An efficient and convenient synthesis of 4-vinylimidazoles using a novel Horner-Wadsworth-Emmons (HWE) reagent: Synthetic studies toward novel histamine H3-ligands

Article abstract of DOI:10.1055/s-2002-31951

A novel Horner-Wadsworth-Emmons (HWE)-type reagent 1 reacted readily with various aldehydes and ketones to produce (E)-vinylimidazoles 2 in good yields. The synthetic utility of 1 was demonstrated by the efficient preparation of four histamine H₃ ligands 3 by simple hydrogenation of 2.

Full text of DOI:10.1055/s-2002-31951

1072
PAPER
An Efficient and Convenient Synthesis of 4-Vinylimidazoles Using a Novel
Horner–Wadsworth–Emmons (HWE) Reagent: Synthetic Studies Toward
Novel Histamine H3-Ligands
Synthesis of 4-
h
V
inylimida
zi
oles nya Harusawa,a Shuji Koyabu,a Yasutoshi Inoue,a Yasuhiko Sakamoto,b Lisa Araki,a Takushi Kurihara*a
a
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
Fax +81(726)901086; E-mail: kurihara@gly.oups.ac.jp
b
R&D Division, AZWELL, Inc., 2-24-3, Sho, Ibaraki, Osaka 567-0806, Japan
Fax +81(726)224999; E-mail: nskrd-12@mbd.sphere.ne.jp
Received 20 February 2002; revised 15 April 2002
O
Abstract: A novel Horner–Wadsworth–Emmons (HWE)-type re-
agent 1 reacted readily with various aldehydes and ketones to pro-
duce (E)-vinylimidazoles 2 in good yields. The synthetic utility of
1 was demonstrated by the efficient preparation of four histamine
H3 ligands 3 by simple hydrogenation of 2.
P(OEt)2
R
R
Tr
N
N
H2
Pd - C
1
R
R'
R'
C
O
Tr
N
N
HN
N
KOtBu
R'
(E) - 2
3
Key words: Horner–Wadsworth–Emmons reaction, vinylimida-
zole, hydrogenation, H3 ligands , immepip
Scheme 1
Imidazoles are important as heterocyclic components of
many drugs and biologically active molecules.1,2 The C-4
substituted imidazole is a common and essential structural
feature of the ligands for the histamine H3 (H3) receptor.3
Further, it was shown that the current H3 ligands have af-
finity for the novel H4 (H4) receptor,4 which was identified
by cloning and pharmacological characterization in 2000.
However, only a limited synthetic method for the H3
ligands has been employed, and many new H3 ligands
have been synthesized using readily available scaffolds
like urocainic acid and histamine.3 In continuation of our
ongoing projects involving synthetic studies on novel H3
and H4 ligands,5 we required a reliable and effective pro-
cedure for C-4 substituted imidazoles.
ate (1) in 86% yield, as air-stable needles (Scheme 2).
This substitution gave a higher yield than the Arbuzov
reaction9 (<10%), which required higher reaction temper-
ature (120 °C) and longer reaction time (12 h) in the case
of 4-(chloromethyl)-1-tritylimidazole and triethyl phos-
phite.
Cl
O
P(OEt)2
Tr N
LiP(O)(OEt)2
N
LiHMDS
HP(O)(OEt)2
-70 °C, THF
Tr
N
N
-70 °C,
then rt
1 (86 %)
Scheme 2
Griffith et al.6 reported an improved synthesis of
vinylimidazoles7
via
Horner–Wadsworth–Emmons
When we first attempted the HWE olefination of cyclo-
hexanecarboxaldehyde using deprotonation of 1 with
LiHMDS, erthro- (42%) and threo-diastereomers (8%) of
-hydroxyphosphonate 4 could be captured, accompanied
with the desired vinylimidazole (E)-2a (34%)
(Scheme 3), although direct observation of the intermedi-
ate (oxyanion of 4) in the HWE reaction has not been gen-
erally possible.8 Further, reaction of threo-4 with NaH
afforded the (E)-olefin 2a (86%),11 but that of erythro-4
caused only a retro-HWE reaction, with recovery of phos-
phonate 1. This result was consistent with the observation
of Bottin-Strzalko et al.12 that the erythro intermediate did
not give the (Z)-olefin.
(HWE) reaction of N-tritylimidazole-4-carboxaldehyde.
