Y(OTf)3-catalyzed diastereoselective [3+2] cycloaddition of N-tosylaziridines and imines; Efficient synthesis of multisubstituted imidazolidines

Article abstract of DOI:10.1055/s-0031-1290816

An efficient Y(OTf)₃-catalyzed generation of azomethine ylides from donor-acceptor aziridines and their [3+2] cycloaddition with imines was developed. The method provides facile access to multisubstituted imidazolidines, which have been extensively used in organic synthesis. Furthermore, a three-component reaction on a gram scale and an asymmetric variation were also developed in this work. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1290816

SPECIAL TOPIC
▌2147
sYpe(ciOal tTopifc)3-Catalyzed Diastereoselective [3+2] Cycloaddition of N-Tosyl-
aziridines and Imines; Efficient Synthesis of Multisubstituted Imidazolidines
Synthesis of Multisubstituted Imidazolidines
Xingxing Wu,a Junliang Zhang*a,b
a
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University,
3663 N. Zhongshan Road, Shanghai 200062, P. R. of China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. of China
Fax +86(21)62235039; E-mail: jlzhang@chem.ecnu.edu.cn
Received: 21.02.2012; Accepted after revision: 09.03.2012
Carriera and co-workers8a–c have developed a novel ap-
Abstract: An efficient Y(OTf)3-catalyzed generation of azometh-
proach to the synthesis of spirotryprostatin and related
ine ylides from donor–acceptor aziridines and their [3+2] cyclo-
horsfiline by the MgI2-catalyzed ring-expansion reaction
addition with imines was developed. The method provides facile
access to multisubstituted imidazolidines, which have been exten-
of 3-spirocyclopropyl-2-oxindoles and imines (Scheme
sively used in organic synthesis. Furthermore, a three-component 1). The groups of Kerr,8d Tang,8e and Johnson8f have inde-
reaction on a gram scale and an asymmetric variation were also de-
veloped in this work.
pendently demonstrated that (E)-aldimines are also com-
petent dipolarophiles in Lewis acid catalyzed [3+2]
Key words: bond cleavage, cycloaddition, ylides, Lewis acid, ste-
reoselectivity
annulations with DA cyclopropanes. With this in mind,
and due to our interest in the carbon–carbon bond cleav-
age of DA azirdines, we sought to obtain the imidazoli-
dines through Lewis acid catalyzed diastereoselective
Donor–acceptor (DA) cyclopropanes, due to their unique [3+2] cycloaddition of imines with AMYs generated from
reactivity profile, have received considerable interest and N-tosylaziridine dicarboxylates under mild conditions.9
have been extensively studied in the past decades.1 Many The products, imidazolidines, are fundamental units of
studies have demonstrated that they can be trapped with many natural products10a,b and biologically active mole-
appropriate dipolarophiles such as aldehydes and imines. cules.10c,d In particular, imidazolidines can be easily trans-
However, reports that extend this methodology to DA formed into imidazoles, which are well-known scaffolds
aziridines are not so common. This is surprising because in many significant biomolecules,10e–j and hydrolyzed to
the strain energy of aziridine (29 kcal/mol) is comparable prepare the corresponding 1,2-diamine compounds,
to that of cyclopropane (27.5 kcal/mol),2 and it is also a which can be used to synthesize organocatalysts and li-
versatile synthetic building-block for convenient access to gands for metal catalysts.10k,l
nitrogen-containing heterocycles, particularly through C–
N bond cleavage.3
R3
R2
previous work
R3
ref. 8d–f
CO2Me
CO2Me
CO2Me
CO2Me
Aziridine-2,3-diesters represent a particular case of DA
aziridines in organic synthesis. Since Huisgen’s pioneering
work,2a they have been largely utilized in 1,3-dipolar
cycloaddition through azomethine ylide (AMY) interme-
diates by the thermal or photolytic ring opening of aziri-
dines.4 A few cases of the generation of AMYs from
aziridines promoted by Lewis acids under mild conditions
have also been reported.5 Calculations performed by
Carrie, Johnson, as well as Engle6 have shown that Lewis
acids favor C–C bond heterolysis of DA aziridines. Very
recently, we and others have expanded this chemistry to
the synthesis of highly substituted heterocycles, such as
pyrolidines and 1,3-oxazolidines by conducting the reac-
tion with the appropriate dipolarophiles.7
R2N
PG
N
N
+
R1
Ar
R1
Ar
Ts
N
Ts
N
this work
CO2Me
CO2Me
CO2Me
CO2Me
N
+
R
PG
R
Scheme 1 Previous studies and this work
Our studies in this area began by choosing N-tosylaziri-
dine 1a11 and imine 2a12a as model substrates, because
they are known to be stable and easily prepared and puri-
fied; moreover, the benzyl moiety is an easily removable
protecting group. A representative selection of Lewis
acids including Sn(OTf)2, Sc(OTf)3, Cu(OTf)2, Fe(OTf)3,
.
In(OTf)2, Mg(OTf)2, Y(OTf)3, Bi(OTf)3, Ni(ClO4)2 6H2O,
Yb(OTf)3, and MgI2 were tested to optimize the reaction
conditions. Most of the Lewis acids were found to pro-
mote the tandem ring-opening-cyclization reaction of
SYNTHESIS 2012, 44, 2147–2154
Advanced online publication: 27.04.2012
DOI: 10.1055/s-0031-1290816; Art ID: SS-2012-C0177-ST
© Georg Thieme Verlag Stuttgart · New York
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1
1
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2148
X. Wu, J. Zhang
SPECIAL TOPIC
aziridines with imines. Notably, Sc(OTf)3 and Yb(OTf)3 both electron-deficient and electron-rich N-benzyl imines
gave high yields but low diastereoselectivities (Table 1, reacted well and gave good to high yields. For instance, 4-
entries 2 and 10), whereas use of Sn(OTf)2, Cu(OTf)2 and bromobenzylaldimine (2b) and 2-fluoro-4-bromobenzyl
Mg(OTf)2 gave higher diastereoselectivities but lower aldimine (2d) both give the desired products in 82–86%
yields (Table 1, entries 1, 3, and 6). To our delight, both yields (Table 2, entries 1 and 3). Moreover, electron-rich
high yield and high diastereoselectivity can be achieved substrates 2f–g also afforded the corresponding imida-
when the reaction was run in 1,2-dichloroethane (DCE) at zolidines in good to high yields (Table 2, entries 5 and 6).
room temperature with 4 Å molecular sieves as additive Some observations are particularly noteworthy: (1) the re-
under the catalysis of 5 mol% Y(OTf)3 (Table 1, entry 7). action of 4-cyanobenzylaldimine (2c) required longer
Other solvents were then screened and it was found that time, which may be due to the coordinating cyano group
the use of tetrahydrofuran (THF) failed to improve the re- competing to bind to the Lewis acid with the ester group;
sult, and the reaction did not take place in toluene (Table (2) when 4-methoxybenzylaldimine was employed as the
1, entries 12–14). The structure and relative stereochem- substrate, the reaction required higher catalyst loading,
istry were established by single crystal X-ray crystallog- possibly owing to the strong coordination between the cat-
raphy analysis of the trans isomer of 3aa (racemic; see the alyst and the lone pair of the nitrogen atom of aldimine;
Supporting Information).13
(3) the products could be generated with excellent diaste-
reoselectivities when the aryl group of aldimines was sub-
stituted by a strong electron-withdrawing group, such as
cyano or fluoro group, which produced a single isomer al-
most completely (Table 2, entries 2 and 3); for electron-
rich aldehyde derived aldimines, only moderate diaste-
reoselectivities were obtained (Table 1, entries 5 and 6).
Gratifyingly, aldimine 2h, derived from furan-2-carbalde-
hyde, afforded the desired adduct in nearly quantitative
yield but with no selectivity (Table 1, entry 7). Finally, a
series of aldimines from aniline were examined; in gener-
al, these demonstrated similar properties to those of N-
benzylaldimines. Both electron-deficient and neutral N-
phenyl imines provided high yields and excellent diaste-
reoselectivities (Table 2, entries 8 and 9); the electron-rich
substituted substrate 2k afforded the corresponding imid-
azolidine in 78% yield with moderate diastereoselectivity
(Table 2, entry 10).
Table 1 Screening Reaction Conditionsa
NBn
C6H4Br-4
NTs
Ts
N
catalyst
Bn
N
CO2Me
CO2Me
(5 mol%)
+
CO2Me
4-BrC6H4
solvent
4 Å MS
r.t.
