Double nucleophilic reaction of amines to the imidazole nucleus and selective synthesis of 5-aminoimidazoles

Article abstract of DOI:10.1016/j.tet.2004.05.088

Reaction of 2-(1-chloro-2,2-dimethylpropyl)-1-methyl-1H-imidazole with an excess of N,N-dimethylamine at room temperature gave an abnormal adduct, trans-4,5-bis(dimethylamino)-1-methyl-2,2-dimethylpropyl-2-imidazoline, which was derived from a serial, double nucleophilic addition into the imidazole nucleus in 74% yield together with a normal S_N product, 1-methyl-2-(1-dimethylamino-2,2-dimethylpropyl)-1H-imidazole in 15% yield. The former was easily converted to 1-methyl-5-(dimethylamino)-2-(2,2-dimethylpropyl) -1H-imidazole by only reflux in toluene in 90% yield. The scope, mechanism and limitation of these reactions are discussed.

Full text of DOI:10.1016/j.tet.2004.05.088

Tetrahedron 60 (2004) 6639–6648
Double nucleophilic reaction of amines to the imidazole nucleus
and selective synthesis of 5-aminoimidazoles
Ikuo Kawasaki, Tomohisa Osaki, Kazuya Tsunoda, Emiko Watanabe, Makie Matsuyama,
*
Akiko Sanai, Abdul Khadeer, Masayuki Yamashita and Shunsaku Ohta
Kyoto Pharmaceutical University, Misasagi Nakauchicho 5, Yamashinaku, Kyoto 607-8414, Japan
Received 26 April 2004; accepted 24 May 2004
Available online 19 June 2004
Abstract—Reaction of 2-(1-chloro-2,2-dimethylpropyl)-1-methyl-1H-imidazole with an excess of N,N-dimethylamine at room temperature
gave an abnormal adduct, trans-4,5-bis(dimethylamino)-1-methyl-2,2-dimethylpropyl-2-imidazoline, which was derived from a serial,
double nucleophilic addition into the imidazole nucleus in 74% yield together with a normal S product, 1-methyl-2-(1-dimethylamino-2,2-
N
dimethylpropyl)-1H-imidazole in 15% yield. The former was easily converted to 1-methyl-5-(dimethylamino)-2-(2,2-dimethylpropyl)-1H-
imidazole by only reflux in toluene in 90% yield. The scope, mechanism and limitation of these reactions are discussed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
1
Electrophilic substitutions of an imidazole nucleus and
2
In the course of our investigations on the synthesis of chiral
imidazole bidentate ligands for transition metals as shown in
Figure 1, we planned the preparation of 1-methyl-2-(1-
aminoalkyl)-1H-imidazole, which would be easily derived
nucleophilic substitutions via lithioimidazoles have been
well known for the preparation of imidazole compounds,
3
and we have applied the reactions of lithioimidazoles and
4
imidazolium salts to the synthesis of several pharma-
5
by a simple S 2 reaction of an amine with 1-methyl-2-(1-
N
12
ceutically interesting compounds and natural products.
While, nucleophilic reactions to the imidazole ring have
been performed mainly through the activation by
chloroalkyl)-1H-imidazole as reported by Miocque. Thus,
1-methyl-2-(1-hydroxy-2,2-dimethylpropyl)-1H-imidazole
1
3
1a was chlorinated with thionyl chloride in CHCl to give
3
6
quaternization of the ring or introduction of an appropriate
electron-withdrawing group such as halogen atom(s) into
the nucleus, other examples have been quite rare. On the
other hand, although the structure of 1,2-disubstituted
5-amino-1H-imidazole is found in some interesting bio-
active compounds such as gonadotropin-releasing
hormone receptor antagonists, preparation methods for
these aminoimidazole derivatives have been almost
unknown in the literature. In this paper, we would like
to present a novel, serial double nucleophilic addition of
amines into the imidazole nucleus to give 1,2-disubstituted
4,5-bis(amino)-2-imidazolines and the highly regio-
selective elimination of 2-imidazoline compounds to
provide 1,2-disubstituted 5-amino-1H-imidazoles.
2-(1-chloro-2,2-dimethylpropyl)-1-methyl-1H-imidazole
hydrochloride 2a as colorless crystals in 86% yield. The
chloride 2a was treated with an excess of N,N-dimethyl-
amine; however, the expected normal SN product 3a was
obtained in only 15% yield, and the unexpected addition
product 4a was obtained in 74% yield as the major
component (Scheme 1, Entry 1 in Table 1). All spectral
data of the latter supported the structure of 4a, and finally it
was confirmed by X-ray crystallographic analysis after
7
8,9
1
0
1
1
9
being derived to the corresponding dipicrate. To our best
9
Keywords: Imidazoles; Nucleophilic reaction; Stereoselective addition.
*
Corresponding author. Tel.: þ81-75-595-4703; fax: þ81-75-595-4795;
e-mail address: sohta@mb.kyoto-phu.ac.jp
Figure 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.088

6640
I. Kawasaki et al. / Tetrahedron 60 (2004) 6639–6648
Scheme 1.
Table 1. Reaction of 2a with various amines
1
2
R
Entry
Amine
R
Yield (%) (Product)
3
4
1
2
3
4
5
6
Me NH
2
Pyrroridine
Piperidine
Me
Me
15 (3a)
6 (3b)
74 (4a)
68 (4b)
61 (4c)
–(CH
–(CH
Bn
Me
2-NH
2
)
4
–
–
2
)
5
13 (3c)
67 (3d)
—
a
BnNH
MeNH(CH
1,2-Diaminobenzene
2
H
–(CH)
H
—
78 (4e)
—
a
b
2
)
2
NHMe
2
NHMe
a
2
–C
6
H
4
78 (3f)
a
Not detected in the reaction mixture.
Obtained product 4e was the cis-isomer shown in Figure 2.
b
1
knowledge, this was the first example of direct nucleophilic
addition under dearomatizing to the imidazole ring without
any electron-withdrawing substituent on the nucleus or
through quarternary imidazolium salts.
and H7a protons and comparison with the H NMR coupling
constant of H3a–H7a in the ring (J¼8.6 Hz) as these values
of H4–H5 in trans-4,5-disubstituted 2-imidazolines 4a–c
(J¼3.8–4.0 Hz).
The reaction of 2a with various amines was also examined,
and the results are shown in Table 1. Reaction of 2a with
secondary amines gave the serial double nucleophilic
addition products 4a–c as major products in 61–74%
yields (Entries 1–3), whereas the reaction with primary
A plausible reaction mechanism for producing the di-
adducts 4a–e is given in Scheme 2. The free imidazole 5
reacted with secondary amines at the 5-position of the
imidazole ring by a nucleophilic tele-substitution reaction
1
4
mechanism to give the intermediate 6, and the second
molecule of R NH might readily add to the unstable
amines gave only S products 3d and 3f in 67, 78% yields,
N
2
respectively (Entries 4 and 6). Interestingly, treatment of
0
ketenediiminal intermediate 6 under assist by protonation
þ
N,N -dimethylethylenediamine provided a bicyclic com-
with H N R to produce 4. Main reason for producing the
2
2
pound as the sole product, 1H-imidazo[4,5-b]piperazine 4e
in good yield (78%) (Entry 5, Fig. 2), and its cis-fused ring
system was confirmed by observation of NOE between H3a
adduct 4 may be difficulty in approach of the amine
molecule to the sterically hindered –CHCl– portion where
a bulky alkyl group attaches.
Then, the reaction of 2b–e with various nucleophiles was
examined, and the results are summarized in Table 2. When
2
compound 2b (R ¼i-Pr) was treated with secondary amines,
di-adducts (4g–i) were obtained in 50–64% overall yield
from 1b (Entries 1–3) together with some SN products
(3g–i) in 17–19% yield. The treatment with a primary
amine gave only S product (3j) in 36% yield (Entry 4), and
N
0
dazo[4,5-b]piperazine (4k) having cis stereochemistry in
N,N -dimethylethylenediamine gave bicyclic 1H-imi-
2
9% yield (Entry 5, Fig. 2). The reaction showed almost the
2
Figure 2.
same tendency as the reaction of 2a (R ¼t-Bu) with amines
Scheme 2.

I. Kawasaki et al. / Tetrahedron 60 (2004) 6639–6648
Table 2. Reaction of 2b–e with various nucleophiles
6641
1
R
2
R
Entry
Nu-X
Nu
Yield (%) (Product)
3
4
a
a
a
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
H
i-Pr
Me NH
Pyrroridine
Piperidine
2
–NMe
–N(CH
–N(CH
–NHBn
–NMe(CH
PhC(O)S–
2
17 (3g)
19 (3h)
17 (3i)
64 (4g)
50 (4h)
a
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
n-C
n-C
2
)
)
4
a
a
2
5
61 (4i)
—
a
b
BnNH
MeNH(CH
PhC(O)SNa
Me NH
Pyrroridine
Me NH
Pyrroridine
Me CHOH
PhOH
Me NH
2
36 (3j)
—
b
a,c
2
)
2
NHMe
2
)
2
NMe
29 (4k)
—
a
b
49 (3l)
31 (3m)
43 (3n)
12 (3p)
18 (3q)
34 (3r)
51 (3s)
6
H
H
13
13
2
–NMe
–N(CH
–NMe
–N(CH
Me
2
46 (4m)
41 (4n)
80 (4p)
72 (4q)
6
2
)
4
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
2
2
10
11
12
13
2
)
4
d
d
b
2
2
CHO–
—
b
PhO–
–NMe
—
e
b
2
2
83 (3t)
—
a
b
c
d
e
Yield from 1b.
