A new boronic-acid based strategy to synthesize 4(5)-(het)aryl-1H-imidazoles

Article abstract of DOI:10.1016/j.tet.2008.03.008

This paper describes the synthesis of a new N-THP protected 5-(1H)-imidazolyl boronic acid pinacol ester and its use in Suzuki cross-coupling reactions with a wide range of (het)aryl halides to provide 4(5)-(het)aryl-1H-imidazoles.

Full text of DOI:10.1016/j.tet.2008.03.008

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4596e4601
www.elsevier.com/locate/tet
A new boronic-acid based strategy to synthesize
4(5)-(het)aryl-1H-imidazoles
a
Nicolas Primas , Clement Mahatsekake , Alexandre Bouillon , Jean-Charles Lancelot ,
b
b
a
´
Jana Sopkova-de Oliveira Santos , Jean-Franc¸ois Lohier , Sylvain Rault
a
c
a,
*
`
a Centre d’Etudes et de Recherche sur le Me´dicament de Normandie, U.F.R des Sciences Pharmaceutiques,
Universite´ de Caen Basse-Normandie, 5 rue Vaube´nard, 14032 Caen Cedex, France
b BoroChem S.A.S., Immeuble Emergence, 7 rue Alfred Kastler, 14000 Caen, France
c Laboratoire de Chimie Mole´culaire et Thio-Organique, U.M.R. C.N.R.S. 6507, ENSI-Caen, Universite´ de Caen, 14050 Caen, France
Received 24 January 2008; received in revised form 25 February 2008; accepted 3 March 2008
Available online 7 March 2008
Abstract
This paper describes the synthesis of a new N-THP protected 5-(1H)-imidazolyl boronic acid pinacol ester and its use in Suzuki cross-coupling
reactions with a wide range of (het)aryl halides to provide 4(5)-(het)aryl-1H-imidazoles.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Imidazole; Boronic ester; N-THP-protecting group; Suzuki cross-coupling; Aryl halides
1. Introduction
with palladium complexes of imidazolylcarbenes. We wish to
present herein a reverse methodology with a possible broader
scope, which consists preparation of 4(5)-imidazolylboronic
acid derivatives and use of them in SuzukieMiyaura cross-
coupling reactions towards a wide range of (het)aryl halides.
In the last decade, very much attention has been paid to the
development of efficient methods for the preparation of 4(5)-
aryl substituted imidazole derivatives because of their important
biological and pharmacological properties. A recent review of
Bellina et al.1 reported biological properties such as antifungal
activity,2 potent b-glucosidase3 or activin receptor-like kinase 5
(ALK5) inhibitors.4 Relatively few methods to access the title
compounds are described. Heerding et al.5a have described the
cross-coupling reaction of 3-thienylboronic acid with 4(5)-
iodoimidazole and very recently, Bellina et al.5b have studied
the Suzuki cross-coupling reaction of 4(5)-bromoimidazole
with various arylboronic acids. They obtained good yields of
the expected coupling products from chloro-, methoxy- and
methylenedioxy-substituted phenylboronic acid. But, they
specified that this method was not effective in the presence of
sensitive groups as the formyl one, for example. Sames et al.5c
have described a CeH direct arylation of SEM-imidazoles
2. Results and discussion
To our knowledge, only one article relates the synthesize of
an imidazolylboronic acid: 1-SEM-1H-imidazolyl-5-boronic
acid 1 (Scheme 1), which has been engaged in one cross-cou-
pling reaction with a bis-iodobenzyldihydroxydiazepindione
with a low yield.6 In our hands, this method, which used an
expensive protecting group and required 10 equiv of trimethyl-
borate was not applicable to produce great quantities of imid-
azole derivatives.
3
4
N
N
N
1) t-BuLi, -78 °C
1) t-BuLi, -78 °C
2) TMS-Cl
THF
HO
5
2
TMS
B
N
N
SEM
N
SEM
1
2) B(OMe)3 10 eq.
3) HCl aq.
THF
1
HO
SEM
* Corresponding author. Tel.: þ33(0)2 31 56 59 10; fax: þ33(0)2 31 93
11 88.
E-mail address: sylvain.rault@unicaen.fr (S. Rault).
Scheme 1.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.008

N. Primas et al. / Tetrahedron 64 (2008) 4596e4601
4597
In order to improve this result, we took into account our
previous work in the pyrazole series7 in which we showed
that tetrahydropyran-2-yl (THP) was an excellent pyrazole
N-protecting group to prepare boronic acid derivatives. This
N-protecting group was stable under Suzuki cross-coupling
conditions and was then easily cleaved under acidic condi-
tions. These good results led us to apply this methodology
in imidazole series.
