Isoprene-catalysed lithiation: deprotection and functionalisation of imidazole derivatives

Article abstract of DOI:10.1016/j.tet.2006.11.032

The isoprene-catalysed lithiation of different 1-substituted imidazoles (1) (such as trityl, allyl, benzyl, vinyl, N,N-dimethylsulfamoyl, para-toluenesulfonyl, tert-butoxycarbonyl, acetyl, trimethylsilyl, tert-butyldimethylsilyl derivatives) leads to the

Full text of DOI:10.1016/j.tet.2006.11.032

Tetrahedron 63 (2007) 947–952
Isoprene-catalysed lithiation: deprotection and
functionalisation of imidazole derivatives
*
Rosario Torregrosa, Isidro M. Pastor and Miguel Yus
Departamento de Quꢀımica Orgaꢀnica, Facultad de Ciencias and Instituto de Sꢀıntesis Orgaꢀnica (ISO),
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Received 3 October 2006; revised 6 November 2006; accepted 10 November 2006
Available online 28 November 2006
Dedicated in the memory of Professor G. Ourisson
Abstract—The isoprene-catalysed lithiation of different 1-substituted imidazoles (1) (such as trityl, allyl, benzyl, vinyl, N,N-dimethylsulfa-
moyl, para-toluenesulfonyl, tert-butoxycarbonyl, acetyl, trimethylsilyl, tert-butyldimethylsilyl derivatives) leads to the cleavage of the pro-
tecting group producing 1H-imidazole. The use of 1-(diethoxymethyl)imidazole (3) in the same lithiation reaction allows the preparation of
the corresponding 2-lithio intermediate, which by reacting with different electrophiles leads to 2-functionalised imidazoles 4.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
and N-substituted-sulfonamides and -carboxamides were
cleaved under very mild conditions11 and, more recently, de-
protection of trityl ethers,12 tritylamines,13 silyl,14 allyloxy-
carbonyl,15 benzyloxycarbonyl,15 pivaloyl16 and benzoyl16
alcohols, amines and thiols has also been reported.
The synthesis of products containing heterocycles is a broad
field of interest, especially in the case of azoles, which
are amply present in compounds with pharmacological and
biological properties.1 Ring-closure reactions of acyclic
precursors and substituent modifications of heterocyclic
compounds are the two main routes for the general prepara-
tion of heterocyclic derivatives. Metallated imidazole inter-
mediates (mainly prepared from the corresponding lithium
precursors) have been widely used in the preparation of
heterocyclic derivatives,2 these compounds have broad
application in synthetic organic chemistry.3,4 Alkyllithium
reagents and lithium amides have been reported as reagents
for these lithiation processes (hydrogen–lithium and halo-
gen–lithium exchanges), and reaction conditions usually
involve low temperature in an ethereal solvent.2,5,6
On the other hand, lithium metal has also been described
to be useful in the preparation of lithium imidazole inter-
mediates, so we have recently developed a new protocol to
prepare 2-lithioimidazole using lithium powder in the pres-
ence of a substoichiometric amount of isoprene.17 By react-
ing this organolithium with carbonyl and imine electrophiles
the corresponding 2-(hydroxyalkyl)- and 2-(aminoalkyl)-1-
methylimidazole derivatives were obtained. However, this
methodology did not allow the direct lithiation of imidazole
because after the N-deprotonation a second lithiation did not
occur. In this article, we report the application of this lithia-
tion methodology to both the removal of the protective group
in several N-protected imidazoles and for the preparation of
2-functionalised-1H-imidazoles.
