-Annulation of gem-Difluoroalkenes and Pyridinium Ylides: Access to Functionalized 2-Fluoroindolizines

Article abstract of DOI:10.1021/acs.joc.0c03041

A [3 + 2]-annulation of gem-difluoroalkenes and pyridinium ylides was developed employing ambient air as the sole oxidant in an open-vessel manner, affording a series of multifunctionalized 2-fluoroindolizines in moderate to good yields. In this reaction, gem-difluoroalkene acts as a C2 synthon and entirely avoids the competitive addition-elimination process, which provides facile access to 2-fluoroindolizines.

Full text of DOI:10.1021/acs.joc.0c03041

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[3 + 2]-Annulation of gem-Difluoroalkenes and Pyridinium Ylides:
Access to Functionalized 2‑Fluoroindolizines
Jun-Qi Zhang, Dandan Hu, Jinyu Song, and Hongjun Ren*
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ABSTRACT: A [3 + 2]-annulation of gem-difluoroalkenes and pyridinium ylides was developed employing ambient air as the sole
oxidant in an open-vessel manner, affording a series of multifunctionalized 2-fluoroindolizines in moderate to good yields. In this
reaction, gem-difluoroalkene acts as a C2 synthon and entirely avoids the competitive addition−elimination process, which provides
facile access to 2-fluoroindolizines.
methods for the synthesis of novel analogues bearing multiple
functional groups such as aryl, alkyl, halogen, ester, and amide,
aiming to ameliorate relevant pharmaceutical effects.10
INTRODUCTION
■
Indolizines, as a privileged structural skeleton, are widely
presented in many natural alkaloids,1 agrochemicals,2 and
pharmacochemistry.3 Moreover, numerous substituted indoli-
zines4 have been found to exhibit broad-spectrum bioactivities
such as antitubercular,5 antibacterial,6 antineoplastic,7 antiin-
flammatory,8 and antioxidant9 (Figure 1). Encouraged by that,
considerable efforts have been devoted to developing new
It is well-known that the introduction of fluorine atom(s)
into organic frameworks could significantly affect their
physical, chemical, and/or biological properties. However,
few facile approaches for fixing fluorinated groups (F, CF3,
HCF2, ClC3F6, ClCF2) on indolizines skeletons were
documented,11 although multifarious strategies to incorporate
fluorinated functional groups on heterocycles have been
successfully established by several research groups,12 Recently,
Tabolin and co-workers13 developed an oxidative [3 + 2]
annulation of nitroalkenes and pyridinium ylides, providing a
general route to 1-fluoroindolizines derivatives but requiring
excess amount of copper(II) as oxidant (Scheme 1a). In 2003,
Chen and his co-worker14 reported an elegant approaches to
synthesize of 2-fluoroindolizines and 1,2-difluoroindolizines via
[3 + 2] cycloaddition of fluoroalkenes (CF2CFX, X = Cl, Br,
CF3) with pyridinium ylides. Soon afterward, Wu, Wang, and
co-workers15 used a similar cyclization strategy to achieve the
Received: January 10, 2021
Published: March 8, 2021
Figure 1. Representative bioactive indolizine derivatives.
https://dx.doi.org/10.1021/acs.joc.0c03041
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a
Scheme 1. Strategies for the Construction of Functionalized
Fluoroindolizines
Table 1. Optimization of the Reaction Conditions
entry
solvent
DMF
DMF
DMF
DMF
base
Et3N
DBU
T (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
80
12
12
12
24
24
24
24
24
12
12
12
48
28
24
12
5
37
15
50
51
57
KOAc
Cs2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
73
CH3CN
CHCl3
DMSO
dioxane
MeOH
THF
dioxane
DMF
DMF/dioxane
DMF/dioxane
trace
trace
31
59
27
39
68
73
77
9
10
11
12
b
13
b
14
15
b
b
16
62
a
General reaction conditions: 1a (0.6 mmol, 1.5 equiv), 2a (0.4
synthesis of 2-fluoroindolizines, in which fluorinated vinyl
tosylate (CF2CFOTs) was utilized as the fluorinated
building block (Scheme 1b). Intriguingly, members of the
fluoroindolizine family, 1,3-disubstituted 2-fluoroindolizines,
were identified as a powerful inhibitor of retinoic acid related
orphan receptor γ (RORγ). However, the current synthetic
routes are still inefficient, relying on a sequential halogenation
and palladium-catalyzed cross-coupling process from mono-
fluorinated indolizines (Scheme 1c).16 Very recently, Fen-
sterbank et al.17 reported a straightforward access to 1,3-
disubstituted 2-fluoroindolizines via Selectfluor-mediated 5-
endo-trig cyclization of 2-pyridylallenes but with only one case
in 41% yield. Therefore, developing a general, mild and metal-
free protocol toward the synthesis of 1,3-disubstituted 2-
fluoroindolizines (Figure 1) is highly desirable.
mmol, 1.0 equiv), base (0.8 mmol, 2.0 equiv), solvent (2.0 mL), 60
°C, under air. 1a (0.8 mmol, 2.0 equiv), 2a (0.4 mmol, 1.0 equiv).
b
employed as the solvent (Table 1, entries 7 and 8). In addition,
several other common solvents such as DMSO, dioxane,
MeOH, and THF were also tested, but only lower yields were
observed for this transformation (Table 1, entries 9−12).
Finally, adjusting the ratio of reactants and employing mixed
solvent slightly enhanced the yield to 77% (Table 1, entry 15).
Thus, the optimal reaction conditions were established as
follows: 1a (2.0 equiv), 2a (1.0 equiv), and K2CO3 (2.0 equiv)
in a mixture of DMF and dioxane (v/v = 1/1) at 60 °C under
air.
Rencently, gem-difluoroalkenes have emerged as versatile
fluorinated synthons in organic synthesis, which have been
successfully converted to diverse fluorides.18 Hence, we
envisioned that it can serve as a electrophilic species reacting
with pyridinium ylides in situ generated from pyridinium salts,
affording the desired 2-fluoroindolizines (Scheme 1d).
With the optimized reaction conditions in hand, the issues
with respect to functional group tolerance and scope of gem-
difluoroalkenes were then investigated, and the related
outcomes are summarized in Scheme 2. Generally, monoaryl-
substituted substrates were applicable. In the case of substrates
having an electron-withdrawing group such as −CO2Me, −F,
−Cl, −Br, and −CF3 at the para-position of the aryl group,
these transformations proceeded smoothly to give the
corresponding products in modest to good yields (41−77%).
Moreover, the structure of 3e was unambiguously determined
by X-ray diffraction analysis. Meta-position-substituted sub-
strate 2f and ortho-substituted substrates 2g and 2h underwent
the reaction without any problem to provide the corresponding
3f−3h with modest yields (45−67%). Furthermore, substrates
bearing disubstituted groups 2i−2n on the aryl group were all
well compatible, and the corresponding 3i−3n were obtained
in 32−70% yields. Notably, condensed aromatics such as 2-
naphthalene 2o and heterocycles such as Ts-protected indole
2p and brominated thiophene 2q were also suitable for the
reaction to give the desired products 3o, 3p, and 3q in modest
to good yields (42−68%). In addition, some aliphatic
difluoroalkenes (2y, 2z) were also investigated in this
reaction.19a However, these reactions failed to give the desired
RESULTS AND DISCUSSION
■
We began the investigation by choosing pyridinium salt 1a and
gem-difluoroalkenes 2a as the model substrates (Table 1). To
our delight, in the presence of 2 equiv of Et3N and open air in
DMF at 60 °C, the desired product 3a was isolated in 37%
yield after 12 h (Table 1, entry 1). Subsequently, other bases
such as DBU, KOAc, Cs2CO3, and K2CO3 were screened for
this transformation (Table 1, entries 2−6), among which
K2CO3 was found to be the most efficient base, delivering the
adduct 3a in 73% yield (Table 1, entry 6). Then, to further
improve the reactivity of the cyclization, other reaction
parameters including solvents and the reaction temperatures
were also examined (Table 1, entries 7−16). The outcomes
showed that the solvents have a great influence on the
reactivity of the reaction. For instance, the conversion was
almost completely suppressed when CHCl3 or CH3CN was
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a
We then turned our attention to examining pyridinium salts.
When −CN was employed to replace the −CO2Et, these
reactions worked well with different substituents on the
aromatic ring of gem-difluoroalkenes such as 4-CO2Me, 4-Br,
and 2-Br, In addition, C2/3/4 methyl-substituted pyridinium
salts also displayed good compatibility with 44−53% yields.
Interestingly, 3-methylpyridine exhibited medium regioselec-
tivity with a ratio of 1:3. Moreover, isonicotinic acid derived
pyridinium salt 1i also could be well tolerated with a slight
decrease in yield (41%). However, the yield suffered great
erosion when C4 methoxy-substituted pyridinium salt 1h was
employed as the reaction partner, giving the desired product 3y
with only 9% yield. It is noteworthy that 4-methylisoquinoline/
isoquinoline-derived pyridinium salt showed excellent regiose-
lectivity in 53−56% yields. After that, this cycloaddition was
further explored with styryl-substituted gem-difluoroalkenes
with various pyridinium salts, which were proven to be
compatible in this reaction, delivering products 3ab−3af with
55−71% yields. Regrettably, other representative pyridinium
salts, such as 1-(2-oxo-2-phenylethyl)pyridin-1-ium bromide
1j, were also investigated in this transformation.19b However,
according to the TLC observation, the corresponding reactions
are very messy or only trace product was observed. It is
noteworthy that a majority of cases exhibited medium yields,
which may be caused by slight decomposition of substrates 2
and some indeterminate side reactions under standard
conditions.
Scheme 2. Substrate Scope of the [3 + 2] Annulation
Next, we attempted to extend the methods to late-stage
modifications of natural products (Scheme 2). Gratifyingly,
gem-difluoroalkenes derived from natural products such as
(−)-menthol, (+)-fenchol, epiandrosterone, cholesterol, and L-
phenylalanine could undergo the cyclization to furnish the
target products 4a−4e in moderate yields (47−71%). The
successful introduction of the 2-fluoroindolizines into such
natural products illustrates the robustness of this protocol.
Synthetic transformations were performed to demonstrate the
synthetic utility of the 2-fluoroindolizine product 3t. The
cyano group in alkaline solution could be efficiently hydrolyzed
to give the corresponding 2-fluoroindolizine-3-carboxylic acid
5a in 93% yield (Scheme 3a), which could serve as a synthetic
precursor. Meanwhile, the adduct 3-cyano-2-fluoroindolizine-
3-carbonitrile (3t) could be readily functionalized by Pd-
catalyzed Suzuki−Miyaura cross-coupling to generate the
biaryl compound 5b in 95% yield (Scheme 3b). Furthermore,
the bromo-containing 2-fluoroindolizine was further modified
with aminopyrimidin-5-ylboronic acid. The ethyl 1-(2-
bromophenyl)-2-fluoroindolizine-3-carboxylate (3g) reacted
with 2-aminopyrimidin-5-yl boronic acid under the standard
Suzuki−Miyaura cross-coupling reaction conditions, providing
the corresponding aminopyrimidinyl analogue 5c in 86% yield
(Scheme 3c). Under the same conditions, the 1-(3-
bromophenyl)-2-fluoroindolizine-3-carboxylate and 1-(4-bro-
mophenyl)-2-fluoroindolizine-3-carboxylate were converted to
their corresponding products 5d and 5e smoothly in 57% and
91% yields, respectively. To demonstrate the practical utility of
the approach. A gram-scale synthesis of 3p was performed in
the presence of 1.3 equiv 1a under standard conditions. As a
result, the amount of 1.14 g of the desired product 3p was
readily isolated through column chromatography in 60% yield
(Scheme 3d).
a
General reaction conditions: 1a (0.8 mmol, 2.0 equiv), 2a (0.4
mmol, 1.0 equiv), K2CO3 (0.8 mmol, 2.0 equiv), solvent (2.0 mL), 60
°C, under air. Reaction temperature = 80 °C.
b
Ultimately, a plausible mechanism is proposed as depicted in
Scheme 4. On the basis of literature precedents,13,20 the
stepwise anionic mechanism is speculated as the more likely
products under standard conditions, which may be caused by
their lower activity than aryl difluoroalkenes.
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Scheme 3. Transformations of 2-Fluoroindolizines
glassware with magnetic stirring, and all reagents obtained from
commercial suppliers were used without further purification.
Reactions were monitored by thin-layer chromatography (TLC) on
silica gel precoated glass plates (0.2 0.03 mm thickness, GF-254,
particle size 0.01−0.04 mm) from Yantai Chemical Industry Research
Institute. TLC were visualized by UV fluorescence (254 nm). Flash
column chromatography was performed with silica gel (particle size
Scheme 4. Mechanistic Proposal
1
0.04−0.05 mm). H NMR 13C NMR, and 19F NMR spectroscopic
data were recorded using Bruker AMX-400 instrument and calibrated
by using the residual solvent peaks as an internal reference (CDCl3
[1H: 7.26, 13C: 77.16]; DMSO [1H: 2.5, 13C: 39.52] and external
CCl3F, respectively. Coupling constants (J) are given in hertz. X-ray
data were recorded on a Bruker APEX-II diffractomrter. High-
resolution mass spectra (HRMS) for all the compounds were
determined on a Micromass GCT-TOF mass spectrometer with
ESI or CI resource.
Substrate Synthesis. 1-(2-Ethoxy-2-oxoethyl)pyridin-1-ium bro-
mide (1a), 1-(cyanomethyl)pyridin-1-ium bromide (1b), 1-(2-
ethoxy-2-oxoethyl)-2-methylpyridin-1-ium bromide (1c), 1-(2-
ethoxy-2-oxoethyl)-2-methylpyridin-1-ium bromide (1d), 1-(2-
ethoxy-2-oxoethyl)-4-methylpyridin-1-ium bromide (1e), 2-(2-
ethoxy-2-oxoethyl)isoquinolin-2-ium bromide (1f), 1-(2-ethoxy-2-
oxoethyl)-4-methoxypyridin-1-ium bromide (1h), and 1-(2-ethoxy-
2-oxoethyl)-4-(ethoxycarbonyl)pyridin-1-ium (1i) were prepared
according to a previously literature procedure:21 To a solution of
pyridines (1 equiv) in THF (0.2 M) was dropwise added alkyl
bromide (1 equiv) at room temperature. After the mixture was stirred
for 24 h at room temperature, the resulting precipitate was filtered off,
washed with Et2O (50 mL), and recrystallized from methanol/toluene
(1:1,10 mL) to give the corresponding pyridinium salts.
Synthesis of 2-(2-Ethoxy-2-oxoethyl)-4-methylisoquinolin-
2-ium Bromide (1g). Step 1: 4-Methylisoquinoline S-2 were
prepared by a modified procedure according to a previously literature
procedure:22a To a solution of 4-bromoisoquinoline S-1 (5.00 g, 24
mmol) in THF (100 mL) under argon were added Ni(PPh)3Cl2 (26
mg, 1 mol %) and methylmagnesium chloride (9.3 mL, 28 mmol, 3 M
in THF). The solution was stirred at room temperature for 18 h,
acidified to pH 1−3 with 1 M HCl, and extracted with EtOAc (3 × 30
mL). The organic layers were combined, dried (Na2SO4), and
concentrated in vacuo. The crude material was purified by silica gel
chromatography (EtOAc/petroleum ether, 1:10) to give 4-methyl-
isoquinoline S-2 (3.4 g, 86%) as a yellow oil.
