Asymmetric friedel-crafts alkylation of indoles with methyl (E)-2-Oxo-4-aryl-3-butenoates catalyzed by Sc(OTf)3/pybox

Article abstract of DOI:10.1002/chem.200701908

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

Full text of DOI:10.1002/chem.200701908

DOI: 10.1002/chem.200701908
Asymmetric Friedel–Crafts Alkylationof Indoles with Methyl ( E)-2-Oxo-4-
aryl-3-butenoates Catalyzed by Sc(OTf)3/pybox**
A
Giovanni Desimoni,*[a] Giuseppe Faita,[a] Marco Toscanini,[a] and Massimo Boiocchi[b]
Abstract: The asymmetric Friedel–
Crafts reaction between a series of sub-
stituted indoles 2a–l and methyl (E)-2-
oxo-4-aryl-3-butenoates 3a–c has been
efficiently catalyzed by the scandium-
to 99% ee, irrespective of the electron-
ic character of the substituent and its
location on the indole ring, albeit with
the exclusion of position 2. The adducts
could be obtained as stable enol tauto-
mers and the equilibrium with the keto
structure is discussed. The X-ray crystal
structure determination of 4m indicat-
ed the 4R absolute configuration, thus
confirming the proposal of Jørgensen
for 4i. The sense of the stereoinduction
can be rationalized by the same octahe-
dral complex 5 between 3, pybox 1,
and scandium triflate already proposed
ACHTREUNG
ACHTREUNG
phenyl-1’,3’-oxazolin-2’-yl]pyridine
for
the
Diels–Alder/hetero-Diels–
(pybox; 1). Substituted 4-(indol-3-yl)-2-
oxo-4-arylbutyric acid methyl esters
4a–n were usually formed in excellent
yields and the enantioselectivity was up
Alder and the Mukaiyama–aldol reac-
tions of pyruvates.
Keywords: asymmetric catalysis
enantioselectivity Friedel–Crafts
reaction · indoles · N ligands
·
·
Introduction
pyruvate,[1–3] ethane di- or tri-carboxylate,[4–7] a,b-unsatu-
rated acyl phosphonate,[8,9] or a nitroalkene.[10–12]
Catalytic enantioselective Friedel–Crafts reactions have at-
tracted the interest of many groups because of the synthetic
relevance of the molecules obtainable with this approach
and for the flexibility of these reactions. A successful cata-
3) A suitably designed catalyst based on a Lewis acid and a
chiral ligand, among which CuII/bis(oxazoline) complexes
are by far preferred,[1,4–7,11,12,13] whereas pyridine bis(oxa-
zoline) (pybox) complexes are less frequently used.[8,14,15]
À
lytic asymmetric addition of aromatic C H bonds to alkenes
requires the synergistic concurrence of three elements:
Our previous investigations focused on the Diels–Alder
reaction of cyclopentadiene with either 3-alkenoyl-2-oxazoli-
dinone or methyl (E)-2-oxo-4-aryl-3-butenoates. The cyclo-
1) An electron-rich aromatic or heteroaromatic ring and in-
doles are by far preferred for the biologic relevance of
these molecules.[1–13]
additions were found to be catalyzed by the scandium
A
triflate complex of (4’S,5’S)-2,6-bis[4’-(triisopropylsilyl)oxy-
AHCTREUNG
2) An electron-poor alkene, which is usually an activated
a,b-unsaturated carbonyl compound, such as an aryliden
methyl-5’-phenyl-1’,3’-oxazolin-2’-yl]pyridine (1) in excellent
yields and enantiomeric excess,[16,17] and the chiral induction
was strongly related to the structure of the reactive inter-
mediate involved in the catalytic cycle. If these a,b-unsatu-
rated carbonyl compounds, when coordinated to the com-
plex [ScIII(1)], undergo an enantioselective reaction with cy-
clopentadiene, it should be expected that indoles could be
used instead of cyclopentadiene, thus giving rise to catalytic
enantioselective Friedel–Crafts reactions. This specific reac-
tion between indoles and b,g-unsaturated a-keto esters has
been carried out in excellent yields and enantiomeric excess
by Jørgensen and co-workers, who used a chiral copper(II)
triflate/tert-butylbis(oxazoline) complex as the catalyst.[1,2]
Hence, both from a synthetic and a mechanistic viewpoint, 1
[a] Prof. G. Desimoni, Prof. G. Faita, Dr. M. Toscanini
Dipartimento di Chimica Organica
dell’Università di Pavia
Viale Taramelli 10, 27100 Pavia (Italy)
Fax :( +39)382-987-323
E-mail:desimoni@unipv.it
[b] Dr. M. Boiocchi
Centro Grandi Strumenti
dell’Università di Pavia
Via Bassi 21, 27100 Pavia (Italy)
[**] pybox=pyridine bis(oxazoline).
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
3630
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3630 – 3636

FULL PAPER
Table 1. Catalytic enantioselective Friedel–Crafts reaction of indole 2a
is worth investigating as a chiral ligand in the asymmetric
catalysis of this reaction.
with 3a catalyzed by Sc
(OTf)3/1.[a]
N
Entry
Solvent
T [8C]
Time
Yield [%][b]
ee [%]
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
ambient
À50
10 min
20 min
20 min
2 h
2 h
10 min
10 min
90
90
quant.
75
85
5
96
96
75
60
97
98
Results and Discussion
À70
À70
Initially, the catalytic activity of the scandium(III) ion in the
G
À70
absence of any chiral ligand was tested in the reaction of
indole 2a with methyl (E)-2-oxo-4-phenyl-3-butenoate (3a)
in CH2Cl2 at À708C (Scheme 1). The reaction was observed
to be very fast (a few minutes), but the crude product, iso-
lated as a white solid, was not the expected, and already de-
scribed, 4-(1H-indol-3-yl)-2-oxo-4-phenylbutyric acid methyl
Et2O
Et2O
À50
95
quant.
À70
[a] Reaction was performed in the presence of 3-Š MS. [b] Yield of the
isolated product of 4a after column chromatography.
