Enantioselective Friedel-Crafts alkylation of indole derivatives catalyzed by new Yb(OTf)3-pyridylalkylamine complexes as chiral Lewis acids

Article abstract of DOI:10.1039/c0ob00461h

New Yb(OTf)₃-pyridylalkylamine complexes have been employed as chiral Lewis acids in the enantioselective Friedel-Crafts alkylation of indole derivatives with trifluoropyruvates. The influence of the substituents as well as the configuration of

Full text of DOI:10.1039/c0ob00461h

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Enantioselective Friedel–Crafts alkylation of indole derivatives catalyzed by
new Yb(OTf)3-pyridylalkylamine complexes as chiral Lewis acids†
Guillaume Grach,a,b Aurelia Dinut,b Sylvain Marque,a Je´roˆme Marrot,a Richard Gil*b and Damien Prim*a
Received 20th July 2010, Accepted 23rd September 2010
DOI: 10.1039/c0ob00461h
New Yb(OTf)3-pyridylalkylamine complexes have been employed as chiral Lewis acids in the
enantioselective Friedel–Crafts alkylation of indole derivatives with trifluoropyruvates. The influence of
the substituents as well as the configuration of the ligands have been studied and allowed us to reach
enantiomeric excesses up to 83%.
Introduction
The Friedel–Crafts (F–C) alkylation is one of the most important
and powerful C–C bond-forming processes in organic chemistry.
Over the past decade, the catalytic asymmetric version of this
reaction has attracted the interest of the scientific community.1 In
this research field copper-based complexes have been extensively
studied for the metal-catalyzed F–C alkylation of aromatics and
heteroaromatics.2 Despite the fact that lanthanides have proved
to be good Lewis acids for catalyzing the F–C reaction,3 the use
of these rare earth metals as chiral Lewis acids in enantioselective
F–C alkylation is scarcely reported and remains challenging.4 Very
recently, Feng and coworkers have developed the first example
of metal controlled reversal of enantioselectivity in asymmetric
F–C alkylation of indoles with b,g-unsaturated-a-ketoesters using
AgAsF6 or Sm(OTf)3-N,N¢-dioxide complexes.5 In this context, we
report here new chiral ytterbium-based Lewis acids as catalysts
for the asymmetric F–C alkylation of indole derivatives by
trifluoropyruvates6 with good yields and enantioselectivities using
simple pyridylalkylamines as ligands.
Results and discussion
The targeted ligands were readily obtained from commercially
available common reactants in one or two steps based on previous
studies (Scheme 1). Ligands L1, L4, L6, L8 and L9 (R1 = H) were
prepared in one step by reductive amination of heteroaromatic
aldehydes with enantiopure amines using sodium triacetoxyboro-
hydride (Method A).7 This process was very efficient as the
desired products were isolated in quantitative yields. Ligands
Scheme 1 Synthesis of the pyridylalkylamine ligands
aUniversite´ de Versailles-Saint-Quentin, Institut Lavoisier de Versailles
L2, L5, L7 and L10 were synthesized with moderate to good
yields (49 to 72%) in two steps by condensation of aldehydes with
enantiopure amines followed by the addition of organometallics
to the neo-formed corresponding imines (Method B).8 Finally L3
was obtained in 90% yield over two steps including the formation
of the corresponding ketimine and further reduction with sodium
borohydride (Method C).9 Thus these methodologies allowed
´
UMR CNRS 8180, 45, avenue des Etats-Unis, 78035 Versailles Cedex,
France
b
´
Equipe de Catalyse Mole´culaire, ICMMO, UMR CNRS 8182, Universite´
Paris-Sud 11, 91405 Orsay Cedex, France
† Electronic supplementary information (ESI) available: 1H NMR and 13
C
NMR spectra and analytical data for the synthesized compounds. CCDC
reference number 767347. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0ob00461h
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Table 1 Screening of ligands in the Friedel–Crafts alkylation of
N-methylindole 1aa
us to prepare a variously substituted ligand family based on a
pyridylalkylamine core.
Diastereomeric ligands L2, L3, L5, L7 and L10 were separated
by column chromatography on silica gel. The absolute configura-
tion of each diastereomer of L2 was determined by comparison of
their optical activity and NMR spectra with literature data.8f,9,10
Configuration of the neo-formed tertiary carbon center in L5,
was assigned according to L2 analytical data. The (1S,1¢R)
absolute configuration of L3 second eluted diastereomer was
unambiguously established by X-ray diffraction analysis of the
corresponding palladium(II) complex (Fig. 1).11,12 Surprisingly,
the established (1S,1¢R) configuration is in disagreement with the
one supposed in the literature.13 In the case of L7 and L10, the
configurations of each diastereomer were not determined.
Entry
L*
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
L1
78
84
78
85
82
80
78
86
84
81
74
77
82
3 (S)
11 (S)
18 (R)
20 (S)
60 (R)
1 (S)
3 (S)
5 (R)
3 (S)
1 (R)
6 (R)
1 (S)
0
(1R,1¢R)-L2
(1S,1¢R)-L2
(1R,1¢R)-L3
(1S,1¢R)-L3
L4
(1R,1¢R)-L5
(1S,1¢R)-L5
L6
9
10
11
12
13
(1¢S)-L7d
L8
L9
(1¢R)-L10d
a Reactions were carried out with Yb(OTf)3 (10 mol %), ligand (10 mol
%), 1a (0.25 mmol), and 2a (0.275 mmol) in DCM (1.5 mL) at r.t.
for 20 h. b Isolated yield (complete conversion was observed for each
reaction). c Determined by chiral HPLC analysis (see ESI†). d Due to harsh
purification, only one diastereomer tested.
Fig. 1 X-ray crystal structure for (1S,1¢R)-L3 palladium dichloride
complex.
(Table 1, entries 9–13). Sc(OTf)3 and Sm(OTf)3 were tested as
metal triflates with (1S,1¢R)-L3 but lower enantioselectivities were
observed: respectively 50 and 30% at room temperature. A similar
decrease in the enantioselectivities was observed in either toluene
or acetonitrile.
We next screened the aforementioned panel of ligands in
the Friedel–Crafts alkylation of N-methylindole 1a to ethyl
trifluoropyruvate 2a catalyzed by Yb(OTf)3-L* complexes. The
catalytic species were prepared in situ by mixing Yb(OTf)3 with
the appropriate ligand in dichloromethane at room temperature.
The pyruvate 2a was then added followed by 1a and the reaction
mixture stirred overnight. The results are gathered in Table 1.
