Isoprene-catalyzed lithiation of imidazole: Synthesis of 2-(hydroxyalkyl)- and 2-(aminoalkyl)imidazoles

Article abstract of DOI:10.1016/j.tet.2005.09.024

2-Lithioimidazole was prepared by means of a new protocol, which consists of a slight excess of lithium metal in the presence of a substoichiometric amount of isoprene (20 mol%) in THF at room temperature. By reacting this organolithium with carbonyl elec

Full text of DOI:10.1016/j.tet.2005.09.024

Tetrahedron 61 (2005) 11148–11155
Isoprene-catalyzed lithiation of imidazole:
synthesis of 2-(hydroxyalkyl)- and 2-(aminoalkyl)imidazoles
*
Rosario Torregrosa, Isidro M. Pastor and Miguel Yus
´ ´ ´ ´
Departamento de Quımica Organica, Facultad de Ciencias and Instituto de Sıntesis Organica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
Received 22 July 2005; revised 6 September 2005; accepted 8 September 2005
Available online 29 September 2005
Abstract—2-Lithioimidazole was prepared by means of a new protocol, which consists of a slight excess of lithium metal in the presence of
a substoichiometric amount of isoprene (20 mol%) in THF at room temperature. By reacting this organolithium with carbonyl electrophiles
2-(hydroxyalkyl)imidazoles 3 were obtained, in good yields. As a result of the reaction of the mentioned lithium intermediate with imines 4,
the corresponding 2-(aminoalkyl)imidazoles 5 were isolated in excellent yields.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives) as electrophiles for functionalizing imidazole
via imidazolium ylides (a non-organometallic compound) as
intermediates.15
Among heterocycles, azoles are important compounds not
only because of their abundance in nature but also for their
widespread presence in compounds with pharmacological
and biological properties.1 The preparation of 2-substituted
1,3-azoles from different acyclic precursors2 or by
transformation of 1,3-azole systems,3 is a broad field of
interest both for synthetic organic and medicinal chemists.
One effective methodology to activate lithium involves
using an arene in substoichiometric amount as electron
carrier.16 Lithium metal is a lithiation agent that has been
widely used especially for the halogen–lithium exchange,
albeit usually it must be activated to permit the preparation
of different organolithium intermediates under mild con-
ditions. Different functionalized organolithium reagents17
have been prepared starting from different substrates (i.e.,
halogenated or non-halogenated compounds,18 as well as
heterocyclic precursors19). In this paper, we describe a new
protocol to prepare 2-lithio-imidazole intermediates by
using lithium metal and a catalytic amount of isoprene under
very mild conditions and their reaction with carbonyl and
imine electrophiles in order to produce 2-(hydroxyalkyl)-
and 2-(aminoalkyl)imidazole derivatives.
During the last three decades, lithium and other metalated
imidazole derivatives (generally prepared starting from the
corresponding lithium precursors) have been very useful
intermediates for the introduction of substituents in the
heterocyclic system.2 These compounds have extensive
application in organic synthesis.4 Lithiation reactions and
halogen–lithium exchanges have been studied using
alkyllithium reagents or lithium amides as lithiating
agents.2,5 In order to prepare these intermediates, reaction
conditions usually involving low temperature in an ethereal
solvent. An extensive variety of electrophiles have been
reacted with these carbanionic compounds allowing the
introduction of different substituents at the two position
(such as alkyl,6 alkenyl,7 hydroxyalkyl,5,8 halogen,9 acyl,10
carboxyl,11 silyl,12 sulfanyl13 or azido14). However, the use
of imine compounds as electrophiles has not been
investigated. Zificsak and Hlasta have very recently
reported the use of N-protected-imines (mainly as sulfonyl
2. Results and discussion
In the course of our recent investigations on dianions20
derived from carboxylic acids and derivatives,21 we worked
with different bases and found that lithium metal is able to
generate 2-lithio-N-methylimidazole and used in some cases
as a deprotonating agent. Thus, when treating N-methyl-
imidazole (NMI, 1) with lithium powder in THF, the
corresponding 2-lithio derivative is generated and can be
trapped by deuterium giving the 2-deutero-N-methylimida-
zole (2, 75% yield, 87% deuterium incorporation,
Scheme 1).
Keywords: Imidazole; Isoprene-catalyzed lithiation; Carbonyl compounds;
Imines; Deprotonation.
Corresponding author. Tel.: C34 965 903548; fax: C34 965 903549;
e-mail: yus@ua.es
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.024

R. Torregrosa et al. / Tetrahedron 61 (2005) 11148–11155
11149
aldehydes and ketones with a-protons (Table 2, entries 1–4,
6 and 9). The present procedure allowed the isolation of the
final products 3 with comparable or better yields than those
already described in the literature.1,2,5
Scheme 1.
The excellent results achieved with carbonyl electrophiles
suggested to us the idea of using imines in this reaction.
Thus, by employing the synthetic procedure described
previously, N-benzylideneaniline (4a) gave the correspond-
ing amino derivative 5a in 94% yield (Scheme 2, Table 3,
entry 1). Reactions with different aryl aldimines 4b–g gave
the corresponding amine derivatives in good yield (Table 3,
entries 2–7), except when nitroaryl imines were used, for
which the final product was detected in the crude product in
poor yield (Table 3, entries 4 and 5). Ketimine 4h prepared
from acetophenone and aniline did not react with the 2-lithio
intermediate. Heating up the reaction gave only traces of
product in the reaction mixture (Table 3, entry 8).