For the synthesis of the starting 1-THP-imidazole 3, we
have applied8 the conditions described by Manfredini et al.9
The imidazole sodium salt was treated with 2-chloro-THP10
in THF to give 3 in good yield (Scheme 2). In a previous pa-
per,8 we have shown that the lithiation reaction using n-BuLi
and an electrophile takes place at the C-2 position as for the
SEM one. We easily prepared 2-halogeno-1-THP-1H-imidaz-
oles 4aec.8 Nevertheless, when we tried to apply the strategy
of Han et al.,6 who introduced temporarily a trimethylsilyl
group at C-2 with the first lithiation of N-SEM-imidazole
and who carried out a second lithiation at C-5 with tert-butyl-
lithium followed by the action of trimethylborate to afford 1,
all our attempts conducted from 1-THP-imidazole 3 failed,
and no boronic species were isolated. Carpenter and Erik-
sen11,12 have reported that TMS group is very labile in imid-
azole series, and in our case the N-THP-protecting group
probably still increases this instability. All the other attempts
with triethylsilyl (TES),13 dimethylisobutyl (DMIBS) or tert-
butyldimethylsilyl group (TBDMS) also failed (Scheme 3).
to afford 5-lithioimidazole, which was slowly quenched at
ꢀ78 ꢁC with 1.1 equiv of triisopropyl borate to give lithium
isopropoxyborate, which was finally in situ transesterified
using pinacol in the presence of acetic acid14 to give the new
2-chloro-1-THP-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
1H-imidazole 5 in 88% yield (Scheme 4). This latter transester-
ification was absolutely necessary to obtain a stable boronic
species. Indeed a simple acidic hydrolysis did not permit to iso-
late the corresponding boronic acid, which seems to be very
instable. To complete our study, it was necessary to remove
the chlorine atom of 5 preserving the boronic ester and the
THP-protecting group. After several attempts, this result was
obtained by dehalogenation with Pd/C under 1 atm of hydrogen
in methanol after 1 h at 0 ꢁC and followed by another 1 h at
room temperature. The new 1-THP-5-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-1H-imidazole 6 was obtained in a
very good yield as a stable white solid (Scheme 4). For 5 and
6, we have not yet founded the conditions to remove the
N-THP group while preserving the boronic ester.
Considering that THP was stable under Suzuki conditions,7
6 was engaged with 4-iodoanisole under standard Suzuki
cross-coupling reaction conditions (DME/H2O, K2CO3 2 equiv,
boronic ester 1.1 equiv, halide 1 equiv, Pd(PPh3)4 0.05 equiv),15
but this reaction was unsuccessful. This ester being prone to de-
boronation.16 We studied this side reaction and we found that
the boronic ester in the presence of water and mineral base
such as K2CO3 or NaHCO3 (2 equiv) in DME was completely
deboronated after 3 h at 90 ꢁC. As a result of the instability of
6 under aqueous conditions, a water-free cross-coupling proto-
col was required. We initially tested K3PO4 in dry DMF at 90 ꢁC
with Pd(PPh3)4 (5 mol %) and 2 equiv of 6. This reaction
afforded the expected compound 7c with a low yield (ca.
40%). The use of microwave assisted Suzuki cross-coupling17
reactions provided a lot of by-products (deboronation, homo-
coupling leading to difficulties to purify the mixture). Fortu-
nately, we finally found that CsF (2.5 equiv) as base, CuI
(0.1 equiv) as co-catalyst18 and boronic ester (1.1 equiv) in
dry DMF at 90 ꢁC were the best conditions, giving the expected
7c with 66% yield (Table 1, Scheme 5). The use of PdCl2(dppf)
(0.05 equiv) instead of Pd(PPh3)4 did not increase the yield
(35%).
1. NaH (3eq.)
(1.5eq.)
Cl
2.
N
1. n-BuLi (1,2eq.)
2. E+ (1,5eq.)
THF -78 °C
N
N
O
N
E= Cl, Br, I
4a-c
E
N
H
N
THF 0 °C to rt 85%
2
O
THP
3
Scheme 2.
