Homonuclear Diels-Alder dimerization of 5-ethenyl-2-phenylsulfanyl-1H-imidazoles and its application to synthesis of 12,12′-dimethylageliferin

Article abstract of DOI:10.1016/j.tet.2006.08.027

Homonuclear Diels-Alder dimerization of various 5-ethenyl-2-phenylsulfanyl-1H-imidazoles provided a novel highly regio- and stereoselective route to the preparation of multifunctionalized 4,5,6,7-tetrahydrobenzimidazoles, which is the basic skeleton of ag

Full text of DOI:10.1016/j.tet.2006.08.027

Tetrahedron 62 (2006) 10182–10192
Homonuclear Diels–Alder dimerization of 5-ethenyl-2-
phenylsulfanyl-1H-imidazoles and its application
to synthesis of 12,120-dimethylageliferin
*
Ikuo Kawasaki, Norihiro Sakaguchi, Abdul Khadeer, Masayuki Yamashita and Shunsaku Ohta
Department of Functional Molecular Chemistry, 21st Century COE Program, Kyoto Pharmaceutical University,
Misasagi Yamashinaku, Kyoto 607-8414, Japan
Received 19 July 2006; revised 6 August 2006; accepted 8 August 2006
Available online 1 September 2006
Abstract—Homonuclear Diels–Alder dimerization of various 5-ethenyl-2-phenylsulfanyl-1H-imidazoles provided a novel highly regio- and
stereoselective route to the preparation of multifunctionalized 4,5,6,7-tetrahydrobenzimidazoles, which is the basic skeleton of ageliferin,
a biologically active pyrrole-imidazole marine alkaloid. The reaction was applied to the synthesis of 12,120-dimethylageliferin.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
at this time our attention was focused on the asymmetric total
synthesis of ageliferins via a biomimetic synthetic route. In
thispaper, wewouldlike to present ahighly regio- and stereo-
selective homonuclear Diels–Alder (DA) dimerization of
various 5-ethenyl-2-phenylsulfanyl-1H-imidazoles 8, 9,
and the first synthesis of a 12,120-dimethyl derivative of
ageliferin 22.9 In 2004, Baran and co-workers reported the
Recently, many types of biologically active pyrrole-imid-
azole alkaloids have been isolated from marine lives such as
sponges, and they have become an important focus of scien-
tific attention.1,2 In 1990, ageliferins 1–3 were isolated from
Agelas sponges and found to have various biological proper-
ties such as actomyosin ATPase,3 antiviral, antibacterial,4
and several other interesting activities.5 The structural skele-
ton of 1–3 in Figure 1 has been considered to be biochemi-
cally synthesized through [4p+2p] cycloaddition1b,3,4 of
the simplest pyrrole-imidazole alkaloids, oroidin 46 or/and
hymenidin 5.7 We have investigated the total synthesis of
several biologically active imidazole marine alkaloids,8 and
total synthesis of 1 by microwave heating of sceptrin,10
a
pyrrole-imidazole alkaloid.11
2. Results and discussion
To examine the reactivity of 5(4)-ethenylimidazoles under
thermal reactionconditions, various DA dimerization precur-
sors, 8a–c and 9a–f, were prepared from 1,2-disubstituted
imidazoles 6 as shown in Scheme 1.12 Formylimidazoles
7 were prepared through 5-lithioimidazoles13 and then
converted to vinylimidazoles, 8a–c, by Wittig reaction.
E-Acrylates 9a–e were prepared from 7 by applying Horner–
Wadsworth–Emmons reaction.14 The amide 9f was obtained
from the ester 9a.
NH2
N
O
O
NH
H
N
X1
N
H
N
Br
Br
NH2
H
N
H
N
1 X1 = X2 = H
N
H
X2
2 X1 = Br, X2 = H
3 X1 = X2 = Br
N
The result of DA dimerization of 8a–c and 9a–f is summa-
rized in Table 1. The desired homonuclear DA dimerization
of 8a–c and 9a,b proceeded successfully (entries 1–5).
Although there have been several examples of intermolecu-
lar DA reactions of 4- or 5-ethenylimidazole derivatives as
the diene component with active dienophiles such as N-phe-
nylmaleimide or 4-phenyl-1,2,4-triazoline-3,5-dione,15,16
homonuclear DA dimerization of imidazole derivatives has
not been developed.
H
Br
NH2
N
N
H
N
X
O
H
4 X = Br
5 X = H
Figure 1.
* Corresponding author. Tel.: +81 75 595 4703; fax: +81 75 595 4795;
e-mail: sohta@mb.kyoto-phu.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.027

I. Kawasaki et al. / Tetrahedron 62 (2006) 10182–10192
10183
N
N
N
SPh
R2
a
c (for 8a, b) or d (for 8c)
SPh
R2
N
H
N
N
R1
R1
R1
O
8a: R1 = Me, R2 = H
6a: R1 = Me
e
7a: R1 = Me, R2 = SPh
8b: R1 = SEM, R2 = H
b
6b: R1 = MOM
6c: R1 = SEM
7b: R1 = MOM, R2 = SPh
7c: R1 = SEM, R2 = SPh
7d: R1 = Me, R2 = TBS
8c: R1 = R2 = Me (E/Z = 72:28)
N
N
N
g
TBS
R2
SPh
N
Me
6d
Br
EtO
H2N
N
N
R1
Me
O
O
9a: R1 = Me, R2 = SPh (E/Z = 97:3)
9b: R1 = MOM, R2 = SPh (E/Z = 99:1)
9c: R1 = H, R2 = SPh (E/Z = 98:2)
9d: R1 = Me, R2 = TBS (E/Z = >99:1)
9e: R1 = Me, R2 = H (E/Z = >99:1)
9f (E/Z = 97:3)
f
Scheme 1. Reagents and conditions: (a) LTMP, DMF, THF, DME, ꢀ78ꢀꢁC, 98% (7a), 83% (7b), 95% (7c); (b) n-BuLi, DMF, THF, ꢀ78 ꢁC, 58%; (c) n-BuLi,
Ph3P+MeBrꢀ, THF, 0 ꢁC to rt, 90% (8a), 77% (8b); (d) PhLi, Ph3P+EtBr , AcOH, t-BuOK, THF, Et2O, ꢀ66 ꢁC to rt, 92% (8c); (e) (EtO)2P(O)CH2CO2Et, LiCl,
DBU, MeCN, rt, 99% (9a), 100% (9b), 86% (9d); (f) 10% HCl aq, EtOH, 60 ꢁC, 71% (from 9b); (g) NH3, MeOH, rt, 59% (from 9a).
Table 1. DA dimerization of the alkenyl imidazoles 8 and 9
R2
R2
SPh
N
N
N
N
N
N
R1
R1
3N
N
Me
N
O
R2
4
+
R3
R3
R3
N
N
R1
R3
2
R2
R2
5
SPh
NH
N1
R1
N
R1
N
Me
R3
6
7
8a-c
9a-f
O
10a-e
11a-b
12
Entry
Starting
Compd
Reaction
Reaction
time (h)
R1
R2
R3
Yield (10+11
or 12) (%)b
Ratio
Product(s)
conditiona
(10/11 or 12)c
1
2
3
4
5
6
7
8
9
8a
8b
8c
9a
9b
9c
9d
9e
9f
A
B
B
A
C
D
D
D
D
30
30
75
30
60
60
60
60
30
Me
SPh
SPh
SPh
SPh
SPh
SPh
TBS
H
H
H
Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
92
36
42
55
14d
0e
—
—
1:0
50:1
4:1
—
—
—
1:1.2
10a
10b
10c
10d/11a
10e/11b
—
—
—
SEM
Me
Me
MOM
H
Me
0e
Me
Me
0d
59
SPh
CONH2
10f/12
a
Reaction conditions: (A) refluxed in xylene at 140 ꢁC; (B) neat in sealed tube at 150 ꢁC; (C) neat in sealed tube at 100 ꢁC; (D) neat in sealed tube at 120 ꢁC.
b
c
d
e
Isolated yield.
Determined by 1H NMR.
Starting material was mainly recovered.
Decomposed.
Fortunately, we found that the plane and stereo structure of
2-phenylsulfanyl-1H-imidazole9gas amodelsubstrateusing
the MOPAC PM3 semiempirical method (Fig. 2, Table 2).18
These results indicated that the ethyl acrylate 9a might
also react as both diene (C4–C5–C6–C7) and dienophile
(C6–C7) in the homonuclear [4p+2p] cycloaddition to
produce the desired product 10d.
the major products 10c–e were consistent with those of age-
liferins.17 Especially, the DA dimerization of 9a proceeded
in regio- and stereoselective fashion to give the multifunc-
tionalized 4,5,6,7-tetrahydrobenzimidazole 10d in 54%
yield (entry 4). On the other hand, the reaction of 9c–e
gave no DA product (entries 6–8); this result shows that the
presence of the alkyl group at the 1-position and the phenyl-
sulfanyl group at the 2-position of the imidazole ring might
be important for the DA dimerization of 5-ethenylimid-
azoles. The amide 9f provided the DA dimerized product in
relatively good yield (59%); however, the structure of the
major product was imide 12 and unfortunately the undesired
5,6-cis-substituted 4,5,6,7-tetrahydrobenzimidazole.
Next, we planned the synthesis of 16a,b starting from diester
10d as model compounds of the ageliferin analogue (Scheme
2). The diol 13 was obtained by LiAlH4 reduction of the
diester 10d in 98% yield. Introduction of the nitrogen
function into the side chain of the 5- and 6-position of the
4,5,6,7-tetrahydrobenzimidazole nucleus was achieved by
Mitsunobu reaction, combination of DEAD, PPh3, and
phthalimide, to give the imide 14. Removal of the phenylsul-
fanyl groups of 14 by desulfurization with a combination of
We calculated the LUMO and HOMO energies and orbital
coefficients of 5-[(2-methoxycarbonyl)ethenyl]-1-methyl-
19
NiCl2 and NaBH4 gave the 2,20-unsubstituted derivative 15

10184
I. Kawasaki et al. / Tetrahedron 62 (2006) 10182–10192
the silyl ether 17 in 99% yield and the stereo structure of
17 was further confirmed by X-ray crystallographic analysis
as shown in Figure 3.20 After removal of the phenylsulfanyl
groups of 17 by desulfurization with NiCl2 and NaBH4,
introduction of azide groups into the 2- and 20-position of
the imidazole nucleus of 18 was achieved by lithiation with
sec-BuLi followed by treatment with trisyl azide21 to give
the diazide 19 in 39% overall yield from 17. The diazide 19
was hydrogenated over 5% Pd/C, and the resulting primary
amino groups were protected with benzaldehyde to afford
the diimine 20 followed by the removal of TBDPS groups
by the action of CsF to give the diol 21 (42% in three steps).
