Transition-Metal-Free Synthesis of Indolizines from Electron-Deficient Alkenes via One-Pot Reaction Using TEMPO as an Oxidant

Article abstract of DOI:10.1055/s-0035-1560973

A one-pot method for the synthesis of multisubstituted indolizines from α-halo carbonyl compounds, pyridines, and electron-deficient alkenes is reported. The oxidative dehydrogenation reaction takes place under transition-metal-free conditions using TEMPO as an oxidant. This protocol uses ready available starting materials in a convenient procedure under mild reaction conditions.

Full text of DOI:10.1055/s-0035-1560973

SYNTHESIS
0
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8
1
1
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3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, 413–420
paper
413
F. Shi et al.
Paper
Synthesis
Transition-Metal-Free Synthesis of Indolizines from Electron-
Deficient Alkenes via One-Pot Reaction Using TEMPO as an Oxidant
Fei Shia,b
Yu Zhang*a,b
Zhaole Lub
Xiaolei Zhub
Weiqiu Kanb
Xiang Wangb
Huayou Hu*a,b
EWG2
R2
EWG1
R1
R1
TEMPO (4 equiv)
Na2CO3, DMF
R2
EWG2
EWG1
+
+
Br
N
N
R1 = benzo, Me, NMe2, CO2R; EWG1 = COAr, CO2R, 4-O2NC6H4
R2 = alkyl, aryl, CO2R; EWG2 = SO2Ph, CN, CO2R, CONMe2, CHO, COR
25 examples, 37–96%
one-pot and transtion-metal-free!
a School of Chemistry and Chemical Engineering, Ningxia
University, Yinchuan 750021, P. R. of China
b Jiangsu Key Laboratory for Chemistry of Low-Dimensional
Materials, School of Chemistry and Chemical Engineering,
Huaiyin Normal University, Huaian 223300, P. R. of China
huayouhu@hytc.edu.cn
Received: 10.09.2015
Accepted after revision: 30.10.2015
Published online: 19.11.2015
Table 1 Screened Reaction Conditions for the Synthesis of Indolizine
4a
DOI: 10.1055/s-0035-1560973; Art ID: ss-2015-h0528-op
CONMe2
O
O
Abstract A one-pot method for the synthesis of multisubstituted in-
dolizines from α-halo carbonyl compounds, pyridines, and electron-de-
ficient alkenes is reported. The oxidative dehydrogenation reaction
takes place under transition-metal-free conditions using TEMPO as an
oxidant. This protocol uses ready available starting materials in a conve-
nient procedure under mild reaction conditions.
TEMPO
N+
+
N
Ph
base, solvent
N
Br–
COPh
3aa, 0.40 mmol
4a, 0.20 mmol
5a
Entry TEMPO Base (mmol)
(mmol)
Solvent (mL)
Temp (°C), Yielda
time (h) (%)
Key words N-ylide, alkenes, 1,3-dipolar cycloaddition, tandem reac-
tion, dehydrogenation
1
2
0.60
0.60
0.60
0.60
0.60
0.60
0.60
0.50
0.30
0.60
0.60
0.60
0.60
0.60
0.80
0.80
Na2CO3 (0.60)
DMF (2.0)
DMF (2.0)
DMF (2.0)
DMF (2.0)
DMF (2.0)
DMF (2.0)
DMF (2.0)
DMF (2.0)
DMF (2.0)
DMF (1.0)
DMF (4.0)
DMF (2.0)
H2O (2.0)
90, 14 87
90, 14 28
90, 14 71
90, 14 74
90, 14 62
90, 14 80
90, 14 77
90, 14 79
90, 14 49
90, 14 70
90, 14 87
90, 14 77
90, 14 trace
b
–
3
KHCO (0.60)
K3PO4 (0.60)
NaOAc (0.60)
Et3N (0.60)
Transition-metal-based reagents are used in numerous
organic reactions as oxidants or catalysts. However, many
of these reagents are highly toxic, expensive, or not ready
available. Furthermore, the energy consumption for the re-
moval of traces of transition metals to the ppm or even ppb
level, which is often required for pharmaceutical interme-
diates or final products, is high. Therefore, the replacement
of transition-metal-based oxidants by organic reagents is a
valuable alternative.1
The indolizine skeleton is abundant in many natural
products, such as erythrinan alkaloids, swainsonine, sla-
framine, gephyrotoxine, cryptowoline, and myrmicarin.2 In-
dolizines are also important heterocyclic compounds that
exhibit a broad array of bioactivity, such as antibacterial,
phosphatase and aromatase inhibiting, antioxidant, antide-
pressant, and antitumor activity.3 Moreover, indolizines are
extensively applied as fluorescence dyes and organic semi-
conductors in materials science.4
4
5
6
7
Cs2CO3 (0.60)
Na2CO3 (0.60)
Na2CO3 (0.60)
Na2CO3 (0.60)
Na2CO3 (0.60)
Na2CO3 (0.40)
Na2CO3 (0.60)
Na2CO3 (0.60)
Na2CO3 (0.60)
Na2CO3 (0.60)
8
9
10
11
12
13
14
15
16c
H2O–DMF (1:2, 2 mL) 90, 14 27
DMF (2.0)
120, 4
98
DMF (2.0)
120, 4
90
a Isolated yield.
