Microwave-assisted elimination reaction of trans-4-(4-Fluorophenyl)-3- chloromethyl-1-methylpiperidine on alumina

Article abstract of DOI:10.1081/SCC-120037925

trans-4-(4-Fluorophenyl)-3-chloromethyl-1-methylpiperidine 3b was subjected to elimination reaction on alumina or KF-alumina under solvent-free conditions and microwave irradiation. Compared with the "classical" method of heating in the presence of an organic base, the microwave-assisted methodology provided higher yields of 4-(4-fluorophenyl)-3-methylene-1-methylpiperidine 7b (65.5-71%) in considerably shorter reaction times (20-40 min). Furthermore, the exocyclic double bond in 7b underwent rearrangement to the endocyclic double bond to furnish compound 8. The effect of alumina and irradiation time on reaction conversion and the extent of isomerization was examined.

Full text of DOI:10.1081/SCC-120037925

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Microwave‐Assisted Elimination Reaction of
trans‐4‐(4‐Fluorophenyl)‐3‐chloromethyl‐1‐methylpiperid
on Alumina
Hana Navrátilová a , Zdeněk Kříž b & Milan Potáček a
a Department of Organic Chemistry, Faculty of Science , Masaryk University , Kotlářská
2, 611 37, Brno, Czech Republic
b National Centre for Biomolecular Research, Faculty of Science , Masaryk University ,
Brno, Czech Republic
Published online: 20 Aug 2006.
To cite this article: Hana Navrátilová , Zdeněk Kříž & Milan Potáček (2004) Microwave‐Assisted Elimination Reaction of
trans‐4‐(4‐Fluorophenyl)‐3‐chloromethyl‐1‐methylpiperidine on Alumina, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:11, 2101-2115, DOI: 10.1081/SCC-120037925
To link to this article: http://dx.doi.org/10.1081/SCC-120037925
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 11, pp. 2101–2115, 2004
Microwave-Assisted Elimination Reaction
of trans-4-(4-Fluorophenyl)-3-chloromethyl-
1-methylpiperidine on Alumina
1,
Hana Navratilova, Zdenek Krız, and Milan Potacek
2
1
*
´
´
ˇ
ˇ´ˇ
´ ˇ
2
1Department of Organic Chemistry and National Centre
for Biomolecular Research, Faculty of Science,
Masaryk University, Brno, Czech Republic
ABSTRACT
trans-4-(4-Fluorophenyl)-3-chloromethyl-1-methylpiperidine 3b was
subjected to elimination reaction on alumina or KF-alumina under
solvent-free conditions and microwave irradiation. Compared with the
“classical” method of heating in the presence of an organic base, the
microwave-assisted methodology provided higher yields of 4-(4-fluoro-
phenyl)-3-methylene-1-methylpiperidine 7b (65.5–71%) in considerably
shorter reaction times (20–40 min). Furthermore, the exocyclic double
bond in 7b underwent rearrangement to the endocyclic double bond to
*
´ ´
Correspondence: Hana Navratilova, Department of Organic Chemistry, Faculty of
´ˇ ´
Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic; E-mail:
hanavra@chemi.muni.cz.
2101
DOI: 10.1081/SCC-120037925
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Navratilova, Krız, and Potacek
2102
furnish compound 8. The effect of alumina and irradiation time on reac-
tion conversion and the extent of isomerization was examined.
Key Words: Elimination reaction; Alumina; Microwave irradiation;
trans-4-(4-Fluorophenyl)-3-chloromethyl-1-methylpiperidine; Dehydro-
halogenation; Paroxetine; Solid support.
INTRODUCTION
(3R,4S)-trans-4-(4-Fluorophenyl)-3-hydroxymethyl-1-methylpiperidine 1b[1]
is a waste enantiomer obtained during the resolution step in the industrial
synthesis[2] of the antidepressive agent paroxetine 2[3] (Fig. 1). The enantio-
meric purity of 1b can be increased by a reverse enrichment procedure.[4]
Transformations on asymmetric centers in 1b proceeding through their
“temporary destruction” is particularly challenging in respect to the possibility
of converting the unwanted (3R,4S)-enantiomer into the opposite one required
for the synthesis of 2. The more accessible of the two chiral centers appears to
be that on C-3. It can be readily attacked by a strong base in an elimination
reaction to furnish 4-(4-fluorophenyl)-1-methyl-3-methylenepiperidine 7.[1]
“Classical” methods to accomplish dehydrohalogenation or dehydrotosylation
usually employ a base/solvent combination (e.g., KOH/ethanol;[5] sodium
methoxide/methanol;[5,6] tBuOK/tBuOH;[6,7] tBuOK/DMSO;[8] tBuOK/
DMF;[7,9] NaH/DMF;[9] alumina/ether[10,11]) at elevated temperatures.
tBuOK as a strong base with low nucleophilicity is one of the most effective
reagents used particularly for dehydrohalogenation either in homogeneous
solution[12] or under PTC conditions.[13] For difficult cases, non-nucleophilic
bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diaza
bicyclo[3.4.0]non-5-ene (DBN) in combination with aromatic solvents are
Figure 1. Structures of compounds.

