Multicomponent synthesis of highly substituted imidazolines via a silicon mediated 1,3-dipolar cycloaddition

Article abstract of DOI:10.1055/s-2003-40196

A diastereoselective multicomponent synthesis of highly functionalized imidazolines is reported. A silicon mediated 1,3 dipolar cycloaddition of the in situ generated münchnone with an imine resulted in the formation of highly substituted imidazolines. The imidazolines contain a four-point diversity and two stereocenters and the cycloaddition reaction is applicable to aryl, alkyl, acyl, and heterocyclic substitutions.

Full text of DOI:10.1055/s-2003-40196

SPECIAL TOPIC
1433
Multicomponent Synthesis of Highly Substituted Imidazolines via a Silicon
Mediated 1,3-Dipolar Cycloaddition
M
ulticompone
.
nt Synthesis
P
of
H
ighly Sub
e
stitute
d
Im
d
idazolines dibhotla, J. J. Tepe*
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
Fax +1(517)3531793; E-mail: tepe@cem.msu.edu
Imidazoles can be generated by treatment of the münch-
Abstract: A diastereoselective multicomponent synthesis of highly
functionalized imidazolines is reported. A silicon mediated 1,3 di-
polar cycloaddition of the in situ generated münchnone with an imi-
ne resulted in the formation of highly substituted imidazolines. The
nones with tosylimines. Addition of the tosylimines re-
sults in an unstable bicyclic adduct that loses carbon
dioxide and benzenesulfinic acid to gain aromaticity.12,15
imidazolines contain a four-point diversity and two stereocenters The phenylsulfonyl leaving group enhances the tendency
and the cycloaddition reaction is applicable to aryl, alkyl, acyl, and
heterocyclic substitutions.
to aromatize (Scheme 2). Münchnones with different sub-
stituents, at the 2- and 4-positions lead regioselectively to
Key words: imidazolines, 1,3-dipolar cycloaddition, diastereo-
selective, heterocycles, imidazoles
products in which a bond is always formed between the 2-
carbon atom of the dipole and the imine nitrogen atom.
This attack was explained on the basis of a dipole–dipole
interaction between partially negative nitrogen of the imi-
1,3-Dipolar cycloadditions are fundamental processes in ne and the electrophilic C-2 atom of the münchnone. The
organic chemistry for the synthesis of diverse heterocyclic yield reported for these reactions is low, at least partly due
compounds.1–3 The reaction of azomethine ylides with to self-condensation of münchnones.12 The problem of
various dipolarophiles results in highly substituted five- self-condensation can be suppressed by using a solid-
membered nitrogen heterocycles.4–6 In addition to being phase approach towards the preparation of imidazoles.13
versatile, it is also an atom economical process. Cycload- The münchnone generated on solid phase was condensed
dition reactions of N-metalated acyclic azomethine ylides with tosylamines to afford the imidazoles in good yields
derived from glycine -iminoesters and -deficient alk- and purities.
enes affords substituted pyrrolidines with four stereogenic
centers.7,8 Achieving diastereoselectivity and enantio-
selectivity in this reaction is presently a field of intense
scientific investigation.9,10
Me
N
R2
R1
N-SO2Ph
SO2Ph
R2
Ph
Ph
O
O
R2
N
N
- CO2
O
N
Ph
Me
1 H
N
- PhSO2H
R
R1
1,3-Dipolar cycloaddition reactions of N-methylated me-
soionic oxazolones (Scheme 1), provides a general route
for the syntheses of pyrroles, pyrrolines, azepines and im-
idazoles.3,11–13 In the synthesis of pyrroles, the cycloaddi-
tion proceeds via a tautomerization of the parent
azalactone to a mesoionic oxazolium 5-oxide, colloquial-
ly referred to as a ‘münchnone’. The münchnone, under-
O
Me
Scheme 2
Surprisingly, the utilization of oxazolones (or azalac-
tones) has been underutilized as an efficient entry into a
stereoselective synthesis of imidazolines. We have recent-
ly reported a highly diastereoselective multicomponent
one-pot synthesis of substituted imidazolines.16 These low
molecular weight scaffolds contain a four point diversity
applicable to alkyl, aryl, acyl, and heterocyclic substitu-
tions. In light of the usefulness of a stereocontrolled syn-
thesis of imidazolines for the preparation of , -diamino
acids,17 diaminocarbene catalysts,18–21 peptide bond mim-
goes
a 1,3-dipolar cycloaddition with a suitable
dipolarophile such as an acetylene (Scheme 1). A moder-
ate equilibrium concentration of the mesoionic tautomer
is essential for the 1,3-dipolar cycloaddition leading to
heterocycle formation.14 By N-methylation, the azalac-
tones are locked in the mesoionic form, which is extreme-
ly reactive with dipoles and affords the pyrroles in very
high yields.
icks and other synthetic intermediates,23–28 we report
22
herein the range and limitations of this extension of the
1,3-dipolar cycloaddition reaction.
CO2Me
Me
N
CO2Me
CO2Me
It has been well documented that azalactones undergo a
Staudinger-type reaction when heated with imines in tol-
uene, yielding -lactams.29–31 The azalactone, which is in
equilibrium with valence tautomeric ketene intermediate,
undergoes a [2+2]-cycloaddition reaction with the imine
(Scheme 3). It can be concluded that either mesoionic ox-
azolium oxide, which has the nitrogen atom unsubstituted,
is not in reasonable concentration and/or the imine nitro-
gen is not nucleophilic enough. Hence formation of
Ph
O
MeO2C
Ph
CO2Me
R1
O
Ph
Me
O
- CO2
CO2Me
N
R1
R1
N
O
Me
Scheme 1
Synthesis 2003, No. 9, Print: 03 07 2003.
Art Id.1437-210X,E;2003,0,09,1433,1440,ftx,en;C01903SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

1434
S. Peddibhotla, J. J. Tepe
SPECIAL TOPIC
ketene is predominant, which reacts readily with the imi- While the complete mechanistic details of this process are
nes to afford the -lactam.29–31 We envisioned that a still under investigation, the reaction does not seem to pro-
Lewis acid coordination to nitrogen of the azalactone, ceed via a ring-opened nitrilium ion intermediate
would increase the equilibrium concentration of münch- (Scheme 4).33 The possibility of a Michael-type addition
none intermediate and mediate the azomethine ylide-imi- via the formation of the nitrilium ion was investigated by
ne cycloaddition reaction (Scheme 3).
first preparing the silyl enol ether with TMSCl (1.0 equiv)
and TEA (1.0 equiv) followed by the addition of the imine
and an additional one equivalent of TMSCl (Scheme 4).
