C5-Regioselective C-H fluorination of 8-aminoquinoline amides and sulfonamides with Selectfluor under metal-free conditions

Article abstract of DOI:10.1039/c7ob03059b

A novel and efficient regioselective C-H fluorination of 8-aminoquinoline amides and sulfonamides at the C5 position was achieved. Using Selectfluor as a "F" reagent and HOAc as an additive, the reaction proceeds smoothly via a radical pathway. This metho

Full text of DOI:10.1039/c7ob03059b

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C5-regioselective C-H fluorination of 8-aminoquinoline amides
and sulfonamides with selectfluor under metal-free conditions
Yingchao Zhang, Chunxia Wen, Jizhen Li*a
Received 00th January 20xx,
Accepted 00th January 20xx
A novel and efficient regioselective C-H fluorination of 8-aminoquinoline amides and sulfonamides at C5 position was
achieved. Using selectfluor as “F” reagent and HOAc as additive, the reaction proceeds smoothly via radical pathway. This
method features metal-free conditions, broad substrate scope and operational simplicity.
DOI: 10.1039/x0xx00000x
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attractive metal-free strategies about C5 highly selective
functionalization on quinolines were also reported recently.13a-13h In
Introduction
Fluoro or fluoro-containing groups substituted quinoline the absence of any TM catalysts, Zhang group established an eco-
COOH
H
moieties are of great importance as these structures usually existed
in advanced functional materials and pharmaceuticals.1 For example,
Mefloquine2 and Brequinar3 are marketed antimalaria and
anticancer drugs respectively, whereas PfEF2 (translation
elongation factor 2) inhibitor4 is potential drug candidate in
preclinical development (Figure 1). The incorporation of fluoro or
fluoro-containing groups into bioactive organic molecules will
remarkably modulate the physicochemical and biological
properties.5a-5c As a result, the direct and efficient construction of C-
F or C-CF3 etc chemical bonds has gained considerable attention
and is a continuous issue in organic synthesis.5d, 5e
NH
O
N
F
N
OH
F
H
N
N
O
N
CF3
N
F
CF3
Pf EF2 inhibitor
Brequinar
Mefloquine
Figure
1 Selected examples of bioactive fluoro and fluoro-
containing groups substituted quinolines.
friendly, convenient and practical method for C5 perfluoroalkylation
of quinolines (eq 4).13k Wu and co-workers provided an oxidative
trifluoromethylation of 8-aminoquinoline scaffolds on the C5
position with NaSO2CF3 as “CF3” source and PIDA as oxidant (eq
5).13d
In view of atom economic point, the direct C-H functionalization
catalyzed by TM (transition metal) has been demonstrated and
developed to be a powerful tool in organic synthesis.6 Except for
the ortho C-H transformation which has been developed well and
usually be controlled via σ-chelation assistance, the remote C-H
activation research is still a big challenge nowadays.7 Since stahl
group firstly reported that the remote C5 chlorination of quinolines
catalyzed by CuCl in acidic conditions through SET (single electron
transfer) process,8 diverse TM catalyzed regioselective C5
functionalization has succeeded continuelly.9 Among them, as
shown in scheme 1, several groups have independently achieved C-
CF3 coupling at the C5 position of quinolines catalyzed by Cu species
(eq 1).10 Later on, Wang and co-workers reported a simple and
novel protocol for nickel-catalyzed C5 difluoroalkylation of 8-
aminoquinoline scaffolds with functionalized difluoromethyl
bromides (eq 2).11 We also successfully achieved C5 selective
fluorination of 8-aminoquinoline derivatives for the first time
catalyzed by cheap TM NiSO4 (eq 3).12 Interestingly, the more
Transition-metal-free conditions have the advantages of being
atom economical, inexpensive, operational simplicity, and
avoidance of the metal pollution to environment.13a,13i,13j
Undoubtedly, metal-free reactions can meet well the requirement
of green chemistry in modern organic synthesis area. Thus, the
above successful metal-free reactions (eq 4 and 5) inspired us to
investigate the regioselective C-F bond formation on quinolines
again. Meanwhile, we also noted that other C5-H selective
functionalization such as halogenation (Cl, Br, I)13a,13c,13e
,
sulfonylation13b and amidation14 were also developed without any
TM catalysts. In view of the reaction mechanism in detail, we found
that these reactions occurred mostly under oxidative additives.
Additionally, whether via SET process or not,13b,13h the N-cation
radicals derived from NH-pyridine moiety, or their resonance
delocalization structures,13e,15 are the key intermediates, which
induced other radical groups to attack the C5 position on quinolines.
We suspected that some “F” reagents acting as “F” donor and
oxidant, could facilitate the metal-free C5 fluorination on quinolines
under suitable conditions. For instance, the electrophilic N-F
reagents, selectfluor (1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo
a.Department of Organic Chemistry, College of Chemistry, Jilin University, Jiefang
Road 2519, Changchun, 130023, China, E-mail: ljz@jlu.edu.cn.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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[2.2.2] octane bis (tetrafluoroborate))15,16,17 and NFSI (N-
Fluorobenzenesulfonimide) 12,14b,18, which have dual functions and
have been applied successfully in many reported F radical addition
reactions. Especially selectfluor, without any initiator, could be
produced F anion and N cation radicals, the latter has been proved
with the strong ability to capture the proton H from the N-H bond
of anilide.15 Herein, we report our research results (eq 6).
good additive to the reaction system with increased yield of 59%
(entry 15 vs 9). Next, we explored the optimal reaction time to
reveal 4 h as the suitable reaction time (entries 16-18). Remarkably,
when NFSI was used instead of selectfluor as “F” source, there was
almost no target fluorination generated (entries 17). After further
exploration of the stoichiometry of selectfluor and the
temperature (entries 19-21), it was found that selectfluor, 2.0
equiv and temperature 90 °C were favorable condition for the
reaction. Thus, selectfluor 2.0 equiv, HOAc 1.2 equiv, reaction time
4 h and temperature 90 °C in DMF was chosen as the best reaction
conditions (entry 20).
Table 1 Optimization of the reaction conditionsa
Time
(h)
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
15
4
Temp
°C
Yieldb
(%)
n.r.
trace
38
34
10
trace
23
trace
49
Entry Additive Solvent
(
)
1
2
—
—
H2O
H2O
25
80
3
4
—
—
H2O
H2O
100
120
140
100
100
100
100
100
100
100
100
100
100
100
100
100
100
90
5
6
7
8
—
—
—
—
H2O
Toluene
DCE
THF
9
—
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
10
11c
12
13
14
15
16
17
18
19d
20e
21e
Cu(OAc)2
PIDA
KHS2O8
NH4OAc
PivOH
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
45
40
33
40
38
58
51
67 (n.r.c
57
)
2
4
4
4
Scheme 1 Methods for preparation of C-5 selective fluoro and
50
70
66
fluoro-containing groups substituted quinolines.