For all the tested ligands, the reaction proceeded with complete
conversion of N-methylindole 1a into the desired 3-substituted
indole 3a after 20 h. Enantiomeric excesses were measured by
chiral HPLC on the purified indole derivative 3a and the absolute
configuration was determined by comparison with specific rota-
tion values reported in the literature. The enantiomeric excesses
varied to a great extent from 20% for the (S) enantiomer to 60%
for the (R) one.
Based on these results, L3 in combination with Yb(OTf)3
appeared as the best catalytic compromise in this reaction.
In order to increase the enantioselectivity we focused our
attention on the reaction conditions using (1R,1¢S)-L3 as the
ligand. In concordance with the aforementioned results, (S)-3a
was obtained with 60% ee under the conditions described in
Table 1 (Table 2, entry 1). We next examined the ligand/metal
ratio (Table 2, entries 1–4). Interestingly, either 2 : 1 or 3 : 1 ratio
provided 3a with low selectivities in favour of the (R) isomer
(entries 3-4). These results could be explained by the intervention
of a high coordination number of Yb complex as catalytic species.
In contrast, the use of a 0.5 : 1 ratio (entry 5) afforded (S)-3a with
56% ee, confirming a detrimental effect of an excess of ligand
compared to metal. These results seemed to point an optimal
1 : 1 ligand/metal ratio. Thus, in order to rigorously control this
ratio, we decided to prepare and isolate the Yb(OTf)3-(1R,1¢S)-
L3 complex on a larger scale.14 The alkylation of 1-methylindole
1a has been carried out using two procedures involving an
in situ prepared complex (procedure A) and an isolated complex
(procedure B). The latter is more reliable since slightly higher
enantioselectivities were obtained proving a better control of the
ligand/metal ratio.
The influence of the presence and/or the nature of the R1
substituent was studied. In the absence of a substituent (R1 =
H, entries 1, 6, 9, 11 and 12) only very low enantioselectivities
could be obtained, regardless of the heterocyclic moiety. Slight
increase of enantioselectivities (5 – 18%) were observed with
L2 and L5 bearing a methyl substituent in the pseudo benzylic
position (R1 = Me, entries 2-3 and 7-8). Gratifyingly, moving
from a methyl to a phenyl group (L3) provided the same level
of enantioselectivity (20%) with the (1R,1¢R) diastereomer and a
good 60% ee with (1S,1¢R)-L3 (Table 1, entries 4-5). It is worth
noting that the opposite senses of induction were observed for the
(1R,1¢R) and the (1S,1¢R) diastereomers in the case of L2 and L3,
highlighting the crucial and beneficial role played by the stereo
center bearing the R1 substituent in the enantiodiscriminating
step. Further screening involving the use of quinolyl- or thienyl-
based ligands as well as tridendate ligands led to poor selectivities
The influence of the temperature was also examined (Table 2,
entries 1, 6–12). At room temperature, the reaction between 1a
and 2a in the presence of 10 mol % of Yb(OTf)3-(1R,1¢S)-L3
complex gave 3a with 61% ee. Lower temperatures were found
beneficial to selectivity. Indeed, selectivities could be enhanced
up to 82% ee at -20 ◦C (entry 10). It was also demonstrated
498 | Org. Biomol. Chem., 2011, 9, 497–503
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Table 2 Study of the reaction conditions of the Friedel–Crafts alkylation of indoles 1a–c
Entry
(1R,1¢S)-L3 (mol %)
T (◦C)
Time
Conv (%)b
Procedure
Product
ee (%)c
1
2
3
4
5
6
7
8
10
10
20
30
5
r.t.
r.t.
r.t.
r.t.
r.t.
0
20 h
20 h
20 h
20 h
20 h
40 h
40 h
48 h
72 h
72 h
96 h
8 d
20 h
72 h
20 h
72 h
20 h
72 h
100
100
100
100
100
100
100
100
100
100d
100
85
100
100
100
100
100
100
A
B
A
A
A
A
B
A
A
B
B
B
B
B
B
B
B
B
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3c
3c
3d
3d
60 (S)
61 (S)
4 (R)
5 (R)
56 (S)
65 (S)
74 (S)
68 (S)
78 (S)
82 (S)
83 (S)
76 (S)
56
10
10
10
10
10
10
10
10
10
10
10
10
10
0
-10
-20
-20
-40
-90
r.t.
-20
r.t.
-20
r.t.
-20
9
10
11
12
13
14
15
16
17
18
74
45
51
54
79
a Procedure A: Yb(OTf)3 (10 mol %), (1R,1¢S)-L3 (x mol %), 1a (0.25 mmol), and 2a (0.275 mmol) in DCM (1.5 mL). Procedure B: Yb(OTf)3-(1R,1¢S)-L3
(10 mol %), 1a–c (0.25 mmol), and 2a,b (0.275 mmol) in DCM (1.5 mL). b Determined by 1H NMR of the crude mixture. c Determined by chiral HPLC
analysis (see ESI†). d The product was isolated in 88% yield.
that temperatures below -20 ◦C, only affected the reaction times
and no further improvement of the enantiomeric excesses were
observed (entries 11-12).
center bearing the R1 substituent on the enantioselectivity. Further
experiments are in progress to improve the selectivity by making
structural modifications of the pyridylalkylamine backbone and
to study the scope of this reaction.
With these conditions in hand we screened different substrates
in this reaction. The F–C alkylation of indole 1b with ethyl
trifluoropyruvate provided 3b with 56% ee at room temperature
◦
and 74% ee at -20 C (Table 2, entries 13-14),15 whereas lower
Experimental
selectivities (45% and 51% at respectively room temperature and
-20 ◦C) were observed with 2-methylindole 1c (entries 15-16).
The alkylation of N-methylindole 1a with methyl trifluoropy-
ruvate 2b instead of ethyl trifluoropyruvate did not affect the
enantioselectivities (entries 17-18) and 3d was obtained with a
79% ee at -20 ◦C. Finally N,N-dimethylaniline and N,N-dimethyl-
m-anisidine were also tested. In both case a full conversion was
observed after 48 h at room temperature confirming the activity
of the catalyst. However racemic mixtures were obtained.
General methods
All non-aqueous reactions were carried out under an atmosphere
of argon in flame- or oven-dried glassware with magnetic stirring.
All reagents and solvents obtained from commercial sources
were used without further purification unless otherwise noted.