After several examinations for introduction of a nitrogen
function by a substitution reaction of 21, we found that the di-
azide compound 22 was obtained in excellent yield (95%) by
the combination of DEAD, PPh3, and DPPA.22 The diazide
22 was converted to the corresponding diamine by selective
reduction with PPh3 in the presence of H2O,23 and then the
diamine was acylated with 4-bromo-2-(trichloroacetyl)pyr-
role24 to give the protected ageliferin analogue 23 (21% yield
in two steps). Finally, hydrolysis of the imino groups of 23
with dilute hydrochloric acid gave 12,120-dimethylageliferin
dihydrochloride 24 as powder.
Figure 2. Approach of the LUMO (upper) to HOMO (lower) orbital of the
methyl ester 9g.
3. Conclusion
in 62% yield. Two-step conversion of 14 and 15 afforded
the pyrrole-imidazole dimers 16a and b in 49 and 72% yields,
respectively.
We have successfully developed a convenient and efficient
preparation method for the highly functionalized 4,5,6,7-
tetrahydrobenzimidazole derivatives by novel homonuclear
DA dimerization reactions of 5-alkenyl imidazoles with high
regio- and stereoselectivity. And the method could be applied
to the first synthesis of an ageliferin derivative 24. We are
currently investigating the scope of this reaction with various
Encouraged by this result, we then planned the synthesis of
12,120-dimethylageliferin 24 (Scheme 3). The hydroxyl
groups of 13 were protected by the TBDPS group to give
Table 2. The LUMO and HOMO energies and orbital coefficients of 9g
3
N
Ph
S8
4
2
7
MeO
5
N1
Me
6
O
9g
Coefficients of p-orbital at the atom positions
Energy (eV)
1a
2
3
4
5
6
7
8
LUMO
HOMO
ꢀ0.9008
ꢀ8.7552
0.35
0.10
ꢀ0.34
0.08
0.21
0.31
L0.27
ꢀ0.28
ꢀ0.37
L0.45
0.10
0.44
0.27
0.12
ꢀ0.49
0.33
a
Position number.
R1
N
R1
N
SPh
N
N
N
CH3
O
N
H
N
O
CH3
CH3
N
N
N
H
R1
d
N
N
b
a
HO
HO
Br
Br
10d
SPh
R1
N
H
O
N
CH3
N
CH3
N
CH3
N
O
O
N
H
O
13
16a: R1 = SPh
16b: R1 = H
14: R1 = SPh
15: R1 = H
c
Scheme 2. Reagents and conditions: (a) LiAlH4, THF, rt, 98%; (b) DEAD, PPh3, phthalimide, THF, 0 ꢁC–rt, 63%; (c) NiCl2$6H2O, NaBH4, THF, MeOH,
0 ꢁC–rt, 62%; (d) NH2NH2, 70 ꢁC, then K2CO3, 4-bromo-2-(trichloroacetyl)pyrrole, DMAc, rt, 49% (16a), 72% (16b).

I. Kawasaki et al. / Tetrahedron 62 (2006) 10182–10192
10185
R1
N
CHPh
CH3
N3
N
N
N
N
N
CH3
N
CH3
e
N
d
c
N
N
N
a
TBDPSO
TBDPSO
N
TBDPSO
TBDPSO
R1
TBDPSO
TBDPSO
13
CHPh
N3
N
CH3
N
CH3
CH3
17: R1 = SPh
18: R1 = H
19
b
20
NH2
N
CHPh
CH3
N
N
CHPh
CH3
N
N
N
H
N
O
O
N
CH3
O
O
H
N
N
h
.
g
2HCl
NH2
N
H
N
N
H
N
Br
Br
N
N
N
Br
Br
R
R
H
N
CHPh
N
CH3
H
CHPh
N
N
N
N
H
CH3
N
H
CH3
21: R = OH
22: R = N3
23
24
f
Scheme 3. Reagents and conditions: (a) TBDPSCl, imidazole, DMF, rt, 99%; (b) NiCl2$6H2O, NaBH4, THF, MeOH, 0 ꢁC–rt, 70%; (c) sec-BuLi, trisyl azide,
THF, DME, ꢀ40 ꢁC to rt, 55%; (d) H2, Pd/C, AcOEt, rt, then PhCHO, PhMe, reflux, 50%; (e) CsF, DMF, 100 ꢁC, 83%; (f) DEAD, PPh3, (PhO)2P(O)N3, THF, rt,
95%; (g) PPh3, THF, H2O, rt, then K2CO3, 4-bromo-2-(trichloroacetyl)pyrrole, DMAc, rt, 21%; (h) 0.5 M HCl aq, EtOH, rt, 76%.
4.1.1. General procedure for 5-formylimidazoles (7a–c),
synthesis of 5-formyl-1-methyl-2-phenylsulfanyl-1H-imid-
azole (7a) as an example. n-BuLi (1.6 M in n-hexane,
49.3 mL, 78.8 mmol) was added to a stirred solution of
2,2,6,6-tetramethylpiperidine (TMP) (13.3 mL, 78.8 mmol)
in THF (50 mL) and DME (50 mL) under N2 at ꢀ78 ꢁC.
After stirring for 30 min at the same temperature, a solution
of 6a12a (10.00 g, 52.56 mmol) in THF (50 mL) was added to
the reaction mixture and the whole was stirred for 1 h at
ꢀ78 ꢁC. Then, DMF (6.10 mL, 78.8 mmol) was slowly
added to the reaction mixture and the whole was stirred for
4 h at ambient temperature. H2O (10 mL) was added to the
mixture and after evaporation of the solvent the products
were extracted with AcOEt (100 mLꢂ2). The organic layer
was dried over anhydrous Na2SO4 and evaporated to give
a crystalline residue, which was purified by recrystallization
from AcOEt/n-hexane to give 7a as yellow needles
1
(11.184 g, 98%); mp 57–58 ꢁC; H NMR (CDCl3): d 3.91
(3H, s, NCH3), 7.32–7.42 (5H, m, Ph), 7.78 (1H, s, 4-H),
9.66 (1H, s, CHO); 13C NMR (CDCl3): d 33.3, 128.4, 129.5,
130.1, 131.5, 133.2, 143.4, 149.6, 178.4; IR (CHCl3): nmax
Figure 3. ORTEP plot of 17.
imidazole substitution patterns and the asymmetric total
synthesis of ageliferins (1–3) and their analogues.
2961, 2807, 1664, 1457, 1325, 1154, 1079 cmꢀ1; MS (EI):
m/z 218 (M+, 100), 190 (24), 148 (19), 136 (13), 121 (33),
109 (20), 91(59), 77 (27); HRMS (EI) m/z218.0509 (M+) (re-
quires C11H10N2OS: 218.0514). Found: C, 60.29; H, 4.59; N,
12.73; C11H10N2OS requires C, 60.53; H, 4.62; N, 12.83.
4. Experimental
4.1. General
4.1.2. 5-Formyl-1-methoxymethyl-2-phenylsulfanyl-1H-
imidazole (7b). Starting with 6b12b (5.507 g, 25.00 mmol),
n-BuLi (23.4 mL, 37.5 mmol), TMP (6.33 mL, 37.5 mmol),
DMF (2.90 mL, 37.5 mmol), THF (48 mL), and DME
(24 mL), 7b was purified by column chromatography
(AcOEt/n-hexane¼1/3) and isolated as a yellow viscous oil
Melting points were measured with a Yanaco MP micro-
melting point apparatus and are uncorrected. IR spectra
were taken with Shimadzu IR-435 spectrophotometer.
NMR (1H, 13C) spectra were measured on Varian UNITY
INOVA 400NB (1H: 400 MHz, 13C: 100 MHz) and the
chemical shifts were expressed in parts per million (ppm)
downfield from tetramethylsilane as the internal standard
(1H) or referenced of solvent peak (13C). MS and HRMS
were measured on JEOL JMS BU-20 (EI) or JEOL JMS-
SX 102A QQ (FAB) spectrometer. Silica gel (Merck Art.
7737) was used for column chromatography.
1
(5.127 g, 83%); H NMR (CDCl3): d 3.36 (3H, s, OCH3),
5.78 (2H, s, NCH2O), 7.38–7.55 (5H, m, Ph), 7.77 (1H, s,
4-H), 9.67 (1H, s, CHO); 13C NMR (CDCl3): d 56.5, 75.5,
129.06, 129.13, 129.5, 132.85, 132.92, 144.2, 152.3, 178.2;
IR (CHCl3): nmax 2972, 2807, 1663, 1473, 1439, 1333,
1149, 1116 cmꢀ1; MS (EI): m/z 248 (M+, 100), 233 (31),
217 (43), 205 (72), 139 (33), 121 (82), 109 (31), 91 (41),

10186
I. Kawasaki et al. / Tetrahedron 62 (2006) 10182–10192
77 (43), 65 (29), 51 (37). HRMS (EI) m/z 248.0617 (M+)
(requires C12H12N2O2S: 248.0619).
4.1.6. 1-[2-(Trimethylsilyl)ethoxymethyl]-2-phenylsul-
fanyl-5-ethenyl-1H-imidazole (8b). Starting with 7c
(600 mg, 1.79 mmol), n-BuLi(5.59 mL, 8.95 mmol), methyl-
triphenylphosphonium bromide (3.20 g, 8.95 mmol), and
THF (9 mL), 8b was purified by column chromatography
(AcOEt/n-hexane¼1/1) and isolated as a yellow viscous oil
(459 mg, 77%); 1H NMR (CDCl3): d ꢀ0.07 (9H, s, SiMe3),
0.82 (2H, t, J¼8.2 Hz, CH2CH2Si), 3.40 (2H, t, J¼8.2 Hz,
CH2CH2Si), 5.32 (1H, dd, J¼1.1, 11.4 Hz, C]CHH), 5.43
(2H, s, NCH2O), 5.72 (1H, dd, J¼1.1, 17.8 Hz, C]CHH),
6.64 (1H, ddd, J¼0.7, 11.4, 17.8 Hz, HC]CH2), 7.16–7.28
(5H, m, Ph), 7.38 (1H, s, 4-H); 13C NMR (CDCl3): d ꢀ1.5,
17.4, 66.1, 73.3, 116.1, 123.1, 126.8, 128.1, 128.4, 129.2,
134.4, 134.7, 138.9; IR (CHCl3): nmax 2935, 1246, 1172,
1088, 856, 834 cmꢀ1; MS (EI): m/z 332 (M+, 31), 237 (23),
259 (26), 73 (100); HRMS (EI) m/z 332.1378 (M+) (requires
C17H24N2OSSi: 332.1379).
