Isoprene as lithiation mediator: Synthesis of 2-substituted 1-alkylimidazole derivatives

Article abstract of DOI:10.1055/s-0032-1316562

The lithiation of different imidazoles bearing a primary (i.e., butyl, pentyl, dodecyl) or secondary (i.e., cyclohexyl, 1-methylheptyl) alkyl substituent on the nitrogen has been successfully achieved by means of an isoprene-mediated protocol. The subsequent reaction of the 2-lithioimidazole intermediates with different electrophiles leads to the formation of interesting 1,2-disubstituted imidazoles. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316562

2630▌
PAPER
paper
Isoprene as Lithiation Mediator: Synthesis of 2-Substituted 1-Alkylimidazole
Derivatives
Imidazole Derivatives via Isoprene-Mediated Lithiation
Regina Martínez, Rosario Torregrosa, Isidro M. Pastor,* Miguel Yus*
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99,
03080 Alicante, Spain
Fax +34(96)5903549; E-mail: ipastor@ua.es; E-mail: yus@ua.es
Received: 23.04.2012; Accepted after revision: 22.05.2012
isoprene or its derivatives after the lithiation process can
Abstract: The lithiation of different imidazoles bearing a primary
be easily removed. Regarding the role of isoprene, it
(i.e., butyl, pentyl, dodecyl) or secondary (i.e., cyclohexyl, 1-meth-
seems to act as a base, after being reduced by Li(s), giving
the 1,1-dimethylallyl anion radical 3, on the basis of den-
ylheptyl) alkyl substituent on the nitrogen has been successfully
achieved by means of an isoprene-mediated protocol. The subse-
quent reaction of the 2-lithioimidazole intermediates with different sity functional theory calculations. Radical 4 can be fur-
electrophiles leads to the formation of interesting 1,2-disubstituted
imidazoles.
ther reduced by the excess lithium to give the anion 5
which can proceed once more as a base (Scheme 1).9
Key words: imidazole derivatives, isoprene-mediated lithiation,
lithium metal, nucleophilic addition, deprotonation
Thus, isoprene-mediated lithiation of different imidazole
derivatives, such as 1-methyl-,10 1-phenyl-,11 and 1-
(diethoxymethyl)-1H-imidazole,12 has been reported by
us. In sharp contrast, the functionalization of other 1-al-
The synthesis of heterocyclic compounds, which consti- kylimidazoles, via the corresponding 2-lithio derivatives,
tute the largest and most varied family of organic com- has been less studied.13 In this paper, we report the appli-
pounds, is a broad field of interest, probably due to the cation of the isoprene-mediated lithiation process for the
remarkable bioactivity of such compounds. Indeed, the preparation of imidazole derivatives bearing a primary or
significant aptitude of heterocyclic moieties to serve both secondary alkyl substituent on the nitrogen.14
as biomimetics and reactive pharmacophores has largely
contributed to their unique value in the synthesis of nu-
Li(s)
merous drugs.1 In fact, more than 67% of the compounds
listed in the Comprehensive Medicinal Chemistry (CMC)
database contain heterocyclic rings.2 Among them, azoles
represent a broad group of heterocyclic systems which
have been extensively considered in bioactive products.3
–
Li+
•
3
Li
Me
Me
Lithium metal in combination with a substoichiometric
amount of an arene, as electron carrier, has become a very
versatile methodology in the preparation of organolithium
intermediates.4 A significant variety of functionalized or-
ganolithium reagents have been prepared by means of this
protocol.5 Additionally, arene-promoted lithiation has
been employed in the preparation of polylithiated
synthons6 and in the generation of active nanoparticles by
activation of transition metals.7 In our laboratory, mecha-
nistic studies on the arene-catalyzed lithiation process
have been undertaken, providing interesting information
regarding this well-established methodology.8
or
N
N
N
N
1
2
Li(s)
Li+
–
•
4
5
Scheme 1 Proposed mechanism for the isoprene-mediated lithiation
of NMI employing lithium metal
During the last few years, we have been working on the The 1-alkylimidazole derivatives 6–11 were easily pre-
preparation of 2-functionalized imidazoles from the cor- pared either by substitution of the corresponding alkyl ha-
responding 2-lithioimidazole derivatives. Lithium metal lide with imidazole, or by ring formation starting from the
is able to form 2-lithio-N-methylimidazole (2-Li-NMI, 2) corresponding alkylamines.3 Thus, imidazole was reacted
starting from the corresponding N-methylimidazole with 1-bromopentane under phase-transfer conditions,
(NMI, 1), but the use of a diene (i.e., isoprene) as a pro- giving the corresponding 1-pentyl-1H-imidazole (6) in
moting agent during the lithiation step turned out to be an good isolated yield (Scheme 2).15 On the other hand, an
interesting improvement.9 Furthermore, the remaining equimolecular mixture of formaldehyde, glyoxal, ammo-
nia and the corresponding amine (i.e., butan-1-amine, do-
decan-1-amine, cyclohexanamine or octan-2-amine) was
heated at 75 °C for three hours, yielding the expected im-
idazoles 7–10 (Scheme 3). This methodology was not suc-
SYNTHESIS 2012, 44, 2630–2638
Advanced online publication: 02.07.2012
DOI: 10.1055/s-0032-1316562; Art ID: SS-2012-Z0384-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

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Imidazole Derivatives via Isoprene-Mediated Lithiation
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Table 1 Lithiation–Deuteration Reaction of Imidazoles 6–8a
cessful when employing tertiary amines, such as tert-
butylamine or adamantylamine. Alternatively, the use of
ammonium acetate as ammonia source and performing
the reaction in acetic acid allowed the preparation of 1-ad-
amantyl-1H-imidazole (11), but not the tert-butylimid-
azole derivative (Scheme 3).
D
1) Li (excess), isoprene, THF, 25 °C
2) D2O, 0–25 °C
N
N
N
R1
N
R1
6–8
12a–14a
Entry
R1
Isoprene Product
(mol%)
D Incorporationb
(%)
N
Br
N
N
NH
1
2
3
4
5
6
7
8
6: (CH2)4Me
7: (CH2)3Me
7: (CH2)3Me
7: (CH2)3Me
8: (CH2)11Me
8: (CH2)11Me
8: (CH2)11Me
8: (CH2)11Me
100
100
150
200
100
200
300
300
12a
13a
13a
13a
14a
14a
14a
14a
>95
10
NaOH (2 M), Et4NBr
toluene, reflux, 24 h
6 (75%)
Scheme 2 Synthesis of 1-pentyl-1H-imidazole (6) from 1-bromo-
25
pentane
>95
<5
NH3 (aq), CH2O (aq)
(C2H2O2)3•2H2O
N
R1
R1NH2
N
<5
MeOH, 75 °C, 3 h
7 [50%, R1 = (CH2)3Me]
8 [60%, R1 = (CH2)11Me]
20
9 (80%, R1 = c-C6H11
)
>95c
10 [75%, R1 = CHMe(CH2)5Me]
a The reactions were carried out using the imidazole derivative 6–8 (1
mmol), lithium powder (3 mmol) and isoprene in THF (5 mL).
b Determined by 1H NMR spectroscopy.
NH4OAc, CH2O (aq)
(C2H2O2)3•2H2O
N
N
c The lithiation step was performed at 45 °C instead of 25 °C.
AcOH, 80 °C, 24 h
11 (15%)
Scheme 3 Synthesis of 1-alkylimidazole derivatives 7–11 from the
corresponding alkylamines by ring formation
1H-imidazoles 12b–g (Figure 1; Table 2, entries 1–6).