CO2Me
4-ClC6H4
1a
3aa
Cl
2a
Entry Catalyst
Solvent
Time Yield
(h)
dr
(%)b
(trans/cis)c
1
2
Sn(OTf)2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH2Cl2
THF
2.5
58
84
56
64
79
37
85
75
85
87
78
76
83
trace
>20:1
3:1
Sc(OTf)3
Cu(OTf)2
Fe(OTf)3
In(OTf)2
Mg(OTf)2
Y(OTf)3
Bi(OTf)3
0.5
3
3
>20:1
>20:1
8:1
4
1
We then examined the scope of this reaction by variation
of the DA aziridines (Scheme 2). The reactions of aziri-
dine 1 bearing either an electron-donating or electron-
withdrawing group proceeded smoothly and generated the
corresponding cycloadducts 3ba–fa in 66–91% yields,
with diastereoisomeric ratios that ranged from 10:1 to
more than 20:1. Notably, with 1b and 1c the reaction re-
quired much longer to reach completion, which may be
caused by the strong electron-withdrawing effect of the
halogen atoms.
5
3
6
10
>50:1
>20:1
>20:1
3:1
7
3
3
8
.
9
3
Ni(ClO4)2 6H2O
Yb(OTf)3
MgI2
10
11
12
13
14
3
3:1
2
>20:1
14:1
3:1
When the acceptor groups were switched to ethyl (1g) or
isopropyl dicarboxylates (1h), the reactions still work
very well under the standard conditions. The results ob-
tained from the reactions of 1i with benzylaldimines 2e,
2a, and 2g further indicate that the electronic effect of the
substituents affects the diastereoselectivity rather than the
efficiency.
Y(OTf)3
2
Y(OTf)3
3
Y(OTf)3
toluene
10
trace
a Reaction conditions (0.2 mmol scale): 1a (0.2 mmol), 2a (1.5 equiv),
catalyst (5 mol%), activated 4 Å MS (100 mg), solvent (2 mL) r.t.
b Isolated combined yield of two isomers.
Considering that the aldimine is readily available from al-
dehyde and amine, the three-component reaction was then
tested on a gram scale and found to proceed smoothly, fur-
nishing the product in 83% yield with high diastereoselec-
tivity (Scheme 3, equation 1). Perhaps more importantly,
a preliminary experiment showed that an enantioselective
variant of this novel reaction can be achieved by the appli-
cation of t-Bu-Pybox14 as the chiral ligand. The reaction
c Determined by 1H NMR spectroscopic analysis of the crude product.
With the optimal conditions in hand, the scope of this
Y(OTf)3-promoted [3+2] cycloaddition was explored by
submitting a range of imine components 2 to the reaction
conditions; the results are presented in Table 2. In general,
Synthesis 2012, 44, 2147–2154
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of Multisubstituted Imidazolidines
2149
of 1a and 2c proceeded well at room temperature to give
the corresponding product in 49% enantiomeric excess,
with a moderate yield (Scheme 3, equation 2). Further ex-
ploration and development of this catalytic asymmetric
[3+2] cycloaddition is under way in our laboratory.
Table 2 Study of the Reaction Scope by Variation of the Imine Com-
ponenta
C6H4Br-4
Y(OTf)3
Ts
N
R1
R2
NR1
N
NTs
CO2Me
CO2Me
(5 mol%)
CO2Me
CO2Me
+
4-BrC6H4
DCE
4 Å MS, r.t.
R2
Ts
1a
2
3
4-BrC6H4
CO2Me
CO2Me
N
CHO
Y(OTf)3
(1)
(5 mol%)
R1
R2
Entry
2
Time 3
(h)
Yield trans/cis
(%)
N
1a
+ BnNH2
+
Bn
5 mmol
4 Å MS
DCE, r.t.
C6H4Cl-4
3aa
83%, dr > 20:1
1
2
3
4
5
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
Ph
Ph
4-BrC6H4
2b
2c
3
3ab 82
3ac 65
3ad 86
18:1
>50:1
>50:1
14:1
5:1
Cl
4-CNC6H4
8
Ts
4-BrC6H4
CO2Me
N
Y(OTf)3 (5 mol%)
2-F-4-BrC6H4 2d
3
CO2Me
t-Bu-Pybox (6 mol%)
(2)
N
1a
+
2c
Bn
Ph
2e
2f
3
3ae
3af
3ag
3ah
3ai
86
DCE, 4 Å MS
r.t., 9 h
C6H4CN-4
3ac
67%, 49% ee
87c
79c
98c
86
4-i-PrC6H4
4-MeOC6H4
2-Furyl
2
6b
7
2g
2h
2i
4.5
2
3:1
Scheme 3 Gram-scale reaction (1) and preliminary examination of
an enantioselective variant with t-Bu-Pybox (2)
1:1
8
Ph
4
>20:1
>20:1
3:1
A model that accounts for the trans selectivity observed in
this cycloaddition is proposed in Scheme 4. Based on pre-
vious work,7,15 a possible path is that the azomethine ylide
B is first produced by C–C bond cleavage of A, formed
from 1 through the selective coordination of Y(OTf)3 to
the dicarboxylate groups. Subsequent diastereoselective
addition of the imine would afford two zwitterionic inter-
mediates, C and D, which can be interconverted through
iminium isomerization. Intermediate D is less stable than
intermediate C, owing to the steric hindrance of R and Ar,
which are both in pseudo axial orientations within the en-
velope transition state, thus the trans isomer is produced
preferentially.
9
4-ClC6H4
4-MeOC6H4
2j
3
3aj
3ak
90
10b
78c
2k
8
a Reaction conditions: 1a (0.4 mmol), 2 (1.5 equiv), Y(OTf)3 (5
mol%), activated 4 Å MS (200 mg), DCE (4 mL), r.t.
b 10 mol% of Y(OTf)3 was used.
c Combined yield of two isomers.
Ar
Y(OTf)3
Ts
N
R2
NTs
CO2R1
CO2R1
BnN
R2
CO2R1
CO2R1
(5 mol%)
+
NBn
2a,e–g
Ar
4 Å MS
DCE, r.t.
1
3
aziridines 1
trans-3
YIII
R3
R
3 = 3-Br (3ba), 66%, >20:1 dr, 14 h
4-F (3ca), 65%, 10:1 dr, 14 h
4-Cl (3da), 91%, 13:1 dr, 2 h
4-Me (3ea)a, 90%,15:1 dr, 6 h
4-i-Pr (3fa)a, 81%, 13:1 dr, 5 h
Ts
N
CO2Me
CO2Me
N
R1
N+
Bn
R1
N+
R2
OMe
Ar
OMe
O
TsN
O
Ts
O
TsN
O
YIII
OMe
O
C6H4Cl-4
YIII
N
H
Ts
N
CO2R1
CO2R1
4-BrC6H4
Bn
Ar
MeO
R2
Ar
R1 = Et (3ga), 82%,14:1 dr, 2 h
i-Pr (3ha), 87%, >20:1 dr, 3 h
YIII
H
OMe
D
R2, Ar repulsion
disfavored
O
N
OMe
C
A
C6H4Cl-4
favored
Ts
N
CO2R1
CO2R1
Ph
R1 = Me
N
R
3 = H (3ie)a, 88%, 8:1 dr, 6 h
Ts
N+
OMe
O
Bn
Cl (3ia)a, 87%, 11:1 dr, 6 h
R1
Ar
MeO (3ig)a,b, 90%, 4:1 dr, 10 h
3 = Cl, R1 = i-Pr (3ja)a, 90%, >20:1 dr, 9 h
–
H
N
YIII
R
MeO
O
R2
2
R3
B
Scheme 2 Study of the reaction scope by variation of the aziridine
component. The temperature was 10 °C. Combined yield of two
isomers.
Scheme 4 Proposal mechanism for the formation of trans-imidazoli-
dines
a
b
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2147–2154

2150
X. Wu, J. Zhang
SPECIAL TOPIC
3.92 (s, 3 H), 3.69 (s, 3 H), 3.55 (d, J = 15.2 Hz, 1 H), 2.72 (d, J =
15.2 Hz, 1 H), 2.32 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.2, 166.4, 143.4, 137.1, 136.8,
134.6, 132.9, 131.6, 130.9, 130.8, 130.4, 128.6, 128.4, 127.9, 127.4,
127.2, 123.3, 122.7, 78.1, 77.5, 72.3, 53.4, 52.9, 49.5, 21.4.
MS (ESI): m/z = 741.0 [M + H+].
HRMS: m/z calcd for C33H31Br2N2O6S+: 741.0279; found:
In conclusion, we have developed an efficient method for
the diastereoselective synthesis of imidazolidines through
Lewis acid catalyzed carbon–carbon bond cleavage of DA
aziridines. Mild conditions, readily available starting ma-
terial, as well as the high yield and good selectivity make
this protocol potentially useful in organic synthesis. Ef-
forts are under way to develop its application, establish an
asymmetric version, and to identify new dipolarophile
partners.
741.0264.
(2S*,5R*)-Dimethyl 1-Benzyl-2-(4-bromophenyl)-5-(4-cyano-
phenyl)-3-tosylimidazolidine-4,4-dicarboxylate (3ac)
Yield: 178.3 mg (65%); white solid; mp 220–222 °C.