1
ester (4a).[1] The IR and H NMR spectra are in agreement
separation of optically enriched 4a from 1. After elution on
silica, the ketonic tautomer 4a is separated, and the experi-
ment simply suggests that the chromatographic support is
the responsible for the tautomerization. The same isomeri-
zation occurs when racemic 4a’ is separated by chiral HPLC
since the enantiomer peaks correspond to those obtained
from enantioenriched 4a. Therefore, the keto–enol equili-
bration is induced by the chromatographic support. A deci-
with the structure of the enol tautomer 4a’; the product can
be crystallized from methanol and is stable in CDCl3, but it
slowly transforms into 4a in solution with dimethyl sulfoxide
1
(DMSO), as evidenced by the H NMR spectrum in this sol-
vent. The same results were obtained by using the cop-
per(II) ion as the catalyst, the Lewis acid most frequently
used in the reaction.
A
The reaction between 2a and
3a catalyzed by the scandium-
A
1
(Scheme 2) was carried out at
different temperatures with dif-
ferent solvents and in the pres-
ence of 3-Š molecular sieves
(MS) to optimize the asymmet-
ric reaction conditions.
1
The H NMR and IR spectro-
scopic analysis of the product
isolated after separation from 1
by column chromatography of
the reaction product shows that
the reaction product corre-
sponds to the ketonic tautomer
4a under all the investigated
conditions. The best results
were obtained by using diethyl
ether or dichloromethane as the
solvent at À50/À708C, since 4a
was obtained in excellent yield
with 96–98% ee (Table 1).
Scheme 1. The catalyzed Friedel–Crafts reaction between 2a and 3a that gives the adduct in the keto 4a or
enol 4a’ forms.
The origin of the tautomeric
preference (i.e., the keto tauto-
mer 4a from the optically
active catalyzed reaction, which
always requires purification of
the product from the pybox
ligand by chromatography, and
the enol tautomer 4a’ in the ab-
sence of chiral catalytic condi-
tions) can be rationalized if a
sample of 4a’ is isolated by
chromatography under the
Scheme 2. The scandium triflate complex of 1 as a chiral catalyst in the Friedel–Crafts reactions between 2a–l
same conditions used for the and 3a–c, which give 4a–n after chromatographic purification.
Chem. Eur. J. 2008, 14, 3630 – 3636
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3631

G. Desimoni et al.
sive further experiment was carried out. The 1H and
13C NMR spectra of the optically active catalyzed reaction
mixture, recorded before any preventive separation of the
product by chromatography, demonstrate that 4a’ is always
the primary reaction product. In any case, this keto–enol
equilibrium has no relevance on the detected selectivity of
the reaction since it does not involve the stereogenic center
of the adduct.
Usually the asymmetric alkylation of the indole is carried
out using a variety of alkylating agents and a few selected
indoles.[10,11] To test the flexibility of the catalyst and evalu-
ate the effect of the substituent in different positions on the
indole ring, the Friedel–Crafts reaction with methyl (E)-2-
oxo-4-phenyl-butenoate (3a) was tested on a large family of
different indoles 2a–l (Table 2).
The absolute configuration of 4i was compared to that de-
termined by Jørgensen and co-workers by X-ray analysis.[1]
Furthermore, the negative [a]D value of the adduct obtained
from the experiment reported in Table 2, entry 8 led to an
assignment of the stereocenter formed in the reaction cata-
lyzed by the scandium(III) triflate complex of 1 as the
A
R configuration. By analogy, the same absolute 4R configu-
ration can be proposed for all the other Friedel–Crafts alky-
lation products 4a–h,j–l.
By using the data in Table 2, the effect induced by the
substituent at different positions of the indole moiety can be
discussed:
1) An alkyl substituent on the nitrogen atom changes nei-
ther reactivity nor selectivity (Table 2, entry 2).
2) Whereas a substituent at po-
sitions
5 or 6 does not
Table 2. Catalytic enantioselective Friedel–Crafts reaction of indoles 2a–l with methyl (E)-2-oxo-4-phenylbu-
tenoate (3a) in diethyl ether at À708C catalyzed by Sc
(OTf)3/1.[a]
change the reactivity and se-
lectivity (Table 2, entries 8
and 9), the same substituent
at position 7 strongly de-
creases the reactivity but
not the selectivity (Table 2,
entry 10).
Entry
2
R1
R2
R4
R5
R6
R7
4
Time
Yield [%][b]
ee [%]
98
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2 f
2g
2h
2i
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
Cl
H
H
H
H
H
H
H
H
OMe
H
Cl
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
Cl
H
H
4a
4b
4c
4d
4e
4 f
4g
4h
4i
10 min
15 min
15 min
24 h
2 h
30 min
24 h
45 min
15 min
2 days
3 days
10 days
quant.
85
95
quant.
92
90
89
97
81
89
97
67
52
98
88
99
95
3) Positions 2 and 4 are close
to the reactive C3 position
and could cause significant
steric hindrance in the reac-
tion. Electron-donating and
-attracting substituents at
position 4 (Table 2, entries 5
and 7) give results compara-
ble or even better than
those obtained with the cor-
responding 5- or 6-substitut-
ed indoles.
98 (R)[c]
94
10
11
12
2j
2k
2 l
4j
4k
4 l
H
H
H
NO2
CO2Me
H
quant.
99
90
35[d]
[a] Reaction was performed in the presence of 3-Š MS. [b] Yield of the isolated product. [c] The absolute con-
figuration was determined by comparing the optical rotation with that reported in ref. [1]. [d] Significant
amounts of starting material were isolated.
The nucleophilicity of the indole, which is a key factor in
the Friedel–Crafts reaction, was reported to increase with
increasing electron-donating character of the substituent in
the 1, 2, and 5 positions.[18,19] The group of indoles 2a–l,
chosen as a cluster of reagents, allowed us to compare the
effect of the electronic character of the substituents and
their positions on the heterocyclic ring on the indole nucleo-
philicity.
Several factors may determine the reactivity of 2, for ex-
ample, nucleophilicity, reagent, and product solubility. As
expected, the time required to accomplish the reaction in-
creases with decreasing nucleophilicity of the indole induced
by electron-attracting substituents and ranges from 10 min
to 3 days at À708C (Table 2, entries 1 and 11). In the case of
the indole bearing the strongest electron-withdrawing sub-
stituent (2l), poor reaction yields of 4l were obtained after
10 days (Table 2, entry 12).
