New access to 1,3-dialkyl-2,3-dihydro-2-imino-1H-imidazoles and their application to the first total synthesis of naamine B, a marine 2,3-dihydro-2-imino-1,3-dimethyl-1H-imidazole alkaloid

Article abstract of DOI:10.1039/b108762b

1,3-Dialkyl-2,3-dihydro-2-imino-1H-imidazole derivatives are synthesized in 49-86% yield by treatment of 1,3-dialkyl-2-(phenylsulfanyl)imidazolium salts with primary carbamates or amides in the presence of a base such as LDA or NaH, and the first total sy

Full text of DOI:10.1039/b108762b

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New access to 1,3-dialkyl-2,3-dihydro-2-imino-1H-imidazoles and
their application to the first total synthesis of naamine B, a marine
2,3-dihydro-2-imino-1,3-dimethyl-1H-imidazole alkaloid
1
Ikuo Kawasaki, Seikou Nakamura, Satomi Yanagitani, Akiko Kakuno, Masayuki Yamashita
and Shunsaku Ohta*
Kyoto Pharmaceutical University, Misasagi Yamashinaku, Kyoto 607-8414, Japan.
E-mail: sohta@mb.kyoto-phu.ac.jp
Received (in Cambridge, UK) 27th September 2001, Accepted 22nd October 2001
First published as an Advance Article on the web 14th November 2001
1,3-Dialkyl-2,3-dihydro-2-imino-1H-imidazole derivatives are synthesized in 49–86% yield by treatment of
1,3-dialkyl-2-(phenylsulfanyl)imidazolium salts with primary carbamates or amides in the presence of a base such as
LDA or NaH, and the first total synthesis of naamine B, a marine 2-imino-2,3-dimethyl-1,3-dihydro-1H-imidazole
alkaloid, is achieved by application of this reaction as a key step.
Introduction
Recently, many types of biologically active imidazole alkaloids
have been isolated from marine organisms such as sponges,
and they have become one of the focuses of scientific attention.1
1,3-Dialkyl-2,3-dihydro-2-imino-1H-imidazoles can be seen as
basic skeletons of several biologically interesting compounds,2
and a marine alkaloid, naamine B 1, was isolated from the
antifungally active extract of the marine sponge Leucetta
chagosensis,1i together with several antitumor (in vivo) imid-
Fig. 1
azole alkaloids,3 and its structure is shown in Fig. 1. Although
there are several examples of the synthesis of 1,3-dialkyl-2,3-
hydroxide ion at the 2-position of the imidazolium salts 2
followed by removal of the thiophenoxide ion from the inter-
mediate 3 to produce 4 as shown in Scheme 1. As an expanded
application of this reaction, we planned the use of appropriate
primary amides or carbamates in the presence of an appro-
priate base instead of the above-mentioned aqueous alkali. The
dihydro-2-imino-1H-imidazoles based on cyclization chem-
istry,2d,f it was reported that attempted direct conversion of an
imidazole compound to the 2-imino derivative was not effect-
ive.4 We have reported total syntheses of several biologically
active imidazole alkaloids such as topsentin,5 nortopsentins
A–D,6 kealiiquinone,7 naamine A,8 naamidine A8 and clath-
results are summarized in Table 1.
ridine,9 and this time we selected naamine B as a synthetic
The 1,3-dialkyl-2-(phenylsulfanyl)imidazolium salts 2a–d
target, which could be classified in one of the structural cate-
gories among the known imidazole marine alkaloids. In this
paper, we would like to disclose a new preparation method
for 1,3-dialkyl-2,3-dihydro-2-imino-1H-imidazole compounds
starting from imidazole compounds and its application to the
total synthesis of 1.