100
a Reaction conditions: 1a (0.2 mmol), Selectfluor (0.3 mmol),
Results and discussion
additive (0.24 mmol)
,
solvent (1.5 mL), in air. b Isolated yield. c
To test this transition metal-free hypothesis, N-(quinolin-8-yl)-
benzamide 1a was chosen as model substrate (Table 1). Firstly, 1.5
equiv selectfluor was used as “F” source in green solvent, water,
without any additive, no reaction was observed after 10 hours at
25°C. We suggested that N-(quinolin-8-yl)-benzamide molecules’
energy at around room temperature was not high enough to initiate
the reaction. Then, the temperature was increased to 80 °C and
100 °C (entries 2-3), while 1a smoothly conversed to C-5 mono-
fluorinated product 2a with very low yield and good yield
respectively. Inspired by these results, we increased the reaction
temperature to 120 °C and 140 °C, respectively for entries 4 and 5.
But, no additional benefit was gained at above 100 oC, as yields
decreased. Subsequently, solvent screening proved that DMF was
the best suitable solvent affording product in isolated yield 49%
(entries 6-9). Then, a range of additives including Cu(OAc)2, PIDA,
KHS2O8, NH4OAc, and PivOH were examined in DMF, but none of
them improved the yields (entries 10-14). Whereas, HOAc was a
Selectfluor was replaced with NFSI. d Selectfluor (1.0 equiv).
e
Selecftluor (2.0 equiv). n.r. = no reaction.
With the optimized reaction conditions in hand, the
limitation and scope was investigated for diverse 8-amino-
quinoline scaffolds. The results were illustrated in Table 2
.
Apparently, N-(8-quinolinyl) amides, regardless arylcarboxamides or
alkylcarboxamides were all converted into corresponding products
(2a-2j, 2k-2q) in good yields 43%-74%. For aryl amides substrates,
different substituents on the benzene ring, including electron-
donating group CH3 (2c, 2g, 2h) and electron-withdrawing group
such as halides chloride and bromine (2b, 2d-2f), had no obvious
electronic effect on the selective fluorination reaction.
Notably, Cl and CH3 groups on the ortho- or para- position of
benzene ring, reactions exhibited similar activity and good yields of
63% and 71% (2b, 2e), 67% and 59% (2c, 2g), suggesting that the
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steric hindrance effect was minimal in this protocol. Moreover, the
heterocyclic amides also worked well and afforded the
Then, we set out to explore the scope of the aminoquinoline
moiety. The introduction of methyl, methoxy or chloride
fluorinated products in yields of 74% and 59% respectively (2i
,
2j), which revealed the functional groups good tolerance. groups into different positions (C-2, C-6 and C-4) of quinoline
Substrates with diverse aliphatic substituents, had lower ring was tolerated, and the corresponding C-5 fluorinated
activity and provided products 2k-2p in yields 43-58%, 2q 67%, products were obtained in preferable yields 49%, 63%, 48%
and no obvious steric hindrance.
and 49% (2r, 2s, 2t, 2u).
Table 2 Substrates scope of 8-aminoquinolinesa
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radical adduct TEMPO-F could be detected by LC-MS (HRMS:
176.0219) and in 46% F-NMR yield
Finally, we were delighted to find that substrates
sulfamides achieved the regioselective C-F bond formation
successfully in yield 23% and 28% (2v 2w). Even the yields are
.
,
O
O
O
low, but the methodology provided direct remote C-H fluorination
of quinolines with low activated sulfonyl substituent for the first
time, which has ever failed using the reported Ni-catalyzed
fluorination method.12 Therefore, it was concluded that various
substrates were tolerated well in the metal-free catalyzed remote
fluorination procedure of quinolineamides and quinolinesulfamides.
In addition, X-ray analysis of 2e crystal unambiguously
confirmed the regioselective C-5 fluorination of the quinolines (see
Supporting Information for details).19 The single-crystal structure of
O2N
N
N
N
H
H
H
N
N
N
O2N
NO2
3
5
4
O
H2N
N
H3C
N
CH3 N
N
7
8
6
Cl
O
O
2e from X-ray diffraction was shown here in Figure 2
.
N
H
N
It is deserved to be mentioned that other quinolines (3-10
)
H
N
were detected under the standard conditions (Figure 3).
However, no any desired product was observed. Due to the
strong electron-withdrawing effect of NO2 group in the
10
9
Figure
3
Ineffective metal-free catalyzed C5-fluorination of
substrates.
H
TEMPO
2d
, <5%
O
(2.0 eq)
HOAc (1.2 eq)
N
H
+ Selectfluor
46%
19F NMR yield
N
DMF, 90 ℃, 4 h
N
F
O
Br
1d
TEMPO-F
([M+H]+ found: 176.0219)
HRLC-MS
Detected by
!
Scheme 2 Control experiments.
So, on the basis of above experimental results and literatures
reported by others,13a,15,17b
plausible mechanism was illustrated
in Scheme 3. Firstly, the interaction between the N-F reagent
a
selectfluor and quinolineamides 1 facilitated the generation of
F radical and key cationic N-radical A.15 Then, the latter captured
Figure 2 Single-crystal X-ray structure of 2e.
benzene ring, quinoline derivatives
3 and 4 did not success in
the proton H in NH moiety of N-(8-quinolinyl) amides 1 to generate
the fluorinated transformation. The naphthylamide derivative compound
B and N-radical intermediate C. C was easily
transformed to intermediate D via spin delocalization. Finally, the F
radical attacked the C-5 position of D through coupling reaction to
give intermediate E. A PT (proton transfer) process took place
automatically to afford the desired product 2.
5
and 10 were ineffective which attributed to the intrinsic low
activity of naphthalene ring, also suggesting that the reaction
may not proceed through an aromatic electrophilic
substitution pathway. It should be noted that both quinoline
analogues without amido bond (6, 8) or without free NH moiety
Cl
N
(7) failed in this remote regioselective C-H activation. The
results indicated that the presence of both of an amide or
sulfamide free NH moiety and carbonyl or sulfonyl group were
required in the fluorination protocol.20 Additionally, when we
adopted N-(8-quinolinyl) amides, of which C-5 position was blocked
by chlorine atom, no any desired C-5 or other C-4, C-7 fluorination
occurred (9). It was concluded that the C-5 selectivity of the
reaction was quite excellent.
N
1
H
H
B
Cl
N
N
N
N
R
C
A
O
spin
delocalization
Selectfluor
F
F
H
H
F
In order to explore the reaction mechanism, control
experiments were performed (Scheme 2). Under the standard
reaction conditions, when radical scavenger TEMPO (2,2,6,6-
tetramethyl-1-piperidinyoxy) (2.0 equiv) was added into the 1d
reaction system, the fluorination process was inhibited and
only trace of terminal product 2d (< 5% yield) was obtained.
This result demonstrated that free radical pathway was
involved in the regioselective C-H fluorination. The fluorine
PT
F
N
N
N
N
NH
N
R
R
R
O
O
O
D
2
E
Scheme 3 Plausible reaction mechanism.