4) When the substituent at position 2 is a methyl group
(indole 2c is a strong nucleophile),[18] the yield and reac-
tion time are comparable to those of 2a and 2b. If the
substituent is a phenyl group (i.e., 2d), the yield is again
excellent, but the reactivity is significantly decreased
(Table 2, entry 3 versus 4). In both cases, the substituent
at position 2 has a negative influence on the enantiose-
lectivity, and the ee values of 4c and 4d are the lowest
obtained in the entire cluster of the tested indoles.
The determination of the enantiomeric excess for 4c re-
quired interpretation of its anomalous HPLC chromatogram
(see the Supporting Information). Pure samples of racemic
and chiral 4c have, in addition to the peaks of the enantio-
mers at 44 and 56 min, a second couple of peaks at 20 and
23 min, whose ratio is the same as the first couple of peaks.
Following the method used for the synthesis of 4a’, racemic
4c’ (Scheme 3) was prepared from 2c, and its HPLC chro-
matogram confirmed the equilibrium 4c/4c’ as the origin of
the phantom peaks. The keto–enol equilibration occurs also
with the enantiomerically enriched product obtained after
On the contrary, the nucleophilicity of 2 does not influ-
ence the enantioselectivity of the reaction since excellent re-
sults were obtained for all the 2-unsubstituted indoles, inde-
pendent of the electron-donating or -attracting character of
the substituents.
3632
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3630 – 3636

Catalytic Enantioselective Friedel–Crafts Reaction
FULL PAPER
purification by column chroma-
tography without any loss of
the product enantiopurity, and
the tautomers are stable
enough to be detected under
chiral-HPLC conditions.
Having examined
a
large
Scheme 3. The enol tautomer
of 4c.
number of indoles with several
groups in different positions, we
treated 2a with 3b and 3c, with
the substituent on the electrophilic reagent. The result
shows that the influence of a substituent on the phenyl
group of 3 is limited since both the reactivities and enantio-
selectivities observed for 4m and 4n are analogous to those
obtained for 4a (Table 3).
Figure 1. An ORTEP view of the crystal structure of 4m (ellipsoids are
drawn at the 50% probability level) labeled with crystallographic atom
names, thus confirming the absolute R configuration.
Table 3. Catalytic enantioselective Friedel–Crafts reaction at À708C of
indole 2a with 3a–c in diethyl ether catalyzed by Sc
(OTf)3/1.[a]
G
Entry
2
3
4
Time
Yield [%][b]
ee [%] (conf.)
ester carbonyl group and triflate ion in axial positions,
which undergoes the sterically less demanding attack to the
Re face of the indole 2a (Figure 3).
1
2
3
2a
2a
2a
3a
3b
3c
4a
4m
4n
10 min
1 h
15 min
quant.
62
85
98
96 (R)
90
This intermediate 5 has already been used to rationalize
the sense of the stereoinduction of the Diels–Alder/hetero-
Diels–Alder reactions of cyclopentadiene on 3,[16,17] and the
Mukaiyama–aldol reaction of pyruvates.[20] The consistency
of the model of the reactive intermediate in so many differ-
ent reactions is not only a good indicator of the flexibility of
the catalyst, but offers promising insight into predicting the
sense of the stereoinduction in new reactions involving di-
carbonylic substrates.
[a] Reaction performed in the presence of 3-Š MS. [b] Yield of the isolat-
ed products.
To confirm the enantioselectivity induced by Sc(OTf)3/1
N
as the catalyst, the absolute configuration of 4m was deter-
mined by X-ray analysis and its structure (Figure 1) allowed
us to confirm the previously assumed R configuration of the
stereocenter.
In the solid state, the molecular crystal is characterized by
À
bifurcated hydrogen bonds, in which the N H group of each
molecule acts as a proton donor towards the two C=O
groups of an adjacent molecule. In particular, the hydrogen
bonds show a major component towards the O(2) atom
(H(1N)···O(2):2.17(4) Š) and a minor component towards
the O(1) atom (H(1N)···O(1):2.53(3) Š). These intramolec-
ular hydrogen bonds form infin-
Experimental Section
General:The melting points were determined by the capillary method
and are uncorrected; 1H and 13C NMR spectra were recorded at 300 and
75 MHz, respectively; the IR spectra were recorded on a Perkin–Elmer
ite molecular chains along the
a axis in the crystal (Figure 2)
and give rise to the unusual
cisoid a-dicarbonyl conforma-
tion.
Conclusion
The R configuration for the
products of the Friedel–Crafts
reaction is consistent with an
octahedral reactive intermedi-
ate 5, obtained by bidentate co-
ordination of 3b to the
scandium
with the ketonic C=O group in
the equatorial position and the H(1N)···O(1) 139(2)8, N(1)···O(2) 3.03(1) Š, H(1N)···O(2) 2.17(4) Š, N(1) H(1N)···O(2) 150(2)8.
G
Figure 2. The infinite molecular chain adopted in the solid state by (R)-4m as determined by X-ray structure
À
À
studies. Features of the N H···O interactions are:N(1)···O(1) 3.31(1) Š, H(1N)···O(1) 2.53(3) Š, N(1)
À
Chem. Eur. J. 2008, 14, 3630 – 3636
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3633

G. Desimoni et al.
CHH), 3.60 ppm (dd, 2J
N
N
13C NMR (75 MHz, CDCl3, 258C, TMS): d=192.1, 160.8, 142.7, 136.1,
128.0, 127.3, 126.1, 125.9, 121.8, 121.0, 119.0, 118.9, 117.8, 110.6, 52.4,
45.2, 37.2 ppm (see the 1H and 13C NMR spectra in ref. [1]); IR (nujol):
n˜ =3357 (NH), 1744 cmÀ1 (C=O).
General procedure for the reaction of 2a–k and 3a–c catalyzed by Sc-
A
(0.30 mmol), pybox (1) (22.2 mg, 0.03 mmol), scandium triflate (14.8 mg,
0.03 mmol), and MS (0.020–0.025 g) were added to anhydrous diethyl
ether or CH2Cl2 (0.3 mL) at ambient temperature in a vial sealed with a
rubber septum. The reaction mixture was stirred for 15 min and cooled at
the temperatures reported in Tables 1–3. The solid indole 2a–f
(0.30 mmol) was added in one portion and the reaction mixture was
stirred until all the starting material had been consumed. The reaction
times are indicated in Tables 1–3. The reaction mixture was quenched
with water, extracted with CH2Cl2, and dried. The crude-product mixture
was separated by column chromatography on silica gel (length:30 cm, di-
ameter:1.5 cm; the eluant is given for each specific product). HPLC
analysis, column, eluant, experimental conditions, and retention times are
given for 4a–k. The melting-point and spectroscopic data refer to race-
mates 4 purified by column chromatography.
