Visible-Light-Mediated [2+2+1] Carbocyclization Reactions of 1,7-Enynes with Bromofluoroacetate to Form Fused Monofluorinated Cyclopenta[ c]quinolin-4-ones

Article abstract of DOI:10.1021/acs.joc.0c00087

Herein, we describe a new protocol for photoinduced radical [2+2+1] carbocyclization reactions of 1,7-enynes with bromofluoroacetate. These reactions, which proceed via a cascade involving fluoroalkylation, 6-exo-dig and 5-endo-trig cyclizations, H-transf

Full text of DOI:10.1021/acs.joc.0c00087

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Article
Visible-Light-Mediated [2+2+1] Carbocyclization
Reactions of 1,7-Enynes with Bromofluoroacetate to Form
Fused Monofluorinated Cyclopenta[c]quinolin-4-ones
Yi Qu, Wentao Xu, Jingjing Zhang, Yuxiu Liu, Yongqiang Li, Hongjian Song, and Qingmin Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00087 • Publication Date (Web): 21 Mar 2020
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Visible-Light-Mediated [2+2+1] Carbocyclization Reactions of
1,7-Enynes
with
Bromofluoroacetate
to
Form
Fused
7
8
Monofluorinated Cyclopenta[c]quinolin-4-ones
9
Yi Qu,a,§ Wentao Xu,a,§ Jingjing Zhang,*,a,b Yuxiu Liu,a Yongqiang Li,a Hongjian Song,*,a and
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Qingmin Wang*,a
aState Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative
Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071,
People’s Republic of China, E-mail: songhongjian@nankai.edu.cn (H.-J. S.); wangqm@nankai.edu.cn
(Q.-M. W).
bTianjin Agricultural University, Tianjin 300384, People’s Republic of China, E-mail:
chemzhangjingjing@163.com (J.-J. Z).
blue light
F
R2
R2
CO2Et
O
F
Ir(ppy)3, K2HPO4
dioxane, rt, 24 h
O
Br
R1
+
O
R4
R1
N
H
N
R3
O
R3 R4
26 examples
up to 91% yield
ABSTRACT: Herein we describe a new protocol for photoinduced radical [2+2+1]
carbocyclization reactions of 1,7-enynes with bromofluoroacetate. These reactions,
which proceed via a cascade involving fluoroalkylation, 6-exo-dig and 5-endo-trig
cyclizations, H-transfer step, and oxidative dehydrogenation, provide an efficient and
general route to a variety of fused monofluorinated cyclopenta[c]quinolin-4-one
derivatives.
INTRODUCTION
Because complex heteroatom-containing polycyclic hydrocarbon motifs can be
found in numerous bioactive molecules, including natural products and
pharmaceuticals,1 considerable research effort has been aimed at developing novel
and efficient methods for their synthesis.2 In addition, methods for incorporating
fluorine atoms into carbocycles and heterocycles have attracted interest because
fluorine-containing compounds show unique electronegativity, hydrophobicity,
metabolic stability, and bioavailability.3,4 In fact, approximately 20% of drugs and 30%
of pesticides currently on the market contain fluorine atoms.5 Recently, radical
enabled bicyclization involved H-transfer of 1,n-enynes were used to synthesize
heteroatom-containing polycyclic hydrocarbon motifs.6 For example, Li group
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reported a visible light-initiated C(sp3)-Br/C(sp3)-H functionalization of a-carbonyl
alkyl bromides through hydride radical shift,7a and Xia group reported a
visible-light-mediated 1,7-enyne bicyclizations protocol for synthesis of
heteroatom-containing polycyclic compounds.7b In previous work, we developed a
copper-catalyzed 1,7-enyne trifluoromethylation/bicyclization reaction with Togni’s
reagent, which serves as a method for the synthesis of CF3-containing heterocycles
such as indenes, dihydroquinolinones, and dihydrocoumarin-fused tetracyclic
compounds.8 In addition, Tang group reported an efficient and general method for
photoredox-catalyzed atom transfer radical addition and cyclization reactions of
perfluoroalkyl halides with 1,7-enynes.9
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Although considerable progress has been made in the synthesis of
fluorine-containing heterocycles, the use of 1,n-enynes for domino cyclizations
initiated by radicals containing a single fluorine atom to afford polycyclic structures
has never been reported. Inspired by recent developments in radical-triggered
1,n-enyne cyclization reactions, and as part of our ongoing work on the preparation of
useful monofluorinated heterocycles, we designed a series of 1,7-enynes with the aim
of preparing monofluorinated cyclopenta[c]quinolin-4-one derivatives via
visible-light-mediated [2+2+1] carbocyclization (Scheme 1).
Scheme 1. Cyclization Reactions of 1,7-Enynes
F
R2
R2
CO2Et
O
Ir(ppy)3, K2HPO4
O
Br
R1
+
O
R4
O
R1
dioxane, rt, 24 h
N
F
N
R3
R3 R4
RESULTS AND DISCUSSION
We began our investigation by examining the reactions of 1,7-enyne 1a (0.2
mmol) with ethyl bromofluoroacetate (2) (0.4 mmol) and K2HPO4 (0.4 mmol) in the
presence of various catalysts in THF at room temperature with irradiation by a blue
LED (approximately 2 cm away from the light source) (Table 1). To our delight,
when fac-Ir(ppy)3 (0.002 mmol) was used as the catalyst, reaction for 24 h afforded
19
desired product 3a in 94% yield (as determined by F NMR spectroscopy, entry 1)
with a diastereomeric ratio of 8:1. Attempting to improve the yield, we evaluated
other bases (K2CO3, Na2HPO4, Na2CO3, Cs2CO3, 2,6-lutidine, and
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1,4-diazabicyclo[2.2.2]octane; entries 2–7), but none of them performed better than
K2HPO4. The other photoredox catalysts we tested (entries 8–11) failed to catalyze
the desired reaction. We also evaluated solvents other than THF (entries 12–18) and
found that dioxane was the most effective, increasing the yield of 3a to 94%. The
yield decreased when the amount of 2, Ir(ppy)3, or base was decreased (entries
19–21). The blue light and the argon atmosphere were necessary for the reaction
(entries 22 and 23). In terms of both yield and diastereoselectivity, the combination of
Ir(ppy)3 as the catalyst, K2HPO4 as the base, and dioxane as the solvent was optimal
(entry 18).
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Table 1. Optimization of Reaction Conditionsa
F
F
Ph
CO2Et
+
Ph
CO2Et
catalyst (1 mol%)
base (2.0 equiv)
blue LED
Ph
O
O
Br
+
O
solvent, rt., 24 h
N
N
O
F
N
O
Ts
Ts
cis
3a
Ts
trans
3a'
1a
2
entry
catalyst
base
solvent
THF
THF
THF
THF
THF
THF
THF
THF
THF
yield (%)b
drc
8:1
1
2
3
4
5
6
7
8
9
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
Acid Red 87
Ru(bpy)3PF6
K2HPO4
K2CO3
90
60
54
67
6:1
Na2HPO4
Na2CO3
10:1
8:1
8:1
Cs2CO3
2,6-lutidine
DABCO
K2HPO4
80
28
3:1
20
>25:1
—
N.R.
N.R.
K2HPO4
—
Ru(bpy)3Cl2·6H2
O
K2HPO4
K2HPO4
THF
THF
N.R.
N.R.
—
—
10
11
[Ir(dtppy)(ppy)2]
PF6
12
13
14
15
16
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
DMF
DMSO
MeCN
MTBE
DME
40
52
28
17
67
8:1
>25:1
10:1
>25:1
9:1
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fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
DCM
44
94
12:1
14:1
10:1
12:1
11:1
—
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
19d
20e
21f
22g
23h
42
77
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71
N.R.
N.R.
—
aReaction conditions, unless otherwise noted: 1a (0.2 mmol), fac-Ir(ppy)3 (0.002 mmol), base (0.4
mmol), 2a (0.4 mmol), solvent (anhydrous, 2 mL), 3 W blue LED (approximately 2 cm away from
the light source), room temperature, under an Ar atmosphere. bDetermined by 19F NMR
spectroscopy with (trifluoromethyl)benzene as an internal standard; N.R. = no reaction.
cDiastereomeric ratio (dr) refers to the ratio of cis compound 3a to trans compound 3a. The
d
amount of fac-Ir(ppy)3 was 0.001 mmol. eThe amount of 2a was 0.24 mmol. fThe amount of base
was 0.24 mmol. gThe reaction was carried out in air. hThe reaction was carried out in the dark.
To explore the generality of the protocol, we carried out reactions of various
benzene-tethered 1,7-enynes 1 (Scheme 2). First, we evaluated the effect of the R1
substituent on the benzene ring. These experiments showed that a variety of
substituents were suitable for constructing cyclopenta[c]quinolin-4-ones 3b–3h in
moderate to excellent yields. Enynes with electron-donating substituents (3b and 3g)
showed higher yields than those with electron-withdrawing substituents (3f and 3h);
and the position of the substituent also affected the yield (compare 3b with 3g and 3f
with 3h). Several substituents, namely, Me, Cl, and F, on the benzene ring were
well-tolerated. We have tried to synthesize the substrate containing pyridine or cis
alkenyl substrates, but we have difficult in synthesizing the alkenyl substrates, the
substrate containing pyridine only can be obtained in trace which was difficult to
separate. Second, we investigated the effects of the R2 substituent on the terminal
alkyne. When R2 was an electron-rich aromatic group, the corresponding products
(3i–3m) were obtained in good yields. In contrast, electron-deficient aromatic groups,
alkyl groups, and heteroaryl groups showed lower reactivities (3n–3p). The structures
of 3b and 3i were determined by X-ray crystallographic analysis.10 In addition, the
protocol was amenable to scale up: the reaction of 1a with 2 carried out on a 4.0
mmol scale under standard conditions was complete within 48 h and gave 3a in 85%
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yield (1.76 g, Scheme 2).
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Scheme 2. Reaction Scope with Respect to R1 and R2 of the 1,7-Enyne.
