Asymmetric Friedel-Crafts alkylation of activated benzenes with methyl (E)-2-oxo-4-aryl-3-butenoates catalyzed by [Pybox/Sc(OTf)3]

Article abstract of DOI:10.1016/j.tet.2010.02.054

The asymmetric Friedel-Crafts reaction between methyl (E)-2-oxo-4-aryl-3-butenoates (1a-c) and activated benzenes (2a-d) has been efficiently catalyzed by the Sc^III triflate complex of (4′S,5′S)-2,6-bis[4′-(triisopropylsilyl) oxymethyl-5′-pheny

Full text of DOI:10.1016/j.tet.2010.02.054

Tetrahedron 66 (2010) 3024–3029
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Asymmetric Friedel–Crafts alkylation of activated benzenes with methyl
(E)-2-oxo-4-aryl-3-butenoates catalyzed by [Pybox/Sc(OTf)3]
*
Giuseppe Faita, Mariella Mella, Marco Toscanini, Giovanni Desimoni
`
Dipartimento di Chimica Organica dell’Universita di Pavia, Viale Taramelli 10, I-27100 Pavia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric Friedel–Crafts reaction between methyl (E)-2-oxo-4-aryl-3-butenoates (1a–c) and
activated benzenes (2a–d) has been efficiently catalyzed by the ScIII triflate complex of (40S,50S)-2,6-
bis[40-(triisopropylsilyl) oxymethyl-50-phenyl-10,30-oxazolin-20-yl]pyridine (pybox 3). The 4,4-diaryl-2-
oxo-butyric acid methyl esters (4) are usually formed in good yields and the enantioselectivity is up to
99% ee. The sense of the stereoinduction can be rationalized with the same octahedral complex (10)
between 1, pybox 3 and Sc triflate already proposed for other reactions involving pyruvates, and cata-
lyzed by the same complex.
Received 19 November 2009
Received in revised form 22 January 2010
Accepted 15 February 2010
Available online 18 February 2010
Keywords:
Asymmetric catalysis
Friedel–Crafts reaction
Enantioselectivity
PYBOX ligand
Ó 2010 Elsevier Ltd. All rights reserved.
Scandium triflate
1. Introduction
1,3-dimethoxybenzene and methyl 4-phenyl-2-oxo-3-butenoate or
ethyl 2-oxo-3-pentenoate, catalyzed by [(40S)-2,2-bis[40-phenyl-
The catalytic enantioselective Friedel–Crafts reaction involving
the formation of a new C–C bond between a double bond and an
activated aromatic ring is one of the most fundamental and flexible
reactions in organic chemistry.1
10,30-oxazolin-20-yl]propane/Cu(OTf)2] (Ph-Box) complex, has been
studied, and the enantioselectivity was 60 and 89% ee, re-
spectively.2 The enantioselective organocatalytic 1,4-addition of
a,b-unsaturated aldehydes and several aromatic amines has been
Indole is the most frequently used aromatic ring because of the
biological relevance of its reaction products;2–18 some selected
examples show that the reaction may occur: (a) with an electron-
reported to give the alkylated products with ee in the range 84–
99%.24
The successful metal-catalyzed asymmetric addition of aromatic
derivatives to alkenes requires the synergistic concurrence of two
elements: an electron-rich benzene, and a suitably designed cata-
lyst based on a Lewis acid and a chiral ligand, which is usually a CuII/
poor alkene, which is usually an activated
bonyl compound such as aryliden-pyruvates,1d–5a,b ethene-di- and
tri-carboxylates,6–9 -unsaturated acyl phosphonates,5c,d,10
nitroalkenes,11–13 0-hydroxy-enones,14 simple enones;15 (b) on
a,b-unsaturated car-
a,b
a
Box complex,1a,25 or [lanthanide/2,6-bis(40-10,30-oxazolin-20-
a
the carbon atom of a carbonyl group following the scheme of an
aldol reaction;16,17 (c) on the carbon atom of an imino group to give
an aromatic amine.18
yl)pyridine (pybox) complex.1a,26
Since our previous research focussed on methyl (E)-2-oxo-4-
aryl-3-butenoates (1a–c), which react either with cyclopentadiene
to give a Diels–Alder reaction,27 or with indole in the above
mentioned Friedel–Crafts reaction,4 with excellent yield and enan-
tioselectivity when catalyzed with the ScIII triflate complex of (40S,50S)-
2,6-bis[40-(triisopropylsilyl)oxymethyl-50-phenyl-10,30-oxazolin-20-yl]
pyridine (3) (TIPS-pybox), the reaction between 1a–c and some
electron-rich benzenes was tested under the same catalytic condi-
tions. The choice of 1a–c was also determined from the results of the
The Friedel–Crafts reaction involving activated benzenes is less
common, but again the reaction with
a-imino esters has been used
to obtain non-natural aromatic
a
-amino acids,19 as in the alkylation
of ethyl trifluoropyruvate to synthesize aromatic
a-hydroxy-
esters.16,20–23
With such wide research around this topic, it seems rather as-
tonishing that only two examples of enantioselective reactions
with activated benzenes have been reported. The reaction between
above research.4,27 These unsaturated
a-dicarbonyl compounds
bind to the catalyst as a bicoordinating reagent, and the resulting
reactive intermediate suggests a defined approach, which is
interesting to test if it corresponds to the experimental stereo-
chemical result.
* Corresponding author. Tel.: þ39 0382 987313; fax: þ39 0382 987866.
E-mail address: desimoni@unipv.it (G. Desimoni).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.054

G. Faita et al. / Tetrahedron 66 (2010) 3024–3029
3025
2. Results and discussion
analogue 4bb, both of which are the result of the electrophilic attack
in the most activated 4-position of 2b. These reactions gave two
further couples of diastereomeric products: 5a and 6a from 2a
(difficult to isolate but clearly detected by 1H- and 13C NMR spec-
troscopy), 5b and 6b from 2b, separated bycolumn chromatography.
These [1:2] products derive from a further electrophilic attack of 1a
and 1b on the activated 5-position of 4ab and 4bb (Scheme 2dTable 2:
entries 1,3). This was experimentally proved running the reaction
between 1b and 4bb, which gave 5b and 6b (Scheme 2).