This resulted merely in isolation of starting materials.
R4
N
O
O
O
NH
R2
R3
O
R1
R3
R1
C
N
N
Toluene
heat
R2
R4
H
30-50%
O
O
N
R1
R4
R2
R4
N
R3
R1
N
N
O
R3
R1
R2
O
N
CO2H
L.A.
R2
Scheme 3
After screening a small number of Lewis acids, we found
that TMSCl promotes the reaction of oxazolones and imi-
nes to afford the imidazoline scaffold in very good yields
and in most cases as single diastereomers (Table 1).16 The
oxazolones were prepared from different N-acyl -amino
acids by EDCI-mediated dehydration to provide the pure
oxazolones in high yields.32
Compound 2g (Table 2)
Figure 1
TMSCl
Et3N
CH2Cl2
O
O
N
OTMS
R2
O
N
R1
R1
R2
R4
N
Table 1 Screening of Lewis Acids
3
XR
Bn
N
TMSCl
Ph
Ph
R4
TMS N
R4
N
O
Ph
Ph
O
H
Ph
R2
R3
R2
CO2H
N
N
L.A.
H2O
N
Me
R1
CH2Cl2
R1
N
H
Me
CO2H
N
R3
CO2TMS
LA
Yield (%)
LA
TMSCl
Yield (%)
Scheme 4
TiCl4
SnCl4
ZnCl2
0
0
0
0
0
0
0
0
0
70
0
Excess of triethylamine also halted the reaction suggest-
ing that acidic conditions were required. However, Lewis
acids such as TiCl4 and BF3·OEt2 or protic acids such as
camphor sulfonic acid (CSA) and methyl sulfonic acid
(MSA) did not promote product formation (Table 1). The
absence of TMSCl resulted in the formation of -lactams
and N-acyl amino acid amide, presumably via the corre-
sponding ketene intermediate (Scheme 3). O-Silylation
with TMSOTf also did not result in any product forma-
tion. This indicates that a nucleophilic counterion is re-
quired to establish an equilibrium between O-silylation
and N-silylation of the azalactone (Scheme 5). In light of
these findings, we propose that the reaction proceeds via
a 1,3-dipolar cycloaddition.
TMSCl–Et3N (1:1)
TMSCl–Et3N (2 :1)
TESCl
0
Et2AlCl
CuCl
70
45
55
0
PH3SiCl
B(OPh)3
AgOTf
YCl3
CH3COCl
CSA
TMSOTf
0
Zr(i-PrO)4
The cycloaddition reactions proceeded well with a wide
variety of imines at slightly elevated temperatures to pro-
vide the highly substituted imidazolines in very good
yields. Only the trans diastereomers (with respect to R2
and R3) of the imidazolines were observed in almost all
cases, as determined by NOE experiments and X-ray crys-
tallography (Figure 1).
The generation of silicon mediated azomethine ylides has
recently also been reported by Komatsu and co-work-
ers.34–36 The authors report the formation of an azome-
thine ylide after a 1,2-silatropic shift of -silylimines
resulting in the formation of pyrrolidines as a mixture of
stereoisomers.
Synthesis 2003, No. 9, 1433–1440 ISSN 1234-567-89 © Thieme Stuttgart · New York

SPECIAL TOPIC
Multicomponent Synthesis of Highly Substituted Imidazolines
1435
Other silyl chlorides such as triphenyl silyl chloride and
triethyl silyl chloride also provided the product as a single
diastereomer, in notably longer reaction times and lower
yields (Tables 1, 45% and 70%, respectively). Additional
support of the proposed mechanism is shown in
Scheme 5, we found that one equivalent of acetyl chloride
resulted in the formation of the imidazoline as well, albeit
in somewhat lower yields (Tables 1, 55%). A, range of
structurally diverse imidazolines were prepared and are
listed in Tables 2 and 3.
H
N
R4
HCl
R3
Cl
R3
O
N
O
O
N
R4
R1
R1
O
O
N
R1
O
R2
R2
TMS
N
TMS
R2
R4
R1
Cl
R4
N
R4
Cl
H
R3
H
R3
R2
N
R3
R2
N
H2O
R1
O
N
O
R1
H
N
N
CO2H
CO2H
R2
The diastereoselectivity appears to primarily arise from
the steric interaction of the bulky silyl group of the azalac-
tone and the R3 moiety of the imine (Figure 2). This re-
TMS
TMS
Scheme 5
Table 2 Diverse Range of Imidazolines Prepared
R4 NH2
R3CHO
R4
N
R4
N
O
R1
O
R1
R1
R3
CO2H
R2
R3
R2
CO2H
+
N
TMSCl (1.3 eq.) / CH2Cl2
reflux
R2
N
N
azalactone
trans
2
cis
3
1
R1
R2
R3
Ph
R4
Yield 1 (%)
Ratio 2:3 Yield 2 (%)
a
b
c
d
e
f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Bn
75
75
75
75
75
75
75
75
75
75
75
75
75
70
70
70
80
69
90
76
60
>95:5
>95:5
>95:5
>95:5
>95:5
–
75
78
74
76
72
0
4-methoxyphenyl
Bn
Ph
4-fluorophenyl
4-pyridinyl
Bn
-CO2Et
4-fluorophenyl
Ph
benzhydryl
g
h
i
Ph
-CH2CO2Me
>95:5
>95:5
75:25
–
70
66
51
75
76
79
71
65
55
68
68
60
30
n.o.d
n.o.
Ph
-CH(CH3)CO2Me
Ph
-CH2CH2CO2Et
ja
Ph
Bn
ka
lb
mc
n
o
4-pyridinyl
Ph
Bn
–
Bn
–
Ph
H
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
75:25
67:33
50:50
Ph
Bn
Ph
4-pyridinyl
-CO2Et
Bn
p
q
r
Ph
4-fluorophenyl
indolyl-3-methyl Ph
-CH2CH2CO2Me Ph
Bn
Bn
Bn
Bn
Bn
s
Ph
Ph
Ph
Ph
t
Me
Me
u
a Derivative j is the ethyl ester of 2a and derivative k is the ethyl ester of 2d; isolated yields after esterification with (COCl)2, EtOH.
b Isolated yield after reduction of 2a with LiAlH4.
c Isolated yield after hydrogenation of 2a with 10% Pd/C , H2.
d n.o. = not optimized.