F
R2
Ir(ppy)3 (1 mol%)
K2HPO4 (2.0 equiv)
blue LED
R2
CO2Et
3
O
2
1
4
R1
5
O
Br
+
R1
O
9
dioxane, rt., 24 h
N
F
N
O
6
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Ts
Ts
1
2
3
, R1 = H, 1.76 g, 85%, dr = 14:1
, R1 = 4-Me, 90%, dr = 7:1
, R1 = 4-F, 65%, dr =9 :1
, R1 = 4-Cl, 76%, dr = 7:1
, R1 = 4-Br, 82%, dr= 7:1
R1 = 4-CO2Me, 81%, dr = 9:1
, R1 = 5-Me, 76%, dr = 15:1
, R1 = 5-CO2Me, 52%, dr > 20:1
3a
F
3b
3c
3d
3e
Ph
CO2Et
F
CO2Et
R1
3f
,
N
O
N
O
3g
3h
Ts
Ts
, 89%, dr = 12:1
3i (X-ray)
3i
MeO
MeO
F
F
F
CO2Et
CO2Et
CO2Et
N
O
N
O
N
O
Ts
Ts
Ts
3k
3l
, 85%, dr = 12:1
, 86%, dr = 12:1
3j
3b(X-ray)
,
88%, dr = 11:1
F
F
nBu
F
CO2Et
F
F
CO2Et
S
CO2Et
CO2Et
Cl
N
O
N
O
N
O
N
O
Ts
Ts
Ts
Ts
3m
, 72%, dr = 9:1
3p
, 36%, dr = 11:1
3o
3n
, 50%, dr = 5:1
, 35%, dr > 20:1
Various R3 substituents (benzyl, methyl, and ethyl) on the nitrogen were also
well-tolerated under the standard conditions (Scheme 3), affording the corresponding
products (3q–3u) in good yields; but the diastereoselectivity of these reactions was
somewhat lower than that observed with the N-Ts enynes. When R4 was a phenyl
group (3v–3z), the diastereoselectivity of the reaction was better than when R4 was a
Me group; the cis/trans ratio exceeded 20:1 in all cases, even when R3 was changed
from Ts to benzenesulfonyl (3y) or 4-methoxybenzenesulfonyl (3z), and the yields
were high. We tried to use 2-bromo-N-ethyl-2-fluoroacetamide as the free radical
precursor, but no desired product can be obtained under the standard conditions.
Beta-substituted methacrylamide derivatives are not suitable to the reaction due to the
steric hindrance and the complexity of products.
Scheme 3. Reaction Scope with Respect to R3 and R4 of the 1,7-Enyne
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F
R2
Ir(ppy)3 (1 mol%)
K2HPO4 (2.0 equiv)
blue LED
Br
R2
CO2Et
3
6
O
R1
4
2
1
R1
O
+
R4
O
dioxane, rt., 24 h
5
N
F
N
R3
O
R3 R4
1
2
3
9
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F
F
F
Ph
F
Ph
Ph
CO2Et
CO2Et
CO2Et
Ph
CO2Et
Cl
Ph
N
O
N
O
N
O
N
O
R3
Ts
3u
, 63%, dr = 5:1
F
3v
, 91%, dr >20:1
F
3t
, R3 = Bn, 88%, dr = 5:1
, 88%, dr = 4:1
3q
3r
, R3 = Me, 90%, dr = 4:1
Ph
CO2Et
, R3 = Et, 77%, dr = 4:1
Ph
CO2Et
3s
MeO
Ph
F
F
Ph
Ph
CO2Et
CO2Et
N
S
O
N
S
O
O
O
F
O
O
Ph
Ph
O
N
O
N
Ts
Ts
OMe
, 91%, dr >20:1
3y
3x,
, 86%, dr >20:1
93%, dr >20:1
3w
, 63%, dr >20:1
3z
To gain insight into the reaction mechanism, we conducted some control
experiments (Scheme 4). When the reaction 1a and 2 was performed in the presence
of 1 equiv of the radical inhibitor TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl), the
yield decreased dramatically (to 34%); and none of the desired product formed in the
presence of the radical scavenger galvinoxyl. Furthermore, TEMPO and galvinoxyl
adducts of ethyl 2-fluoroacetate radical (generated in situ) were detected by LC-MS
(see Supporting Information for details). These results indicate that the reaction may
have proceeded through a radical pathway. Fluorescence quenching analysis revealed
that 2 was an effective quencher of the excited state photocatalyst (see Supporting
Information for details). To determine whether radical propagation was involved, we
performed light on/off experiments with 1d as a substrate, which showed the
irradiation dependence of the reaction yield and thus ruled out the involvement of
radical chain pathway.
Scheme 4. Control Experiments
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F
Ph
CO2Et
C)
a)
Ph
O
F
standard conditions
Ph
CO2Et
Br
+
Ph
O
O
O
standard conditions
radical inhibitors (1.0 equiv)
Cl
Cl
Br
+
F
O
O
N
N
O
TEMPO: 34%
galvinoxyl: 0%
F
N
N
O
Ts
1a
Ts
3a
Ts
Ts
2
adduct of TEMPO and CHFCO2Et
7
3d
1d
2
(C13H25FNO3+ [M+H]+ m/z 262.1813, found 262.1815)
8
9
adduct of galvinoxyl and CHFCO2Et
(C33H48FO4+ [M+H]+ m/z 527.3531, found 527.3537)
b)
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Stern-Volmer Studies
On the basis of control experiments and literature precedents, we propose the
mechanism outlined in Scheme 5. Irradiation of [fac-IIIIr(ppy)3] by visible light
generates the excited state [fac-IIIIr(ppy)3]*, which is oxidized by ethyl bromoacetate
2 to generate radical I.11 The radical of ethyl 2-fluoroacetate (I) is an
electron-deficient radical, which tends to react with more electron-rich alkenes,
therefore, radical I is captured by the C–C double bond of 1,7-enyne 1a, and
subsequent 6-exo-dig cyclization with the C–C triple bond affords radical
intermediate III. Then a H-transfer step shift generates radical intermediate IV, which
undergoes a 5-endo-trig cyclization to form intermediate V.12 The substituents (R2, R3,
and R4) have synergetic effects on diastereoselectivity (Scheme 1). They achieve the
diastereoselectivity mainly by influencing the most favorable spatial configuration of
the intermediate IV to V for the 5-endo-trig cyclization reaction. After oxidization
by fac-IVIr(ppy)3 and loss of a proton, intermediate V is converted to final product 3a.
Scheme 5. Proposed Mechanism
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O
*IrIII(ppy)3
visible light
F
O
5
6
Br
2
IrIII(ppy)3
7
8
9
F
F
Ph
SET
Ph
H
- Br
CO2Et
CO2Et
-H+
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11
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SET
N
O
N
O
O
IrIV(ppy)3
Ts
3a
Ts
VI
F
F
O
Ph
CO2Et
I
H
1a
N
O
Ts
V
F
H
Ph
Ph
F
H
Ph
CO2Et
H-transfer
F
CO2Et
O
CO2Et
N
N
O
N
O
Ts
II
Ts
III
Ts
IV
CONCLUSIONS
In conclusion, we have developed a protocol for visible-light-mediated [2+2+1]
carbocyclization reactions of 1,7-enynes with ethyl bromoacetate 2 for the synthesis
of fused monofluorinated cyclopenta[c]quinolin-4-one derivatives. This novel mild
protocol has good functional group tolerance and high yields. A study of the
mechanism indicated that a radical fluoromethylation and sequential 6-exo-dig and
5-endo-trig cyclization processes are involved. The activity against of two
representative compounds tobacco mosaic virus highlighted the potential utility of this
protocol for the construction of bioactive functionalized polycycles.
EXPERIMENTAL SECTION
General Experimental Information. All solvents and chemicals were used as
purchased unless stated otherwise. Blue light-emitting diode (LED) (3 W, max = 455
nm, intensity: 450 mW) purchased from JIADENG (LS) was used for blue light
irradiation. A fan attached to the apparatus was used to maintain the reaction
temperature at room temperature. The material of the irradiation vessel was
borosilicate glass. 1H, 13C, and 19F Nuclear Magnetic Resonance (NMR) spectra were
recorded on Bruker Avance 400 Ultrashield NMR spectrometers. Chemical shifts (δ)
were given in parts per million (ppm) and were measured downfield from internal
tetramethylsilane. High-resolution mass spectrometry (HRMS) data were obtained on
an FTICR-MS instrument with q-TOF mass analyzer (Ionspec 7.0 T). Single crystal
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X-ray structure data were collected on Rigaku Saturn 70. The melting points were
determined on an X-4 microscope melting point apparatus and are uncorrected.
Conversion was monitored by thin layer chromatography (TLC). Flash column
chromatography was performed over silica gel (200-300 mesh).
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General procedures for the synthesis of 1
To a 100 mL flask were added 2-iodoaniline (10 mmol), Pd(PPh3)2Cl2 (210 mg,
0.3 mmol), CuI (87 mg, 0.3 mmol), Et3N (40 mL). After degassing with argon and
four evacuation/backfill-cycles with argon, alkyne was added dropwise. The reaction
mixture was heated with heating mantle and stirred at 45℃. When the reaction was
complete as monitored by TLC, the resulting mixture was purified by column
chromatography on silica gel to afford the product 2-ethynylaniline.
Method 1 (1a-1p, 1v-1z) ： To a solution of 2-ethynylaniline (5 mmol) in
chloroform/pyridine (30 mL, V/V=1:9) in 100 mL flask were added TsCl (953 mg, 5
mmol), the reaction mixture was stirred at room temperature. When the reaction was
complete as monitored by TLC, concentrated under reduced pressure, dilute
hydrochloric acid was added, the mixture was extracted with ethyl acetate for 3 times.
The combined organic layer was dried over anhydrous Na2SO4, filtered, evaporated to
afford the desired product N-(2-ethynylphenyl)benzenesulfonamides.
Method 2 (1q-1u)：To a solution of 2-ethynylaniline (5 mmol) in THF (30 mL)
were added n-butyllithium (1.6 M in hexanes) (9.4 mL, 15 mmol) at -78℃ under
argon atmosphere in a four-necked flask, R3I was added 2 h later, and the mixture was
warmed to room temperature. When the reaction was complete as monitored by TLC,
water was added to quench reaction under ice bath, the mixture was extracted with
ethyl acetate for 3 times. The combined organic layer was dried over anhydrous
Na2SO4, filtered, evaporated, the resulting mixture was purified by column
chromatography on silica gel to afford the product N-alkyl-2-ethynylanilines.
To
a
solution
of
N-(2-ethynylphenyl)benzenesulfonamides
or
N-alkyl-2-ethynylanilines (1 equiv) and Et3N (2 equiv) in dichloromethane was
added corresponding methacryloyl chloride (1.5 equiv) dropwise, then the mixture
was allowed to warmed to room temperature, when the reaction was complete as
monitored by TLC, water was added, the mixture was extracted with dichloromethane
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for 3 times. The combined organic layer was dried over anhydrous Na2SO4, filtered,
evaporated, the resulting mixture was purified by column chromatography on silica
gel to afford the product 1.
