A facile synthesis of 3-(substituted benzyl)piperidines

Article abstract of DOI:10.1016/j.tet.2003.08.023

A convenient new method has been developed for preparation a series of 3-(substituted benzyl)piperidines by addition of substituted phenylmagnesium bromide to pyridine-3-carboxaldehyde followed by one pot deoxygenation and heteroaromatic ring saturation in the presence of palladium catalyst.

Full text of DOI:10.1016/j.tet.2003.08.023

Tetrahedron 59 (2003) 7897–7900
A facile synthesis of 3-(substituted benzyl)piperidines
a
Bela Agai, Adrienn Nador, Agnes Proszenyak, Gabor Tarkanyi and Ferenc Faigl
a
a
b
a
,
´
´
*
´
´
´
´
´ ´
aDepartment of Organic Chemical Technology, Budapest University of Technology and Economics and Research Group of Hungarian
˝
Academy of Sciences, Muegyetem rkp. 3, 1111 Budapest, Hungary
¨
˝ ´
Gedeon Richter Ltd., Gyomroi ut 19-21, H-1475 Budapest, Hungary
b
Received 18 June 2003; revised 18 July 2003; accepted 13 August 2003
Abstract—A convenient new method has been developed for preparation a series of 3-(substituted benzyl)piperidines by addition of
substituted phenylmagnesium bromide to pyridine-3-carboxaldehyde followed by one pot deoxygenation and heteroaromatic ring saturation
in the presence of palladium catalyst.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
intermediates11–14 then deoxygenated using iodotrimethyl-
silane12,13 or samarium iodide15 to get 3-(substituted
benzyl)pyridines or the formed pyridylmethanol was
oxidated to ketone, an intermediate of alkylidene deriva-
tives of 3-benzylpiperidine.14 Saturation of the pyridine ring
has usually been carried out in a separate hydrogenation
reaction in the presence of platinum,16 platinum oxide,15
palladium17 or Raney-nickel18 catalysts.
Benzylpiperidines and their derivatives possess a range of
physiological and pharmaceutical activities. Substituted
4-benzylpiperidines
exhibit
N-methyl-D-aspartate
(NMDA) antagonist activity,1 as well as high affinity for
other central nervous system receptors.2 2-Benzylpiperidine
derivatives are known dopamine receptor antagonists,3
while the 3-benzylpiperidines show fungicide activity.4
Numerous multistep syntheses are described in the literature
for preparation of this important class of compounds but the
overall yields are usually low and exotic reagents or
conditions are used in many cases. Thus, 3-benzylpiperidine
was synthesized from 2-piperidone by successive lithiation,
benzylation and hydride reduction sequence.4 In other
processes 3-benzoylpyridine was deoxygenated with hydro-
gen iodide and phosphorous then the pyridine ring was
reduced with sodium in alcohol5 or the same starting
material was converted into the target molecule via nickel
catalysed reduction at high pressure and temperature.6
However, synthesis of 3-benzoylpyridine requires special
reagents (naphthalene–lithium or activated zinc,7,8 tri-
methylstannylpyridine,9 homogenous palladium catalyst
and carbon monoxide10), too. In other methods, aryl-3-
pyridylmethanols were synthesized via organometallic
2. Results and discussion
Here, we report a novel, short and efficient synthesis of
3-(substituted benzyl)piperidines starting from readily
pyridine-3-carboxaldehyde (1) and Grignard reagents
prepared from mono-, di-, or trisubstituted bromobenzenes
(2a–i) and continued by a one-pot catalytic deoxygenation
and heteroaromatic ring saturation of the aryl-3-pyridyl-
methanol intermediates (3a–i, Scheme 1).
Addition of 1 to the Grignard-reagents provided 3a–i in
moderate to good yields (Table 1). The crude products were
dissolved in glacial acetic acid and hydrogenated in the
presence of 10% Pd/C (Montecatini) catalyst. Conditions of
the deoxygenation–saturation reaction are listed in Table 1.
Scheme 1.
Keywords: Grignard-reaction; catalytic reduction; catalytic deoxygenation; 3-benzylpiperidine.
*
Corresponding author. Tel.: þ36-1-463-3652; fax: þ36-1-463-3648; e-mail: ffaigl@mail.bme.hu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.023

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B. Agai et al. / Tetrahedron 59 (2003) 7897–7900
7898
Table 1. Preparation of 3-(substituted phenyl)methylpiperidines
Starting material Intermediate
Yield (%)
Hydrogenation
Temperature (8C)
Product
Yield (%)
No.
