Formation of Two 4-Imidazolylmethylphosphonium Salts and their Synthetic Studies Toward Histamine H3-Ligands

Article abstract of DOI:10.1055/s-2003-42442

A simple and convenient preparation of {[1H-imidazol-4(5)-yl]methyl} triphenylphosphonium chloride (5) is described. The phosphonium salt 5 could be applied to the synthesis of 1-[1H-imidazol-4(5)-yl]-5-arylpentan- or 6-arylhexan-3-ones 4a-d exhibiting histamine H₃-antagonistic activities via a 1,3-diazafulvene intermediate 6 generated from 5. Further, two-methylene-enlongated homolog 3 of imifuramine was efficiently synthesized, starting from Wittig olefination of aldehyde 24 using [(1-tritylimidazol-4-yl) methyl]triphenylphosphonium chloride 7.

Full text of DOI:10.1055/s-2003-42442

2844
PAPER
Formation of Two 4-Imidazolylmethylphosphonium Salts and their Synthetic
Studies Toward Histamine H3-Ligands
I
midazolylmet
h
hylphosphon
i
ium Sa
n
lts and Their
y
Synthetic
S
a
tudies Towar
d
HiH
stamine Ligands arusawa,a Makoto Kawamura,a Shuji Koyabu,a Tomoko Hosokawa,a Lisa Araki,a Yasuhiko Sakamoto,b
Takeshi Hashimoto,c Yumiko Yamamoto,c Atsushi Yamatodani,c Takushi Kurihara*a
a
Osaka University of Pharmaceutical Sciences, 4-20-1, Nasahara, Takatsuki, Osaka 569-1094, Japan
Fax +81(72)6901086; E-mail: kurihara@gly.oups.ac.jp
b
R&D Division, AZWELL, Inc., 2-24-3, Sho, Ibaraki, Osaka 567-0806, Japan
Fax +81(72)6224999; E-mail: ya-sakamoto@azwell.co.jp
c
Graduate School of Allied Health Sciences, Faculty of Medicine, Osaka University, Osaka 565-0871, Japan
Fax +81(6)68792562; E-mail: yamatoda@sahs.med.osaka-u.ac.jp
Received 25 August 2003; revised 16 September 2003
many biologically active molecules and drugs have two-
methylene groups between functional groups.
Abstract: A simple and convenient preparation of {[1H-imidazol-
4(5)-yl]methyl}triphenylphosphonium chloride (5) is described.
The phosphonium salt 5 could be applied to the synthesis of 1-[1H-
imidazol-4(5)-yl]-5-arylpentan- or 6-arylhexan-3-ones 4a–d exhib-
iting histamine H3-antagonistic activities via a 1,3-diazafulvene in-
termediate 6 generated from 5. Further, two-methylene-enlongated
homolog 3 of imifuramine was efficiently synthesized, starting
from Wittig olefination of aldehyde 24 using [(1-tritylimidazol-4-
yl)methyl]triphenylphosphonium chloride 7.
NHR
NH2
O
O
HN
N
3
HN
N
1 R = H (imifuramine)
NCN
Key words: imidazole, histamine H3-ligand, phosphonium salts,
diazafulvene, Wittig olefination
2 R =
NHCH3
O
(OUP-16)
(CH2)n
X
HN
N
Introduction
4 n = 2 or 3, X = H or Cl
Figure 1
The C-4 substituted imidazoles are biologically important
heterocyclic compounds1 and they are a common and es-
sential structural feature of the ligands for the histamine
H3-receptor.2 The H3-agonists are regarded as a target for
new therapeutics of bronchial asthma, and H3-antagonists
are now expected to be potential drugs for memory degen-
erative disorders like Alzheimer’s disease.2 Most H3-
ligands are active as well at the novel H4- receptor, which
was identified by cloning and pharmacological character-
ization in the year 2000, but no specific ligands for the H4-
receptor are available.3
As limited synthetic methods for the synthesis of the C-4
substituted imidazoles have been employed, reliable and
effective procedures are still required.1,2 We recently re-
ported a Horner–Wardsworth–Emmons (HWE) type re-
agent 9 as a useful reagent for functionalizing the 4(5)-
methyl group of imidazole (Scheme 1).7 While Lassalle
and co-workers used [(1-tritylimidazole-4(5)-yl)meth-
yl]triphenylphoshphonium chloride (7) in the patent ap-
plications,8 only a little work has been done concerning
Wittig reagents or phosphonium salts incorporating an
imidazole group. In our preparation of the phoshphonium
chloride 7, we found the coexistence of a novel {[1H-im-
idzole-4(5)-yl]methyl}triphenylphosphonium chloride
(5). We herein report a simple and convenient preparation
of triphenylphosphonium salt 5 which generates a 1,3-di-
azafulvene 69 in the presence of a base (Scheme 1). Thus,
the phosphonium salt 5 could be applied to the synthesis
of 1-(1H-imidazol-4-yl)-5-arylpentan- or 6-arylhexan-3-
ones 4a–d exhibiting H3-antagonistic activities. Alterna-
tively, two-metylene-enlongated homolog 3 of imi-
furamine 1 was synthesized via five steps, starting from
Wittig olefination of aldehyde 24 using phosphonium salt
7.
