Organocatalytic asymmetric Mannich-type reaction of N-sulfonylimines with isocyanoacetate leading to optically active 2-imidazoline-4-carboxylates

Article abstract of DOI:10.1016/j.tetasy.2010.04.029

The first asymmetric Mannich-type reaction of methyl isocyanoacetate with N-sulfonylimines catalyzed by cinchona alkaloid derivatives yielded 2-imidazolines with high diastereoselectivities and good enantioselectivities (up to >99:1 dr and 70% ee). This reaction provided a convenient route to access various substituted 2-imidazoline-4-carboxylates and related α,β-diamino acids in high enantiomeric purities.

Full text of DOI:10.1016/j.tetasy.2010.04.029

Tetrahedron: Asymmetry 21 (2010) 1715–1721
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Tetrahedron: Asymmetry
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Organocatalytic asymmetric Mannich-type reaction of N-sulfonylimines
with isocyanoacetate leading to optically active 2-imidazoline-4-carboxylates
a
a
a
b
Zhen-Wei Zhang a, Gui Lu a, , Miao-Miao Chen , Ning Lin , Yong-Bo Li , Tamio Hayashi ,
*
Albert S. C. Chan a,c,
*
a Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China
b Department of Chemistry, Faculty of Science, Kyoto University, Sakyo, Kyoto 606-01, Japan
c Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first asymmetric Mannich-type reaction of methyl isocyanoacetate with N-sulfonylimines catalyzed
by cinchona alkaloid derivatives yielded 2-imidazolines with high diastereoselectivities and good enanti-
oselectivities (up to >99:1 dr and 70% ee). This reaction provided a convenient route to access various
Received 29 March 2010
Accepted 13 April 2010
Available online 24 May 2010
substituted 2-imidazoline-4-carboxylates and related
a
,b-diamino acids in high enantiomeric purities.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
1. Introduction
This reaction can also be conducted in multi-component form
with in situ generated imines, whereas no asymmetric version
has been developed until now.12–14
The construction of 2-imidazolines has received considerable
attention because of their wide applications in the synthesis of bio-
Recently, organocatalytic systems have been developed and
they sometimes challenged the metal-catalyzed systems. In partic-
ular, the use of cinchona alkaloids has been successfully applied in
various organocatalytic transformations.15–33 To the best of our
knowledge, there has been no report on the organocatalytic asym-
metric cyclization of general isocyanoacetates and imines,
although several examples can be used for references. Jorgensen
et al. performed the highly enantioselective and diastereoselective
logically active compounds such as
a,b-diamino acids and also
their presence in biologically active natural products.1,2 The Man-
nich-type reaction of imines with isocyanocarboxylates is an
important method for accessing useful substituted 2-imidazoline
compounds2 and has been previously performed using gold, ruthe-
nium, and copper catalysts.
The base-promoted Mannich-type reaction was first reported
by Schöllkoptf et al.3 and van Leusen et al.4 in 1977. In 1996 Hay-
ashi et al. realized the Au(I)-catalyzed diastereoselective Mannich-
type reaction of isocyanoacetate with N-sulfonylimines in quanti-
tative yields and >90:10 cis selectivity.5 Lin et al. found that the
trans isomer of 2-imidazolines could be formed preferably with
95:5 selectivity in the presence of RuH2(PPh3)4 catalyst.6 Other cat-
alysts such as NHC–CuCl7 and pincer-Pd(II)8 compounds were also
developed recently for 2-imidazoline synthesis with trans
selectivity.
Mannich reaction of
protected -amino esters with cinchona alkaloid 1 (Fig. 1) as an
organocatalyst.30 Gong et al. reported an organocatalytic asymmet-
ric aldol-reaction of -aryl isocyanoacetates with various alde-
a-aryl-substituted cyanoacetates and N-Boc-
a
a
hydes, providing optically active oxazolines with good
stereoselectivities (up to 18:1 dr and 90% ee) by using cinchona
alkaloid 2 as a catalyst.31 For relatively inert imine substrates
and the significantly decreased
a-H acidity of methyl isocyanoace-
tate substrate (compared with
a-aryl-substituted isocyanoace-
The first enantioselective reaction was achieved by Lin in 1999,
using Me2SAuCl and ferrocene-derived diphosphine ligand to af-
ford 88% ee.9,10 In 2008, Szabó et al. also reported another asym-
metric synthesis with a chiral pincer-Pd(II) catalyst and obtained
98% yield and 86% ee for the cis isomer.11
tate),32,33 the development of highly efficient organocatalytic
Mannich-type reactions leading to chiral 2-imidazolines, a class
of medicinally relevant heterocycles, is an important challenge.
Herein we disclosed the first asymmetric catalytic Mannich-
type reaction of methyl isocyanoacetate with N-sulfonylimines
by cinchona alkaloid derivatives to yield 2-imidazolines with high
diastereoselectivities and good enantioselectivities (up to >99:1 dr
and 70% ee). This reaction provided a convenient method to access
various substituted 2-imidazolines and related
in high enantiomeric purities.
a,b-diamino acids
* Corresponding authors. Tel./fax: +86 20 39943048 (G.L.).
