Copper(I)-catalyzed diastereoselective formation of oxazolines and N-sulfonyl-2-imidazolines

Article abstract of DOI:10.1016/j.tetlet.2006.10.040

A simple and short method for the reaction of methyl isocyanoacetate with aldehydes and N-sulfonylimines is presented. The reaction is catalyzed by copper(I) complexes and proceeds with excellent yields and high diastereoselectivities.

Full text of DOI:10.1016/j.tetlet.2006.10.040

Tetrahedron Letters 47 (2006) 8641–8644
Copper(I)-catalyzed diastereoselective formation of oxazolines
and N-sulfonyl-2-imidazolines
*
´
David Benito-Garagorri, Vladica Bocokic and Karl Kirchner
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9, A-1060 Vienna, Austria
Received 12 September 2006; revised 4 October 2006; accepted 6 October 2006
Abstract—A simple and short method for the reaction of methyl isocyanoacetate with aldehydes and N-sulfonylimines is presented.
The reaction is catalyzed by copper(I) complexes and proceeds with excellent yields and high diastereoselectivities.
Ó 2006 Elsevier Ltd. All rights reserved.
The construction of five-membered nitrogen-containing
heterocycles such as oxazolines and imidazolines has
received considerable attention because of the wide
applicability of these compounds to the synthesis of bio-
logically active compounds (e.g., b-hydroxy-a-amino
acids, a,b-diamino acids1a–e and b-substituted ser-
ines1f–h) and their presence in the structure of several
biologically active natural products, such as marine
cyclopeptides2 (e.g., bistratamides C and D).3 The reac-
tion of aldehydes and imines with isocyanocarboxylates
is one of the methods for the preparation of oxazolines
and imidazolines bearing a 1,3-O,N- and 1,3-N,N-ring
system in the heterocycle, respectively (Scheme 1).4
The mechanism of this reaction can be seen as an aldol
mechanism; however, other mechanisms have been pro-
posed.5 Whereas there are several examples covering the
synthesis of oxazolines using strong proazaphospha-
trane bases6 and transition metal complexes such as
Au(I),7 Ag(I),8 Pd(II),9 and Pt(II)5 complexes, there
have been few reports on the catalytic reaction of imines
with isocyanocarboxylates due to the low reactivity of
imines. These include the use of Au(I)10 and Ru(II)11
complexes. It has to be noted that imidazolines have
also been prepared via a multicomponent reaction
(MCR) between amines, aldehydes and isocyanides
using AgOAc as the catalyst.5b,c However, such methods
require the use of relatively expensive transition metals
and long reaction times are needed in order to achieve
reasonable yields. Here, we wish to report that using
simple
Cu(I)
catalysts,
trans-oxazolines
and
N-sulfonylimidazolines can be smoothly obtained in
2 h in quantitative yields with high diastereoselectivity
O
N
O
N
NC
R
CHO
R
COOMe
R
COOMe
COOMe
trans
cis
R'
R'
R'
N
N
N
N
N
NC
H
COOMe
cis
COOMe
trans
COOMe
R
R
R
Scheme 1.
Keywords: Catalysis; Copper; Aldol reaction; Diastereoselective; Oxazolines; Imidazolines.
*
Corresponding author. Tel.: +43 1 58801 15401; fax: +43 1 58801 15499; e-mail: kkirch@mail.zserv.tuwien.ac.at
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.040