Not detected in the reaction mixture.
Obtained product 4k was the cis-isomer shown in Figure 2.
The reaction was carried out in presence of Et N.
3
Yield from 1e.
but the ratio of SN products in Entries 1–3 was slightly
increased.
gave desired di-adducts 4p and 4q in good yields (80, 72%,
respectively) as we expected (Entries 9 and 10); however,
the reaction of 1-unsubstituted imidazole 2e afforded only
SN product 3t in 83% yield (Entry 13). These results might
support the steric hindrance around the –CHCl– moiety
was one of the important factors for the attack of
nucleophiles into the imidazole nucleus as described
above. The reaction of 2b and 2d with other nucleophiles
such as thioate, alcohol and phenol under the same
When 2-(1-chloroheptyl)-1-methyl-1H-imidazole hydro-
1
5
chloride (2c) derived from 1c bearing a primary alkyl
group neighboring the –CHCl– moiety was used as a
substrate, double nucleophilic addition products 4m and 4n
were given in 41–46% yield by the reaction with secondary
amines, but the ratio of normal SN products 3m and 3n
considerably increased to 31–43% (Entries 7 and 8). The
reaction of 2d (R ¼Bn, R ¼t-Bu) with secondary amines
conditions gave only S products 3l, 3r and 3s in moderate
N
yields (34–51%) (Entries 6, 11 and 12); these results also
1
2
Table 3. Reaction of 4 in reflux toluene
1
R
2
R
3
Entry
4
R
Yield (%) (Product)
1
2
3
4
5
t-Bu
t-Bu
t-Bu
i-Pr
4a
4b
4e
4g
4h
Me
–(CH
Me
Me
90 (7a)
83 (7b)
—
66 (7c)
80 (7d)
2
)
4
4
–
–
a
b
Me
–(CH
i-Pr
2
)
a
Starting compound was cis-isomer 4e shown in Figure 2.
Not detected in the reaction mixture.
b

6642
I. Kawasaki et al. / Tetrahedron 60 (2004) 6639–6648
Scheme 3.
showed that one important factor to afford 2-imidazolines 4
was the steric hindrance of nucleophiles as well as their
nucleophilicity.
3. Conclusion
In summary, we have demonstrated a novel dearomatizing
reaction of the imidazole ring by the double nucleophilic
reaction of amines to give 1,2-dialkyl-4,5-diamino-2-
imidazolines and their conversion to 1,2-disubstituted
5-amino-1H-imidazoles.
Reaction of double nucleophilic addition products 4a was
examined (Table 3). Regioselective elimination of one of
the two N,N-dimethylamino groups smoothly proceeded in
boiling toluene to give 1-methyl-5-dimethylamino-2-(2,2-
dimethylpropyl)-1H-imidazole 7a as the sole product in
9
0% yield (Entry 1). The structure of 7a was confirmed by
4. Experimental
4.1. General
the observation of HMBC correlations. Although Stradi
reported a conversion of 4,5-diamino-1,2-diaryl-2-imidazo-
lines to 5-amino-1,2-diaryl-1H-imidazoles in the presence
of triethylamine hydrochloride at 125 8C, the transform-
ation from 4a to 7a could be achieved by only reflux in
toluene without any catalyst.
1
1a
All 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
1
13
(
INOVA 400NB ( H: 400 MHz), JEOL EX-300 ( H:
H and C) spectra were measured on Varian UNITY
1
1
To confirm the reaction mechanism of the selective
elimination of 4a, the reaction was performed in the
presence of CD OD at 120 8C, and it was found that 76%
3
1
3
1
300 MHz, C: 75 MHz) or JEOL EX-270 ( H: 270 MHz,
1
C: 68 MHz) spectrometer and the chemical shifts were
3
of deuterium was incorporated into the methylene group
of the side chain in the product 7a–D. From this result, we
considered that the main reaction course was path-b through
expressed in parts per million downfield from tetramethyl-
silane as the internal standard. Mass spectra (MS) were
measured on JEOL JMS-SX 102A QQ (FAB) or JEOL JMS
BU-20 (EI and CI) spectrometer, respectively. Silica gel
1
6
a tele-elimination mechanism as shown in Scheme 3.
(Merck Art. 7737) or Al O (Nakalai Tesque, Alumina
activated 300) was used for column chromatography.
2 3
This selective elimination reaction was examined toward
several 4,5-diaminoimidazoles 4b, 4e, 4g and 4h and the
results are listed in Table 3. The reaction of 4b, 4g and 4h
provided the corresponding 1,2-disubstituted 5-amino-1H-
imidazoles 7b–d in 66–83% yields (Entries 2, 4 and 5).
However, the reaction of 4e mainly recovered the starting
compound and gave no desired eliminating product (Entry
4.1.1. Synthesis of 2-(1-hydroxy-2-methylpropyl)-1-
methyl-1H-imidazole 1b—general procedure for the
synthesis of the alcohols 1. n-BuLi (1.6 M in n-hexane;
32.8 mL, 52.5 mmol) was added to a stirred solution of
1-methylimidazole (4.4 mL, 55 mmol) in THF (50 mL)
3
), this result might be explained by the faster intra-
molecular cyclization of 6e to 4e than the approach of the
NHMe portion of 6e to the sterically hindered H5 for
under N at 278 8C. After stirring for 30 min at the same
2
temperature, isobutylaldehyde (4.54 mL, 50 mmol) was
added and the whole was stirred for 2 h at ambient
temperature. The mixture was acidified with HCl aq.
–
producing 7e (Scheme 4).
(10%, 50 mL) and washed with diethyl ether (30 mL£2).
Scheme 4.

I. Kawasaki et al. / Tetrahedron 60 (2004) 6639–6648
6643
The aqueous layer was basified with K CO powder and
2
stirring for 2 h at room temperature, solvents were evaporated
to give a crystalline residue, which was recrystallized from
EtOH–AcOEt. The compound was obtained as a colorless
powder, 961 mg (86%). Mp 168–170 8C.
3
extracted with AcOEt (30 mL£3). The organic layer was
dried over anhydrous sodium sulfate and evaporated to give
an oily residue, which was recrystallized from AcOEt-n-
hexane to give 1b as colorless prisms (3.58 g, 46%). Mp
7
7–79 8C.
d (300 MHz, CD OD): 1.15 (9H, s, C(CH ) ), 4.00 (3H, s,
H
3
3 3
NCH ), 5.54 (1H, s, CHCl), 7.62 (1H, d, J¼2.2 Hz, Im-H),
3
d (300 MHz, CDCl ): 0.81 (3H, d, J¼6.8 Hz, CH(CH ) ),
7.66 (1H, d, J¼1.8 Hz, Im-H). d (75 MHz, CD OD): 26.4,
H
3
3 2
C
3
(KBr, cm2 ):
1463, 1514, 1591, 2913, 3396. EI MS (m/z, %): 57 (6), 81
1
1.06 (3H, d, J¼6.6 Hz, CH(CH ) ), 2.06–2.22 (1H, m,
CH(CH ) ), 3.67 (3H, s, NCH ), 4.25 (1H, br, OH), 4.34
36.3, 39.7, 59.7, 121.0, 125.4, 145.3. n
3
2
max
3
2
3
(
6
1H, d, J¼7.9 Hz, CH(OH)), 6.77 (1H, d, J¼1.1 Hz, Im-H),
(11), 95 (36), 121 (13), 130 (100), 132 (32), 151 (15), 171
(5), 186 (M , 4), 188 (1). HRMS (EI): found M 186.0933,
þ
C H ClN requires M 186.0924. Anal. calcd for
þ
.91 (1H, d, J¼1.3 Hz, Im-H). d (75 MHz, CDCl ): 18.6,
C
3
þ
1
cm ): 1464, 1489, 2942, 3099. EI MS (m/z, %): 83 (24),
1
1
9.0, 32.9, 33.9, 72.3, 121.0, 126.6, 149.7. n
(CHCl ,
max
3
9
15
2
2
1
C H Cl N : C, 48.44; H, 7.23; N, 12.55; found: C, 48.51;
9 16 2 2
H, 7.34; N, 12.24.
þ
þ
54.1103, C H N O requires M 154.1106. Anal. calcd for
11 (100), 137 (4), 154 (M , 7). HRMS (EI): found M
þ
8
14 2
C H N O: C, 62.31; H, 9.15; N, 18.17; found: C, 62.12; H,
8
4.1.5. 2-(1-Chloro-2-methylpropyl)-1-methyl-1H-imida-
zole hydrochloride 2b. Obtained, after evaporation of the
solvents from 1b, as a pale yellow crystalline residue, which
was used in the next reaction without further purification.
14 2
9
.26; N, 17.95.
1
3
15
The alcohols 1a and 1c are known compounds in
literature.
d (270 MHz, CDCl ): 0.96 (3H, d, J¼6.6 Hz, CH(CH ) ),
H
3
3 2
4
.1.2. 1-Benzyl-2-(1-hydroxy-2,2-dimethylpropyl)-1H-
1
1.29 (3H, d, J¼6.4 Hz, CH(CH ) ), 2.63–2.77 (1H, m,
3
2
7
imidazole 1d. Obtained, after silica gel column chroma-
tography (AcOEt/n-hexane¼2:1) and recrystallization
CH(CH ) ), 4.10 (3H, s, NCH ), 5.34 (1H, d, J¼10.2 Hz,
3 2 3
CHCl), 7.36 (1H, d, J¼1.8 Hz, Im-H), 7.63 (1H, d,
J¼1.8 Hz, Im-H). d (68 MHz, CDCl ): 19.8, 20.1, 34.1,
from EtOH–Et O, as colorless needles (1.98 g, 41%) from
2
C
3
2
1
1
-benzylimidazole (20 mmol). Mp 113–115 8C.
