Design and efficient synthesis of amino acid derived 2-substituted imidazoles by palladium-catalyzed cross-coupling reactions

Article abstract of DOI:10.1055/s-0028-1083263

Optically active imidazole derivatives featuring an α-amino acid motif substituted at the 2-position can be prepared in moderate to good yields by Negishi as well as Suzuki-Miyaura cross-couplings as the key synthetic steps. The reaction sequence involves

Full text of DOI:10.1055/s-0028-1083263

PAPER
325
Design and Efficient Synthesis of Amino Acid Derived 2-Substituted
Imidazoles by Palladium-Catalyzed Cross-Coupling Reactions
A
mino Acid Deriv
l
ed 2-S
u
e
bstituted
I
m
idazoles Marek, Jiří Kulhánek, Filip Bureš*
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, nám. Čs. legií 565,
Pardubice 532 10, Czech Republic
Fax +420(46)6037068; E-mail: filip.bures@upce.cz
Received 18 September 2008; revised 19 September 2008
known imidazoles
Abstract: Optically active imidazole derivatives featuring an a-
amino acid motif substituted at the 2-position can be prepared in
R1
R1
moderate to good yields by Negishi as well as Suzuki–Miyaura
NHCbz
N
HN
cross-couplings as the key synthetic steps. The reaction sequence
involves N-protection (ethoxymethylation), whereby both generat-
ed regioisomers could be separated by column chromatography, and
selective 2-lithiation. Subsequent transmetalation to zinc or an io-
dine quench affords reactants suitable for Pd-catalyzed Negishi and
Suzuki–Miyaura reactions with (hetero)aromatics.
HN
R2
NH
R2
H
N
N
N
R2
R1 = amino acid residue
2 = H or Ph
R
new imidazoles
Key words: heterocycles, cross-coupling, amino acids, chiral pool,
R
ligands
NHCbz
X = N, O, C
HN
N
Since the first parent imidazole (glyoxaline) synthesis was
reported by Debus,1 heterocyclic compounds incorporat-
ing an imidazole nucleus and diverse imidazole-based
systems have attracted the attention of organic chemists.
Such heteroaromatic compounds are mainly designed,
prepared and further investigated because of their pro-
X
Figure 1 Known and newly proposed a-amino acid derived imida-
zoles
spective
applicability
as
biologically2
or
These compounds bind transition metals predominantly
through the N=C–C–N coordination site where one car-
bon and one nitrogen come from the side chain bearing the
stereogenic center (alpha to the imidazole at C-4) and the
remaining two from the imidazole. We focus in this paper
on the introduction of various (hetero)aromatic substitu-
ents at position C-2 in order to design imidazoles having
a N=C–C=N coordinating pocket similar to those known
for 2,2¢-bypiridine (bipy) or 1,10-phenanthroline (phen)
and related ligands (Figure 1).9 The side chain containing
an asymmetric center (amino acid residue) at position C-
4 is then involved only as a chiral auxiliary.
With C-2 unsubstituted imidazoles (R1 = H) already in
hand,8c our retrosynthetic strategy leading to the target im-
idazoles involved the formation of the imidazole–
(hetero)aromate C(sp2)–C(sp2) bond. According to the lit-
erature, cross-coupling reactions seemed to be optimal for
such C-2 substitutions.10 Organozinc reagents (Negishi
reaction),11 boronic acids (Suzuki–Miyaura reaction),12
organotin compounds (Stille reaction)13 or direct
arylation14 are amongst the most frequently used reactions
in such imidazole functionalizations. The desired C–C
bond can be established through either an imidazole as a
C-2 metalated heterocycle and a (hetero)aromatic halide
as an electrophile or vice versa.
pharmacologically3 active compounds, transition-metal-
coordinating nitrogen ligands,4 ionic liquids5 and activat-
ing agents.6 However, the most widely known naturally
occurring 4-substituted derivative of an imidazole is cer-
tainly the essential amino acid histidine, with its product
of decarboxylation – histamine. Thus, the histamine-relat-
ed molecules are worthwhile synthesizing because of their
acid/base character, thermal and chemical robustness, tau-
tomerism, easy synthesis and possible functionalization
either on the imidazole ring or on the side chain. More-
over, the imidazole nitrogen(s) are able to bind transition
metals and, due to the presence of a stereogenic center ad-
jacent to the imidazole ring, their use as optically active
nitrogen ligands with prospective applications in a wide
range of fields, such as asymmetric synthesis or catalysis
and chiral recognition or induction, has been encouraged.
In general terms, the application of the a-amino acids as
enantiopure synthetic precursors for such systems seems
to be advantageous because of their ready availability and
low cost.7 Recently, we have reported the synthesis of bi-
and tridentate enantiopure imidazole-based nitrogen
ligands featuring an amino acid motif varying mainly in
the nature of the substituent R (amino acid residue).8
SYNTHESIS 2009, No. 2, pp 0325–0331
x
x
.
x
x
.2
0
0
8
Three C-2 unsubstituted imidazoles 1–3, derived from
(S)-alanine, (S)-leucine and (S)-phenylalanine, obtained
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1083263; Art ID: Z21508SS
© Georg Thieme Verlag Stuttgart · New York

326
A. Marek et al.
PAPER
R1
R1
R1
EtOCH2Cl, Et3N, THF
NHCbz
NHCbz
NHCbz
+
PG
N
HN
N
N
N
N
PG
R2
R2
1 R1 = Me (S)-Ala
2 R1 = i-Bu (S)-Leu
3 R1 = Bn (S)-Phe
4a R1 = Me, R2 = H
5a R1 = i-Bu, R2 = H
6a R1 = Bn, R2 = H
4b R1 = Me, R2 = H
5b R1 = i-Bu, R2 = H
6b R1 = Bn, R2 = H
1. n-BuLi, THF, –78 °C
2. I2, THF, 20 °C
7
8
R1 = Me, R2 = I
R1 = i-Bu, R2 = I
PG = ethoxymethyl
Scheme 1 N-Protection and iodination of imdiazoles 1–3
from the condensation of the corresponding a-bromoke- protocol using 2-bromopyridine as an electrophile, which
tones and formamidine in liquid ammonia,8c were used as likewise led to the desired compound 11 in good yield.
starting compounds. In order to perform the desired reac- We did not observe any remarkable changes in the yields
tions with organometallic compounds, imidazoles 1–3 depending on the catalyst and zinc halide used [yields for
needed to be N-protected.
11: Pd(PPh3)4/ZnBr2:68% and PdCl2(PPh3)2/ZnCl2: 69%].