were easily prepared by treatment of 1-alkyl-2-phenylsulfanyl-
1H-imidazoles11 with alkyl halides in refluxed AcOEt as previ-
ously we reported.10 Reaction of 2a in THF with acetamide in
the presence of 2 equivalents of LDA gave the best result, and
the desired 2-acetylimino-1-benzyl-2,3-dihydro-3-methyl-1H-
imidazole 5a was obtained in 86% yield (entry 2). Decreasing
the amount of LDA to 1 equivalent or using 2 equivalents of
either NaH or NaOMe instead of LDA lowered the yield of 5a
(entries 1, 3 and 4), and in several cases the undesired 2-
oxoimidazoline 4a was obtained in 48% to quantitative yield
Results and discussion
In our previous paper, we reported a new synthetic method
for the 1,3-dialkyl-1,3-dihydroimidazol-2-ones 4 by treatment
(entries 3 and 4). The production of 4a indicated that the
of 1,3-dialkyl-2-phenylsulfanyl-1H-imidazolium salts 2 with
unconsumed starting substrate 2a might be hydrolysed during
aqueous alkali, and its application to the synthesis of a regio-
the work-up procedure. The reaction of 2a with benzamide,
tert-butyl carbamate or benzyl carbamate in the presence of
LDA or NaH in THF at 0 ЊC to room temperature gave the
isomer of kealiiquinone, a marine benzimidazole alkaloid
(Scheme 1).10 This reaction would be initiated by attack of the
corresponding iminoimidazolines 5b–d in moderate to fair yield
(entries 5–7). Other imidazolium derivatives such as 2b–d could
be also converted to the corresponding N-Boc imino derivatives
5e–g in 65–70% yield (Entries 8–10). The present method seems
to be efficient for the preparation of multifunctionalized
2-iminoimidazoline derivatives compared with the known
methods based on cyclization to afford the imidazoline ring.2d,f
The present reaction described above was applied to the total
synthesis of naamine B 1 as follows. The known trisubstituted
Scheme 1
DOI: 10.1039/b108762b
J. Chem. Soc., Perkin Trans. 1, 2001, 3095–3099
This journal is © The Royal Society of Chemistry 2001
3095

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Table 1 Preparation of the acylimines 5
Imidazolium salt
Product
Entry
Compd.
R1
R2
X
R3
Base (eq.)
Yield (%)a
Compd.
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2b
2c
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Bn
Bn
Br
Br
Br
Br
Br
Br
Br
I
Me
Me
Me
Me
LDA (1.0)
LDA (2.0)
NaH (2.0)
MeONa (2.0)
LDA (2.0)
LDA (2.0)
NaH (2.0)
LDA (2.0)
LDA (2.0)
LDA (2.0)
70b
86
43c
0d
49
71
54
69
70
65
5a
5a
5a
Ph
5b
5c
5d
5e
5f
ButO
BnO
ButO
ButO
ButO
Br
Br
10
2de
Et
5g
a Isolated yield. b Trace amount of 4a was also obtained. c A by-product 4a was isolated in 48% yield. d Quantitative yield of 4a was obtained.
e The crude quaternary salt was used.
Scheme 2 Reagents and conditions: (a) Zn, conc. HCl, AcOH, 97%; (b) NBS, THF, 72%; (c) t-BuLi, THF, 63%; (d) Et3SiH, TFA, DCM, 80%;
(e) MeI, AcOEt; (f ) LDA, tert-butyl carbamate, 13: 56% and 14: 21% (2 steps); (g) TFA, DCM, quant. (from 13).
imidazole 611a was selected as the starting material, and the
benzylic hydroxy group of 6 was removed by reduction with a
zinc powder–conc. HCl system to give the sulfide 7 in 97% yield
(Scheme 2). The 4-position of the product was brominated by
treatment with NBS in THF,12 and then the resultant bromide 8
was coupled with the aldehyde 913 in the presence of t-BuLi to
give the alcohol 10 in 63% yield from 8.14 Reduction of the
alcohol 10 with the combination of triethylsilane (5 equiv.) and
TFA (6 equiv.)15 proceeded effectively to give the silyl ether 11
in 80% yield. The imidazolium iodide 12 was prepared in the
usual manner, and the salt 12 was treated with tert-butyl carb-
amate in the presence of LDA at Ϫ78 ЊC to give the desired
N-Boc imino compound 13 in 56% yield accompanied by a
21% yield of the 2-oxoimidazoline 14.
structure and were well consistent with the reported data of
natural naamine B 1.
In conclusion, we have successfully developed a prepar-
ative method for 1,3-dialkyl-2,3-dihydro-2-imino-1H-imidazole
derivatives starting from imidazole compounds, and have
achieved the first total synthesis of naamine B in 20% overall
yield from 6.
Experimental
All mps were measured with a Yanaco MP micro-melting-point
apparatus and are uncorrected. IR spectra were taken with a
Shimadzu IR-435 spectrometer. NMR spectra were measured
on a Varian UNITY INOVA 400NB (1H: 400 MHz, 13C:
100 MHz) or a JEOL EX-300 (1H: 300 MHz, 13C: 75 MHz)
spectrometer with tetramethylsilane as internal standard, and
chemical shifts δ are reported in ppm. HRMS was measured on
a JEOL JMS-SX 102A QQ (FAB) or a JEOL JMS BU-20 (EI)
Treatment of iminocarbamate 13 with TFA to remove the
Boc and TBDMS groups gave successfully the powdered
material 1 in quantitative yield. The spectral data (1H-, 13C-
NMR, MS and IR) of the product 1 completely supported the
3096
J. Chem. Soc., Perkin Trans. 1, 2001, 3095–3099

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spectrometer, respectively. Silica gel (Merck Art. 7734) for
column chromatography and silica gel 60 PF254 (Nacalai Tesque
Inc.) for preparative TLC (PLC) were used.
