Fe-catalyzed synthesis of flunarizine and its (Z)-isomer

Full text of DOI:10.1134/S107036321608034X

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 8, pp. 1969–1972. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © R.N. Shakhmaev, A.Sh. Sunagatullina, V.V. Zorin, 2016, published in Zhurnal Obshchei Khimii, 2016, Vol. 86, No. 8, pp. 1395–
1
398.
LETTERS
TO THE EDITOR
Fe-Catalyzed Synthesis of Flunarizine and Its (Z)-Isomer
R. N. Shakhmaev*, A. Sh. Sunagatullina, and V. V. Zorin
Ufa State Petroleum Technological University, ul. Kosmonavtov 1, Ufa, 450062 Russia
*
e-mail: biochem@rusoil.net
Received March 14, 2016
Keywords: flunarizine, Fe-catalysis, iron, cross-coupling, drug
DOI: 10.1134/S107036321608034X
Flunarizine {Sibelium, 1-[bis(4-fluorophenyl)methyl]-
-[(2E)-3-phenylprop-2-en-1-yl]piperazine} is a well-
piperazine 5 with individual (E)- and (Z)-isomers of
1,3-dichloropropene 6 and 7. The peculiarity of 1,3-
dichloropropene stereoisomers, a large-scale waste of
allyl chloride production, is the prominently different
boiling point enabling efficient separation of trans-
and cis-isomers by rectification. Individual stereo-
isomers of 1,3-dichloropropene containing allyl and
vinyl chlorine atoms with different reactivity have
unique synthetic potential. A strategy based on the
functionalization of 1,3-dichloropropene isomers at the
allyl position with N-nucleophiles, followed by stereo-
selective cross-coupling at the vinyl site is very promis-
ing for creating stereochemically pure allylamines [20,
21]. Nucleophilic substitution of the allyl chlorine
atom afforded compounds 3 and 4 in high yields, while
preserving the double bond configuration [22].
4
known drug belonging to calcium channel blockers. It
exhibits vasodilating effect, improves cerebral blood
circulation, and shows antihistamine activity. Flunari-
zine is used to treat migraines, dizziness, vestibular
disorders, and epilepsy [1–4]. Industrial production of
flunarizine is based on condensation of N-cynnamyl-
piperazine with bis(4-fluorophenyl)chloromethane or
of cynnamyl chloride with 1-[bis(4-fluorophenyl)-
methyl]piperazine [5, 6]. Flunarizine can be obtained
by regioselective metal-catalyzed amination of cinnamyl
alcohol with 1-[bis(4-fluorophenyl)methyl]piperazine
using Pt(cod) Cl –DPEPhos [7] and Pd(OAc) –1,10-
2
2
2
phenanthroline catalysts [8]. (E)- and (Z)-isomers of 1-
bis(4-fluorophenyl)methyl]-4-(3-phenylprop-2-en-1-
[
yl)piperazine (E : Z = 1 : 7.4) have been also prepared
via Wittig reaction involving {4-[bis(4-fluorophenyl)-
methyl]piperazin-1-yl}acetaldehyde and benzyltriphenyl-
phosphonium chloride, followed by isomers separation
by column chromatography [9].
Cross-coupling of (E)-vinylchloride 3 with 1.8 eq.
of phenylmagnesium chloride in the presence of 2 mol %
of Fe(acac) and 10 mol% of N-methylpyrrolidone in
3
THF at room temperature led to the formation of
flunarizine 1 in 89% yield. The reaction proceeded
with high stereoselectivity, E : Z = 98 : 2 [isomeric
purity of the starting (E)-1,3-dichloropropene was
Successful application of various Fe-catalyst
systems in cross-coupling reactions of vinyl halides
with Grignard reagents has been earlier reported in [10–
9
9%]. Use of an excess of PhMgCl was necessary to
18]. The main advantages of Fe-containing catalysts
maximize the yield of flunarizine; the reduction in the
reagent load led to incomplete conversion of vinyl
chloride 3. Replacement of PhMgCl with phenylmagne-
sium bromide resulted in a slight (1–2%) decrease in
flunarizine yield. Cross-coupling of (Z)-vinyl chloride
4 with PhMgCl under those conditions provided (Z)-
flunarizine 2 in lower yield (81%) and stereoselectivity
(Z : E = 91 : 9). Side biphenyl was easily separated off
the reaction product by column chromatography
(Scheme 1).
