Arylid-OX and Arylid-BOX derived catalysts: applications in catalytic asymmetric cyclopropanation

Article abstract of DOI:10.1016/j.tetasy.2009.04.005

A novel family of chiral non-racemic monodentate oxazoline ligands known as Arylid-OXs 1a and 1b was prepared in good overall yields. These ligands were screened in bench-mark Cu(I)-catalyzed cyclopropanations and gave ees as high as 58%. Both ¹H NMR and computational studies using 1a indicated that the active catalyst was most likely to be the di-coordinated complex, Cu(I)-1a₂(MeCN)₂. Two novel ortho-substituted Arylid-BOX ligands 2a and 2b were also synthesized in very good yields. These ligands were tested in the same reaction as for 1a and 1b and, although excellent yields could be obtained with 2b, which is assumed to be due to an electron-donating effect from the ortho-methoxy group, a best ee of only 56% was obtained with 2a. In fact, both the enantioselectivities and diastereoselectivities obtained with these ortho-substituted ligands were in line with those previously obtained with the para-substituted series.

Full text of DOI:10.1016/j.tetasy.2009.04.005

Tetrahedron: Asymmetry 20 (2009) 1272–1278
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Arylid-OX and Arylid-BOX derived catalysts: applications in catalytic
asymmetric cyclopropanation
a
b
Elisabete Palma Carreiro a, Anthony J. Burke a, , J. P. Prates Ramalho , Ana Isabel Rodrigues
*
a Departamento de Química and Centro de Química de Évora, Universidade de Évora, Rua Romão Romalho 59, 7000 Évora, Portugal
b Departamento de Tecnologia de Indústrias Químicas, Instituto Nacional de Engenharia, Tecnologia e Inovação, Estrado do Paço do Lumiar, Edifício F, 1649-038 Lisboa, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel family of chiral non-racemic monodentate oxazoline ligands known as Arylid-OXs 1a and 1b was
prepared in good overall yields. These ligands were screened in bench-mark Cu(I)-catalyzed cyclopropana-
tions and gave ees as high as 58%. Both 1H NMR and computational studies using 1a indicated that the active
catalyst was most likely to be the di-coordinated complex, Cu(I)-1a2(MeCN)2. Two novel ortho-substituted
Arylid-BOX ligands 2a and 2b were also synthesized in very good yields. These ligands were tested in the
same reaction as for 1a and 1b and, although excellent yields could be obtained with 2b, which is assumed
to be due to an electron-donating effect from the ortho-methoxy group, a best ee of only 56% was obtained
with 2a. In fact, both the enantioselectivities and diastereoselectivities obtained with these ortho-substi-
tuted ligands were in line with those previously obtained with the para-substituted series.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 25 March 2009
Accepted 17 April 2009
Available online 11 May 2009
1. Introduction
the advantage that they are in general less structurally complex
than di- and multidentate ligands and thus the synthesis in princi-
Chiral non-racemic C2 symmetric bidentate bis-oxazoline (BOX)
ligands first appeared in the literature about 18 years ago, and are
used to form catalysts with appropriate metals, giving very good
enantioselectivities in a number of catalytic asymmetric reactions.1
Cu(I)-BOX catalysts have been shown to be very useful for access-
ing enantio-enriched chiral cyclopropanes. The synthesis of chiral
cyclopropanes remains as a considerable challenge, especially
since the cyclopropane unit is often found in a variety of natural
products and biologically active compounds.2 Over the last few
years, we have developed and tested a number of novel Cu(I)-
BOX catalysts based on a first generation novel BOX family known
as IsBut-BOX3 and a second generation family known as Arylid-
BOX (Fig. 1).4 The latter proved to be more effective and versatile
in some bench-mark Cu(I) asymmetric cyclopropanation reactions
and has been extensively studied. Despite the enormous propen-
sity for functional diversity in this ligand system, until now only
those ligands with a substituent in the para-position have been
evaluated. It was thus of interest to synthesize derivatives with
substituents in other positions, preferably at the ortho-position,
principally because the relevant substituent will be closer to the
metal centre. Despite the large application of bidentate chiral li-
gands in catalytic asymmetric synthesis, monodentate versions
have rarely had the same impact, for the main reason that they fail
to form compact catalytic manifolds that are pivotal for high asym-
metric induction during the reaction. Monodentate ligands offer
ple is less demanding. Some monodentate systems are known
which give very good results. For instance, Feringa used chiral
phosphoramidite ligands for copper-catalyzed dialkylzinc addi-
tions and ees of up to 98% could be obtained.5 Also, Luan et al. stud-
ied a series of monodentate N-heterocyclic carbene ligands in the
asymmetric
a
-arylation of amides and obtained enantioselectivi-
Ar
O
O
Ar
O
O
O
N
N
N
N
N
Ph
Ph
R
R
R
Mono-OX
Arylid-BOX
(2nd generation)
IsbutBOX
(1st generation)
X
H3CO
O
O
O
OCH3
N
N
N
R
Ph
Ph
1a R=Ph
1b R=t-butyl
2a
X=Cl
2b X=OCH3
* Corresponding author.
E-mail address: ajb@dquim.uevora.pt (A.J. Burke).
Figure 1. Mono-Arylid-OX and Arylid-BOX ligands.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.04.005

E. P. Carreiro et al. / Tetrahedron: Asymmetry 20 (2009) 1272–1278
1273
H3CO
H3CO
H3CO
a
b
O
COOH
COCl
OCH3
OCH3
OCH3
4 (85%)
3
5 (100%)
H3CO
H3CO
OH
H
c
O
d
N
OCH3
N
OCH3
O
R
R
1a R=Ph (98%)
6a
6b
R=Ph (81%)
R=t-butyl (61%)
1b
R=t-butyl (55%)
Scheme 1. Reagents and conditions: (a) malonic acid, 70 °C; (b) (COCl)2, DMF, CH2Cl2, 0 °C; (c) (S)-(+)-phenylglycinol or (S)-tert-leucinol, NEt3, CH2Cl2; (d) CH3SO2Cl, NEt3,
CH2Cl2.