2-tert-Butoxycarbonylimino-2,3-dihydro-1,3-dimethyl-1H-
imidazole 5e. This was prepared in a similar manner to that
used for the preparation of 5c except for the use of 2b10 instead
of 2a. Title compound was purified by column chromatography
(CHCl3–MeOH 5 : 1) and obtained as colorless needles (73 mg,
69%), mp 146–149 ЊC (from diethyl ether); νmax (CHCl3) 2954,
1625, 1576, 1360, 1318, 1243, 1162, 1049 cmϪ1; δH (400 MHz;
CDCl3) 1.52 (s, 9H), 3.44 (s, 6H), 6.49 (s, 2H); δC (100 MHz;
CDCl3) 28.5, 33.8, 76.9, 115.5, 150.8, 159.4 [Calc. for C10H17-
N3O2: C, 56.85; H, 8.11; N, 19.89. Found: C, 56.55; H, 8.01; N,
20.15%. FAB-HRMS (pos.) m/z Calc. for C10H18N3O2: M ϩ H,
212.1399. Found: (M ϩ H)ϩ, 212.1405].
General procedure for synthesis of 1,3-dialkyl-2,3-dihydro-
2-imino-1H-imidazoles 5; Synthesis of 1-benzyl-2-tert-butoxy-
carbonylimino-2,3-dihydro-3-methyl-1H-imidazole 5c as an
example
tert-Butyl carbamate (176 mg, 1.5 mmol) was added to a stirred
solution of LDA [prepared from diisopropylamine (1 mmol)
and n-BuLi (1 mmol; 1.6 M in n-hexane)] in THF (4 mL) under
N2 and ice cooling, and the mixture was stirred for 30 min at
0 ЊC, then the salt 2a10 (181 mg, 0.5 mmol) was added to
the mixture and stirring was continued for 12 h at ambient
temperature. Water (1 mL) was added to the reaction mixture
and the solvent was removed under reduced pressure. The
product was extracted with CHCl3 (20 mL × 4) and the organic
layer was dried over anhydrous sodium sulfate. The solvent
was evaporated to give an oily residue, which was purified by
column chromatography (CHCl3–MeOH 20 : 1) on silica gel to
give 5c (102 mg, 71%) as colorless crystals, mp 88–91 ЊC (from
AcOEt–n-hexane); νmax (CHCl3) 2954, 1626, 1557, 1361, 1340,
1233, 1157, 1063 cmϪ1; δH (400 MHz; CDCl3) 1.51 (s, 9H), 3.48
(s, 3H), 5.01 (s, 2H), 6.34 (d, J = 2.6 Hz, 1H), 6.50 (d, J = 2.6 Hz,
1H), 7.24–7.34 (m, 5H); δC (100 MHz; CDCl3) 28.6, 34.0, 49.8,
77.0, 113.9, 116.1, 128.2, 128.4, 128.9, 135.4, 150.9, 159.4
[Calc. for C16H21N3O2: C, 66.88; H, 7.37; N, 14.62. Found:
C, 66.59; H, 7.37; N, 14.41%. FAB-HRMS (pos.) m/z Calc. for
C16H22N3O2: M ϩ H, 288.1712. Found: (M ϩ H)ϩ, 288.1707].
1,3-Dibenzyl-2-phenylsulfanyl-1H-imidazolium bromide 2c
A mixture of 1-benzyl-2-phenylsulfanyl-1H-imidazole11b (146
mg, 0.55 mmol) and benzyl bromide (0.098 mL, 0.83 mmol) in
AcOEt (0.83 mL) was refluxed under stirring for 3 h, and then
kept overnight at room temperature. The crude solid was col-
lected and recrystallized from acetone–diethyl ether to give pure
2c as colorless crystals (229 mg, 95%), mp 170–171 ЊC; νmax
(CHCl3) 2917, 1492, 1449, 1234, 1170, 1091 cmϪ1; δH (400 MHz;
CDCl3) 5.63 (s, 4H), 6.95 (dd, J = 8.2, 1.5 Hz, 2H), 7.27–7.32
(m, 13H), 8.16 (s, 2H); δC (100 MHz; CDCl3) 53.6, 125.4, 128.9,
129.0, 129.1, 129.2, 129.3 (×2), 130.4, 132.5, 137.9 (Calc. for
C23H21BrN2S: C, 63.16; H, 4.84; N, 6.40. Found; C, 63.22; H,
5.04; N, 6.23%).