However, to our knowledge, an HWE reagent incorporat-
ing a functional imidazole group has not been reported to
date.8 Herein, we report an efficient and convenient syn-
thesis of vinyl imidazoles 2 using a novel HWE reagent 1
(Scheme 1), which reacts not only with a variety of alde-
hydes, but also ketones in the presence of KOBu-t to pro-
duce (E)-vinylimidazoles 2. To demonstrate the utility of
the novel HWE reagent 1, an efficient synthesis of four
current H3 ligands was carried out by subsequent hydro-
genation of 2.
Michaelis–Becker reaction9 of 4-(chloromethyl)-1-trityl-
imidazole10 with lithium diethyl phosphonate, prepared in
situ by treatment of diethyl phosphite with LiHMDS,
generated diethyl (1-tritylimidazol-4-yl)methylphosphon-
After investigation of the reaction under various condi-
tions, phosphonate 1 was found to react readily with alde-
hydes, in the presence of tBuOK, to produce C-4
vinylimidazoles 2,13 which can be easily isolated by col-
umn chromatography owing to the readily removable tri-
tyl group. The scope of the olefination using 1 was
Synthesis 2002, No. 8, 04 06 2002. Article Identifier:
1437-210X,E;2002,0,08,1072,1078,ftx,en;F02002SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Synthesis of 4-Vinylimidazoles
1073
examined as shown in Table 1. For all substrates, the re-
actions afforded selectively the E-double bond. Thus,
phosphonate 1 reacted with aliphatic aldehydes (Table 1,
entries 1–5), aromatic and heteroaromatic aldehydes
(Table 1, entries 6–8) to give substituted (E)-vinylimida-
zoles in excellent yields. In the case of 2f and 2h, the vinyl
and aromatic proton signals were overlapped in 1H NMR,
but their E-geometry was clearly determined by the vinyl
proton signals shifted downfield of their deprotected vi-
nylimidazoles, 4-[2-(4-butylphenyl)]vinyl-1H-imidazole
hydrochloride (5f HCl) and 4-(2-thiophen-2-yl)vinyl-1H-
imidazole hydrochloride (5h.HCl) obtained by hydrolysis
[e.g. 5f HCl: = 7.03 (d, 1 H, J = 16.7 Hz), 7.24 (d, 1 H,
J = 16.7 Hz)]. Further, cinnamaldehyde afforded a die-
nylimidazole 2i in good yield (Table 1, entry 9), while cy-
clohexanone afforded the corresponding 2j in moderate
yield (Table 1, entry 10).
Tr
N
Tr
N
O
O
H
(EtO)2P
H
H
N
(EtO)2P
N
a
(E)-2a
+
+
1
HO
H
(34 %)
HO
b
(86%)
b
(Z)-2a
erythro-4
threo-4
(8 %)
(42%)
(a) (i) LiHMDS (1.0 eq), -70 °C, 1h; (ii) cyclohexanecarbaldehyde
(1.0 equiv), -70 °C to rt, over 1h; (b) NaH, DMF, 50 °C
Scheme 3
Table 1 Synthesis of 2 Using 1
Entry
1a
Substrate
Product
Yield (%)
72b
CHO
Tr
N
N
2a
2c
88
CHO
Tr
N
N
N
N
N
N
2b
3a
4d
5e
56
(CH2)2CHO
(CH2)2
Tr
2c
58e
74
(CH2)3CHO
(CH2)3
Tr
2d
NBn
BnN
CHO
Tr
N
N
N
2e
6e
99
87
H3C(H2C)3
CHO
(CH2)3CH3
Tr N
2f
7c
CHO
N
N
Tr
N
N
2g
Synthesis 2002, No. 8, 1072–1078 ISSN 0039-7881 © Thieme Stuttgart · New York

1074
S. Harusawa et al.
PAPER
Table 1 Synthesis of 2 Using 1 (continued)
Entry
8c
Substrate
Product
Yield (%)
85
CHO
S
S
Tr N
N
2h
9e
68
CHO
Tr
N
N
N
N
N
N
2i
10c
11e
58
99
O
Tr
2j
BnN
O
NBn
Tr
2k
a Reaction conditions: reflux, 3 h.
b The yield was based on 1 [ 1 (1.0 equiv), aldehyde (1.2 equiv) and tBuOK (1.0 equiv)].
c Reaction conditions: reflux, 1 h.
d Reaction conditions: r.t., 14 h.
e Reaction conditions: reflux, 2 h.
