Ligand-Assisted Palladium(II)/(IV) Oxidation for sp3C H Fluorination

Article abstract of DOI:10.1002/adsc.201600015

The direct functionalization of inert sp³C H bonds is limited to a few bond types. Although the activation of sp³C H bonds can be accomplished under mild conditions using palladium catalysts, the subsequent functionalization is not trivial due to the high energy required to convert palladium(II) to palladium(IV). We have systematically studied the palladium oxidation using computation-guided experiments for reactions involving strong chelation control. We find that a mild external ligand could significantly accelerate the oxidation of palladium(II) to palladium(IV) for strong bidentate directing groups. The acceleration is believed to be a result of ligand stabilization of both the palladium(II) and palladium(IV) intermediates. (Figure presented.) .

Full text of DOI:10.1002/adsc.201600015

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DOI: 10.1002/adsc.201600015
Very Important Publication
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Ligand-Assisted Palladium(II)/(IV) Oxidation for sp C H
Fluorination
Huan Sun,+a Yi Zhang,+a Ping Chen,+a Yun-Dong Wu,a,b,* Xinhao Zhang,a,*
and Yong Huanga,*
a
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University, Shenzhen
Graduate School, Shenzhen 518055, Peopleꢀs Republic of China
Fax: (+86)-755-2603-3174; e-mail: wuyd@pkusz.edu.cn or zhangxh@pkusz.edu.cn or huangyong@pkusz.edu.cn
College of Chemistry, Peking University, Beijing 100871, Peopleꢀs Republic of China
b
+
These authors contributed equally to this work.
Received: January 5, 2016; Revised: February 18, 2016; Published online: April 13, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600015.
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Abstract: The direct functionalization of inert sp C
trol. We find that a mild external ligand could signifi-
H bonds is limited to a few bond types. Although the cantly accelerate the oxidation of palladium(II) to
activation of sp C H bonds can be accomplished palladium(IV) for strong bidentate directing groups.
under mild conditions using palladium catalysts, the The acceleration is believed to be a result of ligand
subsequent functionalization is not trivial due to the stabilization of both the palladium(II) and palladi-
high energy required to convert palladium(II) to pal- um(IV) intermediates.
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ladium(IV). We have systematically studied the pal-
ladium oxidation using computation-guided experi- Keywords: C H activation; directing group; fluori-
ments for reactions involving strong chelation con- nation; oxidation; palladium
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Introduction
be fast and inconsequential. However, isotope experi-
ments show that the C H metallation step is often
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Direct inert sp C H bond functionalization is argua- not the rate-limiting step for palladium-catalyzed re-
bly one of the most effective methods to chemically actions using a strong bidentate DG.[8c,9] In fact, the
modify hydrocarbon feedstocks.[1] Besides reactivity- C H palladation step could occur at room tempera-
À
dictated radical reactions, the use of a directing group ture without an external ligand for these DGs.[5a,10]
À
(DG) is essential for selective C H bond cleavage Considering the reductive elimination is generally fast
and subsequent functionalization. So far, there are for a Pd(IV) species,[11] the oxidation of Pd(II) to
two types of general DGs specifically designed to Pd(IV) becomes particularly important for this type
3
3
[12]
À
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target inert sp C H bonds: weak coordinating DGs of sp C H functionalization reactions (Scheme 1).
developed by Yu[2] and strong chelating DGs pio- So far, very few studies have been concerned with
neered by Daugulis.[3] The common perception is that this part of the catalytic cycle from both experimental
single point, weakly coordinating DGs require an ex- and theoretical standpoints.[6f,13] Herein, we report our
[4]
À
ternal ligand to assist the key C H metallation step,
mechanistic and computational findings of a drastic
while strong chelating DGs do not.[5] Yu and co-work- ligand effect on the oxidation of Pd for strong chelat-
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ers have shown that amino acid and pyridine ligands ing group-directed sp C H fluorination reactions.
À
can drastically lower the activation barrier of the C
Scheme 1 shows the common mechanistic cycle for
H cleavage step for weak DGs.[6] In sharp contrast, b-functionalization of aliphatic amides bearing
the Daugulis-type strong DGs are primarily used in a strong bidentate DG. Generally, fast chelation of
the absence of a ligand.[7] So far, mechanistic studies the substrate to Pd(OAc)2 is followed by a facile C H
À
of these reactions have primarily been focused on the palladation via the concerted metallation deprotona-
À
C H bond cleavage step of the Pd(II)–Pd(IV)–Pd(II) tion (CMD) mechanism to give the key palladium
cycle,[8] which is the most common catalysis pathway. bridged [5,5] metallacycle B.[5a,7f] The effects of DG
The oxidation of Pd(II) to Pd(IV) is often assumed to and carboxylic anion have been extensively investigat-
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Scheme 1. Catalytic cycle of sp C H functionalization reactions involving a strong chelating DG.
ed for the formation of this intermediate.[5a,c,14] The rafluoroborate (“F”) as the oxidant. This result indi-
À
subsequent Pd(II) to Pd(IV) oxidation (Scheme 1, B cated that the C F reductive elimination might be
to C), on the other hand, has been largely overlooked. faster than the ligand exchange in this scenario. When
Due to the high energy of Pd(IV), the oxidation of we removed AgSCF3 from the reaction, the fluorina-
Pd is not easy. Often, experimentalists screen oxidants tion product was still observed. During this study, we
based on their redox potential. As a result, types of found a very interesting correlation of yield and the
functionalization are quite limited.[7] A major part of electronics of the directing group. While DG-A re-
the literature is concentrated on arylation, alkylation sulted in only a trace amount of the fluorinated prod-
and oxygenation, etc. Many other seemingly viable uct, yield was significantly improved with substrates
bond formations have not been accomplished due to bearing a less electron-donating heterocycle as DG.
the problematic Pd oxidation step. In this work, we The reaction using 8-aminoquinoxaline DG-D afford-
report our mechanistic studies of the effects of DG ed the desired product in 42% yield.
on this oxidation step that led to identification of qui-
noxaline as an external ligand to assist C H fluorina- provement using 8-aminoquinoxaline as DG. The key
tion reactions.
We were intrigued by this substantial yield im-
À
question is which step of the catalytic cycle is acceler-
ated. In order to answer this question, we carried out
a series of mechanistic studies. Firstly, a density func-
À
Results and Discussion
tional theory (DFT) study on the C H insertion step
was conducted for both 8-aminoquinoline and 8-ami-
We recently published a ligand exchange strategy for noquinoxaline phenylpropanamides (Figure 1).[16]
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C(sp ) SCF3 bond synthesis by swopping a fluoride
Although the more electron-donating 8-aminoqui-
off a Pd(IV) center with a SCF3 anion.[15] In this pro- noline DG provides better stabilization than 8-amino-
À
cess, Selectfluor was used as a standalone oxidant. We quinoxaline for each species during the C H cleavage
À
wondered whether this ligand exchange strategy could process, the calculated free energy barriers for C H
3
be exploited for inert sp C H bond functionalization palladation are 19.9 and 18.5 kcalmolÀ1 for 8-amino-
À
(Scheme 2). Interestingly, although the b-trifluorome- quinoline (Q1-TS1) and 8-aminoquinoxaline (Q2-
thylthiolated product could not be obtained, the cor- TS1) substrates, respectively. The slightly higher barri-
responding b-fluoro product was isolated in a small er for 8-aminoquinoline substrate, is attributed to the
quantity using 1-fluoro-2,4,6-trimethylpyridinium tet- exergonic intermediate Q1-Int1. The activation free
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Scheme 2. Initial investigations of the effect of DG on C H fluorination reactions.
[16]
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Figure 1. Free energy profile for the C H insertion step calculated with M06.
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energy difference of the C H activation is very small
Experimentally, the C H palladation intermediate
(1.4 kcalmolÀ1). Therefore, the improved efficiency was identified for both substrates 1a and 1e with
likely originates from later steps in the catalytic cycle. a high resolution mass spectrometer (HR-MS) by
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Scheme 3. Mechanistic experiments for the role of DG.
