Synthesis of 2-Substituted 1-Hydroxyhnidazoles through Directed Lithiation

Article abstract of DOI:10.1021/jo970355+

Benzylation of 3-hydroxyimidazole 1-oxide gave 3-(benzyloxy)imidazole 1-oxide, which was deoxygenated with phosphorous trichloride to produce 1-(benzyloxy)imidazole. 1-(Benzyloxy)imidazole was deprotonated selectively at C-2 by n-butyllithium. The anion formed was reacted with electrophiles to give 1-(benzyloxy)imidazoles with carbon, halogen, silicon, or sulfur substituents at the 2-position. Subsequent debenzylation afforded 2-substituted 1-hydroxyimidazoles which in turn could be deoxygenated to give 2-substituted imidazoles.

Full text of DOI:10.1021/jo970355+

12
J . Org. Chem. 1998, 63, 12-16
Syn th esis of 2-Su bstitu ted 1-Hyd r oxyim id a zoles th r ou gh Dir ected
Lith ia tion
Birgitte Langer Eriksen, Per Vedsø, Sandrine Morel, and Mikael Begtrup*
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2,
DK-2100 Copenhagen, Denmark
Received February 25, 1997X
Benzylation of 3-hydroxyimidazole 1-oxide gave 3-(benzyloxy)imidazole 1-oxide, which was deoxy-
genated with phosphorous trichloride to produce 1-(benzyloxy)imidazole. 1-(Benzyloxy)imidazole
was deprotonated selectively at C-2 by n-butyllithium. The anion formed was reacted with
electrophiles to give 1-(benzyloxy)imidazoles with carbon, halogen, silicon, or sulfur substituents
at the 2-position. Subsequent debenzylation afforded 2-substituted 1-hydroxyimidazoles which in
turn could be deoxygenated to give 2-substituted imidazoles.
In tr od u ction
1-hydroxyimidazoles with functional substituents have
been reported.20-25 The methods used are frequently
effective but not general. No examples of introduction
of functional substituents after the cyclization seem to
have been reported.
In order to get more general access to 1-hydroxyimi-
dazoles with an array of different substituents, a highly
selective method for the introduction of a variety of
substituents in 1-hydroxyimidazole (5a ) after the imida-
zole ring has been formed has now been developed. The
method is based on deprotonation followed by reaction
with an electrophile.
1-Hydroxyimidazoles1-4 are useful intermediates for
the preparation of pharmaceuticals and agricultural
chemicals. They are usually obtained by condensation
of monooximes of 1,2-diketones with ammonia and an
aldehyde5-10 or with an aldimine.11 1-Hydroxyimidazoles
have also been prepared by reaction of R-hydroxylamino
oximes with triethyl orthoformate followed by dehydra-
tion12 or by reaction of olefins and nitrosyl hydrogen
sulfate in the presence of aliphatic nitriles.13-16 1-Hy-
droxyimidazoles have been obtained by selective reduc-
tion of 3-hydroxyimidazole 1-oxide.9,17 prepared by cy-
clization of a 1,2-diketone, an aldehyde, and hydroxyl-
amine. Finally, 1-hydroxyimidazole (5a ) was synthesized
by N-oxidation of imidazole with peroxyphthalic acid18
or 3-chloroperbenzoic acid.19
Resu lts a n d Discu ssion
The starting material in the present approach was
1-(benzyloxy)imidazole (3), which can be prepared in
several ways. The known methods were optimized but
could not compete with a new method described below.
The first method for the preparation of 1-(benzyloxy)-
imidazole (3) is oxidation of imidazole with 3-chloro-
perbenzoic acid followed by O-benzylation without
isolating the intermediate 1-hydroxyimidazole (5a ).19
The overall yield was optimized to 14% (see the Experi-
mental Section), but the method is hampered by two
tedious continuous extractions during workup in
order to remove 3-chlorobenzoic acid and unchanged
imidazole.
All of these reactions produce unsubstituted or alkyl-
or aryl-substituted 1-hydroxyimidazoles. Only a few
* Author to whom correspondence should be addressed. Phone: +45
35 37 08 50. Fax: +45 35 37 22 09. E-mail: begtrup@medchem.dfh.dk.
X Abstract published in Advance ACS Abstracts, December 1, 1997.
(1) Lettau, H. Z. Chem. 1970, 10, 211.
(2) Grimmett, M. R. Adv. Heterocycl. Chem. 1970, 12, 103.
(3) Grimmett, M. R. Adv. Heterocycl. Chem. 1980, 27, 241.
(4) Grimmett, M. R. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; 5,
p 457.
(5) Volkamer, K.; Baumgaertel, H.; Zimmermann, H. Angew. Chem.,
Int. Ed. Engl. 1967, 6, 947.
(6) Volkamer, K.; Zimmermann, H. W. Chem. Ber. 1969, 102, 4177.