Lithium metal is commonly used as a lithiation agent, albeit
it needs activation due to its low reactivity under some reac-
tion conditions. This activation can be done by compounds
acting as electron carriers, so the use of an arene in substoi-
chiometric amount has shown to be a very efficient protocol
for this procedure.7 By means of this procedure different
functionalised organolithium reagents have been prepared
starting from a variety of substrates such as halogenated4,8
or non-halogenated9 compounds, as well as heterocyclic pre-
cursors.10 The arene-catalysed lithiation methodology has
also proved to be useful for the removal of some commonly
employed protective groups: allylic and benzylic alcohols
2. Results and discussion
During the course of our studies on the preparation of
imidazole derivatives using an isoprene-catalysed lithiation
process we decided to examine different N-protected imid-
azoles with this protocol. The trityl group has been used to
protect simple imidazoles and although it is usually cleaved
under acidic conditions or by hydrogenation,18 we observed
that lithiation conditions can be also used for the same detri-
tylation. Thus, when N-tritylimidazole (1a) was treated with
an excess of lithium powder in the presence of 1 equiv of iso-
prene (100 mol %) at room temperature imidazole (2) was
Keywords: Lithium; Isoprene-catalysed lithiation; Imidazole; Deprotection.
* Corresponding author. Fax: +34 965 903549; e-mail: yus@ua.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.032

948
R. Torregrosa et al. / Tetrahedron 63 (2007) 947–952
Table 1. Deprotection of N-protected-imidazoles via isoprene-catalysed
It is also known that N-benzyl protective groups may be
removed by reductive conditions, the major drawback when
using this protective group being the competitive a-metalla-
tion.6 The 1-benzyl-2-imidazolyl anion appears to be ther-
modynamically preferred to the N–Ca anion but it is not
clear which of the two possible anions is kinetically fav-
oured.21 The reaction of 1-benzylimidazole (1c) with lithium
in the presence of 1 equiv of isoprene at room temperature
gave after 1 h the corresponding debenzylated imidazole
with 74% yield (Table 1, entry 9). The only use of lithium
(without catalyst) caused around half of the cleavage of the
benzyl group (Table 1, entry 8), as previously commented
for trityl and allyl groups.
lithiation processa
PG
N
Li
N
H
N
1) Li, isoprene, THF, r.t.
2) H2O
N
1
N
2
N
I
Entry
Substrate
PG
Isoprene (%)
Yield (%)b
No.
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1c
1c
1d
1d
1e
1e
1f
Tr
Tr
Tr
Tr
Allyl
Allyl
Allyl
Bn
0
50
100
45
74
95
5 (DTBB 5 mol %)
0
50
100
0
100
0
100
0
100
0
100
0
100
0
47 (58)c
54
67
Our study continued with 1-vinylimidazole (1d). The vinyl
group has been used to protect imidazole derivatives and it
is usually cleaved by ozonolysis or by using potassium per-
manganate.22 The vinyl group showed to be less susceptible
to the reductive process, so when the compound 1d was
subjected to the isoprene-catalysed lithiation protocol only
43% of the imidazole was isolated after the reaction (Table 1,
entry 11). Anyway, the isoprene improved the cleavage pro-
cess, since the absence of isoprene yielded only 24% of
product 2 (Table 1, entry 10).
85
55
74
24
43
<5
49
49
88
22
90
74
99
88
94
9
Bn
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Vinyl
Vinyl
–SO2NMe2
–SO2NMe2
Ts
Ts
1f
1g
1g
1h
1h
1i
1i
1j
1j
Boc
Boc
Acetyl
Acetyl
–SiMe3
–SiMe3
–SiButMe2
–SiButMe2
100
0
100
0
Next we decided to investigate the deprotection of other
groups at the nitrogen, such as N-sulfonyl, N-carbonyl and
N-alkyloxycarbonyl derivatives. The N,N-dimethylsulfa-
moyl group has been commonly used during the synthesis
of imidazole-containing compounds with potential biologi-
cal and pharmaceutical activity and the removal of the sulfa-
moyl group requires relatively vigorous acidic conditions
(generally, refluxing 30% HBr or refluxing 2 N HCl).23,24
The sulfonamide 1e (prepared in 93% yield from imidazole
and N,N-dimethylchlorosulfonamide in the presence of
triethylamine) showed higher stability under reductive con-
ditions, thus almost all the starting material was recovered
when compound 1e was treated with lithium (less than 5%
deprotection, Table 1, entry 12). In the presence of 1 equiv
of isoprene 49% of the imidazole was isolated (Table 1, entry
13). Incontrast, thedeprotectionofN-(para-toluenesulfonyl)-
imidazole25 (1f) under the same reaction conditions pro-
ceeded smoothly to give up to 88% yield (Table 1, entries
14 and 15). Similar results were obtained when 1-(tert-
butoxycarbonyl)imidazole (1g) was subjected to the com-
mented protocol, although higher influence of the amount
of isoprene was observed (Table 1, entries 16 and 17).26
Finally, N-acetylimidazole (1h) proved to be very labile
under the assayed reductive conditions, even in the absence
of isoprene (Table 1, entries 18 and 19).