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using collision-induced dissociation and ion-mobility ior using the substrate mixture has only one plausible
techniques (Scheme 3a, see the Supporting Informa- explanation: 1d acts as a promotor/ligand for the fluo-
tion for spectra),[17] suggesting that the C H activa- rination of 1a, while 1a acts as an inhibitor for the re-
À
tion could occur smoothly using either DG under the action of 1d.
reaction conditions (Scheme 3a). Secondly, we deter-
We suspected that the role of 1d in promoting the
mined the kinetic isotope effect for substrates 1a and reaction of 1a as being a ligand to accelerate Pd oxi-
1d (Scheme 3b). Interestingly, a smaller KIE value dation. To test this idea, we replaced 1d with N-(qui-
was obtained for 1a compared to 1d (1.4 vs. 2.2). This noxalin-5-yl)acetamide 4, a close analogue without b-
À
result indicates the C H cleavage is the rate-limiting hydrogens. As expected, 4 promoted the b-fluorina-
step for 1d (KIE=2.2), but may not for 1a (KIE= tion of 1a with similar efficiency as 1d (Scheme 4a),
1.4). Based on these data, we proposed that Pd oxida- confirming that both 1d and 4 can serve as standalone
tion using N-fluoropyridinium salts is difficult (rate- ligands for this reaction. Considering that the Pd in-
limiting) for 1a and the subsequent fluorination is termediates have only one vacant site left, we won-
suppressed. On the other hand, the analogue oxida- dered whether the N,N-chelation control is required
tion step is somehow accelerated for 1d, making the for this ligand. We were very pleased to find that the
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C H insertion step rate-limiting for this substrate. fluorination occurs in high yield when simple qui-
However, this rather small KIE difference is not de- noxaline 5 was used! Product 2a was isolated in 90%
finitive, theoretical calculations were performed and yield (Scheme 4b).
verified the shift of the rate-limiting step from 1a to
1d (vide infra).
To understand the function of ligand 5, we carried
out theoretical calculations for the Pd oxidation and
In order to understand the reason behind this subsequent steps. Ligand 5 does not alter the poten-
À
“likely” shift of rate-limiting step, we performed fur- tial energy surface for the C H cleavage step, as the
ther experiments. Both 1a and 1d underwent smooth Pd center is fully coordinated during the CMD pro-
b-acetoxylation using a literature protocol,[7f] again cess (Figure 2, Q1-Int1, Q1-TS1 and Q1-Int2). In the
À
suggesting that the C H activation step is not a prob- absence of quinoxaline (5), comparable relative free
lem for either substrate. However, when a 1:1 mixture energies were calculated for Q1-TS1 and Q1-TS2-
of 1a and 1d was subjected to the same reaction con- HOAc. Although the DG for Q1-TS1 is slighly higher
ditions, the acetoxylation occurred to 1a exclusively, (4.3 kcalmolÀ1) than that for Q1-TS2-HOAc, both
not 1d (Scheme 3c). We believe that 8-aminoquino- steps are mechanistically very different and computa-
line is a stronger chelator for Pd than 8-aminoqui- tional errors would be too significant to draw a defini-
noxaline, therefore attracting all metal catalyst to- tive conclusion on the rate-determining step. In fact,
À
wards the reaction of 1a.
a small KIE (1.4, Scheme 3b) suggests that the C H
However, the situation becomes complicated for cleavage step might not be rate-limiting. In contrast,
the b-fluorination reaction. Under the same condi- we found that 5 drastically lowers the energy of Q1-
tions, 1a reacted in very low conversion (10%), while Int2-Q by about 10.0 kcalmolÀ1, compared to the
1d afforded the fluorinated product 2d in 71% yield. “ligand-free” complex Q1-Int2. In addition, the rela-
When a 1:1 mixture of 1a and 1d was used, it was tive free energy of transition state for Pd oxidation
very surprising that 1a was fluorinated almost exclu- Q1-TS2-Q and Pd(IV) intermediate Q1-Int3-Q is also
sively, although it did not work by itself (Scheme 3d). stabilized significantly. The activation free energy for
On the other hand, the fluorination of 1d was sup- the oxidation of Pd(II) is 14.1 kcalmolÀ1 with 5 vs.
pressed in the presence of 1a! This unexpected behav- 16.4 kcalmolÀ1 without 5. Comparing the C H cleav-
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Scheme 4. Discovery of ligands that promote b-fluorination of C H bonds.
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Figure 2. Free energy profile for for the oxidation of Pd(II) intermediates in the absence and presence of quinoxaline.
age and oxidation steps, Q1-TS2-Q is more stable
As predicted, we found a large primary isotope
than Q1-TS1 by 16.5 kcalmolÀ1. As a result, it is safe effect for the reaction of 1a in the presence of 5
À
À
to conclude that the step of C H bond activation be- (Scheme 5a), confirming that the C H cleavage step
comes the rate-determining step. Therefore, the KIE becomes rate-limiting in the presence of ligand 5. In
of the fluorination of 1a would become significant the absence of this important ligand, the oxidation of
when 5 is used as ligand.
Pd is rate-limiting, and is very slow, resulting in very
Scheme 5. Isotope and ligand effects.
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poor yield (Scheme 3b). These data clearly show that Conclusions
quinoxaline shifts the rate-limiting step by lowering
the activation energy of the oxidation step considera- In summary, we have identified a significant differ-
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bly. In addition to quinoxazline, other nitrogen-con- ence for sp C H fluorination reactions using differ-
taining aryl ligands were also examined (Scheme 5b). ent chelating directing groups. Computational and ex-
Quinoxaline clearly stands out as the best promoter perimental investigation concludes a change of rate-
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for the sp C H fluorination. Very interestingly, quin- limiting step using 8-aminoquinoline vs. 8-aminoqui-
oline failed to improve this reaction. We suspect that noxaline as DG, by affecting the key Pd(II) to Pd(IV)
the quinoline nitrogen is too basic and interferes by oxidation step. This finding led to the discovery of
remaining on the palladium throughout the reaction.
a simple ligand capable of lowering the activation
The requirement of external ligand 5 to assist Pd energy for the oxidation of Pd. This intriguing mecha-
À
oxidation is in agreement with very recent reports of nistic journey provides new clues into oxidative C H
b-fluorination where a stoichiometric amount of Ag functionalization reactions. We expect these results
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salts was required to facilitate this rather difficult oxi- will stimulate the development of new C H function-
dation process.[4e,10,18] The use of either quinoxaline as alization reactions.
ligand or 8-aminoquinoxaline as DG shows a clear ad-
vantage by eliminating precious metal oxidants. In the
case of using 8-aminoquinoxaline as DG, the substrate Experimental Section
itself serves as the ligand to assist the Pd oxidation
and no external ligand is required anymore. The reac- General Methods and Materials
tion scope was briefly examined for the 8-aminoqui-
All reactions were carried out under an argon atmosphere
noxaline-directed fluorination (Table 1). The reaction
(balloon) with dry solvents under anhydrous conditions.
is general for various arylpropanamides. Noticeably
Pd(OAc)2 was purchased from Sinocompound Technology
decreased yield was observed for simple aliphatic
amides. The use of quinoxaline as ligand shows a simi-
lar substrate scope for the 8-aminoquinoline sub-
strates.
Co., Ltd. 1-Fluoro-2,4,6-trimethylpyridin-1-ium tetrafluoro-
borate was purchased from TCI. All other reagents were
purchased and used without further purification unless
specified otherwise. Solvents for chromatography were of
technical grade and distilled prior to use. Flash chromatog-
raphy was performed using 200–300 mesh silica gel with the
indicated solvent system according to standard techniques.
