Synthesis of tri(di)fluoroethylanilines via copper-catalyzed coupling reaction of tri(di)fluoroethylamine with (hetero)aromatic bromides

Article abstract of DOI:10.1039/c9ob02271f

We have realized the first Ullmann type coupling reaction of tri(di)fluoroethylamine with (hetero)aromatic bromides, employing 5-20 mol% Cu₂O and an oxalamide ligand [N-(2,4,6-trimethoxyphenyl)acetamide]. This efficient and practical method has

Full text of DOI:10.1039/c9ob02271f

Organic &
Biomolecular Chemistry
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Synthesis of tri(di)fluoroethylanilines via copper-
catalyzed coupling reaction of tri(di)
fluoroethylamine with (hetero)aromatic bromides†
a,b
Cite this: Org. Biomol. Chem., 2019,
17, 9799
Suo Chen,‡a,b Hui Wang,‡a,b Wei Jiang,c Pei-Xin Ruia and Xiang-Guo Hu
*
We have realized the first Ullmann type coupling reaction of tri(di)fluoroethylamine with (hetero)aromatic
bromides, employing 5–20 mol% Cu2O and an oxalamide ligand [N-(2,4,6-trimethoxyphenyl)acetamide].
This efficient and practical method has the following features: (i) avoids the use of an expensive catalyst;
(ii) does not require anhydrous solvent and strict air extrusion; (iii) uses bench stable and inexpensive
(hetero)aromatic bromides; (iv) is suitable for the synthesis of fluoroalkylated hetero-aromatic substrates;
(v) is suitable for gram-scale synthesis. This work also shows the “negative fluorine effect” for the alkyl-
amines in the copper catalysed coupling reactions.
Received 19th October 2019,
Accepted 4th November 2019
DOI: 10.1039/c9ob02271f
rsc.li/obc
trifluoroethylated anilines. For example, in 2015, Hartwig
et al. reported a general, palladium-catalysed synthesis of
Introduction
The introduction of fluoroalkyl groups can usually impart the trifluoromethylated anilines from aryl bromides and aryl
parent molecules with better pharmacokinetic and pharmaco- chlorides (1a).10 In the same year, Wang et al. reported a
dynamic properties.1,2 In particular, the incorporation of a silver-catalysed insertion reaction for the same purpose
2,2,2-trifluoroethyl group onto the nitrogen atom of anilines (1b).11 However, these two methods all require the use of
can significantly increase their metabolic stability as the P450- expensive and moisture-sensitive catalysts. Other catalytic
mediated oxidation could be inhibited by a fluoroalkyl group.3 methods were reported, but the generality needs to be
Selected pharmaceutically important N-trifluoroethylanilines, tested.12,13 In 2018, we achieved a successful Chan–Lam type
such as T0901317,4 quazepam5 and 6-N,N-bis(2,2,2-trifluoro- coupling for the synthesis of fluoroalkylated anilines, utiliz-
ethyl)amino-trifluoromethylquinolin-2(1H)-ones,6 are shown ing an inexpensive copper catalyst/promoter.14a However, the
in Fig. 1. As a result, it is highly desirable to develop novel reaction is not suitable for medicinally relevant, hetero-
methods for the easy access of trifluoroethylated anilines.
aromatic substrates; moreover, some boronic acids used are
Traditionally, trifluoroethylated anilines can be syn- expensive and not stable.
thesized from a trifluoroethyl chloride or hypervalent-iodine
reagent by nucleophilic substitution,7 from trifluoroethyl-
amine by SNAr reactions8 and from trifluoroacetaldehyde by
reductive aminations.9 Recently, the transition-metal cata-
lysed coupling reaction has gained success in the synthesis of
aNational Engineering Research Center for Carbohydrate Synthesis,
Jiangxi Normal University, Nanchang, 330022, China
bKey Laboratory of Small Functional Organic Molecule, Ministry of Education,
Jiangxi Normal University, Nanchang, Jiangxi 330022, P.R. China.
E-mail: huxiangg@iccas.ac.cn; http://www.escience.cn/people/xiangguohu/
index.html;jsessionid=1EF1BEAF74C7A6D13C9ADE9C1FF99ECE-n2
cResearch Center for Traditional Chinese Medicine Resources and Ethnic Minority
Medicine, Jiangxi University of Traditional Chinese Medicine, China
†Electronic supplementary information (ESI) available. CCDC 1914999 and
1915000. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c9ob02271f
Fig. 1 Selected examples of drugs and drug candidates bearing
ArNHCH2CF3.
‡These authors contributed equally.
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Table 1 Reaction optimization
Entry
Cu salt/ligand
Solvent
Base
Yielda (%)
1b,c
2c,d
3c,e
4c, f
5c,g
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22h
23i
24c
25j
26k
27c,l
CuI/L1
CuI/L2
CuI/L3
CuI/L4
Toluene
DMSO
DMF
tBuOK
K2CO3
K3PO4
Cs2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
Cs2CO3
Na2CO3
NaOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
0
0
0
0
Inspired by the recent success15–18 of the bidentate ligand
enabled copper catalysed Ullmann reaction, we envisioned
that the aforementioned shortcomings of the transition-metal
catalysed synthesis of trifluoroethylanilines could be
addressed if a Ullmann type coupling between aryl bromides
and trifluoroethylamine could be developed. Challenges,
however, exist: (1) compared to other alkylamines, trifluoro-
ethylamine shows lower reactivity in the copper-catalysed
coupling reaction, presumably due to strong negativity of
fluorine.14a,19 (2) Fluoroalkylanilines are not stable under
forcing conditions (e.g., strong bases).10
In continuation of our interest in using fluoroalkylamines
for the synthesis of highly valued compounds,14 we report the
realization of the aforementioned goal by developing a practi-
cal and efficient synthesis of trifluoroethylanilines from in-
expensive, bench-stable aryl bromides and trifluoroethylamine,
which employs 5–20% copper catalyst and does not need anhy-
drous solvent and air extrusion. This reaction can be applied
to the heteroaromatic substrates and is also suitable for
difluoroethylamine. To our knowledge, this method represents
the first example of the Ullmann-type coupling reaction
employing fluoroalkylamines.