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N-(2-(Phenylethynyl)phenyl)-N-tosylmethacrylamide (1a).13a White solid, 0.91 g,
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86% yield; Mp 209–210 ºC, Rf = 0.40 (petroleum ether/EtOAc, 10:1); H NMR (400
MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 7.2 Hz, 1H), 7.51 – 7.36 (m, 3H),
7.29 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.2 Hz, 2H), 7.09 – 7.01 (m, 4H), 5.24 (d, J = 4.8
Hz, 2H), 2.08 (s, 3H), 1.77 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 170.6,
13
144.7, 139.1 138.8, 136.2, 132.7, 132.6, 131.5, 130.0, 129.2, 128.9, 128.8, 128.7,
128.0, 123.8, 123.4, 121.9, 94.8, 85.5, 21.4, 19.2. HRMS (ESI) calcd for
C25H21NO3S[M+H]+ 416.1315, found 416.1315.
N-(4-methyl-2-(phenylethynyl)phenyl)-N-tosylmethacrylamide (1b).13a White
solid, 0.85 g, 80% yield; Mp 160–161 ºC, Rf = 0.40 (petroleum ether/EtOAc, 10:1);
1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.40
– 7.17 (m, 5H), 7.04 (d, J = 7.6 Hz, 4H), 5.24 (s, 2H), 2.38 (s, 3H), 2.07 (s, 3H), 1.77
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.6, 144.7, 139.5, 139.1, 136.3, 136.2,
133.2, 132.3, 131.4, 130.0, 129.9, 128.9, 128.7, 128.0, 123.6, 123.0, 122.0, 94.4, 85.7,
21.4, 21.1, 19.2. HRMS (ESI) calcd for C26H23NO3S[M+H]+ 430.1471, found
430.1471.
N-(4-fluoro-2-(phenylethynyl)phenyl)-N-tosylmethacrylamide (1c). 0.74 g, 74%;
White solid, Mp 173–174 ºC, Rf = 0.30 (petroleum ether/EtOAc, 10:1); 1H NMR (400
MHz, CDCl3) δ 7.91 (d, J = 8.4 Hz, 2H), 7.59 (dd, J = 8.4, 5.2 Hz, 1H), 7.34 – 7.11
(m, 5H), 7.14 – 6.85 (m, 4H), 5.27 (s, 1H), 5.22 (s, 1H), 2.08 (s, 3H), 1.78 (s,
3H).13C{1H} NMR (100 MHz, CDCl3) δ 170.4, 162.2 (d, J = 249.5 Hz), 144.9, 139.0,
136.0, 135.0, 134.3 (d, J = 9.3 Hz) 131.6, 129.9, 129.1, 129.0, 128.1, 125.1(d, J =
10.5 Hz), 123.9, 121.4, 119.1(d, J = 24.1 Hz), 116.4 (d, J = 22.9 Hz), 95.8, 84.5, 21.4,
19.2. 19F NMR (376 MHz, CDCl3) δ -111.3 (dd, J = 13.2, 7.5 Hz). HRMS (ESI) calcd
for C25H20FNO3S [M+H]+ 434.1221, found 434.1220.
N-(4-chloro-2-(phenylethynyl)phenyl)-N-tosylmethacrylamide (1d).13a 0.68 g, 63%
1
yield; White solid, Mp 185–186 ºC, Rf = 0.30 (petroleum ether/EtOAc, 10:1); H
NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.8 Hz, 1H), 7.46 (d,
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4H), 5.29 (s, 1H), 5.23 (s, 1H), 2.07 (s, 3H), 1.78 (s, 3H). C{1H} NMR (100 MHz,
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CDCl3) δ 170.3, 144.9, 139.0, 137.4, 136.0, 135.1, 133.6, 132.3, 131.6, 129.9, 129.9,
129.1, 129.0, 128.1, 124.8, 124.1, 121.4, 95.9, 84.3, 21.4, 19.2. HRMS (ESI) calcd for
C25H20ClNO3S [M+H]+ 450.0925, found 450.0924.
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N-(4-bromo-2-(phenylethynyl)phenyl)-N-tosylmethacrylamide (1e). 0.91 g, 74%;
White solid, Mp 183–184 ºC, Rf = 0.30 (petroleum ether/EtOAc, 10:1); 1H NMR (400
MHz, CDCl3) δ 7.90 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 1.6 Hz, 1H), 7.58– 7.53 (m, 1H),
7.51– 7.46 (m, 1H), 7.38 – 7.16 (m, 3H), 7.05 (t, J = 6.8 Hz, 4H), 5.29 (s, 1H), 5.23 (s,
1H), 2.07 (s, 3H), 1.78 (s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ 170.2, 144.9,
138.9, 137.9, 136.0, 135.2, 133.8, 132.1, 131.6, 129.9, 129.1, 129.0, 128.1, 125.1,
124.2, 123.0, 121.4, 96.0, 84.1, 21.4, 19.1. HRMS (ESI) calcd for C25H20BrNO3S
[M+H]+ 494.0420, found 494.0418.
Methyl (phenylethynyl)-4-(N-tosylmethacrylamido)benzoate (1f).13e 0.81 g, 69%;
1
White solid, Mp 161–162 ºC, Rf = 0.40 (petroleum ether/EtOAc, 7:1); H NMR (400
MHz, CDCl3) δ 8.16 (d, J = 1.6 Hz, 1H), 8.07 (dd, J = 8.4, 2.0 Hz, 1H), 7.90 (d, J =
8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.37 – 7.20 (m, 3H), 7.06 (d, J = 8.0 Hz, 4H),
5.27 (s, 1H), 5.22 (s, 1H), 3.96 (s, 3H), 2.08 (s, 3H), 1.78 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 170.2, 165.5, 145.0, 142.5, 139.0, 136.0, 134.0, 132.7, 131.5, 130.8,
129.9, 129.6, 129.1, 129.0, 128.1, 124.4, 123.7, 121.5, 95.6, 84.6, 52.6, 21.4, 19.1.
HRMS (ESI) calcd for C27H23NO5S [M+H]+ 474.1370, found 474.1373.
N-(5-methyl-2-(phenylethynyl)phenyl)-N-tosylmethacrylamide (1g).13e 0.95 g,
1
87%; White solid, Mp 165–166 ºC, Rf = 0.30 (petroleum ether/EtOAc, 10:1); H
NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 2H), 7.47 (s, 1H), 7.39 (d, J = 7.9 Hz,
1H), 7.33 – 7.18 (m, 4H), 7.12 – 6.99 (m, 4H), 5.26 (d, J = 0.8 Hz, 2H), 2.47 (s, 3H),
13
2.10 (s, 3H), 1.80 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 170.6, 144.7, 139.5,
139.1, 138.6, 136.3, 133.1, 132.4, 131.3, 130.2, 130.0, 128.9, 128.5, 128.0, 123.6,
122.1, 120.4, 94.1, 85.7, 21.5, 21.4, 19.3. HRMS (ESI) calcd for C26H23NO3S[M+H]+
430.1471, found 430.1476.
Methyl 4-(phenylethynyl)-(N-tosylmethacrylamido)benzoate (1h). 0.89 g, 78%;
1
White solid, Mp 148–149 ºC, Rf = 0.40 (petroleum ether/EtOAc, 7:1); H NMR (400
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MHz, CDCl3) δ 8.27 (d, J = 1.6 Hz, 1H), 8.06 (dd, J = 8.4, 1.6 Hz, 1H), 7.92 (d, J =
8.4 Hz, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.35 – 7.29 (m, 1H), 7.24 (t, J = 7.6 Hz, 2H),
7.11 – 7.04 (m, 4H), 5.26 (d, J = 1.2 Hz, 1H), 5.22 (s, 1H), 3.97 (s, 3H), 2.09 (s, 3H),
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1.77 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 170.3, 165.5, 145.0, 139.0, 138.9,
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136.1, 133.4, 132.7, 131.7, 130.5, 130.0, 129.3, 129.0, 128.1, 127.7, 124.3, 121.4,
97.7, 85.1, 52.6, 21.4, 19.2. HRMS (ESI) calcd for C27H23NO5S [M+H]+ 474.1370,
found 474.1369.
N-(2-(p-tolylethynyl)phenyl)-N-tosylmethacrylamide (1i).13a White solid, 0.86 g,
1
78% yield; Mp 184–185 ºC, Rf = 0.30 (petroleum ether/EtOAc, 10:1); H NMR (400
MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.51 – 7.34 (m, 3H),
7.04 (dd, J = 17.6, 8.0 Hz, 4H), 6.93 (d, J = 8.0 Hz, 2H), 5.22 (d, J = 6.8 Hz, 2H),
13
2.34 (s, 3H), 2.10 (s, 3H), 1.76 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 170.5,
144.6, 139.1, 139.0, 138.7, 136.3, 132.6, 132.5, 131.4, 130.0, 129.1, 128.9, 128.8,
128.7, 123.7, 123.6, 118.9, 95.2, 85.0, 21.6, 21.4, 19.2. HRMS (ESI) calcd for
C26H23NO3S [M+H]+ 430.1471, found 430.1474.
N-(2-((4-methoxyphenyl)ethynyl)phenyl)-N-tosylmethacrylamide (1j).13e 0.75 g,
1
71%; White solid, Mp 170–171 ºC, Rf = 0.30 (petroleum ether/EtOAc, 10:1); H
NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 2H), 7.61 (dd, J = 8.0, 1.6 Hz, 1H),
7.48 – 7.34 (m, 3H), 7.08 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.74 (d, J =
8.8 Hz, 2H), 5.23 (d, J = 6.0 Hz, 2H), 3.81 (s, 3H), 2.13 (s, 3H), 1.76 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 170.6, 160.0, 144.6, 139.1, 138.6, 136.3, 133.0, 132.5,
132.4, 130.0, 129.1, 128.9, 128.4, 123.8, 123.7, 114.1, 113.7, 95.1, 84.5, 55.3, 21.4,
19.2. HRMS (ESI) calcd for C26H23NO4S [M+H]+ 446.1421, found 446.1420.
N-(4-methyl-2-(p-tolylethynyl)phenyl)-N-tosylmethacrylamide (1k). 1.10 g, 91%;
White solid, Mp 197–198 ºC, Rf = 0.30 (petroleum ether/EtOAc, 10:1); 1H NMR (400
MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 18.8,
7.6 Hz, 2H), 6.96 (dd, J = 18.8, 8.0 Hz, 4H), 6.85 (d, J = 8.0 Hz, 2H), 5.15 (s, 2H),
2.31 (s, 3H), 2.26 (s, 3H), 2.02 (s, 3H), 1.69 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 170.7, 144.5, 139.4, 139.1, 138.9, 136.3, 136.1, 133.0, 132.2, 131.4, 130.0, 129.7,
128.9, 128.7, 123.5, 123.2, 119.0, 94.7, 21.5, 21.4, 21.1, 19.3. HRMS (ESI) calcd for
C27H25NO3S [M+H]+ 444.1628, found 444.1631.
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N-(2-((4-methoxyphenyl)ethynyl)-4-methylphenyl)-N-tosylmethacrylamide (1l).