1,3-Dibenzyl-2-tert-butoxycarbonylimino-2,3-dihydro-
1H-imidazole 5f
This was prepared in a similar manner to that used for the
preparation of 5c except for the use of 2c (87 mg, 0.2 mmol)
instead of 2a. Title compound was purified by column chrom-
atography (CHCl3–MeOH 20 : 1) and obtained as colorless
crystals (51 mg, 70%), mp 130–132 ЊC (from AcOEt–n-hexane);
νmax (CHCl3) 2957, 1625, 1558, 1331, 1287, 1154, 1073,
1016 cmϪ1; δH (400 MHz; CDCl3) 1.52 (s, 9H), 5.03 (s, 4H), 6.29
(s, 2H), 7.26–7.37 (m, 10H); δC (100 MHz; CDCl3) 28.5, 50.0,
77.1, 114.3, 128.2, 128.5, 128.8, 135.1, 150.4, 159.3 [Calc for
C22H25N3O2: C, 72.70; H, 6.93; N, 11.56. Found; C, 72.42; H,
6.88; N, 11.62%. FAB-HRMS (pos.) m/z Calc. for C22H26N3O2:
M ϩ H, 364.2025. Found: (M ϩ H)ϩ, 364.2029].
2-Acetylimino-1-benzyl-2,3-dihydro-3-methyl-1H-imidazole
5a. This was prepared in a similar manner to that used for the
preparation of 5c except for the use of acetamide instead of
tert-butyl carbamate. Title compound was purified by column
chromatography (CHCl3–MeOH 10 : 1) and obtained as a pale
yellow oil (99 mg, 86%); νmax (CHCl3) 2954, 1575, 1514, 1380
cmϪ1; δH (400 MHz; CDCl3) 2.15 (s, 3H), 3.49 (s, 3H), 4.99
(s, 2H), 6.45 (d, J = 2.6 Hz, 1H), 6.58 (d, J = 2.6 Hz, 1H), 7.25–
7.36 (m, 5H); δC (100 MHz; CDCl3) 25.7, 33.9, 50.1, 114.8,
116.7, 128.4 (×2), 128.9, 134.8, 150.9, 176.3 [EI-HRMS (pos.)
m/z Calc. for C13H15N3O: M, 229.1215. Found: Mϩ, 229.1205].
2-Benzoylimino-1-benzyl-2,3-dihydro-3-methyl-1H-imidazole
5b. This was prepared in a similar manner to that used for the
preparation of 5c except for the use of benzamide instead of
tert-butyl carbamate. Title compound was purified by PLC
(CHCl3–MeOH 50 : 1) and obtained as a pale yellow oil (72 mg,
49%); νmax (CHCl3) 2950, 1591, 1522, 1375, 1322 cmϪ1; δH
(400 MHz; CDCl3) 3.54 (s, 3H), 5.06 (s, 2H), 6.50 (d, J = 2.6 Hz,
1H), 6.61 (d, J = 2.6 Hz, 1H), 7.27–7.46 (m, 8H), 8.23 (dd, J =
8.2, 2.2 Hz, 2H); δC (100 MHz; CDCl3) 34.1, 49.9, 114.5, 116.6,
127.5, 128.2, 128.4, 128.80, 128.81, 130.1, 135.1, 138.5, 151.9,
170.6 [EI-HRMS (pos.) m/z Calc. for C18H17N3O: M, 291.1371.
Found: Mϩ, 291.1361].
1-Benzyl-3-ethyl-2-phenylsulfanyl-1H-imidazolium bromide 2d
n-BuLi (1.6 M in n-hexane; 8.03 mL, 12.84 mmol) was added to
a stirred solution of 1-ethyl-1H-imidazole16 (1.029 g, 10.70
mmol) in THF (43 mL) under N2 at Ϫ78 ЊC. After stirring of
the mixture for 15 min at the same temperature, diphenyl
disulfide (2.803 g, 12.84 mmol) was added and the whole was
stirred for 3 h at Ϫ78 ЊC. The mixture was acidified with 10%
HCl and washed with diethyl ether. The aqueous layer was basi-
fied with K2CO3 powder and extracted with AcOEt (20 mL ×
2). The organic layer was dried over anhydrous sodium sulfate
and evaporated to give an oily residue, which was purified by
column chromatography (AcOEt–n-hexane 1 : 2) on silica gel to
give 1-ethyl-2-phenylsulfanyl-1H-imidazole (2.069 mg, 95%) as
a colorless oil; νmax (CHCl3) 2949, 1580, 1474, 1428, 1270, 1087
cmϪ1; δH (400 MHz; CDCl3) 1.28 (t, J = 7.3 Hz, 3H), 4.04 (q, J =
7.3 Hz, 2H), 7.11–7.27 (m, 7H); δC (100 MHz; CDCl3) 16.1,
42.0, 121.7, 126.5, 127.9, 129.1, 130.5, 135.2, 137.2 [EI-HRMS
(pos.) m/z Calc. for C11H12N2S: M, 204.0721. Found: Mϩ,
204.0724].
