Parallel synthesis of substituted imidazoles from 1,2-aminoalcohols

Article abstract of DOI:10.1016/S0040-4039(02)01839-7

Substituted imidazoles can be prepared efficiently from cyclic or acyclic 1,2-aminoalcohols via a four-step procedure involving acylation of the amine, oxidation of the alcohol, imine formation and cyclization. Examples are presented and the methodology i

Full text of DOI:10.1016/S0040-4039(02)01839-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7687–7690
Parallel synthesis of substituted imidazoles from
1,2-aminoalcohols
Konrad H. Bleicher,a Fernand Gerber,a Yves Wu¨thrich,a Alexander Alaninea and Alfredo Caprettab,*
aF. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland
bInstitute of Molecular Catalysis, Department of Chemistry, Brock University, St. Catharines, Ontario, Canada L2S 3A1
Received 25 July 2002; revised 28 August 2002; accepted 30 August 2002
Abstract—Substituted imidazoles can be prepared efficiently from cyclic or acyclic 1,2-aminoalcohols via a four-step procedure
involving acylation of the amine, oxidation of the alcohol, imine formation and cyclization. Examples are presented and the
methodology is applied in the generation of a library of compounds containing a fused imidazole-azepine motif. © 2002 Elsevier
Science Ltd. All rights reserved.
Imidazoles are found ubiquitously in Nature and are
incorporated as key structural fragments in many bio-
logical and chemical systems.1 While numerous synthe-
ses of these five-membered heterocycles are described in
the literature,2 one approach to substituted imidazoles
involves the use of a-amidoimines (Scheme 1, 4).3
Treatment of these systems with reagents (such as PCl5;
POCl3; or PPh3, C2Cl6, Et3N) that allow for conversion
of the amide to its corresponding chloroimine, results in
cyclization to the imidazole (5). In the route developed
by Engel and Steglich, the a-amidoimines were derived
from amino acid precursors via a Dakin West rear-
rangement. However, other disconnections of the a-
amidoimines are possible. The key imine (4) is clearly
derived from the ketone (3) which in turn can come
from either an a-aminoketone or the a-amidoalcohol
(2). Removal of the acyl group reveals that the starting
point for the synthesis would be the vicinal aminoalco-
hol (1). This is a particularly attractive pathway since
there are established, preparative routes to these
systems4 as well as a number of 1,2-aminoalcohols
commercially available.
The general synthetic route is illustrated in Scheme 1.
The vicinal amino alcohols (1) were treated with EDCI
(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride) and the desired carboxylic acid to allow for
amide formation in high yields.5 Use of acid chlorides
proved to be problematic since significant amounts of
the bisacylated product were formed under these condi-
tions. Utilization of EDCI also tolerated the addition
of small amounts of water to the reaction mixture
Scheme 1. General synthetic route to substituted imidazoles. Reagents and conditions: (i) R3-CO2H, EDCI, CH3CN, H2O; (ii)
SO3·pyridine, DMSO, Et3N; (iii) R4-NH2 and either Ti(i-PrO)4, CH2Cl2 or Si(OEt)4, H+, toluene; (iv) PCl5.
* Corresponding author. Tel.: +1-905-688-5550 ext. 3848; fax: +1-905-682-9020; e-mail: fcaprett@chemiris.labs.brocku.ca
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01839-7

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facilitating dissolution of the amino alcohols (often
used as their hydrochloride salt) and smooth coupling.
While numerous oxidation protocols were investigated
for the conversion of 2“3, a protocol utilizing sulphur
trioxide pyridine complex demonstrated itself to be the
most generally applicable.6 In this way, both secondary
and primary alcohols could be readily oxidized to their
corresponding ketones or aldehydes in roughly 2 h in
excellent yields. Not surprisingly, the ease and degree of
imine formation 4 varied greatly depending on the
nature of the carbonyl and amine employed. With the
majority of cases (aldehydes with alkyl-, benzyl- or aryl
amines and ketones with alkyl- and benzylamines),
imine formation was carried out in dichloromethane in
the presence of a Lewis acid.7 In the more stubborn
cases (those involving ketones and arylamines, for
example 5c), a modification of the Love and Ren’s
protocol,8 involving tetraethoxysilane under acidic con-
ditions, was used.9 The imines were not isolated but
treated directly with phosphorous pentachloride. Under
these conditions, the amidoimine rapidly cyclized to the
imidazole. Other reagents also induced cyclization (for
example, POCl3 or PPh3, C2Cl6), however, the PCl5 was
shown to be the most effective. The entire procedure
could be carried out without isolation or purification of
the intermediates.
Phenylalaninol, 2-amino-1-(3,4-dimethoxyphenyl)pro-
pan-1-ol and 2-aminocyclohexanol were chosen as the
initial vicinal aminoalcohols for investigation since this
collection of substrates contains a variety of functional-
ity (including cyclic or acyclic examples, primary and
secondary alcohols, aliphatic and aromatic fragments).
Similarly, the carboxylic acids (alkyl and aromatic) and
the amines (alkyl-, benzyl- or aryl amines containing
heteroaromatic fragments and other functionality) were
selected so as to provide a broad assortment of conden-
sation components and, thereby, illustrate the general
applicability and scope of the chemistry developed. The
results are summarized in Table 1 with the overall yield
based on the amount of vicinal aminoalcohol used.
1
Note that all compounds were characterized by MS, H
Table 1. Substituted imidazoles prepared via Scheme 1

