Synthesis of 4- and 5-substituted 1-hydroxyimidazoles through directed lithiation and metal-halogen exchange

Article abstract of DOI:10.1021/jo001554n

Electrophiles were introduced regioselectively at the 5-position of 1-(benzyloxy)imidazole by lithiation at C-5 after protection of C-2 with a chloro or a trimethylsilyl group. Subsequent treatment with an electrophile afforded 5-substituted 1-(benzyloxy)-2-chloroimidazoles 8-13 and 5-substituted 1-(benzyloxy)imidazoles 3-5, the 2-(trimethylsilyl) group being lost during workup. Electrophiles were introduced regioselectively at the 4-position of 1-(benzyloxy)imidazole by bromine-lithium exchange of 4-bromo-2-chloro-1-(benzyloxy)imidazoles, protected at C-5 with chloro or trimethylsilyl groups, followed by reaction with an electrophile. The 5-(trimethylsilyl) group was removed via base-catalyzed desilylation. Chlorine at C-2 and O-benzyl groups were removed by palladium-catalyzed hydrogenolysis.

Full text of DOI:10.1021/jo001554n

8344
J . Org. Chem. 2001, 66, 8344-8348
Syn th esis of 4- a n d 5-Su bstitu ted 1-Hyd r oxyim id a zoles th r ou gh
Dir ected Lith ia tion a n d Meta l-Ha logen Exch a n ge
Birgitte Langer Eriksen, Per Vedsø, and Mikael Begtrup*
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2,
DK-2100 Copenhagen, Denmark
begtrup@dfh.dk
Received November 2, 2000
Electrophiles were introduced regioselectively at the 5-position of 1-(benzyloxy)imidazole by lithiation
at C-5 after protection of C-2 with a chloro or a trimethylsilyl group. Subsequent treatment with
an electrophile afforded 5-substituted 1-(benzyloxy)-2-chloroimidazoles 8-13 and 5-substituted
1-(benzyloxy)imidazoles 3-5, the 2-(trimethylsilyl) group being lost during workup. Electrophiles
were introduced regioselectively at the 4-position of 1-(benzyloxy)imidazole by bromine-lithium
exchange of 4-bromo-2-chloro-1-(benzyloxy)imidazoles, protected at C-5 with chloro or trimethylsilyl
groups, followed by reaction with an electrophile. The 5-(trimethylsilyl) group was removed via
base-catalyzed desilylation. Chlorine at C-2 and O-benzyl groups were removed by palladium-
catalyzed hydrogenolysis.
Sch em e 1
In tr od u ction
1-Hydroxyimidazoles (parent compound 1a ) are gain-
ing interest due to their biological activity, which en-
compasses antiviral,1 antihypertensive,2 angiotensin II
antagonist activity,3 bacteriostatic,4 and insecticidal prop-
erties.5 Only a few 1-hydroxyimidazoles with functional
substituents have been described.6
Recently we reported a method for the synthesis of a
variety of 2-substituted 1-hydroxyimidazoles.7 The method
was based on lithiation of 1-(benzyloxy)imidazole (1b )
followed by reaction with an electrophile and subsequent
removal of the benzyl group by palladium-catalyzed
hydrogenolysis or by hydrolysis with hydrochloric acid.
This seems to be the only reported method for introduc-
tion of functional substituents in 1-hydroxyimidazoles per
se. This strategy has now been extended to a protocol
for the regioselective functionalization of the 4- and the
5-positions using lithiation followed by reaction with an
electrophile.
with n-butyllithium at -78 °C. Subsequent addition of
trimethylsilyl chloride (TMSCl) gave rise to 1-(benzyloxy)-
2-(trimethylsilyl)imidazole (2),7 which was selectively
metalated in situ at C-5 by treatment with a second
equivalent of n-butyllithium at -78 °C in the presence
of TMEDA. Subsequent addition of MeOD, DMF, or
TMSCl followed by aqueous workup led to simultaneous
loss of the 2-TMS group with formation of the 5-substi-
tuted 1-(benzyloxy)imidazoles 3-5 in 72-90% yield
(Scheme 1). When hexachloroethane was used as an
electrophile, the expected product 6 was contaminated
with 2-chloro- and 2,5-dichloro-1-(benzyloxyimidazole) (7
and 11) due to loss of a protective trimethylsilyl group
during the course of the reaction. The trimethylsilyl
group was also lost when methyl iodide was used as an
electrophile, giving rise to 2-methyl-substituted byprod-
ucts. Due to this limitation we therefore investigated the
use of a 2-chloro substituent as protection group for the
2-position, since it can be removed by mild, palladium-
catalyzed hydrogenolysis.7 77 was then ortho-lithiated at
C-5 using 1.2 equiv of n-butyllithium/TMEDA. Subse-
quent treatment with carbon, halogen, or tin electrophiles
gave 5-substituted 1-(benzyloxy)-2-chloroimidazoles 8-13
in 88-99% yields (Scheme 2). By way of example the
protective chloro substituent and the benzyl group of 9
could be removed simultaneously by palladium-catalyzed
Resu lts a n d Discu ssion
P r ep a r a tion of 5-Su bstitu ted 1-(Ben zyloxy)im id -
a zoles. As for other 1-substituted imidazoles8 lithiation
at C-5 in 1-(benzyloxy)imidazole is only possible when
the 2-position is protected. As protection groups a tri-
methylsilyl group9-11 and a chlorine12,13 were tested.
When a trimethylsilyl group was used for protection
of the 2-position, 1b was lithiated at C-2 by treatment
* To whom correspondence should be addressed. Phone:
+4535306000. Fax: +4535306040.
(1) Harnden, M. R.; J ennings, L. J .; McKie, C. M. D.; Parkin, A.
Synthesis 1990, 893-895.
(2) Philipp, A. H.; J irkovsky, I. L. U.S. Pat. 4,232,029, 1980; Chem.