The corresponding 1-butyl-2-lithio-1H-imidazole was
prepared employing a higher amount of isoprene (200
mol%) and increasing the temperature during the lithia-
tion step to 45 °C, being afterwards reacted with different
First of all, we conducted a study of the amount of iso-
prene needed for the formation of the corresponding 2-
lithioimidazole derivatives with the primary alkyl substit-
uents (i.e., butyl, pentyl and dodecyl), which were after-
wards quenched with deuterium oxide to determine the
deuterium incorporation. 1-Pentyl-1H-imidazole (6) pro-
duced a high incorporation of deuterium (>95%) when
one equivalent of isoprene was used, giving the corre-
sponding imidazole 12a (Table 1, entry 1). In contrast, a
higher amount of isoprene was required in order to per-
form the lithiation of 1-butyl-1H-imidazole (7) or 1-do-
decyl-1H-imidazole (8). Indeed, the use of one equivalent
of isoprene only produced 10 mol% of deuterium incorpo-
ration in product 13a, up to two equivalents being needed
in order to obtain good results (Table 1, entries 2–4). For-
mation of 2-deutero-1-docecyl-1H-imidazole (14a) was
only possible at room temperature when 300 mol% of iso-
prene was employed during the lithiation process, but
with low deuterium incorporation (Table 1, entry 7). The
deuterium incorporation was increased to 95% by warm-
ing the reaction mixture to 45 °C during the lithiation step
(Table 1, entry 8).
OH
OH
Ph
OH
N
N
N
N
N
N
4
4
4
12b
OH
12c
OH
12d
OH
N
N
N
N
N
N
4
4
4
12e
OH
12f
OH
Ph
CF3
12g
OH
Ph
N
N
N
N
N
N
3
3
3
13b
13c
Cl
13d
OMe
OH
OH
Ph
Et
N
N
N
N
N
Different 2-substituted imidazole derivatives were pre-
pared employing the amount of isoprene stated for the
lithiation–deuteration reactions. Thus, 2-lithio-1-pentyl-
1H-imidazole, which was generated by reaction of 6 with
an excess of lithium powder and one equivalent of iso-
prene at 25 °C during one hour, subsequently underwent
nucleophilic addition to different carbonyl compounds,
OH
N
11
11
3
14c
Cl
14b
OMe
13e
Figure 1 Imidazole derivatives 12–14 prepared from 1-alkylimid-
yielding the corresponding 2-(hydroxyalkyl)-1-pentyl- azoles 6–8
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2630–2638

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R. Martínez et al.
PAPER
carbonyl compounds to generate derivatives 13b–e (Fig- 1H-imidazole (9) were treated with lithium in the pres-
ure 1; Table 2, entries 7–10). Finally, the imidazole deriv- ence of a substoichiometric amount of isoprene (20
ative 8 was also successfully lithiated at 45 °C, albeit an mol%) at room temperature during 90 minutes, producing
excess (300 mol%) of isoprene was needed. The corre- the corresponding 1-cyclohexyl-2-lithio-1H-imidazole
sponding imidazol-2-ylcarbinol derivatives 14b,c (Figure which afterwards underwent nucleophilic addition to pen-
1; Table 2, entries 11 and 12) were isolated after reacting tan-3-one to provide the imidazole derivative 15a in 80%
the 2-lithio intermediate with electrophiles. In general, the isolated yield.17 Moreover, 15a was obtained, with com-
products were obtained with moderate to good yields, ex- parable yield, in a shorter reaction time by employing an
cept in the case of enolizable carbonyl compounds proba- excess of isoprene during the lithiation step (Figure 2; Ta-
bly due to the basic character of the reactive species. ble 2, entry 13). Similarly, the 1-cyclohexyl-2-lithio-1H-
Derivatives with a similar motif of aryl(azolyl)carbinol imidazole intermediate was successfully employed in the
are reported to be effective in the treatment of different preparation of the functionalized imidazoles 15b and 15c
diseases, syndromes and disorders.16
(Figure 2; Table 2, entries 14 and 15). 1-(1-Methylhep-
tyl)-1H-imidazole (10) was, as well, treated with the mix-
ture lithium/isoprene (300 mol%:200 mol%) at room
temperature producing the expected organolithium inter-
Imidazole derivatives bearing a secondary alkyl substitu-
ent on the nitrogen reacted smoothly with lithium in the
presence of isoprene as mediator. Indeed, 1-cyclohexyl-
Table 2 Lithiation of 1-Alkylimidazole Derivatives and Subsequent Reaction with Electrophiles
R2
N
R3
OH
R1
1) Li, isoprene, THF
N
R1
N
N
2) R2COR3, 0–25 °C
3) H2O, 0–25 °C
6–10
12–16
Entry
Starting imidazole Conditionsa
R2
R3
Productb
Yieldc (%)
1
2
6
6
A
A
A
A
A
A
B
B
B
B
C
C
D
D
D
D
D
D
Et
Et
12b
12c
12d
12e
12f
61
28
74
30
54
21
55
56
86
64
73
19
82
53
65
65
92d
94e
Ph
Me
c-Pr
3
6
c-Pr
4
6
–(CH2)5–
t-Bu
i-Bu
Cy
5
6
H
6
6
H
12g
13b
13c
13d
13e
14b
14c
15a
15b
15c
16a
16b
16c
7
7
H
8
7
Ph
CF3
9
7
4-ClC6H4
4-MeOC6H4
4-ClC6H4
Ph
Ph
10
11
12
13
14
15
16
17
18
7
4-MeOC6H4
8
H
8
Et
Et
Me
H
9
Et
9
Ph
9
t-Bu
Et
10
10
10
Et
Me
H
Ph
t-Bu
a The lithiation reactions were conducted, during 1 h, under the following conditions: (A) lithium powder (300 mol%), isoprene (100 mol%),
25 °C; (B) lithium powder (300 mol%), isoprene (200 mol%), 45 °C; (C) lithium powder (300 mol%), isoprene (300 mol%), 45 °C; (D) lithium
powder (300 mol%), isoprene (200 mol%), 25 °C.
b All products were >95% pure (by GLC and/or 300-MHz 1H NMR spectroscopy).
c Isolated yield after column chromatography (silica gel, hexane–EtOAc), based on the starting imidazole 6–10.
d Obtained as a mixture of diastereoisomers (50% de, by 1H NMR spectroscopy).
e Obtained as a mixture of diastereoisomers (9% de, by 1H NMR spectroscopy).
Synthesis 2012, 44, 2630–2638
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Imidazole Derivatives via Isoprene-Mediated Lithiation
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where indicated, the samples were inserted in the modality of direct
insertion probe (DIP) and, where indicated, mass spectra were ob-
tained with an Agilent 1100 Series HPLC system with electrospray
ionization (ESI). High-resolution mass spectrometry (HRMS) anal-
yses were carried out with a Finningan MAT 95S spectrometer. The
purity of volatile compounds and the chromatographic analyses
(GLC) were determined with an Agilent 6890N instrument
equipped with a flame ionization detector and a 30-m capillary col-
umn (diameter: 0.25 mm, film thickness: 0.25 μm), using nitrogen
(2 mL/min) as the carrier gas [Tinjector = 275 °C, Tcolumn = 80 °C (3
min) then 80–270 °C (15 °C/min)]; retention times (tR) are given in
minutes under these conditions. Analytical TLC was performed on
Merck aluminum sheets with silica gel 60 F254. Silica gel 60 (40–
60 microns) was employed for flash chromatography.
mediate which was subsequently reacted with various car-
bonyl compounds giving, after quenching with water, the
corresponding products 16 (Figure 2; Table 2, entries 16–
18). In this case, the reaction with a prochiral electrophile
(i.e., acetophenone or pivalaldehyde) occurred with some
diastereoselectivity. Thus, compounds 16b and 16c were
obtained with 50% and 9% de, respectively.
OH
OH
OH
N
N
N
N
N
N
Synthesis of 1-Alkyl-1H-imidazoles 6–11
15a
OH
15b
OH
15c
OH
1-Pentyl-1H-imidazole (6)15
N
N
N
N
N
N
A soln of 1H-imidazole (1.36 g, 20 mmol) in toluene (8 mL) was
placed in a 50-mL round-bottom flask, then a soln of NaOH (1.60
g, 40 mmol) and Et4NBr (1.05 g, 5 mmol) in H2O (10 mL) was add-
ed. The resulting mixture was heated to reflux, which was followed
by the dropwise addition of 1-bromopentane (2.48 mL, 20 mmol).
The reaction mixture was stirred under reflux for 24 h. After the re-
action mixture was cooled, it was extracted with EtOAc (3 × 10
mL). The resulting organic phase was dried (anhyd MgSO4), and the
solvent was evaporated under reduced pressure. The crude material
was purified by column chromatography (silica gel, EtOAc), giving
the imidazole 6; yield: 2.1 g (75%).