These failures prompted us to adapt the method of
Begtrup,12 which used a chlorine atom to protect the position
2 of O-benzyl imidazole N-oxide before lithiation in position
5. Starting from 2-chloro-1-THP-imidazole 4a, a lithiation
using the complex n-BuLi/TMEDA was carried out at ꢀ78 ꢁC
N
N
1) t-BuLi, -78 °C
2) R1R1R2Si-Cl
THF
1) t-BuLi, -78 °C
RO
3
SiR1R1R2
B
N
2) B(OX)3
3) HCl aq. or pinacol/AcOH
THF
N
RO
THP
THP
TMS-Cl
TES-Cl
R1 = R2 = Me
R1 = R2 = Et
X = Me , iPr
R = H, pinacol
DMIBS-Cl
R1 = Me , R2 = isobutyl
TBDMS-Cl R1 = Me , R2 = tertbutyl
Scheme 3.
H2 1 atm.
Pd/C 10%
1. n-BuLi/TMEDA (1.2eq.)
N
N
N
THP
6
N
2. B(OiPr)3 (1.1eq.)
O
O
B
B
Cl
Cl
MeOH 0 °C
3. pinacol (1eq.)
4. AcOH
THF -78 °C 88%
N
N
O
O
THP
82%
THP
4a
5
Scheme 4.

4598
N. Primas et al. / Tetrahedron 64 (2008) 4596e4601
Table 1
Cross-coupling reaction optimization with 4-iodoanisole
Table 2
Cross-coupling reactionedeprotection sequence
Base (equiv) Solvent Heating
Yielda (%)
AreX
Product
Yielda (%)
35
K2CO3 or NaHCO3 (2) DME/H2O, 3/2 Oil bath, 90 ꢁC, 6 h
0
40
66
H
N
Br
K3PO4 (2)
DMF
DMF
Dioxane
DMF
Oil bath, 90 ꢁC, 6 h
8a
8b
8c
CsF (2.5), CuI 10%
CsF (2.5), CuI (0.1)
CsF (2.5), CuI (0.1)
Oil bath, 90 ꢁC, 12 h
N
Oil bath, 90 ꢁC, 12 h <10
Micro-waves, 130 ꢁC,
30 min
H
31
Br
N
20
58
N
a
Isolated yields were calculated after cross-coupling reaction.
H
N
I
The best conditions were applied to a range of (het)halides
providing 1-THP-5-arylimidazoles 7. Vis-a-vis some difficul-
ties to isolate 7 by column chromatography, we preferred to
carry out the final deprotection without purification at this
stage. The THP cleavage was obtained by treatment with eth-
anol or dioxane (for entries f and h) HCl solution at reflux tem-
perature for 45 min.19 The resulting 4(5)-(het)arylimidazoles
8aej were isolated in good yields after an easy purification
through silica gel chromatography using dichloromethane/
methanol as eluent. The results summarized in Table 2 show
that even in the presence of fragile groups (entries feh),
compound 6 is able to couple either with (het)aryl iodides or
bromides. The results are, nevertheless, better with iodo deriv-
atives. We chose to write the molecules 8aec as 4-arylimid-
azoles according to the X-ray radiocrystallographic analysis
of 8g, which clearly shows that it exists in this form in the solid
state.22
N
MeO
OMe
MeO
H
N
I
8d
37
N
MeO
H
N
I
8e
8f
48
37
57
33
39
N
N
N
Cl
Cl
H
N
Br
CN
I
CN
H
N
4'
2
8g
8g
8h
COOEt
COOEt
3. Conclusion
H
N
Br
In conclusion, we have developed an efficient protocol to
synthesize an N-THP imidazole boronic acid pinacol ester
able to undergo SuzukieMiyaura cross-coupling reaction, al-
lowing the facile introduction of imidazole moiety on various
scaffolds, including most sensitive. Considering the important
biological properties of imidazole derivatives, this new metho-
dology could be of great interest for medicinal chemists.
N
COOEt
COOEt
H
N
Br
N
CHO
CHO
H
N
Br
8i
21
26
34
N
4. Experimental
N
N
H
Br
N
4.1. General procedures
8j
8k
N
N
S
S
Commercial reagents were used as-received without addi-
tional purification. Melting points were determined on a Kofler
¨
H
N
N
N
melting point apparatus and are uncorrected. IR spectra were
taken with a PerkineElmer Spectrum BX FTIR System spec-
trometer. 1H NMR (400 MHz) and 13C NMR (100 MHz) spec-
tra were recorded on a JEOL Lambda 400 Spectrometer.
Br
S
S
a
Isolated yields were calculated after cross-coupling reaction and deprotec-
tion (8g, 8h and 8k are not yet described in the literature).
H
CsF (2.5 eq.)
N
N
N
EtOH/HCl
reflux, 45min
CuI (0.1eq.)
O
B
Ar
Ar-X
Ar
+
N
N
Pd(PPh3)4 (0.05eq.)
