Facile synthesis of optically active imidazole derivatives

Article abstract of DOI:10.3390/12051183

Five optically active imidazole derivatives have been synthesized via a facile 4-step reaction sequence starting from commercially available and inexpensive N-Cbz amino acids. While microwave assisted condensation was unsuccessful, the condensation of the

Full text of DOI:10.3390/12051183

Molecules 2007, 12, 1183-1190
molecules
ISSN 1420-3049
© 2007 by MDPI
www.mdpi.org/molecules
Full Paper
Facile Synthesis of Optically Active Imidazole Derivatives
Ales Marek, Jiri Kulhanek, Miroslav Ludwig and Filip Bures*
Department of Organic Chemistry, Faculty of Chemical Technology, University of Pardubice,
nam. Cs. legii 565, Pardubice, 53210, Czech Republic
* Author to whom correspondence should be addressed; E-mail: filip.bures@upce.cz
Received: 11 May 2007; in revised form: 22 May 2007 / Accepted: 23 May 2007 / Published: 30 May
2007
Abstract: Five optically active imidazole derivatives have been synthesized via a facile
4-step reaction sequence starting from commercially available and inexpensive N-Cbz
amino acids. While microwave assisted condensation was unsuccessful, the condensation
of the corresponding α-bromoketones with formamidine acetate in liquid ammonia was
revealed to be a useful method for the synthesis of such imidazole derivatives. The
derivatives thus prepared are structurally-related to histamine.
Keywords: Imidazole, condensation, optically active ligand
Introduction
From time immemorial, organic chemists have been attempting to synthesize, isolate and
characterize heterocyclic molecules for their unique chemical and physical properties. Despite the fact
that many convenient synthetic methods have been utilized for preparing the basic heterocycles [1], a
facile synthesis of optically active analogues still remains a challenge. Among the many possible
targets enantiopure five-membered heterocyclic derivatives such as imidazole are of particularly
interest. For instance, naturally occurring 4-substituted imidazoles such as histidine or histamine and
their significance as an essential amino acid or its decarboxylation product, are well known. Imidazole
chemistry currently attracts considerable attention, where the imidazole derivatives are widely applied
as N-ligands coordinating transition metals [2-3]. The application of imidazoles in medicinal chemistry

Molecules 2007, 12
1184
[4] or chemistry of natural products/alkaloids [5-6] or of 1,3-disubstituted imidazole salts as ionic
liquids [7-8] are also well known. Although a few examples of the synthesis and applications of
optically active imidazole derivatives have been published [9-13], development of an efficient
synthesis of such derivatives still requires more attention. Recently, we have published the synthesis
and application of enantiopure 2-phenylimidazoles starting from the commercially available α-amino
acids as a source of chirality [14-15]. It would be challenging to synthesize 2,5-unsubstituted
imidazoles bearing similar chains with a chiral amine (depending on the starting amino acids used). In
addition, optically active imidazole derivatives formed upon cross-coupling reactions at the 2 position
with another heterocycles (pyridine, phenanthroline, etc.), in order to further support the ability to bind
transition metal ions, might provide interesting enantiopure nitrogen ligands. A possible application of
such materials in asymmetric catalysis or as histamine-related products is apparent. Hence, we
describe herein the synthesis of the proposed optically active 4-substituted imidazole derivatives as
well as their detailed structural analysis.
Results and Discussion
One of the synthetic pathways used for the construction of the N(1)-C(5) and N(3)-C(4) bonds of
the imidazole ring involves reaction of 1,3-bifunctional electrophiles with various amidines. In order to
prepare a 2-unsubstituted imidazole, formamide must be employed, while the 1,3-bifunctional
electrophiles could be represented by various haloketones [16-18] or hydroxyketones [20]. Sugar
based hydroxyketones or hydroxyaldehydes and their application as suitable 1,3-bifunctional
electrophiles are also well known [20-21]. The condensation may be enhanced by microwave
irradiation [22] as well. Nevertheless, the most used method for imidazole ring construction involves a
condensation of the α-bromoketones with formamidine in liquid ammonia [16-21].
During our investigation in the field of enantiopure imidazole synthesis, we have developed an
efficient method utilizing N-Cbz protected α-amino acids 1 as a suitable chiral starting material.
Activation of the carboxylic function of the α-amino acid via mixed anhydrides 2, followed by its
reaction with diazomethane afforded α-diazoketones 3. Treatment of the α-diazoketones with
hydrobromic acid smoothly provided α-bromoketones 4, while nitrogen was liberated. In this way
prepared α-bromoketones may serve as suitable 1,3-bifunctional electrophiles and, using the known
condition for condensation in liquid ammonia as described above, we have prepared five optically
active imidazole derivatives 5 bearing substituents at position 4 (Scheme 1).
(S)-Cbz-Alanine, (S)-Cbz-valine, (S)-Cbz-leucine, (S)-Cbz-isoleucine and (S)-Cbz-phenylalanine
were used as the starting N-Cbz protected α-amino acids. The condensation reactions of the
α-bromoketones with formamidine acetate were carried out in a pressure vessel containing liquefied
ammonia at 70 °C. The reaction mixture was stirred overnight, extracted and purified by column
chromatography to afford pure imidazoles 5a-e. Yields and selected physical properties of the
compounds prepared are summarized in the Table 1.