4.1.3. 5-Formyl-1-1-[2-(trimethylsilyl)ethoxymethyl]-2-
phenylsulfanyl-1H-imidazole (7c).12e Starting with 6c12c
(0.581 g, 1.90 mmol), n-BuLi (1.78 mL, 2.85 mmol), TMP
(0.48 mL, 2.85 mmol), DMF (0.22 mL, 2.85 mmol), THF
(3.6 mL), and DME (1.8 mL), 7c was purified by column
chromatography (AcOEt/n-hexane¼1/3) and isolated as
1
a yellow viscous oil (0.604 g, 95%); H NMR (CDCl3):
d ꢀ0.02 (9H, s, SiMe3), 0.91 (2H, t, J¼8.2 Hz, CH2CH2Si),
3.59 (2H, t, J¼8.2 Hz, CH2CH2Si), 5.81 (2H, s, NCH2O),
7.36–7.40 (3H, m, Ph), 7.52–7.54 (2H, m, Ph), 7.76 (1H, s,
4-H), 9.66 (1H, s, CHO).
4.1.4. 2-tert-Butyldimethylsilyl-5-formyl-1-methyl-1H-
imidazole (7d). n-BuLi (3.13 mL, 5.00 mmol) was added
to a stirred solution of 6d12d (1.376 g, 5.00 mmol) in THF
(5 mL) under N2 at ꢀ78 ꢁC. After stirring for 20 min at the
same temperature, DMF (0.39 mL, 5.00 mmol) was added
to the reaction mixture and the whole was stirred for 2 h at
ambient temperature. H2O (3 mL) was added to the mixture
and after evaporation of the solvent the products were
extracted with Et2O (20 mLꢂ2). The organic layer was dried
over anhydrous Na2SO4 and evaporated to give an oily
residue, which was purified by column chromatography
(AcOEt/n-hexane¼1/3) to give 7d as a yellow viscous oil
4.1.7. 1-Methyl-2-phenylsulfanyl-5-(1-propenyl)-1H-imid-
azole (8c). PhLi (0.97 M in Et2O/cyclohexane, 27.6 mL,
26.8 mmol) was added to a stirred solution of ethyltriphenyl-
phosphonium bromide (9.95 g, 26.8 mmol) in THF
(22.5 mL) and Et2O (15 mL) under N2 at 0 ꢁC. The reaction
mixture was cooled to ꢀ70 ꢁC, and a solution of 7a
(2.925 mg, 13.40 mmol) in THF (15 mL) and Et2O
(12 mL) was added to it. Then, PhLi (13.8 mL, 13.4 mmol)
was added to the mixture at ꢀ40 ꢁC and the reaction temper-
ature was elevated to ꢀ20 ꢁC. AcOH (0.77 mL, 13.4 mmol)
and t-BuOK (2.26 g, 20.1 mmol) were added to the reaction
mixture and the whole was stirred for 2 h at ambient tem-
perature. H2O (3 mL) was added to the mixture and after
evaporation of the solvent the products were extracted with
AcOEt (30 mLꢂ2). The organic layer was dried over
anhydrous Na2SO4 and evaporated to give an oily residue,
which was purified by column chromatography (AcOEt/
n-hexane¼1/1) to give 8c (E/Z¼72/28) as a yellow viscous
1
(652 mg, 58%); H NMR (CDCl3): d 0.44 (6H, s, SiMe2),
0.98 (9H, s, CMe3), 4.02 (3H, s, NMe), 7.89 (1H, s, 4-H),
9.77 (1H, s, CHO); 13C NMR (CDCl3): d ꢀ4.9, 17.7, 26.4,
34.8, 133.4, 144.5, 159.2, 179.1; IR (CHCl3): nmax 2934,
2830, 1667, 1459, 1250, 1145, 837, 808 cmꢀ1; MS (EI):
m/z 224 (M+, 3), 209 (8), 167 (100), 140 (12), 113 (3);
HRMS (EI) m/z 224.1340 (M+) (requires C11H20N2OSi:
224.1345).
1
4.1.5. General procedure for 5-ethenylimidazoles (8a,b),
synthesis of 1-methyl-2-phenylsulfanyl-5-ethenyl-1H-
imidazole (8a) as an example. n-BuLi (3.13 mL,
5.00 mmol) was added to a stirred solution of methyltri-
phenylphosphonium bromide (1.79 g, 5.00 mmol) in THF
(3 mL) under N2 at 0 ꢁC. After stirring for 1 h at the same
temperature, a solution of 7a (218 mg, 1.00 mmol) in THF
(2 mL) was added to the reaction mixture and the whole
was stirred for 6.5 h at ambient temperature. H2O (3 mL)
was added to the mixture and after evaporation of the solvent
the products were extracted with AcOEt (20 mLꢂ2). The
organic layer was dried over anhydrous Na2SO4 and
evaporated to give an oily residue, which was purified by
column chromatography (AcOEt) and recrystallized from
AcOEt/n-hexane to give 8a as yellow needles (195 mg,
90%); mp 59–62 ꢁC; 1H NMR (CDCl3): d 3.60 (3H, s,
NCH3), 5.30 (1H, dd, J¼1.1, 11.4 Hz, C]CHH), 5.66
(1H, dd, J¼1.1, 17.6 Hz, C]CHH), 6.48 (1H, ddd, J¼0.7,
11.4, 17.6 Hz, HC]CH2), 7.13–7.20 (3H, m, ArH), 7.23–
7.28 (2H, m, ArH), 7.35 (1H, s, 4-H); 13C NMR (CDCl3):
d 31.6, 115.7, 123.2, 126.6, 127.9, 128.0, 129.2, 134.4,
134.8, 138.5; IR (CHCl3): nmax 2960, 1722, 1473, 1440,
1389, 1243, 1213, 1041 cmꢀ1; MS (EI): m/z 216 (M+,
100), 183 (14), 91 (20), 80 (12), 68 (10); HRMS (EI) m/z
216.0714 (M+) (requires C12H12N2S: 216.0721). Found: C,
66.65; H, 5.65; N, 12.75; C12H12N2S requires C, 66.63; H,
5.59; N, 12.95.
oil (2.919 g, 95%). E-8c: H NMR (CDCl3): d 1.89 (3H, t,
J¼2.8 Hz, C]CHMe), 3.56 (3H, s, NCH3), 6.10–6.13 (1H,
m, C]CHMe), 6.14–6.16 (1H, m, CH]CHMe), 7.11–
7.27 (6H, m, Ph and 4-H); 13C NMR (CDCl3) d: 18.7, 31.3,
117.4, 126.3, 126.7, 127.6, 128.6, 129.1, 134.6, 135.2,
137.1; IR (CHCl3): nmax 2934, 1579, 1474, 1478, 1395,
1097 cmꢀ1; MS (EI): m/z 230 (M+, 100), 215 (52), 197
(11), 91 (13), 80 (15); HRMS (EI) m/z 230.0875 (M+)
(requires C13H14N2S: 230.0878).
4.1.8. General procedure for 5-ethenylimidazoles
(9a,b,d), synthesis of 5-[(2-ethoxycarbonyl)ethenyl]-1-
methyl-2-phenylsulfanyl-1H-imidazole (9a) as an exam-
ple. DBU (11.3 mL, 75.6 mmol) was added to a stirred
solution of LiCl (3.20 g, 75.6 mmol) and triethyl phospho-
noacetate (15.0 mL, 75.6 mmol) in CH3CN (250 mL) under
N2 at 0 ꢁC. After stirring for 10 min at the same temperature,
7a (11.000 g, 50.39 mmol) was added to the reaction mixture
and thewholewas stirred for 5 h at ambient temperature. H2O
(10 mL) was added to the mixture and after evaporationof the
solvent the products were extracted with AcOEt (100 mLꢂ
2). The organic layer was dried over anhydrous Na2SO4
and evaporated to give a crystalline residue, which was
purified by recrystallization from AcOEt/n-hexane to give
9a (E/Z¼97/3) as colorless needles (14.083 g, 97%);
mp 64–66 ꢁC. E-9a: 1H NMR (CDCl3): d 1.33 (3H, t,
J¼7.1 Hz, CH2CH3), 3.69 (3H, s, NCH3), 4.26 (2H, q,

I. Kawasaki et al. / Tetrahedron 62 (2006) 10182–10192
10187
J¼7.1 Hz, CH2CH3), 6.31 (1H, d, J¼15.9 Hz, C]CHCO),
7.13–7.20 (5H, m, Ph), 7.48 (1H, dd, J¼0.5, 15.9 Hz,
CH]CHCO), 7.58 (1H, s, 4-H); 13C NMR (CDCl3):
d 14.3, 32.0, 60.7, 117.2, 127.2, 129.0, 129.4, 129.5, 131.5,
132.2, 133.4, 142.5, 166.7; IR (CHCl3): nmax 2964, 1699,
1630, 1441, 1303, 1276, 1178, 1155 cmꢀ1; MS (EI): m/z
288 (M+, 100), 259 (31), 243 (15), 215 (87), 121 (15), 109
(16), 91 (30), 80 (16), 65 (8), 51 (10); HRMS (EI) m/z
288.0930 (M+) (requires C15H16N2O2S: 288.0932). Found:
C, 62.66; H, 5.65; N, 9.69; C15H16N2O2S requires C,
62.48; H, 5.59; N, 9.71.
CH]CHCO), 11.99 (br s, 1H, NH); 13C NMR (CDCl3):
d 14.2, 60.4, 116.2, 126.0, 127.5, 129.3, 129.9, 132.9,
133.7, 136.1, 141.3, 167.4; IR (CHCl3): nmax 3115, 3013,
2832, 1689, 1635, 1472, 1295, 1255, 1170, 972 cmꢀ1
;
MS (EI): m/z 274 (M+, 100), 227 (47), 201 (40), 109 (19),
66 (10); HRMS (EI) m/z 274.0775 (M+) (requires
C14H14N2O2S: 274.0776).
4.1.12. 5-[(2-Carbamoyl)ethenyl]-1-methyl-2-phenyl-
sulfanyl-1H-imidazole (9f). A solution of 9a (507 mg,
1.76 mmol) in MeOH (3 mL, saturated with NH3 gas) was
stirred for 3 days at room temperature. After evaporation of
the solvent, a crystalline residue was purified by recrystalli-
zation from MeOH to give 9f as colorless prisms (270 mg,
4.1.9. 5-[(2-Ethoxycarbonyl)ethenyl]-1-methoxymethyl-
2-phenylsulfanyl-1H-imidazole (9b). Starting with 7b
(4.924 g, 19.83 mmol), DBU (4.4 mL, 29.7 mmol), LiCl
(1.26 g, 29.7 mmol), triethyl phosphonoacetate (5.9 mL,
29.7 mmol), and CH3CN (100 mL), 9b was purified by col-
umn chromatography (AcOEt/n-hexane¼1/3) and recrystal-
lized from AcOEt/n-hexane as colorless needles (6.301 g,
100%, E/Z¼99/1); mp 71–73 ꢁC. E-9b: 1H NMR (CDCl3):
d 1.32 (3H, t, J¼7.1 Hz, CH2CH3), 3.22 (3H, s, OMe), 4.25
(q, 2H, J¼7.1 Hz, CH2CH3), 5.47 (2H, s, NCH2), 6.37 (1H,
d, J¼16.1 Hz, C]CHCO), 7.22–7.32 (5H, m, Ph), 7.58
(1H, dd, J¼0.6, 15.9 Hz, CH]CHCO), 7.58 (1H, s, 4-H);
13C NMR (CDCl3): d 14.2, 56.1, 60.6, 75.1, 118.1, 127.5,
129.0, 129.3, 129.4, 131.4, 132.8, 132.9, 143.3, 166.6; IR
(CHCl3): nmax 2961, 1699, 1629, 1477, 1366, 1303, 1182,
1148, 1110 cmꢀ1; MS (EI): m/z 318 (M+, 100), 275 (20),
227 (26), 121 (20), 91 (14); HRMS (EI) m/z 318.1027 (M+)
(requires C16H18N2O3S: 318.1038). Found: C, 60.11; H, 5.80;
N, 8.71; C16H18N2O3S requires C, 60.36; H, 5.70; N, 8.80.
