Novel nucleophilic C-C bond-forming tele-reaction of imidazole ring

Article abstract of DOI:10.1002/jhet.5570410305

Reaction of 2-(1-chloro-2,2-dimethylpropyl)-1-methyl-1H-imidazoles with diethyl methylmalonate in the presence of NaH gave a normal S_N product, 2-[(1,1-diethoxycarbonylethyl)-2,2-dimethylpropyl]-1-methyl-1H- imidazole (2a), and two tele-reactio

Full text of DOI:10.1002/jhet.5570410305

May-Jun 2004
335
Novel Nucleophilic C-C Bond-forming
tele-Reaction of Imidazole Ring
Shunsaku Ohta*, Kentaro Sato, Ikuo Kawasaki, Yuko Yamaguchi, Satoko Nishio and
Masayuki Yamashita
Kyoto Pharmaceutical University, Misasagi Yamashinaku, Kyoto 607-8414, Japan
E-mail: sohta@mb.kyoto-phu.ac.jp
Received August 6, 2003
Reaction of 2-(1-chloro-2,2-dimethylpropyl)-1-methyl-1H-imidazoles with diethyl methylmalonate in the
presence of NaH gave a normal S product, 2-[(1,1-diethoxycarbonylethyl)-2,2-dimethylpropyl]-1-methyl-
N
1H-imidazole (2a), and two tele -reaction products, 5-(1,1-diethoxycarbonylethyl)-1-methyl-2-(2,2-
dimethylpropyl)-1H-imidazole (3 a) and trans-4,5-di-(1,1-diethoxycarbonylethyl)-4,5-dihydro-1-methyl-2-
(2,2-dimethylpropyl)-1H-imidazole (4a) in 5, 17 and 70 % yields, respectively. The scope and mechanism
of this reaction are discussed.
J. Heterocyclic Chem., 41, 335 (2004).
Introduction.
propyl)-1H-imidazole (3a) and trans-4,5-di(1,1-diethoxy-
carbonylethyl)-4, 5-dihydro-1-methyl-2-(2, 2-dimethyl-
propyl)-1H-imidazole (4a) in 67 % and 11 % yields,
respectively, together with a small amount of a normal SN
product [12], 2-[1-(1,1-diethoxycarbonylethyl)-2,2-
dimethylpropyl]-1-methyl-1H-imidazole (2 a). The struc-
ture of 3a was determined by HMBC correlations, and the
trans-orientation of the 4- and 5- substituents of 4a was
confirmed by the similarity of the 1H-NMR coupling con-
stant (3.0 Hz) of H4 - H5 in the imidazoline ring as the
reported value for 4,5-di(N , N-dimethylamino)-1-methyl-
Electrophilic substitutions of an imidazole nucleus [1]
and nucleophilic substitutions via lithioimidazoles [2]
have been well known for the preparation of imidazole
compounds, and we have applied the reactions of lithioim-
idazoles [3] and imidazolium salts [4] to the syntheses of
several pharmaceutically interesting compounds and nat-
ural products [5]. On the other hand, nucleophilic reactions
on the imidazole ring have been mainly performed through
the activation by quaternization of the ring [6] or introduc-
ing an electron-withdrawing group such as halogen
atom(s) into the nucleus [7], other examples have been
quite rare [8,9]. In the preceding paper, we reported a
nucleophilic addition of amines to the imidazole ring of 2-
(1-chloro-2, 2-dimethylpropyl)-1-methyl-1 H-imidazole
hydrochloride (1a) [10]. In this paper, we would like to
present the first example and a possible mechanism of a C-
C bond-forming nucleophilic tele-reaction [11] of carbon
nucleophiles with 1a and its derivatives without any acti-
vation steps of the imidazole nucleus.
Table 1
Nucleophilic Reaction of Malonates to Imidazole Derivatives
Yield (%) (Product)
1
2
Entry
R
R
1 / NaH /
2
3
4
malonate
1
2
3
4
5
6
7
8
9
t-Bu
t-Bu
t-Bu
t-Bu
i-Pr
Et
Me
Me
Me
Me
Me
Me
H
1 / 3 / 3
1 / 5 / 5
1 / 10 / 10
1 / 6.5 / 5
1 / 5 / 5
1 / 3 / 3
1 / 5 / 5
1 / 5 / 5
1 / 5 / 5
1 / 2 / 2
3 (2a) 67 (3a) 11 (4a)
5 (2a) 26 (3a) 57 (4a)
5 (2a) 17 (3a) 70 (4a)
5 (2a) 34 (3a)
- [a]
Results and Discussion.
9 (2b) 10 (3b) 48 (4b)
35 (2c) 25 (3c) 30 (4c)
16 (2d) 61 (3d) 7 (4d)
We first examined a reaction of 2-(1-chloro-2,2-
dimethylpropyl)-1-methyl-1H-imidazole hydrochloride
(1a) with diethyl methylmalonate in the presence of NaH
(entry 1), and it was found the use of three equivalents of
the malonate and NaH gave two tele-reaction products, 5-
(1,1-diethoxycarbonylethyl)-1-methyl-2-(2,2-dimethyl-
t-Bu
t-Bu
Et
5 (2e)
6 (2f)
3 (2g)
32 (3e) 28 (4e)
t-Bu CH CH=CH
89 (3f)
11 (3g)
- [a]
- [a]
2
2
10 [b] t-Bu
Ph
[a] Not detected in the reaction mixture; [b] Unexpected S product 5 was
N
also obtained in 44 %.

336
S. Ohta, K. Sato, I. Kawasaki, Y. Yamaguchi, S. Nishio and M. Yamashita
Vol. 41
2-(2,2-dimethylpropyl)-2-imidazoline (3.8 Hz) [10]. To
our knowledge, this is the first example of direct nucle-
ophilic addition of a carbon nucleophile to the imidazole
ring without any electron-withdrawing substituent on the
nucleus.
We considered the reaction mechanism as shown in
Scheme 2. Increasing of the amount of the nucleophile
decreased the yield of 3a and increased the yield of 4a
(entries 2 and 3). In the presence of some excess of NaH
over that of diethyl methylmalonate, the di-adduct 4a was
not obtained at all (entry 4) because of the absence of the
proton source. This result might suggest that protonation
of the intermediate 6 by diethyl methylmalonate at the side
chain of the 2-position is an important factor for the for-
mation of 4a, and in the case of entry 4 the reaction might
stop at intermediate 6, which is converted to 3a during
work-up.
show that selectivity between path-a and path-b seems to
depend mainly on the steric hindrance around C5-H of the
intermediate 6 and bulkiness of the nucleophile as well as
basicity of the nucleophile.
Reaction of 1a with diethyl sodiophenylmalonate gave
surprisingly an unexpected other type of tele-product,
diethyl 4-[1-(1-methyl-1H-imidazol-2-yl)-2,2-dimethyl-
propyl]phenylmalonate (5), which might be raised up from
an SN reaction on the 4-position of the phenyl group of the
malonate, in 44 % yield accompanied with a small amount
of 2g and 3g (entry 10). To our knowledge, this type of
unexpected nucleophilic tele-reaction seems to be also a
very rare example in diethyl phenylmalonate [13].