Substituents (R0,R00,R000)
No.
Pressure (bar)
No.
2a
2b
2c
2d
2e
2f
2g
2h
2i
4-CH3O
2-CH3O
4-F
3,5-(CH3)2-4-CH3O
3,4-(CH3O)2
3-CF3
4-CH3
4-[CH2vC(CH3)CH2O]
4-PhCH2O
3a
3b
3c
3d
3e
3f
3g
3h
3i
68
67
83
82
74
86
83
60
54
8
70
80
80
80
75
75
60
80
30
4a
4b
4ca
4d
4e
4fa
4g
5a
76
91
76
75
82
70
89
62
61
10
10
10
10
10
10
10
1
6b
a
Isolated as base by vacuum distillation.
Prepared in the presence of sulfuric acid, isolated as hydrogensulfate salt.
b
The products (4a–g) were isolated as hydrochloride salts in
crystalline form. Yields given in Table 1 refer to the isolated
pure products.
recorded as KBr pellets, and IR spectra of oils were
recorded as thin films on NaCl plates with a Perkin–Elmer
Spectrum 1000 FT-IR spectrophotometer.
In the case of 3h saturation of the double bond in the side
chain occurred parallel with the ring saturation. Thus, we
obtained 3-(4-isobutoxyphenyl)methylpiperidine hydro-
chloride (5). This reaction is a new, simple route to
compound 5 (2h can easily be obtained from 4-bromo-
phenol and cheap b-methallyl chloride).
4.2. General procedure for the preparation of aryl-3-
pyridyl-methanol 3
At 208C, a solution of 1 (200 mmol, 18.9 ml) in tetra-
hydrofuran (100 ml) was added to the Grignard-reagent
prepared from 2a–i (210 mmol) and magnesium turnings
(205 mmol, 4.94 g) in tetrahydrofuran (300 ml). After 10 h
stirring, 80 ml saturated ammonium chloride solution was
poured into the reaction mixture, the phases were separated,
the tetrahydrofuran solution was dried and concentrated in
vacuo. The residue was treated with hexane or ethyl acetate
to get carbinol 3a–i.
Selective debenzylation of 3i was also accomplished under
mild conditions (atmospheric pressure, 308C, methanol/
H2SO4) yielding 3-(4-hydroxyphenyl)methylpyridine (6).
The free hydroxy group is useful for elaboration to further
O-alkyl derivatives of 6 before pyridine ring saturation and
this route is much smoother than demethylation of the
corresponding methoxy derivative.
4.2.1. 4-Methoxyphenyl-3-pyridyl-methanol 3a. Pale
yellow solid; mp 104–1058C (lit.19 mp 106–1078C); IR
(KBr pellets, cm21) nmax 3190, 1515, 1251, 1172, 1031,
806; 1H NMR (CDCl3, 500 MHz) d ppm 3.76 (s, 3H), 4.57
(s, br, 1H), 5.75 (s, 1H), 6.84 (m, 2H), 7.17 (m, 1H), 7.22 (m,
2H), 7.66 (m, 1H), 8.29 (m, 1H), 8.43 (m, 1H). Anal. calcd
for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.42;
H, 6.19; N, 6.37.
3. Conclusions
On the basis of these results we have found this two step
procedure to be simple to accomplish, inexpensive, high-
yielding and benign even on multigram scale. Extended
studies on the scopes and applications of this method are
currently underway.
4.2.2. 2-Methoxyphenyl-3-pyridyl-methanol 3b. Pale
yellow solid; mp 1128C; IR (KBr pellets, cm21) nmax
1
3151, 1586, 1490, 1439, 1241, 1047, 1029, 760; H NMR
(CDCl3, 500 MHz) d ppm 3.76 (s, 3H), 3.93 (s, br, 1H), 6.07
(s, 1H), 6.86 (d, J¼8.5 Hz, 1H), 6.96 (m, 1H), 7.20 (m, 1H),
7.26 (m, 1H), 7.34 (m, 1H), 7.70 (m, 1H), 8.37 (m, 1H), 8.54
(d, J¼1.5 Hz, 1H). Anal. calcd for C13H13NO2: C, 72.54; H,
6.09; N, 6.51. Found: C, 72.65; H, 6.01; N, 6.39.
