Visible-Light-Induced Radical Cascade Cyclization: Synthesis of the ABCD Ring Cores of Camptothecins

Article abstract of DOI:10.1021/acs.joc.7b03283

A new strategy for constructing indolizino[1,2-b]quinolin-9(11H)-ones (ring cores of camptothecins) from readily available isocyanoarenes and N-(alkyl-2-yn-1-yl)pyridin-2(1H)-ones has been developed through a visible-light-induced radical cascade cyclization process. The reaction proceeds under mild conditions with fair to excellent yields. The easy introduction of substituents for both reactants and the broad functional group tolerance of the reaction make it a straightforward route to the cores of the marketed camptothecins and their derivatives.

Full text of DOI:10.1021/acs.joc.7b03283

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Article
Visible-Light-Induced Radical Cascade Cyclization:
Synthesis of the ABCD Ring Cores of Camptothecins
Yao Yuan, Wuheng Dong, Xiaoshuang Gao, Huang Gao, Xiaomin Xie, and Zhaoguo Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03283 • Publication Date (Web): 07 Feb 2018
Downloaded from http://pubs.acs.org on February 8, 2018
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Visible-Light-Induced Radical Cascade Cyclization: Synthesis of the
ABCD Ring Cores of Camptothecins
†
†
†
†
†
†‡
Yao Yuan, Wuheng Dong, Xiaoshuang Gao, Huang Gao, Xiaomin Xie, and Zhaoguo Zhang *
†Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and
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Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Fenglin Road, Shanghai 200032, China
Fax: (+86)-21-5474-8925; phone: (+86)-21-5474-8925; E-mail: zhaoguo@sjtu.edu.cn
ABSTRACT
A new strategy for constructing indolizino[1,2-b]quinolin-9(11H)-ones (ring cores of camptothecins) from
readily available isocyanoarenes and N-(alkyl-2-yn-1-yl)pyridin-2(1H)-ones has been developed through a
visible-light-induced radical cascade cyclization process. The reaction proceeds under mild conditions with
fair to excellent yields. The easy introduction of substituents for both reactants and the broad functional group
tolerance of the reaction make it a straightforward route to the cores of the marketed camptothecins and their
derivatives.
INTRODUCTION
Camptothecin (CPT, Figure 1), a unique pentacyclic quinoline alkaloid which has potent antitumor activities,
1
was isolated by Wani and Wall in 1966. Subsequent investigation and modification of CPT brought fruits
2
with two antitumor agents approved by the FDA: topotecan for small-cell lung cancer and irinotecan for
refractory colorectum cancer.3 Further study showed that the ABCD rings of CPT function as the
4
pharmacophore responsible for binding to DNA. Thus, developing practical and efficient strategies for
acquiring different substituted indolizino[1,2-b]quinolin-9(11H)-ones has great significance to improve the
clinical application of the camptothecin family.
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Figure 1. Camptothecin and representative derivatives.
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To date, there have been quite a number of total syntheses of CPT and derivatives, including several
6
efficient strategies for the construction of ABCD rings. One significant work is a free-radical cascade of
isonitriles and 6-bromo-1-(prop-2-yn-1-yl)pyridin-2(1H)-one reported by Curran and coworkers in 1996,
7
which used Me
3
SnSnMe
3
to generate the radical under UV irradiation (Scheme 1, 1a). To solve the
attendant toxicity issue and separation problems they developed a palladium-catalyzed process from the
8
same two precursors (Scheme 1, 1b). However, this method is limited to terminal substituted propargyl
pyridone and isonitriles with electron-donating groups, and requires high Pd-catalyst loading.
Scheme 1. Cascade cyclization of propargyl pyridone and isocyanoarene.
Recently, visible light photocatalysis has created a new platform for accessing radical chemistry and benefits
9
of its environmentally sustainability and mild operating condition. A series of visible-light-promoted radical
additions of triple bonds (isocyanide, alkyne, cyanide and carbon monoxide) for constructing
(
hetero)aromatic rings has been developed.10 Therefore, we envision that visible-light catalysis would be a
greener way to generate a radical and to realize the cascade cyclization of propargyl pyridinone and
isonitriles.
RESULTS AND DISCUSSION
We carried out our research with 6-iodo-1-(prop-2-yn-1-yl)pyridin-2(1H)-one (1a) and
1-isocyano-4-methoxybenzene (2a) in the presence of a specified catalyst and K
2
CO as base under the
3
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irradiation of a 12 W blue LED in CH
3
CN for 24 h. Initially we chose 2 mol % of fac-Ir(ppy) as the catalyst
3
to practice this reaction because of its superior reductive potential at the excited state compared to other
photocatalysts. To our satisfaction, the target product was obtained in 18% yield (Table 1, entry 1).
According to the reported redox potentials of fac-Ir(ppy)
SCE),9c 0.5 equiv. of NEt
3
(E1/2IV/*III = -1.73 vs SCE and E1/2III/II = -2.19 vs
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9
0
was added into the reaction, which was able to reduce Ir*III into Ir . As expected,
II
3
the yield increased to 32% (Table 1, entry 2). Then we explored diffident types of photocatalysts.
Fortunately, other metal catalysts worked well in this reaction and Ru(bpy) (PF was found to be the best
3
)
6 2
choice, a 95% yield of products were obtained (Table 1, entries 3-5). However, the widely used dye catalyst
Eosin Y was not able to catalyze this transformation (Table 1, entry 6). Next, we screened a range of bases
including Na
Notably, when NEt
yield, along with 14% dehalogenated by-product 4a, which was the reduced product of 1a by NEt
minimize the production of by-product, we reduced the dosage of NEt to improve the yield of 3a. However,
the decrease of NEt made no improvement to the yield and even lowered the conversion of 1a (Table 1,
entries 11-13). Nevertheless, in the presence of 1.0 equiv. of K CO , the loading of NEt can be reduced
down to 0.3 equiv. without the decrease of yield (Table 1, entry 14). Other solvents, such as MeOH, DMF,
DCE and toluene, were not superior to CH CN in this transformation (Table 1, entries 16-19). Finally, the
control experiments confirmed the necessity of visible light, photosensitizer and reductant NEt , and the
yield dropped dramatically without K CO as the base (Table 1, entries 20-23).
Table 1. Optimization of the reaction conditionsa
2
CO
3
, KOAc, DBU, NEt
was served as both base and reductant, the reaction gave the desired product in 81%
. To
3
and all of them were inferior to K
2
CO
3
(Table 1, entries 7-10).
3
3
3
3
2
3
3
3
3
2
3
entry
photocatalyst
base
NEt
3
(equiv.)