(7) Akagane, K.; Allan, F. J .; Allan, G. G.; Friberg, T.; Omuirc-
heartaigh, S.; Thomson, J . B. Bull. Chem. Soc. J pn. 1969, 42, 3204.
(8) Akagane, K.; Allan, G. G.; Chopra, C. S.; Friberg, T.; Mattila,
T.; Omuircheartaigh, S.; Thomson, J . B. Suom. Kemistil. B 1972, 45,
223.
(9) Akagane, K.; Allan, G. G. Shikizai Kyokaishi 1973, 46, 555.
(10) Ertel, H.; Heubach, G. J ustus Liebigs Ann. Chem. 1974, 1399.
(11) Lettau, H. Z. Chem. 1970, 10, 338.
The second method for the preparation of 1-(benzy-
loxy)imidazole (3) was based on O-benzylation of 1-hy-
droxyimidazole (5a ) prepared in fair yield by partial
hydrogenolysis of 3-hydroxyimidazole 1-oxide (1), in its
turn obtained in 80% yield from glyoxal, formaldehyde,
and hydroxylamine.17 The sequence was optimized to
give 1-(benzyloxy)imidazole (3) in 50-55% overall yield.
(12) Volodarskii, L. B.; Vityaeva, E. I. Zh. Org. Khim. 1972, 8, 1887.
(13) Beger, J . J . Prakt. Chem. 1969, 311, 746.
(14) Scheinbaum, M. L.; Dines, M. B. Tetrahedron Lett. 1971, 2205.
(15) Lipshutz, B. H.; Morey, M. C. Tetrahedron Lett. 1984, 25, 1319.
(16) Lipshutz, B. H.; Huff, B.; Vaccaro, W. Tetrahedron Lett. 1986,
27, 4241.
(17) Laus, G.; Stadlweiser, J .; Klo¨tzer, W. Synthesis 1989, 773.
(18) Baus, U.; Reuther, W. Eur. Pat. Appl. EP 1991, 420; Chem.
Abstr. 1991, 115, 29334.
(20) Watson, A. A. J . Org. Chem. 1974, 39, 2911.
(21) Watson, A. A. J . Org. Chem. 1977, 42, 1610.
(22) Harnden, M. R.; J ennings, L. J .; McKie, C. M. D.; Parkin, A.
Synthesis 1990, 893.
(23) Yamada, M.; Fukui, T.; Nunami, K. Synthesis 1995, 1365.
(24) Bock, V.; Kloetzer, W.; Singewald, N.; Strieder, G. Synthesis
1987, 1058.
(19) Begtrup, M.; Vedsø, P. J . Chem. Soc., Perkin Trans. 1 1995,
243.
(25) Hauser, H.; Kloetzer, W.; Krug, V.; Rzehak, J .; Sandrieser, A.;
Singewald, N. Sci. Pharm. 1988, 56, 235.
S0022-3263(97)00355-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/09/1998

Synthesis of 2-Substituted 1-Hydroxyimidazoles
J . Org. Chem., Vol. 63, No. 1, 1998 13
Sch em e 1
loxy)-2-chloroimidazole (4f) also lost its halogen atom to
give 1-hydroxyimidazole (5a ) as the hydrochloride. How-
ever, selective debenzylation of 1-(benzyloxy)-2-chlor-
oimidazole (4f) to 1-hydroxy-2-chloroimidazole hydro-
chloride (5c‚HCl) could be effected with concd hydrochloric
acid (Scheme 2).
Several methods have been devised for the reductive
removal of the N-hydroxy group of 1-hydroxyimidazoles.
Such dehydroxylation has been effected by palladium-
catalyzed hydrogenolysis at room temperature for ex-
tended reaction times24,32 or by using titanium trichlo-
ride,15 sodium borohydride,9 sodium bis(2-methoxyethoxy)
aluminum dihydride (Red-Al, Aldrich),14 or zinc in formic
acid.33 Therefore, the present method for introduction
of substituents in 1-hydroxyimidazole also provides ac-
cess to the corresponding substituted imidazoles. As an
example, 1-hydroxyimidazole (5a ) was reduced by hy-
drogen in the presence of palladium to give imidazole (6a )
in 89% yield. Under these conditions 1-hydroxy-2-
chloroimidazole (5c) lost the halogen. However, reduc-
tion with titanium trichloride proceeded selectively,
producing 2-chloroimidazole (6b) in quantitative yield.
The present approach to the preparation of 2-chloroimi-
dazole (6b) gives higher yields than previous methods.34,35
In conclusion, a new method which seems superior to
previous ones for the preparation of 1-(benzyloxy)imida-
zole (3) has been developed. The benzyloxy group is an
excellent ortho-directing group in lithiation reactions
which give access to 2-substituted 1-(benzyloxy)imida-
zoles (4a -h ). Debenzylation and deoxygenation could be
performed in separate steps under mild conditions com-
patible with sensitive substituents giving rise to 2-sub-
stituted 1-hydroxyimidazoles and imidazoles.