DMF 100 °C
N
O
THP
THP
8
6
7
(1.1eq.)
Global yield = 20-58%
Scheme 5.

N. Primas et al. / Tetrahedron 64 (2008) 4596e4601
4599
Chemicals shifts are expressed in parts per million downfield
4.4. 2-Chloro-1-(tetrahydropyran-2-yl)-5-(4,40,5,50-
from tetramethylsilane as an internal standard. The mass spec-
tra (MS) were taken on a JEOL JMS GCMate spectrometer at
a ionizing potential of 30 eV. Thin layer chrommatographies
(TLC) were performed on 0.2 mm precoated plates of silica
gel 60F-264 (Merck). Visualization was made with ultraviolet
light (234 nm) or by iodine. Column chromatographies were
carried out using silica gel 60 (0.063e0.2 mm) (Merck). Ele-
mental analyses for new compounds were performed at the
‘Institut de Recherche en Chimie Fine’ (Rouen). 2-Chlorote-
trahydropyran was prepared according to the literature.10
tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-imidazole (5)
To a stirred solution under nitrogen of 4a (17.0 g, 91.2 mmol)
in dry THF (350 mL) cooled to ꢀ78 ꢁC were added TMEDA
(16.4 mL, 109.4 mmol, 1.2 equiv) and n-BuLi (2.5 M)
(43.8 mL, 109.4 mmol, 1.2 equiv) over a period of 20 min. After
10 min of stirring at this temperature was added triisopropyl
borate (25.2 mL, 109.4 mmol, 1.2 equiv). The resulting mixture
was allowed to react at this temperature for 2 h and then warmed
to room temperature over a course of 1 h. After an additional
stirring of 1 h, a solution of pinacol (10.77 g, 91.2 mmol,
1 equiv) in THF (30 mL) was added and after 5 min, glacial ace-
tic acid was added until the pH reached 5. After 1 h of stirring at
room temperature, the mixture was filtrated, concentrated, ex-
tracted with ether and washed with a saturated aqueous solution
of NaHCO3. Organic layer was dried over MgSO4 and concen-
trated to obtain 5 (25.10 g, 88%) as a pale beige solid after wash-
ing with hexane. Mp 135 ꢁC. IR (KBr): 2946, 2860, 1548, 1381,
1140, 856, 668, 574. 1H NMR (CDCl3): d 7.42 (s, 1H), 5.63 (dd,
J¼2.7, 11.2 Hz, 1H), 4.16e4.13 (m, 1H), 3.66e3.60 (m, 1H),
2.45e2.39 (m, 1H), 2.01 (m, 1H), 1.78e1.64 (m, 3H), 1.56e
1.53 (m, 3H), 1.33 (m, 12H). 13C NMR (CDCl3): d 140.7,
134.7, 128.4, 84.9, 83.9, 68.9, 30.3, 24.8, 24.6, 23.2. HRMS
(EI) m/z calcd: 312.14118, found: 312.14189. Anal. Calcd for
C14H22N2O3BCl: C, 53.79; H, 7.09; N, 8.96. Found: C, 53.95;
H, 7.23; N, 9.14.
4.2. 1-(Tetrahydropyran-2-yl)-1H-imidazole (3)8
To a slurry of 60% sodium hydride in oil (35.25 g,
881 mmol, 3 equiv) in dry THF (400 mL) at 0 ꢁC under argon
was slowly added imidazole 2 (20 g, 294 mmol, 1 equiv). Af-
ter 30 min of stirring at this temperature was added dropwise
2-chlorotetrahydropyran (53.13 g, 440 mmol, 1.5 equiv) dis-
solved in 50 mL of dry THF. After this addition, the reaction
was then continued at room temperature for the night. The ex-
cess of NaH was hydrolyzed by ice at 0 ꢁC. The mixture was
extracted with ether, dried over magnesium sulfate and con-
centrated on rotary evaporator. The resulting crude oil was
purified by vacuum distillation (bp 85 ꢁC at 0.05 mmHg) to
provide the title compound 2 (33.23 g, 85%) as a white solid.
IR (KBr): 3391, 3115, 2947, 2859, 1652, 1496, 1077, 1043,
1
992, 914, 664, 550 cmꢀ1. H NMR (CDCl3): d 7.65 (s, 1H),
4.5. 1-(Tetrahydropyran-2-yl)-5-(4,40,5,50-tetramethyl-
7.08 (s, 1H), 7.05 (s, 1H), 5.20 (dd, J¼2.6, 9.5 Hz, 1H),
4.05e4.02 (m, 1H), 3.68e3.62 (m, 1H), 2.01e1.89 (m, 3H),
1.69e1.60 (m, 3H). 13C NMR (CDCl3): d 135.5, 129.2,
116.7, 83.9, 67.7, 31.3, 24.7, 22.3.