All reactions were carried out in flame-dried glassware under an an-
hydrous N2 atmosphere with standard vacuum-line techniques. All
solvents were purified and dried according to standard methods pri-
or to use. Infrared (IR) spectra were obtained with a Bruker tensor
IR (neat): 2955, 2836, 2229, 1768, 1752, 1595, 1492, 1438, 1373,
1337, 1269, 1228, 1176, 1154, 1110, 1052, 1007, 946, 906 cm–1.
1H NMR (400 MHz, CDCl3): δ (trans/cis, 50:1) = 7.64 (d, J =
8.0 Hz, 2 H), 7.57 (d, J = 8.0 Hz, 2 H), 7.20–7.34 (m, 5 H), 7.15 (d,
J = 8.0 Hz, 2 H), 7.11 (d, J = 7.2 Hz, 2 H), 6.95 (d, J = 7.6 Hz, 2 H),
6.65 (d, J = 7.6 Hz, 2 H), 6.01 (s, 1 H), 5.06 (s, 1 H), 3.93 (s, 3 H),
3.67 (s, 3 H), 3.50 (d, J = 15.2 Hz, 1 H), 2.77 (d, J = 15.2 Hz, 1 H),
2.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.0, 166.2, 143.5, 139.5, 136.8,
136.3, 134.2, 132.0, 130.9, 130.7, 129.5, 128.6, 128.4, 127.8,
127.33, 127.26, 122.8, 118.2, 113.0, 78.2, 77.4, 72.1, 53.5, 53.0,
49.6, 21.3.
1
27 infrared spectrometer. H and 13C NMR spectra were recorded
with a Bruker 400 MHz spectrometer in CDCl3. All signals are re-
ported in ppm with TMS (δ = 0 ppm) as an internal standard. Enan-
tiomeric ratios were determined by chiral HPLC analysis and
comparison with authentic racemic materials. Aziridines were pre-
pared according to literature procedures.11 N-Benzylimines were
synthesized by condensation of the corresponding aldehydes and
benzyl amine.12a N-Phenylimines were synthesized by using the re-
porting route.12b
Y(OTf)3-Catalyzed Diastereoselective [3+2] Cycloaddition of
N-Tosylaziridines and Imines; Typical Procedure
MS (ESI): m/z = 688.1 [M + H+].
HRMS: m/z calcd for C34H31BrN3O6S+: 688.1121; found: 688.1112.
In an inert atmosphere, a flame-dried vial was charged with a mag-
netic stir bar, activated 4 Å molecular sieves (200 mg), Y(OTf)3
(10.7 mg, 5 mol%), imine 2 (0.6 mmol, 1.5 equiv), and DCE (3 mL).
The mixture was stirred at r.t. for ca. 5 min, then aziridine 1 (0.4
mmol, 1.0 equiv) was added, and washed by DCE (1 mL). The re-
action was stirred at r.t. until complete consumption of the aziridine
was observed (reaction monitored by TLC analysis). The reaction
mixture was then passed over a small plug of silica gel eluted with
CH2Cl2. After evaporation under reduced pressure, the crude prod-
(2S*,5R*)-Dimethyl 1-Benzyl-5-(4-bromo-2-fluorophenyl)-2-
(4-bromophenyl)-3-tosylimidazolidine-4,4-dicarboxylate (3ad)
Yield: 261.7 mg (86%); white solid; mp 97–99 °C.
IR (neat): 3029, 2951, 1756, 1602, 1576, 1484, 1453, 1434, 1410,
1350, 1285, 1211, 1162, 1105, 1089, 1071, 1052, 1010, 997, 941,
906 cm–1.
1H NMR (400 MHz, CDCl3): δ = (trans/cis, 50:1) = 7.45 (t, J =
8.0 Hz, 1 H), 7.18–7.32 (m, 7 H), 7.08 (d, J = 8.4 Hz, 4 H), 6.91 (d,
J = 7.6 Hz, 2 H), 6.70 (d, J = 8.0 Hz, 2 H), 6.00 (s, 1 H), 5.20 (s,
1 H), 3.94 (s, 3 H), 3.76 (s, 3 H), 3.51 (d, J = 15.2 Hz, 1 H), 2.77 (d,
J = 15.2 Hz, 1 H), 2.32 (s, 3 H).
1
uct was subjected to H NMR spectroscopic analysis, which gave
the diastereomeric ratio. The resulting product was purified by flash
chromatography to afford the desired product 3.
(2S*,5R*)-Dimethyl 1-Benzyl-2-(4-bromophenyl)-5-(4-chloro-
phenyl)-3-tosylimidazolidine-4,4-dicarboxylate (3aa)
Yield: 237.1 mg (85%); white solid; mp 209–212 °C.
13C NMR (100 MHz, CDCl3): δ = 167.5, 166.4, 161.5 (d, JC–F
251.0 Hz), 143.4, 136.9, 136.6, 134.3, 131.2, 130.8, 129.7, 128.6,
=
1
128.3, 128.1, 127.7 (d, JC–F = 3.0 Hz), 127.3, 127.2, 123.4 (d, JC–F
10.0 Hz), 122.8, 120.7 (d, JC–F = 12.0 Hz), 119.5 (d, JC–F
25.0 Hz), 77.6, 76.8, 65.3, 53.6, 53.0, 49.7, 21.4.
MS (ESI): m/z = 759.0 [M + H+].
HRMS: m/z calcd for C33H30Br2FN2O6S+:759.0204; found:
759.0170.
=
=
IR (neat): 2955, 2840, 1771, 1752, 1594, 1492, 1435, 1419, 1371,
1337, 1307, 1276, 1261, 1227, 1176, 1155, 1139, 1120, 1086, 1071,
1050, 1034, 1007, 949, 906 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37 (d, J = 8.0 Hz, 2 H), 7.30 (d,
J = 8.0 Hz, 4 H), 7.25 (t, J = 8.0 Hz, 3 H), 7.10–7.17 (m, 4 H), 6.94
(d, J = 8.0 Hz, 2 H), 6.66 (d, J = 7.6 Hz, 2 H), 6.00 (s, 1 H), 4.97 (s,
1 H), 3.92 (s, 3 H), 3.69 (s, 3 H), 3.55 (d, J = 15.2 Hz, 1 H), 2.72 (d,
J = 15.2 Hz, 1 H), 2.32 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.2, 166.4, 143.4, 137.0, 136.7,
135.0, 134.5, 132.3, 130.84, 130.77, 130.0, 128.61, 128.56, 128.40,
127.9, 127.4, 127.2, 122.7, 78.0, 77.5, 72.2, 53.4, 52.9, 49.4, 21.4.
MS (ESI): m/z = 697.1 [M + H+].
HRMS: m/z calcd for C33H31BrClN2O6S+: 697.0788; found:
2
(2S*,5R*)-Dimethyl 1-Benzyl-2-(4-bromophenyl)-5-phenyl-3-
tosylimidazolidine-4,4-dicarboxylate (3ae)
Yield: 227.9 mg (86%); white solid; mp 75–76 °C.
IR (neat): 3062, 3031, 2951, 2842, 1752, 1956, 1492, 1453, 1434,
1415, 1349, 1282, 1208, 1160, 1091, 1072, 1047, 1010, 976, 940,
905 cm–1.
1H NMR (400 MHz, CDCl3): δ (trans/cis, 14:1) = 7.40 (br, 2 H),
7.21–7.36 (m, 8 H), 7.14 (t, J = 7.6 Hz, 4 H), 6.94 (d, J = 8.0 Hz,
2 H), 6.69 (d, J = 7.6 Hz, 2 H), 6.00 (s, 1 H), 5.00 (s, 1 H), 3.92 (s,
3 H), 3.65 (s, 3 H), 3.63 (d, J = 15.2 Hz, 1 H), 2.72 (d, J = 15.2 Hz,
1 H), 2.32 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.3, 166.5, 143.3, 137.13,
137.09, 134.8, 133.7, 130.9, 130.8, 129.2, 128.6, 128.5, 128.4,
127.9, 127.5, 127.1, 122.6, 78.0, 77.7, 73.0, 53.4, 52.8, 49.5, 21.4.
MS (ESI): m/z = 663.1 [M + H+].
HRMS: m/z calcd for C33H32BrN2O6S+: 663.1178; found: 663.1159.
697.0769.
(2S*,5R*)-Dimethyl 1-Benzyl-2,5-bis(4-bromophenyl)-3-tosyl-
imidazolidine-4,4-dicarboxylate (3ab)
Yield: 242.4 mg (82%); white solid; mp 97–99 °C.
IR (neat): 2950, 2844, 1752, 1594, 1487, 1453, 1434, 1411, 1348,
1284, 1209, 1161, 1071, 1051, 1010, 977, 940, 906 cm–1.