The drawbacks of this method are the long reaction time
for the hydrogenolysis (about 1 week); contamination by
imidazole (about 15%, which had to be removed by
continuous extraction prior to benzylation); and the
difficulties in performing the hydrogenolysis on a large
scale.
In a new approach, 3-hydroxyimidazole 1-oxide (1) was
first benzylated to give 3-(benzyloxy)imidazole 1-oxide (2).
The N-oxide 2 without isolation was then deoxygenated
using phosphorous trichloride to give 1-(benzyloxy)-
imidazole (3) in 69% overall yield. This method provides
a quick and simple procedure suitable for large-scale
preparation of 1-(benzyloxy)imidazole (3). This method
is also the best route to 1-hydroxyimidazole (5a ) since
1-(benzyloxy)imidazole (3) could be converted almost
quantitatively into 1-hydroxyimidazole (5a ) by hydro-
genolysis under mild conditions.
The benzyloxy group displays ortho-directing capabili-
ties in metalation reactions with lithium bases, as was
demonstrated recently in the pyrazole26 and the 1,2,3-
triazole series.27
Exp er im en ta l Section
Gen er a l Meth od s. All reactions involving air-sensitive
reagents were performed under nitrogen using syringe-
septum cap techniques. All glassware was flame-dried prior
to use. Flash chromatography36 was performed using silica
gel (Merck 60, 70-230 mesh). Melting points are uncorrected.
All new compounds were colorless, unless otherwise stated.
NMR spectra were recorded on a 200 MHz instrument.19
Hyd r oxy- a n d a lk oxyim id a zoles w er e n ever d istilled in
a m ou n ts exceed in g 100 m g sin ce violen t d ecom p osition
of im id a zole 1-oxid es h a s been r ep or ted ta k in g p la ce a t
ca . 150 °C.37
Ma ter ia ls. All solvents and reagents were obtained from
Fluka or Aldrich and used without further purification with
the following exceptions: Tetrahydrofuran was distilled from
Na/benzophenone under nitrogen prior to use. n-Butyllithium
was titrated prior to use.38 DMF was sequentially dried with
and stored over 3 Å molecular sieves.39
1-(Benzyloxy)imidazole (3) was lithiated by treatment
with n-butyllithium at -78 °C. Quenching by addition
of methanol-O-d showed that metalation takes place
selectively at the 2-position and is complete in less than
5 min. The position of the deuteration was established
by 1H-NMR and 13C-NMR spectroscopy. The carbon
signals of 1-(benzyloxy)imidazole (3) were assigned by the
characteristic C-H coupling constants. The proton
signals were then assigned by means of C-H correlated
spectra (see the Experimental Section).
The metalation can be followed by addition of different
electrophiles. In this way a series of carbon, silicon,
halogen, and sulfur substituents could be introduced
selectively at the 2-position to give the products 4a -h
in high yields (Scheme 1).
All products 4a -h were stable except the 2-trimeth-
ylsilyl compound 4d which could not be isolated since it
underwent quantitative hydrolysis during the aqueous
workup producing 1-(benzyloxy)imidazole (3). The for-
mation of the trimethylsilyl compound 4d , expected to
be unstable,28-30 was proven by the fact that it could be
further deprotonated in situ at C-5.31
The (benzyloxy)imidazoles 4 could be debenzylated by
palladium-catalyzed hydrogenolysis under mild condi-
tions to give the corresponding 2-substituted 1-hydroxy-
imidazoles 5b and 5c. Under these conditions 1-(benzy-
1-(Ben zyloxy)im id a zole (3). Met h od a . A solution of
imidazole (17 g) dissolved in ethyl acetate (3.4 L) was added
to a solution of 55% 3-chloroperbenzoic acid (92.5 g) in ethyl
(28) J utzi, P.; Sakrib, W. Chem. Ber. 1973, 106, 2815.
(29) Carpenter, A. J .; Ngochindo, R. I. J . Chem. Soc., Perkin Trans.
1 1984, 481.
(30) Carpenter, A. J .; Chadwick, D. J . Tetrahedron 1986, 42, 2351.
(31) Eriksen, B. L.; Vedsø, P.; Begtrup, M. Unpublished work.
(32) Towliati, H. Chem. Ber. 1970, 103, 3952.
(33) Lettau, H. Z. Chem. 1971, 11, 10.
(34) Imbach, J . L.; J acquier, R.; Romane, A. Bull. Soc. Chim. Fr.
1967, 451.
(35) Kirk, K. L. J . Org. Chem. 1978, 43, 4381.
(36) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(37) Flynn, A. P. Chem. Br. 1984, 20, 30.
(26) Vedsø, P.; Begtrup, M. J . Org. Chem. 1995, 60, 4995.