Abstr. 1981, 94, 103377.
(3) Kim, K. S. U.S. Pat. 5294722, 1994; Chem. Abstr. 1994, 120,
323571c.
(4) Abramovitch, R. A.; Cue, B. W. U.S. Pat. 4006160, 1977; Chem.
Abstr. 1977, 86, 189707.
(9) J utzi, P.; Sakriss, W. Chem. Ber. 1973, 106, 2815.
(10) Carpenter, A. J .; Chadwick, D. J . Tetrahedron 1986, 42, 2351.
(11) Lipshutz, B. H.; Huff, B.; Hagen, W. Tetrahedron Lett. 1988,
29, 3411.
(12) Suzuki, M.; Tanaka, H.; Miyasaka, T. Chem. Pharm. Bull. 1987,
35, 4056.
(5) Mamalis, P.; Croix, E. S. L.; Mhasalker, S. E. Ger. Offen.
2,254,474, 1973; Chem. Abstr. 1973, 79, 42507g.
(6) For a list of functionalized 1-hydroxyimidazoles see ref 7.
(7) Eriksen, B. L.; Vedsø, P.; Morel, S.; Begtrup, M. J . Org. Chem.
1998, 63, 12-16.
(13) Tanaka, H.; Hirayama, M.; Suzuki, M.; Miysaka, T.; Matsuda,
A.; Ueda, T. Tetrahedron 1986, 42, 1971.
(8) Iddon, B.; Ngochindo, R. I. J . Heterocycl. Chem. 1994, 38, 2487.
10.1021/jo001554n CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/13/2001

4- and 5-Substituted 1-Hydroxyimidazole Synthesis
J . Org. Chem., Vol. 66, No. 25, 2001 8345
Sch em e 2
Sch em e 4a
Sch em e 3
a
Reagents and conditions: (i) NaOMe, MeOH, 20 °C, 3 h; (ii)
K2CO3, MeOH, 20 °C, 1 h; (iii) H2, Pd/C, 0 °C, 2 h.
hydrogenolysis at 0 °C for 2 h, affording the hydrochloride
14 in 96% yield. Similar hydrogenolysis of 11 caused loss
of both chlorine substituents with production of 1-hy-
droxyimidazole hydrochloride (15) in quantitative yield,
suggesting the 5-chloro substituent as protecting group
for the 5-position.
P r ep a r a tion of 4-Su bstitu ted 1-(Ben zyloxy)im id -
a zoles. Attempted deprotonation of 11 using 1.2 equiv
of n-butyllithium/TMEDA failed as indicated by the fact
that no deuterium incorporation was observed upon
quenching with MeOD. Instead a 3:2 mixture of 1-(ben-
zyloxy)-2-chloro-5-deuterioimidazole (8) and 1-(benzyl-
oxy)-5-chloro-2-deuterioimidazole was formed presum-
ably due to chlorine-lithium exchange at C-5 and C-2.
As reported for other 1-substituted imidazoles14 H-4 is
not sufficiently acidic to be abstracted by butyllithium
bases, and therefore bromine-lithium exchange was
attempted.
In the first approach 1-(benzyloxy)-2,5-dichloroimid-
azole (16) was brominated at C-4 to give 17 in 98% yield.
Subsequent bromine-lithium exchange at C-4 was then
effected using 1.5 equiv of n-butyllithium. Quenching the
putative 4-lithio intermediate with various electrophiles
produced 4-substituted 2,5-dichloro-1-(benzyloxy)imid-
azoles 18-23 in 78-96% yields (Scheme 3). Unexpect-
edly, it was not possible to remove the 5-chloro substitu-
ent in 18-23 by palladium-catalyzed hydrogenolysis.
Therefore, a more labile C-5 protecting group had to be
developed. Thus, 4-substituted 1-(benzyloxy)imidazoles
devoid of a 5-substituent could be prepared in an alterna-
tive approach by which 1-(benzyloxy)-2-chloroimidazole
was first dibrominated to give 1-(benzyloxy)-4,5-dibromo-
2-chloroimidazole (31) in 77% yield (Scheme 4). In a one-
pot reaction 31 was then treated with 1.1 equiv of
n-butyllithium to effect regioselective bromine-lithium
exchange at the 5-position. Subsequent addition of 1.1
equiv of TMSCl gave the 5-silylated intermediate 24,
which upon treatment with a second equivalent of
n-butyllithium and an electrophile produced 4-substitut-
ed 1-(benzyloxy)imidazoles 25-28 in 71-91% yields. If
desired, 24 could be isolated after the first bromine-
lithium exchange in 94% yield. This compound was then
lithiated and quenched with methyl iodide, and 26 was
obtained in 86% yield.
When the crude 4,5-dibromo compound 31 was treated
with aqueous sodium sulfite, regioselective reduction took
place at C-5 to give the 4-bromo compound 32 in 78%
overall yield. When 1-(benzyloxy)-4-bromo-2-chloroimid-
azole was treated with n-butyllithium followed by reac-
tion with MeOD, a 1:1 mixture of 1-(benzyloxy)-2-chloro-
5-deuterio-4-bromoimidazole and 8 was obtained. This
indicated poor chemoselectivety and thermodynamical
instability of the initially formed 4-lithio-1-(benzyloxy)-
2-chloroimidazole. This experiment confirms that selec-
tive C-4 lithiation requires a 4-bromoimidazole protected
at the 5-position. Removal of the protective 5-silyl group
of 26 and 27 could be effected under mild basic conditions.
Thus, 1-(benzyloxy)-2-chloro-4-formyl-5-(trimethylsilyl)-
imidazole (27) was desilylated using K2CO3 in methanol
to give 1-(benzyloxy)-2-chloro-4-formylimidazole (30) in
70% yield. Likewise, 1-(benzyloxy)-2-chloro-4-methyl-5-
(trimethylsilyl)imidazole (26) was desilylated by treat-
ment with sodium methoxide to give 1-(benzyloxy)-2-
chloro-4-methylimidazole (29) in 95% yield. The feasibility
of the debenzylation dechlorination protocol described
above was demonstrated by the quantitative palladium-
catalyzed hydrogenolysis at 0 °C for 2 h of compound 29
to give 1-hydroxy-4-methylimidazole, isolated as its
hydrochloride (33).
