Stereoselective synthesis of fluorinated 2,3-dihydroquinolin-4(1 H)-ones via a one-pot multistep transformation

Article abstract of DOI:10.1021/jo202693x

A new organocatalytic one-pot multistep transformation via Knoevenagel condensation/aza-Michael addition/electrophilic fluorination has been developed. Simple starting materials were used under mild conditions to construct fluorinated 2,3-dihydroquinolin-

Full text of DOI:10.1021/jo202693x

Article
pubs.acs.org/joc
Stereoselective Synthesis of Fluorinated 2,3-Dihydroquinolin-4(1H)-
ones via a One-Pot Multistep Transformation
Feng Li, Jing Nie, Jun-Wei Wu, Yan Zheng, and Jun-An Ma*
Department of Chemistry, Tianjin University, Tianjin, 300072, P. R. of China
S
* Supporting Information
ABSTRACT: A new organocatalytic one-pot multistep trans-
formation via Knoevenagel condensation/aza-Michael addi-
tion/electrophilic fluorination has been developed. Simple
starting materials were used under mild conditions to
construct fluorinated 2,3-dihydroquinolin-4(1H)-one deriva-
tives in good to high yields (up to 98%) and diastereose-
lectivities (dr up to 99/1).
with aldehydes.9 Encouraged by these results and as a part of
INTRODUCTION
Fluorinated carbocycles and heterocycles are a common feature
■
our continued interest in the stereoselective synthesis of
organofluorine compounds,4d,e,10 we envisioned that fluori-
nated dihydroquinolinones could be constructed through a
one-pot sequential Knoevenagel condensation/aza-Michael
addition/electrophilic fluorination transformation directly
from β-(2′-anilino)-β-ketoesters 1 and aldehydes (Figure 1).
of many biologically active synthetic and drug targets.1 Among
the possible strategies for assembling such compounds, one-pot
multistep reactions constitute a particularly important ap-
proach.2 The advantage of these transformations is the
formation of several bonds in one pot without the need for
isolation of the intermediates. Furthermore, this approach
allows for the step-economical synthesis of complex and diverse
compounds from readily available starting materials.3 Over the
past decades, a number of one-pot multistep transformations
have been invented in accord with the increasing need for
medicinal agents and the rapid advancement of the field of
organofluorine chemistry.4 Despite this impressive progress, the
development of novel one-pot multistep transformations that
provide efficiently new ways of accessing fluorinated carbo-
cycles and heterocycles is still in great demand.
2,3-Dihydroquinolin-4(1H)-one scaffolds are present in
many natural and unnatural compounds that exhibit important
biological activities.5 Therefore, a large number of methods
have been developed for the synthesis of dihydroquinolinone
derivatives.6 The cyclization of 2′-aminochalcone derivatives or
3-(substituted anilino)propionic acids is a widely used pathway.
However, a survey of the literature reveals that one-pot
multistep transformations for the construction of these
compounds are relatively rare. Hamada and co-workers
reported the Pd-catalyzed allylic amination−thiazolium salt-
catalyzed Stetter reaction cascade via a one-pot sequential
multicatalytic process that provides 3-substituted 2,3-dihydro-
quinolin-4(1H)-ones,7a and Alper developed the multicompo-
nent cyclocarbonylation of o-iodoanilines with allenes and CO
using palladium complex and ionic liquid.7b The Chandrase-
khar8a and Lu8b groups disclosed organocatalytic one-pot
multistep reactions for the synthesis of 2- or 3-substituted 2,3-
disubstituted dihydroquinolin-4(1H)-ones. Recently, a novel
strategy for accessing various trans-2,3-disubstituted dihydro-
quinolin-4(1H)-ones is the Lewis acid-promoted one-pot
multistep transformations of 2-alkynylanilines or -benzamides
Figure 1. One-pot sequential Knoevenagel condensation/aza-Michael
addition/electrophilic fluorination transformation.
Herein, we report the successful implementation of this process
to provide fluorinated 2,3-dihydroquinolin-4(1H)-one deriva-
tives and significant opportunities for structural diversification.
RESULTS AND DISCUSSION
■
We initiated our studies by evaluating the reaction between Ts-
protected β-(2′-anilino)-β-ketoester 1a and benzaldehyde using
organocatalyst in ethanol at room temperature. After substrate
1a completely disappeared (monitored by TLC), additives and
electrophilic fluorinating reagents were then added to the
reaction system. In the presence of L-proline, no desired
fluorinated product was observed; accordingly, two intermedi-
Received: January 6, 2012
Published: February 13, 2012
© 2012 American Chemical Society
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a
Table 1. Effect of Catalysts, Additives, and Electrophilic Fluorinating Reagents on the One-Pot Multistep Transformation
b
yield (%)
c
entry
catalyst (mol %)
solvent
additive/F-reagent
Int-A
Int-C
product 2a
1
2
L-proline (20)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
THF
no additive/NFSI
CH3CO2H/NFSI
no additive/NFSI
CH3CO2H/NFSI
no additive/NFSI
CH3CO2H/NFSI
DABCO/NFSI
DBU/NFSI
30
30
trace
52
trace
50
trace
trace
trace
trace
0
69
39
97
34
96
28
97
97
trace
trace
0
0
0
0
0
0
0
0
0
L-proline (20)
3
pyrrolidine (20)
pyrrolidine (20)
piperidine (20)
piperidine (20)
pyrrolidine (20)
pyrrolidine (20)
DABCO (100)
DBU (100)
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
L-proline (20)
Li2CO3/NFSI
Li2CO3/NFSI
Na2CO3/NFSI
K2CO3/NFSI
Cs2CO3/NFSI
NaOH/NFSI
LiOH/NFSI
85
90
94
93
82
86
85
80
77
80
pyrrolidine (20)
pyrrolidine (20)
pyrrolidine (20)
pyrrolidine (20)
pyrrolidine (20)
pyrrolidine (20)
pyrrolidine (20)
pyrrolidine (20)
pyrrolidine (20)
pyrrolidine (20)
pyrrolidine (20)
pyrrolidine (20)
pyrrolidine (10)
0
0
0
0
0
0
0
0
0
0
0
0
Na2CO3/Selectfluor
Na2CO3/NFPY
Na2CO3/NFSI
0
15
16
0
0
0
toluene
CH2Cl2
CH3CN
EtOH
trace
23
0
28
trace
0
Na2CO3/NFSI
90
85
Na2CO3/NFSI
0
0
a
b
c
1a/benzaldehyde/additive/F-reagent =1: 1.2: 1.2: 1.2 in 1.5 mL of solvents. Isolated yield. The dr value (95/5−97/3) was determined by 19F
NMR analysis of the crude product.
ates A and C were obtained in the yield of 30% and 69%,
Under the optimized experimental conditions, the scope of
the one-pot multistep transformation was explored, and the
results are summarized in Table 2. First, the reaction of Ts-
protected β-(2′-anilino)-β-ketoester 1a with a variety of
aldehydes was examined. Electron-neutral and electron-
donating groups at different positions on the aromatic ring
were tolerated for this one-pot multistep transfomation to give
the fluorinated 2,3-dihydroquinolin-4(1H)-one derivatives 2a−
g in 84−98% yields with excellent diastereoselectivities (trans/
cis: 96/4 to 99/1) (entries 1−7). For the aromatic aldehyde
with multisubstituents, relatively low yield was obtained
probably owing to steric hindrance (entry 8). Aromatic
aldehydes possessing electron-withdrawing substitutents on
the aromatic rings were transformed into the desired product
2j−q in good to high yields, albeit with a lower
diastereoselectivity (entries 9−17). 2-Naphthaldehyde, hetero-
aromatic aldehydes, and aliphatic aldehydes were also viable
substrates, affording the corresponding fluorinated products
2r−v with high diastereoselectivities (entres 18−22). To
further define the scope of our methodology, the reactions of
other Ts-protected β-(2′-anilino)-β-ketoesters 1b−e with
benzaldehyde were also tested. The transformation proceeded
well in 86−97% yields with high dr values (entries 23−26).
These fluorinated products 2 are versatile synthetic
intermediates and can be readily transformed into functional-
ized heterocycle derivatives that are otherwise difficult to
respectively (Table 1, entries 1 and 2). It is interesting that the
1
intermediate B was not detected by H NMR. The use of
pyrrolidine and piperidine gave the similar results (entries 3−
8). However, the addition of DABCO or DBU failed to
produce any detectable products (entries 9 and 10).11 These
results show that strong base additives are necessary for
reasonable reaction rates of the electrophilic fluorination step.
Next, we decided to employ the inorganic bases as additives
(entries 11−17). We were delighted to find that the one-pot
multistep transformation could be performed at room temper-
ature providing the desired fluorinated product 2a with high
diastereoselectivity (dr up to 97/3, determined by 19F NMR),
and the best yield was obtained with Na2CO3. Furthermore,
crystals suitable for X-ray crystallographic analysis were
obtained.12 The stereochemical assignment indicated that the
trans-product was predominantly formed. A substantial change
of the fluorinating reagent and the solvent had a significant
effect on the yield (entries 13 and 18−23). Good results were
attained when N-fluorobenzenesulfonimide (NFSI) and
ethanol were used in this one-pot multistep transformation.
Last, the effect of organocatalyst loading was examined, and
reducing the amount of catalyst from 20 to 10 mol % caused a
drop in yield (94% to 85%), although without any influence on
the stereoselectivity (entry 24).