Furthermore, reactions of 1a with organometallic
reagents such as alkyl Grignard reagents and dialkylzinc
were examined (Scheme 3). The tele-substitution reactions
proceeded by treatment of 1a with five equivalents of
methylmagnesium bromide or n-butylmagnesium chloride
to give the corresponding tri-alkylated tele-reaction prod-
ucts 8a (37 %) and 8b (6 %) together with normal SN prod-
ucts 7a (21 %) and 7b (13 %), respectively. This result
might also show that the absence of acidic proton such as
malonates in the reaction system was preferred as above-
mentioned to provide the mono-adduct via path-a. On the
other hand, the reaction of 1a with four equivalents of
diethylzinc gave only an SN product 7c in 27 % yield.
2-(1-Chloro-2-methylpropyl)-1-methyl-1H-imidazole
hydrochloride (1b) was subjected to similar reaction con-
ditions as that of entry 2 to decrease yield of the addition
products 3b and 4b (10 and 48 %, respectively) (entry 5),
and in the case of 2-(1-chloropropyl)-1-methyl-1H-imida-
zole hydrochloride (1c) increased yield of the SN product
2c (35 %) (entry 6). In entry 6, the nucleophile and the pro-
ton source can approach around the 2-position more easily
than in entries 1 - 5 to increase yield of the SN product 2c.
When the hydrochloride 1a was treated with simple
diethyl malonate instead of diethyl methylmalonate, the
mono-adduct 3d was obtained as the main product in 61 %
yield together with some SN product (2d, 16 %) and di-
adduct (4d, 7 %) (entry 7). The yield of 3d is comparable
with that of 3a in entry 1, and this indicates that the C5-H
of the intermediate 6 (R2 = Na) is abstracted by the adja-
cent carbanion and also the proton source [CH2(COOEt)2]
can approach more easily around the 2-position of the
intermediate. When the reaction of 1a was carried out with
more bulky malonate, diethyl ethylmalonate and diethyl
allylmalonate than diethyl methylmalonate, yield of
di-adducts was decreased very much whereas yield of
mono-adducts was increased (entry 8 and 9). These results
Conclusion.
We have found a novel nucleophilic tele-reaction to the
imidazole nucleus. Further investigations of the present
reaction are currently underway.

May-Jun 2004
Novel Nucleophilic C-C Bond-forming tele-Reaction of Imidazole Ring
337
EXPERIMENTAL
of the solvents, the hydrochloride (1b) was obtained as a pale yel-
low crystalline residue, which was used in the next reaction with-
out further purification; ir (CHCl ): 3360, 3138, 2950, 1594, 1464
-1 1
All melting points were measured with a Yanaco MP micro-
melting-point apparatus and are uncorrected. The infrared spectra
3
cm ; H nmr (270 MHz, CDCl ): δ 0.96 (3H, d, J = 6.6 Hz), 1.29
3
1
were taken with Shimadzu IR-435 spectrophotometer. H nmr
(3H, d, J = 6.4 Hz), 2.63-2.77 (1H, m), 3.40 (1H, br), 4.10 (3H, s),
5.34 (1H, d, J = 10.2 Hz), 7.36 (1H, d, J = 1.8 Hz), 7.63 (1H, d, J =
13
and C nmr spectra were measured on Varian UNITY INOVA
13
1.8 Hz); C nmr (68 MHz, CDCl ): δ 19.8, 20.1, 34.1, 35.8, 55.4,
1
13
1
400NB ( H: 400 MHz, C: 100 MHz), JEOL EX-300 ( H: 300
3
118.7, 124.2, 143.5; ms: m/z 174 (2.8), 172 (M , 10), 137 (100),
132 (25), 130 (75), 121 (90), 96 (48), 81 (27); Hrms Calcd. for
+
13
1
13
MHz, C: 75 MHz) or JEOL EX-270 ( H: 270 MHz, C: 68
MHz) spectrometer and the chemical shifts were expressed in
parts per million downfield from tetramethylsilane as the internal
standard. Mass spectra (MS) were measured on JEOL JMS BU-
20 spectrometer using an electron impact mode (70 eV). Silica
gel (Merck Art. 7734) for column chromatography was used.
+
C H ClN : [M] = 172.0767. Found: 172.0773.
8
13
2
2-(1-Chloropropyl)-1-methyl-1H-imidazole Hydrochloride (1c).
2-(1-Hydroxypropyl)-1-methyl-1H-imidazole was prepared in
a similar manner as that used for preparation of 2-(1-hydroxy-2-
methylpropyl)-1-methyl-1H-imidazole except for use of propanal
instead of 2-methylpropanal. The crude product was purified by
column chromatography (acetone) to give the alcohol as a yellow
2 - ( 1 - C h l o r o - 2 , 2 - d i m e t h y l p r o p y l ) - 1 - m e t h y l - 1 H- i m i d a z o l e
Hydrochloride (1a).
Thionyl chloride (SOCl , 0.73 mL, 10 mmol) was added to a
2
stirred solution of 2-(1-hydroxy-2,2-dimethylpropyl)-1-methyl-
viscous oil, 4.41 g (63 %); ir (CHCl ): 3133, 2941, 1489, 1455
-1 1
3
cm ; H nmr (CDCl , 400 MHz): δ 0.94 (3H, t, J = 7.4 Hz), 1.89
1H-imidazole [3b] (840 mg, 5 mmol) in CHCl (5 mL) under N
3
2
3
(2H, pent., J = 7.3 Hz), 3.69 (3H, s), 4.59 (1H, t, J = 7.0 Hz), 6.76
at 0 °C. After 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 °C; ir (potassium bromide):
13
(1H, d, J = 1.3 Hz), 6.83 (1H, d, J = 1.3 Hz); C nmr (CDCl ,
3
100 MHz): δ 10.1, 28.9, 32.8, 68.1, 121.3, 126.4, 149.7; ms: m/z
+
140 (M , 29), 122 (36), 111 (100), 83 (51), 56 (19); Hrms Calcd.
- 1
1
+
for C H N O: [M] = 140.0950. Found: 140.0947.
3396, 2913, 1591, 1514, 1463 cm
CD OD): δ 1.15 (9H, s), 4.00 (3H, s), 5.54 (1H, s), 7.62 (1H, d, J
; H nmr (300 MHz,
7
12 2
The title compound was prepared in a similar manner as that
used for preparation of 1a except for use of 2-(1-hydroxypropyl)-
1-methyl-1H-imidazole instead of 2-(1-hydroxy-2,2-dimethyl-
propyl)-1-methyl-1H-imidazole. After evaporation of the sol-
vents, the crude hydrochloride 1c was obtained as a pale yellow
crystalline residue, which was purified by recrystallized from
EtOH–AcOEt to give 1c as a colorless powder, 865 mg (89 %),
mp 138-140 °C; ir (potassium bromide): 3400, 2950, 2769, 1677,
3
= 2.2 Hz), 7.66 (1H, d, J = 1.8 Hz); C nmr (75 MHz, CD OD):
13
3
δ 26.4 x 3, 36.3, 39.7, 59.7, 121.0, 125.4, 145.3; ms: m/z 188
+
(1.2), 186 (M , 3.9), 171 (5), 151 (15), 132 (32), 130 (100), 121
(13), 95 (36), 81 (11), 57 (6); Hrms Calcd. for C H ClN :
9
15
2
+
[M] = 186.0924. Found: 186.0933.
Anal. Calcd. for C H ClN : C, 48.44; H, 7.23; N, 12.55.
Found: C, 48.51; H, 7.34; N, 12.24.