The reaction conditions for this new procedure to prepare
2-lithio-N-methylimidazole and the subsequent reaction
with an electrophile was investigated using 3-pentanone
(Table 1). When the lithiation and SE reaction were
performed at room temperature, better results were in
general obtained than at 0 8C (Table 1, compare entries 1–3
and 4–12). The use of an additive, such as isoprene, was a
determining factor to improve the yield of the final product,
from 35 to 62% at 0 8C (Table 1, entries 2 and 3) and getting
up to 96% of product 3a when performing the reaction at
room temperature (Table 1, entries 5–8). The amount of
isoprene could be reduced to 20% without reducing the
yield. On the other hand, using diethyl ether as solvent
instead of tetrahydrofuran, the yield of the product 3a was
reduced to the half (Table 1, entry 8 and footnote e).
Concerning the role of isoprene in the reaction, it can act
both as electron carrier agent22 and as a hydrogen
acceptor.23 The use of other electron carriers (i.e., 4,40-di-
tert-butyl-biphenyl, naphthalene) did not improve the
obtained results (Table 1, entries 9 and 10, and footnote d).
From the above results we concluded that the best
conditions to generate the lithium imidazole intermediate
are slight excess of lithium together with 20% of isoprene in
THF at room temperature. In order to look into the scope of
the reaction we submitted different carbonyl compounds to
the above described protocol. As shown in Table 2, all the
examined electrophiles gave the corresponding 2-(hydroxy-
alkyl)imidazoles (3a–i) with good isolated yields, including
Starting imines 4 were prepared according to the literature
procedure24 from the corresponding carbonyl compound
Table 1. Reaction conditions for generating 2-lithio-N-methylimidazolea
Entry
mmol Li/mmol substrate
Additive (equiv)b
T (8C)
Yield (%)c
1
2
3
4
5
6
7
8
1.2
3
3
3
3
3
3
3
—
—
0
0
0
25
25
25
25
25
26
35
62
86
95
96
95
95
51e
71
84
65
63f
68
Isoprene (1)
—
Isoprene (1)
Isoprene (2)
Isoprene (0.5)
Isoprene (0.2)
9
10
11
3
3
2
DTBB (0.05)d
Naphthalene (0.05)d
—
25
25
25
12
2
Isoprene (0.2)
25
a Reaction carried out using: NMI (5 mmol), Et2CO (5.5 mmol), THF (10 mL).
b Additive added to the lithium suspension prior the addition of NMI. Equivalents of additive referred to the NMI.
c Isolated yield of pure product. Purification was done by recrystallization.
d Stirred with lithium in THF until formation of the arene dianion (dark-green solution) before adding the NMI.
e Reaction carried out in Et2O as solvent instead of THF.
f
Reaction time for lithiation step: 90 min.

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R. Torregrosa et al. / Tetrahedron 61 (2005) 11148–11155
Table 2. Reaction of 2-lithio-N-methylimidazole with different carbonyl compoundsa
Entry
Electrophile
Product
No.
Yield (%)b
95
1
2
3
3a
3b
3c
95
O99
4
5
3d
3e
91
99
6
7
8
3f
80
3g
3h
94
77c
9
3i
79
a Reactions performed with NMI (5 mmol), Li (15 mmol), isoprene (1 mmol), THF (10 mL) and then added electrophile (5.5 mmol).
b Isolated yield of pure product. Purification was done by recrystallization.
c Purification by column chromatography (pHZ6.7–7.3 silica gel, mixtures of hexane and ethyl acetate).
and amine in chloroform in the presence of molecular
sieves.
good yields after acid/base work-up the corresponding
products 5i and 5j (Scheme 3).
The use of N-silylated imines in the reaction shown in
Table 3 would allow the preparation of the corresponding
primary amine derivatives. Thus, N-silylimines 4i and 4j
(prepared from the corresponding aldehydes and lithium
hexamethyldisilazanide)25 were reacted in situ to yield in
3. Conclusions
In this paper, we have developed a new protocol to prepare
2-lithioimidazole using a slightly excess of lithium metal in
the presence of a substoichometric amount of isoprene
(20 mol%) at room temperature. The reaction of this
intermediate with different carbonyl compounds gave the
corresponding 2-(hydroxyalkyl)imidazole derivatives with
excellent yields, that were comparable or better than those
reported in the literature. The reaction of the organolithium
intermediate with imine electrophiles allowed the isolation
of new interesting 2-[(N-arylamino)benzyl]imidazoles in
good yields. Primary amino functionalized imidazoles were
obtained by using N-silylimines.
Scheme 2.

R. Torregrosa et al. / Tetrahedron 61 (2005) 11148–11155
Table 3. Reaction of 2-lithio-N-methylimidazole with different iminesa
11151
Entry
Electrophile
Product
No.