82
85
100
a
Reaction carried out with protected imidazole, lithium (3 mmol/mmol of
substrate), THF (10 mL), 23 ꢀC.
Isolated yield of pure product 2. Purification was done by recrystallisa-
tion.
Reaction carried out with 1-tritylimidazole (2 mmol), lithium (6 mmol),
DTBB (5 mol %), THF (20 mL), 23 ꢀC.
b
c
isolated with 95% yield (Table 1, entry 3), the intermediate I
probablybeinginvolvedintheprocess.Furtherstudiesshowed
that in the absence of isoprene, lithium partially caused the
reductive cleavage of the trityl group producing imidazole
in 45% yield after 1 h reaction (Table 1, entry 1), and using
half an equivalent of isoprene the yield was risen up to 74%
(Table 1, entry 2). In all cases, the corresponding triphenyl-
1
methane was detected in the reaction mixture (GC and H
NMR). Naphthalene and 4,40-di-tert-butylbiphenyl (DTBB)
havebeenreportedto catalysea lithiationprocesstoefficiently
detritylate N-tritylamines,13 thus the use of 5 mol % of DTBB
together with an excess of lithium gave imidazole with a
slightlybetteryield(58%,Table 1,entry4andfootnotec)com-
paredwiththereactionwithout catalyst(45%, Table 1, entry1)
or the use of 5 mol % of isoprene (47%, Table 1, entry 4).
During the studies of stabilities of different nitrogen
protective groups in the imidazole, we tested trialkylsilyl
derivatives, such as 1-(trimethylsilyl)imidazole (1i) and
1-(tert-butyldimethylsilyl)imidazole (1j) and, as expected,
the nitrogen–silicon bond was cleaved in high yield under
lithiation with (94 and 85%, respectively, using 100% iso-
prene, Table 1, entries 21 and 23) or without (88 and 82%,
respectively, Table 1, entries 20 and 22) isoprene catalysis.
In general, the allyl moiety is usually cleaved in N-allyl-
amines, like the corresponding allyl ethers, by treatment
with transition metal reagents.19 Regarding N-allylated
imidazole (1b), it has only been reported to undergo deallyl-
ation by treatment with diisobutylaluminium hydride in
the presence of a catalytic amount of Ni(dppp)Cl2 producing
imidazole with 81% yield.20 Under our reductive conditions,
lithium powder was able to deprotect N-allylimidazole (1b)
at room temperature with 54% yield (Table 1, entry 5), albeit
the use of isoprene improved the process up to 85% yield
when using 1 equiv of the diene (Table 1, entries 6 and 7).
On the other hand, 1-(diethoxymethyl)imidazole (3) showed
to be very stable when it was treated with lithium powder
and isoprene, even at room temperature (<10% imidazole

R. Torregrosa et al. / Tetrahedron 63 (2007) 947–952
949
1
2 detected by H NMR). Thus, our next consideration was
intermediate II, which is stabilised by CIPE (Complex In-
duced Proximity Effect).30 The use of half an equivalent of
isoprene gave lower yield of the final product, thus 3-(1H-
2-imidazolyl)-3-pentanol (4a) was obtained with 63% yield
instead of 75% (Table 2, entry 1, footnote c). Ketones gave in
general better results than aldehydes or an aldimine (Table 2,
compare entries 1–4 with 5–10). Aromatic carbonylic com-
pounds reacted less effectively than the aliphatic ones and
in the case of substituted benzaldehyde no improvement in
the yield was observed using either electron-donating or elec-
tron-withdrawing substituents (Table 2, entries 8 and 9).
to try our lithiation methodology with compound 3 in order
to obtain, after deprotection,27–29 2-functionalised-1H-
imidazole derivatives, which are not available by direct
lithiation–SE reaction from imidazole itself (see above).