4(5)-[(2R,5R)-5-Aminomethyltetrahydrofuran-2-yl]imida-
zole (1, imifuramine) exhibited a clear H3-agonistic activ-
ity from the results of an in vivo brain microdialysis
(Figure 1).4 Further, it has been very recently found that a
methylcyanoguanidine derivative (2, OUP-16) of imi-
furamine showed full agonistic activities for the H4-recep-
tor with 40- to 45-fold selectivity over the H3-receptor.5
The findings of imifuramine and OUP-16 encouraged us
to synthesize 4(5)-{2-[(2R,5R)-5-aminomethyltetrahy-
drofuran-2-yl]ethyl}imidazole (3), which has the two-car-
bon-elongated structure between the imidazole and
tetrahydrofuran of 1, because it is known that elongation
of the alkyl spacer of histamine or H3-agonists influences
the potency and high affinity for the H3-receptor.6 Further,
SYNTHESIS 2003, No. 18, pp 2844–2850
x
x.
x
x
.
2
0
0
3
Advanced online publication: 21.10.2003
DOI: 10.1055/s-2003-42442; Art ID: F07303SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Imidazolylmethylphosphonium Salts and their Synthetic Studies Toward Histamine Ligands
2845
O
Ph3P
H2O
Cl
PPh3
P(OEt)2
PPh3
Cl
PPh3
Cl
TrN
N
Ph3C-N
Cl
N
N
N
TrN
N
TrN
N
HN
N
11
7
6
9
7
5
base
base
base
O
PPh3
PPh3
P(OEt)2
PPh3
Cl
TrN
N
N
N
N
N
TrN
N
HN
N
H
H
6
8
10
O
5
Ph3C-Cl
Scheme 1
Scheme 3
Preparations of 4-Imidazolmethylphosphonium
Salts 5 and 7
generated in the presence of alkali. However, the Zbiral
method would be difficult for the synthesis of 5, which
has unsubstituted imidazole, because this synthetic pro-
cess needs unstable formyl chloride (R = H) as the starting
material (Scheme 4), which exists only for 1 hour at –60
°C and easily decomposes to CO and HCl.12
When we first refluxed a mixture of 1-trityl-4-chlorome-
thylimidazole (11)10 and Ph3P in CH3CN for 40 hours, a
small amount of white precipitate (< 10%) was observed
at the bottom of the flask. After filtration and careful pu-
rification, the precipitate was confirmed as a novel 4-imi-
dazoylmethylphosphonium chloride 5 [mp 276–286 °C
(dec.)] lacking the trityl group of 7, confirmed from spec-
troscopic data and elemental analysis (Scheme 2, a).
Phosphonium chloride 7 was obtained in 90% yield from
the filtrate. On the other hand, in the presence of one
equivalent of water, the reaction liberated 5 in 71% yield
(Scheme 2, b). Although this reaction was accompanied
by the formation of 7 (13%), simple filtration gave almost
pure 5, which could be used without further purification
for the reactions described below.
The formation of 5 is presumed as shown in Scheme 3. A
chloro-counterpart of the formed phosphonium salt 7 at-
tacks the trityl group to form an active diazafulvene 6 by
Hofmann-type elimination with liberation of Ph3P and
tritylchloride. Subsequent addition of Ph3P to 6 followed
by protonation regenerates the imidazole system to pro-
vide 5.
Scheme 4
Synthesis of 1-(1H-Imidazol-4-yl)- -arylalkan-3-
ones Using Phosphonium Salt 5
As the phosphonium salt 5 may represent a masked 1.3-di-
azafulvene, the C–C bond formation at 4(5)-methyl group
of imidazole was first examined by the reaction of 5 with
diethyl malonate or ethyl acetoacetate (16a or 16b) using
the Zbiral procedure (Scheme 5).11 Refluxing of 5 with
16a or 16b in the presence of NaOEt proceeded as expect-
ed to afford 17a13 (70%) or 17b (72%), together with Ph3P
which could be re-used.
Ph3P (1 eq)
CH3CN
Cl
PPh3
Cl
5 (< 10 %)
+
TrN
N
TrN
N
reflux, 40 h
11
7 (90 %)
a
Ph3P (1 eq)
H2O (1 eq)
CH3CN
PPh3
11
7 (13 %)
+
Cl
5 (71 %)
HN
N
reflux, 20 h
b
Scheme 2
A synthetic method of polysubstituted imidazolylmeth-
ylphosphonium salts 13 has been developed by Zbiral and
co-workers using reaction of triphenyl- -acylvinylphos-
phonium bromides 12 with amidines (Scheme 4).11 These
phosphonium salts 13 provided polysubstituted imida-
zoles 15 by addition of nucleophiles to diazafulvene 14
Scheme 5
Synthesis 2003, No. 18, 2844–2850 © Thieme Stuttgart · New York

2846
S. Harusawa et al.
PAPER
NH2
We next directed our efforts to synthesize imidazolyl-ary-
lalkan-3-ones 4, since many H3-antagonists exhibit com-
mon structural features as indicated by Schunack et al.,2
i.e. 4(5)-substituted-1H-imidazole head group, alkyl spac-
er containing a polar group, and a hydrophobic tail group.
Reaction of 5 with ethyl 3-oxo-5-phenylpentanoates 18a14
similarly afforded -ketoester 19a, which was subse-
quently treated with diluted H2SO4 to afford imida-
S
HSCH2CH2NH2
NaOMe, MeOH
reflux , 2h
HN
N
Cl
NCS
20
5
+
4(5)-methylimidazole
zolylphenylpentanone 4a in 55% yield from
(Scheme 6). Synthesis of 4b–d was similarly carried out
from 5 in 50–64% yields.
5
H
H
Cl
21
N
N
S
(21 %, pA2 = 7.6)
HN
N
S
Scheme 7
NaOEt
EtOH
O
O
reflux
15 min
O
O
(CH2)n
OEt
X
As another extension of the phosphonium salt 5, its use in
a Wittig reaction was examined (Scheme 8). When we at-
tempted olefination of cyclohexenecarboxaldehyde using
a phosphorus ylide 22, which was generated by treatment
of 5 with 2 equivalents of LiHMDS in DMF, (Z)-vinylim-
idazole, (Z)-23 (32%) and (E)-vinylimidazole, (E)-23
(26%) could be obtained, after ethoxycarbonylation ow-
ing to easy chromatographic isolation.