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trans-4-(4-Fluorophenyl)-3-chloromethyl-1-methylpiperidine
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recommended.[14] As published recently, some elimination reactions can be
promoted by microwave irradiation[15,16] resulting in higher yields and shorter
reaction times. In the present paper we report our attempts to perform elimin-
ation reaction of chloro, bromo, mesyl, and tosyl derivatives of 1b or rac-1
(Fig. 2) using either “classical” conditions or a supported microwave
methodology.
RESULTS AND DISCUSSION
Preparation of Elimination Products
Elimination reactions with substrates 3, 4, and 6 prepared from alcohol 1
according to standard synthetic procedures[1,2] (Fig. 2) were initially carried
out under “classical” methods using tBOK or DBU at elevated temperature.
The results are introduced in Table 1.
Eliminations attempted with both chloro and tosyl derivatives, 3b and
rac-6, in the presence of tBuOK in polar solvent (DMSO, DMF, t-butanol)
resulted in very complex reaction mixtures containing many unidentified side-
products from which the elimination product 7b or rac-7 could be isolated
only with major difficulties and in a low yield and purity (entries 1,2, and 7).
A better purity of 7b was obtained when 3b underwent dehydrochlorination in
the presence of DBU at higher temperature (entries 3–5). However, yields of
7b obtained at these conditions were still very low. A treatment of a bromo
derivative 4b (entry 6) with DBU in toluene provided a dark brown mixture
containing many side-products and compound 7b was obtained in an extremely
low amount and unsatisfactory level of purity. Apart from very low yields of 7b
or rac-7, the main drawback of this approach was that all reactions required
elevated temperatures (above 1008C) and long reaction times (2–5 hr).
Figure 2. Reaction scheme. Reaction conditions: (i) 3 (Z55Cl):SOCl2 acetonitrile;
(ii) 4 (Z55Br): SOBr2, acetonitrile; (iii) 5 (Z55mesyl): CH3SO2Cl, chloroform, TEA;
(iv) 6 (Z55tosyl): CH3C6H4SO2Cl, chloroform, aq. NaOH; (v) tBuOK, solvent, D;
(vi) DBU, toluene, D; (vii) Al2O3 or Al2O3/KF, MW irradiation.