Step 2: In a 50 mL round-bottom flask, isoquinoline S-2 (5 mmol,
1 equiv) and ethyl bromoacetate (5.5 mmol, 1.1 equiv) in EtOH (5
mL per mmol) were placed. The mixture was heated (oil bath) under
reflux until complete disappearance (detected by TLC) of the starting
materials. Then the reaction was cooled to room temperature. After
an evaporation of the volatile organic solvents, the crude residue was
purified by flash chromatography (silica gel, MeOH/DCM, 1:20) to
give the N-Ar-isoquinolinium salts 1g (1.4 g, 92%) as a white solid.
scenario, although the concerted pathway cannot be
completely excluded. First, pyridinium ylide A, generated by
deprotonation of pyridinium salt 1, attacks the gem-
difluoroalkene 2 to form an intermediate B. Subsequently, B
undergoes an intramolecular ring-closure process, resulting in
the formation of tetrahydroindolizine C which would undergo
β-F elimination to form the intermediate D. Finally, the 2-
fluoroindolizine product 3 is formed through spontaneous
oxidation process (path a). Alternatively, another parallel
reaction pathway (path b) for the formation of product 3 via
sequential oxidation and β-F elimination processes cannot be
excluded according to HRMS experimental observations (see
the Supporting Information for details). In addition, the high
electron-withdrawing property of the two fluorine atoms and
smaller steric hindrance of the terminal CF2 group compared
to the aromatic ring lead to excellent regioselectivity of this
cycloaddition. Therefore, the regioisomer 3′ was not detected
in the reaction.
CONCLUSIONS
■
In conclusion, we have developed a simple and efficient
method for straightforward access to a wide range of C1
functionalized 2-fluoroindolizines by base-mediated [3 + 2]
annulation of gem-difluoroalkenes and pyridinium ylides under
mild conditions. The advantages of this protocol are readily
available starting materials, operational simplicity, inexpensive
reagents and good functional group compatibility, thus
providing a useful route for applications in organic synthesis
and drug discovery.
EXPERIMENTAL SECTION
General Experimental Details. Unless otherwise noted, all
reactions were carried out under an atmosphere of air in oven-dried
■
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Mp: 140−141 °C (EtOH). 1H NMR (400 MHz, DMSO): δ 10.05 (s,
1H), 8.76 (s, 1H), 8.54 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H),
8.34 (td, J = 6.9,1.1 Hz 1H), 8.13−8.09 (m, 1H), 5.82 (s, 2H), 4.26
(q, J = 7.1 Hz, 2H), 2.78 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (101 MHz, DMSO): δ 166.5, 150.0, 137.5, 136.9, 134.7, 134.2,
131.28, 131.26, 126.4, 124.5, 62.4, 60.1, 15.8, 14.0. HRMS (ESI-
TOF): m/z calcd for C14H16BrNO2, [C14H16BrNO2 − Br]+:
230.1176, found: 230.1184.
General Procedure for the Preparation of gem-Difluor-
oalkenes. Following the literature procedure,23a to a solution of
aldehyde (20 mmol, 1.0 equiv) and triphenylphosphine (24 mmol, 1.2
equiv) in DMF (40 mL) was added sodium chlorodifluoroacetate (30
mmol, 1.5 equiv) and the mixture stirred at 110 °C (oil bath) for 1−
10 h. (Caution: During the course of the reaction, vigorous liberation
of CO2 gas was observed.) After the aldehyde consumed completely,
the mixture was cooled to room temperature. Then water was added
to the reaction slowly and the mixture was extracted with Et2O. The
combined organic layer was dried over Na2SO4, filtrated, and
concentrated under reduced pressure. The residue was purified by a
silica gel flash column chromatography to afford the desired gem-
difluoroalkenes.
1-(2,2-Difluorovinyl)-2-methoxybenzene (2g). According to the
general procedure for the preparation of gem-difluoroalkenes, the title
compound (2.44 g) was obtained in 72% yield starting from 2-
methoxybenzaldehyde (2.72 g, 20 mmol). Colorless oil. Chromatog-
1
raphy: petroleum ether. Rf: 0.86 (petroleum ether). H NMR (400
MHz, CDCl3): δ 7.40 (dt, J = 7.8, 1.7 Hz, 1H), 7.17−7.10 (m, 1H),
6.88 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 5.59 (H−F, 3JH−F
=
27.0, 4.3 Hz, 1H), 3.74 (s, 3H). The experimental data is in
accordance with those reported in the previous literature.23a
1-Bromo-2-(2,2-difluorovinyl)benzene (2h). According to the
general procedure for the preparation of gem-difluoroalkenes, the
title compound (2.83 g) was obtained in 65% yield starting from 2-
bromobenzaldehyde (3.67 g, 20 mmol). Colorless oil. Chromatog-
1
raphy: petroleum ether. Rf: 0.90 (petroleum ether). H NMR (400
MHz, CDCl3): δ 7.59 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H),
7.31 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 5.69 (H−F, 3JH−F
=
25.4, 3.8 Hz, 1H). The experimental data is in accordance with those
reported in the previous literature.23e
1,3-Dichloro-2-(2,2-difluorovinyl)benzene (2i). According to the
general procedure for the preparation of gem-difluoroalkenes, the title
compound (3.20 g) was obtained in 77% yield starting from 2,6-
dichlorobenzaldehyde (3.47 g, 20 mmol). Colorless oil. Chromatog-
Methyl 4-(2,2-Difluorovinyl)benzoate (2a). According to the
general procedure for the preparation of gem-difluoroalkenes, the
title compound (2.73 g) was obtained in 69% yield starting from
methyl 4-formylbenzoate (3.28 g, 20 mmol). Colorless oil.
1
raphy: petroleum ether. Rf: 0.95 (petroleum ether). H NMR (400
MHz, CDCl3): δ 7.31 (d, J = 8.1 Hz, 2H), 7.15 (t, J = 8.1 Hz, 1H),
3
5.30 (H−F, JH−F = 26.0 Hz, 1H). 13C{1H} NMR (101 MHz,
1
Chromatography: petroleum ether. Rf: 0.89 (petroleum ether). H
CDCl3): δ 155.9 (C−F, 1JC−F = 289.9, 289.8 Hz), 135.7 (C−F, JC−F
=
NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.3
2.2 Hz), 129.4, 128.0, 77.4−76.2 (m). 19F NMR (377 MHz, CDCl3):
δ −77.42 (dd, J = 26.2, 20.8 Hz, 1F), −83.69 (d, J = 21.0 Hz, 1F).
HRMS (ESI-TOF): m/z calcd for C8H4Cl2F2Na+ [M + Na]+:
230.9550, found: 230.9546.
3
Hz, 2H), 5.29 (H−F, JH−F = 26.0, 3.6 Hz, 1H), 3.88 (s, 3H). The
experimental data is in accordance with those reported in the previous
literature.23a
1-(2,2-Difluorovinyl)-4-fluorobenzene (2b). According to the
general procedure for the preparation of gem-difluoroalkenes, the
title compound (2.37 g) was obtained in 75% yield starting from 4-
fluorobenzaldehyde (2.48 g, 20 mmol). Colorless oil. Chromatog-
1,2-Dichloro-4-(2,2-difluorovinyl)benzene (2j). According to the
general procedure for the preparation of gem-difluoroalkenes, the title
compound (3.12 g) was obtained in 75% yield starting from 2,6-
dichlorobenzaldehyde (3.47 g, 20 mmol). Colorless oil. Chromatog-
1
raphy: petroleum ether. Rf: 0.95 (petroleum ether). H NMR (400
1
raphy: petroleum ether. Rf: 0.93 (petroleum ether). H NMR (400
MHz, CDCl3): δ 7.32−7.28 (m, 2H), 7.06−7.01 (m, 2H), 5.25 (H−
MHz, CDCl3): δ 7.43−7.40 (m, 2H), 7.18 (dd, J = 8.4, 2.1 Hz, 1H),
3
F, JH−F = 26.0, 3.6 Hz, 1H). The experimental data is in accordance
3
with those reported in the previous literature.23b
5.24 (H−F, JH−F = 25.6, 3.4 Hz, 1H). The experimental data is in
accordance with those reported in the previous literature.23a
1-Chloro-4-(2,2-difluorovinyl)benzene (2c). According to the
general procedure for the preparation of gem-difluoroalkenes, the
title compound (2.08 g) was obtained in 60% yield starting from 4-
chlorobenzaldehyde (2.80 g, 20 mmol). Colorless oil. Chromatog-
1-Chloro-3-(2,2-difluorovinyl)-2-fluorobenzene (2k). According
to the general procedure for the preparation of gem-difluoroalkenes,
the title compound (2.99 g) was obtained in 78% yield starting from
3-chloro-2-fluorobenzaldehyde (3.16 g, 20 mmol). Colorless oil.
1
raphy: petroleum ether. Rf: 0.93 (petroleum ether). H NMR (400
1
3
Chromatography: petroleum ether. Rf: 0.94 (petroleum ether). H
MHz, CDCl3): δ 7.36−7.29 (m, 4H), 5.29 (H−F, JH−F = 26.0, 3.6
NMR (400 MHz, CDCl3): δ 7.36 (t, J = 7.3 Hz, 1H), 7.23 (t, J = 7.5
Hz, 1H). The experimental data is in accordance with those reported
3
in the previous literature.23a
Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 5.47 (H−F, JH−F = 25.6, 3.3 Hz,
1H). 13C{1H} NMR (101 MHz, CDCl3): δ 158.9, 156.0−152.8 (m),
128.2 (C−F, JC−F = 2.1 Hz), 125.8 (C−F, JC−F = 10.3 Hz), 123.7 (C−
1-Bromo-4-(2,2-difluorovinyl)benzene (2d). According to the
general procedure for the preparation of gem-difluoroalkenes, the
title compound (3.22 g) was obtained in 74% yield starting from 4-
bromobenzaldehyde (3.67 g, 20 mmol). Colorless oil. Chromatog-
F, JC−F = 4.6 Hz), 120.6 (C−F, JC−F = 18.1 Hz), 119.1 (C−F, JC−F
=
13.3, 6.7 Hz), 73.6 (C−F, 2JC−F = 33.5, 13.2, 7.3 Hz). 19F NMR (377
MHz, CDCl3): δ −79.94 (td, J = 25.3, 24.7, 5.5 Hz, 1F), −80.33 (dd,
J = 24.3, 4.8 Hz, 1F), −119.02 (t, J = 6.2 Hz, 1F). HRMS (ESI-TOF):
m/z calcd for C8H4ClF3Na+ [M + Na]+: 214.9846, found: 214.9840.
4-(2,2-Difluorovinyl)-2-methoxyphenyl 4-methylbenzenesulfo-
nate (2l). According to the general procedure for the preparation of
gem-difluoroalkenes, the title compound (4.82 g) was obtained in 71%
yield starting from 4-formyl-2-methoxyphenyl 4-methylbenzenesulfo-
nate (6.12 g, 20 mmol). White solid. Chromatography: petroleum
ether/EtOAc, 10/1. Rf: 0.41 (petroleum ether/EtOAc, 10/1). Mp:
79−80 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.2
Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.3 Hz, 1H), 6.82 (d, J
1
raphy: petroleum ether. Rf: 0.95 (petroleum ether). H NMR (400
MHz, CDCl3): δ 7.47 (dd, J = 8.4, 1.4 Hz, 2H), 7.20 (d, J = 8.5 Hz,
2H), 5.23 (H−F, 3JH−F = 26.0, 3.6 Hz, 1H). The experimental data is
in accordance with those reported in the previous literature.23a
1-(2,2-Difluorovinyl)-4-(trifluoromethyl)benzene (2e). According
to the general procedure for the preparation of gem-difluoroalkenes,
the title compound (2.99 g) was obtained in 72% yield starting from
4-(trifluoromethyl)benzaldehyde (3.48 g, 20 mmol). Colorless oil.
1
Chromatography: petroleum ether. Rf: 0.94 (petroleum ether). H
NMR (400 MHz, CDCl3): δ 7.59 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.1
3
Hz, 2H), 5.34 (H−F, JH−F = 25.8, 3.5 Hz, 1H). The experimental
3
data is in accordance with those reported in the previous literature.23c
1-Bromo-3-(2,2-difluorovinyl)benzene (2f). According to the
general procedure for the preparation of gem-difluoroalkenes, the
title compound (2.96 g) was obtained in 68% yield starting from 3-
bromobenzaldehyde (3.67 g, 20 mmol). Colorless oil. Chromatog-
= 9.9 Hz, 1H), 6.78 (s, 1H), 5.21 (H−F, JH−F = 25.8, 3.6 Hz, 1H),
3.53 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
1
156.4 (C−F, JC−F = 298.3, 289.5 Hz), 151.9, 145.2, 137.22 (C−F,
JC−F = 2.5 Hz), 133.2, 130.5 (C−F, JC−F = 6.6 Hz), 129.5, 128.7,
124.2, 120.08 (C−F, JC−F = 6.5, 3.7 Hz), 111.77 (C−F, JC−F = 7.1, 3.5
2
Hz), 81.85 (C−F, JC−F = 29.9, 13.2 Hz), 55.6, 21.7. 19F NMR (377
1
raphy: petroleum ether. Rf: 0.90 (petroleum ether). H NMR (400
MHz, CDCl3): δ −81.42 (dd, J = 29.7, 25.7 Hz, 1F), −83.07 (dd, J =
29.1, 4.0 Hz, 1F). HRMS (ESI-TOF): m/z calcd for C16H14F2O4SNa+
[M + Na]+: 363.0473, found: 363.0478.
MHz, CDCl3): δ 7.47 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.25−7.16
3
(m, 2H), 5.19 (H−F, JH−F = 25.8, 3.4 Hz, 1H). The experimental
data is in accordance with those reported in the previous literature.23d
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4-Bromo-2-(2,2-difluorovinyl)-1-methoxybenzene (2m). Accord-
ing to the general procedure for the preparation of gem-
difluoroalkenes, the title compound (3.12 g) was obtained in 63%
yield starting from 5-bromo-2-methoxybenzaldehyde (4.27 g, 20
mmol). Colorless oil. Chromatography: petroleum ether. Rf: 0.85
preparation of gem-difluoroalkenes, the title compound (1.51 g) was
obtained in 81% yield starting from (2R,5S)-2-isopropyl-5-methyl-
cyclohexyl 4-formylbenzoate (1.67 g, 5.8 mmol). The preparation of
starting aldehydes prepared according to a previously literature
procedure.22c Colorless viscous oil. Chromatography: petroleum
1
1
(petroleum ether). H NMR (400 MHz, CDCl3): δ 7.58 (d, J = 2.1
ether. Rf: 0.85 (petroleum ether). H NMR (400 MHz, CDCl3): δ
8.01 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 5.32 (H−F, 3JH−F
=
Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 6.71 (d, J = 8.7 Hz, 1H), 5.63 (H−
F, 3JH−F = 26.4, 4.4 Hz, 1H), 3.80 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 159.4, 156.6−153.6 (m), 130.8 (C−F, JC−F = 2.8 Hz),
130.7 (C−F, JC−F = 1.8 Hz), 121.3 (C−F, JC−F = 6.5 Hz), 113.0,
112.0, 75.7 (C−F, 2JC−F = 32.0, 12.4 Hz), 55.7. 19F NMR (377 MHz,
CDCl3): δ −82.05 (d, J = 27.6 Hz, 1F), −82.33 (td, J = 27.4, 5.1 Hz,
1F). HRMS (ESI-TOF): m/z calcd for C9H7BrF2ONa+ [M + Na]+:
270.9541, found: 270.9549.
26.0, 3.6 Hz, 1H), 4.93 (td, J = 10.9, 4.4 Hz, 1H), 2.13 (dtd, J = 12.0,
4.0, 1.7 Hz, 1H), 1.96 (pd, J = 7.0, 2.8 Hz, 1H), 1.76−1.70 (m, 2H),
1.61−1.50 (m, 2H), 1.18−1.05 (m, 2H), 0.92 (dd, J = 6.8, 3.7 Hz,
7H), 0.80 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
165.7, 156.9 (C−F, 1JC−F = 300.4, 290.5 Hz), 135.0 (C−F, JC−F = 6.6
Hz), 130.0, 129.4 (C−F, JC−F = 2.2 Hz), 127.5 (C−F, JC−F = 6.6, 3.6
2
Hz), 82.2 (C−F, JC−F = 29.7, 13.1 Hz), 75.0, 47.4, 41.1, 34.4, 31.6,
26.7, 23.8, 22.1, 20.8, 16.6. 19F NMR (377 MHz, CDCl3): δ −79.47
(dd, J = 25.8, 24.3 Hz, 1F), −81.32 (dd, J = 24.3, 3.5 Hz, 1F). HRMS
(ESI-TOF): m/z calcd for C19H24F2O2Na+ [M + Na]+: 345.1637,
found: 345.1646.
