Microwave-assisted amination from fluorobenzenes without catalyst and strong base

Article abstract of DOI:10.1016/j.jfluchem.2012.12.001

A facile and versatile amination of fluorobenzenes has been developed in good to excellent yields under microwave irradiation in N-methylpyrrolidinone (NMP) without strong base and catalyst. The presence of additional halogen atom(s) enhanced the leaving ability of fluorine and meta fluorine gave higher activation than the ortho. It is remarkable that 1,2,3-trifluorobenzene, 1,2,4-trifluorobenzene and 1,2,4,5-tetrafluorobenzene can produce the regioselective mono-substituted products.

Full text of DOI:10.1016/j.jfluchem.2012.12.001

Journal of Fluorine Chemistry 146 (2013) 70–75
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Microwave-assisted amination from fluorobenzenes without catalyst and
strong base
*
Xiangguo Meng, Zhengyan Cai, Sa Xiao, Weicheng Zhou
State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-infectives, Shanghai Institute of Pharmaceutical Industry, State Institute of Pharmaceutical Industry,
1111 North Zhongshan No. 1 Rd, Shanghai 200437, PR China
A R T I C L E I N F O
A B S T R A C T
Article history:
A facile and versatile amination of fluorobenzenes has been developed in good to excellent yields under
microwave irradiation in N-methylpyrrolidinone (NMP) without strong base and catalyst. The presence
of additional halogen atom(s) enhanced the leaving ability of fluorine and meta fluorine gave higher
activation than the ortho. It is remarkable that 1,2,3-trifluorobenzene, 1,2,4-trifluorobenzene and
1,2,4,5-tetrafluorobenzene can produce the regioselective mono-substituted products.
ß 2012 Elsevier B.V. All rights reserved.
Received 19 September 2012
Received in revised form 15 November 2012
Accepted 4 December 2012
Available online 12 December 2012
Keywords:
Microwave-assisted
Amination
Fluorobenzenes
Nucleophilic substitution
Regioselectivity
1. Introduction
reaction time, sensitive conditions, and/or strong bases are
required. In addition, the use of transition metals introduces a
Fluorine substituted anilines represent an important N-aryl
motif, which have various potential applications in many areas
such as chemistry [1], natural products [2], agrochemical industry
[3], fluorescence probes [4], pharmaceutical [5], photography
system [6] and materials [7]. Traditional aromatic nucleophilic
substitutions (SNAr), which are limited to only activated aromatic
substrates having electron-withdrawing group such as nitro or
cyano group, generally afford only moderate yields under harsh
conditions to prepare aniline derivatives [8]. Metal-catalyzed
coupling reactions (Buchwald-Hartwig reaction) have received
enormous interest over the past few decades, with great strides
achieved in amination of aryl halides [9–13], triflates [14,15] and
carboxylates [16] as effective electrophiles. Disadvantages are the
high price of metal catalysts, and the need for kinds of relatively
costly ligands. The synthesis of aniline derivatives by the classical
Cu-mediated Ullmann condensation, which needs substantial
amounts of copper and high temperature, has been known since
the beginning of the 20th century. Although Ullmann reactions
[17–20] have been extensively developed in aryl C–N bond
formation, the cost and availability of the catalysts are still major
factors of hindering application [21]. At the same time, long
challenge for removal of trace amount of the heavy metal in the
pharmaceutical product. New strategy, following the standard of
green chemistry, for the preparation of fluorine substituted aniline
is needed.
Microwave irradiation has been an available method in organic
synthesis, which has been applied in heterocycle chemistry,
cycloaddition and catalysis reaction [22–25] etc., since the first
report of a microwave synthesis in the year 1986 up to now [26].