(CH2)n
OEt
X
5
+
HN
N
19a
18a (n=2, X=H)
b
c
d
b (n=3, X=H)
c (n=2, X=Cl)
d (n=3, X=Cl)
O
(CH2)n
X
10% H2SO4,
65 oC, 48h
HN
N
4a 55 (%)a pA2 = 6.0
b
b 64a
c 50a
d 51a
no
6.7
6.5
Scheme 6 a) Two steps yields from 5. b) H3-Antagonistic activities of
4a–d on the in vitro test system on the guinea pig ileum.
Scheme 8
The diazafulvene method was also applied to the C–S
bond formation.11c Reaction of phosphonium salt 5 with
sodium salt of cystenamine afforded thioamine 20 togeth-
er with 4(5)-methylimidazole as by-product, although the
mechanism of production of this material is unclear
(Scheme 7). The crude thioamine 20 was treated with p-
chlorophenyl isothiocyanate to synthesize thiourea deriv-
ative 21 (21% yield from 5), which has an interesting
structural feature. The distance between the imidazole and
the hydrophobic moiety in 21 is ca. 16 Å (estimated from
a molecular-model examination), and it is approximately
equal to that of a potent H3-antagonist, clobenpropit.2
Synthesis of Imifuramine Homolog 3 Incorporating
Ethyl Spacer
The two-carbon-elongated homolog (–)-3 of imifuramine
was synthesized from (2R,5R)-5-[(tert-butyldiphenylsil-
oxy)methyl]tetrahydrofuran-2-carbaldehyde (24) pre-
pared by Koert and co-workers16 (Scheme 9). We first
attempted conversion of 24 into vinylimidazole 25 using
HWE olefination of phosphonate 97 in the presence of t-
BuOK, but the yield was only <10% yield with recovery
of 9. The result may be ascribed to the strong basicity of
the HWE reagent and the nature of aldehyde 24, which
may lead to enolization by proton abstraction at C2. On
the other hand, 24 could be converted into (E)-and (Z)-vi-
nylimidazoles [(E)-25 (39%) and (Z)-25 (32%)] in better
yields by Wittig olefination using ylide 8 generated from
the phosphonium salt 7. After removal of the TBDPS
group of (E)-25 thus obtained with Bu4NF, oxidation of
the resulting primary alcohol (E)-26 into aldehyde (E)-27
was carried out. In the case of Dess–Martin periodinane
oxidation, the isolated yields of (E)-27 were variable (0–
70%) and varied with each batch of Dess–Martin periodi-
nane bought.17 Swern oxidation of (E)-26 gave (E)-27 in
70% yield, and the use of freshly prepared o-iodoxyben-
zoic acid (IBX)18 afforded a quantitative yield of (E)-27.
H3-Antagonistic properties of the synthesized five com-
pounds 4a–d and 21 were examined by a preliminary in
vitro assay using guinea pig ileum preparation.15 The re-
sults indicated that: 1) phenylpentanone 4a is a weak H3-
antagonist (pA2 = 6.0), but one carbon homolog 4b is in-
active; 2) substitution of the phenyl group by a 4-chlo-
rophenyl group enhances H3-antagonistic activities [pA2;
4c (6.7), 4d (6.5)], and 3) thiourea 21 exhibits relatively
more potent antagonistic activitiy (pA2 = 7.6).
Synthesis 2003, No. 18, 2844–2850 © Thieme Stuttgart · New York

PAPER
Imidazolylmethylphosphonium Salts and their Synthetic Studies Toward Histamine Ligands
2847
The reductive amination19 of (E)-27 proceeded to give
benzylamine (E)-28 (78%). Finally, hydrogenation of (E)-
28·2HCl attained the synthesis of (–)-3 in 74% yield,
causing simultaneous removal of the trityl and benzyl
groups as well as saturation of the double bond.7 Similar-
ly, (Z)-vinylimidazole [(Z)-25] was also converted into
(–)-3 through the respective intermediates (Z)-26, 27, and
28 by the same reaction sequence described herein.
Reaction of 11 and Ph3P in CH3CN
A mixture of 1-trityl-4-chloromethylimidazole10 (11, 750 mg, 2.09
mmol) and Ph3P (548 mg, 2.09 mmol) in CH3CN (10 mL) was re-
fluxed for 40 h under Ar. The resulting white precipitate was sepa-
rated by filtration and dried over P2O5 at 100 °C under reduced
pressure to give white powder 5 (69 mg, 10%). The filtrate was
evaporated to give an amorphous residue, which was subsequently
dissolved in water. The aq layer was washed twice with hexane–
EtOAc (1:1) and evaporated to give an amorphous product, which
was then dried over P2O5 at 100 °C under reduced pressure to give
pale yellow powder 7 (1170 mg, 90%).
Phosphonium salt 7 may be more efficient than phospho-
nate 9 for olefination of the aldehydes, which are suscep-
tible to enolization. As the preparation of C-4 substituted
imidazoles using phosphonium salts 5 is experimentally
straightforward, they would become useful tools in the
synthesis of bioactive imidazole compounds.
Although further purification of 5 and 7 was not required for the fol-
lowing experiments, they were purified owing to their elemental
analyses by chromatography using CHCl3–MeOH (65:25 and 6:1,
respectively) as eluent.