E-mail address: lugui@mail.sysu.edu.cn (G. Lu).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.029

1716
Z.-W. Zhang et al. / Tetrahedron: Asymmetry 21 (2010) 1715–1721
Et
N
Et
Ph
N
N
O
O
COO
N
MeO
N
OMe
HO
Ph
N
N
N
1
2
Figure 1. Some cinchona alkaloids for organocatalytic transformations.
PG
N
H2N
PG
R
chiral base (B*)
N
R
*
N
COOMe
R
H2N
*
*
C
N
*
COOH
COOMe
B*
PG
PG
R
N
N
R
C
*
N
*
N
COOMe
C
or
COOMe
*B
O
H
PG
N
(OH or NH in B* forms a hydrogen bond with the imine)
R
Scheme 1. Possible mechanism for the Mannich-type reaction.
Table 1
Screening of organic bases for the reaction of N-Ts imine 3a and methyl isocyanoacetate 4a
organic base
Ts
N
Ts
N
Ts
N
(20 mol%)
CN
COOMe
DCM
r.t.
N
N
MeOOC
cis-5a
MeOOC
trans-5a
4
3a
Entry
Organic base
Time (h)
Yieldb (%)
drc (trans/cis)
1
2
3
4
5
6
Et3N
DBU
DMAP
DABCO
iPr2EtN
(ꢀ)-Sparteine
11
2
25
9
24
2
65
83
70
76
70
82
89/11
95/5
91/9
88/12
82/18
83/17
a
b
c
Reaction conditions: 3a (0.20 mmol), 4 (0.22 mmol), DCM (1 mL). Reaction time was determined by TLC.
Isolated yield of the two isomers after silica gel column chromatography.
Determined by 1H NMR analysis.
Initially experiments of the Mannich-type reaction of methyl
isocyanoacetate 4 with N-p-toluenesulfonylimine 3a were carried
out in the presence of 20 mol% of an organic base. With dichloro-
methane as a solvent, various tertiary amines such as Et3N, DBU,
DMAP, DABCO, i-Pr2EtN, and (ꢀ)-sparteine have been examined
for comparison. In all cases, the reaction proceeded smoothly, giv-
ing the trans product of 2-imidazoline 5a selectively in good yield.
The results are summarized in Table 1. The highest yield (83%) and
diastereoselectivity (95:5 dr) were achieved with a strong base
(DBU, entry 2). Other tertiary amines afforded good yields but with
slightly lower diastereoselectivities. In the absence of any base cat-
2. Results and discussions
2.1. Optimization of the reaction conditions
Encouraged by Gong’s work,31,33 we speculated a possible
mechanism for the Mannich-type reaction catalyzed by a chiral
base (Scheme 1). The chiral base could activate the acidic a-carbon
atom of isocyanoacetate, hence promoting the asymmetric Man-
nich addition of the isocyanoacetate to imines. Subsequent intra-
molecular cyclization afforded 2-imidazoline-4-carboxylate,
which could be converted into a,b-diamino acids after hydrolysis.

Z.-W. Zhang et al. / Tetrahedron: Asymmetry 21 (2010) 1715–1721
1717
HO
N
HO
N
RO
N
MeO
HO
N
N
N
Q-1, R = Ac
Q-2, R = Bz
Q-3, R = Bn
Cinchonidine CD
Quinine Q
RO
N
HO
N
HO
N
HO
MeO
N
N
N
Cinchonine C
Quinidine QD
QD-4 ,R = H
QD-5, R = Ac
Figure 2. Cinchona alkaloid-derived catalysts tested in this study.
alyst, the reaction did not take place under otherwise identical
conditions.
the additive, 56% yield of 2-imidazoline with 91:9 diastereoselec-
tivity and 61% enantioselectivity was obtained (entry 17). The
above-mentioned reaction conditions were then employed in sub-
sequent studies.
Varying the protecting group of the imine has a dramatic impact
on both the rate and asymmetric induction. A strong electron-
withdrawing group such as tosyl was quite necessary for the acti-
vation of the C@N bond to afford the corresponding 2-imidazoline
in good yield and diastereoselectivity, while N-PMP or N-Bn pro-
tected imines led to only trace amounts of the products even after
7 days.
2-Imidazoline 5a was converted to 6a by hydrolysis. The
absolute configuration of 6a was determined to be (2R,3S) by
comparison of the order of peak elution from HPLC analyses
with the literature.11 Thus the absolute configuration of major
trans-5a was assigned as (4R,5S) while major cis-5a was assigned
as (4S,5S).