Yield (%)b
94
1
2
4a
4b
5a
5b
5c
92
88
3
4c
4
5
4d
4e
5d
5e
24c
25c
6
4f
5f
91
7
8
4g
4h
5g
5h
93d
e
—
a Reactions performed with NMI (5 mmol), Li (15 mmol), isoprene (1 mmol), THF (10 mL) and then added electrophile (5.5 mmol).
b Isolated yield of pure product 5. Purification was done by recrystallization.
c Yield based on GLC, the product 5 was not isolated.
d Purification by column chromatography (pHZ6.7–7.3 silica gel, mixtures of hexane and ethyl acetate).
e Reaction carried out at reflux on THF. Less than 3% of compound 5h observed by GLC.
without further purification, except in the case of liquid
electrophiles, which were used freshly distilled. Commer-
cially available anhydrous THF (99.9%, water content
%0.006%, Acros) was used as solvent in all the lithiation
reactions. Melting points were obtained with a Reichert
Thermovar apparatus. IR spectra were measured with a
Nicolet Impact 400 D-FT spectrometer. NMR spectra were
Scheme 3.
1
recorded on a Bruker AC-300 (300 MHz for H NMR and
75 MHz for 13C NMR) using CDCl3 as solvent and TMS as
internal standard; chemical shifts are given in d (ppm) and
coupling constants (J) in Hz. Mass spectra (EI) were
obtained at 70 eV on an Agilent 5973 spectrometer,
fragment ions in m/z with relative intensities (%) in
parenthesis and high resolution mass spectra (HRMS)
analyses were carried out on a Finnigan MAT95S
4. Experimental
4.1. General
All lithiation reactions were carried out under argon
atmosphere in oven-dried glassware. All commercially
available reagents (Acros, Aldrich, Fluka) were used

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R. Torregrosa et al. / Tetrahedron 61 (2005) 11148–11155
spectrometer, when indicated the samples were inserted in
the modality of direct insertion probed (DIP). The purity of
volatile and the chromatographic analyses (GLC) were
determined with an Agilent 6890N instrument equipped
with a flame ionization detector and a 30 m capillary
column (0.25 mm diameter, 0.25 mm film thickness), using
nitrogen (2 mL/min) as carrier gas, TinjectorZ275 8C,
TcolumnZ60 8C (3 min) and 60–270 8C (15 8C/min); reten-
tion times (tr) are given in minutes under these conditions.
Column chromatography was performed using silica gel of
40 mm (J. T. Baker, pHZ6.7–7.3 of 10% aqueous
suspension). Thin-layer chromatography was carried out
on TLC plastic sheets with silica gel 60 F254 (Merck).
Lithium powder was commercially available (MEDAL-
CHEMY S. L.).
(100), 83 (58). HRMS calcd for C9H16N2O 168.1263, found
168.1266.
4.3.2. 1-(1-Methyl-1H-imidazol-2-yl)-cyclohexanol (3b).8
Yield 95%; white solid; tr 12.70; Rf 0.37 (EtOAc/MeOH
8:1); mp 165–166 8C; n (KBr) 3720–2993 cmK1 (OH); dH
1.26–1.36, 1.59–1.79, 1.92–1.95 (1H, 5H and 4H, 3m, 5!
CH2), 3.86 (3H, s, CH3), 3.94 (1H, s, OH), 6.79, 6.80 (1H
and 1H, 2s, CHCH); dC 21.3, 25.2, 36.2 (5C, 5!CH2), 34.7
(CH3), 70.8 (COH), 122.6, 125.0 (CHCH), 152.1 (NCN);
m/z 181 (MCC1, 7%), 180 (30%), 163 (52), 162 (16), 161
(11), 151 (22), 138 (29), 137 (100), 135 (10), 133 (11), 126
(11), 125 (55), 124 (11), 123 (17), 110 (22), 109 (67), 96
(60), 95 (15), 83 (40), 82 (24), 81 (22), 55 (11).
4.3.3. Dicyclopropyl(1-methyl-1H-imidazol-2-yl)-metha-
nol (3c). Yield 99.5%; white solid; tr 12.42; Rf 0.43 (EtOAc/
MeOH 8:1); mp 102–103 8C; n (KBr) 3690–3039 cmK1
(OH); dH 0.28–0.42, 0.46–0.55, 0.66–0.74, 1.25–1.34 (4H,
2H, 2H and 2H, 4m, 4!CH2 and 2!CH ring), 3.85 (3H, s,
CH3), 6.82, 6.85 (1H and 1H, 2s, NCHCHN); dC 0.01, 1.6
(4C, 4!CH2), 18.7 (2C, 2!CH ring), 34.8 (CH3), 70.8
(COH), 123.0, 125.1 (NCHCHN), 152.4 (NCN); m/z 192
(MC, 8%), 177 (19), 175 (10), 163 (24), 152 (10), 151 (100),
149 (37), 136 (13), 135 (32), 123 (23), 121 (17), 109 (54), 96
(23), 95 (11), 83 (46), 82 (10), 81 (10), 69 (13). HRMS
(DIP) calcd for C11H16N2O 192.1263, found 192.1262.
4.2. Procedure for deuteration of 2-lithio-N-Methyl-
imidazole
4.2.1. Preparation of 2-deuterio-N-Methylimidazole (2).
N-Methylimidazole (403 mL, 5 mmol) was added to a
suspension of lithium powder (105 mg, 15 mmol) in THF
(10 mL) at 0 8C. The mixture was stirred for 45 min
allowing the reaction to reach room temperature and then
deuterium oxide (0.5 mL) was added. Water (15 mL) was
added to the reaction mixture and then extracted with
diethyl ether (3!15 mL). The organic phase was dried over
anhydrous magnesium sulfate and after removal of the
solvent under reduced pressure (15 Torr), the desired
product 2 was obtained in 75% yield (87% deuterium
incorporation): dH 3.65 (3H, s, CH3), 6.86, 7.01 (1H and 1H,
2s, CHCH); dC 32.7 (CH3), 119.6, 128.7 (CHCH), 137.0 (t,
JZ31.3 Hz, CD); m/z 84 (MCC1, 9%), 83 (100), 82 (32),
55 (14), 54 (13).