In conclusion, methods for regioselective introduction
of electrophiles into the 4- and the 5-positions of 1-(ben-
zyloxy)imidazole have been developed. In the 5-position
the method is based on proton-lithium exchange and in
the 4-position on halogen-lithium exchange. During
these reactions chloro and trimethylsilyl serve as protect-
ing groups for the 2-position and a trimethylsilyl group
serves as protecting group for the 5-position.
Exp er im en ta l Section
Gen er a l Meth od s a n d Ma ter ia ls. See ref 7. The com-
pounds were never distilled. Violent decomposition of imidazole
1-oxides has been reported to take place at ca. 150 °C.15
(14) Katritzky, A. R.; Slawinski, J . J .; Bunner, F.; Gorun, S. J . Chem.
Soc., Perkin Trans. 1 1989, 1139.
(15) Flynn, A. P. Chem. Br. 1984, 20, 30.

8346 J . Org. Chem., Vol. 66, No. 25, 2001
Eriksen et al.
P r ep a r a t ion of 5-Su b st it u t ed 1-(Ben zyloxy)im id -
a zoles. In Situ P r otection of C-2 Usin g Tr im eth ylsilyl
a s P r otectin g Gr ou p . Sta n d a r d P r oced u r e. Under nitro-
gen, a solution of 1-(benzyloxy)imidazole (1b)7 (174 mg, 1.0
mmol) in tetrahydrofuran (8 mL) was cooled to -78 °C.
n-Butyllithium (1.48 M in hexanes) (0.81 mL, 1.2 mmol) was
added with stirring over 2 min. After the resulting mixture
was stirred for a further 5 min, trimethylchlorosilane (133 µL,
1.05 mmol) was added. Stirring was continued for 1 h, and
TMEDA (0.3 mL, 2 mmol) and n-butyllithium (1.35 mL, 2
mmol) were added. After the resulting mixture had been
stirred for 1 h, the electrophile was added. Stirring was
continued at -78 °C for 1 h, and the reaction mixture was
allowed to warm to 20 °C over the course of 1 h. Stirring was
continued for a further 0.5 h. The mixture was worked up by
addition of saturated aqueous sodium hydrogen carbonate (10
mL), extraction with dichloromethane (3 × 10 mL), drying
(MgSO4), filtration, and removal of the solvents to give the
crude product.
was absent and the signal from H-4 collapsed to a singlet. The
signal from C-5 at 117.8 ppm appeared as a triplet (J CD ) 31.1
Hz).
1-(Ben zyloxy)-2-ch lor o-5-m eth ylim id a zole (9). Methyl
iodide (0.32 mL, 5 mmol) was added, and the mixture was
stirred at -78 °C for 1 h. To destroy excess methyl iodide, 33%
dimethylamine in ethanol (5 mL) was added. The mixture was
worked up as above to give the crude product, which was flash
chromatographed (heptanes-ethyl acetate, 1:1), affording 207
mg (93%) of 9. Anal. Found: C, 59.54; H, 5.09; N, 12.58. Calcd
for C11H11N2OCl: C, 59.33; H, 4.98; N, 12.58. NMR: δH (CDCl3)
7.44-7.36 (5H, m, Ph), 6.54 (1H, q, J ) 1.0 Hz, H-4), 5.10 (2H,
s, CH2), 1.98 (3H, d, J ) 1.0, Me); δC (CDCl3) 132.6 (s), 129.8
(d), 129.6 (d), 128.6 (d), 126.8 (s), 125.7 (s), 121.1 (d), 80.9 (t),
8.4 (q).
1-(Ben zyloxy)-2-ch lor o-5-for m ylim id a zole (10). After
addition of dimethyformamide (0.15 mL, 2 mmol), the mixture
was stirred as in the standard procedure. Then 2 M aqueous
hydrochloric acid (5 mL) was added, and the mixture was
stirred for 1 h. Addition of saturated aqueous sodium hydrogen
carbonate until pH 8 and extractive workup with dichloro-
methane as described above gave a residue which by flash
chromatography (heptanes-ethyl acetate, 1:1) afforded 234 mg
(99%) of 10 as a yellow oil which crystallized from pentane-
ethyl acetate. Recrystallization (pentane-ethyl acetate) gave
mp 50-51 °C. Anal. Found: C, 55.95; H, 3.64; N, 11.83. Calcd
for C11H9N2O2Cl: C, 55.83; H, 3.83; N, 11.84. NMR: δH (CDCl3)
9.59 (1H, d, J ) 1.1 Hz, HCO), 7.59 (1H, d, J ) 0.95 Hz, H-4),
7.48-7.39 (5H, m, Ph), 5.26 (2H, s, CH2); δC (CDCl3) 176.4 (d),
136.2 (d), 135.5 (s), 131.9 (s), 130.3 (d), 129.9 (d), 129.5 (s),
128.7 (d), 82.1 (t).
1-(Ben zyloxy)-2,5-d ich lor oim id a zole (11). After addition
of hexachloroethane (710 mg, 3 mmol) dissolved in THF (2
mL), the mixture was worked up as above to give the crude
product, which was flash chromatographed (heptanes-ethyl
acetate, 1:0 f 2:1) to afford 224 mg (92%) of 11. Mp: 38-40
°C (pentane). Anal. Found: C, 49.27; H, 3.39; N, 11.65. Calcd
for C10H8N2OCl2: C, 49.41; H, 3.32; N, 11.52. NMR: δH (CDCl3)
7.42 (s, 5H, Ph) 6.77 (s, 1H, H-4), 5.16 (s, 2H, CH2); δC (CDCl3)
132.1 (s), 130.0 (d), 129.8 (d), 128.6 (d), 126,9 (s), 121.4 (d),
116.1 (s), 81.76 (t).