---
solvent
yieldb
18
1
2
3
4
5
6
7
8
9
fac-Ir(ppy)
fac-Ir(ppy)
3
3
K
2
K
2
K
2
K
2
K
2
K
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
0.5
32
78
92
>95
6
[Ir(ppy)
Ru(bpy)
Ru(bpy)
Eosin Y
2
dtb-bpy]PF
Cl .6H
(PF
6
0.5
3
2
2
O
0.5
3
6
)
2
0.5
0.5
Ru(bpy)
Ru(bpy)
3
3
(PF
6
6
)
)
2
2
Na
2
CO
3
0.5
71
70
75
(PF
KOAc
DBU
0.5
Ru(bpy)
3
(PF
6
)
2
0.5
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0
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Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
---
3
3
3
3
3
3
3
3
3
3
3
(PF
(PF
(PF
(PF
(PF
(PF
(PF
(PF
(PF
(PF
(PF
6
6
6
6
6
6
6
6
6
6
6
)
)
)
)
)
)
)
)
)
)
)
2
2
2
2
2
2
2
2
2
2
2
NEt
NEt
NEt
NEt
3
3
3
3
0.5
0.2
0.1
0
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
81
77
1
12
78
13
14
15
30
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
0.3
0.1
0.3
0.3
0.3
0.3
0.3
0.3
---
>95 (88 c)
19
0
1
2
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0
16
MeOH
DMF
5
1
1
7
8
10
DCE
76
19
0d
toluene
6
2
CH
CH
CH
CH
3
3
3
3
CN
CN
CN
CN
trace
trace
trace
41
2
1
2
2
Ru(bpy)
3
3
(PF
6
6
)
)
2
2
23
Ru(bpy)
(PF
---
0.3
a
Conditions: 1a (51.8 mg, 0.2 mmol), 2a (53.7 mg, 0.4 mmol), photocatalyst (2 mol %), base (1.0 eq.), solvent
3.0 mL), irradiation with a 12 W blue LED at room temperature under N
atmosphere for 24 h. b 1H NMR yields
(
2
c
d
were reported using dibenzyl ether as an internal standard. Isolated yield. Reaction was run in the dark.
With the optimized reaction conditions in hand, we next examined the scope of this photo-catalyzed cascade
cyclization (Table 2). To our delight, a series of substituted isocyanobenzenes underwent the transformation
smoothly with the corresponding products. For isocyanoarenes bearing a para electron-donating substituent
on the aromatic ring, good yields were obtained (3a, 88% and 3b, 81%); for those with an
electron-withdrawing group in the para position of benzene ring, lower yields (3c, 54% and 3d, 37%) were
obtained even at a higher catalyst loading. This might be attributed to the reduced nucleophilicity of
isocyano-group caused by the electron-withdrawing substituents on isocyanobenzene. Para-halogenated (F,
Cl, Br) substrates are compatible with the reaction conditions to give the expected products (3e-3g, for
the crystal structure of 3e, see supporting information) in good yields (57−80%), which provided the
possibility for further functionalization. Sterically hindered substrates afforded 3h and 3i in 62% and
4
2%, respectively. Both non-substituted and disubstituted isocyanobenzenes were successful substrates
in this transformation, affording 3j, and 3m in up to 92% yields. When 5-isocyanobenzo[d][1,3]dioxole
was used, two regioisomers 3k and 3k’ were isolated in a 6:1 ratio in 64% combined yield. Moreover,
isocyanonaphthalene was also tolerated in this reaction and the corresponding product (3l) together with its
rearrangement regioisomer (3l') was generated in 76% overall yield (rearrangement mechanism11 see
supporting information). Besides, different substituted propargyl pyridinones were explored as well to
expand the diversity of the products. Substrates bearing an alkyl (methyl, ethyl) or a trimethylsilyl group
afforded the desired products in good yields (3n-3p, 68%-89%, for the crystal structure of 3o, see
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supporting information). Phenyl substituted propargyl pyridone provided a moderate yield of 61% (3q).
Table 2. Substrate scopea
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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0
a
Conditions: 1 (0.2 mmol), 2 (0.4 mmol), K
3 mL), irradiation with a 12 W blue LED under nitrogen atmosphere at rt for 24 h. The reaction was conducted
(PF
2 3 3 6 2 3
CO (27.6 mg, 0.2 mmol), Ru(bpy) (PF ) (3.5 mg, 2 mol %), CH CN
b
(
with 5 mol % of Ru(bpy)
3
6 2
) .
1
1
On the basis of the experimental observations and the relevant reports, a plausible mechanism is
proposed in Scheme 2. Visible light irradiation of Ru(bpy) 2+
Ru*(bpy)
2+, which can be reductively quenched by NEt
N-centered radical cation species. Subsequently,
produces a photo-excited state species
3
+
3
3
to afford a Ru(bpy)
3
complex and an
+
a
single-electron transfer from Ru(bpy)
3
to
6-iodo-1-(prop-2-yn-1-yl)pyridin-2(1H)-one (1a) generates the radical intermediate I, which adds onto the
-isocyano-4-methoxybenzene (2a) to produce radical II. Then the following intramolecular radical
cyclization (II-IV) gives the radical intermediate IV. Afterwards, a one electron oxidation of IV by a new
1
2
+
+
Ru*(bpy)
3
generates aryl cation intermediate V and Ru(bpy)
3
(both radical intermediate IV and NEt
3
+
can serve as reductant to generate Ru(bpy)
cation intermediate
-methoxyindolizino[1,2-b]quinolin-9(11H)-one (3a).
3
and finish the catalytic cycle). Ultimately deprotonation of aryl
V
assisted
by base yields the target product
2
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Scheme 2. Proposed mechanism for the reaction
In summary, we have developed a practical and environmentally friendly strategy to construct tetracyclic
ABCD ring cores of camptothecins by photo-redox catalyzed radical cascade cyclization. The reaction
proceeded under mild conditions without the use of tin reagent and was compatible with a broad range of
functional groups in good yields. Further work on developing a new strategy for the synthesis of the chiral E
ring fused pyridinone and use it as starting material to realize the total synthesis of camptothecins is ongoing
in our lab.
EXPERIMENTAL SECTION
General Information
Unless otherwise noted, all reactions were carried out under an atmosphere of nitrogen using standard
Schlenk techniques. Materials were purchased from commercial suppliers and used without further
purification. Anhydrous DMF, CH
3
CN, MeOH, DCE were freshly distilled from calcium hydride,
Anhydrous toluene was freshly distilled from Sodium. H NMR and 13C NMR spectra were recorded on a
1
4
00 MHz spectrometer. The chemical shifts for 1H NMR were recorded in ppm downfield from
tetramethylsilane (TMS) with the solvent resonance as the internal standard. The chemical shifts for 13C
NMR were recorded in ppm downfield using the central peak of deuterochloroform (77.00 ppm) as the
internal standard. Coupling constants (J) are reported in Hz and refer to apparent peak multiplications.
HRMS were obtained on an ESI-TOF mass spectrometer. Flash column chromatography was performed on
silica gel (300-400 mesh).