1-(2,2-Difluorovinyl)-2,4-dimethoxybenzene (2n). According to
the general procedure for the preparation of gem-difluoroalkenes, the
title compound (2.64 g) was obtained in 66% yield starting from 2,4-
dimethoxybenzaldehyde (3.32 g, 20 mmol). Colorless oil. Chroma-
tography: petroleum ether. Rf: 0.80 (petroleum ether). 1H NMR (400
MHz, CDCl3): δ 7.36 (d, J = 8.5 Hz, 1H), 7.23 (s, 1H), 6.48 (dd, J =
(1S,2R,4S)-3,3,5-Trimethylbicyclo[2.2.1]heptan-2-yl 4-(2,2-
difluorovinyl)benzoate (2t). According to the general procedure for
the preparation of gem-difluoroalkenes, the title compound (1.36 g)
was obtained in 77% yield starting from (1S,2R,4S)-3,3,5-
trimethylbicyclo[2.2.1]heptan-2-yl 4-formylbenzoate (1.57 g, 5.5
mmol). The preparation of starting aldehydes prepared according to
a previously literature procedure.22c Colorless viscous oil. Chroma-
tography: petroleum ether. Rf: 0.81 (petroleum ether). 1H NMR (400
MHz, CDCl3): δ 8.03 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H),
5.34 (H−F, 3JH−F = 25.9, 3.6 Hz, 1H), 4.62 (d, J = 1.8 Hz, 1H), 1.96−
1.89 (m, 1H), 1.82−1.75 (m, 2H), 1.67 (dd, J = 10.3, 1.5 Hz, 1H),
1.56−1.48 (m, 1H), 1.27−1.22 (m, 2H), 1.18 (s, 3H), 1.11 (s, 3H),
0.84 (s, 3H).13C{1H} NMR (101 MHz, CDCl3): δ 166.6, 156.9 (C−
F, 1JC−F = 300.4, 290.5 Hz), 135.2 (C−F, JC−F = 6.5 Hz), 130.0, 129.3
(C−F, JC−F = 2.0 Hz), 127.6 (C−F, JC−F = 6.6, 3.6 Hz), 86.9, 82.2
3
8.6, 2.3 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 5.55 (H−F, JH−F = 26.1,
5.3 Hz, 1H), 3.79 (d, J = 1.4 Hz, 6H). The experimental data is in
accordance with those reported in the previous literature.23f
2-(2,2-Difluorovinyl)naphthalene (2o). According to the general
procedure for the preparation of gem-difluoroalkenes, the title
compound (3.07 g) was obtained in 81% yield starting from 2-
naphthaldehyde (3.12 g, 20 mmol). White solid. Chromatography:
petroleum ether. Rf: 0.82 (petroleum ether).1H NMR (400 MHz,
CDCl3): δ 7.85−7.81 (m, 3H), 7.78 (s, 1H), 7.53−7.49 (m, 3H), 5.46
3
(H−F, JH−F = 26.3, 3.8 Hz, 1H). The experimental data is in
accordance with those reported in the previous literature.23a
3-(2,2-Difluorovinyl)-1-tosyl-1H-indole (2p). According to the
general procedure for the preparation of gem-difluoroalkenes, the
title compound (4.46 g) was obtained in 67% yield starting from 1-
tosyl-1H-indole-3-carbaldehyde (5.98 g, 20 mmol). White solid.
Chromatography: petroleum ether/EtOAc, 10/1. Rf: 0.32 (petroleum
ether/EtOAc, 10/1). 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 8.3
Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.64 (s, 1H), 7.48 (d, J = 7.8 Hz,
1H), 7.36 (t, J = 7.7 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 8.1
2
(C−F, JC−F = 29.7, 13.2 Hz), 48.8, 48.6, 41.6, 40.0, 29.9, 27.0, 26.1,
20.4, 19.6. 19F NMR (377 MHz, CDCl3): δ −79.36 (t, J = 25.0 Hz,
1F), −81.20 (dd, J = 24.2, 3.4 Hz, 1F). HRMS (ESI-TOF): m/z calcd
for C19H22F2O2Na+ [M + Na]+: 343.1480, found: 343.1494.
(3S,8R,9S,10S,13S,14S)-10,13-Dimethyl-17-oxohexadecahydro-
1H-cyclopenta[a]phenanthren-3-yl 4-(2,2-Difluorovinyl)benzoate
(2u). According to the general procedure for the preparation of
gem-difluoroalkenes, the title compound (0.40 g) was obtained in 70%
yield starting from (3S,8R,9S,10S,13S,14S)-10,13-dimethyl-17-oxo-
hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-formylbenzoate
(0.53 g, 1.26 mmol). The preparation of starting aldehydes prepared
according to a previously literature procedure.22c White solid.
Chromatography: petroleum ether. Rf: 0.75 (petroleum ether). Mp:
3
Hz, 2H), 5.39 (H−F, JH−F = 26.6 Hz, 1H), 2.32 (s, 3H). The
experimental data is in accordance with those reported in the previous
literature.23g
4-Bromo-2-(2,2-difluorovinyl)thiophene (2q). According to the
general procedure for the preparation of gem-difluoroalkenes, the title
compound (3.17 g) was obtained in 71% yield starting from 4-
bromothiophene-2-carbaldehyde (3.79 g, 20 mmol). Colorless oil.
Chromatography: petroleum ether. Rf: 0.88 (petroleum ether).1H
NMR (400 MHz, CDCl3): δ 7.10 (s, 1H), 6.87 (s, 1H), 5.43 (H−F,
3JH−F = 27.2 Hz, 1H). The experimental data is in accordance with
those reported in the previous literature.23h
1
185−186 °C (CHCl3). H NMR (400 MHz, CDCl3): δ 7.97 (d, J =
3
8.5 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 5.32 (H−F, JH−F = 26.0, 3.6
Hz, 1H), 4.96−4.88 (m, 1H), 2.42 (dd, J = 19.3, 8.8 Hz, 1H), 2.10−
2.01 (m, 1H), 1.97−1.90 (m, 2H), 1.81−1.72 (m, 4H), 1.69−1.61
(m, 2H), 1.57−1.45 (m, 3H), 1.37−1.23 (m, 6H), 1.09 (td, J = 13.5,
3.9 Hz, 1H), 1.03−0.94 (m, 1H), 0.87 (d, J = 13.5 Hz, 6H), 0.73 (td,
J = 11.7, 3.7 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 221.3,
165.7, 156.8 (C−F, 1JC−F = 300.5, 290.5 Hz), 135.0 (C−F, JC−F = 6.8
Hz), 130.0, 129.4 (C−F, JC−F = 2.2 Hz), 127.4 (C−F, JC−F = 6.6, 3.5
Methyl (4-(2,2-Difluorovinyl)benzoyl)-L-phenylalaninate (2r).
According to the general procedure for the preparation of gem-
difluoroalkenes, the title compound (0.76 g) was obtained in 23%
yield starting from methyl (4-formylbenzoyl)-L-phenylalaninate (2.99
g, 9.6 mmol). The preparation of starting aldehydes prepared
according to a previously literature procedure.22b White solid.
Chromatography: petroleum ether/EtOAc, 8/1. Rf: 0.39 (petroleum
2
Hz), 82.1 (C−F, JC−F = 29.7, 13.0 Hz), 74.3, 54.4, 51.5, 47.9, 44.8,
36.8, 35.9, 35.8, 35.1, 34.1, 31.6, 30.9, 28.4, 27.6, 21.9, 20.6, 13.9,
12.4. 19F NMR (377 MHz, CDCl3): δ −79.34 (t, J = 24.8 Hz, 1F),
−81.25 (dd, J = 24.3, 3.5 Hz, 1F). HRMS (ESI-TOF): m/z calcd for
C28H34F2O3Na+ [M + Na]+: 479.2368, found: 479.2376.
1
ether/EtOAc, 8/1). Mp: 82−83 °C (CHCl3). H NMR (400 MHz,
CDCl3): δ 7.69 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.31−
7.24 (m, 3H), 7.13 (d, J = 7.1 Hz, 2H), 6.62 (d, J = 7.6 Hz, 1H), 5.31
3
3
(H−F, JH−F = 26.0, 3.6 Hz, 1H), 5.08 (H−F, JH−F = 6.3 Hz, 1H),
3.76 (s, 3H), 3.31−3.19 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3):
δ 172.2, 166.3, 136.0, 134.1 (C−F, JC−F = 6.9 Hz, 1H), 132.3, 129.4,
128.7, 127.8 (C−F, JC−F = 6.7, 3.5 Hz), 127.5, 127.3, 82.1 (C−F, JC−F
= 13.5 Hz), 81.8 (C−F, JC−F = 13.0 Hz), 53.6, 52.5, 38.0. 19F NMR
(377 MHz, CDCl3): δ −79.71 (t, J = 25.6 Hz, 1F), −81.55 (dd, J =
25.0, 3.6 Hz, 1F). HRMS (ESI-TOF): m/z calcd for
C19H17F2NO3Na+ [M + Na]+: 368.1069, found: 368.1071.
(3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-((R)-6-methyl-
heptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-
1H-cyclopenta[a]phenanthren-3-yl 4-(2,2-difluorovinyl)benzoate
(2v). According to the general procedure for the preparation of
gem-difluoroalkenes, the title compound (1.21 g) was obtained in 73%
yield starting from (3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-
((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetra-
decahydro-1H-cyclopenta[a]phenanthren-3-yl 4-formylbenzoate
(1.55 g, 3.0 mmol). The preparation of starting aldehydes prepared
according to a previously literature procedure.22d White solid.
(2R,5S)-2-Isopropyl-5-methylcyclohexyl 4-(2,2-difluorovinyl)-
benzoate (2s). According to the general procedure for the
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Article
Chromatography: petroleum ether. Rf: 0.78 (petroleum ether). Mp:
(376 MHz, CDCl3): δ −142.79 (s, 1F). HRMS (ESI-TOF): m/z
1
+
141−142 °C (CHCl3). H NMR (400 MHz, CDCl3): δ 8.00 (d, J =
calcd for C19H17FNO4 [M + H]+: 342.1136, found: 342.1149.
8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 5.42 (d, J = 3.9 Hz, 1H), 5.33
Ethyl 2-Fluoro-1-(4-fluorophenyl)indolizine-3-carboxylate (3b).
Following the general procedure, the title compound (49 mg) was
obtained in 41% yield. White solid. Chromatography: petroleum
ether/EtOAc, 30/1. Rf: 0.31 (petroleum ether/EtOAc, 30/1). Mp:
96−97 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.45 (d, J = 7.1
Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.52 (dd, J = 8.2, 5.5 Hz, 2H), 7.15
(m, 3H), 6.87 (td, J = 7.0, 1.2 Hz,1H), 4.43 (q, J = 7.1 Hz, 2H), 1.43
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 161.8 (C−
3
(H−F, JH−F = 26.0, 3.5 Hz, 1H), 4.85 (dtd, J = 12.0, 8.6, 4.6 Hz,
1H), 2.46 (d, J = 7.8 Hz, 2H), 2.04−1.97 (m, 3H), 1.92 (dt, J = 13.3,
3.1 Hz, 1H), 1.82 (ddt, J = 16.9, 7.3, 4.5 Hz, 1H), 1.71 (dd, J = 19.4,
7.6 Hz, 1H), 1.60 (s, 1H), 1.51 (ddt, J = 22.0, 15.2, 6.1 Hz, 5H),
1.39−1.31 (m, 3H), 1.26−1.07 (m, 11H), 1.04−0.97 (m, 3H), 0.92
(d, J = 6.5 Hz, 3H), 0.87 (dd, J = 6.8, 1.4 Hz, 6H), 0.69 (s, 3H).
1
13C{1H} NMR (101 MHz, CDCl3): δ 165.7, 156.9 (C−F, JC−F
=
1
3
F, JC−F = 246.6 Hz, FCAr), 160.9 (C−F, JC−F = 4.2 Hz, CO2Et),
300.4, 290.8 Hz), 139.8, 135.1 (C−F, JC−F = 6.9 Hz), 130.1, 129.4,
127.5 (C−F, JC−F = 6.7, 3.5 Hz), 123.0, 82.2 (C−F, 2JC−F = 29.8, 13.1
Hz), 74.8, 56.8, 56.3, 50.2, 42.5, 39.9, 39.7, 38.4, 37.2, 36.8, 36.3, 36.0,
32.1, 32.0, 28.4, 28.2, 28.0, 24.4, 24.0, 23.0, 22.7, 21.2, 19.5, 18.9,
12.0. 19F NMR (377 MHz, CDCl3): δ −79.32 (t, J = 25.0 Hz, 1F),
−81.27 (dd, J = 24.2, 3.8 Hz, 1F). HRMS (ESI-TOF): m/z calcd for
C36H50F2O2Na+ [M + Na]+: 575.3671, found: 575.3665.
1
3
155.0 (C−F, JC−F = 262.8 Hz, C2), 132.2 (C−F, JC−F = 5.8 Hz,
C8a), 130.5 (C−F, JC−F = 7.9, 1.7 Hz, CAr), 127.6 (C4), 126.8 (C−F,
J
C−F = 2.9 Hz), 123.9, 116.8 (C−F, 4JC−F = 5.4 Hz, C7), 115.9 (C−F,
2JC−F = 21.5 Hz, CAr), 113.3 (C−F, 5JC−F = 3.0 Hz, C5), 101.4 (C−F,
2JC−F = 11.2 Hz, C1), 101.1 (C−F, 2JC−F = 21.2 Hz, C3), 60.2 (CH2),
14.7 (CH3). 19F NMR (376 MHz, CDCl3): δ −144.27 (s, 1F),
+
(E)-(4,4-Difluorobuta-1,3-dien-1-yl)benzene (2w). According to
the general procedure for the preparation of gem-difluoroalkenes, the
title compound (1.92 g) was obtained in 58% yield starting from
cinnamaldehyde (2.64 g, 20 mmol). Colorless oil. Chromatography:
−115.12 (s, 1F). HRMS (ESI-TOF): m/z calcd for C17H14F2NO2
[M + H]+: 302.0987, found: 302.1001.
Ethyl 1-(4-Chlorophenyl)-2-fluoroindolizine-3-carboxylate (3c).
Following the general procedure, the title compound (58 mg) was
obtained in 46% yield. White solid. Chromatography: petroleum
ether/EtOAc, 20/1. Rf: 0.34 (petroleum ether/EtOAc, 20/1). Mp:
98−99 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.45 (d, J = 7.1
Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.43 (d, J
= 8.3 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), 6.88 (t, J = 6.9 Hz, 1H), 4.43
(q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101
1
petroleum ether. Rf: 0.89 (petroleum ether). H NMR (400 MHz,
CDCl3): δ 7.45−7.43 (m, 2H), 7.39−7.36 (m, 2H), 7.31−7.27 (m,
1H), 6.80 (H−F, 4JH−F = 15.94, 10.90, 1.39, 1.39 Hz, 1H), 6.52 (d, J
3
= 15.9 Hz, 1H), 5.18 (H−F, JH−F = 24.1, 10.9, 1.6 Hz, 1H). The
experimental data is in accordance with those reported in the previous
literature.23h
3
(E)-(4,4-Difluoro-2-methylbuta-1,3-dien-1-yl)benzene (2x). Ac-
cording to the general procedure for the preparation of gem-
difluoroalkenes, the title compound (2.23 g) was obtained in 62%
yield starting from (E)-2-methyl-3-phenylacrylaldehyde (2.92 g, 20
mmol). Colorless oil. Chromatography: petroleum ether. Rf: 0.85
MHz, CDCl3): δ 160.8 (C−F, JC−F = 4.1 Hz, CO2Et), 155.1 (C−F,
3
1JC−F = 263.4 Hz, C2), 132.6 (CAr), 132.1 (C−F, JC−F = 5.7 Hz,
C8a), 132.0 (C−F, 4JC−F = 1.8 Hz, CAr), 129.4 (C−F, 3JC−F = 2.7 Hz,
4
CAr), 129.2 (CAr), 127.7 (C4), 124.1 (C6), 116.8 (C−F, JC−F = 5.4
Hz, C7), 113.4 (C−F, 5JC−2F = 3.1 Hz, C5), 101.21(C−F, 2JC−F = 20.6
Hz, C3) 101.16 (C−F, JC−F = 10.8 Hz, C1), 60.3 (CH2), 14.7
(CH3). 19F NMR (376 MHz, CDCl3): δ −143.74 (s, 1F). HRMS
1
(petroleum ether). H NMR (400 MHz, CDCl3): δ 7.40−7.24 (m,
5H), 6.46 (s, 1H), 5.12−5.02 (m, 1H), 2.10 (s, 3H). The
experimental data is in accordance with those reported in the
previous literature.23e
+
(ESI-TOF): m/z calcd for C17H14ClFNO2 [M + H]+: 318.0692,
found: 318.0706.