Analytical thin-layer chromatography (TLC) was performed
on pre-coated, glass-backed silica gel plates. Visualization of
the developed chromatogram was performed by UV absorb-
Table 1. Substrate scope for 8-aminoquinoxaline-directed
fluorination.[a]
1
ance (254 nm). H NMR and 13C NMR data were recorded
on Bruker 400 M nuclear resonance spectrometers unless
otherwise specified, respectively. Chemical shifts (d) in ppm
are reported relative to the residual signals of chloroform
(1H 7.27 ppm or 13C 77.16 ppm). Multiplicities are described
as: s (singlet), bs (broad singlet), d (doublet), t (triplet), q
(quartet), m (multiplet); and coupling constants (J) are re-
ported in Hertz (Hz). 13C NMR spectra were recorded with
total proton decoupling. HR-MS (ESI) analysis was per-
formed by The Analytical Instrumentation Center at Peking
University, Shenzhen Graduate School and HR-MS data are
reported with ion mass/charge (m/z) ratios as values in
atomic mass units.
En- R, Product
try
Yield En- R, Product
Yield
[%]
[%]
try
1
2
3
4
5
6
7
8
Ph, 2d
71
80
90
71
68
9
m-Cl-C6H4, 2l
m-Br-C6H4, 2m 87
o-Cl-C6H4, 2n 69
o-Me-C6H4, 2o 85
2-naphthyl, 2p 91
53
p-Br-C6H4, 2e
p-F-C6H4, 2f
p-Cl-C6H4, 2g
p-CF3-C6H4, 2h
p-CN-C6H4H4, 2i 48
p-NO2-C6H4, 2j
p-Me-C6H4, 2k
10
11
12
13
General Procedure for Starting Material (1a–1s)
Synthesis
14[b] CyCH2, 2q
15[b] Et, 2r
58
45
56
To an oven-dried flask, the acid (1.0 equiv.), DMF (1 drop)
and DCM were added under Ar. Oxalyl chloride (1.5 equiv.)
was added dropwise under ice bath cooling. The mixture
was stirred for 3 h at room temperature and the solvent was
removed under vacuum. The resulting acid chloride was
used immediately without further purification.[19]
To a flask with the acid chloride and THF, a THF solvent
of quinoxalin-5-amine[20] and NEt3 was added dropwise
under ice bath cooling. Then the mixture was stirred over-
night at room temperature. Then the solvent was removed
56
76
16[b] n-Bu, 2s
[a]
The reactions were performed using
1
(0.1 mmol),
Pd(OAc)2 (10 mol%), 1-fluoro-2,4,6-trimethylpyridinium
tetrafluoroborate (“F”, 1.5 equiv.) in toluene (3 mL) for
4–8 h at 808C under an argon atmosphere. Isolated
yields are reported.
20 mol% Pd(OAc)2 was used and the reaction was car-
ried out at 1108C.
[b]
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and the residue was dissolved in DCM and washed with
aqueous NaHCO3 (3 times), 1N HCl and brine. The organic
phase was dried with Na2SO4, concentrated and purified by
flash column to give the desired product.
125.54, 123.27, 117.19, 39.11, 31.12; HR-MS (ESI): m/z=
368.0981, calcd. for C18H14F3N3NaO ([M+Na]+): 368.0987
3-(4-Cyanophenyl)-N-(quinoxalin-5-yl)propanamide (1i):
1
yellow solid; H NMR (400 MHz, chloroform-d): d=9.41 (s,
3-Phenyl-N-(quinolin-8-yl)propanamide (1a):[21] white
1H), 8.87 (d, J=1.9 Hz, 1H), 8.75 (dd, J=7.3, 1.7 Hz, 1H),
8.66 (d, J=1.9 Hz, 1H), 7.83–7.66 (m, 2H), 7.54 (d, J=
8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 3.17 (t, J=7.5 Hz,
2H), 2.88 (t, J=7.5 Hz, 2H); 13C NMR (101 MHz, chloro-
form-d): d=169.88, 146.30, 145.45, 142.80, 142.40, 134.23,
133.07, 132.40, 131.11, 129.33, 123.26, 118.94, 117.14, 110.24,
38.63, 31.23; HR-MS (ESI): m/z=325.1067, calcd. for
C18H14N4ONa ([M+Na]+): 325.1065.
1
solid; H NMR (400 MHz, chloroform-d): d=9.81 (s, 1H),
8.90–8.70 (m, 2H), 8.16 (dd, J=8.3, 1.6 Hz, 1H), 7.63–7.48
(m, 2H), 7.45 (dd, J=8.2, 4.2 Hz, 1H), 7.31 (d, J=4.4 Hz,
4H), 7.26–7.17 (m, 1H), 3.18 (t, J=7.8 Hz, 2H), 2.92 (m, J=
7.7 Hz, 2H); 13C NMR (101 MHz, chloroform-d): d=170.90,
148.23, 140.91, 138.44, 136.50, 134.56, 128.69, 128.54, 128.06,
127.56, 126.38, 121.72, 121.60, 116.64, 39.87, 31.62; HR-MS
(ESI): m/z=299.1155, calcd. for C18H16N2NaO ([M+Na]+):
299.1160.
3-(4-Nitrophenyl)-N-(quinoxalin-5-yl)propanamide (1j):
1
yellow solid; H NMR (400 MHz, chloroform-d): d=9.44 (s,
3-Phenyl-N-(quinoxalin-5-yl)propanamide (1d): white
solid; H NMR (300 MHz, chloroform-d): d=9.46 (s, 1H),
1H), 8.91 (d, J=1.8 Hz, 1H), 8.79 (dd, J=7.3, 1.8 Hz, 1H),
8.70 (d, J=1.8 Hz, 1H), 8.22–8.09 (m, 2H), 7.86–7.73 (m,
2H), 7.53–7.41 (m, 2H), 3.25 (t, J=7.5 Hz, 2H), 2.94 (t, J=
7.5 Hz, 2H); 13C NMR (100 MHz, chloroform-d): d=169.83,
148.55, 146.82, 145.60, 143.01, 142.49, 134.31, 133.21, 131.26,
129.49, 123.99, 123.49, 117.30, 38.74, 31.10; HR-MS (ESI):
m/z=323.1147, calcd. for C17H15N4O3 ([M+H]+): 323.1144.
N-(Quinoxalin-5-yl)-3-(p-tolyl)propanamide (1k): white
1
8.91 (d, J=1.9 Hz, 1H), 8.83 (dd, J=6.1, 2.9 Hz, 1H), 8.71
(d, J=1.8 Hz, 1H), 7.86–7.72 (m, 2H), 7.30 (d, J=4.4 Hz,
4H), 7.22 (m, 1H), 3.15 (t, J=7.8 Hz, 2H), 2.89 (t, J=
7.6 Hz, 2H); 13C NMR (75 MHz, chloroform-d): d=170.91,
145.49, 143.00, 142.43, 140.68, 134.61, 133.30, 131.33, 128.75,
128.53, 126.48, 123.18, 117.22, 39.81, 31.53; HR-MS (ESI):
m/z=300.1108, calcd. for C17H15N3NaO ([M+Na]+):
300.1113.
1
solid; H NMR (400 MHz, chloroform-d): d=9.45 (s, 1H),
8.89 (d, J=1.9 Hz, 1H), 8.82 (dd, J=6.8, 2.3 Hz, 1H), 8.69
(d, J=1.8 Hz, 1H), 7.86–7.70 (m, 2H), 7.18 (d, J=7.8 Hz,
2H), 7.11 (d, J=7.8 Hz, 2H), 3.11 (t, J=7.7 Hz, 2H), 2.87
(t, J=7.7 Hz, 2H), 2.31 (s, 3H); 13C NMR (101 MHz,
chloroform-d): d=170.97, 145.41, 142.93, 142.36, 137.52,
135.90, 134.59, 133.24, 131.26, 129.36, 128.34, 123.09, 117.16,
39.88, 31.07, 21.11; HR-MS (ESI): m/z=314.1262, calcd. for
C18H17N3ONa ([M+Na]+): 314.1269.
