Syntheses of fluorinated phencyclidine analogs

Article abstract of DOI:10.1016/S0022-1139(01)00565-6

Syntheses of several fluorinated phencyclidine (PCP) analogs are described. These compounds are being used to probe PCP binding sites on N-methyl-D-aspartate (NMDA) receptors. The compounds were prepared in good yields by Grignard reaction of appropriate fluorine substituted bromobenzene with carbonitrile intermediates. Syntheses of the known compound 1-[1-(3-fluorophenyl) cyclohexyl]piperidine, and the novel compounds 1-[1-(4-fluorophenyl)cyclohexyl]piperidine, 1-[1-(3-fluorophenyl) cyclohexyl]pyrrolidine, and 1-[1-(4-fluorophenyl)cyclohexyl]pyrrolidine are reported.

Full text of DOI:10.1016/S0022-1139(01)00565-6

Journal of Fluorine Chemistry 114 %2002) 39±42
Syntheses of ¯uorinated phencyclidine analogs
*
Alaba M. Ogunbadeniyi, Adeboye Adejare
Department of Pharmaceutical Sciences, College of Pharmacy, Idaho State University,
Pocatello, ID 83209-8334, USA
Received 18 June 2001; accepted 13 October 2001
Abstract
Syntheses of several ¯uorinated phencyclidine %PCP) analogs are described. These compounds are being used to probe PCP binding sites on
N-methyl-D-aspartate %NMDA) receptors. The compounds were prepared in good yields by Grignard reaction of appropriate ¯uorine
substituted bromobenzene with carbonitrile intermediates. Syntheses of the known compound 1-[1-%3-¯uorophenyl)cyclohexyl]piperidine,
and the novel compounds 1-[1-%4-¯uorophenyl)cyclohexyl]piperidine, 1-[1-%3-¯uorophenyl) cyclohexyl]pyrrolidine, and 1-[1-%4-¯uorophe-
nyl)cyclohexyl]pyrrolidine are reported. # 2002 Elsevier Science B.V. All rights reserved.
Keywords: Fluorinated phencyclidine analogs; Synthesis; Characterization; Grignard reaction; Carbonitrile
1
. Introduction
2. Results and discussion
Substitution of a hydrogen atom with ¯uorine in biologi-
Ring-¯uorinated compounds 3±5, and 6 were synthesized
by a modi®cation of the method of Maddox et al. [10]
involving reaction of substituted Grignard reagents with
carbonitriles. Appropriate dihalogenated benzenes were
each reacted with magnesium to form Grignard reagents
which were then reacted with appropriate carbonitriles.
Reactions between the Grignard reagents and the carboni-
triles were slow and incomplete. In a bid to rectify this,
molar ratio of Grignard reagent to carbonitrile was increased
to be at least 3±1. Even then, there were still signi®cant
quantities of unreacted carbonitriles in the reaction products
and yields were low. Long reaction times were then resorted
to, but these gave problems as side-products which were not
easy to remove were formed in large quantities. Such side
products are not uncommon and have been reported in
literature [11]. The procedures being reported gave desired
products in reasonable yields, 25±65ꢀ.
cally active molecules is known to affect the biological
activities of such molecules [1±5]. As part of our efforts
to obtain selective non-competitive antagonists at the PCP
binding site on NMDA receptor complex, we have prepared
analogs of phencyclidine with ¯uorine on the aromatic ring,
including at o- and p-positions. Also, we have prepared
¯
uorinated analogs where the piperidine ring of phencycli-
dine is replaced with a more constrained pyrrolidine ring to
examine effects of conformational restriction on pharmaco-
logical activities. Incorporation of ¯uorine on the aromatic
ring of each molecule is anticipated to have pronounced
effects on electron distribution and dipole moments within
each molecule because of ¯uorine's high electronegativity.
In addition, it can function as a hydrogen bond acceptor
as a consequence of available electron density. As part
of our continuing interest in syntheses of ¯uorinated
aromatic amines of biological interest [6±9], we describe
herein syntheses of 1-[1-%3-¯uorophenyl)cyclo-hexyl]-
piperidine %3), 1-[1-%4-¯uoro phenyl)cyclohexyl]piperidine
The mechanism of the reaction would seem to explain the
copious amounts of side products formed. Nitrile is a good
leaving group hence it would be easily removed from the
quaternary carbon of the carbonitrile, particularly with
effects the neighboring nitrogen will have on stabilizing
%
1
4), 1-[1-%3-¯uoro- phenyl)cyclohexyl]pyrrolidine %5), and
-[1-%4-¯uorophenyl)cyclohexyl]pyrrolidine %6) Schemes 1
and 2.
resulting tertiary carbocation. The S 1 attack of the
N
Grignard reagent on the carbocation is complicated by
the neighboring piperidine or pyrrolidine which can form
enamine or imine. The reactivities of these groups could
contribute signi®cantly to formation of side products
observed.
*
Corresponding author.
E-mail address: adejarea@otc.isu.edu %A. Adejare).
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 % 0 1 ) 0 0 5 6 5 - 6