Synthesis 2003, No. 9, 1433–1440 ISSN 1234-567-89 © Thieme Stuttgart · New York

1436
S. Peddibhotla, J. J. Tepe
SPECIAL TOPIC
R4
N
sults in the imine approaching from one direction of the
racemic azalactone resulting in the trans-isomer as the
major/sole product. The electronic effects of the R1 posi-
tion also appear to play a significant role in the reactivity
of the azalactone as well as the diastereoselectivity of the
reaction. Reducing the resonance of the stabilized car-
bocation of the dipolarophile by changing R1 from a phe-
nyl to a methyl or benzyl group resulted in a significant
decrease in diastereoselectivity (Table 3). The more reac-
tive and unstable methyl-azalactone provided a 1:1 mix-
ture of the cis- and trans-products. No reactions were
found in which the cis-product was the major product.
R4
R3
R2
O
O
R1
N
R1
R3
R2
N
H
N
Co2H
Si
Major
R4
R4
N
R3
R2
O
O
R1
Si
N
R1
H
R2
N
R3
N
Co2H
Minor
Figure 2
Table 3 Analytical Data
Compound
IR (cm–1)
1H NMR (300 MHz),
13C NMR (75 MHz),
2a
3350, 1738
1.80 (3 H, s), 4.05 (1 H, d, J = 15 Hz), 4.95 (1 H, d, 25.2, 48.8, 70.4, 73.3, 122.3, 127.8, 128.3, 128.5,
J = 14.8 Hz), 5.05 (1 H, s), 7.05 (2 H, s), 7.25–7.54 128.9, 129.1, 129.3, 129.6, 129.7, 132.3, 133.2,
(8 H, m), 7.74 (2 H, t, J = 7.2 Hz), 7.83 (1 H, t,
134, 166.1, 169.5a
J = 6.9 Hz), 8.0 (2 H,d, J = 8.4 Hz)a
2b
3388, 1738
1.80 (3 H, s), 3.80 (3 H, s), 3.95 (1 H, d, J = 15.3
25.3, 48.8, 55.6, 70.9, 74.1, 115.2, 122.2, 123,
Hz), 4.5 (1 H, s), 4.9 (1 H, d, J = 15 Hz), 6.83–6.92 125.5, 127.9, 128.4, 129.2, 129.3, 129.6, 129.9,
(4 H, m), 7.08–7.19 (3 H, m), 7.30–7.40 (3 H, dd,
J1 = 5.1 Hz, J2 = 1.8 Hz), 7.54–7.62 (2 H, t, J = 7.2
Hz), 762–7.68 (1 H, t, J = 7.2 Hz), 7.9 (2 H, d,
J = 6.9 Hz)b
132.8, 134.2, 161.1, 166.3, 168.4c
2c
3450, 1744
3400, 1746
1.98 (3 H, s), 5.98 (1 H, s), 7.05–7.65 (14 H, m)a
25.2, 71.2, 77.9, 116.9, 117, 117.1, 117.3, 123,
125.1, 125.3, 129.3, 129.4, 129.6, 130.1, 130.3,
130.4, 130.5, 132.5, 133.3, 134.5, 160.4, 163.7,
165.3, 170.4a
2d
1.80 (3 H, s), 4.24 (1 H, d, J = 15.9 Hz), 4.90 (1 H, 25.1, 49.1, 70.6, 71.7, 122.1, 123, 127.9, 128.4,
d, J = 14.8 Hz), 5.15 (1 H, s), 7.00–7.15 (2 H, m),
128.8,129.2, 129.4, 132.8, 133.9, 141.4, 149.8,
7.25–7.35 (3 H, m), 7.40–7.50 (2 H, m), 7.70–7.90 166.5, 169.05a
(3 H, m), 7.95–8.05 (2 H, m), 8.6–8.7 (2 H, m)a
2e
2g
2h
2i
3450, 1743
3468, 1747
3431, 1740
3481, 1743
1.20 (3 H, t, J = 7.2 Hz), 2.03 (3 H, s), 4.9 (2 H, dq, 12.8, 24.2, 62.9, 69.1, 75.1, 116.7, 116.9, 121.8,
J1 = 7.2 Hz, J2 = 2.1 Hz), 5.48 (1 H, s), 7.10–7.80
129.3, 129.5, 129.6, 129.7, 131.5, 134.4, 162.1,
(9 H, m)c
164.0, 166.2, 169.9c
1.99 (3 H, s), 3.67 (3 H, s), 3.96 (1 H, d, J = 18.3
24.23, 52.09, 70.83, 75.38, 121.84, 128.26, 128.69,
Hz), 4.53 (1 H, d, J = 18.3 Hz), 5.39 (1 H, s), 7.47– 129.52, 129.75, 131.78, 134.02, 167.59, 168.62,
7.50 (5 H, m), 7.74–7.87 (5 H, m)c
169.19c
1.19 (d, J = 6.9, 3 H), 2.06 (s, 3 H), 3.38 (s, 3 H),
14.9, 25.6, 52.7, 56.7, 71.9, 72.5, 122.2, 128.8,
4.89 (q, J = 6.9, 1 H), 5.44 (s, 1 H), 7.43–7.46 (5 H, 128.9, 129.6, 130.0, 134.5, 135.8, 169.2, 169.4,
m), 7.75–7.85 (5 H, m).