35.8, 55.4, 118.7, 124.2, 143.5. n
(CHCl , cm ): 1464,
max 3
1594, 2950, 3138, 3360. EI MS (m/z, %): 81 (27), 96 (48),
121 (90), 130 (75), 132 (25), 137 (100), 172 (M , 10), 174
þ
(3). HRMS (EI): found M 172.0773, C H ClN requires
d (300 MHz, CDCl ): 1.00 (9H, s, C(CH ) ), 3.08 (1H, br,
3 3
OH), 4.41 (1H, s, CH(OH)), 5.16 (2H, s, NCH ), 6.76 (1H,
2
H
3
þ
8
13
2
þ
d, J¼1.3 Hz, Im-H), 7.02 (1H, d, J¼1.3 Hz, Im-H), 7.08–
M 172.0767.
7
CDCl ): 25.8, 37.0, 50.0, 73.8, 119.9, 126.9, 127.5, 128.1,
.11 (2H, m, Ar-H), 7.27–7.37 (3H, m, Ar-H). d (75 MHz,
C
4.1.6. 2-(1-Chloroheptyl)-1-methyl-1H-imidazole hydro-
chloride 2c. Obtained, after recrystallization from AcOEt–
Et O, as a colorless powder (478 mg, 63%) from 1c
3
2
1
1
1
1
2
28.9, 136.3, 149.0. nmax (CHCl , cm ): 1449, 1475, 1491,
3
622, 2936, 3000–3500. EI MS (m/z, %): 91 (84), 97 (16),
87 (100), 211 (8), 244 (M , 10). HRMS (EI): found M
2
þ
44.1575, C H N O requires M 244.1576. Anal. calcd
þ
(3 mmol). Mp 107–111 8C.
þ
1
5 20 2
for C H N O: C, 73.74; H, 8.25; N, 11.47; found: C,
1
dH (300 MHz, CDCl ): 0.87 (3H, t, J¼6.8 Hz, CH CH ),
5
20
2
3
2
3
7
3.49; H, 8.37; N, 11.75.
1.26–1.69 (8H, m, CH (CH ) CH ), 2.30–2.51 (2H, m,
2 2 4 3
CH C H ), 4.06 (3H, s, NCH ), 5.55 (1H, dd, J¼6.8,
2
5
11
3
4
.1.3. 2-(1-Hydroxy-2,2-dimethylpropyl)-1H-imidazole
e. Following the reported procedure by Curtis and
8.8 Hz, CHCl), 7.35 (1H, d, J¼1.8 Hz, Im-H), 7.47 (1H, d,
J¼1.6 Hz, Im-H). d (75 MHz, CDCl ): 13.9, 22.4, 26.5,
28.2, 31.4, 35.3, 35.5, 49.0, 119.1, 124.0, 143.8. n
max
1
Brown
C
3
1
8
starting from 1-diethoxymethyl-1H-imidazole
and trimethylacetaldehyde, the title compound was obtained
2
1
(CHCl , cm ): 1458, 1518, 1593, 1842, 2422, 2936. EI MS
3
in 35% yield as colorless prisms, mp 179–181 8C
(
(m/z, %): 109 (45), 130 (100), 135 (32), 179 (53), 185 (14),
214 (M , 5), 216 (2). HRMS (EI): found M 214.1251,
þ
C H ClN requires M 214.1237. Anal. calcd for
þ
recrystallized from EtOH–Et O).
2
þ
1
1
19
2
d (300 MHz, DMSO-d ): 0.84 (9H, s, C(CH ) ), 4.24 (1H,
3 3
C H Cl N : C, 52.60; H, 8.03; N, 11.15; found: C,
11 20 2 2
H
6
d, J¼4.4 Hz, CH(OH)), 5.42 (1H, d, J¼4.8 Hz, OH), 6.76
52.28; H, 8.02; N, 11.11.
(
1H, br, Im-H), 6.93 (1H, br, Im-H). d (75 MHz, DMSO-
C
d6): 26.0, 35.4, 75.1, 115.1, 126.5, 149.4. nmax (KBr, cm2 ):
1
4.1.7. 1-Benzyl-2-(1-chloro-2,2-dimethylpropyl)-1H-imi-
dazole hydrochloride 2d. Obtained, after recrystallization
from EtOH–Et O as a colorless powder (218 mg, 73%)
1
448, 1639, 2619, 2942, 3163, 3000–3500. EI MS (m/z, %):
þ
154.1093, C H N O requires M 154.1106. Anal.
6
9 (16), 98 (100), 121 (20), 154 (M , 8). HRMS (EI): found
2
þ
calcd for C H N O: C, 62.31; H, 9.15; N, 18.17; found: C,
þ
M
from 1d (1 mmol). Mp 151–152 8C.
8
14 2
8
14 2
6
1.92; H, 9.09; N, 17.98.
d (300 MHz, DMSO-d ): 1.07 (9H, s, C(CH ) ), 5.53 and
3 3
H
6
5
.725 (1H each, each d, J¼15.4 Hz, NCH ), 5.733 (1H, s,
2
4
.1.4. Synthesis of 2-(1-chloro-2,2-dimethylpropyl)-1-
CHCl), 7.29–7.80 (7H, m, Ar-H and Im-H). d (75 MHz,
C
methyl-1H-imidazole hydrochloride 2a—general pro-
cedure for the synthesis of the chlorides 2. SOCl2
DMSO-d ): 25.9, 37.7, 50.4, 58.4, 121.9, 122.9, 127.6,
6
128.5, 129.0, 134.9, 142.9. nmax (KBr, cm2 ): 1462, 1502,
1
(
2
(
0.73 mL, 10 mmol) was added to a stirred solution of
1
1598, 1626, 2638, 3394. EI MS (m/z, %): 91 (100), 115 (30),
171 (90), 206 (50), 262 (M , 18), 264 (6). HRMS (EI):
3
þ
found M 262.1223, C H ClN requires M 262.1237.
-(1-hydroxy-2,2-dimethylpropyl)-1-methyl-1H-imidazole
840 mg, 5 mmol) in CHCl (5 mL) under N at 0 8C. After
þ
þ
3
2
15 19
2

6644
I. Kawasaki et al. / Tetrahedron 60 (2004) 6639–6648
Anal. calcd for C H Cl N : C, 60.21; H, 6.74; N, 9.36;
2
1.81 (8H, m, NCH CH ), 2.22 (2H, s, CH C(CH ) ), 2.59–
2 2 2 3 3
1
5
20
2
found: C, 60.35; H, 7.05; N, 8.99.
2.78 (8H, m, NCH CH ), 2.90 (3H, s, NCH ), 4.29 (1H, d,
2 2 3
J¼3.8 Hz, Im-H), 4.36 (1H, d, J¼3.8 Hz, Im-H). d
(75 MHz, CDCl ): 23.4, 23.7, 30.0, 31.5, 33.0, 40.3, 46.7,
3
48.2, 82.3, 82.7, 164.9. nmax (CHCl , cm ): 1585, 2912. EI
3
C
4
.1.8. 2-(1-Chloro-2,2-dimethylpropyl)-1H-imidazole
2
1
hydrochloride 2e. Obtained, after evaporation of the
solvents from 1e, as a pale yellow crystalline residue,
which was used in the next reaction without further
purification.
MS (m/z, %): 83 (100), 111 (27), 164 (86), 221 (23), 292
þ
þ
requires M 292.2627.
(M , 9). HRMS (EI): found M 292.2621, C H N
7 32 4
1
þ
4
.1.9. Synthesis of 1-methyl-2-(2,2-dimethyl-1-dimethyl-
4.1.11. 2-[2,2-Dimethyl-1-(1-piperidinyl)propyl]-1-
p
p
p
p
aminopropyl)-1H-imidazole 3a and (4R ,5R )-4,5-di-
hydro-1-methyl-4,5-bis(dimethylamino)-2-(2,2-
dimethylpropyl)-1H-imidazole 4a—general procedure
for the synthesis of 3 and 4 (Entry 1 in Table 1 as an
example). N,N-Dimethylamine aqueous solution (3 mL,
methyl-1H-imidazole 3c and (4R ,5R )-4,5-dihydro-1-
methyl-2-(2,2-dimethylpropyl)-4,5-bis(1-piperidinyl)-
1H-imidazole 4c. Obtained, after Al O column chroma-
2
3
tography (AcOEt/n-hexane¼1:2 to AcOEt only), as a
yellow viscous oil [(3c; 63 mg, 13%), (4c; 389 mg, 61%)]
from piperidine (10 mmol) and 2a (2 mmol).
3
3 mmol) was added to a suspension of 2a (669 mg,
3
mixture was stirred for 4 h at 0 8C. 10% K CO aqueous
mmol) in THF (3 mL) under N and ice cooling, and the
2
3c: dH (300 MHz, CDCl ): 1.04 (9H, s, C(CH ) ), 1.24–
3 3
2
3
3
solution (5 mL) was added to the reaction mixture and the
products were extracted with AcOEt (10 mL£3) and
the organic layer was dried over anhydrous sodium sulfate.