1-(Ben zyloxy)-2-ch lor o-5-iod oim id a zole (12). After ad-
dition of iodine (508 mg, 2 mmol), the mixture was worked up
as above to give the crude product, which was flash chromato-
graphed (heptanes-ethyl acetate, 3:1) to give 314 mg (94%)
of 12. Mp: 63-64 °C. Anal. Found: C, 36.10; H, 2.28; N, 8.31.
Calcd for C10H8N2OClI: C, 35.90; H, 2.41; N, 8.37. NMR: δH
(CDCl3) 7.49-7.41 (m, 5H, Ph), 6.95 (s, 1H, H-4), 5.16 (s, 2H,
CH2); δC (CDCl3) 131.9 (s) 131.5 (d) 130.0 (d), 129.8 (d), 128.7
(d), 128.2 (s), 81.8 (t), 66.3 (s).
1-(Ben zyloxy)-2-ch lor o-5-(t r ib u t ylst a n n yl)im id a zole
(13). After addition of tributylchlorostannane (0.41 mL, 1.5
mmol), the mixture was worked up as above to give the crude
product, which was flash chromatographed (heptanes-ethyl
acetate, 1:0 f 4:1), affording 438 mg (88%) of 13 as an oil.
The compound was unstable, and a correct elemental analysis
could not be obtained. NMR: δH (CDCl3) 7.42 (s, 5H, Ph), 6.81
(s, 1H, H-4), 5.09 (s, 2H, CH2), 1.55-0.84 (m, 27H, 3Bu); δC
(CDCl3) 132.6, 132.5, 129.1, 128.9, 128.4, 127.3, 81.07, 28.47
(J C-Sn ) 9 Hz), 26.8 (J C-Sn ) 34 Hz), 13.2, 10.0 (J C-Sn ) 179
Hz).
Br om in a t ion of 1-(Ben zyloxy)-2,5-d ich lor oim id a zole
(16). 1-(Ben zyloxy)-4-br om o-2,5-d ich lor oim id a zole (17).
Bromine (0.5 mL, 9.7 mmol) was added slowly with stirring
at 0 °C to a mixture of 1-(benzyloxy)-2,5-chloroimidazole (2.0
g, 8.23 mmol), dichloromethane (15 mL), water (15 mL), and
sodium carbonate (2.82 g, mmol). After the resulting mixture
was stirred for 16 h, sodium sulfite (ca 2 g) dissolved in water
(5 mL) was added. The layers were separated, and the aqueous
phase was extracted with dichloromethane (2 × 15 mL).
Drying of the combined organic phases followed by filtration,
evaporation, and flash chromatography (heptanes-ethyl ace-
tate, 1:0 f 4:1) gave 2.61 g (98%) of 17. Mp: 51-52 °C
(pentane). Anal. Found: C, 37.44; H, 2.08; N, 8.59. Calcd for
1-(Ben zyloxy)[5-2H]im id a zole (3). After addition of mono-
deuteriomethanol (MeOD; 0.3 mL, 7.4 mmol), the mixture was
stirred and worked up as described above to give a residue
which upon flash chromatography (heptanes-ethyl acetate,
2:1 f 0:1) gave 156 mg (90%) of 1-(benzyloxy)[5-2H]imidazole.
1
The H NMR spectrum was identical with that of the starting
material except that the signal from H-5 was absent and the
signal from H-4 collapsed to a doublet. The signal from C-5 at
115.1 ppm appeared as a triplet (J CD ) 28.2 Hz).
1-(Ben zyloxy)-5-for m ylim id a zole (4). After addition of
dimethylformamide (0.39 mL, 5 mmol) and stirring as de-
scribed above, 2 M aqueous hydrochloric acid (5 mL) was
added, and the mixture was stirred for 1 h. Addition of
saturated aqueous sodium hydrogen carbonate until pH 8 and
extractive workup with dichloromethane as described above
gave a residue which by flash chromotography (heptanes-
ethyl acetate, 2:1 f 0:1) afforded 145 mg (72%) of 4 as a yellow
oil which crystallized from heptane-ethyl acetate. Mp: 52-
54 °C (heptanes-ethyl acetate). Anal. Found: C, 65.63; H,
5.24; N, 13.87. Calcd for C11H10N2O2: C, 65.34; H, 4.98; N,
13.85. NMR: δH (CDCl3) 9.73 (1H, d, J ) 0.78 Hz, HCO), 7.67
(1H, d, J ) 0.95 Hz, H-4 or H-2), 7.41-7.18 (6H, m, Ph and
H-4 or H-2), 5.22 (2H, s, CH2); δC (CDCl3) 177.0 (d), 137.9 (d),
137.4 (d), 132.4 (s), 129.8 (d), 129.6 (d), 128.6 (d), 127.7 (s),
82.3 (t).
1-(Ben zyloxy)-5-(tr im eth ylsilyl)im id a zole (5). After ad-
dition of trimethylchlorosilane (0.25 mL, 2 mmol), the mixture
was stirred and worked up as described above to give a residue
which upon flash chromotography (heptanes-ethyl acetate, 2:1
f 0:1) gave 221.4 mg (90%) of 5 as a yellow oil. Anal. Found:
C, 63.51; H, 7.39; N, 11.24. Calcd for C13H18N2OSi: C, 63.37;
H, 7.36; N, 11.37. NMR: δH (CDCl3) 7.36-7.29 (6H, m, Ph and
H-4 or H-2), 6.92 (1H, d, J ) 1.0 Hz, H-4 or H-2), 5.04 (2H, s,
CH2), 0.30 (9H, s, SiMe3); δC (CDCl3) 134.1 (d), 133.3 (d), 133.3
(s), 129.0 (d), 128.8 (d), 128.4 (d), 126.0 (s), 82.0 (t) -1.4 (q).