To validate the synthetic utility of the metal-free protocol, the
reaction on a 4.03 mmol (1.00 g) gram-scale of 1a was conducted
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under the standard conditions. As shown in Scheme 4, the desired
product 2a was obtained in 62% isolated yield. The result indicated
that the present strategy was possible for the synthesis of
C-5 fluorinated quinolines in large quantities. The hydrolysis of
the amide 2a was easily achieved through treatment with
NaOH in EtOH to obtain 5-fluoro-8-aminoquinoline without
damaging the C-F bond reported by our group previously.12
dichloromethane (40 mL) under the ice bath conditions. The
resulting mixture was stirred at 25 °C for 10 hours. Then, the
mixture was quenched with saturated aq. NaHCO3 (50 mL), and was
extracted with dichloromethane for three times (3 x 50 mL). The
organic layer was dried over Na2SO4. After filtration and evaporation,
the amides were purified by column chromatography (hexane: ethyl
acetate 10:1-4:1) through silica gel.
Procedure for the synthesis of regioselective C5 fluorinated
N-(8-quinolinyl) amides and sulfonamides (2a-2w)
N-(8-quinolinyl) amide or sulfonamide 1 (0.2 mmol, 1.0 equiv),
Selecfluor (0.4 mmol, 2.0 equiv), HOAc (0.24 mmol, 1.2 equiv) were
mixed in DMF (1.5 mL) and stirred for 4 h in a sealed tube at 90 °C.
The organic layer was washed with H2O, and was extracted with
dichloromethane for three times (3 x 10 mL). Then, the organic layer
was dried over anhydrous Na2SO4, and resulting organic solution
was concentrated under reduced pressure and further purified by
flash chromatography (SiO2, petroleum ether/ethyl acetate gradient
30:1-10:1), yielding the target product 2a-2w.
Scheme 4 Gram-scale reaction of the C5-selective fluorination of
quinolines.
Conclusions
N-(5-fluoroquinolin-8-yl)benzamide (2a)
.
White solid,
isolated yield: 70%. 1H NMR (400 MHz, CDCl3) δ: 10.55 (s, 1H),
8.91 (t, J = 6.6 Hz, 2H), 8.47 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 7.0 Hz,
2H), 7.65-7.52 (m, 4H), 7.29 (d, J = 9.2 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ: 165.34 (s), 153.01 (d, J = 251.2 Hz), 149.14 (s),
138.97 (d, J = 3.0 Hz), 134.99 (s), 131.91 (s), 131.12 (d, J = 4.0
Hz), 129.86 (d, J = 3.6 Hz), 128.83 (s), 127.24 (s), 121.77 (d, J =
2.6 Hz), 118.82 (d, J = 18.3 Hz), 116.04 (d, J = 7.7 Hz), 110.52 (d, J
= 19.7 Hz). 19F NMR (376 MHz, CDCl3) δ: -129.01 (s). HRMS (ESI):
m/z: calcd for [M+H]+ C16H11FN2O: 267.0928, found: 267.0927.
In summary, we have developed a novel non metal-catalyzed
regioselective fluorination of 8-aminoquinoline derivations on C-
5
position. Using selectfluor as fluorinated reagent, and no
additional oxidants, the protocol provides a useful methodology for
the efficient construction of C-F bond on quinoline scaffolds with
broad functional groups compatibility. The plausible radical
mechanism was also demonstrated. The application of fluorinated
modification on bioactive compounds for drug discovery using this
method was underway in our lab.
2-chloro-N-(5-fluoroquinolin-8-yl)benzamide (2b). White solid,
1
isolated yield: 63%. H NMR (400 MHz, CDCl3) δ: 10.35 (s, 1H), 8.92
Experimental section
(dd, J = 8.6, 5.5 Hz, 1H), 8.86 (d, J = 3.1 Hz, 1H), 8.48 (d, J = 8.4 Hz,
1H), 7.82 (dd, J = 7.2, 1.5 Hz, 1H), 7.58-7.49 (m, 2H), 7.48-7.39 (m,
2H), 7.30 (d, J = 9.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 164.72 (s),
153.26 (d, J = 251.7 Hz), 149.23 (s), 138.92 (d, J = 3.2 Hz), 135.63 (s),
131.60 (s), 131.15 (s), 130.97 (d, J = 4.2 Hz), 130.55 (s), 130.14 (s),
129.79 (d, J = 3.7 Hz), 127.19 (s), 121.79 (d, J = 2.7 Hz), 118.81 (d, J =
18.1 Hz), 116.47 (d, J = 7.8 Hz), 110.46 (d, J = 19.7 Hz). 19F NMR (376
MHz, CDCl3) δ: -128.39 (s). HRMS (ESI): m/z: calcd for [M+H]+
C16H10ClFN2O: 301.0538, found: 301.0542.
General
All reagents, starting materials, and solvents were purchased from
commercial sources and used without treatment, unless otherwise
indicated. All the solvents were dried and newly distilled. NMR
spectra were obtained on
a Bruker AMX 400 system using
chloroform-d as deuterated solvents and TMS as internal standard.
The 1H-NMR spectra were recorded at 400 MHz, the 13C-NMR
spectra were recorded at 100 MHz, and the 19F-NMR spectra were
recorded at 376 MHz. All shifts were given in ppm. All coupling
constants (J values) were reported in Hertz (Hz). Single crystal X-ray
diffraction data were collected using a Bruker-AXS SMART APEX2
CCD diffractometer (Mo Kα, λ = 0.71073 Å). High-Resolution Liquid
Chromatography-Mass Spectrometry was recorded on the Bruker
MicrOTOF QⅡ. Column chromatography was performed on silica
gel 100-200 mesh or 200-300 mesh. Ethyl acetate and petroleum
ether were used for column chromatography.
2-methyl-N-(5-fluoroquinolin-8-yl)benzamide (2c). White solid,
1
isolated yield: 67%. H NMR (400 MHz, CDCl3) δ: 10.03 (s, 1H), 8.90
(dd, J = 8.5, 5.5 Hz, 1H), 8.84 (d, J = 4.1 Hz, 1H), 8.48 (dd, J = 8.4, 1.3
Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.55 (dd, J = 8.4, 4.3 Hz, 1H), 7.46-
7.27 (m, 4H), 2.60 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 168.06 (s),
153.05 (d, J = 251.3 Hz), 149.12 (s), 138.82 (d, J = 3.1 Hz), 136.71 (s),
136.46 (s), 131.42 (s), 131.26 (d, J = 4.0 Hz), 130.41 (s), 129.81 (d, J =
3.6 Hz), 127.23 (s), 126.05 (s), 121.75 (d, J = 2.5 Hz), 118.80 (d, J =
18.1 Hz), 116.01 (d, J = 7.7 Hz), 110.46 (d, J = 19.6 Hz), 20.24 (s). 19
F
Procedure for the synthesis of substituted amides 1a-1w
NMR (376 MHz, CDCl3) δ: -128.93 (s). HRMS (ESI): m/z: calcd for
[M+H]+ C17H13FN2O: 281.1085, found: 281.1092.