CH2Cl2 was distilled over CaH2 before use. THF and Et2O were
distilled over sodium metal. Thin layer chromatography (TLC)
was performed on silica gel 60 F254 and the plates were visualized
with UV light (254 nm) or a potassium permanganate solution
(1 g with 2 g of K2CO3 in 200 mL of water). The crude products
were purified by preparative thin layer chromatography on silica
gel 60 PF254 or by column chromatography using silica gel Merck
60. Known compound structures were assigned by comparison
with the literature spectroscopic data. H and 13C NMR spectra
were recorded on a Bru¨cker AM 360, AM 300, DPX 200 and
DPX 250 spectrometers; Chemical shifts for 1H and 13C were
referenced internally according to the residual solvent resonances
and reported in ppm relative to CDCl3 (7.26 ppm for H and
77.0 ppm for 13C). All coupling constants (J values) are given in
Conclusions
In summary, we have developed a new Yb(OTf)3-pyridylalkyamine
catalytic system for the asymmetric F–C alkylation of indole
derivatives with trifluoropyruvates. Screening various structural
parameters has led us to identify a ligand with suitable substitution
and configuration for this reaction. Under optimized conditions,
the desired indole derivatives 3a–d were obtained in 51 to 82% ee
using Yb(OTf)3-(1R,1¢S)-L3 complex. It should be highlighted
that both diastereomers of L3 provided the product with the
opposite configuration showing the importance of the stereo
1
1
hertz (Hz). Data appear in the following order: chemical shift in
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ppm, multiplicity (s, singlet; d, doublet; t, triplet; q, quadruplet;
m, multiplet), coupling constant J, number of protons, and
assignment.
(S)-2-((Pyridin-2-yl)methylamino)-3-methylbutan-1-ol (L8)17.
The reaction was performed on 300 mg (2.80 mmol) of pyridine-
2-carboxaldehyde, 289 mg (2.80 mmol) of (S)-(+)-valinol and
890 mg (4.20 mmol) of sodium triacetoxyborohydride. The crude
product was purified by flash chromatography on silica gel, using
dichloromethane/methanol/ammonia (32% in water) (100/3/2)
as eluent, to afford L8 as an orange oil (80%, 435 mg). [a]2D0 +29.5
General procedure for the synthesis of L1, L4, L6, L8 and L9
To a stirred solution of aldehyde (1 eq) and chiral amine (1 eq) in
1,2-dichloroethane (10 mL for 2.5 mmol of aldehyde) was added
sodium triacetoxyborohydride (1.5 eq). The mixture was stirred at
rt under argon atmosphere for 16 h and the reaction was quenched
by adding saturated aqueous NaHCO3. The aqueous layer was
extracted with EtOAc and the combined organic layers were dried
over MgSO4, filtered and concentrated under vacuum to yield the
crude product.
1
(c 1.02, CHCl3); Lit.16 [a]D20 +28.2 (c 1.00, CH2Cl2). H NMR
(CDCl3, 200 MHz) d 8.55 (d, J = 4.8 Hz, 1H, Ar), 7.65 (dt, J =
7.6, J = 1.8 Hz, 1H, Ar), 7.14–7.30 (m, 2H, Ar), 4.03 and 3.93 (AB
system, JAB = 14.8 Hz, 2H, CH2–N), 3.67 and 3.44 (ABX system,
JAX = 3.9, JBX = 7.2, JAB = 10.9 Hz, 2H, CH2–O), 2.43–2.53 (m,
1H, CH–N), 1.84 (m, J = 6.8 Hz, 1H, CH of i-Pr), 0.99 (d, J =
6.8 Hz, 3H, Me), 0.93 (d, J = 6.8 Hz, 3H, Me). 13C NMR (CDCl3,
90 MHz) d 160.4 (Cquat, Ar), 149.3 (Ar), 136.8 (Ar), 122.5 (Ar),
122.2 (Ar), 65.0 (CH–N), 61.6 (CH2–O), 52.7 (CH2–N), 29.8 (CH
of i-Pr), 19.7 (Me of i-Pr), 19.0 (Me of i-Pr).
(R)-1-Phenyl-N-((pyridin-2-yl)methyl)ethylamine (L1)9. The
reaction was performed on 500 mg (4.67 mmol) of pyridine-2-
carboxaldehyde, 566 mg (4.67 mmol) of (R)-1-phenylethylamine
and 1.48 g (7.00 mmol) of sodium triacetoxyborohydride. The
crude product was purified by flash chromatography on silica gel,
using ethyl acetate/petroleum ether (6/4) as eluent, to afford L1
as an orange oil (91%, 899 mg). [a]2D0 +38.9 (c 1.01, CHCl3); Lit.9
[a]2D0 -46.9 (c 13.1, acetone) for the (S) isomer. 1H NMR (CDCl3,
300 MHz) d 8.60 (d, J = 3.8 Hz, 1H, Ar), 7.65 (t, J = 7.0 Hz, 1H,
Ar), 7.15–7.45 (m, 7H, Ar), 3.88 (q, J = 6.6 Hz, 1H, CH–N), 3.80
(s, 2H, CH2–N), 1.99 (brs, 1H, NH), 1.46 (d, J = 6.6 Hz, 3H, Me).
13C NMR (CDCl3, 90 MHz) d 160.0 (Cquat, Ar), 149.4 (Ar), 145.5
(Cquat, Ar), 136.4 (Ar), 128.6 (2C, Ar), 127.0 (Ar), 126.9 (2C, Ar),
122.5 (Ar), 121.9 (Ar), 58.1 (CH–N), 53.2 (CH2–N), 24.5 (Me).
(R)-1-Phenyl-N-((quinolin-2-yl)methyl)ethylamine (L9). The
reaction was performed on 200 mg (1.27 mmol) of quinoline-
2-carboxaldehyde, 154 mg (1.27 mmol) of (R)-1-phenylethylamine
and 405 mg (1.91 mmol) of sodium triacetoxyborohydride. The
crude product was purified by flash chromatography on silica
gel, using ethyl acetate/petroleum ether/ammonia (32% in water)
(20/80/1) as eluent, to afford L9 as an orange oil (86%, 287 mg).
[a]2D0 +29.1 (c 1.05, CHCl3). 1H NMR (CDCl3, 300 MHz) d 8.13
(d, J = 8.2 Hz, 1H, Ar), 8.03 (d, J = 8.5 Hz, 1H, Ar), 7.76 (d,
J = 8.1 Hz, 1H, Ar), 7.69 (ddd, J = 8.4, J = 7.0, J = 1.3 Hz, 1H,
Ar), 7.53–7.24 (m, 7H, Ar), 3.99 (s, 2H, CH2–N), 3.94 (q, J =
6.7 Hz, 1H, CH–N), 1.50 (d, J = 6.8 Hz, 3H, Me). 13C NMR
(R)-1-Phenyl-N-((6-methylpyridin-2-yl)methyl)ethylamine (L4).