Compound 3 was treated first with an excess of lithium pow-
der in the presence of isoprene (100 mol %) and then with
different electrophiles giving after quenching in acidic aque-
ous medium the corresponding 2-substituted-1H-imidazoles
4 with moderate to high yields (Table 2) via the chelated
Table 2. Preparation of 2-functionalised-1H-imidazole derivativesa
EtO
3. Conclusions
OEt
1) Li, isoprene, THF, 0 ºC
OEt
OEt
Li
H
N
X
N
N
N
R2
In conclusion, we have reported here an efficient procedure
to remove several protective groups from the imidazolic ni-
trogen under mild reaction conditions. The lithium/isoprene
methodology is applicable to successfully cleave sulfonyl,
carbonyl, alkoxycarbonyl, trialkylsilyl and carbon substitu-
ents (such as vinyl, trityl, benzyl and allyl). The treatment of
1-(diethoxymethyl)imidazole with a slight excess of lithium
metal in the presence of isoprene gave no scission of
this group and produced the corresponding organolithium.
This intermediate was reacted with different electrophiles
(carbonyl compounds or imines)31 producing, after acidic
hydrolysis, the corresponding 2-(hydroxyalkyl)- or 2-(N-
phenylamino)benzyl)-1H-imidazole derivatives with mod-
erate to excellent yields.
R1
N
2) Electrophile, THF, 0 ºC
3) HCl (0.1 M)
N
3
4
II
Entry
Electrophile
No.
Product
Structure
Yield (%)b
75 (63)c
OH
H
N
O
1
2
3
4
5
6
7
4a
N
N
N
OH
OH
H
N
O
4b
93
91
55
92
51
59
H
N
O
4c
4. Experimental
4.1. General
O
OH
H
N
4d
N
OH
All lithiation reactions were carried out under argon atmo-
sphere 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 used freshly distilled. Commercially available anhy-
drous THF (99.9%, water content ꢁ0.006%, Fluka) was used
as the solvent in all the lithiation reactions. Melting points
were obtained with an MPA100 Optimelt SRS apparatus. IR
spectra were measured with a Nicolet Impact 400 D-FT
Spectrometer. NMR spectra were recorded on a Bruker
Avance 300 and Bruker Avance 400 (300 and 400 MHz for
1H NMR, and 75 and 100 MHz for 13C NMR) using, except
otherwise stated, CDCl3 as solvent and TMS as internal stan-
dard; chemical shifts are given in d (ppm) and coupling con-
stants (J) in Hz. Mass spectra (EI) were obtained at 70 eVon
an Agilent 5973 spectrometer, fragment ions in m/z with rel-
ative intensities (%) in parenthesis and High Resolution
Mass Spectra (HRMS) analyses were carried out on a Finni-
gan MAT95S spectrometer, when indicated the samples
were inserted in the modality of Direct Insertion Probe
(DIP). The purity of volatile compounds and the chromato-
graphic analyses (GLC) were determined with an Agilent
6890N instrument equipped with a flame ionisation detector
and a 30 m capillary column (0.25 mm diameter, 0.25 mm
film thickness), using nitrogen (2 ml/min) as carrier gas,
Tinjector¼275 ꢀC, Tcolumn¼60 ꢀC (3 min) and 60–270 ꢀC
(15 ꢀC/min); retention times (tR) are given in minutes under
these conditions. Thin layer chromatography was carried out
H
O
N
4e
H
N
O
OH
H
N
H
4f
N
O
OH
H
N
H
4g
N
O
OH
H
N
H
8
9
4h
4i
57
58
N
MeO
F3C
OMe
CF3
O
OH
H
N
H
N
N
HN
H
N
10
4j
48
H
N
a
Reaction carried out with 1-(diethoxymethyl)imidazole (3, 3 mmol), lith-
ium (9 mmol), isoprene (3 mmol), THF (7 mL), 0 ꢀC, and then added the
electrophile (3.6 mmol).