The solvent was evaporated to give an oily residue, which
was separated by Al O column chromatography (AcOEt/
1.35 (2H, m, NCH CH CH ), 1.46–1.53 (4H, m,
2 2 2
NCH CH ), 2.11–2.41 (2H, m, NCH CH ), 2.67–2.96
2
2
2
2
(2H, m, NCH CH ), 3.28 (1H, s, CHC(CH ) ), 3.63 (3H, s,
2
2
3 3
NCH ), 6.79 (1H, d, J¼1.1 Hz, Im-H), 7.02 (1H, d,
3
J¼1.3 Hz, Im-H,). d (75 MHz, CDCl ): 24.4, 26.8, 27.5,
2
3
C
3
n-hexane¼1:1 to AcOEt only) to give 3a (first fraction,
8 mg, 15%) and 4a (second fraction, 534 mg, 74%) as a
yellow viscous oil, respectively.
33.4, 37.2, 54.4, 68.1, 119.8, 126.5, 146.4. n
cm ): 1478, 1655, 2917. HRMS (FABþ): found MH
(CHCl ,
3
max
2
1
þ
8
þ
236.2123, C H N þH requires MH 236.2127.
1
4 25 3
3a: d (400 MHz, CDCl ): 1.06 (9H, s, C(CH ) ), 2.34 (6H,
s, N(CH ) ), 3.38 (1H, s, CHC(CH ) ), 3.64 (3H, s, NCH ),
4c: dH (300 MHz, CDCl ): 1.06 (9H, s, C(CH ) ), 1.42–
3 3 3
1.60 (12H, m, NCH (CH ) ), 2.18 and 2.24 (1H each, each
2 2 3
H
3
3 3
3
2
3 3
3
6
Im-H). d (75 MHz, CDCl ): 27.9, 33.4, 36.9, 44.7, 67.3,
.81 (1H, d, J¼1.3 Hz, Im-H), 7.05 (1H, d, J¼1.3 Hz,
d, J¼13.6 Hz, CH C(CH ) ), 2.45–2.60 (8H, m,
2
3 3
NCH CH ), 2.87 (3H, s, NCH ), 3.95 (1H, d, J¼4.0 Hz,
2 2 3
C
3
21
1
MS (m/z, %): 110 (57), 138 (100), 195 (M , 6). HRMS (EI):
20.0, 126.8, 145.4. nmax (CHCl , cm ): 1477, 2956. EI
Im-H), 4.24 (1H, d, J¼3.9 Hz, Im-H). d (75 MHz, CDCl ):
3
C
3
þ
found M 195.1732, C H N requires M 195.1735.
24.7, 24.8, 26.16, 26.22, 30.1, 31.6, 32.7, 40.3, 48.4, 49.3,
85.0, 86.0, 164.7. nmax (CHCl , cm ): 1590, 2843. HRMS
þ
þ
21
1
1
21
3
3
þ
(
FABþ): found MH 321.3026, C H N þH requires
1
9 36 4
þ
4
a: d (400 MHz, CDCl ): 1.08 (9H, s, C(CH ) ), 2.24 (6H,
H
MH 321.3018.
3
3 3
s, N(CH ) ), 2.30 (6H, s, N(CH ) ), 2.21 (1H, d, J¼13.6 Hz,
3
2
3 2
CH C(CH ) ), 2.26 (1H, d, J¼13.7 Hz, CH C(CH ) 2.90
4.1.12. 2-(1-Benzylamino-2,2-dimethylpropyl)-1-methyl-
1H-imidazole 3d. Obtained, after Al O column chroma-
tography (AcOEt/n-hexane¼2:1 to AcOEt only), as a
yellow viscous oil (347 mg, 67%) from benzylamine
(10 mmol) and 2a (2 mmol).
2
3 3
2
3 3,
(
3H, s, NCH ), 3.96 (1H, d, J¼3.8 Hz, Im-H), 4.25 (1H, d,
3
2 3
J¼3.8 Hz, Im-H). d (75 MHz, CDCl ): 29.9, 31.4, 31.9,
C
3
2
1
3
8.4, 40.0, 40.1, 82.8, 85.5, 164.7. nmax (CHCl , cm ):
3
1
(
464, 1586, 2920. EI MS (m/z, %): 138 (100), 195 (31), 240
þ þ
M , 1.7). HRMS (EI): found M 240.2309, C H N
13 28 4
þ
requires M 240.2314.
d (300 MHz, CDCl ): 0.96 (9H, s, C(CH ) ), 2.37 (1H, br,
H
3
3 3
NH), 3.27–3.31 (2H, overlap, CHC(CH ) and NCH ), 3.35
3
3
2
4
methyl-1H-imidazole 3b and (4R ,5R )-4,5-dihydro-1-
.1.10. 2-[2,2-Dimethyl-1-(1-pyrrolidinyl)propyl]-1-
p
(3H, s, NCH ), 3.76 (1H, d, J¼13.6 Hz, NCH ), 6.74 (1H, d,
3
2
p
J¼1.1 Hz, Im-H), 7.04 (1H, d, J¼1.1 Hz, Im-H), 7.18–7.30
methyl-2-(2,2-dimethylpropyl)-4,5-bis(1-pyrrolidinyl)-
1
(5H, m, Ar-H). d (75 MHz, CDCl ): 26.6, 32.6, 36.0, 51.9,
C
3
H-imidazole 4b. Obtained, after Al O column chroma-
2
60.7, 119.8, 126.6, 127.1, 128.0, 128.1, 140.2, 149.5. n
max
3
2
1
tography (AcOEt/n-hexane¼1:5 to AcOEt only), as a
yellow viscous oil [(3b; 14 mg, 6%), (4b; 199 mg, 68%)]
from pyrrolidine (5 mmol) and 2a (1 mmol).
(CHCl , cm ): 1478, 1598, 2936, 3156. EI MS (m/z, %): 65
3
þ
found M 257.1887, C H N requires M 257.1892.
(17), 91 (38), 152 (11), 200 (100), 257 (M , 1). HRMS (EI):
þ
þ
1
6 23 3
p
p
3
1
2
b: dH (400 MHz, CDCl ): 1.05 (9H, s, C(CH ) ), 1.61–
3
4.1.13. (3aR ,7aS )-3a,4,5,6,7,7a-Hexahydro-1,4,7-tri-
methyl-2-(2,2-dimethylpropyl)-1H-imidazo[4,5-b]pyra-
zine 4e. Obtained, after Al O column chromatography
3 3
.68 (4H, m, NCH (CH ) ), 2.56–2.58 (2H, m, NCH CH ),
2
2 2
2
2
.82 (2H, br, NCH CH ), 3.62 (1H, s, CHC(CH ) ), 3.64
3 3
2
2
2 3
(
3H, s, NCH ), 6.78 (1H, d, J¼1.1 Hz, Im-H,), 7.03 (1H, d,
(AcOEt only to AcOEt/MeOH¼10:1), as a yellow viscous
3
0
J¼1.3 Hz, Im-H). d (75 MHz, CDCl ): 23.6, 28.2, 33.3,
oil (372 mg, 78%) from N,N -dimethylethylenediamine
(10 mmol) and 2a (2 mmol).
C
3
2
1
3
1
6.8, 52.0, 65.1, 119.7, 126.8, 147.1. nmax (CHCl , cm ):
3
þ
477, 2934. HRMS (FABþ): found MH 222.1977,
þ
C H N þH requires MH 222.1970.
d (300 MHz, CDCl ): 1.08 (9H, s, C(CH ) ), 2.15 and 2.23
H
1
3
23
3
3
3 3
(
1H each, each d, J¼13.4 Hz, CH C(CH ) ), 2.49 (3H, s,
2
3 3
4
b: dH (300 MHz, CDCl ): 1.07 (9H, s, C(CH ) ), 1.71–
3 3
CH NCH ), 2.57 (3H, s, CH NCH ), 2.52–2.80 (4H, m,
2 3 2 3
3

I. Kawasaki et al. / Tetrahedron 60 (2004) 6639–6648
6645
CH CH ), 2.87 (3H, s, NCH ), 4.17 (1H, d, J¼8.6 Hz, Im-
3h: dH (300 MHz, CDCl ): 0.79 (3H, d, J¼6.8 Hz,
2
2
3
3
H), 4.55 (1H, d, J¼8.6 Hz, Im-H). d (75 MHz, CDCl ):
CH(CH ) ), 1.02 (3H, d, J¼6.8 Hz, CH(CH ) ), 1.60–
1.78 (4H, m, NCH CH ), 2.26–2.41 (3H, m, NCH CH and
2 2 2 2
C
3
3 2
3 2
2
1
9.9, 31.4, 34.1, 40.5, 42.1, 42.9, 44.7, 45.5, 79.5, 81.1,
66.5. nmax (CHCl , cm ): 1461, 1590, 2899. EI MS (m/z,
2
1
CH(CH ) ), 2.70–2.77 (2H, m, NCH CH ), 3.48 (1H, d,
3 2 2 2
3
%
): 96 (47), 99 (27), 112 (55), 126 (34), 153 (100), 182 (15),
þ
J¼8.4 Hz, CHCHC(CH ) ), 3.68 (3H, s, NCH ), 6.78 (1H,
3
2
3
þ
requires M 238.2157.
2
38 (M , 20). HRMS (EI): found M 238.2153, C H N
26
d, J¼1.1 Hz, Im-H), 7.00 (1H, d, J¼1.1 Hz, Im-H). d
1
3
4
C
þ
(75 MHz, CDCl ): 19.1, 20.5, 23.0, 31.3, 32.9, 49.6, 64.1,
3
2
1
120.1, 127.0, 146.9. nmax (CHCl , cm ): 1478, 1657, 2924.