The reaction was performed on 300 mg (2.48 mmol) of 6-
methylpyridine-2-carboxaldehyde, 300 mg (2.48 mmol) of (R)-
1-phenylethylamine and 787 mg (3.72 mmol) of sodium tri-
acetoxyborohydride. The product was obtained without further
purification as an orange oil (100%, 562 mg). [a]2D0 +32.7 (c 1.00,
(CDCl3, 75 MHz) d 160.3 (Cquat, Ar), 147.8 (Cquat, Ar), 145.5 (Cquat
,
Ar), 136.3 (Ar), 129.4 (Ar), 129.0 (Ar), 128.6 (2C, Ar), 127.6 (Ar),
127.3 (Cquat, Ar), 127.0 (Ar), 126.9 (2C, Ar), 126.0 (Ar), 120.7 (Ar),
58.3 (CH–N), 53.7 (CH2–N), 24.6 (Me). HRMS (ESI) Calcd for
C18H19N2 (MH+): 263.1548; found: 263.1539.
1
N -[(1-(Pyridin-2-yl)ethyl)]-N -[(1¢R)-1¢-phenylethyl]amine
CHCl3). H NMR (CDCl3, 200 MHz) d 7.50 (t, J = 7.5 Hz, 1H,
(L2)8f,10
.
A solution of pyridine-2-carboxaldehyde (500 mg,
Ar), 7.22–7.40 (m, 5H, Ar), 7.00 (d, J = 7.5 Hz, 2H, Ar), 3.84 (q,
J = 6.6 Hz, 1H, CH–N), 3.72 (s, 2H, CH2–N), 2.54 (s, 3H, Me of
Py), 2.24 (brs, 1H, NH), 1.42 (d, J = 6.6 Hz, 3H, Me). 13C NMR
4.67 mmol) and (R)-1-phenylethylamine (622 mg, 5.13 mmol) in
dry THF (20 mL) was stirred at rt over anhydrous MgSO4 for 24 h.
The reaction mixture was filtered through a pad of celite, washed
with DCM and the solvents were removed under vacuum to yield
the corresponding imine (100%, 997 mg).
(CDCl3, 90 MHz) d 159.1 (Cquat, Ar), 157.9 (Cquat, Ar), 145.6 (Cquat
,
Ar), 136.5 (Ar), 128.4 (2C, Ar), 126.9 (Ar), 126.8 (2C, Ar), 121.3
(Ar), 119.2 (Ar), 58.1 (CH–N), 53.2 (CH2–N), 24.5 (Me), 24.4
(Me). HRMS (ESI) Calcd for C15H19N2 (MH+): 227.1548; found:
227.1541.
To a stirred solution of the crude imine (500 mg, 2.38 mmol) in
dry THF (18 mL) at 0 ◦C was added dropwise methylmagnesium
bromide (1.67 mL, 5.00 mmol, 3M solution in diethyl ether).
The mixture was stirred at 50 ◦C for 20 h and the reaction was
quenched by adding water. The aqueous layer was extracted with
Et2O and the combined organic layers were dried over MgSO4,
filtered and concentrated under vacuum. The crude product was
purified by flash chromatography on silica gel, using petroleum
ether/ethyl acetate/ammonia (32% in water) (90/10/1) as eluent,
to afford the two desired diastereoisomers (52%, 281 mg). The
first eluted diastereoisomer (1R,1¢R)-L2 was isolated as an orange
oil (122 mg). [a]D20 +171.1 (c 0.56, CHCl3); Lit.8f [a]2D0 -170.0 (c 1,
(S)-2-((Pyridin-2-yl)methylamino)-2-phenylethanol
(L6)16.
The reaction was performed on 250 mg (2.33 mmol) of pyridine-
2-carboxaldehyde, 320 mg (2.33 mmol) of (S)-(+)-2-phenylglycinol
and 742 mg (3.50 mmol) of sodium triacetoxyborohydride. The
crude product was purified by flash chromatography on silica
gel, using dichloromethane/methanol/ammonia (32% in water)
(100/3/2) as eluent, to afford L6 as an orange oil (83%, 442 mg).
[a]2D0 +72.4 (c 1.02, CHCl3). 1H NMR (CDCl3, 200 MHz) d
8.56 (d, J = 4.9 Hz, 1H, Ar), 7.63 (dt, J = 7.6, J = 1.8 Hz, 1H,
Ar), 7.13–7.41 (m, 7H, Ar), 3.60–3.96 (m, 5H, CH–N, CH2–N,
CH2–O). 13C NMR (CDCl3, 90 MHz) d 159.8 (Cquat, Ar), 149.3
(Ar), 140.8 (Cquat, Ar), 136.7 (Ar), 128.8 (2C, Ar), 127.7 (Ar), 127.6
(2C, Ar), 122.6 (Ar), 122.2 (Ar), 67.2 (CH2–O), 64.7 (CH–N),
52.7 (CH2–N).
1
CHCl3) for (1S,1¢S)-L2. H NMR (CDCl3, 200 MHz) d 8.61 (d,
J = 3.8 Hz, 1H, Ar), 7.61 (dt, J = 7.6, J = 1.8 Hz, 1H, Ar), 7.05–
7.35 (m, 7H, Ar), 3.60 (q, J = 6.7 Hz, 1H, CH–N), 3.45 (q, J =
6.6 Hz, 1H, CH–N), 2.04 (brs, 1H, NH), 1.31 (d, J = 6.7 Hz, 3H,
Me), 1.28 (d, J = 6.6 Hz, 3H, Me). 13C NMR (CDCl3, 90 MHz)
500 | Org. Biomol. Chem., 2011, 9, 497–503
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d 165.1 (Cquat, Ar), 149.8 (Ar), 145.9 (Cquat, Ar), 136.4 (Ar), 128.6
(2C, Ar), 127.0 (3C, Ar), 122.1 (Ar), 121.9 (Ar), 56.5 (CH–N),
55.9 (CH–N), 25.3 (Me), 23.6 (Me). The second diastereoisomer
(1S,1¢R)-L2 was isolated as a dark orange oil (159 mg). [a]2D0 -8.1
(c 0.98, CHCl3); Lit.8f [a]D20 +8.2 (c 1.1, CHCl3) for (1R,1¢S)-L2.1H
NMR (CDCl3, 300 MHz) d 8.54 (d, J = 3.8 Hz, 1H, Ar), 7.59
(dt, J = 7.6, J = 1.8 Hz, 1H, Ar), 7.05–7.35 (m, 7H, Ar), 3.87 (q,
J = 6.6 Hz, 1H, CH–N), 3.81 (q, J = 6.6 Hz, 1H, CH–N), 1.97
(brs, 1H, NH), 1.39 (d, J = 6.6 Hz, 6H, Me).13C NMR (CDCl3, 90
MHz) d 164.8 (Cquat, Ar), 149.4 (Ar), 145.9 (Cquat, Ar), 136.5 (Ar),
128.5 (2C, Ar), 126.9 (Ar), 126.9 (2C, Ar), 121.9 (Ar), 121.4 (Ar),
56.4 (CH–N), 55.4 (CH–N), 23.8 (Me), 22.2 (Me).