The first simple model to test the efficiency of the catalyst was
the reaction of 1 with 1,3,5-trimethoxybenzene (2a). Preliminarily,
the reaction of methyl (E)-2-oxo-4-phenyl-3-butenoate (1a) and 2a
was performed with ScIII triflate in the absence of a chiral ligand in
CH2Cl2 at ꢀ50 ꢁC (Scheme 1), and the yield of 4aa was nearly
quantitative (Table 1dentry 1). Then, the same reaction was run
both at ꢀ50 ꢁC and ꢀ20 ꢁC with 10% mol of [(TIPS-pybox)/Sc(OTf)3]
and 3 Å molecular sieves (MS), the main difference being simply
the time required to consume the starting materials.
O
Ar
H
O
O
CO2Me
MeO
+
OMe
Ar
CO2Me
1a,b
Ar
CO2Me
MeO
OMe
Sc(OTf)3/MS
R
+
3
1a: Ar = Ph
OMe
2a
OMe
R
4ab: R = H; Ar = Ph
1b: Ar = p.BrC6H4
4bb: R = H; Ar = p.BrC6H4
4ac: R = OMe; Ar = Ph
4bc: R = OMe; Ar = p.BrC6H4
1c: Ar = p.NO2C6H4
MeO
O
Ar
H
OMe
Sc(OTf)3 - MS
CO2Me
2b: R = H
from 4bb + 1b
2c: R = OMe
Sc(OTf)3
Ar
MeO
OMe
O
O
Sc(OTf)3
N
4aa: Ar = Ph
Ph
Ph
4ba: Ar = p.BrC6H4
O
Ar
O
N
N
from 1a,b + 2b
4ca: Ar = p.NO2C6H4
3
OTIPS
MeO2C
CO2Me
OTIPS
MeO
OMe
Scheme 1. Reaction of methyl (E)-2-oxo-4-aryl-3-butenoates (1a–c) with 1,3,5-tri-
methoxybenzene (2a).
5a,6a: Ar = Ph
5b,6b: Ar = p.BrC6H4
The structure of 4aa was easily determined by 1H- and 13C NMR
spectroscopy and IR analysis of the product isolated after simple
column chromatographic separation of the reaction product from 3.
The yield was excellent and the ee at ꢀ50 ꢁC and ꢀ20 ꢁC, de-
termined by HPLC on Chiralpak AD column, was 97 and 99%, re-
spectively (Table 1dentries 2,3).
Under the same conditions, the reactions between methyl (E)-2-
oxo-4-(4-bromophenyl)-3-butenoate and the 4-nitro-analogue
(1b,c) and 2a were performed with catalyst based on either ScIII
(Table 1dentries 4,7) or [(3)/Sc(OTf)3] (Table 1dentries 5,6,8,9).
Even if the reactions at ꢀ50 ꢁC give low yields (56 and 20% for 1b
and 1c, respectively), the enantioselectivities are again excellent (ee
>95%). At ꢀ20 ꢁC the ee are slightly lowered (87–89%), but the
yields are significantly higher.
Scheme 2. Reactions between methyl (E)-2-oxo-4-aryl-3-butenoates (1a,b) and 1,3-
dimethoxy- or 1,2,3-trimethoxybenzenes (2b,c).
The above reactions were then performed with [(3)/Sc(OTf)3] as
catalyst at ambient temperature between 1a and 2b, and at ꢀ20 ꢁC
between 1b and 2b. Under these conditions, the bis-addition is
suppressed and the only products obtained are 4ab and 4bb.The
rate of the reactions are lowered, the yields are modest (probably
because of the less Lewis-acid character of ScIII after the co-
ordination with 3), but the ee of 4ab (93%) and 4bb (80%) are again
satisfactory and even better than some results reported in the lit-
erature (Table 2dentries 2,4). The reaction between 1,2,3-trime-
thoxybenzene (2c) and 1a,b, catalyzed by Sc(OTf)3 is sluggish and
must be performed at ambient temperature. The yields are satis-
factory and the attack of the electrophiles occurs in the 4-position
to give 4ac and 4bc (Scheme 2, Table 2dentries 5,6). Unfortunately,
the same reactions, performed with [(3)/Sc(OTf)3] as catalyst, do
not give significant amount of products.
The reaction between 1a,b and 3-methoxy-N,N-dimethylaniline
(2d), performed with Sc(OTf)3, gave 4ad and 4bd as main products,
resulting from the attack of the electrophiles in the most activated
4-position of 2d. The reaction of 1a also gave a couple of di-
astereoisomers 7 and 8, separated by column chromatography,
whose 1H- and 13C NMR spectra show they derive from the in-
termediate 9, which can either collapse to 4ad, or can be quenched
by a second molecule of 1a (Scheme 3).
Table 1
Friedel–Crafts reaction between methyl (E)-2-oxo-4-aryl-3-butenoates (1a–c) and
2a in CH2Cl2 at ꢀ50 ꢁC catalyzed by 10 mol % catalyst
Entry Reagent Catalyst
T/ꢁC Time
Product 4 Yield % 4 ee %
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1c
1c
1c
Sc(OTf)3
ꢀ50 1 h
4aa
4aa
4aa
4ba
4ba
4ba
4ca
90
92
97
70
56
86
84
20
85
d
[3/Sc(OTf)3] ꢀ50 24 h
97 (þ)
>99 (þ)
d
[3/Sc(OTf)3] ꢀ20 5 h
Sc(OTf)3
ꢀ50 1 h
[3/Sc(OTf)3] ꢀ50 24 h
99 (þ)
89 (þ)
d
[3/Sc(OTf)3] ꢀ20 7 h
Sc(OTf)3
ꢀ20 2 h
[3/Sc(OTf)3] ꢀ50 7 days 4ca
[3/Sc(OTf)3] ꢀ20 2 days 4ca
96 (þ)
87 (þ)
The Friedel–Crafts reaction was performed on two further
The main difference from the reactivity reported in Scheme 2 is
that, in this case, 7 and 8 cannot be obtained from 4ad. No by-
product was obtained in a detectable yield from 1b.
When the reactions were performed at ꢀ20 ꢁC with [(3)/
Sc(OTf)3] as catalyst, the bis-addition is suppressed, 4ad and 4bd
are the only reaction products (Scheme 3, Table 3dentries 2,4), the
yields are good and the enantiomeric excess is higher than 90%.
methoxybenzenes: 1,3-dimethoxybenzene (2b), already tested in
the reaction with 1a catalyzed by [(Ph-box)/Cu(OTf)2],2 and 1,2,3-
trimethoxybenzene (2c).