The condensation reaction of 3a with 4 in the presence of cata-
lytic amounts of Q and QD was found to be complete within 6 h
(Table 2, entries 1 and 2), indicating that the catalytic activity of
Q and QD in this process was much higher than 9-protected Q
(Q1-3, entries 5–7) and QD (QD4-5, entries 8 and 9), which re-
quired at least 35 h to complete the reaction. We reasoned that
the stronger Brønsted basicities of Q and QD accelerated the
reaction.
We also monitored the progress of the catalytic reaction in or-
der to gain some mechanistic insights into the condensation reac-
tions. It appeared that the trans/cis ratio and the ee for the trans
isomer were increased very slightly in the reaction system (Ta-
ble 3), high trans selectivity (trans/cis ratio 84:16) was obtained
at the beginning of the reaction (entry 1). No isomerization of
cis-5a to trans-5a was observed at the first 6 h when cis-5a was
treated under the reaction conditions, which revealed that the ste-
reoselectivity of the process was not coming from the isomeriza-
tion of the thermodynamically less stable cis-imidazoline, but
from the induction of the chiral organocatalyst. However, long
reaction times caused partial isomerization of cis-5a (trans/cis
12:88 after 24 h).
When (ꢀ)-sparteine was used as the chiral base in this reaction,
trans-5a was obtained but in almost racemic form. Therefore, we
turned our attention to cinchona alkaloid derivatives which have
been reported as efficient organocatalysts for many asymmetric
nucleophilic addition reactions. It was anticipated that activation
of the less active methyl isocyanoacetate by deprotonation, fol-
lowed by the subsequent cycloaddition of isocyanoesters to imines
would provide optically active 2-imidazolines.
In the presence of 20 mol % of commercially available cinchona
alkaloid Q (Fig. 2), N-Ts imine 3a reacted with methyl isocyanoac-
etate 4 to afford the desired 2-imidazoline 5a in good yield and
high diastereoselectivity, but no enantioselectivity (Table 2, entry
1). Other commercially available cinchona alkaloids showed simi-
lar results (entries 1–4). The stereochemical discrimination could
be markedly improved by using cinchona alkaloids bearing two
or more activating functionalities such as Q-1 or QD-5 (entries 5
and 9). The introduction of a hydroxyl group at the 60-position
helped to form an additional hydrogen bond with the substrate,
while 9-OAc group provided proper steric hindrance to ensure
higher enantioselectivity.
The effect of solvents on the catalytic Mannich-type reaction
was examined in the presence of QD-5 catalyst, and the results
are listed in Table 2 (entries 9–15). It appeared that toluene was
a suitable solvent with respect to reaction time, yield, diastereo-,
and enantioselectivity. Acetonitrile was effective in terms of dia-
stereoselectivity, while 1,4-dioxane afforded a higher yield with
longer reaction time. Adding 4 Å molecular sieves to the reaction
system led to a shorter reaction time and significantly higher
enantioselectivity (entry 16).
When the catalyst loading was varied from 20 to 5 mol %, a de-
crease in yield but comparable enantioselectivity could be ob-
served (entries 16–18). To balance both the yield and the
selectivity, we chose 10 mol % as the catalyst ratio. Thus the opti-
mal reaction conditions for the asymmetric Mannich-type reaction
of isocyanoacetate with imines have been established. Using
10 mol % QD-5 as a catalyst, toluene as a solvent, and 4 Å MS as

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Z.-W. Zhang et al. / Tetrahedron: Asymmetry 21 (2010) 1715–1721
Table 2
Mannich-type reaction of 3a and 4 with different chiral organocatalystsa
Ts
Ts
N
Ts
N
N
catalyst (x mol%)
CN
COOMe
+
solvent
r.t.
N
N
MeOOC
trans-5a
(4R,5S)
MeOOC
cis-5a
(4S,5S)
3a
4
water/conc.HCl/THF
Ts
NH
Ts
NH
+
NHCHO
NHCHO
MeOOC
(2R,3S)-6a
MeOOC
(2S,3S)-6a
þ f
Entry
Catalyst
Catalyst loading (mol %)
Solvent
Time (h)
Yieldb (%)
drc (trans/cis)
ee of transd
pKBH
1
2
3
4
5
6
7
8
Q
QD
C
CD
Q-1
Q-2
Q-3
QD-4
QD-5
QD-5
QD-5
QD-5
QD-5
QD-5
QD-5
QD-5
QD-5
QD-5
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
10
5
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeCN
THF
1,4-Dioxane
MeOH
Et2O
Toluene
Toluene
Toluene
Toluene
5
6
71
73
59
71
42
47
45
50
46
31
36
65
44
39
47
60
56
49
81/19
93/7
91/9
92/8
93/7
85/15
93/7
90/10
81/19
93/7
88/12
86/14
82/18
84/16
90/10
86/14
91/9
5
5
4
9.28
9.28
9.33
9.33
8.61
8.60
8.77
8.82
8.61
42
15
48
70
48
35
70
72
118
216
60
36
72
48
48
48
0
38
28
17
7
44
2
28
26
1
32
47
63
61
61
9
10
11
12
13
14
15
16e
17e
18e
84/16
a
b
c
d
e
f
Reaction conditions: 3a (0.20 mmol), 4 (0.22 mmol), solvent (1 mL). Reaction time was determined by TLC.