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Representative
procedure
for
the
preparation
of
6
-iodo-1-(prop-2-yn-1-yl)pyridin-2(1H)-one (1a)
7
2
-Iodo-6-methoxypyridine : To a solution of 2-bromo-6-methoxypyridine (15.0 g, 79.8 mmol) in
o
anhydrous THF (120 mL) was added dropwise n-BuLi (54.9 mL, 87.8 mmol, 1.6 M,) at -78 C under
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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5
5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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0
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0
1
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3
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9
0
1
2
3
4
5
6
7
8
9
0
o
nitrogen atmosphere over 25 min and kept -78 C for 1 hour. Then a suspension of I
2
(24.3 g, 95.7 mmol) in
o
anhydrous THF (100 mL) was added to the above mixture at -78 C over 35 min and warmed to room
temperature. The reaction was quenched with sat. aq. Na
-methoxy-2-methylpropane (2×100 mL). The organic phase was washed with sat. aq. NaCl (100 mL), dried
Na SO ), filtered, and concentrated in vacuum. The resulting residue was taken on to the next step without
additional purification.
2
S
2
O
3
(200 mL) and extracted by
2
(
2
4
7
6
-Iodopyridin-2(1H)-one : A mixture of 2-iodo-6-methoxypyridine (18.0 g, 76.6 mmol), NaI (18.4 g, 122.5
mmol) and H
2
O (0.7 g, 40 mmol) in CH
3
CN (200 mL) was treated with TMSCl (13.3 g, 122.5 mmol) in
o
CH
3
CN (60 mL) at room temperature for 15 min. Then the mixture was warmed to 65 C and stirred for 12 h.
After completed, the reaction was quenched with the mixture of saturated solution of NaCl and Na
2
SO
3
(1:1,
SO
2
00 mL) for 10 min and extracted by AcOEt (3×100 mL). The organic phase was dried with Na
2
4
,
concentrated in vacuum and purified by high-flash silica gel column chromatography (PE/EA=10/1~1/1).
7
6
-Iodo-1-(prop-2-yn-1-yl)pyridin-2(1H)-one (1a): To a solution of 6-iodopyridin-2(1H)-one (6.7 g, 30.0
o
mmol) in DME (60 mL) and DMF (15 mL) was slowly added NaH (1.5 g, 36.0 mmol, 60%) at 0 C under
nitrogen atmosphere and stirred for 10 min. Then added LiBr (5.3 g, 60.0 mmol) to the mixture and stirred
for 15 min at room temperature. After, the 3-bromoprop-1-yne (7.2 g, 60.0 mmol) was added to the mixture
o
and the whole mixture was warmed to 65 C for 5 h. The reaction was quenched with a saturated solution of
NaCl (60 mL) and extracted by AcOEt (3×60 mL). The organic phase was dried with Na
2
SO and
4
concentrated in vacuum. The residue was purified by silica gel column chromatography (PE/EA=5/2) to
afford 1a (7.9 g, 25.8 mmol, 85% yield) as a white solid.
Representative procedure for the preparation of 1-fluoro-4-isocyanobenzene (2c).
12
N-(4-Fluorophenyl)formamide : A mixture of amine (5.6 g, 50.0 mmol), formic acid (9.2 g, 200.0 mmol)
and catalytic amount of sodium formate (680.1 mg, 10 mmol) in a 100 mL round-bottom flask was stirred
with a magnet at room temperature. The progress of the reaction was monitored by TLC. When the reaction
finished, 70 mL EtOAc was added into the system, and the organic solvent was then washed with H O (3×60
2
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mL) and a saturated solution of NaHCO
3
(60 mL). After drying with Na
2
SO the solvent was removed under
4
reduced pressure. The resulting residue containing the N-(4-fluorophenyl)formamide was taken on to the
next step without additional purification.
1
-Fluoro-4-isocyanobenzene13 (2c): To a solution of N-(4-fluorophenyl)formamide (6.2 g, 44.5 mmol) and
0
1
2
3
4
5
6
7
8
9
0
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2
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9
0
1
2
3
4
5
6
7
8
9
0
NEt
3
(13.5 g, 133.7 mmol) in anhydrous THF (100 mL) was added dropwise POCl
3
(8.2 g, 53.5 mmol) in
o
o
THF (50 mL) at 0 C under nitrogen atmosphere over 35 min. Then the reaction mixture was stirred at 0 C
for 1 hours. After completion, the reaction mixture was poured into a saturated solution of K
2
CO (200 mL)
3
o
at 0 C. Then the mixture was extracted by 2-methoxy-2-methylpropane (2×100 mL). The organic phase was
dried over Na
2
SO and the solvent was removed under reduced pressure. The crude product was purified by
4
reduced pressure distillation (or silica-gel column chromatography) to give 1-fluoro-4-isocyanobenzene as
o
yellow green liquid (2.7 g, 49% yield, 12 mm Hg, 59 C).
A general procedure for constructing indolizino[1,2-b]quinolin-9(11H)-ones under
visible light
A dried Schlenk tube equipped with a stirrer bar which was evacuated and backfilled with nitrogen was
added
-isocyano-4-methoxybenzene (53.7 mg, 0.4 mmol, 2.0 equiv), K
8.1 mg, 0.06 mmol, 0.3 equiv) and Ru(bpy) (PF (3.5 mg, 0.004 mmol, 2.0 mol %). Then 3 mL of CH
6-iodo-1-(prop-2-yn-1-yl)pyridin-2(1H)-one
(51.8
mg,
CO (27.6 mg, 0.2 mmol, 1.0 equiv), NEt
CN
0.2
mmol,
1.0
equiv),
1
2
3
3
(
3
6
)
2
3
was added into the reaction tube via a syringe. The reaction mixture was degassed by the freeze-pump-thaw
method and then irradiated with a 12 W blue LED (distance app. 5 cm) for 24 h. After the completion of the
reaction, the mixture was concentrated in vacuum and the pure product was obtained by flash column
chromatography on silica gel.
Spectral data for substrates
7
o
1
6
-Iodo-1-(prop-2-yn-1-yl)pyridin-2(1H)-one (1a): White solid, 7.9 g, 85% yield. M.P.: 180.0-181.2 C. H
NMR (400 MHz, CDCl ) δ 6.96 (dd, J = 8.8, 7.2 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 6.52 (d, J = 9.2 Hz, 1H),
.07 (d, J = 2.4 Hz, 2H), 2.34 (t, J = 2.4 Hz, 1H). 13C NMR (100 MHz, CDCl
) δ 162.0, 140.3, 120.3, 120.2,
9.7, 73.2, 44.1.