De Esch et al.14 reported a study on the influence of lipo-
philic moieties attached to a 4-1H-imidazole ring on the
histamine H3 receptor activity using H3 antagonists VUF
5514 (pA2 = 7.5) and VUF 5515 (pA2 = 7.8). These com-
pounds have been synthesized by reaction of the oxazo-
line intermediate with ammonia under heating in a
stainless steel bomb. Compounds 2c and 2d thus obtained
could be easily converted into VUF 5514 and VUF 5515
by their hydrogenation (10% Pd/C at 3.0 Kg/cm2), respec-
tively (Table 2, entries 1 and 2). Vinylimidazole 2e simi-
larly afforded a potent and selective H3 antagonist VUF
492915 (pA2 = 8.4) in a patent application (Table 2, entry
3). This two-step operation was further applied to an effi-
cient synthesis of immepip (pD2 = 8.0) which has been
extensively used as an H3 agonist. Immepip was first re-
ported by Vollinga et al.16, the synthesis of which was
achieved by starting from 4-pyridine carboxaldehyde in
20% overall yield, via several steps involving hydrogena-
tion at 50 atmosphere over Pd/C. The present synthetic ap-
proach readily provided immepip via 2k from
commercially available 1-benzyl-4-piperidone in nearly
quantitative yield (Table 1, entry 11 and Table 2, entry 4).
Table 2 Conversion of 2 into H3 Ligands
Entry
1
Substrate
Product
Yield (%)
90
2c
(CH2)4
HN
N
VUF 5514
2
3
2d
92
(CH2)5
HN
N
VUF 5515
2ea
quant
NH
HN
N
VUF 4929
4
2ka
quantb
NH
HN
N
immepip
The preparation of C-4 substituted imidazoles using phos-
phonate 1 is experimentally straightforward and particu-
larly suitable for the study of novel histamine ligands.
Considering the privileged position of imidazole com-
pounds in medicinal chemistry, we believe that the re-
agent 1 will become a useful tool in the synthesis of
bioactive molecules.
a Hydrochlodide of 2 was subjected to hydogenation.
b Isolated as dihydrochloride.
Synthesis 2002, No. 8, 1072–1078 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Vinylimidazoles
1075
[2-Cyclohexyl-2-hydroxy-1-(1-trityl-1H-imidazol-4-yl)]diethyl
Phosphonate (erythro-4)
Oil.
31P NMR (CDCl3–H3PO4): = 28.50.
1H NMR (300 MHz, CDCl3): = 1.00–1.30 (m, 1 H), 1.20 (t, 3 H,
J = 7.2 Hz), 1.23 (t, 3 H, J = 7.2 Hz), 1.62–1.80 (br m, 10 H), 3.42
(dd, 1 H, JH-P = 24.0, JH-H = 1.9 Hz), 3.87 [td, 1 H, JH-P = JH-
H(cyclohexyl) = 9.6 Hz, 1.9 Hz], 3.90–4.12 (m, 4 H), 6.83 (dd, 1 H,
J = 6.0, 3.0 Hz), 7.10–7.38 (m, 15 H), 7.41 (s, 1 H).
MS (EI, 70 eV): m/z = 573 (M+ + 1).
HRMS: m/z calcd for C34H42N2O4P (M+ + 1), 573.2880; found,
The melting points were determined on a hot stage apparatus and
are uncorrected. 1H and 13C NMR spectra were taken with tetrame-
thylsilane as internal reference. Reactions with air- and moisture-
sensitive compounds were carried out under argon. Unless other-
wise noted, all extracts were dried over Na2SO4 or MgSO4, and the
solvent was removed in a rotary evaporator under reduced pressure.
Chromatography was performed on silica gel. THF was distilled
from sodium-benzophenone.
Diethyl (1-Tritylimidazol-4-yl)methylphosphonate (1)
Lithium hexamethyldisilazide (1 M in THF, 31.2 mL, 31.2 mmol)
was added dropwise over 1 h to a solution of diethyl phosphite (4.30
g, 31.2 mmol) in anhyd THF (10 mL) at –70 °C under argon. A so-
lution of 4-(chloromethyl)-1-tritylimidazole10 (9.30 g, 26.0 mmol)
in THF (80 mL) was then added dropwise to the resulting mixture
over 0.5 h. After the reaction mixture was stirred for 15 min at the
same temperature, it was allowed to reach r.t. and stirred for 3 h at
this temperature. The mixture was diluted with sat. aq NH4Cl (150
mL), and the THF was removed under reduced pressure. The result-
ing suspension was extracted with EtOAc (4 100 mL), and the or-
ganic phase was dried and evaporated. The resulting crude solid
mass was purified by column chromatography [MeOH–EtOAc
(1:20)] to give 1 (10.30 g, 86%) as a white powder. This was recrys-
tallized from EtOAc–hexane to give white needles; mp 141–144 °C.