1
59%); mp 142–145 ꢁC. E-9f: H NMR (CDCl3): d 3.66
(3H, s, NMe), 5.99 (1H, br s, NH2), 6.15 (1H, br s, NH2),
6.41 (1H, d, J¼15.4 Hz, C]CHCO), 7.15–7.30 (5H, m,
Ph), 7.47 (1H, d, J¼15.4 Hz, CH]CHCO), 7.54 (1H, s,
4-H); 13C NMR (CDCl3): d 31.8, 119.1, 127.2, 127.4,
128.8, 129.4, 130.9, 131.9, 133.5, 141.7, 167.3; IR (CHCl3):
nmax 3291, 2971, 1672, 1627, 1594, 1443, 1399, 1345,
1288 cmꢀ1; MS (EI): m/z 259 (M+, 100), 241 (6), 215 (40),
150 (10), 121 (12), 109 (8), 91 (17), 80 (12), 66 (7), 51 (7);
HRMS (EI) m/z 259.0783 (M+) (requires C13H13N3OS:
259.0779). Found: C, 59.97; H, 5.24; N, 15.95;
C13H13N3OS requires C, 60.21; H, 5.05; N, 16.20.
4.1.13. General procedure for 5-ethenylimidazoles (10–
12), synthesis of 1-methyl-4-(1-methyl-2-phenylsulfanyl-
1H-imidazol-5-yl)-2-phenylsulfanyl-4,5,6,7-tetrahydro-
1H-benzimidazole (10a) as an example (condition A in
Table 1). A solution of 8a (50 mg, 0.23 mmol) in xylene
(1 mL) was refluxed under N2 for 30 h. After evaporation
of the solvent, the crystalline residue was purified by prepar-
ative TLC (PTLC) (AcOEt/n-hexane¼1/1) to give 10a as
a yellow amorphous (46 mg, 92%); 1H NMR (CDCl3):
d 1.83–2.02 (3H, m, 6-CH2 and 5-H), 2.04–2.13 (1H, m,
5-H), 2.51–2.65 (2H, m, 7-CH2), 3.50 (3H, s, NMe), 3.66
(3H, s, NMe), 4.10 (1H, t, J¼4.4 Hz, 4-H), 6.73 (1H, d,
J¼0.5 Hz, 40-H), 7.10–7.29 (10H, m, Ph); 13C NMR
(CDCl3): d 19.6, 21.1, 29.2, 30.9, 31.5, 32.1, 126.1, 126.4,
127.4, 127.7, 128.6, 129.1, 129.2, 130.8, 135.3, 135.6,
135.9, 136.9, 137.1, 137.9; IR (CHCl3): nmax 2925, 1474,
1439, 1174, 1092 cmꢀ1; MS (EI): m/z 432 (M+, 100), 417
(3), 404 (5), 374 (11), 355 (7), 341 (46), 323 (10), 295 (14),
243 (10), 110 (7), 91 (5); HRMS (EI) m/z 432.1436 (M+)
(requires C24H24N4S2: 432.1442).
4.1.10. 2-tert-Butyldimethylsilyl-5-(2-ethoxycarbonyl-
ethenyl)-1-methyl-1H-imidazole (9d). Starting with 7d
(449 mg, 2.00 mmol), DBU (0.45 mL, 3.00 mmol), LiCl
(127 mg, 3.00 mmol), triethyl phosphonoacetate (0.60 mL,
3.00 mmol), and CH3CN (15 mL), 9d was purified by col-
umn chromatography (AcOEt/n-hexane¼1/1) and isolated
as a yellow viscous oil (507 mg, 86%, E/Z¼99/1). E-9d: 1H
NMR (CDCl3): d 0.33 (6H, s, SiMe2), 0.87 (9H, s, CMe3),
1.23 (3H, t, J¼7.1 Hz, CH2CH3), 3.67 (3H, s, NMe), 4.14
(2H, q, J¼7.1 Hz, CH2CH3), 6.20 (1H, d, J¼15.9 Hz,
C]CHCO), 7.46 (1H, d, J¼15.9 Hz, CH]CHCO), 7.54
(1H, s, 4-H); 13C NMR (CDCl3): d ꢀ4.8, 14.2, 17.7, 26.4,
32.9, 60.4, 116.2, 129.6, 131.0, 132.8, 154.4, 167.0; IR
(CHCl3): nmax 2928, 1694, 1627, 1303, 1271, 1250, 1201,
1147 cmꢀ1; MS (EI): m/z 294 (M+, 11), 279 (5), 249 (7),
237 (100), 165 (37), 135 (6), 113 (10), 75 (41), 59 (8);
HRMS (EI) m/z 294.1764 (M+) (requires C15H26N2O2Si:
294.1763).
4.1.14. 2-Phenylsulfanyl-4-{2-phenylsulfanyl-1-[2-(tri-
methylsilyl)ethoxymethyl]-1H-imidazol-5-yl}-4,5,6,7-
tetrahydro-1H-benzimidazole (10b). Starting with 8b
(33 mg, 0.10 mmol) by the reaction condition B, 10b was
4.1.11. 4-[(2-Ethoxycarbonyl)ethenyl]-2-phenylsulfanyl-
1H-imidazole (9c). A solution of 9b (200 mg, 0.63 mmol)
in HCl aq (10%, 3 mL) and EtOH (3 mL) was heated at
60 ꢁC for 2 h. The reaction mixture was basified by adding
K2CO3 and the products were extracted with AcOEt
(10 mLꢂ2). The organic layer was dried over anhydrous
Na2SO4 and evaporated to give an oily residue, which was
purified by column chromatography (AcOEt) to give 9c as
a yellow viscous oil (122 mg, 71%). E-9c: 1H NMR
(CDCl3): d 1.27 (3H, t, J¼7.1 Hz, CH2CH3), 4.18 (2H, q, J¼
7.1 Hz, CH2CH3), 6.34 (1H, d, J¼15.9 Hz, C]CHCO), 7.14
(1H, s, 5-H), 7.15–7.22 (5H, m, Ph), 7.46 (1H, d, J¼15.9 Hz,
1
isolated as a colorless viscous oil (12 mg, 36%); H NMR
(CDCl3): d ꢀ0.09 (9H, s, SiMe3), ꢀ0.06 (s, 9H, SiMe3),
0.80 (4H, m, 2ꢂCH2CH2Si), 1.82–1.88 (2H, m, 6-CH2),
2.17–2.27 (2H, m, 5-CH2), 2.61–2.70 (2H, m, 7-CH2),
3.31–3.42 (4H, m, 2ꢂCH2CH2Si), 4.18 (1H, br t,
J¼5.3 Hz, 4-H), 5.22, 5.28 (1H each, each d, J¼10.6 Hz,
NCH2), 5.30, 5.35 (1H each, each d, J¼10.6 Hz, NCH2),
6.91 (1H, d, J¼0.7 Hz, 40-H), 7.10–7.26 (10H, m, Ph); 13C
NMR (CDCl3): d ꢀ1.5, ꢀ1.4, 17.7, 17.8, 19.9, 21.3, 30.1,
34.6, 66.1, 66.2, 73.3, 75.4, 122.3, 126.2, 126.3, 127.3, 127.5,
128.3, 129.1, 129.2, 135.7, 135.8, 136.0, 136.4, 139.4, 146.8;

10188
I. Kawasaki et al. / Tetrahedron 62 (2006) 10182–10192
IR (CHCl3): nmax 2930, 1244, 1220, 1170, 1086, 1023, 856,
834 cmꢀ1; MS (EI): m/z 664 (M+, 100), 563 (15), 555 (25),
548 (21), 534 (11), 490 (13), 429 (10), 355 (9), 277 (6),
110 (25), 73 (46); HRMS (EI) m/z 664.2771 (M+) (requires
C34H48N4O2S2Si2: 664.2757).
(18), 91 (14), 77 (10), 57 (8); HRMS (EI) m/z 576.1866
(M+) (requires C30H32N4O4S2: 576.1865).
4.1.17. (4R*,5S*,6S*)-5,6-Bis(ethoxycarbonyl)-1-meth-
oxymethyl-4-(1-methoxymethyl-2-phenylsulfanyl-1H-
imidazol-5-yl)-2-phenylsulfanyl-4,5,6,7-tetrahydro-1H-
benzimidazole (10e) and (4R*,5S*,6R*)-5,6-bis(ethoxy-
carbonyl)-1-methoxymethyl-4-(1-methoxymethyl-2-phe-
nylsulfanyl-1H-imidazol-5-yl)-2-phenylsulfanyl-4,5,6,7-
tetrahydro-1H-benzimidazole (11b). Starting with 9b
(57 mg, 0.18 mmol) by the reaction condition C, a mixture
of 10e and 11b (8 mg, 14%, 10e/11b¼4/1) was obtained by
PTLC (CHCl3/MeOH¼20/1) and 10e was isolated from the
second fraction as a yellow viscous oil and 11b was
isolated from the first fraction as a yellow viscous oil. Com-
4.1.15. (4R*,5R*,6R*)-1,5,6-Trimethyl-4-(1-methyl-2-
phenylsulfanyl-1H-imidazol-5-yl)-2-phenylsulfanyl-
4,5,6,7-tetrahydro-1H-benzimidazole (10c). Starting with
8c (23 mg, 0.10 mmol) by the reaction condition B, 10c
was isolated as a yellow viscous oil (10 mg, 43%); 1H
NMR (CDCl3): d 1.02 (3H, d, J¼6.4 Hz, 5-Me), 1.16 (3H,
d, J¼6.4 Hz, 6-Me), 1.66–1.84 (2H, m, 5- and 6-H), 2.31
(1H, ddd, J¼2.4, 10.4, 15.9 Hz, 7-H), 2.66 (1H, ddd,
J¼1.1, 5.1, 15.9 Hz, 7-H), 3.46 (3H, s, NMe), 3.52 (3H, s,
NMe), 3.69 (1H, br d, J¼10.1 Hz, 4-H), 7.00 (1H, s, 40-H),
7.02–7.26 (10H, m, Ph); 13C NMR (CDCl3): d 17.1, 19.9,
30.0, 30.9, 32.1, 35.7, 41.1, 41.2, 125.8, 126.3, 126.8,
127.7, 128.9, 129.1ꢂ2, 129.2, 135.3, 135.9, 136.1, 136.7,
136.8, 138.1; IR (CHCl3): nmax 3044, 1579, 1474, 1447,
1371, 1092 cmꢀ1; MS (EI): m/z 460 (M+, 73), 445 (8), 404
(48), 369 (15), 327 (9), 295 (100), 230 (10), 202 (10), 150
(8), 109 (9), 91 (10), 77 (9); HRMS (EI) m/z 460.1764
(M+) (requires C26H28N4S2: 460.1755).