tBuOH
DMF
CuI/L5
0
CuI/L14
CuI/L14
CuI/L14
CuI/L14
CuI/L14
CuI/L14
CuI/L6
CuI/L15
CuI/L14
CuI/L14
CuI/L14
CuI/L14
CuCl/L14
Cu2O/L14
CuCl2/L14
Cu(OAc)2/L14
Cu2O/L14
Cu2O/L14
Cu2O/L14
Cu2O/L14
Cu2O/L14
Cu2O/L14
DMSO
DMF
THF
MeCN
MeOH
EtOH
10
Trace
0
0
57
8
28
27
75
70
48
0
78
90
53
42
0
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
3
93
91
95
92
Reaction conditions: 1a (0.25 mmol, 1 equiv.), 2 (1.25 mmol, 5 equiv.),
Cu salts (0.05 mmol, 20 mol%), L (0.05 mmol, 20 mol%), base
(0.38 mmol, 1.5 equiv.), 4 Å MS, solvents (1.0 mL), 120 °C, 24 h.
a Yields were determined by 19F NMR spectroscopy using benzotrifluo-
ride as an internal standard. b 115 °C, 3.5 h. c No 4 Å MS. d rt, 17 h.
e 90 °C, 22 h. f 100 °C, 16 h. g 110 °C, 24 h. h 80 °C. i 100 °C. j 2 equiv.
H2O. k Analytical grade MeOH. l Cu2O (0.025 mmol, 10 mol%), L
(0.025 mmol, 10 mol%).
Results and discussion
Initially, we selected 4-bromobiphenyl 1a and 2,2,2-trifluoro-
ethylamine 2 as the model substrates to explore the optimal
reaction conditions. We first tested various reported con- were screened, and the results showed that MeOH was the best
ditions employing ligands such as 1,10-phenanthroline L1,21 solvent for this procedure (Table 1, entries 7–11 and
L-proline L2,22 N,N-diethylsalicylamide L3,23 quinolin-8-ol Table S2†). An extensive screening of the oxalamide ligands
L4,24 and pipecolinic acid L5,25 however, none of them yielded demonstrated that L14 is the most suitable one (Table 1,
the desired products (Table 1, entries 1–5 and Table S1†). We entries 12 and 13 and Table S3†). Then, different inorganic
next turned our attention to the oxalamide ligands developed bases were tested (Table 1, entries 14–17 and Table S4†), and a
by Ma et al.18 To our delight, the conditions utilizing N-(2,4,6- 75% yield of the target product was obtained with K2CO3 as
trimethoxyphenyl)acetamide L14 in DMSO at 120 °C could the base (Table 1, entry 14). With these encouraging results in
give the product, albeit in 10% yield (Table 1, entry 6).26–28 hand, a number of copper salts29,30 were also screened
Next, solvents such as DMF, THF, MeCN, MeOH, and EtOH (Table 1, entries 18–21 and Table S5†). It is noted that the
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target product was obtained in 90% yield with Cu2O as the torily to give 3i and 3j in 93% and 92% yields, respectively.
catalyst (Table 1, entry 19). Comparison experiments showed Furthermore, 3,5-disubstituted aryl bromides (3k, 3l) are viable
that the yield is slightly higher in the absence of activated 4 Å substrates as well, and good yields of the corresponding pro-
molecular sieves (93%) compared to that in the presence of ducts can be isolated.
this water scavenger (90%) (Table 1, entry 24). Furthermore,
Considering the pharmaceutical importance of the CF2H
the addition of two equivalents of water did not affect the reac- moiety (the slightly acidic C–H bond of CF2H can be utilized
tion efficacy (91%) (Table 1, entry 25). These experiments indi- as a lipophilic hydrogen-bond donor and a bioisostere for
cated that the reaction is not sensitive to moisture. For the hydroxyl and thiol groups),31,32 we became interested in inves-
reason of simplicity, we used commercially available MeOH as tigating if a similar strategy could be applied to synthesize
the solvent and the yield was 95% (Table 1, entry 26). difluoroethylanilines. To test this hypothesis, the reaction of
Furthermore, we could obtain the desired product in 92% difluoroethylamine 6 with 4-bromobiphenyl 1a was investi-
yield when using 10 mol% copper salt and ligand (Table 1, gated briefly (Table S7†). Gratifyingly, as observed in our pre-
entry 27). Under these optimized conditions, possible side pro- vious work,14a difluoroethylamine showed better reactivity
ducts 4 and 5 could not be observed (Table 1, entry 27).
than trifluoroethylamine, and the transformation could
Having established the optimal conditions, we commenced proceed successfully at lower temperature (100 °C) and less
to investigate the generality with various aryl bromides equivalents (2 equiv.) compared with trifluoroethylamine,
(Scheme 1). To our delight, aryl bromides bearing either elec- giving the desired product 7a in 86% yields. Generally, the
tron-donating groups (1a–1b, 1k) or electron-withdrawing reaction exhibited a similar reactivity trend to that observed
groups (1c–1h, 1l) were both compatible with standard con- for trifluoroethylamine. For example, substrates with electron-
ditions, furnishing the desired products in good yields. The rich groups gave high yields compared to those with an elec-
only exception is 1f carrying a para-nitro group, which only tron-withdrawing group at the para-position; ortho-substitution
yielded 3f in 59% yield. Notably, substrates bearing a pharma- is not good for the desired coupling. The structure of 7f was
ceutically relevant trifluoromethyl group (1d, 1l) underwent confirmed by X-ray crystallographic analysis (Scheme 2).33
the transformation smoothly. The sensitive carbonyl group is
One significant limitation of our previous method14a is that
tolerated and 3c was obtained in 85% yield. The influence of it is not suitable for the synthesis of pharmaceutically impor-
the substituent pattern [para-(1a–1f), ortho-(1g), meta-(1h)] on tant fluoroalkylated heteroaromatic compounds. Bearing this
the phenyl ring was evaluated, which indicates that the ortho- in mind, we started to study the possibility of utilizing hetero-
substituent (1g) has a negative effect on this reaction.28 The cyclic bromides for this coupling reaction (Scheme 3). As
substrates like naphthalene and fluorene also worked satisfac- shown in Scheme 3, the reactions occurred smoothly and pro-
Scheme 1 Reaction of 2 with different aryl bromides. Reaction con-
ditions: Aryl bromides (0.5 mmol, 1 equiv.), 2 (2.5 mmol, 5 equiv.), Cu2O
(0.05 mmol, 10 mol%), L14 (0.05 mmol, 10 mol%), MeOH (2.0 mL),
120 °C, K2CO3 (0.75 mmol, 1.5 equiv.), 24 h.