1H NMR (400 MHz, CDCl3): δ (trans/cis, 18:1) = 7.46 (d, J =
8.0 Hz, 2 H), 7.21–7.36 (m, 7 H), 7.08–7.17 (m, 4 H), 6.94 (d, J =
8.0 Hz, 2 H), 6.66 (d, J = 8.0 Hz, 2 H), 5.99 (s, 1 H), 4.95 (s, 1 H),
Synthesis 2012, 44, 2147–2154
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of Multisubstituted Imidazolidines
2151
Dimethyl 1-Benzyl-2-(4-bromophenyl)-5-(4-isopropylphenyl)-
3-tosylimidazolidine-4,4-dicarboxylate (3af)
Yield: 244.8 mg (87%); white solid; dr = 5:1 (trans/cis).
(2S*,5R*)-Dimethyl 2-(4-Bromophenyl)-1,5-diphenyl-3-tosyl-
imidazolidine-4,4-dicarboxylate (3ai)
Yield: 223.2 mg (86%); white solid; mp 183–188 °C.
IR (neat): 2956, 2840, 1751, 1596, 1490, 1433, 1349, 1283, 1209,
1159, 1090, 1072, 1056, 1011, 978, 941, 907 cm–1.
IR (neat): 3037, 2947, 2841, 1756, 1599, 1499, 1453, 1433, 1413,
1343, 1253, 1233, 1152, 1095, 1057, 1038, 1014, 980, 935, 907
cm–1.
1H NMR (400 MHz, CDCl3): δ (trans/cis, 20:1 ) = 7.30 (d, J =
7.6 Hz, 2 H), 7.15–7.28 (m, 5 H), 7.10 (d, J = 7.2 Hz, 2 H), 7.00 (t,
J = 9.4 Hz, 4 H), 6.86 (t, J = 7.4 Hz, 2 H), 6.68 (s, 1 H), 6.58 (t, J =
7.2 Hz, 1 H), 6.44 (d, J = 8.0 Hz, 2 H), 5.88 (s, 1 H), 3.92 (s, 3 H),
3.49 (s, 3 H), 2.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.2, 166.3, 143.5, 141.8, 137.3,
136.6, 134.1, 130.9, 130.7, 128.7, 128.6, 128.2, 127.9, 122.5, 120.6,
120.2, 79.8, 78.0, 70.3, 53.6, 52.7, 21.4.
MS (ESI): m/z = 649.1 [M + H+].
HRMS: m/z calcd for C32H30BrN2O6S+: 649.1023; found: 649.1003.
1H NMR (400 MHz, CDCl3): δ = 6.88–7.40 (m, 15 H),* 6.69 (d, J =
7.6 Hz, 2 H), 6.00 (s, 1 H), 4.97 (s, 1 H), 3.91 (s, 3 H), 3.56–3.66
(m, 4 H), 2.74–2.94 (m, 1 H),* 2.69 (d, J = 14.8 Hz, 1 H), 2.30 (s,
3 H), 1.20 (d, J = 6.8 Hz, 6 H). δ (cis isomer) = 6.88–7.40 (m,
15 H),* 6.81 (d, J = 4.0 Hz, 2 H), 5.26 (s, 1 H), 4.60 (s, 1 H), 3.82
(s, 3 H), 3.55 (d, J = 14.8 Hz, 1 H), 3.44 (d, J = 14.4 Hz, 1 H), 3.23
(s, 3 H), 2.74–2.94 (m, 1 H),* 2.34 (s, 3 H), 1.24 (d, J = 6.8 Hz,
6 H). * Peaks overlap with those of the other isomer.
13C NMR (100 MHz, CDCl3): δ = 168.3, 168.2, 167.1, 166.4, 149.7,
149.6, 143.1, 142.7, 137.8, 137.2, 134.8, 134.6, 133.2, 132.6, 132.1,
131.3, 130.9, 130.8, 130.72, 130.67, 129.9, 128.5, 128.4, 128.3,
128.2, 128.1, 127.9, 127.8, 127.4, 126.9, 126.3, 123.4, 122.4, 79.2,
77.9, 77.6, 72.7, 72.3, 53.2, 53.1, 52.6, 52.2, 50.5, 49.4, 33.8, 33.6,
23.8, 23.7, 21.31, 21.25.
(2S*,5R*)-Dimethyl 2-(4-Bromophenyl)-5-(4-chlorophenyl)-1-
phenyl-3-tosylimidazolidine-4,4-dicarboxylate (3aj)
Yield: 244.9 mg (90%); white solid; mp 202–206 °C.
MS (ESI): m/z = 705.2 [M + H+].
HRMS: m/z calcd for C36H38BrN2O6S+: 705.1623; found: 705.1629.
IR (neat): 2949, 1754, 1597, 1490, 1434, 1413, 1346, 1256, 1236,
1155, 1089, 1064, 1043, 1013, 975, 931, 910 cm–1.
Dimethyl 2-(4-Bromophenyl)-5-(4-methoxyphenyl)-1-phenyl-3-
tosylimidazolidine-4,4-dicarboxylate (3ag)
Yield: 218.9 mg (79%); white solid; dr = 3:1 (trans/cis).
1H NMR (400 MHz, CDCl3): δ (trans/cis, 20:1) = 7.29 (d, J =
7.6 Hz, 2 H), 7.12–7.26 (m, 4 H), 7.09 (d, J = 7.6 Hz, 2 H), 6.98 (d,
J = 7.6 Hz, 4 H), 6.88 (t, J = 7.4 Hz, 2 H), 6.67 (s, 1 H), 6.61 (t, J =
7.2 Hz, 1 H), 6.43 (d, J = 8.0 Hz, 2 H), 5.84 (s, 1 H), 3.91 (s, 3 H),
3.54 (s, 3 H), 2.32 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.0, 166.2, 143.5, 141.5, 137.2,
136.4, 134.4, 132.7, 130.9, 130.6, 129.6, 128.6, 128.4, 128.3, 127.9,
122.6, 121.0, 120.4, 79.9, 77.7, 69.4, 53.6, 52.8, 21.4.
IR (neat): 2952, 2839, 1751, 1611, 1512, 1490, 1453, 1435, 1346,
1282, 1249, 1208, 1158, 1107, 1090, 1072, 1031, 1010, 977, 940,
906.
1H NMR (400 MHz, CDCl3): δ (trans isomer) = 6.75–7.40 (m,
15 H),* 6.68 (d, J = 7.6 Hz, 2 H), 5.99 (s, 1 H), 4.93 (s, 1 H), 3.91
(s, 3 H), 3.77 (s, 3 H), 3.71 (s, 3 H), 3.61 (d, J = 15.2 Hz, 1 H), 2.69
(d, J = 15.2 Hz, 1 H), 2.31 (s, 3 H). δ (cis isomer) = 6.75–7.40 (m,
17 H),* 5.25 (s, 1 H), 4.55 (s, 1 H), 3.82 (s, 6 H), 3.52 (d, J =
14.8 Hz, 1 H), 3.39 (d, J = 14.8 Hz, 1 H), 3.33 (s, 3 H), 2.35 (s,
3 H). * Peaks overlap with those of the other isomer.
MS (ESI): m/z = 683.1 [M + H+].
HRMS: m/z calcd for C32H29BrClN2O6S+: 683.0642; found:
683.0613.
Dimethyl 2-(4-Bromophenyl)-5-(4-methoxyphenyl)-1-phenyl-3-
tosylimidazolidine-4,4-dicarboxylate (trans/cis-3ak)
Diastereomeric ratio 3:1 (trans/cis).
13C NMR (100 MHz, CDCl3): δ (trans/cis mixture) = 168.41,
168.35, 167.1, 166.6, 160.2, 160.0, 143.2, 142.8, 137.9, 137.2,
134.9, 134.6, 133.2, 132.6, 130.84, 130.77, 129.94, 129.87, 128.5,
1228.4, 128.3, 128.09, 128.05, 127.9, 127.5, 127.4, 127.0, 126.6,
125.3, 123.5, 122.5, 113.8, 79.2, 77.9, 77.6, 76.9, 72.5, 72.0, 55.2,
55.1, 53.3, 53.2, 52.8, 52.5, 50.4, 49.3, 21.4, 21.3.
MS (ESI): m/z = 693.1 [M + H+].
HRMS: m/z calcd for C34H34BrN2O7S+: 693.1289; found: 693.1265.
trans-3ak
Yield: 157.2 mg, (58%); white solid; mp 182–186 °C.
IR (neat): 2950, 2839, 1756, 1599, 1512, 1500, 1485, 1435, 1415,
1346, 1305, 1252, 1211, 1156, 1110, 1090, 1063, 1039, 1010, 972,
939, 929, 910 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 7.6 Hz, 2 H), 7.12–
7.23 (m, 2 H), 7.09 (d, J = 7.6 Hz, 2 H), 6.99 (t, J = 7.4 Hz, 4 H),
6.87 (t, J = 7.4 Hz, 2 H), 6.70–6.82 (m, 2 H), 6.68 (s, 1 H), 6.59 (t,
J = 7.2 Hz, 1 H), 6.45 (d, J = 8.0 Hz, 2 H), 5.80 (s, 1 H), 3.92 (s,
3 H), 3.73 (s, 3 H), 3.55 (s, 3 H), 2.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.2, 166.5, 159.7, 143.4, 141.9,
137.4, 136.8, 130.9, 130.7, 129.4, 128.5, 128.2, 127.9, 125.7, 122.5,
120.6, 120.5, 113.6, 79.9, 77.9, 69.9, 55.0, 53.5, 52.8, 21.4.