Figure 3. The assumed reactive intermediate 5 of the Friedel–Crafts alky-
lation reaction between 3b and indole 2a catalyzed by the Sc(OTf)3 com-
plex of pybox 1, which gives (R)-4m.
AHCTREUNG
RX I spectrophotometer; optical rotations were measured on a Perkin–
Elmer 241 polarimeter. The separation and purification of the products
was carried out by column chromatography on silica gel 60 (230–
400 mesh; Merck). The enantiomeric excess (ee) of the products was de-
termined by HPLC using Daicel columns, small differences in the eluant
composition may give reasonably different retention times.
(À)-4-(1H-Indol-3-yl)-2-oxo-4-phenylbutyric acid methyl ester (4a):The
product from Table 2, entry 1 was isolated by column chromatography
(eluant:cyclohexane/ethyl acetate 802:0) as a white solid with 98% ee.
[a]2D0 =À23.3 (c=1.1 in CHCl3) ([a]D20 =À23.9 (c=0.01 in CHCl3) for
99.5% ee in ref. [1]); chiralpak AD column (hexane/iPrOH 80:20, flow
rate=1.0 mLminÀ1) tR =14 min (major), tR =16 min (minor). The 1H and
13C NMR spectra of the reaction mixture, quenched in water, dried, and
without any column chromatography, correspond to those of 4a’ previ-
ously described (see the Supporting Information).
Materials:Hydrocarbon-stabilized ACS grade dichloromethane (Aldrich)
was distilled from calcium hydride and used immediately. The other sol-
vents were dried according to standard procedures. ACS reagent grade
scandium triflate was used (Aldrich). The powdered 3-Š MS (Aldrich)
were heated under vacuum at 3008C for 5 h and kept in sealed vials in a
dryer. (4’S,5’S)-2,6-Bis[4’-(triisopropylsilyl)oxymethyl-5’-phenyl-1’,3’-oxa-
A
zolin-2’-yl]pyridine (1) was prepared as previously described.[21] (E)-2-
Oxo-4-phenylbut-3-enoic acid methyl ester (3a) was prepared following a
previously reported method[22,23] from its potassium salt, which was ob-
tained from benzaldehyde and pyruvic acid in the presence of KOH. The
potassium salt was esterified with methanol to give yellow needles from
diisopropyl ether (m.p. 69–708C; m.p. 70–718C in ref. [23]). Following the
same procedure and starting from a suitable aldehyde, the following
products were prepared:( E)-2-oxo-4-(4-bromophenyl)but-3-enoic acid
methyl ester (3b) in 35% yield as yellow needles from methanol
(m.p. 1208C; m.p. 1228C in ref. [24]); (E)-2-oxo-4-(4-methylphenyl)but-3-
enoic acid methyl ester (3c) in 45% yield as yellow needles from diiso-
propyl ether (m.p. 80–818C; m.p. 818C in ref. [25]).
(À)-4-(1-Methylindol-3-yl)-2-oxo-4-phenylbutyric acid methyl ester (4b):
The racemate was obtained as a white solid from methanol. M.p. 98–
998C (m.p. 1008C in ref. [1]); the 1H and 13C NMR spectra are identical
to those reported in ref. [1]; IR (nujol): n˜ =1729 cmÀ1 (C=O). The prod-
uct from Table 2, entry 2 was isolated by column chromatography
(eluant:cyclohexane/ethyl acetate 901:0) as a white solid with 97% ee.
[a]2D0 =À24.1 (c=1.0 in CHCl3) ([a]D20 =À26.6 (c=0.01 in CHCl3) for
96% ee in ref. [1]); chiralpak IA column (hexane/ethyl acetate 90:10,
flow rate=0.5 mLminÀ1) tR =22 min (major), tR =24 min (minor).
(+)-4-(2-Methylindol-3-yl)-2-oxo-4-phenylbutyric acid methyl ester (4c):
The racemate was obtained as a light yellow oil, which was only stable
for a few days in the refrigerator. 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.84 (s, 1H; NH), 7.5–7.0 (m, 9H; aromatic and indole pro-
General procedure for the reaction between indoles 2a–k and methyl
(E)-2-oxo-4-aryl-3-butenoates 3a–c
tons), 4.95 (dd, 3J
C
ACHTREUNG
Reactions between 2a and 3a catalyzed by scandium (or copper) tri-
A
G
ACHTREUNG
flates:Solid Sc
N
N
6.1 Hz, 1H; CHH), 3.67 (s, 3H; OCH3), 2.44 ppm (s, 3H; CH3);
13C NMR (75 MHz, CDCl3, 258C, TMS): d=192.5, 160.5, 142.6, 134.9,
131.6, 127.9, 126.8, 126.6, 125.7, 120.5, 118.8, 118.6, 111.8, 109.9, 52.3,
43.5, 35.7, 11.6 ppm; IR (film): n˜ =3404 (NH), 1731 cmÀ1 (C=O); elemen-
tal analysis (%) calcd for C20H19NO3 (321.4):C 74.75, H 5.96, N 4.36;
found:C 74.65, H 6.03, N 4.41.
0.03 mmol) was added to a solution of indole 2a (35.1 mg, 0.30 mmol)
and methyl (E)-2-oxo-4-phenyl-3-butenoate (3a) (57.0 mg, 0.30 mmol) in
anhydrous CH2Cl2 (0.3 mL) at À708C in a vial sealed with a rubber
septum. The reaction mixture was stirred for a few minutes until the
yellow solution solidified. The white solid was filtered and washed with
water. The almost pure product 4a’ was crystallized from methanol to
give a pure sample of 4-(1H-indol-3-yl)-2-hydroxy-4-phenyl-2-butenoic
acid methyl ester (4a’) as a white solid. M.p. 156–1578C (methanol);
1H NMR (300 MHz, [D6]DMSO, 258C, trimethylsilane (TMS)): d=10.91
(s, 1H; OH), 8.80 (s, 1H; NH), 7.35–6.85 (m, 10H; aromatic and indole
The product from Table 2, entry 3 was isolated by column chromatogra-
phy (eluant:cyclohexane/ethyl acetate 901:0) as an oil with 67% ee.