Scheme 2 Reaction of 6 with different aryl bromides. Reaction con-
ditions: Aryl bromides (0.5 mmol, 1 equiv.), 6 (1.0 mmol, 2 equiv.), Cu2O
(0.05 mmol, 10 mol%), L14 (0.05 mmol, 10 mol%), MeOH (2.0 mL),
100 °C, K2CO3 (0.75 mmol, 1.5 equiv.), 24 h.
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Scheme 5 Comparison of the reactivity of different amines. Reaction
conditions: 1a (0.5 mmol, 1 equiv.), 2 (0.5 mmol, 1 equiv.), 6 (0.5 mmol, 1
equiv.), Cu2O (0.05 mmol, 10 mol%), L14 (0.05 mmol, 10 mol%), MeOH
(2.0 mL), 120 °C, K2CO3 (0.75 mmol, 1.5 equiv.), 24 h; the ratio of
different products is determined by the 1H NMR.
Scheme 3 Reaction of
2 and 6 with heterocyclic aryl bromides.
Reaction conditions: Aryl bromides (0.25 mmol, 1 equiv.), 2 (1.25 mmol,
5 equiv.), 6 (0.5 mmol, 2 equiv.), Cu2O (0.05 mmol, 20 mol%), L14
(0.05 mmol, 20 mol%), MeOH (1.0 mL), 120 °C or 100 °C, K2CO3
(0.38 mmol, 1.5 equiv.), 24 h.
this series of competitive reactions indicates that amines
exhibit the following reactivity: 11 > 6 > 2. Overall, this work
further demonstrates the “negative fluorine effect”14a,20 on the
reactivity of alkylamines in the copper-catalyzed cross coupling
reaction.
Conclusions
Fig. 2 X-Ray crystal structures of 9e.
In conclusion, we have realized the first Ullmann type coupling
reaction of tri(di)fluoroethylamine with (hetero)aromatic bro-
mides, employing 5–20 mol% Cu2O and N-(2,4,6-trimethoxy-
phenyl)acetamide (an oxalamide ligand). This efficient and
practical method has the following features: (i) avoids the use
of an expensive catalyst; (ii) does not require anhydrous
solvent and strict air extrusion; (iii) uses bench stable and in-
expensive (hetero)aromatic bromides; (iv) is suitable for the
synthesis of fluoroalkylated hetero-aromatic substrates and
gram-scale synthesis. This work also shows the “negative fluo-
rine effect” for the alkylamines in the copper catalysed coup-
ling reactions. In addition to the synthetic utility for the syn-
thesis of pharmaceutically important fluorinated building
blocks, this reaction also showcases the powerfulness of biden-
tate ligands, particularly the oxalamide ligands developed by
Ma et al. enabled the Ullmann reaction in the synthesis of
high-value compounds.
ducts 9a–9f and 10a–10f were obtained in good to high yields,
although 20 mol% of catalyst and ligand were required.
Among heterocyclic substrates tested, the “privileged” indole
gave the highest yields (9f–10f). More attractively, no protec-
tion of N–H was needed. The structure of 9e was confirmed by
X-ray crystallographic analysis (Fig. 2).33
To demonstrate the synthetic utility of this transformation,
we next performed a scale-up reaction of 7b. As shown in
Scheme 4, a gram scale reaction of 1-bromo-4-methoxybenzene
1a with difluoroethylamine 6 proceeded to give 7b in 95%
yield. Importantly, the copper catalyst and the oxalamide
ligand could be lowered to 5 mol%.
Our previous work14a shows that the increase in fluorine
atom in the alkylamine decreases the reactivity in the Chan–
Lam type coupling reaction. We also noticed in this work that
difluoroethylamine was more reactive than trifluoroethyl-
amine. On the basis of these results, we became interested in
evaluating the reactivity of tri(di)fluoroethylamine relative to
other alkylamines. To this end, we selected 2-phenylethan-1-
amine 11 for a competitive reaction. As shown in Scheme 5,
Experimental
General information
All reagents were used as received from commercial sources
without further purification. All solvents were dried over 4 Å
molecular sieves before use unless otherwise stated. The reac-
tion mixtures were stirred using Teflon-coated magnetic stir-
ring bars. Analytical TLC was performed with 0.20 mm silica
gel 60F plates with a 254 nm fluorescent indicator. TLC plates
were visualized by ultraviolet light or by treatment with a spray
of Pancaldi reagent {(NH4)6MoO4, Ce(SO4)2, H2SO4, H2O} or a
Scheme 4 Gram-scale synthesis of 7b with 5 mol% of catalyst and
ligand.
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solution of 0.5% ninhydrin in n-butanol. Chromatographic N-(2,2,2-Trifluoroethyl)-4-(trifluoromethyl)aniline (3d)11
purification of products was carried out by flash column
chromatography on silica gel (230–400 mesh). Melting points
were determined using a WRX-4 visual melting point appar-
Purified by flash column chromatography (petroleum ether/
AcOEt = 50 : 1), colorless and transparent liquid (84 mg, 69%
yield); 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.5 Hz, 2H),
atus. NMR spectra were recorded in CDCl3 (with TMS as the
6.72 (d, J = 8.5 Hz, 2H), 4.21 (s, 1H), 3.81 (q, J = 8.8 Hz, 2H);
internal standard) or D2O or MeOD on a Bruker AV400 (1H at
13C NMR (100 MHz, CDCl3) δ 148.9, 126.9 (q, J = 3.8 Hz), 124.9
400 MHz, 13C at 100 MHz, 19F at 376 MHz) magnetic resonance
(q, J = 280.4 Hz), 124.8 (q, J = 270.0 Hz), 121.0 (q, J = 32.7 Hz),
112.5, 45.5 (q, J = 34.0 Hz).
spectrometer. Chemical shifts (δ) are reported in ppm, and
coupling constants (J) are in Hz. The following abbreviations
were used to explain the multiplicities: s = singlet, d = doublet,
4-((2,2,2-Trifluoroethyl)amino)benzonitrile (3e)10
t = triplet, q = quartet, and m = multiplet. The HRMS were
Purified by flash column chromatography (petroleum ether/
recorded using an ESI model (specified in the section of
AcOEt = 10 : 1), white solid (74 mg, 74% yield); 1H NMR
characterization data). All the reactions were conducted in
(400 MHz, CDCl3) δ 7.47 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 8.8 Hz,
high pressure bottles with PTFE thread (resist 6 atm pressure)
2H), 4.64 (s, 1H), 3.82 (dq, J = 8.0, 6.2 Hz, 2H); 13C NMR
under the protection of a safety shield. In all the experiments,
(100 MHz, CDCl3) δ 149.9, 133.9, 124.7 (q, J = 280.3 Hz), 120.0,
the solvent should never exceed the half volume of the high
112.9, 101.0, 45.1 (q, J = 34.3 Hz).
pressure bottle.