1
pound 10e: H NMR (CDCl3): d 1.16 (3H, t, J¼7.1 Hz,
CH2CH3), 1.20 (3H, t, J¼7.1 Hz, CH2CH3), 3.05 (2H, dd, J¼
1.3, 7.5 Hz, 7-CH2), 3.14 (3H, s, OMe), 3.19 (3H, s, OMe),
3.30–3.36 (1H, m, 6-H), 3.59 (1H, dd, J¼8.4, 9.2 Hz, 5-H),
3.96–4.15 (4H, m, 2ꢂCH2CH3), 4.67 (1H, d, J¼8.4 Hz, 4-
H), 5.19 (1H, br s, NCHH), 5.28 and 5.33 (1H each, each d,
J¼10.8 Hz, NCH2O), 5.61 (1H, br d, J¼10.8 Hz, NCHH),
6.93 (1H, s, 40-H), 7.11–7.23 (10H, m, Ph); 13C NMR
(CDCl3): d 14.0, 14.1, 22.7, 35.4, 41.8, 47.4, 55.7, 56.0,
61.1, 61.3, 75.3, 75.7, 126.5, 126.9, 127.7, 127.9, 128.3,
129.18, 129.22, 130.5, 134.0, 134.6, 135.1, 136.2, 138.4,
139.0, 172.4, 172.7; MS (EI): m/z 636 (M+, 100), 621 (20),
604 (91), 591 (50), 563 (43), 531 (30), 513 (13), 485 (27),
441 (12), 413 (23), 323 (9), 239 (8), 121 (9), 91 (7); HRMS
(EI) m/z 636.2079 (M+) (requires C32H36N4O6S2:
636.2076). Compound 11b: 1H NMR (CDCl3): d 1.19 (3H,
t, J¼7.1 Hz, CH2CH3), 1.25 (3H, t, J¼7.1 Hz, CH2CH3),
3.04–3.19 (3H, m, 6-H and 7-CH2), 3.14 (3H, s, OMe),
3.33 (3H, s, OMe), 3.81 (1H, br t, J¼2.2 Hz, 5-H), 4.09–
4.24 (4H, m, 2ꢂCH2CH3), 4.85 (1H, br t, J¼0.9 Hz, 4-H),
5.30 and 5.35 (1H each, each d, J¼10.6 Hz, NCH2O), 5.51
and 5.57 (1H each, each d, J¼11.1 Hz, NCH2O), 6.55 (1H,
s, 40-H), 7.15–7.38 (10H, m, Ph).
4.1.16. (4R*,5S*,6S*)-5,6-Bis(ethoxycarbonyl)-1-methyl-
4-(1-methyl-2-phenylsulfanyl-1H-imidazol-5-yl)-2-phe-
nylsulfanyl-4,5,6,7-tetrahydro-1H-benzimidazole (10d)
and (4R*,5S*,6R*)-5,6-bis(ethoxycarbonyl)-1-methyl-4-
(1-methyl-2-phenylsulfanyl-1H-imidazol-5-yl)-2-phenyl-
sulfanyl-4,5,6,7-tetrahydro-1H-benzimidazole (11a).
Starting with 9a (29 mg, 0.10 mmol) by the reaction condi-
tion A, a mixture of 10d and 11a (16 mg, 55%, 10d/
11a¼50/1) was obtained and 10d was isolated from the sec-
ond fraction as a yellow amorphous and 11a was isolated
from the first fraction as a yellow viscous oil. Compound
10d; 1H NMR (CDCl3): d 1.15 (3H, t, J¼7.1 Hz, CH2CH3),
1.20 (3H, t, J¼7.1 Hz, CH2CH3), 2.94–3.04 (2H, m,
7-CH2), 3.25–3.39 (2H, m, 5- and 6-H), 3.51 (3H, s, NMe),
3.57 (3H, s, NMe), 3.96–4.14 (4H, m, 2ꢂCH2CH3), 4.49
(1H, br d, J¼8.2 Hz, 4-H), 6.86 (1H, s, 40-H), 7.09–7.24
(10H, m, Ph); 13C NMR (CDCl3): d 13.95, 14.01, 22.9,
31.2, 31.9, 35.9, 41.8, 47.8, 61.2, 61.4, 126.1, 126.6, 127.3,
127.6, 128.0, 129.1, 129.2, 129.7, 133.8, 134.6, 135.4,
135.5, 137.7, 137.8, 172.3, 172.6; IR (CHCl3): nmax 3017,
1725, 1474, 1447, 1368, 1266, 1229, 1177, 1091,
1032 cmꢀ1; MS (EI): m/z 576 (M+, 100), 531 (7), 503 (93),
429 (20), 404 (47), 295 (61), 241 (12), 191 (9), 150 (8),
110 (12), 91(12), 77 (12); HRMS (EI) m/z576.1859 (M+) (re-
quires C30H32N4O4S2: 576.1865). Compound 11a: 1H NMR
(CDCl3): d 1.22 (3H, t, J¼7.1 Hz, CH2CH3), 1.27 (3H, t,
J¼7.1 Hz, CH2CH3), 2.99 (1H, dd, J¼5.0, 14.5 Hz, 7-H),
3.06–3.11 (1H, m, 6-H), 3.16 (1H, ddd, J¼0.9, 10.4,
14.7 Hz, 7-H), 3.37 (1H, dd, J¼2.0, 2.9 Hz, 5-H), 3.54 (3H,
s, NMe), 3.75 (3H, s, NMe), 4.10–4.25 (4H, m, 2ꢂCH2CH3),
4.71 (1H, br t, J¼0.8 Hz, 4-H), 6.55 (1H, d, J¼0.6 Hz, 40-H),
7.10–7.29 (10H, m, Ph); 13C NMR (CDCl3): d 14.0, 14.1,
20.8, 31.1, 31.3, 34.2, 36.9, 46.1, 61.2, 61.3, 126.5, 126.6,
127.81, 127.87, 129.19, 129.25, 129.27, 129.6, 134.2,
134.66, 134.68, 136.4, 137.8, 138.4, 170.9, 172.3; IR
(CHCl3): nmax 2949, 1723, 1579, 1474, 1446, 1367, 1264,
1022 cmꢀ1; MS (EI): m/z 576 (M+, 81), 503 (100), 429
(26), 404 (25), 295 (51), 241 (14), 217 (10), 191 (19), 110
4.1.18. (4R*,5S*,6S*)-5,6-Dicarbamoyl-1-methyl-4-(1-
methyl-2-phenylsulfanyl-1H-imidazol-5-yl)-2-phenylsul-
fanyl-4,5,6,7-tetrahydro-1H-benzimidazole (10f) and
(4R*,5S*,6S*)-1-methyl-4-(1-methyl-2-phenylsulfanyl-
1H-imidazol-5-yl)-2-phenylsulfanyl-4,5,6,7-tetrahydro-
1H-benzimidazole-5,6-dicarboxamide (12). Starting with
9f (52 mg, 0.20 mmol) by the reaction condition D, 10f
was isolated from the second fraction as a yellow viscous
oil (14 mg, 27%) and 12 was isolated from the first fraction
1
as a yellow viscous oil (16 mg, 32%). Compound 10f: H
NMR (CD3OD): d 2.94–2.98 (2H, m, 7-CH2), 3.02 (1H, t,
J¼10.8 Hz, 5-H), 3.13 (1H, dt, J¼5.9, 10.8 Hz, 6-H), 3.53
(3H, s, NMe), 3.56 (3H, s, NMe), 4.43 (1H, d, J¼10.4 Hz,
4-H), 6.99 (1H, s, 40-H), 7.06–7.28 (10H, m, Ph); 13C NMR
(CD3OD): d 18.2, 25.7, 31.7, 32.6, 37.3, 45.4, 115.3, 127.5,
128.0, 128.2, 129.1ꢂ2, 130.5, 130.6, 134.1, 135.9, 136.4,
137.7, 138.7, 141.6, 176.8, 177.5; IR (KBr): nmax 3316, 3199,
2905, 1667, 1630, 1591, 1450 cmꢀ1; HRMS (FAB) m/z
519.1629 (M+H)+ (requires C26H27N6O2S2: 519.1637).
1
Compound 12: H NMR (CDCl3): d 2.97 (1H, dd, J¼7.4,
16.0 Hz, 7-H), 3.27 (1H, dd, J¼1.4, 16.0 Hz, 7-H), 3.50
(3H, s, NCH3), 3.52–3.62 (2H, m, 5- and 6-H), 3.80 (3H, s,
NCH3), 4.80 (1H, br s, 4-H), 6.71 (1H, d, J¼0.6 Hz, 40-H),
7.06–7.28 (10H, m, Ph), 8.51 (1H, br s, NH); 13C NMR

I. Kawasaki et al. / Tetrahedron 62 (2006) 10182–10192
10189
(CDCl3): d 20.6, 31.3, 31.9, 33.1, 40.5, 46.5, 126.1, 126.8,
126.9, 127.4, 128.1, 128.2, 129.3, 129.4, 134.3ꢂ2, 135.5,
135.8, 137.8, 156.5, 177.2, 178.6; IR (CHCl3): nmax 3126,
2928, 1776, 1714, 1578, 1473, 1437, 1347 cmꢀ1; MS (EI):
m/z 501 (M+, 100), 429 (10), 404 (27), 295 (27), 142 (25),
110 (16), 77 (6); HRMS (EI) m/z 501.1289 (M+) (requires
C26H23N5O2S2: 501.1293).
129.3, 131.6, 131.7, 133.7, 134.1, 134.3, 135.3ꢂ2, 136.9,
137.65, 137.69, 168.3, 168.5; IR (CHCl3): nmax 2919, 1708,
1375, 1354, 1174, 1092 cmꢀ1; MS (EI): m/z 750 (M+, 14),
590 (100), 429 (21), 403 (6), 295 (16), 254 (9), 181 (13),
131 (15), 110 (38), 91 (14), 69 (42), 57 (19); HRMS (EI)
m/z 750.2069 (M+) (requires C42H34N6O4S2: 750.2083).