1H NMR (CDCl3): = 1.24 (t, 6 H, J = 8.0 Hz), 3.17 (d, 2 H,
J = 21.6 Hz), 4.02 (quint, 4 H, J = 6.0 Hz), 6.81 (s, 1 H), 7.10–7.40
(m, 16 H).
31P NMR (CDCl3): = 27.0 (s).
MS (SIMS): m/z = 460 (M+).
573.2886.
threo-4
Oil.
31P NMR (CDCl3–H3PO4): = 28.80.
1H NMR (500 MHz, CDCl3): = 1.20 (t, 3 H, J = 7.2 Hz), 1.23 (t,
3 H, J = 7.2 Hz), 1.40 (m, 1 H), 1.55–1.82 (br m , 10 H), 3.44 (dd,
1 H, JH-P = 21.3, JH-H = 8.0 Hz), 3.95 (m, 1 H), 4.00–4.16 (m, 4 H),
6.75 (dd, 1 H, J = 6.0, 3.0 Hz), 7.10–7.37 (m, 15 H), 7.41 (s, 1 H).
MS (SIMS): m/z = 573 (M+ + 1).
HRMS: m/z calcd for C34H42N2O4P (M+ + 1) 573.2880; found,
573.2879.
Preparation of (E)-2a from threo-4
NaH (60% dispersion in oil, 0.5 mg, 0.013 mmol) was added in one
portion to a stirred solution of threo-4 (7 mg, 0.013 mmol) in anhyd
DMF (0.5 mL). The reaction mixture was stirred at 50 °C for 1 h till
formation of a white precipitate and diluted with EtOAc (20 mL).
The organic layer was washed with H2O (3 5 mL), dried, and
evaporated to give a crude oil, which was subsequently purified by
column chromatogrphy to give (E)-2a (4.4 mg, 86%).
HRMS: m/z calcd for C27H29N2O3P (M+) 460.1914; found
460.1898.
Anal Calcd for C27H29N2O3P: C, 86.08; H, 7.22; N, 6.69. Found: C,
86.03; H, 7.32; N, 6.41.
Reaction of 1 with Cyclohexanecarboxaldehyde in the Presence
of LiHMDS
Vinylimidazoles 2; General Procedure
tBuOK (67 mg, 0.6 mmol) was added to a mixture of phosphonate
1 (276 mg, 0.6 mmol) and the appropriate aldehyde (0.5 mmol) in
THF (5 mL). The mixture was refluxed for 1–3 h under argon (TLC
monitoring), and concentrated. After the addition of CHCl3 (20 mL)
and brine (20 mL), the organic layer was separated, and the aqueous
layer was further extracted with CHCl3 (2 20 mL). The combined
organic layer was dried (MgSO4) and evaporated. The residue was
purified by column chromatography (Table 1).
LiHMDS (1 M in THF) (0.5 mL, 0.5 mmol) was added dropwise
over 10 min to a solution of 1 (230 mg, 0.5 mmol) in THF (4 mL)
at –70 °C with stirring, and the resulting yellow solution was stirred
for 10 min. Cyclohexanecarboxaldehyde (56 mg, 0.5 mmol) in THF
(4 mL) was then added dropwise over 5 min to the solution. After
the reaction mixture had been stirred at –70 °C for 1 h, it was al-
lowed to reach r.t. (25 °C) over 1 h. The resulting mixture was
quenched with H2O, and the solvent was removed under reduced
pressure. The residue was dissolved in EtOAc–hexane (1:1, 30 mL),
and the organic layer was washed with H2O (3 20 mL), dried, and
evaporated to give a crude oil. Chromatography on silica gel using
20% EtOAc in hexane to EtOAc as eluent gave (E)-2a (70 mg,
34%), erythro-4 (121 mg, 42%), threo-4 (23 mg, 8%), and 1 (21 mg,
9%) in that order.
2a
Yield: 72%.
2b
Small needles; yield: 88%; mp 211–215 °C (EtOAc–hexane).
1H NMR (300 MHz, CDCl3): = 1.07 (s, 9 H), 6.16 (d, 1 H, J = 16.2
Hz), 6.42 (d, 1 H, J = 16.2 Hz), 6.67 (s, 1 H), 7.10–7.40 (m, 16 H).
(E)-4-(2-Cyclohexylvinyl)-1-trityl-1H-imidazole (2a)
Needles; mp 197–200 °C (hexane–benzene).