Microwave irradiation has certain benefits over conventional
heating such as acceleration of reaction rate, milder reaction
conditions, higher yield, lower energy consumption, enhancement
of the selectivity of reaction and easier workup. More recently, it
has been reported that ArX (X = Cl, Br or I) could couple with
amines to give corresponding anilines using microwave in the
presence of a hygroscopic, strong base (KOtBu) [27]. Aryl triflates,
which need to be prepared from phenols, were used to react with
amines to obtain anilines derivatives under microwave irradiation
[28]. To the best of our knowledge, however, the direct amination
of fluorobenzenes employing microwave techniques without
strong base has not been described. Herein we wish to report
our preliminary research on the microwave-assisted nucleophilic
substitution of fluorobenzenes with 1-methylpiperazine, morpho-
line and piperazine. Without any strong base or catalyst, the
reaction smoothly carried out in relatively short time to give the
desired products in good yields.
* Corresponding author. Fax: +86 21 3505 2484.
E-mail address: profzhouwc@yahoo.com.cn (W. Zhou).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.12.001

X. Meng et al. / Journal of Fluorine Chemistry 146 (2013) 70–75
71
Table 1
Optimization investigation.a
M.W
F
HN
N
CH3
N
N CH3
Base, Solvent
Entry
Solvent
Base
Temp (8C)
Catalyst
Time (h)
Yield (%)b
1
2
3c
4c
5
Fluorobenzene
Fluorobenzene
Fluorobenzene
Fluorobenzene
EtOH
K2CO3
K2CO3
KOH
110
210
110
110
170
160
160
200
235
250
250
–
0.25
0
–
1
0.25
0.25
1
0
–
0
KOtBu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
–
0
–
little
little
little
14
14
28
67
6
H2O
–
1
7
H2O
TBAB
1
8
DMSO
–
–
–
–
3
9
NMP
2
10
11
NMP
6
NMP
20
a
Reaction conditions: 1-fluorobenzene (30 mmol), base (20 mmol), 1-methylpiperazine (10 mmol), 15 mL solvent, and/or 5 mol% TBAB were charged to a 20 mL sealed
microwave vial equipped with a magnetic stir bar, which can bear the maximum operating pressure of 20 bar, at the temperature indicated for 0.25–20 h.
b
Isolated yields.
c
The suspension of KOH or KOtBu in fluorobenzene was so bad that the reactor automatically ceased the heating.
2. Results and discussion
reaction (Table 1, entries 5–7). High boiling point solvent, such as
DMSO and N-methylpyrrolidinone (NMP), were proved to be more
effective for the microwave-assisted amination. DMSO as the
solvent in the presence of K2CO3 delivered the expected 1-methyl-
4-phenylpiperazine (Table 1, entry 8), and NMP gave the better
result, especially when the reaction was carried for long time
(Table 1, entries 9–11).
With the optimized conditions, we evaluated the microwave-
assisted amination of a series of fluorobenzenes (1,2-difluoro-
benzene, 1-cholor-2-fluorobenzene, 1,2,3-trifluorobenzene, 1,2,4-
trifluorobenzene and 1,2,4,5- tetrafluorobenzene) with 1-methyl-
piperazine, morpholine and piperazine (Table 2). The yield of
At first, 1-fluorobenzene, which would have the lowest
reactivity among fluorobenzenes was chosen as our initial
substrate in the reaction with 1-methylpiperazine. The research
protocol included screening for solvent, base, temperature,
reaction time and catalyst. Our preliminary experiments demon-
strated that no product was found when excess of 1-fluorobenzene
was served as solvent in the presence of K2CO3, KOH, or KOtBu
(Table 1, entries 1–4). Some polar protic solvents (EtOH or H2O)
with phase-transfer catalyst tetrabutylammonium bromide