ties of up to 98% ee.6a Ikeda et al.6b have used some chiral mono-
oxazoline ligands with moderate success (a highest ee of 58%
was obtained) in catalytic enantioselective [2+2+2] cycloadditions
with Ni. We thus developed a monodentate version of Arylid-BOX
known as Arylid-OX (Fig. 1) which gave unexpected results in
some bench-mark cyclopropanation reactions. Herein we report
the synthesis of the novel Arylid-OX ligands 1a and 1b (Fig. 1),
the ortho-substituted Arylid-BOXs 2a and 2b, their application in
a bench-mark cyclopropanation reaction and our investigations
on the structure of the active catalyst in the reactions with Ary-
lid-OX ligands.
the Arylid-OXs 1a and 1b, and Arylid-BOXs 2a and 2b both trans-
2,4-dimethoxycinnamic acid 4 (Scheme 1) and arylidene malonic
acids 8a and 8b (Scheme 2) were used. These were obtained via
the procedure reported by Neustadt et al.7 using a simple Knoeve-
nagel condensation with malonic acid and the respective aldehyde.
Our standard synthetic procedure3,4 was subsequently used to
transform the acids to the corresponding ligands. Satisfactory
yields could be obtained in all cases.
These ligands were subsequently used in a series of Cu(I)-cata-
lyzed olefin cyclopropanations with ethyl diazoacetate using
[Cu(MeCN)4]PF6 and Cu(I)(OTf) as pre-catalysts (Scheme 3).
2.1. Arylid-OX
2. Results and discussion
Monodentate Arylid-OXs 1a and 1b were tested in some cata-
lytic asymmetric cyclopropanations with Cu(I) (Table 1). An ee as
high as 58% for the trans-product could be obtained using ligand
The series of Arylid-OX ligands 1a and 1b, and Arylid-BOX li-
gands 2a and 2b was prepared in very good yields using the syn-
thetic pathways shown in Schemes 1 and 2. For the synthesis of
X
X
X
a
b
Cl
Cl
HO
OH
O
O
O
O
O
X=OMe
9a
9b
X=Cl (100%)
X=OMe (100%)
7a X=Cl
8a
8b
X=Cl (67%)
X=OMe (74%)
7b
X
X
OH
OH
O
O
c
H
H
N
N
e
N
N
Ph
O
O
Ph
Ph
Ph
2a (60%)
2b (80%)
10a X = Cl (41%)
10b X = OMe (53%)
Scheme 2. Reagents and conditions: (a) malonic acid, 70 °C; (b) (COCl)2, DMF, CH2Cl2, 0 °C; (c) (S)-(+)-phenylglycinol, NEt3, CH2Cl2; (d) CH3SO2Cl, NEt3, CH2Cl2.

1274
E. P. Carreiro et al. / Tetrahedron: Asymmetry 20 (2009) 1272–1278
H
Cu(I)-ArylidBOX or
+
Cu(I)-ArylidOX
CO2Et
H
CO2Et
CO2Et
N2
Scheme 3. Asymmetric cyclopropanation of styrene—the bench-mark reaction.
Table 1
Catalytic asymmetric cyclopropanation of styrenea
Entry
Ligand (mol %)
Pre-catalyst (mol %)
Yield (%)
cis:transc
cisc,d (ee%)
transc,d (ee%)
Ratio
Cyclopropanes:maleatesc
1
2
3
4
5
6
7
8
9
1a (2.2)
1a (2.2)
1b (2.1)
1a (3.14)
1a (3.14)
1a (4.2)
1a (4.2)
1b (4.2)
1b (4.2)
1b (6.3)
Cu(I)OTf (1)
CuPF6 (2)
CuPF6 (2)
Cu(I)OTf (1)
CuPF6 (2)
Cu(I)OTf (1)
CuPF6 (2)
Cu(I)OTf (1)
CuPF6 (2)
CuPF6 (2)
13b
18b
27e
18b
26b
15b
17b
32e
31e
34e
32:68
36:64
33:67
38:62
36:64
35:65
34:66
39:61
40:60
31:69
3 (1R, 2S)
15 (1R, 2S)
29 (1S,2R)
13 (1R, 2S)
38 (1R, 2S)
19 (1R, 2S)
33 (1R, 2S)
6 (1S,2R)
5 (1R,2R)
20 (1R,2R)
26 (1S,2S)
16 (1R,2R)
32 (1R,2R)
22 (1R,2R)
32 (1R,2R)
7 (1S,2S)
89:11
84:16
91:9
75:25
92:8
78:22
86:14
72:28
82:18
86:14
43 (1S,2R)
51 (1S,2R)
45 (1S,2S)
58 (1S,2S)
10
a
Styrene (4 equiv), Chiral ligand, Cu(I) pre-catalyst, ethyl diazoacetate (1 equiv), CH2Cl2, rt, 24 h.
Determined by gas chromatography using di-n-butylether as the internal standard.
The diastereomeric ratio and the % ee was determined by GC.
The major isomer is indicated in parentheses.
Yield determined from the mass of isolated crude product isomers.
b
c
d
e
1b at a loading level of 6.3 mol % (Table 1, entry 10) with
both 1:1 and 2:1 1a:pre-catalyst the difference in the chemical
shifts was quite small. The fact that some solid precipitated when
a 1:1 mixture of 1a to pre-catalyst was used indicated the forma-
[Cu(MeCN)4]PF6 as the pre-catalyst. In all cases, the trans-isomer
was the predominant isomer. The highest de obtained was 38%
(Table 1, entry 10). Generally, ligand 1b gave better ees than 1a
and this can be ascribed to the presence of a bulkier substituent.
The yields were only moderate and this was due to the forma-
tion of significant quantities of maleate products. In order to find
optimized conditions, different ratios of ligand to Cu(I) were inves-
tigated. In the case of ligand 1a using Cu(I)OTf (entries 1, 4 and 6),
an increase in the ee was observed when the proportion of ligand
was increased. The same was true with the other pre-catalyst,
[Cu(MeCN)4]PF6, (entries 2, 5 and 7). The diastereoselectivities re-
mained generally the same. In the case of ligand 1b with [Cu(-
MeCN)4]PF6 (entries 3, 9 and 10), the ees increased on increasing
the quantity of ligand.
tion of
a di-Arylid-OX-coordinated complex, that is, Cu(I)-
1a2(MeCN)2. In the case of the system that comprises a 3:1
1a:pre-catalyst, the resolution was poorer than that in the previous
cases, leading us to believe that an equilibrium was established be-
tween excess free ligand and the di-coordinated complex. The 1H
NMR studies indicate that the MeCN coordinates with the metal
through vacant coordination sites on the metal.