Isolated yields of the two isomers after silica gel column chromatography.
The dr was determined by 1H NMR.
The ee was determined by HPLC.
4 Å MS (200 mg) was added and the concentration of 3a was increased to 0.50 mol/L.
Refers to the dissociation constant of the protonated base in water, values were calculated with the use of Advanced Chemistry Development (ACD/Labs) Software V8.14
for Solaris (Ó 1994–2006 ACD/Labs).
Table 3
Formation of 5a from 3a and 4 catalyzed by QD-5a
Ts
N
Ts
N
Ts
N
10 mol% QD-5
CN
COOMe
toluene, 4Å MS, r.t.
N
N
MeOOC
cis-5a
(4S,5S)
MeOOC
trans-5a
(4R,5S)
3a
4
Entry
Time (h)
Yieldb (%)
drc (trans/cis)
ee of transd (%)
1
2
3
4
5
6
6
12
18
24
36
48
17
27
33
38
48
62
84/16
85/15
87/13
89/11
90/10
91/9
58 (36)
59 (41)
60 (43)
60 (45)
60 (47)
60 (48)
a
b
c
Reaction conditions: 3a (0.50 mmol), 4 (0.55 mmol), solvent (1 mL) and 4 Å MS (200 mg).
Isolated yields of the two isomers after silica gel column chromatography.
The dr was determined by 1H NMR.
d
The ee was determined by HPLC. Data in parenthesis are the ee of the cis isomer.

Z.-W. Zhang et al. / Tetrahedron: Asymmetry 21 (2010) 1715–1721
1719
Table 4
Mannich-type reaction of various N-Ts imines 3a–n and methyl isocyanoacetate 4a
Ts
N
Ts
R
N
10 mol% QD-5
CN
COOMe
R
toluene, 4Å MS, r.t.
N
MeOOC
3a-n
4
trans-5a-n
(4R,5S)
Entry
R
Product
Time (h)
Yieldb (%)
drc (trans/cis)
ee of transd (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Phenyl a
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
48
48
72
84
84
84
48
60
72
72
72
72
48
60
56
57
49
34
47
44
50
48
61
35
43
78
62
79
91/9
95/5
98/2
>99/1
>99/1
>99/1
96/4
95/5
94/6
91/9
92/8
98/2
95/5
95/5
61
70
68
50
50
38
48
48
5
62
58
53
18
52
4-Methylphenyl b
4-Methoxyphenyl c
3-Methoxyphenyl d
2-Methoxyphenyl e
2,5-Dimethoxyphenyl f
4-Chlorophenyl g
4-Bromophenyl h
4-Nitrophenyl i
4-Isopropylphenyl j
4-tert-Butylphenyl k
2-Naphthyl l
2-Furyl m
2-Thienyl n
a
b
c
Reaction conditions: 3 (0.50 mmol), 4 (0.55 mmol), toluene (1 mL). Reaction time was determined by TLC.
Isolated yields of the two isomers after silica gel column chromatography.
Determined by 1H NMR of the crude product.
d
Determined by HPLC after purification.
2.2. Scope and limitation of the catalytic system
addition offer promise for the synthesis of nitrogen-heterocyclic
compounds as well as useful a,b-diamino acids.
Next we investigated the scope of the imine substrates. A vari-
ety of aromatic and heteroaromatic imines were used in the Man-
nich-type reaction, affording the desired 2-imidazoline products in
good yields and stereoselectivities (Table 4). In all cases, trans 2-
imidazolines were obtained preferably (dr up to 99/1). The steric
effects of the aromatic rings of the imines on the enantioselectivity
of the reaction were significant. The less sterically hindered para-
methoxy-substituted imine afforded 68% ee for the preferable
trans-adduct, while both ortho- and meta-methoxy substituted
imines gave 50% ee (entries 3–5). Hindered 2,5-dimethoxy substi-
tuted imine offered only 38% ee (entry 6). In the presence of QD-5
organocatalyst, the highest enantioselectivity (70% ee) was
achieved in the condensation reaction of imine 3b and methyl iso-
cyanoester 4 (entry 2).
We also found that the enantioselectivity was affected by the
electronic properties of the substituents on the phenyl rings of
the imines. For example, a strong electron-withdrawing para-NO2
group afforded a poor ee value for the trans-adduct (entry 9), while
moderate electron-withdrawing Cl and Br groups provided better
ees (entries 7 and 8); higher ees were obtained with electron-
donating groups such as methyl and methoxy (entries 2 and 3).
The QD-5-catalyzed reaction also worked well for heteroaro-
matic N-Ts imine 3m and 3n, affording good yields and diastere-
oselectivities, albeit at lower enantioselectivity for the trans-5m
adduct (entries 13 and 14).