(TBAB) were tested, but these conditions did not improve the
Table 2
Amination of various fluorobenzenes and amines under microwave irradiation.a
Entry
1
Fluorobenzenes
Amines
Temp (8C)
Time (h)
1
Product
Yield (%)b
27c
1-Methylpiperazine
250
F
F
F
N
N CH3
1
3
6
38c
85c
2
3
1-Methylpiperazine
1-Methylpiperazine
250
220
6
81c
Cl
F
Cl
F
N
N CH3
N CH3
2
1.5
81c
F
F
F
F
N
3a
F
F
N
N CH3
3b
3a:3b = 19:1
4
1-Methylpiperazine
220
3
84c,e
F
F
N
N CH3
F
F
F
F
4a
4b
F
N
N CH3

72
X. Meng et al. / Journal of Fluorine Chemistry 146 (2013) 70–75
Table 2 (Continued )
Entry
Fluorobenzenes
Amines
Temp (8C)
Time (h)
1
Product
Yield (%)b
4a:4b = 17:1
5
1-Methylpiperazine
220
90c
F
F
F
N
N CH3
F
F
F
F
5
6
7
8
Morpholine
Morpholine
Morpholine
250
250
190
6
60c
55c
72c
F
Cl
F
F
F
N
N
O
O
6
6
Cl
F
F
F
7
2.5
F
N
O
8
F
F
9
Morpholine
Morpholine
200
220
2
68c
F
N
F
O
F
F
F
F
F
9
10
1.5
86c
F
F
N
O
F
F
10
11
12
13
Piperazine
Piperazine
Piperazine
250
250
190
2
3
1
70d
F
F
Cl
F
F
N
NH
NH
11
12
61d
Cl
F
F
N
73d,e
F
F
F
N
NH
NH
13a
F
F
N
13b
13a:13b = 21:1
14
Piperazine
220
2
92d,e
F
F
F
N
NH
F
F
F
14a
F
N
NH
14b
14a:14b = 19:1
15
Piperazine
190
1
87d
F
F
F
F
F
N
NH
F
F
15
a
All reactions were carried out under sealed-tube conditions in a Biotage Initiator microwave reactor with the following settings: prestir = 20 s; absorption level: very high;
fixed hold time: on. For a detailed experimental operation, see Section 4
b
Yields of isolated products.
c
Yield was based on amines (fluorobenzene: amine = 3:1).
d
Yield was based on fluorobenzenes (fluorobenzene: amine = 1:3).
e
The ratios were determined by HPLC analysis, which was performed using a Waters 1525Pump, 2998PAD, 2707Autosampler, SunFire C18 4.6 mm 150 mm, 5
mm
column with a 30 min linear gradient from 5:95 to 30:70 CH3CN:0.1%TFA at a flow rate of 2 mL/min, with UV dectection at 236 nm.

X. Meng et al. / Journal of Fluorine Chemistry 146 (2013) 70–75
73
amination product increased along with the extension of the
reaction time in the case of 1,2-difluorobenzene (Table 2, entry 1).
The reactivity of fluorobenzenes was enhanced along with the
increase in the fluorine atoms on the benzene ring (Table 2, entries
6–10). Fluorine atom had a better activation than chlorine (Table 2,
entries 1 and 2, entries 6 and 7, entries 11 and 12). Isomers of
trifluorobenzene (Table 2, entries 3 and 4, entries 13 and 14) put
forward the question of regioselectivity. Because of the weaker
nucleophilicity of morpholine, among the possible products, only 8
chromatography (TLC) was performed on gel F254 plates. The silica
gel (300–400 meshes) for column chromatography was purchased
from the Qingdao Marine Chemical Factory in China. The NMR
spectra were recorded on Varian INOVA-400 (400 MHz) or Bruker
AV400 (400 MHz) spectrometer. 1H spectra were run at 400 MHz
and 13C spectra were run at 100 MHz in CDCl3 or DMSO-d6.
Chemical shifts were related to that of the solvent. 19F NMR spectra
were obtained using CFCl3 as an internal standard. HR-MS were
recorded on an Agilent G-1969A spectrometer. The melting points
were determined by capillary method. Microwave reaction was
performed on Biotage microwave reactor (Initiator Exp EU355301,
108115-45U).
or
9 potential products was produced from corresponding
trifluorobenzene (Table 2, entries 8 and 9). In entry 8, flanking
fluorine atom was activated by both of the other fluorines (ortho and
meta) and the central fluorine was activated by two ortho fluorines.