[1,3,2]dioxaborolan-2-yl)-1H-imidazole (6)
Compound 5 (18.5 g, 59.2 mmol) and 10% palladium on
carbon (3.2 g) in methanol (400 mL) at 0 ꢁC were stirred un-
der hydrogen at 1 atm for 1 h followed by another 1 h at
room temperature. The mixture was filtrate through Celite
and the solvent was removed. Extractive work up of the resi-
due with CH2Cl2 and saturated aqueous solution of NaHCO3
give, after drying over MgSO4 and concentrating, 6 (13.51 g,
82%) as a white solid. Mp 132 ꢁC. IR (KBr): 3435, 3165,
4.3. 2-Chloro-1-(tetrahydropyran-2-yl)-1H-imidazole (4a)8
Under nitrogen, a solution of 3 (18.52 g, 122 mmol) in dry
THF (300 mL) was cooled to ꢀ78 ꢁC. n-Butyllithium (2.5 M
in hexanes) (58.5 mL, 146 mmol, 1.2 equiv) was added drop-
wise. After stirring for 25 min was added hexachloroethane
(43.27 g, 183 mmol, 1.5 equiv) dissolved in 160 mL of THF.
The resulting mixture was then stirred for 1.5 h at ꢀ78 ꢁC and
then allowed to warm at room temperature over a course of
45 min. Stirring was continued for a further 1 h. The mixture
was worked up by the addition of saturated aqueous NaHCO3,
extraction with CH2Cl2, drying over MgSO4 and removal of
the solvents give the crude product, which was purified by vac-
uum distillation to afford 4a (17.86 g, 79%) as a amber solid. Mp
40 ꢁC. IR (KBr): 3146, 3116, 2947, 2856, 1464, 1264, 1085,
1
2966, 2862, 1642, 1156, 759. H NMR (CDCl3): d 7.88 (s,
1H), 7.56 (s, 1H), 5.63 (dd, J¼1.7, 10.2 Hz, 1H), 4.12e4.09
(m, 1H), 3.72e3.66 (m, 1H), 2.08e1.60 (m, 6H), 1.33 (s,
12H). 13C NMR (CDCl3): d 141.7, 138.3, 84.4, 83.7, 68.4,
32.4, 25.0, 24.9, 24.7, 23.1 (a quaternary carbon’s signal
was not observed). HRMS (EI) m/z calcd: 278.18016, found:
278.17998. Anal. Calcd for C14H23N2O3B: C, 60.45; H,
8.33; N, 10.07. Found: C, 60.69; H, 8.52; N, 10.25.
4.6. Typical procedure for the cross-coupling reaction
1
1044, 740, 668. H NMR (CDCl3): d 7.12 (d, J¼1.5 Hz, 1H),
To a mixture of 1-(THP)-5-(4,40,5,50-tetramethyl-1,3,2-di-
oxaborolan-2-yl)-1H-imidazole 6 (1.0 g, 3.6 mmol, 1.1 equiv)
and halocompound (3.3 mmol, 1 equiv) in dry DMF (40 mL)
under argon were added CsF (1.24 g, 8.2 mmol, 2.5 equiv),
CuI (62 mg, 0.33 mmol, 0.1 equiv) and Pd(PPh3)4 (189 mg
,0.16 mmol, 0.05 equiv). The reaction mixture was heated at
90 ꢁC and the consumption of halocompound was followed by
6.96 (d, J¼1.7 Hz, 1H), 5.27 (dd, J¼2.2, 10.2 Hz, 1H), 4.12e
4.09 (m, 1H), 3.71e3.64 (m, 1H), 2.05e1.60 (m, 6H). 13C
NMR (CDCl3): d 131.1, 128.5, 117.6, 83.3, 68.7, 31.6, 24.7,
22.9. HRMS (EI) m/z calcd: 186.05597, found: 186.05648.
Anal. Calcd for C8H11N2OCl: C, 51.48; H, 5.94; N, 15.01.
Found: C, 51.62; H, 6.09; N, 14. 89.

4600
N. Primas et al. / Tetrahedron 64 (2008) 4596e4601
TLC. The resulting mixture was poured into 50 mL of water
and extracted three times with EtOAc. The combined organic
layers were washed with brine, dried over MgSO4, filtered and
concentrated to give 7aek as a brown residue. Purification was
possible by column chromatography using dichloromethane/
MeOH as eluent.