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Scheme 1.
Table 1.
Yield[a] [%] e.e. [%]
20
Comp.
R / Starting amino acid
[α]D
5a
5b
5c
5d
5e
CH3 / (S)-Alanine
(CH3)2CH / (S)-Valine
81/69
99
99
99
99
99
-15.8 (c 1, MeOH)
-31.7 (c 0.52, MeOH)
-28.5 (c 0.46, MeOH)
-35.6 (c 1, MeOH)
-29.0 (c 1, MeOH)
49/42
69/57
72/56
40/37
(CH3)2CHCH2 / (S)-Leucine
CH3CH2(CH3)CH / (S)-Isoleucine
PhCH2 / (S)-Phenylalanine
[a] GC/isolated yields of the final condensation reaction
1
The enantiomeric excesses (e.e.) were determined by H-NMR spectroscopy using (R)-Mosher‘s
acid. The resulting spectra were compared with the spectra obtained from the corresponding racemate.
No racemization was observed throughout the entire reaction sequence. All of the synthesized
1
imidazoles were further characterized by H- and 13C-NMR spectroscopy, EI-MS and elemental
analysis (see Experimental section). The NMR structural analyses of the ligands showed the presence
of strong hydrogen bonds in a common CDCl3 solution, which resulted in hindered imidazole
1
tautomerism and hindered rotation in the protecting carbamate function used. H- and 13C-NMR
spectra then showed broad signals or two set of signals, without expected spin–spin interactions. The
hindered imidazole tautomerism and rotation in the carbamate function was suppressed if measured in
1
13
deuteromethanol. Hence, the H- and C-NMR spectra listed in the Experimental were measured in
CD3OD.
In addition to the condensation reaction carried out in liquid ammonia, microwave assisted reaction
[22] was attempted as well. The α-hydroxyketones 6, obtained from the conversion of the
α-diazoketone 3 using hydrochloric acid [23], were treated with formamidine acetate and irradiated
with microwaves (Scheme 2). Only traces of one corresponding imidazole 5a could be isolated, even