4-Nitro-N-(2,2,2-trifluoroethyl)aniline (3f)
The general procedure for the reaction of 2(6) with different
Purified by flash column chromatography (petroleum
ether/AcOEt 5 : 1), yellow solid (64.9 mg, 59% yield),
aryl bromides
=
A 10 mL high pressure bottle equipped with a magnetic stir
bar was charged with aryl bromides (0.5 mmol, 1 equiv.), Cu2O
(7.1 mg, 0.05 mmol, 10 mol%), L14 (21.0 mg, 0.05 mmol,
10 mol%), K2CO3 (103.6 mg, 0.75 mmol, 1.50 equiv.),
2 (200 μL, 2.5 mmol, 5 equiv.) [6, (70 μL, 1.0 mmol, 2 equiv.)]
and MeOH (2.0 mL). The reaction mixture was heated at
120 °C (6, 100 °C) for 24 h under vigorous stirring. After the
removal of the solvent under vacuum, the residue was purified
by column chromatography.
1
m.p. 113–114 °C; H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 9.2
Hz, 2H), 6.69 (d, J = 9.2 Hz, 2H), 4.84 (s, 1H), 4.04–3.75
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 151.8, 139.8, 126.4,
124.5 (q, J = 280.3 Hz), 112.0, 45.2 (q, J = 34.5 Hz); 19F NMR
(376 MHz, CDCl3)
δ −72.05 (t, J =
8.7 Hz); 19F {1H}
NMR (376 MHz, CDCl3) δ −72.05(s); HRMS (ESI): calcd for
C8H8F3N2O2+ [M + H]+ 221.0532, found 221.0524.
2-((2,2,2-Trifluoroethyl)amino)benzonitrile (3g)10
N-(2,2,2-Trifluoroethyl)-[1,1′-biphenyl]-4-amine (3a)11
Purified by flash column chromatography (petroleum ether/
AcOEt = 10 : 1), white solid (42.8 mg, 43% yield); 1H NMR
(400 MHz, CDCl3) δ 7.45 (ddd, J = 7.4, 4.4, 2.6 Hz, 2H),
6.87–6.75 (m, 2H), 4.94 (s, 1H), 3.88 (qd, J = 8.7, 6.9 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 148.8, 134.5, 133.0, 124.6 (q, J =
280.3 Hz), 118.7, 117.4, 111.0 (q, J = 1.6 Hz), 97.3, 45.2 (q, J =
34.6 Hz).
Purified by flash column chromatography (petroleum ether/
AcOEt = 100 : 1), white solid (111.8 mg, 89% yield); 1H NMR
(400 MHz, CDCl3) δ 7.67–7.56 (m, 2H), 7.52 (d, J = 8.6 Hz,
2H), 7.46 (t,
J = 7.7 Hz, 2H), 7.40–7.30 (m, 1H),
6.92–6.67 (m, 2H), 3.85 (s, 1H), 3.82 (q, J = 8.9 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 145.7, 140.9, 132.1, 128.8,
128.2, 126.56, 126.53, 125.2 (q, J = 280.2 Hz), 113.5, 46.0 (q,
J = 33.8 Hz).
3-Nitro-N-(2,2,2-trifluoroethyl)aniline (3h)11
Purified by flash column chromatography (petroleum ether/
dichloromethane = 5 : 1), yellow solid (103.6 mg, 94% yield);
1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 8.1, 2.1 Hz, 1H), 7.51
(t, J = 2.3 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 6.98 (dd, J = 8.2,
2.5 Hz, 1H), 4.36 (s, 1H), 3.85 (q, J = 9.1 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 149.4, 147.2, 130.2, 124.8 (q, J = 280.1 Hz),
119.1, 113.9, 107.1, 45.7 (q, J = 34.2 Hz).
4-Methoxy-N-(2,2,2-trifluoroethyl)aniline (3b)11
Purified by flash column chromatography (petroleum ether/
AcOEt = 50 : 1), pale yellow liquid (90.3 mg, 88% yield);
1H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 9.0 Hz, 2H), 6.67 (d,
J = 8.9 Hz, 2H), 3.77 (s, 3H), 3.71 (q, J = 9.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 153.2, 140.4, 125.3 (q, J = 279.9 Hz), 115.0,
114.8, 55.7, 47.1 (q, J = 33.0 Hz).
N-(2,2,2-Trifluoroethyl)naphthalen-2-amine (3i)
1-(4-((2,2,2-Trifluoroethyl)amino)phenyl)ethan-1-one (3c)10
Purified by flash column chromatography (petroleum ether/
Purified by flash column chromatography (petroleum ether/ AcOEt
=
50 : 1), white solid (105.4 mg, 93% yield),
AcOEt = 10 : 1), white solid (93.1 mg, 85% yield); 1H NMR m.p. 96–97 °C; 1H NMR (400 MHz, CDCl3) δ 7.81–7.62 (m, 3H),
(400 MHz, CDCl3) δ 7.85 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 7.45 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.31 (ddd, J = 8.1, 6.8, 1.2
8.8 Hz, 2H), 4.76 (s, 1H), 3.94–3.68 (m, 2H), 2.51 (s, 3H); Hz, 1H), 6.99–6.87 (m, 2H), 4.00 (s, 1H), 3.87 (q, J = 9.0 Hz,
13C NMR (100 MHz, CDCl3)
δ
196.7, 150.5, 130.9, 2H); 13C NMR (100 MHz, CDCl3) δ 144.0, 134.9, 129.4, 128.3,
128.5, 124.8 (q, J = 280.2 Hz), 112.1, 45.3 (q, J = 34.1 Hz), 127.8, 126.7, 126.3, 125.2 (q, J = 280.4 Hz), 123.0, 117.5, 105.7,
26.3.
46.1 (q, J = 33.7 Hz); 19F NMR (376 MHz, CDCl3) δ −71.97 (t,
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J = 8.9 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ −71.97(s); HRMS 140.9, 115.2, 114.9 (t, J = 240.5 Hz), 114.8, 55.9, 47.7 (t, J =
(ESI): calcd for C12H11F3N+ [M + H]+ 226.0838, found 226.0832. 25.7 Hz).