In addition, 2-iodopyrazine, 3-bromopyridazine,17 2-io-
dopyrimidine and 8-iodoquinoline also smoothly under-
went the Negishi cross-coupling to afford the C-2
functionalized imidazoles 12–15 in yields of 54–64%. A
similar procedure applied to C-2 unsubstituted imidazole
4a and 2-iodoimidazoles 7 afforded bisimidazole deriva-
tive 16 in moderate yield (34%). It should be noted here
that all of our synthetic attempts to prepare a similar bis-
imidazole derivative using known procedures such as
copper-catalyzed Ullmann coupling16 or palladium-cata-
lyzed oxidative homocoupling,18 failed.
Treatment of 1–3 with chloromethylethyl ether in the
presence of triethylamine afforded the protected imida-
zoles 4–6 in good yields (PG = ethoxymethyl,
Scheme 1),15 however, since the starting 4(5)-substituted
imidazoles 1–3 are unsymmetrical, the formation of two
regioisomers was possible (a and b series). We observed
formation of both regioisomers in a roughly 1:1 ratio
which, importantly, could be separated by two consecu-
tive chromatographic separations. In view of the proposed
structures in Figure 1, since the regioisomers in series b
have the side chain and the PG group on the same side
(cis-arrangement), which would lead to a stereogenic cen- Prepared iodo-derivatives 7 and 8 could also be coupled
ter at a greater distance from the binding site, imidazoles with commercially available boronic acids (phenylboron-
4b–6b were not used for further cross-coupling reactions. ic acid and furan-2-ylboronic acid) under the conditions of
The correct molecular structures of 4–6 were determined Pd(PPh3)4-catalyzed Suzuki–Miyaura reaction, whereby
1
mainly on the basis of H–13C NMR spectroscopy em- imidazoles 17 and 18 were isolated in good yields of 74
ploying HMQC and HMBC methods, which showed in- and 88%, respectively.
teractions between the CH group of the side chain, the
imidazole carbons and the CH2 group of the protecting
group.
The optical purities of the final products 9–18 resemble
those of the starting imidazoles 1–3. The carbamic acid
functionality (Cbz) was tolerated in the presence of orga-
Since it is well known that N-substituted imidazole may nolithium as well as organozinc species.
be selectively lithiated at the C-2 position,10 imidazoles
4a–6a could therefore readily serve as the starting com-
pounds for such lithiations and the subsequent Negishi
cross-coupling reaction. However, in order to generate
In conclusion, we report in this paper the synthesis of ten
new histamine-related, optically pure imidazole deriva-
tives featuring an a-amino acid motif. Either Negishi or
Suzuki–Miyaura cross-couplings proved to be feasible on
electrophilic counterparts suitable for reaction with bo-
ronic acids (Suzuki–Miyaura cross-coupling), we also at-
1. n-BuLi, THF, –78 °C
R
tempted the C-2 lithiation of 4a and 5b followed by an
2. ZnBr2, THF, 20 °C
iodine quench,11a,16 which afforded the desired imidazole
3. Ar-X, Pd cat., reflux
NHCbz
4a–6a
PG
PG
N
iodides 7 and 8, respectively, in moderate yields.
N
Thus, with both the organometallic as well as electrophilic
reactants already in hand, we proceeded to the cross-cou-
pling reactions (Scheme 2, Table 1). As an initial investi-
gation, a standard Negishi reaction11b involving lithiation
of imidazoles 6a and 4a with n-BuLi at –78 °C was con-
ducted; transmetallation with zinc bromide and subse-
quent Pd(PPh3)4-catalyzed coupling with readily available
bromobenzene and 4-iodo-N,N-dimethylaniline afforded
compounds 9 and 10 in 48 and 66% yields, respectively.
Delighted with such a smooth reaction, we followed this
Ar
9–16
Ar-B(OH)2, Pd(PPh3)4
Na2CO3, THF–H2O (4:1)
reflux
R
NHCbz
7–8
N
N
Ar
17,18
Scheme 2 Cross-coupling reactions leading to imidazoles 9–18
Synthesis 2009, No. 2, 325–331 © Thieme Stuttgart · New York

PAPER
Amino Acid Derived 2-Substituted Imidazoles
327
Table 1 Synthesis of Target Imidazoles 9–18 (Scheme 2)
Imidazole Starting compd
R/a-amino acid
Bn/(S)-Phe
ArX/ArB(OH)2
Time (h)
8
Yield (%)
66
[a]D20 (c 0.1, MeOH)
9a
6a
4a
–8.0
Br
10a
Me/(S)-Ala
Me/(S)-Ala
6
48
68
–7.0
Me2N
I
11a
12a
13a
14a
4a
4a
4a
4a
20
–10.0
Br
N
N
Me/(S)-Ala
Me/(S)-Ala
Me/(S)-Ala
20
20
72
64
64
56
–12.0
–11.0
–14.0
I
N
N
Br
N
Br
N
N
N
15a
16a
5a
4a
i-Bu/(S)-Leu
Me/(S)-Ala
20
72
54
34
–27.0
–8.0
Br
Me
EtO
NHCbz
N
N
I
17b
18b
7
8
Me/(S)-Ala
20
6
74
88
–11.0
–39.0
B(OH)2
O
i-Bu/(S)-Leu
B(OH)2
a Negishi reaction.
b Suzuki–Miyaura reaction.
tion values were measured on a Perkin–Elmer 341 instrument, con-
centration c is given in g/100 mL MeOH.
our systems, affording the target compounds in moderate
to good yields.
The mass spectra were measured either on a GC/MS system com-
prised of an Agilent Technologies 6890N gas chromatograph (HP-
5MS column, length 30 m, I.D. 0.25 mm, film 0.25 mm) equipped
with a 5973 Network MS detector (EI 70 eV, mass range 33–550
Da) or on a LC-MS Micromass Quattro Micro API (Waters) instru-
ment with a direct input (ESI+, 0.5 mL/min stream of MeOH, mass
range 200–800 Da and MassLynx software were used).