Since the presence of a fluorine atom at the meta position to the
fluorine as leaving group enhanced its reactivity compared to ortho
position [29,30], compound 8 was obtained as the sole amination
product. Meanwhile, a similar situation happened to entry 9. While
the nucleophilicity both of 1-methylpiperazine and piperazine were
better than morpholine [31], little byproduct were detected by HPLC
analysis(Table2, entries 3and 4, entries 13and 14). 3band 13b were
prepared by reversed-phase preparative HPLC (5–9% CH3CN in
4.2. General procedure
Fluorobenzenes (3eq, 30 mmol), amines (1 eq, 10 mmol), K2CO3
(2 eq) and NMP (15 mL) were charged to a 20 mL microwave vial
equipped with a magnetic stir bar. The vial was capped and heated
in the Biotage Initiator microwave reactor (with following setting:
prestir = 20 s; absorption level = very high; fixed hold time = on)
for 1–6 h at 190–250 8C as indicated. After cooling to 50 8C, the vial
was opened and the contents were transferred to a separatory
funnel containing water (60 mL) and extracted with ethyl acetate
(15 mL Â 4). The combined organic extracts were washed with
water, and dried over anhydrous Na2SO4. After removal of the
solvent, the residues were purified by the column chromatography
on silica gel to give the pure product.
water containing 0.1%TFA, C18 19 mm  100 mm, 5
m
m SunFireTM
prep OBDTM). It was noteworthy that 1,2,4,5-tetrafluorobenzene
was the most reactive substrate in this paper, giving the best yields
in the shortest time (Table 2, entries 5, 10 and 15). The ratio of
fluorobenzenes/amines was changed from 3:1 to 1:3 in order to
avoid the bis-phenyl piperazine (Table 2, entries 11–15). In these
cases, no multi-piperazinyl benzene products were found since
other fluorines were inactivated by piperazinyl group. Additionally,
we investigated the possibility for this amination using traditional
heating methods and found that 1-fluorobenzene did not react with
1-methylpiperazineinNMPat 90 8Cfor5days.Meanwhileunderthe
similar condition, 1,2,4,5-tetrafluorobenzene gave the correspond-
ing aniline only in 10% yield.
4.2.1. 1-Methyl-4-phenylpiperazine
1H NMR(400 MHz, DMSO-d6):
d 7.26–7.22 (t, 2H, J = 7.2 Hz, Ph),
6.98–6.96 (d,
2H, J = 7.6 Hz, Ph), 6.88–6.85 (t, 1H, J = 7.2 Hz, Ph), 3.73–3.46 (m,
4H, piperazine), 3.13–3.00 (m, 4H, piperazine), 2.81 (s, 3H, –CH3)
The 1H NMR data (400 MHz) were very helpful to identify 3a
and 3b. For 3a, the multiple-peak at 7.13 ppm was assigned to the
hydrogen at the meta position to methylpiperazinyl and the
coupling constants of JH–H(o), JH–F(m), JH–F(p) were calculated as
8.4 Hz, 6.1 Hz and 2.0 Hz, respectively, another peak at 7.04 ppm
was assigned to the hydrogen at the para position to methylpiper-
azinyl with the coupling constants of JH–F(o) = 10.0 Hz, JH–
H(o) = 8.4 Hz, JH–F(m) = 6.9 Hz and JH–H(m) = 1.6 Hz. The triple peak
at 6.93 ppm could be assigned to the hydrogen at the ortho position
to methylpiperazinyl. For 3b, only two groups of multiple-peak,
which were assigned to the aromatic protons, were observed at
6.92 ppm (2H) and 6.84 ppm (1H). The similar spectral profile was
found for 13a and 13b (see Section 4).