4. Experimental
4.1. General methods
All reactions were carried out in flame-dried glassware under
a nitrogen atmosphere. All solvents were freshly distilled prior to
use. Unless otherwise stated, commercial reagents were pur-
chased from Alfa Aesar, Acros, Aldrich, or Shanghai Aladdin
chemical companies and were used without further purification.
Purification of the reaction products was carried out by flash col-
umn chromatography using Qing Dao Sea Chemical Reagent sil-
ica gel (200–300 mesh). 1H NMR spectra were recorded on a
Bruker Avance III spectrometer (400 MHz) and the spectra were
referenced internally to the residual proton resonance in CDCl3
(d = 7.26 ppm), or with tetramethylsilane (TMS, d = 0.00 ppm) as
the internal standard. Chemical shifts were reported as parts
per million (ppm) in the d scale downfield from TMS. 13C NMR
spectra were recorded on a Bruker (400 MHz) spectrometer with
complete proton decoupling, and chemical shifts were reported
in ppm from TMS with the solvent as the internal reference
(CDCl3, d = 77.0 ppm). HPLC analyses were conducted on a Shi-
madzu 10A instrument using Daicel Chiralcel OD-H, AD-H, or
AS-H column (0.46 cm diameter ꢁ 25 cm length). Mass spectra
were recorded on an ESI-ion trap mass spectrometer (Shimadzu
LCMS-IT-TOF). Optical rotations were recorded on a Perkin–El-
mer polarimeter (Model 341). Analytical TLC was performed
using EM separations percolated silica gel 0.2 mm layer UV
254 fluorescent sheets.
3. Conclusions
In conclusion, we have developed the first organocatalytic
asymmetric cycloaddition of methyl isocyanoacetate to various
N-sulfonylimines by using cinchona alkaloid-derived catalysts to
form 2-imidazolines with high diastereoselectivities and good
enantioselectivities. The simplicity of operation, mild reaction con-
ditions, high yields, and high stereoselectivity of the nucleophilic
The cinchona alkaloid derivatives Q, QD, C, CD were commer-
cially available. Q-1, Q-2, Q-3 and QD-4, QD-5 were prepared as
previously described.23–25 All N-sulfonylimines 3 and methyl iso-
cyanoacetate
4
were prepared according to literature
methods.34–37

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Z.-W. Zhang et al. / Tetrahedron: Asymmetry 21 (2010) 1715–1721
4.2. General procedure for the Mannich-type cycloaddition
reaction
4.2.5. (4R,5S)-4-(Methoxycarbonyl)-5-(2-methoxyphenyl)-N-
tosyl-2-imidazoline 5e
½
a 2D0
ꢂ
¼ þ24 (c 1.0, THF, 50% ee). 1H NMR (CDCl3, 400 MHz): d
Methyl isocyanoacetate 4 (50
lL, 0.55 mmol) was added in a
7.57 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.29–7.22 (m, 2H),
7.18 (d, J = 8.1 Hz, 2H), 6.91 (t, J = 7.4 Hz, 1H), 6.63 (d, J = 8.2 Hz,
1H), 5.29 (d, J = 7.0 Hz, 1H), 4.68 (dd, J = 7.0, 1.8 Hz, 1H), 3.68 (s,
3H), 3.55 (s, 3H), 2.38 (s, 3H); 13C NMR (CDCl3, 100 MHz): d
170.3, 156.9, 149.7, 149.6, 144.3, 134.7, 129.9, 129.5, 127.3,
125.2, 120.5, 110.6, 77.9, 61.0, 54.9, 52.6, 21.5. HRMS (ESI-TOF):
dropwise manner to a mixture of N-sulfonylimine 3 (0.50 mmol),
catalyst QD-5 (17.6 mg, 10 mol %), and 4 Å MS (200 mg) in 1 mL
toluene at room temperature under a nitrogen atmosphere. The
reaction mixture was stirred at ambient temperature until the
imine was consumed (monitored by TLC). Then the solvent was re-
moved to yield a crude mixture of 2-imidazoline. The trans/cis ratio
was determined by 1H NMR spectroscopy. The product was puri-
fied by flash column chromatography with petrol ether/ethyl ace-
tate as eluent. The ee values were determined by HPLC analyses.
Absolute configurations of the major products were determined
by comparison of the order of peak elution from HPLC analyses
with literature values.11
m/z calcd for
C
19H20N2NaO5S [M+Na]+: 388.1093; found:
388.1094. HPLC conditions: Daicel Chiralcel AS-H column, i-
PrOH/hexane 25:75, flow rate 0.8 mL/min, UV detection at
254 nm, tminor = 9.0 min, tmajor = 10.0 min.