DCM and the solvents were removed under vacuum to yield the
corresponding imine (100%, 451 mg).
To a stirred solution of the crude imine (451 mg, 2.00 mmol) in
dry THF (15 mL) at 0 ◦C was added dropwise methylmagnesium
bromide (2.07 mL, 6.20 mmol, 3M solution in diethyl ether).
The mixture was stirred at 50 ◦C for 20 h and the reaction
was quenched by adding water. The aqueous layer was extracted
with Et2O and the combined organic layers were dried over
MgSO4, filtered and concentrated under vacuum. The crude
product was purified by flash chromatography on silica gel, using
dichloromethane/methanol/ammonia (32% in water) (100/2/2)
as eluent, to afford the two desired diastereoisomers (72%,
326 mg). The first eluted diastereoisomer (1¢S)-L7 was partially
separated and isolated as an orange oil (96 mg). [a]2D0 +5.9 (c 1.02,
CHCl3). 1H NMR (CDCl3, 200 MHz) d 8.49 (d, J = 4.2 Hz, 1H,
Ar), 7.56 (dt, J = 7.7, J = 1.8 Hz, 1H, Ar), 7.05–7.32 (m, 7H, Ar),
3.83–3.94 (m, 2H, CH–N), 3.75 and 3.58 (ABX system, JAX = 4.0,
JBX = 7.9, JAB = 10.7 Hz, 2H, CH2–O), 2.74 (brs, 2H, NH and OH),
1.42 (d, J = 6.6 Hz, 3H, Me). 13C NMR (CDCl3, 75 MHz) d 163.9
(Cquat, Ar), 149.0 (Ar), 140.9 (Cquat, Ar), 136.5 (Ar), 128.5 (2C,
Ar), 127.4 (Ar), 127.3 (2C, Ar), 121.9 (Ar), 121.3 (Ar), 66.3 (CH2–
O), 62.0 (CH–N), 56.1 (CH–N), 21.7 (Me). HRMS (ESI) Calcd
for C15H19N2O (MH+): 243.1497; found: 243.11492. The second
diastereoisomer was not isolated pure and the 1H NMR chemical
shifts were deduced from spectra of the diastereoisomeric mixture.
1H NMR (CDCl3, 200 MHz) d 8.58 (d, J = 5.6 Hz, 1H, Ar), 7.64
(dt, J = 7.6, J = 1.8 Hz, 1H, Ar), 7.05–7.40 (m, 7H, Ar), 3.59–3.96
(m, 4H, 2 CH–N and CH2–O), 1.35 (d, J = 6.7 Hz, 3H, Me).
N-[(1-(6-Methylpyridin-2-yl)ethyl)]-N-[(1¢R)-1¢-phenylethyl]-
amine (L5). A solution of 6-methylpyridine-2-carboxaldehyde
(600 mg, 4.95 mmol) and (R)-1-phenylethylamine (660 mg,
5.45 mmol) in dry THF (25 mL) was stirred at rt over anhydrous
MgSO4 for 24 h. The reaction mixture was filtered through a pad
of celite, washed with DCM and the solvents were removed under
vacuum to yield the corresponding imine (100%, 1.142 g).
To a stirred solution of the crude imine (400 mg, 1.78 mmol) in
dry THF (14 mL) at 0 ◦C was added dropwise methylmagnesium
bromide (1.25 mL, 3.74 mmol, 3M solution in diethyl ether). The
mixture was stirred at 50 ◦C for 20 h and the reaction was quenched
by adding water. The aqueous layer was extracted with Et2O and
the combined organic layers were dried over MgSO4, filtered and
concentrated under vacuum. The crude product was purified by
flash chromatography on silica gel, using petroleum ether/ethyl
acetate/ammonia (32% in water) (95/5/1) as eluent, to afford
the two desired diastereoisomers (49%, 209 mg). The first eluted
diastereoisomer (1R,1¢R)-L5 was partially separated and isolated
N-[(5-Methylthiophen-2-yl)(phenyl)methyl]-N-[(1¢R)-1¢-phenyl-
ethyl]amine (L10).
A
solution of 5-methylthiophen-2-
1
as a light yellow solid (50 mg). [a]2D0 +174.3 (c 0.38, CHCl3). H
carboxaldehyde (500 mg, 3.96 mmol) and (R)-1-phenylethylamine
(528 mg, 4.36 mmol) in dry THF (20 mL) was stirred at rt over
anhydrous MgSO4 for 24 h. The reaction mixture was filtered over
a pad of celite, washed with DCM and the solvents were removed
under vacuum to yield the corresponding imine (81%, 732 mg).