170.4c
1.17 (3 H, t, J = 7.5, 3 H), 1.9 (3 H, s), 2.47–2.52 (1 13.3, 24.8, 30.6, 41.6, 61.0, 70.9, 73.5, 122.7,
H, m), 2.52–2.71 (1 H, m), 3.34–3.39 (1 H, m),
128.9, 129.2, 129.8, 130.1, 132.7, 134.0, 167.3,
3.40–4.09 (3 H, m), 5.42 (1 H, s), 7.46–7.49 (5 H, 169.8, 170.9c
m,), 7.72–7.87 (5 H, m)d
2jf
1730, 1595
1734, 1597
0.84 (3 H, t, J = 7.2 Hz), 1.57 (3 H, s), 3.60 (2 H, q, 13.80, 27.13, 49.12, 60.06, 71.31, 127.98, 128.03,
J = 7.2 Hz), 3.85 (1 H, d, J = 15.3 Hz), 4.32 (1 H,
128.12, 128.67, 129.02, 129.11, 130.96, 136.40,
s), 4.74 (1 H, d, J = 15.3 Hz), 6.98 (2 H, dd, J1 = 6.9 136.80, 166.11, 171.78d
Hz, J2 = 2.1 Hz), 7.27–7.35 (m, 8 H), 7.49–7.51 (2
H, m), 7.76–7.79 (2 H, m)d
2kg
0.86 (3 H, t, J = 7.2 Hz), 1.57 (3 H, s), 3.64 (2 H, q, 13.45, 27.13, 49.47, 60.83, 71.87, 77.94, 122.56,
J = 7.2 Hz), 3.83 (1 H, d, J = 15.3 Hz), 4.27 (1 H,
127.79, 127.93, 128.55, 128.70, 130.21, 130.51,
s), 4.77 (1 H, d, J = 15.3 Hz), 6.97 (2 H, dd, J1 = 7.2 135.82, 146.59, 149.75, 166.02, 171.37d
Hz, J2 = 2.4 Hz), 7.22–7.54 (6 H, m), 7.31–7.54 (2
H, m), 7.78–7.81 (2 H, m), 8.59–8.61 (2 H, m)d
Synthesis 2003, No. 9, 1433–1440 ISSN 1234-567-89 © Thieme Stuttgart · New York

SPECIAL TOPIC
Multicomponent Synthesis of Highly Substituted Imidazolines
13C NMR (75 MHz),
1437
Table 3 Analytical Data (continued)
Compound
IR (cm–1)
3314
1H NMR (300 MHz),
2lg
1.25 (3 H, s), 3.48 (1 H, d, J = 12 Hz), 3.56 (1 H, d, 17.25, 51.67, 61.54, 66.28, 66.93, 127.266, 127.68,
J = 11.8), 3.75 (1 H, d, 12.9), 3.87 (s, 1 H), 3.94 (1 128.26, 128.56, 128.82, 129.06, 131.77, 135.48,
H, d, J = 12.9), 7.28–7.54 (m, 13 H), 7.77–7.79 (m, 138.03, 139.90, 167.91d
2 H), 8.06 (1 H, br s)b
2m
2n
2o
3300, 1736
3400, 1738
3400, 1733
3331, 1736
1.76 (s, 3 H), 5.34 (s, 1 H), 7.34–7.36 (br, 5 H), 7.69 25.32, 55.66, 70.79, 72.57, 123.12, 128.24, 128.96,
(2 H, dd, J = 8.1, 7.2 Hz), 7.81 (1 H, dd, J1 = 6.9
129.42, 129.67, 130.12, 135.42, 136.24, 164.24,
Hz, J2 = 7.2 Hz), 8.15 (2 H, d, J = 8.4 Hz)c
170.77c
3.80 (1 H, d, J = 15.6 Hz), 4.62 (1 H, d, J = 15.6
29.7, 48.3, 75.6, 79.1, 123.1, 125.7, 126.7, 127.3,
Hz), 4.98 (1 H, s), 6.58 (2 H, d, J = 8.1 Hz), 7.05– 127.4, 127.9, 128.1, 128.2, 128.8, 128.9, 129,
7.65 (16 H, m), 7.90 (2 H, d, J = 7.2 Hz)d
129.3, 132.9, 133.8, 136, 143.1, 164.8, 168.1d
4.00 (1 H, d, J = 15.6 Hz), 5.00 (1 H, d, J = 15.6
45.2, 66.3, 75.6, 123.7, 126.5, 126.9, 128.5, 128.6,
Hz), 5.38 (1 H, s), 7.1–7.65 (17 H, m), 8.5 (2 H, d, 128.8, 129.2, 129.3, 131.9, 133.5, 134.4, 136.2,
J = 7.2 Hz)d 143.4, 149.7, 166.6, 166.9d
2p
0.84 (3 H, t, J = 7.2 Hz), 3.89 (2 H, dq, J1 = 7.2 Hz, 13.3, 61.1, 66.1, 76.3, 115.3, 115.6, 117.3, 117.4,
J2 = 3 Hz), 4.73 (1 H, s), 6.70–6.84 (2 H, m), 6.89 125, 126.1, 128.2, 128.6, 133, 134.6, 142, 142.1,
(2 H, t, J = 9 Hz), 7.34–7.5 (3 H, m), 7.55 (3 H, t,
J = 7.5 Hz), 7.65 (2 H, t, J = 8.1Hz), 7.83 (2 H, dd,
J1 = 8.1 Hz, J2 = 2.1 Hz), 8.10–8.22 (2 H, m)d
155.7, 162.1, 169, 176.8d
2q
2r
3420, 1741
1734, 1653
3.95 (1 H, d, J = 16.2 Hz), 4.6 (1 H, d, J = 16.2 Hz), 32.3, 48.5, 70.4, 74.4, 105.8, 111, 119, 121.4,
5.25 (1 H, s), 6.1 (2 H, d, J = 7.8 Hz), 6.90–7.30 (5 122.7, 126.6, 126.7, 127.8, 127.9, 128.6, 128.7,
H, m), 7.30–8.00 (15 H, m)a
128.9, 129.4, 129.7, 132.3, 132.5, 133.7, 136.5,
166, 169.6a
2.05–2.25 (2 H, m), 2.30–2.50 (2 H, m), 3.55 (3 H, 27.6, 30.1, 43.3, 51.6, 52.7, 127.1, 127.2, 127.3,
s), 4.38 (2 H, ddd, J1 = 4 Hz, J2 = 9 Hz, J3 = 25 Hz), 128.2, 128.3, 131.5, 131.6, 133.3, 137.8, 167.5,
4.86 (1 H, q, J = 3.3), 7.10–7.60 (12 H, m), 7.70–
171.4, 173.6d
7.90 (4 H, m)d
2s
2t
3350, 1704
3350, 1624
3.47 (2 H, d, J = 15.6 Hz), 4.31 (2 H, d,
30.7, 47.5, 72.1, 100.2, 126.2, 126.6, 126.8, 127.3,
127.7, 127.9, 128.0, 128.5, 128.6, 129.0, 131.4,
132.5, 133.4, 136.4, 164.4, 171.6a
J = 15.6Hz), 5.80 (1 H, s), 6.40–7.40 (20 H, m)a
1.74 (3 H, s), 3.67 (1 H, d, J = 15.3 Hz), 4.11 (1 H, 22.1, 32.4, 48.1, 70.6, 71.1, 127.6, 128.3, 128.6,
d, J = 14.7 Hz), 4.38 (1 H, s), 4.46 (1 H, d, J = 14.7 128.9, 129.1, 129.2, 129.7, 132.2, 132.8, 133.5,
Hz) 4.59 (1 H, d, J = 15.3 Hz), 6.77 (2 H, d, J = 7
164.8, 175.1d
Hz), 7.00–7.60 (13 H, m)d
3t
3350, 1738
1.14 (3 H, s), 3.94 (1 H, d, J = 15.6 Hz), 4.24 (2 H, 27.1, 38.7, 48.6, 71.5, 73.5, 127.9, 128.3, 128.5,
q, J = 8.7 Hz), 4.56 (1 H, d, J = 15 Hz), 5.74 (1 H, 128.7, 128.9, 129, 129.3, 129.4, 129.5, 129.8,
s), 6.65 (2 H, d, J = 7.5 Hz), 7.00–7.40 (13 H, m)d 120.9, 132.2, 133.5, 134.2, 165.6, 170.6 e
a DMSO-d6.
b CDCl3 and 2 drops of DMSO-d6.
c CD3OD.
d CDCl3.
e DMSO-d6 –CD3OD.
f Derivatives j and k are ethyl esters of 2a and 2d, respectively.
g Derivative l is an alcohol derived from 2a.