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Table 1. Overview of the results of “classical” heating.
Isolated
yield (%)
Entry Substrate
Conditions
Solvent
DMF
1
rac-3
KtBuO(1.5 eq.); 90–958C/2 hr;
135–1408C/1.3 hr
KtBuO (1.3 eq.); 122–1248C/2.5 hr t-BuOH
42a
2
3
3b
3b
21a
DBU (2.6 eq.); 120–1258C/2.3 hr
Toluene
19
(93.6b)
34.8a
18
4
5
3b
3b
DBU (2.0 eq.); 115–1208C/5 hr
DBU (1.9 eq.); 120–1258C/3.5 hr
1,4-Dioxane
Toluene
(95.6b)
12
(61.9b)
22a
6
4b
DBU (1.1 eq.); 120–1258C/3 hr
Toluene
7
rac-6
KtBuO (1.0 eq.); 80–908C/5 hr
DMSO
aA crude product contaminated with many unidentified by-products.
bThe HPLC purity of the elimination product 7b (in %) is introduced in parentheses.
Since the “classical” method described above failed to provide 7b or
rac-7 in a good yield, we decided to apply the microwave-assisted metho-
dology on a solid support (alumina, KSF). The results are presented in Table 2.
Dehydration of 1b attempted on the acidic clay KSF[15] under microwave
irradiation (entry 1) did not give 7b and a slight decomposition of the starting
material to unidentified products (ca. 4%) was only observed. Similarly, a
chloroderivative 3b on calcined alumina (entry 2) gave no elimination reac-
tion and decomposed partly to carbinol 1b. Irradiation of 3b adsorbed on
basic alumina showed quite promising results (entries 3 and 4) such as large
reaction conversion and the formation of the elimination product 7b.
However, a large portion of starting 3b decomposed to alcohol 1b possibly
due to competing displacement of the chloride with the hydroxy group on
basic alumina present in a large excess. When dehydrochlorination was
carried out on basic alumina impregnated with KF,[17] the formation of 1b
considerably decreased in favor of 7b (entries 5 and 6). Due to the presence
of the strong base (KF) an exocyclic double bond in 7b underwent rearrange-
ment being shifted inwards the piperidine ring to form an achiral compound
8.[18] In order to further reduce the displacement reaction, neutral alumina
and neutral alumina/KF (entry 7–12) were employed. It follows from the
results that the overall yields of products 7b and 8 remarkably improved
with a prolonged irradiation time and an increasing support : substrate ratio.
Dehydromesylation and dehydrotosylation were also attempted on basic

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Navratilova, Krız, and Potacek
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alumina (entries 13 and 14). However, both derivatives, rac-5 and rac-6, lar-
gely decomposed to rac-1; an insignificant amount of rac-7 was detected in
the case of a dehydromesylation attempt. Furthermore, the extended
irradiation of 7b on alumina/KF gave rise to compound 8 (entries 15 and 16).
The reaction conversion as well as the yield of isomerization were
strongly dependent on a support : substrate ratio and irradiation time. The
best conversion of 3b and highest overall yield of products, (4S)-4-(4-fluoro-
phenyl)-3-methylene-1-methylpiperidine 7b and 4-(4-fluorophenyl)-1,5-
dimethyl-1,2,5,6-tetrahydropyridine 8 (71%) were obtained with a 20-fold
excess of the solid support and with an irradiation time of 40 min; the relative
content of compound 8 in the product was 86% (entry 11).
It is important to note that microwave irradiation of all solid reaction
mixtures caused a sharp increase of the reaction temperature inside the solid
material, typically to 210–2358C (measured by a fibre-optic thermometer).
When solid mixtures of 3b adsorbed on neutral alumina or on alumina
impregnated with KF (1 : 20) were heated on an oil bath at 202–2048C for
25min (Table 2) the overall yields of 7b and 8 were lower than those found
for the reaction mixtures irradiated with microwaves. Moreover, an increased
formation of the substitution product 1b was found in these experiments.
This shows that besides the demonstrable effect of solid support, micro-
wave irradiation is also a key factor in controlling the outcome of the reaction.
A suggested mechanism of elimination and isomerization is depicted in
Fig. 3.
Figure 3. A putative mechanism of dehydrochlorination and isomerization on
alumina in the presence of fluoride (Rf ¼ 4-fluorophenyl).