0.95 g, 84%; White solid, Mp 159–160 ºC, Rf = 0.30 (petroleum ether/EtOAc, 10:1);
1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.26
(s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H),
6.73 (d, J = 8.8 Hz, 2H), 5.23 (s, 2H), 3.80 (s, 3H), 2.38 (s, 3H), 2.12 (s, 3H), 1.76 (s,
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3H). C{1H} NMR (100 MHz, CDCl3) δ 170.7, 159.9, 144.5, 139.4, 139.1, 136.9,
136.0, 133.0, 132.8, 132.2, 130.0, 129.5, 128.9, 123.5, 123.4, 114.2, 113.6, 94.7, 84.6,
55.3, 21.4, 21.1, 19.2. HRMS (ESI) calcd for C27H25NO4S [M+H]+ 460.1577, found
460.1585.
N-(4-chloro-2-(p-tolylethynyl)phenyl)-N-tosylmethacrylamide (1m).13c 1.01 g,
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88%; White solid, Mp 212–213 ºC, Rf = 0.30 (petroleum ether/EtOAc, 10:1); H
NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.44 (d,
J = 2.4 Hz, 1H), 7.38 (dd, J = 8.4, 2.4 Hz, 1H), 7.05 (dd, J = 14.0, 8.4 Hz, 4H), 6.93
(d, J = 8.0 Hz, 2H), 5.28 (s, 1H), 5.21 (s, 1H), 2.34 (s, 3H), 2.09 (s, 3H), 1.77 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 159.9, 144.5, 139.4, 139.1, 136.4, 136.0,
133.0, 132.8, 132.2, 130.0, 129.5, 128.9, 123.5, 123.4, 114.2, 113.7, 94.7, 84.6, 55.3,
21.4, 21.1, 19.2. HRMS (ESI) calcd for C26H22ClNO3S [M+H]+ 464.1082, found
464.1083.
N-(2-((4-fluorophenyl)ethynyl)phenyl)-N-tosylmethacrylamide (1n).13a White
solid, 0.65 g, 84% yield; Mp 186–187 ºC, Rf = 0.30 (petroleum ether/EtOAc, 10:1);
1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.4 Hz, 2H), 7.69 – 7.52 (m, 1H), 7.51 –
7.30 (m, 3H), 7.18 – 6.98 (m, 3H), 6.92 (t, J = 8.8 Hz, 2H), 5.39 – 4.89 (m, 2H), 2.13
(s, 3H), 1.76 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.6, 162.8(d, J =249.0
Hz), 144.6, 139.0, 138.9, 136.3, 133.5, 133.4, 132.5, 130.0, 129.1 (d, J =25.0 Hz),
128.9, 123.9, 123.3, 118.1 (d, J =3.5 Hz), 115.5, 115.2, 93.8, 85.3, 21.4, 19.2. 19F
NMR (376 MHz, CDCl3) δ -139.4. HRMS (ESI) calcd for C25H20FNO3S [M+H]+
434.1221, found. 434.1217.
N-(2-(hex-1-yn-1-yl)phenyl)-N-tosylmethacrylamide (1o).13e 0.75 g, 78%; White
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solid, Mp 86–87 ºC, Rf = 0.40 (petroleum ether/EtOAc, 15:1); H NMR (400 MHz,
CDCl3) δ 7.92 (d, J = 8.4 Hz, 2H), 7.53 – 7.45 (m, 1H), 7.40 – 7.24 (m, 6H), 5.22 (d,
J = 4.4 Hz, 2H), 2.43 (s, 3H), 1.93 (t, J = 6.4 Hz, 2H), 1.77 (s, 3H), 1.28 – 1.19 (m,
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4H), 0.86 (t, J = 6.8 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.4, 144.4, 139.1,
138.7, 136.5, 133.0, 132.1, 130.0, 129.0, 128.9, 128.2, 124.4, 123.3, 96.8, 76.5, 30.1,
22.2, 21.7, 19.2, 19.0, 13.6. HRMS (ESI) calcd for C23H25NO3S [M+H]+ 396.1628,
found 396.1634.
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N-(2-(thiophen-2-ylethynyl)phenyl)-N-tosylmethacrylamide (1p). 0.70 g, 65%;
White solid, Mp 174–175ºC, Rf = 0.30 (petroleum ether/EtOAc, 10:1); 1H NMR (400
MHz, CDCl3) δ 7.90 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.49 – 7.34 (m, 3H),
7.26 – 7.21 (m, 1H), 7.11 (d, J = 8.0 Hz, 2H), 6.95 – 6.85 (m, 2H), 5.25 (d, J = 3.2 Hz,
2H), 2.20 (s, 3H), 1.79 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.3, 144.7,
139.0, 138.5, 136.1, 133.0, 132.6, 132.3, 129.8, 129.2, 129.0, 128.0, 126.9, 123.9,
123.2, 121.7, 89.1, 88.3, 21.5, 19.2. HRMS (ESI) calcd for C23H19NO3S2 [M+H]+
422.0879, found 422.0881.
N-benzyl-N-(2-(phenylethynyl)phenyl)methacrylamide (1q).13a White solid, 0.55
1
g, 62% yield; Mp 77–78 ºC, Rf = 0.40 (petroleum ether/EtOAc, 15:1); H NMR (400
MHz, CDCl3) δ 7.57 – 7.46 (m, 3H), 7.39 – 7.32 (m, 3H), 7.31 – 7.14 (m, 7H), 6.86 (d,
J = 7.6 Hz, 1H), 5.52 (d, J = 14.4Hz, 1H), 5.01 (d, J = 5.6 Hz, 2H), 4.58 (d, J = 14.4
Hz, 1H), 1.86 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 172.0, 144.5, 140.5, 137.2,
132.9, 131.7, 129.4, 129.2, 128.8, 128.5, 128.3, 127.5, 127.4, 122.8, 122.6, 119.1,
94.9, 86.1, 52.4, 20.3. HRMS (ESI) calcd for C25H21NO [M+H]+ 352.1696, found
352.1700.
N-methyl-N-(2-(phenylethynyl)phenyl)methacrylamide (1r).13d White solid, 0.45
g, 69%; Mp 41–42 ºC, Rf = 0.40 (petroleum ether/EtOAc, 15:1); 1H NMR (400 MHz,
CDCl3) δ 7.58 – 7.49 (m, 3H), 7.37 – 7.26 (m, 5H), 7.18 (d, J = 7.6 Hz, 1H), 5.01 (d,
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J = 11.5 Hz, 2H), 3.37 (s, 3H), 1.84 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ
172.3, 146.4, 140.5, 132.9, 131.7, 129.3, 128.8, 128.5, 128.2, 127.5, 122.6, 122.3,
119.1, 94.8, 85.8, 77.5, 77.1, 36.9, 20.2. HRMS (ESI) calcd for C19H17NO [M+H]+
276.1383, found 276.1389.
N-ethyl-N-(2-(phenylethynyl)phenyl)methacrylamide (1s).13e 0.53 g, 74%; White
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solid, Mp 68–69 ℃, Rf = 0.30 (petroleum ether/EtOAc, 15:1); H NMR (400 MHz,
CDCl3) δ 7.61 – 7.48 (m, 3H), 7.40 – 7.24 (m, 5H), 7.17 (d, J = 7.6 Hz, 1H), 4.98 (s,
2H), 4.07 – 3.73 (m, 2H), 1.84 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100
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MHz, CDCl3) δ 171.8, 144.7, 140.8, 132.9, 131.6, 129.2, 129.0, 128.7, 128.5, 127.4,
123.1, 122.7, 118.9, 94.7, 86.4, 44.4, 20.2, 12.8. HRMS (ESI) calcd for C20H19NO
[M+H]+ 290.1538, found 290.1539.
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N-methyl-N-(4-methyl-2-(phenylethynyl)phenyl)methacrylamide (1t). White solid,
0.47 g, 65%; Mp 81–82 ℃, Rf = 0.40 (petroleum ether/EtOAc, 15:1); 1H NMR (400
MHz, CDCl3) δ 7.57 – 7.45 (m, 1H), 7.39 – 7.33 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H),
7.06 (d, J = 8.0 Hz, 1H), 5.01 (d, J = 15.1 Hz, 1H), 3.35 (s, 1H), 2.36 (s, 1H), 1.83 (s,
1H).13C{1H} NMR (100 MHz, CDCl3) δ 172.5, 143.9, 140.6, 137.5, 133.3, 131.7,
130.1, 128.7, 128.5, 128.0, 122.7, 121.9, 118.8, 85.9, 37.0, 20.9, 20.2. HRMS (ESI)
calcd for C20H19NO [M+H]+ 290.1538, found 290.1537.
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N-(4-chloro-2-(phenylethynyl)phenyl)-N-methylmethacrylamide (1u). Yellow
solid, 0.65 g, 84%; Mp 72–73 ºC, Rf = 0.30 (petroleum ether/EtOAc, 15:1); 1H NMR
(400 MHz, CDCl3) δ 7.62 – 7.46 (m, 3H), 7.40 – 7.28 (m, 4H), 7.12 (d, J = 8.4 Hz,
1H), 5.03 (d, J = 11.2 Hz, 2H), 3.34 (s, 3H), 1.85 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 172.2, 144.9, 140.2, 133.1, 132.6, 131.8, 129.4, 129.2, 128.6, 123.9, 122.1,
119.4, 95.9, 84.5, 36.9, 20.1. HRMS (ESI) calcd for C19H16ClNO [M+H]+ 310.0993,
found 310.0997.
N-(4-methyl-2-(phenylethynyl)phenyl)-2-phenyl-N-tosylacrylamide (1v).13b White
solid, 0.90 g, 74%; Mp 162–164 ºC, Rf = 0.30 (petroleum ether/EtOAc, 5:1); 1H NMR
(400 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H), 7.31 – 7.27 (m, 1H), 7.25 – 7.13 (m,
6H), 7.11 – 6.99 (m, 6H), 6.74 (d, J = 6.9 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 5.73 (s,
1H), 5.39 (s, 1H), 2.29 (s, 3H), 2.10 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
168.7, 144.2, 143.7, 138.3, 135.3, 135.0, 133.2, 131.53, 131.46, 130.5, 128.9, 128.0,
127.9, 127.5, 127.3, 127.2, 127.0, 125.1, 122.6, 121.1, 93.5, 85.0, 20.4, 20.0. HRMS
(ESI) calcd for C31H26NO3S [M+H]+ 492.1628, found 492.1638.