9
15
2
-1
1
1590, 1522, 1378 cm ; H nmr (DMSO-d , 400 MHz): δ 1.05
6
(3H, t, J = 7.3 Hz), 2.38 (2H, pent., J = 7.3 Hz), 3.92 (3H, s), 5.69
(1H, t, J = 7.3 Hz), 7.72 (1H, d, J = 1.8 Hz), 7.80 (1H, d, J = 1.8
2-(1-Chloro-2-methylpropyl)-1-methyl-1H-imidazole Hydro-
chloride (1b).
n -Butyl lithium (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) under N at -78 °C. After stirring
2
for 30 min at the same temperature, 2-methylpropanal (4.54 mL,
50 mmol) was added and the resulting mixture was stirred for 2 h
at ambient temperature. The mixture was then acidified with HCl
aq. (10 %, 50 mL) and washed with diethyl ether (30 mL x 2).
13
Hz); C nmr (DMSO-d , 100 MHz): δ 11.1, 28.2, 34.7, 50.9,
6
119.9, 124.6, 143.8; ms: m/z 160 (2.4), 158 (M , 8.3), 132 (8),
130 (23), 123 (96), 107 (100), 96 (31), 81 (35), 56 (30); Hrms
+
+
Calcd. for C H ClN : [M] = 158.0611. Found: 158.0609.
7
Anal. Calcd. for C H Cl N : C, 43.10; H, 6.20; N, 14.36.
11
2
7
Found: C, 43.38; H, 6.44; N, 14.09.
12
2 2
Synthesis of 2-[1-(1,1-Diethoxycarbonylethyl)-2,2-dimethyl-
p r o p y l ] - 1 - m e t h y l - 1 H-imidazole (2 a ), 5-(1,1-Diethoxy-
carbonylethyl)-1-methyl-2-(2,2-dimethylpropyl)-1 H-imidazole
(3a) and (4R*,5R*)-4,5-Di(1,1-diethoxycarbonylethyl)-4,5-dihy-
dro-1-methyl-2-(2,2-dimethylpropyl)-1H-imidazole (4a).
The aqueous layer was basified with K CO powder and
2
3
extracted with AcOEt (30 mL x 3). The organic layer was dried
over anhydrous sodium sulfate and evaporated to give an oily
residue, which was purified by recrystallized from AcOEt–n-
hexane to give 2-(1-hydroxy-2-methylpropyl)-1-methyl-1H-imi-
dazole as colorless prisms, 3.58 g (47 %), mp 77-79 °C; ir
General Procedure (Entry 2 in Table 1 as an example).
-1
1
(CHCl ): 3099, 2942, 1489, 1464 cm ; H nmr (300 MHz,
3
CDCl ): δ 0.81 (3H, d, J = 6.8 Hz), 1.06 (3H, d, J = 6.6 Hz), 2.14
Sodium hydride (NaH, 60 % in oil, 200 mg, 5 mmol) was
added to a suspension of 1a (223 mg, 1 mmol) in THF (1 mL)
under N and ice cooling, and the mixture was stirred for 5 min at
2
0 °C, then diethyl methylmalonate (0.86 mL, 5 mmol) was added
to the mixture and stirring was continued for 4 h at ambient tem-
perature. Water (1 mL) was added to the reaction mixture and the
products were extracted with AcOEt (5 mL x 3) and the organic
layer was dried over anhydrous sodium sulfate. The solvent was
evaporated to give an oily residue, which was separated by col-
3
(1H, oct., J = 6.7 Hz), 3.67 (3H, s), 4.25 (1H, br s), 4.34 (1H, d, J
13
= 7.9 Hz), 6.77 (1H, d, J = 1.1 Hz), 6.91 (1H, d, J = 1.3 Hz);
nmr (75 MHz, CDCl ): δ 18.6, 19.0, 32.9, 33.9, 72.3, 121.0,
C
3
126.6, 149.7; ms: m/z 154 (M , 7.4), 137 (4), 111 (100), 83 (24);
+
+
Hrms Calcd. for C H N O: [M ] = 154.1106. Found: 154.1103.
8
14 2
Anal. Calcd. for C H N O: C, 62.31; H, 9.15; N, 18.17.
8
Found: C, 62.12; H, 9.26; N, 17.95.
14 2
The title compound was prepared in a similar manner as that
used for preparation of 1a except for use of 2-(1-hydroxy-2-
methylpropyl)-1-methyl-1H-imidazole instead of 2-(1-hydroxy-
2,2-dimethylpropyl)-1-methyl-1H-imidazole. After evaporation
umn chromatography (CHCl /MeOH = 30/1) to give 2a (first
3
fraction, 16 mg, 5 %), 3a (second fraction, 85 mg, 26 %) and 4a
(third fraction, 282 mg, 57 %).

338
S. Ohta, K. Sato, I. Kawasaki, Y. Yamaguchi, S. Nishio and M. Yamashita
Vol. 41
Compound 2a was obtained as a yellow viscous oil; ir (CHCl ):
-1
Compound 4b was obtained in 48 % yield (231 mg) as a yel-
-1 1
low viscous oil; ir (CHCl ): 2936, 1719 cm ; H nmr (400 MHz,
3
2939, 1720, 1478 cm ; H nmr (400 MHz, CDCl ): δ 1.00 (9H,
1
3
s), 1.01 (3H, t, J = 7.1 Hz), 1.29 (3H, t, J = 7.1 Hz), 1.99 (3H, s),
3.70 (3H, s), 3.81-3.88 (2H, m), 3.95 (1H, s), 4.12-4.29 (2H, m),
3
CDCl ): δ 0.97 (3H, d, J = 6.4 Hz), 0.98 (3H, d, J = 6.6 Hz), 1.20-
3
1.30 (12H, m), 1.35 (3H, s), 1.37 (3H, s), 1.93-2.03 (1H, m), 2.07
(2H, d, J = 6.6 Hz), 2.81 (3H, s), 4.08-4.28 (8H, m), 4.35 (1H, d,
13
6.75 (1H, d, J = 1.3 Hz), 6.94 (1H, d, J = 1.1 Hz); C nmr (100
MHz, CDCl ): δ 13.80, 13.84, 17.0, 29.6 x 3, 33.4, 36.8, 47.0,
13
J = 2.9 Hz), 4.46 (1H, d, J = 2.9 Hz); C nmr (100 MHz, CDCl ):
3
59.0, 61.4, 61.7, 119.8, 126.4, 147.5, 170.9, 172.1; ms: m/z 324
3
δ 13.8 x 2, 13.9 x 2, 15.2, 16.7, 22.7, 23.1, 26.3, 33.7, 36.7, 57.8,
57.9, 61.0, 61.2, 61.39, 61.42, 66.7, 69.7, 167.8, 170.0, 170.3,
+
(M , 5), 268 (12), 195 (100), 149 (25), 121 (22); Hrms Calcd. for
+
C H N O : [M] = 324.2049. Found: 324.2048.