5
5
5
16a
16b
16c
Figure 2 Imidazole derivatives 15 and 16 prepared from 1-alkyl-
imidazoles 9 and 10
In conclusion, we have shown that the isoprene-mediated
lithiation methodology is effective in the preparation of 2-
lithioimidazole intermediates having a primary or a sec-
ondary substituent on the nitrogen. Lithiation of imidaz-
oles with a primary alkyl substituent depends on the chain
length: 1-dodecyl-1H-imidazole needs higher amounts of
isoprene and increased temperature than 1-butyl- or 1-
pentyl-1H-imidazole, although 1-butyl-1H-imidazole
also gave better results at 45 °C. Lithiation of imidazoles
bearing a secondary alkyl substituent (i.e., cyclohexyl or
Pale brown oil; GLC: tR = 9.9 min; Rf = 0.21 (EtOAc).
IR (film): 3110 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.1 Hz, 3 H, CH3),
1.26–1.34, 1.77 (2 m, 4 H, 2 H, CH3CH2CH2CH2), 3.91 (t, J = 7.2
Hz, 2 H, NCH2), 6.89, 7.04, 7.45 (3 s, 3 × 1 H, imidazole).
13C NMR (100 MHz, CDCl3): δ = 13.8, 22.1, 28.6, 30.7, 47.0,
118.7, 129.2, 137.0.
MS (EI): m/z (%) = 138 (48) [M+], 137 (10), 123 (12), 111 (97), 96
(32), 95 (13), 83 (13), 82 (100), 81 (76), 70 (18), 68 (23), 55 (38),
1-methylheptyl) on the nitrogen takes place under mild re- 54 (21).
HRMS: m/z [M+] calcd for C8H14N2: 138.1157; found: 138.1167.
action conditions, similarly to a short, primary alkyl sub-
stituent. 1-Adamantyl-1H-imidazole does not form the
corresponding organolithium intermediate under the stud-
ied reaction conditions. Additionally, the nucleophilic ad-
dition of the generated lithiated imidazole derivatives to
different electrophiles allows the preparation of a variety
of imidazol-2-ylcarbinol derivatives which are an inter-
esting class of compounds with potential pharmacological
properties.
1-Butyl-1H-imidazole (7);15 Typical Procedure
A soln of butan-1-amine (0.99 mL, 10 mmol) and 25% aq NH3 (0.75
mL, 10 mmol) in MeOH (4 mL) and a soln of glyoxal (trimer dihy-
drate; 0.70 g, 10 mmol of glyoxal) and 36% aq formaldehyde (0.77
mL, 10 mmol) in a mixture of MeOH (4 mL) and H2O (4 mL) were
slowly and simultaneously added to a round-bottom flask with
MeOH (7 mL) heated to 50 °C. After the addition was finished, the
reaction mixture was heated to 75 °C for 3 h. The reaction mixture
was cooled, Et2O and H2O were added in equal portions until two
phases were observed, and the aqueous layer was extracted with
Et2O (3 × 10 mL). The combination of all the organic phases was
dried (anhyd MgSO4), and the solvent was evaporated under re-
duced pressure. The crude material was purified by column chroma-
tography (silica gel, mixtures of hexane and EtOAc), giving the
imidazole 7; yield: 0.62 g (50%).
All lithiation reactions were carried out under argon atmosphere in
oven-dried glassware. All commercially available reagents (Acros,
Aldrich, Fluka) were used without further purification, except in the
case of liquid electrophiles which were freshly distilled before use.
Lithium powder was commercially available (Medalchemy S.L.).
THF was dried in a Sharlab PS-400-3MD solvent purification sys-
tem using an alumina column. Infrared analysis was performed with
a Nicolet Impact 400D FTIR or a Jasco 4100LE (Pike MIRacle
ATR) spectrophotometer, and wavenumbers are given in cm–1.
NMR spectroscopic data were recorded with Bruker Avance 300
and 400 spectrometers (300 and 400 MHz for 1H NMR, 75 and 100
MHz for 13C NMR) using CDCl3 as the solvent and TMS as the in-
ternal standard. Chemical shifts are given in parts per million (δ),
and coupling constants (J) are given in hertz. Mass spectra (EI) were
obtained at 70 eV with an Agilent 5973 spectrometer, and fragment
ions are given as m/z with relative intensities (%) in parenthesis;
Yellow oil; GLC: tR = 8.9 min; Rf = 0.19 (EtOAc).
IR (film): 3105 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = 7.4 Hz, 3 H, CH3),
1.33, 1.76 (2 m, 2 H, 2 H, CH3CH2CH2), 3.93 (t, J = 7.1 Hz, 2 H,
NCH2), 6.90, 7.04, 7.45 (3 s, 3 × 1 H, imidazole).
13C NMR (100 MHz, CDCl3): δ = 13.5, 19.7, 33.0, 46.7, 118.7,
129.3, 137.0.
MS (EI): m/z (%) = 124 (48) [M+], 97 (85), 82 (100), 69 (22), 68
(35), 55 (71), 54 (37).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2630–2638

2634
R. Martínez et al.
PAPER
HRMS: m/z [M+] calcd for C7H12N2: 124.1000; found: 124.1007.
Yellow solid; mp 105–106 °C (EtOAc); GLC: tR = 15.7 min;
Rf = 0.16 (EtOAc).
IR (KBr): 3112 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.77, 2.10, 2.20 (3 m, 6 H, 6 H, 3
H, adamantyl), 7.07 (m, 2 H, imidazole), 7.65 (s, 1 H, imidazole).
1-Dodecyl-1H-imidazole (8)15
Following the same procedure, although employing dodecan-1-
amine (2.32 mL, 10 mmol), the imidazole 8 was isolated; yield: 1.42
g (60%).
13C NMR (100 MHz, CDCl3): δ = 29.4, 35.9, 43.2, 55.0, 115.3,
Yellow oil; GLC: tR = 15.7 min; Rf = 0.36 (EtOAc).
IR (film): 3105 cm–1.
128.6, 133.5.
MS (EI): m/z (%) = 202 (23) [M+], 136 (11), 135 (100), 107 (11), 93
(23), 91 (10), 79 (26), 77 (11).
HRMS: m/z [M+] calcd for C13H18N2: 202.1692; found: 202.1460.
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.7 Hz, 3 H, CH3),
1.25–1.30 (m, 18 H, 9 × CH2), 1.77 (m, 2 H, NCH2CH2), 3.92 (t,
J = 7.1 Hz, 2 H, NCH2), 6.90, 7.05, 7.46 (3 s, 3 × 1 H, imidazole).
13C NMR (100 MHz, CDCl3): δ = 14.0, 22.6, 26.5, 29.0, 29.2, 29.3,
29.4, 29.5, 31.0, 31.8, 47.0, 118.7, 129.2, 137.0.
Isoprene-Mediated Lithiation; General Procedure
To a 25-mL Schlenk flask were added lithium powder (0.042 g, 6
mmol) and isoprene (2–6 mmol, see Table 2) in THF (5 mL). The
corresponding 1-alkyl-1H-imidazole (2 mmol) was added to the
suspension, and the mixture was stirred for 1 h at 25 or 45 °C (see
Table 2). The flask was placed in an ice–water bath and the electro-
phile (2.2 mmol) was added dropwise; the stirring was continued for
45 min while allowing the mixture to reach r.t. (for deuteration ex-
periments, D2O was added instead of electrophile). The reaction
was quenched, at 0 °C, with H2O (10 mL), the mixture was extract-
ed with EtOAc (3 × 10 mL), and the resulting organic phase was
dried (anhyd MgSO4). The solvent was evaporated under reduced
pressure, and the resulting crude material was purified by column
chromatography (silica gel, mixtures of hexane and EtOAc). Yields
are given in Table 2; physical, spectroscopic and analytical data, as
well as literature references for known compounds, follow.
MS (EI): m/z (%) = 236 (32) [M+], 235 (46), 221 (13), 207 (33), 179
(31), 165 (26), 151 (28), 137 (132), 123 (44), 110 (21), 109 (33), 96
(50), 95 (40), 83 (17), 82 (100), 81 (45), 69 (49), 68 (20), 55 (42),
54 (19).