General Procedure for the Synthesis of 2-Fluoroindolizines.
To a solution of pyridinium salts 1 (0.8 mmol) and gem-
difluoroolefins 2 (0.4 mmol) in a mixture solvent of DMF and
dioxane (2 mL, v/v = 1/1) was added K2CO3 (0.8 mmol). The
mixture was stirred at 60 °C (oil bath) under air atmosphere for 12 h.
After completion of the reaction monitored by TLC, the reaction
mixture went through flash column chromatography (PE/EA = 5/1−
40/1) to afford the desired product 3.
Ethyl 1-(4-Bromophenyl)-2-fluoroindolizine-3-carboxylate (3d).
Following the general procedure, the title compound (101 mg) was
obtained in 70% yield. White solid. Chromatography: petroleum
ether/EtOAc, 20/1. Rf: 0.36 (petroleum ether/EtOAc, 20/1). Mp:
72−73 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.45 (d, J = 7.1
Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.43 (d, J
= 8.3 Hz, 2H), 7.14 (t, J = 7.3 Hz, 1H), 6.87 (t, J = 7.0 Hz, 1H), 4.43
(q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101
3
MHz, CDCl3): δ 160.8 (C−F, JC−F = 4.2 Hz, CO2Et), 155.0 (C−F,
3
1JC−F = 263.6 Hz, C2), 132.1 (CAr), 130.3 (C−F, JC−F = 1.8 Hz,
C8a), 127.7 (CAr), 124.2 (CAr), 120.7 (CAr), 116.8 (C−F, 4JC−F = 5.3
Hz, C7), 113.4 (C−F, 5JC−F = 3.0 Hz, C5), 101.3 (C−F, 2JC−F = 20.8
Hz, C3), 101.2 (C−F, 2JC−F = 10.8 Hz, C1), 60.3 (CH2), 14.7 (CH3).
19F NMR (376 MHz, CDCl3): δ −143.67 (s, 1F). HRMS (ESI-TOF):
m/z calcd for C17H14BrFNO2+ [M + H]+: 362.0186, found: 362.0197.
Ethyl 2-Fluoro-1-(4-(methoxycarbonyl)phenyl)indolizine-3-car-
boxylate (3a). Following the general procedure, the title compound
(105 mg) was obtained in 77% yield. White solid. Chromatography:
petroleum ether/EtOAc, 20/1. Rf: 0.34 (petroleum ether/EtOAc, 20/
1). Mp: 146−147 °C (CHCl3). 1H NMR (400 MHz, CDCl3, COSY):
δ 9.45 (d, J = 7.1 Hz, 1H, H5), 8.11 (d, J = 8.3 Hz, 2H, H1, H2), 7.69
(d, J = 9.0 Hz, 1H, H8), 7.63 (d, J = 8.1 Hz, 2H, H3, H4), 7.16 (t, J =
7.6 Hz, 1H, H7), 6.88 (t, J = 6.9 Hz, 1H, H6), 4.42 (q, J = 7.1 Hz, 2H,
CH2), 3.93 (s, 3H, CH3), 1.42 (t, J = 7.1 Hz, 3H, CH2). 13C{1H}
NMR (101 MHz, CDCl3, HSQC, HMBC): δ 167.0 (CO2Me), 160.7
Ethyl 2-Fluoro-1-(4-(trifluoromethyl)phenyl)indolizine-3-carbox-
ylate (3e). Following the general procedure, the title compound (77
mg) was obtained in 55% yield. White solid. Chromatography:
petroleum ether/EtOAc, 25/1. Rf: 0.31 (petroleum ether/EtOAc, 25/
1). Mp: 104−105 °C (CHCl3). 1H NMR (400 MHz, CDCl3, COSY):
δ 9.47 (d, J = 7.1 Hz, 1H, H5), 7.72−7.66 (m, 5H, H1−H4, H8), 7.17
(t, J = 7.4 Hz, 1H, H7), 6.90 (t, J = 7.0 Hz, 1H, H6), 4.44 (q, J = 7.1
Hz, 2H, CH2), 1.43 (t, J = 7.1 Hz, 3H, CH3). 13C{1H} NMR (101
3
1
(C−F, JC−F = 4.2 Hz, CO2Et), 155.3 (C−F, JC−F = 264.5 Hz, C2),
135.9 (C−F, 3JC−F = 3.0 Hz, C9), 132.2 (C−F, 3JC−F = 5.7 Hz, C8a),
4
130.2 (CAr), 128.3 (C−F, JC−F = 2.2 Hz, CAr), 128.1 (CAr), 127.8
4
(C4), 124.5 (C6), 116.9 (C−F, JC−F = 5.2 Hz, C7), 113.6 (C−F,
5JC−F = 2.8 Hz, C5), 101.6 (C−F, 2JC−F = 21.1 Hz, C3), 101.6 (C−F,
2JC−F = 10.5 Hz, C1), 60.3(CH2), 52.2 (CH3), 14.6 (CH3). 19F NMR
3
MHz, CDCl3, HSQC, HMBC): δ 160.8 (C−F, JC−F = 4.1 Hz,
4652
https://dx.doi.org/10.1021/acs.joc.0c03041
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Article
CO2Et), 154.3 (C−F, JC−F = 264.3 Hz, C2), 133.8 (CAr), 131.2 (C−
F, 3JC−F = 5.5 Hz, C8a), 127.8 (C−F, 3JC−F = 2.1 Hz, CAr), 127.6 (q,
F, 4JC−F = 5.1 Hz, C7), 113.3 (C−F, 5JC−2F = 2.9 Hz, C5), 101.3 (C−
2
F, JC−F = 20.0 Hz, C3), 97.4 (C−F, JC−F = 13.1 Hz, C1), 60.3
(CH2), 14.7 (CH3). 19F NMR (376 MHz, CDCl3): δ −137.27 (s,
3
2JC−F = 32.5 Hz, CAr), 126.8 (C4), 124.9 (q, JC−F = 3.8 Hz, CAr),
+
1F). HRMS (ESI-TOF): m/z calcd for C17H13Cl2FNO2 [M + H]+:
1
4
123.6 (C6), 123.4 (q, JC−F = 272.3 Hz, CF3), 116.7 (C−F, JC−F
=
=
5
2
352.0302, found: 352.0318.
5.2 Hz, C7), 112.6 (C−F, JC−F = 2.9 Hz, C5), 100.5 (C−F, JC−F
2
Ethyl 1-(3,4-Dichlorophenyl)-2-fluoroindolizine-3-carboxylate
(3j). Following the general procedure, the title compound (73 mg)
was obtained in 52% yield. White solid. Chromatography: petroleum
ether/EtOAc, 20/1. Rf: 0.40 (petroleum ether/EtOAc, 20/1). Mp:
20.9 Hz, C3), 99.9 (C−F, JC−F = 10.5 Hz, C1), 59.4 (CH2), 13.6
(CH3). 19F NMR (376 MHz, CDCl3): δ −143.33 (s, 1F), −62.46 (s,
+
3F). HRMS (ESI-TOF): m/z calcd for C18H14F4NO2 [M + H]+:
352.0955, found: 352.0969.
1
124−125 °C (CHCl3). H NMR (400 MHz, CDCl3): δ 9.43 (d, J =
Ethyl 1-(3-Bromophenyl)-2-fluoroindolizine-3-carboxylate (3f).
Following the general procedure, the title compound (92 mg) was
obtained in 64% yield. White solid. Chromatography: petroleum
ether/EtOAc, 20/1. Rf: 0.39 (petroleum ether/EtOAc, 20/1). Mp:
92−93 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.44 (d, J = 7.1
Hz, 1H), 7.70 (s, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.48 (d, J = 7.7 Hz,
1H), 7.44 (d, J = 8.3 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.14 (t, J = 7.5
Hz, 1H), 6.88 (td, J = 6.99, 0.85 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H),
1.43 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 160.7
7.0 Hz, 1H), 7.60 (d, J = 12.2 Hz, 2H), 7.48 (d, J = 8.3 Hz, 1H), 7.36
(d, J = 8.3 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.87 (t, J = 6.8 Hz, 1H),
4.42 (q, J = 6.7 Hz, 2H), 1.42 (t, J = 6.7 Hz, 3H). 13C{1H} NMR
3
(101 MHz, CDCl3): δ 160.6 (C−F, JC−F = 4.1 Hz, CO2Et), 155.0
1
3
(C−F, JC−F = 264.1 Hz, C2), 132.9 (CAr), 131.9 (C−F, JC−F = 5.3
Hz, C8a), 130.9 (C−F, JC−F = 2.8 Hz, CAr), 130.8 (CAr), 130.6 (CAr),
130.2 (C−F, JC−F = 2.2 Hz, CAr), 127.8 (C−F, JC−F = 2.2 Hz, CAr),
127.7 (C4), 124.5 (C6), 116.5 (C−F, 4JC−F = 5.3 Hz, C7), 113.6 (C−
F, 5JC−F = 2.9 Hz, C5), 101.3 (C−F, 2JC−F = 21.8 Hz, C3), 99.9 (C−
3
1
(C−F, JC−F = 4.1 Hz, CO2Et), 155.1 (C−F, JC−F = 264.0 Hz, C2),
133.0 (C−F, JC−F = 2.9 Hz, CAr), 132.1 (C−F, 3JC−F = 5.6 Hz, C8a),
131.5 (C−F, JC−F = 2.0 Hz, CAr), 130.4 (CAr), 129.8 (CAr), 127.7
(C4), 127.3 (C−F, JC−F = 2.0 Hz, CAr), 124.3 (C6), 122.9 (CAr),
2
F, JC−F = 10.6 Hz, C1), 60.3 (CH2), 14.6 (CH3). 19F NMR (376
MHz, CDCl3): δ −144.74 (s, 1F). HRMS (ESI-TOF): m/z calcd for
+
C17H13Cl2FNO2 [M + H]+: 352.0302, found: 352.0312.
4
5
Ethyl 1-(3-Chloro-2-fluorophenyl)-2-fluoroindolizine-3-carboxy-
late (3k). Following the general procedure, the title compound (94
mg) was obtained in 70% yield. White solid. Chromatography:
petroleum ether/EtOAc, 20/1. Rf: 0.38 (petroleum ether/EtOAc, 20/
1). Mp: 112−113 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.48
(d, J = 7.1 Hz, 1H), 7.40 (q, J = 8.0, 7.6 Hz, 3H), 7.20−7.14 (m, 2H),
6.91 (td, J = 7.0, 1.2 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1
116.7 (C−F, JC−F = 5.3 Hz, C7), 113.5 (C−F, JC−F = 2.9 Hz, C5),
101.2 (C−F, 2JC−F = 21.1 Hz, C3), 100.8 (C−F, 2JC−F = 10.7 Hz, C1),
60.3 (CH2), 14.6 (CH3). 19F NMR (377 MHz, CDCl3): δ −143.33
+
(s, 1F). HRMS (ESI-TOF): m/z calcd for C17H14BrFNO2 [M +
H]+: 362.0186, found: 362.0193.
Ethyl 2-Fluoro-1-(2-methoxyphenyl)indolizine-3-carboxylate
(3g). Following the general procedure, the title compound (56 mg)
was obtained in 45% yield. White solid. Chromatography: petroleum
ether/EtOAc, 15/1. Rf: 0.32 (petroleum ether/EtOAc, 15/1). Mp:
80−81 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.44 (d, J = 7.1
Hz, 1H), 7.38 (t, J = 7.9 Hz, 3H), 7.09−7.03 (m, 3H), 6.85 (t, J = 7.0
Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 1.42 (t, J = 7.1 Hz,
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 160.8 (C−F, 3JC−F
=
1
3.9 Hz, CO2Et), 155.6 (C−F, JC−F = 250.6 Hz, FCAr), 155.5 (C−F,
1JC−F = 264.9 Hz, C2), 132.5 (C−F, 3JC−F = 5.7 Hz, C8a), 130.1 (C−
F, JC−F = 1.3 Hz, CAr), 129.7 (CAr), 127.6 (C4), 124.7 (C−F, JC−F
=
2
4.6 Hz, CAr), 124.2 (C6), 122.2 (C−F, JC−F = 18.3 Hz, CAr), 120.0
2
4
3
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 161.0 (C−F, JC−F = 3.9
(C−F, JC−F = 15.9, 2.5 Hz, CAr), 117.3 (C−F, JC−F = 4.2 Hz, C7),
113.5 (C−F, 5JC−F = 2.9 Hz, C5), 101.5 (C−F, 2JC−F = 21.1 Hz, C3),
95.5 (C−F, 2JC−F = 12.2 Hz, C1), 60.3 (CH2), 14.6 (CH3). 19F NMR
(376 MHz, CDCl3): δ −139.71 (s, 1F). HRMS (ESI-TOF): m/z
1
Hz, CO2Et), 155.4 (C−F, JC−F = 264.1 Hz, C2), 157.3 (CAr), 132.9
3
(C−F, JC−F = 6.5 Hz, C8a), 131.9 (CAr), 129.0 (CAr), 127.3 (C4),
123.0 (C6), 120.7 (CAr), 119.2 (C−F, JC−F = 2.1 Hz, CAr), 117.9 (C−
F, 4JC−F = 5.3 Hz, C7), 112.8 (C−F, 5JC−F = 3.0 Hz, C5), 111.3 (CAr),
100.0 (C−F, 2JC−F = 20.4 Hz, C3), 98.8 (C−F, 2JC−F = 11.6 Hz, C1),
60.0 (CH2), 55.7 (CH3), 14.7 (CH3). 19F NMR (376 MHz, CDCl3):
+
calcd for C17H13ClF2NO2 [M + H]+: 336.0597, found: 336.0612.
Ethyl 2-Fluoro-1-(3-methoxy-4-(tosyloxy)phenyl)indolizine-3-
carboxylate (3l). Following the general procedure, the title
compound (112 mg) was obtained in 58% yield. White solid.
Chromatography: petroleum ether/EtOAc, 8/1. Rf: 0.40 (petroleum
ether/EtOAc, 8/1). Mp: 177−178 °C (CHCl3). 1H NMR (400 MHz,
CDCl3): δ 9.43 (d, J = 7.1 Hz, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.65 (d,
J = 8.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.2 Hz, 1H),
7.15 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 7.04 (s, 1H), 6.88
(t, J = 6.9 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.60 (s, 3H), 2.44 (s,
3H), 1.42 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
160.7 (C−F, 3JC−F = 4.1 Hz, CO2Et), 155.0 (C−F, 1JC−F = 263.4 Hz,
C2), 152.1 (CAr), 145.2 (CAr), 137.1 (CAr), 133.4 (CAr), 132.1 (C−F,
3JC−F = 5.6 Hz, C8a), 130.9 (C−F, JC−F = 2.6 Hz, CAr), 129.5 (CAr),
+
δ −140.21 (s, 1F). HRMS (ESI-TOF): m/z calcd for C18H17FNO3
[M + H]+: 314.1187, found: 314.1205.
Ethyl 1-(2-Bromophenyl)-2-fluoroindolizine-3-carboxylate (3h).