N-(4-fluoro-2-(phenylethynyl)phenyl)-2-phenyl-N-tosylacrylamide (1w).13b White
solid, 0.71 g, 58%; Mp 123–124 ºC, Rf = 0.40 (petroleum ether/EtOAc, 5:1); 1H NMR
(400 MHz, CDCl3) δ 7.97 (d, J = 8.2 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.26 – 7.17 (m,
5H), 7.10 – 7.03 (m, 5H), 7.01 (d, J = 7.5 Hz, 2H), 6.71 – 6.57 (m, 2H), 5.75 (s, 1H),
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5.42 (s, 1H), 2.09 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 168.5, 161.0 (d, J =
251.2 Hz), 144.2, 143.9, 135.1, 134.9, 133.7 (d, J = 9.8 Hz), 131.9 (d, J = 3.0 Hz),
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130.6, 128.9, 128.0, 127.5, 127.4, 127.1, 125.1, 124.6 (d, J = 10.7 Hz), 121.9, 120.5,
117.3 (d, J = 24.3 Hz), 114.4 (d, J = 23.0 Hz), 94.9, 83.8, 20.4. HRMS (ESI) calcd for
C30H23FNO3S [M+H]+ 496.1377, found 496.1377.
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N-(2-((4-methoxyphenyl)ethynyl)phenyl)-2-phenyl-N-tosylacrylamide
(1x).13b
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White solid, 0.85 g, 67%; Mp 127–128 ºC, Rf = 0.30 (petroleum ether/EtOAc, 5:1);
1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 6.7 Hz, 1H), 7.24
– 7.12 (m, 4H), 7.10 (d, J = 8.1 Hz, 2H), 7.03 – 6.95 (m, 4H), 6.90 (t, J = 7.1 Hz, 1H),
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6.79 – 6.70 (m, 3H), 5.72 (s, 1H), 5.38 (s, 1H), 3.83 (s, 3H), 2.15 (s, 3H). C{1H}
NMR (100 MHz, CDCl3) δ 169.7, 159.9, 145.3, 144.7, 136.5, 136.5, 136.0, 133.1,
132.9, 131.8, 129.9, 129.0, 128.9, 128.4, 128.2, 127.6, 126.2, 124.4, 122.4, 114.3,
113.7, 95.3, 84.9, 55.4, 21.5. HRMS (ESI) calcd for C31H26NO4S [M+H]+ 508.1577,
found 508.1585.
2-phenyl-N-(2-(phenylethynyl)phenyl)-N-(phenylsulfonyl)acrylamide
(1y).13b
White solid, 0.80 g, 71%; Mp 136–138 ºC, Rf = 0.40 (petroleum ether/EtOAc, 5:1);
1H NMR (400 MHz, CDCl3) δ 8.17 – 8.07 (m, 2H), 7.40 (d, J = 7.6 Hz, 1H), 7.35 –
7.31 (m, 3H), 7.29 (d, J = 7.2 Hz, 1H), 7.23 (t, J = 7.6 Hz, 4H), 7.16 (t, J = 7.4 Hz,
2H), 7.06 (d, J = 7.5 Hz, 2H), 6.99 (d, J = 7.5 Hz, 2H), 6.95 (t, J = 7.9 Hz, 1H), 6.75
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(d, J = 8.1 Hz, 1H), 5.74 (s, 1H), 5.40 (s, 1H). C{1H} NMR (100 MHz, CDCl3) δ
168.7, 144.1, 138.3, 135.6, 134.8, 132.5, 131.8, 131.1, 130.5, 128.8, 128.1, 127.7,
127.4, 127.3, 127.2, 127.1, 127.0, 125.1, 123.0, 121.6, 120.9, 94.1, 84.8. HRMS (ESI)
calcd for C29H22NO3S [M+H]+ 464.1315, found 464.1321.
N-((4-methoxyphenyl)sulfonyl)-2-phenyl-N-(2-(phenylethynyl)phenyl)acrylamide
(1z).13b White solid, 0.95 g, 78%; Mp 158–160 ºC, Rf = 0.40 (petroleum ether/EtOAc,
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5:1); H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.9 Hz, 2H), 7.41 – 7.36 (m, 1H),
7.34 – 7.28 (m, 1H), 7.25 – 7.12 (m, 6H), 7.10 (d, J = 7.1 Hz, 2H), 7.00 (d, J = 7.0 Hz,
2H), 6.96 – 6.89 (m, 1H), 6.76 – 6.69 (m, 3H), 5.76 (s, 1H), 5.39 (s, 1H), 3.55 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 169.7, 163.6, 145.3, 136.9, 136.0, 133.0, 132.2,
132.1, 131.5, 130.6, 129.0, 128.6, 128.4, 128.2, 128.1, 126.2, 124.0, 122.4, 122.1,
113.5, 94.9, 86.0, 55.3. HRMS (ESI) calcd for C30H24NO4S [M+H]+ 494.1421, found
494.1427.
General Procedures for the Synthesis of Monofluorosubstituted Quinoline
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To an oven dried reaction tube was charged with substrate 1 (0.20 mmol),
Ir(ppy)3 (1 mol %) and K2HPO4 (0.40 mmol). The vial was evacuated and backfilled
with argon (this process was repeated three times) and then 2 mL dioxane and ethyl
bromofluoroacetate (0.40 mmol) were added. The reaction mixture was irradiated by
a 3W blue LED bulb (approximately 2 cm away from the light source) at room
temperature for 24 hours before concentrating in vacuo. The reaction mixture was
quenched with water, and then extracted with EtOAc. The organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The
crude mixture was purified by flash column chromatography to give the desired
compound 3.
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2-Ethyl-2-fluoro-3a-methyl-4-oxo-1-phenyl-5-tosyl-3,3a,4,5-tetrahydro-2H-cyclo
penta[c]quinoline-2-carboxylate (3a). White solid, 93 mg, yield 94%, dr = 14:1, Rf =
0.40 (petroleum ether/EtOAc, 10:1); 1H NMR (400 MHz, CDCl3) δ 7.84 (t, J = 8.4 Hz,
3H), 7.37 (m, 6H), 7.21 (m, 2H), 7.15 – 7.05 (m, 2H), 4.46 – 4.11 (m, 2H), 2.63 (m,
2H), 2.43 (s, 3H), 1.43 – 1.21 (m, 6H).13C{1H} NMR (100 MHz, CDCl3) δ 174.0,
170.5(d, J = 32.4 Hz), 145.3, 141.4, 141.3, 136.9, 136.6, 136.3, 135.3, 131.5, 129.5,
129.1, 128.8, 128.7, 128.3, 127.5, 126.5, 124.4, 123.9, 103.1(d, J = 190.0 Hz), 62.4,
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55.4, 45.6, 23.4, 21.7, 14.1. F NMR (376 MHz, CDCl3) δ -139.5 (dd, J = 27.1, 8.1
Hz). HRMS (ESI) calcd for C29H26FNO5S [M+H]+520.1588, found 520.1582.
2-Ethyl-2-fluoro-3a,8-dimethyl-4-oxo-1-phenyl-5-tosyl-3,3a,4,5-tetrahydro-2H-c
yclopenta[c]quinoline-2-carboxylate (3b). White solid, 96 mg, yield 90%, dr = 7:1, Rf
= 0.30 (petroleum ether/EtOAc, 10:1); 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.4
Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.41 – 7.33 (m, 3H), 7.29 (d, J = 8.0 Hz, 2H),
7.19-7.18 (m, 3H), 6.87 (s, 1H), 4.39 – 4.24 (m, 2H), 2.58-2.40 (m, 2H), 2.40 (s, 3H),
2.18 (s, 3H), 1.29-1.26 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 174.1, 170.6(d, J
= 31.4 Hz), 145.2, 141.4, 136.5, 136.3, 132.9, 131.5, 129.9, 129.5, 128.7, 128.3, 127.7,
124.3, 123.8, 103.1 (d, J = 200.0 Hz), 62.4, 55.5, 45.5, 45.3, 23.4, 21.7, 20.9, 14.1. 19F
NMR (376 MHz, CDCl3) δ -139.6 (dd, J = 27.6, 9.7 Hz). HRMS (ESI) calcd for
C30H28FNO5S [M+H]+534.1745, found 534.1747.
2-Ethyl-2,8-difluoro-3a-methyl-4-oxo-1-phenyl-5-tosyl-3,3a,4,5-tetrahydro-2H-c
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yclopenta[c]quinoline-2-carboxylate (3c). White solid, 69 mg, yield 65%, dr = 9:1, Rf
= 0.30 (petroleum ether/EtOAc, 10:1); 1H NMR (400 MHz, CDCl3) δ 7.89 – 7.76 (m,
3H), 7.40 – 7.29 (m, 5H), 7.16 –7.11(m, 2H), 7.13 – 7.05 (m, 1H), 6.79 – 6.74 (m,
1H), 4.31– 4.25 (m, 2H), 2.60 – 2.41(m, 2H), 2.41 (s, 3H), 1.33 – 1.25 (m, 6H).
13C{1H} NMR (100 MHz, CDCl3) δ 173.7, 170.2, 161.6, 159.2, 145.5 , 140.4, 138.2,
138.0, 135.9, 131.4, 130.9, 129.6, 129.2, 128.9, 128.6, 128.3, 126.4, 126.3, 125.9,
116.3, 116.1, 114.2, 114.0, 103.0(d, J = 200.0 Hz), 62.5, 55.3, 45.5, 45.3, 23.4, 23.3,
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21.7, 14.1. F NMR (376 MHz, CDCl3) δ -114.0 (s), -139.7 (dd, J = 27.4, 10.1 Hz).
HRMS (ESI) calcd for C29H25F2NO5S [M+H]+538.1494, found 538.1494.
2-Ethyl-8-chloro-2-fluoro-3a-methyl-4-oxo-1-phenyl-5-tosyl-3,3a,4,5-tetrahydro
-2H-cyclopenta[c]quinoline-2-carboxylate (3d). White solid, 84 mg, yield 76%, dr =
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7:1, Rf = 0.30 (petroleum ether/EtOAc, 10:1); H NMR (400 MHz, CDCl3) δ
7.79-7.75 (m, 3H), 7.43 – 7.29 (m, 6H), 7.17 – 7.16 (m, 2H), 7.06 – 7.03 (m, 1H),
4.31 – 4.24 (m, 2H), 2.61 – 2.41 (m, 2H), 2.41 (s, 3H), 1.29 – 1.27 (m, 6H). 13C{1H}
NMR (100 MHz, CDCl3) δ 173.6, 170.2, 145.6, 145.3, 140.0, 138.2, 138.0, 135.9,
133.8, 132.2, 130.8, 129.6, 129.2, 128.9, 128.7, 128.3, 127.1, 125.7, 125.5, 103.0 (d, J
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= 190.0 Hz), 62.5, 61.7, 56.0, 55.3, 45.5, 45.3, 44.7, 24.1 23.3, 21.7, 14.1. F NMR
(376 MHz, CDCl3) δ -140.3 (dd, J = 27.3, 9.1 Hz). HRMS (ESI) calcd for
C29H25ClFNO5S [M+H]+554.1199, found 554.1190.