4. Experimental
4.1. General
All commercial starting materials were purchased from
FLUKA AG and Merck-Schuchardt and were used without
further purification. Tetrahydrofuran were obtained
anhydrous by distillation from sodium wire after the
characteristic blue color of in situ generated sodium
diphenylketyl had been found to persist. All Grignard-
reactions were carried out under dry nitrogen atmosphere.
4.2.3. 4-Fluorophenyl-3-pyridyl-methanol 3c. Pale yellow
solid; mp 1508C (lit.20 mp of hydrochloride salt 158.38C);
IR (KBr pellets, cm21) nmax 3204, 1602, 1508, 1222, 1060,
811, 685, 565; 1H NMR (DMSO, 500 MHz) d ppm 6.10 (s,
1H), 7.20 (m, 2H), 7.52 (m, 2H), 8.05 (m, 1H), 8.55 (d,
J¼8.0 Hz, 1H), 8.86 (d, J¼8.0 Hz, 1H), 8.96 (t, J¼1.0 Hz,
1H). Anal. calcd for C12H10FNO: C, 76.18; H, 5.33; N, 7.40.
Found: C, 76.29; H, 5.21; N, 7.31.
1H NMR spectra were recorded in hexadeuteriodimethyl-
sulfoxide or deuteriochloroform solution at 300 and
500 MHz (Varian Innova Spectrometers). Chemical shifts
refer to tetramethylsilane (d 0 ppm), coupling constants are
given in Hz. Melting point were determined using Bu¨chi
capillary melting point apparatus. IR spectra of solids were
4.2.4. 3,5-Dimethyl-4-methoxyphenyl-3-pyridyl-metha-
nol 3d. Pale yellow solid; mp 96–978C; IR (KBr pellets,
1
cm21) nmax 3188, 1476, 1224, 1143, 1059, 1012, 714; H

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B. Agai et al. / Tetrahedron 59 (2003) 7897–7900
7899
NMR (DMSO, 500 MHz) d ppm 2.19 (s, 6H), 3.60 (s, 3H),
5.66 (d, J¼4.0 Hz, 1H), 5.92 (d, J¼4.0 Hz, 1H), 7.03 (s,
2H), 7.31 (m, 1H), 7.71 (m, 1H), 8.41 (m, 1H), 8.57 (d,
J¼2.0 Hz, 1H). Anal. calcd for C15H17NO2: C, 74.07; H,
7.04; N, 5.76. Found: C, 73.91; H, 7.16; N, 5.60.
(150 ml) gave the corresponding piperidine hydrochloride
derivative (4a–g) in pure form.
4.3.1. 3-(4-Methoxyphenyl)methylpiperidine hydro-
chloride 4a. White solid; mp 1658C (lit.4 no data); IR
(KBr pellets, cm21) nmax 3423, 2938, 2507, 2403, 1512,
1240, 1180, 1028; 1H NMR (DMSO, 500 MHz) d ppm 1.16
(m, 1H), 1.55–1.76 (m, 3H), 1.96 (m, 1H), 2.46–2.53 (m,
3H), 2.70 (m, 1H), 3.02 (m, 1H), 3.14 (m, 1H), 3.73 (s, 3H),
6.85 (m, 2H), 7.10 (m, 2H), 9.15 (br, s, 2H). Anal. calcd for
C13H20ClNO: C, 64.58; H, 8.34; N, 5.79; Cl, 14.66. Found:
C, 64.36; H, 8.17; N, 5.88; Cl, 14.42.
4.2.5. 3,4-Dimethoxyphenyl-3-pyridyl-methanol 3e. Pale
yellow solid; mp 98–998C (lit.21 no data); IR (KBr pellets,
1
cm21) nmax 3154, 1592, 1515, 1270, 1228, 1136, 1026; H
NMR (CDCl3, 500 MHz) d ppm 3.80 (s, 3H), 3.84 (s, 3H),
4.56 (s, br, 1H), 5.76 (s, 1H), 6.78–6.86 (m, 2H), 6.88
(d, J¼2.0 Hz, 1H), 7.20 (m, 1H), 7.67 (m, 1H), 8.32
(m, 1H), 8.48 (d, J¼2.0 Hz, 1H). Anal. calcd for
C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.39;
H, 6.03; N, 5.54.
4.3.2. 3-(2-Methoxyphenyl)methylpiperidine hydro-
chloride 4b. White solid; mp 1588C (lit.23 no data); IR
(KBr pellets, cm21) nmax 3435, 2937, 2510, 2400, 1495,
1
4.2.6. 3-(Trifluoromethyl)phenyl-3-pyridyl-methanol 3f.