Following the general procedure, the title compound (97 mg) was
obtained in 67% yield. White solid. Chromatography: petroleum
ether/EtOAc, 20/1. Rf: 0.33 (petroleum ether/EtOAc, 20/1). Mp:
90−91 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.41 (d, J = 7.0
Hz, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.26 (s, 2H), 7.19−7.17 (m, 3H),
6.87 (t, J = 6.9 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz,
3
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 160.5 (C−F, JC−F = 4.1
Hz, CO2Et), 154.8 (C−F, 1JC−F = 265.4 Hz, C2) 133.4 (C−F, 3JC−F
=
128.7 (CAr), 127.6 (C4), 124.4, 124.3, 120.7 (CAr), 116.9 (C−F, 4JC−F
3
3.9 Hz, CAr), 131.5 (C−F, JC−F = 5.2 Hz, C8a), 127.6 (C4), 127.0
= 5.2 Hz, C7), 113.5 (C−F, 5JC−F = 2.8 Hz, C5), 113.2 (C−F, JC−F
2.4 Hz, CAr), 101.3 (C−F, 2JC−F = 10.4 Hz, C1), 101.2 (C−F, 2JC−F
=
=
(C−F, JC−F = 3.6 Hz, CAr), 124.6 (C6), 120.7 (C−F, JC−F = 1.8 Hz,
5
CAr), 117.1 (C−F, 4JC−F = 5.1 Hz, C7), 113.6 (C−F, JC−F = 2.9 Hz,
2
20.2 Hz, C3), 60.3 (CH2), 55.8 (OCH3), 21.8 (CH3), 14.6 (CH3).
C5), 110.4 (CAr), 101.4 (C−F, JC−F = 20.5 Hz, C3), 95.3 (C−F,
19F NMR (376 MHz, CDCl3): δ −143.52 (s, 1F). HRMS (ESI-TOF):
2JC−F = 10.8 Hz, C1), 60.4 (CH2), 14.6 (CH3). 19F NMR (376 MHz,
m/z calcd for C25H23FNO6S+ [M + H]+: 484.1225, found: 484.1236.
Ethyl 1-(5-Bromo-2-methoxyphenyl)-2-fluoroindolizine-3-car-
boxylate (3m). Following the general procedure, the title compound
(70 mg) was obtained in 45% yield. White solid. Chromatography:
petroleum ether/EtOAc, 20/1. Rf: 0.36 (petroleum ether/EtOAc, 20/
1). Mp: 64−65 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.44 (d,
J = 7.1 Hz, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.44 (dd, J = 8.8, 2.4 Hz,
1H), 7.34 (d, J = 8.9 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.90−6.84 (m,
2H), 4.43 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H).
CDCl3): δ −139.88 (s, 1F). HRMS (ESI-TOF): m/z calcd for
C17H13BrFNO2Na+ [M + Na]+: 384.0006, found: 384.0011.
Ethyl 1-(2,6-Dichlorophenyl)-2-fluoroindolizine-3-carboxylate
(3i). Following the general procedure, the title compound (45 mg)
was obtained in 32% yield. White solid. Chromatography: petroleum
ether/EtOAc, 20/1. Rf: 0.42 (petroleum ether/EtOAc, 20/1). Mp:
1
100−101 °C (CHCl3). H NMR (400 MHz, CDCl3): δ 9.48 (d, J =
7.1 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 8.4 Hz, 1H), 7.15−
7.09 (m, 2H), 6.92−6.89 (m, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.43 (t, J
= 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 160.9 (C−F,
3
13C{1H} NMR (101 MHz, CDCl3): δ 160.9 (C−F, JC−F = 4.2 Hz,
1
3JC−F = 4.0 Hz, CO2Et), 155.4 (C−F, JC−F = 264.7 Hz, C2), 137.3
1
CO2Et), 155.4 (C−F, JC−F = 264.3 Hz, C2), 156.6 (CAr), 134.3
3
3
(CAr), 132.3 (C−F, JC−F = 6.2 Hz, C8a), 130.0 (CAr), 128.6 (C−F,
(CAr), 132.7 (C−F, JC−F = 6.2 Hz, C8a), 131.6 (CAr), 127.5 (C4),
4
JC−F = 2.5 Hz, CAr), 128.3 (CAr), 127.7 (C4), 123.9 (C6), 117.5 (C−
123.5 (C6), 121.5 (C−F, JC−F = 2.4 Hz, CAr), 117.7 (C−F, JC−F
=
4653
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5
4
5
5.2 Hz, C7), 113.1 (C−F, JC−F = 3.0 Hz, C5), 113.05 (CAr), 112.8
117.1 (C−F, JC−F = 5.0 Hz, C7), 113.6 (C−F, JC−F = 2.8 Hz, C5),
2
2
2
2
(CAr), 101.2 (C−F, JC−F = 20.9 Hz, C3), 97.6 (C−F, JC−F = 12.5
Hz, C1), 60.1 (CH2), 55.9 (OCH3), 14.7 (CH3). 19F NMR (376
MHz, CDCl3): δ −139.50 (s, 1F). HRMS (ESI-TOF): m/z calcd for
110.4 (CAr), 101.4 (C−F, JC−F = 20.4 Hz, C3), 95.3 (C−F, JC−F =
11.0 Hz, C1), 60.4 (CH2), 14.6 (CH3). 19F NMR (376 MHz,
CDCl3): δ −139.71 (s, 1F). HRMS (ESI-TOF): m/z calcd for
C15H12BrFNO2S+ [M + H]+: 367.9751, found: 367.9762.
C18H16BrFNO3 [M + H]+: 392.0292, found: 392.0300.
+
Ethyl 1-(2,4-Dimethoxyphenyl)-2-fluoroindolizine-3-carboxylate
(3n). Following the general procedure, the title compound (84 mg)
was obtained in 61% yield. White solid. Chromatography: petroleum
ether/EtOAc, 10/1. Rf: 0.43 (petroleum ether/EtOAc, 10/1). Mp:
Methyl 4-(3-Cyano-2-fluoroindolizin-1-yl)benzoate (3r). Follow-
ing the general procedure, the title compound (70 mg) was obtained
in 60% yield. White solid. Chromatography: petroleum ether/EtOAc,
20/1. Rf: 0.41 (petroleum ether/EtOAc, 20/1). Mp: 148−149 °C
1
1
100−101 °C (CHCl3). H NMR (400 MHz, CDCl3): δ 9.42 (d, J =
(CHCl3). H NMR (400 MHz, CDCl3): δ 8.22 (d, J = 6.9 Hz, 1H),
7.1 Hz, 1H), 7.34−7.27 (m, 2H), 7.05 (t, J = 8.0 Hz, 1H), 6.83 (t, J =
6.9 Hz, 1H), 6.61−6.58 (m, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.87 (s,
3H), 3.80 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101
8.13 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 8.0 Hz,
2H), 7.21 (t, J = 8.0 Hz, 1H), 6.97 (t, J = 6.9 Hz, 1H), 3.95 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 166.9 (CO2Me), 156.3 (C−F,
1JC−F = 264.5 Hz, C2), 134.7 (C−F, JC−F = 2.9 Hz, CAr), 131.8 (C−F,
3
MHz, CDCl3): δ 161.0 (C−F, JC−F = 4.0 Hz, CO2Et), 160.8 (CAr),
158.5 (CAr), 155.6 (C−F, 1JC−F = 263.0 Hz, C2) 133.1 (C−F, 3JC−F
=
3JC−F = 5.1 Hz, C8a), 130.4 (CAr), 128.7 (CAr), 128.2 (C−F, JC−F
=
6.5 Hz, C8a), 132.4 (CAr), 127.4 (C4), 122.9 (C6), 117.9 (C−F,
4
2.1 Hz, CAr), 126.0 (C4), 124.9 (C6), 118.1 (C−F, JC−F = 5.0 Hz,
5
4JC−F = 5.3 Hz, C7), 112.8 (C−F, JC−F = 3.0 Hz, C5), 111.7 (C−F,
5
3
C7), 114.4 (C−F, JC−F = 2.8 Hz, C5), 110.8 (C−F, JC−F = 3.9 Hz,
CN), 101.4 (C−F, 2JC−F = 9.2 Hz, C1), 85.0 (C−F, 2JC−F = 26.7 Hz,
C3), 52.3 (CH3). 19F NMR (376 MHz, CDCl3): δ −146.60 (s, 1F).
2
J
C−F = 2.4 Hz, CAr), 104.8 (CAr), 100.9 (C−F, JC−F = 21.2 Hz, C3),
2
99.2 (CAr), 98.7 (C−F, JC−F = 13.0 Hz, C1), 60.0 (CH2), 55.7
(OCH3), 55.6 (OCH3), 14.7 (CH3). 19F NMR (376 MHz, CDCl3): δ
−140.37 (s, 1F). HRMS (ESI-TOF): m/z calcd for C19H18FNO4Na+
[M + Na]+: 366.1112, found: 366.1127.
+
HRMS (ESI-TOF): m/z calcd for C17H12FN2O2 [M + H]+:
295.0877, found: 295.0887.
1-(4-Bromophenyl)-2-fluoroindolizine-3-carbonitrile (3s). Fol-
lowing the general procedure, the title compound (56 mg) was
obtained in 45% yield. White solid. Chromatography: petroleum
ether/EtOAc, 25/1. Rf: 0.45 (petroleum ether/EtOAc, 25/1). Mp:
Ethyl 2-Fluoro-1-(naphthalen-2-yl)indolizine-3-carboxylate (3o).
Following the general procedure, the title compound (56 mg) was
obtained in 42% yield. White solid. Chromatography: petroleum
ether/EtOAc, 20/1. Rf: 0.37 (petroleum ether/EtOAc, 20/1). Mp:
1
180−181 °C (CHCl3). H NMR (400 MHz, CDCl3): δ 8.20 (d, J =
1
138−139 °C (CHCl3). H NMR (400 MHz, CDCl3): δ 9.49 (d, J =
6.9 Hz, 1H), 7.65 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.40
(d, J = 8.2 Hz, 2H), 7.17 (t, J = 6.9 Hz, 1H), 6.94 (t, J = 6.9 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3): δ 156.0 (C−F, 1JC−F = 263.3 Hz,
7.1 Hz, 1H), 8.02 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.87 (dd, J = 5.7,
2.4 Hz, 2H), 7.77−7.70 (m, 2H), 7.54−7.48 (m, 2H), 7.14 (t, J = 7.2
Hz, 1H), 6.88 (t, J = 7.1 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 1.46 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 160.9 (C−F, 3JC−F
3
C2), 132.3 (CAr), 131.6 (C−F, JC−F = 5.4 Hz, C8a), 130.1 (C−F,
JC−F = 1.8 Hz, CAr), 128.8 (C−F, JC−F = 2.7 Hz, CAr), 126.0 (C4),
1
= 4.1 Hz, CO2Et), 156.6 (C−F, JC−F = 263.7 Hz, C2), 133.8 (CAr),
4
124.5 (C6), 121.4 (CAr), 118.0 (C−F, JC−F = 5.1 Hz, C7), 114.2
3
132.5 (C−F, JC−F = 5.9 Hz, C8a), 132.3 (CAr), 128.5 (CAr), 128.3
(C−F, 5JC−F = 2.8 Hz, C5), 111.0 (C−F, 3JC−F = 3.9 Hz, CN), 101.2
(C−F, JC−F = 2.9 Hz, CAr), 127.9 (C−F, 3JC−F = 12.5 Hz, CAr), 127.6
(C4), 127.4 (C−F, JC−F = 1.7 Hz, CAr), 127.1 (C−F, JC−F = 1.8 Hz,
2
2
(C−F, JC−F = 9.3 Hz, C1), 84.7 (C−F, JC−F = 25.8 Hz, C3). 19F
NMR (376 MHz, CDCl3): δ −147.44 (s, 1F). HRMS (ESI-TOF): m/
4
CAr), 126.4 (CAr), 126.0 (CAr), 124.0 (C6), 117.1 (C−F, JC−F = 5.4
+
z calcd for C15H9BrFN2 [M + H]+: 314.9928, found: 314.9927.
Hz, C7), 113.3 (C−F, 5JC−F = 2.9 Hz, C5), 102.3 (C−F, 2JC−F = 10.9
Hz, C1), 101.2 (C−F, 2JC−F = 21.1 Hz, C3), 60.2 (CH2), 14.7 (CH3).
19F NMR (376 MHz, CDCl3): δ −143.46 (s, 1F). HRMS (ESI-TOF):
1-(2-Bromophenyl)-2-fluoroindolizine-3-carbonitrile (3t). Fol-
lowing the general procedure, the title compound (70 mg) was
obtained in 56% yield. White solid. Chromatography: petroleum
ether/EtOAc, 20/1. Rf: 0.36 (petroleum ether/EtOAc, 20/1). Mp:
+
m/z calcd for C21H17FNO2 [M + H]+: 334.1238, found: 334.1254.
1
Ethyl 2-Fluoro-1-(1-tosyl-1H-indol-3-yl)indolizine-3-carboxylate
(3p). Following the general procedure, the title compound (123
mg) was obtained in 65% yield. White solid. Chromatography:
petroleum ether/EtOAc, 5/1. Rf: 0.51 (petroleum ether/EtOAc, 5/1).
Mp: 85−86 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.47 (d, J =
7.1 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.74
(s, 1H), 7.54−7.47 (m, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.28 (s, 1H),
7.22 (d, J = 8.3 Hz, 2H), 7.12 (t, J = 7.4 Hz, 1H), 6.89 (t, J = 6.9 Hz,
1H), 4.45 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H).
145−146 °C (CHCl3). H NMR (400 MHz, CDCl3): δ 8.21 (d, J =
6.9 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.43−7.36 (m, 2H), 7.30 (t, J =
8.1 Hz, 2H), 7.14−7.10 (m, 1H), 6.94 (t, J = 6.9 Hz, 1H). 13C{1H}
1
NMR (101 MHz, CDCl3): δ 155.8 (C−F, JC−F = 264.3 Hz, C2),
3
133.3 (CAr), 132.6 (CAr), 131.9 (C−F, JC−F = 5.7 Hz, C8a), 130.3
(C−F, JC−F = 2.6 Hz, CAr), 129.7 (CAr), 127.4 (C4), 125.4 (CAr),
4
124.9 (C6), 123.8 (CAr), 118.4 (C−F, JC−F = 5.0 Hz, C7), 113.8
(C−F, 5JC−F = 2.8 Hz, C5), 110.9 (C−F, 3JC−F = 4.0 Hz, CN), 101.4
2
2
(C−F, JC−F = 11.0 Hz, C1), 84.0 (C−F, JC−F = 26.3 Hz, C3). 19F
3
13C{1H} NMR (101 MHz, CDCl3): δ 160.7 (C−F, JC−F = 4.0 Hz,
NMR (376 MHz, CDCl3): δ −142.62 (s, 1F). HRMS (ESI-TOF): m/
1
+
z calcd for C15H9BrFN2 [M + H]+: 314.9928, found: 314.9938.
CO2Et), 155.5 (C−F, JC−F = 263.4 Hz, C2), 145.2 (CAr), 135.2
(CAr), 132.7 (C−F, 3JC−F = 6.1 Hz, C8a), 130.1 (C−F, JC−F = 3.3 Hz,
Ethyl 2-Fluoro-1-(4-(methoxycarbonyl)phenyl)-5-methylindoli-
zine-3-carboxylate (3u). Following the general procedure, the title
compound (75 mg) was obtained in 53% yield. White solid.