[a]2D0 =+6.64 (c=1.5 in CHCl3); chiralcel OJ column (hexane/iPrOH
70:30, flow rate=0.75 mLminÀ1) tR =44 min (major), tR =56 min (minor)
(a further couple of peaks were observed at 20 min (major) and 23 min
(minor)).
protons), 6.16 (d, 3J(H,H)=10.3 Hz, 1H; vinylic proton), 5.41 (d, 3J-
A
(H,H)=10.3 Hz, 1H; benzylic proton), 3.72 ppm (s, 3H; OCH3);
13C NMR (75 MHz, [D6]DMSO, 258C, TMS): d=164.4, 143.5, 139.4,
136.1, 127.9, 127.3, 125.7, 125.6, 122.2, 120.6, 118.4, 117.9, 116.4, 116.1,
111.1, 51.7, 37.5 ppm; IR (nujol): n˜ =3448 (NH), 1700 (C=O), 1672 cmÀ1
(C=C).
4-(1H-2-Methylindol-3-yl)-2-hydroxy-4-phenyl-2-butenoic acid methyl
ester (4c’):Solid Sc (OTf)3 (0.02 mmol) was added to a solution of 2-
A
methylindole (2c; 0.20 mmol) and methyl (E)-2-oxo-4-phenyl-3-bute-
noate (3a; 0.20 mmol) in anhydrous diethyl ether (0.3 mL) at À708C in a
vial sealed with a rubber septum. The reaction mixture was stirred for a
few minutes until a clear solution was obtained. The reaction mixture
was washed with water, and the organic layer was dried with anhydrous
sodium sulfate and evaporated to give almost pure 4c’. 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=7.85 (s, 1H; NH), 7.3–7.0 (m, 9H; ar-
A sample of pure 4a’, with the above spectroscopic characteristics was
isolated by column chromatography on silica gel (eluant:cyclohexane/
ethyl acetate 75:25) to give pure 4-(1H-indol-3-yl)-2-oxo-4-phenylbutyric
acid methyl ester (4a) as
(300 MHz, CDCl3, 258C, TMS): d=8.04 (bs, 1H; NH), 7.45–7.05 (m,
10H; aromatic and indole protons), 4.95 (t, 3J
(H,H)=7.5 Hz, 1H; CH),
3.79 (s, 3H; OCH3), 3.69 (dd, 2J(H,H)=16.8, 3J
(H,H)=7.5 Hz, 1H;
a
white solid. M.p. 137–1398C; 1H NMR
H
omatic and indole protons), 6.41 (d, 3J
proton), 5.78 (s, 1H; OH) 5.59 (d, 3J
(H,H)=10.1 Hz, 1H; benzylic
A
A
N
ACHTREUNG
3634
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3630 – 3636

Catalytic Enantioselective Friedel–Crafts Reaction
FULL PAPER
proton), 3.83 (s, 3H; OCH3), 2.44 ppm (s, 3H; CH3); 13C NMR, (75 MHz,
CDCl3, 258C, TMS): d=165.7, 142.1, 138.6, 135.0, 131.5, 128.6, 127.8,
127.2, 125.6, 120.5, 118.9, 118.7, 115.1, 111.8, 109.9, 52.4, 36.6, 11.6 ppm;
IR (nujol): n˜ =3401 (NH), 1700 cmÀ1 (C=O); chiralcel OJ column
(hexane/iPrOH 70:30, flow rate=0.75 mLminÀ1) tR =19 min and tR =
22 min.
ethyl acetate. M.p. 1628C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=
8.06 (s, 1H; NH), 7.4–7.1 (m, 9H; aromatic and indole protons), 4.88 (t,
2
3J
3J
N
ACHTREUNG
(H,H)=17.1, 3J
ACHTREUNG
7.5 Hz, 1H; CHH); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=191.8,
160.7, 142.2, 134.4, 128.2, 127.1, 127.0, 126.3, 124.8, 122.3, 122.2, 118.3,
117.6, 111.7, 52.5, 45.1, 37.0 ppm; IR (nujol): n˜ =3347 (NH), 1740 cmÀ1
(C=O); elemental analysis (%) calcd for C19H16ClNO3 (341.8):C 66.77,
H 4.72, N 4.10; found:C 66.63, H 4.78, N 4.03.
(+)-4-(2-Phenylindol-3-yl)-2-oxo-4-phenylbutyric acid methyl ester (4d):
The racemate was obtained as a light-yellow solid from benzene/hexane.
M.p. 98–998C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.12 (s, 1H;
3
NH), 7.6–7.1 (m, 14H; aromatic and indole protons), 5.13 (dd, J
A
The product from Table 2, entry 8 was isolated by column chromatogra-
6.5 and 8.7 Hz, 1H; CH), 3.90 (dd, 2J
CHH), 3.75 (dd, 2J(H,H)=16.9, 3J
(H,H)=6.5 Hz, 1H; CHH), 3.59 ppm
A
N
phy (eluant:cyclohexane/ethyl acetate 802:0) as
a white solid with
95% ee. [a]2D0 =+15.4 (c=0.5 in CHCl3); chiralpak IA column (hexane/
ethyl acetate 85:15, flow rate=0.5 mLminÀ1) tR =27 min (major), tR =
30.5 min (minor).
A
ACHTREUNG
(s, 3H; OCH3); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=192.1, 160.5,
142.9, 135.7, 135.5, 132.2, 128.3, 128.0, 127.8, 126.9, 126.8, 125.8, 121.7,
120.1, 119.4, 112.4, 110.6, 52.2, 44.4, 36.1 ppm; IR (nujol): n˜ =3381 (NH),
1744 cmÀ1 (C=O); elemental analysis (%) calcd for C25H21NO3 (383.4):C
78.31, H 5.52, N 3.65; found:C 78.37, H 5.48, N 3.62.
(À)-(4R)-4-(1H-6-Chloroindol-3-yl)-2-oxo-4-phenylbutyric acid methyl
ester (4i):The racemate was obtained as a white solid. M.p. 157–158 8C
(m.p. 1588C in ref. [1]); the 1H and 13C NMR spectra are identical to
those reported in ref. [1]; IR (nujol): n˜ =3335 (NH), 1732 cmÀ1 (C=O).