Molecules 2007, 12
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after we tried to optimize the reaction conditions. It is also noteworthy that no formation of the
corresponding imidazole was observed if another α-hydroxy- or α-bromoketone used. Hence, the
microwave assisted reaction was shown to be unsuitable for our derivatives.
Scheme 2.
Conclusions
Five novel imidazole derivatives have been synthesized and isolated in satisfactory yields (69-
37%). The crucial step of the reaction sequence was shown to be the condensation of the
corresponding α-bromoketones with formamidine acetate in liquid ammonia. In CDCl3 solutions the
products showed hindered imidazole tautomerism and also hindered carbamate function rotation,
which makes the NMR analysis difficult and, therefore, the spectra were measured in deuteromethanol.
Microwave assisted reaction of the α-hydroxyketones was revealed to be incompatible with the above
discussed intermediates. Overall, we have developed a facile 4-step synthesis of histamine-related
imidazole derivatives starting from the commercially available and inexpensive N-Cbz amino acids.
Cross-couplings of the synthesized imidazoles with other heterocycles, in order to produce even larger
nitrogen ligands with stronger coordinating ability, are now under investigation.
Experimental
General
Reagents and solvents (reagent grade) were purchased from Aldrich or Fluka and used as received.
The α-bromoketones 4 and α-hydroxyketones 6 were synthesized according to the literature
procedures [14, 23]. Evaporation and concentration in vacuo were performed at water aspirator
pressure. The condensation reactions in liquid ammonia were carried out in a ROTH pressure vessel.
The microwave assisted reactions were conducted in a MILESTONE MLS ETHOS 1600 URM oven
(300 W; 2.45 GHz). Column chromatography (CC) was carried out with SiO2 60 (particle size 0.040-
0.063 mm, 230-400 mesh; Merck) and commercially available solvents. Thin-layer chromatography
(TLC) was conducted on aluminium sheets coated with SiO2 60 F254 obtained from Merck, with
visualization by UV lamp (254 or 360 nm). Melting points (M.p.) were measured on a Buchi B-540
1
melting-point apparatus in open capillaries and are uncorrected. H- and 13C-NMR spectra were
recorded in CD3OD at 360 MHz or 90 MHz, respectively, with Bruker AMX 360 instrument at 20 °C.
Chemical shifts are reported in ppm relative to the signal of Me4Si. Residual solvent signals in the 1H-