4.3.4. 1-(1-Methyl-1H-imidazol-2-yl)-1-phenylethanol
(3d).8 Yield 91%; pale yellow solid; tr 13.44; Rf 0.57
(EtOAc/MeOH 8:1); mp 164–165 8C; n (KBr) 3635–
3014 cmK1 (OH); dH 1.93 (3H, s, CCH3), 3.04 (1H, br s,
OH), 3.29 (3H, s, NCH3), 6.78, 6.87 (1H and 1H, 2s,
NCHCHN), 7.20–7.33 (5H, m, ArH); dC 31.6, 34.1 (2!
CH3), 72.9 (COH), 122.7, 124.6, 125.3, 126.9, 128.2 (7C,
ArCH and NCHCHN), 145.5 (ArC), 151.1 (NCN); m/z 203
(MCC1, 12%), 202 (89), 201 (45), 188 (13), 187 (100), 185
(17), 184 (13), 183 (26), 125 (35), 111 (12), 109 (41), 105
(36), 83 (27), 77 (29).
4.3. General procedure for the preparation of
2-(hydroxylalkyl)imidazoles 3
N-Methylimidazole (403 mL, 5 mmol) was added to a
suspension of lithium powder (105 mg, 15 mmol) and
isoprene (101 mL, 1 mmol) in THF (10 mL) at room
temperature. The mixture was stirred for 45 min and then
the corresponding carbonyl compound (5.5 mmol) was
added, continuing the stirring during 45 min at the same
temperature. The reaction mixture was hydrolyzed with
water (15 mL), extracted with ethyl acetate (3!15 mL),
and the organic phase was dried over anhydrous magnesium
sulfate. After removing the solvent under reduced pressure
(15 Torr), the resulting crude was purified by recrystalliza-
tion (from mixtures of ethyl acetate and n-pentane) to yield
compounds 3. Compound 3h was purified by column
chromatography (pHZ6.7–7.3 silica gel, mixtures of
hexane and EtOAc).
4.3.5. (1-Methyl-1H-imidazol-2-yl)diphenylmethanol
(3e).26 Yield 99%; white solid; tr 17.08; Rf 0.74 (EtOAc/
MeOH 8:1); mp 191–192 8C; n (KBr) 3629–2836 cmK1
(OH); dH 2.87 (1H, br s, OH), 3.30 (3H, s, CH3), 6.85, 6.90
(1H and 1H, 2s, NCHCHN), 7.25–7.35 (10H, m, ArH); dC
34.8 (CH3), 78.3 (COH), 123.1, 125.8, 127.2, 127.5, 128.0
(12C, ArCH and NCHCHN), 144.3 (2C, ArC), 150.5
(NCN); m/z 249 (MCKMe, 8%), 248 (49), 247 (100), 165
(22), 157 (19). HRMS (DIP) calcd for C17H16N2O
264.1263, found 264.1240.
4.3.6. 4-(1-Methyl-1H-imidazol-2-yl)-1-propylpiperidin-
4-ol (3f). Yield 80%; pale yellow solid; tr 14.78; Rf 0.27
(MeOH); mp 149–151 8C; n (KBr) 3640–3006 cmK1 (OH);
dH 0.90 (3H, t, JZ7.3 Hz, CH2CH3), 1.45–1.57, 1.73–1.78,
2.03–2.12, 2.28–2.33, 2.40–2.47, 2.59–2.62 (2H, 2H, 2H,
2H, 2H and 2H, 6m, 6!CH2), 3.85 (3H, s, NCH3), 5.08
(1H, br s, OH), 6.60, 6.71 (1H and 1H, 2s, CHCH); dC 12.0
(CH2CH3), 34.6 (NCH3), 20.1, 35.7, 49.1, 60.6 (6C, 6!
CH2), 68.6 (COH), 122.5, 125.4 (CHCH), 151.4 (NCN); m/z
223 (MC, 5%), 206 (19), 205 (100), 204 (23), 194 (26), 176
(13), 162 (11), 137 (31), 135 (12), 125 (76), 112 (13), 109
4.3.1. 3-(1-Methyl-1H-imidazol-2-yl)pentan-3-ol (3a).
Yield 95%; white solid; tr 10.00; Rf 0.36 (EtOAc/MeOH
8:1); mp 114–116 8C; n (KBr) 3640–3011 cmK1 (OH); dH
0.78 (6H, t, JZ7.4 Hz, 2!CH2CH3), 1.86–1.95 (4H, m,
2!CH2), 3.74 (3H, s, NCH3), 3.80 (1H, br s, OH), 6.81,
6.89 (1H and 1H, 2s, CHCH); dC 7.8 (2C, 2!CH2CH3),
32.6 (2C, 2!CH2), 34.5 (NCH3), 75.6 (COH), 122.9, 125.5
(CHCH), 150.2 (NCN); m/z 168 (MC, 5%), 140 (10), 139

R. Torregrosa et al. / Tetrahedron 61 (2005) 11148–11155
11153
(12), 100 (31), 95 (16), 86 (11), 84 (32), 83 (36), 82 (17).