Isolated yield of pure product. Purification was done by recrystallisation.
Reaction carried out using only 1.5 mmol (50 mol %) of isoprene.
b
c

950
R. Torregrosa et al. / Tetrahedron 63 (2007) 947–952
on TLC plastic sheets with silica gel 60 F254 (Merck). Lith-
ium powder was commercially available (MEDALCHEMY
S.L.).
(3.6 mmol) was added, continuing the stirring for 45 min
at the same temperature. The resulting solution was filtered
over HCl (0.1 M, 15 mL) at 0 ꢀC, and the organic layer was
extracted with HCl (0.1 M, 4ꢂ15 mL). The resulting aque-
ous phase was neutralised with NaHCO3, then extracted
with ethyl acetate (4ꢂ20 mL) and finally dried over anhy-
drous magnesium sulfate. After removing the solvent under
reduced pressure (15 Torr), the corresponding products 4
were obtained by recrystallisation.
4.2. General procedure for the deprotection of
1-protected imidazoles
A solution of the corresponding 1-protected imidazole (1,
2 mmol) in THF (2–15 mL depending on the substrate)
was added to a suspension of lithium powder (42 mg,
6 mmol) and isoprene (0.202 mL, 2 mmol) in THF (2 mL)
at room temperature for 1 h. The reaction mixture was
quenched with water (1 mL), and then ethyl acetate was
also added (30 mL). The mixture was filtered and the precip-
itate washed with ethyl acetate (10 mL). The filtrate and the
washings were combined and the solvent was evaporated
under vacuum (15 Torr). The imidazole (2) was purified by
recrystallisation (mixtures of ethyl acetate and n-pentane).
In all cases, compound 2 was characterised by comparison
of its 1H NMR and 13C NMR with those of the literature.32
4.5.1. 3-(1H-2-Imidazolyl)-3-pentanol (4a). Obtained
0.34 g (75% yield) [recrystallisation (ethyl acetate/diethyl
ether)]; white solid; mp 140–142 ꢀC; n (KBr) 3825–
3104 cmꢃ1 (OH); dH (400 MHz, CD3OD): 0.75 (6H, t,
J¼7.4 Hz, 2ꢂCH3), 1.73–1.97 (4H, m, 2ꢂCH2), 4.95 (2H,
br s, OH and NH), 6.93 (2H, s, CHCH); dC (100 MHz,
CD3OD, T¼193 K): 8.5 (2C, 2ꢂCH3), 35.1 (2C, 2ꢂCH2),
76.2 (COH), 116.2, 127.8 (CHCH), 153.5 (NCN); m/z
(DIP) 154 (M+, 10%), 125 (100), 69 (81). HRMS (DIP) calcd
for C8H14N2O 154.1106, found 154.1117.
4.3. N,N-Dimethyl-1H-imidazole-1-sulfonamide (1e)24
4.5.2. Dicyclopropyl(1H-2-imidazolyl)methanol (4b). Ob-
tained 0.50 g (93% yield) [recrystallisation (ethyl acetate/di-
ethyl ether)]; pale yellow solid; mp 103–104 ꢀC; n (KBr)
3730–3158 cmꢃ1 (OH); dH (300 MHz, CD3OD): 0.29–
0.34, 0.38–0.45, 1.31–1.40 (2H, 6H and 2H, respectively,
3m, 4ꢂCH2 and 2ꢂCH ring), 5.28 (2H, br s, OH and NH),
6.91 (2H, s, NCHCHN); dC (75 MHz, CD3OD): 0.9, 1.6
(4C, 4ꢂCH2), 20.8 (2C, 2ꢂCH ring), 73.2 (COH), 121.9
(2C, NCHCHN), 153.9 (NCN); m/z (DIP) 179 (M++1,
3%), 178 (15), 163 (19), 161 (12), 160 (11), 159 (43), 150
(15), 149 (30), 138 (14), 137 (100), 135 (37), 122 (13),
121 (26), 119 (10), 109 (25), 107 (18), 95 (56), 82 (29), 81
(11), 69 (64), 68 (14), 42 (13), 41 (22). HRMS (DIP) calcd
for C10H14N2O 178.1106, found 178.1099.