4.2.2. 1-(2-Fluorophenyl)-4-methylpiperazine (1)
A colorless oil.
1H NMR(400 MHz, CDCl3):
d 7.28–6.95 (m, 4H, Ph), 3.17–3.14 (t,
4H, J = 4.8 Hz, piperazine), 2.64–2.62 (t, 4H, J = 4.8 Hz, piperazine),
2.38 (s, 3H, –CH3)
4.2.3. 1-(2-Chlorophenyl)-4-methylpiperazine (2)
A colorless oil.
1HNMR(400 MHz,CDCl3):
d7.38–7.36(d,1H,J = 7.2 Hz,Ph),7.23–
7.21 (t, 1H, J = 7.2 Hz, 8.0 Hz, Ph), 7.08–7.06 (d, 1H, J = 8.0 Hz, Ph),
7.00–6.96 (t, 1H, J = 7.2 Hz, Ph), 3.12–3.10 (t, 4H, J = 4.0 Hz,
piperazine),2.64–2.62(t,4H,J = 4.0 Hz,piperazine),2.38(s,3H,–CH3)
4.2.4. 1-(2,4,5-Trifluorophenyl)-4-methylpiperazine (5)
3. Conclusion
A colorless oil.
1H NMR(400 MHz, CDCl3)
d 7.28–6.86 (octet, 1H, JH–
We have established a facile and versatile method for the
preparation of halogenated anilines from halogenated fluoroben-
zenes in good or excellent yield under microwave-assisted reaction
without strong base and catalyst. The presence of additional
halogen atom(s) enhanced the leaving ability of fluorine and meta
fluorine gave higher activation than the ortho, so that the
regioselectivity was achieved. It was noteworthy that 1,2,3-
trifluorobenzene, 1,2,4-trifluorobenzene and 1,2,4,5-tetrafluoro-
benzene only produced the mono-substituted products.
F(o) = 11.6 Hz, 10.4 Hz, JH–F(m) = 7.4 Hz, Ph), 6.80–6.73 (sextet, 1H,
JH–F(o) = 12.0 Hz, JH–F(m) = 8.1 Hz, 8.0 Hz, Ph), 3.07–3.05 (t, 4H,
J = 4.4 Hz, piperazine), 2.60–2.58 (t, 4H, J = 4.4 Hz, piperazine), 2.36
(s, 3H, –CH3).
4.2.5. 4-(2-Fluorophenyl)morpholine (6)
A white solid, m.p: 39–40 8C.
1H NMR(400 MHz, CDCl3)
d 7.28–7.02 (m, 2H, Ph), 6.99–6.94
(m, 2H, Ph), 3.90–3.88 (t, 4H, J = 4.8 Hz, morpholine), 3.12–3.10 (t,
4H, J = 4.8 Hz, morpholine)
4. Experimental
4.2.6. 4-(2-Chlorophenyl)morpholine (7)
A white solid, m.p: 66–67 8C.
4.1. General information
1H NMR(400 MHz, CDCl3)
d 7.40–7.38 (q, 1H, JH–H(o) = 8.0 Hz, JH–
The materials and reagents were used as purchased and NMP
was used without any additional purification. Analytical thin-layer
H(m) = 1.4 Hz, Ph), 7.27–7.23 (sextet, 1H, JH–H(o) = 7.8 Hz, 7.6 Hz, JH–
H(m) = 1.5 Hz, Ph), 7.07–7.05 (q, 1H, JH–H(o) = 8.0 Hz, JH–

74
X. Meng et al. / Journal of Fluorine Chemistry 146 (2013) 70–75
H(m) = 1.2 Hz, Ph), 7.03–6.99 (sextet, 1H, JH–H(o) = 7.6 Hz, 7.6 Hz, JH–
H(m) = 1.6 Hz, Ph), 3.91–3.89 (t, 4H, J = 4.4 Hz, morpholine), 3.09–
3.07 (t, 4H, J = 4.4 Hz, morpholine)
7.6 Hz, JH–H(o) = 1.6 Hz, Ph), 7.07–7.05 (q, 1H, JH–H(o) = 7.6 Hz, JH–
H(m) = 1.8 Hz, Ph), 7.00–6.96 (sextet, 1H, JH–H(o) = 7.6 Hz, 7.6 Hz, JH–
H(m) = 1.6 Hz, Ph), 3.08–3.03 (m, 8H, piperazine)
4.2.7. 4-(2,3-Difluorophenyl)morpholine (8)
A white solid, m.p: 77–78 8C.