4.2.6. (4R,5S)-4-(Methoxycarbonyl)-5-(2,5-dimethoxyphenyl)-N-
tosyl-2-imidazoline 5f
½
a 2D0
ꢂ
¼ þ19 (c 1.0, THF, 38% ee). 1H NMR (CDCl3, 400 MHz): d
4.2.1. (4R,5S)-4-(Methoxycarbonyl)-5-phenyl-N-tosyl-2-
imidazoline 5a5
7.57 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.1 Hz,
2H), 6.81 (d, J = 3.0 Hz, 1H), 6.77 (dd, J = 8.9, 3.1 Hz, 1H), 6.60 (d,
J = 8.9 Hz, 1H), 5.27 (d, J = 7.0 Hz, 1H), 4.67 (dd, J = 7.0, 2.0 Hz,
1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.56 (s, 3H), 2.40 (s, 3H); 13C NMR
(CDCl3, 100 MHz): d 170.2, 153.5, 151.0, 149.8, 144.4, 134.6,
129.5, 127.4, 115.0, 114.4, 111.6, 78.3, 60.5, 55.8, 55.5, 52.6, 21.5.
HRMS (ESI-TOF): m/z calcd for C20H23N2O6S [M+H]+: 418.1199;
found: 418.1210. HPLC conditions: Daicel Chiralcel OD-H column,
i-PrOH/hexane 25:75, flow rate 0.8 mL/min, UV detection at
254 nm, tmajor = 9.7 min, tminor = 10.9 min.
1H NMR (CDCl3, 400 MHz): d 7.65 (d, J = 2.2 Hz, 1H), 7.46 (d,
J = 8.3 Hz, 2H), 7.25–7.15 (m, 7H), 5.08 (d, J = 7.5 Hz, 1H), 4.66
(dd, J = 7.5, 2.2 Hz, 1H), 3.71 (s, 3H), 2.40 (s, 3H); 13C NMR (CDCl3,
100 MHz): d 169.8, 150.2, 144.8, 138.1, 134.4, 129.8, 128.9, 128.5,
127.3, 127.0, 79.8, 63.8, 52.9, 21.6. HPLC conditions: Daicel Chiral-
cel OD-H column, i-PrOH/hexane 5:95, flow rate 0.8 mL/min, UV
detection at 254 nm, tmajor = 29.1 min, tminor = 32.9 min.
4.2.2. (4R,5S)-4-(Methoxycarbonyl)-5-(4-methylphenyl)-N-
tosyl-2-imidazoline 5b
4.2.7. (4R,5S)-4-(Methoxycarbonyl)-5-(4-chlorophenyl)-N-tosyl-
2-imidazoline 5g6
½
a 2D0
ꢂ
¼ þ40 (c 1.0, THF, 70% ee). 1H NMR (CDCl3, 400 MHz): d
7.64 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.1 Hz,
2H), 7.04 (s, 4H), 5.01 (d, J = 7.5 Hz, 1H), 4.65 (dd, J = 7.5, 2.2 Hz,
1H), 3.70 (s, 3H), 2.41 (s, 3H), 2.31 (s, 3H); 13C NMR (CDCl3,
100 MHz): d 169.8, 150.1, 144.7, 138.4, 135.1, 134.5, 129.7, 129.5,
127.4, 126.9, 79.9, 63.7, 52.8, 21.6, 21.1. HRMS (ESI-TOF): m/z calcd
for C19H21N2O4S [M+H]+: 372.1144; found: 372.1149. HPLC condi-
tions: Daicel Chiralcel OD-H column, i-PrOH/hexane 20:80, flow
rate 1.0 mL/min, UV detection at 254 nm, tmajor = 8.9 min,
tminor = 9.7 min.
1H NMR (CDCl3, 400 MHz): d 7.65 (d, J = 2.2 Hz, 1H), 7.47 (d,
J = 8.3 Hz, 2H), 7.23–7.19 (m, 4H), 7.10 (d, J = 8.4 Hz, 2H), 5.04 (d,
J = 7.5 Hz, 1H), 4.62 (dd, J = 7.5, 2.2 Hz, 1H), 3.71 (s, 3H), 2.42 (s,
3H); 13C NMR (CDCl3, 100 MHz): d 169.6, 150.0, 145.1, 136.6,
134.6, 134.2, 129.9, 129.0, 128.3, 127.3, 79.8, 63.1, 52.9, 21.6. HPLC
conditions: Daicel Chiralcel OD-H column, i-PrOH/hexane 20:80,
flow rate 1.0 mL/min, UV detection at 254 nm, tminor = 10.0 min,
tmajor = 11.5 min.