Dimethyl 1-Benzyl-2-(4-bromophenyl)-5-(furan-2-yl)-3-tosyl-
imidazolidine-4,4-dicarboxylate (3ah)
Yield: 257.1 mg (98%); white solid; dr = 1:1 (trans/cis).
IR (neat): 2952, 1750, 1596, 1488, 1453, 1434, 1345, 1277, 1234,
1214, 1158, 1106, 1072, 1057, 982, 943 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.80–7.52 (m, 14 H),* 6.18–6.40
(m, 2 H),* 5.76 (s, 1 H), 5.04 (s, 1 H), 3.93 (s, 3 H), 3.58–3.68 (m,
4 H), 2.99 (d, J = 13.6 Hz, 1 H), 2.34 (s, 3 H). δ (cis isomer) = 6.80–
7.52 (m, 14 H),* 6.18–6.40 (m, 2 H),* 5.21 (s, 1 H), 4.81 (s, 1 H),
3.84 (s, 3 H), 3.55 (s, 3 H), 3.40–3.50 (m, 2 H), 2.37 (s, 3 H).
* Peaks overlap with those of the other isomer.
MS (ESI): m/z = 701.1 [M + Na+].
HRMS: m/z calcd for C33H31BrN2O7SNa+: 701.0932; found:
701.0928.
13C NMR (100 MHz, CDCl3): δ = 168.9, 168.1, 167.1, 166.1, 149.0,
148.4, 143.3, 143.19, 143.15, 142.9, 137.6, 137.3, 137.0, 135.4,
134.4, 133.6, 132.5, 131.3, 131.1, 130.8, 129.7, 128.5, 128.4, 128.3,
128.19, 128.17, 128.1, 127.9, 127.4, 127.2, 123.6, 123.3, 111.6,
110.8, 110.7, 110.2, 80.2, 79.6, 77.1, 75.5, 66.9, 63.8, 53.5, 53.3,
53.2, 51.4, 49.2, 21.43, 21.41.
MS (ESI): m/z = 653.1 [M + H+].
HRMS: m/z calcd for C31H30BrN2O7S+: 653.0971; found: 653.0952.
cis-3ak
Yield: 55.2 mg (20%); white solid; mp 87–89 °C.
IR (neat): 2951, 2839, 1757, 1599, 1511, 1434, 1347, 1248, 1157,
1106, 1092, 1067, 1033, 1011, 971, 942, 905 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.43 (m, 4 H), 7.23 (d, J =
8.0 Hz, 2 H), 7.15 (d, J = 7.6 Hz, 2 H), 6.92–7.03 (m, 4 H), 6.87 (d,
J = 8.0 Hz, 2 H), 6.80 (t, J = 7.2 Hz, 1 H), 6.60 (d, J = 8.0 Hz, 2 H),
5.90 (s, 1 H), 5.41 (s, 1 H), 4.01 (s, 3 H), 3.80 (s, 3 H), 3.41 (s, 3 H),
2.36 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2147–2154

2152
X. Wu, J. Zhang
SPECIAL TOPIC
13C NMR (100 MHz, CDCl3): δ = 168.8, 166.0, 159.7, 144.7, 143.1,
137.8, 135.4, 132.3, 131.0, 129.3, 129.0, 128.8, 128.5, 128.1, 123.5,
122.0, 118.7, 113.8, 80.0, 78.0, 72.7, 55.2, 53.8, 52.7, 21.4.
(2S*,5R*)-Dimethyl 1-Benzyl-5-(4-chlorophenyl)-2-(p-tolyl)-3-
tosylimidazolidine-4,4-dicarboxylate (3ea)
Yield: 228.4 mg (90%); white solid; mp 90–93 °C.
MS (ESI): m/z = 701.1 [M + Na+].
HRMS: m/z calcd for C33H31BrN2O7SNa+: 701.0945; found:
IR (neat): 2952, 1756, 1598, 1492, 1452, 1434, 1347, 1285, 1211,
1161, 1089, 1049, 1015, 978, 941, 905 cm–1.
1H NMR (400 MHz, CDCl3): δ (trans/cis, 15:1) = 7.41 (d, J =
7.2 Hz, 2 H), 7.21–7.32 (m, 7 H), 7.15 (d, J = 6.4 Hz, 2 H), 6.90 (d,
J = 8.0 Hz, 2 H), 6.86 (d, J = 6.8 Hz, 2 H), 6.67 (d, J = 6.8 Hz, 2 H),
6.02 (s, 1 H), 5.02 (s, 1 H), 3.89 (s, 3 H), 3.68 (s, 3 H), 3.51 (d, J =
15.2 Hz, 1 H), 2.75 (d, J = 15.2 Hz, 1 H), 2.28 (s, 6 H).
701.0928.
(2S*,5R*)-Dimethyl 1-Benzyl-2-(3-bromophenyl)-5-(4-chloro-
phenyl)-3-tosylimidazolidine-4,4-dicarboxylate (3ba)
Yield: 184.3 mg (66%); white solid; mp 58–61 °C.
13C NMR (100 MHz, CDCl3): δ = 168.3, 166.7, 142.8, 138.3, 137.4,
137.3, 134.9, 132.7, 132.5, 130.3, 129.0, 128.49, 128.45, 128.2,
128.0, 127.4, 127.0, 78.7, 77.4, 71.9, 53.2, 52.9, 49.3, 21.3, 21.1.
MS (ESI): m/z = 633.2 [M + H+].
HRMS: m/z calcd for C34H34ClN2O6S+: 633.1826; found: 633.1821.
IR (neat): 2952, 2842, 1752, 1596, 1572, 1492, 1475, 1434, 1347,
1285, 1229, 1202, 1161, 1089, 1042, 976, 942, 908 cm–1.
1H NMR (400 MHz, CDCl3): δ (trans/cis, 20:1) = 7.38 (d, J =
8.0 Hz, 2 H), 7.20–7.38 (m, 8 H), 7.14 (d, J = 7.2 Hz, 2 H), 6.84–
6.96 (m, 4 H), 6.65 (d, J = 7.6 Hz, 1 H), 6.00 (s, 1 H), 4.94 (s, 1 H),
3.94 (s, 3 H), 3.69 (s, 3 H), 3.56 (d, J = 15.2 Hz, 1 H), 2.71 (d, J =
15.2 Hz, 1 H), 2.29 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.0, 166.4, 143.4, 137.7,
136.84, 136.76, 135.1, 132.3, 132.1, 131.4, 130.1, 129.2, 128.6,
128.4, 127.79, 127.76, 127.4, 127.2, 122.2, 78.0, 77.5, 72.2, 53.4,
52.9, 49.6, 21.4.
(2S*,5R*)-Dimethyl 1-Benzyl-5-(4-chlorophenyl)-2-(4-isopro-
pylphenyl)-3-tosylimidazolidine-4,4-dicarboxylate (3fa)
Yield: 212.8 mg (81%); white solid; mp 143–146 °C.
IR (neat): 2961, 2872, 1750, 1724, 1598, 1492, 1451, 1429, 1413,
1350, 1316, 1287, 1217, 1159, 1135, 1090, 1058, 1015, 980, 944,
906 cm–1.
MS (ESI): m/z = 697.1 [M + H+].
1H NMR (400 MHz, CDCl3): δ (trans/cis, 13:1) = 7.42 (d, J =
8.0 Hz, 2 H), 7.22–7.34 (m, 7 H), 7.15 (d, J = 7.2 Hz, 2 H), 6.87 (t,
J = 9.2 Hz, 4 H), 6.69 (d, J = 7.6 Hz, 2 H), 6.06 (s, 1 H), 5.01 (s,
1 H), 3.90 (s, 3 H), 3.70 (s, 3 H), 3.50 (d, J = 15.2 Hz, 1 H), 2.72–
2.88 (m, 2 H), 2.24 (s, 3 H), 1.18 (d, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 168.2, 166.7, 149.4, 142.5, 137.4,
137.3, 134.9, 132.8, 132.7, 130.3, 130.0, 129.0, 128.5, 128.4, 128.2,
128.0, 127.9, 127.4, 126.9, 125.9, 125.8, 78.7, 77.4, 72.0, 53.2,
52.9, 49.4, 33.7, 24.0, 23.97, 21.3.
HRMS: m/z calcd for C33H31BrClN2O6S+: 697.0801; found:
697.0769.