2.1.2. Computational study
A theoretical study was carried out to verify the observations
obtained from 1H NMR spectroscopy. The following four complexes
were studied: Cu(MeCN)4, Cu(I)-1a(MeCN)3, Cu(I)-1a2(MeCN)2 and
Cu(I)-1a3(MeCN) to determine their relative energies in an attempt
to establish the most viable catalytic complex involved in these
catalytic reactions. Considering the number and size of these sys-
tems, a semi-empirical method proved to be the best choice for
geometry optimization. The novel PM6 Hamiltonian8 included in
the recent version of MOPAC 20079 was employed in this study, fol-
lowed by single point calculations at density functional theory
(DFT) level.
2.1.1. NMR study
To gain an insight into the structure of the active catalyst in-
volved in this reaction, both 1H NMR and computational studies
were carried out. Three types of complexation were conducted,
using ligand 1a and [Cu(MeCN)4]PF6, in the following ratios; 1:1,
2:1 and 3:1 ligand. (1a was mixed with the pre-catalyst in CH2Cl2
at rt for 30 min, the solvent was removed and the remaining solid
was dried carefully). In all cases, the NMR spectra were clean and it
was obvious that complexation had taken place, as the spectra
were different from those of the free ligand. The observed chemical
shifts of the principal signals are shown in Table 2. In the case of
The geometries were fully optimized in Cartesian coordinates
and the stationary points obtained were further characterized by
frequency calculations as minima.
Following the initial geometry optimization with the PM6
method, DFT calculations were carried out on all complexes. The
DFT calculations were performed using the hybrid Becke exchange
functional10 and the correlation functional B3LYP11 as contained in
the Gamess package.12 The Lanl2DZ effective core basis set was
Table 2
1H NMR data for complex formation
**
employed for the metal atom while the 6-31G basis set was used
1a:[Cu(MeCN)4]PF6
dH (ppm)
for all the other atoms.
H1
H2
H3
H4
H5
All the Cu(I) complexes studied were found to have a tetrahe-
dral structure as illustrated in Figure 2 and in agreement to what
is found experimentally for the majority of Cu(I) complexes.13,14
The Cu(I)–N bond distances are depicted in Table 3. In the known
tetrahedral complex [CuI(MeCN)4]–ClO4, Cu–N distances of 1.99 Å
1:0
1:1
2:1
3:1
5.295
5.370
5.350
5.143
4.179
4.950
4.927
4.777
4.697
4.410
4.412
4.306
6.750
6.330
6.349
6.375
7.676
7.875
7.858
7.807

E. P. Carreiro et al. / Tetrahedron: Asymmetry 20 (2009) 1272–1278
1275
Figure 2. Calculated structures for the Cu(I) complexes (a) Cu(I)(MeCN)4, (b) Cu(I)-1a(MeCN)3, (c) Cu(I)-1a2(MeCN)2 and (d) Cu(I)-1a3(MeCN).
Table 3
stability for this complex. This result strongly supports our previ-
ous postulate based on 1H NMR spectroscopy.
Selected bond lengths (Å) for complexes Cu(I)(MeCN)4, Cu(I)-1a(MeCN)3, Cu(I)-
1a2(MeCN)2 and Cu(I)-1a3(MeCN)
Cu(I)(MeCN)4 Cu(I)-1a(MeCN)3 Cu(I)-1a2(MeCN)2 Cu(I)-1a3(MeCN)
2.2. Cu(I)-bis-Arylid-BOX catalysis
Cu–N1
Cu–N2
Cu–N3
Cu–N4
1.971
1.971
1.971
1.971
2.044a
1.964
1.961
1.968
2.050a
2.023a
1.955
1.969
2.024a
2.033a
2.043a
1.965
Bis-Arylid-BOXs 2a and 2b were tested in catalytic asymmetric
cyclopropanations with Cu(I) (Table 5). This study demonstrated
that on using both [Cu(MeCN)4]PF6 and Cu(I)OTf with 2a and 2b
the ees were better with the former pre-catalyst. Ligand 2a gave
the highest ee using [Cu(MeCN)4]PF6 as the pre-catalyst (Table 5,
entry 2, 56% trans-isomer), but it was the catalyst formed from
2b which gave the better yields. This is most likely due to the pres-
ence of the electron-donating group in the ortho position. The des
were only moderate, a maximum of 40% being obtained with both
2a and 2b. We tested ligand 2b with toluene, using [Cu(-
MeCN)4]PF6 (Table 5, entry 5), but there was only a slight increase
in ee for both isomers. The chemical yield had greatly decreased in
relation to using CH2Cl2 (24% as opposed to 100% with CH2Cl2. On
comparing the results obtained using both 2a and 2b with those
found for their para-substituted counterparts4a ([Cu(MeCN)4]PF6
as the pre-catalyst) it can be seen that the ees are similar (53%
and 61% for both the cis and trans isomers—para-chloro-substi-
tuted ligand, and 41% and 48%—para-methoxy-substituted ligand).
The des obtained with 2a and 2b were slightly higher than those of
their para-substituted counterparts, which were about 30%. How-
ever, the yields using the ortho-substituted ligands were better.
In most cases, the quantity of maleate side product was less
than that encountered with the Arylid-OX-based Cu(I) catalysts.
a
Nitrogen atom belonging to the 1a moiety.
were experimentally observed15 and should be compared with the
Cu–N distances in the first column of Table 3. The close agreement
observed here supports the suitability of the PM6 method to deter-
mine the molecular geometries of these complexes. The calculated
Cu–N(oxazoline) distances are slightly longer than the calculated
Cu–N(MeCN) distances for all oxazoline-containing complexes.