MS (EI, 70 eV): m/z = 392 (M+).
HRMS: m/z calcd for C28H28N2 (M+), 392.2251; found, 392.2247.
1H NMR (500 MHz, CDCl3): = 1.1–1.21 (m, 2 H), 1.21–1.35 (m,
2 H), 1.6–1.7 (br, 2 H), 1.7–1.82 (br, 4 H), 2.08 (br m, 1 H), 6.18 (d,
1 H, J = 16.0 Hz), 6.32 (dd, 1 H, J = 16.0, 6.9 Hz), 6.67 (s, 1 H),
7.1–7.2 (br s, 6 H), 7.3–7.4 (m, 10 H).
Anal Calcd for C28H28N2: C, 85.67; H, 7.19; N, 7.14. Found: C,
85.20; H, 7.14; N, 7.08.
13C NMR (D2O): = 26.1, 26.2, 32.9, 40.8, 75.2, 118.1, 118.9,
128.0, 128.3, 129.7, 135.3, 138.9, 139.7, 142.4.
2c
Viscous oil; yield: 56%.
1H NMR (300 MHz, CDCl3): = 2.48 (q, 2 H, J = 8.4 Hz), 2.77 (t,
2 H, J = 8.4 Hz), 6.26 (d, 1 H, J = 15.6 Hz), 6.27–6.48 (dt, 1 H,
J = 15.6, 8.4 Hz), 6.69 (s, 1 H), 7.00–7.60 (m, 15 H).
MS (EI, 70 eV): m/z = 440 (M+).
HRMS: m/z calcd for C32H28N2 (M+), 440.2251; found, 440.2254.
MS (EI, 70 eV): m/z = 418 (M+).
HRMS: m/z calcd for C30H30N2 (M+) 418.2407; found 418.2404.
Anal Calcd for C30H30N2: C, 86.08; H, 7.22; N, 6.69. Found: C,
86.03; H, 7.32; N, 6.41.
Synthesis 2002, No. 8, 1072–1078 ISSN 0039-7881 © Thieme Stuttgart · New York

1076
2d
S. Harusawa et al.
PAPER
2g
Viscous oil; yield: 58%.
Viscous oil; yield: 87%.
1H NMR (300 MHz, CDCl3): = 1.77 (quint, 2 H, J = 7.4 Hz), 2.20
(q, 2 H, J = 7.4 Hz), 2.66 (t, 2 H, J = 7.4 Hz), 6.23 (d, 1 H, J = 15.8
Hz), 6.36 (dt, 1 H, J = 15.8, 7.0 Hz), 6.66 (s, 1 H), 7.05–7.45 (m, 21
H).
MS (EI, 70eV): m/z = 454 (M+).
HRMS: m/z calcd for C33H30N2 (M+), 454.2407; found, 454.2415.
1H NMR (300 MHz, CDCl3): = 6.91 (s, 1 H), 7.00 (d, 1 H, J = 17.0
Hz), 7.04–7.40 (m, 17 H), 7.47 (s, 1 H), 7.73 (d, 1 H, J = 8.1 Hz),
8.43 (br s, 1 H), 8.69 (br s, 1 H).
MS (SIMS): m/z = 414 (M+ + 1).
HRMS: m/z calcd for C29H24N3 (M++1), 414.1969; found,
414.1979.
2e
2h
Viscous oil; yield: 74%.
White powder; yield: 85%; mp 204–207 °C (EtOAc–hexane).
1H NMR (300 MHz, CDCl3): = 1.56 (qd, 2 H, J = 15.0, 4.4 Hz),
1.66–1.78 (dm, 2 H, J = 15.0 Hz), 1.92–2.23 (m, 3 H), 2.88–2.94
(dm, 2 H, J = 15.0 Hz), 3.49 (s, 2 H), 6.19 (d, 1 H, J = 15.5 Hz), 6.32
(dd, 1 H, J = 15.5, 6.7 Hz), 6.68 (s, 1 H), 7.05–7.40 (m, 21 H).
MS (EI, 70 eV): m/z = 509 (M+).
HRMS: m/z calcd for C36H35N3 (M+), 509.2829; found, 509.2827.
1H NMR (300 MHz, CDCl3): = 6.75 (d, 1 H, J = 16.5 Hz), 6.82 (s,
1 H), 6.93–7.00 (m, 2 H), 7.10 (d, 1 H, J = 5.1 Hz), 7.12–7.20 (m, 6
H), 7.3–7.4 (br s, 10 H), 7.41 (s, 1 H).