40
A.M. Ogunbadeniyi, A. Adejare / Journal of Fluorine Chemistry 114 ꢀ2002) 39±42
Scheme 1. Synthesis of intermediates %1) and %2).
Scheme 2. Synthesis of target compounds. For compounds %3) and %5), fluorine is at the m-position while for compounds %4) and %6), it is at the p-position.
3
. Experimental
Perkin-Elmer 16 PC FT-IR spectrophotometer. MS spectra
were obtained by electrospray method using the Finnigan
TSQ-700 mass spectrometer. NMR spectra were obtained
on a Varian 300/54 300 MHz spectrometer. H and 13C
3
.1. Materials
1
3-Bromo¯uorobenzene %99ꢀ), 4-bromo¯uorobenzene
99ꢀ), cyclohexanone %99.8ꢀ), piperidine %99ꢀ), pyrroli-
NMR spectra were recorded in CDCl and referenced to
3
%
dine %>99ꢀ), NaHSO %Acros), NaCN %Aldrich), ammo-
internal TMS %0 ppm) and CDCl %77 ppm) signals, respec-
3
tively. 19F NMR spectra were obtained in CDCl3 and
referenced to CFCl as internal standard %0 ppm). All values
3
nium hydroxide %28±30ꢀ), diethyl ether, HCl, H SO , and
2
4
3
THF %Fisher) magnesium turnings, and NaCl. THF was
distilled over sodium prior to use, under a dry nitrogen
atmosphere.
reported are d values in parts per million. Elemental ana-
lyses were performed by Galbraith laboratories, Knoxville,
TN, and observed values were within Æ0.4ꢀ of theoretical
values. Column chromatographic separations were per-
formed over Acros silica gel no. 7631-86-9 particle size
3
.2. Instrumentation and methods
35±70 mm. Preparative TLC separations were performed
Melting points were determined on a Mel-Temp II capil-
lary melting point apparatus. IR spectra were recorded on a
on Analtech Uniplate silica gel GF 20 cm  20 cm TLC
plates.

