Chiral imidazole derivatives synthesis from enantiopure N-protected α-amino acids

Article abstract of DOI:10.1016/j.tetasy.2005.01.049

A route to the preparation of enantiopure ligands based on a 2-phenylimidazol ring is described. The stereogenic centre is placed into the chain bonded to the fourth carbon of the imidazole ring. The synthesis starts from inexpensive and readily available

Full text of DOI:10.1016/j.tetasy.2005.01.049

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1347–1354
Chiral imidazole derivatives synthesis from enantiopure
N-protected a-amino acids
ˇ*
Filip Bures and Jirı Kulhanek
ˇ´
´
ˇ
Department of Organic Chemistry, University of Pardubice, nam. Cs. Legiı 565, Pardubice 53210, Czech Republic
´
´
Received 21 December 2004; accepted 21 January 2005
Abstract—A route to the preparation of enantiopure ligands based on a 2-phenylimidazol ring is described. The stereogenic centre is
placed into the chain bonded to the fourth carbon of the imidazole ring. The synthesis starts from inexpensive and readily available
N-protected a-amino acids, as the source of chirality, which are converted into appropriate a-diazoketones and, consequently, into
a-bromoketones. These a-bromoketones are good precursors for reactions with amidines to provide the imidazole ring. The depro-
tection into the final products was carried out using hydrogen.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
into a-oxoaldehydes using nitrones. In the first step,
the a-diazoketone is transformed into an a-bromoke-
tone using hydrobromic acid in glacial acetic acid, then
activated with pyridine and, consequently, the reaction
with p-nitroso-N,N-dimethylaniline provides nitrone,
which is then decomposed into a-oxoaldehyde using
diluted sulfuric acid.
Enantiopure imidazole derivatives are very important
ligands in the chemistry of metal complexes. For that
reason, we wanted to synthesize several chiral deriva-
tives of 2-phenylimidazole substituted at the 4-position.
The chain at the 4-position is a source of chirality; the
imidazole ring performs as the complexation molecule
part while the phenyl ring can be modified with suitable
groups to support the required properties.
The preparation of our derivatives starts from inexpen-
sive and readily available N-CBz a-amino acids 1, which
were transformed into a-diazoketones 2 via a mixed
anhydride by treatment with ethereal diazomethane.
The a-diazoketones react with hydrobromic acid to pro-
vide a-bromoketones 3 as in Scheme 1. The next step of
the synthesis is the reaction of a-bromoketones with
benzamidine hydrochloride in a THF/water/K2CO3 sys-
tem7 to afford the CBz-imidazole derivatives 4. The
deprotection into the final enantiopure imidazole 5 is
carried out using hydrogen (Scheme 2).
In the literature it is possible to find some methods
describing the preparation of similar compounds.
McKervey and co-workers1–3 describe the preparation
from N-CBz a-amino acids that were converted into
appropriate a-diazoketones. The oxidation of the diazo
group using DMD (dimethyldioxirane) acetone solution
provides a-oxoaldehydes that are allowed to condense
with benzaldehyde in the presence of ammonium acetate
into 2-phenylimidazole derivatives. The key step of the
synthesis is the oxidation of a-diazoketone. The reaction
is finished in 10 min at room temperature (followed on
TLC), resulting in a solution of a-oxoaldehydes in
acetone.
2. Results and discussion
A series of reactions using either the DMD or nitrone
method were conducted, and from these experiments,
we made a number of observations.
Balenovic and Bregant4,5 and Borkovec et al.6 describe
the transformation of N-phthaloylated a-diazoketones
The disadvantage of the DMD method is the prepara-
tion of an oxidation agent (DMD) from Oxoneꢁ (Al-
drich) in really poor yield (less than 5%), and the
structures of the a-oxoaldehydes were not satisfactorily
*
Corresponding author. Tel.: +42 0466037018; fax: +42
0466037068; e-mail: filip.bures@upce.cz
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.049

ˇ ´
F. Bures, J. Kulhanek / Tetrahedron: Asymmetry 16 (2005) 1347–1354
1348
O
O
O
O
THF/ether
EtOCOCl/Et3N
HN
OCH2Ph
CHN2
HN
OCH2Ph
CH2Br
HN
OCH2Ph
OH
HBr/AcOH
CH2N2/ether
R
R
R
O
O
2
1
3
Scheme 1.
O
NH2
H2/Pd/MeOH
HN
OCH2Ph
N
benzamidine.HCl
THF/H2O/K2CO3
3
R
N
R
N
N
Ph
Ph
5
4
Scheme 2.
explained, either. There is no possible oxidation in big-
ger scale for safety reasons (explosive DMD).
derivatives showed in the NMR spectra, hindered rota-
tion at the carbamic acid function.
In the case of the nitrone-transformation and the CBz
(benzyloxycarbonyl) protecting group, we observed
racemization during the nitrone preparation (using
sodium hydroxide as base). Further disadvantages are
the poor total yield and that a long time is required
for the consuming method, which uses toxic p-nitroso-
N,N-dimethylaniline.
The molecular weights (MWs) of all the studied com-
pounds were unambiguously identified on the basis of
complementary information obtained from the posi-
tive-ion mode (i.e., [M+H]+) and the negative-ion mode
(i.e., [MꢀH]ꢀ) APCI mass spectra. In addition to the
MW determination, tandem mass spectra in both polar-
ity modes provided characteristic neutral losses for some
functional groups, for example, CH3C6H5 (Dm/z 92),
HOCH2C6H5 (108), HCOOCH2C6H5 (136), NH2-
COOCH2C6H5 (151), butene (56) or butane (58),
propane (44) or propene (42) and NH2CH@CHC6H5
(119). All observed fragment ions are in accordance with
the suggested structures. Compounds 5a–f fragment so
easily that the ions corresponding the neutral loss of
ammonia are the base peaks in the first-order APCI
As starting material, a-diazoketones are optimal. It is
not necessary to oxidize them into a-oxoaldehydes,
although transformation into a-bromoketones is prefer-
able. a-Bromoketones are reactive species for condensa-
tion with amidines. The reaction is carried out in THF
at reflux while a water solution of potassium bicarbon-
ate is used as the hydrobromic acid scavenger and liber-
ator of free benzamidine base. Comparing our and the
DMD methods (for derivative 4d), we observed a better
yield (89% vs 71%). The final CBz group removal proved
very simple.
Table 1. CBz derivatives 4 preparation
Compd. Structure
Yield Ee
(%)
½aꢁ2D0(c 1,
(%)/conf. MeOH)
4a
4b
4c
4d
R = –CH3
R = –CH3
89
85
76
65
99 (S)
99 (R)
99 (S)
99 (S)
ꢀ25.4
3. Conclusion
+24.9
R = –CH(CH3)2
R = –CH2Ph
ꢀ45.2
We have developed a route to the preparation of the chi-
ral derivatives of 2,4-disubstituted imidazole from enan-
tiopure amino acid. Following this route we have
synthetized seven CBz protected derivatives and, conse-
quently, seven deprotected enantiopure derivatives of 2-
phenylimidazole. Some of the properties of the prepared
compounds are summarized in Tables 1 and 2. The
yields of the condensation reaction varied from moder-
ate {entry 4f—derivative from (S)-isoleucine} to satis-
factory (all other entries). Enantiomeric purity was
proven from the starting amino acid. Derivatives de-
rived from alanine were prepared in both configurations.