-(But-2-yn-1-yl)-6-iodopyridin-2(1H)-one (1b): White solid, 1.1 g, 81% yield. M.P.: 162.0-163.5 C. H
) δ 6.96 – 6.88 (m, 1H), 6.78 (d, J = 7.2 Hz, 1H), 6.48 (d, J = 9.2 Hz, 1H), 4.99 (s,
3
5
9
1
3
o
1
NMR (400 MHz, CDCl
H), 1.78 (s, 3H). 13C NMR (100 MHz, CDCl
HRMS-ESI (m/z): Calculated for C
3
2
3
) δ162.1, 140.0, 120.2, 120.0, 100.1, 81.1, 72.8, 44.7, 3.9.
+
9
H
9
INO (M + H) : 273.9729, Found: 273.9733.
o
1
6
-Iodo-1-(pent-2-yn-1-yl)pyridin-2(1H)-one (1c): White solid, 1.1 g, 79% yield. M.P.: 146.0-147.2 C. H
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NMR (400 MHz, CDCl
3
) δ 6.92 (t, J = 7.2 Hz, 1H), 6.78 (d, J = 6.8 Hz, 1H), 6.48 (d, J = 9.2 Hz, 1H), 5.01
(
s, 2H), 2.15 (dd, J = 14.4, 7.2 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl
3
) δ 162.1, 140.0,
1
2
6
1
20.1, 120.0, 100.1, 86.8, 73.0, 44.6, 13.6, 12.6. HRMS-ESI (m/z): Calculated for C10
87.9885, Found: 287.9891.
H
11INO (M + H)+:
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-Iodo-1-(3-(trimethylsilyl)prop-2-yn-1-yl)pyridin-2(1H)-one (1d): White solid, 0.5 g, 30% yield. M.P.:
o
1
42.7-144.5 C. H NMR (400 MHz, CDCl ) δ 6.98 – 6.90 (m, 1H), 6.81 (d, J = 6.8 Hz, 1H), 6.51 (d, J = 8.8
3
Hz, 1H), 5.08 (s, 2H), 0.15 (s, 9H). 13C NMR (100 MHz, CDCl
) δ 162.0, 140.1, 120.22, 120.17, 100.0, 98.9,
3
+
9
6
1
0.4, 44.7, -0.2. HRMS-ESI (m/z): Calculated for C11
H
15INOSi (M + H) : 331.9968, Found: 331.9968.
-Iodo-1-(3-phenylprop-2-yn-1-yl)pyridin-2(1H)-one (1e): White solid, 1.2 g, 71% yield. M.P.:
o
1
57.0-158.6 C. H NMR (400 MHz, CDCl
3
) δ 7.43 (d, J = 5.6 Hz, 2H), 7.27 (d, J = 6.0 Hz, 3H), 6.97 – 6.88
) δ
62.0, 140.1, 131.9, 128.7, 128.3, 122.4, 120.1, 100.0, 84.7, 83.0, 44.6. HRMS-ESI (m/z): Calculated for
(
m, 1H), 6.80 (d, J = 6.8 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 5.27 (s, 2H). 13C NMR (100 MHz, CDCl
3
1
+
C
14
H11INO (M + H) : 335.9885, Found: 335.9891.
1-Isocyano-4-methoxybenzene11 (2a): Green liquid, 15.6 g, 97% yield. H NMR (400 MHz, CDCl
) δ 7.31
1
3
(d, J = 8.8 Hz, 2H), 6.89 – 6.84 (m, 2H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl
) δ 162.6, 159.9, 127.7,
3
119.6, 119.4, 119.3, 114.6, 55.6.
1-Isocyano-4-methylbenzene14 (2b): Yellow liquid, 2.5 g (9.5 mm Hg, 69 C). 70% yield. H NMR (400
o
1
MHz, CDCl
δ 163.3, 139.5, 129.8, 125.9, 123.9, 123.8, 123.7, 21.1.
-Fluoro-4-isocyanobenzene15 (2c): Yellow green liquid, 2.7 g (12 mm Hg, 59 C), 49% yield. H NMR
400 MHz, CDCl ) δ 164.4, 163.4,
) δ 7.41 – 7.34 (m, 2H), 7.12 – 7.04 (m, 2H). 13C NMR (100 MHz, CDCl
) δ 108.8.
) δ 7.40 –
3
) δ 7.27 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl
3
)
o
1
1
(
3
3
1
9
1
1
7
1
1
7
4
2
1
61.0, 128.4, 128.3, 122.9, 122.8, 122.7, 122.6, 116.7, 116.4. F NMR (376 MHz, CDCl
3
-Chloro-4-isocyanobenzene11 (2d): White solid, 5.0 g, 72% yield. H NMR (400 MHz, CDCl
1
3
.35 (m, 2H), 7.32 (d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl
) δ 165.7, 135.5, 129.8, 127.7, 125.3,
3
25.1, 125.0.
-Bromo-4-isocyanobenzene11 (2e): White solid, 4.1 g, 85% yield. H NMR (400 MHz, CDCl
1
) δ 7.58 –
3
.53 (m, 2H), 7.30 – 7.25 (m, 2H). 13C NMR (100 MHz, CDCl
) δ 165.9, 132.8, 127.9, 125.6, 125.4, 123.5.
3
-Isocyanobenzonitrile13 (2f): White solid, 0.5 g, 35% yield. H NMR (400 MHz, CDCl
1
) δ 7.75 – 7.71 (m,
3
H), 7.53 – 7.48 (m, 2H). 13C NMR (100 MHz, CDCl
) δ 169.0, 133.6, 129.9, 129.7, 127.3, 117.3, 113.5.
3
-(4-Isocyanophenyl)ethan-1-one16 (2g): Green solid, 1.8 g (2.5 mm Hg, 91 C), 33% yield. H NMR (400
o
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5
5
6
MHz, CDCl
3
) δ 7.99 – 7.98 (m, 1H), 7.97 – 7.95 (m, 1H), 7.45 (d, J = 8.8 Hz, 2H), 2.60 (s, 3H). 13C NMR
(
100 MHz, CDCl
3
) δ 196.2, 167.1, 137.1, 129.4, 126.5, 26.6.
-Isocyano-2-methoxybenzene13 (2h): Yellow liquid, 1.0 g, 69% yield. H NMR (400 MHz, CDCl
1
) δ 7.37
1
–
1
1
3
7.32 (m, 2H), 6.97 – 6.90 (m, 2H), 3.93 (s, 3H). 13C NMR (100 MHz, CDCl
20.7, 116.3, 116.1, 116.0, 112.0, 56.2.
) δ 167.7, 155.1, 130.8, 127.8,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-Isocyano-2-methylbenzene16 (2i): Colorless liquid, 2.7 g (5.5 mm Hg, 51.5 C), 63% yield. H NMR (400
o
1
) δ 7.35 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 6.4 Hz, 2H), 7.25 – 7.19 (m, 1H), 2.45 (s, 3H). 13
MHz, CDCl
3
C
NMR (100 MHz, CDCl ) δ 165.8, 134.6, 130.3, 129.1, 126.5, 126.4, 126.2, 18.3.