HRMS: m/z [M+] calcd for C15H28N2: 236.2252; found: 236.2242.
1-Cyclohexyl-1H-imidazole (9)18
Following the same procedure, although employing cyclo-
hexanamine (1.14 mL, 10 mmol), the imidazole 9 was isolated;
yield: 1.20 g (80%).
Yellow oil; GLC: tR = 11.8 min; Rf = 0.15 (EtOAc).
IR (film): 3110 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.21–1.32, 1.42–1.50, 1.59–1.74,
1.75–1.80, 1.89–1.95, 2.11–2.15 (6 m, 1 H, 2 H, 2 H, 1 H, 2 H, 2 H,
5 × CH2), 3.93 [m, 1 H, NCH(CH2)CH2], 6.97, 7.06, 7.55 (3 s, 3 ×
1 H, imidazole).
2-Deutero-1-pentyl-1H-imidazole (12a)
1H NMR (400 MHz, CDCl3): δ = 0.90 (t, J = 7.0 Hz, 3 H, CH3),
1.22–1.39, 1.78 (2 m, 4 H, 2 H, CH3CH2CH2CH2), 3.92 (t, J = 7.2
Hz, 2 H, NCH2), 6.90 (d, J = 1.2 Hz, 1 H, imidazole), 7.05 (d,
J = 1.2 Hz, 1 H, imidazole).
13C NMR (75 MHz, CDCl3): δ = 25.2, 25.4, 34.4, 56.7, 116.9,
128.9, 135.3.
MS (EI): m/z (%) = 151 (11) [M+ + 1], 150 (100) [M+], 123 (95),
122 (14), 107 (13), 95 (13), 83 (19), 81 (15), 69 (96), 68 (33), 67
(30), 55 (62), 54 (13), 53 (13).
13C NMR (100 MHz, CDCl3): δ = 13.9, 22.1, 28.7, 30.7, 47.0,
118.7, 129.3, 137.0 (t, J = 16.0 Hz).
MS (EI): m/z (%) = 139 (43) [M+], 138 (13), 124 (11), 112 (84), 97
(26), 96 (18), 84 (12), 83 (93), 82 (100), 81 (23), 70 (17), 69 (31),
68 (10), 55 (71), 54 (11).
1-(1-Methylheptyl)-1H-imidazole (10)19
Following the same procedure, although employing octan-2-amine
(1.68 mL, 10 mmol), the imidazole 10 was isolated; yield: 1.35 g
(75%).
3-(1-Pentyl-1H-imidazol-2-yl)pentan-3-ol (12b)
Pale yellow oil; yield: 0.274 g (61%); GLC: tR = 12.8 min; Rf = 0.31
(EtOAc).
Yellow oil; GLC: tR = 9.9 min; Rf = 0.55 (EtOAc).
IR (film): 3105 cm–1.
IR (film): 3114 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.84 (t, J = 6.8 Hz, 3 H, CH2CH3),
1.10–1.26 (m, 8 H, 4 × CH2), 1.44 (d, J = 6.8 Hz, 3 H, NCHCH3),
1.70 (m, 2 H, NCHCH2), 4.10 (m, 1 H, NCHCH3), 6.90, 7.00, 7.47
(3 s, 3 × 1 H, imidazole).
13C NMR (75 MHz, CDCl3): δ = 14.0, 22.2, 22.5, 26.0, 28.8, 31.6,
37.8, 53.7, 116.4, 129.2, 135.8.
1H NMR (400 MHz, CDCl3): δ = 0.77 [t, J = 7.4 Hz, 6 H,
C(OH)(CH2CH3)2], 0.92 (t, J = 7.4 Hz, 3 H, CH2CH2CH3), 1.36 (m,
5 H, CH2CH2CH3 and OH), 1.78 (m, 2 H, NCH2CH2), 1.89 [m, 4 H,
C(OH)(CH2CH3)2], 4.02 (m, 2 H, NCH2), 6.89, 6.92 (2 s, 2 × 1 H, 1
H, imidazole).
13C NMR (100 MHz, CDCl3): δ = 8.1, 14.0, 22.4, 29.0, 31.2, 33.4,
47.1, 76.5, 120.8, 126.0, 150.0.
MS (EI): m/z (%) = 224 (2) [M+], 196 (14), 195 (100), 125 (33), 69
(17).
MS (EI): m/z (%) = 180 (24) [M+], 165 (36), 153 (47), 138 (13), 137
(30), 124 (11), 111 (11), 110 (24), 109 (14), 97 (15), 96 (100), 95
(71), 81 (16), 69 (62), 68 (30), 57 (12), 55 (13).
HRMS: m/z [M+] calcd for C13H24N2O: 224.1889; found: 224.1897.
1-Adamantyl-1H-imidazole (11)
To a 50-mL round-bottom flask was added adamantylamine (3.075
g, 20 mmol), NH4OAc (1.54 g, 20 mmol), H2O (2 mL) and AcOH
(10 mL), and the mixture was heated to 80 °C. Then, a soln of 36%
aq formaldehyde (1.53 mL, 20 mmol) and 40% aq glyoxal (2.30
mL, 20 mmol) in AcOH (5 mL) was added slowly, and the reaction
mixture was stirred for 24 h. The reaction mixture was cooled and
was slowly added to a soln of NaHCO3 (14.7 g) in H2O (150 mL).
The resulting mixture was extracted with CH2Cl2 (3 × 15 mL), then
the extracts were dried (anhyd MgSO4), and the solvent was evapo-
rated under reduced pressure. The obtained yellow solid was puri-
fied by recrystallization (CH2Cl2–hexane) to give the imidazole 11;
yield: 0.61 g (15%).
1-(1-Pentyl-1H-imidazol-2-yl)-1-phenylethanol (12c)
White solid; yield: 0.145 g (28%); mp 174–176 °C (EtOAc); GLC:
tR = 14.6 min; Rf = 0.57 (EtOAc).
IR (KBr): 3113 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.76 (t, J = 7.1 Hz, 3 H, CH2CH3),
0.96–1.11, 1.37–1.42 (2 m, 5 H, 1 H, 3 × CH2), 1.94 (s, 3 H,
CH3COH), 3.67–3.77 (m, 2 H, NCH2), 6.88, 6.92 (2 s, 2 H, imidaz-
ole), 7.22–7.28 (m, 5 H, 5 × ArH).
13C NMR (100 MHz, CDCl3): δ = 13.4, 21.2, 28.4, 29.7, 31.7, 46.4,
72.7, 120.5, 124.3, 125.2, 126.6, 127.9, 146.0, 150.8.
Synthesis 2012, 44, 2630–2638
© Georg Thieme Verlag Stuttgart · New York

PAPER
Imidazole Derivatives via Isoprene-Mediated Lithiation
2635
MS (EI): m/z (%) = 258 (4) [M+], 257 (23), 243 (79), 241 (24), 240
(37), 239 (35), 213 (29), 197 (36), 183 (34), 181 (29), 173 (46), 169
(41), 138 (22), 137 (20), 120 (21), 111 (77), 105 (100), 96 (21), 95
(29), 82 (64), 81 (49), 77 (77), 69 (26), 68 (18), 55 (31), 51 (19).
HRMS: m/z [M+] calcd for C13H24N2O: 224.1889; found: 224.1889.
1-Butyl-2-deutero-1H-imidazole (13a)
Yellow oil.
1H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = 7.3 Hz, 3 H, CH3),
1.33, 1.76 (2 m, 2 × 2 H, CH3CH2CH2), 3.94 (t, J = 7.1 Hz, 2 H,
NCH2), 6.90 (d, J = 1.1 Hz, 1 H, imidazole), 7.05 (d, J = 1.1 Hz, 1
H, imidazole).
13C NMR (100 MHz, CDCl3): δ = 13.5, 19.7, 33.0, 46.7, 118.7,
129.2, 136.4 (t, J = 31.4 Hz).
HRMS: m/z [M+] calcd for C16H22N2O: 258.1732; found: 258.1718.
Dicyclopropyl(1-pentyl-1H-imidazol-2-yl)methanol (12d)
White solid; yield: 0.367 g (74%); mp 52–54 °C (EtOAc); Rf = 0.47
(EtOAc).