over conventional platinum group metals are high
activity, availability, lower cost, and non-toxicity [19].
Herein, we report stereoselective synthesis of flu-
narizine 1 and its (Z)-isomer 2 based on the Fe-
catalyzed cross-coupling of (E)- and (Z)-1-[bis(4-
fluorophenyl)methyl]-4-(3-chloroprop-2-en-1-yl)pipe-
razines 3 and 4 with phenylmagnesium chloride.
Stereochemically pure vinyl chlorides 3 and 4 were
prepared via allylation of 1-[bis(4-fluorophenyl)methyl]-
1
969

1
970
SHAKHMAEV et al.
Scheme 1.
F
F
Cl
Cl
6
PhMgCl, Fe(acac)3
THF, NMP
F
K CO , CH CN
2
3
3
N
N
N
Cl
N
F
F
3
(91%)
F
1 (89%)
N
NH
F
Cl
F
5
Cl
7
PhMgCl, Fe(acac)3
THF, NMP
K CO , CH CN
2
3
3
N
N
N
N
F
F
Cl
4
(88%)
2 (81%)
The structure, stereochemical purity, and configura-
After cooling, the solution was filtered, and the pre-
cipitate was washed with ethyl acetate. The combined
organic layers were concentrated, and the residue was
purified by column chromatography (hexane–ethyl
acetate, 9 : 1 → 2 : 1). Yield 3.31 g (91%), colorless
tion of the prepared compounds were confirmed by
GLC, IR and NMR spectroscopy, and gas chromato-
graphy–mass spectrometry data. Reliable proof of the
configuration of compounds 1 and 2 was the value of
the spin-spin coupling constants of vinyl hydrogen
atoms (15.8 and 11.8 Hz, respectively) as well as
downfield shifting the signal of flunarizine allyl carbon
atom (60.85 ppm) as compared to the same carbon
atom of (Z)-isomer (55.91 ppm). The strongest signals
in the mass spectra of compounds 1–4 were assigned
to cynnamylpiperazine (m/z 201) and 3-chloroprop-2-
en-1-ylpiperazine (m/z 159) fragments formed as a
result of C–N breaking with elimination of bis(4-
fluorophenyl)methyl (m/z 203).
–
1
crystals, mp 89°C. IR spectrum, ν, cm : 1609, 1506,
1
1453, 1288, 1226, 1153, 1137, 1008, 828. Н NMR
spectrum, δ, ppm: 2.43 br.s (4H, CH N), 2.51 br.s (4H,
2
CH N), 3.04 d (2H, CH CH=, J = 7.0 Hz), 4.23 s (1H,
2
2
СHAr ), 5.98 d.t (1H, CH CH=, J = 13.2, 7.0 Hz),
2
2
trans
6.15 d (1H, ClCH=, Jtrans = 13.2 Hz), 6.96 t (4H, CH ,
Ar
13
J = 8.5 Hz), 7.28–7.38 m (4H, CH ). С NMR spec-
Ar
trum, δ , ppm: 51.51 (2CH N), 52.97 (2CH N), 58.10
С
2
2
1
2
(C ), 74.33 (СHAr ), 115.13 d (4CH , J = 20 Hz),
120.59 (C ), 129.20 d (4CH , J = 6.8 Hz), 129.96
C ), 138.11 (2C ), 161.78 d (2CF , J = 244.2 Hz).