3-(4-Bromophenyl)-N-(quinoxalin-5-yl)propanamide (1e):
1
white solid; H NMR (500 MHz, chloroform-d): d=9.40 (s,
1H), 8.90 (d, J=1.8 Hz, 1H), 8.79 (dd, J=7.3, 1.8 Hz, 1H),
8.69 (d, J=1.8 Hz, 1H), 7.83–7.71 (m, 2H), 7.46–7.35 (m,
2H), 7.21–7.11 (m, 2H), 3.09 (t, J=7.6 Hz, 2H), 2.86 (t, J=
7.6 Hz, 2H); 13C NMR (126 MHz, chloroform-d): d=170.45,
145.51, 142.97, 142.44, 139.64, 134.46, 133.22, 131.78, 131.24,
130.32, 123.27, 120.26, 117.21, 39.46, 30.86; HR-MS (ESI):
m/z=378.0210, calcd. for C17H14BrN3NaO ([M+Na]+):
378.0218.
3-(3-Chlorophenyl)-N-(Quinoxalin-5-yl)propanamide (1l):
1
white solid; H NMR (400 MHz, chloroform-d): d=9.44 (s,
1H), 8.91 (d, J=1.8 Hz, 1H), 8.81 (dd, J=7.0, 2.1 Hz, 1H),
8.71 (d, J=1.8 Hz, 1H), 7.85–7.73 (m, 2H), 7.29 (d, J=
1.8 Hz, 1H), 7.25–7.15 (m, 3H), 3.12 (t, J=7.7 Hz, 2H), 2.88
(t, J=7.7 Hz, 2H); 13C NMR (101 MHz, chloroform-d): d=
170.41, 145.52, 142.99, 142.70, 142.47, 134.48, 134.46, 133.27,
131.29, 130.00, 128.68, 126.80, 126.69, 123.28, 117.25, 39.35,
3-(4-Fluorophenyl)-N-(quinoxalin-5-yl)propanamide (1f):
1
white solid; H NMR (400 MHz, chloroform-d): d=9.42 (s,
1H), 8.90 (d, J=1.8 Hz, 1H), 8.81 (dd, J=6.9, 2.1 Hz, 1H),
8.69 (d, J=1.8 Hz, 1H), 7.86–7.71 (m, 2H), 7.32–7.18 (m,
2H), 6.98 (t, J=8.5 Hz, 2H), 3.12 (t, J=7.6 Hz, 2H), 2.86 (t,
J=7.6 Hz, 2H); 13C NMR (101 MHz, chloroform-d): d=
170.64, 162.88, 160.45, 145.52, 143.01, 142.42, 136.30, 134.53,
133.26, 131.28, 130.00, 129.93, 123.26, 117.22, 115.60, 115.39,
39.85, 30.69; 19F NMR (376 MHz, chloroform-d): d=
À116.92 (s, 1F); HR-MS (ESI): m/z=318.1014, calcd. for
C17H14FN3NaO ([M+Na]+): 318.1019.
31.08; HR-MS (ESI): m/z=334.0716, calcd.
for
C17H14ClN3NaO ([M+Na]+): 334.0723.
3-(3-Bromophenyl)-N-(quinoxalin-5-yl)propanamide
(1m): white solid; 1H NMR (400 MHz, chloroform-d): d=
9.43 (s, 1H), 8.91 (d, J=1.9 Hz, 1H), 8.80 (dd, J=6.9,
2.0 Hz, 1H), 8.71 (d, J=1.9 Hz, 1H), 7.85–7.73 (m, 2H),
7.45 (t, J=1.8 Hz, 1H), 7.33 (dt, J=7.9, 1.6 Hz, 1H), 7.22
(d, J=7.6 Hz, 1H), 7.15 (t, J=7.7 Hz, 1H), 3.11 (t, J=
7.7 Hz, 2H), 2.88 (t, J=7.7 Hz, 2H); 13C NMR (101 MHz,
chloroform-d): d=170.37, 145.52, 143.00, 142.46, 134.47,
133.26, 131.58, 131.27, 130.29, 129.62, 127.27, 123.28, 122.74,
117.24, 39.36, 31.05; HR-MS (ESI): m/z=378.0214, calcd.
for C17H14BrN3NaO ([M+Na]+): 378.0218.
3-(4-Chlorophenyl)-N-(quinoxalin-5-yl)propanamide (1g):
1
yellow solid; H NMR (400 MHz, chloroform-d): d=9.41 (s,
1H), 8.90 (d, J=1.9 Hz, 1H), 8.80 (dd, J=7.0, 2.0 Hz, 1H),
8.69 (d, J=1.9 Hz, 1H), 7.84–7.74 (m, 2H), 7.29–7.19 (m,
4H), 3.11 (t, J=7.6 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H);
13C NMR (101 MHz, chloroform-d): d=170.49, 145.52,
142.99, 142.44, 139.13, 134.48, 133.23, 132.23, 131.26, 129.92,
128.83, 123.28, 117.21, 39.56, 30.81; HR-MS (ESI): m/z=
334.0716, calcd. for C17H14ClN3NaO ([M+Na]+): 334.0723.
N-(Quinoxalin-5-yl)-3-[4-(trifluoromethyl)phenyl]propan-
3-(2-Chlorophenyl)-N-(quinoxalin-5-yl)propanamide (1n):
1
white solid; H NMR (400 MHz, chloroform-d): d=9.47 (s,
1H), 8.91 (d, J=1.8 Hz, 1H), 8.83 (dd, J=6.5, 2.5 Hz, 1H),
8.72 (d, J=1.8 Hz, 1H), 7.83–7.73 (m, 2H), 7.40–7.31 (m,
2H), 7.24–7.13 (m, 2H), 3.28 (t, J=7.7 Hz, 2H), 2.93 (t, J=
7.7 Hz, 2H); 13C NMR (101 MHz, chloroform-d): d=170.64,
145.52, 143.01, 142.47, 138.27, 134.61, 134.08, 133.30, 131.31,
130.85, 129.75, 128.07, 127.18, 123.21, 117.20, 37.76, 29.54;
HR-MS (ESI): m/z=334.0718, calcd. for C17H14ClN3NaO
([M+Na]+): 334.0723.
1
amide (1h): white solid; H NMR (400 MHz, chloroform-d):
d=9.41 (s, 1H), 8.88 (d, J=1.8 Hz, 1H), 8.79 (dd, J=7.2,
1.8 Hz, 1H), 8.66 (d, J=1.8 Hz, 1H), 7.84–7.68 (m, 2H),
7.53 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 3.18 (t, J=
7.6 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H); 13C NMR (101 MHz,
chloroform-d): d=170.23, 145.47, 144.81, 142.90, 142.41,
134.38, 133.17, 131.19, 128.87, 128.61, 125.65, 125.61, 125.57,
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N-(Quinoxalin-5-yl)-3-(o-tolyl)propanamide (1o): white
solid; H NMR (400 MHz, chloroform-d): d=9.47 (s, 1H),
degassed with argon 3 times. The mixture was stirred at
808C for 6 h and cooled to room temperature. Then the
mixture was diluted with DCM, and filtered through a short
pad of Celite. After concentration under vacuum, the crude
reaction mixture was purified by silica gel flash chromatog-
raphy.
1
8.90 (d, J=1.8 Hz, 1H), 8.84 (dd, J=6.6, 2.4 Hz, 1H), 8.70
(d, J=1.8 Hz, 1H), 7.84–7.72 (m, 2H), 7.25–7.20 (m, 1H),
7.15 (dtd, J=8.6, 5.9, 2.7 Hz, 3H), 3.16 (t, J=7.7 Hz, 2H),
2.87 (t, J=7.7 Hz, 2H), 2.39 (s, 3H); 13C NMR (101 MHz,
chloroform-d): d=171.02, 145.47, 142.96, 142.41, 138.77,
136.12, 134.59, 133.26, 131.29, 130.49, 128.68, 126.58, 126.33,
123.15, 117.15, 38.42, 28.76, 19.48; HR-MS (ESI): m/z=
314.1265, calcd. for C18H17N3ONa ([M+Na]+): 314.1269.