The product from Table 2, entry 9 was isolated by column chromatogra-
The product from Table 2, entry 4 was isolated by column chromatogra-
phy (eluant:cyclohexane/ethyl acetate 851:5) as a yellow solid with
52% ee. [a]2D0 =+11.2 (c=0.9 in CHCl3); chiralpak AD column (hexane/
iPrOH 80:20, flow rate=1.0 mLminÀ1) tR =23 min (minor), tR =27 min
(major).
phy (eluant:cyclohexane/ethyl acetate 802:0) as
a white solid with
98% ee. [a]2D0 =À18.8 (c=0.9 in CHCl3) ([a]D20 =À18.5 (c=0.01 in CHCl3)
for 97% ee in ref. [1]) chiralpak IA column (hexane/ethyl acetate 85:15,
flow rate=0.5 mLminÀ1) tR =31 min (major), tR =35 min (minor).
(+)-4-(1H-4-Methoxyindol-3-yl)-2-oxo-4-phenylbutyric acid methyl ester
(4e):The racemate was obtained as light-yellow crystals from ethyl ace-
tate/hexane. M.p. 150–1518C; 1H NMR (CDCl3): d=7.95 (s, 1H; NH),
(À)-4-(1H-7-Chloroindol-3-yl)-2-oxo-4-phenylbutyric acid methyl ester
(4j):The racemate was obtained as white needles from ethyl acetate/
hexane. M.p. 105–1078C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=
7.8–7.15 (m, 5H; aromatic protons), 7.09 (t, 3J
ACHTREUNG
indole), 6.94 (d, 3J
A
ACHTREUNG
8.27 (s, 1H; NH), 7.4–7.0 (m, 9H; aromatic and indole protons), 4.93 (t,
2.2 Hz, 1H; 2-H indole), 6.48 (d, 3J
ACHTREUNG
2
3J
3J
N
ACHTREUNG
3
(H,H)=17.1, 3J
ACHTREUNG
(dd, J
ACHTREUNG
OCH3), 3.73 (dd, 2J
(dd, 2J
N
ACHTREUNG
7.6 Hz, 1H; CHH); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=191.8,
160.8, 142.3, 133.3, 128.1, 127.4, 127.2, 126.3, 121.5, 121.2, 119.9, 119.0,
117.6, 116.1, 52.5, 45.0, 37.2 ppm; IR (nujol): n˜ =3392 (NH), 1743 cmÀ1
(C=O); elemental analysis (%) calcd for C19H16ClNO3 (341.8):C 66.77,
H 4.72, N 4.10; found:C 66.89, H 4.77, N 3.99.
G
ACHTREUNG
CDCl3, 258C, TMS): d=192.6, 161.1, 154.0, 143.3, 137.7, 127.7, 127.5,
125.7, 122.7, 120.1, 119.1, 116.1, 103.9, 99.3, 54.4, 52.3, 46.1, 37.9 ppm; IR
(nujol): n˜ =3365 (NH), 1747 cmÀ1 (C=O); elemental analysis (%) calcd
for C20H19NO4 (337.4):C 71.20, H 5.68, N 4.15; found:C 71.25, H 5.77, N
4.08.
The product from Table 2, entry 10 was isolated by column chromatogra-
phy (eluant:cyclohexane/ethyl acetate 802:0) as
a white solid with
94% ee. [a]2D0 =À43.5 (c=1.4 in CHCl3); chiralpak IA column (hexane/
ethyl acetate 85:15, flow rate=0.5 mLminÀ1) tR =21 min (major), tR =
23 min (minor).
The product from Table 2, entry 5 was isolated by column chromatogra-
phy (eluant:cyclohexane/ethyl acetate 802:0) as a yellow solid with
98% ee. [a]2D0 =+47.1 (c=0.7 in CHCl3); chiralcel OJ column (hexane/
iPrOH 70:30, flow rate=0.9 mLminÀ1) tR =65 min (major), tR =198 min
(minor).
(À)-3-(3-Methoxycarbonyl-3-oxo-4-phenylpropyl)-1H-indole-6-carboxylic
acid methyl ester (4k):The racemate was obtained as a white solid from
ethyl acetate/hexane. M.p. 178–1798C (obtained as pale-yellow solid,
(+)-4-(1H-5-Methoxyindol-3-yl)-2-oxo-4-phenylbutyric acid methyl ester
(4 f):The racemate was obtained as a light-yellow solid from methanol.
M.p. 135–1368C (obtained as a yellow semicrystalline oil in ref. [1]); the
1H and 13C NMR spectra are identical to those reported in ref. [1]; IR
(nujol): n˜ =3364 (NH), 1745 and 1734 cmÀ1 (C=O). The product from
Table 2, entry 6 was isolated by column chromatography (eluant:cyclo-
1
m.p. 1808C in ref. [1]); the H and 13C NMR spectra are identical to those
reported in ref. [1]; IR (nujol): n˜ =3354 (NH), 1740 and 1702 cmÀ1 (C=
O). The product from Table 2, entry 11 was isolated by column chroma-
tography (eluant:cyclohexane/ethyl acetate 703:0) as a white solid with
99% ee. [a]2D0 =À4.6 (c=in 0.7 CHCl3) ([a]D20 =À2.9 (c=0.01 in CHCl3)
for 94% ee in ref. [1]); Chiralpak AD column (hexane/iPrOH 80:20, flow
rate=1.0 mLminÀ1) tr =42 min (major), tr =49 min (minor).
hexane/ethyl acetate 80:20) as a light-yellow solid with 88% ee. [a]D20
=
+8.2 (c=0.7 in CHCl3) ([a]2D0 =+5.2 (c=0.01 in CHCl3) for 99.5% ee in
ref. [1]); chiralpak AD column (hexane/iPrOH 80:20, flow rate=
1.0 mLminÀ1) tR =14 min (major), tR =20 min (minor).
