A convenient synthesis of 1-(4-fluorophenyl)-2-(4-pyridyl)cyclopentene from cyclopentanone

Article abstract of DOI:10.1055/s-2007-1000855

In the framework of investigating the role of pyridyl-substituted five-membered heterocycles as potential p38 mitogen-activated protein kinase inhibitors, we synthesized the disubstituted carbocyclic analogue, 1-(4-fluorophenyl)-2-(4-pyridyl)cyclopentene. A multistep synthesis of this compound starting from cyclopentanone is reported. Cyclopentanone was converted into 1-cyclopentenyl-4-fluorobenzene using a Grignard reaction. The oxidation of this product with hydrogen peroxide and formic acid gave 2-(4-fluorophenyl) cyclopentanone. This ketone was activated using a neodymium salt (NdCl ₃·2LiCl) and subsequently reacted with a complexed Grignard reagent (pyMgCl·LiCl) to give the corresponding cyclopentanol derivative. Finally, dehydration of the latter alcohol led to the title compound. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000855

PAPER
225
A Convenient Synthesis of 1-(4-Fluorophenyl)-2-(4-pyridyl)cyclopentene from
Cyclopentanone
S
ynthesis of 1-(4-
a
Fluorophe
s
nyl)-2-(4-
s
pyridyl)c
y
a
clopentene
m
from Cyclopentanone Abu Thaher,a Pierre Koch,b Vicente Del Amo,c Paul Knochel,c Stefan Laufer*b
a
Faculty of Science, Chemistry Department, Islamic University of Gaza, Gaza Strip, Palestine
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tübingen,
Auf der Morgenstelle 8, 72076 Tübingen, Germany
b
Fax +49(7071)295037; E-mail: stefan.laufer@uni-tuebingen.de
Institute of Chemistry and Biochemistry, Ludwig-Maximilians-Universität München, Butenandtstraße 5–13, 81377 München, Germany
c
Received 31 July 2007; revised 26 September 2007
substituted heterocycles and the adenosine triphosphate
(ATP) binding site of p38 MAP kinase.2 The hydrogen
bond between pyridine and Met109 plays a crucial role in
the biological activity of the inhibitors. However, the im-
Abstract: In the framework of investigating the role of pyridyl-sub-
stituted five-membered heterocycles as potential p38 mitogen-acti-
vated protein kinase inhibitors, we synthesized the disubstituted
carbocyclic analogue, 1-(4-fluorophenyl)-2-(4-pyridyl)cyclopen-
tene. A multistep synthesis of this compound starting from cyclo- portance of the second hydrogen bond between hetero-
pentanone is reported. Cyclopentanone was converted into 1-cy-
atom X (N, O) of the heterocycle and Lys53 of p38 MAP
kinase is still unclear and rather speculative.2–6 Herein, we
clopentenyl-4-fluorobenzene using a Grignard reaction. The oxida-
tion of this product with hydrogen peroxide and formic acid gave 2-
describe the preparation of 1-(4-fluorophenyl)-2-(4-py-
(4-fluorophenyl)cyclopentanone. This ketone was activated using a
ridyl)cyclopentene (5) as a disubstituted five-membered
neodymium salt (NdCl3·2LiCl) and subsequently reacted with a
carbocyclic scaffold, instead of the five-membered het-
erocycle, which could be considered a key compound for
understanding the role of X and its interaction with the ac-
tive site Lys53 of p38 MAP kinase. A series of symmetri-
cal and unsymmetrical 1,2-disubstituted cycloalkenes
have been previously reported.7–10 Among these cycloalk-
enes, 1,2-diphenylcyclopentene was prepared by the in-
tramolecular reductive coupling of dibenzoylpropane
using titanium(III) chloride (TiCl3)/lithium aluminum hy-
dride by refluxing the reaction mixture for six days.7
1-Methyl-2-phenylcyclopentene was also prepared from
complexed Grignard reagent (pyMgCl·LiCl) to give the corre-
sponding cyclopentanol derivative. Finally, dehydration of the lat-
ter alcohol led to the title compound.