Molecules 2007, 12
1187
13
1
and C-NMR spectra were used as an internal reference (CD3OD – 3.31 and 49.15 ppm for H- and
13C-NMR, respectively). Coupling constants (J) are given in Hz. The apparent resonance multiplicity
is described as s (singlet), br s (broad singlet), d (doublet), dd (doublet of doublets), t (triplet), q
(quartet) and m (multiplet). Optical rotation values were measured on a Perkin Elmer 341 instrument,
concentration c is given in g/100 mL CH3OH. The mass spectra were measured on GC/MS
configuration comprised of an Agilent Technologies – 6890N gas chromatograph (HP-5MS column,
length 30 m, I.D. 0.25 mm, film 0.25 µm) equipped with a 5973 Network MS detector (EI 70 eV, mass
range 33-550 Da).
General method for the condensations in liquid ammonia
Into a cooled (-78 °C) pressure vessel equipped with a magnetic stirrer, ammonia (100 mL) was
liquefied, followed by addition of the appropriate α-bromoketone (6.3 mmol) and formamidine acetate
(0.65 g; 6.3 mmol). The reaction mixture was stirred 20 h at 70 °C at 23-26 bar, the residual ammonia
evaporated, the residue taken up in CHCl3 (100 mL) and the organic extract washed successively with
sat. aq. potassium carbonate (3 × 100 mL) and water (200 mL). The organic layer was dried (Na2SO4)
and evaporated in vacuo. CC (SiO2; EtOAc/hexane 1:1 to CHCl3/CH3OH/NH4OH 5:1:0.1) afforded
the pure products.
(S)-Benzyl 1-(1H-imidazol-4-yl)ethylcarbamate (5a). Synthesized from α-bromoketone 4a (69 %
20
yield) as a white solid; Rf = 0.55 (SiO2; CHCl3/CH3OH/NH4OH 5:1:0.1); M.p. 119-121 °C; [α]D = -
15.8 (c 1, CH3OH); 1H-NMR: δ = 1.46 (3H, d, J = 6.9, CH3), 4.81 (1H, q, J = 6.9, CH), 5.04-5.11 (2H,
13
m, PhCH2), 6.90 (1H, s, 4-Him), 7.27-7.34 (5H, m, Ar), 7.59 (1H, d, J = 1.2, 2-Him); C-NMR: δ =
21.32 (CH3), 45.92 (CH), 67.53 (PhCH2), 116.27 (5-Cim), 128.95 (Ar), 129.09 (Ar), 129.57 (Ar),
136.48 (2-Cim), 138.50 (Ar), 141.9 (4-Cim), 158.53 (CO); EI-MS (70 eV) m/z (%): 245 (1), 154 (10),
137 (10), 122 (50), 108 (90), 94 (60), 79 (100), 67 (10), 51 (20), 44 (70); Elemental analysis (%) calcd.
for C13H15N3O2 (245.12): C 63.66, H 6.16, N 17.13; found: C 63.66, H 6.15, N 17.06.
(S)-Benzyl 1-(1H-imidazol-4-yl)-2-methylpropylcarbamate (5b). Synthesized from α-bromoketone 4b
(42 % yield) as an amorphous solid; Rf = 0.61 (SiO2; CHCl3/CH3OH/NH4OH 5:1:0.1); M.p. 95-100
20
1
°C; [α]D = -31.7 (c 0.52, CH3OH); H-NMR: δ = 0.86 (3H, d, J = 6.7, CH3), 0.92 (3H, d, J = 6.7,
CH3), 2.07-2.16 (1H, m, CH), 4.50 (1H, d, J = 7.2, NCH), 5.03-5.11 (2H, m, PhCH2), 6.93 (1H, s, 4-
13
Him), 7.25-7.35 (5h, m, Ar), 7.64 (1H, d, J = 1.1, 2-Him); C-NMR: δ = 18.94 (CH3), 20.15 (CH3),
33.92 (CH), 56.26 (NCH), 67.61 (PhCH2), 117.19 (5-Cim), 128.90 (Ar), 129.09 (Ar), 129.58 (Ar),
136.25 (2-Cim), 138.53 (Ar), 140.04 (4-Cim), 158.68 (CO); EI-MS (70 eV) m/z (%): 274 (20), 230 (20),
166 (100), 136 (10), 122 (10), 108 (30), 91 (30), 79 (30), 53 (10), 45 (70); Elemental analysis (%)
calcd. for C15H19N3O2 (273.15): C 65.91, H 7.01, N 15.37; found: C 65.91, H 7.01, N 15.21.
(S)-Benzyl 1-(1H-imidazol-4-yl)-3-methylbutylcarbamate (5c). Synthesized from α-bromoketone 4c
(57 % yield) as an amorphous solid; Rf = 0.63 (SiO2; CHCl3/CH3OH/NH4OH 5:1:0.1); M.p. 32-36 °C;
1
[α]D20 = - 28.5 (c 1, CH3OH); H-NMR: δ = 0.93 (6H, d, J = 6.1, 2 × CH3), 1.61-1.70 (3H, m, CH +
CH2), 4.78 (1H, t, J = 7.9, NCH), 5.05-5.11 (2H, m, PhCH2), 6.90 (1H, s, 4-Him), 7.24-7.33 (5H, m,