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Dehydrochlorination on KF/alumina is a typical example of a concerted
E2 process.[11] The isomerization proceeds as prototropic rearrangement via
cyclic transition state.[19] Thus, the fluoride ion attached on the solid support
acts as a base and abstracts the hydrogen on C-4 in 7 to form a resonance-
stabilized transition state. Subsequently, carbon C-8 combines with one proton
from alumina to furnish a more stable compound 8. The isomerization is ener-
getically favored because the resultant 3,4-double bond in 8 is in conjugation
with the aromatic group. Moreover, it is a well known fact[19] that an exocyclic
double bond in six-membered rings tends to undergo a rearrangement to an
endocyclic double bond.
Structure Optimization and Energy Computations
Structures of compounds 7a (the antipode of 7b) and 8 were optimized in
vacuo using UHF/6-31G(d,g) basis set in the Gaussian software package.[20]
For all optimizations the standard convergence criteria were used. Figure 4
illustrates optimized structures of both compounds. Bond lengths, bond
angles, and torsional angles attributed to the allylic part of structures 7a and
8 are listed in Table 3.
Energy computations showed that the isomerization product 8 is thermo-
dynamically more stable than 7a. The energy difference between both
Figure 4. Optimized structures of compounds 7a and 8.

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Navratilova, Krız, and Potacek
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Table 3. Selected bond lengths, bond angles, and torsional
angles in calculated structures 7a and 8 (atom numbering scheme
of 8 is identical with that of 7a).
Structure 7a
Structure 8
˚
Bond lengths (A)
C(3)–C(4)
C(3)–C(8)
1.51
1.31
1.53
1.53
1.32
1.50
1.50
1.50
C(4)–C(5)
C(4)–C(10)
Bond angles (8)
C(2)–C(3)–C(4)
C(3)–C(4)–C(5)
C(8)–C(3)–C(4)
C(3)–C(4)–C(10)
Torsional angles (8)
C(2)–C(3)–C(4)–C(5)
C(3)–C(4)–C(5)–C(6)
C(2)–C(3)–C(4)–C(10)
C(3)–C(4)–C(10)–C(20)
114.7
106.9
122.9
112.5
121.4
120.9
125.1
123.3
252.0
52.1
75.4
1.3
15.4
2177.0
71.1
41.9
structures is 32.8 kJ/mol. Among the factors contributing to higher stability
of 8 is the conjugation of the 3,4-double bond with the aromatic ring system.
As seen in Fig. 4, a significant structural feature of 7a is that the 4-fluoro-
phenyl group occupies the axial position so that the repulsion between the
exocyclic double bond and the phenyl ring is minimized. The restraining
of the aromatic substituent in 7a in equatorial position resulted in consider-
able deformation of the piperidine ring providing a conformer whose energy
was 24.6 kJ/mol higher than that of the “axial” conformer. We have assumed
that the “axial” conformer represents the global minimum structure of
compound 7a.

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2109
CONCLUSION
A solvent-free supported microwave methodology for dehydrochlorination
of compound 3b provided significantly better yields in comparison with “clas-
sical” heating in the presence of organic base and solvent. Under microwave
irradiation the exocyclic double bond in 7b easily underwent the rearrangement
to the endocyclic double bond to furnish compound 8. The reaction conversion
as well as the extent of isomerization depended on the support : substrate ratio,
irradiation time and on the type of alumina. The best overall yields of 7b and 8
(65.5–71%) were obtained with neutral alumina impregnated with KF at the
support : substrate ratio of ca. 20 and with the irradiation time ranging from
20 to 40min. Quantum mechanics calculations revealed that the isomerization
product 8 is thermodynamically more stable than 7a.
EXPERIMENTAL
General
Microwave-assisted reactions were carried out in a microwave reactor
Synthewave 402 (Prolabo, France) with a maximum output of 300 W at a
frequency of 2.45 GHz using a glass reactor (a 1 mL reactor with 5 mm ID;
a 10 mL reactor with 25 mm ID). The temperature during experiments
was monitored by a fiber-optic thermometer (ReFlex, Nortech Fibronic Inc.,
Canada) using a probe (TP-21-M02) inserted in a glass stirrer. The ther-
mometer resolution was 0.18C, the accuracy was +18C; the temperature
range was 2408C to þ2508C. Reactors filled with a reaction mixture were
spun during the irradiation. HPLC analysis of reaction products was carried
out on Shimadzu 10ADvp chromatograph (Shimadzu pump LC 10ADvp,
Shimadzu detector SPD 10Avp, Rheodyne injector 7725i with a 20 mL
loop) using a Merck Lichrospher RP-8 Select B column (125 mm ꢀ 4 mm,
particle size 5 mm) and the mobile phase consisting of 24% (v/v) acetonitrile
and 76% (v/v) 0.1 M potassium phosphate buffer (pH 3.51). The flow rate ran-
ged from 0.7 to 1.0 mL/min; UV detection was performed at 210 nm. Samples
for HPLC analysis were diluted with the mobile phase to reach concentrations
in the range of 0.5–1 mg/mL. Melting points of rac-6 and 7b were measured
on a Franz Ku¨stner melting point apparatus and were uncorrected. The
elemental analysis of 7b was performed on a Perkin Elmer 2400 analyzer
(CHNS/O) using acetanilide as a reference. UV spectra were measured in
methanol using a Unicam cell (length of 1 cm) on a Shimadzu UV-1601
spectrophotometer in the range 190–350 nm. IR spectra of rac-6 and 7b
were recorded in KBr pellets on an ATI Mattson FTIR spectrometer in the