MS (SIMS): m/z = 418 (M+).
HRMS: m/z calcd for C28H22N2S1 (M+), 418.1499; found, 418.1503.
Anal Calcd for C28H22N2S: C, 80.35; H, 5.30; N, 6.69. Found: C,
80.05; H, 5.25; N, 6.63.
2f
Prisms; yield: 99%; mp 157–159 °C (EtOAc–hexane).
5h HCl
1H NMR (300 MHz, CDCl3): = 0.92 (t, 3 H, J = 8.4 Hz), 1.35
(sext, 2 H, J = 8.4 Hz), 1.59 (quint, 2 H, J = 8.4 Hz), 2.58 (t, 2 H,
J = 8.4 Hz), 6.85 (s, 1 H), 6.89 (d, 1 H, J = 16.4 Hz), 7.10–7.40 (m,
20 H), 7.45 (s, 1 H).
13C NMR (CD3OD): = 13.9, 22.4, 33.5, 35.4, 75.4, 119.3, 119.6,
126.1, 127.1, 128.1, 128.6, 129.8, 135.1, 139.3, 139.5, 141.9, 142.3.
A solution of 2h (131 mg, 0.313 mmol) in aq 2 N HCl (4 mL)–EtOH
(5 mL) was refluxed for 1 h to give 5h HCl (63 mg, 95%) as white
powder using the same procedure as for the preparation of 5f HCl.
1H NMR (300 MHz, CD3OD): = 6.80 (d, 1 H, J = 16.4 Hz), 7.00
(dd, 1 H, J = 5.0, 3.6 Hz), 7.15 (d, 1 H, J = 3.6 Hz), 7.35 (d, 1 H,
J = 16.4 Hz), 7.36 (d, 1 H, J = 5.0 Hz), 7.50 (s, 1 H), 8.68 (S, 1 H).
MS (EI, 70 eV): m/z = 468 (M+).
HRMS: m/z calcd for C34H32N2 (M+), 468.2564; found, 468.2563.
2i
Needles; yield: 68%; mp 225–228 °C (EtOAc–hexane).
1H NMR (300 MHz, CD3OD): = 6.50 (d, 1 H, J = 15.3 Hz), 6.68
(d, 1 H, J = 15.3 Hz), 6.81 (s, 1 H), 6.88 (dd, 1 H, J = 15.3, 11.0 Hz),
7.05 (dd, 1 H, J = 15.3, 11.0 Hz), 7.15–7.20 (br s, 5 H), 7.26–7.44
(br s, 16 H).
Anal Calcd for C34H32N2: C, 87.14; H, 6.88; N, 5.98. Found: C,
87.04; H, 6.91; N, 5.98.
4-[2-(4-Butylphenyl)]vinyl-1H-imidazole Hydrochloride
(5f HCl)
Anal Calcd for C32H26N2: C, 87.64; H, 5.98; N, 6.39. Found: C,
87.21; H, 5.97; N, 6.31.
To determine the (E)-geometry of 2f, it was converted into the un-
substituted imidazole, 5f HCl as follows. A solution of 2f (194 mg,
0.415 mmol) in aq 2 N HCl (6 mL)–EtOH (4 mL) was refluxed for
1 h and then diluted with H2O (10 mL). After neutralization by ad-
dition of NaHCO3, the mixture was extracted with CHCl3 (5 10
mL). The extract was dried and evaporated to give a residue, which
was subsequently chromatographed using MeOH–CHCl3 (1:9) as
eluent to give 5f (74 mg, 80%) as an oil.
2j
White powder; yield: 58%; mp 222–223 °C (EtOAc–hexane).
1H NMR (300 MHz, CDCl3): = 1.60 (m, 6 H), 2.23 (m, 2 H), 2.64
(m, 2 H), 5.98 (s, 1 H), 6.65 (s, 1 H), 7.10–7.38 (m, 15 H), 7.40 (s,
1 H).
1H NMR (500 MHz, CD3OD): = 0.95 (t, 3 H, J = 8.4 Hz), 1.38
(sext, 2 H, J = 8.4 Hz), 1.60 (quint, 2 H, J = 8.4 Hz), 2.62 (t, 2 H,
J = 8.4 Hz), 7.1 (br s, 4 H), 7.14 (d, 2 H, J = 7.9 Hz), 7.38 (d, 2 H,
J = 7.9 Hz).
MS (EI, 70 eV): m/z = 404 (M+).
HRMS: m/z calcd for C29H28N2 (M+), 404.2251; found, 404.2248.