A.M. Ogunbadeniyi, A. Adejare / Journal of Fluorine Chemistry 114 ꢀ2002) 39±42
41
1
3
.3. Preparation of 1-piperidinocyclohexanecarbonitrile ꢀ1)
H NMR %CDCl ): 7.3±6.9 %m, 4H, 4Ar±H); 2.2±1.25
3
%
b, 20H, 10CH2); 13C NMR %CDCl ): 129 %s, 1C, 1CF); 123
%s, 1C, 1Ar±C); 114 %s, 2C, 2Ar±CH); 113 %d, 2C, 2Ar±CH);
3
To a solution of sodium bisul®te %11.5 g, 0.11 mol) in
5 ml of water was added 9.8 g %0.1 mol) of cyclohexanone.
2
61 %s, 1C, 1Â4 8C); 47 %s, 2C, 2CH ); 34 %s, 2C, 2CH ); 27
2
2
A solution of 5.4 g %0.11 mol) of sodium cyanide and 8.5 g
0.1 mol) piperidine in 20 ml water was then added and the
%s, 2C, 2CH ); 26.5 %s, 1C, 1CH ); 25.2 %s, 1C, 1CH ); 22.5
2 2 2
%
%s, 2C, 2CH2); 19F NMR %CDCl ): À104 ppm; MS ESI
3
‡
‡
reaction allowed to stir overnight at room temperature. The
product was ®ltered off, washed with water, and dried under
vacuum to give 15.92 g %82.1ꢀ) of a white crystalline solid,
mp 65±67 8C.
%m/z, species, ꢀ): 262, [M ‡ H] , 100; 263, [M ‡ 2] , 20.
3.6. Preparation of 1-[1-ꢀ4-fluorophenyl)cyclohexyl]-
piperidine ꢀ4)
À1
1
IR %CHCl ) cm : 2230 %CBN); H NMR %CDCl ): 2.7±1.1
b, 20H, 10CH2); C NMR %CDCl ): 120 %s, 1C, CN); 61 %s,
3
3
1
3
%
A mixture of 4-bromo¯uorobenzene %2.0 g, 0.011 mol),
magnesium turnings %1.1 g, 0.045 mol), and a few crystals of
iodine in 10 ml THF were stirred vigorously under nitrogen
at room temperature for 2 h. After this step, a solution of
nitrile 1 %2.11 g, 0.011 mol) in 15 ml THF was added
dropwise and the reaction stirred overnight. The reaction
was quenched carefully with water and extracted with ether
3
1
2
C,4 8C);48%s,2C,2CH );34%s,2C,2CH );27%s,2C,2CH );
2
2
2
5%s,1C,CH );24%s,1C,CH );22%s,2C,2CH );MSESI%m/z,
‡
2
2
‡
2
species, ꢀ): 166, [M À CN] , 100; 193, [M ‡ H] , 57.
3
.4. Preparation of 1-pyrrolidinocyclohexanecarbonitrile
ꢀ
2)
%3 ml  20 ml). The ether extracts were combined and
3
5ꢀ Hydrochloric acid %5.0 ml, 0.051 mol) was slowly
added to a mixture of pyrrolidine %3.63 g, 0.051 mol) and ice
0 g. Cyclohexanone %5.0 g, 0.051 mol) was added to the
mixture. A solution of sodium cyanide %2.75 g, 0.056 mol) in
5 ml water was then added dropwise while stirring vigor-
extracted with 2N HCl %3 ml  20 ml). The aqueous extract
was made alkaline with aqueous ammonia and back
extracted with ether %3 ml  20 ml). The ether extract was
then dried over sodium sulfate and the solvent evaporated to
obtain 1.6 g %56ꢀ) of a golden brown oil which was puri®ed
by column chromatography and then by preparative TLC
using chloroform:hexane, 4:1 as eluent to obtain a yellowish
oil. The hydrochloride salt was prepared by bubbling HCl
gas into an ethereal solution of 0.25 g of the oil and the
solvent evaporated. The off-white solid obtained was recrys-
tallized in chloroform:ether to obtain 0.11 g %44ꢀ;
3
1
ously. The reaction was stirred at room temperature over-
night and extracted with chloroform %2 ml  20 ml). The
chloroform extract was dried over sodium sulfate and the
solvent evaporated to obtain 8.0 g %88ꢀ) of a yellowish oil.
À1
1
IR %CHCl ) cm : 2250 %CBN); H NMR %CDCl ): 2.7±
3
3
1
3
1
.2 %b, 18H, 9CH2); C NMR %CDCl ): 120 %s, 1C, CN); 61
3
%
CH ); 23 %s, 2C, 2CH ); 21 %s, 2C, 2CH ).
s, 1C, 4 8C); 48 %s, 2C, 2CH ); 36 %s, 2C, 2CH ); 25 %s, 1C,
net ˆ 25ꢀ) of an off-white solid, mp 220±221 8C.
2
2
1
H NMR %CDCl ): 7.2±6.9 %m, 4H, 4Ar±H); 2.2±1.3 %b,
3
2
2
2
2
0H, 10CH2); 13C NMR %CDCl ): 160 %s, 1C, 1CF); 136 %s,
1C, 1Ar±C); 129 %s, 2C, 2Ar±CH); 114 %d, 2C, 2Ar±CH); 61
3
3.5. Preparation of 1-[1-ꢀ3-fluorophenyl)cyclohexyl]-
piperidine ꢀ3)
%s, 1C, 1 Â 4 8C); 47 %s, 2C, 2CH ); 34 %s, 2C, 2CH ); 27 %s,
2
2
2
C, 2CH ); 26.6 %s, 1C, 1CH ); 25 %s, 1C, 1CH ); 22.6 %s, 2C,
2 2 2
1
9
A mixture of 3-bromo¯uorobenzene %3.0 g, 0.017 mol),
magnesium turnings %1.7 g, 0.068 mol), and a few crystals of
iodine in 10 ml THF were stirred vigorously under nitrogen
at room temperature for 2 h. After this, a solution of nitrile 1
2CH2); F NMR %CDCl ): À104.7 ppm; MS ESI %m/z,
‡ ‡
3
species, ꢀ): 262, [M ‡ H] , 100; 263, [M ‡ 2] , 22.
Anal. Calc. for C H ClFN.0.05H 0: C, 68.55; H, 8.46;
1
7
25
2
F, 6.38; N, 4.70. Found: C, 68.35; H 8.47; F 6.36; N
4.69.
%
3.26 g, 0.017 mol) in 15 ml THF was added dropwise, and
the reaction stirred overnight at room temperature. The
reaction was quenched carefully with water and extracted
with ether %3 ml  20 ml). The ether extracts were combined
and extracted with 2N HCl %3 ml  20 ml). The aqueous
extract was made alkaline with aqueous ammonia and back
extracted with ether %3 ml  20 ml). The ether extract was
then dried over sodium sulfate and the solvent evaporated to
obtain 2.4 g %54ꢀ) of a brown oil which was puri®ed by
column chromatography and preparative TLC using chlor-
oform:hexane, 4:1 as eluent to obtain a yellowish oil. The
hydrochloride salt was prepared by bubbling HCl gas into
the ethereal solution of 0.5 g of the oil and the solvent
evaporated to give an off-white solid. Recrystallization from
chloroform:ether gave 0.42 g %84ꢀ; net ˆ 45ꢀ) of an off-
white solid, mp 239±241 8C.
3.7. Preparation of 1-[1-ꢀ3-fluoropheny)lcyclohexyl]-
pyrrolidine ꢀ5)
A mixture of 3-bromo¯uorobenzene %2.0 g, 0.011 mol),
magnesium turnings %1.1 g, 0.045 mol), and a few crystals of
iodine in 10 ml THF were stirred vigorously under nitrogen
at room temperature for 2 h. After this step, a solution of
nitrile 2 %2.0 g, 0.011 mol) in 5 ml THF was added dropwise
and the reaction stirred overnight. The reaction was
quenched carefully with water and extracted with ether
%3 ml  20 ml). The ether extracts were combined and
extracted with 2 N HCl %3 ml  20 ml). The aqueous extract
was basi®ed with aqueous ammonia and back extracted with
ether %3 ml  20 ml). The ether extract was then dried over