(27) Uhlmann, P.; Felding, J .; Vedsø, P.; Begtrup, M. Unpublished
work.
(38) Suffert, J . J . Org. Chem. 1989, 54, 509.
(39) Burfield, D. R.; Smithers, R. H. J . Org. Chem. 1978, 43, 3966.

14 J . Org. Chem., Vol. 63, No. 1, 1998
Eriksen et al.
Sch em e 2
acetate (1 L).40 Stirring for 3 d, removal of the ethyl acetate,
addition of water (250 mL), filtration, and extraction of the
residue with water (5 × 50 mL) gave a combined aqueous
solution which was evaporated to ca. 150 mL. 3-Chlorobenzoic
acid and some imidazole were then removed by continuous
extraction with diethyl ether for 2 d. The pH of the aqueous
solution was then adjusted to 10 by addition of trisodium
phosphate (16.4 g), and unchanged starting material was
removed by continuous extraction with diethyl ether for 2 d.
To the aqueous solution was added 33% aqueous sodium
hydroxide (30 g). Evaporation to dryness, drying at 0.1 mmHg
at 100 °C for 3 h, dissolution in DMF (68 mL) in a nitrogen
atmosphere, cooling to 0 °C, addition of benzyl bromide (9.54
mL) during 10 min, stirring at room temperature for 18 h,
addition of saturated aqueous sodium hydrogen carbonate (35
mL) and water (170 mL), extraction with dichloromethane (3
× 100 mL), drying (MgSO4), removal of the dichloromethane,
and flash chromatography (heptane-ethyl acetate, 2:1 f 0:1)
gave 6.28 g (14%) of 1-(benzyloxy)imidazole (3) as a yellow oil
(reported25 bp 150 °C/0.05 mmHg). δH (CDCl3): 7.26-7.39 (6H,
m, Ph and H-2), 6.92 (1H, t, J ) 1.25 Hz, H-5), 6.87 (t, J )
1.25 Hz, H-4), 5.08 (2H, s, CH2). δC (CDCl3):41 133.3 (s, C-1′),
131.4 (ddd, J C-2,H-2 ) 213.2 Hz, J C-2,H-5 ) 9.0 Hz, and J C-2,H-4
) 5.6 Hz, C-2), 129.3 (dt, C-3′), 129.3 (dt, C-4′), 128.6 (ddd,
C-2′), 125.2 (ddd, J C-4,H-4 ) 192.6 Hz, J C-4,H-5 ) 11.4 Hz, and
J C-4,H-2 ) 8.8 Hz, C-4), 115.3 (ddd, J C-5,H-5 ) 194.0 Hz, J C-5,H-4
) 16.1 Hz, and J C-5,H-2 ) 3.0 Hz, C-5), 82.3 (t, CH2). The
heteroaromatic proton signals were separated in C6D6 (δ
(C6D6): 7.37 (t, J ) 1.2 Hz, H-2), 7.10 (t, J ) 1.2 Hz, H-5),
6.69 (t, J ) 1.2 Hz, H-4). The proton signals were assigned
by CH correlated spectra.
1-(Ben zyloxy)im id a zole (3). Meth od b. To 3-hydroxy-
imidazole 1-oxide (1) (5.0 g, 50 mmol) dissolved in 4 M
hydrochloric acid (35 mL) was added 10% palladium on carbon
(0.26 g), and the mixture was hydrogenated at 95 °C and 1
atm until 1.5 L of hydrogen had been consumed (65-145 h).
Filtration, removal of the solvents, and coevaporation twice
with toluene gave 6.4 g of a 15:80:5 mixture of imidazole,
1-hydroxyimidazole (5a ), and unchanged starting material (1)
(1H-NMR).44 To this mixture was added trisodium phosphate
(1.0 g, 2.6 mmol) and 33% aqueous sodium hydroxide (ca. 7
mL) until the pH was adjusted to 10. The solution was
extracted with diethyl ether overnight in order to remove
imidazole. The absence of imidazole in the aqueous solution
1
should be confirmed by H-NMR. The water was removed at
40 °C and 0.1 mmHg. The residue was then coevaporated with
toluene (3 × 20 mL) and dried at 0.1 mmHg over P2O5 until
constant weight.
Under nitrogen the residue was dissolved in dry dimethyl-
formamide (20 mL). At 0 °C a 55% suspension of sodium
hydride in mineral oil (50 mmol) and benzyl bromide (6.54 mL,
55 mmol) were added. After the mixture was stirred at 20 °C
for 16 h, saturated aqueous sodium hydrogen carbonate (10
mL) was added with caution. Dilution with water (50 mL),
extraction with diethyl ether (5 × 100 mL), drying (MgSO4),
removal of diethyl ether, removal of DMF by drying at 0.01
mmHg overnight, and flash chromatography (heptane-ethyl
acetate, 2:1 f 0:1) gave 4.35-4.8 g (50-55%) of 1-(benzyloxy)-
imidazole (3), Rf 0.45 (ethyl acetate-acetic acid, 1:0.01),
identical with the material above.