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a
Table 2. Scope of the One-Pot Multistep Transformation for the Synthesis of Fluorinated 2,3-Dihydroquinolin-4(1H)-ones
product 2
b
c
entry
substrate 1
R1
R2
R3
yield (%)
-trans/cis
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Et
C6H5
2a
2b
2c
2d
2e
2f
94
93
93
84
85
98
92
52
85
92
89
86
83
83
82
84
88
97
85
90
80
72
95
86
92
97
97/3
98/2
97/3
98/2
96/4
96/4
99/1
98/2
97/3
94/6
93/7
87/13
75/25
80/20
90/10
85/15
70/30
94/6
99/1
98/2
98/2
99/1
93/7
99/1
98/2
99/1
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
3-MeOC6H4
3-PhOC6H4
3,4-OCH2OC6H3
2,4,6-(MeO)3C6H2
4-FC6H4
3
4
5
6
7
2g
2h
2i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
4-ClC6H4
4-BrC6H4
2-ClC6H4
2-BrC6H4
4-NO2C6H4
4-CF3C6H4
3,4-Cl2C6H3
3,5-(CF3)2C6H3
2-naphthyl
2-furanyl
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
2t
2-thiophene-yl
Et
nPr
2u
2v
2w
2x
2y
2z
C6H5
4,5-(MeO)2
4-Cl
tBu
tBu
tBu
C6H5
C6H5
5-F
C6H5
a
b
c
Substrate 1/aldehyde/Na2CO3/NFSI = 1:1.2:1.2:1.2 in EtOH (1.5 mL). Isolated yield after flash chromatography. Determined by 19F NMR
analysis of the crude product.
access. For example, decarboxylation of compound 2a gave 3-
fluoro-2-phenyl-1-tosyl-2,3-dihydroquinolin-4(1H)-one 3 in
98% yield with 70:30 dr (Scheme 1). In addition, a reduction
process using NaBH4 gives rise to the corresponding α-fluoro-
β-hydroxyesters 4 in high yield and excellent diastereoselectiv-
ity. Furthermore, the single stereoisomer of 4 proved to be
crystalline, thus allowing the determination of the relative
configuration of three adjacent stereogenic centers by means of
X-ray crystallographic analysis.12
This methodology was further extended to electrophilic
chlorinating and brominating reagents to demonstrate the
scope of this one-pot multistep transformation (Scheme 2).13 It
was found that in the presence of pyrrolidine and Na2CO3, the
reaction of Ts-protected β-(2′-anilino)-β-ketoester 1a and
benzaldehyde with NCS and NBS affords the corresponding
chlorinated and brominated products 5 and 6 in high yields
with excellent diastereoselectivities.
this convenient process provided the products in good to high
yields and diastereoselectivities (dr up to 99/1) from simple
starting materials and under mild conditions. The further
development of catalytic enantioselective systems and the full
extension of this one-pot multistep transformation with other
halogenation agents will be reported in due course.
EXPERIMENTAL SECTION
■
1
General Information. H, 13C, and 19F NMR were recorded at
400 MHz (1H NMR), 100 MHz (13C NMR), as well as 376 MHz (19F
NMR). Chemical shifts were reported in ppm downfield from internal
Me4Si and external CCl3F, respectively. Multiplicity was indicated as
follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
dd (doublet of doublet), br (broad). Coupling constants were reported
in hertz (Hz).
Materials. Tetrahydrofuran (THF) and toluene were distilled from
sodium/benzophenone; CH2Cl2 (DCM) were distilled from CaH2;
CH3CN were distilled from P2O5; EtOH were distilled from sodium
prior to use. All commercially available reagents were used without
further purification. Analytical thin-layer chromatography was
performed on 0.20 mm silica gel plates. Silica gel (200−300 mesh)
was used for flash chromatography.
Representative Procedure for the Preparation of the
Starting Materials 1. (1) Preparation of methyl 2-(4-
methylphenylsulfonamido)benzoate: To a solution of methyl 2-
CONCLUSION
■
In summary, we have developed a novel and efficient one-pot
multistep procedure for the facile synthesis of fluorinated 2,3-
dihydroquinolin-4(1H)-one derivatives. When pyrrolidine was
used as the organocatalyst and Na2CO3 as the base additive,
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Scheme 1. Synthetic Transformation of 2a and the Crystal Structures of the Compounds 2a and 4
(satd), extracted with EtOAc (2 × 50 mL), washed with brine (60
mL), dried over Na2SO4, filtered, and concentrated. Purification by
column chromatography (EtOAc/petroleum ether = 1/8) yielded 1a
Scheme 2. Organocatalytic One-Pot Multistep
Transformation via Knoevenagel Condensation/Aza-
Michael Addition/Electrophilic Chlorination and
Bromination
1
(2.43 g, 52% yield) as a white solid: mp 130−131 °C; H NMR (400
MHz, CDCl3) δ 1.43 (s, 9H), 2.37 (s, 3H), 3.85 (s, 2H), 7.06 (t, J =
7.2 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 7.2 Hz, 1H), 7.72 (t,
J = 8.0 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 11.28 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 196.8, 166.0, 143.9, 140.5, 136.5, 135.2, 131.5,
130.0, 127.2, 122.4, 121.2, 118.7, 82.4, 77.4, 76.9, 76.5, 48.3, 27.8, 21.4;
IR (KBr) ν 2980, 2937, 1735, 1650, 1576, 1496, 1452, 1328, 1165,
1121, 1083, 1013, 942, 669, 568 cm−1; MS (ESI) found m/z 407.1 [M
+ NH4]+; HRMS (ESI) found m/z 412.1338 [M + Na]+, calcd for
C20H23NO5S + Na 412.1326.
aminobenzoate (7.56 g, 50 mmol) in CH2Cl2 (50 mL) was added
pyridine (4.85 mL, 60 mmol) dropwise over 10 min. The reaction
mixture was stirred for 60 min, and a solution of 4-methylbenzene-1-
sulfonyl chloride (11.44 g, 60 mmol) in CH2Cl2 was added dropwise.
After being stirred overnight, the reaction was quenched with the
addition of saturated aqueous NH4Cl (100 mL). The layers were
separated, and the aqueous layer was extracted with CH2Cl2 several
times. The combined organic layers were washed with brine (100 mL)
and dried over MgSO4. Evaporation of the solvent under the reduced
pressure and purification by column chromatography (EtOAc/
petroleum ether =1/8 to 1/2) afforded the desired compound as a
white solid (12.8 g, 84% yield): mp 115−116 °C; 1H NMR (400 MHz,
CDCl3) δ 2.38 (s, 3H), 3.89 (s, 3H), 7.03−7.06 (m, 1H), 7.23−7.24
(m, 2H), 7.29 (m, 1H), 7.45−7.47 (m, 1H), 7.70−7.77 (m, 2H),
7.92−7.94 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 168.3, 143.9,
140.6, 136.5, 134.5, 131.2, 129.6, 127.3, 122.8, 119.0, 115.9, 52.4, 21.5;
MS (ESI) found m/z 328.0 [M + Na]+; HRMS (ESI) found m/z
328.0624 [M + Na]+, calcd for C15H15NO4S + Na 328.0619.
(2) Preparation of tert-butyl 3-(2-(4-methylphenylsulfonamido)-
phenyl)-3-oxopropanoate 1a:6m To a N2-purged 250 mL round-
bottom flask were added anhydrous THF (40 mL) and diisopropyl-
amine (10.1 mL, 72 mmol). The solution was cooled to −78 °C, n-
BuLi (31.3 mL, 2.4 M in hexane) was added, and the resulting solution
was warmed slowly to 0 °C over 60 min. The solution was cooled to
−78 °C, and tert-butyl acetate (6.5 mL, 48 mmol) in THF (40 mL)
was added dropwise over 30 min. After 90 min, methyl 2-(4-
methylphenylsulfonamido)benzoate (3.67 g, 12 mmol) in THF (30
mL) was added. The solution was allowed to warm to room
temperature overnight and quenched by adding aqueous NH4Cl
Ethyl 3-(2-(4-Methylphenylsulfonamido)phenyl)-3-oxopropa-
noate (1b). Compound 1b was prepared according to the above-
mentioned procedure: white solid; 2.64 g, 61% yield; mp 85−86 °C;
1H NMR (400 MHz, CDCl3) δ 1.24 (t, J = 7.2 Hz, 3H), 2.35 (s, 3H),
3.93 (s, 2H), 4.16−4.22 (m, 2H), 7.06 (t, J = 7.2 Hz, 1H), 7.23 (d, J =
8.0 Hz, 2H), 7.44−7.48 (m, 1H), 7.67−7.74 (m, 4H), 11.21 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 196.6, 166.9, 144.0, 140.5, 136.3,
135.5, 131.6, 129.7, 127.2, 122.6, 121.1, 118.8, 61.6, 47.0, 21.5, 14.0; IR
(KBr) ν 2978, 2937, 1739, 1652, 1602, 1576, 1494, 1452, 1327, 1161,
1091, 1033, 917, 659, 565 cm−1; MS (ESI) found m/z 379.1 [M +
NH4]+; HRMS (ESI) found m/z 384.0878 [M + Na]+, calcd for
C18H19NO5S + Na 384.0882.
tert-Butyl 3-(4,5-Dimethoxy-2-(4-methylphenylsulfonamido)-
phenyl)-3-oxopropanoate (1c). Compound 1c was prepared
according to the above-mentioned procedure: white solid, 2.68 g,
1
50% yield; mp 120−121 °C; H NMR (400 MHz, CDCl3) δ 1.38 (s,
9H), 2.33 (s, 3H), 3.74 (s, 2H), 3.80 (s, 3H), 3.89 (s, 3H), 7.09 (s,
1H), 7.19 (d, J = 8.0 Hz, 2H), 7.27 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H),
11.37 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 194.8, 166.2, 154.7,
144.1, 143.9, 136.8, 136.3, 129.6, 127.2, 114.1, 112.9, 102.2, 82.2, 56.2,
56.1, 48.7, 27.8, 21.4; IR (KBr) ν 2978, 2937, 1730, 1639, 1575, 1520,
1448, 1399, 1355, 1264, 1160, 1090, 993, 909, 676, 546 cm−1; MS
(ESI) found m/z 467.2 [M + NH4]+; HRMS (ESI) found m/z
472.1412 [M + Na]+, calcd for C22H27NO7S + Na 472.1406.
tert-Butyl 3-(4-Chloro-2-(4-methylphenylsulfonamido)phenyl)-3-
oxopropanoate (1d). Compound 1d was prepared according to the
above-mentioned procedure: pink solid, 2.84 g, 56% yield; mp 113−
1
114 °C; H NMR (400 MHz, CDCl3) δ 1.42 (s, 9H), 2.37 (s, 3H),
3.85 (s, 2H), 7.00−7.02 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.56 (d, J =
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2
8.8 Hz, 1H), 7.73 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 11.35 (s, 1H); 13
C
(100 MHz, CDCl3) δ 183.9 (d, 2JCF = 20.1 Hz), 163.1 (d, JCF = 26.1
Hz), 160.1, 144.6, 141.0, 136.2, 135.0, 129.5, 129.3, 128.6, 127.8,
125.4, 123.9, 123.6, 114.0, 92.5 (d, 1JCF = 192.6 Hz), 84.3, 65.7 (d, 2JCF
= 26.7 Hz), 55.3, 27.2, 21.5; 19F NMR (376 MHz, CDCl3) δ −141.3
(d, J = 20.3 Hz), −169.1; IR (KBr) ν 2980, 2934, 1752, 1698, 1599,
1515, 1459, 1369, 1306, 1256, 1165, 1059, 661, 567 cm−1; MS (ESI)
found m/z 543.2 [M + NH4]+; HRMS (ESI) found m/z 548.1513 [M
+ Na]+, calcd for C28H28FNO6S + Na 548.1519.
