Facile preparation of acetals and enol ethers derived from 1-arylpiperidin-4-ones

Article abstract of DOI:10.1039/a606191e

When primary aromatic amines 6 are heated under reflux with slight excesses each of crude 1,5-dichloro-pentan-3-one 4 and toluene-4-sulfonic acid monohydrate in dry methanol solution, and an excess of trimethyl orthoformate is then added to the reactants,

Full text of DOI:10.1039/a606191e

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Facile preparation of acetals and enol ethers derived from
1-arylpiperidin-4-ones
Montserrat Faja, Colin B. Reese,* Quanlai Song and Pei-Zhuo Zhang
Department of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
When primary aromatic amines 6 are heated under reflux with slight excesses each of crude 1,5-dichloro-
pentan-3-one 4 and toluene-4-sulfonic acid monohydrate in dry methanol solution, and an excess of
trimethyl orthoformate is then added to the reactants, the corresponding 1-arylpiperidin-4-one dimethyl
acetals 9 are obtained in good (74–81%) overall yields. The dimethyl acetals 9 undergo hydrolysis in
formic acid–water (9 :1 v/v) at room temperature to give the parent 1-arylpiperidin-4-ones 8 in virtually
quantitative yields. When the dimethyl acetals 9 are allowed to react with an excess each of N,N-diiso-
propylethylamine and boron trifluoride–diethyl ether complex in dichloromethane solution at 0 ЊC they
are converted in good yields into the corresponding enol ethers 10, which are required as reagents in the
solid phase synthesis of oligoribonucleotides.
Introduction
O
OH
H
H
OH
We have developed an automated solid phase synthesis of
oligo- and poly-ribonucleotides (RNA sequences)1–3 in which
the 2Ј-hydroxy functions of the ribonucleoside residues are pro-
tected with 1-aryl-4-methoxypiperidin-4-yl groups,4 such as
the 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl (Fpmp)5 and
1-(2-chloro-4-methylphenyl)-4-methoxypiperidin-4-yl (Ctmp)4
groups (as in 1a and 1b, respectively).
i
ii
ArNH2
6
Cl
Cl
Cl
Cl
N
Ar
4
5
7
iii
OMe
O
OMe
MeO
OMe
OMe
O
v
iv
B
O
2′
N
N
N
Ar
Ar
Ar
N
N
OMe
O
O–
O
O
O
9
10
8
P
R1
Cl
F
Scheme 1 Reagents and conditions: i, NaBH4, EtOH, H2O; ii, K2CO3,
NaI, DMF, 100 ЊC; iii, DCC, CF3CO2H, Me2SO, C5H5N, C6H6; iv,
CH(OMe)3, TsOH.H2O, MeOH, reflux; v, TsOH (ca. 1.0 mol%),
150 ЊC, ca. 20 mmHg
N
R2
Me
1a R1 = F, R2 = H
b R1 = Cl, R2 = Me
2
3
quantity of toluene-4-sulfonic acid (TsOH), the required enol
ether reagents 10 (e.g. 2 and 3) are obtained.4,5
The reagents required 4,5 for the introduction of these acetal
protecting groups are 1-(2-fluorophenyl)- and 1-(2-chloro-
4-methylphenyl)-4-methoxy-1,2,5,6-tetrahydropyridines (2 and
3, respectively). As no completely general method was available
for the preparation of 1-arylpiperidin-4-ones 8 when we started
our work on synthesis of RNA sequences, we developed 5 the
procedure indicated in outline in Scheme 1. We showed 6 many
years ago that 1,5-dichloropentan-3-one 4 can be prepared
in virtually quantitive yield by allowing 3-chloropropionyl
chloride to react with ethylene in the presence of aluminium
chloride in dichloromethane solution. 1,5-Dichloropentan-3-
one 4 is a relatively unstable compound which tends to
decompose on distillation;6 however, the crude material can
be reduced with sodium borohydride to give5,7 1,5-
dichloropentan-3-ol 5, which is a stable distillable liquid, in
good yield. In the presence of potassium carbonate and sodium
iodide, 1,5-dichloropentan-3-ol 5 reacts5 with a variety of pri-
mary aromatic amines (ArNH2 6) in DMF solution at 100 ЊC to
give the corresponding 1-arylpiperidin-4-ols 7 in satisfactory
to good yields. The latter compounds 7 can be converted 5,8
into 1-arylpiperidin-4-ones 8 by Moffatt oxidation.9 When the
corresponding dimethyl acetals 9, which are prepared 4,5 from
the ketones 8 in the usual way, are heated with a catalytic
Results and discussion
We have always believed that, if the right experimental condi-
tions could be found, it should be possible to shorten the above
enol ether synthesis (Scheme 1) by two steps [i.e. the reduction
and oxidation steps; steps (i) and (iii), respectively]. We have
now succeeded in avoiding the reduction and oxidation steps,
and report a one pot conversation of primary aromatic amines
6 into 1-arylpiperidin-4-one dimethyl acetals 9 in very good
overall yields. We also describe a much improved procedure for
the conversion of the dimethyl acetals 9 into the enol ether
reagents 10.