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Navratilova, Krız, and Potacek
2110
range of 4000–400 cm21 with the resolution of 4 cm21. MS spectra of rac-6
and 7b were recorded on a Fisons Trio 1000 in EI mode. Optical rotation of 7b
was determined on AA-5 automatic polarimeter (manufactured by Optical
Activity Ltd., England) at 589.4 nm using a standard polarimeter tube with
the length of 1 dm. NMR spectra of compounds were recorded at 303 K on
Avance Bruker instruments (Avance 300, Avance 500 DRX) using a 5 mm
QNP probehead. Complete assignment for 1H and 13C resonances of reported
compounds was achieved on the basis of a chemical-shift consideration, 13C
editing method (APT), 1H-1H homonuclear correlations (COSY), 1H-13C
heteronuclear correlations (HSQC). In proton spectra, the signal of TMS was
used for internal calibration. Carbon resonances were referenced to the centre
line in the triplet of the solvent signal (77.00 ppm for CDCl3). 1,8-diazabicyclo
[5.4.0] undec-7-ene (DBU) (98%) was obtained from Janssen Chimica. Thio-
nyl bromide (97%) and methanesulfonyl chloride (98%) were obtained from
Fluka, thionyl chloride (98%) and toluenesulfonyl chloride (98%) were
purchased from Aldrich. Acetonitrile (HPLC purity) was obtained from
Riedel-de Haen. All solid supports (basic activated alumina: Brockmann I.,
50 : 6A 150 mesh, 58A; neutral activated alumina: Brockmann I., 150 mesh;
calcined alumina 100 þ 325 mesh; neutral activated alumina: Brockmann I.,
507C, 150 mesh; Montmorillonite KSF) were purchased from Aldrich.
Basic and neutral aluminas were impregnated with KF according to the pro-
cedure in Ref.[17] (12.9 mmol KF per 1 g alumina). All other solvents and
reagents were of either p.a. or of pure quality. Enantiopure carbinol 1b
(95% ee) was prepared by crystallization of non-racemic samples.[4] Deriva-
tives 3b and 5b were synthesized according to procedures in Refs.[1,2]
(3R,4S)-3-Bromomethyl-4-(4-fluorophenyl)-1-methylpiperidine 4b. To
a suspension of 1b (9.77 g, 43.75 mmol) in acetonitrile (25 mL) cooled to
0–58C, was added thionyl bromide (97%, 9 mL, 0.112 mmol) dropwise with
vigorous stirring keeping the temperature below 108C. On the addition of thio-
nyl bromide, the solid dissolved and the reaction mixture turned dark orange.
The reaction solution was warmed at mild reflux for 60 min then cooled
down to room temperature followed by stripping off the solvent at reduced
pressure to yield an oily residue. The oil was repeatedly suspended in aceto-
nitrile and concentrated in vacuo to remove unreacted thionyl bromide. The
resultant residue was dissolved in methanol (140 mL) and acetonitrile
(30 mL), treated with charcoal followed by filtration and evaporation of the sol-
.
vent to obtain 4b HBr as fine yellow crystals. A suspension of crystals in
diethyl ether (100 mL) was shaken with saturated solution of NaHCO3
(80 mL). The dark orange organic layer was separated, the yellow aqueous
layer was reextracted with diethyl ether (80 mL). Organics were joined, washed
with water (50 mL), dried over MgSO4, treated with Silicagel, filtered, and
finally evaporated to dryness to yield 4b as a dark brown solid (12.1 g,