A
solution of dimethylchlorosulfonamide (1.19 mL,
11 mmol), imidazole (0.69 g, 10 mmol) and triethylamine
(1.7 mL, 12 mmol) in toluene (16 mL) was stirred at room
temperature for 16 h. The resulting mixture was filtered
and the precipitate washed with toluene (10 mL). The filtrate
and the washings were combined and the solvent was evap-
orated under vacuum (15 Torr). The product was obtained by
distillation of the impurities (ca. 60 ꢀC, 0.1 Torr). Obtained
1.61 g (93% yield); white solid (formed on standing); tR
10.44; mp 41–43 ꢀC; dH (400 MHz, CDCl3): 2.86 (6H, s,
2ꢂCH3), 7.15, 7.31 (1H and 1H, 2s, NCHCHN), 7.93 (1H,
s, NCHN); dC (100 MHz, CDCl3): 37.6 (2C, CH3), 117.3,
130.0 (2C, NCHCHN), 136.2 (NCHN); m/z 177 (M++2,
2%), 176 (3), 175 (31), 108 (100), 69 (20).
4.5.3. 2-(1H-2-Imidazolyl)-2-adamantanol (4c). Obtained
0.59 g (91% yield) (product obtained after washing with
ethyl acetate); white solid; mp 215–217 ꢀC; n (KBr) 3735–
2985 cmꢃ1 (OH); dH (300 MHz, DMSO-d6): 1.48–1.52,
1.58–1.64, 1.78–1.83, 2.29–2.35 (2H, 5H, 3H and 4H, re-
spectively, 4m, 5ꢂCH2 and 4ꢂCH ring), 4.88 (1H, br s,
OH), 6.77 and 6.97 (1H and 1H, 2s, NCHCHN), 11.60
(1H, br s, NH); dC (75 MHz, DMSO-d6): 26.6, 26.8, 35.3
(4C, 4ꢂCH ring), 32.2, 34.3, 37.6 (5C, 5ꢂCH2), 71.9
(COH), 115.4, 126.1 (NCHCHN), 152.5 (NCN); m/z (DIP)
222 (M++4, 2%), 221 (17), 220 (100), 219 (27), 218 (6),
202 (31), 201 (20), 200 (22), 192 (27), 191 (10), 163 (12),
160 (10), 159 (12), 149 (10), 136 (20), 126 (11), 125 (11),
124 (12), 123 (10), 100 (14), 97 (22), 96 (33), 84 (12), 83
(25), 82 (11), 71 (13), 70 (17), 69 (11). HRMS (DIP) calcd
for C13H18N2O 218.1419, found 218.1409.
4.4. 1-(Diethoxymethyl)-1H-imidazole (3)27–29
A solution of imidazole (6.87 g, 0.1 mol) and para-toluene-
sulfonic acid (0.5 g) in triethyl orthoformate (67 mL,
0.4 mol) was heated at 130 ꢀC until no more ethanol was
distilled (ca. 4 h). The excess of orthoformate was distilled
under vacuum (75–79 ꢀC, 15 Torr) and Na2CO3 (0.5 g) was
added to the reaction mixture. The product was obtained
pure by distillation (85 ꢀC, 0.1 Torr). Obtained 14.50 g
(85% yield). Colourless oil; tR 9.99; dH (300 MHz, CDCl3):
1.25 (6H, t, J¼7.0 Hz, 2ꢂCH3), 3.59 (4H, q, J¼7.0 Hz,
2ꢂCH2), 6.06 (1H, s, CH(OEt)2), 7.07, 7.10 (2H, 2s,
CHCH), 7.73 (1H, s, NCHN); dC (75 MHz, CDCl3): 14.6
(2C, 2ꢂCH3), 60.9 (2C, 2ꢂCH2), 101.3 (CH(OEt)2), 116.1,
129.3 (CHCH), 135.0 (NCN); m/z 170 (M+, 0.75%), 125
(20), 103 (100), 97 (24), 75 (41), 69 (15), 68 (22).