b No base added.
c One-pot procedure: pyridine (1a, 0.40 mmol) and α-bromoacetophenone
(2a, 0.42 mmol) was mixed and then heated at 60 °C for 2 h in a test tube,
the thus-formed 3aa was used immediately without isolation.
Therefore, the development of new methods for the
synthesis of indolizines is currently a ‘hot topic’ in organic
chemistry.5 One of the most efficient ways to synthesize in-
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414
F. Shi et al.
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Synthesis
EWG2
R2
EWG1
EWG2
R2
EWG1
Previous works, two-pot procedure
oxidant
base
R1
R1
R2
R1
EWG1
N+
X–
EWG1
+
+
X
EWG2
N
N
ref. 6a–g
isolated
oxidant = TPCD, TPND or MnO2
Our previous work, one-pot procedure
R1
oxidant
base or no base
R1
R2
R1
EWG1
N+
X–
EWG1
+
X
+
EWG2
N
N
ref. 6h–i
formed in situ
oxidant = Cu(OAc)2 or K2Cr2O7
This work, transition-metal-free, one-pot
R1
EWG2
R2
EWG1
TEMPO
R1
R2
R1
X
EWG1
N+
EWG1
+
+
EWG2
N
N
Na2CO3
X–
formed in situ
X = Cl or Br, EWG = electron-withdrawing group
Scheme 1 Schematic comparison of this work with previous work
dolizines is by a 1,3-dipolar cycloaddition reaction between
an electron-deficient alkene and a pyridinium ylide, which
produces the indolizine through oxidative dehydrogenation
in the presence of an oxidant. The oxidants include freshly
prepared manganese dioxide, tetrakis(pyridine)cobalt(II)
dichromate (TPCD), tetrakis(pyridine)nickel(II) dichromate
(TPND), copper acetate monohydrate, chromium trioxide,
and potassium dichromate, which are all transition-metal-
based reagents.6 Therefore, there is great demand for a
ready available and easily removed non-transition-metal
oxidant that is used in a one-pot reaction for the synthesis
of indolizine.
2,2,6,6-Tetramethylpiperidin-1-oxyl (TEMPO) is a com-
mercially available organic compound that is generally used
as radical trapping reagent. Recently, TEMPO has also been
reported to be used as an oxidant or organocatalyst in oxi-
dation reactions.7 As a consequence of our interest in indol-
izines,6h,i,8 we wished to explore the use of TEMPO as an ox-
idant in the synthesis of indolizines from electron-deficient
alkenes. Herein, we report a transition-metal-free, one-pot
protocol for the synthesis of indolizines from electron-
deficient alkenes using TEMPO as the oxidant (Scheme 1).