Key words: Grignard reactions, carbocycles, medicinal chemistry,
neodymium salt, inhibitors
Extensive studies have been carried out on pyridyl-substi-
tuted five-membered heterocycles as p38 mitogen-acti-
vated protein (MAP) kinase inhibitors.1 Figure 1 shows
the most important interactions between these pyridyl-
O
NH
hydrophobic
pocket I
Lys53
HN
NH
Thr106
CH3
H
phosphate-
binding site
N
H
O
hydrogen
bond
OH
F
His107
Leu108
NH
N
X
O
CH3
R
HN
Y
H3C
N
X = N, O
Y = N, C, S, O
R = alkyl, aryl
H
O
N
hydrogen
bond
ribose-
binding site
S
O
H3C
Met109
hydrophobic
pocket II
Figure 1 Important interactions between an inhibitor and the ATP binding site of p38 MAP kinase
SYNTHESIS 2008, No. 2, pp 0225–0228
x
x
.
x
x
.2
0
0
7
Advanced online publication: 18.12.2007
DOI: 10.1055/s-2007-1000855; Art ID: T11907SS
© Georg Thieme Verlag Stuttgart · New York

226
B. Abu Thaher et al.
PAPER
the corresponding dicarbonyl compound using TiCl3/
zinc–copper couple.8 Via another route, disubstituted cy-
clopentene derivatives were prepared from 1,2-dibro-
mocyclopentene by treatment with alkyl iodide or benzyl
bromide in two separate reactions.10 1,2-Diphenylcyclo-
pentene has been used as a starting material for prepara-
tion of the corresponding alcohol,10 or to characterize the
structure of its radical anion by electron spin resonance
spectroscopy.11 To the best of our knowledge, the synthe-
sis of compound 5 has not yet been described. According-
ly, we report herein a new synthetic route for the
preparation of the unsymmetrical pyridyl-substituted cy-
clopentene 5.
F
O
O
O
i
F
41%
1
3
6
F
Scheme 2 Palladium-catalyzed a-arylation of ketone 1; Reagents
and conditions: (i) 1-bromo-4-fluorobenzene (1 equiv), compound 1
(1.2 equiv), Pd(dba)2 (1 mol%), P(t-Bu)3 (1.2 mol%), K3PO4 (3
equiv), toluene, 100 °C, 7 h.
Many attempts to prepare the disubstituted alcohol 4 from
the enolizable ketone 3 using the standard Grignard re-
agent (pyMgCl) were unsuccessful. Attempts to prepare
4-pyridylmagnesium chloride, bromide, and iodide from
their corresponding 4-halopyridines using active Rieke
magnesium15 followed by the addition of ketone 3 gave no
result. After workup of the reaction, only the starting ma-
terial ketone 3 was recovered. Itami et al. reported the bro-
mine–magnesium exchange of 4-bromopyridine with
isopropylmagnesium chloride to give 4-pyridylmagne-
sium chloride.16 The reaction of the Grignard reagent pre-
pared by this method with ketone 3 was also unsuccessful.
Another possible method of halogen–metal exchange
described by Furukawa et al. involves the reaction of 4-io-
dopyridine with ethylmagnesium bromide in tetra-
hydrofuran (THF) at room temperature;17 however, this
approach was also unsuccessful, even when the reaction
time and temperature were changed. Using an analogous
method to Wibaut and Heeringa,18 a red color appeared
during the synthesis of pyMgCl which was a good indica-
tion of the formation of the organomagnesium compound.
After adding ketone 3 to this Grignard solution, no prod-
uct was detected.