EI MS (m/z, %): 123 (93), 138 (100), 164 (99), 207 (M , 1).
3
þ
HRMS (EI): found M 207.1737, C H N requires M
207.1735.
4.1.14. 2-[1-(2-Aminophenylamino)-2,2-dimethyl-
propyl]-1-methyl-1H-imidazole 3f. Obtained, after Al O
þ
þ
2
3
12 21 3
column chromatography (AcOEt/n-hexane¼1:3), as a solid
(403 mg, 78%) from o-phenylenediamine (10 mmol) and 2a
(2 mmol).
4h: dH (300 MHz, CDCl ): 0.91 (3H, d, J¼6.2 Hz,
3
CH(CH ) ), 0.92 (3H, d, J¼6.6 Hz, CH(CH ) ), 1.62–
3
2
3 2
d (300 MHz, CDCl ): 1.12 (9H, s, C(CH ) ), 3.44 (3H, s,
H 3 3
1.72 (8H, m, NCH CH ), 1.86–2.15 (3H, m, CH -
2 2 2
3
NCH ), 3.58–3.77 (2H, br, NH ), 3.99 (1H, d, J¼10.3 Hz,
CHC(CH ) ), 2.49–2.69 (8H, m, NCH CH ), 2.82 (3H, s,
3 2 2 2
3
2
NH), 4.09 (1H, d, J¼9.5 Hz,, CHC(CH ) ), 6.49–6.71 (5H,
NCH ), 4.22 (1H, d, J¼3.3 Hz, Im-H), 4.25 (1H, d,
3
3
3
m, Ar-H and Im-H), 6.97 (1H, d, J¼1.1 Hz, Im-H). d
J¼3.3 Hz, Im-H). d (75 MHz, CDCl ): 22.3, 22.9, 23.2,
C
C
3
(
75 MHz, CDCl ): 26.7, 32.9, 36.7, 60.2, 116.4, 118.0,
3
23.7, 26.4, 31.7, 36.6, 46.5, 48.4, 82.2, 82.4, 165.8. n
max
2
1
1
19.7, 120.0, 121.2, 127.0, 136.4, 137.7, 149.5. n
2
(CHCl , cm ): 1460, 1592, 2934. EI MS (m/z, %): 164
3
max
1
þ
found M 278.2478, C H N requires M 278.2470.
(
CHCl , cm ): 1497, 1608, 2936, 3186, 3381. EI MS
3
(100), 179 (7), 207 (28), 263 (5), 278 (M , 5). HRMS (EI):
þ
þ
EI): found M 258.1848, C H N requires M
þ
(
(
m/z, %): 83 (100), 119 (34), 201 (13), 258 (M , 10). HRMS
þ
1
6 30 4
þ
1
5
22
4
2
58.1844.
4.1.17. 1-Methyl-2-[2-methyl-1-(1-piperidinyl)propyl]-
p
p
1
H-imidazole (3i) and (4R ,5R )-4,5-dihydro-1-methyl-
4
1
4
.1.15. 1-Methyl-2-(2-methyl-1-dimethylaminopropyl)-
p
2-(2-methylpropyl)-4,5-bis(1-piperidinyl)-1H-imidazole
(4i). Obtained, after Al O column chromatography
(AcOEt/n-hexane¼1:5), as a yellow viscous oil [(3i;
115 mg, 17%), (4i; 562 mg, 61%) from piperidine
(15 mmol)] and crude 2b (starting from 3 mmol of 1b).
p
H-imidazole 3g and (4R ,5R )-4,5-dihydro-1-methyl-
,5-bis(dimethylamino)-2-(2-methylpropyl)-1H-imida-
2
3
zole 4g. Obtained, after Al O column chromatography
2
3
(
AcOEt/n-hexane¼1:1 to AcOEt/MeOH¼10:1), as a yellow
viscous oil [(3g; 155 mg, 17%), (4g; 723 mg, 64%)] from
crude 2b (starting from 5 mmol of 1b).
3i: dH (300 MHz, CDCl ): 0.66 (3H, d, J¼6.4 Hz,
3
CH(CH ) ), 1.07 (3H, d, J¼6.6 Hz, CH(CH ) ), 1.26–
3
2
3 2
3
g: dH (300 MHz, CDCl ): 0.68 (3H, d, J¼6.6 Hz,
1.63 (6H, m, NCH (CH ) ), 2.37–2.49 (5H, m, NCH CH
2 2 3 2 2
3
CH(CH ) ), 1.08 (3H, d, J¼6.6 Hz, CH(CH ) ), 2.24 (6H,
and CH(CH ) ), 3.21 (1H, d, J¼10.1 Hz, CHCH(CH ) ),
3
2
3 2
3 2
3 2
s, N(CH ) ), 2.32–2.46 (1H, m, –CH(CH ) ), 3.24 (1H, d,
3
3.64 (3H, s, NCH ), 6.77 (1H, d, J¼1.1 Hz, Im-H), 7.01
2
3 2
3
J¼9.9 Hz, CHCH(CH ) ), 3.65 (3H, s, NCH ), 6.79 (1H, d,
(1H, d, J¼1.1 Hz, Im-H). d (75 MHz, CDCl ): 20.1, 20.3,
24.6, 26.4, 29.4, 32.8, 50.5, 66.9, 119.8, 126.8, 147.2. n
max
3
2
3
C
3
J¼1.1 Hz, Im-H,), 7.02 (1H, d, J¼1.3 Hz, Im-H). d
C
2
1
(
75 MHz, CDCl ): 19.7, 20.1, 29.8, 32.6, 41.1, 65.7,
3
(CHCl , cm ): 1452, 1478, 1580, 2915. EI MS (m/z, %):
3
2
1
þ
found M 221.1891, C H N requires M 221.1892.
1
MS (m/z, %): 97 (14), 123 (24), 138 (100), 181 (M , 1).
19.8, 126.8, 146.2. nmax (CHCl , cm ): 1479, 2924. EI
123 (98), 138 (87), 178 (100), 221 (M , 3). HRMS (EI):
þ
3
þ
HRMS (EI): found M 181.1591, C H N requires M
þ
1
3 23 3
þ
þ
1
0 19 3
1
81.1579.
4i: dH (300 MHz, CDCl ): 1.007 (3H, d, J¼6.2 Hz,
3
CH(CH ) ), 1.010 (3H, d, J¼6.4 Hz, CH(CH ) ), 1.42–
1.59 (12H, m, NCH (CH ) ), 2.01–2.26 (3H, m, CH -
2 2 3 2
3
2
3 2
4
g: dH (300 MHz, CDCl ): 0.94 (3H, d, J¼5.7 Hz,
3
CH(CH ) ), 0.95 (3H, d, J¼6.4 Hz, CH(CH ) ), 1.93–
CH(CH ) ), 2.40–2.62 (8H, m, NCH CH ), 2.89 (3H, s,
3 2 2 2
3
2
3 2
2
.25 (3H, m, CH CH(CH ) ), 2.15 (6H, s, N(CH ) ), 2.21
2
NCH ), 4.00 (1H, d, J¼3.7 Hz, Im-H), 4.23 (1H, d,
3 2
3 2
3
(
6H, s, N(CH ) ), 2.82 (3H, s, NCH ), 3.89 (1H, d,
3
J¼3.5 Hz, Im-H). d (75 MHz, CDCl ): 22.4, 23.0, 24.5,
2
3
C
3
J¼3.7 Hz, Im-H), 4.14 (1H, d, J¼3.7 Hz, Im-H). d
24.7, 26.0, 26.1, 26.6, 31.5, 36.5, 48.1, 49.1, 84.2, 85.8,
165.7. nmax (CHCl , cm ): 1460, 1592, 2914. EI MS (m/z,
C
21
(
75 MHz, CDCl ): 22.2, 22.8, 26.3, 30.9, 36.5, 38.2, 39.8,
3
3
2
1
8
2.7, 85.4, 165.5. nmax (CHCl , cm ): 1594, 2933. EI MS
3
%): 84 (91), 97 (100), 178 (90), 221 (25), 291 (20), 306
þ
2). HRMS (EI): found M 226.2153, C H N requires
þ
þ þ
(M , 18). HRMS (EI): found M 306.2779, C H N
18 34 4
(
m/z, %): 91 (62), 138 (58), 181 (37), 205 (100), 226 (M ,
þ
þ
requires M 306.2783.
1
M 226.2157.
1
2 26 4
4.1.18. 2-(1-Benzylamino-2-methylpropyl)-1-methyl-1H-
imidazole 3j. Obtained, after Al O column chromato-
graphy (AcOEt/n-hexane¼1:5), as a yellow viscous oil
(176 mg, 36%) from benzylamine (10 mmol) and crude 2b
(starting from 2 mmol of 1b).
4
1
2
.1.16. 1-Methyl-2-[2-methyl-1-(1-pyrrolidinyl)propyl]-
p
2
3
p
H-imidazole 3h and (4R ,5R )-4,5-dihydro-1-methyl-
-(2-methylpropyl)-4,5-bis(1-pyrrolidinyl)-1H-imida-
zole 4h. Obtained, after Al O column chromatography
2
3
(
AcOEt/n-hexane¼1:5 to AcOEt/MeOH¼10:1), as a yellow
viscous oil [(3h; 118 mg, 19%), (4h; 418 mg, 50%)] from
pyrrolidine (15 mmol) and crude 2b (starting from 3 mmol
of 1b).
d (300 MHz, CDCl ): 0.77 (3H, d, J¼6.8 Hz, CH(CH ) ),
H
3
3 2
1.05 (3H, d, J¼6.6 Hz, CH(CH ) ), 1.95–2.11 (1H, m,
3
2
CH(CH ) ), 2.22 (1H, br, NHCH ), 3.41 (1H, d, J¼7.9 Hz,
3
2
2

6646
I. Kawasaki et al. / Tetrahedron 60 (2004) 6639–6648
þ
223.2034, C H N requires M 223.2048.