Molecules 2007, 12
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13
Ar), 7.58 (1H, d, J = 1.2, 2-Him); C-NMR: δ = 22.55 (CH3), 23.38 (CH3), 26.17 (CH2), 45.42 (CH),
48.44 (CH), 67.53 (PhCH2), 116.60 (5-Cim), 128.89 (Ar), 129.07 (Ar), 129.57 (Ar), 136.43 (2-Cim),
138.55 (Ar), 141.44 (4-Cim), 158.42 (CO); EI-MS (70 eV) m/z (%): 287 (1), 230 (20), 196 (10), 186
(20), 136 (10), 122 (100), 108 (50), 91 (60), 79 (60), 67 (10), 51 (10), 39 (10); Elemental analysis (%)
calcd. for C16H21N3O2 (287.16): C 66.88, H 7.37, N 14.62; found: C 66.64, H 7.34, N 14.55.
(1S,2R)-Benzyl-1-(1H-imidazol-4-yl)-2-methylbutylcarbamate (5d). Synthesized from α-bromoketone
4d (56 % yield) as an amorphous solid; Rf = 0.60 (SiO2; CHCl3/CH3OH/NH4OH 5:1:0.1); M.p. 45-49
1
°C; [α]D20 = - 35.6 (c 0.46, CH3OH); H-NMR: δ = 0.81 (3H, d, J = 6.7, CH3), 0.90 (3H, t, J = 7.3,
CH3), 1.15 + 1.54 (2H, 2 × m, CH2), 1.87-1.94 (1H, m, CH), 4.57 (1H, d, J = 7.3, NCH), 5.00-5.10
(2H, m, PhCH2), 6.91 (1H, s, 4-Him), 7.25-7.32 (5H, m, Ar), 7.60 (1H, d, J = 0.8, 2-Him); 13C-NMR: δ
= 11.79 (CH3), 16.41 (CH3), 26.28 (CH2), 40.33 (CH), 55.08 (CH), 67.57 (PhCH2), 117.31 (5-Cim),
128.87 (Ar), 129.06 (Ar), 129.55 (Ar), 136.35 (2-Cim), 138.50 (Ar), 139.93 (4-Cim), 158.54 (CO); EI-
MS (70 eV) m/z (%): 287 (1), 230 (20), 186 (20), 136 (20), 122 (100), 108 (70), 91 (60), 79 (70), 67
(20), 51 (20), 39 (20); Elemental analysis (%) calcd. for C16H21N3O2 (287.16): C 66.88, H 7.37, N
14.62; found: C 66.70, H 7.25, N 14.62.
(S)-Benzyl 1-(1H-imidazol-4-yl)-2-phenylethylcarbamate (5e). Synthesized from α-bromoketone 4e
(37 % yield) as a brown solid; Rf = 0.65 (SiO2; CHCl3/CH3OH/NH4OH 5:1:0.1); M.p. 138-140 °C;
[α]D20 = -29.0 (c 1, CH3OH); H-NMR: δ = 2.99 (1H, dd, J (H,H) = 13.6, J (H,H) = 8.8, CH2), 3.20
1
2
3
2
3
(1H, dd, J (H,H) = 13.6, J (H,H) = 6.1, CH2), 3.92-5.05 (4H, m, CH + NH + CH2 - merged with
13
residual CH3OH), 6.85 (1H, s, 4-Him), 7.11-7.32 (10H, m, 2 × Ar), 7.62 (1H, d, J = 1.1, 2-Him); C-
NMR: δ = 42.50 (CH2), 52.21 (NCH), 67.41 (PhCH2), 116.42 (5-Cim), 127. 48 (Ar), 128.74 (Ar),
128.99 (Ar), 129.35 (Ar), 129.55 (Ar), 130.53 (Ar), 136.52 (2-Cim), 138.52 (Ar), 139.77 (4-Cim),
141.59 (Ar), 158.26 (CO); EI-MS (70 eV) m/z (%): 230 (10), 213 (20), 169 (80), 142 (30), 122 (100),
115 (30), 108 (60), 91 (60), 79 (60), 65 (20), 51 (20). Elemental analysis (%) calcd. for C19H21N3O2
(321.15): C 71.01, H 5.96, N 13.08; found: C 70. 97, H 5.96, N 13.08.
Microwave assisted condensation
A few drops of water were added to a mixture of 6a (0.2 g; 0.84 mmol) and formamidine acetate
(0.17 g; 1.68 mmol), which was then treated for 2 × 2 min in a 360 W microwave oven. The resulting
mass was taken up in CHCl3 (10 mL), washed successively with water (2 × 10 mL) and concentrated
in vacuo. The crude product was purified in the same way as described above for the condensation in
liquid ammonia. Yield 7.5 %.
Acknowledgements
This research was supported by the Ministry of Education, Youth and Sport (MSM 0021627501)
and by the Czech Science Foundation (203/07/P013).

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Sample Availability: Samples of the compounds 5a-e are available from the authors.
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