A mixture of 1-ethyl-2-phenylsulfanyl-1H-imidazole (390
mg, 1.91 mmol) and benzyl bromide (0.341 mL, 2.87 mmol) in
AcOEt (2.9 mL) was refluxed under stirring for 3 h, and then
kept overnight at room temperature. The solvent was evapor-
ated off to give a brown syrup, which was washed with AcOEt
(5 mL × 2) and evaporated to give a crude salt 2d (676 mg, 94%)
as a brown gum, which was used in the next reaction with-
out further purification; νmax (CHCl3) 2919, 1477, 1439, 1233,
1-Benzyl-2-benzyloxycarbonylimino-2,3-dihydro-3-methyl-
1H-imidazole 5d. This was prepared in a similar manner to that
used for the preparation of 5c except for the use of benzyl
carbamate and NaH instead of tert-butyl carbamate and LDA
respectively. Title compound was purified by column chrom-
atography (CHCl3–MeOH 50 : 1) and obtained as pale yellow
needles (86 mg, 54%), mp 93–95 ЊC (from AcOEt–n-hexane);
νmax (CHCl3) 2964, 1627, 1570, 1380, 1079 cmϪ1; δH (400 MHz;
CDCl3) 3.46 (s, 3H), 4.99 (s, 2H), 5.16 (s, 2H), 6.37 (d, J =
2.6 Hz, 1H), 6.50 (d, J = 2.6 Hz, 1H), 7.21–7.45 (m, 10H); δC
(100 MHz; CDCl3) 34.0, 49.9, 66.6, 114.2, 116.3, 127.2, 127.7,
128.1, 128.2, 128.3, 128.7, 135.1, 138.3, 150.7, 159.2 [Calc. for
C19H19N3O2: C, 71.01; H, 5.96; N, 13.08. Found: C, 70.77; H,
5.92; N, 12.99%. EI-HRMS (pos.) m/z Calc. for C19H19N3O2:
M, 321.1477. Found: Mϩ, 321.1466].
J. Chem. Soc., Perkin Trans. 1, 2001, 3095–3099
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1090 cmϪ1; δH (400 MHz; CDCl3) 1.39 (t, J = 7.3 Hz, 3H), 4.44
(q, J = 7.3 Hz, 2H), 5.70 (s, 2H), 7.02–7.04 (m, 2H), 7.19–7.37
(m, 8H), 8.30 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H); δC
(100 MHz; CDCl3) 15.3, 45.4, 53.4, 125.2, 125.7, 128.7, 128.9,
129.0, 129.08, 129.10, 129.11, 130.4, 132.8, 136.9 [FAB-HRMS
(pos.) m/z Calc. for C18H19N2S: M Ϫ Br, 302.1869. Found:
(M Ϫ Br)ϩ, 302.1863].
dropwise to a stirred solution of 8 (72 mg, 0.18 mmol) and 9
(253 mg, 0.95 mmol) in THF (1 mL) under N2 at Ϫ78 ЊC. After
stirring of the mixture for 10 min at the same temperature,
water (2 mL) was added. The product was extracted with
AcOEt (10 mL × 3) and the organic layer was dried over
anhydrous sodium sulfate. The solvent was evaporated off to
give an oily residue, which was purified by column chrom-
atography (AcOEt–n-hexane 1 : 3) on silica gel to give 10
(65 mg, 63%) as a pale yellow oil; νmax (CHCl3) 2913, 1606,
1579, 1504, 1447, 1270, 1243, 841 cmϪ1; δH (400 MHz; CDCl3)
0.10 (s, 6H), 0.96 (s, 9H), 3.27 (s, 3H), 3.74 (s, 3H), 3.76 (s, 3H),
3.77 (s, 2H), 5.74 (br s, 1H), 6.72–6.83 (m, 5H), 6.94–7.26 (m,
7H); δC (100 MHz; CDCl3) Ϫ4.7, 18.4, 25.7, 29.0, 31.4, 55.2,
55.5, 69.7, 111.8, 114.0, 119.5, 120.0, 126.3, 127.2, 128.8, 129.1,
129.2, 129.4, 135.1, 135.8, 136.2, 142.5, 144.8, 150.3, 158.2
[EI-HRMS (pos.) m/z Calc. for C32H40N2O4SSi: M, 576.2478.
Found: Mϩ, 576.2482].