8642
D. Benito-Garagorri et al. / Tetrahedron Letters 47 (2006) 8641–8644
by the reaction of methyl isocyanoacetate with aromatic
aldehydes and N-sulfonylimines. Due to the fact that the
trans products are easily accessible with this method, it
can be regarded as a useful complement to other already
published procedures, in which the cis products are
usually obtained.10
that, depending on the metal salt/ligand ratio, CuCl
can form several complexes with different stoichiome-
tries and geometries with triphenylphosphine.13 The
trigonal planar complex [(PPh3)2CuCl], formed in situ
in the course of the reaction, seems to offer the best
steric and electronic properties in the reaction between
3a and methyl isocyanoacetate: when CuCl and PPh3
were used in a 1:2 ratio, the reaction proceeded selec-
tively to give exclusively trans-4a (Table 2, entry 4).
Other CuCl:PPh3 ratios by using equimolar amounts
of metal salt and phosphine or larger excesses of phos-
phine resulted either in decreased yields or in decreased
diastereoselectivities presumably due to the formation of
copper complexes with different geometries (entries 3–7).
When these conditions were applied to imine 3b, how-
ever, the diastereoselectivity decreased (entry 5). Thus,
an optimization of the catalyst was performed by screen-
ing the activity of several CuCl/ligand systems (Table 2).
Although the reaction of isocyanocarboxylates with
aldehydes catalyzed by Cu2O was reported over 30 years
ago,12 1:1 mixtures of cis- and trans-imidazolines were
obtained. We discovered that by using a different cop-
per(I) salt, CuCl, the reaction between benzaldehyde
and methyl isocyanoacetate proceeded in 80% yield in
2 h with the selective formation of the trans product
(Table 1, entry 1). The yield of the reaction could be
improved to quantitative by adding PPh3 in a 1:2 ratio
in respect to CuCl (entry 2). The same procedure was
then applied to other aldehydes (entries 3–7). In all
cases, the reaction proceeded quantitatively to give trans
oxazolines with over 85% diastereoselectivity both with
electron withdrawing and electron donating groups in
the aromatic ring. In the absence of copper salt, the
reaction does not take place under otherwise the same
reaction conditions.
The best catalyst turned out to be the N-heterocyclic
carbene complex H,14 which gave good yields and selec-
tivities both for imines 3a and 3b. With these conditions
in hand, several other N-sulfonylimines were tested, all
of which gave the corresponding imidazolines in a quan-
titative yield and over 85% diastereoselectivity (Table 3).
Only in the case of imine 3d, a slightly lower diastereo-
meric ratio was observed, which may be attributed to
the electron donating methoxy group (Table 3, entry
4). Like for the oxazolines, no reaction took place if
the reaction was performed in the absence of copper
catalyst.
For the synthesis of imidazolines, when the N-aryl-
substituted benzaldehyde-N-phenylimine was used, only
traces of the coupling product were observed; given the
low reactivity of imines towards nucleophilic addition, a
strong electron withdrawing group, that is, tosyl, was
introduced on the nitrogen atom of the imines in order
to activate the C@N bond. If the reaction is performed
solely with CuCl, a nearly 50:50 trans:cis ratio was
observed for the imines 3a and 3b (Table 2, entries 1
and 2). Contrary to the synthesis of oxazolines, where
PPh3 only seemed to influence the yield of the reaction,
the use of an additive proved to be crucial for the diaste-
reoselective preparation of imidazolines. It is known
In summary, we have shown that the coupling of alde-
hydes and N-sulfonylimines with methyl isocyanoace-
tate can be achieved in short reaction times (2 h) with
good diastereoselectivities and in high yields using sim-
ple Cu(I) catalysts. The simplicity of the procedure,
the mildness of the reaction conditions and the inexpen-
sive nature of the metal make this method an attractive
alternative to similar reactions catalyzed by other transi-
tion metals. The use of different isocyanides as well as
the expansion of this method in the enantioselective syn-
thesis of oxazolines using chiral phosphines is currently
under investigation.
Table 1. Synthesis of oxazolinesa
O
N
NC
CuCl, PPh3
R
CHO
CH2Cl2, 2 h, 40 °C
R
COOMe
COOMe
1a R = phenyl
1b R = 4-chlorophenyl
1c R = 4-nitrophenyl
Typical procedures: Oxazolines: Methyl isocyanoacetate
(1 equiv) was added to a mixture of the catalyst, iPr2EtN
(10 mol %) and aldehyde (1 equiv) in CH2Cl2 under an
argon atmosphere. The reaction mixture was stirred
for 2 h at 40 °C after which it was allowed to cool down
to room temperature. The products were isolated from
the crude reaction mixture by flash chromatography
with ethyl acetate/hexanes (1:1) as eluent. Imidazolines:
The reaction procedure was identical to that for oxazo-
lines, with the exception that no iPr2EtN was used.
2a-h
1d R = 4-methoxyphenyl
1e R = 2-chloro-5-nitrophenyl
1f R = 2-chloro-6-fluorophenyl
1g R = 2-methylphenyl
1h R = isopropyl
Entry
Aldehyde
Yieldb of 2 (%)
Ratioc of trans/cis
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
>99
>99
>99
>99
>99
>99
>99
>99
>99/ < 1
86/14
90/10
91/9
86/14
96/4
trans-2e: 1H NMR (d, CDCl3, 20 °C): 3.84 (s, 3H,
COOCH3), 4.54 (d, J = 6.3 Hz, 1H, CH), 6.10 (d,
J = 6.3 Hz, 1H, CH), 7.20 (s, 1H, CH), 7.59 (d,
J = 8.5 Hz, 1H, Ph), 8.20–8.13 (m, 2H, Ph). trans-2f:
1H NMR (d, CDCl3, 20 °C): 3.78 (s, 3H, COOCH3),
4.77 (dd, J = 8.7 Hz, J = 1.7 Hz, 1H, CH), 6.17 (d,
J = 8.7 Hz, 1H, CH), 7.04–6.98 (m, 2H, CH and Ph),
1g
1h
88/12
>99/ < 1
a Conditions: 1 equiv aldehyde, 1 equiv methyl isocyanoacetate,
10 mol % iPr2EtN, 5 mol % CuCl, 10 mol % PPh3, CH2Cl2, 40 °C,
2 h.
b Isolated yield by silica gel column chromatography.
c Determined by 1H NMR spectroscopy.