5
Rf 0.32 (CHCl3–MeOH, 65:25); white powder; mp 276–286 °C
(dec.).
1H NMR (DMSO): = 5.08 (d, J = 14.4 Hz, 2 H), 6.73 (s, 1 H),
7.51–7.93 (m, 16 H).
31P NMR (CD3OD): = 23.06 (s), 23.13 (s) (tautomer).
MS (SIMS): m/z = 343 [M+ – Cl].
HRMS: m/z [M+ – Cl] calcd for C22H20N2P: 343.1366; found:
343.1357.
Anal. Calcd for C22H20ClN2P·0.8MeOH: C, 67.70; H, 5.78; N, 6.93.
Found: C, 67.88; H, 5.50; N, 7.11.
7
Rf 0.65 (CHCl3–MeOH, 65:25); white powder; mp 214–246 °C
(dec.).
1H NMR (CDCl3): = 5.31 (d, J = 13.6 Hz, 2 H), 6.90–7.01 (m, 5
H), 7.18–7.40 (m, 9 H), 7.58–7.98 (m, 18 H).
MS (SIMS): m/z = 585 [M+ – Cl].
HRMS: m/z [M+ – Cl] calcd for C41H34N2P: 585.2457; found:
585.2450.
Anal. Calcd for C41H34ClN2P·0.5MeOH: C, 78.23; H, 5.70; N, 4.40.
Found: C, 78.24; H, 5.67; N, 4.00.
Preparation of {[1H-imidzole-4(5)-yl]methyl}triphenylphos-
phonium Chloride (5)
Water (54 mg, 3.0 mmol) was added to a solution of 1-trityl-4-chlo-
romethylimidazole (1077 mg, 3.0 mmol) and Ph3P (786 mg, 3.0
mmol) in CH3CN (10 mL). The mixture was refluxed for 20 h to
yield a white precipitate which was subsequently filtered and dried
over to give 5 (806 mg, 71%). 7 (248 mg, 13%) was also obtained
as an amorphous product from the filtrate by the same method as de-
scribed above.
Scheme 9 (a) (i) 7 (1.2 equiv), BuLi (1.2 equiv), THF, –70 °C; (ii)
24, –70 °C, then r.t.; (b) 9 (1.2 equiv), t-BuOK (1.2 equiv), reflux, 17
h; (c) Bu4NF, THF, 0 °C; (d) IBX, THF, reflux; (e) (i) BnNH2, MS 3
Å, EtOH; (ii) NaBH4; (f) (i) 1 N HCl; (ii) H2/Pd-C.
Ethyl 2-Carboethoxy-3-[1H-imidazol-4(5)-yl]propionate (17a)
Phosphonium salt 5 (189 mg, 0.5 mmol) was added to a mixture of
diethyl malonate (400 mg, 2.5 mmol) and 1 M solution of NaOEt
(2.5 mL, 2.5 mmol). The whole mixture was refluxed for 1 h to give
a white suspension. The resulting mixture was then acidified to pH
3 with 1 N HCl and evaporated. The residue was dissolved in water
(10 mL) and washed with cold benzene (20 mL). The aq layer was
neutralized by addition of NaHCO3, and then extracted with CHCl3
(4 × 15 mL) by salting-out techniques. The combined organic layer
was dried and concentrated to give 17a13 (84 mg, 70%) as a viscous
oil.
The melting points were determined on a hot stage apparatus and
are uncorrected. IR spectra were recorded on a Shimadzu IR 435
pectrometer. 1H and 13C NMR were taken with tetramethylsilane as
an internal reference on a Varian Gemini-200, Varian Mercury-300
and Varian UNITY INOVA-500 spectromters. Reactions with air-
and moisture-sensitive compounds were carried out under Ar. Un-
less otherwise noted, all extracts were dried over Na2SO4 or MgSO4,
and the solvents were removed in a rotary evaporator under reduced
pressure. Chromatography was performed on silica gel. THF was
distilled from Na-benzophenone.
IR (film): 1660–1780 cm–1.
Synthesis 2003, No. 18, 2844–2850 © Thieme Stuttgart · New York

2848
S. Harusawa et al.
PAPER
1H NMR (CDCl3): = 1.21 (t, J = 7.2 Hz, 6 H), 3.12 (d, J = 8.0 Hz,
2 H), 3.76 (t, J = 8.0 Hz, 1 H), 4.15 (q, J = 7.2 Hz, 4 H), 6.80 (s, 1
H), 7.58 (s, 1 H).
MS (SIMS): m/z = 241 [M+ + 1].
HRMS: m/z [M+ +1] calcd for C11H17N2O4: 241.1187; found:
1H NMR (CDCl3): = 2.62–2.94 (m, 8 H), 6.75 (s, 1 H), 7.04 (d,
J = 8.0 Hz, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 7.51 (s, 1 H).
MS (EI, 70 eV): m/z = 262 [M+].
HRMS: m/z [M+] calcd for C14H15ClN2O: 262.0872; found:
262.0864.
241.1190.
Anal. Calcd for C14H15ClN2O: C, 64.00; H, 5.75; N, 10.66. Found:
C, 64.13; H, 5.97; N, 10.70.
Ethyl 2-[1H-Imidazol-4(5)-ylmethyl]-3-oxo-butyrate (17b)
A mixture of 5 (189 mg, 0.5 mmol), ethyl acetoacetate (195 mg, 1.5
mmol), and 1 M solution of NaOEt (1.5 mL, 1.5 mmol) was re-
fluxed for 1 h to give a viscous oil 17b (76 mg, 72%) using the same
procedure as for the preparation of 17a.
4d
Yield: 51%; needles; mp 85–86 °C (EtOAc–hexane).