+
170.4, 170.6; ms: m/z 484 (M , 3), 311(100), 268 (41), 237 (53),
17 28 2 4
Compound 3a was obtained as a yellow viscous oil; ir
+
129 (12), 74 (10); Hrms Calcd. for C
484.2784. Found: 484.2782.
H
24 40
N O : [M]
2
=
8
-1
(CHCl ): 2926, 1721, 1463 cm ; H nmr (300 MHz, CDCl ): δ
1
3
1.01 [9H, s, C(CH ) ], 1.26 [6H, t, J = 7.2 Hz, (OCH CH ) ],
3
3 3
2
1.90 [3H, s, CCH (CO Et) ], 2.59 [2H, s, CH C(CH ) ], 3.49
3 2
2-[1-(1,1-Diethoxycarbonylethyl)propyl]-1-methyl-1H- i m i d a-
zole (2c), 5-(1,1-Diethoxycarbonylethyl)-1-methyl-2-propyl-1H-
imidazole (3 c ) and (4R* , 5 R* ) - 4 , 5 - D i ( 1 , 1 - d i e t h o x y c a r -
bonylethyl)-4,5-dihydro-1-methyl-2-propyl-1H-imidazole (4c).
3
(3H, s, NCH ), 4.23 [4H, q, J = 7.3 Hz, (OCH CH ) ], 6.92 (1H,
2
2
2
3 3
3
s, Im-H); C nmr (75 MHz, CDCl ): δ 13.9 x 2 [(OCH CH ) ],
2
3 2
13
3
2
3 2
21.9 [CCH (CO Et) ], 29.6 x 3 [C(CH ) ], 32.5 (NCH ), 32.9
3
[C(CH ) ], 40.0 [CH C(CH ) ], 53.4 [CCH (CO Et) ], 62.0 x 2
2
2
3 3
3
These compounds were prepared in a similar manner as that
used for preparation of 2a, 3a and 4a except for use of 1c instead
of 1a. Title compounds were separated by column chromatogra-
phy (AcOEt).
3 3
2
3 3
3
2
[(OCH CH ) ], 126.6 (C-4), 128.7 (C-5), 149.2 (C-2), 170.4 x 2
2
2 3 2
[(COOEt) ]; ms: m/z 324 (M , 8), 268 (100), 251 (29), 195 (96),
+
2
167 (10), 149 (35), 121 (19), 57 (10); Hrms Calcd. for
+
N O : [M] = 324.2049. Found: 324.2047.
Compound 2c was obtained in 35% yield (104 mg) as a yellow
C
H
17 28
Compound 4a was obtained as a yellow viscous oil; ir
2 4
-1
viscous oil; ir (CHCl ): 2940, 1721, 1456 cm ; H nmr (400
1
3
MHz, CDCl ): δ 0.69 (3H, t, J = 7.3 Hz), 1.08 (3H, t, J = 7.0 Hz),
-1
1
(CHCl ): 2954, 1719 cm ; H nmr (400 MHz, CDCl ): δ 1.04
3
3
(9H, s), 1.22-1.29 (12H, m), 1.37 (3H, s), 1.39 (3H, s), 2.14 (1H,
3
1.28 (3H, t, J = 7.1 Hz), 1.63-1.71 (1H, m), 1.72 (3H, s), 1.88-
2.00 (1H, m), 3.59 (1H, dd, J = 11.5, 2.9 Hz), 3.67 (3H, s), 3.94-
4.02 (2H, m), 4.24 (2H, q, J = 7.1 Hz), 6.74 (1H, d, J = 1.1 Hz),
d, J = 14.3 Hz), 2.19 (1H, d, J = 14.5 Hz), 2.81 (3H, s), 4.08-4.27
13
(8H, m), 4.37 (1H, d, J = 3.0 Hz), 4.49 (1H, d, J = 3.0 Hz);
nmr (100 MHz, CDCl ): δ 13.8, 13.87, 13.88, 13.91, 15.4, 16.8,
C
13
6.98 (1H, d, J = 1.1 Hz); C nmr (100 MHz, CDCl ,): δ 12.3,
3
13.8, 14.0, 15.8, 25.0, 32.8, 41.2, 57.9, 61.2, 61.5, 119.9, 127.3,
3
29.9 x 3, 31.4, 34.4, 40.2, 57.7, 57.9, 60.9, 61.1, 61.3, 61.4, 66.7,
+
147.4, 171.3, 171.5; ms: m/z 296 (M , 8), 251 (9), 223 (17), 195
+
69.9, 166.6, 170.0, 170.3, 170.4, 170.6; ms: m/z 498 (M , 3), 325
+
(8), 123 (100), 96 (11); Hrms Calcd. for C
296.1736. Found: 296.1739.
H
15 24
N O : [M]
2 4
=
(76), 268 (100), 251 (30), 195 (43), 153 (13), 97 (13); Hrms
Calcd. for C
+
N O : [M] = 498.2941. Found: 498.2939.
H
25 42
2 8
Compound 3c was obtained in 25 % yield (74 mg) as a yellow
2-[1-(1,1-Diethoxycarbonylethyl)-2-methylpropyl]-1-methyl-
1H-imidazole (2 b), 5-(1,1-Diethoxycarbonylethyl)-1-methyl-2-
(2-methylpropyl)-1H-imidazole (3b) and (4R*,5R*)-4,5-Di(1,1-
diethoxycarbonylethyl)-4, 5-dihydro-1-methyl-2-(2-methyl-
propyl)-1H-imidazole (4b).
-1
viscous oil; ir (CHCl ): 2940, 1722, 1459 cm ; H nmr (400
1
3
MHz, CDCl ): δ 1.01 (3H, t, J = 7.3 Hz), 1.27 (6H, t, J = 7.1 Hz),
3
1.72-1.84 (2H, m), 1.89 (3H, s), 2.63 (2H, t, J = 7.7 Hz), 3.48
13
(3H, s), 4.23 (4H, q, J = 7.1 Hz), 6.88 (1H, s); C nmr (100 MHz,
CDCl ): δ 13.9 x 3, 20.7, 21.7, 29.4, 31.7, 53.2, 62.0 x 2, 126.5,
+
3
128.7, 150.8, 170.3 x 2; ms: m/z 296 (M , 9), 268 (25), 223 (100),
These compounds were prepared in a similar manner as that
used for preparation of 2a, 3a and 4a except for use of 1b instead
of 1a. Title compounds were separated by column chromatogra-
+
195 (22), 149 (38); Hrms Calcd. for C
296.1736. Found: 296.1733.
Compound 4c was obtained in 30 % yield (139 mg) as a yellow
H
N O : [M]
=
15 24
2 4
phy (CHCl /MeOH = 20/1).
3
Compound 2b was obtained in 9 % yield (28 mg) as a yellow
-1
1
viscous oil; ir (CHCl ): 2945, 1719, 1604, 1444 cm ; H nmr
3
(400 MHz, CDCl ): δ 0.96 (3H, t, J = 7.4 Hz), 1.22-1.29 (12H,
-1
viscous oil; ir (CHCl ): 2940, 1720 cm ; H nmr (400 MHz,
1
3
CDCl ): δ 0.65 (3H, d, J = 6.6 Hz), 0.94 (3H, d, J = 6.6 Hz), 1.03
3
m), 1.33 (3H, s), 1.35 (3H, s), 1.53-1.66 (2H, m), 2.10-2.22 (2H,
m), 2.81 (3H s), 4.08-4.30 (8H, m), 4.32 (1H, d, J = 2.9 Hz), 4.47
3
(3H, t, J = 7.1 Hz), 1.29 (3H, t, J = 7.1 Hz), 1.80 (3H, s), 2.19-
2.32 (1H, m), 3.66 (3H, s), 3.67 (1H, d, J = 8.3 Hz), 3.88-3.93
(2H, m), 4.17-4.30 (2H, m), 6.72 (1H, d, J = 1.3 Hz), 6.94 (1H, d,
13
(1H, d, J = 2.9 Hz); C nmr (100 MHz, CDCl ): δ 13.8, 13.90,
3
13.92, 13.94, 14.2, 15.2, 16.4, 20.1, 30.0, 33.5, 57.7, 58.0, 61.0,
61.2, 61.39, 61.42, 66.6, 69.4, 168.4, 170.0, 170.4 x 2, 170.6; ms:
+
m/z 470 (M , 1), 297 (100), 268 (10), 223 (61), 149 (10), 74 (9);
13
J = 1.1 Hz); C nmr (100 MHz, CDCl ): δ 13.8, 13.9, 15.5, 21.5,
3
21.7, 31.6, 32.9, 45.3, 57.7, 61.4, 61.6, 119.5, 127.1, 148.4,
+
171.0, 171.5; ms: m/z 310 (M , 11), 268 (12), 237 (9), 195 (55),
+
N O : [M] = 470.2628. Found:
Hrms Calcd. for C
470.2629.