To a stirred solution of◦the crude imine (350 mg, 1.53 mmol)
in dry Et2O (20 mL) at 0 C was added dropwise phenyllithium
(1.78 mL, 3.20 mmol, 1.8 M solution in dibutyl ether). The mixture
was stirred at rt for 18 h and the reaction was quenched by
adding water. The aqueous layer was extracted with Et2O and
the combined organic layers were dried over MgSO4, filtered and
concentrated under vacuum. The crude product was purified by
flash chromatography on silica gel, using petroleum ether/diethyl
ether (98/2) as eluent, to afford the two desired diastereoisomers
(53%, 249 mg). The first eluted diastereoisomer (1¢R)-L10 was
partially separated and isolated as a colourless oil (46 mg). [a]D20
+42.5 (c 0.16, CHCl3). 1H NMR (CDCl3, 200 MHz) d 7.23–7.42
(m, 10H, Ar), 6.48–6.51 (m, 1H, Ar), 6.38–6.42 (m, 1H, Ar), 4.69
(s, 1H, CH–N), 3.64 (q, J = 6.6 Hz, 1H, CH–N), 2.41 (s, 3H,
Me), 1.80 (brs, 1H, NH), 1.33 (d, J = 6.6 Hz, 3H, Me). 13C NMR
NMR (CDCl3, 200 MHz) d 7.49 (t, J = 7.6 Hz, 1H, Ar), 7.20–7.37
(m, 5H, Ar), 7.00 (d, J = 7.6 Hz, 1H, Ar), 6.91 (d, J = 7.6 Hz,
1H, Ar), 3.58 (q, J = 6.7 Hz, 1H, CH–N), 3.48 (q, J = 6.7 Hz,
1H, CH–N), 2.56 (s, 3H, Me of Py), 1.99 (brs, 1H, NH), 1.28
(d, J = 6.7 Hz, 6H, Me). 13C NMR (CDCl3, 60 MHz) d 163.9
(Cquat, Ar), 158.2 (Cquat, Ar), 145.6 (Cquat, Ar), 136.4 (Ar), 128.4
(2C, Ar), 126.9 (Ar), 126.9 (2C, Ar), 121.3 (Ar), 118.6 (Ar), 56.4
(CH–N), 55.8 (CH–N), 25.1 (Me), 24.7 (Me), 23.6 (Me). HRMS
(ESI) Calcd for C18H21N2 (MH+): 241.1705; found: 241.1693. The
second diastereoisomer (1S,1¢R)-L5 was partially separated and
isolated as a light yellow oil (130 mg). [a]2D0 -4.9 (c 0.96, CHCl3).1H
NMR (CDCl3, 300 MHz) d 7.47 (t, J = 7.6 Hz, 1H, Ar), 7.20–7.32
(m, 5H, Ar), 7.00 (d, J = 7.3 Hz, 1H, Ar), 6.97 (d, J = 7.4 Hz,
1H, Ar), 3.84 (q, J = 6.6 Hz, 1H, CH–N), 3.79 (q, J = 6.6 Hz, 1H,
CH–N), 2.53 (s, 3H, Me of Py), 2.31 (brs, 1H, NH), 1.39 (d, J =
6.6 Hz, 3H, Me), 1.36 (d, J = 6.6 Hz, 3H, Me). 13C NMR (CDCl3,
75 MHz) d 164.0 (Cquat, Ar), 158.2 (Cquat, Ar), 145.9 (Cquat, Ar),
136.4 (Ar), 128.4 (2C, Ar), 126.9 (Ar), 126.8 (2C, Ar), 121.3 (Ar),
118.6 (Ar), 56.4 (CH–N), 55.7 (CH–N), 25.1 (Me), 24.7 (Me), 23.6
(Me). HRMS (ESI) Calcd for C18H21N2 (MH+): 241.1705; found:
241.1698.
(CDCl3, 75 MHz) d 147.2 (Cquat, Ar), 145.2 (Cquat, Ar), 143.1 (Cquat
,
Ar), 138.9 (Cquat, Ar), 128.5 (4C, Ar), 127.6 (2C, Ar), 127.4 (Ar),
127.0 (Ar), 126.8 (2C, Ar), 124.4 (Ar), 124.0 (Ar), 59.9 (CH–
N), 54.9 (CH–N), 24.7 (Me), 15.3 (Me). HRMS (ESI) Calcd for
C20H21NNaS (M+Na+): 330.1292; found: 330.1298. The second
diastereoisomer was not isolated pure and the 1H NMR chemical
shifts were deduced from the spectra of the diastereoisomeric
mixture. 1H NMR (CDCl3, 200 MHz) d 7.20–7.45 (m, 10H, Ar),
(S)-2-(1-(Pyridin-2-yl)ethylamino)-2-phenylethanol (L7).
A
solution of pyridine-2-carboxaldehyde (213 mg, 2.00 mmol)
and (S)-(+)-2-phenylglycinol (300 mg, 2.2 mmol) in dry THF
(25 mL) was stirred at rt over anhydrous MgSO4 for 24 h. The
reaction mixture was filtered through a pad of celite, washed with
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6.55–6.63 (m, 2H, Ar), 4.81 (s, 1H, CH–N), 3.85 (q, J = 6.7 Hz,
1H, CH–N), 2.46 (s, 3H, Me), 1.70 (brs, 1H, NH), 1.38 (d, J =
6.7 Hz, 3H, Me).
(CH–N), 64.7 (CH–N), 21.4 (Me). HRMS (ESI-, MeOH) Calcd
for C20H19N235Cl2104Pd (M–H): 460.9966; found: 460.9968.
Synthesis of ethyl 3,3,3-trifluoro-2-hydroxy-2-(1-methyl-1H-
indol-3-yl)propanoate 3a6d,6e using procedure A. In a flame dried
schlenk tube, Yb(OTf)3 (15.5 mg, 0.025 mmol) and (1R,1¢S)-L3
(7.2 mg, 0.025 mmol) were dissolved in freshly distilled CH2Cl2
(0.5 mL) under argon atmosphere. The mixture was stirred 2 h at rt
and a solution of ethyl trifluoropyruvate (46.8 mg, 0.275 mmol) in
freshly distilled CH2Cl2 (0.5 mL) was added. The reaction mixture
was stirred for another 1.5 h at rt and the schlenk tube was placed
at -20 ◦C. A solution of N-methylindole (32.8 mg, 0.25 mmol) in
freshly distilled CH2Cl2 (0.5 mL) was added and the mixture was
stirred at -20 ◦C. After completion of the reaction (72 h at -20 ◦C,
monitored by TLC), water was added and the aqueous layer
was extracted several times with CH2Cl2. The combined organic
layers were dried over MgSO4, filtered and concentrated under
vacuum. The crude product was purified by preparative TLC,
using pentane/diethyl ether (7/3) as eluent, to afford 3a as a white
solid (82%, 62 mg) with 78% ee determined by HPLC analysis
[CHIRALPAK IA column 250 ¥ 4.6 (L ¥ I.D.) 5 mm, hexane/2-
N -[(Pyridin-2-yl)(phenyl)methyl)]-N -[(1¢R)-1¢-phenylethyl]-
amine (L3)13.
A solution of 2-benzoylpyridine (2.00 g,
10.92 mmol), (R)-1-phenylethylamine (1.45 g, 12.01 mmol) and
4-methylbenzenesulfonic acid (207 mg, 1.09 mmol) in toluene
(50 mL) was refluxed for 40 h using a Dean–Stark apparatus.