4.7.3. 4(5)-(4-Methoxyphenyl)-1H-imidazole (8c)
White solid (58%). Following typical procedure using 4-io-
doanisole as halocompound. Mp 128 ꢁC (lit.21 137e138 ꢁC).
1H NMR (CDCl3): d 7.66e7.63 (m, 3H), 7.25 (s, 1H), 6.90
(d, J¼6.6 Hz, 1H), 3.81 (s, 3H). 13C NMR (CDCl3):
d 158.8, 138.4, 135.4, 128.8, 126.2, 125.8, 114.6, 55.3.
4.6.1. 5-(4-Methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-
1H-imidazole (7c)
White solid. Following typical cross-coupling procedure
4.7.4. 4(5)-(3-Methoxyphenyl)-1H-imidazole (8d)
White solid (37%). Following typical procedure using 3-io-
1
doanisole as halocompound. Mp 104 ꢁC. H NMR (CDCl3):
1
using 4-iodoanisole (66%) as halocompound. Mp 106 ꢁC. H
d 10.83 (br s, 1H), 7.59 (s, 1H), 7.25 (s, 1H), 7.20e7.13 (m,
3H), 6.68 (d, J¼8.0 Hz, 1H), 3.61 (s, 3H). 13C NMR (CDCl3):
d 126.6, 105.0, 102.5, 101.0, 96.5, 84.1, 82.9, 79.5, 77.0, 21.8.
NMR (CDCl3): d 7.81 (s, 1H), 7.38 (d, J¼7.8 Hz, 2H), 7.02
(s, 1H), 6.98 (d, J¼7.8 Hz, 2H), 5.00 (d, J¼9.8 Hz, 1H),
4.14e4.12 (m, 1H), 3.86 (s, 3H), 3.58 (t, J¼10.8 Hz, 1H),
2.07e1.91 (m, 3H), 1.72e1.56 (m, 3H). 13C NMR (CDCl3):
d 159.5, 130.4, 127.3, 122.1, 114.1, 82.3, 68.2, 55.3, 31.4,
24.8, 23.3 (two quaternary carbon’s signals were not ob-
served). HRMS (EI) m/z calcd: 258.13681, found: 258.13693.
4.7.5. 4(5)-(2-Chlorophenyl)-1H-imidazole (8e)
White solid (48%). Following typical procedure using
1-chloro-2-iodobenzene as halocompound. Mp 93 ꢁC. 1H
NMR (CDCl3): d 7.93 (d, J¼7.6 Hz, 1H), 7.70 (s, 13H),
7.65 (s, 1H), 7.42 (d, J¼8.0 Hz, 1H), 7.29 (t, J¼7.6 Hz, 1H),
7.18 (t, J¼7.6 Hz, 1H). 13C NMR (CDCl3): d 135.1, 131.7,
131.2, 130.6, 129.9, 128.1, 127.2, 119.5 (a quaternary carbon’s
signal was not observed).
4.6.2. 3-[1-(Tetrahydro-2H-pyran-2-yl)-1H-imidazol-5-yl]-
pyridine (7i)
White solid. Following typical cross-coupling procedure
using 3-bromopyridine (36%) as halocompound. Mp 79 ꢁC. 1H
NMR (CDCl3): d 8.72 (d, J¼2.2 Hz, 1H), 8.64 (dd, J¼4.9,
1.7 Hz, 1H), 7.88 (s, 1H), 7.81 (dt, J¼8.0, 2.0 Hz, 1H), 7.39
(dd, J¼7.8, 4.9 Hz, 1H), 7.15 (s, 1H), 4.99 (dd, J¼10.8, 2.2 Hz,
1H), 4.15e4.11 (m, 1H), 3.62e3.48 (m, 1H), 2.09e1.95 (m,
3H), 1.72e1.57 (m, 3H). 13C NMR (CDCl3): d 149.6, 149.3,
136.3, 136.2, 129.8, 129.0, 126.1, 123.5, 82.6, 68.2, 31.2, 24.7,
23.3. HRMS (EI) m/z calcd: 229.1215, found: 229.1214.
4.7.6. 2-(1H-Imidazol-4(5)-yl)benzonitrile (8f)
White solid (37%). Following typical procedure using 2-bro-
mobenzonitrile as halocompound. Mp 162 ꢁC. 1H NMR
(CDCl3): d 12.4 (br s, 1H), 8.06 (d, J¼8.1 Hz, 1H), 7.83e7.78
(m, 3H), 7.69 (t, J¼7.5 Hz, 1H), 7.38 (t, J¼7.5 Hz, 1H). 13C
NMR (CDCl3): d 137.5, 136.3, 133.9, 133.2, 127.3, 126.6,
119.6, 115.5, 106.6 (a quaternary carbon’s signal was not ob-
served). HRMS (EI) m/z calcd: 169.06399, found: 169.06412.