The first step was accomplished easily by the addition of
4-fluorophenylmagnesium chloride to cyclopentanone
(1). The reaction led to 1-cyclopentenyl-4-fluorobenzene
(2), which was converted into 2-(4-fluorophenyl)cyclo-
pentanone (3) by oxidation. The preparation of compound
4 was challenging. We eventually overcame this problem
by treatment of the reactive reagent 4-pyridylmagnesium
chloride–lithium chloride complex (pyMgCl·LiCl)12 with
ketone 3 in the presence of a neodymium salt
(NdCl3·2LiCl),13 leading to the corresponding disubstitut-
ed cyclopentanol 4. Finally, dehydration of alcohol 4 led
to 1-(4-fluorophenyl)-2-(4-pyridyl)cyclopentene (5) as
the major product (Scheme 1). Further work on the prep-
aration of analogues of this compound for biological test-
ing is currently underway.
The synthesis of compound 5 was quite challenging with
the most-demanding step being the addition of the pyridyl
substituent to cyclopentanone derivative 3. After a long
list of unsuccessful attempts we prepared this alcohol 4, as
mentioned above, and dehydrated it to yield the target
molecule 5.
We also tried to prepare 2-(4-fluorophenyl)cyclopen-
tanone (3) by the palladium-catalyzed a-arylation of ke-
tone 1.14 Heating ketone 1 with 1-bromo-4-fluorobenzene
in the presence of a palladium catalyst [Pd(dba)2], the
ligand tri-tert-butylphosphine, and a base (K3PO4) in tol-
uene yielded the disubstituted ketone 2,2-bis(4-fluorophe-
To pave the way for obtaining alcohol 4, we used recently
reported THF-soluble lanthanide halides (LnCl3·2LiCl,
Ln = La, Nd). These convenient reagents were found to be
very helpful for the addition of various Grignard reagents
to inert and/or enolizable ketones.13 The reaction of the
more-reactive Grignard reagent pyMgCl·LiCl with ketone
3 in the presence of LaCl3·2LiCl was unsuccessful. How-
ever, on addition of NdCl3·2LiCl, ketone 3 was activated
sufficiently. The addition of Grignard reagent
pyMgCl·LiCl to the activated ketone 3 was complete after
nyl)cyclopentanone (6) instead of
3 (Scheme 2).
Surprisingly, the disubstitution took place at the same car-
bon atom. Even the use of 1.5 equivalents of the base in-
stead of 3 equivalents gave product 6.
Starting from cyclopentanone (1), 1-cyclopentenyl-4- 10 hours at room temperature to give the disubstituted cy-
fluorobenzene (2) was obtained under standard Grignard clopentanol 4 in about 60% yield. The addition is highly
reaction conditions. The oxidation of cyclopentene deriv- stereoselective and the trans-alcohol 4 is formed because
ative 2 with hydrogen peroxide in the presence of formic of steric hindrance, as determined by X-ray crystal analy-
acid yielded 2-(4-fluorophenyl)cyclopentanone (3) sis.19
(Scheme 1).
N
N
O
O
HO
i
ii
iii
iv
F
F
58%
84%
61%
54%
F
F
1
2
3
4
5
Scheme 1 Reagents and conditions: (i) 4-fluorophenylmagnesium bromide, Et2O, reflux; (ii) H2O2, HCO2H; (iii) NdCl3·2LiCl, 1 h at r.t., then
pyMgCl·LiCl (2 equiv), 0 °C, then 8–10 h at r.t.; (iv) TsOH, H2SO4, toluene, reflux, 1 h.
Synthesis 2008, No. 2, 225–228 © Thieme Stuttgart · New York

PAPER
Synthesis of 1-(4-Fluorophenyl)-2-(4-pyridyl)cyclopentene from Cyclopentanone
227
Attempts to dehydrate alcohol 4 with hydrochloric acid20
or p-toluenesulfonic acid (TsOH)21 under reflux failed.
FC6H4), 133.9 (d, J = 3.4 Hz, C-1 4-FC6H4), 161.7 (d, J = 243.5 Hz,
C-4 4-FC6H4), 217.6 (C-1 cyclopentyl).
Dehydration of 4 by treatment with triphenylphosphine/ GC-MS: m/z = 178.1 [M+].
iodine in dichloromethane was also unsuccessful,22 as was
HRMS (EI): m/z calcd for C11H11OF: 178.0794; found: 178.0804.
the use of phosphorus pentoxide in dry diethyl ether. Fi-
nally, the dehydration of alcohol 4 with TsOH and few
drops of concentrated sulfuric acid in toluene under reflux
gave the desired alkene 5 as the major product.