(2S*,5R*)-Dimethyl 1-Benzyl-5-(4-chlorophenyl)-2-(4-fluoro-
phenyl)-3-tosylimidazolidine-4,4-dicarboxylate (3ca)
Yield: 165.1 mg (65%); white solid; mp 83–86 °C.
IR (neat): 2952, 1753, 1602, 1509, 1492, 1453, 1415, 1348, 1284,
1225, 1158, 1089, 1049, 1015, 977, 939, 906 cm–1.
1H NMR (400 MHz, CDCl3): δ (trans/cis, 10:1) = 7.39 (d, J =
7.6 Hz, 2 H), 7.21–7.36 (m, 7 H), 7.13 (d, J = 7.2 Hz, 2 H), 6.93 (d,
J = 7.6 Hz, 2 H), 6.68–6.81 (m, 4 H), 6.06 (s, 1 H), 4.97 (s, 1 H),
3.91 (s, 3 H), 3.70 (s, 3 H), 3.54 (d, J = 15.2 Hz, 1 H), 2.70 (d, J =
15.2 Hz, 1 H), 2.29 (s, 3 H).
MS (ESI): m/z = 661.2 [M + H+].
HRMS: m/z calcd for C36H38ClN2O6S+: 661.2147; found: 661.2134.
(2S*,5R*)-Diethyl 1-Benzyl-2-(4-bromophenyl)-5-(4-chloro-
phenyl)-3-tosylimidazolidine-4,4-dicarboxylate (3ga)
Yield: 237.8 mg (82%); white solid; mp 109–112 °C.
1
13C NMR (100 MHz, CDCl3): δ = 168.2, 166.5, 162.8 (d, JC–F
=
246.0 Hz), 143.2, 137.3, 136.9, 135.0, 132.5, 131.5, 130.9 (d,
4
3JC–F = 8.0 Hz), 130.1, 128.6 (d, JC–F = 6.0 Hz), 128.4, 127.9,
IR (neat): 2978, 2361, 2343, 1756, 1737, 1490, 1597, 1346, 1272,
1299, 1200, 1160, 1090, 1048, 1010, 939, 925 cm–1.
127.4, 127.2, 114.7 (d, 2JC–F = 21.0 Hz), 78.1, 77.5, 72.1, 53.4, 52.9,
49.5, 21.3.
MS (ESI): m/z = 637.2 [M + H+].
HRMS: m/z calcd for C33H31ClFN2O6S+: 637.1579; found:
637.1570.
1H NMR (400 MHz, CDCl3): δ (trans/cis, 14:1) = 7.39 (d, J =
7.2 Hz, 2 H), 7.21–7.46 (m, 7 H), 7.08–7.20 (m, 4 H), 6.94 (d, J =
7.2 Hz, 2 H), 6.67 (d, J = 7.2 Hz, 2 H), 5.97 (s, 1 H), 4.93 (s, 1 H),
4.34–4.48 (m, 2 H), 4.15–4.28 (m, 1 H), 3.96–4.10 (m, 1 H), 3.56
(d, J = 15.2 Hz, 1 H), 2.73 (d, J = 15.2 Hz, 1 H), 2.32 (s, 3 H), 1.36
(t, J = 6.0 Hz, 3 H), 1.23 (t, J = 6.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.8, 165.8, 143.3, 137.2, 136.9,
135.0, 134.7, 132.6, 130.8, 130.3, 128.6, 128.5, 128.4, 128.1, 127.4,
127.2, 122.6, 78.0, 77.6, 72.1, 62.8, 62.3, 49.4, 21.4, 14.0, 13.7.
(2S*,5R*)-Dimethyl 1-Benzyl-2,5-bis(4-chlorophen-yl)-3-tosyl-
imidazolidine-4,4-dicarboxylate (3da)
Yield: 236.8 mg (91%); white solid; mp 89–94 °C.
IR (neat): 3052, 2952, 2842, 1753, 1597, 1491, 1453, 1435, 1414,
1285, 1209, 1162, 1089, 1052, 1014, 978, 941, 906 cm–1.
MS (ESI): m/z = 725.1 [M + H+].
HRMS: m/z calcd for C35H35BrClN2O6S+: 725.1115; found:
1H NMR (400 MHz, CDCl3): δ (trans/cis, 13:1) = 7.38 (d, J =
7.6 Hz, 2 H), 7.30 (d, J = 7.6 Hz, 4 H), 7.25 (d, J = 8.0 Hz, 3 H),
7.13 (d, J = 6.4 Hz, 2 H), 6.99 (d, J = 7.6 Hz, 2 H), 6.94 (d, J =
7.2 Hz, 2 H), 6.72 (d, J = 7.2 Hz, 2 H), 6.02 (s, 1 H), 4.97 (s, 1 H),
3.92 (s, 3 H), 3.69 (s, 3 H), 3.55 (d, J = 15.2 Hz, 1 H), 2.71 (d, J =
15.2 Hz, 1 H), 2.31 (s, 3 H).
725.1082.
(2S*,5R*)-Diisopropyl 1-Benzyl-2-(4-bromophenyl)-5-(4-chlo-
rophenyl)-3-tosylimidazolidine-4,4-dicarboxylate (3ha)
Yield: 262.5 mg (87%); white solid; mp 66–69 °C.
13C NMR (100 MHz, CDCl3): δ = 168.3, 166.4, 143.4, 137.2, 136.8,
135.1, 134.5, 134.2, 132.4, 130.5, 130.1, 128.64, 128.59, 128.4,
128.0, 127.9, 127.4, 127.2, 78.0, 77.5, 72.2, 53.4, 52.9, 49.5, 21.4.
MS (ESI): m/z = 653.1 [M + H+].
HRMS: m/z calcd for C33H31Cl2N2O6S+: 653.1276; found:
IR (neat): 2982, 1760, 1740, 1596, 1490, 1453, 1414, 1374, 1348,
1282, 1229, 1212, 1159, 1103, 1035, 1012, 943, 906 cm–1.
1H NMR (400 MHz, CDCl3): δ (trans/cis, 20:1) = 7.35–7.48 (m,
4 H), 7.20–7.32 (m, 5 H), 7.13 (t, J = 7.8 Hz, 4 H), 6.95 (d, J =
7.6 Hz, 2 H), 6.67 (d, J = 7.6 Hz, 2 H), 5.89 (s, 1 H), 5.14–5.36 (m,
1 H), 4.89–5.13 (m, 1 H), 4.89 (s, 1 H), 3.54 (d, J = 15.2 Hz, 1 H),
2.72 (d, J = 15.2 Hz, 1 H), 2.32 (s, 3 H), 1.37 (d, J = 6.0 Hz, 6 H),
1.32 (d, J = 6.4 Hz, 3 H), 1.05 (d, J = 6.0 Hz, 3 H).
653.1274.
Synthesis 2012, 44, 2147–2154
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of Multisubstituted Imidazolidines
2153
13C NMR (100 MHz, CDCl3): δ = 167.4, 165.3, 143.2, 137.2, 136.9,
134.8, 134.6, 132.6, 130.7, 128.5, 128.4, 128.3, 128.2, 127.4, 127.1,
122.5, 77.8, 71.7, 70.9, 70.6, 49.3, 21.8, 21.64, 21.56, 21.4, 21.2.
(2S*,5R*)-Diisopropyl 1-Benzyl-5-(4-chlorophenyl)-2-phenyl-
3-tosylimidazolidine-4,4-dicaboxylate (3ja)
Yield: 243.5 mg (90%); white solid; mp 113–118 °C.
MS (ESI): m/z = 753.1 [M + H+].
HRMS: m/z calcd for C37H39BrClN2O6S+: 753.1407; found:
IR (neat): 2983, 2925, 1750, 1730, 1597, 1493, 1455, 1414, 1375,
1338, 1283, 1223, 1207, 1160, 1090, 1038, 944, 905 cm–1.
1H NMR (400 MHz, CDCl3): δ (trans/cis, 20:1) = 7.48 (d, J =
8.0 Hz, 2 H), 7.40 (d, J = 7.6 Hz, 2 H), 7.18–7.32 (m, 5 H), 7.08–
7.20 (m, 3 H), 7.02 (t, J = 7.4 Hz, 2 H), 6.89 (d, J = 7.6 Hz, 2 H),
6.79 (d, J = 7.6 Hz, 2 H), 5.97 (s, 1 H), 5.23–5.35 (m, 1 H), 4.86–
4.98 (m, 2 H), 3.50 (d, J = 15.2 Hz, 1 H), 2.72 (d, J = 15.2 Hz, 1 H),
2.24 (s, 3 H), 1.26–1.40 (m, 9 H), 1.05 (d, J = 6.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.3, 165.5, 142.6, 137.32,
137.27, 135.5, 134.6, 132.8, 130.9, 128.8, 128.3, 128.22, 128.16,
128.1, 127.6, 127.3, 126.9, 78.4, 77.7, 71.3, 70.6, 70.4, 49.1, 21.7,
21.6, 21.5, 21.2, 21.1.
753.1395.