1-(Ben zyloxy)im id a zole (3). Meth od c. 1-Hydroxyimi-
dazole 3-oxide (1) (10.04 g, 100 mmol) and 85% potassium
hydroxide (8.6 g, 130 mmol) was dissolved in methanol (100
mL). When the solution was clear, benzyl bromide (11.9 mL,
100 mmol) was added during 2 min, and the mixture was
refluxed for 1 h. Filtration and extraction of the filter cake
with MeOH (2 × 80 mL) and removal of the solvent gave a
brown oil which was suspended in chloroform (100 mL). The
suspension was cooled to 0 °C, and phosporous trichloride (62
mL, 7 equiv) was added at such a rate that the internal
temperature was kept under 25 °C. The mixture was refluxed
for 1.5 h and cooled. Solvents and excess PCl3 were removed
in vacuo. Treatment by addition of toluene (100 mL) and
evaporation was repeated twice. Addition of water (250 mL)
and Et2O (200 mL), adjustment to pH 10 by addition of K2-
CO3 (ca. 75 g), separation of the organic layer, extraction of
the aqueous solution with Et2O (3 × 150 mL), drying of the
combined organic phases (MgSO4), filtration, evaporation, and
flash chromatography (heptane-CH2Cl2-PriOH, 1:1:0 f 1:1:
5%) gave 12.0 g (69%) of 1-(benzyloxy)imidazole as a yellow
oil which crystallized upon cooling. Mp 31-33 °C, Rf 0.26
(heptane-CH2Cl2-PriOH, 1:1:5%), identical with the material
above.
3-Hyd r oxyim id a zole 1-Oxid e (1).17 A stirred mixture of
40% aqueous glyoxal (7.6 mL), 37% aqueous formaldehyde (6.0
mL), and methanol (15 mL) was cooled to 0 °C, and a solution
of hydroxylammonium chloride (9.26 g) in water (11.2 mL) was
added, followed by addition of concd hydrochloric acid (1.33
mL) over 1 min. The resulting solution was stirred for 24 h
at 20 °C and then, cooled to 0 °C, and the pH was adjusted to
4.1 (pH meter) with 33% aqueous sodium hydroxide while the
temperature was kept below 20 °C. This caused precipitation.
After the mixture was stirred for 1 h at 0 °C, the precipitate
was filtered off, washed with water (10 mL, 0 °C), methanol
(10 mL, 0 °C), and ether (20 mL), and dried to yield 5.35 g
(80%) of 3-hydroxyimidazole 1-oxide (1), mp 178-180 °C.
Recrystallization from water did not raise the melting point
(reported17 mp 178-180 °C).
(40) Imidazole and 3-chloroperbenzoic acid should not be mixed in
the dry state because this may lead to a violent reaction.
(41) The carbon signals of 1-(benzyloxy)imidazole (3) were assigned
assuming that δC-2 > δC-4 > δC-5, as in other 1-substituted imida-
zoles.42,43 The assignment was confirmed by the characteristic large
one bond C-H coupling of C-2 and the distinct two and three C-H
3
couplings of C-5 (2J C-5,H-4 ) 16.1 and J C-5,H-2 ) 3.0 Hz) which are
Lith ia tion sSta n d a r d P r oced u r e. Under nitrogen, a
solution of 1-(benzyloxy)imidazole (3) (174 mg, 1.0 mmol) in
tetrahydrofuran (8 mL) was cooled to -78 °C. n-Butyllithium
(1.68 M in hexanes, 0.71 mL, 1.2 mmol) was added with
different from those of C-4 (both in the range 8.8-11.6 Hz).42,43 The
assignment of the 1H- and 13C-NMR signals of the 2-substituted
1-(benzyloxy)imidazoles (6a -h ) was based on the NMR chemical shifts
of 1-(benzyloxy)imidazole (3) and coupled 13C-NMR spectra.
(42) Wasylishen, R. E.; Tomlinson, G. Can. J . Biochem. 1977, 55,
579.
(43) Begtrup, M.; Elguero, J .; Faure, J .; Camps, P.; Estopa, C.;
Ilavsky, D.; Fruchier, A.; Marzin, C.; de Mendoza, J . Magn. Reson.
Chem. 1988, 26, 134.
(44) All starting material is consumed if the reaction time is
increased, but the yield of 4 decreases due to its further reduction to
imidazole.