2-Ethyl-8-bromo-2-fluoro-3a-methyl-4-oxo-1-phenyl-5-tosyl-3,3a,4,5-tetrahydro
-2H-cyclopenta[c]quinoline-2-carboxylate (3e). White solid, 98 mg, yield 82%, dr =
7:1, Rf = 0.30 (petroleum ether/EtOAc, 10:1); 1H NMR (400 MHz, CDCl3) δ 7.80 (d,
J = 8.4 Hz, 2H), 7.71 (d, J = 8.4Hz, 1H), 7.54 – 7.51 (m,1H), 7.45 – 7.27 (m, 6H),
7.19 – 7.14 (m, 2H), 4.40 – 4.23 (m, 2H), 2.84 – 2.49 (m, 2H), 2.42 (s, 3H), 1.33 –
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1.27(m, 6H). C{1H} NMR (100 MHz, CDCl3) δ 173.5, 170.2, 145.6, 139.8, 138.2,
138.0, 135.9, 134.4, 132.1, 130.8, 130.0, 129.7, 129.3, 128.9, 128.7, 128.3, 126.0,
125.8, 120.0, 102.9 (d, J = 200.0 Hz), 62.5, 55.3, 45.5, 45.2, 23.4, 23.3, 21.7, 14.1,
13.7. 19F NMR (376 MHz, CDCl3) δ -144.6 (dd, J = 27.4, 10.0 Hz). HRMS (ESI)
calcd for C29H25BrFNO5S [M+H]+598.0694, found 598.0692.
2-Ethyl-8-methyl-2-fluoro-3a-methyl-4-oxo-1-phenyl-5-tosyl-3,3a,4,5-tetrahydro
-2H-cyclopenta[c]quinoline-2,8-dicarboxylate (3f). White solid, 93 mg, yield 81%, dr
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= 9:1, Rf = 0.40 (petroleum ether/EtOAc, 10:1); H NMR (400 MHz, CDCl3) δ 8.04
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(dd, J = 8.8, 2.0 Hz, 1H), 7.90 (d, J = 8.4Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.77 (d, J
= 1.2 Hz, 1H), 7.40 – 7.36 (m, 3H), 7.32 (d, J = 8.0 Hz, 2H), 7.20 – 7.18 (m, 2H),
4.40 – 4.23 (m, 2H), 3.83 (s, 3H), 2.76 – 2.51 (m, 2H), 2.43 (s, 3H), 1.30-1.27 (m,
6H).13C{1H} NMR (100 MHz, CDCl3) δ 173.7, 170.2, 165.7, 145.6, 140.2, 138.8,
138.2, 138.0, 136.0, 130.9, 130.1, 129.6, 129.1, 128.8, 128.3, 124.1, 123.9, 103.0 (d, J
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= 202.0 Hz), 62.5, 55.2, 52.4, 45.5, 23.4, 21.7, 14.1. F NMR (376 MHz, CDCl3) δ
-139.5 (dd, J = 27.4, 10.1 Hz). HRMS (ESI) calcd for C31H28FNO9S [M+H]+578.1643,
found 578.1635.
2-Ethyl-2-fluoro-3a,7-dimethyl-4-oxo-1-phenyl-5-tosyl-3,3a,4,5-tetrahydro-2H-c
yclopenta[c]quinoline-2-carboxylate (3g). White solid, 81 mg, yield 76%, dr = 15:1,
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Rf = 0.40 (petroleum ether/EtOAc, 10:1); H NMR (400 MHz, CDCl3) δ 7.73 (d, J =
8.0 Hz, 1H), 7.54 (s, 1H), 7.32 – 7.19 (m, 3H), 7.15 – 7.05 (m, 1H), 6.95 – 6.71 (m,
1H), 4.32 – 3.88 (m, 1H), 2.66 – 2.38 (m, 1H), 2.45 (s, 4H), 1.50 – 1.06 (m, 4H).
13C{1H} NMR (100 MHz, CDCl3) δ 174.2, 170.6 (d, J = 32.7 Hz), 145.2, 141.4, 139.7,
135.9 (d, J = 22.9 Hz), 135.3, 131.7, 129.5, 128.8, 128.7, 128.6, 128.2, 127.4, 127.2,
125.0, 121.0, 103.1 (d, J = 197.0 Hz), 62.4, 55.4, 45.6 , 45.3, 23.5 (d, J = 6.2 Hz),
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21.7 (d, J = 6.8 Hz), 14.1. F NMR (376 MHz, CDCl3) δ -141.0 (dd, J = 27.1, 9.8
Hz). HRMS (ESI) calcd for C30H28FNO5S [M+H]+534.1745, found 534.1741.
2-Ethyl-7-methyl-2-fluoro-3a-methyl-4-oxo-1-phenyl-5-tosyl-3,3a,4,5-tetrahydro
-2H-cyclopenta[c]quinoline-2,7-dicarboxylate (3h). White solid, 60 mg, yield 52%,
dr > 20:1, Rf = 0.40 (petroleum ether/EtOAc, 5:1); 1H NMR (400 MHz, CDCl3) δ 8.34
(s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.23 -7.19 (m, 5H), 7.08 –
6.95 (m, 3H), 4.25 – 4.11 (m, 2H), 3.81 (s, 3H), 2.61-2.42 (m, 2H), 2.29 (s, 3H), 1.16
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-1.14 (m, 3H). C{1H} NMR (100 MHz, CDCl3) δ 173.6, 170.2 (d, J = 32.7 Hz),
165.8, 145.6, 140.4, 138.8, 136.0, 135.4, 131.0, 130.9, 130.8, 129.6, 129.2, 128.8,
128.7,128.4, 128.2, 127.5, 125.3, 103.0 (d, J = 200.0 Hz), 62.5, 55.3, 52.6, 45.7, 23.3,
21.7, 14.1. 19F NMR (376 MHz, CDCl3) δ -140.0 (dd, J = 27.5, 9.6 Hz). HRMS (ESI)
calcd for C31H28FNO9S [M+H]+578.1643, found 578.1644.
2-Ethyl-2-fluoro-3a-methyl-4-oxo-1-(p-tolyl)-5-tosyl-3,3a,4,5-tetrahydro-2H-cyc
lopenta[c]quinoline-2-carboxylate (3i). White solid, 95 mg, yield 89%, dr = 12:1, Rf
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= 0.40 (petroleum ether/EtOAc, 10:1); H NMR (400 MHz, CDCl3) δ 7.81-7.92 (m,
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3H), 7.40 – 7.35 (m, 1H), 7.29 – 7.26 (m, 2H), 7.28 – 7.12 (m, 6H), 4.31 – 3.98 (m,
2H), 2.72 – 2.48 (m, 2H), 2.40 (s, 3H), 2.35 (s, 3H), 1.29 – 1.25 (m, 6H).13C{1H}
NMR (100 MHz, CDCl3) δ 174.1, 170.6, 145.3, 140.7, 138.7, 136.8, 136.7, 136.3,
135.3, 129.5, 129.4, 129.0, 128.6, 128.4, 128.3, 127.5, 126.5, 124.4, 124.1, 103.1 (d, J
= 190.0 Hz), 62.4, 55.4, 45.6, 45.4, 23.4, 23.3, 21.7, 21.3, 14.1. 19F NMR (376 MHz,
CDCl3) δ -139.7 (dd, J = 27.5, 9.6 Hz). HRMS (ESI) calcd for C30H28FNO5S
[M+H]+534.1745, found 534.1749.
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2-Ethyl-2-fluoro-1-(4-methoxyphenyl)-3a-methyl-4-oxo-5-tosyl-3,3a,4,5-tetrahyd
ro-2H-cyclopenta[c]quinoline-2-carboxylate (3j). White solid, 96 mg, yield 88%, dr =
11:1, Rf = 0.30 (petroleum ether/EtOAc, 10:1); 1H NMR (400 MHz, CDCl3) δ 7.91 –
7.77 (m, 3H), 7.39 – 7.37(m, 1H), 7.29 – 7.27 (m, 3H), 7.16 – 7.11 (m, 3H), 6.87 (d, J
= 8.8 Hz, 2H), 4.39 – 4.24 (m, 2H), 3.83 (s, 3H), 2.58 – 2.41(m, 2H), 2.41 (s, 3H),
1.30 (t, J = 7.2 Hz, 3H), 1.24 (s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ 174.2, 170.6,
159.9, 145.3, 140.1, 136.5, 136.3, 135.3, 130.0, 129.5, 129.0, 128.2, 127.4, 126.5,
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124.4, 123.5, 114.2, 103.0 (d, J = 200.0 Hz), 62.4, 55.3, 45.6,23.3, 21.7, 14.1. F
NMR (376 MHz, CDCl3) δ -140.0 (dd, J = 27.4, 8.9 Hz). HRMS (ESI) calcd for
C30H28FNO6S [M+H]+550.1694, found 550.1686.
2-Ethyl-2-fluoro-3a,8-dimethyl-4-oxo-1-(p-tolyl)-5-tosyl-3,3a,4,5-tetrahydro-2H-
cyclopenta[c]quinoline-2-carboxylate (3k). White solid, 94 mg, yield 86%, dr = 12:1,
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Rf = 0.30 (petroleum ether/EtOAc, 10:1); H NMR (400 MHz, CDCl3) δ 7.80 (d, J =
8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.28 – 7.26 (m, 2H), 7.20 – 7.08 (m, 5H), 6.93
(d, J = 1.2 Hz, 1H), 4.39 – 4.22 (m, 2H), 2.64 – 2.50 (m, 2H), 2.36 (s, 3H), 2.32 (s,
3H) 2.20 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.25 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 174.16, 170.7, 145.2, 140.7, 138.7, 136.5, 136.3, 132.9, 129.9, 129.5, 129.4,
129.0, 128.8, 128.6, 128.4, 128.2, 127.7, 124.3, 124.1, 103.1 (d, J = 191.9 Hz), 62.3,
55.5, 45.5, 45.3, 23.3, 21.7, 21.4, 20.9, 14.1. 19F NMR (376 MHz, CDCl3) δ -139.9
(dd, J = 27.5, 9.5 Hz). HRMS (ESI) calcd for C31H30FNO5S [M+H]+548.1901, found
548.1896.