HRMS calcd for C12H21N3O 223.1685, found 223.1668.
134.7, 137.3, 151.6 (ArC), 158.8 (CHN); m/z 217 (MCC2,
32%), 216 (45), 215 (94), 214 (100), 104 (10), 77 (40), 51
(10).
4.3.7. 2,2-Dimethyl-1-(1-methyl-1H-imidazol-2-yl)pro-
pan-1-ol (3g).27 Yield 94%; white solid; tr 10.69; Rf 0.37
(EtOAc/MeOH 8:1); mp 83–85 8C; n (KBr) 3705–
3011 cmK1 (OH); dH 0.97 [9H, s, C(CH3)3], 3.67 (3H, s,
NCH3), 4.22 (1H, br s, OH), 4.39 (1H, s, CHOH), 6.77, 6.92
(1H and 1H, 2s, CHCH); dC 25.8 [3C, C(CH3)3], 33.5
(NCH3), 37.1 [C(CH3)3], 74.0 (CHOH), 120.8, 126.7
(CHCH), 148.8 (NCN); m/z 168 (MC, 4%), 112 (45), 111
(100), 83 (10).
4.4.3. N-(4-Nitrobenzylidene)aniline (4d).31 Yield 95%;
orange solid; tr 16.97; Rf 0.29 (hexane/EtOAc 8:1); mp
79–80 8C; n (KBr) 1599 (C]N), 1518, 1344 cmK1 (C–NO2);
dH 7.24–7.33, 7.40–7.46, 8.05–8.09, 8.29–8.34 (3H, 2H, 2H
and 2H, 4m, 9!ArH), 8.55 (1H, s, CHN); dC 120.9, 123.9,
127.0, 129.3, 129.4 (9C, ArCH), 141.5, 149.2, 150.8 (ArC),
157.3 (CHN); m/z 227 (MCC1, 15%), 226 (100), 225 (45),
179 (44), 152 (10), 104 (17), 77 (39), 51 (11).
4.3.8. (1-Methyl-1H-imidazol-2-yl)-phenylmethanol
(3h).28 Yield 77%; amber solid; tr 13.93; Rf 0.49 (EtOAc/
MeOH 8:1); mp 109–110 8C; n (KBr) 3601–2968 cmK1
(OH); dH 3.33 (3H, s, CH3), 5.94 (1H, s, CHOH), 6.59, 6.68
(1H and 1H, 2s, NCHCHN), 7.15–7.32 (5H, m, ArH), 8.03
(1H, br s, OH); dC 33.0 (CH3), 68.4 (CHOH), 121.8, 125.5,
125.6, 126.8, 127.9 (7C, ArCH and NCHCHN), 141.0
(ArC), 149.1 (NCN); m/z 189 (MCC1, 13%), 188 (100),
187 (56), 171 (20), 170 (11), 169 (17), 111 (48), 109 (10),
105 (16), 97 (32), 83 (23), 82 (14), 81 (13), 79 (13), 77 (32).
4.4.4. N-(3-Nitrobenzylidene)aniline (4e).32 Yield 89%;
yellow solid; tr 16.99; Rf 0.31 (hexane/EtOAc 8:1); mp 63–
64 8C; n (KBr) 1613 (C]N), 1529, 1350 cmK1 (C–NO2);
dH 7.23–7.31, 7.40–7.45, 7.62–7.68, 8.23–8.33 (3H, 2H, 1H
and 2H, 4m, 8!ArH), 8.53, 8.73 (1H and 1H, 2s, ArH and
CHN); dC 120.9, 123.4, 125.5, 126.8, 129.3, 129.7, 134.0
(9C, ArCH), 137.8, 148.6, 150.8 (ArC), 157.1 (CHN); m/z
227 (MCC1, 15%), 226 (100), 225 (40), 180 (11), 179 (17),
152 (10), 104 (18), 77 (32).
4.4.5. N-Benzylidene-4-methoxyaniline (4f).30 Yield 90%;
yellow solid; tr 15.74; Rf 0.44 (hexane/EtOAc 8:1); mp 70–
71 8C; n (KBr) 1622 cmK1 (C]N); dH 3.81 (3H, s, CH3),
6.90–6.94, 7.22–7.25, 7.44–7.46, 7.86–7.90 (2H, 2H, 3H
and 2H, 4m, 9!ArH), 8.47 (1H, s, CHN); dC 55.4 (CH3),
114.3, 122.2, 128.5, 128.7, 131.0 (9C, ArCH), 136.4, 144.9,
158.2 (ArC), 158.3 (CHN); m/z 212 (MCC1, 14%), 211
(88), 210 (14), 197 (15), 196 (100), 167 (21).