Reagents and solvents were reagent-grade and were purchased from
Penta and used as received. THF was freshly distilled from Na/ben-
zophenone under N2. The starting imidazoles 1–3 were synthesized
according to literature procedures.8c Column chromatography 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 aluminum sheets coated
with SiO2 60 F254 obtained from Merck, with visualization by UV
lamp (254 or 360 nm). Melting points (mp) were measured on a Bü-
chi B-540 melting-point apparatus in open capillaries and are uncor-
rected. 1H and 13C NMR spectra were recorded in CDCl3 at 360/500
MHz and 90/125 MHz, respectively, with Bruker AMX 360 or
Bruker Avance 500 instruments at 25 °C. Chemical shifts are re-
ported in ppm relative to TMS. Residual solvent signal in the 1H and
13C NMR spectra was used as an internal reference (CDCl3: d = 7.25
and 77.23 ppm). Coupling constants (J) are given in Hz. Cbz phenyl
protons and carbons are marked as Ph. The pyridine, pyrazine, py-
ridazine, pyrimidine, quinoline and furane protons are marked as
Py, Prz, Pdz, Pym, Qun and Fur, respectively. 1H–1H COSY,
HMBC and HMQC NMR techniques were also used. Optical rota-
N-Protection (Ethoxymethylation) of Imidazoles 1–3; General
Procedure
Et3N (0.9 mL, 6.5 mmol) and ethoxymethylchloride (0.3 mL, 3.27
mmol) were added to a solution of imidazole 1–3 (3.27 mmol) in
THF (30 mL) and the reaction mixture was stirred for 2 h at 25 °C.
The solvent was evaporated, H2O (30 mL) was added and the reac-
tion mixture was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were dried (Na2SO4) and the solvent evaporated. The
crude product was purified by two consecutive column chromato-
graphic separations [SiO2; hexane–EtOAc–MeOH–NH3(aq),
3:5:1:0.1] to afford a pure mixture of both regioisomers, which
could be further separated using a second column (SiO2; EtOAc–
hexane, 3:1).
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328
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(S)-Benzyl 1-[1-(Ethoxymethyl)-1H-imidazol-5-yl]ethylcar-
(S)-Benzyl 1-[1-(Ethoxymethyl)-1H-imidazol-4-yl]ethylcar-
bamate (4a)
bamate (4b)
Yield: 466 mg (47%); oil; ee >95%; Rf = 0.75 [hexane–EtOAc–
MeOH–NH3(aq), 3:5:1:0.1], Rf = 0.14 (EtOAc–hexane, 3:1); [a]D
–8.0 (c 0.1, MeOH).
Yield: 416 mg (42%); oil; ee >95%; Rf = 0.66 [hexane–EtOAc–
MeOH–NH3(aq), 3:5:1:0.1], Rf = 0.05 (EtOAc–hexane, 3:1); [a]D
–4.0 (c 0.1, MeOH).
20
20
1H NMR (360 MHz, CDCl3): d = 1.13 (t, J = 7.0 Hz, 3 H, CH3CH2),
1.46 (d, J = 6.8 Hz, 3 H, CH3CH), 3.38 (q, J = 7.0 Hz, 2 H,
CH2CH3), 4.78–4.85 (m, 1 H, CHNH), 5.02–5.08 (m, 2 H, CH2Ph),
5.13 (s, 2 H, OCH2N), 5.62–5.64 (m, 1 H, NH), 6.86 (s, 1 H, 5-Him),
7.25–7.31 (m, 5 H, Ph), 7.46 (s, 1 H, 2-Him).
1H NMR (360 MHz, CDCl3): d = 1.13 (t, J = 7.0 Hz, 3 H, CH3CH2),
1.54 (d, J = 6.7 Hz, 3 H, CH3CH), 3.39 (q, J = 6.7 Hz, 2 H,
CH2CH3), 5.01–5.09 (m, 3 H, CHNH and CH2Ph), 5.14 and 5.36
(dd, J = 11.5, 10.5 Hz, 2 H, OCH2N), 5.19 (s, 1 H, NH), 6.96 (s,
1 H, 4-Him), 7.28–7.34 (m, 5 H, Ph), 7.50 (s, 1 H, 2-Him).
13C NMR (90 MHz, CDCl3): d = 14.8 (CH3CH2), 21.5 (CH3CH),
45.2 (CH), 64.5 (CH3CH2), 66.6 (PhCH2), 76.9 (OCH2N), 114.8 (5-
Cim), 128.0 (Ph), 128.1 (Ph), 128.5 (Ph), 136.8 (Ph), 137.2 (2-Cim),
144.8 (4-Cim), 155.8 (CO).
13C NMR (90 MHz, CDCl3): d = 14.8 (CH3CH2), 21.5 (CH3CH),
45.2 (CH), 64.5 (CH3CH2), 66.6 (PhCH2), 76.9 (OCH2N), 127.4 (4-
Cim), 128.3 (Ph), 128.4 (Ph), 128.7 (Ph), 133.4 (5-Cim), 136.5 (Ph),
138.9 (2-Cim), 155.6 (CO).
EI-MS (70 eV): m/z (%) = 303 [M+] (1), 195 (15), 180 (40), 168
(30), 151 (70), 122 (15), 108 (100), 91 (50), 79 (95), 59 (100), 51
(20).
EI-MS (70 eV): m/z (%) = 244 (10), 166 (35), 122 (20), 108 (100),
91 (50), 79 (95), 59 (100), 51 (20), 41 (20).
Anal. Calcd for C16H21N3O3: C, 63.35; H, 6.98; N, 13.85. Found: C,
63.36; H, 7.17; N, 14.03.
Anal. Calcd for C16H21N3O3: C, 63.35; H, 6.98; N, 13.85. Found: C,
63.25; H, 7.07; N, 13.93.
(S)-Benzyl 1-[1-(Ethoxymethyl)-1H-imidazol-5-yl]-3-methylbu-
tylcarbamate (5b)
(S)-Benzyl 1-[1-(Ethoxymethyl)-1H-imidazol-4-yl]-3-methylbu-
tylcarbamate (5a)
Yield: 395 mg (35%); oil; ee >95%; Rf = 0.63 [hexane–EtOAc–
20
Yield: 406 mg (36%); oil; ee >95%; Rf = 0.71 [hexane–EtOAc–
MeOH–NH3(aq), 3:5:1:0.1], Rf = 0.10 (EtOAc–hexane, 3:1); [a]D
–16.0 (c 0.1, MeOH).
20
MeOH–NH3(aq), 3:5:1:0.1], Rf = 0.18 (EtOAc–hexane, 3:1); [a]D
–32.0 (c 0.1, MeOH).
1H NMR (360 MHz, CDCl3): d = 0.90–0.92 [m, 6 H, (CH3)2CH],
1.10 (t, J = 6.9 Hz, 3 H, CH3CH2), 1.59–1.70 [m, 3 H,
CH2CH(CH3)2], 3.36 (q, J = 6.7 Hz, 2 H, CH2CH3), 4.92–5.13 (m,
4 H, CHNH and CH2Ph), 5.50 (dd, J = 10.9, 9.0 Hz, 2 H, OCH2N),
6.89 (s, 1 H, 4-Him), 7.25–7.28 (m, 5 H, Ph), 7.43 (s, 1 H, 2-Him).