2-Ethyl-2-fluoro-1-(4-methoxyphenyl)-3a,8-dimethyl-4-oxo-5-tosyl-3,3a,4,5-tetra
hydro-2H-cyclopenta[c]quinoline-2-carboxylate (3l). White solid, 95 mg, yield 85%,
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dr = 12:1, Rf = 0.30 (petroleum ether/EtOAc, 10:1); H NMR (400 MHz, CDCl3) δ
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7.96 – 7.74 (m, 3H), 7.68 (d, J = 8.4 Hz, 1H), 7.33 – 7.28 (m, 1H), 7.23 – 7.18 (m,
1H), 7.17 – 7.12 (m, 2H), 7.08 – 6.92 (m, 2H), 6.92 – 6.70 (m, 3H), 4.40 – 4.23 (m,
2H), 3.83 (s, 3H), 2.70 – 2.42 (m, 2H), 2.39 (s, 3H), 2.21 (s, 3H), 1.33 – 1.26 (m,
3H).13C{1H} NMR (100 MHz, CDCl3) δ 174.2, 170.8, 159.9, 145.2, 140.1, 139.1,
136.5, 136.2, 133.0, 132.2, 130.0, 129.8, 129.5, 128.8, 128.2, 127.7, 124.3, 123.6,
114.11, 113.63, 103.0 (d, J = 195.9 Hz), 67.1, 62.4, 55.3, 45.4, 23.2, 21.4, 19.2, 14.1.
19F NMR (376 MHz, CDCl3) δ -140.6 (dd, J = 18.3, 9.1 Hz). HRMS (ESI) calcd for
C31H30FNO6S [M+H]+564.1851, found 564.1842.
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2-Ethyl-8-chloro-2-fluoro-3a-methyl-4-oxo-1-(p-tolyl)-5-tosyl-3,3a,4,5-tetrahydr
o-2H-cyclopenta[c]quinoline-2-carboxylate (3m). White solid, 81 mg, yield 72%, dr
= 9:1, Rf = 0.30 (petroleum ether/EtOAc, 10:1); 1H NMR (400 MHz, CDCl3) δ 7.78 –
7.74 (m, 3H), 7.37 – 7.28 (m, 3H), 7.18 (d, J = 8.0 Hz, 2H), 7.08 – 7.05 m, 3H), 4.39
– 4.23 (m, 2H), 2.58 – 2.48 (m, 2H), 2.40 (s, 3H), 2.31 (s, 3H), 1.37 – 1.25 (m,
6H).13C{1H} NMR (100 MHz, CDCl3) δ 173.7, 170.3, 145.5, 139.2, 139.1, 138.3,
138.0, 135.9, 133.8, 132.2, 129.6, 129.1, 128.8, 128.5, 128.3, 128.1, 127.7, 127.1,
125.8, 125.7, 102.9 (d, J = 191.9 Hz), 62.6, 55.2, 45.2, 23.2, 21.7, 21.4, 14.1.19F NMR
(376 MHz, CDCl3) δ -140.9 (dd, J = 27.4, 9.6 Hz). HRMS (ESI) calcd for
C30H27ClFNO5S [M+H]+568.1355, found 568.1351.
2-Ethyl-8-chloro-2-fluoro-3a-methyl-4-oxo-1-(p-tolyl)-5-tosyl-3,3a,4,5-tetrahydr
o-2H-cyclopenta[c]quinoline-2-carboxylate (3n). Oil, 39 mg, yield 35%, dr >20:1, Rf
= 0.30 (petroleum ether/EtOAc, 10:1); 1H NMR (400 MHz, CDCl3) δ 7.90 – 7.75 (m,
3H), 7.45 – 7.28 (m, 3H), 7.22 – 6.97 (m, 6H), 4.40 – 4.17 (m, 2H), 2.82 – 2.48 (m,
2H), 2.42 (s, 3H), 1.37 – 1.15 (m, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 173.9,
170.4, 162.9 (d, J = 274.0 Hz), 145.4, 136.2, 135.3, 132.6, 130.8, 130.7, 129.5, 129.3,
128.3, 127.3, 126.5, 124.4, 123.7, 116.0, 115.8, 103.1 (d, J = 194.0 Hz), 62.5, 55.4,
45.4, 23.4, 21.7, 14.1. 19F NMR (376 MHz, CDCl3) δ -111.6 (ddd, J = 14.3, 8.9, 5.4
Hz), -139.3 (dd, J = 28.3, 10.5 Hz). HRMS (ESI) calcd for C29H25F2NO5S
[M+H]+538.1494, found 538.1493.
2-Ethyl-1-butyl-2-fluoro-3a-methyl-4-oxo-5-tosyl-3,3a,4,5-tetrahydro-2H-cyclop
enta[c]quinoline-2-carboxylate (3o). Yellow oil, 49 mg, yield 50%, dr = 5:1, Rf =
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0.40 (petroleum ether/EtOAc, 15:1); H NMR (400 MHz, CDCl3) δ 8.00 – 7.66 (m,
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3H), 7.49 – 7.20 (m, 5H), 4.34 – 4.20 (m, 2H), 2.58 – 2.37 (m, 5H), 1.46 – 1.19 (m,
8H), 1.19 – 1.01 (m, 3H), 1.01 – 0.83 (m, 4H).13C{1H} NMR (100 MHz, CDCl3) δ
174.5, 170.6 (d, J = 32.8 Hz), 145.1, 140.0 (d, J = 9.0 Hz), 138.1 (d, J = 21.0 Hz),
136.2, 135.0, 130.9, 129.4, 128.9), 128.2, 126.7, 124.4, 103.4 (d, J = 194.5 Hz), 65.6,
62.2, 55.2, 45.0 (d, J = 23.3 Hz), 30. 5, 25.1, 23.2 (d, J = 6.4 Hz), 23.0, 21.7, 19.2,
13.9 (d, J = 29.2 Hz). 19F NMR (376 MHz, CDCl3) δ -140.5 (dd, J = 26.4, 12.4 Hz).
HRMS (ESI) calcd for C27H30FNO5S [M+H]+500.1901, found 500.1900.
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2-Ethyl-2-fluoro-3a-methyl-4-oxo-1-(thiophen-2-yl)-5-tosyl-3,3a,4,5-tetrahydro-
2H-cyclopenta[c]quinoline-2-carboxylate (3p). White solid, 37 mg, yield 36%, dr =
11:1, Rf = 0.40 (petroleum ether/EtOAc, 10:1); 1H NMR (400 MHz, CDCl3) δ 7.82 (d,
J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.7 Hz,
1H), 7.37 – 7.27 (m, 2H), 7.20 – 7.10 (m, 3H), 7.03 (t, J = 4.0 Hz,1H), 4.38 – 4.22 (m,
2H), 2.76 – 2.43 (m, 2H), 2.35 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.18 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 173.7, 170.3, 145.3, 135.9, 135.3, 132.3, 129.6, 129.5,
128.5, 128.1, 127.6, 127.3, 126.9, 126.6, 125.1, 124.3, 102.7(d, J = 193.0 Hz), 62.5,
55.9, 45.0, 23.0, 21.7, 14.1. 19F NMR (376 MHz, CDCl3) δ -139.9 (dd, J = 27.7, 11.3
Hz). HRMS (ESI) calcd for C27H24FNO5S2 [M+H]+526.1153, found 526.1150.
2-Ethyl-5-benzyl-2-fluoro-3a-methyl-4-oxo-1-phenyl-3,3a,4,5-tetrahydro-2H-cyc
lopenta[c]quinoline-2-carboxylate (3q). White solid, 80 mg, yield 88%, dr = 5:1, Rf =
0.30 (petroleum ether/EtOAc, 15:1); 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.40
– 7.31 (m, 5H), 7.29 – 7.20 (m, 6H), 7.13 – 7.05 (m, 1H), 6.98 – 6.93 (m, 2H), 6.82 –
6.76 (m, 1H), 5.58 (d, J = 16.4 Hz, 1H), 4.75 (d, J = 16.4 Hz, 1H), 4.18 – 4.05 (m,
2H), 1.52 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 174.0,
171.2 (d, J = 23.1 Hz), 143.0, 139.7, 136.9, 136.0, 132.6, 130.0, 129.1, 128.9, 128.7,
128.4, 127.9, 127.3, 126.2, 122.8, 116.0, 103.7 (d, J = 194.8 Hz), 62.3, 52.7, 46.7,
45.6, 25.6 14.1. 19F NMR (376 MHz, CDCl3) δ -136.8 (dd, J = 29.4, 7.6 Hz). HRMS
(ESI) calcd for C29H26FNO3 [M+H]+456.1969, found 456.1971.
2-Ethyl-2-fluoro-3a,5-dimethyl-4-oxo-1-phenyl-3,3a,4,5-tetrahydro-2H-cyclopen
ta[c]quinoline-2-carboxylate (3r). Yellow oil, 68 mg, yield 90%, dr = 4:1, Rf = 0.40
(petroleum ether/EtOAc, 15:1); 1H NMR (400 MHz, CDCl3) δ 7.32 (dq, J = 11.3, 3.2
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Hz, 4H), 7.22 – 7.15 (m, 2H), 7.12 – 6.98 (m, 2H), 6.82 (td, J = 7.6, 0.8 Hz, 1H), 4.42
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– 4.27 (m, 2H), 3.48 – 3.39 (m, 3H), 3.18 – 2.68 (m, 2H), 1.44 (s, 3H), 1.35 – 1.16 (m,
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3H). C{1H} NMR (100 MHz, CDCl3) δ 173.7, 171.0, 143.1, 140.2, 135.6, 132.6,
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129.9, 129.1, 128.6, 128.3, 127.8, 122.6, 119.8, 115.2, 103.6 (d, J = 194.2 Hz), 67.1,
62.2, 52.5, 45.6, 45.4, 30.0, 25.5, 14.1.19F NMR (376 MHz, CDCl3) δ -137.5 (dd, J =
29.6, 7.6 Hz). HRMS (ESI) calcd for C23H22FNO3 [M+H]+380.1656, found 380.1645.
2-Ethyl-5-ethyl-2-fluoro-3a-methyl-4-oxo-1-phenyl-3,3a,4,5-tetrahydro-2H-cyclo
penta[c]quinoline-2-carboxylate (3s). Yellow oil, 60 mg, yield 77%, dr = 4:1, Rf =
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0.30 (petroleum ether/EtOAc, 15:1); H NMR (400 MHz, CDCl3) δ 7.58 – 6.94 (m,
9H), 6.81 (dd, J = 16.1, 8.5 Hz, 1H), 4.45 – 3.70 (m, 5H), 3.21 – 2.60 (m, 2H), 1.52 –
1.08 (m, 9H).13C{1H} NMR (100 MHz, CDCl3) δ 173. 2 171.1, 143.3, 143.2, 139.2,
135.6, 135.3, 133.3, 132.6, 131.6, 130.4, 130.0, 129.1, 129.0, 128.7, 128.6, 128.5,
128.3, 128.2, 122.4, 120.0, 115.1, 114.9, 103.6 (d, J = 194.1 Hz), 62.2, 52.4, , 45.4,
37.8, 25.37, 25.3, 14.1, 12.6.19F NMR (376 MHz, CDCl3) δ -137.5 (dd, J = 29.5, 7.4
Hz). HRMS (ESI) calcd for C24H24FNO3 [M+H]+394.1813, found 394.1806.