ScIII catalysis of the reaction between 1a,b (the reactionwith 1c is
sluggish at ambient temperature) and 2b at ꢀ20 ꢁC gave two main
products: 4ab, a product already described by Jørgensen,2 and its

3026
G. Faita et al. / Tetrahedron 66 (2010) 3024–3029
Table 2
Friedel–Crafts reaction in CH2Cl2 between methyl (E)-2-oxo-4-aryl-3-butenoates (1a,b) and 1,3,-dimethoxybenzene (2b) (at ꢀ20 ꢁC) or 1,2,3-trimethoxybenzene (2c) (at
ambient temperature) catalyzed by 10 mol % catalyst
Entry
1
2
Catalyst
T/ꢁC
Time
Product
4 Yield %
4 ee %
Config.
1
2
3
4
5
6
1a
1a
1b
1b
1a
1b
2b
2b
2b
2b
2c
2c
Sc(OTf)3
ꢀ20
t.a.
ꢀ20
ꢀ20
t.a.
24 h
24 h
12 h
2 days
48 h
24 h
4aba
4ab
4bbc
4bb
4ac
57
65
42
30
64
52
d
[3/Sc(OTf)3]b
Sc(OTf)3
93 (þ)
d
(4R)
[3/Sc(OTf)3]
Sc(OTf)3
Sc(OTf)3
80 (þ)
d
t.a.
4bc
d
a
In addition 29% yield of a mixture of 5a and 6a.
Catalyst: 20 mol %.
In addition 8% yield of 5b and 7% of 6b.
b
c
N
1a
O
O
Ar
H
3
Sc(OTf)3/MS
Sc(OTf)3
3
+
Ar
CO2Me
CO2Me
OMe
1a,b
Me2N
OMe
2d
4ad: Ar = Ph
4bd: Ar = p.BrC6H4
Sc(OTf)3
4ad + 1a
Sc(OTf)3
from 1a + 2d
10
O
Ph
O
O
H
H
O
H
MeO2C
CO2Me
Re-face
(4R)-4aa, 4ab, 4ad
MeO2C
H
H
H
Ph
CO2Me
H
Ph
Ph
H
Me2N
OMe
N
OMe
Figure 1. The assumed reacting intermediate 10 of the Friedel–Crafts alkylation re-
action between 1a and activated benzenes 2, catalyzed by the Sc(OTf)3 complex of
pybox 3, which gives the (R)-products.
9
7,8
Scheme 3. Reaction of methyl (E)-2-oxo-4-aryl-3-butenoates (1a,b) with 3-methoxy-
N,N-dimethylaniline (2d).
3. Conclusion
Table 3
In conclusion, this research deals with the asymmetric Friedel–
Crafts reaction between methyl (E)-2-oxo-4-aryl-3-butenoates
(1a–c) and activated benzenes (2a–d) catalyzed by the ScIII triflate
complex of (40S,50S)-2,6-bis[40-(triisopropylsilyl) oxymethyl-50-
phenyl-10,30-oxazolin-20-yl]pyridine (pybox 3). The 4,4-diaryl-2-
oxo-butyric acid methyl esters (4), which are usually formed in
good yields and the enantioselectivity up to 99% ee, have the ab-
solute configuration (R), whose formation can be rationalized with
the octahedral intermediate (10).
Friedel–Crafts reaction between methyl (E)-2-oxo-4-aryl-3-butenoates (1a,b) and 3-
methoxy-N,N-dimethylaniline (2d) in CH2Cl2 at ꢀ20 ꢁC catalyzed by 10 mol % catalyst
Entry Reagent Catalyst
T/ꢁC Time (h) Product 4 Yield % 4 ee %
1
2
3
4
1a
1a
1b
1b
Sc(OTf)3
[3/Sc(OTf)3] ꢀ20
Sc(OTf)3
ꢀ20
ꢀ20
2
4
2
4ada
4ad
4bd
4bd
69
70
82
83
d
92 (þ)
d
[3/Sc(OTf)3] ꢀ20 10
93 (þ)
a
In addition 20% yield of 8 and 5% of 9.
Intermediate 10 has already been proposed to rationalize the
sense of the stereoinduction of the Friedel–Crafts alkylation of indole
with 1,4 the Diels–Alder/Hetero-Diels–Alder reactions of cyclo-
pentadiene,27 and the Mukaiyama–aldol reaction of pyruvates.28
The constancy of the model of the reacting intermediate in so
many different reactions is a good index of the flexibility of the
catalyst derived by pybox 3, and offers promising perspectives to
predict the stereoinduction in new reactions involving dicarbonyl
derivatives.
Based on the absolute configuration determined by X-ray anal-
ysis of a chiral Friedel–Crafts adduct formed under enantioselective
catalysis with [(Ph-Box)/Cu(OTf)2], the (R) configuration was
assigned to the (þ)-4ab product.2 This is the same enantiomer
obtained from the reaction between 1a and 2b catalyzed by [(3)/
Sc(OTf)3] (Table 2dentry 2). Hence it seems reasonable to assign
the same absolute configuration to the major enantiomers obtained
under these catalytic conditions.
The (R) configuration for the products of the Friedel–Crafts re-
action between 1a–c and the activated benzenes 2a–d is consistent
with an octahedral reacting intermediate (10), obtained by
a bidentate coordination of 1a–c to the ScIII complex of 3 with the
ketonic C]O group equatorial, the ester carbonyl in the axial po-
sition and a triflate ion or a water molecule axial, which undergoes
the sterically less demanding attack of substituted benzenes to the
(Re)-face of the coordinated electrophile (Fig. 1) to give (R)-
products.
4. Experimental section
4.1. General and material
Melting points were determined by the capillary method and
are uncorrected. 1H- and 13C NMR spectra were recorded at 300 and
75 MHz, respectively (CDCl3, 25 ꢁC, TMS). IR spectra were registered
on a Perkin-Elmer RX I spectrophotometer. Optical rotations were
measured on a Perkin-Elmer 241 polarimeter. Separation and

G. Faita et al. / Tetrahedron 66 (2010) 3024–3029
3027
purification of the products was carried out by column chroma-
tography using Merck silica gel 60 (230–400 mesh). The enantio-
meric excess (ee) of the products was determined by HPLC using
Daicel columns (see text). Dichloromethane was hydrocarbon-
stabilised Aldrich ACS grade, distilled from calcium hydride and
used immediately. Scandium triflate was the Aldrich ACS reagent;
powdered molecular sieves 3 Å were heated under vacuum at
300 ꢁC for 5 h and kept in sealed vials in a dryer. (40S,50S)-2,6-Bis[40-
(triisopropylsilyl)oxymethyl-50-phenyl-10,30-oxazolin-20-yl]pyridine
(3) was prepared as previously described.29 (E)-2-Oxo-4-phenyl-
but-3-enoic acid methyl ester (1a) was prepared, following the
literature method,30,31 from etherification with methanol of the
potassium salt, obtained from benzaldehyde and pyruvic acid in the
presence of KOH: yellow needles from diisopropyl ether, mp
69–70 ꢁC (lit.,31 mp 70–71 ꢁC). Following the same procedure, and
starting from the suitable aldehyde, the following products were
prepared: (E)-2-Oxo-4-(4-bromophenyl)-but-3-enoic acid methyl
ester (1b), yield 35%, yellow needles from methanol, mp 120 ꢁC
(lit.,32 mp 122 ꢁC); (E)-2-oxo-4-(4-nitrophenyl)-but-3-enoic acid
methyl ester (1c), yield 32%, bright orange crystals from ethyl ac-
etate, mp 182–183 ꢁC (lit.,33 mp 182.5–183.5 ꢁC).