13C NMR (90 MHz, CDCl3): d = 14.7 (CH3CH2), 22.4 and 22.6
[(CH3)2CH], 25.0 [(CH3)2CH], 43.9 (CH), 43.9 (CH2CH), 64.0
(CH3CH2), 66.8 (PhCH2), 74.7 (OCH2N), 127.4 (4-Cim), 128.1 (Ph),
128.2 (Ph), 128.6 (Ph), 133.2 (5-Cim), 136.5 (Ph), 138.5 (2-Cim),
155.8 (CO).
1H NMR (360 MHz, CDCl3): d = 0.88 [d, J = 6.6 Hz, 6 H,
(CH3)2CH], 1.11 (t, J = 6.9 Hz, 3 H, CH3CH2), 1.47–1.57 [m, 1 H,
CH(CH3)2], 1.69 (t, J = 7.2 Hz, 2 H, CHCH2), 3.34 (q, J = 6.3 Hz,
2 H, CH2CH3), 4.74–4.79 (m, 1 H, CHNH), 4.98–5.12 (m, 4 H,
CH2Ph and OCH2N), 5.86 (d, J = 8.8 Hz, 1 H, NH), 6.85 (s, 1 H, 5-
Him), 7.25–7.30 (m, 5 H, Ph), 7.46 (s, 1 H, 2-Him).
13C NMR (90 MHz, CDCl3): d = 14.8 (CH3CH2), 22.6 and 22.7
[(CH3)2CH], 24.9 [(CH3)2CH], 44.6 (CH2CH), 47.6 (CHNH), 64.5
(CH3CH2), 66.6 (PhCH2), 76.3 (OCH2N), 115.4 (5-Cim), 128.0 (Ph),
128.1 (Ph), 128.5 (Ph), 136.8 (Ph), 137.4 (2-Cim), 143.8 (4-Cim),
156.0 (CO).
EI-MS (70 eV): m/z (%) = 288 (20), 244 (20), 180 (40), 108 (60),
91 (100), 79 (55), 59 (70), 44 (15).
EI-MS (70 eV): m/z (%) = 345 [M+] (1), 288 (30), 244 (20), 194
(20), 180 (90), 153 (30), 135 (30), 122 (20), 108 (70), 91 (70), 79
(70), 59 (100), 41 (15).
Anal. Calcd for C19H27N3O3: C, 66.06; H, 7.88; N, 12.16. Found: C,
65.99; H, 8.08; N, 12.14.
Anal. Calcd for C19H27N3O3: C, 66.06; H, 7.88; N, 12.16. Found: C,
66.01; H, 8.01; N, 12.24.
(S)-Benzyl 1-[1-(Ethoxymethyl)-1H-imidazol-5-yl]-2-phenyl-
ethylcarbamate (6b)
Yield: 446 mg (36%); oil; ee >95%; Rf = 0.52 [hexane–EtOAc–
20
(S)-Benzyl 1-[1-(Ethoxymethyl)-1H-imidazol-4-yl]-2-phenyl-
ethylcarbamate (6a)
MeOH–NH3(aq), 3:5:1:0.1], Rf = 0.1 (EtOAc–hexane, 3:1); [a]D
–23.0 (c 0.1, MeOH).
Yield: 446 mg (36%); oil; ee >95%; Rf = 0.58 [hexane–EtOAc–
MeOH–NH3(aq), 3:5:1:0.1], Rf = 0.25 (EtOAc–hexane, 3:1); [a]D
–30.0 (c 0.1, MeOH).
1H NMR (360 MHz, CDCl3): d = 1.07 (t, J = 7.0 Hz, 3 H, CH3CH2),
3.15–3.30 (m, 4 H, CHCH2Ph and CH3CH2), 5.97–5.07 (m, 3 H,
CHNH and CH2Ph), 5.12–5.20 (m, 2 H, NH and OCH2N), 5.31 (d,
J = 10.0 Hz, 1 H, OCH2N), 7.00 (s, 1 H, 4-Him), 7.13–7.32 (m,
10 H, Ph and ArH), 7.54 (s, 1 H, 2-Him).
13C NMR (90 MHz, CDCl3): d = 14.8 (CH3CH2), 41.5 (CHCH2Ph),
57.8 (CH), 64.2 (CH3CH2), 67.1 (PhCH2O), 74.9 (OCH2N), 127.0
(4-Cim), 127.0 (Ar), 128.3 (Ph), 128.4 (Ar), 128.7 (Ph), 128.8 (Ph),
129.5 (Ar), 132.3 (5-Cim), 136.5 (Ph), 137.0 (Ar), 138.6 (2-Cim),
155.6 (CO).
20
1H NMR (360 MHz, CDCl3): d = 1.10 (t, J = 6.9 Hz, 3 H, CH3CH2),
3.09–3.13 (dd, J = 9.2, 5.8 Hz, 1 H, CHCH2Ph), 3.22–3.25 (m, 3 H,
CHCH2Ph and CH3CH2), 4.94–4.99 (m, 1 H, CHNH), 5.02–5.09
(m, 4 H, CH2Ph and OCH2N), 6.17–6.21 (m, 1 H, NH), 6.58 (s, 1 H,
5-Him), 7.04 (d, J = 6.1 Hz, 2 H, ArH), 7.12–7.17 (m, 3 H, ArH),
7.29–7.32 (m, 5 H, Ph), 7.47 (s, 1 H, 2-Him).
13C NMR (90 MHz, CDCl3): d = 14.8 (CH3CH2), 41.9 (CHCH2Ph),
50.9 (CH), 64.2 (CH3CH2), 66.6 (PhCH2O), 76.2 (OCH2N), 115.9
(5-Cim), 126.3 (Ar), 128.0 (Ph), 128.1 (Ph), 128.1 (Ar), 128.5 (Ph),
129.5 (Ar), 136.8 (Ph), 137.4 (2-Cim), 138.1 (Ar), 142.1 (4-Cim),
155.9 (CO).
Anal. Calcd for C22H25N3O3: C, 69.64; H, 6.64; N, 11.07. Found: C,
69.63; H, 6.65; N, 11.12.
Iodination; General Procedure
Anal. Calcd for C22H25N3O3: C, 69.64; H, 6.64; N, 11.07. Found: C,
69.59; H, 6.81; N, 11.15.