Chromatography: petroleum ether/EtOAc, 20/1. Rf: 0.39 (petroleum
ether/EtOAc, 20/1). Mp: 103−104 °C (CHCl3). 1H NMR (400
MHz, CDCl3): δ 8.11 (d, J = 8.0 Hz, 2H), 7.64−7.60 (m, 3H), 7.13
(dd, J = 8.0, 8.0 Hz, 1H), 6.71 (d, J = 4.0 Hz, 1H), 4.42 (q, J = 8.0 Hz,
CAr), 127.6 (C4), 127.0 (CAr), 125.1 (CAr), 124.3 (C6), 123.8 (CAr),
4
123.5 (CAr), 121.2 (C−F, JC−F = 2.9 Hz, CAr), 117.4 (C−F, JC−F
=
5
5.1 Hz, C7), 113.8 (CAr), 113.4 (C−F, JC−F = 3.0 Hz, C5), 112.3
2
(C−F, JC−F = 2.1 Hz, CAr), 101.4 (C−F, JC−F = 20.8 Hz, C3), 93.4
2
(C−F, JC−F = 12.9 Hz, C1), 60.2 (CH2), 21.6 (CH3), 14.7 (CH3).
19F NMR (376 MHz, CDCl3): δ −140.29 (s, 1F). HRMS (ESI-TOF):
m/z calcd for C26H22FN2O4S [M + H]+: 477.1279, found: 477.1282.
Ethyl 1-(4-Bromothiophen-2-yl)-2-fluoroindolizine-3-carboxy-
late (3q). Following the general procedure, the title compound
(100 mg) was obtained in 68% yield. White solid. Chromatography:
petroleum ether/EtOAc, 40/1. Rf: 0.33 (petroleum ether/EtOAc, 40/
1). Mp: 80−81 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.41 (d,
J = 7.1 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.19−7.15 (m, 3H), 6.87 (t,
J = 6.9 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H).
2H), 3.93 (s, 3H), 2.62 (s, 3H), 1.42 (t, J = 8.0 Hz, 3H). 13C{1H}
3
NMR (101 MHz, CDCl3): δ 167.0 (CO2Me), 159.6 (C−F, JC−F
=
1
4.1 Hz, CO2Et), 156.2 (C−F, JC−F = 264.0 Hz, C2), 138.9 (CAr),
135.9 (C−F, JC−F = 2.9 Hz, CAr), 134.1 (C−F, 3JC−F = 5.5 Hz, C8a),
130.1 (CAr), 128.5 (C−F, JC−F = 1.9 Hz, CAr), 128.0 (C4), 124.8
(C6), 115.6 (C−F, 5JC−F = 2.7 Hz, C5), 114.6 (C−F, 4JC−F = 5.1 Hz,
C7), 103.5 (C−F, 2JC−F = 22.6 Hz, C3), 101.3 (C−F, 2JC−F = 10.8 Hz,
C1), 61.0 (CH2), 52.2 (CH3), 22.5 (CH3), 14.6 (CH3). 19F NMR
(376 MHz, CDCl3): δ −144.13 (s, 1F). HRMS (ESI-TOF): m/z
13C{1H} NMR (101 MHz, CDCl3): δ 160.5 (C−F, JC−F = 4.1 Hz,
3
CO2Et), 154.8 (C−F, 1JC−F = 264.8 Hz, C2), 133.4 (C−F, JC−F = 4.0
Hz, CAr), 131.5 (C−F, 3JC−F = 5.1 Hz, C8a), 127.6 (C4), 127.0 (C−
F, JC−F = 3.6 Hz, CAr), 124.6 (C6), 120.7 (C−F, JC−F = 1.5 Hz, CAr),
+
calcd for C20H19FNO4 [M + H]+: 356.1293, found: 356.1310.
Mixture of Ethyl 2-Fluoro-1-(4-(methoxycarbonyl)phenyl)-6-
methylindolizine-3-carboxylate and Ethyl 2-Fluoro-1-(4-
4654
https://dx.doi.org/10.1021/acs.joc.0c03041
J. Org. Chem. 2021, 86, 4646−4660

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
4
(methoxycarbonyl)phenyl)-8-methylindolizine-3-carboxylate (3v).
Following the general procedure, the title compound (63 mg) was
obtained in 44% yield. White solid. Chromatography: petroleum
ether/EtOAc, 15/1. Rf: 0.44 (petroleum ether/EtOAc, 15/1). Mp:
121−122 °C (CHCl3). Characteristic signals of the major (7-
substituted) isomer: 1H NMR (400 MHz, CDCl3): δ 9.39 (d, J = 4.0
Hz, 1H), 8.07 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 6.82 (dd,
J = 28.0, 4.0 Hz, 2H), 4.45−4.38 (m, 2H), 3.94 (s, 3H), 2.04 (s, 3H),
1.39 (t, J = 8.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 167.0
= 10.9 Hz, C1), 94.7 (C−F, JC−F = 4.8 Hz, C7), 60.1 (CH2), 55.6
(CH3), 52.3 (CH3), 14.7 (CH3). 19F NMR (376 MHz, CDCl3): δ
−141.79 (s, 1F). HRMS (ESI-TOF): m/z calcd for C20H19FNO5+ [M
+ H]+: 372.1242, found: 372.1247.
Ethyl 2-Fluoro-1-(4-(methoxycarbonyl)phenyl)pyrrolo[2,1-a]-
isoquinoline-3-carboxylate (3z). Following the general procedure,
the title compound (87 mg) was obtained in 56% yield. White solid.
Chromatography: petroleum ether/EtOAc, 15/1. Rf: 0.47 (petroleum
ether/EtOAc, 15/1). Mp: 139−140 °C (CHCl3). 1H NMR (400
MHz, CDCl3): δ 9.21 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 8.2 Hz, 2H),
7.72 (d, J = 8.3 Hz, 1H), 7.60−7.56 (m, 3H), 7.40 (t, J = 7.3 Hz, 1H),
7.20 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 4.41 (q, J = 7.1 Hz,
2H), 3.97 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101
(CO2Me), 160.7 (C−F, 3JC−F = 4.2 Hz, CO2Et), 155.5 (C−F, 1JC−F
=
261.1 Hz, C2), 136.6 (C−F, JC−F = 1.7 Hz, CAr), 131.6 (CAr), 130.1
(CAr), 128.9 (C4), 128.10 (C−F, JC−F = 2.2 Hz, CAr), 128.0 (C−F,
3JC−F = 5.2 Hz, C8a), 124.7 (C6), 116.3 (C−F, JC−F = 5.1 Hz, C7),
4
112.7 (C−F, 5JC−F = 2.9 Hz, C5), 102.8 (C−F, 2JC−F = 12.6 Hz, C1),
3
MHz, CDCl3): δ 166.9 (CO2Me), 160.6 (C−F, JC−F = 4.1 Hz,
2
1
100.6 (C−F, JC−F = 20.8 Hz, C3), 60.1 (CH2), 52.2 (CH3), 20.6
CO2Et), 155.0 (C−F, JC−F = 261.4 Hz, C2), 136.7 (CAr), 130.9
(CH3), 14.5 (CH3). 19F NMR (376 MHz, CDCl3): δ −143.64 (s,
(CAr), 130.1 (CAr), 129.9 (CAr), 129.6 (CAr), 129.0 (CAr), 127.9 (C4),
1
1F). Characteristic signals of the minor (5-substituted) isomer: H
127.8 (C−F, JC−F = 4.2 Hz, CAr), 127.2 (C−F, JC−F = 6.8 Hz, CAr),
5
NMR (400 MHz, CDCl3): δ 9.30 (s, 1H), 8.10 (d, J = 8.46 Hz, 2H),
7.03 (d, J = 9.07 Hz, 1H), 3.93 (s, 3H), 2.34 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3): δ 166.9 (CO2Me), 160.8 (C−F, 3JC−F = 4.1 Hz,
CO2Et), 60.1 (CH2), 52.1 (CH3), 18.6 (CH3), 14.5 (CH3). 19F NMR
(376 MHz, CDCl3): δ −143.38 (s, 1F). HRMS (ESI-TOF): m/z
124.5 (C−F, JC−F = 3.9 Hz, CAr), 124.2, 123.7, 112.9 (C−F, JC−F
2.6 Hz, C5), 105.8 (C−F, 2JC−F = 13.3 Hz, C1), 102.3 (C−F, 2JC−F
=
=
19.6 Hz, C3), 60.4 (CH2), 52.3 (CH3), 14.5 (CH3). 19F NMR (376
MHz, CDCl3+): δ −144.66 (s, 1F). HRMS (ESI-TOF): m/z calcd for
C23H19FNO4 [M + H]+: 392.1293, found: 392.1303.
+
calcd for C20H19FNO4 [M + H]+: 356.1293, found: 356.1309.
Ethyl 2-Fluoro-1-(4-(methoxycarbonyl)phenyl)-6-methylpyrrolo-
[2,1-a]isoquinoline-3-carboxylate (3aa). Following the general
procedure, the title compound (86 mg) was obtained in 53% yield.
White solid. Chromatography: petroleum ether/EtOAc, 20/1. Rf: 0.41
(petroleum ether/EtOAc, 20/1). Mp: 160−161 °C (CHCl3). 1H
NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 8.17 (d, J = 8.0 Hz, 2H),
7.80−7.74 (m, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.48 (t, J = 7.6 Hz, 1H),
7.24 (t, J = 7.7 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 2.49
(s, 3H), 1.42 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3):
δ 167.0 (CO2Me), 160.8 (C−F, 3JC−F = 7.1 Hz, CO2Et), 154.8 (C−F,
1JC−F = 260.7 Hz, C2) 137.00 (C−F, JC−F = 1.1 Hz), 131.0 (CAr),
Ethyl 2-Fluoro-1-(4-(methoxycarbonyl)phenyl)-7-methylindoli-
zine-3-carboxylate (3w). Following the general procedure, the title
compound (67 mg) was obtained in 47% yield. White solid.
Chromatography: petroleum ether/EtOAc, 15/1. Rf: 0.41 (petroleum
ether/EtOAc, 15/1). Mp: 99−100 °C (CHCl3). 1H NMR (400 MHz,
CDCl3): δ 9.35 (d, J = 4.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 2H), 7.64 (d,
J = 8.0 Hz, 2H), 7.47 (s, 1H), 6.74 (dd, J = 7.2, 1.7 Hz, 1H), 4.42 (q, J
= 7.1 Hz, 2H), 3.94 (s, 3H), 2.38 (s, 3H), 1.42 (t, 3H). 13C{1H}
3
NMR (101 MHz, CDCl3): δ 167.1 (CO2Me), 160.8 (C−F, JC−F
=
1
4.2 Hz, CO2Et), 155.6 (C−F, JC−F = 264.4 Hz, C2), 136.1 (C−F,
JC−F = 2.9 Hz, CAr), 135.7 (CAr), 132.7 (C−F, JC−F = 5.4 Hz, C8a),
3
130.2 (CAr), 129.8 (CAr), 129.6 (CAr), 127.9, 127.6 (C−F, JC−F = 4.1
Hz), 127.0, 124.5 (C−F, JC−F = 3.7 Hz), 124.1, 124.0, 122.4, 119.1
(C−F, 5JC−F = 2.6 Hz, C5), 105.4 (C−F, 2JC−F = 13.0 Hz, C1), 102.0
130.2 (CAr), 128.3 (C−F, JC−F = 2.1 Hz, CAr), 127.9 (C4), 127.3
(C6), 116.1 (C−F, 5JC−F = 2.8 Hz, C5), 115.5 (C−F, 4JC−F = 5.0 Hz,
C7), 100.9 (C−F, 2JC−F = 20.9 Hz, C3), 100.3 (C−F, 2JC−F = 10.4 Hz,
C1), 60.2 (CH2), 52.2 (CH3), 21.6 (CH3), 14.7 (CH3). 19F NMR
(376 MHz, CDCl3): δ −142.63 (s, 1F). HRMS (ESI-TOF): m/z
2
(C−F, JC−F = 19.7 Hz, C3), 60.4 (CH2), 52.3 (CH3), 16.7 (CH3),
14.6 (CH3). 19F NMR (376 MHz, CDCl3): δ −145.68 (s, 1F). HRMS
(ESI-TOF): m/z calcd for C24H21FNO4+ [M + H]+: 406.1449, found:
406.1457.
+
calcd for C20H19FNO4 [M + H]+: 356.1293, found: 356.1306.
Diethyl 2-Fluoro-1-(4-(methoxycarbonyl)phenyl)indolizine-3,7-
dicarboxylate(3x). Following the general procedure, the title
compound (68 mg) was obtained in 41% yield. White solid.
Chromatography: petroleum ether/EtOAc, 15/1. Rf: 0.45 (petroleum
ether/EtOAc, 15/1). Mp: 111−112 °C (CHCl3). 1H NMR (400
MHz, CDCl3): δ 9.43 (d, J = 7.4 Hz, 1H), 8.35 (s, 1H), 8.13 (d, J =
8.4 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.4 Hz, 1H), 4.46−
4.36 (m, 4H), 3.95 (s, 3H), 1.44−1.37 (m, 6H). 13C{1H} NMR (101
MHz, CDCl3): δ 166.9 (CO2Me), 164.9 (CO2Et), 160.4 (C−F, 3JC−F
= 4.2 Hz, CO2Et), 155.1 (C−F, 1JC−F = 265.9 Hz, C2), 134.9 (C−F,
Ethyl (E)-2-Fluoro-5-methyl-1-styrylindolizine-3-carboxylate
(3ab). Following the general procedure, the title compound (77
mg) was obtained in 60% yield. White solid. Chromatography:
petroleum ether/EtOAc, 20/1. Rf: 0.40 (petroleum ether/EtOAc, 20/
1). Mp: 123−124 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.61
(d, J = 8.8 Hz, 1H), 7.56 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H),
7.29 (d, J = 6.6 Hz, 1H), 7.19 (d, J = 3.1 Hz, 2H), 7.16 (d, J = 8.7 Hz,
1H), 6.72 (d, J = 6.9 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 2.64 (s, 3H),
1.49 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 159.6
3
1
3
(C−F, JC−F = 4.0 Hz, CO2Et), 156.9 (C−F, JC−F = 265.9 Hz, C2),
JC−F = 3.1 Hz, CAr), 130.6 (C−F, JC−F = 5.5 Hz, C8a), 130.3 (CAr),
3
128.7 (CAr), 128.6 (C−F, JC−F = 2.0 Hz, CAr), 127.0 (C4), 125.6
(C6), 119.6 (C−F, 4JC−F = 5.5 Hz, C7), 112.4 (C−F, 5JC−F = 2.6 Hz,
C5), 104.7 (C−F, 2JC−F = 10.3 Hz, C1), 103.5 (C−F, 2JC−F = 21.1 Hz,
C3), 61.8 (CH2), 60.8 (CH2), 52.3 (CH3), 14.5 (CH3), 14.4 (CH3).
19F NMR (376 MHz, CDCl3): δ −141.43 (s, 1F). HRMS (ESI-TOF):
138.7 (CAr), 138.3 (CAr), 134.5 (C−F, JC−F = 6.4 Hz, C8a), 128.8
(CAr), 128.2 (C−F, 3JC−F = 6.9 Hz, Calkene), 127.1 (CAr), 126.0 (C4),
123.9 (C6), 115.9 (C−F, 4JC−F = 3.4 Hz, Calkene), 115.2 (C−F, 5JC−F
=
=
4
2
2.7 Hz, C5), 114.3 (C−F, JC−F = 5.2 Hz, C7), 103.8 (C−F, JC−F
2
22.3 Hz, C3), 99.6 (C−F, JC−F = 9.9 Hz, C1), 61.0 (CH2), 22.5
+
m/z calcd for C22H21FNO6 [M + H]+: 414.1347, found: 414.1349.
(CH3), 14.6 (CH3). 19F NMR (376 MHz, CDCl3): δ −140.15 (s,
+
1F). HRMS (ESI-TOF): m/z calcd for C20H19FNO2 [M + H]+:
Ethyl 2-Fluoro-7-methoxy-1-(4-(methoxycarbonyl)phenyl)-
indolizine-3-carboxylate (3y). Following the general procedure, the
title compound (15 mg) was obtained in 9% yield. White solid.
Chromatography: petroleum ether/EtOAc, 15/1. Rf: 0.42 (petroleum
ether/EtOAc, 15/1). Mp: 126−127 °C (CHCl3). 1H NMR (400
MHz, CDCl3): δ 9.33 (d, J = 7.7 Hz, 1H), 8.12 (d, J = 8.1 Hz, 2H),
7.62 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 2.7 Hz, 1H), 6.60 (dd, J = 7.8,
2.7 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 3.84 (s, 3H) 1.41
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 167.1
324.1394, found: 324.1413.