2-(4-Fluorophenyl)-1-(4-pyridyl)cyclopentanol (4)
In a dried, argon-flushed 50-mL Schlenk flask equipped with a sep-
tum and a magnetic stirring bar was placed 0.33 M NdCl3·2LiCl in
THF (3.2 mL, 1.05 mmol). Neat cyclopentanone 3 (178 mg, 1.0
mmol) was added, and the resulting mixture was stirred for 1 h at
r.t. To another dried, argon-flushed 50-mL Schlenk flask equipped
with a septum and a magnetic stirring bar was added 4-iodopyridine
(410 mg, 2.00 mmol). After cooling this second flask to 0 °C,
i-PrMgCl·LiCl (1.39 M in THF, 1.6 mL, 2.20 mmol) was added and
the mixture was stirred for 1 h at 0 °C. The flask containing the ac-
tivated ketone was then cooled to 0 °C, and the prepared
pyMgCl·LiCl in the second flask was quickly added to it dropwise.
The resulting mixture was then stirred for 10 h at r.t. After the reac-
tion was finished, sat. aq NH4Cl (2 mL) and H2O (10 mL) were add-
ed. The aqueous layer was extracted with Et2O (4 × 10 mL), and the
combined extracts were dried (Na2SO4) and evaporated to dryness.
The crude product was purified by flash column chromatography
(silica gel, hexane–EtOAc, 3:1) to give colorless needlelike crys-
tals.
All commercially available reagents and solvents were used without
further purification. Melting points were determined with a Büchi
melting point B-545 apparatus. IR spectra were recorded with a Per-
kin–Elmer Spectrum One [attenuated total reflection (ATR) tech-
1
nique] spectrometer, and H and 13C NMR spectra were obtained
with a Bruker Advance 200 instrument. Chemical shifts are report-
ed relative to the residual solvent peak. GC-MS analysis was carried
out on a HP6890 series GC system to which a HP5973 mass selec-
tive detector was attached, and MS and HRMS were carried out on
a Thermo Finnigan TSQ70 instrument.
1-Cyclopentenyl-4-fluorobenzene (2)23
To a stirred solution of 4-fluorophenylmagnesium bromide, synthe-
sized from 1-bromo-4-fluorobenzene (17.5 g, 0.1 mol) and magne-
sium (2.4 g, 0.1 mol) in Et2O, was added cyclopentanone (1) (6.73
g, 0.08 mol) in Et2O (10 mL) dropwise. After the addition was com-
plete, the mixture was refluxed for 2 h. The product was hydrolyzed
by adding ice (10 g) and a precipitate formed. Then 6 M HCl was
added until the precipitate dissolved. The organic phase was sepa-
rated and the aqueous layer was extracted with Et2O (3 × 50 mL).
The combined organic phases were washed consecutively with sat.
NaHSO3 soln, sat. NaHCO3 soln, and H2O, dried (Na2SO4), and
evaporated under vacuum. The crude product was purified by vac-
uum fractional distillation (79.1 °C, 240 Pa) and the collected col-
orless oil was crystallized in the refrigerator to afford the product.
Yield: 148 g (58%).
Mp 147–148 °C.
IR (ATR): 3066 (br), 2968, 1602, 1554, 1507, 1410, 1311, 1214,
1157, 1060, 1022, 1005, 990, 818 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.93–2.47 (m, 7 H, H-3/H-4/H-5
cyclopentyl, OH), 3.37 (2d, J1 = 11.2 Hz, J2 = 7.7 Hz, 1 H, H-2 cy-
clopentyl), 6.81–6.97 (m, 4 H, 4-FC6H4), 7.26 (d, J = 4.55 Hz, 2 H,
H-3/H-5 py), 8.46 (d, J = 4.55 Hz, 2 H, H-2/H-6 py).