2-Ethyl-2-fluoro-3a,5,8-trimethyl-4-oxo-1-phenyl-3,3a,4,5-tetrahydro-2H-cyclop
enta[c]quinoline-2-carboxylate (3t). Yellow oil, 69 mg, yield 88%, dr = 4:1, Rf = 0.30
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(petroleum ether/EtOAc, 15:1); H NMR (400 MHz, CDCl3) δ 7.38 – 7.27 (m, 4H),
7.23 – 6.88 (m, 4H), 4.42 – 4.27 (m, 2H), 3.45 – 3.35 (m, 3H), 3.17 – 2.97 (m, 1H),
2.78 – 2.67 (m, 1H), 2.07 (s, 3H), 1.41 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 173.6, 170.9, 143.3, 137.9, 133.3, 132.7, 132.0, 131.0, 130.5,
129.1, 128.5, 128.4, 128.3, 119.7, 115.0, 103.6(d, J = 194.1 Hz), 62.2, 52.6, 45.6, 30.0,
25.5, 20.5, 14.1. 19F NMR (376 MHz, CDCl3) δ -138.8 (dd, J = 29.5, 6.5 Hz). HRMS
(ESI) calcd for C24H24FNO3 [M+H]+394.1813, found 394.1813.
2-Ethyl-8-bromo-2-fluoro-3a,5-dimethyl-4-oxo-1-phenyl-3,3a,4,5-tetrahydro-2H
-cyclopenta[c]quinoline-2-carboxylate (3u). Yellow oil, 57 mg, yield 63%, dr = 5:1,
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Rf = 0.30 (petroleum ether/EtOAc, 10:1); H NMR (400 MHz, CDCl3) δ 7.43 – 6.89
(m, 8H), 4.46 – 3.81 (m, 2H), 3.42 (s, 3H), 3.19 – 2.39 (m, 2H), 1.40 (s, 3H), 1.33 (t, J
= 6.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 173.4, 170.8, 141.7, 138.8, 137.2,
131.8, 130.1, 129.7, 128.9, 128.71, 128.3, 128.0, 127.8, 121.3, 116.4, 103.4(d, J =
194.9 Hz), 62.3, 52.4, 45.5, 30.2, 25.4, 14.1. 19F NMR (376 MHz, CDCl3) δ -137.7 (d,
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J = 29.9 Hz). HRMS (ESI) calcd for C23H21ClFNO3 [M+H]+414.1267, found
414.1262.
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yclopenta[c]quinoline-2-carboxylate (3v). White solid, 108 mg, yield 91%, dr > 20:1,
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Rf = 0.30 (petroleum ether/EtOAc, 5:1); H NMR (400 MHz, CDCl3) δ 7.80 (d, J =
8.3 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.41 – 7.35 (m, 3H), 7.29 (dd, J = 13.3, 6.6 Hz,
4H), 7.12 (ddd, J = 8.2, 4.7, 2.4 Hz, 6H), 7.02 – 6.92 (m, 2H), 4.22 – 4.05 (m, 3H),
3.20 (dd, J = 27.0, 15.5 Hz, 1H), 2.66 (t, J = 15.0 Hz, 1H), 2.38 (d, J = 19.7 Hz, 3H),
2.12 (d, J = 8.5 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
171.2, 169.9, 145.2, 140.2, 140.1, 139.8, 139.6, 138.9, 138.8, 136.5, 136.2, 132.4,
131.4, 129.7, 129.5, 129.0, 128.7, 128.3, 127.7, 127.4, 126.3, 125.3, 124.5, 103.6 (d, J
= 194.6 Hz), 64.3, 62.2, 47.5, 21.7, 20.9, 13.9. 19F NMR (376 MHz, CDCl3) δ -104.2
(dd, J = 27.0, 14.5 Hz). HRMS (ESI) calcd for C35H30FNO5S [M+H]+596.1901, found
596.1899.
2-Ethyl-2,8-difluoro-4-oxo-1,3a-diphenyl-5-tosyl-3,3a,4,5-tetrahydro-2H-cyclop
enta[c]quinoline-2-carboxylate (3w). White solid, 75 mg, yield 63%, dr > 20:1, Rf =
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0.40 (petroleum ether/EtOAc, 5:1); H NMR (400 MHz, CDCl3) δ 7.86 – 7.74 (m,
2H), 7.62 – 7.54 (m, 1H), 7.48 – 7.11 (m, 13H), 6.95 – 6.80 (m, 2H), 4.21 – 4.09 (m,
2H), 3.29 – 3.14 (m, 1H), 2.72 – 2.62 (m, 1H), 2.41 (d, J = 5.8 Hz, 3H), 1.19 – 1.00
(m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 169.6, 160.4 (d, J = 246.9 Hz),
145.5, 138.4, 135.8, 130.8, 129.5, 129.4, 128.9, 128.8, 128.3, 127.9, 126.7, 126.7,
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126.2, 116.1, 115.8, 113.8, 103.6 (d, J = 194.9 Hz), 64.2, 62.4, 47.5, 47.2, 13.9. F
NMR (376 MHz, CDCl3) δ 136.0 (dd, J = 13.4, 7.9 Hz), 109.91 (dd, J = 26.9, 15.0
Hz). HRMS (ESI) calcd for C34H27F2NO5S [M+H]+ 600.1651, found 600.1647.
2-Ethyl-2-fluoro-1-(4-methoxyphenyl)-4-oxo-3a-phenyl-5-tosyl-3,3a,4,5-tetrahyd
ro-2H-cyclopenta[c]quinoline-2-carboxylate (3x). White solid, 113 mg, yield 93%,
dr > 20:1, Rf = 0.30 (petroleum ether/EtOAc, 5:1); 1H NMR (400 MHz, CDCl3) δ 7.83
(t, J = 14.9 Hz, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.34 – 7.02 (m, 12H), 6.88 (dd, J = 22.6,
8.6 Hz, 2H), 4.24 – 4.11 (m, 2H), 3.89 – 3.78 (m, 3H), 3.28 – 3.12 (m, 1H), 2.65 (t, J
= 14.7 Hz, 1H), 2.40 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 171.2, 170.0, 160.1, 145.3, 139.7, 139.5, 138.7, 138.6, 136.2, 134.8, 130.3,
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129.5, 128.8, 128.6, 128.4, 128.2, 127.7, 127.2, 126.6, 126.4, 125.8, 124.7, 123.4,
114.2, 103.6(d, J = 194.3 Hz), 64.0, 62.2, 55.3, 47.5, 21.7, 13.9. 19F NMR (376 MHz,
CDCl3) δ -140.7 (dd, J = 27.1, 13.9 Hz). HRMS (ESI) calcd for C35H30FNO6S
[M+H]+612.1851, found 612.1845.
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2-Ethyl-2-fluoro-4-oxo-1,3a-diphenyl-5-(phenylsulfonyl)-3,3a,4,5-tetrahydro-2H
-cyclopenta[c]quinoline-2-carboxylate (3y). White solid, 97 mg, yield 86%, dr > 20:1,
1
Rf = 0.30 (petroleum ether/EtOAc, 5:1); H NMR (400 MHz, CDCl3) δ 7.95 (t, J =
14.0 Hz, 2H), 7.62 (t, J = 7.5 Hz, 2H), 7.57 – 7.47 (m, 2H), 7.44 – 7.34 (m, 3H), 7.28
(dd, J = 10.5, 7.2 Hz, 2H), 7.23 – 7.08 (m, 7H), 7.03 (t, J = 7.5 Hz, 1H), 4.19 – 4.08
(m, 2H), 3.21 (dd, J = 26.8, 15.5 Hz, 1H), 2.67 (t, J = 15.4 Hz, 1H), 1.10 (t, J = 7.1 Hz,
13
3H). C{1H} NMR (100 MHz, CDCl3) δ 171.1, 169.8, 140.2, 140.0, 139.9, 139.1,
138.6, 138.6, 134.7, 134.1, 131.3, 129.0, 128.9, 128.7, 128.2, 127.8, 127.2, 126.7,
19
126.3, 125.4, 125.3, 124.7, 103.8(d, J = 195.3 Hz), 67.1, 64.2, 62.3, 47.3, 13.9. F
NMR (376 MHz, CDCl3) δ -140.1 (dd, J = 26.7, 15.2 Hz). HRMS (ESI) calcd for
C33H26FNO5S [M+H]+ 568.1588, found 568.1585.
2-Ethyl-2-fluoro-5-((4-methoxyphenyl)sulfonyl)-4-oxo-1,3a-diphenyl-3,3a,4,5-tet
rahydro-2H-cyclopenta[c]quinoline-2-carboxylate (3z). White solid, 108 mg, yield
91%, dr > 20:1, Rf = 0.30 (petroleum ether/EtOAc, 5:1); 1H NMR (400 MHz, CDCl3)
δ 7.88 (d, J = 8.9 Hz, 2H), 7.61 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 2.5 Hz, 3H), 7.32 –
7.24 (m, 2H), 7.20 – 7.07 (m, 7H), 7.05 – 6.91 (m, 3H), 4.23 – 4.11 (m, 2H), 3.82 (s,
3H), 3.25 (dd, J = 27.0, 15.5 Hz, 1H), 2.69 (t, J = 15.1 Hz, 1H), 1.10 (t, J = 7.1 Hz,
3H).13C{1H} NMR (100 MHz, CDCl3) δ 171.1, 169.9, 164.1, 140.1, 139.9, 139.7,
138.8, 134.8, 131.4, 130.8, 130.3, 129.0, 128.9, 128.7, 127.7, 127.2, 126.5, 126.3,
125.4, 124.7, 114.0, 103.8 (d, J = 194.3 Hz), 64.2, 62.3, 55.8, 47.5, 13.9.19F NMR
(376 MHz, CDCl3) δ 110.3 (dd, J = 26.9, 14.6 Hz). HRMS (ESI) calcd for
C34H28FNO6S [M+H]+598.1694, found 598.1689.
ASSOCIATED CONTENT
Investigations of the mechanism, crystal data and structure refinement of 3b and
3i, NMR spectra for compounds 1 and 3.
AUTHOR INFORMATION
Corresponding Author
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*E-mail: songhongjian@nankai.edu.cn (H.-J. S.).
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*E-mail: wangqm@nankai.edu.cn (Q.-M. W).
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*E-mail: chemzhangjingjing@163.com (J.-J. Z).
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§Y. Q. and W. T. X. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (21977056,
21732002, 21672117) and the Fundamental Research Funds for the Central
Universities, Nankai University (63191523) for generous financial support for our
programs.
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