All other properties are given in the Experimental at
appropriate compounds. Most of the CBz protected
ꢀ13.5 (c 1,
CHCl3)
ꢀ48.7
4e
4f
R = –CH2CH(CH3)2 88
R = –CH(CH3)CH2CH3 42
99 (S)
99 (S)
ꢀ50.2
O
H2C
H2C
CH2
N
OCH2Ph
H
4g
70
99 (S)
ꢀ34.2
N
NH

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F. Bures, J. Kulhanek / Tetrahedron: Asymmetry 16 (2005) 1347–1354
1349
Table 2. Deprotection into the final products 5
Compd. Structure Yield Ee
solution. The solution was stirred for further 30 min,
the temperature then allowed to reach ꢀ10 ꢂC and the
diazomethane solution in ether (2–3 equiv) was added
dropwise. The suspension was stirred for an additional
3 h and allowed to reach ambient temperature. The tri-
ethylamine hydrochloride was then filtered off and the
filtrate was evaporated to half of its original volume.
The resulting solution was washed with saturated aque-
ous sodium hydrogen carbonate (50 mL) and brine
(50 mL). The organic layer was dried and evaporated
to give a crude product, which was purified by crystalli-
zation (dichloromethane–hexane) or on silica gel (ethyl
acetate–hexane 1:1).
20
½aꢁD (c 1,
(%)
(%)/conf. MeOH)
5a
5b
5c
5d
5e
5f
R = –CH3
R = –CH3
99
99
99
99
99
99 (S)
99 (R)
99 (S)
99 (S)
99 (S)
99 (S)
+4.1
ꢀ4.0
+2.7
+23.9
+2.6
+4.5
R = –CH(CH3)2
R = –CH2Ph
R = –CH2CH(CH3)2
R = –CH(CH3)CH2CH3 99
H2C
H2C
CH2
NH
H
5g
99
99 (S)
+12.1
N
NH
4.1.1. (3-Diazo-1-(S)-methyl-2-oxopropyl)carbamic acid
benzyl ester 2a. Prepared from 1a by the general meth-
od to give title compound 2a as pale yellow needles,
20
yield 96%, mp 89–90 ꢂC, ½aꢁ ¼ ꢀ59:1 (c 1, MeOH).
D
Found: C 58.1; H 5.2; N 17.1. C12H13N3O3 requires C
58.3; H 5.3; N 17.0. 1H NMR (d/ppm, 500 MHz,
CDCl3) 1.30 (3H, d, J = 7.1, CH3), 4.11 + 4.24 (1H, m,
CBzNHCH), 5.06 (2H, 2d, J = 12.4, PhCHCO), 5.40
(1H, br s, CHN2), 5.52 + 5.61 (1H, br s, CBzNHCH),
7.26–7.33 (5H, m, ArH). 13C NMR (d/ppm, 125 MHz,
CDCl3) 18.5, 53.7, 54.5, 67.1, 128.2, 128.3, 128.6,
136.4, 155.9, 194.1.
mass spectra in both polarity modes, that is,
[M+HꢀNH3]+ or [MꢀHꢀNH3]ꢀ.
4. Experimental
1H NMR spectra were recorded in CDCl3 or DMSO at
500 or 360 MHz with Bruker AVANCE 500 or AMX
360 instruments. The 13C spectra were recorded in
CDCl3 or DMSO at 125 MHz on a Bruker AVANCE
500 or at 90 MHz with AMX 360 instrument. NMR
techniques such as COSY, HMBC and HMQC were
used. Chemical shifts are reported in ppm with residual
CHCl3 (7.25 ppm), DMSO (2.55) and CDCl3
(77.23 ppm), DMSO (39.51) as references. J values are
given in hertz.
4.1.2. (3-Diazo-1-(R)-methyl-2-oxopropyl)carbamic acid
benzyl ester 2b. Prepared from 1b by the general meth-
od to give title compound 2b as pale yellow needles,
20
yield 90%, mp 77–79 ꢂC, ½aꢁ ¼ ꢀ58:8 (c 1, MeOH).
D
Found: C 58.1; H 5.2; N 17.1. C12H13N3O3 requires C
58.3; H 5.3; N 17.0. 1H NMR (d/ppm, 500 MHz,
CDCl3) 1.30 (3H, d, J = 7.1, CH3), 4.11 + 4.24 (1H, m,
CBzNHCH), 5.06 (2H, 2d, J = 12.4, PhCH2CO), 5.40
(1H, br s, CHN2), 5.52 + 5.61 (1H, br s, CBzNH),
7.26–7.33 (5H, m, ArH). 13C NMR (d/ppm, 125 MHz,
CDCl3) 18.5, 53.7, 54.5, 67.1, 128.2, 128.3, 128.6,
136.4, 155.9, 194.1.
The positive-ion and negative-ion APCI mass spectra
were measured on Esquire 3000 ion trap analyzer (Bru-
ker Daltonics, Bremen, Germany) within the mass range
m/z = 50–1000. Samples were dissolved in acetonitrile
and analyzed by direct infusion at a flow rate of
40 lL/min. The ion source temperature was 300 ꢂC,
the APCI probe temperature was 350 ꢂC, the flow rate
and the pressure of nitrogen were 3 L/min and 25 psi,
respectively. The tuning of the mass spectrometer was
optimized for the target mass m/z 300. For MS/MS mea-
surements, the isolation width of precursor ions was 4
m/z, and the collision amplitude was 0.9 V in all cases.
4.1.3. (3-Diazo-1-(S)-(1-methylethyl)-2-oxopropyl)car-
bamic acid benzyl ester 2c. Prepared from 1c by the
general method to give the title compound 2c as pale yel-
20
D
low needles, yield 93%, mp 30–31 ꢂC, ½aꢁ ¼ ꢀ31:5 (c 1,
MeOH). Found: C 61.0; H 6.2; N 15.1. C14H17N3O3 re-
quires C 61.1; H 6.2; N 15.3. 1H NMR (d/ppm,
360 MHz, CDCl3) 0.84 (3H, d, J = 6.8, CH3), 0.94
(3H, d, J = 6.8, CH3), 2.04 (1H, m, CH(CH3)2)
3.95 + 4.10 (1H, m, CBzNHCH), 5.06 (2H, m,
PhCH2CO), 5.39 (1H, br s, CHN2), 5.59 (1H, d,
J = 8.8, CBzNH), 7.23–7.36 (5H, m, ArH). 13C NMR
(d/ppm, 90 MHz, CDCl3) 17.4, 19.5, 31.2, 54.8, 63.0,
67.1, 128.1, 128.2, 128.6, 136.3, 156.5, 193.6.
Optical rotations were measured on Perkin–Elmer 341
instrument, concentration c is given in g/100 mL. The
diazomethane solution was prepared from N-nitroso-
N-methylurea. The deprotections were carried out in
an ROTH pressure vessel.