Found: C, 66.73; H, 4.82; N, 10.81; C42H34N6O4S2$1/3H2O
requires C, 66.65; H, 4.62; N, 11.10.
4.1.19. (4R*,5R*,6S*)-5,6-Bis(hydroxymethyl)-1-methyl-
4-(1-methyl-2-phenylsulfanyl-1H-imidazol-5-yl)-2-phe-
nylsulfanyl-4,5,6,7-tetrahydro-1H-benzimidazole (13).
Lithium aluminum hydride (602 mg, 15.9 mmol) was added
to a stirred solution of 10d (3.000 g, 5.20 mmol) in THF
(30 mL) under N2 at 0 ꢁC. After stirring for 21 min at ambient
temperature, saturated NaHCO3 aq (20 mL) was added to the
mixture and after evaporation of the solvent the products
were extracted with CHCl3 (100 mLꢂ3). The organic layer
was dried over Na2SO4 and evaporated to give a crystalline
residue, which was purified by recrystallization from
EtOH/Et2O to give 13 as colorless powder (2.522 g, 98%);
4.1.21. General procedure for 15 and 18 by desulfuriza-
tion, synthesis of (4R*,5R*,6S*)-5,6-bis[(1,3-dihydro-
1,3-dioxo-2H-isoindol-2-yl)methyl]-1-methyl-4-(1-methyl-
1H-imidazol-5-yl)-4,5,6,7-tetrahydro-1H-benzimidazole
(15) as an example. NaBH4 (45 mg, 1.18 mmol) was
added to a stirred solution of 14 (45 mg, 0.060 mmol) and
NiCl2$6H2O (21 mg, 0.89 mmol) in THF (2 mL) and
MeOH (6 mL) under N2 at 0 ꢁC. The reaction mixture was
stirred for 1 h at ambient temperature. HCl aq (36%, 2 mL)
was added to the mixture and the whole was stirred for
10 min and was basified by 28% NH3 aq. The products
were extracted with AcOEt (20 mLꢂ5). The organic layer
was dried over anhydrous Na2SO4 and evaporated to give
an oily residue, which was purified by PTLC (CHCl3/
MeOH¼5/1) to give 15 as a colorless amorphous (20 mg,
1
mp 119–123 ꢁC; H NMR (DMSO-d6): d 1.93–2.00 (1H,
m, 5-H), 2.07–2.15 (1H, m, 6-H), 2.59 (1H, ddd, J¼2.0,
10.1, 16.3 Hz, 7-H), 2.74 (1H, dd, J¼5.5, 15.6 Hz, 7-H),
3.30–3.35 (1H, m, CH2OH), 3.48 (3H, s, NMe), 3.55 (3H,
s, NMe), 3.62–3.65 (3H, m, CH2OH), 4.15 (1H, br d,
J¼9.3 Hz, 4-H), 4.65 (1H, t, J¼5.0 Hz, OH), 4.70 (1H, t, J¼
5.0 Hz, OH), 6.83 (1H, s, 40-H), 6.97–7.28 (10H, m, Ph); 13C
NMR (DMSO-d6): d 23.3, 30.8, 31.7, 33.5, 37.3, 42.4, 58.9,
62.4, 126.0, 126.1, 126.3, 126.7, 128.1, 129.35, 129.40,
130.0, 133.9, 134.7, 135.6, 135.9, 137.3, 137.7; IR (KBr):
nmax 3371, 2874, 1474, 1448, 1386, 736 cmꢀ1; MS (EI):
m/z 492 (M+, 62), 461 (29), 404 (49), 295 (100), 241 (20),
191 (11), 150 (12), 109 (15), 77 (19), 51 (7); HRMS (EI)
m/z 492.1667 (M+) (requires C26H28N4O2S2: 492.1653).
Found: C, 63.11; H, 5.84; N, 11.16; C26H28N4O2S2 requires
C, 63.39; H, 5.73; N, 11.37.
1
62%); H NMR (CD3OD): d 2.38–2.46 (1H, m, 6-H), 2.55
(1H, dd, J¼3.6, 16.4 Hz, 7-H), 2.72–2.78 (1H, m, 5-H),
2.90 (1H, dd, J¼5.8, 16.6 Hz, 7-H), 3.23 (1H, dd, J¼3.6,
13.8 Hz, NCH2), 3.60 (3H, s, NMe), 3.79 (3H, s, NMe),
3.81–3.89 (3H, m, NCH2), 4.06 (1H, br s, 4-H), 6.44 (1H,
s, 40-H), 7.54 (1H, s, 20-H), 7.62 (1H, s, 2-H), 7.71–7.80
(8H, m, Ar). 13C NMR (CD3OD): d 30.1, 31.5, 32.4, 34.9,
36.3, 41.8, 41.9, 42.3, 124.1, 124.2, 126.4, 127.1, 128.2,
128.5, 130.5, 133.1, 135.4, 135.5, 138.9, 139.3, 169.87,
169.93; IR (KBr): nmax 3365, 2908, 1763, 1702, 1395,
1357, 715 cmꢀ1; MS (EI): m/z 534 (M+, 12), 374 (100),
213 (11), 187 (21), 160 (12), 132 (9), 104 (7), 77 (7); HRMS
(EI) m/z 534.2027 (M+) (requires C30H26N6O4: 534.2015).
4.1.20. (4R*,5R*,6S*)-5,6-Bis[(1,3-dihydro-1,3-dioxo-
2H-isoindol-2-yl)methyl]-1-methyl-4-(1-methyl-2-phe-
nylsulfanyl-1H-imidazol-5-yl)-2-phenylsulfanyl-4,5,6,7-
tetrahydro-1H-benzimidazole (14). DEAD (40% in tolu-
ene, 1.28 mL, 2.94 mmol) was added to a stirred solution
of 13 (181 mg, 0.37 mmol), triphenylphosphine (771 mg,
2.94 mmol), and phthalimide (433 mg, 2.94 mmol) in THF
(2 mL) under N2 at 0 ꢁC. The reaction mixture was stirred
for 18 h at ambient temperature. HCl aq (10%, 1 mL) was
added to the mixture and the aqueous phase was washed
with AcOEt (10 mLꢂ2), basified by K2CO3, and extracted
with AcOEt (10 mLꢂ3). The organic layer was dried over
anhydrous Na2SO4 and evaporated to give an oily residue,
which was purified by column chromatography (AcOEt/
n-hexane¼1/1) and recrystallization from AcOEt/n-hexane
gave 14 as colorless needles (174 mg, 63%); mp 124–
125 ꢁC; 1H NMR (CDCl3): d 2.30–2.35 (1H, m, 6-H), 2.58
(1H, dd, J¼3.3, 16.5 Hz, 7-H), 2.73–2.78 (1H, m, 5-H),
2.95 (1H, dd, J¼5.7, 16.5 Hz, 7-H), 3.23 (1H, dd, J¼2.7,
13.8 Hz, NCH2), 3.56 (3H, s, NMe), 3.79 (3H, s, NMe),
3.86 (1H, dd, J¼5.3, 14.1 Hz, NCH2), 3.94 (1H, dd, J¼9.8,
14.1 Hz, NCH2), 3.97 (1H, dd, J¼11.0, 13.8 Hz, NCH2),
4.10 (1H, d, J¼1.5 Hz, 4-H), 6.76 (1H, d, J¼0.9 Hz, 40-H),
7.01–7.31 (10H, m, Ar), 7.67–7.84 (8H, m, Ar); 13C NMR
(CDCl3): d 20.8, 31.2, 31.6, 35.0, 35.2, 41.1ꢂ2, 41.2,
123.3, 123.4, 126.1, 126.4, 127.4, 127.6, 128.1, 129.2ꢂ2,
4.1.22. General procedure for pyrrole-imidazole dim-
mers (16a,b), synthesis of (4R*,5R*,6S*)-5,6-bis[(4-bromo-
1H-pyrrol-2-yl)-carbonylaminomethyl]-1-methyl-4-(1-
methyl-2-phenylsulfanyl-1H-imidazol-5-yl)-2-phenylsul-
fanyl-4,5,6,7-tetrahydro-1H-benzimidazole (16a) as an
example. A solution of 14 (57 mg, 0.08 mmol) in hydrazine
monohydrate (3 mL) was heated at 70 ꢁC under N2 for 9 h.
After evaporation of the solvent, the residue was dissolved
in DMAc (3 mL). 4-Bromo-2-(trichloroacetyl)pyrrole24
(177 mg, 0.61 mmol) and K2CO3 (84 mg, 0.61 mmol)
were added to the reaction mixture and the whole was stirred
for 3 h at room temperature. After evaporation of the
solvent, H2O (1 mL) was added and the products were
extracted with CHCl3 (20 mLꢂ2). The organic layer was
dried over anhydrous Na2SO4 and evaporated to give an
oily residue, which was purified by column chromatography
(CHCl3/MeOH¼10/1) to give 16a as a yellow amorphous
1
(31 mg, 49%); H NMR (CD3OD): d 2.35–2.43 (2H, m,
5- and 6-H), 2.61 (1H, dd, J¼4.5, 16.5 Hz, 7-H), 2.84
(1H, dd, J¼5.2, 16.4 Hz, 7-H), 3.29–3.34 (2H, m, NCH2),
3.39 (1H, dd, J¼5.9, 14.1 Hz, NCH2), 3.53 (3H, s, NMe),
3.55 (3H, s, NMe), 3.66 (1H, dd, J¼4.8, 14.1 Hz, NCH2),
4.08 (1H, d, J¼4.6 Hz, 4-H), 6.76 (1H, d, J¼1.5 Hz, pyr-
role), 6.82 (1H, d, J¼1.5 Hz, pyrrole), 6.83 (1H, s, 40-H),
6.90 (1H, d, J¼1.5 Hz, pyrrole), 6.91 (1H, d, J¼1.6 Hz,

10190
I. Kawasaki et al. / Tetrahedron 62 (2006) 10182–10192
1
pyrrole), 7.04–7.25 (m, 10H, Ph); 13C NMR (CD3OD): d 23.0,
31.6, 32.5, 35.7, 37.8, 41.9, 43.0, 43.6, 97.5, 97.6, 113.3,
113.7, 114.1, 122.9, 123.1, 127.3, 127.4, 127.6, 127.9,
128.4, 128.8, 129.7, 130.5ꢂ2, 131.1, 135.7, 136.1, 136.3,
138.4, 139.0, 162.7, 162.8; IR (KBr): nmax 3392, 2973,
1629, 1577, 1449, 1380, 1318, 919 cmꢀ1; HRMS (FAB) m/z
833.0703 (M+H)+ (requires C36H35Br2N8O2S2: 833.0691).