EWG
O
O
Br
TEMPO (4.0 equiv)
R1
COPh
EWG
+
R1
+
N+
Br–
N
N
60 °C, 2 h
DMF, Na2CO3, 120 °C
Ph
1a, 0.40 mmol
2a, 0.42 mmol
3aa
4, 0.20 mmol
5
CO2t-Bu
CO2Me
COPh
CO2Bu
CONMe2
CO2Me
COPh
CO2Et
CO2Me
COPh
CO2Me
N
N
N
N
N
N
N
COPh
COPh
5f, 94%
COPh
COPh
5a, 90%
5b, 91%
5c, 84%
5d, 77%
5e, 84%
5g, 84%
O
O
CHO
CN
COPh
p-Tol
COPh
O
CO2Me
Ph
CN
Et
p-Tol
N
N
N
N
N
N
N
COPh
COPh
5j, 78%
COPh
5n, 42%
COPh
5h, trace
Scheme 2 The scope of the electron-deficient alkene
COPh
5k, 42%
COPh
5i, 37%
5l, 51%
5m, 45%
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F. Shi et al.
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Synthesis
O
SO2Ph
O
O
O
Br
TEMPO (4.0 equiv)
S
+
+
Ph
N+
Br–
+
N
60 °C, 2 h
N
DMF, Na2CO3, 120 °C
O
N
Ph
Ph
COPh
COPh
5o, 63% + 5o', 31%
1a, 0.40 mmol
2a, 0.42 mmol
3aa
4o, 0.20 mmol
O
NO2
TEMPO (4.0 equiv)
Br
+
N+
Br–
+
+
N
60 °C, 2 h
N
DMF, Na2CO3, 120 °C
COPh
1a, 0.40 mmol
2a, 0.42 mmol
3aa
4p, 0.20 mmol
5p', 37%
O
NO2
O
Br
TEMPO (4.0 equiv)
+
N+
Br–
N
60 °C, 2 h
Ph
N
DMF, Na2CO3, 120 °C
COPh
1a, 0.40 mmol
2a, 0.42 mmol
3aa
4q, 0.20 mmol
5q', 46%
Scheme 3 Reactions of alkenes containing a leaving group
In the preliminary study, in order to optimize the reac-
tion conditions, we chose 1-(2-oxo-2-phenylethyl)pyridin-
ium bromide (3aa, 0.40 mmol, 2.0 equiv) and N,N-dimethyl-
acrylamide (4a, 0.20 mmol, 1.0 equiv) as our model sub-
strates. Fortunately, the desired product 5a was isolated in
87% yield with sodium carbonate (0.60 mmol, 3.0 equiv) as
the base and TEMPO (0.60 mmol, 3.0 equiv) as the oxidant
in N,N-dimethylformamide (2.0 mL) at 90 °C for 14 hours
(Table 1, entry 1). In the absence of a base, 5a was obtained
in only 28% yield (entry 2). Bases that were stronger or
weaker than sodium carbonate were less efficient (entries
3–7). The addition of a lower amount of sodium carbonate
or TEMPO also decreased the yield of 5a (entries 8, 9, and
12). Attempts to use water or aqueous N,N-dimethylform-
amide as the solvent also failed (entries 13 and 14). In an
attempt to shorten the reaction time, TEMPO (0.80 mmol,
4.0 equiv) was used at a higher temperature (120 °C) and
the reaction was complete within four hours giving 5a in
nearly quantitative yield (98%, entry 15). Next, a one-pot
procedure was applied in this transformation: 3aa was
CONMe2
O
O
O
R1
TEMPO (4.0 equiv)
+
R1
Br
N
N
R2
+
N+
Br–
N
R1
60 °C, 4 h
DMF, Na2CO3, 120 °C
R2
R2
O
6
1, 0.40 mmol 2, 0.42 mmol
3
4a, 0.20 mmol
CONMe2
CONMe2
CONMe2
MeO2C
CONMe2
CONMe2
COPh
N
N
N
N
N
N
COPh
COPh
COPh
6e, 46%
COPh
6b, 59%
6c, 64%
6d, 96%
6f, 75%
CONMe2
CONMe2
CONMe2
CONMe2
N
N
N
N
OEt
O
NO2
O
O
OMe
6g, 66%
6h, 75%
6i, 66%
6j, 74% NO2
Scheme 4 The scope of pyridine and α-halo carbonyl compounds
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 413–420

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F. Shi et al.