We first tried to react 1,5-dichloropentan-3-one6 4 with a
primary aromatic amine in the presence of a relatively strongly
basic tertiary amine (e.g. triethylamine) in the hope of effecting
a series of two elimination and two Michael addition reactions
according to Scheme 2. However, under such basic conditions,
considerable darkening occurred and none of the desired
1-arylpiperidin-4-one 8 could be detected in the products.
The situation was quite different when the primary aromatic
amine and 1,5-dichloropentan-3-one 4 were heated together
in the absence of an additional base. After some preliminary
J. Chem. Soc., Perkin Trans. 1, 1997
191

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O
O
O
ArNH2
base
6
4
8
Cl
Cl
NHAr
NHAr
Scheme 2
Table 1 Preparation of 1-arylpiperidin-4-one acetals 9, ketones 8 and
enol ethers 10a
O
O
MeO
OMe
i
ii
Starting
ArNH2
6
Entry
material Product Yield (%) Mp(bp)/ЊC
Cl
Cl
N
Ar
N
Ar
1
2
3
4
5
6a
6b
6c
6d
6e
9a
9b
9c
9d
9e
81
74
77
81
75
72–73
67–68
109–111
62–63
34–36 (136–138 at
34–36 1 mmHg)
—
4
9
8
iii
OMe
6
6f
9f
76
(148–150 at
1 mmHg)
7
8
9
10
11
12
9a
9c
9e
9a
9d
9f
8a
8c
8e
99
99
99
67–68
57–58
38–39
30–31
55–57
—
N
Ar
᎐
10a (᎐ 2) 83
10d (᎐ 3) 85
10f
᎐
10
᎐
᎐
F
Cl
72.5
(153–156 at
1 mmHg)
a Ar =
d Ar =
;
b Ar =
;
c Ar =
;
a
See Scheme 3 and Experimental section for full experimental details.
Cl
Cl
experiments, it was found that when the primary aromatic
amine was heated, under gentle reflux, with a ca. 10% excess
each of crude 1,5-dichloropentan-3-one 4 and toluene-4-
sulfonic acid monohydrate in dry methanol for 2-4 h, a mixture
of 1-arylpiperidin-4-one 8 and its dimethyl acetal 9 was
obtained. An excess of trimethyl orthoformate was then added
(Scheme 3) and heating was continued for a further period of
1 h. Little or no darkening of the reaction solution was observed
and the 1-arylpiperidin-4-one dimethyl acetal 9 was obtained as
virtually the sole product. Indeed, the overall isolated yields of
the mainly crystalline dimethyl acetals 9 were 74–81% (Table 1),
based on the primary aromatic amines 6 as starting materials.
Thus our original procedure5 (Scheme 1) for the preparation of
the dimethyl acetals 9 has essentially been shortened by three
steps and the overall yields have been increased considerably.
The preparation of the dimethyl acetals 9a-f (Table 1, entries
1–6) was carried out on a 0.1 molar scale but could be easily
scaled up; thus these compounds have become readily accessible
and relatively inexpensive provided that the primary aromatic
amine starting materials 6 themselves are also inexpensive.