and isolated as a colorless amorphous (263 mg, 70%); H
NMR (CDCl3): d 0.99 (9H, s, CMe3), 1.04 (9H, s, CMe3),
2.11 (1H, br t, J¼9.9 Hz, 5-H), 2.38–2.47 (1H, m, 6-H),
2.53 (1H, dd, J¼1.8, 15.4 Hz, 7-H), 2.60 (1H, dd, J¼5.9,
15.2 Hz, 7-H), 3.44 (3H, s, NMe), 3.46 (3H, s, NMe), 3.76
(2H, d, J¼2.6 Hz, 5-CH2O), 3.84 (1H, dd, J¼4.9, 10.3 Hz,
6-CH2O), 3.88 (1H, dd, J¼3.3, 10.4 Hz, 6-CH2O), 4.24
(1H, br d, J¼9.7 Hz, 4-H), 6.55 (1H, s, 40-H), 7.19–7.55
(18H, m, Ph), 7.57–7.62 (4H, m, Ph); 13C NMR (CDCl3):
d 19.28, 19.30, 22.7, 26.7, 26.9, 30.8, 31.8, 32.6, 37.5,
42.2, 61.3, 65.0, 125.0, 126.4, 127.56, 127.59, 127.62,
129.6, 129.7, 132.7, 133.19, 133.22, 133.4, 133.6, 135.4,
135.5, 135.6, 136.4, 136.7, 137.8; IR (KBr): nmax 3339,
2908, 1498, 1466, 1445, 1105, 820 cmꢀ1; MS (EI): m/z 752
(M+, 53), 695 (8), 483 (100), 319 (7), 263 (10), 213 (17),
159 (9), 135 (33), 95 (10), 57 (6); HRMS (EI) m/z
752.3941 (M+) (requires C46H56N4O2Si2: 752.3941).
4.1.23. (4R*,5R*,6S*)-5,6-Bis[(4-bromo-1H-pyrrol-2-yl)-
carbonylaminomethyl]-1-methyl-4-(1-methyl-1H-imid-
azol-5-yl)-4,5,6,7-tetrahydro-1H-benzimidazole (16b).
Starting with 15 (49 mg, 0.09 mmol), hydrazine mono-
hydrate (3 mL), DMAc (3 mL), 4-bromo-2-(trichloroacetyl)-
pyrrole24 (213 mg, 0.73 mmol), and K2CO3 (101 mg,
0.73 mmol), 16b was purified by column chromatography
(CHCl3/MeOH¼5/1) and isolated as a colorless amorphous
1
(41 mg, 72%); H NMR (CD3OD): d 2.29–2.36 (2H, m,
5- and 6-H), 2.57 (1H, dd, J¼4.6, 16.7 Hz, 7-H), 2.82 (1H,
dd, J¼4.2, 13.6 Hz, 7-H), 3.34–3.40 (3H, m, NCH2), 3.55
(3H, s, NMe), 3.57 (3H, s, NMe), 3.65 (1H, dd, J¼4.0,
13.9 Hz, NCH2), 3.98 (1H, d, J¼4.2 Hz, 4-H), 6.61 (1H, s,
40-H), 6.77 (1H, d, J¼1.5 Hz, pyrrole), 6.84 (1H, d,
J¼1.6 Hz, pyrrole), 6.91 (1H, d, J¼1.6 Hz, pyrrole), 6.93
(1H, d, J¼1.5 Hz, pyrrole), 7.50 (2H, s, 2- and 20-H); 13C
NMR (CD3OD): d 21.3, 31.4, 32.2, 35.5, 38.4, 41.8, 43.4,
43.5, 97.47, 97.54, 113.3, 113.7, 122.9, 123.0, 126.7,
127.40, 127.43, 128.1, 134.7, 135.1, 138.5, 139.4, 162.7,
162.8; IR (KBr): nmax 3371, 3262, 2937, 1723, 1622, 1271,
1119 cmꢀ1; HRMS (FAB) m/z 617.0627 (M+H)+ (requires
C24H27Br2N8O2: 617.0624).
4.1.26. (4R*,5R*,6S*)-2-Azido-4-(2-azido-1-methyl-1H-
imidazol-5-yl)-5,6-bis[(tert-butyldiphenylsiloxy)methyl]-
1-methyl-4,5,6,7-tetrahydro-1H-benzimidazole (19).
sec-BuLi (1.0 M in cyclohexane, 3.4 mL, 3.4 mmol) was
added to a stirred solution of 18 (855 mg, 1.14 mmol) in
THF (6 mL) and DME (6 mL) under N2 at ꢀ40 ꢁC. After stir-
ring for 10 min at the same temperature, trisyl azide (738 mg,
2.39 mmol) was added to the reaction mixture and the whole
was stirred for 30 min at ꢀ40 ꢁC. H2O (1 mL) was added to
the mixture and after evaporation of the solvent the products
were extracted with CHCl3 (20 mLꢂ3). The organic layer
was dried over anhydrous Na2SO4 and evaporated to give
a crystalline residue, which was purified by column chroma-
tography (CHCl3/MeOH¼50/1) to give 19 as a yellow amor-
4.1.24. (4R*,5R*,6S*)-5,6-Bis[(tert-butyldiphenylsiloxy)-
methyl]-1-methyl-4-(1-methyl-2-phenylsulfanyl-1H-imid-
azol-5-yl)-2-phenylsulfanyl-4,5,6,7-tetrahydro-1H-
benzimidazole (17). TBDPSCl (2.54 mL, 9.76 mmol) was
added to a solution of 12 (2.186 g, 4.44 mmol) and imidazole
(1.51 g, 22.19 mmol) in DMF (5 mL). After stirring for 7 h at
room temperature, saturated NaHCO3 aq (3 mL) was added
to the reaction mixture and the products were extracted
with Et2O (20 mLꢂ2). The organic layer was dried over
anhydrous Na2SO4 and evaporated to give an oily residue,
which was purified by column chromatography (AcOEt/
n-hexane¼1/3) to give 17 as a colorless amorphous
1
phous (521 mg, 55%); H NMR (CDCl3): d 0.99 (9H, s,
CMe3), 1.02 (9H, s, CMe3), 2.11–2.17 (1H, m, 5-H), 2.34–
2.40 (1H, m, 6-H), 2.45–2.48 (2H, m, 7-CH2), 3.21 (3H, s,
NMe), 3.23 (3H, s, NMe), 3.72 (2H, d, J¼2.6 Hz,
5-CH2O), 3.78 (1H, dd, J¼5.9, 10.3 Hz, 6-CH2O), 3.83 (1H,
dd, J¼3.9, 10.2 Hz, 6-CH2O), 4.07 (1H, br d, J¼8.6 Hz,
4-H), 6.35 (1H, d, J¼0.5 Hz, 40-H), 7.24–7.44 (12H, m, Ph),
7.46–7.49 (4H, m, Ph), 7.56–7.59 (4H, m, Ph); IR (CHCl3):
nmax 2933, 2126, 1482, 1108 cmꢀ1; HRMS (FAB) m/z
835.4042 (M+H)+ (requires C46H55N10O2Si2: 835.4048).
1
(4.261 g, 99%); H NMR (CDCl3): d 0.99 (9H, s, CMe3),
4.1.27. (4R*,5R*,6S*)-2-Benzylidenamino-4-(2-benzyl-
idenamino-1-methyl-1H-imidazol-5-yl)-5,6-bis[(tert-
butyldiphenylsiloxy)methyl]-1-methyl-4,5,6,7-tetra-
hydro-1H-benzimidazole (20). A mixture of 19 (142 mg,
0.17 mmol) and Pd/C (10%, 100 mg) in AcOEt (3 mL) was
stirred under H2 (1 atm) for 12 h at room temperature. Pd/C
was removed by filtration, the filtrate was evaporated, and
the residue was dissolved in toluene (1 mL). Benzaldehyde
(0.04 mL, 0.42 mmol) was added to the mixture and the
whole was refluxed for 8 h. After evaporation of the solvent,
the residue was purified by column chromatography (AcOEt/
n-hexane¼1/3) to give 20 as a yellow amorphous (81 mg,
1.02 (9H, s, CMe3), 2.17–2.23 (1H, m, 5- or 6-H), 2.39–
2.47 (1H, m, 5- or 6-H), 2.55 (2H, br d, J¼6.6 Hz, 7-CH2),
3.40 (3H, s, NMe), 3.46 (3H, s, NMe), 3.69–3.84 (4H, m,
2ꢂOCH2), 4.31 (1H, br d, J¼6.2 Hz, 4-H), 6.65 (1H, s,
40-H), 7.01–7.42 (22H, m, Ph), 7.44–7.61 (8H, m, Ph); 13C
NMR (CDCl3) d: 19.28, 19.32, 23.0, 26.9ꢂ2, 30.8, 31.8,
33.6, 37.4, 42.0, 62.2, 65.1, 125.8, 126.4, 126.8, 127.7,
127.9, 128.6, 128.9, 129.10, 129.13, 129.69, 129.74, 129.8,
133.07, 133.12, 133.4, 133.5, 135.2, 135.4, 135.51, 135.53,
135.9, 136.3, 136.6, 136.8, 136.9; IR (CHCl3): nmax 2916,
1467, 1437, 1100 cmꢀ1; HRMS (FAB) m/z 969.4097
(M+H)+ (requires C58H65N4O2S2Si2: 969.4087).