NMR (100 MHz, CDCl3) δ 196.2, 170.4, 166.0, 144.4, 141.7, 136.1,
132.8, 129.8, 127.3, 122.6, 119.3, 118.3, 82.7, 48.2, 27.8, 21.5; IR
(KBr) ν 2980, 2933, 1731, 1654, 1597, 1562, 1494, 1396, 1330, 1164,
1092, 936, 667, 573 cm−1; MS (ESI) found m/z 441.1 [M + NH4]+;
HRMS (ESI) found m/z 446.0817 [M + Na]+, calcd for
C20H22ClNO5S + Na 446.0805.
tert-Butyl 3-(5-Fluoro-2-(4-methylphenylsulfonamido)phenyl)-3-
oxopropanoate (1e). Compound 1e was prepared according to the
above-mentioned procedure: pink solid, 2.35 g, 48% yield; mp 117−
tert-Butyl 3-fluoro-2-(2-methoxyphenyl)-4-oxo-1-tosyl-1,2,3,4-
tetrahydroquinoline-3-carboxylate (2d): white solid; 132.4 mg,
84% yield; 98:2 dr; mp 72−73 °C; H NMR (400 MHz, CDCl3) δ
1
1
118 °C; H NMR (400 MHz, CDCl3) δ 1.42 (s, 9H), 2.36 (s, 3H),
3.77 (s, 2H), 7.19−7.23 (m, 3H), 7.39 (dd, J = 9.2 Hz, 2.8 Hz, 1H),
1.08 (s, 9H), 2.32 (s, 3H), 3.68 (s, 3H), 6.75−6.80 (m, 2H), 6.83 (d, J
= 8.4 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H),
7.21−7.26 (m, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H),
7.97 (t, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 183.1 (d,
7.69 (d, J = 8.0 Hz, 2H), 7.72 (dd, J = 9.2 Hz, 4.8 Hz, 1H), 10.87 (s,
1
1H); 13C NMR (100 MHz, CDCl3) δ 195.9, 165.5, 157.5 (d, JCF
=
3
243.4 Hz), 144.1, 136.5, 136.1, 129.7, 127.2, 122.7 (d, JCF = 5.7 Hz),
2
3
2
2JCF = 20.9 Hz), 162.9 (d, JCF = 25.9 Hz), 156.9, 144.5, 141.7, 135.7,
2
122.5 (d, JCF = 22.4 Hz), 121.5 (d, JCF = 7.2 Hz), 117.4 (d, JCF
=
23.4 Hz), 82.7, 48.3, 27.8, 21.5; IR (KBr) ν 2980, 2933, 1732, 1661,
1598, 1585, 1496, 1395, 1335, 1163, 1090, 900, 668, 549 cm−1; MS
(ESI) found m/z 425.2 [M + NH4]+; HRMS (ESI) found m/z
430.1103 [M + Na]+, calcd for C20H22FNO5S + Na 430.1100.
General Procedure for One-Pot Multistep Transformation
via Knoevenagel Condensation/Aza-Michael Addition/Electro-
philic Halogenation. To a solution of 1a (116.9 mg, 0.3 mmol) and
benzaldehyde (38.3 mg, 0.36 mmol) in ethanol (1.5 mL) was added
pyrrolidine (4.3 mg, 20 mol %) at room temperature, and the mixture
was stirred for 24 h. Then sodium carbonate (38.2 mg, 0.36 mmol)
and electrophilic halogenating reagent (0.36 mmol) were added
sequentially to the reaction mixture. Upon completion of the reaction
(monitored by TLC), the solvent was removed in vacuum. The
residue was mixed with 5 mL of water and extracted with CH2Cl2 (3 ×
10 mL). The combined organic phases were washed with brine (10
mL) and dried over anhydrous Na2SO4. Filtration and concentration
of the filtrate gave the crude product, which was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate 10/1) to
provide the desired product as a white solid.
135.2, 130.0, 129.5, 128.6, 128.3, 127.9, 124.7, 122.5, 120.7, 110.8, 91.9
1
2
(d, JCF = 190.5 Hz), 83.7, 60.4 (d, JCF = 29.9 Hz), 55.0, 27.1, 21.5;
19F NMR (376 MHz, CDCl3) δ −141.5 (d, J = 21.8 Hz), −171.2; IR
(KBr) ν 2980, 2937, 1755, 1696, 1599, 1459, 1357, 1306, 1249, 1165,
1088, 1059, 1027, 660, 570 cm−1; MS (ESI) found m/z 543.2 [M +
NH4]+; HRMS (ESI) found m/z 548.1534 [M + Na]+, calcd for
C28H28FNO6S + Na 548.1519.
tert-Butyl 3-fluoro-2-(3-methoxyphenyl)-4-oxo-1-tosyl-1,2,3,4-
tetrahydroquinoline-3-carboxylate (2e): white solid; 133.9 mg, 85%
1
yield; 96:4 dr; mp 102−103 °C; H NMR (400 MHz, CDCl3) δ 1.04
(s, 9H), 2.32 (s, 3H), 3.64 (s, 3H), 6.02 (d, J = 21.6 Hz, 1H), 6.70 (s,
1H), 6.76 (d, J = 8.0 Hz, 1H), 6.84 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.12−
7.17 (m, 3H), 7.29 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.60−
7.65 (m, 1H), 7.91−7.93 (m, 1H), 7.98 (d, J = 8.4 Hz, 1H); 13C NMR
2
(100 MHz, CDCl3) δ 183.9 (d, 2JCF = 20.0 Hz), 162.9 (d, JCF = 26.7
Hz), 159.6, 144.7, 141.1, 136.9, 136.1, 134.8, 129.8, 129.6, 128.4,
1
127.8, 125.6, 124.4, 123.9, 120.4, 114.5, 113.9, 92.7 (d, JCF = 193.0
2
Hz), 84.3, 66.0 (d, JCF = 27.2 Hz), 55.1, 27.1, 21.5; 19F NMR (376
MHz, CDCl3) δ −140.9 (d, J = 21.4 Hz), 169.3; IR (KBr) ν 2980,
2935, 1754, 1699, 1599, 1458, 1369, 1303, 1166, 1088, 1060, 662, 575
cm−1; MS (ESI) found m/z 543.2 [M + NH4]+; HRMS (ESI) found
m/z 548.1509 [M + Na]+, calcd for C28H28FNO6S + Na 548.1519.
tert-Butyl 3-fluoro-4-oxo-2-(3-phenoxyphenyl)-1-tosyl-1,2,3,4-
tetrahydroquinoline-3-carboxylate (2f): white solid; 172.7 mg, 98%
yield; 96:4 dr; mp 69−70 °C; 1H NMR (400 MHz, CDCl3) δ 1.12 (s,
9H), 2.32 (s, 3H), 6.13 (d, J = 21.2 Hz, 1H), 6.75 (s, 1H), 6.89 (d, J =
7.6 Hz, 2H), 6.93−6.96 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.16 (d, J =
8.0 Hz, 2H), 7.19−7.24 (m, 2H), 7.29 (t, J = 7.6 Hz, 2H), 7.55−7.58
(m, 1H), 7.82−7.84 (m, 1H), 7.93 (d, J = 8.4 Hz, 1H); 13C NMR (100
tert-Butyl 3-fluoro-4-oxo-2-phenyl-1-tosyl-1,2,3,4-tetrahydroqui-
noline-3-carboxylate (2a): white solid; 139.7 mg, 94% yield; 97:3 dr;
mp 140−141 °C; 1H NMR (400 MHz, CDCl3) δ (ppm) 1.02 (s, 9H),
2.33 (s, 3H), 6.16 (d, J = 21.2 Hz, 1H), 7.15−7.19 (m, 4H), 7.23 (t, J
= 7.6 Hz, 2H), 7.28−7.31 (m, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.61−
7.65 (m, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H); 13C
2
NMR (100 MHz, CDCl3) δ (ppm) 183.8 (d, JCF = 20.0 Hz), 162.9
2
(d, JCF = 26.2 Hz), 144.7, 141.1, 136.1, 135.7, 135.6, 134.8, 129.6,
1
129.0, 128.7, 128.5, 128.2, 127.8, 125.6, 124.2, 123.8, 92.6 (d, JCF
=
192.9 Hz), 84.4, 66.2 (d, JCF = 26.9 Hz), 27.1, 21.5; 19F NMR (376
MHz, CDCl3) δ (ppm) −141.2 (d, J = 21.0 Hz), −169.4; IR (KBr) ν
2981, 2931, 1753, 1696, 1599, 1477, 1457, 1359, 1304, 1166, 1088,
662, 569 cm−1; MS (ESI) found m/z 513.1 [M + NH4]+, HRMS (ESI)
found m/z 518.1421 [M + Na]+, calcd for C27H26FNO5S + Na
518.1413.
2
2
MHz, CDCl3) δ 183.7 (d, 2JCF = 19.9 Hz), 162.8 (d, JCF = 26.4 Hz),
157.9, 155.8, 144.7, 140.9, 137.4, 137.3, 136.1, 134.7, 130.1, 129.9,
129.6, 128.4, 127.8, 125.7, 124.3, 123.9, 123.8, 122.7, 119.6, 118.4,
1
2
117.3, 92.6 (d, JCF = 193.8 Hz), 84.5, 65.8 (d, JCF = 27.3 Hz), 27.2,
21.5; 19F NMR (376 MHz, CDCl3) δ −141.1 (d, J = 21.0 Hz), 169.3;
IR (KBr) ν 2980, 2931, 1754, 1698, 1488, 1458, 1369, 1304, 1255,
1167, 1088, 662, 572 cm−1; MS (ESI) found m/z 605.2 [M + NH4]+;
HRMS (ESI) found m/z 610.1680 [M + Na]+, calcd for C33H30FNO6S
+ Na 610.1676.
tert-Butyl 3-fluoro-4-oxo-2-(p-tolyl)-1-tosyl-1,2,3,4-tetrahydro-
quinoline-3-carboxylate (2b): white solid; 142.1 mg, 93% yield;
98:2 dr; mp 66−67 °C; 1H NMR (400 MHz, CDCl3) δ 1.05 (s, 9H),
2.28 (s, 3H), 2.32 (s, 3H), 6.14 (d, J = 20.8 Hz, 1H), 7.02−7.07 (m,
4H), 7.16 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.58−7.63 (m,
3H), 7.93−7.97 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 183.9 (d,
tert-Butyl 2-(benzo[d][1,3]dioxol-5-yl)-3-fluoro-4-oxo-1-tosyl-
1,2,3,4-tetrahydroquinoline-3-carboxylate (2g): white solid; 148.9
mg, 92% yield; 99:1 dr; mp 126−127 °C; 1H NMR (400 MHz,
CDCl3) δ 1.13 (s, 9H), 2.32 (s, 3H), 5.88 (s, 2H), 6.09 (d, J = 20.8 Hz,
1H), 6.56 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.75 (dd, J = 8.0 Hz, 1.2
Hz, 1H), 7.17 (t, J = 7.2 Hz, 3H), 7.26−7.33 (m, 2H), 7.58−7.64 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 183.7 (d, 2JCF = 20.1 Hz), 163.0
2
2JCF = 20.2 Hz), 163.0 (d, JCF = 26.2 Hz), 144.6, 141.1, 138.9, 136.1,
135.0, 132.6, 132.5, 129.5, 129.3, 128.5, 128.1, 127.8, 125.4, 124.1,
1
2
123.7, 92.6 (d, JCF = 192.7 Hz), 84.3, 66.0 (d, JCF = 26.8 Hz), 27.1,
21.5, 21.0; 19F NMR (376 MHz, CDCl3) δ −141.3 (d, J = 20.7 Hz),
169.2; IR (KBr) ν 2980, 2930, 1752, 1698, 1598, 1476, 1458, 1357,
1302, 1165, 1088, 1060, 660, 572 cm−1; MS (ESI) found m/z 527.2
[M + NH4]+; HRMS (ESI) found m/z 532.1581 [M + Na]+, calcd for
C28H28FNO5S + Na 532.1570.