4.1.4. (3-Diazo-1-(S)-benzyl-2-oxopropyl)carbamic acid
benzyl ester 2d. Prepared from 1d by the general meth-
od to give title compound 2d as a pale yellow solid, yield
20
4.1. a-Diazoketone preparation (general method)
98%, mp 80–81 ꢂC, ½aꢁ ¼ ꢀ42:1 (c 1, MeOH). Found:
D
C 66.7; H 5.3; N 12.9. C18H17N3O3 requires C 66.9; H
1
The N-protected a-amino acid (27.0 mmol) in dry ether
(60 mL) and THF (60 mL) was stirred under argon at
ꢀ25 ꢂC. Triethylamine (27.0 mmol; 3.8 mL) and ethyl-
chloroformate (27.0 mmol, 2.6 mL) were added to this
5.3; N 13.0. H NMR (d/ppm, 360 MHz, CDCl3) 3.05
(2H, d, J = 6.7, PhCH2CH), 4.50 (1H, m, CBzNHCH),
5.09 (2H, m, PhCH2CO), 5.22 (1H, br s, CHN2), 5.40
(1H, br s, CBzNH), 7.18–7.36 (10H, m, ArH). 13C

ˇ ´
F. Bures, J. Kulhanek / Tetrahedron: Asymmetry 16 (2005) 1347–1354
1350
1
NMR (d/ppm, 90 MHz, CDCl3) 38.3, 54.4, 58.7, 66.9,
127.0, 127.9, 128.1, 128.4, 128.5, 129.2, 135.9, 136.0,
155.6, 192.6.
requires C 48.0; H 4.7; N 4.7, Br 26.6. H NMR (d/
ppm, 500 MHz, CDCl3) 1.38 (3H, d, J = 7.1, CH3),
4.02 (2H, 2 · d, J = 13.0, CH2Br), 4.63 (1H, m,
CBzNHCH), 5.07 (2H, 2 · d, PhCH2CO), 5.41 + 5.49
(1H, br s, CBzNH), 7.31–7.33 (5H, m, ArH). 13C
NMR (d/ppm, 125 MHz, CDCl3) 18.0, 31.6, 53.8, 67.3,
128.3, 128.5, 128.7, 136.2, 155.9, 201.3.
4.1.5. (3-Diazo-1-(S)-(2-methylpropyl)-2-oxopropyl)car-
bamic acid benzyl ester 2e. Prepared from 1e by the
general method to give title compound 2e as pale yellow
20
needles, yield 91%, mp 64–65 ꢂC, ½aꢁ ¼ ꢀ53:6 (c 1,
D
MeOH). Found: C 62.0; H 6.5; N 14.3. C15H19N3O3 re-
quires C 62.3; H 6.6; N 14.5. 1H NMR (d/ppm,
500 MHz, CDCl3) 0.91 + 0.92 (6H, 2 · d, J = 6.3,
2 · CH3), 1.45 + 1.53 (2H, m, CH2CH(CH3)2), 1.95
(1H, m, CH2CH(CH3)2), 4.12 + 4.24 (1H, m,
CBzNHCH), 5.07 (2H, m, PhCH2CO), 5.43 (1H, br s,
CHN2), 5.46 (1H, br s, CBzNH), 7.29–7.33 (5H, m,
ArH). 13C NMR (d/ppm, 125 MHz, CDCl3) 21.9, 23.2,
24.8, 41.5, 54.0, 56.5, 67.1, 128.2, 128.3, 128.6, 136.4,
156.2, 194.4.
4.2.2. (3-Bromo-1-(R)-methyl-2-oxopropyl)carbamic acid
benzyl ester 3b. Prepared from 2b by the general
method to give the title compound 3b as a white solid,
20
yield 97%, mp 78–79 ꢂC, ½aꢁ ¼ þ33:2 (c 1, MeOH).
D
Found: C 47.9; H 4.6; N 4.2, Br 26.2. C12H14BrNO3 re-
1
quires C 48.0; H 4.7; N 4.7, Br 26.6. H NMR (d/ppm,
500 MHz, CDCl3) 1.38 (3H, d, J = 7.1, CH3), 4.02
(2H, 2 · d, J = 13.0, CH2Br), 4.63 (1H, m, CBzNHCH),
5.07 (2H, 2 · d, PhCH2CO), 5.41 + 5.49 (1H, br s,
CBzNH), 7.31–7.33 (5H, m, ArH). 13C NMR (d/ppm,
125 MHz, CDCl3) 18.0, 31.6, 53.8, 67.3, 128.3, 128.5,
128.7, 136.2, 155.9, 201.3.
4.1.6. (3-Diazo-1-(S)-(1-methylpropyl)-2-oxopropyl)car-
bamic acid benzyl ester 2f. Prepared from 1f by the
general method to give title compound 2f as pale yellow
4.2.3. (3-Bromo-1-(S)-(1-methylethyl)-2-oxopropyl)car-
bamic acid benzyl ester 3c. Prepared from 2c by the
general method to give title compound 3c as a white
20
needles, yield 89%, mp 63–64 ꢂC, ½aꢁ ¼ ꢀ42:1 (c 1,
D
MeOH). Found: C 61.9.; H 6.4; N 14.2. C15H19N3O3
requires C 62.3; H 6.6; N 14.5. 1H NMR (d/ppm,
500 MHz, CDCl3) 0.87 (3H, t, J = 7.4, CH2CH3), 0.92
(3H, d, J = 6.8, CHCH3), 1.08 + 1.41 (2H, 2 · m,
CH3CH2), 1.81 (1H, m, CH3CHCH2CH3), 4.01 + 4.13
(1H, m, CHNHCBz), 5.08 (2H, m, PhCH2CO), 5.40
(1H, br s, CHN2), 5.50 (1H, d, J = 8.8, CBzNH), 7.26–
7.34 (5H, m, ArH). 13C NMR (d/ppm, 125 MHz,
CDCl3) 11.6, 15.8, 24.7, 37.8, 55.0, 62.5, 67.2, 128.2,
128.3, 128.7, 136.4, 156.4, 193.6.
20
solid, yield 98%, mp 74–75 ꢂC, ½aꢁ ¼ ꢀ22:5 (c 1,
D
MeOH). Found: C 51.0; H 5.6; N 4.2, Br 24.6.
C14H18BrNO3 requires C 51.2; H 5.5; N 4.3, Br 24.4.
1H NMR (d/ppm, 500 MHz, CDCl3) 0.82 (3H, d,
J = 6.5, CH3), 1.00 (3H, d, J = 6.5, CH3), 2.20 (1H, m,
CH(CH3)2), 4.04 (2H, 2 · d, J = 13.5, CH2Br), 4.57
(1H, k, J = 5.0, CBzNHCH), 5.09 (2H, 2 · d, J = 12.0,
PhCH2CO), 5.50 (1H, d, J = 8.5, CBzNH), 7.27–7.37
(5H, m, ArH). 13C NMR (d/ppm, 125 MHz, CDCl3)
17.0, 19.8, 30.2, 33.1, 63.0, 67.3, 128.2, 128.6, 129.1,
136.1, 156.5, 200.8.