The binding energy for each complex was obtained by calculating
the difference in energy between the optimized structure for each
complex and the sum of the energies of the optimized isolated
moieties. Selected energy values calculated with the B3LYP/6-
**
31G //PM6 method are depicted in Table 4. This study clearly
shows that it is the di-oxazoline-coordinated complex—Cu(I)-
1a2(MeCN)2—which has the lowest
DE value indicating a higher
Table 4
Calculated energies for complexes Cu(I)(MeCN)4, Cu(I)-1a(MeCN)3, Cu(I)-1a2(MeCN)2
and Cu(I)-1a3(MeCN) at the B3LYP/G-31G //PM6 level
*
Chemical unit
Total energy (a.u.)
D
E (kcal/mol)
D
Erel (kcal/mol)
3. Conclusions
Cu(I)
1a
MeCN
Cu(I)(MeCN)4
Cu(I)-1a(MeCN)3
Cu(I)-1a2(MeCN)2
Cu(I)-1a3(MeCN)
ꢀ195.7599954
ꢀ1015.2558668
ꢀ132.6776021
ꢀ726.7069097
ꢀ1609.2982735
ꢀ2491.8870626
ꢀ3374.4607609
—
—
—
—
—
—
The two chiral monodentate ligands 1a and 1b were screened in
a bench-mark cyclopropanation reaction with styrene and ethyl
diazoacetate using two different Cu(I) sources. Although satisfac-
tory ees could be obtained (up to 58%) the yields were only moder-
ate. Surprisingly, ees as high as those obtained using the Arylid-BOX
ꢀ148.410
ꢀ156.629
ꢀ163.234
ꢀ160.368
0.000
ꢀ8.220
ꢀ14.820
ꢀ11.960

1276
E. P. Carreiro et al. / Tetrahedron: Asymmetry 20 (2009) 1272–1278
Table 5
Catalytic asymmetric cyclopropanation of styrene using Cu(I)-2a and Cu(I)-2ba
Entry
Ligand (mol %)
Pre-catalyst (mol %)
Yieldb (%)
cis:transc
cisc,d (ee%) (1R,2S)
transc,d (ee%) (1R,2R)
Ratio
Cyclopropanes:maleatesc
1
2
3
2a (2.2)
2a (2.2)
2b (2.2)
2b (2.2)
2b (2.2)
Cu(I)OTf(2)
CuPF6(2)
Cu(I)OTf(2)
CuPF6(2)
19
60
100
100
24
32:68
30:70
34:66
31:69
30:70
38
50
10
41
48
49
56
10
50
35
81:19
95:5
99.5:0.5
95:5
4
5e
CuPF6(2)
97:3
a
Styrene (4 equiv), Chiral ligand, Cu(I) pre-catalyst, ethyl diazoacetate (1 equiv), CH2Cl2, rt, 24 h.
Determined by gas chromatography using di-n-butylether as the internal standard.
The diastereomeric ratio and the % ee was determined by GC.
The major isomer is indicated in parentheses.
b
c
d
e
Solvent was toluene, 40 °C.
ligands 2a and 2b were obtained. Mechanistic studies using NMR
green solid (due to the unstable nature of this compound it was
stored in the freezer at ꢀ10 °C). Yield: 2.17 g (100%). A two-necked
round-bottomed flask (50 mL) fitted with a magnetic stirring bar
spectroscopy and computational calculations indicate that the ac-
tive catalyst is most likely to be; Cu(I)-1a2(MeCN)2. On screening
the ortho-substituted Arylid-BOX ligands 2a and 2b in the same test
reaction, despite obtaining some excellent yields a highest ee of 56%
(trans-isomer) was obtained. The ees were the same as those ob-
tained for the para-substituted phenyl-Arylid-BOX series.
We are currently investigating ligands 1a and 1b and other
derivatives in other catalytic asymmetric reactions, including using
such ligands to form hetero-Cu(I) complexes for screening in the
asymmetric cyclopropanation reaction.
was charged with
a solution of (S)-phenylglycinol (1.25 g,
9.12 mmol) and dry CH2Cl2 (20 mL) and the solution was cooled
to 0 °C using an ice bath. Dry triethylamine (1.27 mL, 9.12 mmol)
was added via syringe. A solution of trans-3-(2,4-dimethoxy-
phenyl)acryloyl chloride 5 (1.06 g, 4.68 mmol) in CH2Cl2 (5 mL)
was slowly added via syringe to the vigorously stirred reaction
mixture over 30 min. The ice bath was removed, and the reaction
mixture was stirred at room temperature for a further 4 h. The
reaction mixture was washed with 2 M HCl (12 mL), saturated
aqueous NaHCO3 (15 mL) and the aqueous layer was back-ex-
tracted with CH2Cl2 (15 mL). The combined organic extracts were
washed with brine (15 mL), and the aqueous layer was back-ex-
tracted with CH2Cl2 (15 mL). The combined organic extracts were
dried over anhydrous MgSO4, filtered and concentrated in vacuo
to give (S)-trans-N-(2-hydroxy-1-phenylethyl)-2,4-dimethoxyc-
innamamide 6a as an orange solid. The crude product was purified
by column chromatography (silica gel, EtOAc) to afford amide 6a as
a white solid. Yield: 1.23 g (81%); mp 152.2–153.3 °C; 1H NMR
(300 MHz, CDCl3): d = 7.8 (d, 1H, J = 15.7 Hz, RCH@CRH), 7.35–
7.25 (m, 6H, CH(Ar), 6.54–6.41 (m, 4H, NH, RCH@CHR, CH(Ar)),
5.18–5.14 (m, 1H, CH), 3.95–3.82 (m, 2H, CH2), 3.80 (s, 3H, –
OCH3), 3.79 (s, 3H, –OCH3) ppm. 13C NMR (100 MHz, CDCl3):
d = 167.67, 162.20, 159.75, 139.16, 137.37, 130.78, 128.82,
127.78, 126.81, 118.44, 116.74, 105.03, 92.42, 66.80, 56.41, 55.38,
4. Experimental
4.1. General remarks
trans-2,4-Dimethoxycinnamic acid 4, 2-(2-chlorobenzyli-
dene)malonic acid 8a, and 2-(2-methoxybenzylidene)malonic acid
8b, were prepared as reported previously.7 All reagents were ob-
tained from Aldrich, Fluka, Alfa Aesar or Acros. Solvents were dried
using common laboratory methods. Column chromatography was
carried out on silica gel (sds, 70–200
lm) and flash column chro-
matography (Merck, 40–63 m and sds, 40-63
l
lm). TLC was car-
ried out on aluminium-backed Kisel-gel 60 F254 plates (Merck).