(2S*,5R*)-Dimethyl 1-Benzyl-2,5-diphenyl-3-tosyl Imidazoli-
dine-4,4-dicarboxylate (3ie)
Yield: 204.8 mg (88%); white solid; mp 188–194 °C.
IR (neat): 3028, 2957, 1760, 1737, 1597, 1494, 1291, 1229, 1211,
1091, 1048, 1030, 976, 951, 918 cm–1.
1H NMR (400 MHz, CDCl3): δ (trans/cis, 8:1) = 7.42–7.50 (m,
2 H), 7.26–7.35 (m, 5 H), 7.18–7.26 (m, 3 H), 7.17 (d, J = 6.8 Hz,
3 H), 7.05 (t, J = 7.4 Hz, 2 H), 6.88 (d, J = 8.0 Hz, 2 H), 6.82 (d, J =
7.2 Hz, 2 H), 6.09 (s, 1 H), 5.07 (s, 1 H), 3.89 (s, 3 H), 3.66 (s, 3 H),
3.59 (d, J = 15.2 Hz, 1 H), 2.72 (d, J = 15.2 Hz, 1 H), 2.26 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.3, 166.7, 142.8, 137.53,
137.47, 135.8, 134.0, 129.1, 128.9, 128.4, 128.34, 128.28, 128.2,
127.9, 127.8, 127.5, 126.9, 78.8, 77.6, 72.7, 53.2, 52.7, 49.4, 21.3.
MS (ESI): m/z = 675.2 [M + H+].
HRMS: m/z calcd for C37H40ClN2O6S+: 675.2322; found: 675.2290.
Three-Component Reaction Performed on a Gram Scale
In a flame-dried nitrogen-flushed flask, a solution of BnNH2 (0.56
g, 6 mmol), p-chlorobenzaldehyde (0.84 g, 6 mmol) and 4 Å MS (1
g) in anhydrous DCE (30 mL) was stirred for 1 h. Aziridine 1a (2.34
g, 5 mmol) and Y(OTf)3 (134.03 mg, 5 mol%) were added to this
mixture, which was stirred at r.t. for 15 h. After filtration to remove
the MS, the solution was concentrated under reduced pressure. The
crude product was purified by flash chromatography to afford 3aa
MS (ESI): m/z = 585.2 [M + H+].
HRMS: m/z calcd for C33H33N2O6S+: 585.2067; found: 585.2054.
(2S*,5R*)-Dimethyl 1-Benzyl-5-(4-chlorophenyl)-2-phenyl-3-
tosylimidazolidine-4,4-dicarboxylate (3ia)
Yield: 215.1 mg (87%); white solid; mp 168–171 °C.
(2.89 g, 83%), the identity of which was confirmed by 1H and 13
NMR spectroscopic analysis.
C
IR (neat): 2947, 2926, 2860, 1758, 1597, 1493, 1457, 1437, 1380,
1345, 1291, 1281, 1228, 1205, 1161, 1135, 1088, 1058, 1014, 980,
944, 921 cm–1.
Asymmetric Cycloaddition of 1a with 2c
In an inert atmosphere, a flame-dried vial was charged with a mag-
netic stir bar, activated 4Å molecular sieves (100 mg), Y(OTf)3
(5.40 mg, 5 mol%), t-Bu-Pybox (3.95 mg, 6 mol%) and DCE (2
mL). The mixture was stirred at r.t. for 3 h, then imine 2c (66.1 mg,
0.3 mmol, 1.5 equiv) was added, followed by aziridine 1a (93.48
mg, 0.2 mmol, 1.0 equiv). The mixture was stirred at r.t. until com-
plete consumption of the aziridine was observed (reaction moni-
tored by TLC analysis). The reaction mixture was then passed over
a small plug of silica gel, eluted with CH2Cl2. After evaporation un-
der reduced pressure, the resulting product was purified by flash
chromatography to afford the product 3ac (91.8 mg, 67%). The en-
antiomeric excess was determined by chiral HPLC analysis [Chiral-
cel OD-H; hexane–i-PrOH, 75:25; 0.8 mL/min; Rt = 16.19 (minor),
13.09 (major) min]: ee = 49%.
1H NMR (400 MHz, CDCl3): δ (trans/cis, 11:1) = 7.42 (d, J =
8.0 Hz, 2 H), 7.26–7.35 (m, 5 H), 7.13–7.24 (m, 5 H), 7.05 (t, J =
7.2 Hz, 2 H), 6.88 (d, J = 7.6 Hz, 2 H), 6.79 (d, J = 7.6 Hz, 2 H),
6.09 (s, 1 H), 5.03 (s, 1 H), 3.89 (s, 3 H), 3.70 (s, 3 H), 3.52 (d, J =
15.2 Hz, 1 H), 2.73 (d, J = 15.2 Hz, 1 H), 2.26 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 168.1, 166.7, 142.9, 137.3, 137.2,
135.5, 134.9, 132.6, 130.3, 129.0, 128.5, 128.4, 128.2, 128.0,
127.84, 127.81, 127.4, 127.0, 78.8, 77.4, 71.9, 53.2, 52.9, 49.4,
21.3.
MS (ESI): m/z = 619.2 [M + H+].
HRMS: m/z calcd for C33H32ClN2O6S+: 619.1678; found: 619.1664.
Dimethyl 1-Benzyl-5-(4-methoxyphenyl)-2-phenyl-3-tosylimid-
azolidine-4,4-dicarboxylate (3ig)
Yield: 220.8 mg (90%); white solid; dr = 4:1 (trans/cis).
Acknowledgment
IR (neat): 2953, 2933, 2861, 2841, 1781, 1756, 1734, 1613, 1513,
1456, 1440, 1339, 1305, 1285, 1253, 1228, 1212, 1155, 1091, 1059,
1031, 986, 950, 936 cm–1.
1H NMR (400 MHz, CDCl3): δ (trans isomer) = 6.75–7.55 (m,
18 H),* 6.08 (s, 1 H), 4.99 (s, 1 H), 3.89 (s, 3 H), 3.76 (s, 3 H), 3.71
(s, 3 H), 3.52–3.64 (m, 1 H),* 2.69 (d, J = 15.2 Hz, 1 H), 2.46 (s,
3 H). δ (cis isomer) = 6.75–7.55 (m, 18 H),* 5.34 (s, 1 H), 4.56 (s,
1 H), 3.81 (s, 6 H), 3.46–3.64 (m, 1 H),* 3.37 (d, J = 14.8 Hz, 1 H),
3.31 (s, 3 H), 2.27 (s, 3 H). * Peaks overlap with those of the other
isomer.
We are grateful to NSFC (20972054), the Ministry of Education of
China (20090076110007, NCET), and the 973 program
(2009CB825300) for financial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.omnorinIftangonmSorniuifIatoprtngiSutpor
References
13C NMR (100 MHz, CDCl3): δ = 168.6, 168.3, 167.0, 166.8, 160.1,
159.9, 142.7, 142.2, 138.0, 137.6, 137.5, 135.8, 135.5, 133.2, 131.1,
130.0, 129.1, 129.0, 128.4, 128.3, 128.2, 128.1, 128.03, 127.96,
127.9, 127.8, 127.7, 127.44, 127.37, 126.8, 125.6, 113.7, 79.7, 78.7,
77.4, 76.8, 72.3, 71.7, 55.2, 55.1, 53.1, 52.7, 52.3, 50.0, 49.2, 29.6,
21.3.
MS (ESI): m/z = 615.2 [M + H+].
HRMS: m/z calcd for C34H35N2O7S+: 615.2169; found: 615.2160.
(1) For reviews on Lewis acid catalyzed cycloaddition of donor-
acceptor cyclopropanes, see: (a) Reissig, H.-U.; Zimmer, R.
Chem. Rev. 2003, 103, 1151. (b) Yu, M.; Pagenkopf, B. L.
Tetrahedron 2005, 61, 321. (c) Xiao, Y.; Zhang, J. In
Handbook of Cyclization Reactions, Vol. 2; Ma, S., Ed.;
Wiley-VCH: Weinheim, 2010, 733. (d) Young, I. S.; Kerr,
M. A. Angew. Chem. Int. Ed. 2003, 42, 3023. (e) Sibi, M. P.;
Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2005, 127, 5764.
(f) Young, I. S.; Kerr, M. A. J. Am. Chem. Soc. 2007, 129,
1465. (g) Kang, Y.-B.; Sun, X.-L.; Tang, Y. Angew. Chem.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2147–2154

2154
X. Wu, J. Zhang
SPECIAL TOPIC
Int. Ed. 2007, 46, 3918. (h) Jackson, S. K.; Karadeolian, A.;
Driega, A. B.; Kerr, M. A. J. Am. Chem. Soc. 2008, 130,
4196. (i) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li,
W.; Johnson, J. S. J. Am. Chem. Soc. 2008, 130, 8642.
(j) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009,
131, 3122.