A solution of imidazole 4a or 5a (3.30 mmol) in anhydrous THF (15
mL) was treated with n-BuLi (2 equiv, 1.6 M in hexane) under N2
at –78 °C until a red-brown color was established. A solution of I2
(2.5 g, 9.90 mmol) in THF (5 mL) was added and the mixture was
stirred for 2 h at –78 °C and for an additional 12 h at 25 °C. The re-
Synthesis 2009, No. 2, 325–331 © Thieme Stuttgart · New York

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Amino Acid Derived 2-Substituted Imidazoles
329
action was quenched with Na2S2O3 (sat., 20 mL) and extracted with
CH2Cl2 (3 × 50 mL). The combined organic layers were dried
(Na2SO4), the solvent evaporated and the crude product was puri-
fied by column chromatography (SiO2; EtOAc–hexane, 1:2).
1H NMR (360 MHz, CDCl3): d = 1.16 (t, J = 7.0 Hz, 3 H, CH3CH2),
3.15 (dd, J = 8.5, 4.4 Hz, 1 H, CHCH2Ph), 3.28–3.38 (m, 3 H,
CHCH2Ph and CH3CH2), 4.94–5.00 (m, 1 H, CHNH), 5.09 (s, 2 H,
OCH2N), 5.16–5.12 (m, 2 H, CH2Ph), 5.70 (d, J = 7.5 Hz, 1 H, NH),
6.63 (s, 1 H, 5-Him), 7.09 (d, J = 6.6 Hz, 2 H, ArH), 7.16–7.25 (m,
3 H, ArH), 7.28–7.33 (m, 5 H, Ph), 7.42–7.48 (m, 3 H, 2-ArH), 7.75
(d, J = 6.9 Hz, 2 H, 2-ArH).
(S)-Benzyl 1-[1-(Ethoxymethyl)-2-iodo-1H-imidazol-4-yl]ethyl-
carbamate (7)
Yield: 524 mg (37%); oil; ee >95%; Rf = 0.27 (SiO2; EtOAc–hex-
13C NMR (90 MHz, CDCl3): d = 15.0 (CH3CH2), 42.1 (CHCH2Ph),
50.1 (CH), 64.4 (CH3CH2), 66.7 (PhCH2O), 75.8 (OCH2N), 118.4,
126.4, 128.1, 128.3, 128.6, 128.9, 129.2, 129.3, 129.8, 130.3, 136.9,
138.3, 140.6, 148.6, 155.9 (1 C missing).
ane, 1:2); [a]D20 –8.0 (c 0.1, MeOH).
1H NMR (500 MHz, CDCl3): d = 1.17 (t, J = 6.8 Hz, 3 H, CH3CH2),
1.47 (d, J = 6.8 Hz, 3 H, CH3CH), 3.48 (q, J = 7.0 Hz, 2 H,
CH2CH3), 4.78–4.81 (m, 1 H, CHNH), 5.04–5.11 (m, 2 H, CH2Ph),
5.16 (s, 2 H, OCH2N), 5.30 (d, J = 6.7 Hz, 1 H, NH), 7.01 (s, 1 H,
5-Him), 7.27–7.35 (m, 5 H, Ph).
13C NMR (90 MHz, CDCl3): d = 15.0 (CH3CH2), 21.6 (CH3CH),
45.4 (CH), 64.8 (CH3CH2), 66.8 (PhCH2), 68.3 (OCH2N), 89.8 (2-
Cim), 119.5 (5-Cim), 128.2 (Ph), 128.3 (Ph), 128.7 (Ph), 136.8 (Ph),
147.9 (4-Cim), 155.8 (CO).
ESI-MS: m/z = 478 [M+ + Na].
Anal. Calcd for C28H29N3O3: C, 73.82; H, 6.42; N, 9.22. Found: C,
73.63; H, 6.59; N, 9.38.
(S)-Benzyl 1-{2-[4-(Dimethylamino)phenyl]-1-(ethoxymethyl)-
1H-imidazol-4-yl}ethylcarbamate (10)
Yield: 203 mg (48%); oil; ee >95%; Rf = 0.66 (SiO2; EtOAc–hex-
EI-MS (70 eV): m/z (%) = 429 (5), 294 (60), 277 (50), 248 (15), 221
(15), 108 (35), 91 (100), 79 (40), 59 (90).
ane, 5:1); [a]D20 –7.0 (c 0.1, MeOH).
1H NMR (360 MHz, CDCl3): d = 1.21 (t, J = 7.0 Hz, 3 H, CH3CH2),
1.53 (d, J = 6.6 Hz, 3 H, CH3CH), 2.99 [s, 6H, (CH3)2N], 3.52 (q,
J = 6.8 Hz, 2 H, CH2CH3), 4.83–4.87 (m, 1 H, CHNH), 4.96–5.12
(m, 2 H, CH2Ph), 5.17 (s, 2 H, OCH2N), 5.54 (d, J = 6.4 Hz, 1 H,
NH), 6.74 (d, J = 8.9 Hz, 2 H, 2-ArH), 6.9 (s, 1 H, 5-Him), 7.26–7.34
(m, 5 H, Ph), 7.58 (d, J = 8.9 Hz, 2 H, 2-ArH).
Anal. Calcd for C16H20IN3O3: C, 44.77; H, 4.70; I, 29.56; N, 9.79.
Found: C, 44.49; H, 4.79; I, 29.49; N, 9.95.
(S)-Benzyl 1-[1-(Ethoxymethyl)-2-iodo-1H-imidazol-4-yl]-3-
methylbutylcarbamate (8)
Yield: 762 mg (49%); oil; ee >95%; Rf = 0.18 (SiO2; EtOAc–hex-
13C NMR (90 MHz, CDCl3): d = 15.1 (CH3CH2), 22.0 (CH3CH),
40.5 [(CH3)2N], 45.5 (CH), 64.5 (CH3CH2), 66.6 (PhCH2), 75.9
(OCH2N), 112.1, 116.4, 117.9, 128.1, 128.2, 128.6, 130.1, 137.0,
142.8, 149.6, 151.0, 155.9.
ane, 1:2); [a]D20 –30.0 (c 0.1, MeOH).
1H NMR (500 MHz, CDCl3): d = 0.90 (d, J = 6.4 Hz, 6 H,
(CH3)2CH], 1.18 (t, J = 6.9 Hz, 3 H, CH3CH2), 1.51–1.58 [m, 1 H,
CH(CH3)2], 1.68 [t, J = 7.1 Hz, 2 H, CH2CH(CH3)2], 3.46 (q,
J = 7.0 Hz, 2 H, CH2CH3), 4.69–4.73 (m, 1 H, CHNH), 5.02–5.08
(m, 2 H, CH2Ph), 5.16 (s, 2 H, OCH2N), 5.30 (d, J = 8.64 Hz, 1 H,
NH), 7.02 (s, 1 H, 5-Him), 7.22–7.34 (m, 5 H, Ph).