(+)-4-(1H-5-Nitroindol-3-yl)-2-oxo-4-phenylbutyric acid methyl ester
(4l):The racemate was obtained as a light-yellow solid from ethyl ace-
tate/hexane. M.p. 150–1518C; 1H NMR (300 MHz, CDCl3, 258C, TMS):
(+)-4-(1H-4-Chloroindol-3-yl)-2-oxo-4-phenylbutyric acid methyl ester
(4g):The racemate was obtained as white crystals from ethyl acetate/
hexane. M.p. 140–1418C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=
8.17 (s, 1H; NH), 7.4–7.0 (m, 9H; aromatic and indole protons), 5.57 (t,
d=8.52 (s, 1H; NH), 8.41 (d, 3J
N
3
(dd, J
ACHTREUNG
and indole protons), 4.97 (t, 3J
OCH3), 3.73 (dd, 2J
(dd, 2J
ACHTREUNG
3J
(H,H)=7.6 Hz, 1H; CH), 3.80 (s, 3H; OCH3), 3.68 and 3.65 ppm (two
R
N
pseudo-singlets, 2H; CH2); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=
191.9, 160.9, 142.9, 137.4, 127.9, 127.5, 126.0, 125.8, 122.9, 122.7, 122.4,
120.5, 118.5, 109.5, 52.4, 46.5, 36.7 ppm; IR (nujol): n˜ =3354 (NH),
1743 cmÀ1 (C=O); elemental analysis (%)calcd for C19H16ClNO3 (341.8):
C 66.77, H 4.72, N 4.10; found:C 66.52, H 4.63, N 4.21.
G
ACHTREUNG
CDCl3, 258C, TMS): d=191.5, 160.7, 141.7, 141.2, 139.0, 128.3, 127.1,
126.6, 125.4, 123.9, 120.4, 117.6, 116.2, 110.7, 52.6, 45.0, 36.8 ppm; IR
(nujol): n˜ =3357 (NH), 1739 cmÀ1 (C=O); elemental analysis calcd (%)
for C19H16N2O5 (352.3):C 64.77, H 4.58, N 7.95; found:C 64.89, H 4.47,
N 8.01.
The product from Table 2, entry 7 was isolated by column chromatogra-
phy (eluant:cyclohexane/ethyl acetate 802:0) as a white solid with 99%
ee. [a]2D0 =+13.3 (c=0.9 in CHCl3); chiralcel OJ column (hexane/iPrOH
70:30, flow rate=0.9 mLminÀ1) tR =84 min (minor), tR =119 min (major).
The product from Table 2, entry 12 was isolated by column chromatogra-
phy (eluant:cyclohexane/ethyl acetate 752:5) as a yellowish solid with
90% ee. [a]2D0 =+59.1 (c=0.4 in CHCl3); Chiralpak IA column (hexane/
ethyl acetate 85:15, flow rate=0.75 mLminÀ1) tr =49 min (major), tr =
56 min (minor).
(+)-4-(1H-5-Chloroindol-3-yl)-2-oxo-4-phenylbutyric acid methyl ester
(4h):The racemate was obtained as a light-cream solid from hexane/
Chem. Eur. J. 2008, 14, 3630 – 3636
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3635

G. Desimoni et al.
(À)-(4R)-4-(1H-Indol-3-yl)-2-oxo-4-(4-bromophenyl)butyric acid methyl
ester (4m):The racemate was obtained as a white solid from methanol/
water. M.p. 166–1678C; 1H NMR (300 MHz, [D6]DMSO, 258C, TMS):
d=10.9 (s, 1H; NH), 7.4–7.3 (m, 7H; aromatic and indole protons), 7.04
Acknowledgement
This work was supported by the Ministero dell’Università e della Ricerca
(MiUR) (PRIN 2006) and by the University of Pavia.
(t, 3J
indole proton), 4.70 (t, 3J
3.73 (dd, 2J(H,H)=18.0, 3J
(H,H)=18.0, 3J
(H,H)=7.7 Hz, 1H; CHH), 2.31 ppm (s, 3H; CH3);
A
N
AHCTREUNG
A
ACHTREUNG
[1] K. B. Jensen, J. Thorhauge, R. G. Hazel, K. A. Jørgensen, Angew.
Chem. 2001, 113, 164–167; Angew. Chem. Int. Ed. 2001, 40, 160–
163.
[2] K. A. Jørgensen, Synthesis 2003, 1117–1125, and references therein.
[3] M. P. A. Lyle, N. D. Draper, P. D. Wilson, Org. Lett. 2005, 7, 901–
904.
A
ACHTREUNG
13C NMR (75 MHz, [D6]DMSO, 258C, TMS): d=192.0, 160.8, 143.9,
136.3, 131.0, 129.9, 126.0, 122.1, 121.1, 119.0, 118.5, 118.4, 116.7, 111.4,
52.6, 44.7, 36.2 ppm; IR (nujol): n˜ =3341 (NH), 1735 cmÀ1 (C=O); ele-
mental analysis calcd (%) for C19H16BrNO3 (386.2):C 59.08, H 4.18, N
3.63; found:C 59.25, H 4.22, N 3.52.
[4] J. Zhou, M.-C. Ye, Z.-Z. Huang, Y. Tang, J. Org. Chem. 2004, 69,
1309–1320.
The product from Table 3, entry 2 was isolated by column chromatogra-
[5] M.-C. Ye, B. Li, J. Zhou, X.-L. Sun, Y. Tang, J. Org. Chem. 2005, 70,
6108–6110.
[6] S. Yamazaki, Y. Iwata, J. Org. Chem. 2006, 71, 739–743.
[7] R. Rasappan, M. Hager, A. Gissibl, O. Reiser, Org. Lett. 2006, 8,
6099–6102.
[8] a) D. A. Evans, K. A. Scheidt, K. R. Fandrick, H. W. Lam, J. Wu, J.
Am. Chem. Soc. 2003, 125, 10780–10781; b) D. A. Evans, K. R. Fan-
drick, H. J. Song, K. A. Scheidt, R. Xu, J. Am. Chem. Soc. 2007, 129,
10029–10041.
[9] N. Takenaka, J. P. Abell, H. Yamamoto, J. Am. Chem. Soc. 2007, 129
742–743.
[10] S.-F. Lu, D.-M. Du, J. Xu, Org. Lett. 2006, 8, 2115–2118.
[11] Y.-X. Jia, S.-F. Zhu, Y. Yang, Q.-L. Zhou, J. Org. Chem. 2006, 71,
75–80.
[12] P. K. Singh, A. Bisai, V. K. Singh, Tetrahedron Lett. 2007, 48, 1127–
1129.
phy (eluant cyclohexane/ethyl acetate 85:15) as
a white solid with
96% ee. [a]2D0 =À3.6 (c=0.9 in CHCl3); Chiralcel AD column (hexane/
iPrOH 80:20, flow rate=1.0 mLminÀ1) tr =13 min (major), tr =20 min
(minor).