Plates were visualized either by UV light or by phosphomolybdic
acid in ethanol. Gas chromatographic (GC) analyses of the products
were performed on a Hewlett Packard (HP) 6890 series instrument
equipped with a flame ionization detector (FID). The chromato-
55.35 ppm. IR (KBr) mmax
: 3291, 3064.24, 3031.16, 2960.27,
2939.23, 2873.67, 2839.95, 1652.38, 1616.66, 1575.96, 1544.47,
1502.36, 1455.85, 1420, 1351.75, 1318.22, 1290.59, 1212.07,
1161.54, 1118.42, 1037.96, 975.72, 836.85, 798.59, 751.29,
graph was fitted with
a cyclosil-B capillary column (30 m,
250 m, 0.25 m) (Agilent 112-2532). The melting points were re-
l
l
corded on a Barnstead Electrothermal 9100 apparatus and was
uncorrected. The NMR spectra were recorded on either a Bruker
AMX300 or a Bruker Avance 400 instrument. Mass spectra were re-
corded on a VG Autospec M(Waters-Micromass) spectrometer
using the FAB technique and Waters-Micromass GC-TOF and
MicroTOF Focus (Bruker Daltonics) using the TOF technique. In-
fra-red spectra were measured with a Perkin Elmer Paragon 1000
model.
698.05, 523.39 cmꢀ1. ½a D22
¼ þ13:7 (c 1.22, CHCl3). FAB-MS m/z:
ꢁ
328.16 [M+H]+.
Compound 6b: The same procedure as described previously was
used in the reaction of trans-2,4-dimethoxycinnamoyl chloride 4
(1.12 g, 4.96 mmol) with (S)-tert-leucinol (0.64 g, 5.45 mmol) and
dry triethylamine (1.06 mL, 7.44 mmol) to give (S)-trans-N-(1-hy-
droxy-3,3-dimethylbutan-2-yl)-(2,4-dimethoxycinnamamide 6b
as a white solid after purification by column chromatography (sil-
ica gel, EtOAc); Yield: 0.92 g (61%). mp 64–65 °C; 1H NMR
(300 MHz, CDCl3): d = 7.83 (d, 1H, J = 15 Hz, RCH@CHR), 7.36 (d,
1H, J = 9 Hz, CH(Ar)), 6.53 (d, 1H, J = 16 Hz, RCH@CHR), 6.39 (t,
2H, J = 6.6 Hz, CH(Ar)), 6.15 (d, 1H, J = 9 Hz, N–H), 4.03–3.88 (m,
2H, CH, CHH), 3.80 (s, 3H, –OCH3), 3.79 (s, 6H, –OCH3), 3.65–3.58
(m, 1H, CHH), 0.99 (s, 9H, (CH3)3) ppm. 13C NMR (75 MHz, CDCl3):
d = 168.39, 162.04, 159.57, 136.81, 130.43, 118.79, 116.81, 104.95,
4.2. Ligand synthesis
4.2.1. General procedure for the synthesis of cinnamamides 6a
and 6b
A dry two-necked round-bottomed flask (50 mL) equipped with
a magnetic stirrer bar was charged with trans-2,4-dimethoxycin-
namic acid 4 (2.0 g, 9.61 mmol), dimethylformamide (0.08 mL,
1.03 mmol) and CH2Cl2 (20 mL). The solution was cooled to 0 °C,
and oxalyl chloride (1.73 mL, 1.98 mmol) was added dropwise over
a 30-min period and the solution was stirred at room temperature
until the evolution of gas ended. The solvent was evaporated in va-
cuo to give trans-2,4-dimethoxycinnamoyl chloride 5 as a dark
98.31, 63.01, 59.66, 55.35, 33.75, 26.97 ppm. IR (KBr) mmax
:
3290.35, 3075.35, 2961.10, 2837.86, 1651.53, 1605.25, 1545.18,
1545.18, 1504.74, 1419.70, 1355.60, 1298.89, 1268.05, 1211.12,
1160.20, 1138.74, 1033.08, 985.76, 833.11, 798.31, 731.20,
634.75 598.38 cmꢀ1. ½a D21
¼ ꢀ3:3 (c 1.17, CHCl3). TOF-MS m/z:
ꢁ

E. P. Carreiro et al. / Tetrahedron: Asymmetry 20 (2009) 1272–1278
1277
308.19 [M+H]+ HRMS (TOF) found, 308.18563; C17H26N1O4 re-
quires 307.17836.
round-bottomed flask (50 mL) fitted with a magnetic stirring bar
was charged with solution of (S)-phenylglycinol (1.0 g,
a
7.30 mmol) and dry CH2Cl2 (20 mL) and the solution was cooled
to 0 °C using an ice bath. Dry triethylamine (1.27 mL, 9.13 mmol)
was added via syringe. A solution of 2-(2-chlorobenzylidene)malo-
nyl chloride 9a (0.96 g, 3.6 mmol) in CH2Cl2 (5 mL) was slowly
added via syringe to the vigorously stirred reaction mixture over
30 min. The ice bath was removed, and the reaction mixture was
stirred at room temperature for 4 h. The reaction mixture was
washed with 2 M HCl (12 mL), saturated aqueous NaHCO3
(15 mL) and the aqueous layer was back-extracted with CH2Cl2
(10 mL). The combined organic extracts were washed with brine
(15 mL), and the aqueous layer was back-extracted with CH2Cl2
(15 mL). The combined organic extracts were dried over anhydrous
MgSO4, filtered and concentrated in vacuo to give (S,S)-N,N0-bis(2-
hydroxy-1-phenylethyl)-2-(2-chlorobenzylidene)malonamide 10a
as a yellow solid. The crude product was purified by column chro-
matography (silica gel, EtOAc) to afford the amide 11a as a white
solid. Yield: 0.69 g (41%); mp 79–80 °C; 1H NMR (300 MHz, CDCl3):
d = 8.12 (d, 1H, J = 8.1 Hz, NH), 7.88 (s, 1H, RCH@CR2), 7.41 (d, 1H,
J = 8.1 Hz, NH), 7.32–7.12 (m, 10H, CH(Ar)), 7.02–7.00 (m, 3H,
CH(Ar)), 6.90–6.85 (m, 2H, CH(Ar)), 5.22–5.12 (m, 2H, CH), 3.93–
3.62 (m, 4H, CH2) ppm. 13C NMR (75 MHz, CDCl3): d = 167.66,
164.43, 138.39, 137.59, 136.57, 134.35, 133.10, 131.78, 130.49,
129.83, 129.50, 128.80, 128.68, 128.56, 127.80, 127.70, 126.88,
4.2.2. General procedure for the synthesis of Arylid-OXs (1a and
1b)
A solution of methanesulfonyl chloride (0.21 g, 1.8 mmol) in dry
CH2Cl2 (1 mL) was added dropwise over 20 min to a solution of
cinnamamide 6a (0.3 g, 6.12 mmol) and dry triethylamine
(0.51 mL, 3.67 mmol) in dry CH2Cl2 (15 mL) and the solution was
stirred between ꢀ5 and ꢀ10 °C. The reaction mixture was allowed
to warm to room temperature and stirring was continued for
3 days. The reaction mixture was then poured into a saturated
aqueous NH4Cl solution (15 mL). The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (2 ꢂ 10 mL).