N-(2,2,2-Trifluoroethyl)-9H-fluoren-2-amine (3j)
Purified by flash column chromatography (petroleum ether/ Purified by flash column chromatography (petroleum ether/
AcOEt
50 : 1), white solid (131.6 mg, 92% yield), EtOAc = 5 : 1), white solid (77.1 mg, 77% yield); 1H NMR
1-(4-((2,2-Difluoroethyl)amino)phenyl)ethan-1-one (7c)14a
=
m.p. 119–120 °C; 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = (400 MHz, CDCl3) δ 7.84 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.8 Hz,
19.3, 7.9 Hz, 2H), 7.49 (d, J = 7.4 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 5.92 (tt, J = 55.8, 4.0 Hz, 1H), 4.39 (s, 1H), 3.61 (td, J =
1H), 7.23 (td, J = 7.4, 1.2 Hz, 1H), 6.88 (d, J = 2.2 Hz, 1H), 6.71 14.5, 4.0 Hz, 2H), 2.50 (s, 3H); 13C NMR (100 MHz, CDCl3)
(dd, J = 8.3, 2.2 Hz, 1H), 3.99 (s, 1H), 3.89–3.74 (m, 4H); δ 196.7, 151.2, 130.9, 127.9, 114.2 (t, J = 241.0 Hz), 111.9, 45.7
13C NMR (100 MHz, CDCl3) δ 145.8, 145.4, 142.4, 142.0, 133.7, (t, J = 26.0 Hz), 26.1.
126.8, 125.4, 125.2 (q, J = 280.1 Hz), 124.9, 120.8, 118.9, 112.5,
N-(2,2-Difluoroethyl)-4-(trifluoromethyl)aniline (7d)
109.9, 46.5 (q, J = 33.4 Hz), 37.1; 19F NMR (376 MHz, CDCl3)
δ −72.19 (t, J = 8.8 Hz); 19F {1H} NMR (376 MHz, CDCl3) Purified by flash column chromatography (petroleum ether/
δ −72.19(s); HRMS (ESI): calcd for C15H13F3N+ [M + H]+ EtOAc = 50 : 1), tawny liquid (85 mg, 75% yield); 1H NMR
264.0995, found 264.0988.
(400 MHz, CDCl3) δ 7.44 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz,
2H), 5.92 (tt, J = 55.8, 4.0 Hz, 1H), 4.21 (s, 1H), 3.59 (tdd, J =
14.5, 6.7, 4.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 149.5,
3,5-Dimethoxy-N-(2,2,2-trifluoroethyl)aniline (3k)
Purified by flash column chromatography (petroleum ether/ 127.0 (q, J = 3.8 Hz), 124.9 (q, J = 270.4 Hz), 120.4 (q, J = 32.8
AcOEt = 20 : 1), colorless liquid (102.3 mg, 87% yield); Hz), 114.3 (t, J = 242.3 Hz), 112.4, 46.0 (t, J = 26.1 Hz); 19F NMR
1H NMR (400 MHz, CDCl3) δ 5.97 (s, 1H), 5.86 (d, J = 2.0 Hz, (376 MHz, CDCl3) δ −61.27(s), −122.67 (dt, J = 55.8, 14.5 Hz);
2H), 3.76 (s, 6H), 3.75–3.69 (m, 2H); 13C NMR (100 MHz, 19F {1H} NMR (376 MHz, CDCl3) δ −61.27(s), −122.67(s);
CDCl3) δ 161.9, 148.4, 125.0 (q, J = 279.9 Hz), 92.2, 91.2, 55.3, HRMS (ESI): calcd for C9H9F5N+ [M + H]+ 226.0650, found
46.1 (q, J = 33.8 Hz); 19F NMR (376 MHz, CDCl3) δ −72.28 (t, 226.0643.
J = 8.9 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ −72.28(s);
HRMS (ESI): calcd for C10H13F3NO2 [M + H]+ 236.0893,
+
4-((2,2-Difluoroethyl)amino)benzonitrile (7e)10
found 236.0888.
Purified by flash column chromatography (petroleum ether/
EtOAc = 8 : 1), white solid (66 mg, 72% yield); 1H NMR
(400 MHz, CDCl3) δ 7.47 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.8 Hz,
N-(2,2,2-Trifluoroethyl)-3,5-bis(trifluoromethyl)aniline (3l)
Purified by flash column chromatography (petroleum ether/ 2H), 5.92 (tt, J = 55.6, 3.9 Hz, 1H), 4.36 (s, 1H), 3.60 (td, J =
AcOEt = 50 : 1), pale yellow liquid (113.4 mg, 73% yield); 14.5, 3.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 150.3, 134.0,
1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 7.06 (s, 2H), 4.40 120.0, 114.0 (t, J = 241.2 Hz), 112.7, 100.8, 45.6 (t, J = 25.8 Hz).
(s, 1H), 3.85 (q, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3)
N-(2,2-Difluoroethyl)-4-nitroaniline (7f)
δ 146.2, 131.9 (q, J = 33.0 Hz), 123.7 (q, J = 280.5 Hz), 122.5
(q, J = 272.7 Hz), 111.6 (d, J = 4.1 Hz), 111.52–111.27 (m), 44.57 Purified by flash column chromatography (petroleum
(q, J = 34.3 Hz); 19F NMR (376 MHz, CDCl3) δ −63.30(s), −72.22 ether/EtOAc
= 5 : 1), yellow solid (42.4 mg, 42% yield),
(t, J = 8.8 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ −63.30(s), m.p. 110–111 °C; 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J =
−72.22(s); HRMS (ESI): calcd for C10H7F9N+ [M + H]+ 312.0429, 9.2 Hz, 2H), 6.64 (d, J = 9.2 Hz, 2H), 5.95 (tt, J = 55.5, 3.8 Hz,
found 312.0426.
1H), 4.80 (t, J = 6.7 Hz, 1H), 3.66 (tdd, J = 14.6, 6.6, 3.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 152.5, 139.2, 126.5, 114.0 (t, J =
242.8 Hz), 111.7, 45.7 (t, J = 25.9 Hz); 19F NMR (376 MHz,
N-(2,2-Difluoroethyl)-[1,1′-biphenyl]-4-amine (7a)14a
Purified by flash column chromatography (petroleum ether/ CDCl3) δ −122.51 (dt, J = 55.7, 14.6 Hz); 19F {1H} NMR
AcOEt = 100 : 1), white solid (100.3 mg, 86% yield); 1H NMR (376 MHz, CDCl3)
δ −122.51(s); HRMS (ESI): calcd for
(400 MHz, CDCl3) δ 7.58–7.51 (m, 2H), 7.48 (d, J = 8.2 Hz, 2H), C8H9F2N2O2+ [M + H]+ 203.0627, found 203.0626.