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2111
97.6% theory): HPLC: 93.2%; 1H NMR (300.13 MHz, CDCl3): d 7.15 (m, 2H,
H-20 and 60), 6.94 (m, 2H, H-30 and 50), 3.23 (m, 1H, H-2), 3.18 (dd,
3
2JH,H ¼ 10.5 Hz, JH,H ¼ 1.5 Hz, 1H, H-8), 3.14 (m, 1H, H-6), 2.95 (dd,
3
2JH,H ¼ 10.5 Hz, JH,H ¼ 5.1 Hz, 1H, H-8), 2.50 (s, 3H, NCH3), 2.50 (m,1H,
2
H-4), 2.30 (dd, JH,H ¼ 3JH,H ¼ 10.8 Hz, 1H, H-2), 2.44–2.22 (overlapped
1
m, 2H, H-3 and 6), 2.11 (ddd, 1H, H-5), 1.81 (m, 1H, H-5). 13C f Hg NMR
1
(75.47 MHz, CDCl3):
d
161.82 (d, JC,F ¼ 246.5 Hz, C-40), 137.37
4
3
(d, JC,F ¼ 3.3 Hz, C-10), 128.96 (d, JC,F ¼ 7.7 Hz, C-20, 60), 115.70
2
(d, JC,F ¼ 21.0 Hz, C-30,50), 59.23 (C-2), 55.21 (C-6), 45.15 (NCH3), 43.70
(C-4), 41.15 (C-3), 35.29 (C-8), 32.24 (C-5).
(1/2)-[4-(4-Fluorophenyl)-1-methyl-3-piperidyl]toluenesulfonate rac-6.
To a stirred solution of rac-1 (2.25 g, 10.07 mmol) in toluene (15 mL) at room
temperature, was added toluenesulfonyl chloride (3.85 g, 19.8 mmol) in one
portion followed by the addition of an aqueous solution of NaOH (8.3 M,
3.0 mL, 24.9 mmol). The reaction mixture was heated up to 70–758C for
1.5 hr, then allowed to cool to room temperature followed by dilution with
diethyl ether (30 mL) and extraction with water (20 mL). The organic layer
was separated, washed with water (3 ꢀ 30 mL) until the pH of the aqueous
layer became neutral, then dried over MgSO4 and evaporated to give a yellow
oily residue rac-6 (2.8 g, 74.2% theory) which crystallized on standing at room
temperature: m.p.: 94–968C; 1H NMR (300.13 MHz, CDCl3): d 7.55
3
3
(d, JH,H ¼ 8.2 Hz, 2 H, H-300 and 500); 7.19 (d, JH,H ¼ 8.2 Hz, 2 H, H-200
and 600); 6.91 (m, 2H, H-20 and 60); 6.80 (m, 2H, H-30 and 50); 3.66 (dd,
2JH,H ¼ 9.6 Hz, JH,H ¼ 2.6 Hz, 1H, HR-8); 3.50 (dd, JH,H ¼ 9.6 Hz,
3JH,H ¼ 6.6 Hz, 1H, HS-8); 2.92 (m, 1H, H-2); 2.82 (m, 1H, H-6); 2.36
(s, 3H, 400-CH3); 2.22 (s, NCH3, 3H); 2.22 (m, 1H, H-4); 2.04–1.85 (over-
3
2
lapped m, 2H, H-3 and 6); 1.84 (dd, JH,H ¼ 3JH,H ¼ 10.9 Hz, 1H, H-2);
2
1.72–1.64 (overlapped m, 2H, 2 ꢀ H-5); 13C f Hg (75.47 MHz, CDCl3): d
1
1
4
161.49 (d, JC,F ¼ 244.4 Hz, C-40), 144.72 (C-100), 138.45 (d, JC,F ¼ 3.3 Hz,
3
C-10), 132.54 (C-400), 129.69 (C-200 and 600), 126.62 (d, JC,F ¼ 7.7 Hz, C-20,
2
60), 127.78 (C-300 and 500), 115.37 (d, JC,F ¼ 21.0 Hz, C-30 and 50), 70.71
(C-8), 58.54 (C-2), 55.80 (C-6), 46.22 (NCH3), 42.88 (C-4), 41.43 (C-3),
34.19 (C-5), 21.50 (400-CH3); UV (methanol) lmax (1): 201.6 (15010), 225.8
(9440), 265.8 (1300), 271.2 (1030); 1210 ¼ 11300; IR (KBr) n 2940, 2897,
2847, 2792; 1598, 1510, 1467, 1362 (SO2 stretch), 1224, 1179 (SO2 stretch),
1096, 1032, 921, 840, 821, 764, 670, 556 cm21; EIMS (70 eV) m/z (relative
intensity, %): Mþ 377 (21.0), 222 (33.9), 206 (19.4), 192 (15.5), 133 (11.6),
109 (23.0), 91 (31.4), 58 (100).
(4S)-4-(4-Fluorophenyl)-1-methyl-3-methylenepiperidine 7b. A solu-
tion of 3b (12.4 g, 51.29 mmol) in dry toluene (6 mL) was treated with DBU
(14.0 mL, 91.74 mmol) at 120–1258C for 4 hr under argon. The reaction
mixture was cooled to ambient temperature and diluted with diethyl ether