ESI-MS: m/z = 445 [M+ + Na].
Anal. Calcd for C24H30N4O3: C, 68.22; H, 7.16; N, 13.26. Found: C,
67.84; H, 7.49; N, 13.41.
13C NMR (90 MHz, CDCl3): d = 15.0 (CH3CH2), 22.5 and 22.7
[(CH3)2CH], 25.0 [(CH3)2CH], 44.5 (CH2CH), 47.7 (CHNH), 64.8
(CH3CH2), 66.7 (PhCH2), 78.3 (OCH2N), 90.0 (2-Cim), 120.0 (5-
Cim), 128.1 (Ph), 128.2 (Ph), 128.5 (Ph), 136.8 (Ph), 147.0 (4-Cim),
156.0 (CO).
(S)-Benzyl 1-[1-(Ethoxymethyl)-2-(pyridin-2-yl)-1H-imidazol-
4-yl]ethylcarbamate (11)
Yield: 258 mg (68%); oil; ee >95%; Rf = 0.48 (SiO2; EtOAc–hex-
ane, 5:1); [a]D20 –10.0 (c 0.1, MeOH).
1H NMR (360 MHz, CDCl3): d = 1.13 (t, J = 7.0 Hz, 3 H, CH3CH2),
1.53 (d, J = 6.7 Hz, 3 H, CH3CH), 3.47 (q, J = 6.9 Hz, 2 H,
CH2CH3), 4.87–4.89 (m, 1 H, CHNH), 5.07–5.12 (m, 2 H, CH2Ph),
5.57 (d, J = 6.3 Hz, 1 H, NH), 5.95 (s, 2 H, OCH2N), 7.03 (s, 1 H,
5-Him), 7.19 (t, J = 4.9 Hz, 1 H, Py), 7.27–7.37 (m, 5 H, Ph), 7.71 (t,
J = 7.8 Hz, 1 H, Py), 8.11 (d, J = 8.0 Hz, 1 H, Py), 8.54 (d, J = 4.8
Hz, 1 H, Py).
13C NMR (90 MHz, CDCl3): d = 15.7 (CH3CH2), 21.6 (CH3CH),
45.1 (CH), 64.1 (CH3CH2), 66.3 (PhCH2), 76.6 (OCH2N), 117.9,
122.6, 122.9, 127.8, 128.3, 128.3, 136.5, 143.2, 144.4, 148.1, 150.1,
155.5 (1 C missing).
Anal. Calcd for C19H26IN3O3: C, 48.42; H, 5.56; I, 26.92; N, 8.92.
Found: C, 48.46; H, 5.82; I, 26.67; N, 9.01.
Negishi Cross-Coupling to Generate Target Imidazoles 9–16;
General Procedure
A solution of imidazole 4a–6a (1.0 mmol) in anhydrous THF (25
mL) was treated with n-BuLi (2 equiv, 1.6 M in hexane) under N2
at –78 °C until the reaction mixture turned dark red. The reaction
was stirred for 20 min at –78 °C then a freshly prepared solution of
ZnBr2 (225 mg, 1.0 mmol) in anhydrous THF (5 mL) was added.
The reaction mixture was allowed to reach 25 °C and stirred for 30
min. A solution of ArX (1.3 mmol) in anhydrous THF (5 mL) and
Pd(PPh3)4 (50 mg, 0.043 mmol) were added, and the reaction was
refluxed for 1 h whereupon ZnBr2 (450 mg, 2.0 mmol) was added
and the suspension was refluxed until TLC showed that the reaction
was complete (see Table 1 for the reaction times). The reaction was
quenched by adding an aqueous solution of Chelaton III (0.6 M, 10
mL) and the pH was adjusted to 8 using 10% solution of Na2CO3.
The product was extracted with CH2Cl2 (3 × 50 mL), the solvent
was evaporated and the crude product was purified by column chro-
matography.
ESI-MS: m/z = 403 [M+ + Na].
Anal. Calcd for C21H24N4O3: C, 66.30; H, 6.36; N, 14.73. Found: C,
66.19; H, 6.45; N, 14.79.
(S)-Benzyl 1-[1-(Ethoxymethyl)-2-(pyrazin-2-yl)-1H-imidazol-
4-yl]ethylcarbamate (12)
Yield: 244 mg (64%); oil; ee >95%; Rf = 0.33 (SiO2; EtOAc–hex-
ane, 5:1); [a]D20 –12.0 (c 0.1, MeOH).
1H NMR (500 MHz, CDCl3): d = 1.13 (t, J = 7.0 Hz, 3 H, CH3CH2),
1.53 (d, J = 6.7 Hz, 3 H, CH3CH), 3.49 (q, J = 6.9 Hz, 2 H,
CH2CH3), 4.88–4.92 (m, 1 H, CHNH), 5.07–5.12 (m, 2 H, CH2Ph),
5.52 (d, J = 6.9 Hz, 1 H, NH), 5.86 (s, 2 H, OCH2N), 7.09 (s, 1 H,
5-Him), 7.27–7.35 (m, 5 H, Ph), 8.47 (s, 2 H, Prz), 9.39 (s, 1 H, Prz).
(S)-Benzyl 1-[1-(Ethoxymethyl)-2-phenyl-1H-imidazol-4-yl]-2-
phenylethylcarbamate (9)
Yield: 300 mg (66%); oil; ee >95%; Rf = 0.25 (SiO2; acetone–hex-
ane, 1:2); [a]D20 –8.0 (c 0.1, MeOH).
Synthesis 2009, No. 2, 325–331 © Thieme Stuttgart · New York

330
A. Marek et al.
PAPER
13C NMR (90 MHz, CDCl3): d = 14.9 (CH3CH2), 21.7 (CH3CH),
45.3 (CH), 64.6 (CH3CH2), 66.6 (PhCH2), 77.0 (OCH2N), 119.3,
128.0, 128.1, 128.5, 136.7, 141.9, 142.5, 143.0, 144.2, 144.8, 145.9,
155.5.
Anal. Calcd for C28H32N4O3: C, 71.16; H, 6.83; N, 11.86. Found: C,
71.02; H, 7.00; N, 12.05.
Benzyl (1S,1¢S)-1,1¢-[1,1¢-Bis(ethoxymethyl)-1H,1¢H-2,2¢-biimi-
dazole-4,4¢-diyl]bis(ethane-1,1-diyl)dicarbamate (16)
Yield: 205 mg (34%); oil; ee >95%; Rf = 0.39 (SiO2; acetone–hex-
ane, 1:1); [a]D20 –8.0 (c 0.1, MeOH).