1
50%); H NMR (CDCl3): d 1.02 (9H, s, CMe3), 1.03 (9H,
s, CMe3), 2.26–2.32 (1H, m, 5-H), 2.42–2.51 (1H, m, 6-H),
2.63 (2H, d, J¼7.0 Hz, 7-CH2), 3.61 (3H, s, NMe), 3.63
(3H, s, NMe), 3.78–3.85 (4H, m, 2ꢂCH2O), 4.34 (1H, d,
J¼8.2 Hz, 4-H), 6.54 (1H, s, 40-H), 7.23–7.61 (26H, m,
Ph), 7.89–7.96 (4H, m, Ph), 9.09 (1H, s, NCHPh), 9.19
(1H, s, NCHPh); 13C NMR (CDCl3): d 19.31, 19.34, 22.6,
26.9, 27.0, 28.8, 29.8, 33.4, 37.4, 42.1, 62.3, 65.2, 125.75,
4.1.25. (4R*,5R*,6S*)-5,6-Bis[(tert-butyldiphenylsiloxy)-
methyl]-1-methyl-4-(1-methyl-1H-imidazol-5-yl)-4,5,6,7-
tetrahydro-1H-benzimidazole (18). Starting with 17
(485 mg, 0.50 mmol), NiCl2$6H2O (1.663 g, 7.00 mmol),
NaBH4 (794 mg, 21.00 mmol), THF (15 mL), and MeOH
(45 mL), 18 was purified by PTLC (CHCl3/MeOH¼20/1)

I. Kawasaki et al. / Tetrahedron 62 (2006) 10182–10192
10191
125.81, 127.6, 128.6, 128.7, 128.81, 128.83, 129.65, 129.68,
129.70, 131.19, 131.22, 133.2, 133.4, 133.5, 133.7, 134.0,
135.50, 135.58, 135.60, 136.3, 136.4, 149.4, 150.0, 158.1,
158.2; IR (CHCl3): nmax 2910, 1606, 1468, 1423,
1108 cmꢀ1; HRMS (FAB) m/z 959.4860 (M+H)+ (requires
C60H67N6O2Si2: 959.4864).
added to a stirred solution of 22 (50 mg, 0.09 mmol) in
THF (0.5 mL) and the whole was stirred for 1.5 h at room
temperature. After evaporation of the solvent, the residue
was dissolved in DMAc (0.5 mL). 4-Bromo-2-(trichloro-
acetyl)pyrrole24 (164 mg, 0.56 mmol) and K2CO3 (78 mg,
0.56 mmol) were added to the reaction mixture and thewhole
was stirred for 3 h at room temperature. K2CO3 was removed
by filtration and the filtrate was evaporated to give an oily
residue, which was purified by PTLC (CHCl3/MeOH¼10/1)
4.1.28. (4R*,5R*,6S*)-2-Benzylidenamino-4-(2-benzyl-
idenamino-1-methyl-1H-imidazol-5-yl)-5,6-bis(hydroxy-
methyl)-1-methyl-4,5,6,7-tetrahydro-1H-benzimidazole
(21). CsF (16 mg, 0.11 mmol) was added to a solution of 20
(10 mg, 0.01 mmol) in DMF (0.1 mL) and the whole was
stirred at 80 ꢁC for 9 h. After evaporation of the solvent,
the residue was purified by PTLC (CHCl3/MeOH¼5/1)
and recrystallization from MeOH gave 21 as yellow powder
(4 mg, 83%); mp 273–274 ꢁC; 1H NMR (CDCl3, CD3OD):
d 1.99–2.05 (1H, m, 5-H), 2.26 (1H, ddd, J¼4.8, 9.5,
14.5 Hz, 6-H), 2.67–2.82 (2H, m, 7-CH2), 3.59 (1H, dd,
J¼3.7, 11.5 Hz, CH2O), 3.69 (3H, s, NMe), 3.71 (3H, s,
NMe), 3.77–3.87 (3H, m, CH2O), 4.20 (1H, d, J¼9.3 Hz,
4-H), 6.77 (1H, s, 40-H), 7.42–7.53 (6H, m, Ph), 7.83–7.98
(4H, m, Ph), 8.94 (1H, s, NCHPh), 9.04 (1H, s, NCHPh);
13C NMR (CDCl3, CD3OD): d 22.6, 28.3, 29.2, 33.3, 37.8,
44.6, 60.0, 63.6, 125.0, 126.1, 128.18, 128.22, 128.36,
128.42, 131.2, 131.3, 133.1, 133.2, 135.5ꢂ2, 149.1, 149.4,
158.8, 159.0; IR (CHCl3): nmax 2909, 1722, 1369, 1239,
1209, 1041 cmꢀ1; HRMS (FAB) m/z 483.2513 (M+H)+ (re-
quires C28H31N6O2: 483.2508). Found: C, 69.46; H, 6.41; N,
17.24; C28H30N6O2 requires C, 69.69; H, 6.27; N, 17.41.
1
to give 23 as a yellow amorphous (16 mg, 21%); H NMR
(CD3OD): d 2.37–2.42 (1H, m, 5- or 6-H), 2.46–2.52 (1H,
m, 5- or 6-H), 2.66 (1H, dd, J¼6.0, 17.2 Hz, 7-H), 2.89–
2.94 (1H, m, 7-H), 3.42–3.47 (3H, m, NCH2), 3.65–3.71
(1H, m, NCH2), 3.68 (3H, s, NMe), 3.70 (3H, s, NMe),
4.06 (1H, br d, J¼5.3 Hz, 4-H), 6.70 (1H, s, 40-H), 6.77
(1H, d, J¼1.5 Hz, pyrrole), 6.81 (1H, d, J¼1.5 Hz, pyrrole),
6.86 (1H, d, J¼1.5 Hz, pyrrole), 6.90 (1H, d, J¼1.5 Hz, pyr-
role), 7.43–7.53 (6H, m, Ph), 7.89–7.95 (4H, m, Ph), 8.94
(2H, s, NCHPh); 13C NMR (CD3OD): d 21.3, 29.5, 30.3,
35.5, 37.8, 38.4, 42.9, 43.4, 97.5ꢂ2, 113.3, 113.6, 122.9,
123.0, 127.3, 127.4, 127.5, 129.88, 129.93, 129.97, 130.08,
130.17, 130.21, 132.9, 133.1, 135.4, 137.36, 137.40,
151.2ꢂ2, 160.9ꢂ2, 162.7, 162.8; IR (KBr): nmax 3340,
2903, 1617, 1583, 1317 cmꢀ1; HRMS (FAB) m/z 823.1465
(M+H)+ (requires C38H37Br2N10O2: 823.1468).
4.1.31. (4R*,5R*,6S*)-2-Amino-4-(2-amino-1-methyl-
1H-imidazol-5-yl)-5,6-bis[(4-bromo-1H-pyrrol-2-yl)-
carbonylaminomethyl]-1-methyl-4,5,6,7-tetrahydro-1H-
benzimidazole (24) (12,120-dimethylageliferin). A solu-
tion of 23 (6 mg, 0.007 mmol) in EtOH (0.5 mL) and HCl
(0.5 M, 0.5 mL) was stirred for 30 min at room temperature.
After evaporation of the solvent, the residue was washed with
AcOEt (10 mL) and dried to give 24 as a yellow amorphous
(4 mg, 76%); 1H NMR (CD3OD): d 2.37–2.44 (1H, m, 5- or
6-H), 2.44–2.50 (1H, m, 5- or 6-H), 2.55 (1H, br d, J¼
17.0 Hz, 7-H), 2.75 (1H, dd, J¼17.0, 5.0 Hz, 7-H), 3.406
(3H, s, NMe), 3.414 (3H, s, NMe), 3.42–3.49 (2H, m,
NCH2), 3.56 (1H, dd, J¼9.5, 5.1 Hz, NCH2), 3.67 (1H, dd,
J¼9.5, 4.2 Hz, NCH2), 3.95 (1H, br s, 4-H), 6.73 (1H, br s,
40-H), 6.83 (1H, d, J¼1.5 Hz, pyrrole), 6.90 (1H, d,
J¼1.5 Hz, pyrrole), 6.92 (1H, d, J¼1.5 Hz, pyrrole), 6.95
(1H, d, J¼1.5 Hz, pyrrole); IR (KBr): nmax 3285, 2993,
1659, 1634 cmꢀ1; HRMS (FAB) m/z 647.0839 (M+H)+
(requires C24H29Br2N10O2: 647.0842).
4.1.29. (4R*,5R*,6S*)-5,6-Bis(azidomethyl)-2-benzyliden-
amino-4-(2-benzylidenamino-1-methyl-1H-imidazol-5-
yl)-1-methyl-4,5,6,7-tetrahydro-1H-benzimidazole (22).
DEAD (40% in toluene, 0.18 mL, 0.42 mmol) was added
to a stirred solution of 21 (48 mg, 0.10 mmol), triphenyl-
phosphine (107 mg, 0.41 mmol), and DPPA (0.107 mL,
0.50 mmol) in THF (1 mL) under N2 at 0 ꢁC. After stirring
for 1.5 h, the solvent was evaporated and saturated NaHCO3
aq (1 mL) was added to the residue, the products were ex-
tracted with CHCl3 (10 mLꢂ3). The organic layer was dried
over anhydrous Na2SO4 and evaporated to give an oily res-
idue, which was purified by PTLC (AcOEt) to give 22 as a
yellow amorphous (50 mg, 95%); 1H NMR (CDCl3): d
2.13–2.19 (1H, m, 5- or 6-H), 2.27–2.36 (1H, m, 5- or 6-H),
2.69 (1H, ddd, J¼1.8, 9.0, 15.9 Hz, 7-H), 2.77 (1H, ddd,
J¼1.1, 5.7, 16.1 Hz, 7-H), 3.58–3.65 (4H, m, 2ꢂCH2N3),
3.67 (3H, s, NMe), 3.70 (3H, s, NMe), 4.17 (1H, d,
J¼8.4 Hz, 4-H), 6.81 (1H, s, 40-H), 7.39–7.58 (6H, m, Ph),
7.88–7.97 (4H, m, Ph), 9.08 (1H, s, NCHPh), 9.23 (1H, s,
NCHPh); 13C NMR (CDCl3): d 23.8, 29.0, 30.0, 34.7,
35.9, 41.2, 51.0, 54.1, 125.5, 126.3, 128.6, 128.7, 128.87,
128.92, 131.4, 131.5, 131.9, 133.4, 136.0, 136.1, 149.9,
150.6, 158.9, 159.0; IR (CHCl3): nmax 2916, 2089, 1476,
1420, 1266, 961 cmꢀ1; MS (EI): m/z 532 (M+, 63), 504
(17), 490 (21), 419 (50), 394 (39), 292 (31), 250 (60), 236
(100), 170 (31), 145 (29), 94 (59), 77 (46); HRMS (EI)
m/z 532.2573 (M+) (requires C28H28N12: 532.2559).
4.2. X-ray crystallography
4.2.1. Compound 17. Crystal data: C58H64N4O2S2Si2,
M¼969.46, triclinic, a¼14.419(7), b¼14.670(3), c¼
ꢁ
ꢁ
ꢁ
˚
13.487(5) A, a¼101.91(2) , b¼102.32(4) , g¼82.14(2) ;
V¼2714(1) A ; Z¼2, m(Cu Ka)¼16.53 cmꢀ1; T¼296 K;
3
˚
R1¼0.075 for 8620 observations, space group P-1(#2).
Acknowledgements
We are grateful for financial support in part by the Frontier
Research Program and the 21st Century COE Program
‘Development of Drug Discovery Frontier Integrated from
Traditional to Proteome0 from the Ministry of Education,
Culture, Sports, Science, and Technology (MEXT) of Japan,
and a Grant-In-Aid for the promotion of the advancement of
4.1.30. (4R*,5R*,6S*)-2-Benzylidenamino-4-(2-benzyl-
idenamino-1-methyl-1H-imidazol-5-yl)-5,6-bis[(4-bromo-
1H-pyrrol-2-yl)-carbonylaminomethyl]-1-methyl-
4,5,6,7-tetrahydro-1H-benzimidazole (23). Triphenyl-
phosphine (56 mg, 0.21 mmol) and 1 drop of H2O were

10192
I. Kawasaki et al. / Tetrahedron 62 (2006) 10182–10192
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Yamashita, M.; Ohta, S. J. Chem. Soc., Chem. Commun. 1994,
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