Reactions were carried out in oven-dried glassware under nitrogen
atmosphere, unless otherwise noted. All commercial reagents were
used without further purification. All solvents were reagent grade.
THF was freshly distilled from sodium/benzophenone under nitro-
gen. Toluene, CH2Cl2, and TMSCl were freshly distilled from CaH2
under nitrogen. All reactions were magnetically stirred and moni-
tored by TLC with Analtech 0.25 mm pre-coated silica gel plates.
Column chromatography was carried out on silica gel 60 (230–400
mesh) supplied by EM Science. Yields refer to chromatographically
and spectroscopically pure compounds unless otherwise stated.
Melting points were determined on a Mel-Temp (Laboratory devic-
es) apparatus with a microscope attachment. Infrared spectra were
recorded on a Nicolet IR/42 spectrometer. 1H and 13C NMR spectra
were recorded on a Varian Gemini-300 spectrometer or a Varian
VXR-500 spectrometer. Chemical shifts are reported relative to the
residue peaks of the solvent CDCl3 ( 7.24 for 1H and 77.0 for 13C)
and DMSO-d6 ( 2.49 for 1H and 39.5 for 13 C). HRMS were ob-
tained at the Mass Spectrometry Laboratory of the University of
South Carolina, Department of Chemistry & Biochemistry with a
Micromass VG-70S mass spectrometer. Gas chromatography/low-
resolution mass spectra were recorded on a Hewlet–Packard 5890
Series II gas chromatograph connected to a TRIO-1 EI mass spec-
trometer. All chemicals were obtained from Aldrich Chemical Co.
and used as received.
Synthesis 2003, No. 9, 1433–1440 ISSN 1234-567-89 © Thieme Stuttgart · New York

1438
S. Peddibhotla, J. J. Tepe
SPECIAL TOPIC
Synthesis of 2-Oxazolin-5-ones; General Procedure32
A solution of benzoyl amino acid (2 mmol) and EDCI (2 mmol) in
CH2Cl2 (20 mL) was stirred (0 °C for 1 h for racemic compounds,
15 min for optically active compounds). The reaction mixture was
washed successively with cold (containing ice) H2O (10 mL), aq
NaHCO3 (10 mL), and H2O (10 mL) The solution was dried over
anhyd MgSO4, filtered, and the solvent removed in vacuo to give
the oxazolones as solids or oils.
dl-(4S,5S)-1-(4-Fluorophenyl)-4-methyl-2-phenyl-4,5-dihydro-
1H-imidazole-4,5-dicarboxylic acid 5-ethyl Ester (2e)
A solution of ethyl glyoxalate (0.058 g, 0.57 mmol) as a 50% solu-
tion in toluene (1.03 gmL–1), 4-fluoroaniline (0.063 g, 0.57 mmol)
in anhyd CH2Cl2 (15 mL) was refluxed under nitrogen for 2 h. 2-
Phenyl-4-methyl-4H-oxazolin-5-one (0.1 g, 0.57 mmol) and chlo-
rotrimethylsilane (0.08 g, 0.74 mmol) were added and the mixture
was refluxed under nitrogen for 6 h and then stirred overnight at r.t.
The reaction mixture was evaporated to dryness under vacuum. The
product was purified by column chromatography on silica gel using
EtOAc–MeOH (4:1); yield: 72% (0.152 g); white solid; mp 190–
193 °C.
dl-(4S,5S)-1-Benzyl-4-methyl-2,5-diphenyl-4,5-dihydro-1H-im-
idazole-4-carboxylic Acid (2a)
A solution of benzaldehyde (0.06 g, 0.57 mmol), benzylamine
(0.061 g, 0.57 mmol) in anhyd CH2Cl2 (15 mL) was refluxed under
nitrogen for 2 h. 2-Phenyl-4-methyl-4H-oxazolin-5-one (0.1 g, 0.57
mmol) and chlorotrimethylsilane (0.08 g, 0.74 mmol) were added
and the mixture was refluxed under nitrogen for 6 h and then stirred
overnight at r.t. The solvent was evaporated under vacuum. The
product was precipitated using CH2Cl2–hexanes (1:1); yield: 75%
(0.155 g); white solid; mp 185–190 °C (dec.).
HRMS (EI): m/z calcd for C20H18FN2O4 [M – H], 369.1251; found,
369.1255.
dl-(4S,5S)-1-Methoxycarbonylmethyl-4-methyl-2,5-diphenyl-
4,5-dihydro-1H-imidazole-4-carboxylic Acid (2g)
To a well stirred solution of 2-phenyl-4-methyl-4H-oxazolin-5-one
(0.5 g, 2.85 mmol) and TMSCl (0.37 g, 3.42 mmol) in anhyd
CH2Cl2 (50 mL) was added a solution of (benzylidene-amino)-ace-
tic acid methyl ester (0.6 g, 3.42 mmol) in anhyd CH2Cl2 (20 mL)
and the mixture was refluxed under nitrogen for 10 h and then
stirred overnight at r.t. The reaction mixture was evaporated to dry-
ness under vacuum. The product was precipitated using CH2Cl2–
hexanes (1:1); yield: 70% (0.70 g); white solid; mp 215–217 °C
(dec.)
HRMS (EI): m/z calcd for C24H21N2O2 [M – H], 369.1603; found,
369.1610.
dl-(4S,5S)-1-Benzyl-5-(4-methoxyphenyl)-4-methyl-2-phenyl-
4,5-dihydro-1H-imidazole-4-carboxylic Acid (2b)
A solution of p-anisaldehyde (0.077 g, 0.57 mmol), benzylamine
(0.061 g, 0.57 mmol) in anhyd CH2Cl2 (15 mL) was refluxed under
nitrogen for 2 h. 2-Phenyl-4-methyl-4H-oxazolin-5-one (0.1 g, 0.57
mmol) and chlorotrimethylsilane (0.08 g, 0.74 mmol) were added
and the mixture was refluxed under nitrogen for 6 h and then stirred
overnight at r.t. The reaction mixture was evaporated to dryness un-
der vacuum. The product was precipitated using CH2Cl2–hexanes
(1:1); yield: 78% (0.180); mp 205–208 °C (dec.).