Mass spectrum, m/z (I , %): 362 (0.8) [M] , 203 (41),
2
Ar
CF
3
3
Ar
CF
2
1
(
Ar Ar CF
The advantages of the proposed method of the
synthesis of flunarizine and its (Z)-isomer are the use
of commercially available 1,3-dichloropropene isomers,
high yield, mild conditions, and short reaction duration
as well as low cost and non-toxicity of Fe-containing
catalyst.
+
rel
2
01 (19), 183 (30), 161 (31), 159 (100), 132 (13), 123
(
(
32), 75 (34), 56 (15), 42 (22). Mass spectrum
HRMS), m/z: 362.1348 [M] (calculated for
+
C H ClF N : 362.1361).
2
0
21
2
2
1
-[Bis(4-fluorophenyl)methyl]-4-[(2E)-3-chloro-
1-[Bis(4-fluorophenyl)methyl]-4-[(2Z)-3-chloro-
prop-2-en-1-yl]piperazine (4) was prepared similarly.
prop-2-en-1-yl]piperazine (3). A mixture of 1.22 g
0.011 mol) of (E)-1,3-dichloropropene 6, 2.07 g
0.015 mol) of K CO , 50 mL of anhydrous aceto-
–
1
(
(
Yield 3.19 g (88%). IR spectrum, ν, cm : 1603, 1506,
1
1456, 1296, 1223, 1153, 1135, 1007, 827. Н NMR spec-
2
3
nitrile, and 2.88 g (0.01 mol) of 1-[bis(4-fluorophenyl)-
methyl]piperazine 5 was stirred for 0.5 h at room
temperature, and then for 4 h under reflux until amine
trum, δ, ppm: 2.43 br.s (4Н, CH N), 2.57 br.s (4Н,
2
CH N), 3.26 d (2Н, CH CH=, J = 7.0 Hz), 4.23 s (1H,
2
2
СHAr ), 5.91 q (1H, CH CH=, J = 7.0 Hz), 6.19 d
2
2
5
was completely consumed (monitoring with GLC).
(1H, ClCH=, Jcis = 7.0 Hz), 6.96 t (4H, CH , J =
Ar
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 8 2016

Fe-CATALYZED SYNTHESIS OF FLUNARIZINE AND ITS (Z)-ISOMER
1971
1
3
13
8
С
.6 Hz), 7.28–7.38 m (4H, CH ). С NMR spectrum,
(4H, CH , J = 8.6 Hz), 7.21–7.36 m (9H, CH ). С
Ar
Ar
Ar
1
δ , ppm: 51.30 (2CH N), 53.03 (2CH N), 54.17 (C ),
NMR spectrum, δ , ppm: 51.48 (2CH N), 53.24
(2CH N), 55.91 (C ), 74.30 (СHAr ), 115.30 d (4CH ,
2 2 Ar
2
2
С 2
2
1
7
1
9
4.24 (СHAr ), 115.33 d (4CH , J = 20.1 Hz),
2
Ar
CF
3
2
3
2
21.13 (C ), 127.42 (C ), 129.16 d (4CH , J
.0 Hz), 138.02 (2C ), 161.75 d (2CF , J = 244.2
Hz). Mass spectrum, m/z (I , %): 362 (1) [M] , 203
=
JCF = 20.3 Hz), 126.85 (CH ), 128.08 (2CH ),
Ar
CF
Ar Ar
1
2
3
128.79 (2CH C ), 129.17 d (4CH , J = 6.8 Hz),
Ar, Ar CF
131.64 (C ), 136.91 (C ), 138.14 (2C ), 161.74 d
(2CF , J = 244.2 Hz). Mass spectrum, m/z (I , %):
Ar CF rel
404 (1.2) [M] , 287 (13), 203 (24), 202 (16), 201
(100), 183 (17), 118 (8), 117 (79), 116 (7), 115 (29),
91 (14). Mass spectrum (HRMS), m/z: 404.2049 [M]
Ar
Ar
CF
+
3
rel
Ar Ar
1
(
1
(
42), 201 (17), 183 (26), 161 (32), 159 (100), 132 (17),
23 (22), 75 (24), 56 (18), 42 (19). Mass spectrum
+
+
HRMS), m/z: 362.1350 [M] (calculated for
+
C H ClF N : 362.1361).