4.5.4. 1-(1H-2-Imidazolyl)-1-phenylethanol (4d).27 Ob-
tained 0.31 g (55% yield) [recrystallisation (2-propanol)];
yellow solid; mp 168–170 ꢀC; n (KBr) 3695–3124 cmꢃ1
(OH); dH (300 MHz, CD3OD): 1.92 (3H, s, CH3), 4.95
(2H, br s, OH and NH), 6.94 (2H, s, NCHCHN), 7.16–
7.21, 7.24–7.29, 7.41–7.44 (1H, 2H and 2H, respectively,
3m, ArH); dC (75 MHz, CD3OD): 30.0 (CH3), 73.9
(COH), 122.3 (2C, NCHCHN), 126.2, 128.0, 129.1 (5C,
5ꢂArCH), 147.9 (ArC), 154.8 (NCN); m/z (DIP) 189
(M++1, 6%), 188 (45), 187 (12), 174 (11), 173 (100), 170
4.5. General procedure for the preparation of 2-func-
tionalised-1H-imidazoles (4)
A solution of 1-(diethoxymethyl)-1H-imidazole (3, 0.51 g,
3 mmol) in THF (2 mL) was added to a suspension of lith-
ium powder (63 mg, 9 mmol) and isoprene (0.303 mL,
3 mmol) in THF (5 mL) at 0 ꢀC. The mixture was stirred
for 90 min and then the corresponding electrophile

R. Torregrosa et al. / Tetrahedron 63 (2007) 947–952
951
(12), 169 (32), 155 (11), 145 (12), 111 (13), 105 (32), 95
(36), 77 (24), 69 (16), 43 (13).
(2H, s, NCHCHN), 7.61 (4H, s, ArH); dC (100 MHz,
CD3OD): 70.7 (CHOH), 122.8 (2C, NCHCHN), 125.7 (q,
J¼271.3 Hz, CF3), 126.3 (2C, m, 2ꢂArCH), 128.1 (2C,
2ꢂArCH), 130.8 (q, J¼32.3 Hz, CCF3), 147.9 (ArC),
150.9 (NCN); m/z (DIP) 245 (M++3, 6%), 244 (56), 243
(100), 242 (68), 241 (17), 226 (10), 225 (22), 224 (61),
223 (18), 214 (10), 174 (10), 173 (22), 157 (12), 156 (16),
155 (39), 145 (29), 128 (19), 127 (19), 99 (12), 98 (22), 97
(15), 95 (12), 71 (15), 70 (34), 69 (32), 68 (12). HRMS
(DIP) calcd for C11H9F3N2O 242.0667, found 242.0659.
4.5.5. 1-(1H-2-Imidazolyl)-2,2-dimethyl-1-propanol
(4e).33 Obtained 0.42 g (92% yield) [recrystallisation (etha-
nol)]; white solid; mp 237–238 ꢀC; n (KBr) 3736–
3110 cmꢃ1 (OH); dH (400 MHz, DMSO-d6): 0.85 (9H, s,
3ꢂCH3), 4.25 (1H, s, CHOH), 5.45 (1H, br s, OH), 6.77,
6.94 (1H and 1H, 2s, CHCH), 11.64 (1H, br s, NH); dC
(100 MHz, DMSO-d6): 26.0 (3C, 3ꢂCH3), 35.5
[C(CH3)3], 75.1 (CHOH), 115.1, 126.5 (CHCH), 149.4
(NCN); m/z (DIP) 154 (M+, 5%), 98 (100), 97 (85), 69 (12).