Preliminary experiments have indicated 10 that if methanol
and trimethyl orthoformate [Scheme 3, step (i)] are replaced
by ethanol and triethyl orthoformate, 1-arylpiperidin-4-one
diethyl acetals are obtained, also in very good yields. If the par-
ent 1-arylpiperidin-4-ones 8 themselves are required, we believe
that they are best prepared by first isolating the pure dimethyl
acetals 9 and then subjecting them to acidic hydrolysis [Scheme
3, step (ii)]. Thus when dimethyl acetals 9a, 9c and 9e were
dissolved in formic acid–water (9:1 v/v) and the solutions were
stirred at room temperature for 2 h, the corresponding ketones
8a, 8c and 8e were obtained and isolated as colourless crystal-
line solids in virtually quantitive yields (Table 1, entries 7–9).
Our main purpose for undertaking the present study was to
Cl
;
e Ar = Ph; f Ar =
;
Me
Scheme 3 Reagents and conditions: i, TsOHؒH2O, MeOH, reflux, 2–4
h, then CH(OMe)3, reflux, 1 h; ii, HCO2H–H2O (9:1 v/v), room temp.,
2 h; iii, Pri2NEt, Et2O–BF3, CH2Cl2, 0 ЊC, 2–4 h
and his co-workers11,12 have shown that when acetals are
allowed to react with a slight (usually less than twofold) excess
each of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and
N,N-diisopropylethylamine (HünigЈs base) in dichloromethane
solution at a relatively low temperature (Ϫ20 to 25 ЊC), the cor-
responding enol ethers are obtained in high yields. This reaction
appears to be general. Unfortunately, TMSOTf is an expensive
reagent and its use would considerably increase the overall cost
᎐
᎐
of preparing the enol ethers [such as 10a (᎐2) and 10d (᎐3)],
᎐
᎐
which are required for oligoribonucleotide synthesis. We now
report that boron trifluoride–diethyl ether complex, which on a
molar basis is some 50–100 times cheaper than TMSOTf, is
equally effective in the conversion of 1-arylpiperidin-4-one
dimethyl acetals 9 into the corresponding enol ethers 10.
᎐
᎐
We have prepared the three enol ethers 10a (᎐2), 10d (᎐3) and
᎐
᎐
10f (Table 1, entries 10–12) that we believe at present 13 to be
the most useful reagents for the introduction of 2Ј-protecting
groups in the solid phase synthesis of RNA sequences. In each
case, we started with 0.2 mol of the appropriate primary
aromatic amine 6 which was converted [Scheme 3, step (i)] into
the corresponding 1-arylpiperidin-4-one dimethyl acetal 9. The
crude acetals were then dissolved in dichloromethane and the
resulting solutions were treated first with 2.4 molar equivalents
(with respect to aromatic amine 6) of Hünig’s base followed by
2.0 molar equivalents of boron trifluoride–diethyl ether com-
plex at 0 ЊC. The reactions [Scheme 3, step (iii)] were allowed to
᎐
᎐
make the enol ethers 10 [particularly 10a (᎐2) and 10d (᎐3)],
᎐
᎐
required for oligoribonucleotide synthesis,1–3 more readily
accessible.We had previously prepared 5 these reagents 10 by
heating the corresponding dimethyl acetals 9 with a catalytic
quantity of toluene-4-sulfonic acid at 150 ЊC under reduced
pressure [Scheme 1, step (v)].These reaction conditions are
rather drastic and often the enol ether 10 obtained was con-
taminated both with ketone 8 and starting material 9. Gassman
proceed for 2–4 h, and the enol ethers 10a (᎐2), 10d (᎐3) and 10f
᎐
᎐
᎐
᎐
(Table 1, entries 10–12) were all obtained in good yields.
Furthermore, the enol ethers were all isolated in a higher state
of purity than they had been obtained by the acid-catalysed
extrusion procedure4,5 [Scheme 1, step (v)]. There would appear
to be little doubt that the Hünig’s base/boron trifluoride–
diethyl ether complex procedure for the conversation of
192
J. Chem. Soc., Perkin Trans. 1, 1997

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1-arylpiperidin-4-one dimethyl acetals 9 into the corresponding
enol ethers 10 could readily be scaled up. It also seems likely
that this procedure might find more general use in the con-
version of acetals into enol ethers.
N, 5.27. C13H18ClNO2 requires: C, 61.05; H, 7.09; N, 5.48%)
(18.97 g, 74%), mp 67–68 ЊC; Rf 0.68; δH (CDCl3) 1.95 (4 H, m),
3.03 (4 H, m), 3.24 (6 H, s), 6.94 (1 H, m), 7.05 (1 H, m), 7.19
(1 H, m), 7.34 (1 H, m); δC(CDCl3) 32.9, 47.6, 48.6, 98.4, 120.7,
123.5, 127.5, 129.0, 130.6, 149.6.