IR (nujol): 1705 cm–1.
1H NMR (CDCl3): = 1.91 (quint, J = 7.2 Hz, 2 H), 2.42 (t, J = 7.2
Hz, 2 H), 2.56 (t, J = 7.2 Hz, 2 H), 2.62–2.95 (m, 4 H), 6.73 (s, 1 H),
7.03 (d, J = 8.8 Hz, 2 H), 7.21 (d, J = 8.8 Hz, 2 H), 7.55 (s, 1 H).
MS (EI, 70 eV): m/z = 276 [M+].
HRMS: m/z [M+] calcd for C15H17ClN2O: 276.1028; found:
IR (film): 1710, 1735 cm–1.
1H NMR (CDCl3): = 1.24 (t, J = 7.2 Hz, 3 H), 2.24 (s, 3 H), 3.15
(d, J = 8.0 Hz, 2 H), 3.95 (t, J = 8.0 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2
H), 6.80 (s, 1 H), 7.56 (s, 1 H).
MS (SIMS): m/z = 211 [M+ + 1].
HRMS: m/z [M+ + 1] calcd for C10H15N2O3: 211.1082; found:
276.1025.
Anal. Calcd for C15H17ClN2O: C, 65.10; H, 6.19; N, 10.12. Found:
C, 64.99; H, 6.19; N, 10.03.
211.1078.
1-[1H-imidazol-4(5)-yl]-5-arylpentan-3-ones (4a) or 1-[1H-imi-
dazol-4(5)-yl]-6-arylhexan-3-ones (4b); General Procedure
A mixture of 1 M EtOH solution of NaOEt (1.0 mL, 1.0 mmol) and
18 (1.5 mmol) was stirred at r.t. for 10 min under Ar. Phosphonium
salt 5 (189 mg, 0.5 mmol) was added to the mixture, and the whole
mixture was refluxed for 15 min. The resulting mixture was then
acidified to pH 3 with 1 N HCl and evaporated to give a residue,
which was dissolved in water (10 mL). The aq solution was washed
with benzene (20 × 2 mL). The aq solution was neutralized by addi-
tion of NaHCO3, and extracted with CHCl3 (3 × 15 mL) by salting-
out techniques. The combined organic layer was dried (MgSO4) and
evaporated to give crude 19. It was dissolved in 3.6 N aq H2SO4 (2
mL) and heated at 65 °C for 48 h. The reaction mixture was then di-
luted with water (10 mL), neutralized with NaHCO3, and extracted
with CHCl3 (3 × 15 mL) by salting-out techniques. The combined
organic layer was dried (MgSO4) and concentrated to give a residue,
which was subsequently purified by column chromatography.
1-(4-Chlorophenyl)-3-{2-[1H-imidazol-4(5)-ylmethylsulfanyl]-
ethyl}thiourea (21)
A mixture of 0.5 M MeOH solution of NaOMe (4.0 mL, 2.0 mmol)
and cysteamine (1.0 mmol) was stirred at r.t. for 10 min under Ar.
After 5 (378 mg, 1.0 mmol) was added, the whole mixture was re-
fluxed for 2 h and then evaporated. The residue was dissolved in
cold water (12 mL) and washed with benzene (20 × 2 mL). After the
aq layer was diluted with cold MeOH (12 mL), the resulting solu-
tion was extracted with CHCl3 (5 × 15 mL) by salting-out tech-
niques. The combined organic layer was dried (MgSO4) and
concentrated to give crude 20, which was subsequently dissolved in
THF (4 mL). 4-Chlorophenyl isothiocyanate (254 mg, 1.5 mmol)
was added to the THF solution and the mixture was stirred at r.t. for
3 h under Ar and then evaporated. The residue was purified by col-
umn chromatography to give 21 (68 mg, 21%) as a white amor-
phous product.
1H NMR (CDCl3): = 2.72 (t, J = 7.2 Hz, 2 H), 3.67–3.79 (m, 4 H),
7.02 (s, 1 H), 7.34 (s, 4 H), 7.62 (s, 1 H).
MS (SIMS): m/z = 327 [M+ + 1].
HRMS: m/z [M+ +1] calcd for C13H16ClN4S2: 327.0504; found:
4a
Yield: 55%; viscous oil.
IR (film): 1705 cm–1.
1H NMR (CDCl3): = 2.64–2.96 (m, 8 H), 6.76 (s, 1 H), 7.12–7.36
(m, 5 H), 7.57 (s, 1 H).
327.0503.
MS (SIMS): m/z = 229 [M+ + 1].
HRMS: m/z [M+ + 1] calcd for C14H17N2O: 229.1339; found:
Wittig Reaction of Phosphorus Ylide 22 with Cyclohexanecar-
baldehyde
1 M THF solution of LiHMDS (1.5 mL, 1.5 mmol) was added drop-
wise to a suspension of 5 (284 mg, 0.75 mmol) in DMF (10 mL) at
–40 °C, and the resulting deep red solution was stirred for 0.5 h at
the same temperature. A solution of cyclohexancarbaldehyde (56
mg, 0.5 mmol) in DMF (2 mL) was added dropwise to the solution.
After 15 min, it was allowed to reach r.t. (26 °C) and stirred for 1.5
h. Then, pyridine (0.12 mL, 1.5 mmol), ethyl chloroformate (0.14
mL, 1.5 mmol), and a cat. amount of 4-DMAP were added, and the
whole mixture was stirred for 0.5 h. Water was added to the result-
ing mixture which was subsequently extracted with EtOAc (20 × 3
mL). The organic layer was dried and evaporated to give a crude oil.