Anal Calcd for C29H28N2: C, 86.10; H, 6.98; N, 6.92. Found: C,
86.21; H, 6.97; N, 6.90.
MS (SIMS): m/z = 227 (M+ + 1).
HRMS: m/z calcd for C15H19N2 (M+ + 1), 227.1547; found,
4-(4-Phenylbutyl)-1H-imidazole (VUF5514)14
227.1546.
A solution of 2c (252 mg, 0.57 mmol) in MeOH–EtOAc (1:3, 10
mL) was hydrogenated with 10% Pd/C (150 mg) as catalyst at a ini-
tial pressure of 3.0 kg/cm2 for 15 h. The catalyst was removed by
filtration through a Celite pad, and the filtrate was concentrated to
give a crude oil, which was subsequently purified by column chro-
matography using MeOH–CH2Cl2 (1:9) as eluent to give VUF5514
(103 mg, 90%) as a viscous oil.
1H NMR (300 MHz, CD3OD): = 1.70 (m, 4 H), 2.26 (m, 4 H),
4.40–5.80 (br s, 1 H), 7.78 (s, 1 H), 7.10–7.20 (m, 5 H), 7.56 (s, 1
H).
5f HCl
Viscous oil.
1H NMR (500 MHz, CD3OD): = 0.91 (t, 3 H, J = 8.4 Hz), 1.33
(sext, 2 H, J = 8.4 Hz), 1.58 (quint, 2 H, J = 8.4 Hz), 2.60 (t, 2 H,
J = 8.4 Hz), 7.03 (d, 1 H, J = 16.7 Hz), 7.24 (d, 1 H, J = 16.7 Hz),
7.21 (d, 2 H, J = 7.6 Hz), 7.46 (d, 2 H, J = 7.6 Hz), 7.62 (s, 1 H),
8.92 (s, 1 H).
13C NMR (CD3OD): = 14.4, 23.3, 34.7, 36.4, 112.5, 117.0, 127.9,
130.0, 134.2, 134.4, 135.3.
MS (SIMS): m/z = 201 (M+ + 1).
HRMS: m/z calcd for C13H17N2 (M+ + 1), 201.1391; found,
201.1396.
Synthesis 2002, No. 8, 1072–1078 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Vinylimidazoles
1077
4-(4-Phenylpentyl)-1H-imidazole (VUF5515)14
This compound was synthesized from 2d (132 mg, 0.29 mmol) ac-
cording to the synthetic procedure for VUF5514 and was obtained
as a colorless oil in 92% yield.
1H NMR (300 MHz, CD3OD): = 1.30–1.50 (m, 2 H), 1.60–1.80
(m, 4 H), 2.61 (t, 2 H, J = 7.6 Hz), 2.64 (t, 2 H, J = 7.6 Hz), 7.08–
7.36 (m, 6 H), 8.45 (s, 1 H).
Immepip 2HBr
50% Aq HBr solution (240 mg, 5 equiv) was added to a solution of
immepip (48 mg) in EtOH (20 mL). The mixture was stirred at r.t.
for 15 min and evaporated to give a residue, which was subsequent-
ly washed with acetone (4 3 mL) and dried to give immepip 2HBr
(95 mg, quant) as white powder; mp 237–239 °C (Lit.16b mp 221.1–
222.7 °C).
1H NMR (D2O): = 1.46 (qd, 2 H, J = 13.0, 5.0 Hz), 1.92 (dm, 2 H,
J = 13.0 Hz), 1.99 (m, 1 H), 2.75 (d, 2 H, J = 7.0 Hz), 2.99 (tm, 2 H,
J = 13.0 Hz, 2 H), 3.43 (dm, 2 H, J = 13.0 Hz), 7.28 (s, 1 H), 8.59
(s, 1 H).
MS (SIMS): m/z : 215 (M+ + 1).
HRMS: m/z : calcd for C14H19N2 (M+ + 1), 215.1547; found,
201.1551.
13C NMR (D2O): = 29.2, 31.3, 34.4, 45.3, 117.8, 132.4, 134.5.
Preparation of Immepip [4-(1H-imidazol-4-yl)methylpiperi-
dine] via 2k
.
Anal Calcd for C9H15N3 2HBr: C, 33.05; H, 5.24; N, 12.85. Found:
2k
C, 32.80; H, 5.24; N, 12.70.