4.3.9. Cyclohexyl(1-methyl-1H-imidazol-2-yl)methanol
(3i).29 Yield 79%; pale yellow solid; tr 14.15; Rf 0.46
(EtOAc/MeOH 8:1); mp 110–111 8C; n (KBr) 3690–
2994 cmK1 (OH); dH 0.86–1.29, 1.63–1.66, 1.75–1.87,
2.08–2.13 (6H, 2H, 2H and 1H, 4m, 5!CH2 and CH
ring), 3.68 (3H, s, CH3), 4.35 (1H, d, JZ8.4 Hz, CHOH),
4.85 (1H, br s, OH), 6.76, 6.87 (1H and 1H, 2s, CHCH); dC
25.7, 25.9, 26.3, 29.2, 29.3 (5!CH2), 33.0, 43.3 (CH ring
and CH3), 71.4 (CHOH), 121.0, 126.5 (CHCH), 149.6
(NCN); m/z 194 (MC, 3%), 112 (78), 111 (100), 83 (11).
4.4.6. N-Benzylidene-4-chloroaniline (4g).30 Yield 92%;
pale yellow solid; tr 15.14; Rf 0.56 (hexane/EtOAc 8:1); mp
60–61 8C; n (KBr) 1626 cmK1 (C]N); dH 7.13–7.16, 7.33–
7.36, 7.47–7.49, 7.87–7.90 (2H, 2H, 3H and 2H, 4m, 9!
ArH), 8.42 (1H, s, CHN); dC 122.2, 128.8, 128.9, 129.2,
131.6 (9C, ArCH), 131.4, 135.9, 150.5 (ArC), 160.7 (CHN);
m/z 217 (MCC2, 33%), 216 (44), 215 (100), 214 (99), 138
(11), 111 (25), 75 (15).
4.4. General procedure for the preparation of imines
4b–h
To a solution of a carbonyl compound (10 mmol) in
chloroform (30 mL) was added an amine (12 mmol) and
molecular sieve (3.7 g) at room temperature. After being
stirred for a certain period of time (TLC), the crude was
rinsed with K2CO3–brine solution (3!20 mL) and the
crude product was concentrated under reduced pressure
(15 Torr). Imines 4 were purified by recrystallization from
mixtures of ethyl acetate and n-pentane. Imines 4b and 4c
were washed very carefully with cold n-pentane due to their
solubility. The imine 4h was purified by distillation.
4.4.7. N-(1-Phenylethylidene)aniline (4h).30 Yield 87%;
amber oil; tr 14.19; Rf 0.43 (hexane/EtOAc 8:1); n (film)
1638 cmK1 (C]N); dH 2.16 (3H, s, CH3), 6.76–6.79, 7.02–
7.07, 7.28–7.33, 7.38–7.40, 7.93–7.96 (2H, 1H, 2H, 3H and
2H, 5m, 10!ArH); dC 17.1 (CH3), 119.2, 123.0, 127.0,
128.2, 128.8, 130.3 (10C, ArCH), 139.3, 151.5 (ArC), 165.2
(C]N); m/z 196 (MCC1, 8%), 195 (50), 181 (14), 180
(100), 77 (32).
4.4.1. N-(4-Methoxybenzylidene)aniline (4b).30 Yield
79%; pale yellow solid; tr 15.80; Rf 0.42 (hexane/EtOAc
8:1); mp 55–56 8C; n (KBr) 1621 cmK1 (C]N); dH 3.85
(3H, s, CH3), 6.96–6.98, 7.18–7.22, 7.35–7.40, 7.83–7.86
(2H, 3H, 2H and 2H, 4m, 9!ArH), 8.37 (1H, s, CHN); dC
55.4 (CH3), 114.1, 120.8, 125.5, 129.1, 130.5 (9C, ArCH),
129.2, 152.2, 162.2 (ArC), 159.7 (CHN); m/z 212 (MCC1,
12%), 211 (87), 210 (100), 167 (11), 77 (21).
4.5. General procedure for the preparation of 2-(amino-
alkyl)imidazoles 5a–g
N-Methylimidazole (403 mL, 5 mmol) was added to a
suspension of lithium powder (105 mg, 15 mmol) and
isoprene (101 mL, 1 mmol) in THF (7 mL) at room
temperature. The mixture was stirred for 45 min and then
a solution of the corresponding imine compound (5.5 mmol)
in THF (3 mL) was added (except for imines 5c and 5g
where the resulting solution of the organolithium was
filtered to remove the lithium excess and then added to a
solution of the imine), continuing the stirring during 45 min
at the same temperature. The reaction mixture was
4.4.2. N-(4-Chlorobenzylidene)aniline (4c).30 Yield 82%;
pale yellow solid; tr 15.21; Rf 0.61 (hexane/EtOAc 8:1); mp
60–61 8C; n (KBr) 1622 cmK1 (C]N); dH 7.19–7.26, 7.37–
7.45, 7.82–7.85 (3H, 4H and 2H, 3m, 9!ArH), 8.41 (1H, s,
CHN); dC 120.8, 126.2, 129.0, 129.2, 129.9 (9C, ArCH),

11154
R. Torregrosa et al. / Tetrahedron 61 (2005) 11148–11155
hydrolyzed with water (15 mL), extracted with ethyl acetate
(3!15 mL), and the organic phase was dried over
anhydrous magnesium sulfate. After removing the solvent
under reduced pressure (15 Torr), the resulting crude was
purified by recrystallization (from mixtures of ethyl acetate
and n-pentane) to yield compounds 5. Compound 5g was
purified by column chromatography (pHZ6.7–7.3 silica
gel, mixtures of hexane and EtOAc).
dH 3.48 (3H, s, CH3), 5.42 (1H, br s, NH), 5.53 (1H, s,
CHNH), 6.54–6.57, 6.75, 6.97–6.98, 7.01–7.04, 7.20–7.24,
7.27–7.32, 7.36–7.39 (2H, 1H, 1H, 2H, 1H, 2H and 2H, 7m,
9!ArH and NCHCHN); dC 32.8 (CH3), 55.1 (CHNH),
114.5, 121.6, 127.1, 127.3, 127.8, 128.8, 129.0, (11C, ArCH
and NCHCHN), 122.2, 139.4, 145.0, 147.2 (ArC and NCN);
m/z 299 (MCC2, 4%), 298 (2), 297 (12), 172 (13), 171
(100). HRMS calcd for C17H16ClN3 297.1033, found
297.1026.