HRMS (EI): m/z calcd for C20H21N2O4 [M + H] 352.1501, found,
353.1507.
dl-(4S,5S)-1-(1-Methoxycarbonyl-ethyl)-4-methyl-2,5-diphe-
nyl-4,5-dihydro-1H-imidazole-4-carboxylic Acid (2h)
To a well stirred solution of 2-phenyl-4-methyl-4H-oxazolin-5-one
(0.25 g, 1.5 mmol) and TMSCl (0.23 ml, 1.8 mmol) in anhyd
CH2Cl2 (50 mL) added a solution of 2-(benzylidene-amino)-propi-
onic acid methyl ester (0.34 g, 1.8 mmol) in anhyd CH2Cl2 (20 mL)
and the mixture was refluxed under nitrogen for 10 h and then
stirred overnight at r.t. The reaction mixture was evaporated to dry-
ness under vacuum. The product was precipitated using CH2Cl2–
hexanes (1:1); yield: 66% (0.340 g); white solid; mp 222–226 °C.
HRMS (EI): m/z calcd for C25H23N2O3 [M – H], 399.1709; found,
399.1717.
dl-(4S,5S)-1-(4-Fluorophenyl)-4-methyl-2,5-diphenyl-4,5-dihy-
dro-1H-imidazole-4-carboxylic acid 2c
A solution of benzaldehyde (0.060 g, 0.57 mmol), 4-fluoroaniline
(0.063 g, 0.57 mmol) in anhyd CH2Cl2 (15 mL) was refluxed under
nitrogen for 2 h. 2-Phenyl-4-methyl-4H-oxazolin-5-one (0.1 g, 0.57
mmol) and chlorotrimethylsilane (0.08 g, 0.74 mmol) were added
and the mixture was refluxed under nitrogen for 6 h and then stirred
overnight at r.t. The reaction mixture was evaporated to dryness un-
der vacuum. The product was precipitated using CH2Cl2–hexanes
(1:1) to give the titled compound; yield: 74% (0.160 g); white solid;
mp 230–232 °C.
HRMS (EI): m/z calcd for C21H23N2O4 [M + H], 367.1658;
found, 367.1642.
dl-(4S,5S)-1-(2-Ethoxycarbonyl-ethyl)-4-methyl-2,5-diphenyl-
4,5-dihydro-1H-imidazole-4-carboxylic Acid (2i)
To a well stirred solution of 2-phenyl-4-dimethyl-4H-oxazolin-5-
one (1.0 g, 5.7 mmol) and TMSCl (1 mL, 6.8 mmol) in anhyd
CH2Cl2 (80 mL) added a solution of 3-(benzylidene-amino)-propi-
onic acid ethyl ester (1.4 gm, 6.8 mmol) in anhyd CH2Cl2 (60 mL)
and the mixture was refluxed under nitrogen for 10 h and then
stirred overnight at r.t. The reaction mixture was evaporated to dry-
ness under vacuum. The product was precipitated CH2Cl2–hexanes
(1:1); yield: 51%; (1.08 g); mp 218–220 °C (dec.).
HRMS (EI): m/z calcd for C23H18FN2O2 [M – H], 373.1352; found,
373.1359.
dl-(4S,5S)-1-Benzyl-4-methyl-2-phenyl-5-pyridin-4yl-4,5-dihy-
dro-1H-imidazole-4-carboxylic Acid (2d)
A solution of pyridin-4-carboxylaldehyde (0.061 g, 0.57 mmol),
benzylamine (0.061 g, 0.57 mmol) in anhyd CH2Cl2 (15 mL) was
refluxed under nitrogen for 2 h. 2-Phenyl-4-methyl-4H-oxazolin-5-
one (0.1 g, 0.57 mmol) and chlorotrimethylsilane (0.08 g, 0.74
mmol) were added and the mixture was refluxed under nitrogen for
6 h and then stirred overnight at r.t. The reaction mixture was evap-
orated to dryness under vacuum. The product was precipitated using
EtOAc–MeOH (4:1); yield: 76% (0.161 g); off-white solid; mp
185–190 °C.
HRMS (EI): m/z calcd for C22H25N2O4 [M + H], 381.1814;
found, 381.1813.
dl-(4S,5S)-1-Benzyl-4-methyl-2,5-diphenyl-4,5-dihydro-1H-im-
idazole-4-carboxylic Acid Ethyl Ester (2j)
To a well-stirred suspension of imidazoline-4-carboxylic acid 2a
(0.1 g, 0.27 mmol) in anhyd CH2Cl2 (30 mL) at 0°C was added a so-
lution of oxalyl chloride (0.14 g, 1.1 mmol) in anhyd CH2Cl2 (5
mL). A solution of DMF (0.001 mL) in anhyd CH2Cl2 (1 mL) was
added to the reaction mixture and the mixture was stirred at 0 °C for
another 2 h. The CH2Cl2 was evaporated under vacuum and the re-
action mixture cooled to 0 °C after which absolute EtOH (20 mL)
was added. The solution was allowed to stir for an additional 1 h.
The solvent was evaporated under vacuum and the reaction mixture
HRMS (EI): m/z calcd for C23H20N3O2 [M – H], 370.1556; found,
370.1556.
Synthesis 2003, No. 9, 1433–1440 ISSN 1234-567-89 © Thieme Stuttgart · New York

SPECIAL TOPIC
Multicomponent Synthesis of Highly Substituted Imidazolines
1439
diluted with anhyd CH2Cl2 (30 mL) and washed with sat. NaHCO3
(10 mL) and H2O (10 mL). The organic layer was dried over
Na2SO4 and was concentrated under vacuum to yield the crude
product, which was further purified by silica-gel column chroma-
tography (EtOAc); overall yield (2 steps from azlactone): 75%
(0.095 g); colorless oil.
was refluxed under nitrogen for 6 h and then stirred overnight at r.t.
The product was purified by silica-gel column chromatography
(EtOH–EtOAc, 1:5); yield: 65% (2.1 g); off-white solid; mp 153–
155 °C.