3-(Naphthalen-2-yl)-N-(quinoxalin-5-yl)propanamide (1p):
3-Fluoro-3-phenyl-N-(quinolin-8-yl)propanamide
(2a):
1
white solid; H NMR (400 MHz, chloroform-d): d=10.00 (s,
1H), 8.81 (dt, J=6.2, 1.7 Hz, 2H), 8.17 (dd, J=8.2, 1.7 Hz,
1H), 7.61–7.50 (m, 2H), 7.50–7.31 (m, 6H), 6.20 (dd, J=9.2,
3.6 Hz, 0.5H), 6.09 (dd, J=9.1, 3.6 Hz, 0.5H), 3.27 (td, J=
15.2, 9.1 Hz, 1H), 3.04 (ddd, J=34.1, 15.2, 3.6 Hz, 1H);
13C NMR (101 MHz, chloroform-d): d=167.54, 167.51 (d,
J=3.0 Hz), 148.40, 139.20, 139.01 (d, J=19.0 Hz), 138.47,
136.50, 134.37, 128.90, 128.84, 128.05, 127.49, 125.71, 125.64
(d, J=7.0 Hz), 122.01, 121.81 (d, J=20.0 Hz), 116.89, 92.19,
90.48 (d, J=171.0 Hz), 46.46, 46.20 (d, J=26.0 Hz);
19F NMR (376 MHz, chloroform-d): d=À173.70 (s, 1F);
HR-MS (ESI): m/z=317.1058, calcd. for C18H15N2FNaO
([M+Na]+): 317.1066.
1
white solid; H NMR (400 MHz, chloroform-d): d=9.42 (s,
1H), 8.91–8.76 (m, 2H), 8.52 (d, J=1.8 Hz, 1H), 7.85–7.67
(m, 6H), 7.51–7.38 (m, 3H), 3.31 (t, J=7.6 Hz, 2H), 2.98 (t,
J=7.7 Hz, 2H); 13C NMR (101 MHz, chloroform-d): d=
170.88, 145.39, 142.89, 142.32, 138.09, 134.54, 133.76, 133.21,
132.32, 131.23, 128.40, 127.72, 127.60, 127.10, 126.79, 126.16,
125.52, 123.14, 117.20, 39.71, 31.72; HR-MS (ESI): m/z=
350.1261, calcd. for C21H17N3ONa ([M+Na]+): 350.1269.
4-Cyclohexyl-N-(quinoxalin-5-yl)butanamide (1q): yellow
1
solid; H NMR (300 MHz, chloroform-d): d=9.49 (s, 1H),
3-Fluoro-3-phenyl-N-(quinoxalin-5-yl)propanamide (2d):
1
8.92 (d, J=1.9 Hz, 1H), 8.83 (dd, J=6.0, 3.1 Hz, 1H), 8.74
(d, J=1.9 Hz, 1H), 7.85–7.71 (m, 2H), 2.54 (t, J=7.6 Hz,
2H), 1.92–1.57 (m, 9H), 1.31 (m, 4H), 0.99–0.84 (m, 2H);
13C NMR (75 MHz, chloroform-d): d=172.07, 145.47,
143.02, 142.43, 134.76, 133.34, 131.36, 123.02, 117.14, 38.57,
37.61, 37.13, 33.40, 26.78, 26.48, 23.09; HR-MS (ESI): m/z=
320.1736, calcd. for C18H23N3NaO ([M+Na]+): 320.1739.
N-(Quinoxalin-5-yl)pentanamide (1r): yellow solid;
1H NMR (300 MHz, chloroform-d): d=9.50 (s, 1H), 8.90
(dd, J=10.8, 2.0 Hz, 1H), 8.83 (dd, J=6.0, 3.1 Hz, 1H), 8.73
(dd, J=10.9, 2.0 Hz, 1H), 7.84–7.70 (m, 2H), 2.65–2.46 (m,
2H), 1.89–1.71 (m, 2H), 1.57–1.34 (m, 2H), 0.99 (t, J=
7.3 Hz, 3H); 13C NMR (75 MHz, chloroform-d): d=172.04,
145.48, 143.05, 142.44, 134.77, 133.34, 131.36, 123.04, 117.12,
38.05, 27.79, 22.54, 13.98; HR-MS (ESI): m/z=252.1106,
calcd. for C13H15N3NaO ([M+Na]+): 252.1113.
white solid; H NMR (400 MHz, chloroform-d): d=9.70 (s,
1H), 8.92 (d, J=1.9 Hz, 1H), 8.85 (dd, J=7.4, 1.7 Hz, 1H),
8.75 (d, J=1.9 Hz, 1H), 7.86–7.74 (m, 2H), 7.49–7.33 (m,
5H), 6.18 (dd, J=9.1, 3.5 Hz, 0.5H), 6.06 (dd, J=9.1,
3.5 Hz, 0.5H), 3.25 (td, J=15.4, 9.1 Hz, 1H), 3.04 (ddd, J=
33.9, 15.3, 3.6 Hz, 1H); 13C NMR (101 MHz, chloroform-d):
d=167.58, 167.56 (d, J=2.0 Hz), 145.59, 143.01, 142.61,
138.96, 138.77 (d, J=19.0 Hz), 134.43, 133.38, 131.23, 128.99,
128.89, 125.64, 125.57 (d, J=7.0 Hz), 123.62, 117.50, 92.14,
90.43 (d, J=171 Hz), 46.43, 46.17 (d, J=26.0 Hz); 19F NMR
(376 MHz, chloroform-d): d=À173.67 (s, 1F); HR-MS
(ESI): m/z=318.1014, calcd. for C17H14N3FNaO ([M+
Na]+): 318.1019.
3-(4-Bromophenyl)-3-fluoro-N-(quinoxalin-5-yl)propana-
1
mide (2e): white solid; H NMR (400 MHz, chloroform-d):
d=9.65 (s, 1H), 8.93 (d, J=1.8 Hz, 1H), 8.82 (dd, J=7.5,
1.6 Hz, 1H), 8.74 (d, J=1.8 Hz, 1H), 7.88–7.75 (m, 2H),
7.59–7.50 (m, 2H), 7.38–7.29 (m, 2H), 6.14 (dd, J=8.7,
4.0 Hz, 0.5H), 6.02 (dd, J=8.7, 4.0 Hz, 0.5H), 3.22 (td, J=
15.5, 8.7 Hz, 1H), 3.02 (ddd, J=31.9, 15.2, 4.0 Hz, 1H);
13C NMR (101 MHz, chloroform-d): d=167.14, 167.10 (d,
J=4.0 Hz), 145.63, 143.03, 142.64, 138.02, 137.82 (d, J=
20.0 Hz), 134.30, 133.34, 132.08, 131.82, 131.22, 127.36,
127.29 (d, J=7.0 Hz), 123.75, 123.03, 117.54, 91.49, 89.77 (d,
J=172 Hz), 46.23, 45.97 (d, J=26.0 Hz); 19F NMR
(376 MHz, chloroform-d): d=À174.67 (s, 1F); HR-MS
(ESI): m/z=396.0126, calcd. for C17H13N3FBrNaO ([M+
Na]+): 396.0124.
N-(Quinoxalin-5-yl)heptanamide (1s): yellow solid;
1H NMR (500 MHz, chloroform-d): d=9.49 (s, 1H), 8.91 (d,
J=1.8 Hz, 1H), 8.83 (dd, J=6.9, 2.2 Hz, 1H), 8.74 (d, J=
1.8 Hz, 1H), 7.86–7.70 (m, 2H), 2.56 (t, J=7.6 Hz, 2H), 1.82
(p, J=7.6 Hz, 2H), 1.50–1.40 (m, 2H), 1.35 (tq, J=6.2,
2.9 Hz, 4H), 0.90 (td, J=5.8, 4.7, 2.1 Hz, 3H); 13C NMR
(126 MHz, chloroform-d): d=172.06, 145.44, 143.01, 142.44,
134.76, 133.35, 131.36, 123.01, 117.15, 38.31, 31.70, 29.07,
25.68, 22.64, 14.17; HR-MS (ESI): m/z=280.1419, calcd. for
C15H19N3NaO ([M+Na]+): 280.1426.