IR (KBr): 3147, 3005 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.27–0.34, 0.37–0.43, 0.46–0.53,
0.69–0.75 (4 m, 4 × 2 H, 2 × CH2CH2CH), 0.92 (t, J = 6.8 Hz, 3 H,
CH3), 1.20–1.27 (m, 2 H, 2 × CH2CH2CH), 1.34–1.38, 1.84 (2 m, 4
H, 2 H, CH3CH2CH2CH2), 4.05 (br s, 1 H, OH), 4.14 (m, 2 H,
NCH2), 6.90 (s, 2 H, imidazole).
13C NMR (100 MHz, CDCl3): δ = 13.9, 19.2, 22.4, 29.0, 30.1, 31.3,
47.3, 70.6, 120.9, 125.5, 152.4.
MS (EI): m/z (%) = 125 (58) [M+], 98 (93), 83 (100), 82 (96), 81
(12), 70 (20), 69 (31), 56 (13), 55 (85), 54 (10).
(1-Butyl-1H-imidazol-2-yl)cyclohexylmethanol (13b)
Yellow oil; yield: 0.260 g (55%); GLC: tR = 14.9 min; Rf = 0.20
(EtOAc).
IR (film): 3115 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.96 (t, J = 7.3 Hz, 3 H, CH3),
0.99–1.41, 1.60–1.87 (2 m, 9 H, 6 H, 7 × CH2 and OH), 2.03–2.05
(d, J = 8.0 Hz, 1 H, HOCHCH), 3.93 (t, J = 7.5 Hz, 2 H, NCH2),
4.37 (d, J = 8.0 Hz, 1 H, HOCH), 6.84, 6.96 (2 s, 2 × 1 H, imidaz-
ole).
MS (HPLC, ESI): m/z = 249 [M+ + 1], 231 [M+ + 1 – 18].
1-(1-Pentyl-1H-imidazol-2-yl)cyclohexanol (12e)
White solid; yield: 0.142 g (30%); mp 86–88 °C (EtOAc); GLC:
tR = 14.8 min; Rf = 0.22 (EtOAc).
IR (KBr): 3253 cm–1.
13C NMR (100 MHz, CDCl3): δ = 13.7, 19.9, 25.8, 26.0, 26.3, 28.8,
29.4, 33.2, 43.7, 45.6, 71.1, 119.4, 127.0, 149.1.
MS (EI): m/z (%) = 236 (4) [M+], 219 (12), 154 (59), 153 (100), 123
(35), 112 (10), 97 (75), 81 (11), 69 (15), 55 (13).
HRMS: m/z [M+] calcd for C14H24N2O: 236.1889; found: 236.1901.
1H NMR (400 MHz, CDCl3): δ = 0.91 (t, J = 6.9 Hz, 3 H, CH3),
1.29–1.38, 1.66–1.70, 1.73–1.84, 1.88–1.93, 1.99–2.09 (5 m, 5 H, 4
H, 3 H, 2 H, 3 H, 8 × CH2 and OH), 4.18 (m, 2 H, NCH2), 6.87 (d,
J = 1.2 Hz, 1 H, imidazole), 6.90 (d, J = 1.2 Hz, 1 H, imidazole).
13C NMR (100 MHz, CDCl3): δ = 13.9, 22.2, 22.4, 25.4, 29.0, 31.4,
37.3, 47.1, 71.7, 120.7, 126.3, 151.8.
MS (EI): m/z (%) = 336 (12) [M+], 335 (12), 219 (100), 207 (32),
194 (18), 193 (86), 181 (47), 179 (20), 175 (15), 165 (29), 137 (64),
123 (39), 109 (11), 96 (14), 95 (23), 82 (26), 81 (25), 69 (35), 55
(27), 54 (11).
1-(1-Butyl-1H-imidazol-2-yl)-2,2,2-trifluoro-1-phenylethanol
(13c)
White solid; yield: 0.334 g (56%); mp 123–125 °C (EtOAc);
Rf = 0.70 (EtOAc).
IR (KBr): 3068 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.73 (t, J = 7.3 Hz, 3 H, CH3),
1.06, 1.25–1.35 (2 m, 2 × 2 H, CH3CH2CH2), 3.55–3.67 (m, 2 H,
NCH2), 4.96 (br s, 1 H, OH), 7.00 (d, J = 1.1 Hz, 1 H, imidazole),
7.14 (d, J = 1.1 Hz, 1 H, imidazole), 7.45–7.51 (m, 5 H, 5 × ArH).
13C NMR (100 MHz, CDCl3): δ = 13.4, 19.7, 32.2, 46.6, 76.2 (q,
J = 29.8 Hz), 122.0, 124.2 (q, J = 286 Hz), 127.0, 127.2, 128.4,
129.1, 136.0, 143.7.
MS (DIP, EI): m/z (%) = 299 (10) [M+ + 1], 298 (27) [M+], 297
(10), 269 (28), 256 (11), 251 (14), 241 (12), 230 (15), 229 (90), 199
(60), 187 (10), 173 (100), 165 (17), 149 (13), 144 (10), 133 (10),
123 (11), 117 (10), 105 (51), 95 (39), 91 (18), 77 (34), 69 (10), 57
(11), 55 (10), 43 (15), 41 (14).
HRMS: m/z [M+] calcd for C14H24N2O: 236.1889; found: 236.1848.
2,2-Dimethyl-1-(1-pentyl-1H-imidazol-2-yl)propan-1-ol (12f)
Pale yellow solid; yield: 0.242 g (54%); mp 72–74 °C (EtOAc);
GLC: tR = 12.8 min; Rf = 0.59 (EtOAc).
IR (KBr): 3110 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.86–0.91 (t, J = 6.8 Hz, 3 H,
CH2CH3), 0.96 [s, 9 H, C(CH3)3], 1.29–1.32 (m, 4 H, CH2CH2CH3),
1.75 (m, 2 H, NCH2CH2), 3.67 (br s, 1 H, OH), 3.89 (m, 2 H, NCH2),
4.36 (s, 1 H, HCOH), 6.82, 6.95 (2 s, 1 H, 1 H, imidazole).
13C NMR (100 MHz, CDCl3): δ = 13.8, 22.2, 25.9, 28.8, 30.7, 37.0,
46.3, 73.6, 118.8, 127.1, 148.5.
MS (EI): m/z (%) = 224 (3) [M+], 168 (13), 167 (100), 137 (19), 97
(49).
HRMS: m/z [M+] calcd for C15H17F3N2O: 298.1293; found:
298.1289.
HRMS: m/z [M+] calcd for C13H24N2O: 224.1889; found: 224.1895.
(1-Butyl-1H-imidazol-2-yl)(4-chlorophenyl)phenylmethanol
(13d)
Yellow oil; yield: 0.585 g (86%); Rf = 0.69 (EtOAc).
3-Methyl-1-(1-pentyl-1H-imidazol-2-yl)butan-1-ol (12g)
Colorless oil; yield: 0.094 g (21%); GLC: tR = 12.8 min; Rf = 0.40
(EtOAc).
IR (film): 3176 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.90–0.95 (m, 3 H, CH2CH3),
0.96–0.99 [m, 6 H, CH(CH3)2], 1.33–1.37 (m, 4 H, CH2CH2CH3),
1.70–1.90 [m, 6 H, CH2CH(CH3)2, NCH2CH2 and OH], 3.93–4.00
(m, 2 H, NCH2), 4.76–4.80 (m, 1 H, HCOH), 6.87, 6.97 (2 s, 2 × 1
H, 1 H, imidazole).
IR (film): 3058 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.68 (t, J = 7.2 Hz, 3 H, CH3),
0.93–1.03, 1.10–1.17 (2 m, 2 × 2 H, CH3CH2CH2), 3.55–3.63 (m, 2
H, NCH2), 6.90–6.92, 6.98–7.00 (2 m, 2 × 1 H, imidazole), 7.18–
7.36 (m, 9 H, 9 × ArH).
13C NMR (100 MHz, CDCl3): δ = 13.5, 19.8, 32.2, 47.1, 77.2,
121.1, 126.4, 127.2, 127.5, 127.8, 127.9, 128.1, 129.2, 129.3, 144.4,
150.2.