3
Isocyanobenzene17 (2j): Green liquid, 2.0 g (12 mm Hg, 56 C), 57% yield. H NMR (400 MHz, CDCl
o
1
) δ
3
1
3
7.41 – 7.32 (m, 5H). C NMR (100 MHz, CDCl
3
) δ 164.0, 129.1, 129.0, 125.9.
-Isocyanobenzo[d][1,3]dioxole15 (2k): White solid, 1.7 g, 83% yield. H NMR (400 MHz, CDCl
1
) δ 6.90
5
3
(
dd, J = 8.2, 1.6 Hz, 1H), 6.82 (d, J = 1.6 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.03 (s, 2H). 13C NMR (100
MHz, CDCl ) δ 162.7, 148.5, 148.1, 120.9, 120.4, 120.3, 120.1, 108.5, 107.3, 102.3.
3
11
1
1
8
1
-Isocyanonaphthalene (2l): Glaucous liquid, 3.0 g, 81% yield. H NMR (400 MHz, CDCl ) δ 8.16 (d, J =
3
.4 Hz, 1H), 7.91 – 7.84 (m, 2H), 7.68 – 7.53 (m, 3H), 7.44 – 7.38 (m, 1H). 13C NMR (100 MHz, CDCl
67.3, 133.1, 129.5, 128.0, 127.6, 127.5, 127.1, 124.6, 124.1, 123.2, 123.1, 122.9, 122.4.
) δ
3
-Isocyano-3,5-dimethylbenzene11 (2m): Colorless liquid, 4.0 g (4 mm Hg, 67 C), 76% yield. H NMR
o
1
1
(
400 MHz, CDCl
3
) δ 7.00 (s, 1H), 6.96 (s, 2H), 2.30 (s, 6H). 13C NMR (100 MHz, CDCl
) δ 163.1, 139.2,
3
130.9, 126.3, 126.1, 126.0, 123.7, 20.8.
Spectral data for products
2
-Methoxyindolizino[1,2-b]quinolin-9(11H)-one6d (3a): Yellow solid, 46.5 mg, 88% yield. M.P.:
o
1
2
67.3-268.9 C. H NMR (400 MHz, CDCl ) δ 8.23 (s, 1H), 8.09 (d, J = 9.6 Hz, 1H), 7.66 (dd, J = 8.8, 6.8
3
Hz, 1H), 7.45 (dd, J = 9.2, 2.4 Hz, 1H), 7.23 (d, J = 6.8 Hz, 1H), 7.14 (d, J = 2.8 Hz, 1H), 6.69 (d, J = 8.8 Hz,
1
1
2
2
7
H), 5.24 (s, 2H), 3.97 (s, 3H). 13C NMR (100 MHz, CDCl
) δ 161.7, 158.7, 150.7, 146.5, 145.0, 140.5,
3
31.0, 129.4, 129.3, 129.1, 123.4, 119.9, 105.4, 100.3, 55.7, 50.0.
-Methylindolizino[1,2-b]quinolin-9(11H)-one6d (3b): Yellow solid, 40.0 mg, 81% yield. M.P.:
o
1
38.0-239.7 C. H NMR (400 MHz, CDCl
.62 (m, 1H), 7.60 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 6.62 (d, J = 8.8 Hz, 1H), 5.15
s, 2H), 2.48 (s, 3H). 13C NMR (100 MHz, CDCl
: CD OD = 5 : 1) δ 162.0, 151.2, 146.7, 145.9, 141.2,
3
: CD OD = 5 : 1) δ 8.24 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.69 –
3
(
3
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38.2, 133.0, 130.7, 128.4, 128.2, 128.1, 126.8, 119.3, 101.8, 49.9, 21.3.
9
-Oxo-9,11-dihydroindolizino[1,2-b]quinoline-2-carbonitrile6d (3c): Yellow solid, 28.0 mg, 54% yield.
o
1
M.P.: 297.2-298.5 C. H NMR (400 MHz, CDCl
H), 7.71 (dd, J = 8.8, 6.8 Hz, 1H), 7.35 (d, J = 6.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 5.33 (s, 2H). 13C NMR
100 MHz, CDCl ) δ 161.5, 156.0, 150.0, 145.2, 140.5, 134.3, 131.4, 131.3, 131.1, 130.5, 127.4, 122.0,
3
) δ 8.44 (s, 1H), 8.35 – 8.27 (m, 2H), 7.94 (d, J = 7.6 Hz,
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
3
118.3, 111.4, 102.2, 50.0.
o
1
2
-Acetylindolizino[1,2-b]quinolin-9(11H)-one (3d): Yellow solid, 20.5 mg, 37% yield. M.P.: >300 C. H
: CD OD = 5 : 1) δ 8.49 (s, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 6.8 Hz, 1H),
NMR (400 MHz, CDCl
3
3
8
5
1
.13 (d, J = 8.8 Hz, 1H), 7.68 (dd, J = 8.8, 6.8 Hz, 1H), 7.35 (d, J = 6.8 Hz, 1H), 6.68 (d, J = 10.0 Hz, 1H),
.21 (s, 2H), 2.67 (s, 3H). 13C NMR (100 MHz, CDCl
: CD OD = 5 : 1) δ 197.9, 162.0, 154.7, 150.4, 145.4,
3
3
41.2, 135.5, 133.1, 130.2, 130.0, 129.5, 128.7, 127.4, 120.7, 102.8, 50.0, 26.6. HRMS-ESI (m/z):
+
Calculated for C17
H
13
N
2
O
2
(M + H) : 277.0977, Found: 277.0978.
2-Fluoroindolizino[1,2-b]quinolin-9(11H)-one6d (3e): Yellow solid, 40.5 mg, 80% yield. M.P.: 262.9-264.4
o
1
C. H NMR (400 MHz, CDCl
(m, 1H), 7.49 (t, J = 9.2 Hz, 2H), 7.30 (d, J = 6.8 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 5.18 (s, 2H). 13C NMR
(100 MHz, CDCl : CD OD = 5 : 1) δ 162.4, 162.1, 160.0, 152.1, 145.7, 145.6, 141.3, 131.6, 131.5, 130.9,
130.8, 129.4, 129.1, 129.0, 121.2, 120.9, 111.5, 111.3, 102.0, 50.0. 19F NMR (376 MHz, CDCl
: CD OD =
3
: CD
3
OD = 5 : 1) δ 8.31 (s, 1H), 8.09 (dd, J = 8.8, 5.2 Hz, 1H), 7.70 – 7.62
3
3
3
3
5
: 1) δ -33.05 (td, J = 8.3, 5.5 Hz).