H3 and H5 aromatic proton), 5.29 (1H, t, J 7.6 Hz, benzylic proton),
3.91 (1H, dd, J 17.7, 7.6 Hz, CHH), 3.84 (3H, s, OMe), 3.80 (3H, s, OMe),
3.77 (6H, s, 2 OMe), 3.69 (1H, dd, J 17.7 Hz, 7.6 Hz, CHH); dC (75 MHz
CDCl3) 192.3, 160.9, 160.1, 158.2, 151.2, 145.5, 127.7, 127.4, 122.7,
109.8, 90.5, 55.1, 54.8, 52.4, 41.6, 33.6.
4.2.5. Methyl
4-(2,4-dimethoxyphenyl)-2-oxo-4-phenylbutanoate
(4ab). Eluant: cyclohexane/ethyl acetate 80:20, colourless oil;
nmax (liquid film) 1730 cmꢀ1 (C]O); dH (300 MHz CDCl3) 7.23–
7.31 (4H, m, aromatic protons), 7.20 (1H, m, aromatic proton),
6.99 (1H, d, J 9.0 Hz, H6 aromatic proton), 6.41–6.45 (2H, m, H3
and H5 aromatic protons), 4.96 (1H, t, J 7.6 Hz, benzylic proton),
3.84 (3H, s, OMe), 3.78 (3H, s, OMe), 3.77 (3H, s, OMe), 3.64
(1H, dd, J 16.8, 7.6 Hz, CHH), 3.49 (1H, dd, J 16.8, 7.7 Hz, CHH);
dC (75 MHz CDCl3) 192.4, 161.2, 159.5, 157.5, 143.0, 128.5, 128.3,
128.1 127.8, 127.7, 126.2, 123.9, 104.1, 98.7, 55.2, 52.8, 44.5, 38.6.
These NMR spectra are identical to those reported in the
literature.2
4.2.6. Methyl 4-[5-(3-methoxycarbonyl-3-oxo-1-phenylpropyl)-2,4-
dimethoxyphenyl]-2-oxo-4-phenylbutanoate (5a and 6a). Eluant:
cyclohexane/ethyl acetate 80:20, thick colourless oil; nmax (Nujol
mull) 1733 cmꢀ1 (C]O); dH (300 MHz CDCl3) (mixture of di-
astereoisomers) 7.30–7.16 (10Hþ10H, m, aromatic protons), 6.86
and 6.81 (2H, sþs, H6 of both diastereoisomer), 6.37 and 6.36 (2H,
sþs, H3 of both diastereoisomer), 4.89 (1H, t, J 7.6 Hz, benzylic
proton of one diastereoisomer), 4.88 (1H, t, J 7.6 Hz, benzylic proton
of one diastereoisomer), 3.81 (3Hþ3H, s, 2 OMe of one di-
astereoisomer), 3.78 (3Hþ3H, s, 2 OMe of one diastereoisomer),
3.76 (3Hþ3Hþ3Hþ3H, s, 4 OMe), 3.54–3.46 (4Hþ4H, m, CH2); dC
(75 MHz CDCl3) 192.5, 192.3, 161.2, 161.1, 156.27, 156.25, 142.9,
142.8, 128.6, 128.21, 128.19, 127.9, 127.7, 127.6, 126.2, 125.9, 122.9,
95.5, 55.4, 52.7, 44.3, 38.9, 38.8.
4.2. Reaction between (E)-2-oxo-4-arylbut-3-enoic acid
methyl ester (1a–c) and arenes (2a–d)
4.2.1. Reaction catalyzed by scandium triflate. General procedure. A
mixture of (E)-2-oxo-4-arylbut-3-enoic acid methyl ester (1a–c)
(0.30 mmol) and scandium triflate (0.03 mmol) in anhydrous
CH2Cl2 (0.3 mL) was stirred for 15 min at ambient temperature in
a rubber septum sealed vial and then cooled at the temperature
reported in Table 1. The required arene (2a–d) (0.40 mmol) was
added (when liquid with a microsyringe) and stirring was contin-
ued at the temperature and for the time reported in Tables 1–3. The
reaction was decomposed in water, extracted with CH2Cl2, dried,
and the reaction mixture was separated by column chromatogra-
phy (silicagel, 30 cm length, 1.5 cm diameter).
4.2.7. Methyl 4-(4-bromophenyl)-4-(2,4-dimethoxyphenyl)-2-oxo-
butanoate (4bb). Eluant: cyclohexane/ethyl acetate 90:10, colour-
less oil; [Found: C, 55.9; H, 4.8. C19H19BrO5 requires C, 56.03; H,
4.70%]; nmax (liquid film) 1733 cmꢀ1 (C]O); dH (300 MHz CDCl3)
7.39 (2H, d, J 8.4 Hz, ortho-Br aromatic protons), 7.14 (2H, d, J
8.4 Hz, meta-Br aromatic protons), 6.98 (1H, d, J 9.1 Hz, H6 aro-
matic proton), 6.43 (2H, m, H3 and H5 aromatic proton), 4.89 (1H,
t, J 7.5 Hz, benzylic proton), 3.84 (3H, s, OMe), 3.79 (3H, s, OMe),
3.76 (3H, s, OMe), 3.61 (1H, dd, J 17.2, 7.9 Hz, CHH), 3.48 (1H, dd, J
17.2, 7.3 Hz, CHH); dC (75 MHz CDCl3) 193.7, 160.7, 159.3, 157.1,
141.7, 130.9, 129.2, 127.9, 122.9, 119.6, 103.7, 98.3, 55.1, 54.7, 54.8,
52.5, 43.7 37.8.