After cooling, the solvent was removed and the residue was
dried under vacuum. The crude imine was dissolved in MeOH
(60 mL) and sodium borohydride (413 mg, 10.92 mmol) was added
portionwise at 0 ◦C. The mixture was stirred overnight at rt and the
reaction was quenched by adding saturated aqueous NH4Cl. The
aqueous layer was extracted with EtOAc. The combined organic
layers were washed with a saturated aqueous NaCl solution, dried
over MgSO4, filtered and concentrated under vacuum. The crude
product was purified by flash chromatography on silica gel, using
petroleum ether/ethyl acetate (from 95/5 to 90/10) as eluent, to
afford the two desired diastereoisomers (91%, 2.86 g). The first
eluted diastereoisomer (1R,1¢R)-L3 was partially separated and
isolated as a light yellow oil (432 mg). [a]2D0 +11.4 (c 1.00, CHCl3);
◦
propanol (v/v: 9/1) at 0.5 mL min-1, 254 nm, 20 C]: 18.64 min
1
Lit.13 [a]2D0 +11.5 (c 1, CHCl3). H NMR (CDCl3, 200 MHz) d
1
(S), 21.72 min (R). H NMR (CDCl3, 250 MHz) d 7.94 (d, J =
8.60 (d, J = 4.9 Hz, 1H, Ar), 7.63 (dt, J = 7.6, J = 1.8 Hz, 1H,
Ar), 7.10–7.35 (m, 12H, Ar), 4.78 (s, 1H, CH–N), 3.65 (q, J =
6.6 Hz, 1H, CH–N), 2.63 (brs, 1H, NH), 1.38 (d, J = 6.6 Hz, 3H,
Me). 13C NMR (CDCl3, 90 MHz) d 162.8 (Cquat, Ar), 149.7 (Ar),
145.7 (Cquat, Ar), 143.4 (Cquat, Ar), 136.5 (Ar), 128.6 (2C, Ar), 128.6
(2C, Ar), 127.7 (2C, Ar), 127.2 (Ar), 127.1 (Ar), 127.0 (2C, Ar),
122.8 (Ar), 122.1 (Ar), 65.3 (CH–N), 55.9 (CH–N), 24.5 (Me).
The second diastereoisomer (1S,1¢R)-L3 was partially separated
and isolated as a light yellow oil (554 mg). [a]2D0 +103.4 (c 1.00,
CHCl3); Lit.13 [a]D20 +101.2 (c 1.23, CHCl3).1H NMR (CDCl3, 200
MHz) d 8.56 (d, J = 4.9 Hz, 1H, Ar), 7.50 (dt, J = 7.6, J = 1.8 Hz,
1H, Ar), 7.20–7.35 (m, 10H, Ar), 7.05–7.12 (m, 2H, Ar), 4.71 (s,
1H, CH–N), 3.66 (q, J = 6.7 Hz, 1H, CH–N), 2.63 (brs, 1H, NH),
1.41 (d, J = 6.6 Hz, 3H, Me). 13C NMR (CDCl3, 90 MHz) d 162.4
(Cquat, Ar), 149.6 (Ar), 146.0 (Cquat, Ar), 143.2 (Cquat, Ar), 137.0
(Ar), 130.0 (2C, Ar), 129.2 (2C, Ar), 129.1 (2C, Ar), 128.6 (Ar),
127.8 (Ar), 127.4 (2C, Ar), 122.7 (Ar), 122.3 (Ar), 65.4 (CH–N),
55.4 (CH–N), 25.2 (Me).
7.9 Hz, 1H, Ar), 7.16–7.36 (m, 4H, Ar), 4.30–4.56 (m, 3H, OH and
CH2), 3.76 (s, 3H, N–Me), 1.37 (t, J = 7.2 Hz, 3H, Me of CO2Et).
Preparation of the Yb(OTf)3-(1R,1¢S)-L3 complex. In a flame
dried schlenk tube, Yb(OTf)3 (322.6 mg, 0.520 mmol) and
(1R,1¢S)-L3 (150 mg, 0.520 mmol) were dissolved in freshly
distilled CH2Cl2 (30 mL) under argon atmosphere. The mixture
was stirred 18 h at rt and the solvent was evaporated under vacuum
to give a white powder (472 mg). The complex was stored and
weighed under argon in a glove box.
General procedure for the alkylation of indoles 1a–c using
procedure B. In a flame dried schlenk tube, Yb(OTf)3-(1R,1¢S)-
L3 complex (22.7 mg, 0.025 mmol) and ethyl or methyl trifluo-
ropyruvate 2a,b (0.275 mmol) were dissolved in freshly distilled
CH2Cl2 (1 mL) under argon atmosphere. The mixture was stirred
2 h at rt and the schlenk tube was placed at -20 ◦C. A solution of
indole 1a–c (0.25 mmol) in freshly distilled CH2Cl2 (0.5 mL) was
added and the mixture was stirred at -20 ◦C. After completion of
the reaction (72 h at -20 ◦C, monitored by TLC), water was added
and the aqueous layer was extracted several times with CH2Cl2.
The combined organic layers were dried over MgSO4, filtered and
concentrated under vacuum to yield the crude product.
This reaction was also performed with the (S)-1-phenylethyl-
amine to give (1S,1¢S)-L3 and (1R,1¢S)-L3 with similar results.
Preparation of the PdCl2-(1S,1¢R)-L3 complex. To a stirred
solution of (1S,1¢R)-L3 (50 mg, 0.17 mmol) in MeOH (4 mL) was
added Na2PdCl4 (51 mg, 0.17 mmol). The mixture was stirred at
rt for 16 h, then the solvent was removed by evaporation under
vacuum. The residue was then filtered through a pad of silica gel
[firstly eluted with ethyl acetate/petroleum ether (4/6) to remove
traces of L3 and then eluted with ethyl acetate] to afford the
corresponding palladium complex as a yellow solid (96%, 76 mg).