3
(CO2Me), 160.8 (C−F, JC−F = 4.3 Hz, CO2Et), 157.6, 156.2 (C−F,
1JC−F = 264.3 Hz, C2), 136.31 (C−F, JC−F = 2.9 Hz, CAr), 134.08 (C−
F, 3JC−F = 5.6 Hz, C8a), 130.3, 129.4, 128.1, 127.8, 107.6 (C−F, 5JC−F
= 2.9 Hz, C5), 100.1 (C−F, 2JC−F = 20.7 Hz, C3), 100.0 (C−F, 2JC−F
4655
https://dx.doi.org/10.1021/acs.joc.0c03041
J. Org. Chem. 2021, 86, 4646−4660

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
+
Ethyl (E)-2-Fluoro-1-styrylindolizine-3-carboxylate (3ac). Follow-
ing the general procedure, the title compound (72 mg) was obtained
in 58% yield. White solid. Chromatography: petroleum ether/EtOAc,
15/1. Rf: 0.46 (petroleum ether/EtOAc, 15/1). Mp: 81−82 °C
(CHCl3). 1H NMR (400 MHz, CDCl3, COSY): δ 9.37 (d, J = 7.1 Hz,
1H, H6), 7.62 (d, J = 8.9 Hz, 1H, H9), 7.50 (d, J = 7.6 Hz, 2H, H4,
H5), 7.36 (t, J = 7.6 Hz, 2H, H2, H3), 7.24 (t, J = 7.3 Hz, 1H, H1),
7.17−7.11 (m, 3H, Halkene, H8), 6.85 (t, J = 6.9 Hz, 1H, H7), 4.43 (q,
J = 7.1 Hz, 2H, CH2), 1.45 (t, J = 7.1 Hz, 3H, CH3). 13C{1H} NMR
(s, 1F). HRMS (ESI-TOF): m/z calcd for C23H19FNO2 [M + H]+:
360.1394, found: 360.1403.
Ethyl 2-Fluoro-1-(4-((((2R,5S)-2-isopropyl-5-methylcyclohexyl)-
oxy)carbonyl)phenyl)indolizine-3-carboxylate (4a). Following the
general procedure, the title compound (104 mg) was obtained in 56%
yield. Colorless viscous oil. Chromatography: petroleum ether/
EtOAc, 15/1. Rf: 0.44 (petroleum ether/EtOAc, 15/1). [α]20 D
=
−12.1 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3): δ 9.45 (d, J = 6.8
Hz, 1H), 8.13 (d, J = 7.7 Hz, 2H), 7.69 (d, J = 8.8 Hz, 1H), 7.64 (d, J
= 7.6 Hz, 2H), 7.15 (t, J = 7.5 Hz, 1H), 6.87 (t, J = 6.5 Hz, 1H), 4.96
(t, J = 8.3 Hz, 1H), 4.42 (q, J = 6.9, 2H), 2.15 (d, J = 11.0 Hz, 1H),
2.00 (t, J = 6.4 Hz, 1H), 1.73 (d, J = 11.2 Hz, 2H), 1.56 (d, J = 9.8 Hz,
2H), 1.42 (t, J = 6.9 Hz, 3H), 1.19−1.08 (m, 2H), 0.94−0.92 (m,
7H), 0.81 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
3
(101 MHz, CDCl3, HSQC, HMBC): δ 160.7 (C−F, JC−F = 4.0 Hz,
CO2Et), 155.9 (C−F, 1JC−F = 266.2 Hz, C2), 138.2 (CAr), 132.6 (C−
3
3
F, JC−F = 6.6 Hz, C8a), 128.8 (CAr), 128.3 (C−F, JC−F = 6.8 Hz,
C9), 127.6 (C4), 127.2 (CAr), 126.0 (CAr), 123.8 (C6), 116.6 (C−F,
4JC−F = 5.2 Hz, C7), 115.7 (C−F, 4JC−F = 3.3 Hz, C10), 113.3 (C−F,
3
165.9 (CO2R), 160.6 (C−F, JC−F = 4.1 Hz, CO2Et), 155.2 (C−F,
5JC−F = 2.8 Hz, C5), 101.7 (C−F, JC−F = 20.7 Hz, C3), 99.7 (C−F,
2
1JC−F = 264.6 Hz, C2), 135.5 (C−F, JC−F = 2.8 Hz, CAr), 132.1 (C−F,
2JC−F = 9.6 Hz, C1), 60.3 (CH2), 14.7 (CH3). 19F NMR (376 MHz,
CDCl3): δ −139.09 (S, 1F). HRMS (ESI-TOF): m/z calcd for
3JC−F = 5.5 Hz, C8a), 130.1 (CAr), 128.8 (CAr), 128.2 (C−F, JC−F
=
4
1.9 Hz, CAr), 127.7 (C4), 124.4 (C6), 116.8 (C−F, JC−F = 5.1 Hz,
C7), 113.5 (C−F, 5JC−F = 2.9 Hz, C5), 101.4 (C−F, 2JC−F = 10.0 Hz,
C1), 101.4 (C−F, 2JC−F = 20.6 Hz, C3), 74.8, 60.2 (CH2), 47.3, 41.0,
34.4, 31.5, 26.6, 23.7, 22.1, 20.8, 16.6, 14.5 (CH3). 19F NMR (376
MHz, CDCl3+): δ −142.85 (s, 1F). HRMS (ESI-TOF): m/z calcd for
C28H33FNO4 [M + H]+: 466.2388, found: 466.2397.
+
C19H17FNO2 [M + H]+: 310.1238, found: 310.1253.
(E)-2-Fluoro-1-styrylindolizine-3-carbonitrile (3ad). Following the
general procedure, the title compound (57 mg) was obtained in 55%
yield. White solid. Chromatography: petroleum ether/EtOAc, 15/1.
Rf: 0.40 (petroleum ether/EtOAc, 15/1). Mp: 124−125 °C (CHCl3).
1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 6.9 Hz, 1H), 7.66 (d, J =
9.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.28
(s, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.06 (q, J = 16.5 Hz, 2H), 6.89 (t, J
= 6.9 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 156.7 (C−F,
Ethyl 2-Fluoro-1-(4-((((1S,2R,4S)-3,3,5-trimethylbicyclo[2.2.1]-
heptan-2-yl)oxy)carbonyl)phenyl)indolizine-3-carboxylate (4b).
Following the general procedure, the title compound (131 mg) was
obtained in 71% yield. White solid. Chromatography: petroleum
ether/EtOAc, 15/1. Rf: 0.47 (petroleum ether/EtOAc, 15/1). Mp:
103−104 °C (CHCl3); [α]20 D = +14.6 (c 1, CHCl3); 1H NMR (400
MHz, CDCl3): δ 9.46 (d, J = 7.1 Hz, 1H), 8.16 (d, J = 8.3 Hz, 2H),
7.71 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.16 (t, J = 7.1 Hz,
1H), 6.88 (t, J = 6.9 Hz, 1H), 4.65 (d, J = 1.6 Hz, 1H), 4.43 (q, J = 7.1
Hz, 2H), 2.01−1.94 (m, 1H), 1.83−1.78 (m, 2H), 1.68 (d, J = 10.3
Hz, 1H), 1.57−1.49 (m, 1H), 1.42 (t, J = 7.1 Hz, 3H), 1.28−1.20 (m,
5H), 1.13 (s, 3H), 0.88 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3):
3
1JC−F = 265.8 Hz, C2), 137.6 (CAr), 132.0 (C−F, JC−F = 6.1 Hz,
3
C8a), 129.4 (C−F, JC−F = 6.2 Hz, Calkene), 128.8 (CAr), 127.6 (C4),
4
126.1 (CAr), 125.7 (CAr), 124.0 (C6), 117.8 (C−F, JC−F = 5.0 Hz,
4
5
C7), 114.7 (C−F, JC−F = 3.3 Hz, Calkene), 114.0 (C−F, JC−F = 2.7
3
2
Hz, C5), 110.9 (C−F, JC−F = 3.8 Hz, CN), 99.7 (C−F, JC−F = 8.2
Hz, C1), 85.0 (C−F, JC−F = 26.4 Hz, C3). 19F NMR (376 MHz,
2
CDCl3): δ −143.54 (s, 1F). HRMS (ESI-TOF): m/z calcd for
+
C17H12FN2 [M + H]+: 263.0979, found: 263.0997.
3
Ethyl (E)-2-Fluoro-1-(1-phenylprop-1-en-2-yl)indolizine-3-car-
boxylate (3ae). Following the general procedure, the title compound
(72 mg) was obtained in 56% yield. White solid. Chromatography:
petroleum ether/EtOAc, 15/1. Rf: 0.48 (petroleum ether/EtOAc, 15/
1). Mp: 46−47 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.41 (d,
J = 7.1 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.40−7.24 (m, 4H), 7.25−
7.21 (m, 1H), 7.07 (d, J = 7.1 Hz, 1H), 6.80 (td, J = 7.0, 1.0 Hz, 1H),
6.70 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.34 (s, 3H), 1.42 (t, J = 7.1
δ 166.7 (CO2R), 160.6 (C−F, JC−F = 4.0 Hz, CO2Et), 155.2 (C−F,
1JC−F = 264.4 Hz, C2), 135.6 (C−F, JC−F = 2.9 Hz, CAr), 132.2 (C−F,
3JC−F = 5.7 Hz, C8a), 130.1 (CAr), 128.6 (CAr), 128.3 (C−F, JC−F
=
4
2.0 Hz, CAr), 127.7 (C4), 124.4 (C6), 116.8 (C−F, JC−F = 5.1 Hz,
C7), 113.5 (C−F, 5JC−F = 2.7 Hz, C5), 101.4 (C−F, 2JC−F = 20.6 Hz,
2
C3), 101.2 (C−F, JC−F = 9.8 Hz, C1), 86.7, 60.2 (CH2), 48.7, 48.5,
41.5, 39.9, 29.8, 26.9, 26.0, 20.4, 19.5, 14.5 (CH3). 19F NMR (376
MHz, CDCl3+): δ −142.86 (s, 1F). HRMS (ESI-TOF): m/z calcd for
C28H31FNO4 [M + H]+: 464.2232, found: 464.2240.
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 160.8 (C−F, 3JC−F
=
1
4.0 Hz, CO2Et), 155.3 (C−F, JC−F = 263.6 Hz, C2), 137.8 (CAr),
Ethyl 1-(4-((((3S,8R,9S,10S,13S,14S)-10,13-Dimethyl-17-oxohexa-
decahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)-
phenyl)-2-fluoroindolizine-3-carboxylate (4c). Following the general
procedure, the title compound (151 mg) was obtained in 63% yield.
White solid. Chromatography: petroleum ether/EtOAc, 15/1. Rf: 0.33
(petroleum ether/EtOAc, 15/1). Mp: 218−219 °C (CHCl3); [α]20 D
3
4
132.3 (C−F, JC−F = 6.7 Hz, C8a), 129.9 (C−F, JC−F = 1.4 Hz,
3
Calkene), 129.1 (CAr), 128.3 (CAr), 128.1 (C−F, JC−F = 3.0 Hz,
4
Calkene), 127.4 (C4), 126.6 (CAr), 123.4 (C8), 117.7 (C−F, JC−F
=
=
5
2
5.4 Hz, C7), 112.9 (C−F, JC−F = 3.0 Hz, C5), 105.6 (C−F, JC−F
2
10.4 Hz, C1), 100.9 (C−F, JC−F = 21.7 Hz, C3), 60.1 (CH2), 18.9
(C−F, JC−F = 3.0 Hz, CH3), 14.7 (CH3). 19F NMR (376 MHz,
4
1
= +40.5 (c 1, CHCl3); H NMR (400 MHz, CDCl3): δ 9.47 (d, J =
CDCl3): δ −139.70 (s, 1F). HRMS (ESI-TOF): m/z calcd for
7.1 Hz, 1H), 8.12 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.9 Hz, 1H), 7.64
(d, J = 8.1 Hz, 2H), 7.18 (d, J = 7.4 Hz, 1H), 6.90 (t, J = 7.0 Hz, 1H),
4.96 (tt, J = 10.8, 4.7 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 2.43 (dd, J =
19.2, 8.8 Hz, 1H), 2.11−2.02 (m, 1H), 1.99−1.90 (m, 2H), 1.82−
1.76 (m, 4H), 1.68 (t, J = 10.4 Hz, 3H), 1.53 (dt, J = 20.9, 10.5 Hz,
3H), 1.42 (t, J = 7.1 Hz, 3H), 1.36 (d, J = 11.0 Hz, 2H), 1.31−1.25
(m, 3H), 1.12 (td, J = 13.3, 3.2 Hz, 1H), 1.02 (td, J = 12.9, 12.0, 5.1
Hz, 1H), 0.88 (d, J = 17.0 Hz, 6H), 0.75 (t, J = 11.2 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3): δ 221.3 (C = O), 166.0 (CO2R),
160.8 (C−F, 3JC−F = 4.1 Hz, CO2Et), 155.3 (C−F, 1JC−F = 264.4 Hz,
+
C20H19FNO2 [M + H]+: 324.1394, found: 324.1414.
Ethyl (E)-2-Fluoro-1-styrylpyrrolo[2,1-a]isoquinoline-3-carboxy-
late (3af). Following the general procedure, the title compound
(102 mg) was obtained in 71% yield. White solid. Chromatography:
petroleum ether/EtOAc, 20/1. Rf: 0.37 (petroleum ether/EtOAc, 20/
1). Mp: 122−123 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.10
(d, J = 7.4 Hz, 1H), 8.24 (d, J = 7.3 Hz, 1H), 7.57 (dd, J = 12.6, 7.7
Hz, 3H), 7.49 (q, J = 6.3, 5.5 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.34−
7.30 (m, 2H), 7.13 (d, J = 16.3 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H),
4.43 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
3
C2), 135.6 (C−F, JC−F = 2.8 Hz, CAr), 132.3 (C−F, JC−F = 5.7 Hz,
3
(101 MHz, CDCl3): δ 160.6 (C−F, JC−F = 4.1 Hz, CO2Et), 155.5
C8a), 130.2 (CAr), 128.9 (CAr), 128.3 (C−F, JC−F = 1.9 Hz, CAr),
1
3
127.8 (C4), 124.5 (C6), 116.9 (C−F, 4JC−F = 5.3 Hz, C7), 113.6 (C−
(C−F, JC−F = 264.0 Hz, C2), 137.9 (CAr), 132.7 (C−F, JC−F = 6.5
3
5
2
Hz, C8a), 129.3 (CAr), 128.8 (CAr), 128.2 (C−F, JC−F = 4.4 Hz,
F, JC−F = 2.8 Hz, C5), 101.61 (C−F, JC−F = 20.3 Hz, C3), 101.56
(C−F, 2JC−F = 11.0 Hz, C1), 74.3, 60.3 (CH2), 54.5, 51.5, 47.9, 44.9,
36.9, 36.0, 35.9, 35.2, 34.2, 31.7, 31.0, 28.5, 27.7, 21.9, 20.6, 14.7
(CH3), 14.0, 12.4. 19F NMR (376 MHz, CDCl3): δ −142.87 (s, 1F).
HRMS (ESI-TOF): m/z calcd for C37H43FNO5 [M + H]+: 600.3120,
found: 600.3128.