The combined organic layers were washed with brine, dried
(MgSO4), filtered and concentrated to afford the crude product.
The crude product was purified by column chromatography (silica
gel, EtOAc/Hex (1:1)) giving the (+)-(S)-trans-2-(2,4-dimethoxy-
phenyl)-(4-phenyloxazoline-2-yl)ethene 1a as a white semi-solid.
Yield: 0.278 g (98%). 1H NMR (300 MHz, CDCl3): d = 7.64 (d, 1H,
J = 16.4 Hz, RCH@CHR), 7.41 (d, 1H, J = 8.6 Hz, CH(Ar)), 7.33–7.29
(m, 2H, CH(Ar)), 7.26–7.21 (m, 3H, CH(Ar)), 6.71 (d, 1H, J = 16 Hz,
RCH@CHR), 6.48 (dd, 1H, J = 8.5 and 2.3 Hz, CH(Ar)), 6.42 (d, 1H,
J = 2.3 Hz, CH(Ar), 5.26 (dd, 1H, J = 10 and 8 Hz, CHH), 4.66 (dd,
1H, J = 10 and 8 Hz, CHH), 4.14 (t, 1H, J = 8.2 Hz, CH), 3.81 (d, 3H,
J = 6 Hz, –OCH3), 3.78 (d, 3H, J = 6 Hz, –OCH3) ppm. 13C NMR
(100 MHz, CDCl3): d = 165.30, 162.08, 159.22, 142.51, 135.69,
129.50, 128.96, 128.64, 127.43, 126.63, 117.21, 112.94, 105.13,
98.38, 74.24, 69.82, 55.37 ppm. IR (NaCl, CHCl3): mmax 3035.14,
3025.48, 3016.37, 2962.79, 1646.10, 1607.91, 1576.04, 1504.34,
1465.94, 1421.05, 1363.97, 1269.68, 1161.88, 1033.79, 994.42,
126.72, 66.03, 66.43, 56.42, 55.98 ppm. IR (KBr)
mmax: 3270.75,
3061.11, 3031.37, 2928.83, 2875.23, 1664.61, 1529.25, 1454.52,
1373.48, 1262.64, 1205.16, 1053.98, 1035.17, 950.65, 910.67,
839.09,
804.63,
756.08,
699.96,
636.69,
531.42 cmꢀ1
.
½
a 2D0
ꢁ
¼ þ62:2 (c 1.03, CHCl3). TOF-MS m/z: 465.16 [M+H]+; HRMS
(TOF) found 465.15756, C26H26N2O4Cl1 requires 464.15029.
839.88, 790.23, 776.47, 700.94, 665.69 cmꢀ1. ½a D22
ꢁ
¼ þ7:7 (c 0.57,
Compound 10b: The same procedure as described previously
was used in the reaction of 2-(2-methoxy-benzylidene)malonyl
chloride 9b (0.95 g, 3.65 mmol) with (S)-phenylglycinol (1.0 g,
7.3 mmol) and dry triethylamine (1.27 mL, 9.13 mmol) to
give (S,S)-N,N0-bis(2-hydroxy-1-phenylethyl)-2-(2-methoxyben-
zylidene)malonamide 10b as a white solid after purification by col-
umn chromatography (silica gel, EtOAc); Yield: 0.884 g (53%). mp
130.2–131.7 °C; 1H NMR (400 MHz, CDCl3): d = 8.4 (d, 1H,
J = 7.8 Hz, NH), 7.95 (s, 1H, RCH@CR2), 7.32–7.17 (m, 11H, CH(Ar)),
7.03–7.01 (m, 2H, NH, CH(Ar)), 6.72–6.66 (m, 2H, CH(Ar)), 5.20–
5.13 (m, 2H, CH), 3.87–3.63 (m, 4H, CH2), 3.55 (s, 3H, –OCH3),
3.32 (sb, 1H, –OH), 2.06 (sb, 1H, –OH) ppm. 13C NMR (100 MHz,
CDCl3): d = 168.50, 164.77, 157.47, 138.65, 137.92, 136.51,
131.04, 130.70, 129.88, 128.65, 127.69, 127.63, 126.88, 126.71,
122.42, 120.50, 110.68, 66.46, 65.61, 56.37, 55.88, 55.14 ppm. IR
CHCl3). FAB-MS m/z: 310.17 [M+H]+.