1H NMR (500 MHz, CDCl3): d = 1.03 (t, J = 6.5 Hz, 3 H, CH3CH2),
1.12 (t, J = 7.0 Hz, 3 H, CH3CH2), 1.51 (d, J = 6.0 Hz, 3 H,
CH3CH), 1.58 (d, J = 5.5 Hz, 3 H, CH3CH), 3.33–3.38 (m, 2 H,
CH2CH3), 3.42–3.46 (m, 2 H, CH2CH3), 4.87–4.90 (m, 1 H,
CHNH), 5.07–5.17 (m, 6 H, 2 × CH2Ph and CHNH), 5.29 (d,
J = 8.0 Hz, 1 H, NH), 5.62–5.86 and 6.05–6.12 (2 × m, 4 H,
2 × OCH2N), 7.02 (s, 2 H, 2 × 5-Him), 7.30–7.35 (m, 10 H, Ph).
13C NMR (90 MHz, CDCl3): d = 15.0 and 15.1 (CH3CH2), 20.8 and
21.8 (CH3CH), 42.1 and 45.4 (CHNH), 63.9 and 64.7 (CH3CH2),
66.9 and 67.1 (PhCH2), 73.7 and 76.6 (OCH2N), 117.0, 126.8,
128.3, 128.4, 128.7, 135.5, 136.5, 136.8, 137.8, 139.5, 143.3, 155.6,
155.9.
ESI-MS: m/z = 404 [M+ + Na].
Anal. Calcd for C20H23N5O3: C, 62.98; H, 6.08; N, 18.36. Found: C,
62.61; H, 6.12; N, 18.59.
(S)-Benzyl 1-[1-(Ethoxymethyl)-2-(pyridazin-3-yl)-1H-imida-
zol-4-yl]ethylcarbamate (13)
Yield: 244 mg (64%); oil; ee >95%; Rf = 0.20 (SiO2; EtOAc–hex-
ane, 5:1); [a]D20 –11.0 (c 0.1, MeOH).
1H NMR (500 MHz, CDCl3): d = 1.14 (t, J = 7.0 Hz, 3 H, CH3CH2),
1.53 (d, J = 6.6 Hz, 3 H, CH3CH), 3.55 (q, J = 7.0 Hz, 2 H,
CH2CH3), 4.89–4.92 (m, 1 H, CHNH), 5.08–5.10 (m, 2 H, CH2Ph),
5.52 (d, J = 6.5 Hz, 1 H, NH), 6.05 (s, 2 H, OCH2N), 7.15 (s, 1 H,
5-Him), 7.28–7.35 (m, 5 H, Ph), 7.49–7.52 (m, 1 H, Pdz), 8.30 (dd,
J = 8.5, 1.5 Hz, 1 H, Pdz), 9.06 (dd, J = 5.0, 1.5 Hz, 1 H, ArH).
13C NMR (90 MHz, CDCl3): d = 15.1 (CH3CH2), 21.8 (CH3CH),
45.4 (CH), 64.8 (CH3CH2), 66.7 (PhCH2), 77.7 (OCH2N), 119.3,
126.4, 126.9, 128.2, 128.3, 128.6, 132.1, 136.8, 141.8, 144.6, 150.4,
155.5.
ESI-MS: m/z = 627 [M+ + Na].
Anal. Calcd for C32H40N6O6: C, 63.56; H, 6.67; N, 13.90. Found: C,
63.42; H, 6.77; N, 14.05.
ESI-MS: m/z = 404 [M+ + Na].
Suzuki–Miyaura Cross-Coupling to Generate Target Imida-
zoles 17, 18; General Procedure
Anal. Calcd for C20H23N5O3: C, 62.98; H, 6.08; N, 18.36. Found: C,
62.73; H, 6.35; N, 18.56.
Pd(PPh3)4 (15.9 mg, 0.014 mmol), ArB(OH)2 (0.36 mmol) and an
aqueous solution of Na2CO3 (0.2 mL, 2M) were successively added
to a degassed solution of 2-iodoimidazole 7 or 8 (0.28 mmol) in
THF–H2O (4:1, 20 mL). The reaction mixture was refluxed until
TLC showed that the reaction was complete (see Table 1 for the re-
action times). The product was extracted with CH2Cl2 (3 × 20 mL),
the solvent evaporated and the crude product purified by column
chromatography.
(S)-Benzyl 1-[1-(Ethoxymethyl)-2-(pyrimidin-2-yl)-1H-imida-
zol-4-yl]ethylcarbamate (14)
Yield: 213 mg (56%); oil; ee >95%; Rf = 0.18 (SiO2; acetone–hex-
ane, 1:1); [a]D20 –14.0 (c 0.1, MeOH).
1H NMR (360 MHz, CDCl3): d = 1.09 (t, J = 7.0 Hz, 3 H, CH3CH2),
1.51–1.54 (m, 3 H, CH3CH), 3.44–3.48 (m, 2 H, CH2CH3), 4.86–
4.90 (m, 1 H, CHNH), 5.00–5.07 (m, 2 H, CH2Ph), 5.55 (d, J = 7.2
Hz, 1 H, NH), 5.92 (s, 2 H, OCH2N), 7.09 (s, 1 H, 5-Him), 7.17 (t,
J = 4.9 Hz, 1 H, Pym), 7.21–7.29 (m, 5 H, Ph), 8.77 (d, J = 4.8 Hz,
2 H, Pym).
13C NMR (90 MHz, CDCl3): d = 14.9 (CH3CH2), 21.8 (CH3CH),
45.3 (CH), 64.7 (CH3CH2), 66.5 (PhCH2), 77.6 (OCH2N), 119.7,
128.0, 128.3, 128.6, 136.8, 148.1, 144.4, 155.8, 156.2, 157.4, 157.9.
(S)-Benzyl 1-[1-(Ethoxymethyl)-2-phenyl-1H-imidazol-4-
yl)ethylcarbamate (17)
Yield: 78 mg (74%); oil; ee >95%; Rf = 0.63 (SiO2; acetone–hex-
ane, 1:1); [a]D20 –11.0 (c 0.1, MeOH).
1H NMR (500 MHz, CDCl3): d = 1.22 (t, J = 7.0 Hz, 3 H, CH3CH2),
1.54 (d, J = 6.7 Hz, 3 H, CH3CH), 3.51 (q, J = 6.9 Hz, 2 H,
CH2CH3), 4.84–4.91 (m, 1 H, CHNH), 5.08–5.14 (m, 2 H, CH2Ph),
5.19 (s, 2 H, OCH2N), 5.49 (d, J = 6.3 Hz, 1 H, NH), 6.97 (s, 1 H,
5-Him), 7.27–7.34 (m, 5 H, Ph), 7.40–7.46 (m, 3 H, 2-ArH), 7.71 (d,
J = 8.0 Hz, 2 H, 2-ArH).
