H, tt,
6
: colorless solid; mp 113ꢀ115 oC; 1H NMR (400 MHz, CDCl3):
= 7.7, 1.9 Hz), 7.49‒7.47 (2H, m), 7.33 (1H, d, = 7.8 Hz), 7.30‒7.27 (2H,
= 6.2, 1.6 Hz), 2.52 (2H, tt, = 6.2, 1.6 Hz), 1.95‒1.89 (2H,
δ 8.71 (1H, dq, J = 4.9,
J
J
J
J
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m), 1.82‒1.76 (2H, m); 13C NMR (100 MHz, CDCl3):
δ
154.1, 150.7, 149.8, 148.4, 136.1, 131.3,
128.3, 127.2, 126.2, 124.5, 122.0, 121.5, 119.4, 23.3, 23.0, 22.9, 21.6; IR (neat): νmax/cmꢀ1 1850,
1720, 1557, 1500, 1430, 1280, 1095, 1035; HRMS (ESIꢀTOF) (m/z) [M+H]+ calcd for C19H18NO
276.1383 found 276.1385.
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2-(Pent-4-yn-2-yl)pyridine (7). The title compound was prepared according to the general
procedure by stirring a mixture of 2ꢀ(4ꢀbromopentꢀ4ꢀenꢀ2ꢀyl)pyridine 1p (45 mg, 0.2 mmol),
o
Cs2CO3 (133.0 mg , 0.4 mmol) and DMF (2.0 mL) at 80 C for 25 h. The crude product was
purified by silica gel column chromatography (5% EtOAc in petroleum ether) to afford
7 (12.5 mg,
42% yield) as a colorless oil; 1H NMR (400 MHz, CDCl3):
δ
8.54 (1H, d, J = 4.7 Hz), 7.60 (1H, td,
J
= 7.7, 1.7 Hz), 7.18 (1H, d, J = 7.8 Hz), 7.11 (1H, dd, J = 7.3, 5.4 Hz), 3.16‒3.07 (1H, m), 2.62
(1H, ddd,
(3H, d,
J
= 16.7, 6.6, 2.6 Hz), 2.51 (1H, ddd,
J = 16.7, 6.6, 2.6 Hz), 1.92 (1H, t, J = 5.2 Hz), 1.39
J
= 7.0 Hz); 13C NMR (100 MHz, CDCl3): δ 164.1, 149.3, 136.3, 121.8, 121.6, 83.0, 69.4,
40.9, 25.8, 19.7; IR (neat): νmax/cmꢀ1 2120, 1520, 1470, 1402, 1150, 1018; HRMS (ESIꢀTOF) (m/z
)
[M+H]+ calcd for C10H12N 146.0964 found 146.0978.
Acknowledgements
We are grateful to the NSFC (Nos. 81330075 and 21172202) for financial support.
Supporting Information. 1H and 13C NMR spectra of compounds 2a
ꢀl, 3ꢀ7.
References
1
(a) Li, J. J., Ed. Heterocyclic Chemistry in Drug Discovery, Wiley: Hoboken, NJ, 2013.; (b) Chen,
D.; Su, S.ꢀJ.; Cao, Y. J. Mater. Chem. 2014 , 9565‒9578.
Sharma, V.; Kumar, V. Med. Chem. Res. 2014 23, 3593‒3606.
For recent reviews, see: (a) Čerņaks, D. Chem. Heterocycl. Comp. 2016
Sadowski, B.; Klajn, J.; Gryko, D. T. Org. Biomol. Chem 2016, 14, 7804‒7828.
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Wang, F.; Shen, Y.; Hu, H.; Wang, X.; Wu, H.; Liu, Y. J. Org. Chem. 2014
Katrizky, A. R.; Qiu, G.; Yang, B.; He, H.ꢀY. J. Org. Chem 1999
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2015 54, 15545‒15549.; (b) Liu, R.ꢀR.; Hong, J.ꢀJ.; Lu, C.ꢀJ.; Xu, M.; Gao, J.ꢀR.; Jia, Y.ꢀX. Org.
Lett 2015 17, 3050‒3053.; (c) Xiang, L.; Yang, Y.; Zhou, X.; Liu, X.; Li, X.; Kang, X.; Yan, R.;
Huang, G. J. Org. Chem. 2014 79, 10641‒10647.
For recent examples, see: (a) Oh, K. H.; Kim, S. M.; Park, S. Y.; Park, J. K. Org. Lett. 2016
2204‒2207.; (b) Meng, X.; Liao, P.; Liu, J.; Bi, X. Chem. Commun 2014 50, 11837‒11839.; (c)
Zhang, L.; Li, X.; Liu, Y.; Zhang, D. Chem. Commun 2015 51, 6633‒6636.
(a) Chen, P.; Meng, Y.; Yang, Q.; Wu, J.; Xiao, Y.; Gorja, D. R.; Song, C.; Chang, J. RSC Adv.
2015 , 79906‒79914; (b) Chen, P.; Meng, Y.; Wang, H.; Han, F.; Wang, Y.; Song, C.; Chang, J
Org. Lett 2016 18, 3914‒3917.
Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chemicals, 5th ed.; Butterworthꢀ
Heinemann: Oxford, 2003
,
17, 5376‒5379.; (b) Brioche, J.; Meyer, C.; Cossy, J. Org. Lett
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2015
,
17, 2800‒2803. (c)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
,
79, 9556‒9566. (d)
.
, 64, 7618‒7621.
,
.
,
,
7
8
9
, 18,
.
,
.
,
,
5
.
.
,
.
10 v. Euler, H. Arkiv fore Kemi 1959, 14, 419‒428.
11 Sshida, H. Chem. Pharm. Bull. 1988, 36, 3826‒3832.
12 (a) Urban, R.; Monatsh. Chem. 1965, 96, 9ꢀ24; (b) Pauls, H. Chemische Berichte 1977, 110,
1294‒1303.
13 Barrett, P. A. J. Chem. Soc. 1958, 338‒349.
14 Tsuge, O. Heterocycles 1983, 20, 593‒596.
15
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