Synthesis of 2-Substituted 1-Hydroxyimidazoles
J . Org. Chem., Vol. 63, No. 1, 1998 15
stirring during 2 min. After the mixture was stirred for an
additional 5 min, the electrophile was added. Stirring was
continued at -78 °C for 1 h, and then the reaction mixture
was allowed to warm to 20 °C in the course of 1 h. Stirring
was continued at 20 °C for an additional 0.5 h. The mixture
was worked up by addition of saturated aqueous sodium
hydrogen carbonate (10 mL), extraction with dichloromethane
(5 × 10 mL), drying (MgSO4), filtration, and removal of the
dichloromethane to give the crude product.
128.6, 127.1, 123.9 (J C-4,H-4 ) 196.3 Hz and J C-4,H-5 ) 8.1 Hz,
C-4), 117.7 (J C-5,H-5 ) 196.7 Hz and J C-5,H-4 ) 15.2 Hz, C-5),
81.7.
1-(Ben zyloxy)-2-iod oim id a zole (4g). After addition of
iodine (567 mg, 2.2 equiv) and stirring as described in the
standard procedure, Na2S2O3‚5H2O (1 g) dissolved in 10 mL
of water was added. Normal workup then gave 289 mg of a
residue which upon flash chromatography (heptane-ethyl
acetate, 2:1 f 0:1) afforded 260 mg (87%) of 1-(benzyloxy)-2-
iodoimidazole (4g), mp 78-79 °C (from ethyl acetate-pentane).
Anal. Found: C, 40.18; H, 2.60; N, 9.25. Calcd for C10H9N2-
OI: C, 40.02; H, 3.02; N, 9.33. δH (CDCl3): 7.41 (5H, s), 6.97
(1H, d, J ) 1.4 Hz), 6.96 (1H, d, J ) 1.4 Hz), 5.13 (2H, s). δC
(CDCl3): 132.7, 129.8, 129.6, 128.9 (J C-4,H-4 ) 197.5 Hz and
J C-4,H-5 ) 8.3 Hz, C-4), 128.7, 119.7 (J C-5,H-5 ) 194.3 Hz and
J C-5,H-4 ) 15.5 Hz, C-5), 83.5 (J C-2,H-4 ) 7.6 Hz and J C-2,H-5
) 11.4 Hz, C-2), 82.1. The compound should be stored in a
refrigerator since it turns yellow on standing at room temper-
ature.
P r ep a r a t ion of 2-Su b st it u t ed 1-(Ben zyloxy)im id a -
zoles. 1-(Ben zyloxy)-2-[2H]im id a zole (4a ). After addition
of monodeuteriomethanol (CH3OD, 0.20 mL), the mixture
was worked up as above to give a crude product which was
flash chromatographed (heptane-ethyl acetate, 2:1 f 0:1),
affording 146 mg (84 %) of 1-(benzyloxy)-2-[2H]imidazole (4a ).
1
The H spectrum (in C6D6 solution) was identical with that of
the starting material except that the signal from H-2 was
absent and the signals from H-4 and H-5 each collapsed to
doublets. The signal from C-2 appeared as a triplet (J CD
32.5 Hz).
)
1-(Ben zyloxy)-2-(m eth ylth io)im id a zole (4h ). After ad-
dition of dimethyl disulfide (0.25 mL, 3 equiv), the mixture
was stirred and worked up as in the standard procedure to
give 215 mg of a residue which was flash chromatographed
(heptane-ethyl acetate, 4:1 f 0:1) to give 199 mg (91%) of
1-(benzyloxy)-2-(methylthio)imidazole (4h ) as an oil. Ball-
tube distillation (135 °C, 0.2 mmHg) afforded a colorless
sample. Anal. Found: C, 59.26; H, 5.02; N, 12.50. Calcd for
C11H12N2OS: C, 59.98; H, 5.49; N, 12.72. δH (CDCl3): 7.40
(5H, s), 6.87 (2H, s), 5.11 (2H, s), 2.60 (3H, s). δC (CDCl3):
138.3, 133.1, 129.6, 129.3, 128.6, 125.1, 117.4, 81.1, 14.7.
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 (5a ). 1-(Benzyloxy)imidazole (3) (1.34
g), 10% palladium on carbon (263 mg), and methanol (65 mL)
were stirred under hydrogen at 1 bar and 0 °C for 1 h.
Filtration through kieselguhr and removal of the solvent gave
624 mg (96%) of 1-hydroxyimidazole (5a ), mp 91-92 °C (from
methanol-ethyl acetate, reported17 mp 93 °C). The signals
from H-4 and H-5 collapsed in D2O solution as a doublet
(J H-4,H-2 ) J H-5,H-2 ) 1.9 Hz). Separate signals for H-4 and
H-5 were observed in DMSO as broad singlets. The unam-
biguous assignment of the signals from H-4 and H-5 and from
C-4 and C-5 will be discussed in a separate paper. δH (DMSO-
d6): 7.82 (1H, bs), 7.24 (1H, bs), 6.85 (1H, bs). δC (DMSO-d6):
131.5 (ddd, J ) 223.8, 4.7, and 4.4 Hz, C-2), 123.3 (ddd, J )
205.7, 12.2, and 4.6 Hz), 118.2 (ddd, J ) 203.5, 10.7, and 6.5
Hz).