ESI-MS: m/z = 404 [M+ + Na].
Anal. Calcd for C20H23N5O3: C, 62.98; H, 6.08; N, 18.36. Found: C,
62.44; H, 6.36; N, 18.67.
13C NMR (90 MHz, CDCl3): d = 15.1 (CH3CH2), 22.0 (CH3CH),
45.5 (CH), 64.7 (CH3CH2), 66.7 (PhCH2), 76.0 (OCH2N), 117.3,
128.2, 128.3, 128.7, 128.9, 129.2, 129.3, 130.3, 136.9, 143.7, 148.7,
155.9.
(S)-Benzyl 1-[1-(Ethoxymethyl)-2-(quinolin-8-yl)-1H-imidazol-
4-yl]-3-methylbutylcarbamate (15)
Yield: 255 mg (55%); oil; ee >95%; Rf = 0.36 (SiO2; EtOAc–hex-
ane, 5:1); [a]D20 –27.0 (c 0.1, MeOH).
ESI-MS: m/z = 402 [M+ + Na].
1H NMR (360 MHz, CDCl3): d = 0.88–0.90 (m, 3 H, CH3CH2), 0.96
[d, J = 6.8 Hz, 6 H, (CH3)2CH], 1.55–1.74 [m, 1 H, (CH3)2CH],
1.80 (t, J = 6.4 Hz, 2 H, CH2CH), 3.18 (q, J = 7.0 Hz, 2 H,
CH2CH3), 4.86–4.91 (m, 1 H, CHNH), 5.05–5.17 (m, 4 H, CH2Ph
and OCH2N), 5.54 (d, J = 8.7 Hz, 1 H, NH), 7.14 (s, 1 H, 5-Him),
7.27–7.33 (m, 5 H, Ph), 7.40–7.43 (m, 1 H, Qun), 7.62 (t, J = 7.3
Hz, 1 H, Qun), 7.93 (t, J = 8.2 Hz, 1 H, Qun), 8.19 (dd, J = 1.6, 8.3
Hz, 1 H, Qun), 8.88 (dd, J = 1.7, 4.1 Hz, 1 H, Qun).
Anal. Calcd for C22H25N3O3: C, 69.64; H, 6.64; N, 11.07. Found: C,
69.41; H, 6.82; N, 11.02.
(S)-Benzyl 1-[1-(Ethoxymethyl)-2-(furan-2-yl)-1H-imidazol-4-
yl]-3-methylbutylcarbamate (18)
Yield: 101 mg (88%); oil; ee >95%; Rf = 0.1 (SiO2; EtOAc–hexane,
1:4); [a]D20 –39.0 (c 0.1, MeOH).
1H NMR (360 MHz, CDCl3): d = 0.92 [d, J = 6.2 Hz, 6 H,
(CH3)2CH], 1.17 (t, J = 6.9 Hz, 3 H, CH3CH2), 1.54–1.61 [m, 1 H,
(CH3)2CH], 1.75 (t, J = 6.8 Hz, 2 H, CH2CH), 3.49 (q, J = 6.9 Hz,
2 H, CH2CH3), 4.75–4.82 (m, 1 H, CHNH), 5.03–5.14 (m, 2 H,
CH2Ph), 5.36 (s, 2 H, OCH2N), 5.41 (d, J = 8.7 Hz, 1 H, NH), 6.48–
6.49 (m, 1 H, Fur), 6.87 (d, J = 2.8 Hz, 1 H, Fur), 6.92 (s, 1 H, 5-
Him), 7.27–7.32 (m, 5 H, Ph), 8.51 (d, J = 1.0 Hz, 1 H, Fur).
13C NMR (90 MHz, CDCl3): d = 14.8 (CH3CH2), 22.7 and 22.9
[(CH3)2CH], 25.1 [(CH3)2CH], 44.9 (CH2CH), 47.9 (CHNH), 64.2
(CH3CH2), 66.6 (PhCH2), 77.0 (OCH2N), 116.6, 121.6, 126.6,
128.0, 128.1, 128.5, 128.6, 128.7, 129.9, 130.2, 133.1, 136.6, 137.0,
142.9, 146.4, 150.9, 156.1.
ESI-MS: m/z = 495 [M+ + Na].
Synthesis 2009, No. 2, 325–331 © Thieme Stuttgart · New York

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Amino Acid Derived 2-Substituted Imidazoles
331
13C NMR (90 MHz, CDCl3): d = 15.0 (CH3CH2), 22.6 and 22.7
[(CH3)2CH], 25.0 [(CH3)2CH], 44.7 (CH2CH), 47.6 (CHNH), 64.5
(CH3CH2), 66.6 (PhCH2), 76.1 (OCH2N), 110.6, 111.6, 117.7,
128.1, 128.2, 128.6, 136.9, 139.8, 142.8, 143.3, 144.8, 156.0.
(10) (a) Zificsak, C. A.; Hlasta, D. J. Tetrahedron 2004, 60,
8991. (b) Schnürch, M.; Flasik, R.; Khan, A. F.; Spina, M.;
Mihovilovic, M. D.; Stanetty, P. Eur. J. Org. Chem. 2006,
3283. (c) Chinchilla, R.; Nájera, C.; Yus, M. Chem. Rev.
2004, 104, 2667.
ESI-MS: m/z = 434 [M+ + Na].
(11) (a) Prasad, A. S. B.; Stevenson, T. M.; Citineni, J. R.;
Nyzam, V.; Knochel, P. Tetrahedron 1997, 53, 7237.
(b) Bell, A. S.; Roberts, D. A.; Ruddock, K. S. Tetrahedron
Lett. 1988, 29, 5013. (c) Evans, D. A.; Bach, T. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1326. (d) Havez, S.;
Begtrup, M.; Vedsø, P.; Andersen, K.; Ruhland, T. Synthesis
2001, 909. (e) Utas, J. E.; Olofsson, B.; Åkermark, B. Synlett
2006, 1965.
Anal. Calcd for C23H29N3O4: C, 67.13; H, 7.10; N, 10.21. Found: C,
66.96; H, 7.23; N, 10.37.
Acknowledgment
This research was supported by the Ministry of Education, Youth
and Sport (MSM 0021627501) and by the Czech Science Founda-
tion (203/07/P013).
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Synthesis 2009, No. 2, 325–331 © Thieme Stuttgart · New York