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´ ´ ˇ´ˇ ´ˇ
Navratilova, Krız, and Potacek
2112
(125 mL) followed by extraction with 0.5 M hydrochloric acid to adjust the
pH of the aqueous layer to 7–8. The yellowish organic layer was separated,
the brown aqueous layer was shaken again with diethyl ether (70 mL). The
combined organic extracts were washed with water (30 mL), dried over
MgSO4 and concentrated in vacuo to obtain brownish crystals. The product
was purified on a Silicagel column (230–400 mesh) eluted by a dichloro-
methane/methanol mixture (10 : 1) to yield 7b as yellow crystals (1.3 g,
12.3%): m.p. 52–548C; Found: C 76.13, H 7.91, N 6.82. Calc. for
C13H16N1F1: C 76.06, H 7.86, N 6.82; HPLC: 98.2%; [a]2D0 þ71.28 (c 1.00,
1
methanol); H NMR (500.12 MHz, CDCl3): d 7.14 (m, 2H, H-20 and 60),
6.97 (m, 2H, H-30 and 50), 4.84 (d, 4JH,H ¼ 1.5 Hz, 1H, H-8trans), 4.16 (s, 1H,
2
3
H-8cis), 3.29 (dd, JH,H ¼ 11.9 Hz, JH,H ¼ 1.6 Hz, 1H, H-2), 3.15 (m, 1H,
2
H-4), 2.94 (m, 1H, H-6), 2.67 (d, JH,H ¼ 3JH,H ¼ 11.9 Hz, 1H, H-2), 2.30
(s, 3H, NCH3), 2.21 (m, 1H, H-6), 1.98 (ddd, 1H, H-5), 1.85 (m, 1H, H-5);
1
13C NMR (125.77 MHz, CDCl3): d 161.55 (d, JC,F ¼ 245 Hz, C-40), 147.71
4
3
(C-3), 137.74 (d, JC,F ¼ 3 Hz, C-10), 130.00 (d, JC,F ¼ 8 Hz, C-20 and 60),
2
115.07 (d, JC,F ¼ 21 Hz, C-30 and 50), 110.73 (C-8), 63.12 (C-2), 55.93 (C-
6), 47.01 (C-4), 46.09 (NCH3), 32.99 (C-5); UV (methanol) lmax (1): 205.0
(9090), 265.2 (850), 271.2 (770); 1210 ¼ 7960; IR (KBr) n 2944, 2851,
2781, 2758, 1649, 1602, 1509, 1446, 1372, 1261, 1221, 1132, 1098, 1063,
920, 849, 826, 799, 544 cm21; EIMS (35 eV) m/z (relative intensity, %):
Mþ 205 (72.2), 190 (44.5), 147 (36.1), 133 (36.3), 109 (42.2), 82 (100).
General Procedure for Microwave-Assisted Elimination
Reaction on Alumina
A substrate 1b, 3b, 5b, 6b, or 7b (20–100 mg) was dissolved in a few
drops of dichloromethane, then mixed with an amount of solid support
(KSF, different types of alumina) sufficient to allow a support : substrate
ratio in the range of 4.1–33.6. The resulting solid was allowed to dry on
air. Approximately 0.5 mL of the powder was transferred into a glass reactor
(1 mL) and irradiated by microwaves for a given period of time. The solid was
cooled down and extracted with 25 mL of a chloroform : methanol mixture
(1 : 1). The suspension was filtered and the filtrate was evaporated to yield a
yellow oily residue which was analyzed by HPLC.
4-(4-Fluorophenyl)-1,5-dimethyl-1,2,5,6-tetrahydropyridine 8. An oily
chloroderivative 3b (444 mg, 1.83 mmol) was properly mixed with neutral
Al2O3/KF[17] (9.1 g; support : substrate ratio of 20.5). The yellowish powder
was placed in a 10 mL glass reactor and rotated. The mixture was kept
under argon and irradiated with microwaves for 10 min. The temperature
inside the reaction mixture increased to 2308C within 2 min of irradiation,