Chromatography on silica gel using 7% EtOAc in hexane as eluent
gave (Z)-ethyl 4-(2-cyclohexylvinyl)imidazole-1-carboxylate [(Z)-
23] (40 mg, 32%) and (E)-23 (32 mg, 26%) in that order.
229.1341.
4b
Yield: 64%; viscous oil.
IR (film): 1705 cm–1.
1H NMR (CDCl3): = 1.94 (quint, J = 8.0, 8.0 Hz, 2 H), 2.41 (t, J =
8.0 Hz, 2 H), 2.60 (t, J = 8.0 Hz, 2 H), 2.70–2.94 (m, 4 H), 6.78 (s,
1 H), 7.02–7.38 (m, 5 H), 7.53 (s, 1 H).
MS (SIMS): m/z = 243 [M+ + 1].
HRMS: m/z [M+ + 1] calcd for C15H19N2O, 243.1496; found,
243.1495.
4c
(Z)-23
Viscous oil.
Yield: 57%; prisms; mp 103–106 °C (EtOAc–hexane).
IR (nujol): 1695 cm–1.
1H NMR (CDCl3): = 1.10–1.38 (m, 5 H), 1.46 (t, J = 8.0 Hz, 3 H),
1.56–1.89 (m, 5 H), 2.70–2.90 (br, 1 H), 4.51 (q, J = 8.0 Hz, 2 H),
Synthesis 2003, No. 18, 2844–2850 © Thieme Stuttgart · New York

PAPER
Imidazolylmethylphosphonium Salts and their Synthetic Studies Toward Histamine Ligands
2849
5.54 (dd, J = 11.6, 10.0 Hz, 1 H), 6.15 (d, J = 11.6 Hz, 1 H), 7.29 (s,
1H NMR (CDCl3): = 1.60–2.20 (m, 4 H), 3.42–3.70 (m, 2 H),
1 H), 8.09 (s, 1 H).
4.14–4.23 (m, 1 H), 4.57 (q, J = 7.2 Hz, 1 H), 6.30 (dd, J = 15.6, 7.2
Hz, 1 H), 6.45 (d, J = 15.6 Hz, 1 H), 6.77 (s, 1 H), 7.08–7.40 (m, 16
H).
MS (SIMS): m/z = 437 [M+ + 1].
HRMS: m/z [M+ + 1] calcd for C29H29N2O2: 437.2227; found:
13C NMR (CDCl3): = 14.2, 25.7, 32.6, 37.6, 64.4, 114.0, 118.2,
136.4, 139.7, 140.9, 148.6.
MS (EI, 70 eV): m/z = 248 [M+].
HRMS: m/z [M+] calcd for C14H20N2O2: 248.1524; found:
248.1527.
437.2224.
(Z)-26
(E)-23
Viscous oil.
Yield: 66%; white powder.
1H NMR (CDCl3): = 1.60–2.25 (m, 4 H), 3.40–3.72 (m, 2 H),
4.13–4.22 (m, 1 H), 5.38 (q, J = 8.4 Hz, 1 H), 5.59 (dd, J = 12.0, 8.4
Hz, 1 H), 6.33 (d, J = 12.0 Hz, 1 H), 6.80 (s, 1 H), 7.08–7.43 (m, 16
H).
MS (EI, 70 eV): m/z: 436 [M+].
HRMS: m/z [M+] calcd for C29H28N2O2: 436.2149; found:
1H NMR (CDCl3): = 1.10–1.38 (m, 5 H), 1.44 (t, J = 8.0 Hz, 3 H),
1.55–1.95 (m, 5 H), 2.00–2.20 (br, 1 H), 4.48 (q, J = 8.0 Hz, 2 H),
6.29 (d, J = 16.0 Hz, 1 H), 6.42 (dd, J = 16.0, 6.6 Hz, 1 H), 7.20 (s,
1 H), 8.08 (s, 1 H).
13C NMR (CDCl3): = 14.2, 26.0, 32.7, 40.9, 64.3, 112.3, 117.7,
137.0, 138.4, 142.1, 148.6.
436.2149.
MS (EI, 70 eV): m/z = 248 [M+].
HRMS: m/z [M+] calcd for C14H20N2O2: 248.1524; found:
248.1525.
(2R,5R)-5-[(E)-2-(1-Tritylimidazol-4-yl)vinyl]-tetrahydrofur-
an-2-carbaldehyde [(E)-27]
Freshly prepared IBX (96 mg, 0.35 mmol) was added to a solution
of (E)-26 (100 mg, 0.23 mmol) in THF (4 mL), and the resulting
suspension was refluxed for 2 h. The solvent was evaporated to give
a residue, which was subsequently dissolved in CH2Cl2 (10 mL).
Sat. aq solution of NaHCO3 (10 mL) containing Na2S2O3·5H2O
(595 mg) was added to the CH2Cl2 solution, and the resulting mix-
ture was stirred for 10 min. The CH2Cl2 layer was separated and the
aq layer was extracted with CH2Cl2 (3 × 20 mL). The combined
CH2Cl2 layer was dried (Mg SO4) and evaporated to give (E)-27
(100 mg, quant.) as a white amorphous product.
4-{(E)-2-[(2R,5R)-5-tert-Butyldiphenylsiloxymethyl-tetrahydro-
furan-2-yl]vinyl}-1-tritylimidazole [(E)-25] and (Z)-25
A 1.6 M hexane solution of BuLi (7.05 mL, 11.28 mmol) was added
dropwise over 50 min to a suspension of 7 (6.99 g, 11.28 mmol) in
THF (100 mL) at –70 °C, and the resulting red brown suspension
was stirred for 15 min at the same temperature. A solution of alde-
hyde 2416 (3.46 g, 9.40 mmol) in THF (20 mL) was added dropwise
over 40 min to the suspension. After stirring for 0.5 h, it was al-
lowed to reach r.t. After evaporation of the solvent, water (100 mL)
was added to the residue, which was subsequently extracted with
CHCl3 (3 × 100 mL). The organic layer was dried (MgSO4) and
evaporated to give a crude oil. Chromatography on silica gel using
EtOAc–hexane (1:3) as eluent gave (Z)-25 (1.99 g, 32%) and (E)-
25 (2.49 g, 39%) in that order.