-Chloroindolizino[1,2-b]quinolin-9(11H)-one (3f): Yellow solid, 37.9 mg, 71% yield. M.P.: >300 C. H
: CD OD = 5 : 1) δ 8.27 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H),
.66 (dd, J = 8.8, 7.2 Hz, 2H), 7.31 (d, J = 6.8 Hz, 1H), 6.65 (d, J = 9.2 Hz, 1H), 5.18 (s, 2H). 13C NMR (100
o
1
2
NMR (400 MHz, CDCl
3
3
7
MHz, CDCl
3
: CD
3
OD = 5 : 1) δ 166.0, 156.8, 150.9, 150.0, 145.2, 137.8, 135.6, 134.57, 134.56, 133.5,
+
1
2
2
32.7, 130.8, 124.2, 106.2, 54.0. HRMS-ESI (m/z): Calculated for C15
69.0480.
-Bromoindolizino[1,2-b]quinolin-9(11H)-one6d (3g): Yellow solid, 36.0 mg, 57% yield. M.P.: >300 C. H
: CD OD = 5 : 1) δ 8.27 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H),
.78 (dd, J = 8.8, 2.0 Hz, 1H), 7.66 (dd, J = 9.2, 7.2 Hz, 1H), 7.31 (dd, J = 7.2, 1.2 Hz, 1H), 6.66 (d, J = 9.2
Hz, 1H), 5.19 (s, 2H). 13C NMR (100 MHz, CDCl
: CD OD = 5 : 1) δ 162.0, 154.1, 152.8, 147.1, 145.6,
41.3, 134.1, 130.6, 130.2, 129.5, 129.2, 122.0, 120.2, 102.4, 50.1.
H
10ClN
2
O (M + H) : 269.0482, Found:
o
1
NMR (400 MHz, CDCl
3
3
7
3
3
1
4
-Methoxyindolizino[1,2-b]quinolin-9(11H)-one (3h): Yellow solid, 32.6 mg, 62% yield. M.P.:
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2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
2
1
82.4-283.7 C. H NMR (400 MHz, CDCl
H), 7.48 (dd, J = 8.0, 1.2 Hz, 1H), 7.40 (dd, J = 6.8, 0.8 Hz, 1H), 7.15 (dd, J = 7.6, 1.2 Hz, 1H), 6.72 (dd, J
9.2, 1.2 Hz, 1H), 5.27 (d, J = 0.8 Hz, 2H), 4.14 (s, 3H). 13C NMR (100 MHz, CDCl
) δ 161.6, 155.5, 151.9,
3
) δ 8.34 (s, 1H), 7.66 (dd, J = 9.2, 6.8 Hz, 1H), 7.58 – 7.53 (m,
=
3
1
46.0, 140.8, 140.4, 130.9, 129.3, 129.2, 128.0, 120.4, 120.0, 108.5, 101.5, 56.3, 49.9. HRMS-ESI (m/z):
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
Calculated for C16
H
13
N
2
O
2
(M + H) : 265.0977, Found: 265.0977.
4
-Methylindolizino[1,2-b]quinolin-9(11H)-one6d (3i): Yellow solid, 21.0 mg, 42% yield. M.P.: 227.1-228.8
o
1
C. H NMR (400 MHz, CDCl ) δ 8.22 (s, 1H), 7.69 – 7.61 (m, 2H), 7.59 (d, J = 7.2 Hz, 1H), 7.47 (t, J = 7.6
3
Hz, 1H), 7.25 (d, J = 6.4 Hz, 1H), 6.69 (d, J = 9.2 Hz, 1H), 5.19 (s, 2H), 2.84 (s, 3H). 13C NMR (100 MHz,
CDCl ) δ 161.7, 151.8, 148.0, 146.7, 140.4, 137.9, 130.9, 130.4, 128.2, 128.1, 127.5, 126.1, 120.3, 100.8,
0.0, 18.1.
Indolizino[1,2-b]quinolin-9(11H)-one (3j): Yellow solid, 35.0 mg, 75% yield. M.P.: 244.0-245.4 C. H
NMR (400 MHz, CDCl ) δ 8.33 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 7.6
Hz, 1H), 7.71 – 7.58 (m, 2H), 7.29 (d, J = 6.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 5.25 (s, 2H). 13C NMR (100
3
5
7
o
1
3
MHz, CDCl
101.1, 50.0.
3
) δ 161.7, 153.1, 148.9, 146.2, 140.5, 131.0, 130.5, 129.8, 128.7, 128.22, 128.15, 127.8, 120.7,
[1,3]Dioxolo[4,5-g]indolizino[1,2-b]quinolin-9(11H)-one7 (3k): White solid, 30.5 mg, 55% yield.
o
1
M.P.: >300 C. H NMR (400 MHz, CDCl
H), 7.22 (d, J = 6.8 Hz, 1H), 7.06 (s, 1H), 6.57 (d, J = 8.8 Hz, 1H), 6.06 (s, 2H), 5.09 (s, 2H). 13C NMR
150 MHz, CDCl : CD OD = 5 : 1) δ 162.1, 150.8, 145.9, 144.9, 144.2, 141.3, 141.2, 128.2, 123.6, 123.0,
19.6, 114.7, 114.4, 102.8, 101.9, 50.1.
3
: CD OD = 5 : 1) δ 8.13 (s, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.31 (s,
3
1
(
3
3
1
7
[
1,3]Dioxolo[4,5-f]indolizino[1,2-b]quinolin-10(12H)-one (3k'): Yellow solid, 5 mg, 9% yield. M.P.: >300
o
1
C. H NMR (400 MHz, CDCl
3
: CD
3
OD = 5 : 1) δ 8.29 (s, 1H), 7.70 – 7.62 (m, 2H), 7.39 (d, J = 8.8 Hz,
: CD OD
5 : 1) δ 162.2, 152.1, 150.0, 149.3, 147.1, 146.4, 141.4, 130.1, 127.3, 126.1, 118.9, 104.8, 103.0, 102.4,
1
H), 7.28 (s, 1H), 6.62 (d, J = 9.2 Hz, 1H), 6.16 (s, 2H), 5.16 (s, 2H). 13C NMR (150 MHz, CDCl
3
3
=
1
01.4, 50.1.
Benzo[h]indolizino[1,2-b]quinolin-10(8H)-one (3l): Yellow solid, 43.4 mg, 76% yield as a mixture of 3l :
o
1
3
l' = 5 : 1. M.P.: 241.7-243.5 C. H NMR (400 MHz, CDCl
.88 (m, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.77 – 7.72 (m, 2H), 7.68 (dd, J = 9.2, 7.2 Hz, 2H), 7.31 (d, J = 6.8
) δ 161.7, 151.2, 147.5, 146.8,
40.5, 133.8, 131.3, 130.5, 129.5, 129.1, 129.0, 128.0, 127.5, 126.6, 125.3, 124.7, 120.0, 100.7, 50.2.