4.2.12. 1-(2,4,5-Trifluorophenyl)piperazine (15)
A colorless oil.
1H NMR(400 MHz, CDCl3)
d
7.28–6.96 (m, 1H, JH–H(o) = 8.4 Hz,
1H NMR(400 MHz, CDCl3 + D2O)
d 7.26–6.82 (octet, 1H, JH–
8.2 Hz, JH–F(m) = 6.0 Hz, JH–F(p) = 2.3 Hz, Ph), 6.84–6.77 (m, 1H, JH–
F(o) = 9.6 Hz, JH–H(o) = 8.4 Hz, JH–F(m) = 7.0 Hz, JH–H(m) = 1.4 Hz, Ph),
6.72–6.67 (m, 1H, JH–H(o) = 8.4 Hz, JH–F(m) = 7.0 Hz, JH–F(p) = 1.4 Hz,
JH–H(m) = 1.4 Hz, Ph), 3.89–3.87 (m, 4H, morpholine), 3.13–3.11 (m,
4H, morpholine)
F(o) = 11.2 Hz, 10.2 Hz, JH–F(m) = 7.5 Hz, Ph), 6.76–6.69 (sextet, 1H,
JH–F(o) = 12.0, JH–F(m) = 8.0 Hz, 8.0 Hz, Ph), 3.01–2.94 (m, 8H, piper-
azine)
4.3. Purification of 3a, 4a, 13a and 14a
13C NMR(100 MHz, DMSO-d6)
d 152.44–149.91 (q, 1C, JC–
F = 241.8 Hz, JC–F(o) = 11.7 Hz, Ph), 144.60–144.29 (d, 1C, JC–
F = 230.3 Hz, Ph), 142.30–141.98 (q, 1C, JC–F(o) = 18.1 Hz, JC–
F(m) = 8.9 Hz, Ph), 124.93–124.79 (q, 1C, JC–F(m) = 8.5 Hz, JC–
F(p) = 4.7 Hz, Ph), 114.77 (s, 1C, Ph), 110.34–110.17 (d, 1C, JC–
F(o) = 17.3 Hz, Ph), 66.53 (s, 2C, morpholine), 50.88–50.85 (d, 2C,
morpholine).
The major product (as colorless oil) of entry 3 after column
chromatography was 3a which was contaminated with 3b. The
component was separated by salt formation in HCl/MeOH, and the
major product (3a) was purified by crystallization from ethyl
acetate/ethanol. The mother solution was served for preparing 3b
by preparative HPLC. Compounds 4a, 13a and 14a were purified in
the similar manner.
19F NMR(376 MHz, DMSO-d6)
HR-MS: for C10H11F2NO [M+H]+ calculated 200.0887, found
200.0888.
d
À139.20 (d, 1F), -149.94 (d, 1F)
4.3.1.1. 1-(2,3-Difluorophenyl)-4-methylpiperazine hydrochloride
(3a HCl)
4.2.8. 4-(2,5-Difluorophenyl)morpholine (9)
A white solid, m.p: 84–85 8C.
A solid, m.p: 220–222 8C.