þ
CHCH(CH ) ), 3.43 (1H, d, J¼13.6 Hz, NCH ), 3.48 (3H, s,
(43), 180 (68), 223 (M , 1). HRMS (EI): found M
þ
3
2
2
NCH ), 3.73 (1H, d, J¼13.4 Hz, NCH ), 6.76 (1H, d,
3
2
13 25 3
J¼1.1 Hz, Im-H), 7.01 (1H, d, J¼0.9 Hz, Im-H), 7.18–7.32
(
5H, m, Ar-H). d (75 MHz, CDCl ): 19.5, 19.6, 32.5, 33.6,
C
4m: dH (300 MHz, CDCl ): 0.88 (3H, t, J¼6.8 Hz,
3
3
5
nmax (CHCl , cm ): 1460, 1485, 1599, 1657, 2950, 3300–
1.5, 59.9, 120.3, 126.7, 127.2, 128.0, 128.2, 140.3, 149.7.
2
CH CH ), 1.28–1.41 (8H, m, CH (CH ) CH ), 1.59–1.69
2
3
2
2 4
3
1
(2H, m, CH C H ), 2.21 (6H, s, N(CH ) ), 2.19–2.30 (2H,
2 5 11 3 2
3
3
2
2
500. CI MS (m/z, %): 83 (12), 91 (62), 123 (22), 138 (50),
þ
m, CH C H ), 2.27 (6H, s, N(CH ) ), 2.90 (3H, s, NCH ),
2 6 13 3 2 3
þ
00 (100), 244 (M þH, 52). HRMS (CIþ): found MH
3.96 (1H, d, J¼3.5 Hz, Im-H), 4.20 (1H, d, J¼3.3 Hz,
þ
44.1820, C H N þH requires MH 244.1814.
Im-H). d (75 MHz, CDCl ): 13.9, 22.4, 26.9, 27.9, 28.9,
C
1
5
21
3
3
29.5, 30.8, 31.6, 38.3, 39.9, 82.6, 85.4, 166.6. n
cm ): 1449, 1594, 2773, 2907. EI MS (m/z, %): 124
(CHCl3,
max
p
p
21
4
.1.19. (3aR ,7aS )-3a,4,5,6,7,7a-Hexahydro-1,4,7-tri-
þ
(EI): found M 268.2620, C H N requires M
268.2627.
methyl-2-(2-methylpropyl)-1H-imidazo[4,5-b]pyrazine
k. Obtained, after Al O column chromatography (AcOEt/
(33), 139 (100), 152 (44), 223 (45), 268 (M , 7). HRMS
þ
þ
4
2
3
15 32
4
MeOH¼10:1), as a yellow viscous oil (193 mg, 29%) from
0
starting from 3 mmol of 1b).
N,N -dimethylethylenediamine (15 mmol) and crude 2b
(
4.1.22. 1-Methyl-2-[1-(1-pyrrolidinyl)heptyl]-1H-imida-
p
p
zole 3n and (4R ,5R )-2-heptyl-4,5-dihydro-1-methyl-
4,5-bis(1-pyrrolidinyl)-1H-imidazole 4n. Obtained, after
Al O column chromatography (AcOEt/n-hexane¼1:2 to
d (300 MHz, CDCl ): 1.015 (3H, d, J¼6.4 Hz, CH(CH ) ),
H
3
3 2
1
CH(CH ) ), 2.20–2.30 (2H, m, CH CH(CH ) ), 2.53–2.84
.019 (3H, d, J¼6.6 Hz, CH(CH ) ), 1.98–2.10 (1H, m,
3
2
2 3
AcOEt only), as a yellow viscous oil [(3n; 106 mg, 43%),
(4n; 130 mg, 41%)] from pyrrolidine (5 mmol) and 2c
(1 mmol).
3 2 2 3 2
(
4H, m, (CH ) ), 2.50 (3H, s, NCH ), 2.62 (3H, s, NCH ),
2 2 3 3
2
.89 (3H, s, NCH ), 4.24 (1H, d, J¼8.4 Hz, Im-H), 4.53
3
(
1H, d, J¼8.4 Hz, Im-H). d (75 MHz, CDCl ): 22.5, 22.6,
C
3
2
nmax (CHCl , cm ): 1450, 1598, 2919. EI MS (m/z, %): 85
6.6, 32.2, 36.4, 42.0, 43.0, 44.6, 45.2, 77.4, 80.8, 168.1.
3n: dH (300 MHz, CDCl ): 0.84 (3H, t, J¼6.8 Hz,
3
2
1
CH CH ), 0.98–1.30 (8H, m, CH (CH ) CH ), 1.65–1.77
2
3
3
2
2 4
3
þ
(58), 114 (100), 142 (63), 185 (57), 198 (39), 224 (M , 2).
þ
HRMS (EI): found M 224.1992, C H N requires M
(4H, m, NCH (CH ) ), 1.84–2.00 (2H, m, CH C H ),
2 2 2 2 5 11
2.25–2.38 (2H, m, NCH CH ), 2.60–2.68 (2H, m,
2 2
þ
1
2
24
4
2
24.2001.
NCH CH ), 3.62 (1H, dd, J¼5.7, 9.4 Hz, CHC H ), 3.72
2
2
6 13
(
3H, s, NCH ), 6.77 (1H, d, J¼1.1 Hz, Im-H), 6.93 (1H, d,
3
4.1.20. S22-Methyl-1-(1-methyl-1H-imidazol-2-yl)-
propyl thiobenzoate 3l. Obtained, after Al O column
J¼1.1 Hz, Im-H). d (75 MHz, CDCl ): 13.9, 22.4, 23.1,
C
3
26.4, 29.2, 31.6, 32.5, 32.8, 51.0, 61.5, 120.7, 126.7, 148.2.
nmax (CHCl , cm ): 1457, 1493, 2780, 2909. EI MS (m/z,
2
3
2
1
chromatography (AcOEt/n-hexane¼1:2), as a yellow
3
þ
found M 249.2207, C H N requires M 249.2205.
viscous oil (400 mg, 49%) from sodium benzenethioate
(
%): 96 (24), 109 (100), 180 (65), 249 (M , 1). HRMS (EI):
þ
þ
15 mmol), NaH (15 mmol) and crude 2b (starting from
mmol of 1b).
1
5 27 3
3
4
CH CH ), 1.23–1.40 (8H, m, CH (CH ) CH ), 1.56–1.82
n: dH (300 MHz, CDCl ): 0.88 (3H, t, J¼6.8 Hz,
3
d (300 MHz, CDCl ): 1.00 (3H, d, J¼6.6 Hz, CH(CH ) ),
H
3
3 2
2
3
2
2 4
3
1
.16 (3H, d, J¼7.0 Hz, CH(CH ) ), 2.42–2.58 (1H, m,
(10H, m, CH C H , and NCH CH ), 2.26 (2H, t, J¼7.9 Hz,
CH C H ), 2.60–2.77 (8H, m, NCH CH ), 2.91 (3H, s,
2 6 13 2 2
3
2
2
5
11
2
2
CH(CH ) ), 3.71 (3H, s, NCH ), 4.80 (1H, d, J¼8.4 Hz,
3
2
3
CHCH(CH ) ), 6.76 (1H, d, J¼1.5 Hz, Im-H), 7.00 (1H, d,
NCH ), 4.26 (1H, d, J¼3.1 Hz, Im-H), 4.32 (1H, d,
3
2
3
J¼1.1 Hz, Im-H), 7.40–7.59 (3H, m, Ar-H), 7.95–7.99
J¼3.1 Hz, Im-H). d (75 MHz, CDCl ): 13.9, 22.4, 23.2,
C
3
(
2H, m, Ar-H). d (75 MHz, CDCl ): 20.3, 20.8, 32.8, 33.1,
C
23.7, 26.8, 28.0, 28.9, 29.5, 31.4, 31.6, 46.4, 48.5, 82.2,
82.6, 166.6. nmax (CHCl , cm ): 1476, 1593, 1666, 2906.
3
2
1
4
nmax (CHCl , cm ): 1485, 1652, 1698, 2946. EI MS (m/z,
5.2, 120.3, 127.3, 127.9, 128.6, 133.5, 136.5, 147.5, 191.3.
2
3
1
EI MS (m/z, %): 71 (54), 165 (96), 178 (37), 249 (100), 320
3
þ
EI): found M 274.1152, C H N OS requires M
þ þ
(M , 13). HRMS (EI): found M 320.2924, C H N
19 36 4
%
(
): 105 (55), 137 (100), 169 (99), 274 (M , 10). HRMS
þ
74.1140.
þ
þ
requires M 320.2940.
1
5 18 2
2
4
.1.23. 1-Benzyl-2-(1-dimethylamino-2,2-dimethyl-
p
p
4
.1.21. 1-Methyl-2-(1-dimethylaminoheptyl)-1H-imida-
propyl)-1H-imidazole 3p and (4R ,5R )-1-benzyl-4,5-
dihydro-4,5-bis(dimethylamino)-2-(2,2,-dimethyl-
propyl)-1H-imidazole 4p. Obtained, after Al O column
p
p
zole 3m and (4R ,5R )-2-heptyl-4,5-dihydro-1-methyl-
,5-bis(dimethylamino)-1H-imidazole 4m. Obtained, after
Al O column chromatography (AcOEt/n-hexane¼1:1 to
4
2
3
chromatography (AcOEt/n-hexane¼1:3 to AcOEt only), as
a yellow viscous oil (3p; 32 mg, 12%) and a solid (4p;
253 mg, 80%) from 2d (1 mmol).