3
) δ 9.34 (d, J = 7.2 Hz, 1H), 8.21 (s, 1H), 7.92 –
7
Hz, 1H), 6.71 (d, J = 9.2 Hz, 1H), 5.18 (s, 2H). 13C NMR (100 MHz, CDCl
3
1
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+
HRMS-ESI (m/z): Calculated for C19
H
13
N
2
O (M + H) : 285.1028, Found: 285.1030.
1
,3-Dimethylindolizino[1,2-b]quinolin-9(11H)-one (3m): Yellow solid, 50.0 mg, 92% yield. M.P.:
o
1
2
91.2-292.3 C. H NMR (400 MHz, CDCl ) δ 8.40 (s, 1H), 7.81 (s, 1H), 7.65 (dd, J = 9.2, 7.2 Hz, 1H), 7.26
3
(
t, J = 8.0 Hz, 2H), 6.70 (d, J = 9.2 Hz, 1H), 5.21 (s, 2H), 2.69 (s, 3H), 2.54 (s, 3H). 13C NMR (100 MHz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl
3
) δ 161.8, 152.4, 150.0, 146.5, 140.6, 140.5, 134.4, 130.8, 127.6, 127.2, 126.9, 125.8, 120.3, 100.8,
+
5
2
2
0.2, 22.0, 19.0. HRMS-ESI (m/z): Calculated for C17
H
15
N
2
O (M + H) : 263.1184, Found: 263.1188.
-Methoxy-12-methylindolizino[1,2-b]quinolin-9(11H)-one (3n): Yellow solid, 38.0 mg, 68% yield. M.P.:
o
1
66.6-268.0 C. H NMR (400 MHz, CDCl ) δ 8.05 (d, J = 9.2 Hz, 1H), 7.64 (dd, J = 8.8, 6.8 Hz, 1H), 7.41
3
(
dd, J = 9.2, 2.8 Hz, 1H), 7.20 – 7.15 (m, 2H), 6.67 (d, J = 8.8 Hz, 1H), 5.13 (s, 2H), 3.97 (s, 3H), 2.66 (s,
3
1
2
H). 13C NMR (100 MHz, CDCl
) δ 161.8, 158.7, 149.9, 147.1, 144.9, 140.6, 137.7, 131.8, 129.2, 128.2,
3
(M + H)+:
22.5, 119.8, 101.8, 100.3, 55.7, 49.8, 15.5. HRMS-ESI (m/z): Calculated for C17
79.1134, Found: 279.1135.
H
15
N
2
O
2
12-Ethyl-2-methoxyindolizino[1,2-b]quinolin-9(11H)-one (3o): Yellow solid, 44.2 mg, 76% yield. M.P.:
o
1
209.4-210.9 C. H NMR (400 MHz, CDCl
8.8 Hz, 1H), 7.19 (s, 1H), 7.13 (d, J = 6.8 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 5.11 (s, 2H), 3.94 (s, 3H), 3.03
(q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl
) δ 161.7, 158.7, 150.1, 147.1,
3
) δ 8.03 (d, J = 9.2 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.38 (d, J =
3
145.3, 143.4, 140.5, 131.9, 128.0, 127.2, 122.2, 119.7, 101.6, 100.3, 55.7, 49.3, 23.1, 13.6. HRMS-ESI (m/z):
+
Calculated for C18
H
17
N
2
O
2
(M + H) : 293.1290, Found: 293.1290.
2
-Methoxy-12-(trimethylsilyl)indolizino[1,2-b]quinolin-9(11H)-one (3p): Yellow solid, 60.0 mg, 89%
o
1
yield. M.P.: 286.0-287.9 C. H NMR (400 MHz, CDCl
3
) δ 8.09 (d, J = 9.2 Hz, 1H), 7.64 (dd, J = 8.8, 7.2 Hz,
1
1
1
H), 7.48 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 9.2, 2.4 Hz, 1H), 7.20 (d, J = 6.8 Hz, 1H), 6.67 (d, J = 9.2 Hz,
H), 5.27 (s, 2H), 3.96 (s, 3H), 0.64 (s, 9H). 13C NMR (100 MHz, CDCl
3
) δ 161.6, 158.1, 149.5, 146.6, 144.0,
41.4, 140.6, 135.3, 133.3 132.2, 122.0, 119.7, 107.0, 100.0, 55.7, 51.9, 1.6. HRMS-ESI (m/z): Calculated
+
for C19
H
21
N
2
O
2
Si (M + H) : 337.1372, Found: 337.1375.
2
-Methoxy-12-phenylindolizino[1,2-b]quinolin-9(11H)-one (3q): Yellow solid, 41.2 mg, 61% yield. M.P.:
o
1
275.2-277.0 C. H NMR (400 MHz, CDCl
3
) δ 8.15 (d, J = 9.6 Hz, 1H), 7.70 – 7.65 (m, 1H), 7.63 – 7.53 (m,
3H), 7.46 (t, J = 6.8 Hz, 3H), 7.28 (s, 1H), 7.06 (s, 1H), 6.68 (d, J = 8.8 Hz, 1H), 5.07 (s, 2H), 3.79 (s, 3H).
13C NMR (100 MHz, CDCl
) δ 161.7, 158.9, 150.3, 147.0, 145.7, 142.5, 140.6, 135.0, 131.4, 129.4, 129.3,
3
128.8, 128.4, 128.0, 122.8, 119.9, 103.9, 100.5, 55.6, 50.2. HRMS-ESI (m/z): Calculated for C22
H
17
N
2
2
O (M
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1
1
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1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
H) : 341.1290, Found: 341.1295.
1-(Prop-2-yn-1-yl)pyridin-2(1H)-one18 (4a): Brown liquid , 14% NMR yield. H NMR (400 MHz, CDCl
1
)
3
δ 7.62 – 7.55 (m, 1H), 7.34 – 7.26 (m, 1H), 6.51 (dd, J = 8.8, 3.6 Hz, 1H), 6.23 – 6.13 (m, 1H), 4.70 (t, J =
2
7
.8 Hz, 2H), 2.46 (m, 1H). 13C NMR (101 MHz, CDCl
5.38, 37.61.
3
) δ 161.97, 139.80, 135.90, 120.60, 106.34, 76.97,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ASSOCIATED CONTENT
SUPPORTING INFORMATION
The NMR spectra is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
The authors acknowledge the financial support provided by the National Natural Science Foundation of
China (No. 21232003). We also express gratitude for the support and valuable suggestions regarding
SC-XRD measurements from Ms. Xiao-li Bao and Ms. Ling-ling Li of the Instrumental Analysis Center of
Shanghai Jiao Tong University.
REFERENCES
(
1) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail, A. T.; Sim, G. A. J. Am. Chem. Soc.
1966, 88, 3888-3890.
(
(
2) Ormrod, D.; Spencer, C. M. Drugs 1999, 58, 533-551.