Preparation of amides 1a-1w according to literature procedures
reported previously from 8-aminoquinoline and corresponding acyl
3-bromo-N-(5-fluoroquinolin-8-yl)benzamide (2d). White solid,
1
chloride: A solution of 8-aminoquinoline (1.44 g, 10.0 mmol) and isolated yield: 55%. H NMR (400 MHz, CDCl3) δ: 10.49 (s, 1H), 8.93
(d, J = 3.0 Hz, 1H), 8.87 (dd, J = 8.6, 5.4 Hz, 1H), 8.48 (d, J = 8.5 Hz,
1H), 8.20 (s, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.58
(dd, J = 8.4, 4.2 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.29 (d, J = 9.3 Hz,
NEt3 (1.01 g, 11.0 mmol) in dichloromethane (10 mL) was added
dropwise to a stirring solution of an acid chloride (11.0 mmol) in
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1H). 13C NMR (100 MHz, CDCl3) δ: 163.76 (s), 153.21 (d, J = 251.8 Hz), Hz). 19F NMR (376 MHz, CDCl3) δ: -129.10 (s). HRMS (ESI): m/z: calcd
149.26 (s), 138.95 (s), 136.99 (s), 134.85 (s), 130.78 (d, J = 4.0 Hz), for [M+H]+ C14H9FN2OS: 273.0492, found:273.0495.
130.57 (s), 130.34 (s), 129.92 (d, J = 3.6 Hz), 125.66 (s), 123.08 (s),
N-(5-fluoroquinolin-8-yl)furan-2-carboxamide (2J). White
121.85 (d, J = 2.5 Hz), 118.84 (d, J = 18.3 Hz), 116.27 (d, J = 7.8 Hz),
solid, isolated yield: 59%. 1H NMR (400 MHz, CDCl3) δ: 10.59 (s, 1H),
110.50 (d, J = 19.8 Hz). 19F NMR (376 MHz, CDCl3) δ: -128.39 (s).
HRMS (ESI): m/z: calcd for [M+H]+ C16H10BrFN2O: 345.0033,
8.95 (d, J = 3.8 Hz, 1H), 8.83 (dd, J = 8.6, 5.4 Hz, 1H), 8.47 (d, J = 8.4
Hz, 1H), 7.63 (s, 1H), 7.57 (dd, J = 8.4, 4.2 Hz, 1H), 7.33-7.26 (m, 2H),
6.60 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 156.29 (s), 153.14 (d, J =
251.4 Hz), 149.24 (s), 148.27 (s), 144.53 (s), 138.90 (d, J = 3.2 Hz),
130.75 (d, J = 3.9 Hz), 129.83 (d, J = 3.8 Hz), 121.76 (d, J = 2.6 Hz),
118.87 (d, J = 18.2 Hz), 116.23 (d, J = 7.8 Hz), 115.15 (s), 112.46 (s),
110.51 (d, J = 19.7 Hz). 19F NMR (376 MHz, CDCl3) δ: -128.74 (s).
HRMS (ESI): m/z: calcd for [M+H]+ C14H9FN2O2: 257.0721, found:
347.0013, found: 345.0039, 347.0019.
4-chloro-N-(5-fluoroquinolin-8-yl)benzamide (2e). White solid,
isolated yield: 71%. 1H NMR (400 MHz, CDCl3) δ: 10.51 (s, 1H), δ
8.91 (d, J = 4.1 Hz, 1H), 8.87 (dd, J = 8.6, 5.4 Hz, 1H), 8.48 (d, J = 8.4
Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.60-7.51 (m, 3H), 7.29 (d, J = 9.1
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 164.20 (s), 153.14 (d, J = 251.6
Hz), 149.20 (s), 138.93 (d, J = 3.1 Hz), 138.19 (s), 133.38 (s), 130.88
(d, J = 4.0 Hz), 129.94 (d, J = 3.6 Hz), 129.10 (s), 128.67 (s), 121.83 257.0726.
(d, J = 2.5 Hz), 118.85 (d, J = 18.3 Hz), 116.15 (d, J = 7.7 Hz), 110.53
N-(5-fluoroquinolin-8-yl)pivalamide (2k). White solid, isolated
yield: 48%. H NMR (400 MHz, CDCl3) δ: 10.07 (s, 1H), 8.87 (dd, J =
(d, J = 19.7 Hz). 19F NMR (376 MHz, CDCl3) δ: -128.57 (s). HRMS
(ESI): m/z: calcd for [M+H]+ C16H10ClFN2O: 301.0538, found:
301.0532.
1
4.2, 1.5 Hz, 1H), 8.75 (dd, J = 8.6, 5.5 Hz, 1H), 8.43 (dd, J = 8.4, 1.5
Hz, 1H), 7.52 (dd, J = 8.4, 4.2 Hz, 1H), 7.24 -7.13 (m, 1H), 1.42 (s, 9H).
2-bromo-N-(5-fluoroquinolin-8-yl)benzamide (2f). White solid, 13C NMR (100 MHz, CDCl3) δ: 177.10 (s), 152.71 (d, J = 250.5 Hz),
isolated yield: 57%. 1H NMR (400 MHz, CDCl3) δ: 10.11 (s, 1H), 8.99-
149.04 (s), 138.94 (d, J = 3.0 Hz), 131.22 (d, J = 4.1 Hz), 129.76 (d, J =
8.81 (m, 2H), 8.46 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 7.8 Hz, 2H), 7.53 3.6 Hz), 121.59 (d, J = 2.5 Hz), 118.72 (d, J = 18.1 Hz), 115.65 (d, J =
7.6 Hz), 110.42 (d, J = 19.4 Hz), 40.27 (s), 27.73 (s). 19F NMR (376
(dd, J = 8.2, 4.1 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.7 Hz,
1H), 7.29 (d, J = 9.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 165.74 (s), MHz, CDCl3) δ: -129.81 (s). HRMS (ESI): m/z: calcd for [M+H]+
153.28 (d, J = 251.7 Hz), 149.20 (s), 138.88 (s), 138.17 (s), 133.70 (s),
131.55 (s), 130.88 (s), 129.84 (s), 129.71 (d, J = 23.0 Hz), 127.67 (s),
121.78 (s), 119.68 (s), 118.82 (d, J = 18.3 Hz), 116.46 (d, J = 7.5 Hz),
110.45 (d, J = 19.7 Hz). 19F NMR (376 MHz, CDCl3) δ: -128.27 (s).
HRMS (ESI): m/z: calcd for [M+H]+ C16H10BrFN2O: 345.0033,
347.0013, found: 345.0037, 347.0019.
C14H15FN2O: 247.1241, found: 247.1245.
N-(5-fluoroquinolin-8-yl)acetamide (2l). White solid, isolated
yield: 48%. 1H NMR (400 MHz, CDCl3) δ: 9.59 (s, 1H), 8.86 (d, J = 4.1
Hz, 1H), 8.72 (dd, J = 8.6, 5.5 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 7.53
(dd, J = 8.4, 4.2 Hz, 1H), 7.21 (t, J = 9.2 Hz, 1H), 2.34 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ: 168.61 (s), 152.80 (d, J = 250.8 Hz), 148.94 (s),
138.44 (d, J = 2.1 Hz), 131.04 (d, J = 4.1 Hz), 129.82 (d, J = 3.7 Hz),
121.64 (d, J = 2.5 Hz), 118.71 (d, J = 18.1 Hz), 115.94 (d, J = 7.6 Hz),
110.42 (d, J = 19.6 Hz), 25.03 (s). 19F NMR (376 MHz, CDCl3) δ: -
129.40 (s). HRMS (ESI): m/z: calcd for [M+H]+ C11H9FN2O: 205.0772,
found: 205.0774.