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Synthesis
formed in situ from pyridine (1a, 0.40 mmol) and α-bromo-
acetophenone (2a, 0.42 mmol) at 60 °C for two hours and
then used directly. Using 3aa formed by this route gave 5a
in 90% yield, which is comparable to the yield of the two-
step procedure (entry 16).
To understand the reaction mechanism, the reaction
mixture was analyzed by GC-MS before workup and it con-
tained 2,2,6,6-tetramethylpiperidin-1-ol in addition to un-
reacted TEMPO. A control experiment using oxoammonium
–
salt 8 (TEMPO+ BF4 , 2.0 equiv were used due to higher oxi-
The scope of the alkene was examined. A series of dif-
ferent electron-deficient alkenes 4 that reacted with 3aa,
formed from 1a and 2a, in a one-pot reaction were studied
under the standard conditions (Scheme 2). Most electron-
deficient alkenes reacted with in situ formed 3aa and gave
the corresponding product 5 smoothly. However, coumarin
(4h) only gave the corresponding product 5h in trace
amounts. Alkenes bearing a phenyl group (R1 = Ph, p-Tol)
gave the corresponding products 5i,k,n in moderate yields,
possibly due to steric hindrance. Notably, nitroalkenes 4p,q
gave the product 5p′ and 5q′ that do not contain a nitro
group (Scheme 3), but phenyl vinyl sulfone (4o) gave two
products 5o and 5o′ in 63% and 31% yields, respectively.
This is because that the nitro group is a better leaving group
compared to the phenylsulfonyl group.
dation state)9 as the oxidant was also conducted and, as
shown in Scheme 5, the expected product 5a was isolated
but in only 25% yield.
N+
O
8
–
BF4
O
N
(2.0 equiv)
Na2CO3 (3.0 equiv)
N
N+
COPh
+
DMF, 120 °C, 4 h
Br–
N
O
COPh
4a, 0.20 mmol
3aa, 0.40 mmol
5a, 25%
Scheme 5 The control experiments
To study the substrate scope of the pyridine and α-halo
carbonyl compound, various pyridines and α-halo carbonyl
compounds were reacted with N,N-dimethylacrylamide
(4a) under the standard conditions (Scheme 4). Various
pyridines smoothly produced the corresponding products
6a–f. Several types of α-halo carbonyl compound were ap-
plied in this transformation, including derivatives of α-bro-
moacetophenone and an α-bromoacetate, and these gave
6g–i in good yields. Of note is the synthesis of 6j in 74%
yield starting from 1-(bromomethyl)-4-nitrobenzene.
We have successful isolated a tetrahydroindolizine in-
termediate A4, although we failed to isolate sufficient
amounts of the other three intermediates (A1, A2 and A3,
see details in the Supporting Information) according to ref-
erence.10 Then intermediate A4 reacts with TEMPO or 8 un-
der different conditions. As shown in Scheme 6, both TEM-
PO and 8 can serve as an oxidant in the presence or absence
of sodium carbonate. The highest yield of 9 (89%) are
achieved using TEMPO as the oxidant in the absence of so-
dium carbonate. Using 8 as the oxidant, the yields of 9 in
the presence or absence of sodium carbonate are less than
O
N
CO2Me
standard conditions
COPh
Br
+
+
N
MeO2C
Ph
MeO2C
CO2Me
1d
2a
4e
9, 87%
N
N
TEMPO (4 equiv)
DMF, 120 °C, 4 h
COPh
COPh
MeO2C
MeO2C
CO2Me
CO2Me
9
A4
with Na2CO3 (3 equiv), 70%
without Na2CO3, 89%
N
N
8 (2 equiv)
COPh
COPh
DMF, 120 °C, 4 h
MeO2C
MeO2C
CO2Me
CO2Me
9
A4
with Na2CO3 (3 equiv), 69%
without Na2CO3, 60%
Scheme 6 The control experiments
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F. Shi et al.
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Synthesis
70%. However, one-pot reaction of 1d, 2a, and 4e gives 9 in
87% yield, which is much higher than 70%. These results
also indicate that sodium carbonate only plays an import-
ant role in the formation of intermediate A, while TEMPO is
the real oxidant.