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trans-4-(4-Fluorophenyl)-3-chloromethyl-1-methylpiperidine
2113
then remained in the range of 210–2308C while the output of the microwave
reactor dropped to 20%. The powder was cooled down, mixed thoroughly,
placed in a reactor and irradiated for another 10 min. The product was obtained
by extraction of the powder with a mixture chloroform : ethanol (1 : 1),
followed by filtration and evaporation of solvent to yield a brown oil. Purifi-
cation of the crude reaction product was accomplished by column chromatog-
raphy (Silicagel, chloroform : methanol 10 : 1) providing compound 8 as a
yellowish oil (0.15 g, 40% yield): HPLC: 90.4% of 8, 8.0% of 7b, 1.6%
1
minor impurities; H NMR (300.13 MHz, CDCl3): d 7.04 (m, 2H, H-20 and
60), 6.92 (m, 2H, H-30 and 50), 2.96 (s, 2H, H-2), 2.65 (m, 2H, H-6), 2.38
(s, 3H, NCH3), 2.37 (m, 2H, H-5), 1.47 (s, 3H, CH3); 13C NMR
1
(75.47 MHz, CDCl3):
4
d
161.49 (d, JC,F ¼ 245 Hz, C-40), 137.96
3
(d, JC,F ¼ 3 Hz, C-10), 129.80 (d, JC,F ¼ 8 Hz, C-20 and 60), 129.54, 126.77
2
(C-3, C-4), 114.91 (d, JC,F ¼ 21 Hz, C-30 and 50), 58.64 (C-2), 51.97 (C-6),
44.69 (NCH3), 31.44 (C-5), 17.72 (CH3); EIMS (70 eV) m/z (relative inten-
sity, %): Mþ 205.1 (78.1), 190.4 (83.5), 174.8 (12.2), 146.7 (100), 133.0
(37.7), 108.9 (41.4), 94.4 (24.0), 81.9 (27.1).
ACKNOWLEDGMENTS
ˇ
The authors thank Mr. R. Kares for his technical assistance and Professor
A. Loupy for fruitful discussions. Financial support from the Ministry of
Education of the Czech Republic (Grant No. J07/98: 143100011 and COST
OC D 10.20) is gratefully acknowledged.
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Received in Poland May 10, 2003

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