K. H. Bleicher et al. / Tetrahedron Letters 43 (2002) 7687–7690
7689
Scheme 2. Synthetic route to imidazole-azepine library. Reagents and conditions: (i) m-CPBA, CH2Cl2; (ii) NaN3, acetone/H2O;
(iii) PPh3, H2O, THF; (iv) 2,4-dichlorobenzoic acid, EDCl, CH3CN, H2O; (v) SO3·pyridine, DMSO, Et3N; (vi) R-NH2, Ti(i-PrO)4,
CH2Cl2; (vii) PCl5.
and 13C NMR.10 Examples 5r, 5s, 5t and 5u (those
logically interesting small molecules. The carboxylic
acid, aminoalcohol and primary amine building blocks
are available commercially as collections in large sets of
variable structures. Alternatively, the aminoalcohols
can be accessed via amino acids or, as demonstrated
above, from olefins (perhaps derived from metathesis
reactions). The robustness of the chemistry developed
coupled with the large set of starting materials insures
an efficient library synthesis and structural diversity
within these compound collections. Details concerning
these imidazole libraries and the application of the
chemistry to solid phase imidazole synthesis as well as
solid supported reagents will be reported in due course.
derived from 2-aminocyclohexanol) were among the
most intriguing as these systems represent imidazole
annulations. It should be noted that while this method-
ology works well with six-membered cyclic systems
containing the requisite 1,2-aminoalcohol moiety,
exploratory efforts to carry out the same chemistry on
five-membered analogues were unsuccessful.
If one considers the numerous routes available to 1,2-
aminoalcohols, those originating from an alkene moiety
are especially appealing. As a result, an extension of the
imidazole annulation chemistry was developed during
the preparation of the imidazole-azepine library shown
in Scheme 2. Benzyl 2,3,6,7-tetrahydro-1H-azepine-1-
carboxylate 6 was converted to epoxide 7 under stan-
dard mCPBA conditions then opened to the vicinal
azidoalcohol 8 via treatment with NaN3. Reduction to
9 proceeds well using Staudinger conditions. With the
required 1,2-aminoalcohol in place, application of the
chemistry developed above allows for facile introduc-
tion of the substituted imidazole fragment. Acylation
with 2,4-dichlorobenzoic acid and EDCI gave 10 which
was readily oxidized to 11. Treatment with a series of
amines allowed for preparation of the imines (of the
general type 12) that were cyclized to the imidazoles 13
using the chemistry described above in overall yields
ranging from 50 to 62% (based on the amount of 11
employed). This family of compounds effectively
demonstrates the usefulness of the methodology and
shows that one can now conceive of virtually any
isolated double bond as a potential site for the intro-
duction of an imidazole.
Acknowledgements
The authors wish to thank F. Hoffmann-La Roche AG
(for funding and hosting AC during his sabbatical),
Brock University and the Natural Sciences and Engi-
neering Research Council of Canada for their financial
support.
References
1. For a review on imidazoles, see: (a) Grimmet, M. R. In
Comprehensive Hetereocyclic Chemistry, Potts, K. T., Ed.;
Pergamon Press: Oxford, 1984; Vol. 4, pp. 345–498; (b)
Grimmet, M. R. In Comprehensive Hetereocyclic Chem-
istry II, Shinkai, I., Ed.; Pergamon Press: Oxford, 1996;
Vol. 3, pp. 77–220.
2. For examples, see Ref. 1 and (a) Gordon, T. D.; Singh,
J.; Hansen, P. E.; Morgan, B. A. Tetrahedron Lett. 1993,
34, 1901–1904; (b) Bilodeau, M. T.; Cunnigham, A. M. J.
Org. Chem. 1998, 63, 2800–2801; (c) Njar, V. C. O.
Synthesis 2000, 2019–2028; (d) Jetter, M. C.; Reitz, A. B.
Synthesis 1998, 829–831.
From a medicinal chemistry point of view, the method-
ology developed is ideally suited for use with a wide
range of readily available building blocks in a parallel
fashion resulting in a combinatorial array of pharmaco-