4-methyl-N-(5-fluoroquinolin-8-yl)benzamide (2g). White
solid, isolated yield: 59%. 1H NMR (400 MHz, CDCl3) δ: 10.52 (s, 1H),
8.96-8.86 (m, 2H), 8.47 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.7 Hz, 2H),
7.56 (dd, J = 8.3, 4.2 Hz, 1H), 7.35 (d, J = 7.7 Hz, 2H), 7.29 (t, J = 9.2
Hz, 1H), 2.46 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 165.32 (s), 152.92
(d, J = 251.1 Hz), 149.08 (s), 142.40 (s), 138.97 (d, J = 2.8 Hz), 132.19
(s), 131.24 (d, J = 4.0 Hz), 129.83 (d, J = 3.8 Hz), 129.48 (s), 127.25
(s), 121.71 (d, J = 2.4 Hz), 118.82 (d, J = 18.1 Hz), 115.94 (d, J = 7.6
Hz), 110.53 (d, J = 19.6 Hz), 21.56 (s). 19F NMR (376 MHz, CDCl3) δ: -
129.27 (s). HRMS (ESI): m/z: calcd for [M+H]+ C17H13FN2O: 281.1085,
found: 281.1089.
N-(5-fluoroquinolin-8-yl)butyramide (2m). White solid,
isolated yield: 48%. 1H NMR (400 MHz, CDCl3) δ: 9.62 (s, 1H), 8.86
(d, J = 3.5 Hz, 1H), 8.74 (dd, J = 8.2, 5.8 Hz, 1H), 8.44 (d, J = 8.4 Hz,
1H), 7.53 (dd, J = 8.3, 4.1 Hz, 1H), 7.21 (t, J = 9.2 Hz, 1H), 2.53 (t, J =
7.5 Hz, 2H), 1.90-1.80 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ: 171.58 (s), 152.74 (d, J = 250.6 Hz), 148.93 (s),
138.54 (d, J = 2.9 Hz), 131.10 (d, J = 3.9 Hz), 129.78 (d, J = 3.6 Hz),
121.60 (d, J = 2.6 Hz), 118.72 (d, J = 18.0 Hz), 115.86 (d, J = 7.6 Hz),
110.43 (d, J = 19.6 Hz), 40.09 (s), 19.13 (s), 13.82 (s). 19F NMR (376
MHz, CDCl3) δ: -129.55 (s). HRMS (ESI): m/z: calcd for [M+H]+
C13H13FN2O: 233.1085, found: 233.1089.
3,5-dimethyl-N-(5-fluoroquinolin-8-yl)benzamide (2h). White
solid, isolated yield: 62%. 1H NMR (400 MHz, CDCl3) δ: 10.46 (s, 1H),
8.98-8.86 (m, 2H), 8.47 (d, J = 8.4 Hz, 1H), 7.65 (s, 2H), 7.56 (dd, J =
8.4, 4.2 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 7.23 (d, J = 12.4 Hz, 1H),
2.44 (s, 6H). 13C NMR (100 MHz, CDCl3) δ: 165.80 (s), 152.94 (d, J =
251.0 Hz), 149.11 (s), 138.99 (d, J = 3.1 Hz), 138.51 (s), 135.05 (s),
133.53 (s), 131.25 (d, J = 4.2 Hz), 129.82 (d, J = 3.7 Hz), 124.98 (s),
121.70 (d, J = 2.6 Hz), 118.81 (d, J = 18.2 Hz), 116.04 (d, J = 7.7 Hz),
110.52 (d, J = 19.6 Hz), 21.39 (s). 19F NMR (376 MHz, CDCl3) δ: -
129.26 (s). HRMS (ESI): m/z: calcd for [M+H]+ C18H15FN2O: 295.1241,
found: 295.1238.
N-(5-fluoroquinolin-8-yl)cyclohexanecarboxamide (2n). White
1
solid, isolated yield: 43%. H NMR (400 MHz, CDCl3) δ: 9.76 (s, 1H),
8.88 (dd, J = 4.3, 1.6 Hz, 1H), 8.77 (dd, J = 8.7, 5.5 Hz, 1H), 8.47 (dd, J
= 8.4, 1.5 Hz, 1H), 7.55 (dd, J = 8.4, 4.3 Hz, 1H), 7.26- 7.19 (m, 1H),
2.49 (m, 1H), 2.17-2.01 (m, 2H), 1.96-1.82 (m, 2H), 1.78-1.57 (m,
3H), 1.45-1.24 (m, 3H). 13C NMR (100 MHz, CDCl3) δ: 174.71 (s),
152.68 (d, J = 250.7 Hz), 148.89 (s), 138.61 (d, J = 2.6 Hz), 131.16 (d,
J = 4.0 Hz), 129.81 (d, J = 3.7 Hz), 121.58 (d, J = 2.5 Hz), 118.71 (d, J =
18.0 Hz), 115.90 (d, J = 7.6 Hz), 110.45 (d, J = 19.5 Hz), 46.82 (s),
29.75 (s), 25.77 (s), 25.75 (s). 19F NMR (376 MHz, CDCl3) δ: -129.73
N-(5-fluoroquinolin-8-yl)thiophene-2-carboxamide (2i). White
solid, isolated yield: 74%. 1H NMR (400 MHz, CDCl3) δ: 10.33 (s, 1H),
8.94-8.88 (m, 1H), 8.84 (dd, J = 8.6, 5.4 Hz, 1H), 8.46 (d, J = 8.4 Hz,
1H), 8.19-8.13 (m, 1H), 7.68 (d, J = 5.0 Hz, 1H), 7.55 (dd, J = 8.4, 4.2
Hz, 1H), 7.44 (dd, J = 5.0, 3.0 Hz, 1H), 7.28 (t, J = 9.1 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ: 160.90 (s), 152.96 (d, J = 251.2 Hz), 149.11
(s), 138.79 (d, J = 3.0 Hz), 138.19 (s), 131.02 (d, J = 4.0 Hz), 129.85
(d, J = 3.6 Hz), 128.93 (s), 126.78 (s), 126.27 (s), 121.74 (d, J = 2.5
Hz), 118.82 (d, J = 18.2 Hz), 115.99 (d, J = 7.6 Hz), 110.53 (d, J = 19.7
6 | J. Name., 2012, 00, 1-3
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(s). HRMS (ESI): m/z: calcd for [M+H]+ C16H17FN2O: 273.1398, found: Hz, 2H), 7.63-7.54 (m, 3H), 7.42 (d, J = 8.5 Hz, 1H), 7.19 (t, J = 9.2 Hz,
1H), 2.80 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 165.17 (s), 158.32 (s),
273.1395.