1-Benzyl-2-tert-butoxycarbonylimino-3-ethyl-2,3-dihydro-
1H-imidazole 5g
This was prepared in a similar manner to that used for the
preparation of 5c except for the use of a solution of 2d (128 mg,
0.34 mmol) in THF (1.0 mL)–CH2Cl2 (0.2 mL) instead of
crystalline 2a. Title compound was purified by column chrom-
atography (CHCl3–MeOH 20 : 1) and obtained as colorless
crystals (67 mg, 65%), mp 156–157 ЊC (from AcOEt–n-hexane);
νmax (CHCl3) 2958, 1625, 1558, 1331, 1290, 1158, 1085,
1017 cmϪ1; δH (400 MHz; CDCl3) 1.36 (t, J = 7.3 Hz, 3H), 1.51
(s, 9H), 3.90 (q, J = 7.3 Hz, 2H), 5.00 (s, 2H), 6.34 (d, J = 2.6 Hz,
1H), 6.54 (d, J = 2.6 Hz, 1H), 7.25–7.37 (m, 5H); δC (100 MHz;
CDCl3) 14.1, 28.4, 41.1, 49.9, 76.8, 113.7, 114.2, 128.1, 128.5,
128.7, 135.1, 149.9, 159.2 [Calc. for C17H23N3O2: C, 67.75;
H, 7.69; N, 13.94. Found: C, 67.46; H, 7.53; N, 14.20%. FAB-
HRMS (pos.) m/z Calc. for C17H24N3O2: M ϩ H, 302.1869.
Found: (M ϩ H)ϩ, 302.1863].
4-[3(-tert-Butyldimethylsiloxy)-4-methoxybenzyl]-5-
(4-methoxybenzyl)-1-methyl-2-phenylsulfanyl-1H-imidazole 11
To a stirred solution of 10 (23 mg, 0.04 mmol) in CH2Cl2
(0.5 mL) were added triethylsilane (0.032 mL, 0.20 mmol) and
TFA (0.018 mL, 0.24 mmol) under N2 and ice-cooling. The
solution was stirred for 3.5 h at ambient temperature and
quenched by the addition of saturated aq. NaHCO3 (3 mL).
The products were extracted with AcOEt (10 mL × 2) and the
organic layer was dried over anhydrous sodium sulfate. The
solvent was evaporated off to give an oily residue, which was
purified by PLC (AcOEt–n-hexane 1 : 1) on silica gel to give 11
(18 mg, 80%) as a pale yellow oil; νmax (CHCl3) 2918, 1505,
1458, 1438, 1272, 1240, 839 cmϪ1; δH (400 MHz; CDCl3) 0.11 (s,
6H), 0.96 (s, 9H), 3.28 (s, 3H), 3.76 (s, 6H), 3.84 (s, 2H), 3.90 (s,
2H), 6.71–6.86 (m, 7H), 7.04–7.24 (m, 5H); δC (100 MHz;
CDCl3) Ϫ4.7, 18.4, 25.7, 29.2, 31.5, 33.3, 55.2, 55.6, 112.1,
114.0, 121.3, 121.5, 126.0, 127.0, 128.8, 129.1, 129.6, 129.9,
133.3, 135.3, 135.9, 140.3, 144.8, 149.2, 158.2 [EI-HRMS
(pos.) m/z Calc. for C32H40N2O3SSi: M, 560.2529. Found: Mϩ,
560.2519].
5-(4-Methoxybenzyl)-1-methyl-2-phenylsulfanyl-1H-imidazole 7
Zn powder (320 mg) was added to a mixture of 611a (261 mg,
0.8 mmol) and conc. HCl (0.8 mL) in AcOH (8 mL), and the
whole was stirred at 80 ЊC for 3 h. The reaction mixture was
filtered and the filtrate was concentrated, diluted with water
(3 mL), and basified by addition of K2CO3 powder. The prod-
ucts was extracted with AcOEt (20 mL × 4), and the organic
phase was dried over anhydrous sodium sulfate. The solvent
was evaporated off to give an oily residue, which was purified
by PLC (AcOEt) to give 7 (151 mg, 97%) as a pale yellow oil;
νmax (CHCl3) 2935, 1608, 1506, 1449, 1241, 1173, 1093, 1031
cmϪ1; δH (300 MHz; CDCl3) 3.39 (s, 3H), 3.79 (s, 3H), 3.89 (s,
2H), 6.84 (d, J = 8.6 Hz, 2H), 6.97–7.26 (m, 8H); δC (75 MHz;
CDCl3) 30.5, 31.2, 55.2, 114.1, 126.3, 127.6, 129.0 (×2), 129.1,
129.3, 134.4, 135.3, 137.6, 158.4 [EI-HRMS (pos.) m/z Calc. for
C18H18N2OS: M, 310.1140. Found: Mϩ, 310.1135].