4.2.2. Methyl 4-(2,4,6-trimethoxyphenyl)-2-oxo-4-phenylbutano-ate
(4aa). Eluant: cyclohexane/ethyl acetate 85:15, soft white nee-
dles, mp 56–57 ꢁC (methanol/diisopropyl ether/hexane); [Found:
C, 67.1; H, 6.1. C20H22O6 requires C, 67.03; H, 6.19%]; nmax (Nujol
mull) 1733 cmꢀ1 (C]O); dH (300 MHz CDCl3) 7.31–7.12 (5H, m, Ph
aromatic protons), 6.12 (2H, s, H3 and H5 aromatic proton), 5.16
(1H, t, J 8.1 Hz, benzylic proton), 3.82 (3H, s, OMe), 3.81 (1H, dd, J
17.6, 7.7 Hz, CHH), 3.79 (3H, s, OMe), 3.76 (6H, s, 2 OMe), 3.73 (1H,
dd, J 17.6, 7.7 Hz, CHH); dC (75 MHz CDCl3) 193.1, 161.2, 159.6,
158.4, 143.3, 127.4, 127.0, 125.2, 111.1, 90.6, 55.1, 54.7, 52.2, 42.4,
33.8.
4.2.8. Methyl
4-[5-(3-methoxycarbonyl-3-oxo-1-(4-bromophenyl)
propyl)-2,4-dimethoxyphenyl]-2-oxo-4-(4-bromophenyl) butanoate
(5b). Elution with cyclohexane/ethyl acetate 85:15, after 4bb, gave
5b as thick colourless oil; [Found: C, 53.3; H, 4.28. C30H28Br2O8
requires C, 53.27; H 4.17%]; nmax (Nujol mull) 1733 cmꢀ1 (C]O); dH
(300 MHz CDCl3) 7.39 (4H, d, J 8.4 Hz, orto-Br aromatic protons),
7.05 (4H, d, J 8.4 Hz, meta-Br aromatic protons), 6.72 (1H, s, H6),
6.36 (1H, s, H3), 4.81 (2H, t, J 7.6 Hz, benzylic proton), 3.84 (6H, s, 2
OMe), 3.76 (6H, s, 2 OMe), 3.47 (4H, d, J 7.6 Hz, 2CH2); dC (75 MHz
CDCl3) 191.6, 160.7, 156.0, 141.4, 130.9, 129.1, 126.9, 121.8, 119.6, 95.1,
55.0, 52.5, 43.5, 38.0.
4.2.3. Methyl
4-(4-bromophenyl)-4-(2,4,6-trimethoxyphenyl)-2-
oxobutanoate (4ba). Eluant: cyclohexane/ethyl acetate 85:15, col-
ourless oil; [Found: C, 55.1; H, 4.9. C20H21BrO6 requires C, 54.93; H,
4.84%]; nmax (liquid film) 1731 cmꢀ1 (C]O); dH (300 MHz CDCl3)
7.34 (2H, d, J 8.4 Hz, ortho-Br aromatic protons), 7.16 (2H, d, J 8.4 Hz,
meta-Br aromatic protons), 6.10 (2H, s, H3 and H5 aromatic proton),
4.89 (1H, t, J 7.5 Hz, benzylic proton), 3.82 (3H, s, OMe), 3.79 (3H, s,
OMe), 3.76 (6H, s, 2 OMe), 3.71 (2H, d, J 8.1 Hz, CH2); dC (75 MHz
CDCl3) 192.7, 159.7, 158.3, 142.3, 130.4, 128.8, 118.9, 110.6, 90.6, 55.1,
54.7, 52.3, 42.1, 33.3.
4.2.9. Methyl
4-[5-(3-methoxycarbonyl-3-oxo-1-(4-bromophenyl)
4.2.4. Methyl 4-(2,4,6-trimethoxyphenyl)-4-(4-nitrophenyl)-2-oxo-
butanoate (4ca). Eluant: cyclohexane/ethyl acetate 85:15, light
yellow oil; [Found: C, 59.6; H, 5.3; N, 3.3. C20H21NO8 requires C,
59.55; H, 5.25; N, 3.47%]; nmax (liquid film) 1733 cmꢀ1 (C]O); dH
(300 MHz CDCl3) 8.08 (2H, d, J 8.5 Hz, ortho-nitro aromatic pro-
tons), 7.42 (2H, d, J 8.5 Hz, meta-nitro aromatic protons), 6.11 (2H, s,
propyl)-2,4-dimethoxyphenyl]-2-oxo-4-(4-bromophenyl) butanoate
(6b). Elution with cyclohexane/ethyl acetate 85:15, after 5b, gave
6b as thick colourless oil; [Found: C, 53.4; H 4.0. C30H28Br2O8 re-
quires C, 53.27; H, 4.17%]; nmax (Nujol mull) 1733 cmꢀ1 (C]O); dH
(300 MHz CDCl3) 7.37 (4H, d, J 8.4 Hz, orto-Br aromatic protons),
7.04 (4H, d, J 8.4 Hz, meta-Br aromatic protons), 6.79 (1H, s, H6),

3028
G. Faita et al. / Tetrahedron 66 (2010) 3024–3029
6.35 (1H, s, H3), 4.82 (2H, t, J 7.6 Hz, benzylic proton), 3.84 (6H, s, 2
OMe), 3.76 (6H, s, 2 OMe), 3.54 (2H, dd, J 17.1, 7.7 Hz, 2CHH), 3.47
(2H, dd, J 17.1, 7.7 Hz, 2CHH); dC (75 MHz CDCl3) 191.7, 165.3, 160.7,
156.0, 151.2, 141.5, 130.9, 129.0, 127.2, 121.9, 119.6, 95.1, 55.0, 52.5,
43.4, 38.1.
(6H, s, NMe2); dC (75 MHz CDCl3) 194.5,191.2,161.1,160.2,156.6,150.2,
142.1,139.4,128.5,128.12,128.06,127.7,127.5,126.6,125.9,118.0,104.4,
95.9, 54.7, 52.8, 52.3, 52.1, 44.6, 43.3, 41.5, 40,0.
