1966
J. E. Utas et al.
LETTER
OMe
In CHCl3, the target phenols 1a,b showed broad, down-
field peaks for the phenolic protons at 10 ppm for 1a and
at 10.7 ppm for 1b. This strongly indicates a high degree
of intramolecular hydrogen bonding, as suggested by our
calculations. Further studies of the properties of these
interesting compounds are underway and will be reported
separately.
OMe
1) PBr3 (81%)
OH
ZnBr
2) Zn dust
6a
7a
OMe
OH
O
tBu
tBu
1) MeI, K2CO3 (47%)
2) NaBH4 (94%)
OH
H
To summarize, novel 2-substituted imidazoles could be
synthesized by a palladium-catalyzed cross-coupling be-
tween benzylzinc reagents and 2-iodoimidazoles. The
coupling is a promising alternative to existing routes to-
wards these heterocycles, and is insensitive to steric
hindrance in the benzylic moiety whereas the substituent
in the 1-position of the imidazole seems important.
tBu
tBu
OMe
tBu
8
6b
ZnBr
1) PBr3 (88%)
2) Zn dust
tBu
7b
Scheme 2 Synthesis of zinc reagents 7
Preparation of Zinc Reagents – Synthesis of 2-Methoxybenzyl-
zinc Bromide (7a)
Fortunately, the coupling of zinc reagent 7a with 2-iodo-
imidazole 5a in the presence of PdCl2(PPh3)3 was success-
ful, yielding compound 9a in 62% (Scheme 3). In an at-
tempt to improve the yield, two other metal catalysts were
employed in the coupling.10 Pd(OAc)2 together with tri(o-
Zn dust (1.48 g, 22.7 mmol) was suspended in anhyd THF (5 mL)
in a dried three-neck flask and heated to 60 °C under inert atmo-
sphere. 1,2-Dibromoethane (0.08 mL, 0.93 mmol) was added and
the mixture was stirred for 15 min at 60 °C. The flask was cooled to
r.t. and TMSCl (0.1 mL, 0.78 mmol) was added. The mixture was
tolyl)phosphine resulted in 59% yield of 9a whereas stirred for 30 min at r.t., then a solution of 2-methoxybenzyl bro-
mide (3.8 g, 18.9 mmol) in THF (20 mL) was added over 2 h and
NiCl2(dppp)2 only gave traces of the desired product. As
the flask was sealed and stored in the fridge over night to let the Zn-
the two Pd catalysts gave similar results, Pd(OAc)2 was
dust settle. The concentration of the Zn reagent was not determined;
chosen for further reactions due to easier purification.
100% conversion was assumed. The solution could be stored in the
fridge and the supernatant liquid was subsequently used in the Pd-
coupling.
OMe
OMe
R1
R1
N
I
N
ZnBr
Pd(OAc)2,
General Pd-Coupling Procedure – Synthesis of 2-(2-Methoxy-
benzyl)-1-methylimidazole (9a)
N
N
(o-tolyl)3P
R2
R2
Pd(OAc)2 (15 mg, 0.068 mmol) and tri(o-tolyl)phosphine (41 mg,
0.13 mmol) were dissolved in anhyd THF (1 mL) under inert atmo-
sphere. The mixture was stirred for 5 min before addition of imida-
zole 5a14 (0.28 g, 1.35 mmol). The reaction mixture was cooled to
0 °C and the solution of 7a (9 mL, 5 equiv) was added over 5 min,
and then the reaction was stirred at r.t. over night. Then, H2O and
CHCl3 were added and the pH of the aqueous layer was adjusted to
ca. 14 with NaOH (aq). The aqueous layer was extracted 3 times
with CHCl3, the combined organic layers were washed with 1 M
NaOH, dried with MgSO4, and the solvent was evaporated. Column
chromatography of the residue with EtOAc–MeOH = 14:1 afforded
9a as a pale yellow oil (0.16 g, 59%). 1H NMR (400 MHz, CDCl3):
d = 7.20 (dt, 1 H, J = 7.7, 1.6 Hz), 6.98–6.96 (m, 2 H), 6.89–6.85
R1
R1
7a: R1 = H
7b: R1 = tBu
5a: R2 = Me
5b: R2 = Bn
9a: R1 = H, R2 = Me (59%)
9b: R1 = tBu, R2 = Me (94%)
9c: R1 = H, R2 = Bn (25%)
BBr3
1a (81%)
1b (47%)
Scheme 3 Synthesis of target molecules 1
To our delight, the Pd(OAc)2-catalyzed coupling of tert-
butyl-substituted zinc reagent 7b with imidazole 5a re-
sulted in compound 9b in excellent yield. Unfortunately,
the coupling of 7a with 1-benzyl-substituted imidazole
5b8 was sluggish, and product 9c could only be isolated in
25% yield together with recovered starting material.
(m, 2 H), 6.80 (s, 1 H), 4.07 (s, 2 H), 3.85 (s, 3 H), 3.48 (s, 3 H). 13
C
NMR (100 MHz, CDCl3): d = 156.5, 146.6, 129.9, 127.7, 127.2,
125.7, 120.6, 120.6, 110.2, 55.3, 32.6, 26.7. IR (CH2Cl2): 3054,
2987, 1494, 1421 cm–1.
Demethylation of the coupling products 9a,b was accom-
plished with BBr3 to yield the desired target molecules 1a
and 1b.16
2-(1-Methyl-imidazol-2-ylmethyl)phenol (1a)
Mp 171.5–172.5 °C. 1H NMR (300 MHz, CDCl3): d = 11.00–9.00
(br s, 1 H), 7.15 (t, 1 H, J = 7.8 Hz), 7.07 (d, 1 H, J = 7.2 Hz), 6.97
(d, 1 H, J = 7.8 Hz), 6.90 (s, 1 H), 6.80 (t, 1 H, J = 7.2 Hz), 6.73 (s,
1 H), 4.00 (s, 2 H), 3.67 (s, 3 H). 13C NMR (100 MHz, CDCl3): d =
157.3, 147.8, 129.9, 129.1, 126.3, 124.0, 120.7, 120.1, 119.4, 33.2,
30.2. IR (KBr tablet): 2940, 1594, 1501, 1455 cm–1.
Finally, NMR studies were performed to elucidate
whether hydrogen bonds were present in compounds
1a,b. In CHCl3, the phenolic proton of 2,4-di(tert-
butyl)phenol has a chemical shift of 4.62 ppm. Upon
addition of 1-methylimidazole (1:1), intermolecular
hydrogen bonds form to some extent, resulting in a down-
field shift of the phenolic proton to 5.84 ppm. In an
unpolar solvent, such as benzene-d6, the hydrogen
bonding becomes more pronounced, shifting the phenolic
proton down to 11 ppm.
2,4-Di-tert-butyl-6-(1-methylimidazol-2-ylmethyl)phenol (1b)
Mp 158–161 °C. 1H NMR (400 MHz, CDCl3): d = 10.7 (br s, 1 H),
7.24 (d, 1 H, J = 2.4 Hz), 6.97 (d, 1 H, J = 2.4 Hz), 6.88 (d, 1 H,
J = 1.4 Hz), 6.71 (d, 1 H, J = 1.4 Hz), 3.98 (s, 2 H), 3.70 (s, 3 H),
1.43 (s, 9 H), 1.29 (s, 9 H). 13C NMR (100 MHz, CDCl3): d = 153.7,
Synlett 2006, No. 12, 1965–1967 © Thieme Stuttgart · New York