IR (CHCl3): 1724 (CHO) cm–1.
1H NMR (CDCl3) = 1.70–2.30 (m, 4 H), 4.40 (t, J = 8.0 Hz, 1 H),
4.68 (q, J = 5.3 Hz, 1 H), 6.30 (dd, J = 14.7, 5.3 Hz, 1 H), 6.48 (d,
J = 14.7 Hz, 1 H), 6.77 (s, 1 H), 7.06–7.40 (m, 16 H), 9.68 (s, 1 H).
MS (EI, 70 eV): m/z = 434 [M+].
HRMS: m/z [M+] calcd for C29H26N2O2: 434.1992; found:
(E)-25
Viscous oil.
434.1990.
1H NMR (CDCl3): = 1.03 (s, 9 H), 1.65–2.20 (m, 4 H), 3.64 (dd,
J = 10.6, 5.3 Hz, 1 H), 3.68 (dd, J = 10.6, 4.4 Hz, 1 H), 4.15–4.24
(m, 1 H), 4.55 (q, J = 6.2 Hz, 1 H), 6.27 (dd, J = 15.5, 6.2 Hz, 1 H),
6.42 (d, J = 15.5 Hz, 1 H), 6.74 (s, 1 H), 7.10–7.70 (m, 26 H).
MS (EI, 70 eV): m/z = 675 [M+ + 1].
HRMS: m/z [M+ + 1] calcd for C45H47N2O2Si: 675.3404; found:
(Z)-27
Yield: 96%; white amorphous product.
1H NMR (CDCl3): = 1.60–2.30 (m, 4 H), 4.34 (t, J = 8.0 Hz, 1 H),
5.40–5.50 (m, 1 H), 5.58 (dd, J = 12.0, 8.4 Hz, 1 H), 6.33 (d, J =
12.0 Hz, 1 H), 6.85 (s, 1 H), 7.06–7.43 (m, 16 H), 9.55 (s, 1 H).
MS (EI, 70 eV): m/z = 434 [M+].
675.3410.
HRMS: m/z [M+] calcd for C29H26N2O2: 434.1992; found:
434.1982.
(Z)-25
Viscous oil.
1H NMR (CDCl3): = 1.03 (s, 9 H), 1.60–2.20 (m, 4 H), 3.48 (dd,
J = 10.0, 6.4 Hz, 1 H), 3.66 (dd, J = 10.0, 4.8 Hz, 1 H), 4.10–4.22
(m, 1 H), 5.20 (q, J = 8.0 Hz, 1 H), 5.58 (dd, J = 12.0, 8.0 Hz, 1 H),
6.28 (d, J = 12.0 Hz, 1 H), 6.77 (s, 1 H), 7.05–7.75 (m, 26 H).
4-{(E)-2-[(2R,5R)-5-Benzylaminomethyltetrahydro-furan-2-
yl]vinyl}-1-tritylimidazole [(E)-28]
To a solution of (E)-27 (78 mg, 0.18 mmol) and benzylamine (547
mg, 5.12 mmol) in EtOH (4 mL) was added powdered 3A molecular
sieves (200 mg). After stirring of the mixture at r.t. for 3 h, NaBH4
(195 mg, 5.12 mmol) was added and the mixture was stirred for 17
h at r.t. The reaction mixture was filtered through Celite pad and
EtOH was evaporated to give a residual oil, which was subsequently
purified by chromatography to give (E)-28 (73 mg, 78%) as an oil.
1H NMR (CDCl3) = 1.60–2.20 (m, 4 H), 2.60–2.80 (m, 2 H), 3.00–
3.35 (br s, 1 H), 3.86 (d, J = 5.2 Hz, 2 H), 4.20–4.32 (m, 1 H), 4.52
(q, J = 6.5 Hz, 1 H), 6.28 (dd, J = 15.6, 6.5 Hz, 1 H), 6.42 (d, J =
15.6 Hz, 1 H), 6.75 (s, 1 H), 7.05–7.40 (m, 21 H).
MS (EI, 70 eV): m/z = 675 [M+ + 1].
HRMS: m/z calcd for C45H47N2O2Si: 675.3404; found: 675.3415.
4-{(E)-2-[(2R,5R)-5-Hydroxymethyltetrahydrofuran-2-yl]vi-
nyl}-1-tritylimidazole [(E)-26]
A 1 M THF solution of TBAF (4.1 mL, 4.1 mmol) was added to a
solution of (E)-25 (2.49 g, 3.69 mmol) in THF (80 mL) at 0 °C. Af-
ter the reaction mixture was stirred at r.t. for 3 h, the solvent was re-
moved by evaporation to give a residue. It was then purified by
column chromatography using EtOAc to give (E)-26 (1.22 g, 76%)
as white powder; mp 201–207 °C.
MS (SIMS): m/z = 526 [M+ + 1].
Synthesis 2003, No. 18, 2844–2850 © Thieme Stuttgart · New York

2850
S. Harusawa et al.
PAPER
(6) (a) Vollinga, R. C.; Menge, W. M. P. B.; Leurs, R.;
HRMS: m/z [M+ + 1] calcd for C36H36N3O: 526.2856; found:
526.2843.