4.2.15. Methyl 4-(4-bromophenyl)-4-(4-dimethylamino-2-methoxy
phenyl)-2-oxolbutanoate (4bd). Eluant: cyclohexane/ethyl acetate
80:20, light yellow crystals, mp 104–105 ꢁC (cyclohexane/hexane);
[Found: C, 57.2; H, 5.3; N, 3.2. C20H22BrNO4 requires C, 57.15; H,
5.28; N 3.33%]; nmax (Nujol mull) 1732 cmꢀ1 (C]O); dH (300 MHz
CDCl3) 7.39 (2H, d, J 8.4 Hz, ortho-Br aromatic protons), 7.16 (2H, d, J
8.4 Hz, meta-Br aromatic protons), 6.92 (1H, d, J 8.4 Hz, H6 aromatic
proton), 6.27 (1H, dd, J 8.4, 2.4 Hz, H5 aromatic proton), 6.22 (1H, d,
J 2.4 Hz, H3 aromatic proton), 4.87 (1H, t, J 7.6 Hz, benzylic proton),
3.84 (3H, s, OMe), 3.78 (3H, s, OCH3), 3.61 (1H, dd, J 17.0, 8.0 Hz,
CHH), 3.47 (1H, dd, J 17.0, 7.25 Hz, 2CHH), 2.94 (6H, s, NMe2); dC
(75 MHz CDCl3) 191.9, 160.8, 156.9, 150.4, 142.3, 130.8, 129.2, 127.9,
119.4, 118.5, 104.1, 95.7, 54.6, 52.4, 43.9, 40.1, 37.8.
4.2.10. Methyl 4-(2,3,4-trimethoxyphenyl)-2-oxo-4-phenylbutano-
ate (4ac). Eluant: cyclohexane/ethyl acetate 80:20, colourless oil;
[Found: C, 67.2; H, 6.2. C20H22O6 requires C, 67.03; H, 6.19%]; nmax
(liquid film) 1730 cmꢀ1 (C]O); dH (300 MHz CDCl3) 7.29–7.25 (4H,
m, aromatic protons), 7.20 (1H, m, aromatic proton), 6.75 (1H, d, J
8.6 Hz, H6 aromatic proton), 6.63 (1H, d, J 8.6 Hz, H5 aromatic
proton), 4.94 (1H, t, J 7.7 Hz, benzylic proton), 3.84 (9H, s, 3 OMe),
3.70 (3H, s, OMe), 3.59 (2H, d, J 7.7 Hz, CH2); dC (75 MHz CDCl3)
191.8, 160.8, 152.1, 151.0, 142.9, 141.9, 128.7, 127.9, 127.3 125.9, 121.4,
106.5, 60.1, 55.4, 52.4, 44.2, 38.6.
4.2.11. Methyl
4-(4-bromophenyl)-4-(2,3,4-trimethoxyphenyl)-2-
oxobutanoate (4bc). Eluant: cyclohexane/ethyl acetate 85:15, col-
ourless oil; [Found: C, 55.1; H 5.0. C20H21BrO6 requires C, 54.93; H
4.84%]; nmax (liquid film) 1732 cmꢀ1 (C]O); dH (300 MHz CDCl3)
7.40 (2H, d, J 8.4 Hz, ortho-Br aromatic protons), 7.14 (2H, d, J 8.4 Hz,
meta-Br aromatic protons), 6.85 (1H, d, J 8.6 Hz, H6 aromatic pro-
ton), 6.62 (1H, d, J 8.6 Hz, H5 aromatic proton), 4.88 (1H, t, J 7.6 Hz,
benzylic proton), 3.84 (9H, s, 3 OMe), 3.71 (3H, s, OMe), 3.56 (2H, d, J
7.6 Hz, CH2); dC (75 MHz CDCl3) 191.5, 160.7, 152.3, 151.0, 142.0,
141.95, 131.0, 129.1, 128.0, 121.2, 119.7, 106.5, 60.1, 55.4, 52.5, 43.9,
38.1.
4.3. Reaction between methyl 4-(4-bromophenyl)-4-(2,4-
dimethoxyphenyl)-2-oxobutanoate (4bb) and (E)-2-oxo-4-
(4-bromophenyl)-but-3-enoic acid methyl ester (1b)
In a rubber septum sealed vial a mixture of 4bb (0.022 g,
0.055 mmol), scandium triflate (0.010 g, 0.02 mmol) and 1b (0.018 g,
0.067 mmol) in anhydrous CH2Cl2 (0.3 mL) was stirred for 8 h at
ambient temperature. The reaction was decomposed in water,
extracted with CH2Cl2, dried, and the reaction mixture was column
chromatographed (silicagel, 30 cm length, 1.5 cm diameter) with cy-
clohexane/ethyl acetate 85:15 aseluant. The fractions of unreacted 1b
(0.007 g)and 4bb (0.009 g)were eluted first, thenonediastereomeric
methyl 4-[5-(3-methoxycarbonyl-3-oxo-1-(4-bromophenyl)propyl)-
2,4-dimethoxyphenyl]-2-oxo-4-(4-bromo phenyl)butanoate (5b,
0.0035 gd10% yield) was separated, followed by its stereoisomer 6b
(0.0175 gd49% yield). The 1H NMR and IR spectra of 5b and 6b were
identical to those previously described.
4.2.12. Methyl
4-(4-dimethylamino-2-methoxyphenyl)-2-oxo-4-
phenylbutanoate (4ad). Eluant: cyclohexane/ethyl acetate 85:15,
4ad was eluted first as a colourless oil; [Found: C, 70.5; H, 6.7; N, 4.2.
C20H23NO4 requires C, 70.36; H, 6.79; N 4.10%]; nmax (liquid film)
1730 cmꢀ1 (C]O); dH (300 MHz CDCl3) 7.30 (4H, m, aromatic pro-
tons), 7.20 (1H, m, aromatic proton), 6.94 (1H, d, J 8.3 Hz, H6aromatic
proton), 6.28 (2H, m, H3 and H5 aromatic proton), 4.95 (1H, t, J
7.7 Hz, benzylic proton), 3.84 (3H, s, OMe), 3.80 (3H, s, OMe), 3.65
(1H, dd, J 17.2, 7.7 Hz, 2CHH), 3.49 (1H, dd, J 17.2, 7.6 Hz, 2CHH), 2.95
(6H, s, NMe2); dC (75 MHz CDCl3) 192.2, 160.9, 157.0, 150.3, 143.1,
128.1, 127.8, 127.4, 119.3, 104.3, 95.9, 54.7, 52.3, 44.2, 40.2, 38.2.