(À)-4-(1H-Indol-3-yl)-2-oxo-4-(4-methylphenyl)butyric acid methyl ester
(4n):The racemate was obtained as
a white solid from methanol.
M.p. 1388C; 1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.03 (s, 1H;
NH), 7.5–7.0 (m, 9H; aromatic and indole protons), 4.92 (t, 3J
(H,H)=
AHCTREUNG
2
3
ACHTREUNG
7.6 Hz, 1H; CH), 3.80 (s, 3H; OCH3), 3.72 (dd, J
A
(H,H)=
7.3 Hz, 1H; CHH), 3.61 (dd, 2J(H,H)=16.9, 3J
G
ACHTREUNG
CHH), 2.31 ppm (s, 3H; CH3); 13C NMR (75 MHz, CDCl3, 258C, TMS):
d=192.2, 160.8, 139.6, 136.1, 135.6, 128.7, 127.1, 125.9, 121.8, 121.0, 119.0,
118.9, 118.0, 110.6, 52.4, 45.2, 36.8, 20.5 ppm; IR (nujol): n˜ =3360 (NH),
1747 (C=O), 1738 cmÀ1 (C=O); elemental analysis calcd (%) for
C20H19NO3 (321.4):C 74.75, H 5.96, N 4.36; found:C 74.89, H 5.99, N
4.48.
[13] For a review on bis(oxazolines), see:G. Desimoni, G. Faita, K. A.
Jørgensen, Chem. Rev. 2006, 106, 3561–3651.
The product from Table 3, entry 3 was isolated by column chromatogra-
phy (eluant:cyclohexane/ethyl acetate 802:0) as
a white solid with
[14] D. A. Evans, K. R. Fandrick, H.-J. Song, J. Am. Chem. Soc. 2005,
127, 8942–8943.
[15] For a review of pybox, see:G. Desimoni, G. Faita, P. Quadrelli,
Chem. Rev. 2003, 103, 3119–3154.
90% ee. [a]2D0 =À11.3 (c=1.6 in CHCl3); Chiralcel AD column (hexane/
iPrOH 80:20, flow rate=1.0 mLminÀ1) tr =14 min (major), tr =18 min
(minor).
[16] G. Desimoni, G. Faita, M. Mella, F. Piccinini, M. Toscanini, Eur. J.
Org. Chem. 2007, 1529–1534.
[17] G. Desimoni, G. Faita, M. Toscanini, M. Boiocchi, Chem. Eur. J.
2007, 13, 9478–9485.
[18] S. Lakhdar, M. Werstermaier, F. Terrier, R. Goumont, T. Boubaker,
A. R. Ofial, H. Mayr, J. Org. Chem. 2006, 71, 9088–9095.
[19] S. Lakhdar, R. Goumont, G. Berionni, T. Boubaker, S. Kurbatov, F.
Terrier, Chem. Eur. J. 2007, 13, 8317–8324.
X-ray crystallographic study:Diffraction data for a crystal of 4m were
collected at ambient temperature by means of an Enraf–Nonius CAD4
four-circle diffractometer with graphite-monochromatized MoKa X-ray
radiation (l=0.71073 Š). Crystal data for 4m: C19H16BrNO3; Mr =
386.23; T=293 K; crystal dimensions=0.45”0.14”0.09 mm3; orthorhom-
bic; P212121 (No. 19); a=9.6759(13), b=12.6207(11), c=14.0733(9) Š;
V=1718.6(3) Š3; Z=4; 1calcd =1.493;
F ;
(000)=784; m=2.407 mmÀ1
G
2qmax=508; 3828 measured reflections, 3066 independent reflections
(Rint =0.026), 1832 strong reflections (Io>2s(Io)), 221 refined parame-
ters, R1=0.0526 (strong data) and 0.1168 (all data), wR2=0.0704 (strong
data) and 0.0844 (all data), GOF=1.002, 0.27, and À0.36 maximum
(max.) and minimum (min.) residual electron density. Data reductions
(including intensity integration, background, Lorentz, and polarization
corrections) were performed with the WinGX package.[26] Absorption ef-
fects were evaluated with the psi-scan method[27] and absorption correc-
tion was applied to the data (min./max. transmission factors were 0.654/
0.807). Crystal structures were solved by direct methods (SIR 97)[28] and
refined by full-matrix least-square procedures on F2 using all reflections
(SHELXL 97).[29] Anisotropic displacement parameters were refined for
all non-hydrogen atoms. Hydrogen atoms bonded to carbon atoms were
placed at calculated positions with the appropriate AFIX instructions
and refined using a riding model; hydrogen-bonding interactions with the
[20] G. Desimoni, G. Faita, F. Piccinini, M. Toscanini, Eur. J. Org. Chem.
2006, 5228–5230.
[21] G. Desimoni, G. Faita, M. Guala, A. Laurenti, M. Mella, Chem. Eur.
J. 2005, 11, 3816–3824.
[22] E. D. Secher, H. F. Ryder, J. Am. Chem. Soc. 1952, 74, 4392.
[23] H. Audrain, J. Thorhauge, R. G. Hazell, K. A. Jørgensen, J. Org.
Chem. 2000, 65, 4487.
[24] M. Reimer, E. Tobin, J. Am. Chem. Soc. 1940, 62, 2518.
[25] M. Reimer, E. Chase, J. Am. Chem. Soc. 1938, 60, 2470.
[26] L. J. Farrugia, J. Appl. Crystallogr. 1999, 32, 837–838.
[27] A. C. T. North, D. C. Phillips, F. S. Mathews, Acta. Crystallogr. 1968,
A24, 351–359.
[28] A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C. Giaco-
vazzo, A. Guagliardi, A. G. G. Moliterni, G. Polidori, R. Spagna, J.
Appl. Crystallogr. 1999, 32, 115–119.
[29] G. M. Sheldrick, SHELX97 Programs for Crystal Structure Analysis,
University of Gçttingen, Germany, 1997.
À
N(1) atom were located in the DF map and refined restraining the N H
distance to be 0.89Æ0.02 Š.
CCDC–668902 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received:December 4, 2007
Published online:February 27, 2008
3636
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3630 – 3636