4.5.1. [(1-Methyl-1H-imidazol-2-yl)-phenylmethyl]-phe-
nyl-amine (5a).33 Yield 94%; pale yellow solid; tr 18.51; Rf
0.77 (EtOAc/MeOH 8:1); mp 125–126 8C; n (KBr)
3377 cmK1 (NH); dH 3.54 (3H, s, CH3), 5.24 (1H, br s,
NH), 5.61 (1H, s, CHNH), 6.64–6.70, 6.77, 7.00, 7.09–7.14,
7.23–7.25, 7.29–7.34, 7.39–7.42 (3H, 1H, 1H, 2H, 1H, 2H
and 2H, 7m, 10!ArH and NCHCHN); dC 32.9 (CH3), 55.1
(CHNH), 113.4, 117.8, 121.5, 127.2, 127.3, 127.7, 128.8,
129.1 (12C, ArCH and NCHCHN), 139.9, 146.5, 147.7
(ArC and NCN); m/z 264 (MCC1, 3%), 263 (16), 172 (14),
171 (100).
4.6. General procedure for the preparation of 2-(amino-
alkyl)imidazoles 5i and 5j
To a solution of hexamethyldisilazane (530 mL, 2.5 mmol)
in THF (1.0 mL) was added a 1.6 M solution of
n-butyllithium in hexane (1.6 mL, 2.6 mmol) at 0 8C and
the mixture was stirred for 5 min at the same temperature,
and after that, it was added drop-wise to a solution of the
corresponding aldehyde (2.2 mmol) in THF (1.0 mL) at
0 8C. Stirring was continued at the same temperature for
30 min. The resulting N-trimethylsilylimine solution was
used in the synthesis of 2-(aminoalkyl)imidazoles 5i and 5j
when reacting with the corresponding organolithium
derived from N-methylimidazole.
4.5.2. N-[(4-Methoxyphenyl)(1-methyl-1H-imidazol-2-
yl)methyl]aniline (5b). Yield 92%; pale yellow solid; tr
21.27; Rf 0.69 (EtOAc/MeOH 8:1); mp 151–152 8C; n (KBr)
3397 cmK1 (NH); dH 3.53, 3.74 (3H and 3H, 2s, 2!CH3),
5.57 (1H, s, CHNH), 6.63–6.69, 6.77, 6.82–6.85, 6.99, 7.08–
7.14, 7.30–7.33 (3H, 1H, 2H, 1H, 2H and 2H, 6m, 9!ArH
and NCHCHN); dC 32.9 (NCH3), 54.5, 55.2 (CHNH and
OCH3), 113.5, 114.2, 117.7, 121.4, 127.1, 128.5, 129.1
(11C, ArCH and NCHCHN), 131.9, 146.5, 147.9, 159.0
(ArC and NCN); m/z 293 (MC, 9%), 202 (15), 201 (100),
186 (12), 170 (14). HRMS calcd for C18H19N3O 293.1528,
found 293.1527.
N-Methylimidazole (161 mL, 2 mmol) was added to a
suspension of lithium powder (42 mg, 6 mmol) and isoprene
(40 mL, 0.4 mmol) in THF (4 mL) at room temperature. The
resulting mixture was stirred for 45 min at the same
temperature. The excess of lithium was filtered off under
argon atmosphere and the resulting mixture was added drop-
wise to a cooled (0 8C) THF solution of the corresponding
N-(trimethylsilyl)imine prepared as indicated above. The
reaction mixture was allowed to reach room temperature,
hydrolyzed with 3 M hydrochloric acid (15 mL) and
extracted with ethyl acetate (3!20 mL). The aqueous
layer was then basified with 2.5 M sodium hydroxide
(25 mL) and extracted with ethyl acetate (3!25 mL). The
organic layer was dried over anhydrous magnesium sulfate
and evaporated (15 Torr). The resulting residue was purified
by column chromatography (pHZ6.7–7.3 silica gel,
mixtures of ethyl acetate and methanol) to yield the
compound 5i or by destillation of the impurities (TZ
50 8C, 0.1 Torr) to obtain the product 5j.