7.41 (t, J = 7.7 Hz, 2H), 7.33–7.23 (m, 1H), 6.79 (d, J = 8.2 Hz,
2-((2,2-Difluoroethyl)amino)benzonitrile (7g)
2H), 5.98 (tt, J = 56.0, 4.1 Hz, 1H), 3.60 (td, J = 14.3, 4.1 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 145.7, 140.9, 132.3, 128.9, Purified by flash column chromatography (petroleum ether/
128.2, 126.58, 126.56, 114.5 (t, J = 240.8 Hz), 113.9, 46.8 (t, J = AcOEt = 10 : 1), colorless and transparent liquid (47.2 mg, 51%
1
26.1 Hz).
yield); H NMR (400 MHz, CDCl3) δ 7.43 (ddd, J = 8.1, 6.7, 1.7
Hz, 2H), 6.88–6.63 (m, 2H), 5.93 (tt, J = 55.6, 4.0 Hz, 1H), 4.78
(s, 1H), 3.66 (td, J = 14.2, 4.0 Hz, 2H); 13C NMR (100 MHz,
N-(2,2-Difluoroethyl)-4-methoxyaniline (7b)10
Purified by flash column chromatography (petroleum ether/ CDCl3) δ 149.3, 134.5, 133.2, 118.2, 114.2 (t, J = 243.0 Hz),
EtOAc = 50 : 1), pale yellow liquid (87.8 mg, 93% yield); 110.8, 97.1, 45.8 (t, J = 26.6 Hz); 19F NMR (376 MHz, CDCl3) δ
1H NMR (400 MHz, CDCl3) δ 6.80 (d, J = 8.9 Hz, 2H), 6.64 (d, −122.17 (dt, J = 55.5, 14.2 Hz); 19F {1H} NMR (376 MHz, CDCl3)
J = 8.9 Hz, 2H), 5.91 (tt, J = 56.2, 4.3 Hz, 1H), 3.76 (s, 3H), 3.48 δ −122.17(s); HRMS (ESI): calcd for C9H9F2N2 [M + H]+
+
(td, J = 14.4, 4.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 153.1, 183.0728, found 183.0727.
9804 | Org. Biomol. Chem., 2019, 17, 9799–9807
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N-(2,2-Difluoroethyl)-3-nitroaniline (7h)14a
4.2 Hz), 112.0–111.8 (m), 46.0 (t, J = 25.7 Hz); 19F NMR
(376 MHz, CDCl3) δ −63.26(s), −122.73 (dt, J = 55.6, 14.4 Hz);
19F {1H} NMR (376 MHz, CDCl3) δ −63.26(s), −122.73(s);
HRMS (ESI): calcd for C10H8F8N+ [M + H]+ 294.0524, found
294.0527.
Purified by flash column chromatography (petroleum ether/
EtOAc = 10 : 1), yellow solid (92.4 mg, 90% yield); 1H NMR
(400 MHz, CDCl3) δ 7.67–7.55 (m, 1H), 7.48 (t, J = 2.3 Hz, 1H),
7.33 (t, J = 8.2 Hz, 1H), 6.95 (dd, J = 8.0, 2.4 Hz, 1H), 5.95 (tt,
J = 55.7, 3.9 Hz, 1H), 4.25 (s, 1H), 3.63 (dddd, J = 14.6, 10.7, 6.7,
3.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 149.6, 147.9, 130.2,
119.2, 114.2 (t, J = 242.4 Hz), 113.5, 106.8, 46.2 (t, J = 25.8 Hz).
N-(2,2,2-Trifluoroethyl)pyridin-3-amine (9a)10
Purified by flash column chromatography (petroleum ether/
EtOAc = 1 : 1), white solid (35.7 mg, 81% yield); 1H NMR
(400 MHz, CDCl3) δ 8.12 (d, J = 2.9 Hz, 1H), 8.06 (d, J = 4.7 Hz,
1H), 7.14 (dd, J = 8.3, 4.6 Hz, 1H), 6.99 (ddd, J = 8.4, 3.0,
1.3 Hz, 1H), 4.21 (s, 1H), 3.78 (qd, J = 8.8, 7.0 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 142.5, 140.5, 136.4, 124.9 (q, J =
280.0 Hz), 123.9, 119.1, 45.7 (q, J = 34.0 Hz).
N-(2,2-Difluoroethyl)naphthalen-2-amine (7i)
Purified by flash column chromatography (petroleum
ether/AcOEt = 50 : 1), white solid (99.1 mg, 95% yield),
m.p. 93–94 °C; 1H NMR (400 MHz, CDCl3) δ 7.73–7.58 (m, 3H),
7.39 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H), 7.28–7.18 (m, 1H),
6.91–6.83 (m, 2H), 5.97 (tt, J = 56.1, 4.2 Hz, 1H), 3.93 (s, 1H),
3.61 (td, J = 14.4, 4.3 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 144.5, 135.0, 129.5, 128.15, 127.8, 126.78, 126.2, 122.8, 117.8,
117.49–110.91 (m), 105.1, 46.5 (t, J = 26.1 Hz); 19F NMR
(376 MHz, CDCl3) δ −122.42 (dt, J = 56.0, 14.4 Hz); 19F {1H}
NMR (376 MHz, CDCl3) δ −122.42(s); HRMS (ESI): calcd for
C12H12F2N+ [M + H]+ 208.0932, found 208.0933.