1H NMR(400 MHz, DMSO-d6)
d 7.16–7.10 (m, 1H, JH–
1H NMR (400 MHz, CDCl3)
d
7.00–6.94 (m, 1H, JH–F(o) = 12 Hz,
H(o) = 8.4 Hz, JH–F(m) = 6.1 Hz, JH–F(p) = 2.0 Hz, Ph), 7.07–7.00 (m, 1H,
JH–F(o) = 10.0 Hz, JH–H(o) = 8.4 Hz, JH–F(m) = 6.9 Hz, JH–H(m) = 1.6 Hz,
Ph), 6.95–6.91 (m, 1H, JH–H(o) = 7.8 Hz, JH–F(m) = 6.4 Hz, JH–
H(m) = 1.2 Hz, Ph), 3.30 (brs, 8H, piperazine), 2.79 (s,3H, –CH3)
JH–H(o) = 8.8 Hz, JH–F(m) = 5.1 Hz, Ph), 6.67–6.58 (m, 2H, Ph), 3.89–
3.86 (t, 4H, J = 4.4 Hz, morpholine), 3.11–3.08 (t, 4H, J = 4.4 Hz,
morpholine)
13C NMR(100 MHz, CDCl3):
d 160.34–157.94 (q, 1C, JC–
F = 239 Hz, JC–F(p) = 2.1 Hz, Ph), 152.86–150.43 (q, 1C, JC–F = 239 Hz,
JC–F(p) = 2.7 Hz, Ph), 141.14–140.95 (t, 1C, JC–F(m) = 9.5 Hz,
JC–F(o) = 19.1 Hz, Ph), 116.69–116.35 (q, 1C, JC–F(o) = 23.9 Hz, JC–
F(m) = 10.1 Hz, Ph), 107.93–107.62 (q, 1C, JC–F(o) = 23.9 Hz, JC–
F(m) = 8.0 Hz, Ph), 105.94–105.68 (d, 1C, JC–F(o) = 25.5 Hz, Ph),
66.77 (s, 2C, morpholine), 50.56 (d, 2C, morpholine)
4.3.1.2. 1-(2,5-Difluorophenyl)-4-methylpiperazine (4a)
A colorless oil.
1H NMR(400 MHz, CDCl3)
d 6.96–6.89 (m, 1H, JH–F(o) = 12.0 Hz,
JH–H(o) = 8.8 Hz, JH–F(m) = 5.2 Hz, Ph), 6.65–6.60 (m, 1H, JH–
F(o) = 13.2 Hz, JH–F(m) = 6.6 Hz, JH–H(m) = 3.3 Hz, Ph), 6.59–6.54 (m,
1H, Ph), 3.13–3.10 (t, 4H, J = 4.8 Hz, piperazine), 2.59–2.57 (t, 4H,
J = 4.8 Hz, piperazine), 2.35 (s, 3H, –CH3)
19F NMR(376 MHz, DMSO-d6)
HR-MS: for C10H11F2NO [M+H]+ calculated 200.0881, found
200.0873.
d
À117.00 (d, 1F), À128.11 (d, 1F)
13C NMR(100 MHz, DMSO-d6)
d 160.17–157.79 (d, 1 C, JC–
F = 238.7 Hz, Ph), 152.54–150.16 (d, 1C, JC–F = 238.6 Hz, Ph),
140.00–139.81 (t, 1C, JC–F(o) = 19.8 Hz, JC–F(m) = 9.9 Hz, Ph),
117.65–117.31 (q, 1C, JC–F(o) = 23.4 Hz, JC–F(m) = 10.0 Hz, Ph),
109.19–108.87 (q, 1C, JC–F(o) = 23.9 Hz, JC-F(m) = 8.3 Hz, Ph),
107.43–107.17 (d, 1C, JC–F(o) = 26.3 Hz, Ph), 52.48 (s, 2C, pipera-
zine), 47.12–47.09 (d, 2C, piperazine), 42.42 (s, 1C, –CH3)
4.2.9. 4-(2,4,5-Trifluorophenyl)morpholine (10)
A white solid, m.p: 59–60 8C.