H
2 3 3 8
2
8
+
137 (100), 123 (10), 96 (46); Hrms Calcd. for C H N O : [M]
16 26
2 4
= 310.1892. Found: 310.1897.
Compound 3b was obtained in 10 % yield (30 mg) as a yellow
2-[1-(1, 1-Diethoxycarbonylmethyl)-2, 2-dimethylpropyl]-1-
m e t h y l - 1H-imidazole (2 d), 5-(1,1-Diethoxycarbonylmethyl)-1-
m e t h y l - 2 - ( 2 , 2 - d i m e t h y l p r o p y l ) - 1H-imidazole (3 d ) and
( 4R* , 5R*)-4,5-Di(1,1-diethoxycarbonylmethyl)-4,5-dihydro-1-
methyl-2-(2,2-dimethylpropyl)-1H-imidazole (4d).
-1
viscous oil; ir (CHCl ): 2936, 1722, 1460 cm ; H nmr (400
1
3
MHz, CDCl ): δ 0.97 (6H, d, J = 6.8 Hz), 1.27 (6H, t, J = 7.0 Hz),
3
1.90 (3H, s), 2.04-2.20 (1H, m), 2.55 (2H, d, J = 7.3 Hz), 3.48
13
(3H, s), 4.23 (4H, q, J = 7.0 Hz), 6.90 (1H, s); C nmr (100 MHz,
CDCl ,): δ 13.9 x 2, 21.8, 22.5 x 2, 28.0, 31.9, 36.3, 53.3, 62.0 x
+
These compounds were prepared in a similar manner as that
used for preparation of 2 a, 3a and 4a except for use of diethyl mal-
onate instead of diethyl methylmalonate. Title compounds were
separated by column chromatography (AcOEt/n-hexane = 1/1).
3
2, 126.6, 128.6, 150.4, 170.4 x 2; ms: m/z 310 (M , 27), 268
(100), 237 (87), 195 (20), 163 (9); Hrms Calcd. for C
+
[M] = 310.1892. Found: 310.1897.
H N O :
16 26 2 4

May-Jun 2004
Novel Nucleophilic C-C Bond-forming tele-Reaction of Imidazole Ring
339
Compound 2d was obtained in 16 % yield (51 mg) as a yellow
CDCl ): δ 0.90 (3H, t, J = 7.3 Hz), 0.97 (3H, t, J = 7.3 Hz), 1.03
3
-1
viscous oil; ir (CHCl ): 2940, 1741, 1720, 1479 cm ; H nmr
1
(9H s), 1.25-1.31 (12H, m), 1.70-1.80 (1H, m), 1.90-1.96 (1H,
m), 2.08-2.18 (4H, m), 2.79 (3H, s), 4.05-4.27 (8H, m), 4.55 (1H,
3
(270 MHz, CDCl ): δ 0.96 (9H, s), 1.03 (3H, t, J = 7.1 Hz), 1.30
3
13
br s), 4.59 (1H, d, J = 2.4 Hz); C nmr (100 MHz, CDCl ): δ 9.5,
(3H, t, J = 7.2 Hz), 3.54 (1H, d, J = 10.6 Hz), 3.70 (3H, s), 3.89
(2H, q, J = 7.1 Hz), 4.15 (1H, d, J = 10.6 Hz), 4.16-4.31 (2H, m),
13
6.72 (1H, d, J = 1.3 Hz), 6.89 (1H, d, J = 1.3 Hz); C nmr (75
3
9.6, 13.9, 13.96, 13.98, 14.04, 25.1, 25.5, 29.8 x 3, 31.3, 33.4,
40.3, 60.8 x 2, 61.15, 61.19, 61.23, 62.2, 68.0, 68.6, 166.1, 169.3,
+
170.0, 170.1, 170.3; ms: m/z 526 (M , 1), 339 (100), 282 (74),
MHz, CDCl ): δ 13.8, 13.9, 27.9 x 3, 33.1, 35.4, 45.0, 54.2, 61.3,
+
3
61.7, 119.8, 126.7, 148.2, 168.3, 169.5; ms: m/z 310 (M , 3), 254
265 (38), 209 (13), 153 (19), 143 (11), 97(11); Hrms Calcd. for
C
+
N O : [M] = 526.3254. Found: 526.3260.
(19), 181 (100), 135 (12), 96 (14); Hrms Calcd. for C
H N O :
16 26 2 4
H
27 46
2
8
+
[M] = 310.1892. Found: 310.1903.
Compound 3d was obtained in 61 % yield (188 mg) as a yel-
2-[1-(1,1-Diethoxycarbonyl-3-butenyl)-2,2-dimethylpropyl]-1-
methyl-1 H-imidazole (2f ) and 5-(1,1-diethoxycarbonyl-3-
butenyl)-1-methyl-2-(2,2-dimethylpropyl)-1H-imidazole (3f).
-1 1
low viscous oil; ir (CHCl ): 2934, 1730, 1464 cm ; H nmr (300
3
MHz, CDCl ,): δ 1.00 (9H, s), 1.28 (6H, t, J = 7.1 Hz), 2.59 (2H,
3
s), 3.51 (3H, s), 4.15-4.35 (4H, m), 4.69 (1H, d, J = 0.3 Hz), 7.00
These compounds were prepared in a similar manner as that
used for the preparation of 2a, 3a and 4a except for the use of
diethyl allylmalonate instead of diethyl methylmalonate. Title
compounds were separated by column chromatography
(AcOEt/n-hexane = 1/1).
13
(1H, d, J = 0.5 Hz); C nmr (75 MHz, CDCl ): δ 13.9 x 2, 29.5 x
3
3, 31.5, 32.8, 40.0, 49.4, 62.0 x 2, 122.5, 127.8, 148.3, 166.6 x 2;
+
ms: m/z 310 (M , 12), 254 (100), 182 (26), 110 (29); Hrms Calcd.