1-(4-Chlorophenyl)-4,4-dimethoxypiperidine 9c. Compound
9c was obtained as a pale yellow crystalline solid (Found, from
colourless material recrystallised from aqueous methanol and
dried in vacuo over sodium hydroxide pellets: C, 61.07; H, 7.18;
N, 5.30. C13H18ClNO2 requires: C, 61.05; H, 7.09; N, 5.48%)
(19.76 g, 77%), mp 109–111 ЊC; Rf 0.45; δH (CDCl3) 1.88 (4 H,
m), 3.20 (4 H, m), 3.23 (6 H, s), 6.85 (2 H, m), 6.89 (2 H, m);
δC(CDCl3) 32.1, 46.7, 47.6, 98.3, 117.7, 124.2, 128.9, 149.7.
Experimental
Melting points were measured with a Büchi melting point
apparatus and are uncorrected. 1H NMR spectra were measured
at 360 MHz with a Bruker AM 360 spectrometer; 13C NMR
spectra were measured at 90.6 MHz with the same spectro-
meter. Chemical shifts δ are given in ppm relative to tetra-
methylsilane and J values are given in Hz. Merck silica gel
60 F254 plates were developed in a solvent system consisting
of light petroleum (bp 40–60 ЊC)–ethyl acetate (7:1 v/v).
Triethylamine and N,N-diisopropylethylamine were dried by
heating, under reflux, over calcium hydride, and were then
distilled; dichloromethane was dried by distillation over
phosphorus pentaoxide.
1-(2-Chloro-4-methylphenyl)-4,4-dimethoxypiperidine
9d.
Compound 9d was obtained as a pale yellow crystalline solid
(Found, from colourless material recrystallised from aqueous
methanol and dried in vacuo over sodium hydroxide pellets: C,
62.30; H, 7.36; N, 5.05. C14H20ClNO2 requires: C, 62.33; H,
7.47; N, 5.19%) (21.92 g, 81%), mp 62–63 ЊC; Rf 0.69; δH (CDCl3)
1.94 (4 H, m), 2.26 (3 H, s), 2.99 (4 H, m), 3.23 (6 H, s), 6.97
(2 H, m), 7.17 (1 H, m); δC(CDCl3) 20.8, 33.3, 47.9, 49.2, 98.8,
120.8, 128.4, 129.0, 131.3, 133.8, 147.5.
Preparation of 1-aryl-4,4-dimethoxypiperidines 9
Toluene-4-sulfonic acid monohydrate (20.92 g, 0.11 mol) and
crude 1,5-dichloropentan-3-one6 (17.05 g ca. 0.11 mol) were
added to a stirred solution of primary aromatic amine 6 (0.10
mol) in dry methanol (100 cm3). The reactants were then
heated under gentle reflux. After an appropriate time (2 h for
6a–d, 4 h for 6e and 3 h for 6f), trimethyl orthoformate (32.8
cm3, 0.30 mol) was added, and the reactants were again heated
under reflux. After a further period of 1 h, the products were
cooled (ice–water bath) and triethylamine (46 cm3, 0.33 mol)
was added. The resulting mixture was evaporated under
reduced pressure and the residue was partitioned between light
petroleum (bp 40–60 ЊC, 150 cm3) and saturated aqueous
sodium hydrogen carbonate (150 cm3). The organic layer was
separated and the aqueous layer was back-extracted with light
petroleum (bp 40–60 ЊC, 2 × 50 cm3). The combined organic
layers were dried (MgSO4) and the solvent was evaporated
under reduced pressure to give a crude product.
(a) The residual crude 1-aryl-4, 4-dimethoxypiperidines 9a–d,
derived from 2-fluoroaniline 6a, 2-chloroaniline 6b, 4-
chloroaniline 6c and 2-chloro-4-methylaniline 6d, respectively,
were dissolved in dry methanol (100 cm3) and the solution was
evaporated under reduced pressure. After this process had been
repeated, the residue was redissolved in methanol (200 cm3) at
room temperature. Water (150 cm3) was added dropwise over a
period of 1 h, with stirring, to the resulting solution. Crystal-
lisation was allowed to occur overnight at room temperature
and then for a further period of 1 h at 0 ЊC (ice–water bath). The
crystalline precipitates were then collected by filtration, washed
with methanol–water (1:1 v/v) and dried in vacuo over sodium
hydroxide pellets.