1-Hyd r oxyim id a zole Hyd r och lor id e (5a ‚HCl). Simi-
larly, 1-(benzyloxy)-2-chloroimidazole (4f) (187 mg) in 2 h gave,
after drying at 0.02 mmHg, 108 mg (99%) of 1-hydroxyimida-
zole hydrochloride (5a ‚HCl) as a hygroscopic crystal mass
which was reprecipitated from methanol-ethyl acetate (re-
ported18 deliquescent crystals). δH (D2O): 8.78 (1H, t, J ) 1.8
Hz), 7.52 (1H, t, J ) 1.8 Hz), 7.34 (1H, t, J ) 1.8 Hz). δC
(CDCl3): 129.0, 122.8, 119.0.
1-Hyd r oxy-2-for m ylim id a zole (5b). Similarly, 1-(benzy-
loxy)-2-formylimidazole (4c) (196 mg) in 1 h gave 106 mg (97%)
of 1-hydroxy-2-formylimidazole (5b), which when recrystallized
from ethyl acetate-heptane had mp 149 °C dec. Anal.
Found: C, 42.59; H, 3.73; N, 24.27. Calcd for C4H4N2O2:
42.86; H, 3.60; N, 24.99. δH (DMSO-d6): 9.70 (1H, s), 7.64 (1H,
bs), 7.20 (1H, bs). δC (DMSO-d6): 178.3, 138.6, 127.4, 123.1.
Deben zyla tion w ith Hyd r och lor ic Acid . 1-Hyd r oxy-
im id a zole Hyd r och lor id e (5a ‚HCl). 1-(Benzyloxy)imidazole
(3) (182 mg) and concd hydrochloric acid (5 mL) were refluxed
for 2 h. Washing with dichloromethane (3 × 10 mL), back-
extraction of the dichloromethane solutions with concd hydro-
chloric acid (10 mL), and evaporation of the combined aqueous
solutions to dryness gave 124 mg (98%) of 1-hydroxyimidazole
hydrochloride (5a ‚HCl), identical with the material described
above.
1-(Ben zyloxy)-2-m eth ylim id a zole (4b). Methyl iodide (5
equiv) was added, and the mixture was stirred at -78 °C for
1 h. In order to destroy excess of methyl iodide, 33% dim-
ethylamine in ethanol (5 mL) was added at -78 °C, and the
mixture was worked up as above to give 179 mg (95%) of
1-(benzyloxy)-2-methylimidazole (4b) as a yellow oil. Ball-
tube distillation at 150 °C/2 mmHg gave an analytical speci-
men. Anal. Found: C, 69.94; H, 6.39; N, 14.82. Calcd for
C11H12N2O: C, 70.19; H, 6.43; N, 14.88. δH (CDCl3): 7.26-
7.41 (5H, m), 6.88 (1H, d, J ) 1.5 Hz), 6.79 (1H, d, J ) 1.5
Hz), 5.05 (2H, s), 2.13 (3H, s). δC (CDCl3): 139.7, 133.0, 129.4,
129.2, 128.4, 123.3 (J C-4,H-4 ) 191.5 Hz and J C-4,H-5 ) 8.3 Hz,
C-4), 114.4 (J C-5,H-5 ) 193.3 Hz and J C-5,H-4 ) 15.7 Hz, C-5),
81.0, 11.0.
1-(Ben zyloxy)-2-for m ylim id a zole (4c). After addition of
dimethylformamide (0.38 mL, 4.8 equiv), 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 NaHCO3 to
adjust the pH to 10 and extractive workup with dichlo-
romethane as described above gave a residue which by flash
chromatography (heptane-ethyl acetate, 4:1 f 0:1) afforded
188 mg (93%) of 1-(benzyloxy)-2-formylimidazole (4c). Mp:
57-58 °C (ethyl acetate-heptane). Anal. Found: C, 65.14;
H, 5.06; N, 13.76. Calcd for C11H10N2O2: C, 65.34; H, 4.98;
N, 13.85. δH: 9.76 (1H, d, J ) 0.8 Hz), 7.38 (5H, s), 7.07 (1H,
d, J ) 1.0 Hz), 6.99 (1H, t, J ) 0.9 Hz), 5.23 (2H, s). δC
(CDCl3): 178.9 (J C-H ) 187.5 Hz, CdO), 138.5 (J C-2,CHO ) 29.1
Hz, J C-2,H-4 ) 8.8 Hz, and J C-2,H-5 ) 5.6 Hz, C-2), 132.5, 129.8,
129.5, 128.6, 127.4 (J C-4,H-4 ) 195.5 Hz and J C-4,H-5 ) 8.4 Hz,
C-4), 121.8 (J C-5,H-5 ) 195.3 Hz and J C-5,H-4 ) 16.3 Hz, C-5),
82.4.