Colorless oil; bp 134–1388C/0.1 mm Hg (lit.19 no data); IR
(film, cm21) nmax 3169, 1427, 1330, 1164, 1123, 1073, 799,
1459, 1438, 1245, 1024; H NMR (DMSO, 500 MHz) d
ppm 1.20 (m, 1H), 1.54–1.78 (m, 3H), 2.02 (m, 1H), 2.47–
2.58 (m, 3H), 2.72 (m, 1H), 3.00 (m, 1H), 3.15 (m, 1H), 3.78
(s, 3H), 6.88 (m, 1H), 6.98 (d, J¼8.5 Hz, 1H), 7.11 (d,
J¼8.4 Hz, 1H), 7.21 (d, 1H), 8.95 (s, br, 2H). Anal. calcd for
C13H20ClNO: C, 64.74; H, 8.45; N, 5.61; Cl, 14.72. Found:
C, 64.36; H, 8.17; N, 5.88; Cl, 14.42.
1
704; H NMR (CDCl3, 500 MHz) d ppm 5.81 (s, br, 1H),
6.42 (s, br, 1H), 7.18 (m, 1H), 7.39 (m, 1H), 7.45–7.52 (m,
2H), 7.64–7.70 (m, 2H), 8.20 (m, 1H), 8.34 (m, 1H). Anal.
calcd for C13H10F3NO: C, 61.66; H, 3.98, N, 5.53. Found: C,
61.81; H, 4.09; N, 5.61.
4.3.3. 3-(4-Fluorophenyl)methylpiperidine 4c. Colorless
oil; bp 768C/0.1 mm Hg (lit.24 no data); IR (film, cm21
)
4.2.7. 4-Tolyl-3-pyridyl-methanol 3g. Pale yellow solid;
mp 132–1338C (lit.22 mp 130–1328C); IR (KBr pellets,
1
nmax 3304, 2928, 1601, 1510, 1415, 1276, 1221, 1156; H
NMR (CDCl3, 300 MHz) d ppm 1.05 (m, 1H), 1.39 (m, 1H),
1.58–1.80 (m, 4H), 2.27 (dd, J¼10.2, 12.0 Hz, 1H), 2.36–
2.58 (m, 3H), 2.92–3.02 (m, 2H), 6.94 (m, 2H), 7.07 (m,
2H). Anal. calcd for C12H16FN: C, 74.57; H, 8.34; N, 7.25.
Found: C, 74.72; H, 8.11; N, 7.38.
1
cm21) nmax 3155, 2855, 1425, 1061, 1040, 1028, 801; H
NMR (CDCl3, 500 MHz) d ppm 2.33 (s, 3H), 3.70 (s, br,
1H), 5.79 (s, 1H), 7.26–7.10 (m, 5H), 7.68 (m, 1H), 8.35
(dd, J¼4.8, 1.8 Hz, 1H), 8.49 (d, J¼2.4 Hz, 1H). Anal. calcd
for C13H13NO: C, 78.36; H, 6.58; N, 7.84. Found: C, 78.19;
H, 6.35; N, 7.97.
4.3.4. 3-(3,5-Dimethoxy-4-methylphenyl)methylpiper-
idine hydrochloride 4d. White solid; mp 1808C; IR (KBr
pellets, cm21) nmax 3428, 2949, 2538, 2412, 1444, 1227,
4.2.8. 4-(2-Methylallyloxy)phenyl-3-pyridyl-methanol
3h. Pale yellow solid; mp 115–1168C; IR (KBr pellets,
cm21) nmax 3148, 2854, 1610, 1513, 1426, 1235, 1172,
1
1148, 1013; H NMR (DMSO, 500 MHz) d ppm 1.16 (m,
1
1060, 1016; H NMR (CDCl3, 500 MHz) d ppm 1.81 (s,
1H), 1.55–1.77 (m, 3H), 1.93 (m, 1H), 2.19 (s, 6H), 2.38–
2.45 (m, 2H), 2.50 (m, 1H), 2.70 (m, 1H), 3.03 (m, 1H), 3.16
(m, 1H), 3.62 (s, 3H), 6.82 (s, 2H), 8.94 (s, br, 2H). Anal.
calcd for C15H24ClNO2: C, 63.04; H, 9.14; N, 4.90; Cl,
12.40. Found: C, 62.91; H, 9.22; N, 4.75; Cl, 12.51.
3H), 4.00 (s, br, 1H), 4.41 (s, 2H), 4.97 (s, 1H), 5.07 (s, 1H),
5.77 (s, 1H), 6.87 (m, 2H), 7.17–7.25 (m, 3H), 7.67 (m, 1H),
8.34 (dd, J¼5.0, 1.5 Hz, 1H), 8.48 (d, J¼2.0 Hz, 1H). Anal.
calcd for C16H17NO2: C, 75.27; H, 6.71; N, 3.58. Found: C,
75.42; H, 6.87; N, 3.76.