4.2.8. (4R,5S)-4-(Methoxycarbonyl)-5-(4-bromophenyl)-N-tosyl-
4.2.3. (4R,5S)-4-(Methoxycarbonyl)-5-(4-methoxyphenyl)-N-
tosyl-2-imidazoline 5c5
2-imidazoline 5h
a 2D0
ꢂ
¼ þ20 (c 1.0, THF, 48% ee). 1H NMR (CDCl3, 400 MHz): d
1H NMR (CDCl3, 400 MHz): d 7.64 (d, J = 2.4 Hz, 1H), 7.46 (d,
J = 7.8 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H),
6.76 (d, J = 8.2 Hz, 2H), 5.05 (d, J = 7.5 Hz, 1H), 4.66 (dd, J = 7.5,
2.4 Hz, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 2.40 (s, 3H); 13C NMR (CDCl3,
100 MHz): d 169.9, 159.8, 150.0, 144.6, 134.6, 130.0, 129.7, 128.3,
127.3, 114.2, 79.8, 63.5, 55.3, 52.8, 21.6. HPLC conditions: Daicel
Chiralcel OD-H column, i-PrOH/hexane 25:75, flow rate 1.0 mL/
min, UV detection at 254 nm, tminor = 11.7 min, tmajor = 13.3 min.
½
7.64 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.5 Hz,
2H), 7.22 (d, J = 8.1 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 5.03 (d,
J = 7.5 Hz, 1H), 4.62 (dd, J = 7.5, 2.2 Hz, 1H), 3.70 (s, 3H), 2.42 (s,
3H); 13C NMR (CDCl3, 100 MHz): d 169.5, 150.0, 145.1, 137.1,
134.2, 131.9, 129.9, 128.6, 127.3, 122.7, 79.7, 63.2, 52.9, 21.6.
HRMS (ESI-TOF): m/z calcd for C18H18BrN2O4S [M+H]+: 436.0092;
found: 436.0094. HPLC conditions: Daicel Chiralcel AS-H column,
i-PrOH/hexane 25:75, flow rate 1.0 mL/min, UV detection at
254 nm, tmajor = 10.6 min, tminor = 23.1 min.
4.2.4. (4R,5S)-4-(Methoxycarbonyl)-5-(3-methoxyphenyl)-N-
tosyl-2-imidazoline 5d
a 2D0
ꢂ
¼ þ22 (c 1.0, THF, 50% ee). 1H NMR (CDCl3, 400 MHz): d
4.2.9. (4R,5S)-4-(Methoxycarbonyl)-5-(4-nitrophenyl)-N-tosyl-
2-imidazoline 5i6
½
7.64 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.19–7.13 (m, 3H),
6.79–6.76 (m, 2H), 6.58 (s, 1H), 5.07 (d, J = 7.5 Hz, 1H), 4.66 (dd,
J = 7.5, 2.2 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 2.40 (s, 3H); 13C
NMR (CDCl3, 100 MHz): d 169.7, 159.9, 150.1, 144.8, 139.4, 134.5,
129.9, 129.7, 127.3, 119.4, 114.2, 112.0, 79.8, 63.7, 55.1, 52.8,
21.5. HRMS (ESI-TOF): m/z calcd for C19H20N2NaO5S [M+Na]+:
388.1093; found: 388.1105. HPLC conditions: Daicel Chiralcel AS-
H column, i-PrOH/hexane 25:75, flow rate 1.0 mL/min, UV detec-
tion at 254 nm, tmajor = 13.4 min, tminor = 28.6 min.
1H NMR (CDCl3, 400 MHz): d 8.15 (d, J = 8.4 Hz, 2H), 7.67 (d,
J = 2.2 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H),
7.28 (d, J = 8.0 Hz, 2H), 5.13 (d, J = 7.6 Hz, 1H), 4.63 (dd, J = 7.6,
1.5 Hz, 1H), 3.72 (s, 3H), 2.43 (s, 3H); 13C NMR (CDCl3, 100 MHz):
d 169.2, 150.2, 147.9, 145.6, 145.4, 133.6, 130.1, 127.8, 127.4,
124.1, 79.8, 62.9, 53.1, 21.6. HPLC conditions: Daicel Chiralcel
AD-H column, i-PrOH/hexane 25:75, flow rate 1.0 mL/min, UV
detection at 254 nm, tminor = 43.0 min, tmajor = 45.9 min.

Z.-W. Zhang et al. / Tetrahedron: Asymmetry 21 (2010) 1715–1721
1721
4.2.10. (4R,5S)-4-(Methoxycarbonyl)-5-(4-isopropylphenyl)-N-
and 2-imidazoline 5a (0.233 g, 0.65 mmol) for 8 h at room temper-
ature. The crude mixture was purified by chromatography using
CH2Cl2/MeOH (80:1) as eluent to afford 6a. The NMR data of 6a
were identical with the literature values.8 HPLC conditions: Daicel
Chiralcel OJ-H column, i-PrOH/hexane 15:85, flow rate 1.0 mL/min,
UV detection at 210 nm, syn diastereomer tr(2R,3R) = 21.9 min,
tosyl-2-imidazoline 5j
½
a 2D0
ꢂ
¼ þ35 (c 1.0, THF, 62% ee). 1H NMR (CDCl3, 400 MHz): d
7.65 (d, J = 2.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.2 Hz,
2H), 7.06–7.01 (m, 4H), 5.10 (d, J = 7.4 Hz, 1H), 4.68 (dd, J = 7.4,
2.1 Hz, 1H), 2.81–2.88 (m, 1H), 3.70 (s, 3H), 2.37 (s, 3H), 1.20 (d,
J = 6.9 Hz, 6H); 13C NMR (CDCl3, 100 MHz): d 169.9, 150.0, 149.4,
144.5, 135.2, 134.8, 129.6, 127.3, 127.0, 126.8, 79.8, 63.7, 52.8,
33.8, 24.0, 23.9, 21.5. HRMS (ESI-TOF): m/z calcd for C21H25N2O4S
[M+H]+: 400.1457; found: 400.1470. HPLC conditions: Daicel Chi-
ralcel OD-H column, i-PrOH/hexane 20:80, flow rate 1.0 mL/min,
UV detection at 254 nm, tmajor = 7.3 min, tminor = 8.5 min.