4.4. Reaction catalyzed by [scandium triflate/pybox (3)]
complex. General procedure
4.2.13. Dimethyl
3-[(4-dimethylamino-2-methoxyphenyl)(phenyl)
E)-2-Oxo-4-arylbut-3-enoic
acid
methyl
ester
(1a–c)
methyl]-2,6-dioxo-4-phenylheptandioate (7). The elution with
cyclohexane/ethyl acetate 85:15, after 4ad, gave 7 as thick light
yellow oil; [Found: C, 69.9; H, 6.2; N, 2.4. C31H33NO7 requires C,
70.04; H, 6.26; N, 2.63%]; nmax (Nujol mull) 1733 cmꢀ1 (C]O); dH
(300 MHz CDCl3) 7.34 (1H, d, J 8.4 Hz, H6 aromatic proton), 7.28–
6.99 (m, 10H, aromatic protons), 6.37 (1H, dd, J 8.4, 1.8 Hz, H5 ar-
omatic proton), 6.10 (1H, d, J 1.8 Hz, H3 aromatic proton), 4.99 (1H,
dd, J 11.7, 6.7 Hz, H3), 4.63 (1H, d, J 11.7 Hz, H benzyl), 3.80 (1H, m,
H4), 3.83 (3H, s, OMe), 3.77 (3H, s, OMe), 3.46 (3H, s, OMe), 3.26 (1H,
dd, J 18.4, 6.7 Hz, H5), 3.10 (1H, dd, J 18.4, J 7.6 Hz,1H, H50), 2.95 (6H,
s, NMe2); dC (75 MHz CDCl3) 195.6, 191.0, 161.4, 160.3, 157.0, 150.4,
142.2, 139.0, 128.5, 127.9, 127.8, 127.5, 126.5, 125.6, 117.4, 104.6, 95.8,
54.6, 52.2, 43.9, 42.6, 40.7, 40,1.
(0.33 mmol), pybox 3 (0.03 mmol), scandium triflate (0.03 mmol)
and molecular sieves 3 Å (about 0.040 g) were added to anhydrous
CH2Cl2 (0.3 mL) at ambient temperature in a rubber septum sealed
vial. The mixture was stirred for 15 min and then cooled at the
temperature reported in Table 1–3. The required arene (2a–d)
(0.40 mmol) was added (when liquid with a microsyringe) and
stirring was continued for the time reported in Tables 1–3. The
reaction was decomposed in water, extracted with CH2Cl2, dried,
and the reaction mixture was separated by column chromatogra-
phy (silicagel, 30 cm length, 1.5 cm diameter) with the eluant
reported above for each single product. The enantiomeric mixtures
were HPLC analyzed under the conditions reported below for each
product, and the [a] value was determined.
4.2.14. Dimethyl
3-[(4-dimethylamino-2-methoxyphenyl)(phenyl)
4.4.1. (þ)-Methyl 4-(2,4,6-trimethoxyphenyl)-2-oxo-4-phenylbu-ta-
noate (4aa). The mixture of enantiomers was analyzed on a Chir-
alpak AD column with hexane/2-propanol [96:4] as eluant (1.0 mL/
methyl]-2,6-dioxo-4-phenylheptanedioate (8). The elution with cy-
clohexane/ethyl acetate 85:15, after 7, gave 8 as thick oil; [Found: C,
70.0; H, 6.2; N, 2.7. C31H33NO7 requires C, 70.04; H, 6.26; N, 2.63%];
nmax (Nujol mull) 1733 cmꢀ1 (C]O); dH (300 MHz CDCl3) 7.47 (1H, d, J
8.4 Hz, H6 aromatic proton), 7.32–7.07 (10H, m, aromatic protons),
6.17 (1H, dd, J 8.4, 2.2 Hz, H5 aromatic proton), 6.07 (1H, d, J 2.2 Hz, H3
aromatic proton), 4.94 (1H, dd, J 11.3, 7.4 Hz, H3), 4.66 (1H, d, J 11.3 Hz,
H benzyl), 3.81 (1H, m, H4), 3.76 (3H, s, OMe), 3.75 (3H, s, OMe), 3.54
(3H, s, OMe), 3.06 (1H, d, J 7.25 Hz, H5), 2.94 (1H, d, J 6.7 Hz, H50), 2.86
min) and the average retention times were: 16 (minor enantiomer)
20
and 19.7 min (major enantiomer). ee 99.5%. [
a
]
þ44.5 (c 5.3, CHCl3).
D
4.4.2. (þ)-Methyl 4-(4-bromophenyl)-4-(2,4,6-trimethoxyphenyl)-2-
oxobutanoate (4ba). The mixture of enantiomers was analyzed on
a Chiralpak AD column with hexane/2-propanol [96:4] as eluant
(1.0 mL/min) and the average retention times were: 15.8 (minor

G. Faita et al. / Tetrahedron 66 (2010) 3024–3029
3029
20
enantiomer) and 24.4 min (major enantiomer). ee 99%. [
(c 0.5, CHCl3).
a
]
þ29.2
active products obtained from [pybox 3/ScIII]-catalyzed reactions are
reported. Supplementary data associated with this article can be
found in online version at doi:10.1016/j.tet.2010.02.054.
D
4.4.3. (þ)-Methyl 4-(2,4,6-trimethoxyphenyl)-4-(4-nitrophenyl)-2-
oxobutanoate (4ca). The mixture of enantiomers was analyzed on
a Chiralpak AD column with hexane/2-propanol [90:10] as eluant
References and notes
(1.0 mL/min) and the average retention times were: 19.7 (minor
enantiomer) and 27.8 min (major enantiomer). ee 95.5%. [a]
D
þ90.9 (c 3.4, CHCl3).
1. For recent reviews on enantioselective Friedel–Crafts reactions see (a) Poulsen,
T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108, 2903–2918; (b) Bandini, M.; Melloni,
A.; Tommasi, S.; Umani-Ronchi, A. Synlett 2005, 1199–1222; (c) Bandini, M.;
Melloni, A.; Umani-Ronchi, A. Angew. Chem. 2004, 116, 560–566; Angew. Chem.,
Int. Ed. 2004, 550–566; (d) Jørgensen, K. A. Synthesis 2003, 1117–1125; (e) Bolm,
C.; Hildebrand, J. P.; Mun˜iz, J. P.; Hermanns, N. Angew. Chem. 2001, 113, 3382–
3407; Angew. Chem., Int. Ed. 2001, 3284–3308.
2. Jensen, K. B.; Thorhauge, J.; Hazel, R. G.; Jørgensen, K. A. Angew. Chem. 2001, 113,
164–167; Angew. Chem., Int. Ed. 2001, 160–163.
3. Lyle, M. P. A.; Draper, N. D.; Wilson, P. D. Org. Lett. 2005, 7, 901–904.
4. Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. Chem.dEur. J. 2008, 14,
3630–3636.
5. (a) Evans, D. A.; Fandrick, K. R. Org. Lett. 2006, 8, 2249–2252; (b) Evans, D. A.;
Fandrick, K. R.; Song, H. J. J. Am. Chem. Soc. 2005, 127, 8942–8943; (c) Evans, D.