4.3.5. 3-(3,4-Dimethoxyphenyl)methylpiperidine hydro-
chloride 4e. White solid; mp 1588C; IR (KBr pellets, cm21
)
4.2.9. 4-Benzyloxyphenyl-3-pyridyl-methanol 3i. Pale
yellow solid; mp 161–1628C; IR (KBr pellets, cm21) nmax
3141, 1608, 1510, 1243, 1232, 1005, 748; 1H NMR (DMSO,
300 MHz) d ppm 5.07 (s, 2H), 5.72 (d, J¼6.5 Hz, 1H), 5.95
(d, J¼6.5 Hz, 1H), 6.96 (m, 2H), 7.25–7.46 (m, 8H), 7.70
(m, 1H), 8.41 (dd, J¼4.5, 1.2 Hz, 1H), 8.57 (d, J¼1.5 Hz,
1H). Anal. calcd for C19H11NO2: C, 79.99; H, 3.89; N, 4.91.
Found: C, 80.08; H, 3.98; N, 5.09.
1
nmax 3434, 2937, 2528, 2418, 1524, 1263, 1142, 1021; H
NMR (DMSO, 500 MHz) d ppm 1.18 (m, 1H), 1.54–1.80
(m, 3H), 1.99 (m, 1H), 2.42–2.56 (m, 3H), 2.71 (m, 1H),
3.01 (m, 1H), 3.16 (m, 1H), 3.72 (s, 3H), 3.74 (s, 3H), 6.68
(dd, J¼13.5, 3.5 Hz, 1H), 6.79 (d, J¼3.5 Hz, 1H), 6.87 (d,
J¼13.5 Hz, 1H), 8.92 (s, br, 1H), 9.18 (s, br, 1H). Anal.
calcd for C14H22ClNO3: C, 58.43; H, 7.70; N, 4.87; Cl,
12.32. Found: C, 58.32; H, 7.93; N, 4.62; Cl, 12.08.
4.3. General procedure for hydrogenation
4.3.6. 3-(3-Trifluoromethylphenyl)methylpiperidine 4f.
Colorless oil; bp 116–1188C/0.1 mm Hg; IR (film, cm21
)
In an autoclave, a mixture of 10% Pd/C catalyst (3 g) and
acetic acid solution (250 ml) of 3a–i (100 mmol) was
hydrogenated (pressure and temperature are given in
Table 1) until consumption of the hydrogen gas stopped.
The catalyst was filtered off, the solution was concentrated
in vacuo then the residue was solved in 20% hydrochloric
acid (20 ml) and concentrated again in vacuo. Treatment of
the acetic acid free residue with acetone or diethyl ether
nmax 3291, 2930, 1450, 1334, 1164, 1125, 1074, 806, 704;
1H NMR (CDCl3, 500 MHz) d ppm 1.09 (m, 1H), 1.42
(m, 1H), 1.64 (m, 1H), 1.68–1.78 (m, 2H), 1.86 (s, br, 1H),
2.30 (dd, J¼10.2, 12.0 Hz, 1H), 2.48–2.58 (m, 3H), 2.93–
3.02 (m, 2H), 7.29–7.46 (m, 4H). Anal. calcd for
C13H16F3N: C, 64.20; H, 6.63; N, 5.76. Found: C, 64.05;
H, 6.86; N, 5.81.

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B. Agai et al. / Tetrahedron 59 (2003) 7897–7900
7900
3. Cardellini, M.; Claudi, F.; Perlini, V.; Balduini, W.; Cattabeni,
F.; Cimino, M. Il Farmaco Ed. Sci. 1987, 42, 307–317.
4. Carter, P. A.; Singh, S. European Patent EP 435 387, 1991;
Chem. Abstr., 115, 183134g.
4.3.7. 3-(4-Tolyl)methylpiperidine hydrochloride 4g.