P r ep a r a tion of 5-Su bstitu ted 1-(Ben zyloxy)-2-ch lor o-
im id a zoles 8-13. Sta n d a r d P r od ed u r e. Under nitrogen, a
solution of 1-(benzyloxy)-2-chloroimidazole (7)7 (208.5 mg, 1.0
mmol) in tetrahydrofuran (8 mL) was cooled to -78 °C.
TMEDA (0.18 mL, 1.2 mmol) and n-butyllithium (1.33 M in
hexanes) (0.90 mL, 1.2 mmol) were added with stirring over 2
min. After the resulting mixture was stirred for a further 3
min, the electrophile was added. Stirring was continued at -78
°C for 1 h, and the reaction mixture was allowed to warm to
20 °C over the course of 1 h. Stirring was continued at 20 °C
for a further 0.5 h. The mixture was worked up by addition of
saturated aqueous sodium hydrogen carbonate (10 mL),
extraction with dichloromethane (3 × 10 mL), drying (MgSO4),
filtration, and removal of the solvents to give the crude
product.
1-(Ben zyloxy)-2-ch lor o[5-2H]im id a zole (8). After addi-
tion of MeOD (0.3 mL, 7.4 mmol), the mixture was stirred and
worked up as described above to give a residue which upon
flash chromotography (heptanes-ethyl acetate, 2:1 f 0:1) gave
187.6 mg (90%) of 8. The 1H NMR spectrum was identical with
that of the starting material except that the signal from H-5
C
10H8N2OCl2Br: C, 37.30; H, 2.19; N, 8.70. NMR: δH (CDCl3)

4- and 5-Substituted 1-Hydroxyimidazole Synthesis
J . Org. Chem., Vol. 66, No. 25, 2001 8347
7.44 (s, 5H, Ph), 5.20 (s, 2H, CH2); δC (CDCl3) 131.5, 130.1,
130.0, 128.7, 126.0, 115.3, 107.9, 82.1.
(78%) of 23. Anal. Found: C, 46.13; H, 3.07; N, 9.54. Calcd for
C11H8N2O3Cl2: C, 46.02; H, 2.81; N, 9.75. NMR: δH (DMSO)
7.52-7.45 (m, 5H, Ph), 5.34 (s, 2H, CH2); δC (DMSO) 161.6,
132.6, 130.8, 130.3, 129.1, 127.7, 123.9, 122.3, 82.3.
P r epar ation of4-Su bstitu ted 1-(Ben zyloxy)-2,5-dich lor o-
im id a zoles 18-23. Sta n d a r d P r oced u r e. Under nitrogen,
a solution of 17 (323 mg, 1.0 mmol) in tetrahydrofuran (5 mL)
was cooled to -78 °C. n-Butyllithium (1.61 M in hexanes) (0.93
mL, 1.5 mmol) was added with stirring over 2 min. After the
resulting mixture was stirred for a further 1 min, the electro-
phile was added. Stirring was continued at -78 °C for 1 h,
and the reaction mixture was allowed to warm to 20 °C over
the course of 1 h. Stirring was continued at 20 °C for a further
0.5 h. The mixture was worked up by addition of saturated
aqueous sodium hydrogen carbonate (10 mL), extraction with
dichloromethane (3 × 10 mL), drying (MgSO4), filtration, and
removal of the solvents to give the crude product.
Br om in a tion of 7. 1-(Ben zyloxy)-4,5-d ibr om o-2-ch lor o-
im id a zole (31). Bromine (0.79 mL, 15.37 mmol) was added
to a mixture of 1-(benzyloxy)-2-chloroimidazole (916.9 mg, 4.39
mmol) and sodium carbonate (1.67 g, 15.8 mmol) in DMF (10
mL). The mixture was stirred for 20 h at room temperature
and quenched with saturated aqueous sodium sulfite (10 mL).
Extraction with diethyl ether (3 × 20 mL), drying, filtration,
and evaporation followed by flash chromatography (heptanes-
ethyl acetate, 1:0 f 4:1) gave 1.25 g (77%) of 31. Mp: 65-66
°C. Anal. Found: C, 33.00; H, 2.19; N, 7.56. Calcd for C10H7N2-
OClBr2: C, 32.78; H, 1.93; N, 7.64. NMR: δH (CDCl3) 7.46-
7.42 (m, 5H, Ph), 5.16 (s, 2H, CH2); δC (CDCl3) 131.6, 130.1,
130.0, 128.8, 127.0, 111.8, 101.6, 82.1.
Su lfit e R ed u ct ion of 31. 1-(Ben zyloxy)-4-b r om o-2-
ch lor oim id a zole (32). Bromine (0.71 mL, 13.8 mmol) was
added to a mixture of 7 (826 mg, 3.96 mmol) and sodium
carbonate (1.57 g, 14.2 mmol) in DMF (4 mL). The mixture
was stirred for 20 h at room temperature and quenched with
saturated aqueous sodium sulfite (5 mL). Extraction with
diethyl ether (3 × 20 mL), drying, filtration, and evaporation
gave 31, which, without further purification, was dissolved in
methanol (40 mL). Sodium sulfite·7H2O (10 g, 39.6 mmol) and
water (20 mL) were added, and the mixture was refluxed for
24 h. Extraction with dichloromethane (3 × 50 mL), drying,
filtration, and evaporation followed by flash chromatography
(heptanes-ethyl acetate, 1:0 f 4:1) gave 891 mg (78%) of 32.
Mp: 71 °C (ethyl acetate-pentanes). Anal. Found: C, 42.06;
H, 2.98; N, 9.65. Calcd for C10H8N2OClBr: C, 41.77; H, 2.80;
N, 9.74. NMR: δH (CDCl3) 7.43 (s, 5H, Ph), 5.16 (s, 2H, CH2);
δC (CDCl3) 131.6, 130.1, 130.0, 128.8, 127.0, 111.8, 101.6, 82.1.