2
(d, JCF = 26.4 Hz), 148.2, 147.7, 144.7, 140.9, 136.3, 134.8, 129.6,
129.4, 128.6, 127.8, 125.5, 124.6, 123.6, 122.5, 119.5, 108.3, 101.3, 92.5
1
2
(d, JCF = 192.9 Hz), 84.5, 67.9, 65.8 (d, JCF = 27.1 Hz), 27.3, 21.5;
19F NMR (376 MHz, CDCl3) δ −141.3 (d, J = 20.7 Hz), −169.1; IR
(KBr) ν 2981, 2931, 2908, 1753, 1698, 1599, 1490, 1458, 1362, 1300,
1251, 1167, 1035, 929, 662, 569 cm−1; MS (ESI) found m/z 557.1 [M
+ NH4]+; HRMS (ESI) found m/z 562.1313 [M + Na]+, calcd for
C28H26FNO7S + Na 562.1312.
tert-Butyl 3-fluoro-2-(4-methoxyphenyl)-4-oxo-1-tosyl-1,2,3,4-
tetrahydroquinoline-3-carboxylate (2c): white solid; 146.6 mg, 93%
yield; 97:3 dr; mp 144−145 °C; 1H NMR (400 MHz, CDCl3) δ 1.08
(s, 9H), 2.30 (s, 3H), 3.72 (s, 3H), 6.13 (d, J = 20.4 Hz, 1H), 6.74 (d, J
= 8.4 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.27
(t, J = 7.6 Hz, 1H), 7.57−7.62 (m, 3H), 7.92−7.95 (m, 2H); 13C NMR
2402
dx.doi.org/10.1021/jo202693x | J. Org. Chem. 2012, 77, 2398−2406

The Journal of Organic Chemistry
Article
tert-Butyl 3-fluoro-4-oxo-1-tosyl-2-(2,4,6-trimethoxyphenyl)-
1,2,3,4-tetrahydroquinoline-3-carboxylate (2h): white solid; 91.3
mg, 52% yield; 98:2 dr; mp 76−77 °C; 1H NMR (400 MHz, CDCl3) δ
1.16 (s, 9H), 2.32 (s, 3H), 2.99 (s, 3H), 3.76 (s, 3H), 3.90 (s, 3H),
5.89 (s, 1H), 6.14 (s, 1H), 7.01 (d, J = 25.6 Hz, 1H), 7.10 (t, J = 7.6
Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.41−7.45 (m, 1H), 7.66 (d, J = 8.0
Hz, 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.98 (dd, J = 7.6 Hz, 1.2 Hz, 1H);
NMR (376 MHz, CDCl3) δ −1416 (d, J = 19.9 Hz), −171.5; IR
(KBr) ν 2982, 2931, 1758, 1699, 1599, 1476, 1459, 1358, 1301, 1168,
1067, 660, 570 cm−1; MS (ESI) found m/z 547.1 [M + NH4]+; HRMS
(ESI) found m/z 552.1029 [M + Na]+, calcd for C27H25ClFNO5S +
Na 552.1024.
tert-Butyl 2-(2-bromophenyl)-3-fluoro-4-oxo-1-tosyl-1,2,3,4-tet-
rahydroquinoline-3-carboxylate (2m): white solid; 142.9 mg, 83%
yield; 75:25 dr; mp 144−145 °C; 1H NMR (400 MHz, CDCl3) δ 1.13
(s, 9H), 2.34 (s, 3H), 6.98 (d, J = 5.2 Hz, 1H), 7.16−7.21 (m, 5H),
7.32 (t, J = 8.0 Hz, 2H), 7.60−7.67 (m, 3H), 7.97−8.05 (m, 2H); 13C
2
13C NMR (100 MHz, CDCl3) δ 181.8 (d, JCF = 22.7 Hz), 163.2 (d,
2JCF = 24.7 Hz), 161.8, 160.0, 159.1, 144.0, 142.2, 135.9, 134.3, 129.3,
1
127.9, 127.2, 123.1, 123.0, 121.1, 106.5, 106.4, 91.4 (d, JCF = 185.3
NMR (100 MHz, CDCl3) δ 183.3 (d, 2JCF = 20.7 Hz), 162.5 (d, 2JCF
=
2
Hz), 90.8, 90.6, 83.1, 57.6 (d, JCF = 29.7 Hz), 56.3, 55.4, 53.5, 27.2,
21.4; 19F NMR (376 MHz, CDCl3) δ −141.5 (d, J = 25.6 Hz),
−169.8; IR (KBr) ν 2978, 2939, 1751, 1700, 1601, 1459, 1359, 1309,
1228, 1207, 1161, 1049, 659, 569 cm−1; MS (ESI) found m/z 608.2
[M + Na]+; HRMS (ESI) found m/z 608.1725 [M + Na]+, calcd for
C30H32FNO8S + Na 608.1730.
25.8 Hz), 144.9, 141.7, 136.5, 133.3, 130.3, 129.7, 129.4, 128.9, 128.0,
1
127.9, 127.8, 125.3, 124.7, 122.8, 119.6, 91.5 (d, JCF = 194.2 Hz),
2
84.5, 64.2 (d, JCF = 28.8 Hz), 27.2, 21.5; 19F NMR (376 MHz,
CDCl3) δ −141.2 (d, J = 20.3 Hz), −171.0; IR (KBr) ν 2982, 2932,
1757, 1699, 1599, 1459, 1359, 1300, 1169, 1064, 658, 569 cm−1; MS
(ESI) found m/z 591.0 [M + NH4]+; HRMS (ESI) found m/z
596.0524 [M + Na]+, calcd for C27H25BrFNO5S + Na 596.0519.
tert-Butyl 3-fluoro-2-(4-nitrophenyl)-4-oxo-1-tosyl-1,2,3,4-tetra-
hydroquinoline-3-carboxylate (2n): white solid; 134.5 mg, 83%
yield; 80:20 dr; mp 146−147 °C; 1H NMR (400 MHz, CDCl3) δ 1.02
(s, 9H), 2.34 (s, 3H), 6.20 (d, J = 21.2 Hz, 1H), 7.19 (d, J = 8.4 Hz,
2H), 7.34 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4
Hz, 2H), 7.69 (d, J = 6.8 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 8.02 (d, J
= 8.8 Hz, 1H), 8.14 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
tert-Butyl 3-fluoro-2-(4-fluorophenyl)-4-oxo-1-tosyl-1,2,3,4-tetra-
hydroquinoline-3-carboxylate (2i): white solid; 130.9 mg, 85% yield;
97:3 dr; mp 71−72 °C; 1H NMR (400 MHz, CDCl3) δ 1.06 (s, 9H),
2.32 (s, 3H), 6.15 (d, J = 21.2 Hz, 1H), 6.94 (t, J = 8.4 Hz, 2H), 7.16−
7.21 (m, 4H), 7.29 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.63
(t, J = 7.6 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H);
2
13C NMR (100 MHz, CDCl3) δ 183.7 (d, JCF = 20.1 Hz), 164.2,
2
162.8 (d, JCF = 26.0 Hz), 161.7, 144.8, 140.8, 136.2, 130.1, 130.0,
1
129.6, 128.6, 127.8, 125.7, 124.1, 123.8, 115.7, 115.5, 92.5 (d, JCF
=
2
2
193.3 Hz), 84.6, 65.4 (d, JCF = 27.3 Hz), 27.2, 21.5; 19F NMR (376
MHz, CDCl3) δ −141.6 (d, J = 20.7 Hz), −169.2, −111.9, −112.1; IR
(KBr) ν 2981, 2934, 1754, 1699, 1630, 1601, 1511, 1458, 1364, 1304,
1164, 667, 571 cm−1; MS (ESI) found m/z 531.2 [M + NH4]+; HRMS
(ESI) found m/z 536.1306 [M + Na]+, calcd for C27H25F2NO5S + Na
536.1319.
2
δ 183.3 (d, JCF = 20.0 Hz), 162.2 (d, JCF = 26.4 Hz), 148.0, 145.2,
142.9, 140.5, 136.4, 133.8, 129.8, 129.0, 128.5, 127.8, 127.4, 126.2,
124.1, 123.8, 92.5 (d, 1JCF = 196.6 Hz), 85.3, 65.1 (d, 2JCF = 28.5 Hz),
27.2, 21.5; 19F NMR (376 MHz, CDCl3) δ −142.9 (d, J = 21.1 Hz),
−168.8; IR (KBr) ν 2981, 2933, 1759, 1701, 1599, 1526, 1476, 1459,
1349, 1306, 1167, 1088, 661, 569 cm−1; MS (ESI) found m/z 558.0
[M + NH4]+; HRMS (ESI) found m/z 563.1268 [M + Na]+, calcd for
C27H25FN2O7S + Na 563.1264.
tert-Butyl 2-(4-chlorophenyl)-3-fluoro-4-oxo-1-tosyl-1,2,3,4-tetra-
hydroquinoline-3-carboxylate (2j): white solid; 146.2 mg, 92% yield;
1
tert-Butyl 3-fluoro-4-oxo-1-tosyl-2-(4-(trifluoromethyl)phenyl)-
1,2,3,4-tetrahydroquinoline-3-carboxylate (2o): white solid; 138.6
mg, 82% yield; 90:10 dr; mp 60−61 °C; 1H NMR (400 MHz, CDCl3)
δ 1.01 (s, 9H), 2.35 (s, 3H), 6.20 (d, J = 21.2 Hz, 1H), 7.19 (d, J = 8.0
Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.54−7.59
(m, 4H), 7.68 (t, J = 6.8 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 8.03 (d, J =
94:6 dr; mp 146−147 °C; H NMR (400 MHz, CDCl3) δ 1.06 (s,
9H), 2.32 (s, 3H), 6.13 (d, J = 21.2 Hz, 1H), 7.14−7.18 (m, 4H), 7.23
(d, J = 8.4 Hz, 2H), 7.27−7.31 (m, 1H), 7.57 (d, J = 8.4 Hz, 2H),
7.61−7.65 (m, 1H), 7.91−7.93 (m, 1H), 7.98 (d, J = 8.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 183.6 (d, 2JCF = 20.2 Hz), 162.7 (d, 2JCF
=
26.3 Hz), 144.9, 140.7, 136.3, 135.0, 134.5, 134.4, 134.3, 129.6, 129.5,
2
8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 183.5 (d, JCF = 19.9
1
128.8, 128.5, 127.8, 125.7, 124.1, 123.8, 92.4 (d, JCF = 194.0 Hz),
Hz), 162.5 (d, 2JCF = 26.3 Hz), 145.0, 140.8, 139.9, 136.3, 134.2, 129.7,
2
84.8, 65.3 (d, JCF = 27.6 Hz), 27.2, 21.5; 19F NMR (376 MHz,
128.5, 128.4, 127.8, 127.4, 125.9, 125.7, 125.6, 124.4, 124.0, 92.6 (d,
CDCl3) δ −141.9 (d, J = 20.7 Hz), −169.2; IR (KBr) ν 2980, 2933,
1756, 1699, 1598, 1494, 1477, 1459, 1370, 1307, 1166, 1089, 1061,
661, 570 cm−1; MS (ESI) found m/z 547.1 [M + NH4]+; HRMS (ESI)
found m/z 552.1034 [M + Na]+, calcd for C27H25ClFNO5S + Na
552.1024.