4.1.7. 2-(S)-(2-Diazo-1-oxoethyl)pyrrolidine-1-carboxylic
acid benzyl ester 2g. Prepared from 1g by the general
method to give the title compound 2g as a yellow oil,
4.2.4. (3-Bromo-1-(S)-benzyl-2-oxopropyl)carbamic acid
benzyl ester 3d. Prepared from 2d by the general meth-
od to give title compound 3d as a white solid, yield
20
yield 93%, ½aꢁ ¼ ꢀ94:4 (c 1, MeOH). Found: C 61.2;
D
H 5.4; N 15.1. C14H15N3O3 requires C 61.5; H 5.5; N
15.4. 1H NMR (d/ppm, 360 MHz, CDCl3) 1.84 (2H,
m, CH2CH2CH2), 2.04 (2H, m, CHCH2CH2), 3.52
(2H, m, CH2CH2N), 4.29 (1H, m, CH2CHN), 5.12
(2H, 2 · d, J = 12.6, PhCH2CO), 5.25 + 5.46 (1H, br s,
CHN2), 7.25–7.33 (5H, m, ArH). 13C NMR (d/ppm,
125 MHz, CDCl3) 23.6 + 24.4, 29.7 + 31.2, 46.9 + 47.4,
52.7 + 53.3, 64.0, 67.2, 127.7, 127.9, 128.1, 128.4,
128.5, 136.4 + 136.6, 154.5 + 155.3, 194.5 + 195.3.
20
99%, mp 102–103 ꢂC, ½aꢁ ¼ ꢀ45:9 (c 1, MeOH).
D
Found: C 57.4; H 4.8; N 3.6, Br 21.0. C18H18BrNO3 re-
1
quires C 57.5; H 4.8; N 3.7, Br 21.2. H NMR (d/ppm,
360 MHz, CDCl3) 3.12 (2H, m, J = 7.0, PhCH2CH),
3.89 (2H, 2 · d, J = 13.6, CH2Br), 4.87 (1H, k, J = 7.2,
CBzNHCH), 5.10 (2H, 2 · d, J = 12.5, PhCH2CO),
5.39 (1H, br d, J = 7.4, CBzNH), 7.19 (2H, d, J = 6.9,
ArH), 7.33–7.42 (8H, m, ArH). 13C NMR (d/ppm,
125 MHz, CDCl3) 33.2, 38.1, 59.0, 67.5, 127.6, 128.3,
128.5, 128.8, 129.2, 129.3, 135.6, 136.3, 155.7, 201.2.
4.2. a-Bromoketone preparation (general method)
To a solution of a-diazoketone 2 (20.0 mmol) in glacial
acetic acid (50 mL), 48% hydrobromic acid (7 mL) was
added dropwise with stirring. After stirring for 1 h the
reaction mixture was poured on the ice and the precipi-
tate collected or extracted with dichloromethane and
washed with water. Crystallization from ether-pet. ether
gave the pure product.
4.2.5. (3-Bromo-1-(S)-(2-methylpropyl)-2-oxopropyl)car-
bamic acid benzyl ester 3e. Prepared from 2e by the
general method to give title compound 3e as a pale yel-
20
low oil, yield 97%, ½aꢁ ¼ ꢀ26:1 (c 1, MeOH). Found: C
D
52.8; H 6.0; N 4.3, Br 23.5. C15H20BrNO3 requires C 52;
H 5.9; N 4.1, Br 23.4. 1H NMR (d/ppm, 500 MHz,
CDCl3) 0.92 + 0.94 (6H, 2 · d, J = 6.5, 2 · CH3),
1.44 + 1.59 (2H, m, CH2CH(CH3)2), 1.69 (1H, m,
CH2CH (CH3)2), 4.06 (2H, 2 · d, CH2Br), 4.60 (1H,
m, CBzNHCH), 5.07 (2H, 2 · d, PhCH2CO), 5.52
(1H, br s, CBzNH), 7.27–7.37 (5H, m, ArH). 13C
NMR (d/ppm, 125 MHz, CDCl3) 13.9, 21.5, 23.3, 24.9,
40.5, 56.6, 67.2, 128.1, 128.6, 128.8, 136.1, 156.3, 201.6.
4.2.1. (3-Bromo-1-(S)-methyl-2-oxopropyl)carbamic acid
benzyl ester 3a. Prepared from 2a by the general
method to give the title compound 3a as a white solid,
20
yield 98%, mp 82–83 ꢂC, ½aꢁ ¼ ꢀ33:7 (c 1, MeOH).
D
Found: C 47.9; H 4.6; N 4.5.1, Br 26.4. C12H14BrNO3

ˇ ´
F. Bures, J. Kulhanek / Tetrahedron: Asymmetry 16 (2005) 1347–1354
1351
4.2.6. (3-Bromo-1-(S)-(1-methylpropyl)-2-oxopropyl)car-
bamic acid benzyl ester 3f. Prepared from 2f by the
general method to give title compound 3f as a white
APCI-MS: 320 [MꢀH]ꢀ, 228 [MꢀHꢀCH3C6H5ꢀ, 212
[MꢀHꢀHOCH2C6H5]ꢀ, 186 [MꢀCOOCH2C6H5]ꢀ,
169 [MꢀHꢀNH2COOCH2C6H5]ꢀ (100%). Negative-
ion APCI-MS/MS of m/z 320: 275 [MꢀHꢀNH2COH]ꢀ,
212 [MꢀHꢀHOCH2C6H5]ꢀ, 210 [MꢀHꢀCH3C6H5ꢀ
H2O]ꢀ (100%), 186 [MꢀCOOCH2C6H5]ꢀ, 169 [MꢀHꢀ
NH2COOCH2C6H5]ꢀ.
20
solid, yield 98%, mp 83–84 ꢂC, ½aꢁ ¼ ꢀ26:1 (c 1,
D
MeOH). Found: C 52.2; H 5.7; N 4.0, Br 23.0.
C15H20BrNO3 requires C 52.6; H 5.9; N 4.1, Br 23.4.
1H NMR (d/ppm, 500 MHz, CDCl3) 0.87 (3H, t,
J = 7.3, CH2CH3), 0.96 (3H, d, J = 6.8, CHCH3),
1.07 + 1.31 (2H, 2 · m, CH3CH2), 1.92 (1H, m,
CH3CHCH2CH3), 4.04 (2H, 2 · d, J = 13.7, CH2Br),
4.57 (1H, k, J = 5.0, CBzNHCH), 5.08 (2H, 2 · d,
PhCH2CO), 5.33 (1H, d, J = 8.5, CBzNH), 7.30–7.36
(5H, m, ArH). 13C NMR (d/ppm, 125 MHz, CDCl3)
11.6, 16.2, 24.4, 33.3, 37.1, 62.8, 67.4, 128.3, 128.5,
128.8, 136.2, 156.5, 201.0.
4.3.2. 2-Phenyl-4-(1-(R)-benzyloxycarbonylaminoethyl)-
1H-limidazole 4b. Prepared from 3b by the general
method to give title compound 4b as a white solid, yield
20
85%, mp 158–159 ꢂC, ½aꢁ ¼ þ24:9 (c 1, MeOH).
D
Found: C 71.0; H 6.1; N 13.2. C19H19N3O2 requires C
71.0; H 6.0; N 13.1. 1H NMR (d/ppm, 500 MHz,
DMSO) 1.48 (3H, d, J = 6.9, CH3), 4.78 + 4.90 (1H,
m, CBzNHCH), 5.11 (2H, 2 · d, PhCH2CO),
6.91 + 7.08 (1H, s, Him), 7.35 + 7.49 (8H, m, ArH),
7.97 (2H, d, J = 7.5, ArH), 12.33 + 12.39 (1H, br s).