3) Kalra, A. V.; Kim, J.; Klinz, S. G.; Paz, N.; Cain, J.; Drummond, D. C.; Nielsen, U. B.; Fitzgerald, J. B.
Cancer Research 2014, 74, 7003-7013.
4) Perzyna, A.; Marty, C.; Facompré, M.; Goossens, J.-F.; Pommery, N.; Colson, P.; Houssier, C.; Houssin,
R.; Hénichart, J.-P.; Bailly, C. J. Med. Chem. 2002, 45, 5809-5812.
5) (a) Meyers, A. I.; Nolen, R. L.; Collington, E. W.; Narwid, T. A.; Strickland, R. C. J. Org. Chem. 1973,
(
(
38, 1974-1982. (b) Corey, E. J.; Crouse, D. N.; Anderson, J. E. J. Org. Chem. 1975, 40, 2140-2141. (c) Tang,
C. S. F.; Morrow, C. J.; Rapoport, H. J. Am. Chem. Soc. 1975, 97, 159-167. (d) Wani, M. C.; Ronman, P. E.;
Lindley, J. T.; Wall, M. E. J. Med. Chem. 1980, 23, 554-560. (e) Comins, D. L.; Baevsky, M. F.; Hong, H. J.
Am. Chem. Soc. 1992, 114, 10971-10972. (f) Shen, W.; Coburn, C. A.; Bornmann, W. G.; Danishefsky, S. J. J.
Org. Chem. 1993, 58, 611-617. (g) Fang, F. G.; Xie, S.; Lowery, M. W. J. Org. Chem. 1994, 59, 6142-6143.
(
h) Du, W.; Curran, D. P. Synlett 2003, 9, 1299-1302. (i) Peters, R.; Althaus, M.; Nagy, A.-L. Org. Biomol.
Chem. 2006, 4, 498-509. (j) Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. J. Org. Chem. 2007, 72, 6270-6272. (k)
Peters, R.; Diolez, C.; Rolland, A.; Manginot, E.; Veyrat, M. Heterocycles 2007, 72, 255-273. (l) Zhang,
L.-P.; Bao, Y.; Kuang, Y.-Y.; Chen, F.-E. Helv. Chim. Acta 2008, 91, 2057-2061. (m) Yu, S.; Huang, Q. Q.;
Luo, Y.; Lu, W. J. Org. Chem. 2012, 77, 713-717. (n) Li, K.; Ou, J.; Gao, S. Angew. Chem. Int. Ed. 2016, 55,
14778-14783.
(
6) (a) Comins, D. L.; Nolan, J. M. Org. Lett. 2001, 3, 4255-4257. (b) Nguyen, T.; Wicki, M. A.; Snieckus,
V. J. Org. Chem. 2004, 69, 7816-7821. (c) Dai, W.; Petersen, J. L.; Wang, K. K. Org. Lett. 2006, 8,
4665-4667. (d) Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. Org. Lett. 2007, 9, 2003-2006.
(
(
7) Curran, D. P.; Liu, H.; Josien, H.; Ko, S.-B. Tetrahedron 1996, 52, 11385-11404.
8) Curran, D. P.; Du, W. Org. Lett. 2002, 4, 3215-3218.
(9) (a) Narayanam, J. M.; Stephenson, C. R. Chem. Soc. Rev. 2011, 40, 102-113. (b) Shi, L.; Xia, W. Chem.
ACS Paragon Plus Environment

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2
3
4
5
6
7
8
9
Soc. Rev. 2012, 41, 7687-7697. (c) Prier, C. K.; Rankic, D. A.; Macmillan, D. W. Chem. Rev. 2013, 113,
5
322-5363. (d) Chen, J. R.; Hu, X. Q.; Lu, L. Q.; Xiao, W. J. Chem. Soc. Rev. 2016, 45, 2044-2056. (e) Kim,
H.; Lee, C. Angew. Chem. Int. Ed. 2012, 51, 12303-12306. (f) Cheng, J.; Li, W.; Duan, Y.; Cheng, Y.; Yu,
S.; Zhu, C. Org. Lett. 2017, 19, 214-217. (g) Tutkowski, B.; Meggers, E.; Wiest, O. J. Am. Chem. Soc. 2017,
139, 8062-8065. (h) Primer, D. N.; Molander, G. A. J. Am. Chem. Soc. 2017, 139, 9847-9850. (i) Zhao, J.;
Brosmer, J. L.; Tang, Q.; Yang, Z.; Houk, K. N.; Diaconescu, P. L.; Kwon, O. J. Am. Chem. Soc. 2017, 139,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
807-9810. (j) Huang, H.; Yu, C.; Zhang, Y.; Zhang, Y.; Mariano, P. S.; Wang, W. J. Am. Chem. Soc. 2017,
139, 9799-9802.
(
10) (a) Sun, X.; Yu, S. Synlett 2016, 27, 2659-2675. (b) Jiang, H.; Cheng, Y.; Wang, R.; Zheng, M.; Zhang,
Y.; Yu, S. Angew. Chem., Int. Ed. 2013, 52, 13289-13292. (c) Jiang, H.; Cheng, Y.; Wang, R.; Zhang, Y.;
Yu, S. Chem. Commun. 2014, 50, 6164-6167. (d) Jiang, H.; Cheng, Y.; Zhang, Y.; Yu, S. Org. Lett. 2013, 15,
4
884-4887. (e) Xiao, T.; Dong, X.; Tang, Y.; Zhou, L. Adv. Synth. Catal. 2012, 354, 3195-3199. (f) Deng,
G.-B.; Wang, Z.-Q.; Xia, J.-D.; Qian, P.-C.; Song, R.-J.; Hu, M.; Gong, L.-B.; Li, J.-H. Angew. Chem. Int.
Ed. 2013, 52, 1535-1538. (g) Hari, D. P.; Hering, T.; König, B. Org. Lett. 2012, 14, 5334-5337.
(
(
(
(
(
11) Sun, X.; Li, J.; Ni, Y.; Ren, D.; Hu, Z.; Yu, S. Asian J. Org. Chem. 2014, 3, 1317-1325.
12) Brahmachari, G.; Laskar, S. Tetrahedron Lett. 2010, 51, 2319-2322.
13) Kamijo, S.; Jin, T.; Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 9453-9454.
14) Kim, S.; Hong, S. H. Adv. Synth. Catal. 2015, 357, 1004-1012.
15) Kerschgens, I. P.; Gademann, K. Synthesis 2015, 47, 3153-3160.
(16) Dumonteil, G.; Hiebel, M. A.; Scherrmann, M. C.; Berteina-Raboin, S. RSC Adv. 2016, 6,
3517-73521.
17) Zakrzewski, J.; Huras, B.; Kiełczewska, A. Synthesis 2016, 48, 85-96.
7
(
(18) Casaschi, A.; Grigg, R.; Sansano, J. M. Tetrahedron 2001, 57, 607-615.
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