4.7. Typical procedure for deprotection
4.7.7. Ethyl 2-(1H-imidazol-4(5)-yl)benzoate (8g)
To a solution of crude 7 in EtOH (5 mL) was added etha-
nol/HCl solution (10 mL) and the reaction mixture was
refluxed for 45 min (dioxane/HCl for 7f and 7h). After neutral-
ization with saturated aqueous NaHCO3, the resulting solution
was extracted with EtOAc and the organic layers were washed
with brine and dried over MgSO4. The solvent was removed
under vacuum and the crude product was purified by column
chromatography (dichloromethane/MeOH) to afford the
expected 4(5)aryl-1H-imidazoles 8aek.
White solid. Following typical procedure using ethyl 2-io-
dobenzoate (57%) or ethyl 2-bromobenzoate (33%) as halo-
compound. Mp 97 ꢁC. 1H NMR (CDCl3): d 7.76 (d,
J¼7.8 Hz, 1H), 7.66 (d, J¼7.8 Hz, 1H), 7.63 (s, 1H), 7.49
(dt, J¼7.6, 1.3 Hz, 1H), 7.33 (dt, J¼7.6, 1.2 Hz, 1H), 7.26
(s, 1H), 4.30 (q, J¼7.1 Hz, 2H), 1.28 (t, J¼7.1 Hz, 3H). 13C
NMR (CDCl3): d 170.0, 132.0, 130.5, 129.9, 129.6, 127.2,
62.0, 14.4 (two quaternary carbon’s signals were not ob-
served). HRMS (EI) m/z calcd: 216.0899, found: 216.0893.
Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.96.
Found: C, 66.82; H, 5.80; N, 13.15. See Ref. 22 for crystallo-
graphic data.
4.7.1. 4(5)-Phenyl-1H-imidazole (8a)
White solid (35%). Following typical procedure using bro-
mobenzene as halocompound. Mp 130 ꢁC (lit.20 131e132 ꢁC).
1H NMR (CDCl3): d 7.73e7.69 (m, 3H), 7.40e7.35 (m, 3H),
7.27e7.24 (m, 1H). 13C NMR (CDCl3): d 139.3, 135.6, 132.9,
128.8, 127.0, 124.9, 116.4.
4.7.8. 2-(1H-Imidazol-4(5)-yl)benzaldehyde (8h)
White solid (39%). Following typical procedure using 2-
bromobenzaldehyde as halocompound. Mp 200 ꢁC. H NMR
1
4.7.2. 4(5)-p-Tolyl-1H-imidazole (8b)
(DMSO): d 10.51 (s, 1H), 7.83 (s, 1H), 7.77e7.72 (m, 2H),
7.67 (s, 1H), 7.62 (t, J¼7.3 Hz, 1H), 7.39 (t, J¼7.3 Hz, 1H).
13C NMR (DMSO): d 193.7, 137.9, 137.6, 136.6, 133.4,
133.1, 128.7, 127.0, 126.6, 116.3. HRMS (EI) m/z calcd:
172.06365, found: 172.06381. Anal. Calcd for C10H8N2O:
C, 69.76; H, 4.68; N, 16.27. Found: C, 69.98; H, 4.82; N,
16.41.
White solid (20%). Following typical procedure using
4-bromotoluene as halocompound. Mp 128 ꢁC (lit.20 112e
1
114 ꢁC). H NMR (CDCl3): d 8.48 (br s, 1H), 7.64 (s, 1H),
7.59 (d, J¼8.0 Hz, 2H), 7.28 (s, 1H), 7.16 (d, J¼8.2 Hz,
2H), 2.33 (s, 3H). 13C NMR (CDCl3): d 138.1, 136.7, 135.5,
129.9, 129.4, 124.8, 115.7, 21.1.

N. Primas et al. / Tetrahedron 64 (2008) 4596e4601
4601
Stevenson, R. W.; Mack, C. M.; Cassella, J. V. Bioorg. Med. Chem.
Lett. 2003, 13, 3593.