A.; Fandrick, K. R.; Song, H. J.; Scheidt, K. A.; Xu, R. J. Am. Chem. Soc. 2007, 129,
10029–10041; (d) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J.
J. Am. Chem. Soc. 2003, 125, 10780–10781.
20
4.4.4. (þ)-(4R)-Methyl
4-(2,4-dimethoxyphenyl)-2-oxo-4-phenyl
butanoate (4ab). The mixture of enantiomers was analyzed on
a Chiralpak AD column with hexane/2-propanol [95:5] as eluant
(1.0 mL/min) and the average retention times were: 16.6 (minor
enantiomer) and 18.7 (major enantiomer) [lit.2 Chiralpak AD col-
umn, hexane/2-propanol [95:5], (0.5 mL/min), retention times:
23.8 (minor enantiomer) and 26.6 min (major enantiomer)]. ee
20
20
20
93%. [
a
]
þ24.6 (c 1.6, CHCl3); [
a
]
þ25.4 (c 1.5, CH2Cl2) [lit.2: [
a]
D
D
D
þ15.0 (c 1.02, CH2Cl2) for 60% ee].
6. Zhou, J.; Ye, M.-C.; Huang, Z.-Z.; Tang, Y. J. Org. Chem. 2004, 69, 1309–1320.
7. Ye, M.-C.; Li, B.; Zhou, J.; Sun, X.-L.; Tang, Y. J. Org. Chem. 2005, 70, 6108–6110.
8. Yamazaki, S.; Iwata, Y. J. Org. Chem. 2006, 71, 739–743.
9. Rasappan, R.; Hager, M.; Gissibl, A.; Reiser, O. Org. Lett. 2006, 8, 6099–6102.
10. Takenaka, N.; Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 742–743.
11. Lu, S.-F.; Du, D.-M.; Xu, J. Org. Lett. 2006, 8, 2115–2118.
12. Jia, Y.-X.; Zhu, S.-F.; Yang, Y.; Zhou, Q.-L. J. Org. Chem. 2006, 71, 75–80.
13. Singh, P. K.; Bisai, A.; Singh, V. K. Tetrahedron Lett. 2007, 48, 1127–1129.
14. Palomo, C.; Oiarbide, M.; Kardak, B. G.; Linden, A. J. Am. Chem. Soc. 2005, 127,
4154–4155.
4.4.5. (þ)-Methyl 4-(4-bromophenyl)-4-(2,4-dimethoxyphenyl)-2-
oxobutanoate (4bb). The mixture of enantiomers was analyzed on
a Chiralpak AD column with hexane/2-propanol [90:10] as eluant
(1.0 mL/min) and the average retention times were: 14.4 (minor
20
enantiomer) and 16.7 min (major enantiomer). ee 80%. [
(c 5.3, CHCl3).
a
]
þ44.5
D
15. Blay, G.; Fernandez, I.; Pedro, J. R.; Vila, C. Org. Lett. 2007, 9, 2601–2604.
16. Zhuang, W.; Gathergood, N.; Hazel, R. G.; Jørgensen, K. A. J. Org. Chem. 2001, 66,
1009–1013.
17. Dong, H. M.; Lu, H. H.; Lu, L. Q.; Chen, C. B.; Xiao, W. J. Adv. Synth. Catal. 2007,
349, 1597–1603.
18. Jia, Y. X.; Xie, J. H.; Duan, H. F.; Wang, L. X.; Zhou, Q. L. Org. Lett. 2006, 8,
1621–1624.
19. Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G.; Gasparri Fava, G.; Ferrari Belicchi,
M. J. Org. Chem. 1985, 50, 5018–5022.
4.4.6. (þ)-Methyl 4-(4-dimethylamino-2-methoxyphenyl)-2-oxo-4-
phenylbutanoate (4ad). The mixture of enantiomers was analyzed
on a Chiralpak AD column with hexane/2-propanol [96:4] as eluant
(1.0 mL/min) and the average retention times were: 21.5 (minor
20
enantiomer) and 24.4 min (major enantiomer). ee 92%. [
(c 0.7, CHCl3).
a
]
þ35.2
D
20. Ishii, A.; Soloshonok, V. A.; Mikami, K. J. Org. Chem. 2000, 65, 1597–1599.
21. Gathergood, N.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2000, 122,
12517–12522.
22. Saaby, S.; Bayo´ n, P.; Aburel, P. S.; Jørgensen, K. A. J. Org. Chem. 2002, 67,
4352–4361.
23. Yuan, Y.; Wang, X.; Li, X.; Ding, K. J. Org. Chem. 2004, 69, 146–149.
24. Paras, N. A.; MacMillan, D. W. J. Am. Chem. Soc. 2002, 124, 7894–7895.
25. Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106, 3561–3651.
26. Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2003, 103, 3119–3154.
27. (a) Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. Chem.dEur. J. 2007, 13,
9478–9485; (b) Desimoni, G.; Faita, G.; Mella, M.; Piccini, F.; Toscanini, M. Eur. J.
Org. Chem. 2007, 1529–1534.
4.4.7. (þ)-Methyl
4-(4-bromophenyl)-4-(4-dimethylamino-2-me-
thoxyphenyl)-2-oxobutanoate (4bd). The mixture of enantiomers
was analyzed on a Chiralpak AD column with hexane/2-propanol
[96:4] as eluant (1.0 mL/min) and the average retention times
were: 24.6 (minor enantiomer) and 31 min (major enantiomer). ee
20
92%. [
a
]
þ36.8 (c 3.6, CHCl3).
D
Acknowledgements
28. Desimoni, G.; Faita, G.; Piccini, F.; Toscanini, M. Eur. J. Org. Chem. 2006,
5228–5230.
29. Desimoni, G.; Faita, G.; Guala, M.; Laurenti, A.; Mella, M. Chem.dEur. J. 2005, 11,
3816–3824.
`
This work was supported by the Ministero dell’Universita e della
Ricerca (MUR) and by the University of Pavia.
30. Secher, E. D.; Ryder, H. F. J. Am. Chem. Soc. 1952, 74, 4392.
31. Audrain, H.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2000, 65,
4487.
32. Reimer, M.; Tobin, E. J. Am. Chem. Soc. 1940, 62, 2518.
33. Stecher, E. D.; Dunn, F.; Gelblum, E. J. Am. Chem. Soc. 1957, 79, 4748.
Supplementary data
The 1H- and 13C NMR spectra of 4 obtained from ScIII-catalyzed
Friedel–Crafts and some significant HPLC chromatograms of optically