+
N O : [M] = 310.1892. Found: 310.1903.
for C
H
16 26
Compound 4d was obtained in 7 % yield (32 mg) as a yellow
2 4
Compound 2f was obtained in 6 % yield (20 mg) as a yellow
-1
viscous oil; ir (CHCl ): 2943, 1722 cm ; H nmr (270 MHz,
1
-1
viscous oil; ir (CHCl ): 2941, 1722, 1387 cm ; H nmr (400
1
3
CDCl ): δ 1.04 (9H, s), 1.17 (3H, t, J = 7.1 Hz), 1.33 (3H, t, J =
3
MHz, CDCl ): δ 1.00 (9H, s), 1.24-1.29 (12H, m), 2.09 (1H, d, J
3
3
7.1 Hz), 2.64 (2H, d, J = 7.1 Hz), 3.63 (3H, s), 3.71 (1H, s), 3.88-
4.39 (4H, m), 4.89-4.95 (2H, m), 5.70-5.86 (1H, m), 6.75 (1H, d,
= 13.9 Hz), 2.13 (1H, d, J = 13.9 Hz), 2.88 (3H, s), 3.67 (1H, d, J
= 6.4 Hz), 3.70 (1H, d, J = 4.2 Hz), 4.12-4.25 (8H, m), 4.28-4.30
13
J = 1.1 Hz), 7.01 (1H, d, J = 1.1 Hz); C nmr (68 MHz, CDCl ):
13
(1H, br s), 4.46 (1H, dd, J = 6.4, 5.1 Hz); C nmr (100 MHz,
CDCl ): δ 13.9 x 3, 14.0, 29.8 x 3, 31.5, 34.0, 39.8, 56.4, 56.8,
3
δ 13.9, 14.0, 29.8 x 3, 33.4, 37.4, 39.3, 49.4, 61.10, 61.14, 61.5,
+
117.2, 119.4, 126.9, 134.7, 146.6, 170.2, 171.0; ms: m/z 350 (M ,
1), 253 (18), 221 (100), 207 (33), 175 (20), 147 (17), 137 (33);
3
61.2, 61.4, 61.5, 61.6, 64.4, 68.0, 166.0, 167.2, 167.55, 167.64,
+
167.8; ms: m/z 470 (M , 17), 414 (74), 342 (84), 311 (100), 270
+
N O : [M] = 350.2205. Found:
Hrms Calcd. for C
350.2210.
Compound 3f was obtained in 89 % yield (310 mg) as a yellow
H
(42), 254 (99), 133 (37), 115 (40); Hrms Calcd. for C
+
[M] = 470.2628. Found: 470.2632.
H N O :
23 38 2 8
1 9 3 0
2
4
2-[1-(1, 1-Diethoxycarbonylpropyl)-2, 2-dimethylpropyl]-1-
methyl-1H-imidazole (2 e), 5-(1,1-Diethoxycarbonylpropyl)-1-
m e t h y l - 2 - ( 2 , 2 - d i m e t h y l p r o p y l ) - 1 H-imidazole (3 e ) and
(4R* , 5R*)-4,5-Di(1,1-diethoxycarbonylpropyl)-4,5-dihydro-1-
methyl-2-(2,2-dimethylpropyl)-1H-imidazole (4e).
-1
1
viscous oil; ir (CHCl ): 2936, 1724, 1467 cm ; H nmr (400
3
MHz, CDCl ): δ 1.00 (9H, s), 1.25 (6H, t, J = 7.1 Hz), 2.59 (2H,
3
s), 3.10 (2H, d, J = 7.3 Hz), 3.49 (3H, s), 4.21 (4H, q, J = 7.1 Hz),
13
5.07-5.16 (2H, m), 5.87-5.97 (1H, m), 6.99 (1H, s); C nmr (100
MHz, CDCl ): δ 14.0 x 2, 29.6 x 3, 32.6, 32.9, 39.4, 40.0, 57.5,
3
61.9 x 2, 118.9, 127.4 x 2, 133.0, 149.1, 169.1 x 2; ms: m/z 350
These compounds were prepared in a similar manner as that
used for preparation of 2a, 3a and 4a except for use of diethyl
ethylmalonate instead of diethyl methylmalonate. Title com-
pounds were separated by column chromatography
+
(M , 22), 309 (84), 294 (100), 277 (67), 253 (67), 221 (27), 207
+
(77), 122 (23), 57 (27); Hrms Calcd. for C
350.2205. Found: 350.2210.
H
19 30
N O : [M]
2 4
=
(CHCl /MeOH = 20/1).
3
Compound 2e was obtained in 5 % yield (18 mg) as a yellow
2-[1-(1, 1-Diethoxycarbonyl-1-phenylmethyl)-2, 2-dimethyl -
propyl]-1-methyl-1H-imidazole (2 g), 5-(1,1-Diethoxycarbonyl-
1-phenylmethyl)-1-methyl-2-(2,2-dimethylpropyl)-1 H-imida-
zole (3g) and 2-{1-[4-(1,1-Diethoxycarbonylmethyl)phenyl]-2,2-
dimethylpropyl}-1-methyl-1H-imidazole (5).
-1
viscous oil; ir (CHCl ): 2939, 1716, 1479 cm ; H nmr (400
1
3
MHz, CDCl ): δ 0.83 (3H, t, J = 7.3 Hz), 1.03 (9H, s), 1.21 (3H,
3
t, J = 7.1 Hz), 1.33 (3H, t, J = 7.1 Hz), 1.81-1.95 (2H, m), 3.63
(3H, s), 3.72 (1H, s), 3.97-4.38 (4H, m), 6.76 (1H, d, J = 1.3 Hz),
13
7.02 (1H, d, J = 1.3 Hz); C nmr (100 MHz, CDCl ): δ 10.4,
These compounds were prepared in a similar manner as that
used for preparation of 2a, 3a and 4a except for the use of diethyl
phenylmalonate instead of diethyl methylmalonate. Title com-
pounds were separated by column chromatography (AcOEt/n-
hexane = 1/1).
3
13.8, 13.9, 27.8, 29.6 x 3, 33.2, 37.2, 49.9, 60.9, 61.1, 61.7,
+
119.4, 126.9, 146.8, 170.5, 171.8; ms: m/z 338 (M , 1), 209
(100), 163 (49), 151 (19), 135 (17); Hrms Calcd. for
C
+
N O : [M] = 338.2205. Found: 338.2209.
H
18 30
Compound 3e was obtained in 32 % yield (109 mg) as a yellow
2 4
Compound 2g was obtained in 3 % yield (10 mg) as colorless
needles (n-hexane), mp 113-115 °C; ir (CHCl ): 2942, 1730,
-1
1
viscous oil; ir (CHCl ): 2935, 1720, 1462 cm ; H nmr (400
3
MHz, CDCl ): δ 1.00 (9H, s), 1.01 (3H, t, J = 7.4 Hz), 1.26 (6H,
3
1479 cm ; H nmr (400 MHz, CDCl ): δ 0.72 (9H, s), 1.04 (3H,
-1 1
3
3
t, J = 7.1 Hz), 2.39 (2H, q, J = 7.4 Hz), 2.59 (2H, s), 3.48 (3H, s),
t, J = 7.1 Hz), 1.22 (3H, t, J = 7.1 Hz), 3.59 (3H, s), 3.74-3.82
(1H, m), 3.92-4.00 (1H, m), 4.20 (1H, s), 4.21-4.35 (2H, m), 6.70
(1H, d, J = 1.1 Hz), 6.98 (1H, d, J = 1.1 Hz), 7.25-7.34 (3H, m),
13
4.23 (4H, q, J = 7.2 Hz), 6.96 (1H, s); C nmr (100 MHz,
CDCl ): δ 9.6, 13.9 x 2, 28.0, 29.6 x 3, 32.5, 32.8, 39.9, 57.7,
+
3
61.7 x 2, 127.3, 127.5, 148.9, 169.4 x 2; ms: m/z 338 (M , 9), 282
(100), 265 (35), 209 (64), 163 (22), 135 (12), 111 (16); Hrms
13
7.88 (2H, d, J = 7.0 Hz); C nmr (100 MHz, CDCl ): δ 13.7 x 2,
3
29.2 x 3, 33.3, 37.2, 48.1, 61.4, 61.6, 67.1, 119.6, 126.6, 126.7 x
+
2, 127.3 x 2, 131.9, 135.1, 147.7, 169.2, 171.7; ms: m/z 386 (M ,
+
N O : [M] = 338.2205. Found: 338.2214.