P r ep a r a tion of 4-Su bstitu ted 1-(Ben zyloxy)-2-ch lor o-
5-(tr im eth ylsilyl)im id a zoles 25-28. Sta n d a r d P r oced u r e.
Under nitrogen, a solution of 31 (367 mg, 1.0 mmol) in
tetrahydrofuran (5 mL) was cooled to -78 °C. n-Butyllithium
(1.62 M in hexanes) (0.68 mL, 1.1 mmol) was added with
stirring over 2 min. After the resulting mixture was stirred
for a further 1 min, trimethylchlorosilane (0.138 mL, 1.1 mmol)
was added. After the resulting mixture was stirred for 0.5 h
at -78 °C, n-butyllithium (1.62 M in hexanes) (0.68 mL, 1.1
mmol) was added over 2 min. After the resulting mixture was
stirred for a further 1 min, the electrophile was added. Stirring
was continued at -78 °C for 1 h, and the reaction mixture
was allowed to warm to 20 °C over the course of 1 h. Stirring
was continued at 20 °C for a further 0.5 h. The mixture was
worked up by addition of saturated aqueous sodium hydrogen
carbonate (10 mL), and extraction with dichloromethane (3 ×
10 mL), drying (MgSO4), filtration, and removal of the solvents
gave the crude product.
1-(Ben zyloxy)-4-br om o-2-ch lor o-5-(tr im eth ylsilyl)im id -
a zole (24). Instead of addition of the second equivalent of
n-butyllithium, the reaction mixture was quenched with
saturated aqueous sodium hydrogen carbonate (10 mL), and
the reaction mixture was allowed to warm to 20 °C. Addition
of water (10 mL), extraction with dichloromethane (3 × 20
mL), drying (MgSO4), filtration, and removal of the solvents
gave the crude product. Chromatography (ethyl acetate-
heptanes, 0:1 f 1:4) provided 338 mg (94%) of 24. Mp: 65 °C
(heptanes). Rf (EtOAc-heptanes, 1: 4): 0.56. Anal. Found: C,
43.65; H, 4.49; N, 7.77. Calcd for C13H16N2OBrClSi: C, 43.41;
H, 4.48; N, 7.79. NMR: δH (CDCl3): 7.43 (s, 5H, Ph), 5.13 (s,
2H, CH2), 0.42 (s, 9H, SiMe3); δC (CDCl3) 132.2, 129.7, 129.5,
128.9, 128.5, 127.3, 118.9, 81.9, -0.24.
1-(Ben zyloxy)-2,5-d ich lor oim id a zole (18). After addition
of methanol (0.2 mL, 4.9 mmol), the mixture was worked up
as described above to give a residue which upon flash chro-
matography (heptanes-ethyl acetate, 1:0 f 2:1) gave 217 mg
(89%) of 18, identical with the material described above.
1-(Ben zyloxy)-2,5-dich lor o-4-m eth ylim idazole (19).Meth-
yl iodide (0.32 mL, 5 mmol) was added, and the mixture was
stirred at -78 °C for 1 h. To destroy excess methyl iodide, 33%
dimethylamine in ethanol (5 mL) was added. The mixture was
worked up as above to give the crude product, which was flash
chromatographed (heptanes-ethyl acetate, 1:1), affording 219
mg (85%) of 19. Mp: below room temperature. Anal. Found:
C, 51.67; H, 3.91; N, 11.02. Calcd for C11H10N2OCl2: C, 51.39;
H, 3.92; N, 10.90. NMR: δH (CDCl3) 7.43 (s, 5H, Ph), 5.15 (s,
2H, CH2), 2.14 (s, 3H, Me); δC (CDCl3) 131.1 (s), 130.0 (d), 129.7
(d), 129.5 (s), 128.6 (d), 125.2 (s), 112.0 (s), 81.6 (t), 12.5 (q).
1-(Ben zyloxy)-2,5-d ich lor o-4-for m ylim id a zole (20). Af-
ter addition of dimethylformamide (0.15 mL, 2 mmol), the
mixture was stirred as in the standard procedure. Then 2 M
aqueous hydrochloric acid (5 mL) was added, and the mixture
was stirred for 1 h. Addition of saturated aqueous sodium
hydrogen carbonate until pH 8 and extractive workup with
dichloromethane as described above gave a residue which upon
flash chromatography (heptanes-ethyl acetate, 1:1) afforded
252 mg (93%) of 20 as a yellow oil which crystallized from
pentane-ethyl acetate. Recrystallization (pentane) gave mp
85-86 °C. Anal. Found: C, 48.84; H, 2.93; N, 10.37. Calcd for
C
11H8N2O2Cl2: C, 48.73; H, 2.97; N, 10.33. NMR: δH (CDCl3)
9.74 (s, 1H, CHO), 7.47-7.27 (m, 5H, Ph), 5.27 (s, 2H, CH2);
δC (CDCl3) 182.7 (d), 131.2 (s), 130.3 (d), 130.3 (d), 129.8 (s),
128.9 (d), 122.1 (s), 82.5 (t). One signal was hidden by another
absorption.
1-(Ben zyloxy)-2,5-d ich lor o-4-iod oim id a zole (21). After
addition of iodine (508 mg, 2 mmol), the mixture was worked
up as above to give the crude product, which was flash
chromatographed (heptanes-ethyl acetate, 1:0 f 4:1), afford-
ing 352 mg (96%) of 21. Mp: 56 °C (pentane). Anal. Found:
C, 32.85; H, 1.96; N, 7.54. Calcd for C10H7N2OCl2I: C, 32.55;
H, 1.91; N, 7.59. NMR: δH (CDCl3) 7.42 (s, 5H, Ph), 5.20 (s,
2H, CH2); δC (CDCl3) 131.7, 130.3, 130.2, 128.9, 127.6, 121.1,
82.2, 75.4.