13C NMR (50 MHz, CDCl3): d = 22.4 (C-4 cyclopentyl), 30.0 (C-3
cyclopentyl), 42.8 (C-5 cyclopentyl), 57.2 (C-2 cyclopentyl), 82.9
(C-1 cyclopentyl), 115.0 (d, J = 20.9 Hz, C-3/C-5 4-FC6H4), 120.3
(C-3/C-5 py), 130.0 (d, J = 7.9 Hz, C-2/C-6 4-FC6H4), 132.8 (d, J =
16 Hz, C-1 4-FC6H4), 149.0 (C-2/C-6 py), 156.1 (C-4 py), 161.9 (d,
J = 244.2 Hz, C-4 4-FC6H4).
Yield: 7.95 g (61%).
1H NMR (200 MHz, CDCl3): d = 1.98–2.16 (m, 2 H, H-4 cyclopen-
tenyl), 2.58–2.64 (m, 2 H, H-5 cyclopentenyl), 2.72–2.80 (m, 2 H,
H-3 cyclopentenyl), 6.15–6.20 (m, 1 H, H-2 cyclopentenyl), 7.03–
7.14 (m, 2 H, H-3/H-5 4-FC6H4), 7.41–7.51 (m, 2 H, H-2/H-6 4-
FC6H4).
MS (FAB): m/z = 258.1 [M+ + 1].
HRMS (EI): m/z calcd for C16H16NOF: 257.1216; found: 257.1226.
2-(4-Fluorophenyl)cyclopentanone (3)
1-(4-Fluorophenyl)-2-(4-pyridyl)cyclopentene (5)
A mixture of 85% HCO2H (20 mL) and 30% H2O2 (4.5 mL) was
stirred and warmed at 40 °C for 10 min. Cyclopentene 2 (5.34 g, 30
mmol) was added portionwise while maintaining a temperature of
30–35 °C. The mixture was stirred for 1 h and then left without stir-
ring at r.t. overnight. Then, Et2O (50 mL) was added and the mixture
was washed with sat. NaHCO3 soln (3 × 30 mL). The aqueous layer
was extracted with Et2O (3 × 30 mL), and the collected organic
phases were dried (Na2SO4) and evaporated under vacuum. The
crude product was purified by flash chromatography (silica gel,
hexane–EtOAc, 3:1). A thick colorless oil was obtained and was
crystallized in the refrigerator to afford the product.
Alcohol 4 (100 mg, 0.39 mmol), one crystal of TsOH in toluene (15
mL), and 3–5 drops of concd H2SO4 were refluxed for 1 h. The mix-
ture was then cooled to r.t., sat. NaHCO3 soln (30 mL) was added,
the mixture was extracted with EtOAc (3 × 30 mL). The organic
phase was washed with H2O (20 mL), dried (Na2SO4), and evapo-
rated. The crude product was purified by thick-layer chromatogra-
phy (silica gel, hexane–EtOAc, 1:1). The plates were put in the
eluent 3 × for good separation to give a thick, colorless oil that so-
lidified in the refrigerator to afford the product.
Yield: 50 mg (54%).
IR (ATR): 2954, 1593, 1508, 1409, 1222, 1158, 819 cm–1.
Yield: 4.50 g (84%).
1H NMR (200 MHz, CDCl3): d = 2.00–2.15 (m, 2 H), 2.70–2.77 (m,
4 H), 6.84–6.98 (m, 2 H), 7.04–7.15 (m, 4 H), 8.41–8.43 (m, 2 H).
IR (ATR): 2966, 2880, 1738, 1602, 1509, 1406, 1221, 1159, 1141,
1120, 866, 836, 818, 800 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.85–2.26 (m, 4 H, H-3/H-4 cy-
clopentyl), 2.41–2.49 (m, 2 H, H-5 cyclopentyl), 3.24–3.34 (m, 1 H,
H-2 cyclopentyl), 6.96–7.05 (m, 2 H, H-3/H-5 4-FC6H4), 7.12–7.19
(m, 2 H, H-2/H-6, 4-FC6H4).