2-tert-Butoxycarbonylimino-4-[3(-tert-butyldimethylsiloxy)-
4-methoxybenzyl]-2,3-dihydro-5-(4-methoxybenzyl)-
1,3-dimethyl-1H-imidazole 13 and 4-[3(-tert-butyldimethyl-
siloxy)-4-methoxybenzyl]-5-(4-methoxybenzyl)-1,3-dimethyl-
2,3-dihydro-1H-imidazol-2-one 14
4-Bromo-5-(4-methoxybenzyl)-1-methyl-2-phenylsulfanyl-
1H-imidazole 8
A mixture of 11 (72 mg, 0.13 mmol) and methyl iodide (0.1 mL,
1.6 mmol) in AcOEt (1 mL) was refluxed under stirring for 1 h.
The solvent was evaporated off to give the crude salt 12, which
was used in the next reaction without further purification.
tert-Butyl carbamate (46 mg, 0.39 mmol) was added to a
stirred solution of LDA [prepared from diisopropylamine
(0.312 mmol) and n-BuLi (0.26 mmol; 1.6 M in n-hexane)] in
THF (1 mL) under N2 and ice-cooling, and the mixture was
stirred for 30 min at 0 ЊC, then a solution of the salt 12 in THF
(0.8 mL) was added to the mixture and stirring was continued
for 12 h at ambient temperature. Water (3 mL) was added to the
reaction mixture and the solvent was removed under reduced
pressure. The product was extracted with CHCl3 (15 mL × 3)
and the organic layer was dried over anhydrous sodium sulfate.
The solvent was evaporated off to give an oily residue, which
was purified by PLC (CHCl3–MeOH 20 : 1) on silica gel to give
13 (Rf 0.20, 42 mg, 56%) and 14 (Rf 0.34, 13 mg, 21%) as a
colorless oil.
NBS (251 mg, 1.41 mmol) was added to a solution of 7
(364 mg, 1.17 mmol) in THF (2.3 mL) at 0 ЊC under N2, and
the whole was stirred at 0 ЊC for 4 h. After addition of water
(15 mL), the product was extracted with AcOEt (50 mL × 2),
and the the organic phase was dried over anhydrous sodium
sulfate. The solvent was evaporated off to give an oily residue,
which was purified column chromatography (AcOEt–n-hexane
1 : 5) on silica gel to give 8 (327 mg, 72%) as colorless needles,
mp 73–77 ЊC (from n-hexane); νmax (CHCl3) 2965, 1607, 1506,
1239, 1093 cmϪ1; δH (400 MHz; CDCl3) 3.38 (s, 3H), 3.78 (s,
3H), 3.94 (s, 2H), 6.83 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz,
2H), 7.12–7.27 (m, 5H); δC (75 MHz; CDCl3) 29.8, 32.3, 55.3,
114.2, 115.7, 126.7, 127.9, 128.4, 128.8, 129.2, 132.1, 134.2,
137.1, 158.3 [Calc. for C18H17BrN2OS: C, 55.53; H, 4.40; N,
7.20. Found: C, 55.62; H, 4.59; N, 6.99%. EI-HRMS (pos.) m/z
Calc. for C18H17BrN2OS: M, 388.0244. Found: Mϩ, 388.0243.
EI-MS (pos.) m/z (% base): 391 (9), 390 (39), 389 (16), 388 (38),
387 (8), 121 (100)].
Compound 13; νmax (CHCl3) 2910, 1623, 1551, 1521, 1335,
1244, 1163, 1047, 838 cmϪ1; δH (400 MHz; CDCl3) 0.12 (s, 6H),
0.96 (s, 9H), 1.48 (s, 9H), 3.27 (s, 3H), 3.28 (s, 3H), 3.775 (s, 3H),
3.783 (s, 3H), 3.82 (s, 2H), 3.87 (s, 2H), 6.58 (dd, J = 8.2, 2.2 Hz,
1H), 6.63 (d, J = 2.2 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.82 (d,
J = 8.6 Hz, 2H), 7.00 (d, J = 8.6 Hz, 2H); δC (100 MHz; CDCl3)
Ϫ4.7, 18.4, 25.6, 28.2, 28.5 (×2), 31.0, 31.1, 55.2, 55.4, 77.5,
4-{[3(-tert-Butyldimethylsiloxy)-4-methoxyphenyl]hydroxy-
methyl}-5-(4-methoxybenzyl)-1-methyl-2-phenylsulfanyl-
1H-imidazole 10
t-BuLi (1.56 M in pentane; 0.58 ml, 0.90 mmol) was added
3098
J. Chem. Soc., Perkin Trans. 1, 2001, 3095–3099

View Article Online
Keifer, R. E. Schwartz, M. E. S. Koker, R. G. Hughes, Jr., D.