1H NMR(400 MHz, CDCl3)
d 6.96–6.89 (octet, 1H, JH–
F(o) = 11.6 Hz, 10.0 Hz, JH–F(m) = 7.6 Hz, Ph), 6.80–6.73 (sextet, 1H,
JH–F(o) = 12.0 Hz, JH–F(m) = 8.0 Hz, 8.0 Hz, Ph), 3.88–3.85 (t, 4H,
J = 4.8 Hz, morpholine), 3.04–3.02 (t, 4H, J = 4.8 Hz, morpholine)
19F NMR(376 MHz, DMSO-d6)
HR-MS: for C11H14F2N2 [M+H]+ calculated 213.1198, found
213.1202.
d
À116.74 (d, 1F), 127.94 (d, 1F)
13C NMR(100 MHz, DMSO-d6)
d 151.63–149.12 (q, 1C, JC–
F = 243.1 Hz, JC–F(m) = 8.1 Hz, Ph), 147.53–145.18 (q, 1C, JC–
F = 225.0 Hz, JC–F(m) = 12.6 Hz, Ph), 145.02–142.75 (q, 1C, JC–
F = 226.8 Hz, JC–F(o) = 13.5 Hz, Ph), 137.34 (s, 1 C, Ph), 108.38–
108.14 (m, 1C, Ph), 107.00–106.51 (m, 1C, Ph), 66.48 (s, 2C,
morpholine), 50.95–50.93 (d, 2C, morpholine)
4.3.1.3. 1-(2,3-Difluorophenyl)piperazine (13a)
A colorless oil.
1H NMR(400 MHz, CDCl3 + D2O)
d 7.01–6.94 (m, 1H, JH–
H(o) = 8.0 Hz, 8.0 Hz, JH–F(m) = 5.7 Hz, JH–F(p) = 2.2 Hz, Ph), 6.82–
6.75 (m, 1H, JH–F(o) = 9.6 Hz, JH–H(o) = 8.0 Hz, JH–F(m) = 6.8 Hz, JH–
H(m) = 1.2 Hz, Ph), 6.73–6.69 (m, 1H, JH–H(o) = 7.8 Hz, JH–
F(m) = 6.2 Hz, Ph), 3.10–3.06 (m, 8H, piperazine)
19F NMR(376 MHz, DMSO-d6)
À144.61 (d, 1F)
d
À124.19 (d, 1F), À142.08 (q, 1F),
HR-MS: for C10H10F3NO [M+H]+ calculated 218.0787, found
218.0794.
4.3.1.4. 1-(2,5-Difluorophenyl)piperazine (14a)
4.2.10. 1-(2-Fluorophenyl)piperazine (11)
A colorless oil.
A colorless oil.
1H NMR(400 MHz, CDCl3 + D2O)
d 6.94–6.90 (m, 1H, Ph), 6.64–
1H NMR(400 MHz, CDCl3 + D2O)
3.07 (m, 8H, piperazine)
d
7.29–6.94 (m, 4H, Ph), 3.09–
6.59 (m, 1H, Ph), 6.58–6.55 (m, 1H, Ph), 3.02–3.00 (m, 8H,
piperazine)
4.2.11. 1-(2-Chlorophenyl)piperazine (12)
4.4. Purification of 3b and 13b by preparative HPLC
A colorless oil.
1H NMR(400 MHz, CDCl3 + D2O)
d
7.39–7.36 (q, 1H, JH–H(o) = 7.6
3b (or 13b) in the mixture of 3a (or 13a) and 3b (or 13b) was
Hz, JH–H(m) = 1.4 Hz, Ph), 7.26–7.22 (sextet, 1H, JH–H(o) = 7.6 Hz,
prepared by reversed-phase preparative HPLC. Preparative HPLC

X. Meng et al. / Journal of Fluorine Chemistry 146 (2013) 70–75
75
was performed using SunFireTM prep OBDTM C18 19 Â 100 mm,
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