MS (DIP, EI): m/z (%) = 340 (7) [M+], 307 (21), 306 (100), 305
(31), 287 (13), 249 (16), 231 (11), 229 (54), 199 (14), 173 (54), 165
(10), 105 (42), 95 (16), 77 (32).
13C NMR (100 MHz, CDCl3): δ = 13.9, 22.0, 22.2, 23.2, 24.6, 28.8,
30.8, 45.6, 45.9, 64.7, 119.6, 126.9, 149.7.
MS (DIP, EI): m/z (%) = 224 (1) [M+], 155 (23), 154 (11), 141 (14),
140 (100), 126 (36), 95 (35).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2630–2638

2636
R. Martínez et al.
PAPER
HRMS: m/z [M+] calcd for C20H21ClN2O: 340.1342; found:
HRMS: m/z [M+] calcd for C24H38N2O: 370.2984; found: 370.2983.
340.1329.
3-(1-Cyclohexyl-1H-imidazol-2-yl)pentan-3-ol (15a)
White solid; yield: 0.387 g (82%); mp 132–134 °C (EtOAc); GLC:
tR = 11.8 min; Rf = 0.24 (EtOAc).
IR (KBr): 3113 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.78 (t, J = 7.4 Hz, 6 H,
2 × CH2CH3), 1.23–1.42, 1.58–1.68, 1.76–1.80, 1.85–2.00 (4 m, 4
H, 4 H, 1 H, 6 H, 7 × CH2 and OH), 4.21–4.27 (m, 1 H, CH-cyclo-
hexyl), 6.95, 6.98 (2 s, 2 × 1 H, imidazole).
13C NMR (100 MHz, CDCl3): δ = 8.0, 25.2, 26.0, 33.3, 34.9, 56.2,
75.4, 117.7, 126.0, 149.4.
MS (EI): m/z (%) = 236 (4) [M+], 207 (50), 125 (100), 69 (17).
HRMS: m/z [M+] calcd for C14H24N2O: 236.1889; found: 236.1892.
(1-Butyl-1H-imidazol-2-yl)[bis(4-methoxyphenyl)]methanol
(13e)
White solid; yield: 0.469 g (64%); mp 107–108 °C (EtOAc);
Rf = 0.55 (EtOAc).
IR (KBr): 3109 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.72 (t, J = 7.2 Hz, 3 H,
CH3CH2CH2), 1.03, 1.14–1.22 (2 m, 2 × 2 H, CH3CH2CH2), 3.61
(m, 2 H, NCH2), 3.80 (s, 6 H, 2 × OCH3), 6.85 (m, 4 H, 4 × ArH),
6.91 (d, J = 1.3 Hz, 1 H, imidazole), 7.01 (d, J = 1.3 Hz, 1 H, imid-
azole), 7.15 (m, 4 H, 4 × ArH).
13C NMR (100 MHz, CDCl3): δ = 13.5, 30.9, 32.4, 47.1, 55.3, 77.9,
113.3, 121.0, 126.3, 129.0, 136.9, 150.6, 159.0.
MS (DIP, EI): m/z (%) = 367 (20) [M+ + 1], 366 (86) [M+], 260
(16), 259 (100), 226 (32), 203 (29), 151 (23), 135 (65), 95 (12), 77
(13).
HRMS: m/z [M+] calcd for C22H26N2O3: 366.1943; found:
366.1910.
1-(1-Cyclohexyl-1H-imidazol-2-yl)-1-phenylethanol (15b)
Pale yellow solid; yield: 0.286 g (53%); mp 207–209 °C (EtOAc);
GLC: tR = 11.9 min; Rf = 0.52 (EtOAc).
IR (KBr): 3140, 3120 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.67–0.76, 0.84–0.87, 0.99–1.55,
1.71–1.75, 1.86–1.90 (5 m, 1 H, 1 H, 7 H, 1 H, 1 H, 5 × CH2 and
OH), 2.16 (s, 3 H, CH3), 4.04–4.12 (m, 1 H, CH), 6.89, 6.92 (2 s, 1
H, 1 H, imidazole), 7.20–7.22, 7.27–7.29 (2 m, 4 H, 1 H, 5 × ArH).
13C NMR (100 MHz, CDCl3): δ = 25.2, 25.6, 25.7, 31.8, 33.3, 34.2,
55.2, 72.9, 117.7, 124.7, 125.8, 126.9, 128.1, 146.1, 150.6.
MS (DIP, EI): m/z (%) = 271 (11) [M+ + 1], 270 (55) [M+], 255
(12), 188 (14), 187 (35), 174 (12), 173 (100), 171 (18), 169 (12),
145 (18), 111 (28), 105 (13), 95 (19), 77 (10), 55 (11), 44 (11).
2-Deutero-1-dodecyl-1H-imidazole (14a)
Yellow oil.
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.7 Hz, 3 H, CH3),
1.25–1.30 (m, 18 H, 9 × CH2), 1.77 (m, 2 H, NCH2CH2), 3.92 (t,
J = 7.2 Hz, 2 H, NCH2), 6.90 (d, J = 1.1 Hz, 1 H, imidazole), 7.05
(d, J = 1.1 Hz, 1 H, imidazole).
13C NMR (100 MHz, CDCl3): δ = 14.0, 22.6, 26.5, 29.0, 29.2, 29.3,
29.4, 29.5, 31.0, 31.8, 47.0, 118.7, 129.2, 136.4 (t, J = 31.7 Hz).
HRMS: m/z [M+] calcd for C17H22N2O: 270.1732; found: 270.1738.
MS (EI): m/z (%) = 237 (53) [M+], 236 (42), 235 (31), 222 (19), 208
(42), 194 (41), 180 (39), 166 (35), 152 (37), 138 (37), 124 (44), 123
(30), 111 (30), 110 (15), 109 (18), 97 (59), 96 (62), 95 (19), 83
(100), 82 (73), 70 (44), 69 (34), 55 (45).
1-(1-Cyclohexyl-1H-imidazol-2-yl)-2,2-dimethylpropan-1-ol
(15c)
White solid; yield: 0.307 g (65%); mp 172–174 °C (EtOAc); GLC:
tR = 11.8 min; Rf = 0.60 (EtOAc).
(4-Chlorophenyl)(1-dodecyl-1H-imidazol-2-yl)methanol (14b)
Yellow solid; yield: 0.549 g (73%); mp 31–33 °C; Rf = 0.48
(EtOAc).
IR (KBr): 3142 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.9 Hz, 3 H, CH3),
1.09–1.32 (m, 19 H, 9 × CH2 and OH), 1.38–1.51 (m, 2 H,
NCH2CH2), 3.67 (m, 2 H, NCH2), 5.84 (s, 1 H, HOCH), 6.83 (d,
J = 1.2 Hz, 1 H, imidazole), 6.93 (d, J = 1.2 Hz, 1 H, imidazole),
7.25–7.31 (m, 4 H, 4 × ArH).
IR (KBr): 3114 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.01 [s, 9 H, C(CH3)3], 1.22–1.29,
1.35–1.45, 1.50–1.55, 1.65–1.69, 1.75–1.78, 1.86–1.95, 1.98–2.01
(7 m, 1 H, 2 H, 1 H, 1 H, 1 H, 2 H, 2 H, 5 × CH2), 4.00–4.05 (m, 1
H, CH-cyclohexyl), 4.40 (s, 1 H, HCOH), 6.92, 7.01 (2 s, 2 × 1 H,
imidazole).
13C NMR (100 MHz, CDCl3): δ = 25.2, 25.8, 30.9, 33.7, 35.3, 36.8,
55.3, 73.6, 115.7, 127.3, 147.9.
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.7, 26.5, 29.1, 29.2, 29.3,
29.4, 29.5, 29.6, 30.4, 31.9, 46.0, 68.7, 120.5, 126.8, 127.9, 128.6,
133.6, 139.7, 148.2.
MS (DIP, EI): m/z (%) = 379 (3) [M+ + 3], 378 (15) [M+ + 2], 377
(12) [M+ + 1], 376 (43) [M+], 345 (15), 265 (11), 251 (14), 236 (20),
235 (100), 207 (11), 97 (22), 43 (11), 41 (11).