Isotope experiments were also conducted to under-
stand the reaction mechanism. D5-3aa was prepared from
pyridine-d5 in ethyl acetate; D7-3aa was generated by deu-
terium exchange from D5-3aa and ethanol-d6. The in situ
competitive reactions were conducted under the standard
reaction conditions for one hour (Scheme 7). The ratios of
5a/D4-5a were 1.04 (3aa with D5-3aa) and 1.56 (3aa with
D7-3aa), respectively. These results indicated that the cleav-
age of the C–H bond at 3-position to form intermediate B is
the rate-determining step.
Based on these results and previous works,6 a possible
reaction mechanism is presented in Scheme 8. Intermediate
A was formed in situ through 1,3-dipolar cycloaddition and
oxidized to radical B and then to intermediate C by TEMPO
through radical hydrogen abstraction. When the electron-
withdrawing group at the 1-position of C is a leaving group,
an elimination reaction occurs to form 5′. Otherwise, prod-
uct 5 is obtained by elimination of molecular hydrogen or
oxidization by TEMPO.
In conclusion, a one-pot method for the synthesis indol-
izine from pyridines, α-halo carbonyl compounds, and elec-
tron-deficient alkenes under transitional-metal-free condi-
tions is reported. Commercially available TEMPO is used as
the oxidant in this transformation. These economic, effi-
cient, easily handled, and transition-metal-free conditions
should attract the interest of scientists in the fields of syn-
thetic, medicinal, and materials chemistry.
H/D
O
H/D
N
H/D
H/D
H/D
O
H/D
H/D
N
1 h
N+
+
Ph
All organic solutions were concentrated by rotary evaporation under
reduced pressure. Flash column chromatography was performed em-
ploying 300–400 mesh silica gels. Petroleum ether = PE. TLC was per-
formed using plates pre-coated to a depth of 0.25 mm with 300–400
mesh silica gel impregnated with a fluorescent indicator. All chemi-
cals and solvents were obtained from commercial vendors and used
without further purification. Melting points are uncorrected. IR spec-
tra were obtained using a Thermo-Fisher Nicolet iS50. HRMS were re-
corded on a TOF-Q spectrometer. 1H and 13C NMR spectra were re-
corded on a Bruker 400 NMR spectrometer referenced to residual pro-
ton in the NMR solvent (CHCl3: δ = 7.26). Compounds 5a–q and 6a are
known.6,8 Compounds 5a–j,m,q′6h 5k,l,n,o6i 5o′,6j and 910 have previ-
ously been reported in the literature.
N
O
Br–
H/D
4a
COPh
H/D
3aa/D5-3aa = 1: 1
5a/D4-5a = 1.04
H/D
O
H/D
N
H/D
H/D
O
H/D
H/D
N
1 h
N+
+
H/D
Ph
N
O
H/D
Br–
H/D
H/D
COPh
4a
H/D
5a/D4-5a = 1.56
3aa/D7-3aa = 1: 1
standard conditions
Scheme 7 The isotope experiments
R1
R1
+
N+
X–
EWG1
X
EWG1
N
EWG2
R3
R3
R2
R1
R1
R1
base
– HX
R2
N+
X-
EWG1
N+
EWG1
+
N
EWG2
–
EWG1
EWG2
R3
R2
EWG1
R3
A
EWG2
R3
EWG2
R3
slow
R2
R2
R1
R1
R1
+
TEMPO
+
TEMPO
N
N
N
EWG1
EWG2
EWG1
A
B
C
EWG2
R3
R3 = H
EWG2 = leaving group
R2
R2
R1
R1
R2
EWG1
R1
– H2 or TEMPOH
fast
N
N
– HEWG2
fast
N
EWG1
EWG1
C
5
5'
Scheme 8 The proposed mechanism
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Synthesis
Indolizines 5, 6 and 9; General Procedure
3-Benzoyl-7-(dimethylamino)-N,N-dimethylindolizine-1-carbox-
amide (6e)
Pyridine derivative 1 (0.40 mmol, 2.0 equiv) and α-halo carbonyl
compound 2 (0.42 mmol, 2.1 equiv) in DMF (0.20 mL) were heated at
60 °C in a test tube with a stopper for 4 h to form 3 in situ. Then
alkene 4 (0.20 mmol, 1.0 equiv), Na2CO3 (0.60 mmol, 3.0 equiv),
TEMPO (0.80 mmol, 4.0 equiv), and further DMF (1.80 mL) were add-
ed to the tube; the mixture was heated at 120 °C for an additional 4 h
(TLC monitoring). The mixture was cooled to r.t., poured into water,
and extracted with CHCl3 (3 × 10 mL). The combined extracts were
washed with sat. brine, dried (Na2SO4), and filtered; solvent was re-
moved under reduce pressure. The residue was purified by flash chro-
matography (silica gel, PE–EtOAc) to give the corresponding indol-
izine.