N-(2,2,2-Trifluoroethyl)pyridin-2-amine (9b)10
Purified by flash column chromatography (petroleum ether/
EtOAc = 20 : 1), white solid (27.4 mg, 62% yield); 1H NMR
(400 MHz, CDCl3) δ 8.12 (dd, J = 5.1, 1.8 Hz, 1H), 7.45 (ddd, J =
8.7, 7.2, 1.9 Hz, 1H), 6.68 (ddd, J = 7.3, 5.0, 1.0 Hz, 1H), 6.49
(d, J = 8.3 Hz, 1H), 4.62 (s, 1H), 4.11 (qd, J = 9.2, 6.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 157.0, 148.0, 137.8, 125.1 (q, J =
279.3 Hz), 114.7, 108.3, 43.0 (q, J = 33.8 Hz).
N-(2,2-Difluoroethyl)-9H-fluoren-2-amine (7j)
Purified by flash column chromatography (petroleum ether/
5-Methyl-N-(2,2,2-trifluoroethyl)pyridin-3-amine (9c)
AcOEt
=
50 : 1), white solid (104.6 mg, 85% yield),
m.p. 117–118 °C; 1H NMR (400 MHz, CDCl3) δ 7.63 (dd, J =
17.3, 7.9 Hz, 2H), 7.48 (d, J = 7.4 Hz, 1H), 7.33 (t, J = 7.5 Hz,
1H), 7.21 (td, J = 7.5, 1.2 Hz, 1H), 6.89–6.82 (m, 1H), 6.69 (dd,
J = 8.2, 2.2 Hz, 1H), 5.97 (tt, J = 56.1, 4.3 Hz, 1H), 3.96 (s, 1H),
3.83 (s, 2H), 3.60 (td, J = 14.4, 4.3 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 146.3, 145.4, 142.4, 142.1, 133.3, 126.8, 125.4, 124.9,
120.9, 118.8, 114.7 (t, J = 240.8 Hz), 112.4, 109.7, 46.9 (t, J =
26.0 Hz), 37.1; 19F NMR (376 MHz, CDCl3) δ −122.57 (dt, J =
56.3, 14.3 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ −122.57(s);
HRMS (ESI): calcd for C15H14F2N+ [M + H]+ 246.1089, found
246.1082.
Purified by flash column chromatography (petroleum ether/
EtOAc = 1 : 1), white solid (39.6 mg, 83% yield), m.p. 46–47 °C;
1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 23.4 Hz, 2H), 6.82 (s,
1H), 4.22 (s, 1H), 3.89–3.63 (m, 2H), 2.28 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 140.7, 133.4, 125.0 (q, J = 280.0 Hz), 120.1,
45.7 (q, J = 33.9 Hz), 18.6; 19F NMR (376 MHz, CDCl3) δ −72.28
(t, J = 8.8 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ −72.28(s);
+
HRMS (ESI): calcd for C8H10F3N2 [M + H]+ 191.0791, found
191.0787.
5-Methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine (9d)
Purified by flash column chromatography (petroleum ether/
EtOAc = 5 : 1), white solid (33.6 mg, 70% yield), m.p. 60–61 °C;
1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.30 (dd, J = 8.4, 2.3
Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 4.66 (s, 1H), 4.06 (qd, J = 9.1,
6.8 Hz, 2H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.1,
147.1, 139.2, 125.1 (q, J = 279.5 Hz), 123.6, 108.0, 43.3 (q, J =
34.0 Hz), 17.6; 19F NMR (376 MHz, CDCl3) δ −72.67 (t, J =
9.1 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ −72.67(s); HRMS
(ESI): calcd for C8H10F3N2+ [M + H]+ 191.0791, found 191.0785.
N-(2,2-Difluoroethyl)-3,5-dimethoxyaniline (7k)
Purified by flash column chromatography (petroleum ether/
EtOAc = 20 : 1), colorless liquid (99.8 mg, 92% yield); H NMR
1
(400 MHz, CDCl3) δ 5.95 (tt, J = 56.2, 2.1 Hz, 1H), 5.91 (t, J =
4.2 Hz, 1H), 5.84 (d, J = 2.1 Hz, 2H), 3.76 (s, 6H), 3.49 (td, J =
14.4, 4.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 161.9, 148.8,
120.2–109.6 (m), 92.1, 90.8, 55.24, 55.19, 46.45 (t, J = 26.3 Hz);
19F NMR (376 MHz, CDCl3) δ −122.60 (dt, J = 56.0, 14.4 Hz);
19F {1H} NMR (376 MHz, CDCl3) δ −122.60(s); HRMS (ESI):
calcd for C10H14F2NO2+ [M + H]+ 218.0987, found 218.0985.
N-(2,2,2-Trifluoroethyl)quinolin-3-amine (9e)
Purified by flash column chromatography (petroleum ether/
EtOAc = 3 : 1), white solid (42.6 mg, 75% yield), m.p. 78–79 °C;
N-(2,2-Difluoroethyl)-3,5-bis(trifluoromethyl)aniline (7l)
Purified by flash column chromatography (petroleum ether/ 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 2.9 Hz, 1H), 8.02–7.94
EtOAc = 30 : 1), pale yellow liquid (120.8 mg, 83% yield); (m, 1H), 7.71–7.59 (m, 1H), 7.54–7.40 (m, 2H), 7.18 (d, J =
1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.02 (s, 2H), 5.95 (tt, 2.8 Hz, 1H), 4.54 (s, 1H), 3.88 (qd, J = 8.8, 6.9 Hz, 2H); 13C
J = 55.5, 3.8 Hz, 1H), 4.32 (s, 1H), 3.62 (td, J = 14.6, 3.8 Hz, 2H); NMR (100 MHz, CDCl3) δ 142.8, 142.7, 139.8, 129.04, 128.98,
13C NMR (100 MHz, CDCl3) δ 147.8, 132.9 (q, J = 32.9 Hz), 127.4, 126.3, 126.1, 125.0 (q, J = 281.1 Hz), 111.7, 45.7 (q, J =
123.5 (q, J = 272.8 Hz), 114.1 (q, J = 242.5 Hz), 112.4 (d, J = 34.1 Hz); 19F NMR (376 MHz, CDCl3) δ −71.87 (t, J = 8.8 Hz);
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19F {1H} NMR (376 MHz, CDCl3) δ −71.87(s); HRMS (ESI): (100 MHz, CDCl3) δ 155.7 147.3, 138.7, 122.9, 114.7 (t, J = 241.2
calcd for C11H10F3N2+ [M + H]+ 227.0791, found 227.0784.
Hz), 108.1, 44.3 (t, J = 26.5 Hz), 17.5; 19F NMR (376 MHz,
CDCl3) δ −123.11 (dt, J = 56.6, 14.7 Hz); 19F {1H} NMR
N-(2,2,2-Trifluoroethyl)-1H-indol-5-amine (9f)
(376 MHz, CDCl3)
δ −123.11(s); HRMS (ESI): calcd for
Purified by flash column chromatography (petroleum ether/ C8H11F2N2+ [M + H]+ 173.0885, found 173.0882.