1-(Ben zyloxy)-2,5-d ich lor o-4-(t r ib u t ylst a n n yl)im id -
a zole (22). After addition of tributylchlorostannane (0.41 mL,
1.5 mmol), the mixture was worked up as above to give the
crude product, which was flash chromatographed (heptanes-
ethyl acetate, 1:0 f 4:1), affording 441 mg (83%) of 22 as an
oil. Anal. Found: C, 49.60; H, 6.63; N, 5.27. Calcd for C22H34N2-
OCl2Sn: C, 49.66; H, 6.44; N, 5.26. NMR: δH (CDCl3) 7.45-
7.42 (m, 5H, Ph), 5.17 (s, 2H CH2),1.6-0.8 (m, 27H, 3 Butyl);
δC (CDCl3) 133.4, 132.2, 129.9, 129.5, 128.5, 123.6, 81.3, 28.5
(J C-Sn ) 10 Hz), 27.0 (J C-Sn ) 28 Hz), 13.5, 9.6. (t, J C-Sn ) 180
Hz).
1-(Ben zyloxy)-2,5-d ich lor oim id a zole-4-ca r boxylic Acid
(23). Lithiation was performed as described above. Then the
septum was removed, and solid CO2 (1.5 g) was added. Stirring
was continued for 1 h at -78 °C, and the mixture was allowed
to warm to room temperature over the course of 1 h. HCl (1
M, 10 mL) was added, and stirring was continued for a further
1 h. The THF was removed, which induced precipitation.
Filtration, washing with HCl (1 M), and drying gave 252 mg
1-(Ben zyloxy)-2-ch lor o-5-(tr im eth ylsilyl)im idazole (25).
After addition of methanol (0.2 mL, 4.9 mmol), the mixture
was worked up as above to give a residue which was flash
chromatographed (heptanes-ethyl acetate, 1:0 f 4:1) to
produce 255.3 mg (91%) of 25. Mp: 53-54 °C. Anal. Found:
C, 55.88; H, 6.12; N, 9.98. Calcd for C13H17N2OClSi: C, 55.60;
H, 6.10; N, 9.98. NMR: δH (CDCl3): 7.48-7.42 (m, 5H, Ph),
6.91 (s, H-4), 5.15 (s, 2H, CH2), 0.34 (s, 9H, SiMe3); δC (CDCl3)

8348 J . Org. Chem., Vol. 66, No. 25, 2001
Eriksen et al.
132.8 (s), 132.4 (d), 129.9 (s), 129.5 (d), 129.3 (d), 128.8 (d),
81.3 (t), -1.3 (q). One signal was hidden by another absorption.
1-(Ben zyloxy)-2-ch lor o-4-m eth yl-5-(tr im eth ylsilyl)im id-
a zole (26). Meth od a . Methyl iodide (0.32 mL, 5 mmol) was
added, and the mixture was stirred at -78 °C for 1 h. To
destroy excess methyl iodide, 33% dimethylamine in ethanol
(5 mL) was added. The mixture was worked up as above to
give the crude product, which was flash chromatographed
(heptanes-ethyl acetate, 1:0 f 4:1), affording 215 mg (71%)
of 26. Anal. Found: C, 57.03, H, 6.51, N, 9.51. Calcd for
mixture was worked up as above to give the crude product,
which was flash chromatographed (heptanes-ethyl acetate,
4:1), affording 354 mg (87%) of yellow 28. Mp: 50-51 °C. Anal.
Found: C, 38.67; H, 3.83; N, 6.76. Calcd for C13H16N2OClISi:
C, 38.38; H, 3.96; N, 6.88. NMR: δH (CDCl3) 7.44 (s, 5H, Ph),
5.11 (s, 2H, CH2), 0.44 (s, 3H, SiMe3); δC (CDCl3) 132.2, 132.0,
130.2, 129.7, 129.4, 128.8, 85.5, 81.9, -0.43.
Desilyla tion w ith Sod iu m Meth oxid e. 1-(Ben zyloxy)-
2-ch lor o-4-m eth ylim id a zole (29). To a mixture of sodium
(160 mg, 7 mmol) in methanol (2 mL) was added 26 (166 mg,
0.56 mmol) in methanol (2 mL). Stirring for 3 h, addition of
saturated aqueous sodium hydrogen carbonate (5 mL) and
water (5 mL), extraction with dichloromethane (3 × 10 mL),
drying, filtration, and evaporation followed by flash chroma-
tography (heptanes-ethyl acetate, 4:1) afforded 119 mg (95%)
of 29 as a white crystalline compound. Mp: 50-51 °C (ethyl
acetate-pentane). Anal. Found: C, 59.60; H, 4.95; N, 12.55.
Calcd for C11H11N2OCl: C, 59.33; H, 4.98; N, 12.58. NMR: δH
(CDCl3) 7.43-7.37 (m, 5H, Ph), 6.61 (q, J ) 0.9 Hz, 1H, H-5)
5.10 (s, 2H, CH2), 2.11 (d, J ) 0.6 Hz, 3H, Me); δC (CDCl3)
133.3 (s), 133.0 (s), 129.8 (d), 129.6 (d), 128.8 (d), 125.9 (s),
114.0 (d), 81.7 (t), 14.1 (q).
C
14H19N2OClSi: C,57.35; H, 6.50; N, 9.50. NMR: δH (CDCl3)
7.47-7.40 (m, 5H, Ph), 5.10 (s, 2H, CH2), 2.24 (s, 3H, Me), 0.35
(s, 9H, SiMe3); δC (CDCl3) 141.6 (s), 132.8 (s), 129.4 (d), 129.2
(d), 128.7 (d), 127.7(s), 123.8 (s), 81.1 (t), 15.8 (q), -0.4 (q).