13C NMR (d/ppm, 125 MHz, DMSO) 21.3, 45.3, 65.1,
113.1, 124.8, 127.7, 127.8, 128.3, 128.7, 130.8, 137.4,
144.8, 144.9, 155.5. Positive-ion APCI-MS: m/z 322
[M+H]+ (100%), 171 [M+HꢀNH2COOCH2C6H5]+. Po-
4.2.7. 2-(S)-(2-Bromo-1-oxoethyl)pyrrolidine-1-carbox-
ylic acid benzyl ester 3g. Prepared from 2g by the gen-
eral method to give title compound 3g as a yellow oil,
20
yield 95%, ½aꢁ ¼ ꢀ5:1 (c 1, MeOH). Found: C 51.2;
D
H 5.0; N 4.1, Br 24.3. C14H16BrNO3 requires C 51.6;
H 4.9; N 4.3, Br 24.5. 1H NMR (d/ppm, 360 MHz,
CDCl3) 2.11 (2H, m, CH2CH2CH2), 2.22 (2H, m,
CHCH2CH2), 3.58 (2H, m, CH2CH2N), 4.42 (1H, m,
CH2CHN), 4.53 (2H, 2 · d, J = 14.1, CH2Br), 5.18
(2H, 2 · d, J = 12.4, PhCH2CO), 7.30–7.44 (5H, m,
ArH). 13C NMR (d/ppm, 125 MHz, CDCl3) 23.8 +
25.1, 29.6 + 31.0, 45.8 + 47.1, 52.5 + 53.0, 60.8, 67.5,
127.9, 128.1, 128.4, 128.6, 128.9, 136.1 + 136.6,
154.2 + 155.1, 194.8 + 195.7.
sitive-ion
APCI-MS/MS
of
m/z
322:
230
[M+HꢀCH3C6H5]+, 186 [M+HꢀHCOOCH2C6H5]+,
171 [M+HꢀNH2COOCH2C6H5]+ (100%). Negative-
ion APCI-MS: 320 [MꢀH]ꢀ, 228 [MꢀHꢀCH3C6H5]ꢀ,
212 [MꢀHꢀHOCH2C6H5]ꢀ, 186 [MꢀCOOCH2C6H5]ꢀ,
169 [MꢀHꢀNH2COOCH2C6H5]ꢀ (100%). Negative-ion
APCI-MS/MS of m/z 320: 275 [MꢀHꢀNH2COH]ꢀ, 212
[MꢀHꢀHOCH2C6H5]ꢀ, 210 [MꢀHꢀCH3C6H5ꢀH2O]ꢀ
(100%), 186 [MꢀCOOCH2C6H5]ꢀ, 169 [MꢀHꢀ
NH2COOCH2C6H5]ꢀ.
4.3. Condensation (general method)
A
mixture of benzamidine hydrochloride (4.7 g,
4.3.3. 2-Phenyl-4-(1-(S)-benzyloxycarbonylamino-2-
methylpropyl)-1H-imidazole 4c. Prepared from 3c by
the general method to give the title compound 4c as a
30 mmol) and potassium bicarbonate (8.3 g, 60 mmol)
in water (10 mL) and THF (40 mL) was stirred and
heated to reflux. a-Bromoketone 3 (15 mmol) in THF
(30 mL) was added into this refluxed mixture dropwise
over a 1 h period. The reaction mixture was then heated
at reflux overnight. THF was then removed under re-
duced pressure and water layer extracted with dichloro-
methane. The extract was washed with water and brine,
dried and evaporated to afford crude product 4, which
was purified by silica gel chromatography (ethyl ace-
tate–hexane 1:1).
20
white solid, yield 76%, mp 138–139 ꢂC, ½aꢁ ¼ ꢀ45:2
D
(c 1, MeOH). Found: C 72.3; H 6.7; N 12.1.
1
C21H23N3O2 requires C 72.2; H 6.6; N 12.0. H NMR
(d/ppm, 500 MHz, DMSO) 0.89 (3H, d, J = 6.7, CH3),
0.92 (3H, d, J = 6.7, CH3), 2.06 + 2.15 (1H, m,
(CH3)2CH), 4.50 + 4.60 (1H, m, CBzNHCH), 5.09
(2H, 2 · d J = 17.2, PhCH2CO), 6.92 + 7.09 (1H, s,
Him), 7.34–7.49 (8H, m, ArH), 7.95 (2H, d, J = 7.3,
ArH), 12.27 + 12.39 (1H, br s). 13C NMR (d/ppm,
125 MHz, DMSO) 18.4, 19.6, 32.2, 55.4, 65.2, 114.2,
124.6, 124.8, 127.7, 127.9, 128.4, 128.7, 130.8, 137.4,
143.0, 144.8, 156.1. Positive-ion APCI-MS: m/z 350
[M+H]+ (100%), 306 [M+Hꢀpropane]+, 240 [M+Hꢀ
CH3C6H5ꢀH2O]+, 199 [M+HꢀNH2COOCH2C6H5]+.
Positive-ion APCI-MS/MS of m/z 350: 199 [M+Hꢀ
NH2COOCH2C6H5]+ (100%). Negative-ion APCI-MS:
348 [MꢀH]ꢀ, 240 [MꢀHꢀHOCH2C6H5]ꢀ, 197 [MꢀHꢀ
NH2COOCH2C6H5]ꢀ (100%). Negative-ion APCI-MS/
MS of m/z 348: 240 [MꢀHꢀHOCH2C6H5]ꢀ, 197
[MꢀHꢀNH2COOCH2C6H5]ꢀ (100%).
4.3.1. 2-Phenyl-4-(1-(S)-benzyloxycarbonylaminoethyl)-
1H-limidazole 4a. Prepared from 3a by the general
method to give title compound 4a as a white solid, yield
89%, mp 152–153 ꢂC, ½aꢁ ¼ ꢀ25:4 (c 1, MeOH).
20
D
Found: C 70.9; H 6.0; N 13.2. C19H19N3O2 requires C
71.0; H 6.0; N 13.1. 1H NMR (d/ppm, 500 MHz,
DMSO) 1.48 (3H, d, J = 6.9, CH3), 4.78 + 4.90 (1H,
m, CBzNHCH), 5.11 (2H, 2 · d, PhCH2CO),
6.91 + 7.08 (1H, s, Him), 7.35 + 7.49 (8H, m, ArH),
7.97 (2H, d, J = 7.5, ArH), 12.33 + 12.39 (1H, br s).
13C NMR (d/ppm, 125 MHz, DMSO) 21.3, 45.3, 65.1,
113.1, 124.8, 127.7, 127.8, 128.3, 128.7, 130.8, 137.4,
144.8, 144.9, 155.5. Positive-ion APCI-MS: m/z 322
[M+H]+ (100%), 171 [M+HꢀNH2COOCH2C6H5]+.
Positive-ion APCI-MS/MS of m/z 322: 230 [M+
HꢀCH3C6H5]+, 186 [M+HꢀHCOOCH2C6H5]+, 171
[M+HꢀNH2COOCH2C6H5]+ (100%). Negative-ion
4.3.4. 2-Phenyl-4-(1-(S)-benzyloxycarbonylamino-2-phe-
nylethyl)-1H-imidazole 4d. Prepared from 3d by
the general method to give title compound 4d as a white
20
solid, yield 65%, mp 171–172 ꢂC, ½aꢁ ¼ ꢀ13:5 (c 1,
D
CHCl3). Found: C 75.7; H 5.9; N 10.6. C25H23N3O2
requires C 75.6; H 5.8; N 10.6. 1H NMR (d/ppm,

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F. Bures, J. Kulhanek / Tetrahedron: Asymmetry 16 (2005) 1347–1354
1352
500 MHz, DMSO) 3.04 + 3.29 (2H, 2 · m, CH2Ph), 4.91
(1H, k, J = 5.4, CBzNHCH), 5.02 (2H, 2 · d,
PhCH2CO), 6.95 + 7.08 (1H, s, Him), 7.34–7.49 (8H,
m, ArH), 7.94 (2H, d, J = 7.2, ArH), 12.43 (1H, br s,).