2
1JCF = 194.8 Hz), 84.9, 65.4 (d, JCF = 27.7 Hz), 27.1, 21.5; 19F NMR
(376 MHz, CDCl3) δ −142.0 (d, J = 21.1 Hz), −169.4, −62.9; IR
(KBr) ν 2981, 2934, 1758, 1700, 1599, 1477, 1459, 1370, 1327, 1167,
1069, 1017, 667, 569 cm−1; MS (ESI) found m/z 581.2 [M + NH4]+;
HRMS (ESI) found m/z 586.1279 [M + Na]+, calcd for
C28H25F4NO5S + Na 586.1287.
tert-Butyl 2-(4-bromophenyl)-3-fluoro-4-oxo-1-tosyl-1,2,3,4-tet-
rahydroquinoline-3-carboxylate (2k): white solid; 153.3 mg, 89%
yield; 93:7 dr; mp 147−148 °C; 1H NMR (400 MHz, CDCl3) δ 1.06
(s, 9H), 2.31 (s, 3H), 6.11 (d, J = 21.2 Hz, 1H), 7.09 (d, J = 8.8 Hz,
2H), 7.16 (d, J = 8.0 Hz, 2H), 7.26−7.30 (m, 1H), 7.38 (d, J = 8.4 Hz,
2H), 7.57 (d, J = 8.4 Hz, 2H), 7.60−7.65 (m, 1H), 7.91 (d, J = 7.6 Hz,
1H), 7.98 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 183.6
tert-Butyl 2-(3,4-dichlorophenyl)-3-fluoro-4-oxo-1-tosyl-1,2,3,4-
tetrahydroquinoline-3-carboxylate (2p): white solid; 142.2 mg,
84% yield; 85:15 dr; mp 155−156 °C; 1H NMR (400 MHz,
CDCl3) δ 1.09 (s, 9H), 2.36 (s, 3H), 6.05 (d, J = 20.8 Hz, 1H), 7.06
(dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.18−7.22 (m, 3H), 7.31−7.35 (m, 2H),
7.56 (d, J = 8.0 Hz, 2H), 7.66−7.70 (m, 1H), 7.91 (dd, J = 7.6 Hz, 1.2
Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
2
2
(d, JCF = 20.1 Hz), 162.6 (d, JCF = 26.2 Hz), 144.9, 140.7, 136.3,
134.9, 134.8, 134.5, 131.8, 129.8, 129.6, 128.5, 127.8, 125.8, 124.1,
123.8, 123.1, 92.4 (d, 1JCF = 194.1 Hz), 84.8, 65.4 (d, 2JCF = 27.5 Hz),
27.2, 21.5; 19F NMR (376 MHz, CDCl3) δ −141.9 (d, J = 20.7 Hz),
−169.1; IR (KBr) ν 2981, 2932, 1755, 1697, 1651, 1633, 1457, 1371,
1165, 1088, 668, 571 cm−1; MS (ESI) found m/z 591.1 [M + NH4]+;
HRMS (ESI) found m/z 596.0529 [M + Na]+, calcd for
C27H25BrFNO5S + Na 596.0519.
2
2
183.4 (d, JCF = 19.7 Hz), 162.4 (d, JCF = 26.5 Hz), 145.1, 140.6,
136.3, 133.3, 132.7, 130.6, 130.2, 129.7, 128.5, 127.8, 127.4, 127.1,
126.0, 124.0, 118.8, 92.5 (d, 1JCF = 195.5 Hz), 85.1, 64.8 (d, 2JCF = 28.3
Hz), 27.2, 21.5; 19F NMR (376 MHz, CDCl3) δ −142.2 (d, J = 21.1
Hz), −169.0; IR (KBr) ν 2981, 2933, 1756, 1699, 1599, 1473, 1458,
1354, 1306, 1287, 1169, 666, 572 cm−1; MS (ESI) found m/z 581.0
[M + NH4]+; HRMS (ESI) found m/z 586.0627 [M + Na]+, calcd for
C27H24Cl2FNO5S + Na 586.0634.
tert-Butyl 2-(2-chlorophenyl)-3-fluoro-4-oxo-1-tosyl-1,2,3,4-tetra-
hydroquinoline-3-carboxylate (2l): white solid; 136.7 mg, 86% yield;
87:13 dr; mp 52−53 °C; 1H NMR (400 MHz, CDCl3) δ 1.14 (s, 9H),
2.35 (s, 3H), 6.98−7.03 (m, 2H), 7.19−7.31 (m, 5H), 7.42 (d, J = 8.0
Hz, 1H), 7.66 (t, J = 8.0 Hz, 3H), 7.98 (dd, J = 8.0 Hz, 1.6 Hz, 1H),
8.03 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 183.3 (d,
tert-Butyl 2-(3,5-bis(trifluoromethyl)phenyl)-3-fluoro-4-oxo-1-
tosyl-1,2,3,4-tetrahydroquinoline-3-carboxylate (2q): white solid;
166.7 mg, 88% yield; 70:30 dr; mp 157−158 °C; 1H NMR (400 MHz,
CDCl3) δ 0.96 (s, 9H), 2.38 (s, 3H), 6.16 (d, J = 21.6 Hz, 1H), 7.21
(d, J = 8.0 Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H),
7.72−7.77 (m, 3H), 7.87 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz, 1H);
2
2JCF = 20.7 Hz), 162.5 (d, JCF = 25.5 Hz), 144.8, 141.8, 136.4, 134.4,
130.0, 129.9, 129.7, 129.6, 128.9, 127.9, 127.1, 125.2, 122.8, 122.6, 92.0
1
2
2
(d, JCF = 195.1 Hz), 84.4, 61.5 (d, JCF = 29.1 Hz), 27.5, 21.5; 19F
13C NMR (100 MHz, CDCl3) δ 183.5 (d, JCF = 19.4 Hz), 162.0 (d,
2403
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2JCF = 26.8 Hz), 145.4, 140.5, 139.0, 138.9, 136.4, 133.4, 132.2 (q, JCF
7.34 (d, J = 8.0 Hz, 2H), 7.47−7.54 (m, 2H), 7.89 (d, J = 8.4 Hz, 2H),
8.02 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 186.8 (d,
= 33.5 Hz), 129.8, 128.3, 127.9, 127.8, 126.7, 125.3, 124.9, 124.1,
122.8, 121.4, 93.0 (d, 1JCF = 198.2 Hz), 85.4, 64.9 (d, 2JCF = 29.3 Hz),
26.9, 21.5; 19F NMR (376 MHz, CDCl3) δ −142.2 (d, J = 21.8 Hz),
−6.31; IR (KBr) ν 2981, 2931, 1762, 1717, 1600, 1462, 1372, 1352,
1279, 1229, 1167, 1138, 681, 665 cm−1; MS (ESI) found m/z 649.1
[M + NH4]+; HRMS (ESI) found m/z 654.1148 [M + Na]+, calcd for
C29H24F7NO5S + Na 654.1161.
2
2JCF = 17.1 Hz), 164.6 (d, JCF = 26.2 Hz), 144.7, 140.1, 137.1, 135.2,
1
129.9, 127.9, 127.8, 124.1, 123.9, 121.2, 93.2 (d, JCF = 202.1 Hz),
2
85.7, 60.7 (d, JCF = 26.9 Hz), 29.9, 27.6, 21.5, 19.8, 13.8; 19F NMR
(376 MHz, CDCl3) δ −170.1 (d, J = 1.5 Hz); IR (KBr) ν 2966, 2934,
2875, 1758, 1709, 1600, 1460, 1369, 1300, 1167, 1087, 659, 574 cm−1;
MS (ESI) found m/z 479.2 [M + NH4]+; HRMS (ESI) found m/z
484.1578 [M + Na]+, calcd for C24H28FNO5S + Na 484.1570.
Ethyl 3-fluoro-4-oxo-2-phenyl-1-tosyl-1,2,3,4-tetrahydroquino-
line-3-carboxylate (2w): white solid; 133.2 mg, 95% yield; 93:7 dr;
tert-Butyl 3-fluoro-2-(naphthalen-2-yl)-4-oxo-1-tosyl-1,2,3,4-tet-
rahydroquinoline-3- carboxylate (2r): white solid; 158.7 mg, 97%
yield; 94:6 dr; mp 79−80 °C; 1H NMR (400 MHz, CDCl3) δ 0.88 (s,
9H), 2.30 (s, 3H), 6.39 (d, J = 21.2 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H),
7.20−7.22 (m, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.457.48 (m, 2H), 7.62−
7.70 (m, 4H), 7.72−7.77 (m, 3H), 7.99−8.04 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 183.9 (d, 2JCF = 19.9 Hz), 163.0 (d, 2JCF = 26.5
Hz), 144.7, 141.2, 136.3, 134.8, 133.2, 132.9, 129.6, 128.6, 128.5,
128.2, 128.1, 127.8, 127.5, 126.8, 126.6, 125.6, 124.9, 124.2, 123.8, 92.7
1
mp 87−88 °C; H NMR (400 MHz, CDCl3) δ 0.81 (t, J = 7.2 Hz,
3H), 2.33 (s, 3H), 3.74−3.82 (m, 1H), 3.91−3.99 (m, 1H), 6.25 (d, J
= 20.4 Hz, 1H), 7.13−7.24 (m, 6H), 7.27−7.31 (m, 2H), 7.62−7.66
(m, 3H), 7.98−8.02 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 183.1
2
2
(d, JCF = 20.0 Hz), 164.5 (d, JCF = 25.9 Hz), 144.7, 141.2, 136.5,
135.0, 134.9, 134.8, 129.6, 129.1, 128.9, 128.7, 127.9, 125.4, 123.2, 92.7
1
2
(d, JCF = 193.1 Hz), 84.5, 66.4 (d, JCF = 27.0 Hz), 27.0, 21.5; 19F
NMR (376 MHz, CDCl3) δ −141.1 (d, J = 21.4 Hz), −168.9; IR
(KBr) ν 2980, 2931, 1753, 1698, 1598, 1458, 1368, 1299, 1165, 1061,
662, 570 cm−1; MS (ESI) found m/z 563.2 [M + NH4]+; HRMS (ESI)
found m/z 568.1573 [M + Na]+, calcd for C31H28FNO5S + Na
568.1570.