2
3
AcOEt only), as a yellow viscous oil [(3m; 69 mg, 31%),
4m; 124 mg, 46%)] from 2c (1 mmol).
(
3
CH CH ), 1.11–1.34 (8H, m, CH (CH ) CH ), 1.78–2.07
m: dH (300 MHz, CDCl ): 0.85 (3H, t, J¼6.8 Hz,
3p: d (300 MHz, CDCl ): 0.97 (9H, s, C(CH ) ), 2.30 (6H,
H
s, N(CH ) ), 3.37 (1H, s, CHC(CH ) ), 5.12 and 5.18 (1H
3 2 3 3
3
3
3 3
2
3
2
2 4
3
(
2H, m, CH C H ), 2.23 (6H, s, N(CH ) ), 3.56 (1H, dd,
2
each, each d, J¼15.8 Hz, NCH ), 6.85 (1H, d, J¼1.3 Hz,
5
11
3 2
2
J¼4.6, 10.1 Hz, CHC H ), 3.67 (3H, s, NCH ), 6.80 (1H,
Im-H), 7.11 (1H, d, J¼1.1 Hz, Im-H), 7.12–7.37 (5H, m,
6
13
3
d, J¼1.1 Hz, Im-H), 6.96 (1H, d, J¼1.1 Hz, Im-H). d
Ar-H). d (75 MHz, CDCl ): 27.8, 37.2, 45.0, 50.0, 67.2,
C
C
3
(
75 MHz, CDCl ): 14.0, 22.5, 27.0, 28.1, 29.3, 31.7, 32.7,
3
119.5, 127.0, 127.2, 128.0, 128.8, 136.7, 146.0. n
max
2
1
21
4
1
1.6, 61.5, 120.8, 126.7, 147.5. nmax (CHCl , cm ): 1455,
3
(CHCl , cm ): 1450, 1471, 2928. EI MS (m/z, %): 91
3
þ
480, 2763, 2909. EI MS (m/z, %): 96 (32), 109 (100), 138
(12), 123 (3), 173 (2), 214 (100), 257 (3), 271 (M , 1).

I. Kawasaki et al. / Tetrahedron 60 (2004) 6639–6648
6647
þ
þ
HRMS (EI): found M 271.2041, C H N requires M
1
imidazole 3s. Obtained, after Al O column chromato-
2 3
7
25
3
2
71.2048.
graphy (AcOEt/n-hexane¼1:3), as a colorless powder
(82 mg, 51%) from phenol (3 mmol), Et N (2.5 mmol)
and 2d (0.5 mmol). Mp 84–87 8C.
3
4p: d (300 MHz, CDCl ): 1.11 (9H, s, C(CH ) ), 2.18 (6H,
s, N(CH ) ), 2.21 (6H, s, N(CH ) ), 2.37 (2H, s,
H
3
3 3
3
2
3 2
CH C(CH ) ), 3.91 (1H, d, J¼4.0 Hz, Im-H), 4.27 (1H, d,
d (300 MHz, CDCl ): 1.14 (9H, s, C(CH ) ), 5.06 and 5.37
3 3
2
3 3
H
3
J¼15.8 Hz, NCH ), 4.33 (1H, d, J¼4.4 Hz, Im-H), 4.57
(1H each, each d, J¼15.4 Hz, NCH ), 5.19 (1H, s,
2
2
(
(
1H, d, J¼15.4 Hz, NCH ), 7.21–7.35 (5H, m, Ar-H). d
CHC(CH ) ), 6.58 (1H, d, J¼1.1 Hz, Im-H), 6.74–6.91
3 3
2
C
75 MHz, CDCl ): 30.2, 31.7, 38.4, 40.3, 40.4, 47.3, 81.1,
3
(5H, m, Ar-H), 7.02 (1H, d, J¼1.5 Hz, Im-H), 7.11–7.18
8
cm ): 1587, 2923, 3132. EI MS (m/z, %): 91 (17), 124 (53),
2.2, 127.4, 127.8, 128.5, 137.3, 164.1. n
2
(CHCl3,
max
(5H, m, Ar-H). d (75 MHz, CDCl ): 26.7, 37.1, 50.6, 83.7,
C
3
1
115.5, 120.6, 121.1, 127.5, 127.6, 127.9, 128.5, 129.4,
21
þ
found M 316.2613, C H N requires M 316.2627.
2
14 (100), 225 (69), 271 (96), 316 (M , 2). HRMS (EI):
þ
136.4, 144.9, 158.2. nmax (CHCl , cm ): 1489, 1584, 1595,
3
þ
2936. EI MS (m/z, %): 91 (15), 169 (4), 227 (100), 263 (12),
1
9 32 4
þ þ
20 (M , 1). HRMS (EI): found M 320.1886, C H N O
21 24 2
3
þ
requires M 320.1889.
4
propyl]-1H-imidazole 3q and (4R ,5R )-1-benzyl-4,5-
.1.24. 1-Benzyl-2-[2,2-dimethyl-1-(1-pyrrolidinyl)-
p
p
dihydro-2-(2,2-dimethylpropyl)-4,5-bis(1-pyrrolidinyl)-
1
4.1.27. 2-(2,2-Dimethyl-1-dimethylaminopropyl)-1H-
imidazole 3t. Obtained, after recrystallization of the crude
extracts from AcOEt, as colorless prisms (150 mg, 83%)
from 2e (starting from 1 mmol of 1e). Mp 134–136 8C.
H-imidazole 4q. Obtained, after Al O column chroma-
2 3
tography (AcOEt/n-hexane¼1:3 to AcOEt only), as a
yellow viscous oil (3q; 27 mg, 18%) and a solid (4q;
1
32 mg, 72%) from pyrrolidine (2.5 mmol) and 2d
0.5 mmol).
(
d (300 MHz, DMSO-d ): 0.97 (9H, s, C(CH ) ), 2.15 (6H,
H
6
3 3
s, N(CH ) ), 3.24 (1H, s, CHC(CH ) ), 6.87 (1H, br, Im-H),
3
2
3 3
3
1
3
q: dH (300 MHz, CDCl ): 0.99 (9H, s, C(CH ) ), 1.54–
3 3
6.99(1H, br, Im-H). d (75 MHz, DMSO-d ):27.6, 35.9, 44.8,
C 6
3
70.2, 114.5, 127.2, 144.7. nmax (KBr, cm2 ): 1441, 2807,
1
.67 (4H, m, NCH (CH ) ), 2.30–2.85 (4H, m, NCH CH ),
2
2 2
2
2
.65 (1H, s, CHC(CH ) ), 5.14 (2H, s, NCH ), 6.82 (1H, d,
3
2931, 3097. EIMS(m/z, %):83(21), 95(8),108(6),124(100),
3
2
þ þ
181 (M , 3). HRMS (EI): found M 181.1589, C H N
10 19 3
J¼1.3 Hz, Im-H), 7.09 (1H, d, J¼1.3 Hz, Im-H), 7.11–7.37
þ
requires M 181.1579. Anal. calcd for C H N : C, 66.26; H,
10 19 3
(
5H, m, Ar-H). d (75 MHz, CDCl ): 23.6, 28.1, 37.0, 50.0,
C
3
5
nmax (CHCl , cm ): 1451, 1473, 2937. EI MS (m/z, %): 91
2.1, 64.8, 119.3, 127.2, 127.3, 128.0, 128.8, 136.5, 146.7.
2
10.56; N, 23.18; found: C, 66.09; H, 10.57; N, 23.14.
4.2. Synthesis of 5-amino-1-methylimidazoles 7
A toluene (1 mL) solution of 4 (0.5 mmol) was heated at
1
3
þ
M 297.2224, C H N requires M 297.2205.
(
13), 213 (12), 240 (100), 297 (M , 0.2). HRMS (EI): found
þ
þ
1
9 27 3
4
1
2
4
q: dH (300 MHz, CDCl ): 1.09 (9H, s, C(CH ) ), 1.67–
3
120 8C with stirring under N until no starting material (4)
2
3 3
.76 (8H, m, NCH (CH ) ), 2.34 (2H, s, CH (CH ) ), 2.57–
2
remained on TLC (5–12 h). The solution was cooled to rt,
and the solvent was evaporated to give an oily residue,
which was purified by Al O column chromatography
2 2
2
3 3
.67 (8H, m, NCH CH ), 4.28 (1H, d, J¼4.0 Hz, Im-H),
2
2
.29 (1H, d, J¼15.8 Hz, NCH ), 4.53–4.59 (2H, m, Im-H
2
2 3
and NCH ), 7.22–7.34 (5H, m, Ar-H). d (75 MHz,
2
CDCl ): 23.5, 24.0, 30.2, 31.7, 40.4, 46.5, 47.7, 47.8,
3
(AcOEt/n-hexane¼1:2 to AcOEt only) to obtain pure 7 as a
C
yellow viscous oil.