HRMS (EI): m/z calcd for C28H23N2 [(M – H) – CO2], 387.1526;
found, 387.1539.
HRMS (EI): m/z calcd for C26H27N2O2, 399.2073; found, 399.2072
dl-(4S,5S)- 1-Benzyl-2,4-diphenyl-5-pyridin-4-yl-4,5-dihydro-
1H-imidazole-4-carboxylic Acid (2o)
dl-(4S,5S)-1-Benzyl-4-methyl-2-phenyl-5-pyridin-4-yl-4,5-dihy-
dro-1H-imidazole-4-carboxylic Acid Ethyl Ester (2k)
A solution of pyridin-4-carboxylaldehyde (0.61 g, 0.57 mmol), ben-
zylamine (0.61 g, 5.7 mmol) in anhyd CH2Cl2 (120 mL) was re-
fluxed under nitrogen for 2 h. 2,4-Diphenyl-4H-oxazolin-5-one
(1.35 g, 5.7 mmol) and chlorotrimethylsilane (0.8 g, 7.4 mmol)
were added and the mixture was refluxed under nitrogen for 6 h and
then stirred overnight at r.t. The product was precipitated using
CH2Cl2–Et2O; yield 55% (1.35 g); off-white solid.
To a well-stirred suspension of dl-(3S,4S)-1-benzyl-4-methyl-2-
phenyl-5-pyridin-4yl-4,5-dihydro-1H-imidazole-4-carboxylic acid
(2d) (0.1 g, 0.27 mmol) in anhyd CH2Cl2 (30 mL) at 0°C added a
solution of oxalyl chloride (0.14 g, 1.1 mmol) in anhyd CH2Cl2 (5
mL). A solution of DMF (0.001 mL) in anhyd CH2Cl2 (1 mL) was
added to the reaction mixture and was stirred at 0 °C for another 2
h. The CH2Cl2 was evaporated under vacuum and the reaction mix-
ture cooled to 0 °C after which absolute EtOH (20 mL) was added.
The solution was allowed to stir for an additional 1 h. The solvent
was evaporated under vacuum and the reaction mixture diluted with
CH2Cl2 (30 mL) and washed with sat.NaHCO3 (10 mL) and H2O
(10 mL). The organic layer was dried over NaHSO4 and was con-
centrated under vacuum to yield the crude product, which was fur-
ther purified by silica-gel column chromatography (ethyl acetate);
overall yield (from azlactone): 76% (0.97 g); pale yellow oil.
MS (EI): m/z calcd for C29H24FN3O2 [M +H], 434.34186; found,
434.1852.
dl-(4S,5S)-1-(4-Fluorophenyl)-2,4-diphenyl-4,5-dihydro-1H-
imidazole-4,5-dicarboxylic Acid 5-Ethyl Ester (2p)
A solution of ethyl glyoxalate (0.85 g, 8.3 mmol) as 50% solution
in toluene (1.03 g/mL), 4-fluoroaniline (0.93 g, 8.3 mmol) in anhyd
CH2Cl2 (250 mL) was refluxed under nitrogen for 2 h. 2,4-Diphe-
nyl-4H-oxazolin-5-one (2 g, 8.3 mmol) and chlorotrimethylsilane
(1.16, 10.8 mmol) were added and the mixture was refluxed under
nitrogen for 6 h and then stirred overnight at r.t. The reaction mix-
ture was evaporated to dryness under vacuum. The product was pre-
cipitated using CH2Cl2–Et2O; yield: 68% (2.4 g); white solid.
HRMS (EI): m/z calcd for C25H27N3O2, 400.2025; found, 400.2038.
dl-(4S, 5S)-1-Benzyl-4-methyl-2,5-diphenyl-4,5-dihydro-1H-
imidazol-4-yl)-methanol (2l)
To a well stirred suspension of LiAlH4 (0.12g, 0.3 mmol) in anhyd
THF (5 mL) was added a solution of 1-benzyl-4-methyll-2,5-diphe-
nyl-4,5-ihydro-1H-imidazole-4-carboxylic acid (0.1 gm, 0.27
mmol) in anhyd THF (5 mL) dropwise at 0 °C, the mixture was
stirred at the same temperature for 15 min quenched with ice cold
sat. NH4Cl solution (caution: NH4Cl solution kept at 0 oC for about
30 min.; and should be added with extreme care; highly exothermic
reaction and the reaction mixture should be at 0 °C) followed by
10% HCl (ca 10 mL). The reaction mixture was diluted with an ex-
cess of EtOAc (100 mL) washed with H2O (20 mL) dried over an-
hyd Na2SO4, filtered, and the solvent evaporated under reduced
pressure to yield the crude product which was purified by column
chromatography (EtOAc); overall yield (2 steps): 79% (0.076 g);
viscous oil.
HRMS (FAB): m/z calcd for C25H22FN2O4 [M + H], 433.1486;
found: 433.1565.
dl-(4S,5S)-1-Benzyl-4-(1H-indol-3-ylmethyl)-2,5-diphenyl-4,5-
dihydro-1H-imidazole-4-carboxylic Acid (2q)
A solution of benzaldehyde (0.6 g, 5.7 mmol), benzylamine (0.61 g,
5.7 mmol) in anhyd CH2Cl2 (120 mL) was refluxed under nitrogen
for 2 h. 4-(1H-Indol-3-ylmethyl)-2-phenyl-4H-oxazol-5-one (1.65
g, 5.7 mmol) and chlorotrimethylsilane (0.8 g, 7.4 mmol) were add-
ed and the mixture was refluxed under nitrogen for 6 h and then
stirred overnight at r.t. The product was purified by column chroma-
tography on silica gel EtOH–EtOAc (1:5); yield: 68% (3.1 g); off-
white solid; mp >250 °C (dec.).
HRMS (EI): m/z calcd for C32H26N3O2 [M – H], 484.2025; found,
484.2011.
HRMS (FAB): m/z calcd for C24H25N2O [M + H], 357.1888; found,
357.1967.
dl-(4S,5S)-1-Benzyl-4-(2-methoxycarbonyl-ethyl)-2,5-diphenyl-
4,5-dihydro-1H-imidazole-4-carboxylic Acid (2r)
dl-(4S,5S)-4-Methyl-2,5-diphenyl-4,5-dihydro-1H-imidazole-4-
carboxylic Acid (2m)
A solution of benzaldehyde (0.252 g, 2.4 mmol), benzylamine
(0.258 g, 2.4 mmol) in anhyd CH2Cl2 (100 mL) was refluxed under
nitrogen for 2 h. 3-(5-Oxo-2-phenyl-4,5-dihydro-oxazol-4-yl)-pro-
pionic acid methyl ester (1e) (0.5 g, 2 mmol) and chlorotrimethylsi-
lane (0.282 g, 2.6 mmol) were added and the mixture was refluxed
under nitrogen for 6 h and then stirred overnight at r.t. The reaction
mixture was evaporated to dryness under vacuum. The product was
precipitated using CH2Cl2–hexanes (1:1); yield: 60% (0.54 g);
white solid.