D. Benito-Garagorri et al. / Tetrahedron Letters 47 (2006) 8641–8644
Table 2. Optimization of the catalyst for the synthesis of imidazolinesa
8643
Ph2P
PPh2
Ph2P
PPh2 Ph2P
PPh2
O
O
Ph2P
PPh2
A
B
C
D
Ar
N
Ar
N
N
Ar
N
N
Cu Cl
Ar
Ar
N
NH
N
Ar: 2,6-iPr-Ph
PPh2
Ar
F
G
H
E
Entry
Imine
Catalyst
Yieldb of 4 (%)
Ratioc of trans/cis
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3a
3b
3a
3a
3b
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
CuCl (5 mol %)
CuCl (5 mol %)
>99
>99
54
>99
96
97
75
>99
31
76
92
57
14
Traces
Traces
>99
>99
52/48
40/60
84/16
>99/<1
64/36
90/10
84/16
83/17
98/2
CuCl (5 mol %) + PPh3 (5 mol %)
CuCl (5 mol %) + PPh3 (10 mol %)
CuCl (5 mol %) + PPh3 (10 mol %)
CuCl (5 mol %) + PPh3 (15 mol %)
CuCl (5 mol %) + PPh3 (20 mol %)
CuCl (5 mol %) + P(OPh)3 (10 mol %)
CuCl (5 mol %) + A (5 mol %)
CuCl (5 mol %) + B (5 mol %)
CuCl (5 mol %) + C (5 mol %)
CuCl (5 mol %) + D (5 mol %)
CuCl (5 mol %) + E (5 mol %)
CuCl (5 mol %) + F (5 mol %)
CuCl (5 mol %) + G (5 mol %)
H (5 mol %)
97/3
86/14
67/33
98/2
—
—
96/4
95/5
H (5 mol %)
a Conditions: 1 equiv imine, 1 equiv methyl isocyanoacetate, catalyst (5–20 mol%), CH2Cl2, 40 °C, 2 h.
b Isolated yield by silica gel column chromatography.
c Determined by 1H NMR spectrospcopy.
1
7.32–7.18 (m, 2H, Ph). trans-4e: H NMR (d, CDCl3,
20 °C): 2.34 (s, 3H, CH3), 3.62 (s, 3H, COOCH3), 4.59
(d, J = 6.3 Hz, 1H, CH), 5.48 (d, J = 6.3 Hz, 1H, CH),
7.23–7.19 (m, 3H, Ph), 7.37–7.32 (m, 1H, Ph), 7.48–
7.42 (m, 1H, Ph), 7.56–7.52 (m, 1H, Ph), 7.67 (d,
J = 2.1 Hz, 1H, CH), 7.99 (s, 1H, Ph). trans-4f: 1H
NMR (d, CDCl3, 20 °C): 2.32 (s, 3H, CH3), 3.62 (s,
3H, COOCH3), 4.71 (dd, J = 7.5 Hz, J = 1.8 Hz, 1H,
CH), 5.64 (d, J = 7.5 Hz, 1H, CH), 7.17–7.06 (m, 4H,
Ph and CH), 7.55–7.43 (m, 4H, Ph).
Table 3. Synthesis of imidazolinesa
Acknowledgements
Ts
Ts
N
Financial support by the ‘Fonds zur Fo¨rderung der wis-
senschaftlichen Forschung’ is gratefully acknowledged
(Project No. P16600-N11). D.B.-G. thanks the Basque
Government (Eusko Jaurlaritza/Gobierno Vasco) for a
doctoral fellowship.
N
N
NC
H, CH2Cl2, 2 h, 40 °C
H
COOMe
COOMe
R
R
3a R = H
3b R = 4-Cl
3c R = 4-NO2
3d R = 4-OMe
4a-f
3e R = 2-Cl, 5-NO2
3f R = 2-Cl, 6-F
References and notes
Entry
Imine
Yieldb of 4 (%)
Ratioc of trans/cis
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96/4
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85/15
83/17
89/11
85/15
a Conditions: 1 equiv imine, 1 equiv methyl isocyanoacetate, 5 mol %
H, CH2Cl2, 40 °C, 2 h.
b Isolated yield by silica gel column chromatography.
c Determined by 1H NMR spectroscopy.

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