7
cm ): 1457, 1586, 2933. EI MS (m/z, %): 70 (51), 91 (93),
7.9, 80.9, 127.2, 127.6, 128.4, 137.8, 164.0. n
2
(CHCl3,
max
1
4.2.1. 1-Methyl-5-dimethylamino-2-(2,2-dimethyl-
propyl)-1H-imidazole 7a. Yield, 88 mg (90%). dH
(300 MHz, CDCl ): 1.00 (9H, s, C(CH ) ), 2.51 (2H, s,
þ
1
50 (42), 240 (100), 277 (86), 297 (36), 368 (M , 1). HRMS
þ
þ
(
EI): found M 368.2952, C H N requires M 368.2940.
2
3
36
4
3
3 3
CH C(CH ) ), 2.64 (6H, s, N(CH ) ), 3.40 (3H, s, NCH ),
3
2
3 3
3 2
4.1.25. 1-Benzyl-2-[1-(1-methylethoxy)-2,2-dimethyl-
propyl]-1H-imidazole 3r. Obtained, after Al O column
6.50 (1H, s, Im-H). d (75 MHz, CDCl ): 29.5, 29.6, 32.7,
C 3
40.4, 44.8, 112.8, 143.0, 143.8. nmax (CHCl , cm ): 1465,
3
2
1
2
3
chromatography (AcOEt/n-hexane¼1:2), as colorless nee-
1491, 1567, 2926. EI MS (m/z, %): 70 (9), 138 (100), 180
þ
þ
C H N requires M 195.1735.
dles (48 mg, 34%) from 2-propanol (5 mmol), Et N
3
(4), 195 (M , 14). HRMS (EI): found M 195.1720,
þ
(
3 mmol) and 2d (0.5 mmol). Mp 47–50 8C.
1
1 21 3
d (300 MHz, CDCl ): 0.92 (3H, d, J¼5.9 Hz, CH(CH ) ),
4.2.2. 1-Methyl-2-(2,2-dimethylpropyl)-5-(1-pyrroli-
dinyl)-1H-imidazole 7b. Yield, 92 mg (83%). dH
(300 MHz, CDCl ): 0.99 (9H, s, C(CH ) ), 1.90–1.95
(4H, m, NCH (CH ) ), 2.52 (2H, s, CH C(CH ) ), 3.00–
2 2 2 2 3 3
3.05 (4H, m, NCH CH ), 3.41 (3H, s, NCH ), 6.46 (1H, s,
2 2 3
H
3
3 2
0
3
.97 (9H, s, C(CH ) ), 1.02 (3H, d, J¼6.2 Hz, CH(CH ) ),
3 2
3
3
3 2
.42 (1H, hept., J¼6.1 Hz, CH(CH ) ), 4.39 (1H, s,
3
3 3
CHC(CH ) ), 5.21 and 5.50 (1H each, each d, J¼15.8 Hz,
3
3
NCH ), 6.72 (1H, d, J¼1.5 Hz, Im-H), 7.01 (1H, d,
2
J¼1.1 Hz, Im-H), 7.09–7.12 (2H, m, Ar-H), 7.27–7.36
Im-H). d (75 MHz, CDCl ): 24.5, 29.6, 30.3, 32.8, 40.4,
C 3
2
1
(
3H, m, Ar-H). d (75 MHz, CDCl ): 21.0, 22.8, 26.7, 36.7,
C
52.8, 111.6, 141.8, 142.9. nmax (CHCl , cm ): 1464, 1490,
3
3
5
1
0.4, 70.7, 82.0, 120.5, 127.0, 127.5, 127.7, 128.7, 137.3,
2
1566, 2934. EI MS (m/z, %): 96 (3), 122 (6), 164 (100), 206
þ
1
þ
C H N requires M 221.1892.
47.2. nmax (CHCl , cm ): 1475, 2931. EI MS (m/z, %): 91
3
(4), 221 (M , 14). HRMS (EI): found M 221.1898,
þ
þ
(43), 187 (100), 229 (79), 286 (M , 4). HRMS (EI): found
þ
M 286.2037, C H N O requires M 286.2045.
1
3 23 3
þ
1
8 26 2
4.2.3. 1-Methyl-5-dimethylamino-2-(2-methylpropyl)-
1H-imidazole 7c. Yield, 60 mg (66%). dH (300 MHz,
4
.1.26. 1-Benzyl-2-(2,2-dimethyl-1-phenoxypropyl)-1H-

6648
I. Kawasaki et al. / Tetrahedron 60 (2004) 6639–6648
CDCl ): 0.97 (6H, d, J¼6.6 Hz, CH(CH ) ), 2.01–2.17 (1H,
Yamashita, M.; Ohta, S. Chem. Pharm. Bull. 1996, 44, 1831.
(c) Kawasaki, I.; Taguchi, N.; Yamashita, M.; Ohta, S. Chem.
Pharm. Bull. 1997, 45, 1393. (d) Kawasaki, I.; Katsuma, H.;
Nakayama, Y.; Yamashita, M.; Ohta, S. Heterocycles 1998,
48, 1887. (e) Ohta, S.; Tsuno, N.; Maeda, K.; Nakamura, S.;
Taguchi, N.; Yamashita, M.; Kawasaki, I. Tetrahedron Lett.
2000, 41, 4623. (f) Kawasaki, I.; Sakaguchi, N.; Fukushima,
N.; Fujioka, N.; Nikaido, F.; Yamashita, M.; Ohta, S.
Tetrahedron Lett. 2002, 43, 4377. (g) Nakamura, S.;
Kawasaki, I.; Kunimura, M.; Matsui, M.; Noma, Y.;
Yamashita, M.; Ohta, S. J. Chem. Soc., Perkin Trans. 1
2002, 1061. (h) Nakamura, S.; Kawasaki, I.; Yamashita, M.;
Ohta, S. Heterocycles 2003, 60, 583.
3
3 2
m, CH(CH ) ), 2.48 (2H, d, J¼7.3 Hz, CH CHC(CH ) ),
3
2
2
3 2
2
Im-H). d (75 MHz, CDCl ): 22.5, 27.7, 28.9, 36.5, 44.9,
.64 (6H, s, N(CH ) ), 3.38 (3H, s, NCH ), 6.47 (1H, s,
3 2 3
C
3
2
1
1
2
1
12.7, 143.8, 144.1. nmax (CHCl , cm ): 1461, 1497, 1568,
3
933. EI MS (m/z, %): 70 (12), 124 (5), 138 (100), 166 (6),
þ
þ
81 (M , 26). HRMS (EI): found M 181.1585, C H N
0 19 3
1
þ
requires M 181.1579.
4
1
.2.4. 1-Methyl-2-(2-methylpropyl)-5-(1-pyrrolidinyl)-
H-imidazole 7d. Yield, 83 mg (80%). dH (300 MHz,
CDCl ): 0.97 (6H, d, J¼6.6 Hz, CH(CH ) ), 1.87–1.96 (4H,
3
3 2
m, NCH (CH ) ), 2.00–2.18 (1H, m, CH(CH ) ), 2.48 (2H,
2
2 2
3 2
d, J¼7.2 Hz, CH CH(CH ) ), 3.00–3.04 (4H, m,
NCH CH ), 3.40 (3H, s, NCH ), 6.42 (1H, s, Im-H). d
C
6. (a) Begtrup, M. Angew. Chem. Int. Ed. 1974, 13, 347.
(b) Grimmett, M. R. Comprehensive Organic Chemistry;
Sammes, P. G., Ed.; Pergamon: Oxford, 1979; Vol. 4, p 357.
(c) Itoh, T.; Hasegawa, H.; Nagata, K.; Ohsawa, A. J. Org.
Chem. 1994, 59, 1319. (d) Itoh, T.; Miyazaki, M.; Hasegawa,
H.; Nagata, K.; Ohsawa, A. Chem. Commun. 1996, 1217.
7. (a) Hand, E. S.; Paudler, W. W. J. Org. Chem. 1978, 43, 2900.
2
3 2
2
2
3
(
75 MHz, CDCl ): 22.5, 24.4, 27.8, 29.4, 36.5, 52.8, 111.6,
3
2
1
1
EI MS (m/z, %): 96 (4), 122 (8), 164 (100), 207 (M , 19).
41.7, 143.8. nmax (CHCl , cm ): 1459, 1496, 1567, 2938.
3
þ
HRMS (EI): found M 207.1750, C H N requires M
þ
þ
1
2 21 3
2
07.1735.
(
b) Achour, R.; Essassi, E. M.; Zniber, R. Tetrahedron Lett.
988, 29, 195. (c) Yamanaka, H.; Ohba, S.; Sakamoto, T.
1
Acknowledgements
Heterocycles 1990, 31, 1115. (d) Burger, K.; H o¨ ß, E.; Geith,
K. Synthesis 1990, 360. (e) Subrayan, R. P.; Rasmussen, P. G.
Tetrahedron 1995, 51, 6167. (f) Tennant, G.; Wallis, C. J.;
Weaver, G. W. J. Chem. Soc., Perkin Trans. 1 1999, 629.
8. (a) Oxidative addition of alcohol: Olofson, A.; Yakushijin, K.;
Horne, D. A. J. Org. Chem. 1998, 63, 1248. (b) [2þ2]
Photocycloaddition: Nakano, T.; Rodr ´ı guez, W.; De Roche,
S. Z.; Larrauri, J. M.; Rivas, C.; P e´ rez, C. J. Heterocycl. Chem.
1980, 17, 1777.
We are grateful for financial support in part by the Frontier
Research Program 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
education and research in graduate schools in subsidies for
ordinary expenses of private schools from the Promotion
and Mutual Aid Corporation for Private Schools.
9
. Ohta, S.; Osaki, T.; Nishio, S.; Furusawa, A.; Yamashita, M.;
Kawasaki, I. Tetrahedron Lett. 2000, 41, 7503.
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5