White solid; mp 1748C (lit.4 no data); IR (KBr pellets,
1
cm21) nmax 3408, 2945, 2511, 2404, 1516, 1446; H NMR
(CDCl3, 300 MHz) d ppm 1.12 (m, 1H), 1.74–1.89 (m, 3H),
2.25 (m, 1H), 2.30 (s, 3H), 2.42–2.61 (m, 3H), 2.70 (m, 1H),
2.24–2.44 (m, 2H), 6.99–7.09 (m, 4H), 9.32 (s, br, 1H),
9.60 (s, br, 1H). Anal. calcd for C13H20ClN: C, 69.16; H,
8.93; N, 6.20; Cl, 15.70. Found: C, 68.92; H, 8.75; N, 6.01;
Cl, 15.78.
5. Tschitschibabin, A. E. Chem. Ber. 1903, 36, 2711–2713.
6. McElvain, N. J. Am. Chem. Soc. 1933, 55, 4625–4626.
´
´
7. Gomez, I.; Alonso, E.; Ramon, D. J.; Yus, M. Tetrahedron
2000, 53, 4043–4052. Sakamoto, T.; Kondo, Y.; Murata, N.;
Yamanaka, H. Tetrahedron Lett. 1992, 33, 5373–5374.
8. Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1991,
56, 1445–1453.
4.3.8. 3-(4-Isobutoxyphenyl)methylpiperidine 5. Color-
less oil; bp 124–1268C/0.2 mm Hg (lit.23 no data); IR (film,
cm21) nmax 3299, 2928, 1612, 1512, 1471, 1244, 1174,
1037; 1H NMR (CDCl3, 300 MHz) d ppm 1.00 (d,
J¼6.6 Hz, 6H), 1.10 (m, 1H), 1.40 (m, 1H), 1.55–1.70
(m, 2H), 1.75 (m, 1H), 2.02 (s, br, 1H), 2.06 (m, 1H), 2.26
(dd, J¼10.2, 12.0 Hz, 1H), 2.32–2.47 (m, 2H), 2.51 (m,
1H), 2.96 (m, 2H), 3.68 (d, J¼6.6 Hz, 1H), 6.80 (m, 2H),
7.02 (m, 2H). Anal. calcd for C16H25NO: C, 77.68; H, 10.19;
N, 5.66. Found: C, 77.52; H, 10.28; N, 5.54.
9. Yamamoto, Y.; Yanagi, A. Chem. Pharm. Bull. 1982, 30,
2003–2010.
10. Couve-Bonnaire, S.; Carpentier, J.-F.; Mortreux, A.; Castanet,
Y. Tetrahedron Lett. 2001, 42, 3689–3691.
11. Furukawa, N.; Shibutani, T.; Fujihara, H. Tetrahedron Lett.
1987, 28, 5845–5848.
12. Stoner, E. J.; Cothron, D. A.; Balmer, M. K.; Roden, B. A.
Tetrahedron 1995, 51, 11043–11062.
13. Cain, G. A.; Holler, E. R. Chem. Commun. 2001, 1168–1169.
14. Ackerley, N.; Brewster, A. G.; Brown, G. R.; Clarke, D. S.;
Foubister, A. J.; Griffin, S. J.; Hudson, J. A.; Smithers, M. J.;
Whittamore, P. R. O. J. Med. Chem. 1995, 38, 1608–1628.
15. Kato, Y.; Mase, T. Tetrahedron Lett. 1999, 40, 8823–8826.
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1946, 65, 793–795.
4.3.9. 3-(4-Hydroxyphenyl)methylpyridine hydrogen-
sulfate 6. White solid; mp 1028C; IR (KBr pellets, cm21
)
1
nmax 3291, 2785, 1553, 1512, 1211, 1171, 1068, 1004; H
NMR (DMSO, 300 MHz) d ppm 4.06 (s, 2H), 6.66–6.78
(m, 2H), 7.04–7.16 (m, 2H), 7.98 (dd, J¼8.1, 5.7 Hz, 1H),
8.40 (d, J¼8.1 Hz, 1H), 8.77 (d, J¼5.7 Hz, 1H), 8.82 (s,
1H), 9.40–10.10 (s, br, 3H). Anal. calcd for C12H13NO5S:
C, 50.89; H, 4.63; N, 4.94; S, 11.32. Found: C, 51.08; H,
4.87; N, 5.09; S, 11.61.
17. Vollinga, R. C.; Koning, J. P.; Jansen, F. P.; Leurs, R.; Menge,
W. M. P. B.; Timmerman, H. J. Med. Chem. 1994, 37,
332–333.
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