13C NMR (d/ppm, 125 MHz, DMSO) 40.8, 51.4, 65.0,
113.9, 124.9, 127.4, 127.5, 128.1, 128.3, 128.4, 128.8,
129.3, 131.3, 134.3, 137.5, 139.2, 143.7, 145.1, 155.7.
Positive-ion APCI-MS: m/z 398 [M+H]+ (100%), 306
[M+HꢀCH3C6H5]+, 262 [M+HꢀHCOOCH2C6H5]+,
247 [M+HꢀNH2COOCH2C6H5]+. Positive-ion APCI-
MS/MS of m/z 398: 247 [M+HꢀNH2COOCH2C6H5]+
(100%). Negative-ion APCI-MS: 396 [MꢀH]ꢀ, 262 [Mꢀ
COOCH2C6H5]ꢀ, 245 [MꢀHꢀNH2COOCH2C6H5]ꢀ
(100%). Negative-ion APCI-MS/MS of m/z 396: 245
[MꢀHꢀNH2COOCH2C6H5]ꢀ (100%).
propene]+, 157 [M+HꢀNH2COOCH2C6H5ꢀbutene]+.
[MꢀHꢀHOCH2C6H5]ꢀ, 211 [MꢀHꢀNH2COOCH2-
C6H5]ꢀ (100%). Negative-ion APCI-MS/MS of m/z
362: 211 [MꢀHꢀNH2COOCH2C6H5]ꢀ (100%).
Negative-ion
APCI-MS:
362
[MꢀH]ꢀ,
254
4.3.7. 2-Phenyl-4-(1-benzyloxycarbonyl)pyrrolidine-2-
(S)-yl-1H-imidazole 4g. Prepared from 3g by the gen-
eral method to give the title compound 4g as a yellow
20
oil, yield 70%, ½aꢁ ¼ ꢀ34:2 (c 1, MeOH). Found: C
D
72.3; H 5.9; N 12.1. C21H21N3O2 requires C 72.6; H
1
6.1; N 12.1. H NMR (d/ppm, 500 MHz, DMSO) 1.89
(2H, m, CH2CH2CH2), 2.12 (2H, m, CHCH2CH2),
3.54 (2H, m, CH2CH2N), 4.98 (1H, m, CH2CHN),
5.12 (2H, 2 · d, J = 13.0, PhCH2CO), 6.98 (1H, s,
Him), 7.35–7.50 (8H, m, ArH), 7.94 (2H, d, J = 8.0,
ArH), 12.38 + 12.40 (1H, br s). 13C NMR (d/ppm,
125 MHz, DMSO) 22.6 + 22.4, 31.8 + 32.9, 46.1 +
46.6, 55.3 + 55.7, 65.0 + 65.5, 113.7 + 113.9, 124.7,
127.5, 127.9, 128.3, 128.7, 130.8, 131.3, 134.3, 137.3,
145.0, 153.9 + 154.1. Positive-ion APCI-MS: m/z 348
4.3.5. 2-Phenyl-4-(1-(S)-benzyloxycarbonylamino-3-meth-
ylbutyl)-1H-imidazole 4e. Prepared from 3e by the
general method to give the title compound 4e as a
20
white solid, yield 88%, mp 146–147 ꢂC, ½aꢁ ¼ ꢀ48:7
D
(c 1, MeOH). Found: C 72.6; H 7.0; N 11.7.
1
C22H25N3O2 requires C 72.7; H 6.9; N 11.6. H NMR
[M+H]+
(100%),
304
[M+HꢀCO2]+,
240
(d/ppm, 500 MHz, DMSO) 0.95 (6H, d, J = 5.6,
CH(CH3)2), 1.69 (3H, m, CH2CH), 4.71 + 4.82 (1H,
m, CBzNHCH), 5.08 (2H, 2 · d, J = 15.9 Hz,
PhCH2CO), 6.87 + 7.04 (1H, s, Him), 7.35–7.51 (8H,
m, ArH), 7.94 (2H, d, J = 8.0, ArH), 12.28 + 12.35
(1H, br s). 13C NMR (d/ppm, 125 MHz, DMSO) 22.0,
23.0, 24.5, 44.3, 47.8, 65.1, 113.4, 124.8, 125.4, 127.7,
127.9, 128.4, 128.7, 130.8, 137.5, 144.6, 144.9, 155.8.
Positive-ion APCI-MS: m/z 364 [M+H]+ (100%), 228
[M+HꢀHCOOCH2C6H5]+, 213 [M+HꢀNH2COO-
CH2C6H5]+ Positive-ion APCI-MS/MS of m/z 364: 272
[M+HꢀCH3C6H5]+, 228 [M+HꢀHCOOCH2C6H5]+,
213 [M+HꢀNH2COOCH2C6H5]+ (100%), 157 [M+Hꢀ
NH2COOCH2C6H5ꢀbutene]+. Negative-ion APCI-
MS: 362 [MꢀH]ꢀ, 254 [MꢀHꢀHOCH2C6H5]ꢀ, 228
[MꢀCOOCH2C6H5]ꢀ, 211 [MꢀHꢀNH2COOCH2C6H5]ꢀ
(100%). Negative-ion APCI-MS/MS of m/z 362: 317
[MꢀHꢀNH2COH]ꢀ, 254 [MꢀHꢀHOCH2C6H5]ꢀ, 252
[MꢀHꢀCH3C6H5ꢀH2O]ꢀ, 211 [MꢀHꢀNH2COOCH2-
C6H5]ꢀ (100%).
[M+HꢀHOCH2C6H5]+, 214 [MꢀCOOCH2C6H5]+, 212
[M+HꢀHCOOCH2C6H5]+. Positive-ion APCI-MS/MS
of m/z 348: 304 [M+HꢀCO2]+, 287 [M+HꢀCO2ꢀNH3]+
(100%), 240 [M+HꢀHOCH2C6H5]+, 212 [M+HꢀHCO-
OCH2C6H5]+, 197 [M+HꢀHOCH2C6H5ꢀNHCO]+,
145 [C6H5(C@NCH@CHNH2)]+. Negative-ion APCI-
MS: 346 [MꢀH]ꢀ (100%), 238 [MꢀHꢀHOCH2C6H5]ꢀ.
Negative-ion APCI-MS/MS of m/z 346: 238 [MꢀHꢀ
HOCH2C6H5]ꢀ
(100%),
210
[MꢀHꢀHOCH2-
C6H5ꢀCO]ꢀ, 195 [MꢀHꢀHOCH2C6H5ꢀCOꢀCH3]ꢀ.
4.4. Deprotection (general method)
The Pd catalyst on active carbon (0.5 g, 10%, Aldrich)
was added into the protected imidazole 4 (15 mmol)
solution in methanol (80 mL) and the reaction mixture
in pressure vessel saturated with hydrogen (300 kPa)
until TLC showed reaction completion. Filtra-
tion and evaporation of the solvent gave the pure
product 5.