Timmerman, H. J. Med. Chem. 1995, 38, 266. (b) Vollinga,
R. C.; Menge, W. M. P. B.; Leurs, R.; Timmerman, H. J.
Med. Chem. 1995, 38, 2244. (c) De Esch, I. J. P.; Gaffar, A.;
Menge, W. M. P. B.; Timmerman, H. Bioorg. Med. Chem.
1999, 7, 3003. (d) Kazuta, Y.; Hirano, K.; Natsume, K.;
Yamada, S.; Kimura, R.; Matsumoto, S.; Furuichi, K.;
Matsuda, A.; Shuto, S. J. Med. Chem. 2003, 46, 1980.
(7) Harusawa, S.; Koyabu, S.; Inoue, Y.; Sakamoto, Y.; Araki,
L.; Kurihara, T. Synthesis 2002, 1072.
(8) (a) Lassalle, G.; Purcell, T.; Galtier, D.; Williams, P. H.;
Galli, F. Eur. Pat. Appl., EP 565396, 1993. (b) Perard, S.;
Zard, L.; Rossey, G. Eur. Pat. Appl., EP 614986, 1994.
(c) Lassalle, G.; Galtier, D.; Galli, F. Eur. Pat. Appl., EP
643047, 1995. (d) Galtier, D.; Lassalle, G. Eur. Pat. Appl.,
EP 643046, 1995. (e) Lassalle, G.; Galtier, D.; Galli, F. Fr
Demande., FR 2710067, 1995. (f) Lassalle, G.; Purcell, T.;
Galtier, D.; Williams, P. H.; Galli, F. US Pat., US 5453430,
1996. (g) Yokohama, S.; Takeda, Y.; Kawakoshi, K.;
Yamamoto, K. Jpn. Kokai Tokkyo Koho, JP 11279156,
1999.
(Z)-28
Yield: 68%; oil.
1H NMR (CDCl3) = 1.50–2.20 (m, 4 H), 2.30–2.80 (br s, 1 H),
2.65 (d, J = 8.0 Hz, 2 H), 3.80 (s, 2 H), 4.27 (quint, J = 6.4 Hz, 1 H),
5.30 (q, J = 8.0 Hz, 1 H), 5.58 (dd, J = 12.0, 8.0 Hz, 1 H), 6.30 (d,
J = 12.0 Hz, 1 H), 7.79 (s, 1 H), 7.00–7.60 (m, 21 H).
MS (SIMS): m/z = 526 [M+ + 1].
HRMS: m/z [M+ + 1] calcd for C36H36N3O1: 526.2856; found:
526.2850.
(–)-4(5)-{2-[(2S,5R)-5-Aminomethyltetrahydrofuran-2-yl]eth-
yl}imidazole [(–)-3]
A solution of (E)-28 (73 mg, 0.14 mmol) in aq 1 N HCl (0.7 mL)–
EtOH (5 mL) was stirred at r.t. for 10 min, and evaporated to give a
white residue (28·2HCl). A solution of the dihydrochloride in
MeOH (5 mL) was subsequently hydrogenated with 10% Pd-C (100
mg) as catalyst at initial pressure of 3.2 kg/cm2 for 48 h. The catalyst
was removed by filtration and the filtrate was concentrated to give
a residue, which was subsequently placed on a column. Chromatog-
raphy using CHCl3–MeOH–28% NH4OH (30:2:1) as the eluent
gave 3 (20 mg, 74%) as a colorless oil; [ ]D –19.2 (c 2.00, MeOH).
(9) (a) Bruice, T. C.; Herz, J. L. J. Am. Chem. Soc. 1964, 86,
4109. (b) Harusawa, S.; Murai, Y.; Moriyama, H.; Imazu,
T.; Ohishi, H.; Yoneda, R.; Kurihara, T. J. Org. Chem. 1996,
61, 4405.
(10) (a) Coates, I. H.; Charles, N. P.; William, O. A. Eur. Pat.
Appl., EP 306323, 1989. (b) Cordi, A. A.; Snyers, M. P.;
Giraud-Mangin, D.; Van der Maesen, C.; Van Hoeck, J. P.;
Beuze, S.; Ellens, E.; Napora, F.; Gillet, C. L.; Gorissen, H.;
Calderon, P.; Remacle, M. D.; Janssens de Varebeke, P.;
Van Dorsser, W.; Roba, J. Eur. J. Med. Chem. 1990, 25, 557.
(11) (a) Zbiral, E.; Hugl, E. Phosphorus 1972, 2, 29. (b) Zbiral,
E. Synthesis 1974, 775. (c) Webb, R. L.; Lewis, J. J. J.
Heterocycl. Chem. 1981, 18, 1301.
(12) (a) Staab, H. A.; Datta, A. P. Angew. Chem., Int. Ed. Engl.
1964, 3, 132. (b) Devos, A.; Remion, J.; Frisque-Hesbain,
A. M.; Colens, A.; Ghosez, L. J. Chem. Soc., Chem.
Commun. 1979, 1180. (c) Villeneuve, G. B.; Chan, T. H.
Tetrahedron Lett. 1997, 38, 6489.
1H NMR (CD3OD): = 1.45–2.12 (m, 6 H), 2.50–2.76 (m, 4 H),
3.88–4.05 (m, 2 H), 6.77 (s, 1 H), 7.47 (s, 1 H).
SIMS: m/z = 196 [M+ + 1].
HRMS: m/z [M+ + 1] calcd for C10H18N3O: 196.1449; found:
196.1431.
References
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Synthesis 2003, No. 18, 2844–2850 © Thieme Stuttgart · New York