1
2
(d, JCF = 193.7 Hz), 66.1 (d, JCF = 26.2 Hz), 62.4, 21.5, 13.2; 19F
NMR (376 MHz, CDCl3) δ −142.4 (d, J = 20.3 Hz), −169.2; IR
(KBr) ν 2982, 2926, 1757, 1697, 1596, 1457, 1359, 1294, 1166, 1085,
697, 569 cm−1; MS (ESI) found m/z 490.1 [M + Na]+; HRMS (ESI)
found m/z 490.1100 [M + Na]+, calcd for C25H22FNO5S + Na
490.1100.
tert-Butyl 3-fluoro-2-(furan-2-yl)-4-oxo-1-tosyl-1,2,3,4-tetrahy-
tert-Butyl 3-fluoro-6,7-dimethoxy-4-oxo-2-phenyl-1-tosyl-1,2,3,4-
droquinoline-3-carboxylate (2s): white solid; 123.8 mg, 85% yield;
tetrahydroquinoline-3-carboxylate (2x): white solid; 143.3 mg, 86%
1
1
99:1 dr; mp 159−160 °C; H NMR (400 MHz, CDCl3) δ 1.28 (s,
yield; 99:1 dr; mp 185−186 °C; H NMR (400 MHz, CDCl3) δ 1.04
9H), 2.33 (s, 3H), 6.24 (d, J = 3.2 Hz, 1H), 7.27 (d, J = 1.6 Hz, 1H),
6.38 (d, J = 14.4 Hz, 1H), 7.17−7.24 (m, 4H), 7.53−7.57 (m, 1H),
7.66 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.98−8.00 (m, 1H);
(s, 9H), 2.36 (s, 3H), 3.93 (s, 3H), 3.99 (s, 3H), 6.09 (d, J = 20.8 Hz,
1H), 7.15−7.20 (m, 4H), 7.25 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.2 Hz,
1H), 7.38 (s, 1H), 7.54 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H); 13C NMR
2
13C NMR (100 MHz, CDCl3) δ 182.9 (d, JCF = 20.1 Hz), 162.9 (d,
2
(100 MHz, CDCl3) δ 182.1 (d, 2JCF = 20.1 Hz), 163.5 (d, JCF = 26.2
2JCF = 25.5 Hz), 148.0, 147.9, 144.6, 142.9, 140.6, 135.9, 135.3, 129.5,
Hz), 155.7, 147.2, 144.6, 136.8, 135.7, 135.6, 135.0, 128.5, 129.0,
1
1
128.7, 128.4, 127.8, 117.0, 108.7, 106.7, 92.1 (d, JCF = 191.6 Hz),
128.8, 127.9, 124.9, 122.7, 122.1, 110.5, 110.2, 90.5 (d, JCF = 192.9
2
84.2, 66.7 (d, JCF = 26.8 Hz), 56.5, 56.1, 27.1, 21.5; 19F NMR (376
2
Hz), 84.3, 59.1 (d, JCF = 27.8 Hz), 27.5, 21.5; 19F NMR (376 MHz,
MHz, CDCl3) δ −138.7 (d, J = 20.7 Hz), −168.9; IR (KBr) ν 2980,
2932, 1750, 1683, 1602, 1508, 1455, 1419, 1274, 1164, 1087, 661, 570
cm−1; MS (ESI) found m/z 578.1 [M + Na]+; HRMS (ESI) found m/
z 578.1623 [M + Na]+, calcd for C29H30FNO7S + Na 578.1625.
tert-Butyl 7-chloro-3-fluoro-4-oxo-2-phenyl-1-tosyl-1,2,3,4-tetra-
hydroquinoline-3-carboxylate (2y): white solid; 146.2 mg, 92% yield;
CDCl3) δ −148.1 (d, J = 14.7 Hz); IR (KBr) ν 2982, 2933, 1754,
1700, 1599, 1477, 1459, 1368, 1302, 1166, 1085, 664, 568 cm−1; MS
(ESI) found m/z 508.0 [M + Na]+; HRMS (ESI) found m/z 508.1204
[M + Na]+, calcd for C25H24FNO6S + Na 508.1206.
tert-Butyl 3-fluoro-4-oxo-2-(thiophene-2-yl)-1-tosyl-1,2,3,4-tetra-
hydroquinoline-3-carboxylate (2t): white solid; 135.4 mg, 90% yield;
1
1
98:2 dr; mp 150−151 °C; H NMR (400 MHz, CDCl3) δ 1.06 (s,
98:2 dr; mp 147−148 °C; H NMR (400 MHz, CDCl3) δ 1.17 (s,
9H), 2.34 (s, 3H), 6.20 (d, J = 19.6 Hz, 1H), 7.16−7.27 (m, 7H), 7.33
(t, J = 7.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.8 Hz, 1H),
8.02 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 182.5 (d,
9H), 2.32 (s, 3H), 6.56 (d, J = 16.0 Hz, 1H), 6.90 (dd, J = 5.2 Hz, 4.0
Hz, 1H), 7. 01 (d, J = 2.8 Hz, 1H), 7.14−7.18 (m, 3H), 7.30 (t, J = 7.6
Hz, 1H), 7.59−7.64 (m, 3H), 7.92 (d, J = 8.4 Hz, 1H), 7.98−8.00 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 183.2 (d, 2JCF = 19.6 Hz), 162.9
2
2JCF = 20.5 Hz), 162.7 (d, JCF = 25.8 Hz), 145.1, 142.8, 141.9, 135.2,
2
135.1, 134.6, 129.9, 129.7, 129.3, 128.9, 128.2, 127.9, 125.7, 122.8,
(d, JCF = 25.8 Hz), 144.6, 140.2, 136.3, 136.1, 136.0, 135.4, 129.6,
1
2
1
121.6, 91.7 (d, JCF = 191.9 Hz), 84.6, 66.3 (d, JCF = 26.3 Hz), 27.2,
21.5; 19F NMR (376 MHz, CDCl3) δ −142.0 (d, J = 19.9 Hz),
−169.8; IR (KBr) ν 2981, 2932, 1753, 1702, 1592, 1456, 1417, 1370,
1305, 1168, 1083, 1057, 666, 571 cm−1; MS (ESI) found m/z 552.1
[M + Na]+; HRMS (ESI) found m/z 552.1027 [M + Na]+, calcd for
C27H25ClFNO5S + Na 552.1024.
129.0, 128.9, 127.8, 126.5, 126.1, 125.7, 123.7, 123.6, 91.7 (d, JCF
=
193.0 Hz), 84.4, 61.9 (d, JCF = 28.1 Hz), 27.3, 21.5; 19F NMR (376
MHz, CDCl3) δ −144.0 (d, J = 4.2 Hz), −167.7; IR (KBr) ν 2979,
2932, 1751, 1699, 1598, 1459, 1361, 1299, 1165, 1088, 660, 563 cm−1;
MS (ESI) found m/z 524.0 [M + Na]+; HRMS (ESI) found m/z
524.0972 [M + Na]+, calcd for C25H24FNO5S2 + Na 524.0978.
tert-Butyl 2-ethyl-3-fluoro-4-oxo-1-tosyl-1,2,3,4-tetrahydroqui-
noline-3-carboxylate (2u): white solid; 107.4 mg, 80% yield; 98:2
2
tert-Butyl 3,6-difluoro-4-oxo-2-phenyl-1-tosyl-1,2,3,4-tetrahydro-
quinoline-3-carboxylate (2z): white solid; 149.4 mg, 97% yield; 99:1
1
1
dr; mp 140−141 °C; H NMR (400 MHz, CDCl3) δ 1.00 (s, 9H),
dr; mp 145−146 °C; H NMR (400 MHz, CDCl3) δ 0.74 (t, J = 7.6
2.34 (s, 3H), 6.12 (d, J = 21.6 Hz, 1H), 7.15−7.19 (m, 4H), 7.25 (t, J
= 7.6 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 7.34−7.39 (m, 1H), 7.55 (d, J
= 8.0 Hz, 2H), 7.59 (dd, J = 8.0 Hz, 3.2 Hz, 1H), 8.02 (dd, J = 9.2 Hz,
Hz, 3H), 1.38−1.44 (m, 11H), 2.43 (s, 3H), 5.07 (dd, J = 9.6 Hz, 4.4
Hz, 1H), 7.15−7.19 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.49−7.55 (m,
2H), 7.91 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 7.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 186.8 (d, 2JCF = 17.3 Hz), 164.6 (d, 2JCF = 26.2
Hz), 144.7, 140.0, 137.1, 135.2, 129.9, 127.8, 124.2, 124.0, 121.3, 93.2
2
4.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 183.3 (d, JCF = 20.3
Hz), 162.6 (d, 2JCF = 26.3 Hz), 160.0 (d, JCF = 247.8 Hz), 144.9, 137.3
(d, JCF = 2.5 Hz), 135.5 (d, JCF = 8.8 Hz), 134.4, 129.7, 129.1, 128.8,
128.1, 127.8, 126.8 (d, JCF = 7.3 Hz), 126.1 (d, JCF = 6.6 Hz), 123.4 (d,
1
2
(d, JCF = 202.1 Hz), 85.7, 62.1 (d, JCF = 26.5 Hz), 27.7, 21.5, 20.7,
10.9; 19F NMR (376 MHz, CDCl3) δ −170.3 (d, J = 3.8 Hz), −145.3
(d, J = 16.2 Hz); IR (KBr) ν 2978, 2934, 2879, 1756, 1707, 1601,
1477, 1459, 1361, 1292, 1166, 1087, 659, 574 cm−1; MS (ESI) found
m/z 465.2 [M + NH4]+; HRMS (ESI) found m/z 470.1418 [M +
Na]+, calcd for C23H26FNO5S + Na 470.1413.