4.3.6. 2-Phenyl-4-(1-(S)-benzyloxycarbonylamino-2-meth-
ylbutyl)-1H-imidazole 4f. Prepared from 3f by the
general method to give title compound 4f as a white
4.4.1. 2-Phenyl-4-(1-(S)-aminoethyl)-1H-limidazole 5a.
Prepared from 4a by the general method to give title
compound 5a as a white solid, yield 99%, mp 158–
20
20
solid, yield 42%, mp 128–129 ꢂC, ½aꢁ ¼ ꢀ50:2 (c 1,
160 ꢂC, ½aꢁ ¼ þ4:1 (c 1, MeOH). Found: C 70.6; H
D
D
MeOH). Found: C 72.7; H 7.0; N 11.9. C22H25N3O2 re-
quires C 72.7; H 6.9; N 11.6. 1H NMR (d/ppm,
500 MHz, DMSO) 0.83 (3H, d, J = 6.6, CHCH3), 0.89
(3H, t, J = 7.3, CH2CH3), 1.14 + 1.53 (2H, m,
CH3CH2), 1.82 + 1.90 (1H, m, CH3CHCH2CH3),
4.55 + 4.66 (1H, t, J = 9.2, CBzNHCH), 5.07 (2H,
J = 16.2, PhCH2CO), 6.91 + 7.09 (1H, s, Him), 7.35–
7.7.48 (8H, m, ArH), 7.94 (2H, d, J = 7.6, ArH),
12.24 + 12.38 (1H, br s). 13C NMR (d/ppm, 125 MHz,
DMSO) 11.4, 15.8, 24.8, 38.7, 54.2, 65.2, 114.3, 124.6,
124.8, 127.7, 127.9, 128.4, 128.7, 130.8, 137.4, 142.7,
144.7, 155.9. Positive-ion APCI-MS: m/z 364 [M+H]+,
306 [M+Hꢀbutane]+, 254 [M+HꢀCH3C6H5ꢀH2O]+,
213 [M+HꢀNH2COOCH2C6H5]+ (100%). Positive-ion
APCI-MS/MS of m/z 364: 213 [M+HꢀNH2COOCH2-
C6H5]+ (100%), 171 [M+HꢀNH2COOCH2C6H5ꢀ
7.0; N 22.3. C11H13N3 requires C 70.6; H 7.0; N 22.4.1.
1H NMR (d/ppm, 500 MHz, DMSO) 1.55 (3H, d, J =
6.8, CH3), 4.37 (1H, k, J = 6.7, NH2CH), 7.22 (1H, s,
Him), 7.37 (1H, t, J = 7.2, ArH), 7.48 (2H, t, J = 7.6,
ArH), 8.03 (2H, d, J = 7.3, ArH). 13C NMR (d/ppm, 125
MHz, DMSO) 19.6, 43.9, 118.5, 124.1, 124.9, 128.1,
128.7, 130.7, 145.8. Positive-ion APCI-MS: m/z 188
[M+H]+, 171 [M+HꢀNH3]+ (100%). Positive-ion APCI-
MS/MS of m/z 188: 171 [M+HꢀNH3]+ (100%). Nega-
tive-ion APCI-MS: 186 [MꢀH]ꢀ, 169 [MꢀHꢀNH3]ꢀ
(100%). Negative-ion APCI-MS/MS of m/z 186: 169
[MꢀHꢀNH3]ꢀ (100%), 143 [C6H5(C@NCH@CNH)]ꢀ.
4.4.2. 2-Phenyl-4-(1-(R)-aminoethyl)-1H-limidazole 5b
Prepared from 4b by the general method to give the
20
D
title compound 5b as an oil, yield 99%, ½aꢁ ¼ ꢀ4:0 (c

ˇ ´
F. Bures, J. Kulhanek / Tetrahedron: Asymmetry 16 (2005) 1347–1354
1353
1, MeOH). Found: C 70.3; H 6.9; N 22.1. C11H13N3
requires C 70.6; H 7.0; N 22.4.1. 1H NMR (d/ppm,
500 MHz, DMSO) 1.55 (3H, d, J = 6.8, CH3), 4.37
(1H, k, J = 6.7, NH2CH), 7.22 (1H, s, Him), 7.37 (1H,
t, J = 7.2, ArH), 7.48 (2H, t, J = 7.6, ArH), 8.03 (2H,
d, J = 7.3, ArH). 13C NMR (d/ppm, 125 MHz, DMSO)
19.6, 43.9, 118.5, 124.1, 124.9, 128.1, 128.7, 130.7, 145.8.
Positive-ion APCI-MS: m/z 188 [M+H]+, 171
[M+HꢀNH3]+ (100%). Positive-ion APCI-MS/MS of
m/z 188: 171 [M+HꢀNH3]+ (100%). Negative-ion
APCI-MS: 186 [MꢀH]ꢀ, 169 [MꢀHꢀNH3]ꢀ (100%).
Negative-ion APCI-MS/MS of m/z 186: 169
[MꢀHꢀNH3]ꢀ (100%), 143 [C6H5(C@NCH@CNH)]ꢀ.
NH2CH), 7.02 (1H, s, Him), 7.35 (1H, t, J = 7.3, ArH),
7.46 (2H, t, J = 7.4, ArH), 7.97 (2H, d, J = 7.3, ArH).
13C NMR (d/ppm, 125 MHz, DMSO) 22.3, 22.8, 24.4,
46.0, 46.7, 118.1, 124.8, 125.1, 127.8, 128.7, 130.5,
145.1. Positive-ion APCI-MS: m/z 230 [M+H]+, 213
[M+HꢀNH3]+ (100%). Positive-ion APCI-MS/MS of
m/z 230: 213 [M+HꢀNH3]+ (100%), 172 [M+H-bu-
tane]+. Negative-ion APCI-MS: 228 [MꢀH]ꢀ, 211
[MꢀHꢀNH3]ꢀ (100%). Negative-ion APCI-MS/MS of
m/z
228:
211
[MꢀHꢀNH3]ꢀ
(100%),
196
[MꢀHꢀNH3ꢀCH3]ꢀ, 184 [MꢀHꢀNH3ꢀHCN]ꢀ, 169
[MꢀHꢀNH3ꢀpropene]ꢀ,
143
[C6H5(C@NCH@
CNH)]ꢀ.