4.5.3. N-[(4-Chlorophenyl)(1-methyl-1H-imidazol-2-yl)
methyl]aniline (5c). Yield 88%; beige solid; tr 20.39; Rf
0.88 (EtOAc/MeOH 8:1); n (KBr) 3393 cmK1 (NH); dH
3.57 (3H, s, CH3), 5.20 (1H, br s, NH), 5.60 (1H, s, CHNH),
6.61–6.64, 6.67–6.72, 6.80, 7.00, 7.10–7.15, 7.25–7.30,
7.34–7.37 (2H, 1H, 1H, 1H, 2H, 2H and 2H, 7m, 9!ArH
and NCHCHN); dC 32.9 (CH3), 54.3 (CHNH), 113.5, 118.1,
121.6, 127.4, 128.7, 129.0, 129.2, (11C, ArCH and
NCHCHN), 133.5, 138.5, 146.2, 147.3 (ArC and NCN);
m/z 299 (MCC2, 6%), 298 (4), 297 (19), 207 (33), 206 (14),
205 (100), 170 (61), 155 (14). HRMS calcd for C17H16ClN3
297.1033, found 297.1064.
4.6.1. (1-Methyl-1H-imidazol-2-yl)(phenyl)methan-
amine (5i). Yield 70%; yellow oil; tr 13.90; Rf 0.47
(EtOAc/MeOH 1:1); n (film) 3710–2960 cmK1 (NH2); dH
2.61 (2H, s, NH2), 3.38 (3H, s, CH3), 5.17 (1H, s, CHNH2),
6.79, 7.00 (1H and 1H, 2s, NCHCHN), 7.22–7.35 (5H, m,
ArH); dC 32.6 (CH3), 53.3 (CHNH2), 121.4, 126.7, 126.8,
127.5, 128.8 (7C, ArCH and NCHCHN), 142.5, 149.5 (ArC
and NCN); m/z 188 (MCC1, 13%), 187 (100), 186 (22),
172 (20), 170 (10), 169 (14), 110 (49), 106 (13), 83 (23), 77
(13). HRMS calcd for C11H13N3 187.1109, found 187.1113.
4.5.4.
4-Methoxy-N-[(1-methyl-1H-imidazol-2-yl)
(phenyl)methyl]aniline (5f). Yield 91%; amber oil; tr
20.93; Rf 0.76 (EtOAc/MeOH 8:1); n (film) 3690–
3169 cmK1 (NH); dH 3.43, 3.63 (3H and 3H, 2s, 2!CH3),
4.95 (1H, br s, NH), 5.53 (1H, s, CHNH), 6.58–6.61, 6.67–
6.71, 6.96, 7.16–7.22, 7.25–7.30, 7.36–7.38 (2H, 3H, 1H,
1H, 2H and 2H, 6m, 9!ArH and NCHCHN); dC 32.6
(NCH3), 55.4, 55.9 (CHNH and OCH3), 114.5, 114.8, 121.3,
127.0, 127.2, 127.4, 128.5 (11C, ArCH and NCHCHN),
139.9, 140.6, 147.6, 152.1 (ArC and NCN); m/z 294 (MCC
1, 4%), 293 (20), 172 (13), 171 (100). HRMS calcd for
C18H19N3O 293.1528, found 293.1544.
4.6.2. 2,2-Dimethyl-1-(1-methyl-1H-imidazol-2-yl)pro-
pan-1-amine (5j). Yield 87%; yellow oil; tr 11.18; Rf 0.56
(EtOAc/MeOH 1:1); n (film) 3720–3029 cmK1 (NH2); dH
0.98 [9H, s, C(CH3)3], 2.03 (2H, br s, NH2), 3.63 (3H, s,
NCH3), 3.68 (1H, s, CHNH2), 6.77, 6.98 (1H and 1H, 2s,
CHCH); dC 26.2 [3C, C(CH3)3], 33.0 (NCH3), 36.5
[C(CH3)3], 56.0 (CHNH2), 120.0, 126.9 (CHCH), 150.1
4.5.5. 4-Chloro-N-[(1-methyl-1H-imidazol-2-yl)(phenyl)
methyl]aniline (5g). Yield 93%; yellow oil; tr 21.13; Rf
0.82 (EtOAc/MeOH 8:1); n (film) 3690–3179 cmK1 (NH);

R. Torregrosa et al. / Tetrahedron 61 (2005) 11148–11155
11155
(NCN); m/z 167 (MC, 1%), 110 (100), 83 (13). HRMS calcd
for C9H17N3 167.1422, found 167.1424.
Organolithium Compounds; Wiley: Chichester, 2004; Vol. 1,
Chapter 11, pp 647–747.
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Heteroat. Chem. 1997, 17, 73–107. (e) Najera, C.; Yus, M.
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This work was generously supported by the Direccion
General de Ensen˜anza Superior (DGES) of the Spanish
´
Curr. Org. Chem. 2003, 7, 867–926. (f) Najera, C.; Sansano,
J. M.; Yus, M. Tetrahedron 2003, 59, 9255–9303. (g) Ref. 4b.
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(h) Chinchilla, R.; Najera, C.; Yus, M. Tetrahedron 2005, 61,
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Ministerio de Ciencia y Tecnologıa (MCyT, grant no.
CTQ2004-01261) and the Generalitat Valenciana (GV,
grant no. GRUPOS 03/135). R. T. thanks the GV for a
scholarship.
3139–3176. (i) See also the special issue of Tetrahedron
Symposium-in-Print dedicated to ‘Functionalised Organo-
lithium Compounds’; Tetrahedron 2005, 61, 3125–3450
(Guest editors: Najera, C.; Yus, M.). (j) Yus, M.; Foubelo, F.
In Functionalised Organometallics; Knochel, P., Ed.;
Wiley-VCH: Weinheim, 2005.
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