Calcd. for C
Compound 4e was obtained in 28 % yield (147 mg) as a yellow
H
18 30
2 4
16), 329 (100), 257 (28), 151 (71); Hrms Calcd. for C
+
[M] = 386.2205. Found: 386.2204.
H N O :
22 30 2 4
-1
1
viscous oil; ir (CHCl ): 2937, 1717 cm ; H nmr (400 MHz,
3

340
S. Ohta, K. Sato, I. Kawasaki, Y. Yamaguchi, S. Nishio and M. Yamashita
Vol. 41
Anal. Calcd. for C
H
N O : C, 68.37; H, 7.82; N, 7.25.
13
Hz), 7.00 (1H, d, J = 1.3 Hz); C nmr (100 MHz, CDCl ): δ
22 30
2
4
Found: C, 68.12; H, 7.82; N, 7.38.
3
14.0, 22.7, 27.9 x 3, 29.7, 30.8, 32.8, 35.1, 46.8, 119.3, 126.8,
Compound 3g was obtained in 11 % yield (42 mg) as a yellow
+
150.6; ms: m/z 208 (M , 18), 189 (46), 151 (100), 137 (22), 123
-1
viscous oil; ir (CHCl ): 2937, 1724, 1464 cm ; H nmr (400
1
+
3
MHz, CDCl ): δ 0.99 (9H, s), 1.28 (6H, t, J = 7.1 Hz), 2.56 (2H,
(17), 109 (91), 96 (34); Hrms Calcd. for C
H N : [M] =
13 24 2
3
s), 3.01 (3H, s), 4.31 (4H, q, J = 7.1 Hz), 7.11 (1H, s), 7.26-7.36
208.1939. Found: 208.1938.
Compound 8b was obtained in 6 % yield (13 mg) as a yellow
13
(5H, m); C nmr (100 MHz, CDCl ): δ 13.9 x 2, 29.6 x 3, 32.5,
-1 1
viscous oil; ir (CHCl ): 2929, 2920, 1463, 1351 cm ; H nmr
3
32.9, 39.9, 62.4 x 2, 63.3, 127.4, 128.1, 128.3 x 2, 128.6 x 2,
3
(400 MHz, CDCl ): δ 0.95 (3H, t, J = 7.4 Hz), 1.00 (9H, s), 1.37-
3
1.46 (2H, m), 1.56-1.64 (2H, m), 2.49 (2H, dt, J = 0.7, 7.7 Hz),
+
128.9, 136.1, 149.0, 168.4 x 2; ms: m/z 386 (M , 14), 330 (100),
313 (50), 257 (51), 211 (30), 183 (12), 115 (13), 57 (16); Hrms
Calcd. for C
13
2.56 (2H, s), 3.43 (3H, s), 6.70 (1H, s); C nmr (100 MHz,
+
N O : [M] = 386.2205. Found: 386.2199.
H
22 30
Compound 5 was obtained in 44 % yield (171 mg) as colorless
2
4
CDCl ): δ 13.9, 22.4, 24.5, 29.7 x 3, 30.2, 30.6, 32.8, 40.1, 123.8,
+
3
131.7, 146.3; ms: m/z 208 (M , 11), 193 (14), 151 (100), 137
-1
plates (n-hexane), mp 118-120 °C; ir (CHCl ): 2936, 1722 cm ;
3
H nmr (400 MHz, CDCl ): δ 1.06 (9H, s), 1.24 (3H, t, J = 7.1
(19), 123 (12), 110 (32), 58 (14); Hrms Calcd. for C
+
[M] = 208.1939. Found: 208.1934.
H
13 24
N :
2
1
3
Hz), 1.25 (3H, t, J = 7.1 Hz), 3.46 (3H, s), 3.77 (1H, s), 4.13-4.26
2-(1-Ethyl-2,2-dimethylpropyl)-1-methyl-1H-imidazole (7c).
(4H, m), 4.58 (1H, s), 6.70 (1H, d, J = 1.3 Hz), 7.00 (1H, d, J =
13
1.1 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.46 (2H, d, J = 8.2 Hz); C
nmr (100 MHz, CDCl ): δ 13.9 x 2, 28.1 x 3, 32.8, 35.6, 52.5,
This was prepared in a similar manner as that used for the
preparation of 2a, 3a and 4a except for use of a diethyl zinc (1.0
M solution in n-hexane) instead of NaH and diethyl methyl-
malonate. The title compound was purified by column chro-
3
57.4, 61.6 x 2, 119.7, 126.5, 128.4 x 2, 130.5 x 2, 130.8, 138.7,
+
148.3, 168.1 x 2; ms: m/z 386 (M , 2), 330 (100), 257 (52), 227
(9), 183 (13), 170 (9); Hrms Calcd. for C
386.2205. Found: 386.2197.
+
H N O : [M]
22 30 2 4
=
matography (Et O) and obtained as a pale yellow viscous oil, 49
-1
2
mg (27 %); ir (CHCl ): 2933, 1475, 1361 cm ; H nmr (400
1
3
MHz, CDCl ): δ 0.65 (3H, t, J = 7.2 Hz), 0.94 (9H, s), 1.73-1.96
Anal. Calcd. for C
H N O : C, 68.37; H, 7.82; N, 7.25.
22 30 2 4
Found: C, 68.17; H, 7.76; N, 7.33.
3
(2H, m), 2.39 (1H, dd, J = 11.7, 3.1 Hz), 3.58 (3H, s), 6.74 (1H, d,
13
J = 1.1 Hz), 7.00 (1H, d, J = 1.3 Hz); C nmr (100 MHz, CDCl ):
3
δ 13.0, 22.9, 27.9 x 3, 32.8, 35.0, 48.8, 119.3, 126.8, 150.3; ms:
1-Methyl-2-(1,2,2-trimethylpropyl)-1H-imidazole (7a) and 1,5-
Dimethyl-2-(2,2-dimethylpropyl)-1H-imidazole (8a).
+
m/z 180 (M , 8), 165 (9), 151 (8), 123 (97), 109 (100), 96 (20), 58
These compounds were prepared in a similar manner as that
used for preparation of 2a, 3a and 4a except for use of a methyl-
magnesium bromide (0.9 M solution in THF) instead of NaH and
diethyl methylmalonate. Title compounds were separated by col-
+
N : [M] = 180.1626. Found:
(13); Hrms Calcd. for C
180.1634.
H
11 20
2
Acknowledgements.
umn chromatography (CHCl /MeOH = 10/1).
3
Compound 7a was obtained in 21 % yield (35 mg) as a yellow
We are grateful for financial supports 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.