Meth od b. n-Butyllithium (1.58 M in hexanes) (2.28 mL,
3.60 mmol) was added with stirring over 2 min to a solution
of 24 (1079 mg, 3 mmol) in dry tetrahydrofuran (15 mL) at
-78 °C. After the resulting mixture was stirred for a further
2 min, methyl iodide (0.29 mL, 4.5 mmol) was added. Stirring
was continued for a further 1 h at -78 °C. After addition of
33% dimethylamine in ethanol (5 mL), the reaction mixture
was allowed to warm to 20 °C. Addition of saturated aqueous
sodium hydrogen carbonate (15 mL) and water (15 mL),
extraction with dichloromethane (3 × 30 mL), drying (MgSO4),
filtration, and removal of the solvents gave the crude product,
which was flash chromatographed (heptanes-ethyl acetate,
1:0 f 4:1), affording 761 mg (86%) of 26, identical with the
material above.
Deben zyla tion w ith Hyd r ogen /P a lla d iu m on Ca r bon .
1-Hyd r oxyim id a zole Hyd r och lor id e (15). 18 (182 mg, 0.75
mmol), 10% palladium on carbon (50 mg), and methanol (6
mL) were stirred under hydrogen at 1 bar and 0 °C for 2 h.
Filtration through kieselguhr and removal of the solvent gave
90 mg (100 %) of 15, identical with the material described
previously.7,17
1-(Ben zyloxy)-2-ch lor o-4-for m yl-5-(tr im eth ylsilyl)im id-
a zole (27). After addition of dimethylformamide (0.2 mL, 2.6
mmol), the mixture was stirred as in the standard procedure.
Then 2 M aqueous hydrochloric acid (5 mL) was added, and
the mixture was stirred for 1 h. Addition of saturated aqueous
sodium hydrogen carbonate until pH 8 and extractive workup
with dichloromethane as described above gave a residue which
upon flash chromatography (heptanes-ethyl acetate, 1:0 f
4:1) afforded 231 mg (75%) of 27.16 Mp: 45 °C. Rf (ethyl
acetate-heptanes, 1:4): 0.36. Anal. Found: C, 54.30; H, 5.44;
N, 9.16. Calcd for C14H17N2O2ClSi: C, 54.45; H, 5.55; N, 9.07.
NMR: δH (CDCl3) 9.80 (s, CHO) 7.45 (s, 5H, Ph), 5.16 (s, 2H,
CH2), 0.46 (s, 3H, SiMe3); δC (CDCl3) 186.4, 142.1, 136.8, 132.0,
131.9, 129.9, 129.6, 128.9, 82.2, -1.0.
1-(Ben zyloxy)-2-ch lor o-4-for m ylim idazole (30). The crude
product present in the dichloromethane solution was dissolved
in methanol (10 mL). Addition of potassium carbonate (290
mg), stirring for 1 h at room temperature, addition of water
(20 mL), extraction with dichloromethane (3 × 20 mL), drying
(MgSO4), filtration, and removal of the solvents gave the crude
product, which after chromatography (heptanes-ethyl acetate,
10:1 f 4:1) afforded 167 mg (70%) of 30. Mp: 83 °C (ethyl
acetate-pentane). Rf (EtOAc-heptanes 1:4): 0.19. Anal.
Found: C, 56.05; H, 3.88; N, 11.79. Calcd for C11H9N2O2Cl:
C, 55.83; H, 3.83; N, 11.84. NMR: δH (CDCl3) 9.65 (s, CHO)
7.49-7.35 (m, 6H, Ph), 5.20 (s, 2H, CH2); δC (CDCl3) 184.9,
135.4, 131.9, 130.3, 130.0, 129.9, 129.1, 122.5, 82.4.
1-Hyd r oxy-5-m eth ylim id a zole Hyd r och lor id e (14). 9
(348 mg, 1.56 mmol), 10% palladium on carbon (65 mg), and
methanol (10 mL) were stirred under hydrogen at 1 bar and 0
°C for 2 h. Filtration through kieselguhr and removal of the
solvent gave 201.1 mg (96%) of 14. Mp: 159-160 °C. Anal.
Found: C, 35.51; H, 5.03; N, 20.56. Calcd for C4H7N2OCl: C,
35.70; H, 5.24; N, 20.82. NMR: δH (D2O) 8.65 (d, J ) 1.93 Hz,
1H), 7.08 (s, 1H), 2.24 (d, J ) 1.93 Hz); δC (D2O) 131.0, 130.7,
115.3, 8.0.
1-Hyd r oxy-4-m eth ylim id a zole Hyd r och lor id e (33). 29
(167 mg, 0.75 mmol), 10% palladium on carbon (38 mg), and
methanol (4 mL) were stirred under hydrogen at 1 bar and 0
°C for 2 h. Filtration through kieselguhr and removal of the
solvent followed by addition of 4 M HCl and removal of the
solvent gave 100 mg (99%) of 33 as a semicrystalline com-
pound. Anal. Found: C, 33.63; H, 4.87; N, 19.41. Calcd for
C4H6N2O, 1.25 mol of HCl: C, 33.44; H, 5.09; N, 19.50. NMR:
δH (D2O) 8.65 (s, 1H), 7.19 (s, 1H), 2.22 (s, 3H); δC (D2O) 129.7,
129.1, 117.3, 10.1.
Ack n ow led gm en t. This work was supported by the
Danish Council for Technical and Scientific Research
and the Lundbeck Foundation.
Su p p or tin g In for m a tion Ava ila ble: Spectral data of
compound 13. This material is available free of charge via the
Internet: http://pubs.acs.org.
1-(Ben zyloxy)-2-ch lor o-4-iod o-5-(t r im et h ylsilyl)im id -
a zole (28). After addition of iodine (508 mg, 2.0 mmol), the
J O001554N
(17) Baus, U.; Reuther, W. Eur. Pat. Appl. EP, 1991; Chem. Abstr.
1991, 115, 29334.
(16) The compound slowly desilylates to 30 on silica gel.