42
A.M. Ogunbadeniyi, A. Adejare / Journal of Fluorine Chemistry 114 ꢀ2002) 39±42
sodium sulfate and the solvent evaporated to obtain 2.36 g
87ꢀ) of a yellow-oil which was puri®ed by column chro-
matography using chloroform:hexane, 4:1 as eluent. The
hydrochloride salt of the yellow-oil obtained was prepared
by bubbling HCl gas into an ethereal solution of 0.13 g of the
oil and the solvent evaporated to give 0.097 g %75ꢀ;
evaporated to give 0.6 g %60ꢀ; net ˆ 26ꢀ) of a white solid,
%
mp 223±225 8C.
H NMR %CDCl ): 7.3 %m, 2H, 2Ar±H); 7.1%m, 2H, 2Ar±
1
3
H); 2.6±1.1 %b, 18H, 9CH2); 13C NMR %CDCl ): 160 %s, 1C,
Ar±CF); 130 %s, 1C, Ar±C); 114 %d, 4C, 4Ar±CH); 61 %s, 1C,
3
4 8C); 45 %s, 2C, 2CH ); 35 %s, 2C, 2CH ); 26 %s, 1C, CH );
2
2
2
1
9
net ˆ 65ꢀ) of a white solid, mp 247±249 8C.
23 %d, 4C, 4CH2) F NMR %D O): À106 ppm; MS ESI %m/z,
2
1
‡ ‡
H NMR %CDCl ): 7.3±6.9 %m, 4H, 4Ar±H); 2.5±1.2
3
species, ꢀ): 248, [M ‡ H] , 100; 249, [M ‡ 2] , 18.
%
b, 18H, 9CH ); 13C NMR %CDCl ): 161 %s, 1C, Ar±CF);
Anal. Calc. for C H ClFN: C, 67.71; H, 8.17; F, 6.69; N,
16 23
2
3
1
1
29 %s, 1C, Ar±CH); 124 %s, 1C, Ar±C); 115 %s, 1C, Ar±CH);
13 %s, 1C, Ar±CH); 60 %s, 1C, 4 8C); 45 %s, 2C, 2CH ); 35
4.94. Found: C, 67.83; H, 8.17; F, 6.63; N, 4.76.
2
19
%
s, 2C, 2CH ); 25 %s, 2C, CH ); 23 %d, 4C, 4CH ); F NMR
2 2 2
‡
Acknowledgements
%
CDCl ): À104; MS ESI %m/z, species, ꢀ): 248, [M ‡ H] ,
3
‡
1
6
3
00; 249, [M ‡ 2] , 22.
Financial support by NIH %NINDS Grant no. 1 R15
NS36393-01A1) is gratefully acknowledged. Assistance
of Dr. Paul W. Brown in obtaining MS spectra is also
gratefully acknowledged.
Anal. Calc. for C H ClFN.0.2H O: C, 66.86; H, 8.13; F,
1
6
23
2
.60; N, 4.87. Found: C 66.80; H 8.32; F 6.23; N 4.87.
.8. Preparation of 1-[1-ꢀ4-fluorophenyl)cyclohexyl]-
pyrrolidine ꢀ6)
References
A mixture of 4-bromo¯uorobenzene %2.0 g, 0.011 mol),
magnesium turnings %1.1 g, 0.045 mol), and a few crystals of
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at room temperature for 2 h. After this step, a solution of
nitrile 2 %2.0 g, 0.011 mol) in 5 ml THF was added dropwise
and the reaction stirred overnight. The reaction was
quenched carefully with water and extracted with ether
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