2,2-D-3-Phenyl-N-(quinoxalin-5-yl)propanamide (1d-d2):
1
white solid; H NMR (500 MHz, chloroform-d): d=9.46 (s,
1H), 8.91 (d, J=1.8 Hz, 1H), 8.83 (dd, J=6.8, 2.3 Hz, 1H),
8.71 (d, J=1.8 Hz, 1H), 7.83–7.74 (m, 2H), 7.34–7.28 (m,
4H), 7.26–7.18 (m, 1H), 2.88 (s, 2H); 13C NMR (126 MHz,
chloroform-d): d=170.92, 145.51, 143.04, 142.43, 134.64,
133.33, 131.33, 128.88, 128.76, 128.53, 126.49, 123.20, 117.23,
39.69, 29.85; HR-MS (ESI): m/z=302.1239, calcd. for
C17H13D2N3NaO ([M+Na]+): 302.1238.
3-Fluoro-3-(4-fluorophenyl)-N-(quinoxalin-5-yl)propana-
1
mide (2f): white solid; H NMR (400 MHz, chloroform-d):
d=9.67 (s, 1H), 8.93 (d, J=1.8 Hz, 1H), 8.83 (dd, J=7.5,
1.6 Hz, 1H), 8.74 (d, J=1.8 Hz, 1H), 7.89–7.74 (m, 2H),
7.50–7.39 (m, 2H), 7.10 (t, J=8.6 Hz, 2H), 6.16 (dd, J=8.8,
3.9 Hz, 0.5H), 6.04 (dd, J=8.8, 3.9 Hz, 0.5H), 3.25 (td, J=
15.3, 8.8 Hz, 1H), 3.02 (ddd, J=32.2, 15.2, 3.9 Hz, 1H);
13C NMR (101 MHz, chloroform-d): d=167.30, 167.27 (d,
J=3.0 Hz), 145.62, 143.04, 142.62, 134.80, 134.59 (d, J=
21.0 Hz), 134.34, 133.35, 131.22, 127.71, 127.64, 127.62,
127.56, 123.71, 117.52, 116.01, 115.79, 91.55, 89.83 (d, J=
162.0 Hz), 46.32, 46.06 (d, J=26.0 Hz); 19F NMR (376 MHz,
chloroform-d): d=À112.66 (s, 1F), À171.73 (s, 1F); HR-MS
À
General Procedure for C H Fluorination
To a Schlenk tube were added SM (0.1 mmol), Pd(OAc)2
(10 mol%), 1-fluoro-2,4,6-trimethylpyridin-1-ium tetrafluor-
oborate (1.5 equiv.) and toluene (3 mL) and the tube was
Adv. Synth. Catal. 2016, 358, 1946 – 1957
1954
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FULL PAPERS
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(ESI): m/z=336.0918, calcd. for C17H13N3F2NaO ([M+
Na]+): 336.0924.
7.6 Hz, 2H), 7.22 (d, J=7.9 Hz, 2H), 6.12 (dd, J=9.0,
3.6 Hz, 0,5H), 6.03 (dd, J=9.1, 3.6 Hz, 0.5H), 3.25 (td, J=
15.3, 9.0 Hz, 1H), 3.02 (ddd, J=33.6, 15.2, 3.6 Hz, 1H), 2.37
(s, 3H); 13C NMR (126 MHz, chloroform-d): d=167.70,
167.68 (d, J=2.0 Hz), 145.57, 143.04, 142.60, 138.94, 135.95,
135.79 (d, J=16.0 Hz), 134.49, 133.41, 131.23, 129.55, 125.74,
125.69 (d, J=5.0 Hz), 123.59, 117.51, 91.98, 90.63 (d, J=
135.0 Hz), 46.32, 46.12 (d, J=20.0 Hz), 21.35; 19F NMR
(376 MHz, chloroform-d): d=À171.59 (s, 1F); HR-MS
(ESI): m/z=332.1173, calcd. for C18H16N3FNaO ([M+
Na]+): 332.1175.
3-(4-Chlorophenyl)-3-fluoro-N-(quinoxalin-5-yl)propana-
1
mide (2g): white solid; H NMR (500 MHz, chloroform-d):
d=9.65 (s, 1H), 8.92 (d, J=1.8 Hz, 1H), 8.82 (dd, J=7.6,
1.5 Hz, 1H), 8.74 (d, J=1.8 Hz, 1H), 7.88–7.75 (m, 2H),
7.39 (s, 4H), 6.14 (dd, J=8.7, 3.9 Hz, 0.5H), 6.05 (dd, J=
8.8, 4.0 Hz, 0.5H), 3.23 (td, J=15.4, 8.8 Hz, 1H), 3.02 (ddd,
J=32.0, 15.2, 3.9 Hz, 1H); 13C NMR (126 MHz, chloroform-
d): d=167.16, 167.13(d, J=3.0 Hz), 145.62, 143.03, 142.63,
137.48, 137.32 (d, J=16.0 Hz), 134.88, 134.31, 133.34, 131.21,
129.12, 127.08, 127.02 (d, J=6.0 Hz), 123.74, 117.53, 91.28,
89.91 (d, J=137.0 Hz), 46.22, 46.02 (d, J=20.0 Hz);
19F NMR (376 MHz, Cchloroform-d): d=À174.16 (s, 1F);
HR-MS (ESI): m/z=352.0625, calcd. for C17H13N3ClFNaO
([M+Na]+): 352.0629.
3-Fluoro-N-(quinoxalin-5-yl)-3-[4-(trifluoromethyl)phe-
nyl]propanamide (2h): white solid; 1H NMR (400 MHz,
chloroform-d): d=9.65 (s, 1H), 8.93 (d, J=1.9 Hz, 1H), 8.83
(dd, J=7.5, 1.6 Hz, 1H), 8.74 (d, J=1.9 Hz, 1H), 7.89–7.75
(m, 2H), 7.68 (d, J=8.1 Hz, 2H), 7.64–7.56 (m, 2H), 6.25
(dd, J=8.6, 4.0 Hz, 0.5H), 6.14 (dd, J=8.7, 4.0 Hz, 0.5H),
3.24 (ddd, J=16.2, 15.3, 8.6 Hz, 1H), 3.06 (ddd, J=32.0,
15.3, 4.0 Hz, 1H); 13C NMR (101 MHz, chloroform-d): d=
166.94, 166.90 (d, J=4.0 Hz), 145.67, 143.06, 142.65, 134.25,
133.34, 131.22, 125.98, 125.94, 125.91, 125.87, 125.80, 123.84,
117.57, 91.33, 89.60 (d, J=173.0 Hz), 46.28, 46.02 (d, J=
26.0 Hz); 19F NMR (376 MHz, chloroform-d): d=À62.71 (s,
1F), À177.49 (s, 1F); HR-MS (ESI): m/z=386.0887, calcd.
for C13H13N3F4NaO ([M+Na]+): 386.0892.
3-(3-Chlorophenyl)-3-fluoro-N-(quinoxalin-5-yl)propana-
mide (2l): white solid; 1H NMR (500 MHz, chloroform-d):
d=9.66 (s, 1H), 8.93 (d, J=1.8 Hz, 1H), 8.83 (d, J=7.5 Hz,
1H), 8.75 (d, J=1.9 Hz, 1H), 7.92–7.74 (m, 2H), 7.48 (s,
1H), 7.33 (d, J=4.6 Hz, 3H), 6.15 (dd, J=8.9, 3.8 Hz,
0.5H), 6.05 (dd, J=9.0, 3.7 Hz, 0.5H), 3.22 (td, J=15.5,
8.9 Hz, 1H), 3.03 (ddd, J=33.1, 15.2, 3.8 Hz, 1H); 13C NMR
(126 MHz, chloroform-d): d=167.08, 167.06 (d, J=2.5 Hz),
145.64, 143.04, 142.64, 141.02, 140.85 (d, J=21.4 Hz), 134.95,
134.32, 133.36, 131.22, 130.22, 129.12, 125.82, 125.76 (d, J=
7.6 Hz), 123.77, 123.75, 123.72, 117.55, 91.14, 89.76 (d, J=
173.9 Hz), 46.23, 46.03 (d, J=25.2 Hz); 19F NMR (376 MHz,
chloroform-d): d=À175.46 (s, 1F); HR-MS (ESI): m/z=
352.0623, calcd. for C17H13N3ClFNaO ([M+Na]+): 352.0629.