Compound 1b: Using the same procedure as described previ-
ously, cinnamamide 6b (0.40 g, 1.3 mmol) was reacted with meth-
anesulfonyl chloride (0.22 g, 1.95 mmol) and dry triethylamine
(0.55 mL, 3.91 mmol) to give the (S)-trans-2-(2,4-dimethoxy-
phenyl)-(4-tert-butyloxazoline-2-yl)ethene 1b as a yellow semi-
solid after purification by column chromatography (silica gel,
EtOAc:Hex (1:2)). Yield: 0.21 g (55%). 1H NMR (300 MHz, CDCl3):
d = 7.54 (d, 1H, J = 16.4 Hz, RCH@CHR), 7.42 (d, 1H, J = 8.5 Hz,
CH(Ar)), 6.68 (d, 1H, J = 16.4 Hz, CRH@CHR), 6.5 (dd, 1H, J = 7.5
and 3 Hz, CH(Ar)), 6.44 (d, 1H, J = 2.3 Hz, CH(Ar)), 4.30–4.23 (m,
1H, CH), 4.13 (t, 1H, J = 9 Hz, CHH), 3.97 (dd, 1H, J = 8 and 9 Hz,
CHH), 3.85 (s, 3H, –OCH3), 3.83 (s, 3H, –OCH3), 0.93 (s, 9H,
C(CH3)3) ppm. 13C NMR (100 MHz, CDCl3): d = 164.01, 161.90,
159.04, 134.84, 129.22, 113.13, 105.02, 98.26, 75.83, 68.13, 55.22,
33.72, 25.75 ppm. IR (NaCl, CHCl3): mmax 3030.34, 3019.90,
2967.63, 1640.46, 1601.90, 1505.25, 1458.14, 1301.40, 1277.66,
1206.28, 1163.33, 1121.82, 1033.77, 931.21, 841.06, 780.98,
(KBr) mmax
:
3333.23, 3247.66, 3061.21, 2939.26, 2939.26,
2878.50, 2837.51, 1656.85, 1601.89, 1534.53, 1489.62, 1462.37,
1436.63, 1373.17, 1283.52, 1247.93, 1196.21, 1127.67, 1050.56,
1027.27, 901.51, 850.75, 753.43, 700.98, 637.15, 526.94 cmꢀ1
.
663.41 cmꢀ1. ½a 2D1
ꢁ
¼ ꢀ38:3 (c 1.44, CHCl3). TOF-MS m/z: 290.18
½
a 2D2
ꢁ
¼ þ62:2 (c 0.85, CHCl3). FAB-MS m/z: 416.27 [M+H]+.
[M+H]+. HRMS (TOF) found 290.17507 C17H24N1O3 requires
289.16779.
4.2.4. General procedure for the synthesis of Arylid-Box 2a and
2b
4.2.3. General procedure for the synthesis of malonamides 10a
and 10b
A solution of methanesulfonyl chloride (0.15 g, 1.3 mmol) in dry
dichloromethane (1 mL) was added dropwise over 20 min to a
solution of malonamide 10a (0.2 g, 0.43 mmol) and dry triethyl-
amine (0.36 mL, 2.58 mmol) in dry dichloromethane (10 mL) and
the solution was stirred between ꢀ5 and ꢀ10 °C. The reaction mix-
ture was allowed to warm to room temperature and stirring was
continued for 3 days. The reaction mixture was then poured into
a saturated aqueous NH4Cl solution (10 mL). The organic layer
was separated and the aqueous layer was extracted with CH2Cl2
(2 ꢂ 5 mL). The combined organic layers were washed with brine,
dried (MgSO4), filtered and concentrated to afford the crude prod-
uct. The crude product was purified by column chromatography
A dry two-necked round-bottomed flask (50 mL) equipped with
a
magnetic stir bar was charged with 2-(2-chlorobenzyli-
dene)malonic acid 8a (4.8 g, 21.0 mmol), dimethylformamide
(0.23 mL, 2.94 mmol) and CH2Cl2 (30 mL). The solution was cooled
to 0 °C, and oxalyl chloride (4.6 mL, 53 mmol) was added dropwise
over 30 min and the solution was stirred at room temperature until
the evolution of gas ended. The solution was evaporated in vacuo
to give 2-(2-chlorobenzylidene)malonyl chloride 9a as a yellow
semi-solid (due to the unstable nature of this compound it was
stored in the freezer at –10 °C). Yield: 5.14 g (100%). A two-necked

1278
E. P. Carreiro et al. / Tetrahedron: Asymmetry 20 (2009) 1272–1278
(silica gel, EtOAc:Hex (1:2)) giving the (+)-bis[(S)-4-phenyloxazo-
line-2-yl]-2-(2-chlorophenyl)ethene 2a as white semi-solid.
pump. After the addition of ethyl diazoacetate, the mixture was
stirred for 16 h. The reaction mixture was firstly passed through
a short pad of silica gel (washed with CH2Cl2) to remove the cata-
lyst complex, the products were then isolated by column chroma-
tography (hexane/EtOAc 9:1). All cyclopropane products were
obtained as a mixture of cis and trans diastereomers, and the ratio
was determined using GC analysis. Isolated yields, diastereoselec-
tivities and enantioselectivities are given in Tables 1 and 5.
a
Yield: 0.11 g (60%). 1H NMR (300 MHz, CDCl3): d = 7.99 (s, 1H,
R2C@CHR), 7.65 (d, J = 7.2 Hz, CH(Ar)), 7.45–7.18 (m, 12H, CH(Ar)),
5.47 (t, 1H, J = 9.3 Hz, CH), 5.35–5.29 (m, 1H, CH), 4.84–4.69 (m, 2H,
CH2), 4.27–4.18 (m, 2H, CH2) ppm. 13C NMR (75 MHz, CDCl3):
d = 163.02, 161.36, 141.97, 141.70, 138.80, 132.83, 128.68,
128.54, 126.91, 126.73, 126.66, 120.82, 74.92, 70.33 ppm. IR (NaCl,
CHCl3):
mmax 3030.55, 3016.64, 3011.29, 1671.60, 1639.05, 1494.09,
1473.40, 1454.80, 1409.44, 1355.76, 1261.55, 1230.10, 1209.92,
Acknowledgments
1182.48, 1021.59, 935.88, 790.36, 755.96, 665.58 cmꢀ1
.
½
a 2D0
ꢁ
¼ þ50:3 (c 1.89, CHCl3). TOF-MS m/z: 428.13 [M+H]+; HRMS
We thank the Fundação para a Ciência e a Tecnologia and the
Programma Opercional para Ciência e Inovação for generous finan-
cial support in the form of a research grant (PPCDT/QUI/55779/
2004), including a PhD grant to EPC (SFRH/BD/277688/2006) that
was partly funded by the European Community fund FEDER. The
personnel of the C.A.C.T.I (University of Vigo, Spain) are acknowl-
edged for analytical data.