Phosphonate 1 (276 mg, 0.6 mmol) and KOBu-t (67 mg, 0.6 mmol)
were added to a solution of 1-benzyl-4-piperidone (95 mg, 0.5
mmol) in THF (6 mL). After the reaction mixture was refluxed for
2 h, sat. aq NH4Cl (1 mL) was added and evaporated. The residue
was dissolved with saturated aq NH4Cl (10 mL) and extracted with
CHCl3 (3 20 mL), and the CHCl3 layer was dried (MgSO4) and
evaporated. The resulting oily residue was purified by column chro-
matography (EtOAc) to give 2k (246 mg, 99%) as a colorless vis-
cous oil.
4-(1H-Imidazol-4-yl)ethylpiperidine (VUF4929)15
Vinylimidazole 2e (196 mg, 0.385 mmol) was converted into
VUF4929 (68 mg, quant, free amine) according to the synthetic pro-
cedure of immepip described above.
1H NMR (300 MHz)(CD3OD): = 1.19 (qd, 2 H, J = 13.0, 3.5 Hz),
1.36–1.52 (m, 2 H), 1.60 (q, 2 H, J = 7.2 Hz), 1.70–1.82 (dm, 2 H,
J = 13.0 Hz), 2.50–2.70 (m, 4 H), 3.00–3.10 (dm, 2 H, J = 13.0 Hz),
6.78 (s, 1 H), 7.59 (s, 1 H).
1H NMR (300MHz, CDCl3): = 2.30–2.40 (m, 2 H), 2.42–2.60 (m,
4 H), 2.79–2.90 (m, 2 H), 3.52 (s, 2 H), 6.02 (s, 1 H), 6.66 (s, 2 H)
7.08–7.44 (m, 21 H).
VUF4929 2HCl
The free amine was stirred with aq 1 N HCl–EtOH at r.t. for 15 min
and evaporated to give VUF4929 2HCl as a white powder; mp 216–
220 °C.
1H NMR (500 MHz, CD3OD): = 1.47 (qd, 2 H, J = 13.0, 3.5 Hz),
1.65–1.75 (m, 3 H), 1.97–2.04 (dm, 2 H, J = 13.0 Hz), 2.80 (t, 2 H,
J = 7.2 Hz), 3.00 (t, 2 H, J = 13.0 Hz), 3.37–3.43 (dm, 2 H, J = 13.0
Hz), 7.36 (s, 1 H), 8.81 (s, 1 H).
13C NMR (CD3OD): = 22.4, 29.7, 34.2, 35.6, 45.2, 116.8, 134.7,
135.3.
MS (EI, 70eV): m/z = 179 (M+).
MS (EI, 70eV): m/z = 495 (M+).
HRMS: m/z: 495.2681 (calcd for C35H33N3: 495.2673).
Immepip 2HCl
A solution of 2k (162 mg, 0.327 mmol) in aq 1 N HCl (1.5 mL)–
EtOH (5 mL) was stirred at r.t. for 10 min, and evaporated to give a
residue (2k 2HCl). A solution of the dihydrochloride in MeOH (20
mL) was subsequently hydrogenated with 10% Pd/C (120 mg) as
catalyst at an initial pressure of 3.0 kg/cm2 for 15 h. The catalyst
was removed by filtration and the filtrate was concentrated to give
a residue, which was subsequently dissolved with H2O (20 mL).
The aqueous solution was washed with benzene (3 20 mL) and
evaporated to give immepip 2HCl (80 mg, quant) as a white pow-
der; mp 235–239 °C.
HRMS: m/z calcd for C10H17N3 (M+), 179.1422; found, 179.1424.
Acknowledgments
1H NMR (500 MHz, CD3OD): = 1.52 (m, 2 H), 1.92 (d, 2 H,
J = 13.0 Hz), 2.02 (br, 1 H), 2.77 (d, 2 H, J = 7.0 Hz), 3.01 (t, 2 H,
J = 13.0 Hz), 3.41 (d, 2 H, J = 13.0 Hz), 7.42 (s, 1 H), 8.85 (s, 1 H).
13C NMR (CD3OD): = 29.4, 31.4, 34.7, 45.0, 118.0, 132.7, 135.0.
MS (EI, 70 eV): m/z = 165 (M+).
We thank Prof. A. Yamatodani, School of Allied Health Science,
Faculty of Medicine, Osaka University, for encouraging us in this
study. Financial support of this work by the Ministry of Education,
Science, and Culture of Japan [Grant No. 11672127] is gratefully
acknowledged.
HRMS: m/z calcd for C9H15N3 (M+) 165.1265; found 165.1263.
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Synthesis 2002, No. 8, 1072–1078 ISSN 0039-7881 © Thieme Stuttgart · New York