3-(3-Bromophenyl)-3-fluoro-N-(quinoxalin-5-yl)propana-
1
mide (2m): white solid; H NMR (400 MHz, chloroform-d):
d=9.65 (s, 1H), 8.92 (d, J=1.8 Hz, 1H), 8.82 (dd, J=7.5,
1.6 Hz, 1H), 8.74 (d, J=1.8 Hz, 1H), 7.89–7.72 (m, 2H),
7.62 (d, J=1.8 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.36 (d, J=
7.7 Hz, 1H), 7.31–7.22 (m, 1H), 6.14 (dd, J=8.9, 3.7 Hz,
0.5H), 6.03 (dd, J=9.0, 3.7 Hz, 0.5H), 3.21 (td, J=15.4,
8.9 Hz, 1H), 3.02 (ddd, J=33.3, 15.3, 3.7 Hz, 1H); 13C NMR
(101 MHz, chloroform-d): d=167.07, 167.04 (d, J=3.0 Hz),
145.62, 142.98, 142.63, 141.21, 141.02 (d, J=19.0 Hz), 134.26,
133.30, 132.03, 131.19, 130.47, 128.69, 128.61 (d, J=8.0 Hz),
124.25, 124.18 (d, J=7.0 Hz), 123.71, 122.99, 117.51, 91.22,
89.49 (d, J=173.0 Hz), 46.24, 45.99 (d, J=25.0 Hz);
19F NMR (376 MHz, chloroform-d): d=À175.45 (s, 1F):
HR-MS (ESI): m/z=396.0119, calcd. for C17H13N3FBrNaO
([M+Na]+): 396.0124.
3-(4-Cyanophenyl)-3-fluoro-N-(quinoxalin-5-yl)propana-
mide (2i): white solid; 1H NMR (500 MHz, chloroform-d):
d=9.63 (s, 1H), 8.94 (d, J=1.9 Hz, 1H), 8.81 (dd, J=7.6,
1.3 Hz, 1H), 8.74 (d, J=1.9 Hz, 1H), 7.90–7.75 (m, 2H),
7.72 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.1 Hz, 2H), 6.24 (dd,
J=8.5, 4.1 Hz, 0.5H), 6.14 (dd, J=8.5, 4.1 Hz, 0.5H), 3.23
(td, J=15.9, 8.5 Hz, 1H), 3.06 (ddd, J=31.2, 15.4, 4.2 Hz,
1H); 13C NMR (126 MHz, chloroform-d): d=166.62, 166.58
(d, J=5.0 Hz), 145.70, 144.18, 144.02 (d, J=20.0 Hz), 143.06,
142.66, 134.16, 133.30, 132.74, 131.20, 126.17, 126.11 (d, J=
7.6 Hz), 123.92, 118.44, 117.58, 112.87, 90.90, 89.51 (d, J=
175,1 Hz), 46.02, 45.82 (d, J=25.2 Hz); 19F NMR (376 MHz,
chloroform-d): d=À178.97 (s, 1F); HR-MS (ESI): m/z=
343.0970, calcd. for C18H13N4FNaO ([M+Na]+): 343.0971.
3-Fluoro-3-(4-nitrophenyl)-N-(quinoxalin-5-yl)propana-
3-(2-Chlorophenyl)-3-fluoro-N-(quinoxalin-5-yl)propana-
1
mide (2n): white solid; H NMR (400 MHz, chloroform-d):
d=9.72 (s, 1H), 8.93 (d, J=1.8 Hz, 1H), 8.86 (dd, J=7.3,
1.7 Hz, 1H), 8.75 (d, J=1.8 Hz, 1H), 7.91–7.72 (m, 2H),
7.61 (dd, J=7.5, 1.9 Hz, 1H), 7.44–7.27 (m, 3H), 6.52 (dd,
J=9.3, 2.6 Hz, 0.5H), 6.41 (dd, J=9.1, 2.7 Hz, 0.5H), 3.20
(ddd, J=37.3, 15.8, 3.0 Hz, 1H), 3.11–3.00 (m, 1H);
13C NMR (101 MHz, chloroform-d): d=167.21, 145.58,
143.01, 142.61, 136.84, 136.62 (d, J=22.0 Hz), 134.43, 133.35,
131.27, 131.07, 131.01 (d, J=6.0 Hz), 129.88, 129.85, 127.42,
126.69, 126.59 (d, J=10.0 Hz), 123.58, 117.49, 89.34, 87.61
(d, J=173.0 Hz), 44.75, 44.50 (d, J=25.0 Hz); 19F NMR
(376 MHz, chloroform-d): d=À181.80 (s, 1F); HR-MS
(ESI): m/z=352.0621, calcd. for C17H13N3ClFNaO ([M+
Na]+): 352.0629.
1
mide (2j): white solid; H NMR (400 MHz, chloroform-d):
d=9.65 (s, 1H), 8.94 (d, J=1.9 Hz, 1H), 8.82 (d, J=7.5 Hz,
1H), 8.74 (d, J=1.8 Hz, 1H), 8.28 (d, J=8.4 Hz, 2H), 7.83
(dt, J=16.1, 8.3 Hz, 2H), 7.65 (d, J=8.3 Hz, 2H), 6.31 (dd,
J=8.4, 4.2 Hz, 0.5H), 6.19 (dd, J=8.4, 4.2 Hz, 0.5H), 3.25
(td, J=15.9, 8.4 Hz, 1H), 3.08 (ddd, J=30.9, 15.3, 4.2 Hz,
1H); 13C NMR (101 MHz, chloroform-d): d=166.54, 166.50
(d, J=4.0 Hz), 148.22, 146.06, 145.86 (d, J=20.0 Hz), 145.72,
143.03, 142.67, 134.11, 133.29, 131.23, 126.38, 126.30 (d, J=
8.0 Hz), 124.17, 123.94, 117.60, 90.93, 89.19 (d, J=174.0 Hz),
46.06, 45.81 (d, J=25.0 Hz); 19F NMR (376 MHz, chloro-
form-d): d=À178.91 (s, 1F); HR-MS (ESI): m/z=363.0861,
calcd. for C17H13N4FNaO3 ([M+Na]+): 363.0869.
3-Fluoro-N-(quinoxalin-5-yl)-3-(o-tolyl)propanamide (2o):
1
white solid; H NMR (500 MHz, chloroform-d): d=9.75 (s,
3-Fluoro-N-(quinoxalin-5-yl)-3-(p-tolyl)propanamide (2k):
white solid; H NMR (500 MHz, chloroform-d): d=9.71 (s,
1H), 8.92 (d, J=1.9 Hz, 1H), 8.84 (dd, J=7.4, 1.5 Hz, 1H),
8.75 (d, J=1.9 Hz, 1H), 7.89–7.72 (m, 2H), 7.35 (d, J=
1H), 8.93 (d, J=1.8 Hz, 1H), 8.87 (dd, J=7.6, 1.5 Hz, 1H),
8.76 (d, J=1.9 Hz, 1H), 7.88–7.76 (m, 2H), 7.57–7.47 (m,
1H), 7.32–7.24 (m, 2H), 7.23–7.17 (m, 1H), 6.40 (dd, J=9.4,
2.9 Hz, 0.5H), 6.30 (dd, J=9.3, 2.9 Hz, 0.5H), 3.22 (td, J=
1
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15.6, 9.3 Hz, 1H), 3.01 (ddd, J=35.9, 15.4, 2.9 Hz, 1H), 2.44
(s, 3H); 13C NMR (126 MHz, chloroform-d): d=167.81,
145.54, 142.96, 142.63, 137.04, 136.89 (d, J=18.9 Hz), 134.73,
134.69 (d, J=5.0 Hz), 134.46, 133.39, 131.23, 130.90, 128.81,
126.52, 125.24, 125.18 (d, J=7.5 Hz), 123.57, 117.49, 89.45,
88.09 (d, J=171.4 Hz), 45.34, 45.14 (d, J=25.2 Hz), 19.04;
19F NMR (376 MHz, chloroform-d): d=À175.34 (s, 1F);
HR-MS (ESI): m/z=332.1168, calcd. for C18H16N3FNaO
([M+Na]+): 332.1175.
d=À178.57 (s, 1F); HR-MS (ESI): m/z=298.1324, calcd.
for C15H18N3FNaO ([M+Na]+): 298.1332.