153.28 (d, J = 250.7 Hz), 138.52 (s), 135.19 (s), 131.79 (s), 130.46 (d,
J = 4.2 Hz), 129.88 (d, J = 3.4 Hz), 128.83 (s), 127.19 (s), 122.55 (d, J
N-(5-fluoroquinolin-8-yl)-3-phenylpropanamide (2o). White
1
= 2.4 Hz), 116.87 (d, J = 18.2 Hz), 116.03 (d, J = 7.8 Hz), 109.52 (d, J =
solid, isolated yield: 58%. H NMR (400 MHz, CDCl3) δ: 9.59 (s, 1H),
19.7 Hz), 25.50 (s). 19F NMR (376 MHz, CDCl3) δ: -129.19 (s). HRMS
8.82 (dd, J = 4.2, 1.6 Hz, 1H), 8.74 (dd, J = 8.6, 5.4 Hz, 1H), 8.43 (dd, J
= 8.4, 1.6 Hz, 1H), 7.52 (dd, J = 8.4, 4.2 Hz, 1H), 7.35-7.28 (m, 4H),
(ESI): m/z: calcd for [M+H]+ C17H13FN2O: 281.1085, found: 281.1088.
7.25-7.17 (m, 2H), 3.20-3.10 (t, J = 7.8 Hz, 2H), 2.93-2.83 (t, J = 7.8
N-(4-chloro-5-fluoroquinolin-8-yl)benzamide (2u)
.
White
：10.59 (s,
Hz, 2H). 13C NMR (100MHz, CDCl3) δ: 170.57 (s), 152.82 (d, J = 250.9
Hz), 148.92 (s), 140.71 (s), 138.51 (d, J = 3.0 Hz), 130.96 (d, J = 4.1
Hz), 129.78 (d, J = 3.7 Hz), 128.57 (s), 128.39 (s), 126.27 (s), 121.63
(d, J = 2.5 Hz), 118.71 (d, J = 18.1 Hz), 115.96 (d, J = 7.7 Hz), 110.43
(d, J = 19.6 Hz), 39.66 (s), 31.48 (s). 19F NMR (376 MHz, CDCl3) δ: -
129.34 (s). HRMS (ESI): m/z: calcd for [M+H]+ C18H15FN2O: 295.1241,
found: 295.1238.
1
solid, isolated yield: 49%. H NMR (400 MHz, CDCl3) δ
1H), 9.17-8.93 (m, 1H), 8.73 (dd, J = 6.5, 4.9 Hz, 1H), 8.07 (dd, J =
6.6, 4.9 Hz, 2H), 7.66-7.55 (m, 4H), 7.37 (dd, J = 12.1, 8.8 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ: 165.24 (s), 158.39 (s), 153.34 (d, J =
251.4 Hz), 138.59 (s), 135.26 (s), 131.86 (s), 130.53 (d, J = 4.8
Hz), 129.94 (d, J = 3.9 Hz), 128.89 (s), 127.26 (s), 122.61 (d, J =
3.1 Hz), 116.93 (d, J = 17.9 Hz), 116.10 (d, J = 7.7 Hz), 109.59 (d, J
= 18.6 Hz). 19F NMR (376 MHz, CDCl3) δ: -119.89 (s). HRMS (ESI):
m/z: calcd for [M+H]+ C16H10ClFN2O: 301.0538, found: 301.0538.
N-(5-fluoroquinolin-8-yl)-2-phenylacetamide (2p). White
1
solid, isolated yield: 48%. H NMR (400 MHz, CDCl3) δ: 9.82 (d, J =
4-methyl-N-(5-fluoroquinolin-8-yl)benzenesulfonamide (2v).
White solid, isolated yield: 23%. 1H NMR (400 MHz, CDCl3) δ: 9.06
(d, J = 87.3 Hz, 1H), 8.80 (d, J = 3.9, 1.6 Hz, 1H), 8.51-8.33 (m, 1H),
7.81-7.71 (m, 3H), 7.55-7.46 (m, 1H), 7.20-7.11 (m, 3H), 2.29 (s, 3H).
13C NMR (100 MHz, CDCl3) δ: 153.53 (d, J = 251.7 Hz), 149.37 (d, J =
39.5 Hz), 143.88 (d, J = 16.7 Hz), 139.01 (s), 136.18 (s), 133.25 (d, J =
22.4 Hz), 129.66 (dd, J = 21.7, 7.3 Hz), 127.23 (s), 126.73 (s), 122.67
(s), 121.96 (d, J = 2.7 Hz), 115.16 (d, J = 8.2 Hz), 110.18 (d, J = 20.4
Hz), 21.46 (s). 19F NMR (376 MHz, CDCl3) δ: -128.34 (s). HRMS (ESI):
m/z: calcd for [M+H]+ C16H13FN2O2S: 317.0755, found: 317.0758.
90.9 Hz, 1H), 8.88-8.60 (m, 2H), 8.26 (dd, J = 8.3, J =1.3 Hz, 1H),
7.51-7.39 (m, 4H), 7.33 (dd, J = 13.1, 6.1 Hz, 2H), 7.18 (t, J = 9.2 Hz,
1H), 3.88 (s, 2H). 13C NMR (100 MHz, CDCl3) δ: 169.47 (s), 153.06 (d,
J = 251.1 Hz), 138.81 (s), 134.75 (s), 131.07 (d, J = 4.1 Hz), 129.84 (d,
J = 3.6 Hz), 129.68 (s), 129.14 (s), 127.52 (s), 121.70 (d, J = 2.6 Hz),
118.80 (d, J = 18.1 Hz), 116.02 (d, J = 7.7 Hz), 110.50 (d, J = 19.6 Hz),
45.43 (s), 29.84 (s). 19F NMR (376 MHz, CDCl3) δ: -129.08 (s). HRMS
(ESI): m/z: calcd for [M+H]+ C17H13FN2O: 281.1085, found: 281.1087.
N-(5-fluoroquinolin-8-yl)-2-(o-tolyl)acetamide (2q). White
1
solid, isolated yield: 67%. H NMR (400 MHz, CDCl3) δ: 9.64 (s, 1H),
N-(5-fluoroquinolin-8-yl)benzenesulfonamide (2w). White
1
8.73-8.66 (m, 2H), 8.38 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (dd, J = 8.4, 4.2
Hz, 1H), 7.39-7.26 (m, 5H), 7.21-7.15 (t, J = 9.2 Hz, 1H), 3.89 (s, 2H),
2.40 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 169.21 (s), 152.90 (d, J =
250.9 Hz), 149.00 (s), 138.71 (d, J = 2.7 Hz), 137.25 (s), 133.09 (s),
130.91 (d, J = 4.0 Hz), 130.81 (s), 130.59 (s), 129.59 (d, J = 3.6 Hz),
127.83 (s), 126.64 (s), 121.54 (d, J = 2.6 Hz), 118.62 (d, J = 18.2 Hz),
solid, isolated yield: 28%. H NMR (400 MHz, CDCl3) δ: 9.19 (s, 1H),
8.79 (dd, J = 6.7, 2.7 Hz, 1H), 8.49-8.33 (m, 1H), 7.88 (dd, J = 15.2,
7.4 Hz, 2H), 7.83-7.74 (m, 1H), 7.54-7.32 (m, 5H). 13C NMR (100
MHz, CDCl3) δ: 153.69 (d, J = 252.5 Hz), 149.43 (d, J = 39.7 Hz),
139.08 (d, J = 9.9 Hz), 133.10 (dd, J = 28.0, 17.8 Hz), 129.81 (d, J =
3.6 Hz), 128.93 (d, J = 11.9 Hz), 127.17 (s), 126.72 (s), 126.23 (s),
125.26 (s), 122.37 (d, J = 70.5 Hz), 116.04-114.25 (m), 110.20 (d, J =
20.5 Hz). 19F NMR (376 MHz, CDCl3) δ: -127.95 (s). HRMS (ESI): m/z:
calcd for [M+H]+ C15H11FN2O2S: 303.0598, found: 303.0600.