1
JCF = 23.0 Hz), 114.2 (d, JCF = 21.4 Hz), 92.5 (d, JCF = 193.5 Hz),
2
84.7, 66.3 (d, JCF = 27.0 Hz), 27.1, 21.5; 19F NMR (376 MHz,
CDCl3) δ −140.3 (d, J = 5.7 Hz), −169.4, −114.1, −118.1; IR (KBr) ν
2981, 2932, 1755, 1702, 1485, 1436, 1370, 1307, 1156, 1067, 659, 592
cm−1; MS (ESI) found m/z 536.0 [M + Na]+; HRMS (ESI) found m/
z 536.1312 [M + Na]+, calcd for C27H25F2NO5S + Na 536.1319.
tert-Butyl 3-chloro-4-oxo-2-phenyl-1-tosyl-1,2,3,4-tetrahydroqui-
noline-3-carboxylate (5): 142.8 mg, 93% yield; >99:1 dr; mp 160−
tert-Butyl 3-fluoro-4-oxo-2-propyl-1-tosyl-1,2,3,4-tetrahydroqui-
noline-3-carboxylate (2v): white solid; 99.7 mg, 72% yield; 99:1 dr;
1
mp 133−134 °C; H NMR (400 MHz, CDCl3) δ 0.74 (t, J = 7.2 Hz,
3H), 1.15−1.29 (m, 2H), 1.34−1.42 (m, 10H), 1.71−1.79 (m, 1H),
2.42 (s, 3H), 5.15 (dd, J = 9.2 Hz, 4.8 Hz, 1H), 7.14−7.18 (m, 1H),
1
161 °C; H NMR (400 MHz, CDCl3) δ (ppm) 1.12 (s, 9H), 2.31 (s,
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Article
3H), 6.32 (s, 1H), 7.16−7.19 (m, 7H), 7.28 (d, J = 5.6 Hz, 1H), 7.46−
7.50 (m, 1H), 7.64−7.69 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 182.4, 162.9, 144.7, 140.3, 136.3, 136.2, 135.8, 129.6, 129.4,
128.9, 128.3, 127.8, 127.6, 122.9, 121.2, 117.9, 85.5, 68.4, 67.0, 27.3,
21.4; IR (KBr) ν 2982, 2931, 1748, 1696, 1598, 1478, 1456, 1358,
1279, 1164, 1087, 1027, 658, 568 cm−1; MS (ESI) found m/z 534.1
[M + Na]+; HRMS (ESI) found m/z 534.1117 [M + Na]+, calcd for
C27H26ClNO5S + Na 534.1118.
2a and 4 (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: majun_an68@tju.edu.cn.
■
Notes
tert-Butyl 3-bromo-4-oxo-2-phenyl-1-tosyl-1,2,3,4-tetrahydro-
The authors declare no competing financial interest.
quinoline-3-carboxylate (6): 150.2 mg, 90% yield; >99:1 dr; mp
1
178−179 °C; H NMR (400 MHz, CDCl3) δ (ppm) 1.40 (s, 9H),
ACKNOWLEDGMENTS
2.32 (s, 3H), 6.69 (s, 1H), 7.08 (d, J = 8.0 Hz, 2H), 7.11−7.15 (m,
1H), 7.21−7.23 (m, 4H), 7.31−7.37 (m, 3H), 7.40−7.46 (m, 2H),
8.07−8.09 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 183.2,
165.2, 144.5, 140.9, 136.5, 135.4, 134.7, 129.6, 129.4, 129.0, 128.8,
128.7, 127.6, 122.9, 121.2, 117.9, 85.5, 68.4, 67.0, 27.3, 21.4; IR (KBr)
ν 2981, 2931, 1732, 1715, 1598, 1456, 1359, 1255, 1186, 936, 663, 567
cm−1; MS (ESI) found m/z 573.1 [M + NH4]+; HRMS (ESI) found
m/z 578.0621 [M + Na]+, calcd for C27H26BrNO5S + Na 578.0613.
Procedure for the Decarboxylation of Sequential Product. p-
Toluenesulfonic acid (17.3 mg, 0.1 mmol) was added to a solution of
tert-butyl 3-fluoro-4-oxo-2-phenyl-1-tosyl-1,2,3,4-tetrahydroquinoline-
3-carboxylate 2a (49.6 mg, 0.1 mmol) in toluene (10 mL), and the
solution was heated at 80 °C for 24 h. The mixture was then allowed
to cool to room temperature, diluted with EtOAc (15 mL), and
washed with brine. The combined organic layers were dried over
anhydrous Na2SO4. After concentration, the residue was purified by
flash column chromatography (petroleum ether/EtOAc 10/1) to
afford 3 (38.8 mg, 98% yield, 70:30 dr) as a pale yellow solid: mp
■
We gratefully appreciate the National Natural Science
Foundation of China (NSFC) (Nos. 20772091, 20972110,
and 20902067) for financial support.
REFERENCES
■
(1) For recent reviews, see: (a) Zhu, S. Z.; Wang, Y.; Peng, W.; Song,
L. P.; Jin, G. F. Curr. Org. Chem. 2002, 6, 1057. (b) He, P.; Zhu, S. Z.
Mini-Rev. Org. Chem. 2004, 1, 417;(c) Special Issue on “Fluorine in
the Life Sciences”. ChemBioChem 2004, 5, 557. (d) Chambers, R. D.
Fluorine in Organic Chemistry; Blackwell: Oxford, U.K., 2004.
(e) Meng, W.-D.; Qing, F.-L. Curr. Top. Med. Chem. 2006, 6, 1499.
(f) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303.
(g) Sandford, G. J. Fluorine Chem. 2007, 128, 90. (h) Kirk, K. L. Org.
Process Res. Dev. 2008, 12, 305. (i) Purser, S.; Moore, P. R.; Swallowb,
S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(2) For recent reviews, see: (a) Nicolaou, K. C.; Montagnon, T.;
Snyder, S. A. Chem. Commun. 2003, 551. (b) Fogg, D. E.; dos Santos,
E. N. Coord. Chem. Rev. 2004, 248, 9456. (c) Lee, J. M.; Na, Y.; Han,
H.; Chang, S. Chem. Soc. Rev. 2004, 33, 302. (d) Wasilke, J.-C.; Obrey,
S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001.
1
166−167 °C; H NMR (400 MHz, CDCl3) δ (ppm) 2.43 (s, 3H),
5.20 (dd, J = 46.0 Hz, 6.0 Hz, 1H), 6.22 (d, J = 8.0 Hz, 1H), 7.21−7.24
(m, 4H), 7.28−7.31 (m, 4H), 7.57 (t, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0
Hz, 2H), 7.91 (t, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
2
(e) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
́
(ppm) 188.8 (d, JCF = 14.0 Hz), 145.2, 140.2, 136.4, 135.7, 133.2,
(f) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int.
Ed. 2006, 45, 7134. (g) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed.
130.3, 128.6, 128.5, 127.8, 127.7, 126.9, 125.8, 124.5, 124.1, 88.8 (d,
1JCF = 200.0 Hz), 61.4 (d, 2JCF = 22.2 Hz), 21.6; 19F NMR (376 MHz,
CDCl3) δ −197.7 (d, J = 45.9 Hz), −179.4 (dd, J = 46.6 Hz, 13.9 Hz);
IR (KBr) ν 2893, 1702, 1598, 1476, 1459, 1351, 1164, 1089, 1057,
662, 569 cm−1; MS (ESI) found m/z 418.1 [M + Na]+; HRMS (ESI)
found m/z 418.0888 [M + Na]+, calcd for C22H18FNO3S + Na
418.0889.
2006, 45, 354. (h) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew.
̈
Chem., Int. Ed. 2007, 46, 1570. (i) Tietze, L. F.; Kinzel, T.; Brazel, C.
C. Acc. Chem. Res. 2009, 42, 367. (j) Albrecht, Ł.; Jiang, H.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2011, 50, 8492. (k) Climent, M. J.; Corma,
A.; Iborra, S. Chem. Rev. 2011, 111, 1072.
(3) For step-economy in organic synthesis, see: (a) Wender, P. A.;
Croatt, M. P.; Witulski, B. Tetrahedron 2006, 62, 7505. (b) Wender, P.
A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41,
40.
Procedure for the Reduction of Sequential Product. To a
solution of 2a (99.2 mg, 0.2 mmol) in 3 mL of MeOH was added
NaBH4 (76 mg, 2.0 mmol) in portions at 0 °C. The resultant mixture
was stirred overnight at room temperature (monitored by TLC). The
mixture was evaporated in vacuum. The residue was treated with water
(10 mL), and extracted with dichloromethane (10 mL × 3). The
organic layer was washed with brine and dried over MgSO4.
Concentration and flash chromatography (petroleum ether/ethyl
acetate 10/1 as eluant) afforded 4 (95.6 mg, 96% yield, >99:1 dr)
(4) For recent reviews, see: (a) Wilkinson, S. C.; Salmon, R.;
Gouverneur, V. Future Med. Chem 2009, 1, 847. (b) Zhu, S. Z.; Song,
L. P.; Jin, G. F.; Dai, B. F.; Hao, J. Curr. Org. Chem. 2009, 13, 1015.
For selected recent examples, see: (c) Lourie, L. F.; Serguchev, Y. A.;
Shevchenko, G. V.; Ponomarenko, M. V.; Chernega, A. N.; Rusanov,
E. B.; Howard, J. A. K. J. Fluorine Chem. 2006, 127, 377. (d) Cui, H.-F.;
Dong, K.-Y.; Zhang, G.-W.; Wang, L.; Ma, J.-A. Chem. Commun. 2007,
2284. (e) Nie, J.; Zhu, H.-W.; Cui, H.-F.; Hua, M.-Q.; Ma, J.-A. Org.
Lett. 2007, 9, 3053. (f) Vardelle, E.; Gamba-Sanchez, D.; Martin-
Mingot, A.; Jouannetaud, M.-P.; Thibaudeau, S.; Marrot, J. Chem.
Commun. 2008, 1473. (g) Kishi, Y.; Nagura, H.; Inagi, S.; Fuchigami,
T. Chem. Commun. 2008, 3876. (h) Zhou, C.; Ma, Z.; Gu, Z.; Fu, C.;
Ma, S. J. Org. Chem. 2008, 73, 772. (i) Rudler, H.; Parlier, A.; Hamon,
L.; Herson, P.; Daran, J.-C. Chem. Commun. 2008, 4150. (j) Schuler,
M.; Silva, F.; Bobbio, C.; Tessier, A.; Gouverneur, V. Angew. Chem., Int.
Ed. 2008, 47, 7927. (k) Cui, H.; Li, P.; Chai, Z.; Zheng, C.; Zhao, G.;
Zhu, S. J. Org. Chem. 2009, 74, 1400. (l) Wu, T.; Yin, G.; Liu, G. J. Am.