4.5.10. N-[1H-2-Imidazolyl(phenyl)methyl]aniline (4j).
Obtained 0.36 g (48% yield) [recrystallisation (dichloromꢃe1-
thane)]; white solid; mp 159–161 ꢀC; n (KBr) 3424 cm
(NH); dH (300 MHz, CD3OD): 5.65 (1H, s, CHNH), 6.59–
6.64, 7.02–7.07, 7.22–7.40 (3H, 2H and 5H, respectively,
3m, 10ꢂArH), 6.96 (2H, s, NCHCHN); dC (75 MHz,
CD3OD): 58.5 (CHNH), 114.7, 118.9, 128.4, 128.8, 129.8,
129.9 (10C, 10ꢂArCH), 122.8 (2C, NCHCHN), 142.1,
148.8, 150.7 (2ꢂArC and NCN); m/z (DIP) 252 (M++3,
1%), 251 (7), 250 (19), 249 (19), 158 (56), 157 (100), 156
(23), 130 (12), 95 (18), 94 (57), 93 (61), 77 (21). HRMS
(DIP) calcd for C16H15N3 249.1266, found 249.1262.
4.5.6. Cyclohexyl(1H-2-imidazolyl)methanol (4f).34 Ob-
tained 0.27 g (51% yield) [recrystallisation (ethanol/diethyl
ether)]; white solid; mp 206–208 ꢀC; n (KBr) 3719–
3120 cmꢃ1 (OH); dH (400 MHz, DMSO-d6): 0.85–1.14,
1.29–1.33, 1.56–1.74 (5H, 1H and 5H, respectively, 3m,
5ꢂCH2 and CH ring), 4.30 (1H, d, J¼6.4 Hz, CHOH),
5.38 (1H, br s, OH), 6.78, 6.95 (1H and 1H, 2s, CHCH),
11.74 (1H, br s, NH); dC (100 MHz, DMSO-d6): 25.8,
25.9, 26.3, 28.3, 28.9 (5ꢂCH2), 43.6 (CH ring), 71.9
(CHOH), 115.7, 126.7 (CHCH), 150.6 (NCN); m/z (DIP)
183 (M++3, 1%), 182 (5), 181 (7), 180 (3), 100 (42), 99
(100), 98 (93), 97 (38), 70 (12), 69 (12), 55 (13), 43 (10),
41 (11).
Acknowledgements
4.5.7. 1H-2-Imidazolyl(phenyl)methanol (4g).29 Obtained
0.31 g (59% yield) [recrystallisation (ethanol/diethyl
ether)]; white solid; mp 192–194 ꢀC; n (KBr) 3656–
2955 cmꢃ1 (OH); dH (300 MHz, CD3OD): 4.97 (2H, br s,
OH and NH), 5.83 (1H, s, CHOH), 6.94 (2H, s, NCHCHN),
7.21–7.34, 7.39–7.42, (3H and 2H, respectively, 2m, ArH);
dC (75 MHz, CD3OD): 71.5 (CHOH), 122.5 (2C,
NCHCHN), 127.5, 128.7, 129.4 (5C, 5ꢂArCH), 143.4
(ArC), 151.6 (NCN); m/z (DIP) 177 (M++3, 9%), 176 (80),
175 (100), 174 (53), 173 (11), 158 (14), 157 (29), 156
(70), 155 (35), 147 (10), 146 (13), 129 (13), 105 (19), 99
(15), 98 (26), 97 (12), 95 (10), 80 (13), 79 (13), 78 (24),
77 (35), 71 (22), 70 (36), 69 (22), 51 (15).
This work was generously supported by the Spanish
ꢀ
01261) and the Generalitat Valenciana (GV; grant no. GRU-
POS03/135 and GV05/52). R.T. thanks the GV for a
fellowship. We also thank MEDALCHEMY S.L. for a gift
of chemicals, especially lithium powder.
Ministerio de Educacion y Ciencia (grant no. CTQ2004-
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