Chromatography (PE–EtOAc, 1:2); yellow solid; yield: 30.6 mg (46%);
mp 179–180 °C.
IR (KBr): 2971, 2936, 1643, 1617, 1560, 1464, 1430, 1384 cm–1
1H NMR (400 MHz, CDCl3): δ = 9.78 (d, J = 7.8 Hz, 1 H), 7.77–7.71 (m, 2
H), 7.53–7.40 (m, 3 H), 7.30 (s, 1 H), 7.12 (d, J = 2.8 Hz, 1 H), 6.63 (dd,
J = 7.8, 2.8 Hz, 1 H), 3.12 (s, 6 H), 3.10 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 182.8, 167.3, 148.8, 143.2, 140.9,
130.5, 129.8, 128.73, 128.66, 128.1, 119.6, 106.0, 104.5, 95.8, 40.0.
HRMS (APCI): m/z [M + H]+ calcd for C20H22N3O2: 336.1707; found:
336.1710.
.
3-Benzoyl-N,N,7-trimethylindolizine-1-carboxamide (6b)
Methyl 3-Benzoyl-1-(dimethylcarbamoyl)indolizine-7-carboxyl-
ate (6f)
Chromatography (PE–EtOAc, 2:1); yellow solid; yield: 36.2 mg (59%);
mp 100–102 °C.
Chromatography (PE–EtOAc, 2:1); yellow solid; yield: 52.3 mg (75%);
mp 172–173 °C.
IR (KBr): 1617, 1567, 1541, 1535, 1457 cm–1
.
IR (KBr): 2971, 1732, 1632, 1611, 1560, 1461, 1384 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.82 (d, J = 7.1 Hz, 1 H), 7.86 (s, 1 H),
7.77 (d, J = 7.4 Hz, 2 H), 7.54 (t, J = 7.4 Hz, 1 H), 7.47 (t, J = 7.4 Hz, 2 H),
7.38 (s, 1 H), 6.88 (d, J = 7.2 Hz, 1 H), 3.13 (s, 6 H), 2.44 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 9.85 (d, J = 7.0 Hz, 1 H), 8.69 (s, 1 H),
7.78 (d, J = 7.4 Hz, 2 H), 7.59–7.52 (m, 2 H), 7.52–7.42 (m, 3 H), 3.93 (s,
3 H), 3.12 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 184.7, 166.6, 140.3, 140.1, 138.0,
13C NMR (100 MHz, CDCl3): δ = 185.6, 165.7, 165.3, 139.6, 137.5,
131.8, 129.0, 128.5, 127.9, 126.7, 126.3, 122.7, 121.8, 113.8, 112.9,
52.6.
131.2, 128.9, 128.3, 128.1, 126.8, 121.1, 118.1, 117.6, 108.5, 21.5.
HRMS (APCI): m/z [M + H]+ calcd for C19H19N2O2: 307.1141; found:
307.1147.
HRMS (APCI): m/z [M + H]+ calcd for C20H19N2O4: 351.1345; found:
1-Benzoyl-N,N-dimethylpyrrolo[1,2-a]quinoline-3-carboxamide
351.1343.
(6c)
Chromatography (PE–EtOAc, 2:1); red solid; yield: 44.0 mg (64%); mp
50–52 °C.