1-Phenyl-4,4-dimethoxypiperidine 9e. Compound 9e was
obtained as a pale yellow oil (16.65 g, 75%), bp 136–138 ЊC at 1
mmHg. This material was dissolved in light petroleum (bp 40–
60 ЊC, 150 cm3) and the solution was filtered through a short
column of silica gel (20 g). The column was then washed with
light petroleum (bp 40–60 ЊC)–ethyl acetate (98:2 v/v). The
combined filtrate and washings were evaporated under reduced
pressure, and the residue was redissolved in methanol (100
cm3). The solution was cooled (ice–water bath) until crystallis-
ation commenced. Water (100 cm3) was then added dropwise
over a period of 1 h to the stirred mixture at room temperature.
Crystallisation was allowed to occur at room temperature over-
night and then for a further period of 1 h at 0 ЊC (ice–water
bath). The colourless crystalline precipitate of 1-phenyl-4,4-
methoxypiperidine was collected by filtration and washed with
cold methanol–water (1:1 v/v) (Found, from material dried in
vacuo over sodium hydroxide pellets: C, 70.44; H, 8.63; N, 6.35.
C13H19NO2 requires: C, 70.56; H, 8.65; N, 6.33%), mp 34–36 ЊC;
Rf 0.51; δH (CDCl3) 1.89 (4 H, m), 3.22 (10 H, m), 6.82 (1 H, m),
6.93 (2 H, m), 7.24 (2 H, m); δC(CDCl3) 32.4, 46.9, 47.8, 98.7,
116.7, 119.6, 129.3, 151.3.
1-(3-Chlorophenyl)-4,4-dimethoxypiperidine 9f. Compound
9f was obtained as a pale yellow oil (HRMS: found M+,
12
255.1028.
C
1H1835Cl14N16O2 requires M, 255.1026) (19.44 g,
13
76%), bp 148–150 ЊC at 1 mmHg; Rf 0.55; δH (CDCl3) 1.86 (4 H,
m), 3.22 (10 H, m), 6.77 (2 H, m), 6.88 (1 H, m), 7.13 (1 H, m);
δC(CDCl3) 32.0, 46.2, 47.6, 98.4, 114.3, 116.1, 118.9, 130.0,
134.9, 152.1.
(b) Tridodecylamine (0.25 g, 0.48 mmol) was added to each
of the crude 1-aryl-4,4-dimethoxypiperidines 9e and 9f, derived
from aniline 6e and 3-chloroaniline 6f, respectively, and the
crude materials were purified by distillation under reduced
pressure (oil pump).
1-(2-Fluorophenyl)-4,4-dimethoxypiperidine 9a. Compound
9a was obtained as a pale yellow crystalline solid (Found, from
colourless material recrystallised from aqueous methanol and
dried in vacuo over sodium hydroxide pellets: C, 65.21; H, 7.66;
N, 5.70. Calc. for C13H18FNO2: C, 65.25; H, 7.58; N, 5.85%)
(19.45 g, 81%), mp 72–73 ЊC (lit.,5 mp 69–70 ЊC); Rf 0.62;
δH (CDCl3) 1.95 (4 H, m), 3.10 (4 H, m), 3.24 (6 H, s), 6.89–7.07
(4 H, m); δC(CDCl3) 32.7, 47.6, 47.9 (d, JC,F 3.3), 98.2, 116.1
(d, JC,F 20.9), 119.4 (d, JC,F 2.9), 122.3 (d, JC,F 7.9), 124.4
(d, JC,F 3.5), 140.3 (d, JC,F 8.5), 155.8 (d, JC,F 245.8).
Preparation of 1-arylpiperidin-4-ones 8
A solution of pure 1-aryl-4, 4-dimethoxypiperidine 9 (10 mmol)
in formic acid–water (9:1 v/v; 10 cm3) was stirred at room tem-
perature. After 2 h, the products were evaporated to dryness
under reduced pressure. The residue was evaporated under
reduced pressure first with toluene (2 × 10 cm3) and then
with acetonitrile (2 × 10 cm3), and was then crystallised from
aqueous methanol.