tr(2S,3S) = 40.5 min,
anti
diastereomer
tr(2S,3R) = 10.8 min,
tr(2R,3S) = 14.7 min. Specific rotation: ½a D20
ꢂ
¼ þ8:0 (c 1.0, THF); cor-
responding to a trans/cis ratio of 91:9 for which the enantiomeric
excess was trans 61% and cis 48%.
Acknowledgments
4.2.11. (4R,5S)-4-(Methoxycarbonyl)-5-(4-tert-butylphenyl)-N-
We thank the Scientific Research Foundation for the Returned
Overseas Chinese Scholars and the Program for New Century Excel-
lent Talents in University (both from the State Education Ministry
of China), the Project of International Science and Technology
Cooperation (from the Ministry of Science and Technology of Chi-
na) for financial support of this study.
tosyl-2-imidazoline 5k
½
a 2D0
ꢂ
¼ þ32 (c 1.0, THF, 58% ee). 1H NMR (CDCl3, 400 MHz): d
7.66 (d, J = 2.2 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz,
2H), 7.12 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 5.14 (d,
J = 7.4 Hz, 1H), 4.68 (dd, J = 7.4, 2.1 Hz, 1H), 3.70 (s, 3H), 2.36 (s,
3H), 1.27 (s, 9H); 13C NMR (CDCl3, 100 MHz): d 169.8, 151.6,
149.9, 144.4, 134.9, 134.7, 129.6, 127.3, 126.8, 125.7, 79.8, 63.6,
52.8, 34.5, 31.3, 21.5. HRMS (ESI-TOF): m/z calcd for C22H27N2O4S
[M+H]+: 414.1613; found: 414.1627. HPLC conditions: Chiralcel
OD-H column, i-PrOH/hexane 20:80, flow rate 1.0 mL/min, UV
detection at 254 nm, tmajor = 6.9 min, tminor = 8.3 min.
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4.2.13. (4R,5S)-4-(Methoxycarbonyl)-5-(2-furyl)-N-tosyl-2-
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1H NMR (CDCl3, 400 MHz): d 7.56 (d, J = 2.0 Hz, 1H), 7.52 (d,
J = 8.2 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.16 (s, 1H), 6.39 (d,
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J = 7.6, 2.0 Hz, 1H), 3.73 (s, 3H), 2.41 (s, 3H); 13C NMR (CDCl3,
100 MHz): d 169.5, 149.4, 148.5, 144.6, 143.4, 134.7, 129.8, 127.2,
110.7, 110.5, 75.6, 56.9, 53.0, 21.6. HPLC conditions: Daicel Chiral-
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detection at 254 nm, tmajor = 17.4 min, tminor = 21.5 min.
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4.2.14. (4R,5S)-4-(Methoxycarbonyl)-5-(2-thienyl)-N-tosyl-2-
imidazoline 5n8
1H NMR (CDCl3, 400 MHz): d 7.58 (d, J = 2.2 Hz, 1H), 7.51 (d,
J = 8.4 Hz, 2H), 7.30–7.20 (m, 3H), 7.01 (dd, J = 3.2, 0.7 Hz, 1H),
6.88 (dd, J = 5.0, 3.5 Hz, 1H), 5.46 (d, J = 7.4 Hz, 1H), 4.77 (dd,
J = 7.4, 2.2 Hz, 1H), 3.71 (s, 3H), 2.40 (s, 3H); 13C NMR (CDCl3,
100 MHz): d 169.4, 149.6, 144.8, 141.0, 134.6, 129.8, 127.4, 127.3,
126.8, 126.7, 80.0, 59.6, 53.0, 21.5. HPLC conditions: Daicel Chiral-
cel AS-H column, i-PrOH/hexane 25:75, flow rate 1.0 mL/min, UV
detection at 254 nm, tmajor = 13.1 min, tminor = 19.3 min.
4.2.15. Methyl 2-formylamino-3-[(4-methylphenyl)sulfonyl]-
amino-3-phenylpropanoate 6a8,9,11
Compound 6a was obtained by stirring a mixture of water
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