N,N-Dimethyl-3-(4-nitrobenzoyl)indolizine-1-carboxamide (6g)
Chromatography (PE–EtOAc, 1:2); red solid; yield: 44.3 mg (66%); mp
199–200 °C.
IR (KBr): 1632, 1541, 1456, 1411, 1384 cm–1
.
IR (KBr): 2972, 2936, 1685, 1654, 1617, 1560, 1462, 1427, 1384 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.11–8.02 (m, 3 H), 7.83 (d, J = 9.3 Hz, 1
H), 7.76 (d, J = 7.9 Hz, 1 H), 7.63 (t, J = 7.4 Hz, 1 H), 7.56 (d, J = 9.4 Hz, 2
H), 7.52 (d, J = 7.8 Hz, 2 H), 7.44 (t, J = 7.5 Hz, 1 H), 7.28 (s, 1 H), 3.12 (s,
6 H).
13C NMR (100 MHz, CDCl3): δ = 184.8, 166.5, 138.9, 138.7, 133.2,
132.8, 130.1, 128.8, 128.5, 128.4, 127.54, 127.50, 127.3, 125.3, 125.1,
120.1, 117.6, 111.4.
1H NMR (400 MHz, CDCl3): δ = 9.94 (d, J = 7.0 Hz, 1 H), 8.33 (d, J = 8.7
Hz, 2 H), 8.06 (d, J = 9.0 Hz, 1 H), 7.92 (d, J = 8.7 Hz, 2 H), 7.42 (td, J =
7.9, 1.2 Hz, 1 H), 7.35 (s, 1 H), 7.11 (td, J = 6.9, 1.4 Hz, 1 H), 3.13 (s, 6
H).
13C NMR (100 MHz, CDCl3): δ = 182.3, 165.9, 149.2, 145.7, 139.9,
129.7, 128.8, 127.3, 126.4, 123.6, 121.95, 119.56, 115.7, 110.8.
HRMS (APCI): m/z [M + H]+ calcd for C22H19N2O2: 343.1441; found:
343.1445.
HRMS (APCI): m/z [M + H]+ calcd for C18H16N3O4: 338.1135; found:
338.1141.
3-Benzoyl-N,N-dimethylpyrrolo[2,1-a]isoquinoline-1-carboxam-
ide (6d)
3-(4-Methoxybenzoyl)-N,N-dimethylindolizine-1-carboxamide
(6h)
Chromatography (PE–EtOAc, 2:1); yellow solid; yield: 66.3 mg (96%);
mp 57–60 °C.
Chromatography (PE–EtOAc, 1:2); yellow solid; yield: 48.2 mg (75%);
mp 145–146 °C.
IR (KBr): 1631, 1575, 1561, 1541, 1457, 1418 cm–1
.
IR (KBr): 2972, 2935, 1622, 1603, 1560, 1526, 1473, 1417, 1352 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.59 (d, J = 7.6 Hz, 1 H), 8.24–8.13 (m, 1
H), 7.84 (d, J = 7.6 Hz, 2 H), 7.77–7.70 (m, 1 H), 7.64–7.53 (m, 3 H),
7.49 (t, J = 7.6 Hz, 2 H), 7.28 (s, 1 H), 7.18 (d, J = 7.5 Hz, 1 H), 3.24 (s, 3
H), 2.94 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 185.7, 168.3, 134.0, 132.5, 131.6,
129.6, 129.2, 128.5, 128.3, 128.3, 127.1, 125.4, 124.7, 124.2, 124.2,
123.6, 114.4, 113.3, 39.0, 35.2.
1H NMR (400 MHz, CDCl3): δ = 9.85 (d, J = 7.0 Hz, 1 H), 8.02 (d, J = 9.0
Hz, 1 H), 7.80 (d, J = 8.7 Hz, 2 H), 7.43 (s, 1 H), 7.30 (td, J = 7.9, 1.2 Hz, 1
H), 7.03–6.94 (m, 3 H), 3.87 (s, 3 H), 3.13 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 184.2, 166.6, 162.4, 139.1, 132.7,
131.1, 128.5, 126.0, 125.8, 121.6, 119.3, 114.7, 113.6, 109.3, 55.5.