Chem. Soc. 2009, 131, 16354. (m) Kishi, Y.; Inagi, S.; Fuchigami, T.
Eur. J. Org. Chem. 2009, 103. (n) Wang, H.-F.; Cui, H.-F.; Chai, Z.; Li,
P.; Zheng, C.-W.; Yang, Y.-Q.; Zhao, G. Chem.Eur. J. 2009, 15,
13299. (o) Wilkinson, S. C.; Lozano, O.; Schuler, M.; Pacheco, M. C.;
Salmon, R.; Gouverneur, V. Angew. Chem., Int. Ed. 2009, 48, 7083.
(p) Cui, H.-F.; Yang, Y.-Q.; Chai, Z.; Li, P.; Zheng, C.-W.; Zhu, S.-Z.;
Zhao, G. J. Org. Chem. 2010, 75, 117. (q) Lozano, O.; Blessley, G.;
Campo, T. M.; Thompson, A. L.; Giuffredi, G. T.; Bettati, M.; Walker,
1
as a white solid: mp 193−194 °C; H NMR (400 MHz, CDCl3) δ
(ppm) 0.59 (s, 9H), 2.41 (s, 3H), 2.85 (d, J = 3.6 Hz, 1H), 3.93 (d, J =
13.2 Hz, 2.8 Hz, 1H), 5.73 (d, J = 30.4 Hz, 1H), 7.21−7.26 (m, 3H),
7.30−7.37 (m, 3H), 7.41−7.49 (m, 6H), 7.95 (d, J = 8.0 Hz, 1H); 13C
2
NMR (100 MHz, CDCl3) δ (ppm) 163.5 (d, JCF = 31.7 Hz), 144.3,
3
138.5, 135.3, 134.5, 132.5 (q, JCF = 6.0 Hz), 129.8, 128.3, 128.1,
127.7, 127.1, 127.0, 126.1, 124.0, 102.5 (d, 1JCF = 191.7 Hz), 82.7, 70.7
2
2
(q, JCF = 23.9 Hz), 64.6 (d, JCF = 31.2 Hz), 26.6, 21.6; 19F NMR
(376 MHz, CDCl3) δ (ppm) −197.7 (d, J = 46.2 Hz), −179.4 (dd, J =
47.0 Hz, 14.7 Hz); IR (KBr) ν 3442, 2918, 2850, 1727, 1496, 1458,
1361, 1157, 666, 567 cm−1; MS (ESI) found m/z 515.2 [M + NH4]+;
HRMS (ESI) found m/z 520.1571 [M + Na]+, calcd for C27H28FNO5S
+ Na 520.1570.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, and 19F NMR spectra for intermediates 1a−e and the
products 2a−z and 3−6. Crystallographic data for compounds
2405
dx.doi.org/10.1021/jo202693x | J. Org. Chem. 2012, 77, 2398−2406

The Journal of Organic Chemistry
Article
M.; Borman, R.; Gouverneur, V. Angew. Chem., Int. Ed. 2011, 50, 8105.
(r) Lin, R.; Ding, S.; Shi, Z.; Jiao, N. Org. Lett. 2011, 13, 4498. (s) Xu,
T.; Mu, X.; Peng, H.; Liu, G. Angew. Chem., Int. Ed. 2011, 50, 8176.
(5) For a review, see: (a) Wagman, A. S.; Wentland, M. P. In
Comprehensive Medicinal Chemistry II; Taylor, J. B., Triggle, D. J., Eds.;
Elsevier: Amsterdam, 2006; Vol. 7, pp 567−596. For selected
examples, see: (b) Beifuss, U.; Feder, G.; Bes, T.; Uson, I. Synlett 1998,
649. (c) Chen, W.; Egar, A. L.; Hursthouse, M. B.; Malik, K. M. A.;
Mathews, J. E.; Roberts, S. M. Tetrahedron Lett. 1998, 39, 8495.
(d) Xia, Y.; Yang, Z.-Y.; Xia, P.; Bastow, K. F.; Tachibana, Y.; Kuo, S.-
C.; Hamel, E.; Hackl, T.; Lee, K.-H. J. Med. Chem. 1998, 41, 1155.
(e) Zhang, S.-X.; Kuo, S.-C.; Brossi, A.; Hamel, E.; Tropsha, A.; Lee,
K.-H. J. Med. Chem. 2000, 43, 167.
Melchiorre, P.; Sambri, L. Angew. Chem., Int. Ed. 2005, 44, 6219.
(g) Meshram, H. M.; Reddy, P. N.; Sadashiv, K.; Yadav, J. S.
Tetrahedron Lett. 2005, 46, 623. (h) Meshram, H. M.; Reddy, P. N.;
Vishnu, P.; Sadashiv, K.; Yadav, J. S. Tetrahedron Lett. 2006, 47, 991.
(i) Mei, Y.; Bentley, P. A.; Du, J. Tetrahedron Lett. 2008, 49, 3802.
(j) Mei, Y.; Bentley, P. A.; Du, J. Tetrahedron Lett. 2008, 49, 3802.
(k) Cui, H.-F.; Dong, K.-Y.; Nie, J.; Zheng, Y.; Ma, J.-A. Tetrahedron
Lett. 2010, 51, 2374.
(6) For selected examples, see: (a) Nieman, J. A.; Ennis, M. D. J. Org.
Chem. 2001, 66, 2175. (b) Cheng, D.; Zhou, J.; Saiah, E.; Beaton, G.
Org. Lett. 2002, 4, 4411. (c) Ma, D.; Xia, C.; Jiang, J.; Zhang, J.; Tang,
W. J. Org. Chem. 2003, 68, 442. (d) Kumar, K. H.; Muralidharan, D.;
Perumal, P. T. Synthesis 2004, 63. (e) Shintani, R.; Yamagami, T.;
Kimura, T.; Hayashi, T. Org. Lett. 2005, 7, 5317. (f) Naseem Ahmed,
N.; van Lier, J. E. Tetrahedron Lett. 2006, 47, 2725. (g) Kasiotis, K. M.;
Fokialakis, N.; Haroutounian, S. A. Synthesis 2006, 1791. (h) Lee, J. I.;
Jung, H. J. J. Korean Chem. Soc. 2007, 51, 106. (i) Larghi, E. L.; Obrist,
B. V.; Kaufman, T. S. Tetrahedron 2008, 64, 5236. (j) Yoshitomi, Y.;
Arai, H.; Makino, K.; Hamada, Y. Tetrahedron 2008, 64, 11568.
(k) Lei, B.-L.; Ding, C.-H.; Yang, X.-F.; Wan, X.-L.; Hou, X.-L. J. Am.
Chem. Soc. 2009, 131, 18250. (l) Zhao, T.; Xu, B. Org. Lett. 2010, 12,
212. (m) Liu, X.; Lu, Y. Org. Lett. 2010, 12, 5592. (n) Saito, A.; Kasai,
J.; Konishi, T.; Hanzawa, Y. J. Org. Chem. 2010, 75, 6980.
(7) (a) Nemoto, T.; Fukuda, T.; Hamada, Y. Tetrahedron Lett. 2006,
47, 4365. (b) Ye, F.; Alper, H. J. Org. Chem. 2007, 72, 3218.
(8) (a) Chandrasekhar, S.; Vijeender, K.; Sridhar, C. Tetrahedron Lett.
2007, 48, 4935. (b) Liu, X.; Lu, Y. Org. Biomol. Chem. 2010, 8, 4063.
(9) (a) Saito, A.; Kasai, J.; Odaira, Y.; Fukaya, H.; Hanzawa, Y. J. Org.
Chem. 2009, 74, 5644. (b) Okamoto, N.; Takeda, K.; Ishikura, M.;
Yanada, R. J. Org. Chem. 2011, 76, 9139.
(10) For recent reviews, see: (a) Ma, J.-A.; Cahard, D. J. Fluorine
Chem. 2007, 128, 975. (b) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108,
PR1. (c) Zheng, Y.; Ma, J.-A. Adv. Synth. Catal. 2010, 352, 2745.
(d) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111,
455. For selected recent examples, see: (e) Zhang, G.-W.; Wang, L.;
Nie, J.; Ma, J.-A. Adv. Synth. Catal. 2008, 350, 1457. (f) Nie, J.; Zhang,
G.-W.; Wang, L.; Fu, A.; Zheng, Y.; Ma, J.-A. Chem. Commun. 2009,
2356. (g) Nie, J.; Zhang, G.-W.; Wang, L.; Zheng, D.-H.; Zheng, Y.;
Ma, J.-A. Eur. J. Org. Chem. 2009, 3145. (h) Pei, Z.-K.; Zheng, Y.; Nie,
J.; Ma, J.-A. Tetrahedron Lett. 2010, 51, 4658. (i) Wang, T.; Zhang, G.-
W.; Teng, Y.; Nie, J.; Zheng, Y.; Ma, J.-A. Adv. Synth. Catal. 2010, 352,
2773. (j) Cui, H.-F.; Wang, L.; Yang, L.-J.; Nie, J.; Zheng, Y.; Ma, J.-A.
Tetrahedron 2011, 67, 8470. (k) Nie, J.; Li, X.-J.; Zheng, D.-H.; Zhang,
F.-G.; Cui, S.; Ma, J.-A. J. Fluorine Chem. 2011, 132, 468. (l) Wang, L.;
Meng, W.; Zhu, C.-L.; Zheng, Y.; Nie, J.; Ma, J.-A. Angew. Chem., Int.
Ed. 2011, 50, 9442.
(11) The use of inorganic bases, such as LiOH, NaOH, Li2CO3,
Na2CO2, and K2CO2, failed to give any intermediates (A, B, or C)
under the present conditions.
(12) The relative configuration of compounds 2a and 4 was
confirmed by X-ray crystal structure analysis. CCDC 844931 (2a) and
CCDC 846735 (4) contain the supplementary crystallographic data
for this paper (see the Supporting Information). These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(13) For one-pot multistep syntheses of chlorinated and brominated
carbonyl compounds, see: (a) Yang, D.; Yan, Y.-L.; Lui, B. J. Org.
Chem. 2002, 67, 7429. (b) Marigo, M.; Bachmann, S.; Halland, N.;
Braunton, A.; Jørensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 5507.
(c) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc.
2004, 126, 4108. (d) Halland, N.; Lie, M. A.; Kjæsgaard, A.; Marigo,
M.; Schiøt, B.; Jørgensen, K. A. Chem.Eur. J. 2005, 11, 7083.
(e) Meketa, M. L.; Mahajan, Y. R.; Weinreb, S. M. Tetrahedron Lett.
2005, 46, 4749. (f) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.;
2406
dx.doi.org/10.1021/jo202693x | J. Org. Chem. 2012, 77, 2398−2406