1-(Ben zyloxy)-2-(ter t-bu tyldim eth ylsilyl)im idazole (4e).
After addition of tert-butyldimethylchlorosilane (284 mg, 1.35
equiv) dissolved in tetrahydrofuran (1.8 mL), the mixture was
stirred and worked up as described above to give a residue
which upon flash chromatography (heptane-ethyl acetate-
triethylamine, 2:1:0.075 f 0:1:0.025) gave 208 mg (72%) of
1-(benzyloxy)-2-(tert-butyldimethylsilyl)imidazole (4e) as an
oil. δH (CDCl3): 7.36-7.44 (5H, m), 7.07 (1H, d, J ) 1.2 Hz),
6.96 (1H, d,J ) 1.2 Hz), 5.11 (2H, s), 0.94 (9H, s), 0.39 (6H, s).
δC (CDCl3): 144.1, 133.7, 129.1, 128.9, 128.7, 126.9, 117.2, 82.2,
26.4, 17.4, -5.8. Attempted ball-tube distillation at 1 mmHg
led to clean desilylation producing the starting material 3.
1-(Ben zyloxy)-2-ch lor oim id a zole (4f). After addition of
hexachloroethane (474 mg, 2.0 equiv) dissolved in tetra-
hydrofuran (1.9 mL), the mixture was stirred and worked
up as in the standard procedure to give a residue which by
flash chromatography (heptane-ethyl acetate, 2:1 f 0:1) gave
193 mg (93%) of 1-(benzyloxy)-2-chloroimidazole (4f), mp
51-52 °C. Recrystallization (ethyl acetate-heptane) raised
the mp to 56 °C. Anal. Found: C, 57.70; H, 4.42; N, 13.40.
Calcd for C10H9N2OCl: C, 57.57; H, 4.35; N, 13.43). δH
(CDCl3): 7.35-7.43 (5H, m), 6.82 (1H, d J ) 1.6 Hz), 6.76 (1H,
d J ) 1.6 Hz), 5.12 (2H, s). δC (CDCl3): 132.6, 129.7, 129.6,
1-Hyd r oxy-2-ch lor oim id a zole Hyd r och lor id e (5c‚HCl).
1-(Benzyloxy)-2-chloroimidazole (4f) (283 mg) and concd hy-
drochloric acid (5 mL) were refluxed for 2 h. Washing with
dichloromethane (3 × 10 mL), back-extraction of the dichlo-
romethane solutions with concd hydrochloric acid (10 mL),

16 J . Org. Chem., Vol. 63, No. 1, 1998
Eriksen et al.
evaporation of the combined aqueous solutions to dryness, and
coevaporation twice with 2 mL of toluene afforded 187 mg
(89%) of 1-hydroxy-2-chloroimidazole hydrochloride (5c‚HCl),
mp 173 °C (from methanol-ethyl acetate). Anal. Found: C,
23.48; H, 2.40; N, 18.12. Calcd for C3H4N2OCl2: C, 23.25; H,
2.60; N, 18.08). δH (D2O): 7.56 (1H, d, J ) 2.45 Hz), 7.34 (1H,
d, J ) 2.45 Hz). δC (D2O): 131.0, 120.6, 118.2.
(10 mL), and a 15% solution of titanium trichloride in 20%
aqueous HCl (2.9 mL) was added at 0 °C during 5 min.
Stirring for 1 h, adjusting the pH to 10 with saturated aqueous
sodium hydrogen carbonate, and continuous extraction
with diethyl ether for 20 h gave 172 mg (100%) of 2-chloroimi-
dazole (6b), mp 162-163 °C (reported34 mp 164-165 °C). δH
(CDCl3): 7.03.
R ed u ct ion of 1-Hyd r oxyim id a zoles. Im id a zole (6a ).
1-Hydroxyimidazole (5a ) (69 mg), 10% palladium on carbon
(32 mg), and methanol (5 mL) were stirred under hydrogen at
1 bar and 20 °C for 24 h. Filtration through kieselguhr and
removal of the solvent gave 50 mg (89%) of imidazole (6a ), mp
88 °C (reported45 mp 89-91 °C).
Ack n ow led gm en t. This work was supported by the
Danish Council for Technical and Scientific Research
and the Lundbeck Foundation. The NMR spectrometer
is a gift from the Velux Foundation of 1981, the Danish
Council for Technical and Scientific Research, the Ib
Henriksen Foundation, and the Torkil Steenbeck
Foundation.
2-Ch lor oim id a zole (6b ). 1-Hydroxy-2-chloroimidazole
hydrochloride (5c‚HCl) (259 mg) was dissolved in methanol
(45) Debus, H. Liebigs Ann. Chem. 1858, 107, 199.
J O970355+