(TOF) found 429.2073; C26H22N2O2Cl1 requires 428.12916.
Compound 2b: Using the same procedure as described previ-
ously, malonamide 10b (0.40 g, 8.69 mmol) was reacted with
methanesulfonyl chloride (0.25 g, 2.17 mmol) and dry triethyl-
amine (0.73 mL, 5.21 mmol) to give the (+)-bis[(S)-4-phenyloxazo-
line-2-yl]-2-(2-methoxyphenyl)ethene 2b as a white solid after
crystallization with CH2Cl2/EtOAc/Hex. Yield: 0.29 g (80%); mp
167.0–168.0 °C 1H NMR (300 MHz, CDCl3): d = 8.05 (s, 1H,
R2C@CHR), 7.60 (d, 1H, J = 6.6 Hz, CH(Ar)), 7.36–7.27 (m, 8H,
CH(Ar)), 7.25–7.22 (m, 3H, CH(Ar)), 6.89 (t, 2H, J = 6.9 Hz, CH(Ar)),
5.48–5.32 (m, 2H, CH), 4.81–4.72 (m, 2H, CH2), 4.26–4.18 (m, 2H,
CH2), 3.85 (s, 3H, –OCH3) ppm. 13C NMR (75 MHz, CDCl3):
d = 163.63, 162.22, 156.81, 142.29, 142.00, 137.72, 129.41,
128.61, 128.49, 126.98, 126.74, 123.30, 120.35, 118.17, 110.68,
References
1. For recent reviews see: (a) Dagorne, S.; Bellemin-Laponnaz, S.; Maisse-François,
A. Eur. J. Inorg. Chem. 2007, 913; (b) Desimoni, G.; Faita, G.; Jørgensen, K. A.
Chem. Rev. 2006, 3561; (c) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104,
4151; (d) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry
1998, 9, 1.
2. (a) Patai, S.; Rappoport, Z. The Chemistry of the Cyclopropyl Group; Wiley and
Sons: New York, NY, 1987; (b)Small Ring Compounds in Organic Synthesis VI; de
Meijere, A., Ed.; Springer: Berlin, Germany, 2000; Vol. 207.
3. Carreiro, E. P.; Chercheja, S.; Burke, A. J.; Ramalho, J. P. P.; Rodrigues, A. I. J. Mol.
Catal. A: Chem. 2005, 236, 38.
4. (a) Carreiro, E. P.; Chercheja, S.; Moura, N.; Gertrudes, S. C.; Burke, A. J. Inorg.
Chem. Commun. 2006, 9, 823; (b) Burke, A. J.; Carreiro, E. P.; Chercheja, S.;
Moura, N. M. M.; Ramalho, J. P. P.; Rorigues, A. I.; Santos, C. I. M. J. Organomet.
Chem. 2007, 692, 4863.
74.84, 74.81, 70.20, 70.10, 55.49 ppm. IR (KBr)
mmax: 3057.47,
3024.99, 3002.36, 2972.93, 2941.31m 2908.30, 2852.81, 2605.41,
2496.44, 1676.68, 1633.40, 1597.21, 1576.55, 1489.23, 1467.47,
1450.61, 1403.22, 1355.34, 1318.32, 1299.83, 1250.74, 1200.81,
1176.47, 1113.87, 1018.05, 962.11, 936.94, 910.55, 756.63,
701.76, 641.56, 596.73, 526.34 cmꢀ1
.
½
a 2D0
ꢁ
¼ þ137:8 (c 0.94,
5. Feringa, B. L. Acc. Chem. Acc. Chem. Res. 2000, 33, 346.
CHCl3). TOF-MS m/z: 425.18 [M+H]+. HRMS (TOF) found,
6. (a) Luan, X.; Mariz, R.; Robert, C.; Gatti, M.; Blumentrintt, S.; Linden, A.; Dorta,
R. Org. Lett. 2008, 10(24), 5569; (b) Ikeda, S.; Kondo, H.; Arii, T.; Odashima, K.
Chem. Commun. 2002, 2422.
425.18597; C27H25N2O3 requires 424.17869.
7. Neustadt, B. R.; Smith, E. M.; Nechuta, T. L.; Bronnenkant, A. A.; Haslanger, M.
F.; Watkins, R. W.; Foster, C. J.; Sybertz, E. J. J. Med. Chem. 1994, 37, 2461.
8. Stewart, J. J. P. J. Mol. Model. 2007, 13, 1173–1213.
9. MOPAC2007, James J. P. Stewart, Stewart Computational Chemistry, Version
7.319L web: http://OpenMOPAC.net.
4.3. Cyclopropanations using [Cu(OTf)]2ꢃ(C6H6) and
[Cu(MeCN)4]PF6 pre-catalysts
Pre-catalyst (0.014 mmol, 1 mol %) or (0.028 mmol, 2 mol %)
was added to a two-necked round-bottomed flask containing the
chiral ligand (2.1–6.3 mol %) in CH2Cl2 (1 ml) and the solution
was stirred at room temperature for 15 min under a nitrogen
atmosphere. Alkene (14 mmol) and a solution of ethyl diazoacetate
(0.159 g, 1.4 mmol) in CH2Cl2 (1 ml) or toluene (1 ml) were then
added to the reaction mixture over a period of 16 h using a syringe
10. Beck, A. D. J. Chem. Phys. 1993, 98, 5648.
11. Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. 1988, 37, 785.
12. Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon, M. S.; Jensen,
J. H.; Koseki, S.; Matsunga, N.; Nguyen, K. A.; Su, S. J.; Windus, T. L.; Dupuis, M.;
Montgomery, J. A. J. Comput. Chem. 1993, 14, 1347.
13. Piguet, C.; Bernardinelli, G.; Hopfgartner, G. Chem. Rev. 1997, 97, 2005.
14. Mirica, L. M.; Ottenwaelder, X.; Stack, T. D. P. Chem. Rev. 2004, 104, 1013.
15. Csoregh, I.; Kierkegaard, P.; Norrestam, R. Acta Crystallogr., Sect. B 1975, 31, 314.