13C NMR (50 MHz, CDCl3): d = 20.6 (C-4 cyclopentyl), 31.6 (C-3
cyclopentyl), 38.1 (C-5 cyclopentyl), 54.4 (C-2 cyclopentyl), 115.3
(d, J = 21.3 Hz, C-3/C-5 4-FC6H4), 129.5 (d, J = 7.9 Hz, C-2/C-6 4-
13C NMR (50 MHz, CDCl3): d = 21.9 (cyclopentenyl), 37.8 (cyclo-
pentenyl), 39.8 (cyclopentenyl), 115.3 (d, J = 21.3 Hz, C-3/C-5 4-
FC6H4), 122.8 (C-3/C-5 py), 129.5 (d, J = 7.9 Hz, C-2/C-6 4-
FC6H4), 133.2 (d, J = 3.5 Hz, C-1 4-FC6H4), 134.5, 141.9, 146.5,
148.6 (C-2/C-6 py), 161.9 (d, J = 245.7 Hz, C-4 4-FC6H4).
MS (FAB): m/z = 240.2 [M+ + 1].
HRMS (EI): m/z calcd for C16H14NF: 239.1110; found: 239.1096.
Synthesis 2008, No. 2, 225–228 © Thieme Stuttgart · New York

228
B. Abu Thaher et al.
PAPER
2,2-Bis(4-fluorophenyl)cyclopentanone (6)
(5) Fitzgerald, C. E.; Patel, S. B.; Becker, J. W.; Cameron, P.
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In a dried, argon-flushed Schlenk flask equipped with a magnetic
stirring bar was placed K3PO4 (9.50 g, 45 mmol). Toluene (40 mL),
1-bromo-4-fluorobenzene (2.62 g, 15 mmol), cyclopentanone (1.51
g, 18 mmol), P(t-Bu)3 (0.04 M in toluene, 4.5 mL, 0.18 mmol), and
Pd(dba)2 (86 mg, 0.15 mmol) were added, and the mixture was
stirred at 100 °C for 7 h and then cooled to r.t. The mixture was fil-
tered through Celite, washed with toluene, and concentrated in vac-
uo. Purification by chromatography (silica gel, hexane–EtOAc, 3:1)
afforded a colorless oil.
Yield: 0.54 g (41%).
IR (ATR): 3050, 2050, 1891, 1737, 1596, 1495, 1395, 1321, 1226,
1158, 1125, 1108, 1015, 1005, 819, 803, 764.
1H NMR (200 MHz, CDCl3): d = 1.87–2.01 (m, 2 H, H-4 cyclopen-
tyl), 2.45 (t, J = 7.6 Hz, 2 H, H-3 cyclopentyl), 2.68 (t, J = 6.6 Hz,
2 H, H-5 cyclopentyl), 6.95–7.03 (m, 4 H, H-3/H-3¢/H-5/H-5¢ 4-F
C6H4), 7.17–7.22 (m, 4 H, H-2/H-2¢/H-6/H-6¢ 4-F C6H4).
13C NMR (50 MHz, CDCl3): d = 18.7 (C-4 cyclopentyl), 37.9 (C-3
cyclopentyl), 38.2 (C-5 cyclopentyl), 61.1 (C-2 cyclopentyl), 115.2
(d, J = 21.2 Hz, C-3/C-3¢/C-5/C-5¢ 4-FC6H4), 129.5 (d, J = 7.9 Hz,
C-2/C-2¢/C-6/C-6¢ 4-FC6H4), 137.7 (d, J = 3.2 Hz, C-1/C-1¢ 4-
FC6H4), 161.6 (d, J = 244.7 Hz, C-4/C-4¢ 4-FC6H4), 217.3 (C-1 cy-
clopentyl).
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HRMS (EI): m/z calcd for C17H14OF2: 272.1013; found: 272.1015.
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Acknowledgment
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The authors thank the Alexander von Humboldt foundation (AvH)
for funding.
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Synthesis 2008, No. 2, 225–228 © Thieme Stuttgart · New York