AcOEt 5 : 1), white solid (45.0 mg, 84% yield),
m.p. 126–127 °C; 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H),
=
N-(2,2-Difluoroethyl)quinolin-3-amine (10e)
7.29–7.21 (m, 1H), 7.15 (t, J = 2.8 Hz, 1H), 6.95 (d, J = 2.3 Hz, Purified by flash column chromatography (petroleum ether/
1H), 6.68 (dd, J = 8.6, 2.3 Hz, 1H), 6.52–6.36 (m, 1H), 3.79 (q, EtOAc = 3 : 1), white solid (40.5 mg, 77% yield), m.p. 73–74 °C;
J = 9.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 140.4, 130.9, 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 2.9 Hz, 1H), 7.96 (dd,
128.8, 125.5 (q, J = 279.8 Hz), 125.0, 112.2, 111.9, 103.5, 102.0, J = 6.2, 3.4 Hz, 1H), 7.62 (dd, J = 6.2, 3.4 Hz, 1H), 7.45 (dt, J =
47.9 (q, J = 33.0 Hz); 19F NMR (376 MHz, CDCl3) δ −72.10 (t, J = 6.3, 3.5 Hz, 2H), 7.10 (d, J = 2.8 Hz, 1H), 5.98 (tt, J = 55.8,
8.9 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ −72.10(s); HRMS 4.1 Hz, 1H), 4.42 (s, 1H), 3.62 (tdd, J = 14.5, 6.6, 4.1 Hz, 2H);
+
(ESI): calcd for C10H10F3N2 [M
215.0783.
+
H]+ 215.0791, found 13C NMR (100 MHz, CDCl3) δ 143.1, 142.7, 140.4, 129.1, 129.1,
126.2, 125.8, 114.4 (t, J = 242.3 Hz), 111.0, 46.1 (t, J = 26.1 Hz);
19F NMR (376 MHz, CDCl3) δ −122.23 (dt, J = 55.8, 14.5 Hz);
N-(2,2-Difluoroethyl)pyridin-3-amine (10a)10
Purified by flash column chromatography (petroleum ether/ calcd for C11H11F2N2+ [M + H]+ 209.0885, found 209.0879.
EtOAc = 2 : 3), brown liquid (33.2 mg, 84% yield); 1H NMR
19F {1H} NMR (376 MHz, CDCl3) δ −122.23(s); HRMS (ESI):
N-(2,2-Difluoroethyl)-1H-indol-5-amine (10f)
(400 MHz, CDCl3) δ 8.20–7.89 (m, 2H), 7.12 (dd, J = 8.3, 4.6 Hz,
1H), 6.95 (ddd, J = 8.3, 3.0, 1.3 Hz, 1H), 5.92 (tt, J = 55.8, Purified by flash column chromatography (petroleum ether/
4.0 Hz, 1H), 4.09 (s, 1H), 3.55 (tdd, J = 14.5, 6.7, 4.0 Hz, 2H); EtOAc
=
5 : 1), brown solid (39.4 mg, 80% yield),
13C NMR (100 MHz, CDCl3) δ 143.1, 140.1, 136.3, 123.9, 119.1, m.p. 111–112 °C; 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H),
114.4 (t, J = 242.2 Hz), 46.1 (t, J = 26.0 Hz).
N-(2,2-Difluoroethyl)pyridin-2-amine (10b)
7.23 (d, J = 8.6 Hz, 1H), 7.15 (t, J = 2.8 Hz, 1H), 6.92 (d, J =
2.3 Hz, 1H), 6.67 (dd, J = 8.6, 2.3 Hz, 1H), 6.43 (t, J = 2.8 Hz,
1H), 5.98 (tt, J = 56.4, 4.3 Hz, 1H), 3.57 (td, J = 14.4, 4.4 Hz,
Purified by flash column chromatography (petroleum ether/ 3H); 13C NMR (100 MHz, CDCl3) δ 140.8, 130.8, 128.8, 125.0,
EtOAc = 20 : 1), colorless and transparent liquid (22.5 mg, 57% 115.0 (t, J = 241.3 Hz), 112.4, 112.0, 103.1, 102.0, 48.1 (t, J =
yield); 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 4.4 Hz, 1H), 25.8 Hz); 19F NMR (376 MHz, CDCl3) δ −122.70 (dt, J = 56.3,
7.42 (ddd, J = 8.7, 7.1, 1.9 Hz, 1H), 6.64 (ddd, J = 7.2, 5.1, 14.4 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ −122.70(s); HRMS
1.0 Hz, 1H), 6.46 (dd, J = 8.3, 1.0 Hz, 1H), 5.97 (tt, J = 56.6, 4.3 (ESI): calcd for C10H11F2N2+ [M + H]+ 197.0885, found 197.0881.
Hz, 1H), 4.66 (s, 1H), 3.78 (tdd, J = 14.6, 6.5, 4.3 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 157.6, 148.0, 137.6, 114.6 (t, J =
241.7 Hz), 114.1, 108.4, 44.1 (t, J = 26.6 Hz); 19F NMR Conflicts of interest
(376 MHz, CDCl3) δ −123.14 (dt, J = 56.5, 14.7 Hz); 19F {1H}
There are no conflicts to declare.
NMR (376 MHz, CDCl3) δ −123.14(s); HRMS (ESI): calcd for
C7H9F2N2+ [M + H]+ 159.0728, found 159.0726.
N-(2,2-Difluoroethyl)-5-methylpyridin-3-amine (10c)
Acknowledgements
Purified by flash column chromatography (petroleum ether/
EtOAc = 1 : 1), white solid (40.2 mg, 93% yield), m.p. 43–44 °C;
1H NMR (400 MHz, CDCl3) δ 7.96–7.80 (m, 2H), 6.76 (t, J =
2.1 Hz, 1H), 5.91 (tt, J = 55.8, 4.1 Hz, 1H), 4.08 (s, 1H), 3.53
(tdd, J = 14.5, 6.5, 4.1 Hz, 2H), 2.26 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 142.8, 140.7, 133.7, 133.5, 119.9, 114.5 (t,
J = 242.1 Hz), 46.1 (t, J = 26.0 Hz), 18.6; 19F NMR (376 MHz,
CDCl3) δ −122.65 (dt, J = 55.6, 14.2 Hz); 19F {1H} NMR
We thank the Natural Science Foundation of Jiangxi province
(20171BAB213007, 2018BBE50004) and the Outstanding Young
Talents Scheme of Jiangxi Province (20171BCB23039) for
funding this research.
Notes and references
(376 MHz, CDCl3)
δ
−122.65(s); HRMS (ESI): calcd for
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