To a well-stirred suspension of imidazoline-4-carboxylic acid 2a
(0.1 g, 0.27 mmol) and cyclohexene (0.1 mL, 1.25 mmol) in anhyd
THF (30 mL) was added 10% Pd/C (45 mg, 0.06 mmol). The sus-
pension was refluxed for 36 h. The reaction mixture cooled to r.t.
and EtOH (10 mL) was added. The mixture was filtered through
Celite, washed with EtOH, and the filtrate was evaporated under re-
duced pressure. The crude product was purified by column silica-
gel chromatography (EtOH); overall yield: 71% (0.070 g); white
solid; mp 222–224 °C (dec.).
HRMS (FAB): m/z calcd for C27H27N2O4 [M + H], 443.1893; found,
443.1971.
HRMS (FAB): m/z calcd for C17H17N2O2 [M + H], 281.1212; found,
281.1289.
dl-(4S,5S)-1,2-dibenzyl-4,5-diphenyl-4,5-dihydro-1H-imida-
zole-4-carboxylic Acid (2s)
A solution of benzaldehyde (0.6 g, 5.7 mmol), benzylamine (0.61 g,
5.7 mmol) in anhyd CH2Cl2 (120 mL) was refluxed under nitrogen
for 2 h. 2-Benzyl-4-phenyl-4H-oxazolin-5-one (1.43 g, 5.7 mmol)
and chlorotrimethylsilane (0.8 g, 7.4 mmol) were added and the
dl-(4S,5S)-1-Benzyl-2,4,5-triphenyl-4,5-dihydro-1H-imidazole-
4-carboxylic Acid (2n)
A solution of benzaldehyde (0.6 g, 5.7 mmol), benzylamine (0.61 g,
5.7 mmol) in anhyd CH2Cl2 (120 mL) was refluxed under nitrogen
for 2 h. 2,4-Diphenyl-4H-oxazolin-5-one (1.35 g, 5.7 mmol) and
chlorotrimethylsilane (0.8 g, 7.4 mmol) were added and the mixture
Synthesis 2003, No. 9, 1433–1440 ISSN 1234-567-89 © Thieme Stuttgart · New York

1440
S. Peddibhotla, J. J. Tepe
SPECIAL TOPIC
mixture was refluxed under nitrogen for 6 h and then stirred over-
night at r.t. The product was a mixture of diastereomers (3:1 ratio);
yield: 60%. The above trans-diastereomer was obtained by repeated
precipitation from MeOH–Et2O.
(8) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jorgensen, K.
A. Angew. Chem. Int. Ed. 2002, 42, 4236.
(9) Gothelf, K. V.; Jorgensen, K. A. Chem. Rev. 1998, 98, 863.
(10) Gothelf, K. V.; Jensen, K. B.; Jorgensen, K. A. Sci. Prog.
1999, 82, 327.
HRMS (FAB): m/z calcd for C30H27N2O2 [M + H] 447.2010; found,
447.2072.
(11) Padwa, A.; Burgess, E. M.; Gingrich, H. L.; Roush, D. M. J.
Org. Chem. 1982, 47, 786.
(12) Consonni, R.; Croce, P. D.; Ferraccioli, R.; La Rosa, C. J.
Chem. Res., Synop. 1991, 188.
(13) Bilodeau, M. T.; Cunningham, A. M. J. Org. Chem. 1998,
63, 2800.
(14) Gotthardt, H.; Huisgen, R.; Bayer, H. O. J. Am. Chem. Soc.
1970, 92, 4340.
(15) Croce, P. D.; Ferraccioli, R.; La Rosa, C. Tetrahedron 1999,
55, 201.
(16) Peddibhotla, S.; Jayakumar, S.; Tepe, J. J. Org. Lett. 2002,
4, 3533.
(17) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem. Int.
Ed. 1998, 37, 2580.
(18) Perry, M. C.; Burges, K. Tetrahedron: Asymmetry 2003, 14,
951.
(19) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.; Lee, H. M.; Yang,
C.; Nolan, S. P. J. Organomet. Chem. 2002, 653, 69.
(20) Alexakis, A.; Winn, C. L.; Guillen, F.; Pytkowicz, J.;
Roland, S.; Mangeney, P. Adv. Synth. Catal. 2003, 345, 345.
(21) Guillen, F.; Winn, C. L.; Alexakis, A. Tetrahedron:
Asymmetry 2001, 12, 2083.
dl-(4S,5S)-1,2-Dibenzyl-4-methyl-5-phenyl-4,5-dihydro-1H-im-
idazole-4-carboxylic Acid (2t) and dl-(4S,5R)-1,2-Dibenzyl-4-
methyl-5-phenyl-4,5-dihydro-1H-imidazole-4-carboxylic Acid
(3t)
A solution of benzaldehyde (1.13g, 10.58 mmol), benzylamine
(1.13g, 10.58 mmol) in anhyd CH2Cl2 (250 mL) was refluxed under
nitrogen for 2 h. 2-Benzyl-4-methyl-4H-oxazolin-5-one (2g, 10.58
mmol) and chlorotrimethylsilane (1.48 g, 10.58 mmol) were added
and the mixture was refluxed under nitrogen for 6 h and then stirred
overnight at r.t. The reaction mixture was evaporated to dryness un-
der vacuum. The product cis-isomer 3t was precipitated using
CH2Cl2–Et2O; yield: 30% (0.6 g); white solid. The trans-isomer 2t
was then precipitated out from the mother liquor. A small amount
was then reprecipitated to remove traces of 3t; yield: 17% (0.15g).
2t
HRMS (FAB): m/z calcd for C25H25N2O2 [M + H], 385.1898; found,
385.1916.
3t
HRMS (FAB): m/z calcd for C25H25N2O2 [M + H], 385.1898; found,
385.1917.
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Acknowledgment
The authors gratefully acknowledge financial support provided by
Michigan State University and the Donors of the Petroleum Rese-
arch Fund, administered by the American Chemical Society. In ad-
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Synthesis 2003, No. 9, 1433–1440 ISSN 1234-567-89 © Thieme Stuttgart · New York