MS (DIP, EI): m/z (%) = 236 (4) [M+], 180 (11), 179 (61), 98 (12),
97 (100).
HRMS: m/z [M+] calcd for C14H24N2O: 236.1889; found: 236.1878.
3-[1-(1-Methylheptyl)-1H-imidazol-2-yl]pentan-3-ol (16a)
Yellow oil; yield: 0.346 g (65%); GLC: tR = 14.0 min; Rf = 0.51
(EtOAc).
IR (film): 3176 cm–1.
HRMS: m/z [M+] calcd for C22H33ClN2O: 376.2281; found:
376.2279.
1H NMR (400 MHz, CDCl3): δ = 0.77 [t, J = 7.3 Hz, 6 H,
C(OH)(CH2CH3)2], 0.86 (t, J = 6.7 Hz, 3 H, CH2CH2CH3), 1.23–
1.30, 1.67–1.74 (2 m, 8 H, 2 H, 5 × CH2), 1.36 (d, J = 6.6 Hz, 3 H,
CH3CH), 1.84–2.03 [m, 4 H, C(OH)(CH2CH3)2], 4.46–4.53 (m, 1
H, CH), 6.93, 6.94 (2 s, 2 × 1 H, imidazole).
13C NMR (100 MHz, CDCl3): δ = 8.0, 14.0, 22.5, 22.6, 26.4, 29.0,
31.5, 33.1, 38.1, 52.6, 75.5, 116.8, 126.2, 149.6.
MS (EI): m/z (%) = 266 (2) [M+], 238 (10), 237 (54), 125 (100), 95
(11), 69 (21).
HRMS: m/z [M+] calcd for C16H30N2O: 266.2358; found: 266.2333.
1-(1-Dodecyl-1H-imidazol-2-yl)-1-phenylpropan-1-ol (14c)
Yellow oil; yield: 0.141 g (19%); Rf = 0.53 (EtOAc).
IR (film): 3074 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.84–0.88 (m, 6 H, 2 × CH3),
1.26–1.96 (m, 20 H, 10 × CH2), 2.43 (m, 2 H, HOCCH2), 2.90 (br s,
1 H, OH), 3.61–3.69 (m, 2 H, NCH2), 6.85, 6.99 (2 s, 2 × 1 H, im-
idazole), 7.26–7.30 (m, 5 H, 5 × ArH).
13C NMR (100 MHz, CDCl3): δ = 7.5, 14.1, 22.7, 26.5, 29.0, 29.3,
29.5, 29.6, 30.5, 30.9, 31.9, 35.0, 46.5, 75.7, 120.8, 125.6, 126.1,
127.0, 128.1, 143.8, 150.4.
MS (DIP, EI): m/z (%) = 370 (6) [M+], 342 (26), 341 (100), 173
(11), 105 (7).
1-[1-(1-Methylheptyl)-1H-imidazol-2-yl]-1-phenylethanol (16b)
Yield: 0.552 g (92%).
Synthesis 2012, 44, 2630–2638
© Georg Thieme Verlag Stuttgart · New York

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Imidazole Derivatives via Isoprene-Mediated Lithiation
2637
Major Diastereoisomer
13C NMR (75 MHz, CDCl3): δ = 14.0, 22.5, 22.8, 25.9, 26.5, 29.1,
31.5, 36.7, 36.9, 51.8, 73.5, 115.1, 127.6, 148.2.
MS (EI): m/z (%) = 267 (1) [M+ + 1], 266 (3) [M+], 210 (10), 209
(64), 179 (15), 98 (10), 97 (100), 69 (10).
White solid; mp 115–117 °C (EtOAc); Rf = 0.52 (EtOAc).
IR (KBr): 3110 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.71 (d, J = 6.7 Hz, 3 H, CH3CH),
0.85 (t, J = 6.9 Hz, 3 H, CH3CH2), 1.13–1.24, 1.45–1.54 (2 m, 8 H,
2 H, 5 × CH2), 2.02 (s, 3 H, CH3COH), 3.20 (br s, 1 H, OH), 4.23
(sextet, J = 6.9 Hz, 1 H, CH3CH), 6.89, 7.01 (2 m, 2 × 1 H, imidaz-
ole), 7.20–7.31 (m, 5 H, 5 × ArH).
HRMS: m/z [M+] calcd for C16H30N2O: 266.2358; found: 266.2348.
Acknowledgment
13C NMR (100 MHz, CDCl3): δ = 14.0, 21.0, 21.9, 22.5, 26.0, 29.0,
31.6, 37.9, 51.8, 73.3, 117.0, 125.0, 126.5, 127.0, 128.2, 145.6,
150.7.
MS (DIP, EI): m/z (%) = 301 (12) [M+ + 1], 300 (54) [M+], 285
(18), 255 (26), 229 (10), 188 (15), 187 (52), 179 (15), 173 (100),
171 (22), 169 (15), 149 (16), 145 (23), 111 (40), 105 (34), 96 (15),
95 (35), 77 (23), 69 (24), 57 (13), 55 (12), 43 (40), 41 (23).
Financial support from the Ministerio de Ciencia e Innovación (MI-
CINN) of Spain (Project Nos. CTQ2007-65218, CTQ2011-24165,
Consolider Ingenio 2010 CSD2007-00006), the Generalitat Valen-
ciana (PROMETEO/2009/0349 and FEDER) and the Universidad
de Alicante is acknowledged. We also thank Medalchemy S.L. for
a gift of chemicals, especially lithium powder.
HRMS: m/z [M+] calcd for C19H28N2O: 300.2202; found: 300.2200.
References
Minor Diastereoisomer
(1) (a) Schobert, R.; Gordon, G. J. Curr. Org. Chem. 2002, 6,
1181. (b) Eicher, T.; Hauptmann, S. The Chemistry of
Heterocycles: Structure, Reactions, Syntheses and
Applications, 2nd ed.; Wiley-VCH: Weinheim, 2003.
(c) Polshettiwar, V.; Varma, R. S. Pure Appl. Chem. 2008,
80, 777. (d) Pastor, I. M.; Yus, M. Curr. Chem. Biol. 2009,
3, 385.
(2) (a) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J.
J. Comb. Chem. 1999, 1, 55. (b) Xu, J.; Stevenson, J.
J. Chem. Inf. Comput. Sci. 2000, 40, 1177. (c) Bur, S. K.;
Padwa, A. Chem. Rev. 2004, 104, 2401.
(3) (a) Grimmett, M. R. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R.; Rees, C. W.; Scriven, E. F.
V., Eds.; Pergamon: Oxford, 1996, 77–220. (b) Grimmett,
M. R. Imidazole and Benzimidazole Synthesis; Academic
Press: London, 1997. (c) Zificsak, C. A.; Hlasta, D. J.
Tetrahedron 2004, 60, 8991.
(4) (a) Yus, M. Chem. Soc. Rev. 1996, 25, 155. (b) Ramón, D.
J.; Yus, M. Eur. J. Org. Chem. 2000, 225. (c) Yus, M. Synlett
2001, 1197. (d) Yus, M. In The Chemistry of Organolithium
Compounds; Mareck, I., Ed.; Wiley & Sons: Chichester,
2004, Chap. 11.
(5) (a) Nájera, C.; Yus, M. Trends Org. Chem. 1991, 2, 155.
(b) Nájera, C.; Yus, M. Org. Prep. Proced. Int. 1995, 27,
383. (c) Nájera, C.; Yus, M. Recent Res. Dev. Org. Chem.
1997, 1, 67. (d) Guijarro, D.; Yus, M. Recent Res. Dev. Org.
Chem. 1998, 2, 713. (e) Yus, M.; Foubelo, F. In Targets in
Heterocyclic Systems; Attanasi, O. A.; Spinelli, D., Eds.;
Italian Society of Chemistry: Rome, 2002, 136–171.
(f) Nájera, C.; Yus, M. Curr. Org. Chem. 2003, 7, 867.
(g) Yus, M. Pure Appl. Chem. 2003, 75, 1453.
White solid; mp 110–112 °C (EtOAc); Rf = 0.41 (EtOAc).