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3. Engel, N.; Steglich, W. Liebigs Ann. Chem. 1978, 1916–
organic layer was then dried over sodium sulphate, evap-
orated under a reduced pressure and the residue purified
by column chromatography using silica gel.
1927.
4. For examples, see: (a) Andersson, M. A.; Epple, R.;
Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 2002, 41, 472–475; (b) Schaus, S. E.; Larrow, J. F.;
Jacobsen, E. N. J. Org. Chem. 1997, 62, 4197.
5. General procedure for amide formation. The aminoalcohol
(1 mmol), carboxylic acid (1.1 mmol) and EDCI (210 mg,
1.1 mmol) were suspended in acetonitrile (25 ml) and
sufficient water was added dropwise to allow for com-
plete dissolution of all the reagents. The reaction mixture
was stirred at room temperature for 18 h at which time
the solvent was evaporated under a reduced pressure and
material used directly in the following step. Alternatively,
the residue could be purified by column chromatography
using silica gel.
6. General procedure for the oxidation. The amidoalcohol (1
mmol) was dissolved in DMSO (10 ml) and Et3N (600
mg, 6 mmol) and cooled to 0°C. The reaction mixture
was then treated with a solution of SO3·pyridine complex
(477 mg, 3 mmol) in DMSO (10 ml) and allowed to warm
to room temperature. After 2 h, the reaction mixture was
added to CH2Cl2 (4×40 ml) in a separatory funnel and
washed with 0.1N HCl (3×40 ml). The organic layer was
then dried with sodium sulphate and evaporated under a
reduced pressure. The residue could be purified by
column chromatography using silica gel or used directly
in the following step.
7. General procedure for imine formation and cyclization to
the imidazole. The aldehyde or ketone (1 mmol) generated
in the previous step was dissolved in CH2Cl2 (10 ml) and
treated with the amine (2 mmol) and Ti(iOPr)4 (284 mg,
1 mmol). The reaction mixture was stirred at room
temperature for 18 h at which time PCl5 (833 mg, 4
mmol) was added. The mixture was allowed to stir for a
further 5 h. The solvent was evaporated under a reduced
pressure and the residue suspended in ethyl acetate (3×20
ml) and then washed with 0.1N NaOH (3×20 ml). The
8. Love, B. E.; Ren, J. J. Org. Chem. 1993, 58, 5556–5557.
9. Alternate procedure for imine formation and cyclization to
the imidazole. The ketone (1 mmol) and the amine (2
mmol) were dissolved in toluene (10 ml) and treated with
Si(OEt)4 (416 mg, 2 mmol) and a drop of conc. H2SO4.
The solution was heated to reflux for 18 h. The reaction
was then cooled to room temperature and treated with
PCl5 (833 mg, 4 mmol). The mixture was allowed to stir
for a further 5 h. The solvent was evaporated under a
reduced pressure and the residue suspended in ethyl
acetate (3×20 ml) then washed with 0.1N NaOH (3×20
ml). The organic layer was then dried over sodium sul-
phate, evaporated under a reduced pressure and the
residue purified by column chromatography using silica
gel.
10. Representative spectroscopic data. 5a: 1H NMR (DMSO-
d6, 500 MHz) l 0.86 (3H, t), 1.22 (2H, m), 1.72 (2H, m),
2.68 (3H, s), 3.81 (s, 3H), 3.83 (t, 2H), 3.94 (s, 3H),
7.10–7.76 (8H, m): 13C NMR: (DMSO-d6, 125 MHz) l
14.4, 20.7, 25.9, 31.8, 50.2, 2×56.0, 111.9, 112.7, 124.5,
126.0, 2×126.9, 127.3, 128.2, 2×128.6, 130.2, 145.54,
148.7, 149.6, 150.5; HRMS for C22H26N2O2: calculated
350.1994, observed 350.1983. 5k: 1H NMR (DMSO-d6,
500 MHz) l 0.83 (6H, d), 2.68 (3H, s), 2.73 (1H, m), 3.98
(d, 2H), 7.27–7.69 (8H, m); 13C NMR (DMSO-d6, 125
MHz) l 2×20.6, 25.9, 34.8, 55.9, 125.8, 127.2, 2×128.2,
2×128.4, 2×128.8, 129.9, 131.8, 132.9, 133.1, 136.0, 138.2,
150.6; HRMS for C20H20Cl2N2: calculated 358.1004,
1
observed 358.1009. 5r: H NMR (DMSO-d6, 500 MHz) l
0.76 (3H, t), 1.17 (2H, m), 1.57 (2H, m), 1.81 (4H, m),
2.65 (2H, m), 2.72 (2H, m), 3.99 (2H, t), 7.58 (3H, m),
7.75 (2H, m); 13C NMR (DMSO-d6, 125 MHz) l 13.6,
19.4, 20.4, 22.2, 22.3, 23.4, 31.9, 44.4, 128.7, 128.9, 2×
129.1, 2×129.3, 129.4, 130.6, 143.5; HRMS for C17H22N2:
calculated 254.1783, observed 254.1790.