Chem. 2005, 70, 8242. (e) Kang, Y. B.; Tang, Y.; Sun, X.-L.
Org. Biomol. Chem. 2006, 4, 299. (f) Parsons, A. T.; Smith,
A. G.; Neel, A. J.; Johnson, J. S. J. Am. Chem. Soc. 2010,
132, 9688.
(9) For cycloaddition reactions of azomethine ylides to imines,
see: (a) Amornraksa, K.; Barr, D.; Donegan, G.; Grigg, R.;
Ratananukul, P.; Sridharan, V. Tetrahedron 1989, 45, 4649.
(b) Groundwater, P. W.; Sharif, T.; Arany, A.; Hibbs, D. E.;
Hursthouse, M. B.; Garnett, I.; Nyerges, M. J. Chem. Soc.,
Perkin Trans. 1 1998, 2837. (c) Erkizia, E.; Aldaba, E.;
Vara, Y.; Arrieta, A.; Gornitzka, H.; Cossio, F. P. ARKIVOC
2005, (ix), 189. (d) Xie, H.; Zhu, J.; Chen, Z.; Li, S.; Wu, Y.
J. Org. Chem. 2010, 75, 7468.
(10) (a) Berlinck, R. G. S.; Burtoloso, A. C. B.; Kossuga, M. H.
Nat. Prod. Rep. 2008, 25, 919. (b) Berlinck, R. G. S.;
Kossuga, M. H. Nat. Prod. Rep. 2005, 22, 516. (c) Pejchal,
V.; Stepankova, S.; Padelkova, Z.; Imramovsky, A.;
Jampilek, J. Molecules 2011, 16, 7565. (d) De Luca, L. Curr.
Med. Chem. 2006, 13, 1. (e) Haneda, S.; Okui, A.; Ueba, C.;
Hayashi, M. Tetrahedron 2007, 63, 2414. (f) Nicolaou, K.
C.; Mathison, C. J. N.; Montagnon, T. Angew. Chem. Int. Ed.
2003, 42, 4077. (g) Mohammadpoor-Baltork, I.; Zolfigol,
M. A.; Abdollahi-Aibeik, M. Synlett 2004, 2803.
(2) (a) Huisgen, R.; Scheer, W.; Mader, H. Angew. Chem., Int.
Ed. Engl. 1969, 8, 602. (b) Wiberg, K. B. In The Chemistry
of Cyclobutanes, Part I; Rappoport, Z.; Liebman, J. F., Eds.;
John Wiley & Sons Ltd: Chichester, 2005, 4.
(3) (a) Kametani, T.; Honda, T. Advances in Heterocyclic
Chemistry 1986, 39, 181. (b) Pearson, W. H.; Lian, B. W.;
Bergmeier, S. C. In Comprehensive Heterocyclic Chemistry
II, Vol. 1A; Padwa, A., Ed.; Pergamon Press: Oxford, 1996,
1. (c) Rai, K. M. L.; Hassner, A. In Comprehensive
Heterocyclic Chemistry II, Vol. 1A; Padwa, A., Ed.;
Pergamon Press: Oxford, 1996, 61. (d) Zhou, P.; Chen,
B.-C.; Davis, F. A. In Aziridines and Epoxides in Organic
Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006,
87.
(4) (a) Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159.
(b) Heimgartner, H.; Mloston, G. In Electronic
Encyclopedia of Reagents in Organic Synthesis [Online];
Paquette, L.; Rigby, J.; Crich, D.; Wipf, P., Eds.; John Wiley
& Sons: Chichester, 2004, Article RN0042. (c) Mloston, G.;
Urbaniak, K.; Heimgartner, H. Helv. Chim. Acta 2002, 85,
2056. (d) Vaultier, M.; Danion-Bougot, R.; Tonnard, F.;
Carrie, R. Bull. Soc. Chim. Fr. 1985, 5, 803. (e) Mamoun,
O.; Benhaoua, H. Bull. Soc. Chim. Fr. 1994, 103, 753.
(f) Vebrel, J.; Cerutti, E.; Carrie, R. C. R. Seances Acad. Sci.,
Ser. C 1979, 288, 265. (g) Grabowsky, S.; Pfeuffer, T.;
Morgenroth, W.; Paulmann, C.; Schirmeister, T.; Luger, P.
Org. Biomol. Chem. 2008, 6, 2295. (h) Grabowsky, S.;
Pfeuffer, T.; Checinska, L.; Weber, M.; Morgenroth, W.;
Luger, P.; Schirmeister, E. J. Org. Chem. 2007, 17, 2759.
(i) Schirmeister, T. Liebigs Ann. 1997, 9, 1895. (j) Person,
H.; Luanglath, K.; Baudru, M.; Foucaud, A. Bull. Soc. Chim.
Fr. 1976, 11, 1989. (k) Pankova, A. S.; Voronin, V. V.;
Kuznetsov, M. A. Tetrahedron Lett. 2009, 50, 5990.
(5) For Lewis acid promoted C–C bond cleavage of N-aryl-
aziridine dicarboxylates leading to azomethine ylides, see:
(a) Vaultier, M.; Carrie, R. Tetrahedron Lett. 1978, 1195.
(b) Pohlhaus, P. D.; Bowman, R. K.; Johnson, J. S.
J. Am. Chem. Soc. 2004, 126, 2294.
(h) Ishihara, M.; Togo, H. Synlett 2006, 227. (i) Huh, D. H.;
Ryu, H.; Kim, Y. G. Tetrahedron 2004, 60, 9857. (j) Bellina,
F.; Cauteruccio, S.; Fiore, A. D.; Marchetti, C.; Rossi, R.
Tetrahedron 2008, 64, 6060. (k) Lucet, D.; Le Gall, T.;
Mioskowski, C. Angew. Chem. Int. Ed. 1998, 37, 2580.
(l) Cardona, F.; Goti, A. Nat. Chem. 2009, 1, 269.
(11) For synthesis of N-tosylaziridine dicarboxylates, see:
(a) Fan, R.; Ye, Y. Adv. Synth. Catal. 2008, 350, 1526.
(b) Fan, R. Wang L.; Ye, Y.; Zhang, J. Tetrahedron Lett.
2009, 50, 3857.
(12) (a) Derdau, V.; Snieckus, V. J. Org. Chem. 2011, 66, 1992.
(b) Silva-Filho, L. C.; Júnior, V. L.; Constantino, M. G.; José
da Silva, G. V. Synthesis 2008, 2527.
(13) CCDC 867532 (trans-3aa) contains the supplementary
crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(14) For selected examples using t-Bu-Pybox as chiral ligand for
enantioselective catalysis, see: (a) Evans, D. A.; Murry, J.
A.; Matt, P.; Norcross, R. D.; Miller, S. J. Angew. Chem. Int.
Ed. 1995, 34, 798. (b) Schaus, S. E.; Jacobsen, E. N. Org.
Lett. 2000, 2, 1001. (c) Clark, J. S.; Clarke, M.; Clough, J.;
Blakea, A. J.; Wilsona, C. Tetrahedron Lett. 2004, 45, 9447.
(d) Wang, J.; Shao, Z.; Ding, K.; Yu, W. Y.; Chan, A. C. S.
Adv. Synth. Catal. 2009, 351, 1250. (e) Kawatsura, M.;
Kajita, K.; Hayase, S.; Itoh, T. Synlett 2010, 889.
(15) (a) Chen, Z.; Wei, L.; Zhang, J. Org. Lett. 2011, 13, 1170.
(b) Wang, T.; Zhang, J. Chem.–Eur. J. 2011, 17, 86.
(c) Wang, T.; Zhang, J. Chem. Commun. 2011, 47, 5578.
(d) Zhang, J.; Chen, Z.; Wu, H.-H.; Zhang, J. Chem.
Commun. 2012, 48, 1817. (e) Wei, L.; Zhang, J. Chem.
Commun. 2012, 48, 2636.
(6) Paasche, A.; Arnone, M.; Fink, R. F.; Schirmeister, T.;
Engels, B. J. Org. Chem. 2009, 74, 5244.
(7) (a) Li, L.; Wu, X.; Zhang, J. Chem. Commun. 2011, 47,
5049. (b) Wu, X.; Li, L.; Zhang, J. Chem. Commun. 2011,
47, 7824. (c) Li, L.; Zhang, J. Org. Lett. 2011, 13, 5940.
(d) Jiang, Z.; Wang, J.; Lu, P.; Wang, Y. Tetrahedron 2011,
67, 9609.
(8) (a) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.;
Carreira, E. M. Angew. Chem. Int. Ed. 1999, 38, 3186.
(b) Lerchner, A.; Carreira, E. M. J. Am. Chem. Soc. 2002,
124, 14826. (c) Meyers, C.; Carreira, E. M. Angew. Chem.
Int. Ed. 2003, 42, 694. (d) Carson, C. A.; Kerr, M. A. J. Org.
Synthesis 2012, 44, 2147–2154
© Georg Thieme Verlag Stuttgart · New York