IR (KBr): 3115 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.50–0.60, 0.86–0.92, 0.95–1.05,
1.08–1.16, 1.24–1.37 (5 m, 2 H, 1 H, 2 H, 3 H, 2 H, 5 × CH2), 0.84
(t, J = 7.2 Hz, 3 H, CH3CH2), 1.18 (d, J = 6.6 Hz, 3 H, CH3CH), 2.02
(s, 3 H, CH3COH), 3.02 (br s, 1 H, OH), 4.19 (m, 1 H, CH3CH),
6.89, 7.00 (2 m, 2 × 1 H, imidazole), 7.20–7.35 (m, 5 H, 5 × ArH).
13C NMR (100 MHz, CDCl3): δ = 14.0, 22.1, 22.4, 26.0, 28.8, 31.5,
32.5, 37.3, 52.1, 73.5, 117.1, 125.0, 126.5, 127.1, 128.2, 145.6,
150.5.
MS (EI): m/z (%) = 301 (11) [M+ + 1], 300 (56) [M+], 299 (14), 285
(18), 255 (26), 229 (10), 188 (15), 187 (52), 179 (12), 173 (100),
171 (20), 169 (15), 149 (14), 145 (24), 111 (39), 105 (34), 96 (15),
95 (34), 77 (23), 69 (23), 57 (11), 55 (11), 43 (39), 41 (22).
HRMS: m/z [M+] calcd for C19H28N2O: 300.2202; found: 300.2190.
2,2-Dimethyl-1-[1-(1-methylheptyl)-1H-imidazol-2-yl]propan-
1-ol (16c)20
Yield: 0.500 g (94%).
Major Diastereoisomer
Colorless solid; mp 69–71 °C (EtOAc); GLC: tR = 14.1 min;
Rf = 0.26 (hexane–EtOAc, 1:1).
IR (KBr): 3701–3005 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.85 (t, J = 6.9 Hz, 3 H, CH3CH2),
0.99 [s, 9 H, C(CH3)3], 1.22 (m, 8 H, 4 × CH2), 1.44 (d, J = 6.6 Hz,
3 H, CH3CH), 1.64–1.66 (m, 2 H, CH2CH), 3.08 (br s, 1 H, OH),
4.17–4.29 (m, 1 H, CH3CH), 4.37 (s, 1 H, HCOH), 6.89, 7.05 (2 s,
2 × 1 H, imidazole).
13C NMR (75 MHz, CDCl3): δ = 14.0, 21.5, 22.5, 25.7, 25.9, 28.9,
31.5, 36.9, 38.8, 51.8, 73.4, 115.0, 127.7, 148.7.
MS (EI): m/z (%) = 267 (2) [M+ + 1], 266 (4) [M+], 210 (13), 209
(82), 179 (15), 98 (10), 97 (100).
(h) Chinchilla, R.; Nájera, C.; Yus, M. Tetrahedron 2005,
61, 3139. (i) Guijarro, D.; Pastor, I. M.; Yus, M. Curr. Org.
Chem. 2011, 15, 375. (j) Guijarro, D.; Pastor, I. M.; Yus, M.
Curr. Org. Chem. 2011, 15, 2362.
(6) (a) Foubelo, F.; Yus, M. Trends Org. Chem. 1998, 7, 1.
(b) Alonso, F.; Meléndez, J.; Yus, M. Russ. Chem. Bull.
2003, 52, 2628. (c) Foubelo, F.; Yus, M. Curr. Org. Chem.
2005, 9, 459.
HRMS: m/z [M+] calcd for C16H30N2O: 266.2358; found: 266.2338.
Minor Diastereoisomer
(7) (a) Guijarro, A.; Gómez, C.; Yus, M. Trends Org. Chem.
2001, 8, 65. (b) Alonso, F.; Radivoy, G.; Yus, M. Russ.
Chem. Bull. 2003, 52, 2563. (c) Alonso, F.; Yus, M. Chem.
Soc. Rev. 2004, 33, 284. (d) Alonso, F.; Riente, P.; Yus, M.
Acc. Chem. Res. 2011, 44, 379.
(8) (a) Yus, M.; Herrera, R. P.; Guijarro, A. Tetrahedron Lett.
1999, 42, 3455. (b) Yus, M.; Herrera, R. P.; Guijarro, A.
Chem.–Eur. J. 2002, 8, 2574. (c) De la Viuda, M.; Yus, M.;
Guijarro, A. J. Phys. Chem. B 2011, 115, 14610.
Colorless solid; mp 79–81 °C (EtOAc); GLC: tR = 14.2 min;
Rf = 0.20 (hexane–EtOAc, 1:1).
IR (KBr): 3706–2999 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H, CH3CH2),
1.02 [s, 9 H, C(CH3)3], 1.27–1.35 (m, 11 H, 4 × CH2 and CH3CH),
1.76–1.78 (m, 2 H, CH2CH), 2.90 (br s, 1 H, OH), 4.22–4.33 (m, 1
H, CH3CH), 4.38 (s, 1 H, HCOH), 6.89, 7.03 (2 s, 2 × 1 H, imidaz-
ole).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2630–2638

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PAPER
2006, 144, 305159. (d) Farre-Gomis, A. J. Eur. Patent
1632227, 2006; Chem. Abstr. 2006, 144, 267311.
(e) Abadias, M. US Patent 20060040924, 2006; Chem.
Abstr. 2006, 144, 226326. (f) Buschmann, H. H.; Gutierrez-
Silva, B.; Holenz, J.; Farre-Gomis, A. J. PCT Int.
(9) Guijarro, A.; De la Viuda, M.; Torregrosa, R.; Peñafiel, I.;
Pastor, I. M.; Yus, M.; Nájera, C. ARKIVOC 2011, (v), 12.
(10) Torregrosa, R.; Pastor, I. M.; Yus, M. Tetrahedron 2005, 61,
11148.
(11) Torregrosa, R.; Pastor, I. M.; Yus, M. ARKIVOC 2008, (vii),
8.
2005097099, 2005; Chem. Abstr. 2005, 143, 399851.
(g) Merce-Vidal, R.; Frigola-Constansa, J. PCT Int.
2000007542, 2000; Chem. Abstr. 2000, 132, 146651.
(h) Weichert, A.; Albus, U.; Jansen, H.-W. PCT Int.
2001030327, 2001; Chem. Abstr. 2001, 134, 320860.
(17) Performing the lithiation step over 45 min gave the final
product 15a in, only, 48% yield: Torregrosa, R. Ph.D.
Dissertation; University of Alicante: Spain, 2007.
(18) Cuevas-Yáñez, E.; Serrano, J. M.; Huerta, G.; Muchowski,
J. M.; Cruz-Almanzara, R. Tetrahedron 2004, 60, 9391.
(19) Corelli, F.; Summa, V.; Brogi, A.; Monteagudo, E.; Botta,
M. J. Org. Chem. 1995, 60, 2008.
(12) Torregrosa, R.; Pastor, I. M.; Yus, M. Tetrahedron 2007, 63,
947.
(13) (a) Iddon, B. Heterocycles 1985, 23, 417. (b) Iddon, B.;
Ngochindo, R. I. Heterocycles 1994, 38, 2487.
(14) For a previous communication, see: Pastor, I. M.;
Torregrosa, R.; Yus, M. Lett. Org. Chem. 2010, 7, 373.
(15) Khabnadideh, S.; Rezaei, Z.; Khalafi-Nezhad, A.;
Bahrinajafi, R.; Mohamadi, R.; Farrokhroz, A. A. Bioorg.
Med. Chem. Lett. 2003, 13, 2863.
(16) (a) Farre-Gomis, A. J. PCT Int. 2006087147, 2006; Chem.
Abstr. 2006, 145, 263337. (b) Farre-Gomis, A. J. Eur. Patent
1690537, 2006; Chem. Abstr. 2006, 145, 218029. (c) Farre-
Gomis, A. J. PCT Int. 2006027226, 2006; Chem. Abstr.
(20) Torregrosa, R.; Pastor, I. M.; Yus, M. ECSOC-11 2007,
communication a005; http://www.mdpi.org/ecsoc-11.
Synthesis 2012, 44, 2630–2638
© Georg Thieme Verlag Stuttgart · New York