4.4.6. 2-Phenyl-4-(1-(S)-amino-2-methylbutyl)-1H-imid-
azole 5f. Prepared from 4f by the general method to
give title compound 5f as an oil, yield 99%,
4.4.3. 2-Phenyl-4-(1-(S)-amino-2-methylpropyl)-1H-imid-
azole 5c. Prepared from 4c by the general method to
give the title compound 5c as an oil, yield 99%,
20
20
½aꢁ ¼ þ4:5 (c 1, MeOH). Found: C 73.4; H 8.4; N
D
½aꢁ ¼ þ2:7 (c 1, MeOH). Found: C 72.1; H 7.9; N
D
18.5. C14H19N3 requires C 73.3; H 8.4; N 18.3. 1H
NMR (d/ppm, 360 MHz, DMSO) 0.85–0.92 (6H, m,
CHCH3 + CH2CH3), 1.13+1.54 (2H, 2 · m, CH3CH2),
1.84 (1H, m, CH3CHCH2CH3), 3.88 (1H, m, NH2CH),
7.07 (1H, s, Him), 7.35 (1H, t, J = 7.2, ArH), 7.46 (2H, t,
J = 7.7, ArH), 7.97 (2H, d, J = 7.3, ArH). 13C NMR (d/
ppm, 125 MHz, DMSO) 11.6, 15.4, 24.9, 38.8, 53.3,
117.9, 124.9, 125.1, 128.0, 128.8, 130.8, 145.1. Positive-
ion APCI-MS: m/z 230 [M+H]+, 213 [M+HꢀNH3]+
(100%), 172 [M+Hꢀbutane]+. Positive-ion APCI-MS/
MS of m/z 230: 213 [M+HꢀNH3]+ (100%). Negative-
ion APCI-MS: 228 [MꢀH]ꢀ, 211 [MꢀHꢀNH3]ꢀ
(100%). Negative-ion APCI-MS/MS of m/z 228: 211
[MꢀHꢀNH3]ꢀ (100%), 196 [MꢀHꢀNH3-CH3]ꢀ, 184
[MꢀHꢀNH3ꢀHCN]ꢀ, 169 [MꢀHꢀNH3ꢀpropene]ꢀ,
143 [C6H5(C@NCH@CNH)]ꢀ.
19.5. C13H17N3 requires C 72.5; H 8.0; N 19.5. 1H
NMR (d/ppm, 500 MHz, DMSO) 0.89 (3H, d,
J = 5.7, CH3), 0.90 (3H, d, J = 5.7, CH3), 1.98 (1H,
m, (CH3)2CH), 3.66 (1H, d, J = 5.7, NH2CH), 6.96
(1H, s, Him), 7.34 (1H, t, J = 7.4, ArH), 7.45 (2H, t,
J = 7.8, ArH), 7.95 (2H, d, J = 7.4, ArH). 13C NMR
(d/ppm, 125 MHz, DMSO) 18.1, 19.6, 33.6, 48.7,
117.3, 124.5, 124.7, 126.7, 128.7, 131.1, 144.6. Posi-
tive-ion APCI-MS: m/z 216 [M+H]+, 199 [M+
H!ꢀNH3]+ (100%). Positive-ion APCI-MS/MS of m/z
216: 199 [M+HꢀNH3]+ (100%). Negative-ion APCI-
MS: 214 [MꢀH]ꢀ, 197 [MꢀHꢀNH3]ꢀ (100%). Nega-
tive-ion APCI-MS/MS of m/z 214: 197 [MꢀHꢀNH3]ꢀ
(100%).
4.4.4. 2-Phenyl-4-(1-(S)-amino-2-phenylethyl)-1H-imid-
azole 5d. Prepared from 4d by the general method to
4.4.7. 2-Phenyl-4-pyrrolidine-2-(S)-yl-1H-imidazole 5g.
Prepared from 4g by the general method to give the title
give title compound 5d as a white solid, mp 80–81 ꢂC,
20
20
D
yield 99%, ½aꢁ ¼ þ23:9 (c 1, MeOH). Found: C
D
77.3; H 6.5; N 15.9. C17H17N3 requires C 77.5; H 6.5;
compound 5g as a yellow oil, yield 99%, ½aꢁ ¼ þ12:1
(c 1, MeOH). Found: C 73.0; H 7.0; N 19.4. C13H15N3
requires C 73.2; H 7.1; N 19.7. 1H NMR (d/ppm,
360 MHz, DMSO) 1.77 (3H, m, CH2CH2CH2 +
CHCH2CH2), 2.05 (1H, m, CHCH2CH2) 2.83 (1H, m,
CH2CH2NH), 3.03 (1H, m, CH2CH2NH), 4.08 (1H,
m, CH2CHNH), 7.03 (1H, s, Him), 7.35 (1H, t, J = 7.1,
ArH), 7.46 (2H, t, J = 7.8, ArH), 7.95 (2H, d, J = 7.4,
ArH). 13C NMR (d/ppm, 90 MHz, DMSO) 25.1, 33.2,
46.1, 54.2, 118.7, 124.7, 125.2, 127.8, 128.7, 131.0,
144.9. Positive-ion APCI-MS: m/z 214 [M+H]+, 197
[M+HꢀNH3]+ (100%). Positive-ion APCI-MS/MS of
m/z 214: 197 [M+HꢀNH3]+ (100%), 171 [M+Hꢀ
NH3ꢀC2H4]+. Negative-ion APCI-MS: 212 [MꢀH]ꢀ
(100%). Negative-ion APCI-MS/MS of m/z 212: 195
[MꢀHꢀNH3 ]ꢀ (100%).
N
16.0. 1H NMR (d/ppm, 500 MHz, DMSO)
2.97 + 3.20 (2H, 2 · m, CH2Ph), 4.21 (1H, t, J = 7.0,
NH2CH), 6.99 (1H, s, Him), 7.19–7.30 (4H, m, ArH),
7.37 (1H, t, J = 7.3, ArH), 7.47 (2H, t, J = 7.5, ArH),
7.99 (2H, d, J = 7.3, ArH). 13C NMR (d/ppm,
125 MHz, DMSO) 43.9, 50.7, 118.0, 124.9, 125.4,
126.1, 128.0, 128.2, 128.8, 129.4, 131.0, 139.7, 145.0.
Positive-ion APCI-MS: m/z 264 [M+H]+, 247
[M+HꢀNH3]+ (100%), 143 [C6H5(C@NCH@CNH)]+.
Positive-ion APCI-MS/MS of m/z 264: 247
[M+HꢀNH3]+ (100%). Negative-ion APCI-MS: 262
[MꢀH]ꢀ, 245 [MꢀHꢀNH3]ꢀ (100%). Negative-ion
APCI-MS/MS of m/z 262: 245 [MꢀHꢀNH3]ꢀ, 170
[MꢀHꢀCH3C6H5]ꢀ (100%), 143 [C6H5(C@NCH@
CNH)]ꢀ.
4.4.5. 2-Phenyl-4-(1-(S)-amino-3-methylbutyl)-1H-imid-
azole 5e. Prepared from 4e by the general method to
give title compound 5e as an oil, yield 99%,
Acknowledgements
Support of this research under Grant 203/02/0750 from
the Czech Grant Agency is gratefully acknowledged.
Authors would like to thanks to M. Holcapek for pre-
cise MS spectra recording (grant project No. 203/05/
2106 sponsored by the Grant Agency of the Czech
Republic).
20
½aꢁ ¼ þ2:6 (c 1, MeOH). Found: C 73.2; H 8.2; N
D
18.1. C14H19N3 requires C 73.3; H 8.4; N 18.3. 1H
NMR (d/ppm, 500 MHz, DMSO) 0.91 (3H, d, J = 6.1,
CH(CH3)2), 0.94 (3H, d, J = 6.2, CH(CH3)2) 1.55 (1H,
m, CH2CH), 1.67 (2H, m, CHCH2) 3.95 (1H, m,
ˇ

ˇ ´
F. Bures, J. Kulhanek / Tetrahedron: Asymmetry 16 (2005) 1347–1354
1354
4. Balenovic, K.; Cerar, D.; Filipovic, L. J. Org. Chem. 1953,
18, 868–871.
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