2
0
21
2
2
(
calculated for C H F N : 404.2064).
26 26 2 2
1
-[Bis(4-fluorophenyl)methyl]-4-[(2E)-3-phenyl-
1
13
prop-2-en-1-yl]piperazine (flunarizine) (1). A solution
of PhMgCl in THF (0.9 mL, 2 mol/L) was added
slowly to a solution of 0.363 g (1 mmol) of vinyl
H and C NMR spectra were registered using a
1
13
AM-300 spectrometer [300.13 ( H), 75.46 MHz ( C)]
in CDCl . IR spectra were recorded using an IR
3
chloride 3, 7 mg (0.02 mmol) of Fe(acac) , and 9.6 μL
Prestige-21 Shimadzu FTIR spectrophotometer for the
samples in mineral oil and hexachlorobutadiene. GC–
MS analysis was performed using a GCMS-QP2010S
Shimadzu spectrometer [electron ionization at 70 eV,
detected mass range of 33–500 Da, HP-1MS capillary
column (30 m × 0.25 mm × 0.25 µm), the evaporator
temperature 300°C, ionization chamber temperature
200°C, temperature programming mode from 50 to
3
(
0
0.1 mmol) of N-methylpyrrolidone in 3 mL of THF at
°C under argon atmosphere. The resulting mixture
was stirred at room temperature for 1 h, and then 2 mL
of water and 8 mL of ethyl acetate were added to the
mixture. The organic layer was separated, and the
aqueous layer was treated with ethyl acetate (2 × 5 mL).
The combined organic layers were washed with
saturated NaCl, dried over Na SO , and concentrated.
–
1
300°C at 10 deg min , and then at 300°C for 15 min,
2
4
–
1
The reaction product was purified by column
chromatography (hexane–ethyl acetate, 9 : 1 → 2 : 1).
Yield 0.361 g (89%), colorless crystals, mp 96–99°C.
carrier gas helium (1.1 mL min )]. Mass spectra were
recorded with a MAT 95XP Finnigan high-resolution
spectrometer. Column chromatography was performed
on 70–230 mesh silica gel (Fluka).
–
1
IR spectrum, ν, cm : 1601, 1507, 1455, 1377, 1220,
1
1
155, 1138, 1003, 968, 825. Н NMR spectrum, δ,
ppm: 2.41 br.s (4H, CH N), 2.53 br.s (4H, CH N), 3.16
ACKNOWLEDGMENTS
2
2
d (2H, CH CH=, J = 6.8 Hz), 4.23 s (1H, СHAr ), 6.26
2
2
d.t (1H, CH CH=, J
= 15.8, 6.8 Hz), 6.51 d (1H,
This work was financially supported by the
Ministry of Education and Science of Russia in the
frame of the basic part of the governmental task
(project no. 49).
2
trans
PhCH=, Jtrans = 15.8 Hz), 6.95 t (4H, CH , J = 8.7 Hz),
Ar
1
3
7
5
(
(
1
.16–7.38 m (9H, CH ). С NMR spectrum, δ , ppm:
Ar С
1
1.60 (2CH N), 53.30 (2CH N), 60.85 (C ), 74.36
СHAr ), 115.28 d (4CH , J = 22.6 Hz), 126.25
2CH ), 126.34 (C ), 127.42 (CH ), 128.49 (2CH ),
Ar Ar Ar
29.23 d (4CH , J = 6.9 Hz), 133.08 (C ), 136.88
2
2
2
2 Ar CF
2
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3
3
Ar CF
1
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