1-(2-Fluorophenyl)piperidin-4-one 8a. Compound 8a was
obtained as colourless crystals (Found: C, 68.19; H, 6.09; N,
7.18. Calc. for C11H12FNO: C, 68.38; H, 6.26; N, 7.25%) (1.92 g,
99%), mp 67–68 ЊC (lit.,5 64 ЊC); Rf 0.44; δH (CDCl3) 2.62 (4 H, t,
J 6.1), 3.40 (4 H, t, J 6.0), 6.95–7.10 (4 H, m); δC(CDCl3) 41.7,
50.8 (d, JC,F 3.0), 116.4 (d, JC,F 20.6), 119.7 (d, JC,F 2.3), 123.2
(d, JC,F 8.0), 124.6 (d, JC,F 3.5), 139.2 (d, JC,F 8.9), 155.7 (d, JC,F
245.7), 208.2.
1-(2-Chlorophenyl)-4,4-dimethoxypiperidine 9b. Compound
9b was obtained as a pale yellow crystalline solid (Found, from
colourless material recrystallised from aqueous methanol and
dried in vacuo over sodium hydroxide pellets: C, 60.96; H, 7.01;
1-(4-Chlorophenyl)piperidin-4-one 8c. Compound 8c was
obtained as colourless crystals (Found: C, 62.99; H, 5.64;
N, 6.55. Calc. for C11H12ClNO: C, 63.01; H, 5.77; N, 6.68%)
J. Chem. Soc., Perkin Trans. 1, 1997
193

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(2.07 g, 99%), mp 57–58 ЊC (lit.,5 55–56 ЊC); Rf 0.24; δH (CDCl3)
2.54 (4 H, t, J 6.1), 3.57 (4 H, t, J 6.1), 6.89 (2 H, m), 7.24 (2 H,
m); δC(CDCl3) 40.6, 48.8, 117.1, 124.7, 129.3, 147.8, 207.8.
1-Phenylpiperidin-4-one 8e. Compound 8a was obtained as
colourless crystals (Found: C, 75.35; H, 7.45; N, 8.18. Calc. for
C11H13NO: C, 75.40; H, 7.48; N, 7.99%) (1.75 g, 99%), mp 38–
39 ЊC (lit.,14 37–38 ЊC); Rf 0.32; δH (CDCl3) 2.53 (4 H, t, J 6.2),
3.58 (4 H, t, J 6.1), 6.87 (1 H, m), 6.96 (2 H, m), 7.28 (2 H, m),
δC(CDCl3) 40.8, 48.7, 115.9, 119.9, 129.5, 149.2, 208.3.
(2 H, m), 3.30 (2 H, t, J 5.8), 3.56 (3 H, s), 3.67 (2 H, m), 4.69
(1 H, m), 6.87–7.06 (4 H, m); δC(CDCl3) 28.4, 48.1 (d, JC,F 3.1),
54.2, 91.4, 116.1 (d, JC,F 20.7), 119.4 (d, JC,F 2.7), 122.2 (d, JC,F
8.0), 124.4 (d, JC,F 3.4), 139.8 (d, JC,F 8.7), 154.2, 155.8 (d, JC,F
245.6).
1-(2-Chloro-4-methylphenyl)-4-methoxy-1,2,5,6-tetrahydro-
pyridine 10d. The residue was recrystallised from methanol–
water (1:1 v/v) in the same way as 10a to give 1-(2-chloro-4-
methylphenyl)-4-methoxy-1,2,5,6-tetrahydropyridine 10d (40.7 g,
85%) (Found: C 65.51; H, 6.68; N, 5.75. Calc. for C13H16ClNO:
C, 65.68; H, 6.78; N, 5.89%) as pale yellow crystals, mp 55–
57 ЊC; Rf 0.91; δH (CDCl3) 2.26 (3 H, d, J 0.5), 2.33 (2 H, m), 3.21
(2 H, m), 3.56 (3 H, s), 3.61 (2 H, m), 4.70 (1 H, m), 6.99
(2 H, m), 7.18 (1 H, m); δC(CDCl3) 20.6, 28.7, 48.9, 49.4, 54.4,
91.9, 120.6, 128.2, 128.6, 131.3, 133.6, 146.6, 154.5.