115.75 (d, J = 7.8 Hz), 110.32 (d, J = 19.6 Hz), 43.21 (s), 19.71 (s). 19
F
NMR (376 MHz, CDCl3) δ: -129.20 (s). HRMS (ESI): m/z: calcd for
[M+H]+ C18H15FN2O: 295.1241, found: 295.1237.
N-(5-fluoro-6-methylquinolin-8-yl)benzamide (2r). White
solid, isolated yield: 49%. 1H NMR (400 MHz, CDCl3) δ: 10.52 (s, 1H),
8.83 (dd, J = 4.4, 2.9 Hz, 2H), 8.41 (dd, J = 8.4, 1.4 Hz, 1H), 8.07 (dd, J
= 7.8, 1.4 Hz, 2H), 7.60-7.50 (m, 4H), 2.51 (d, J = 2.4 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ: 165.30 (s), 150.44 (d, J = 248.1 Hz), 148.09
(s), 137.79 (d, J = 2.8 Hz), 135.05 (s), 131.86 (s), 130.46 (d, J = 4.1
Hz), 129.31 (d, J = 4.2 Hz), 128.83 (s), 127.23 (s), 121.72 (d, J = 2.6
Hz), 118.82 (d, J = 18.2 Hz), 115.99 (d, J = 7.6 Hz), 110.53 (d, J = 19.7
Hz). 14.82 (d, J = 3.6 Hz). 19F NMR (376 MHz, CDCl3) δ: -133.73 (s).
HRMS (ESI): m/z: calcd for [M+H]+ C17H13FN2O: 281.1085, found:
281.1086.
Conflicts of interest
There are no conflicts to declare.
Acknowledgment
This work was mainly supported by National Natural Science
Foundation of China (NSFC No. 51573069) and Department of
Science & Technology of Jilin Province (Grant No. 20170414052GH).
N-(5-fluoro-6-methoxyquinolin-8-yl)benzamide (2s). White
solid, isolated yield: 63%. 1H NMR (400 MHz, CDCl3) δ: 10.65 (s, 1H),
9.02 (d, J = 8.5 Hz, 1H), 8.77 (dd, J = 4.2, 1.4 Hz, 1H), 8.43 (dd, J =
8.5, 1.4 Hz, 1H), 8.10 (d, J = 7.0 Hz, 2H), 7.63-7.49 (m, 4H), 4.14 (s,
3H). 13C NMR (100 MHz, CDCl3) δ: 165.45 (s), 146.67 (s), 143.56 (d, J
= 9.2 Hz), 140.62 (d, J = 247.4 Hz), 134.76 (s), 133.48 (d, J = 35.8 Hz),
132.04 (s), 131.52 (s), 130.16 (s), 128.68 (dd, J = 22.7, 19.7 Hz),
127.23 (s), 122.11 (s), 119.41 (d, J = 15.1 Hz), 106.32 (s), 57.29 (s).
19F NMR (376 MHz, CDCl3) δ: -153.44 (s). HRMS (ESI): m/z: calcd for
[M+H]+ C17H13FN2O2: 297.1034, found: 297.1036.
References and Notes
1
(a) J. Z. Li, M. Goto, X. M. Yang and K. H. Lee, Bioorg. Med.
Chem. Lett., 2016, 26, 68-71; (b) R. S. H. Liu and J. Liu, J. Nat.
Prod., 2011, 74, 512-517; (c) T. J. Taylor, C. N. Burress and F.
P. Gabbaï, Organometallics, 2007, 26, 5252-5263; (d) A.
Vitale, R. Bongiovanni and B. Ameduri, Chem. Rev., 2015,
115, 8835-8866; (e) S. Mishra and S. Daniele, Chem. Rev.,
2015, 115, 8379-8448; (f) D. E. Yerien, S. Bonesi and A.
Postigo, Org. Biomol. Chem., 2016, 14, 8398-8427.
N-(5-fluoro-2-methylquinolin-8-yl)benzamide (2t). White
solid, isolated yield: 48%. 1H NMR (400 MHz, CDCl3) δ: 10.60 (s, 1H),
8.85 (dd, J = 8.6, 5.5 Hz, 1H), 8.33 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 6.9
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A. Lilienkampf, J. L. Mao, B. J. Wan, Y. H. Wang, S. G.
Franzblau and A. P. Kozikowsk, J. Med. Chem., 2009, 52
2109-2118.
C. Papageorgiou, A. V. Matt, J. Joergensen and C.
Heusser, J. Med. Chem., 2001, 44, 1986-1992.
B, Baragaña, N. R. Norcross, C. Wilson and I. H. Gilbert, J.
Med. Chem., 2016, 59, 9672-9685.
(a) S. L. Degorce, B. Barlaam and E. Cadogan, J. Med. Chem.,
2016, 59, 6281-6292; (b) J. D. Becherer, E. E. Boros and T. Y.
Carpenter, J. Med. Chem., 2015, 58, 7021-7056; (c) A.
Chem., 2016,
5
, 724-728; (e) Y. Wang, Y. Wang, K. Jiang, Q.
,
Zhang and D. Li, Org. Biomol. Chem., 2016, 14, 10180-10184;
(f) D. Z. Ji, X. He, Y. Z. Xu, Z. Y. Xu, Y. C. Bian, W.X. Liu, Q. H.
Zhu and Yungen Xu, Org. Lett., 2016, 18, 4478-4481; (g) X. X.
Chen, J. X. Wang, J. T. Ren, H. Xie, Y. X. Zhao, Y. M. Li, M.
Sun, Synlett, 2017, 28, 1840-1844; (h) C. Sen, T. Sahoo and S.
3
4
5
C. Ghosh, ChemistrySelect, 2017,
2, 2745-2749; (i) S.
Roscales and A. G. Csa′ky, Chem. Soc. Rev., 2014, 43, 8215-
8225; (j) A. Bhunia, S. R. Yetra and A. T. Biju, Chem. Soc. Rev.,
2012, 41, 3140-3152. (k) J. Xu, L. Qiao, B. B. Ying, X. L. Zhu, C.
Huang, A. Moretto and K. Janz, J. Med. Chem., 2010, 53
6003-6017. (d) C. F. Ni and J. B. Hu, Chem. Soc. Rev., 2016, 14 (a) H. Sahoo, M. K. Reddy, I. Ramakrishna and M. Baidya,
45, 5441-5454; (e) X. L. Pan, H. G. Xia and J. Wu, Org. Chem. Chem. Eur. J., 2016, 22, 1592-1596; (b) Y. Yin, J. Xie, F. Q.