Calkene), 127.7 (CAr), 127.63 (CAr), 127.55 (C4), 127.2 (CAr), 126.4
(CAr), 125.5 (C−F, 4JC−F = 3.8 Hz, Calkene), 124.3 (C6), 124.1 (CAr),
4
5
117.4 (C−F, JC−F = 3.2 Hz, C7), 112.6 (C−F, JC−F = 2.5 Hz, C5),
104.3 (C−F, 2JC−F = 10.1 Hz, C1), 102.6 (C−F, 2JC−F = 19.9 Hz, C3),
60.4 (CH2), 14.6 (CH3). 19F NMR (376 MHz, CDCl3): δ −143.76
4656
https://dx.doi.org/10.1021/acs.joc.0c03041
J. Org. Chem. 2021, 86, 4646−4660

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Ethyl 1-(4-((((3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-((R)-
6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetrade-
cahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)carbonyl)phenyl)-
2-fluoroindolizine-3-carboxylate (4d). Following the general proce-
dure, the title compound (169 mg) was obtained in 61% yield. White
solid. Chromatography: petroleum ether/EtOAc, 15/1. Rf: 0.47
(petroleum ether/EtOAc, 15/1). Mp: 139−140 °C (CHCl3); [α]20 D
To a mixture of 3t (94 mg, 0.3 mmol), phenylboronic acid (925
mg, 0.36 mmol), Pd(PPh3)2Cl2 (10 mg, 0.015 mmol), and sodium
carbonate (63 mg, 0.6 mmol) in a round-bottom flask (10 mL) was
added a mixture of 1, 4-dioxane (3 mL) and water (1 mL). The
solution was bubbled with argon for 0.5 h before being heated to 80
°C for 12 h. Upon cooling to room temperature, the solvent was
removed under vacuum and the resulting product was extracted with
EtOAc. The organics was washed thoroughly with water, dried over
anhydrous Na2SO4, and then evaporated to dryness. The residue was
purified by column chromatography (SiO2, petroleum ether/EtOAc
30:1) to give 89 mg of 5b as a white solid (95%).
1
= +20.5 (c 1, CHCl3); H NMR (400 MHz, CDCl3): δ 9.48 (d, J =
6.5 Hz, 1H), 8.13 (d, J = 7.7 Hz, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.65
(d, J = 7.5 Hz, 2H), 7.18 (t, J = 8.2 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H),
5.43 (s, 1H), 4.89 (d, J = 7.8 Hz, 1H), 4.44 (d, J = 7.0 Hz, 2H), 2.49
(d, J = 7.1 Hz, 2H), 2.03−1.97 (m, 3H), 1.92 (d, J = 13.3 Hz, 1H),
1.83 (dd, J = 8.1, 4.4 Hz, 1H), 1.77−1.71 (m, 1H), 1.59−1.33 (m,
13H), 1.24 (d, J = 13.9 Hz, 2H), 1.18−0.99 (m, 11H), 0.93−0.86 (m,
9H), 0.69 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 166.0
1-([1,1′-Biphenyl]-2-yl)-2-fluoroindolizine-3-carbonitrile (5b).
White solid. Rf: 0.36 (petroleum ether/EtOAc, 30/1). Mp: 180−
181 °C (CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 6.9 Hz,
1H), 7.53−7.46 (m, 4H), 7.19 (d, J = 4.8 Hz, 6H), 6.94 (t, J = 7.3 Hz,
1H), 6.81 (t, J = 6.8 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ
3
1
(CO2R), 160.9 (C−F, JC−F = 4.0 Hz, CO2Et), 155.4 (C−F, JC−F
=
1
264.2 Hz, C2), 139.9 (Calkene), 135.7 (C−F, JC−F = 2.4 Hz, CAr),
156.1 (C−F, JC−F = 262.9 Hz, C2), 142.7 (CAr), 141.3 (CAr), 132.0
3
3
132.4 (C−F, JC−F = 5.4 Hz, C8a), 130.3 (CAr), 129.0 (CAr), 128.4
(C−F, JC−F = 6.0 Hz, C8a), 131.8 (CAr), 130.8 (CAr), 128.7 (CAr),
4
(CAr), 127.9 (C4), 124.6 (C6), 123.0 (Calkene), 117.0 (C−F, JC−F
4.9 Hz, C7), 113.7 (C−F, 5JC−F = 1.8 Hz, C5), 101.58 (C−F, 2JC−F
=
=
128.6 (CAr), 128.2 (CAr), 127.6 (CAr), 127.4 (C−F, JC−F = 2.7 Hz,
4
CAr), 127.0 (C4), 125.4 (CAr), 123.5 (C6), 118.1 (C−F, JC−F = 5.1
21.3 Hz, C3), 101.57 (C−F, 2JC−F = 10.7 Hz, C1), 74.8, 60.4 (CH2),
56.9, 56.4, 50.3, 42.6, 40.0, 39.8, 38.5, 37.3, 36.9, 36.4, 36.0, 32.2,
32.1, 28.5, 28.3, 28.2, 24.5, 24.1, 23.1, 22.8, 21.3, 19.6, 19.0, 14.8
(CH3), 12.1. 19F NMR (376 MHz, CDCl3): δ −142.79 (s, 1F).
HRMS (ESI-TOF): m/z calcd for C45H59FNO4 [M + Na]+:
696.4423, found: 696.4443.
5
3
Hz, C7), 113.6 (C−F, JC−F = 2.7 Hz, C5), 111.3 (C−F, JC−F = 4.0
Hz, CN), 102.0 (C−F, 2JC−F = 11.2 Hz, C1), 83.9 (C−F, 2JC−F = 26.7
Hz, C3). 19F NMR (376 MHz, CDCl3): δ −144.74 (s, 1F). HRMS
+
(ESI-TOF): m/z calcd for C21H14FN2 [M + H]+: 313.1136, found:
313.1145.
General Procedure. To a mixture of 2-fluoroindolizine (1 equiv),
2-aminopyrimidin-5-yl boronic acid (1.2 equiv), Pd(PPh3)2Cl2 (5 mol
%) and potassium carbonate (2 equiv) in a Schlenk flask (15 mL) was
added a mixture of 1,4-dioxane (3 mL) and water (1 mL). The
solution was bubbled with argon for 0.5 h before heated to 80 °C for
12 h. Upon cooling to room temperature, the solvent was removed
under vacuum, and the resulting product was extracted with EtOAc.
The organics were washed thoroughly with water and dried over
anhydrous Na2SO4. The residue was purified by column chromatog-
raphy (SiO2, petroleum ether/EtOAc 1:2) to give the corresponding
product.
Ethyl 1-(2-(2-Aminopyrimidin-5-yl)phenyl)-2-fluoroindolizine-3-
carboxylate (5c). According to the general procedure for the Suzuki
cross-coupling reaction, the title compound (158 mg) was obtained in
86% yield starting from 3g (177 mg, 0.49 mmol). White solid. Rf: 0.49
(petroleum ether/EtOAc, 1/2). Mp: 151−152 °C (CHCl3). 1H NMR
(400 MHz, CDCl3): δ 9.35 (d, J = 7.0 Hz, 1H), 8.11 (s, 2H), 7.43−
7.40 (m, 4H), 7.13 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.77
(t, J = 6.8 Hz, 1H), 5.40 (s, 2H), 4.37−4.33 (m, 2H), 1.34 (t, J = 7.0
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 161.7 (CAr), 160.6
Ethyl (S)-2-Fluoro-1-(4-((1-methoxy-1-oxo-3-phenylpropan-2-
yl)carbamoyl)phenyl)indolizine-3-carboxylate (4e). Following the
general procedure, the title compound (92 mg) was obtained in 47%
yield. White solid. Chromatography: petroleum ether/EtOAc, 10/1.
Rf: 0.32 (petroleum ether/EtOAc, 10/1). Mp: 105−106 °C (CHCl3);
1
[α]20 D = +64.1 (c 1, CHCl3); H NMR (400 MHz, CDCl3): δ 7.72
(d, J = 8.0 Hz, 2H), 7.47 (t, J = 8.8 Hz, 3H), 7.21−7.13 (m, 3H), 7.06
(d, J = 7.4 Hz, 2H), 6.99 (t, J = 7.9 Hz, 1H), 6.73 (t, J = 7.2 Hz, 1H),
6.59 (d, J = 6.9 Hz, 1H), 5.01 (q, J = 6.2 Hz, 1H), 4.30 (q, J = 7.1 Hz,
2H), 3.65 (s, 3H), 3.23−3.10 (m, 2H), 2.50 (s, 3H), 1.31 (t, J = 7.1
Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 172.2 (CO2NR),
3
166.6 (CO2R), 159.5 (C−F, JC−F = 4.1 Hz, CO2Et), 156.0 (C−F,
1JC−F = 263.9 Hz, C2), 138.8 (CAr), 136.0 (CAr), 134.7 (C−F, JC−F
=
3
2.8 Hz, CAr), 134.0 (C−F, JC−F = 5.7 Hz, C8a), 131.6 (CAr), 129.3
(CAr), 128.7 (CAr), 128.6 (CAr), 127.6 (C4), 127.2 124.6 (C6), 115.5
4
(C−F, JC−F = 2.7 Hz, CAr), 114.5 (C−F, JC−F = 5.2 Hz, C7), 103.3
(C−F, 2JC−F = 22.5 Hz, C3), 101.2 (C−F, 2JC−F = 10.9 Hz, C1), 61.0
(CH2), 53.7, 52.4, 37.9, 22.4, 14.5 (CH3). 19F NMR (376 MHz,
DMSO): δ −144.41 (s, 1F). HRMS (ESI-TOF): m/z calcd for
C28H25FN2O5Na+ [M + Na]+: 511.1640, found: 511.1649.
3
1
(C−F, JC−F = 4.0 Hz, CO2Et), 157.5 (CAr), 154.7 (C−F, JC−F
=
263.1 Hz, C2), 136.2 (CAr), 132.3 (CAr), 132.2 (C−F, 3JC−F = 6.1 Hz,
C8a), 129.9 (CAr), 128.6 (C−F, JC−F = 2.3 Hz, CAr), 128.5 (CAr),
128.1 (CAr), 127.5 (C4), 125.2 (CAr), 123.7 (C6), 116.6 (C−F, 4JC−F
= 5.1 Hz, C7), 113.1 (C−F, 5JC−F = 2.6 Hz, C5), 101.03 (C−F, 2JC−F
= 12.8 Hz, C1), 101.02 (C−F, 2JC−F = 20.6 Hz, C3), 60.1 (CH2), 14.5
(CH3). 19F NMR (377 MHz, CDCl3): δ −141.32 (s, 1F). HRMS
Transformations of 2-Fluoroindolizines. To a solution of
cyano-substituted indolizine 3t (62 mg, 0.2 mmol) in EtOH/H2O (v/
v = 10/1, 10 mL) was added finely powdered KOH (15 mg), and the
mixture was refluxed for 5 h. After the starting 3t was consumed
(TLC monitoring), the mixture was cooled to 0 °C and acidified to
pH 2 with concd HCl. The product was extracted with EtOAc, the
combined organic phases were dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by column
chromatography (SiO2, petroleum ether/EtOAc 3:1) to give 62 mg
of 5a as a white solid (93%).
(ESI-TOF): m/z calcd for C21H18FN4O2 [M + H]+: 377.1408,
+
found: 377.1423.
Ethyl 1-(3-(2-Aminopyrimidin-5-yl)phenyl)-2-fluoroindolizine-3-
carboxylate (5d). According to the general procedure for the Suzuki
cross-coupling reaction, the title compound (43 mg) was obtained in
57% yield starting from 3f (72 mg, 0.2 mmol). White solid.
Chromatography: petroleum ether/EtOAc, 1/2. Rf: 0.42 (petroleum
ether/EtOAc, 1/2). Mp: 132−133 °C (CHCl3). 1H NMR (400 MHz,
DMSO): δ 9.38 (d, J = 7.1 Hz, 1H), 8.63 (s, 2H), 7.85 (d, J = 9.0 Hz,
1H), 7.74 (s, 1H), 7.61−7.54 (m, 2H), 7.49 (d, J = 7.3 Hz, 1H), 7.33
(t, J = 7.5 Hz, 1H), 7.12 (t, J = 6.9 Hz, 1H), 6.81 (s, 2H), 4.36 (q, J =
7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz,
1-(2-Bromophenyl)-2-fluoroindolizine-3-carboxylic Acid (5a).
White solid. Rf: 0.41 (petroleum ether/EtOAc, 3/1). Mp: 195−196
1
°C (MeOH). H NMR (400 MHz, DMSO): δ 9.60 (d, J = 7.2 Hz,
1H), 7.78 (d, J = 7.8 Hz, 1H), 7.50−7.45 (m, 2H), 7.36 (ddd, J = 8.3,
6.4, 2.8 Hz, 1H), 7.23 (d, J = 8.9 Hz, 1H), 7.14 (t, J = 6.8 Hz, 1H),
6.96 (td, J = 7.1, 1.3 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO): δ
161.0 (C−F, 3JC−F = 3.3 Hz, CO2H), 151.9 (C−F, 1JC−F = 254.0 Hz,
C2), 133.0 (C−F, JC−F = 4.4 Hz, CAr), 130.9 (C−F, JC−F = 2.2 Hz,
3
3
DMSO): δ 163.1 (CAr), 159.7 (C−F, JC−F = 4.0 Hz, CO2Et), 156.2
CAr), 130.1 (C−F, JC−F = 6.4 Hz, C8a), 129.9 (CAr), 127.9 (C4),
(CAr), 154.1 (C−F, 1JC−F = 261.3 Hz, C2), 136.2 (CAr), 131.7 (C−F,
3JC−F = 5.8 Hz, C8a), 130.65 (C−F, JC−F = 2.4 Hz, CAr), 129.7 (CAr),
127.1 (C4), 126.9 (CAr), 125.3 (CAr), 125.0 (CAr), 124.1 (C6), 122.0
(CAr), 117.2 (C−F, 4JC−F = 5.0 Hz, C7), 114.2 (C−F, 5JC−F = 2.2 Hz,
C5), 101.3 (C−F, 2JC−F = 10.8 Hz, C1), 100.1 (C−F, 2JC−F = 21.2 Hz,
4
126.9 (CAr), 124.5 (C6), 123.2 (CAr), 116.8 (C−F, JC−F = 4.8 Hz,
C7), 113.0 (C−F, 5JC−F = 2.9 Hz, C5), 102.4 (C−F, 2JC−F = 23.4 Hz,
2
C3), 99.9 (C−F, JC−F = 13.5 Hz, C1), 79.2 (CAr). 19F NMR (376
MHz, DMSO): δ −145.67 (s, 1F). HRMS (ESI-TOF): m/z calcd for
C15H9BrFNO2Na+ [M + Na]+: 355.9693, found: 355.9699.
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J. Org. Chem. 2021, 86, 4646−4660

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
C3), 59.9 (CH2), 14.4 (CH3). 19F NMR (377 MHz, CDCl3): δ
Notes
+
−143.63 (s, 1F). HRMS (ESI-TOF): m/z calcd for C21H18FN4O2
The authors declare no competing financial interest.
[M + H]+: 377.1408, found: 377.1413.
Ethyl 1-(4-(2-aAminopyrimidin-5-yl)phenyl)-2-fluoroindolizine-
3-carboxylate (5e). According to the general procedure for the
Suzuki cross-coupling reaction, the title compound (106 mg) was
obtained in 91% yield starting from 3c (112 mg, 0.31 mmol). White
solid. Chromatography: petroleum ether/EtOAc, 10/1. Rf: 0.46
(petroleum ether/EtOAc, 1/2). Mp: 198−199 °C (CHCl3). 1H NMR
(400 MHz, CDCl3): δ 9.48 (d, J = 7.1 Hz, 1H), 8.60 (s, 2H), 7.72 (d,
J = 9.0 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H),
7.16 (t, J = 7.3 Hz, 1H), 6.90 (td, J = 7.0, 1.2 Hz, 1H), 5.20 (s, 2H),
4.45 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Leading Innovative and
Entrepreneur Team Introduction Program of Zhejiang (No.
2019R01005) and the launching scientific research funds from
Taizhou University.
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ASSOCIATED CONTENT
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Accession Codes
CCDC 2010054 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Hongjun Ren − Advanced Research Institute and Department
of Chemistry, Taizhou University, Taizhou 318000, P.R.
China; Email: renhj@tzc.edu.cn
Authors
Jun-Qi Zhang − Advanced Research Institute and Department
of Chemistry, Taizhou University, Taizhou 318000, P.R.
China
Dandan Hu − Advanced Research Institute and Department of
Chemistry, Taizhou University, Taizhou 318000, P.R.
China
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