À
General Procedure for C H Acetoxylation
To a 2-dram vial equipped with a stirrer was added SM,
Pd(OAc)2 (10 mol%), PhI(OAc)2 (1.5 equiv.), acetic anhy-
dride (2.5 equiv.) and o-dichlorobenzene. The mixture was
stirred at 808C for 12 h. After completion, the reaction mix-
ture was concentrated under vacuum. Purification of the res-
idue was done by flash chromatography.
3-Fluoro-3-(naphthalen-2-yl)-N-(quinoxalin-5-yl)propana-
1
mide (2p): white solid; H NMR (400 MHz, chloroform-d):
3-Oxo-1-phenyl-3-(quinolin-8-ylamino)propyl
acetate
d=9.70 (s, 1H), 8.91 (d, J=1.8 Hz, 1H), 8.86 (dd, J=7.2,
1.8 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H), 7.98–7.75 (m, 6H),
7.54 (ddd, J=14.6, 7.4, 2.5 Hz, 3H), 6.35 (dd, J=8.9, 3.8 Hz,
0.5H), 6.23 (dd, J=8.9, 3.7 Hz, 0.5H), 3.35 (td, J=15.4,
8.9 Hz, 1H), 3.14 (ddd, J=32.9, 15.2, 3.8 Hz, 1H); 13C NMR
(101 MHz, chloroform-d): d=167.53, 167.50 (d, J=3.0 Hz),
145.58, 143.00, 142.58, 136.27, 134.41, 133.57, 133.36, 133.23,
131.23, 128.92, 128.33, 127.92, 126.72, 125.10, 125.02 (d, J=
8.0 Hz), 123.64, 123.05, 123.00 (d, J=5.0 Hz), 117.52, 92.33,
90.61 (d, J=172.0 Hz), 46.47, 46.21 (d, J=26.0 Hz);
19F NMR (376 MHz, chloroform-d): d=À173.38 (s, 1F);
HR-MS (ESI): m/z=368.1170, calcd. for C21H14N3FNaO
([M+Na]+): 368.1175.
4-Cyclohexyl-3-fluoro-N-(quinoxalin-5-yl)butanamide
(2q): white solid; 1H NMR (400 MHz, chloroform-d): d=
9.72 (s, 1H), 8.92 (d, J=1.8 Hz, 1H), 8.83 (dd, J=7.3,
1.7 Hz, 1H), 8.76 (d, J=1.8 Hz, 1H), 7.90–7.70 (m, 2H),
5.28 (td, J=9.0, 8.1, 4.0 Hz, 0.5H), 5.20–5.10 (m, 0.5H),
2.96–2.68 (m, 2H), 1.85 (m, 1H), 1.73 (m, J=13.9, 12.3, 9.7,
6.2 Hz, 5H), 1.58–1.44 (m, 2H), 1.24–1.07 (m, 3H), 0.97 (m,
2H); 13C NMR (101 MHz, chloroform-d): d=168.42, 168.39
(d, J=3.0 Hz), 145.55, 143.04, 142.66, 134.59, 133.46, 131.25,
123.50, 117.44, 90.39, 88.71(d, J=168.0 Hz), 44.91, 44.68 (d,
J=23.0 Hz), 42.89, 42.69 (d, J=20.0 Hz), 34.08, 33.95, 32.87,
26.55, 26.37, 26.21; 19F NMR (376 MHz, chloroform-d): d=
À178.47 (s, 1F); HR-MS (ESI): m/z=338.1644, calcd. for
C18H22N3FNaO ([M+Na]+): 338.1645.
(3a): white solid; 1H NMR (400 MHz, chloroform-d): d=
9.99 (s, 1H), 8.86–8.72 (m, 2H), 8.17 (dd, J=8.3, 1.7 Hz,
1H), 7.60–7.49 (m, 2H), 7.46 (dt, J=8.0, 3.0 Hz, 3H), 7.37
(t, J=7.3 Hz, 2H), 7.31 (dd, J=8.5, 6.0 Hz, 1H), 6.33 (dd,
J=9.1, 4.2 Hz, 1H), 3.22 (dd, J=15.1, 9.1 Hz, 1H), 3.00 (dd,
J=15.1, 4.2 Hz, 1H), 2.12 (s, 3H); 13C NMR (101 MHz,
chloroform-d): d=169.94, 167.74, 148.24, 139.75, 138.44,
136.55, 134.40, 128.82, 128.42, 128.06, 127.56, 126.45, 121.84,
121.77, 116.86, 72.85, 45.28, 21.32; HR-MS (ESI): m/z=
357.1211, calcd. for C20H18N2NaO3 ([M+Na]+): 357.1215.
3-Oxo-1-phenyl-3-(quinoxalin-5-ylamino)propyl
acetate
(3d): white solid; 1H NMR (400 MHz, chloroform-d): d=
9.66 (s, 1H), 8.93 (d, J=1.9 Hz, 1H), 8.80 (dd, J=7.5,
1.6 Hz, 1H), 8.73 (d, J=1.9 Hz, 1H), 7.87–7.72 (m, 2H),
7.49–7.41 (m, 2H), 7.40–7.33 (m, 2H), 7.33–7.27 (m, 1H),
6.32 (dd, J=8.9, 4.4 Hz, 1H), 3.21 (dd, J=15.1, 8.9 Hz, 1H),
3.00 (dd, J=15.1, 4.4 Hz, 1H), 2.12 (s, 3H); 13C NMR
(101 MHz, chloroform-d): d=169.86, 167.77, 145.51, 142.96,
142.45, 139.50, 134.42, 133.31, 131.34, 128.87, 128.51, 126.40,
123.40, 117.49, 72.74, 45.19, 21.29; HR-MS (ESI): m/z=
358.1162, calcd. for C29H17N3NaO3 ([M+Na]+): 358.1168.
Acknowledgements
This work is financially supported by the National Natural
Science Foundation of China (21372013, 21572004 for Y. H.,
21133002 for Y. W. and 21232001 for X. Z.), the Shenzhen
Peacock Program (KQTD201103) and the Shenzhen innova-
tion funds (CXZZ20130517152257071). Y. H. thanks the
MOE for the Program for New Century Excellent Talents in
University.
3-Fluoro-N-(quinoxalin-5-yl)pentanamide
(2r):
white
1
solid; H NMR (400 MHz, chloroform-d): d=9.73 (s, 1H),
8.92 (d, J=1.9 Hz, 1H), 8.83 (dd, J=7.3, 1.7 Hz, 1H), 8.76
(d, J=1.9 Hz, 1H), 7.85–7.73 (m, 2H), 5.11 (m, 0.5H), 4.98
(m, 0.5H), 2.98–2.73 (m, 2H), 1.90–1.74 (m, 2H), 1.07 (t, J=
7.5 Hz, 3H); 13C NMR (101 MHz, chloroform-d): d=168.40,
168.37 (d, J=3.0 Hz), 145.55, 143.02, 142.65, 134.57, 133.44,
131.24, 123.50, 117.44, 93.26, 91.58 (d, J=168.0 Hz), 43.97,
43.75 (d, J=22.0 Hz), 28.33, 28.12 (d, J=21.0 Hz), 9.41, 9.35
(d, J=6.0 Hz); 19F NMR (376 MHz, chloroform-d): d=
À179.67 (s, 1F): HR-MS (ESI): m/z=270.1011, calcd. for
C13H14N3FNaO ([M+Na]+): 270.1019.
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