Front., 2016, , 1163-1185. huang, L. W. Qi, B. Zhang, Adv. Synth. Catal., 2017, 359
,
S. and P. F. Zhang, Org. Chem. Front., 2017, 4, 1116-1120;
3
,
6
7
For reviews on transition-metal-catalyzed C-H bond
functionalization, see: (a) D. L. Boger and T. J. Barker, J. Am.
Chem. Soc., 2012, 134, 13588-13591; (b) Q. P. Ding, C. Q. Ye, 15 D. Liang, Y. N. Li, S. L. Gao, R. L. Li, X. G. Li, B. L. Wang and H.
1037-1042; (c) M. D. Reddy, F. R. Fronczek and E. B. Watkins,
Org. Lett., 2016, 18, 5620-5623.
S. Z. Pu and B. P. Cao, Tetrahedron, 2014, 70, 409-416; (c) D.
Yang, Green Chem., 2017, 19, 3344-3349.
16 C. X. Wang, J. W. Cai, M. Zhang and X. M. Zhao, J. Org.
Chem., 2017, 82, 1260-1265.
M. Burl, R. D. Miller and C. A. Walsh, Chem. Rev., 1994, 94
31-75; (d) L. Yang and H. M. Huang, Chem. Rev., 2015, 115
,
,
3468-3517; (e) G. Y. Song, F. Wang and X. W. Li, Chem. 17 (a)C. R. Pitts, S. Bloom, R. Woltornist, D. J. Auvenshine, L. R.
Soc. Rev., 2012, 41, 3651-3678.
For selected examples, see: (a) X. F. Cong and X. M. Zeng,
Org. Lett., 2014, 16, 3716-3719; (b) G. Rouquet and N.
Ryzhkov, M. A. Siegler and T. Lectka, J. Am. Chem. Soc.,
2014, 136, 9780-9791; (b) C. W. Kee, K. F. Chin, M. W. Wong,
C. H. Tan, Chem Commun., 2014, 50, 8211-8214.
Chatani, Chem. Sci., 2013,
and Naoto Chatani, Chem. Sci., 2013,
Truong, K. Klimovica and O. Daugulis, J. Am. Chem. Soc.,
2013, 135, 9342-9345; (e) H. M. Omer and P. Liu, J. Am.
Chem. Soc., 2017, 139, 9909-9920; (f) F. F. Wang, Q. Y. Hu
4, 2201-2208; (c) Yoshinori Aihara 18 (a) D. V. Liskin, P. A. Sibbald, C. F. Rosewall and F. E. Michael,
4
, 664-670; (d) T.
J. Org. Chem., 2010, 75, 6294-6296; (b) S. Ortgies and A.
Breder, Org. Lett., 2015, 17, 2748-2751; (c) E. L. Ingalls, P. A.
Sibbald, W. Kaminsky and F. E. Michael, J. Am. Chem. Soc.,
2013, 135, 8854-8856.
and W. Zhang, Org. Lett., 2017, 19, 3636-3639; (g) R. Y. Tang, 19 Note: The identity of 2a was also verified through
G. Li and J. Q. Yu, Nature, 2014, 507, 215-220; (h) L. Wan, N.
Dastbaravardeh, G. Li and J. Q. Yu, J. Am. Chem. Soc., 2013,
135, 18056-18059; (i) D. Leow, G. Li, T. S. Mei and J. Q. Yu, 20 (a) X. F. Cong and X. M. Zeng, Org. Lett., 2014, 16, 3716-
comparison of the X-ray structure data with the data in our
prior publication.12
Nature, 2012, 486, 518-522.
3719; (b) G. S. Chen, X. J. Zhang, Z. H. Zeng and J. D. Liu,
ChemistrySelect, 2017, , 1979-1982; (c) H. Chen, P. H. Li, M.
Wang and L. Wang, Org. Lett., 2016, 18, 4794-4797.
8
9
(a) M. D. Reddy, F. R. Fronczek and E. B. Watkins, Org. Lett.,
2016, 18, 5620-5623; (b) A. M. Suess, M. Z. Ertem, C. J.
Cramer and S. S. Stahl, J. Am. Chem. Soc., 2013, 135, 9797-
9804.
2
For selected examples of remote C5 functionalization, see:
(a) J. S. Ding, W. R. Li, K. Q. Ye and J. Z. Li, ChemistrySelect,
2016, 1, 5874-5878; (b) H. l. Guo, M. M. Chen, P. Jiang, M.
Wang, C. S. Xie and Y. H. Zhang, Tetrahedron, 2015, 71, 70-
76; (c) J. Xu, C. Shen, X. L. Zhu, P. F. Zhang, M. J. Ajitha, K. W.
Huang and X. G. Liu, Chem. Asian J., 2016, 11, 882-892; (d) X.
X. Liu, Z. Y. Wu, X. L. Luo, Y. Q. He and G. H.Huang, RSC Adv.,
2016,
Ying, C. Shen and P. F. Zhang, Org. Biomol. Chem., 2016, 14
6, 71485-71488; (e) J. Xu, X. L. Zhu, G. B. Zhou, B. B.
,
3016-3021; (f) C. G. Wu, H. Zhou, Q. L. Wu, M. N. He, P. Li,
Q. Su and Y. Mu, Synlett, 2016, 27, 868-875; (g) X. He, Y. Z.
Xu, L. X. Kong, H. H. Wu, D. Z. Ji, Z. B. Wang, Y. G. Xu and Q.
H. Zhu, Org. Chem. Front., 2017, 4, 1046-1050. (h) X. S. Wu,
Y. Zhao and H. B. Ge, Org. Biomol. Chem., 2016, 14, 3016-
3021.
10 (a) Z. Wu, Y. He, C. Ma, X. Zhou, X. Liu, Y. Li, T. Hu, P. Wen
and G. Huang, Asian J. Org. Chem., 2016, , 724-728; (b) Y.
5
Kuninobu, M. Nishi and M. Kanai, Org. Biomol. Chem., 2016,
14, 8092-8100; (c) L. K. Jin, G. P. Lua and C. Cai, Org. Chem.
Front., 2016, 3, 1309-1313.
11 H. Chen, P.H. Li, M. Wang and L. Wang, Org. Lett., 2016, 18
,
4794-4797.
12 J. S. Ding, Y. C. Zhang and J. Z. Li, Org. Chem. Front., 2017,
1528-1532.
4,
13 (a) J. C. Chen, T. Y. Wang, Y. P. Liu, T. Wang, A. Lin, H. Q. Yao
and J. Y. Xu, Org. Chem. Front., 2017, , 622-626; (b) Y.
Wang, Y. Wang, Q. Zhang and D. Li, Org. Chem. Front., 2017,
, 514-518; (c) J. Y. Jiao, Y. J. Mao, A. W. Feng, X. F. Li, M. T.
4
4
Li and X. H. Zhang, Tetrahedron, 2017, 73, 1482-1488; (d) Z.
Y. Wu, Y. Q. He, C. W. Ma and G. S. Huang, Asian J. Org.
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