Preparation of 1-aryl-4-methoxy-1,2,5,6-tetrahydropyridines 10
1-Aryl-4,4-dimethoxypiperidines 9 were prepared as above but
on double the scale (i.e. from 0.20 mol of the primary aromatic
amine 6). After the addition of triethylamine, the products were
evaporated under reduced pressure and then partitioned
between light petroleum (bp 40–60 ЊC, 300 cm3) and saturated
aqueous sodium hydrogen carbonate (300 cm3). The organic
layer was separated, and the aqueous layer was back-extracted
with light petroleum (bp 40–60 ЊC, 2 × 75 cm3). The combined
organic layers were dried (MgSO4) and concentrated under
reduced pressure. The residue was evaporated with toluene
(2 × 50 cm3) under reduced pressure and then dissolved in
dichloromethane (300 cm3). The solution obtained was cooled
to 0 ЊC (ice–water bath) in an atmosphere of argon. Dry N,N-
diisopropylethylamine (53.6 cm3, 0.48 mol) was added, and
then boron trifluoride–diethyl ether complex (49.2 cm3, 0.40
mol) was added dropwise over a period of 5 min to the stirred
solution maintained at 0 ЊC. After 2–4 h (3 h in the preparation
of 10a, 2 h in the preparation of 10d and 4 h in the preparation
of 10f), the products were allowed to warm up to room tem-
perature and were washed with saturated aqueous sodium
hydrogen carbonate (500 cm3). The organic layer was separated
and the aqueous layer was back-extracted with dichlorometh-
ane (2 × 50 cm3). The combined organic layers were dried
(MgSO4) and evaporated under reduced pressure. Light pet-
roleum (bp 40–60 ЊC, 300 cm3) was added to the residue, and
the resulting suspension was filtered through a bed of silica gel
(20 g). The silica gel was washed with light petroleum (bp 40–
60 ЊC)–ethyl acetate (98:2 v/v; 3 × 75 cm3). The combined fil-
trate and washings were concentrated under reduced pressure,
and the residue was co-evaporated with methanol (2 × 50
cm3).
1-(3-Chlorophenyl)-4-methoxy-1,2,5,6-tetrahydropyridine 10f.
Distillation of the residue gave 1-(3-chlorophenyl)-4-methoxy-
1,2,5,6-tetrahydropyridine 10f (32.48 g, 72.5%) (HRMS: found
M+, 223.0765.
C
1H1435Cl14N16O requires M, 223.0764) as
12
12
pale yellow liquid, bp 153–156 ЊC at 1 mmHg; Rf 0.82;
δH (CDCl3) 2.29 (2 H, m), 3.39 (2 H, t, J 5.8), 3.53 (3 H, s) 3.71
(2 H, m), 4.64 (1 H, m), 6.75 (2 H, m), 6.85 (1 H, m), 7.12
(1 H, m); δC(CDCl3) 28.2, 45.4, 46.5, 54.3, 90.8, 113.3, 115.0,
118.4, 130.1, 135.0, 151.7, 154.1.
Acknowledgements
We thank the EPSRC and Cruachem Limited for generous
financial support.
References
1 T. S. Rao, C. B. Reese, H. T. Serafinowska, H. Takaku and
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10 C. B. Reese and C. Visintin, unpublished observations.
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1449.
1-(2-Fluorophenyl)-4-methoxy-1,2,5,6-tetrahydropyridine 10a.
The residue was dissolved in methanol (200 cm3) and the solu-
tion was cooled to 0 ЊC (ice–water bath). After crystallisation
had commenced, water (200 cm3) was added slowly over a
period of 2 h to the stirred, cooled suspension. After a further
period of 4 h, pale yellow crystals of 1-(2-fluorophenyl)-4-
methoxy-1,2,5,6-tetrahydropyridine 10a (34.5 g, 83%) were
13 W. Lloyd, C. B. Reese and P.-Z. Zhang, unpublished observations.
14 M. J. Gallagher and F. G. Mann, J. Chem. Soc., 1962, 5110.
collected by filtration and washed with cold methanol–water
Paper 6/06191E
Received 9th September 1996
Accepted 16th October 1996
12
(1:1 v/v) (HRMS: found M+, 207.1048. Calc. for
C
1H1419F-
12
14N16O, 207.1059), mp 30–31 ЊC; Rf 0.85; δH (CDCl3) 2.32
194
J. Chem. Soc., Perkin Trans. 1, 1997