HRMS (APCI): m/z [M + H]+ calcd for C19H19N2O3: 323.1390; found:
323.1396.
HRMS (APCI): m/z [M + H]+ calcd for C22H19N2O2: 343.1441; found:
343.1446.
Ethyl 1-(Dimethylcarbamoyl)indolizine-3-carboxylate (6i)
Chromatography (PE–EtOAc, 3:2); yellow solid; yield: 34.3 mg (66%);
mp 83–85 °C.
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IR (KBr): 2971, 2933, 1685, 1654, 1617, 1560, 1529, 1419, 1376 cm–1
.
References
1H NMR (400 MHz, CDCl3): δ = 9.44 (d, J = 7.1 Hz, 1 H), 8.03 (dd, J = 9.0,
1.5 Hz, 1 H), 7.63 (s, 1 H), 7.21–7.14 (m, 1 H), 6.90 (td, J = 6.9, 1.4 Hz, 1
H), 4.37 (q, J = 7.1 Hz, 2 H), 3.18 (s, 6 H), 1.39 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.6, 161.2, 138.6, 127.3, 124.0,
121.8, 119.7, 114.0, 113.4, 108.3, 60.1, 14.5.
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HRMS (APCI): m/z [M + H]+ calcd for C14H17N2O3: 261.1234; found:
261.1235.
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N,N-Dimethyl-3-(4-nitrophenyl)indolizine-1-carboxamide (6j)
Chromatography (PE–EtOAc, 1:1); red solid; yield: 45.9 mg (74%); mp
143–144 °C.
IR (KBr): 2971, 2939, 1636, 1617, 1560, 1466, 1413, 1384 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.35–8.27 (m, 3 H), 7.95 (d, J = 9.1 Hz, 1
H), 7.70 (d, J = 8.6 Hz, 2 H), 7.10 (s, 1 H), 6.99 (dd, J = 9.2, 6.7 Hz, 1 H),
6.72 (t, J = 6.7 Hz, 1 H), 3.19 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 167.0, 146.2, 138.1, 136.4, 127.7,
124.6, 122.8, 122.5, 121.5, 120.5, 116.4, 113.2, 109.0.
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310.1186.
Synthesis of 5a with Oxoammonium Salt as the Oxidant
Isolated pyridinium salt 3aa (0.40 mmol, 2.0 equiv), alkene 4a (0.20
mmol, 1.0 equiv), Na2CO3 (0.60 mmol, 3.0 equiv), oxoammonium salt
8 (0.40 mmol, 2.0 equiv due to higher oxidant state) and 2.0 mL of
DMF were added to a test tube. Then the mixture was heated at 120
°C for 4 h (TLC monitoring). The mixture was cooled to r.t., poured
into water, and extracted with CHCl3 (3 × 10 mL). The combined ex-
tracts were washed with sat. brine, dried (Na2SO4), and filtered; sol-
vent was removed under reduced pressure. The residue was purified
by flash chromatography (silica gel, PE–EtOAc) to give the corre-
sponding indolizine.
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Synthesis of 9 from A4
Isolated A4 (0.20 mmol, 1.0 equiv), without or with Na2CO3 (0.60
mmol, 3.0 equiv), oxoammonium salt 8 (0.40 mmol, 2.0 equiv due to
higher oxidant state) or TEMPO (0.80 mmol, 4.0 equiv) and 2.0 mL of
DMF were added to a test tube. The mixture was heated at 120 °C for
4 h (TLC monitoring). The mixture was cooled to r.t., poured into wa-
ter, and extracted with CHCl3 (3 × 10 mL). The combined extracts
were washed with sat. brine, dried (Na2SO4), and filtered; solvent was
removed under reduced pressure. The residue was purified by flash
chromatography (silica gel, PE–EtOAc) to give the corresponding in-
dolizine.
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Acknowledgment
We are grateful to funding of NSFC (No.: 21202058, 21401063), Edu-
cation Department of Jiangsu Province (No. 13KJA150001) and CPSF
(No.: 2012M511645, 2013T60483) for their financial support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560973.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 413–420