4.7.9. 3-(1H-Imidazol-4(5)-yl)pyridine (8i)
White solid (21%). Following typical procedure using 3-bro-
mopyridine as halocompound. Mp 108 ꢁC. 1H NMR (CDCl3):
d 9.00 (s, 1H), 8.48 (s, 1H), 7.49e7.47 (m, 1H), 7.37e7.30
(m, 2H), 7.23 (s, 1H). 13C NMR (CDCl3): d 147.1, 145.8,
136.4, 132.5, 130.0, 123.8, 114.9 (a quaternary carbon’s signal
was not observed). HRMS (EI) m/z calcd: 145.06399, found:
145.06332.
5. (a) Heerding, D. A.; Chan, G.; DeWolf, W. E.; Fosberry, A. P.; Janson,
C. A.; Jaworski, D. D.; McManus, E.; Miller, W. H.; Moore, T. D.; Payne,
D. J.; Qiu, X.; Rittenhouse, S. F.; Slater-Radosti, C.; Smith, W.; Takata,
D. T.; Vaidya, K. S.; Yuan, C. C. K.; Huffman, W. F. Bioorg. Med.
Chem. Lett. 2001, 11, 2061; (b) Bellina, F.; Cauteruccio, S.; Rossi, R.
´
J. Org. Chem. 2007, 72, 8543; (c) Toure, B. B.; Lane, B. S.; Sames, D.
Org. Lett. 2006, 8, 1979.
6. Han, Q.; Chang, C. H.; Li, R.; Ru, Y.; Jadhav, P. K.; Lam, P. Y. S. J. Med.
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´
7. Gerard, A.-L.; Bouillon, A.; Mahatsekake, C.; Collot, V.; Rault, S.
Tetrahedron Lett. 2006, 47, 4665.
4.7.10. 4(5)-(Thiophen-3-yl)-1H-imidazole (8j)
White solid (26%). Following typical procedure using
1
8. Primas, N.; Bouillon, A.; Lancelot, J.-C.; Sopkova-de Oliveira Santos, J.;
Lohier, J.-F.; Rault, S. Lett. Org. Chem. 2008, 5, 8.
3-bromothiophene as halocompound. Mp 121 ꢁC. H NMR
(CDCl3): d 9.10 (br s, 1H), 7.65 (s, 1H), 7.49e7.47 (m, 1H),
7.37e7.30 (m, 2H), 7.23 (s, 1H). 13C NMR (CDCl3):
d 135.3, 134.7, 134.3, 126.1, 125.5, 118.9, 115.6. HRMS
(EI) m/z calcd: 150.0252, found: 150.0252.
9. Manfredini, S.; Baraldi, P. G.; Bazzanini, R.; Guarneri, M.; Simoni, D.
J. Chem. Soc., Chem. Commun. 1994, 583.
10. Meltzer, P. C.; Wang, P.; Blundell, P.; Madras, B. K. J. Med. Chem. 2003,
46, 1538.
11. Carpenter, A. J.; Chadwick, D. J. Tetrahedron 1986, 42, 2351.
12. (a) Eriksen, B. L.; Vedso, P.; Begtrup, M. J. Org. Chem. 2001, 66, 8344;
(b) Eriksen, B. L.; Vedso, P.; Morel, S.; Begtrup, M. J. Org. Chem. 1998,
63, 12.
13. (a) Wang, L.; Wang, G. T.; Wang, X.; Tong, Y.; Sullivan, G.; Park, D.;
Leonard, L. M., et al. J. Med. Chem. 2004, 47, 612; (b) Lee, Y.; Martasek,
P.; Roman, L. J.; Masters, B. S. S.; Silverman, R. B. Bioorg. Med. Chem.
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4.7.11. 2-(1H-Imidazol-4(5)-yl)thiazole (8k)
Yellow solid (34%). Following typical procedure using
2-bromothiazole as halocompound. Mp 136 ꢁC. 1H NMR
(CDCl3): d 7.78 (d, J¼2.7 Hz, 1H), 7.75 (s, 1H), 7.64 (s,
1H), 7.27 (br s, 1H). 13C NMR (CDCl3): d 163.3, 142.8,
135.7, 136.1, 117.9, 115.6. HRMS (EI) m/z calcd 151.0204,
found: 151.0204. Anal. Calcd for C6H5N3S: C, 47.66; H,
3.33; N, 27.79. Found: C, 47.87; H, 3.48; 27.99.
14. Coudret, C. Synth. Commun. 1996, 26, 3543.
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Acknowledgements
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´
This work was supported by the ‘Conseil Regional de Basse-
Normandie’ and BoroChem S.A.S. We thank Dr. Remi Legay
for high resolution mass spectrometry analysis.
´
References and notes
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