112.3, 114.3, 120.7, 120.8, 122.8, 123.0, 128.3, 128.75, 128.80,
145.2, 148.4, 149.9, 158.0, 158.5 [FAB-HRMS (pos.) m/z
Calc. for C32H48N3O5Si: M ϩ H, 582.3363. Found: (M ϩ H)ϩ,
582.3358].
Compound 14; νmax (CHCl3) 2916, 1669, 1646, 1506, 1457,
1243, 1092, 838 cmϪ1; δH (400 MHz; CDCl3) 0.12 (s, 6H), 0.98
(s, 9H), 3.030 (s, 3H), 3.034 (s, 3H), 3.73 (s, 2H), 3.78 (s, 5H),
3.79 (s, 3H), 6.64–6.66 (m, 2H), 6.75 (d, J = 8.8 Hz, 1H), 6.82 (d,
J = 8.6 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H); δC (100 MHz; CDCl3)
Ϫ4.7, 18.4, 25.6, 27.7, 27.8, 28.2, 28.4, 55.2, 55.5, 112.1, 114.1,
117.4, 117.6, 120.7, 120.8, 128.8, 129.8, 130.3, 145.1, 149.7,
153.7, 158.3 [EI-HRMS (pos.) m/z Calc. for C27H38N2O4Si:
M, 482.2601. Found: Mϩ, 482.2597].
Rittschof and K. L. Rinehart, J. Org. Chem., 1991, 56, 2965; (g)
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3 B. R. Copp, C. R. Fairchild, L. Cornell, A. M. Casazza, S. Robinson
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5 I. Kawasaki, H. Katsuma, Y. Nakayama, M. Yamashita and
S. Ohta, Heterocycles, 1998, 48, 1887.
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7 (a) I. Kawasaki, N. Taguchi, M. Yamashita and S. Ohta, Chem.
Pharm. Bull., 1997, 45, 1393; (b) I. Kawasaki, N. Taguchi,
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8 S. Ohta, N. Tsuno, S. Nakamura, N. Taguchi, M. Yamashita,
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9 S. Ohta, N. Tsuno, K. Maeda, S. Nakamura, N. Taguchi, M.
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11 The 1-alkyl-2-phenylsulfanyl-1H-imidazoles were easily prepared
from the corresponding 1-alkyl-2-lithio-1H-imidazoles by treatment
with diphenyl disulfide; (a) S. Ohta, T. Yamamoto, I. Kawasaki, M.
Yamashita, H. Katsuma, R. Nasako, K. Kobayashi and K. Ogawa,
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Naamine B 1
TFA (0.2 mL) was added to a solution of 13 (24 mg, 0.04 mmol)
in CH2Cl2 (0.5 mL) at 0 ЊC under N2, and the solution was
stirred for 48 h at ambient temperature. The products were
extracted with CHCl3 (10 mL × 3) after addition of saturated
aq. NaHCO3 (1 mL), and the organic phase was dried over
anhydrous sodium sulfate. The solvent was evaporated to give
an oily residue, which was purified column chromatography
(CHCl3–MeOH 5 : 1) on silica gel to give 1 (15 mg, 100%) as a
white amorphous powder; νmax (KBr) 3312, 3143, 2907, 1680,
1609, 1508 cmϪ1; δH (400 MHz; CDCl3 ϩ CD3OD) 3.26 (br s,
3H), 3.27 (br s, 3H), 3.80 (s, 3H), 3.85 (br s, 2H), 3.87 (s, 3H),
3.89 (br s, 2H), 6.57 (dd, J = 8.2, 2.2 Hz, 1H), 6.62 (d, J =
2.2 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H),
7.03 (d, J = 8.8 Hz, 2H); δC (100 MHz; CDCl3 ϩ CD3OD)
27.8, 27.9, 29.7, 29.8, 55.2, 55.8, 111.4, 114.1, 114.4, 118.8,
122.67, 122.73, 127.4, 128.4, 128.7, 146.3, 146.4, 146.6, 158.7
[EI-HRMS (pos.) m/z Calc. for C21H25N3O3: M, 367.1896.
Found: Mϩ, 367.1889].
Acknowledgements
This research was supported in part by the Frontier Research
Program and a Grant-In-Aid for Encouragement of Young
Scientists (to I. K.) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) of Japan.
13 G. R. Pettit, S. B. Singh and G. M. Cragg, J. Org. Chem., 1985, 50,
3404.
14 We examined several reaction conditions for the preparation of 10
and found that this reaction procedure gave the best result (see
Experimental section).
15 (a) F. A. Carey and H. S. Temper, J. Am. Chem. Soc., 1969, 91, 2967;
(b) C. T. West, S. J. Donnelly, D. A. Kooistra and M. P. Doyle, J. Org.
Chem., 1973, 38, 2675.
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