-1
viscous oil; ir (CHCl ): 2932, 1473, 1359 cm ; H nmr (400
1
3
MHz, CDCl ): δ 0.95 (9H, s), 1.29 (3H, d, J = 7.1 Hz), 2.69 (1H,
3
q, J = 7.1 Hz), 3.59 (3H, s), 6.73 (1H, d, J = 1.1 Hz), 6.97 (1H, d,
13
J = 1.1 Hz); C nmr (100 MHz, CDCl ): δ 15.2, 27.5 x 3, 33.0,
3
35.0, 40.0, 119.4, 126.7, 151.3; ms: m/z 166 (M , 8), 151 (8), 110
+
+
(100), 96 (14), 71 (16); Hrms Calcd. for C
166.1470. Found: 166.1465.
H
10 18
N : [M]
2
=
REFERENCES AND NOTES
Compound 8a was obtained in 37 % yield (61 mg) as a yellow
-1
1
viscous oil; ir (CHCl ): 2927, 1464, 1435, 1400, 1361 cm ; H
3
nmr (400 MHz, CDCl ): δ 1.00 (9H, s), 2.17 (3H, d, J = 0.9 Hz),
13
[1] M. R. Grimmett, in Advances in Heterocyclic Chemistry, Vol
27, A. R. Katritzky and A. Boulton, eds, Academic Press, New York,
1980, pp 241.
3
2.57 (2H, s), 3.43 (3H, s), 6.71 (1H, d, J = 1.1 Hz); C nmr (100
MHz, CDCl ): δ 10.0, 29.6 x 3, 30.6, 32.8, 40.2, 124.4, 127.0,
+
3
146.3; ms: m/z 166 (M , 16), 151 (7), 110 (100), 95 (10), 71 (7);
[2] B. Iddon and R. I. Ngochindo, Heterocycles, 38, 2487 (1994).
[3a] S. Ohta, T. Yamamoto, I. Kawasaki, M. Yamashita, H.
Katsuma, R. Nasako, K. Kobayashi and K. Ogawa, Chem. Pharm. Bull.,
40, 2681 (1992); [b] S. Ohta, T. Yamamoto, I. Kawasaki, M. Yamashita,
Y. Nagashima and T. Yoshikawa, Chem. Pharm. Bull., 42, 821 (1994).
[4a] S. Nakamura, N. Tsuno, M. Yamashita, I. Kawasaki, S. Ohta
and Y. Ohishi, J. Chem. Soc., Perkin Trans 1, 429 (2001); [b] I.
Kawasaki, S. Nakamura, S. Yanagitani, A. Kakuno, M. Yamashita and S.
Ohta, J. Chem. Soc., Perkin Trans 1, 3095 (2001).
[5a] I. Kawasaki, N. Taguchi, T. Yamamoto, M. Yamashita and S.
Ohta, Tetrahedron Lett., 36, 8251 (1995); [b] I. Kawasaki, M. Yamashita
and S. Ohta, Chem. Pharm. Bull., 44, 1831 (1996); [c] I. Kawasaki, N.
Taguchi, M. Yamashita and S. Ohta, Chem. Pharm. Bull., 4 5, 1393
(1997); [d] I. Kawasaki, H. Katsuma, Y. Nakayama, M. Yamashita and S.
Ohta, Heterocycles, 48, 1887 (1998); [e] S. Ohta, N. Tsuno, K. Maeda, S.
Nakamura, N. Taguchi, M. Yamashita and I. Kawasaki, Tetrahedron Lett.,
4 1, 4623 (2000); [f] I. Kawasaki, N. Sakaguchi, N. Fukushima, N.
Fujioka, F. Nikaido, M. Yamashita and S. Ohta, Tetrahedron Lett., 43,
+
N : [M] = 166.1470. Found: 166.1474.
Hrms Calcd. for C
H
10 18
2
1-Methyl-2-[1-(1,1-dimethylethyl)pentyl]-1H-imidazole (7 b)
and 5-Butyl-1-methyl-2-(2,2-dimethylpropyl)-1H-imidazole
(8b).
These compounds were prepared in a similar manner as that
used for preparation of 2a, 3a and 4a except for use of a n-butyl-
magnesium chloride (0.9 M solution in THF) instead of NaH and
diethyl methylmalonate. Title compounds were separated by col-
umn chromatography (CHCl /MeOH = 20/1).
3
Compound 7b was obtained in 13 % yield (26 mg) as a yellow
-1
viscous oil; ir (CHCl ): 2927, 1474, 1361 cm ; H nmr (400
1
3
MHz, CDCl ): δ 0.82 (3H, t, J = 7.3 Hz), 0.89-0.97 (2H, m), 0.94
3
(9H, s), 1.20-1.30 (2H, m), 1.65-1.73 (1H, m), 1.87-1.97 (1H, m),
2.45 (1H, dd, J = 11.8, 2.8 Hz), 3.57 (3H, s), 6.74 (1H, d, J = 1.1

May-Jun 2004
Novel Nucleophilic C-C Bond-forming tele-Reaction of Imidazole Ring
341
4377 (2002); [g] S. Nakamura, I. Kawasaki, M. Kunimura, M. Matsui, Y.
Noma, M. Yamashita and S. Ohta, J. Chem. Soc., Perkin Trans 1, 1061
(2002); [h] S. Nakamura, I. Kawasaki, M. Yamashita and S. Ohta,
Heterocycles, 60, 583 (2003).
[9] T. Nakano, W. Rodríguez, S. Z. De Roche, J. M. Larrauri, C.
Rivas and C. Pérez, J. Heterocyclic Chem., 17, 1777 (1980).
[10] S. Ohta, T. Osaki, S. Nishio, A. Furusawa, M. Yamashita and
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[6a] M. Begtrup, Angew. Chem., Int. Ed., 13, 347 (1974); [b] M.
Grimmett in Comprehensive Organic Chemistry, Vol 4, P. G. Sammers,
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H. Hasegawa, K. Nagata and A. Ohsawa, Chem. Commun., 1217 (1996).
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(1978); [b] R. Achour, E. M. Essassi and R. Zniber, Tetrahedron Lett., 29,
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31, 1115 (1990); [d] K. Burg e r, E. Höß and K. Geith, Synthesis, 360
(1990); [e] R. P. Subrayan and P. G. Rasmussen, Tetrahedron, 51, 6167
(1995); [f] G. Tennant, C. J. Wallis and G. W. Weaver, J. Chem. Soc.,
Perkin Trans 1, 629 (1999).
[11a] J. Suwinski and K. Swierczek, Tetrahedron, 57, 1639 (2001);
[b] J. F. Arens, Bull. Soc. Chiem. Fr., 3037 (1968).
[12a] R. I. Fryer, R. F. Lauer, E. J. Trybulski, S. Vitone, A. Walser
and G. Zenchoff, J. Heterocyclic Chem., 20, 1605 (1983); [b] T. S.
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Njoya, N. Boufatah, A. Gellis, P. Rathelot, M. P. Crozet and P. Vanelle,
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[13] Representative examples: [a] O. A. Attanasi, L. De
Crescentini, P. Filippone and F. Mantellini, Synlett, 554 (2001); [b] R. E.
Banks, M. K. Besheesh, S. N. Mohialdin-Khaffaf and I. Sharif, J. Chem.
Soc., Perkin Trans 1, 2069 (1996); [c] W. E. Barnette, J. Am. Chem. Soc.,
106, 452 (1984); [d] T. S. Everett, S. T. Purrington and C. L. Bumgardner,
J. Org. Chem., 49, 3702 (1984); [e] C. G. Kruse, A. Wijsman and A. Van
der Gen, J. Org. Chem., 44, 1847 (1979).
[8] A. Olofson, K. Yakushijin and D. A. Horne, J. Org. Chem.,
63, 1248 (1998).