1H NMR ([d6]DMSO, 300 MHz) d 8.43 (d, J = 6.0 Hz, 1H, Ar),
8.09 (d, J = 7.2 Hz, 2H, Ar), 7.95 (d, J = 8.1 Hz, 2H, Ar), 7.72 (dt,
J = 7.7, J = 1.3 Hz, 1H, Ar), 7.40–7.55 (m, 3H, Ar), 7.05–7.25 (m,
5H, Ar), 6.54 (s, 1H, NH), 5.45 (s, 1H, CH–N), 4.04–4.15 (m, 1H,
CH–N), 1.74 (d, J = 6.7 Hz, 3H, Me). 13C NMR ([d6]DMSO, 75
MHz) d 165.7 (Cquat, Ar), 148.3 (Ar), 139.8 (Ar), 138.4 (Cquat, Ar),
137.8 (Cquat, Ar), 129.6 (2C, Ar), 129.0 (Ar), 128.9 (2C, Ar), 128.5
(2C, Ar), 128.3 (Ar), 127.9 (2C, Ar), 123.4 (Ar), 122.7 (Ar), 73.5
Ethyl
3,3,3-trifluoro-2-hydroxy-2-(1-methyl-1H-indol-3-yl)-
The reaction was performed according to
propanoate 3a6d,6e
.
procedure B with 46.8 mg (0.275 mmol) of ethyl trifluoropyruvate
and 32.8 mg (0.25 mmol) of N-methylindole. The crude product
was purified by preparative TLC, using pentane/diethyl ether
(7/3) as eluent, to afford 3a as a white solid (82%, 62 mg) with
82% ee determined by HPLC analysis [CHIRALPAK IA column
250 ¥ 4.6 (L ¥ I.D.) 5 mm, hexane/2-propanol (v/v: 9/1) at
0.5 mL min-1, 254 nm, 20 ◦C]: 18.78 min (S), 21.83 min (R). [a]2D0
+22.0 (c 0.5, CHCl3); Lit.6d [a]D20 +21.3 (c 2.19, CHCl3) for (S)-3a
for 89% ee. The analyses are identical as previously.
Ethyl
3b6c–6e
3,3,3-trifluoro-2-hydroxy-2-(1H-indol-3-yl)propanoate
The reaction was performed according to procedure
.
502 | Org. Biomol. Chem., 2011, 9, 497–503
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The Royal Society of Chemistry 2011
©

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B with 46.8 mg (0.275 mmol) of ethyl trifluoropyruvate and
29.3 mg (0.25 mmol) of indole. The crude product was purified by
preparative TLC, using pentane/diethyl ether (7/3) as eluent, to
afford 3b as a colorless oil (78%, 56 mg) with 74% ee determined
by HPLC analysis [CHIRALPAK IA column 250 ¥ 4.6 (L ¥ I.D.)
5 m◦m, hexane/2-propanol (v/v: 85/15) at 0.7 mL min-1, 254 nm,
20 C]: 13.05 min (major), 15.85 min (minor). [a]2D0 +11.6 (c 0.54,
Alkylations, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2009;
(b) T. B. Poulsen and K. A. Jørgensen, Chem. Rev., 2008, 108, 2903;
(c) D. Almasi, D. A. Alonso and C. Na´jera, Tetrahedron: Asymmetry,
2007, 18, 299; (d) M. Bandini, A. Meloni, S. Tommasi and A. Umani-
Ronchi, Synlett, 2005, 1199; (e) M. Bandini, P. G. Cozzi, P. Melchiorre
and A. Umani-Ronchi, Angew. Chem., Int. Ed., 2004, 43, 84; (f) M.
Bandini, A. Meloni and A. Umani-Ronchi, Angew. Chem., Int. Ed.,
2004, 43, 550; (g) K. A. Jørgensen, Synthesis, 2003, 1117.
2 See ref. 1a, 1b and references cited therein.
3 (a) M. Soueidan, J. Collin and R. Gil, Tetrahedron Lett., 2006, 47,
5467; (b) W-B. Yi and C. Cai, J. Fluorine Chem., 2005, 126, 831; (c) C.
Unaleroglu, B. Temelli and A. S. Demir, Synthesis, 2004, 15, 2574; (d) K.
Mikami, Y. Mikami, Y. Matsumoto, J. Nishikido, F. Yamamoto and
H. Nakajima, Tetrahedron Lett., 2001, 42, 289; (e) D. Barbier-Baudry,
A. Dormond, S. Richard and J. R. Desmurs, J. Mol. Catal. A: Chem.,
2000, 161, 23; (f) A. Kawada, S. Mitamura, J. Matsuo, T. Tsuchiya and
S. Kobayashi, Bull. Chem. Soc. Jpn., 2000, 73, 2325; (g) W. Zhang and
P. G. Wang, J. Org. Chem., 2000, 65, 4732; (h) D. Baudry-Barbier, A.
Dormond and F. Duriau-Montagne, J. Mol. Catal. A: Chem., 1999,
149, 215.
4 D. A. Evans, K. A. Scheidt, K. R. Fandrick, H. W. Lam and J. Wu,
J. Am. Chem. Soc., 2003, 125, 10780.
5 Y. Liu, D. Shang, X. Zhou, Y. Zhu, L. Lin, X. Liu and X. Feng, Org.
Lett., 2010, 12, 180.
6 For asymmetric F–C alkylations of indole derivatives with trifluoropy-
ruvates, see: (a) S. Nakamura, K. Hyodo, Y. Nakamura, N. Shibata and
T. Toru, Adv. Synth. Catal., 2008, 350, 1443; (b) B. To¨ro¨k, M. Abid, G.
London, J. Esquibel, M. To¨ro¨k, S. C. Mhadgut, P. Yan and G. K. S.
Prakash, Angew. Chem., Int. Ed., 2005, 44, 3086; (c) M. P. A. Lyle, N. D.
Draper and P. D. Willson, Org. Lett., 2005, 7, 901; (d) W. Zhuang, N.
Gathergood, R. G. Hazell and K. A. Jørgensen, J. Org. Chem., 2001,
66, 1009; (e) N. Gathergood, W. Zhuang and K. A. Jørgensen, J. Am.
Chem. Soc., 2000, 122, 12517.
1
CHCl3); Lit.6d [a]D20 +12.3 (c 1.91, CHCl3) for 3b for 83% ee. H
NMR (CDCl3, 250 MHz) d 8.24 (brs, 1H, NH), 7.94 (d, J =
7.5 Hz, 1H, Ar), 7.55–7.12 (m, 4H, Ar), 4.58 (s, 1H, OH), 4.45
(dq, J = 10.7, 7.1 Hz, 2H, CH2), 4.41 (dq, J = 10.7, 7.1 Hz, 2H,
CH2), 1.36 (t, J = 7.1 Hz, 3H, Me of CO2Et).
Ethyl
3,3,3-trifluoro-2-hydroxy-2-(2-methyl-1H-indol-3-yl)-
propanoate 3c. The reaction was performed according to
procedure B with 46.8 mg (0.275 mmol) of ethyl trifluoropyruvate
and 32.8 mg (0.25 mmol) of 2-methylindole. The crude product
was purified by preparative TLC, using pentane/diethyl ether
(7/3) as eluent, to afford 3a as a colorless oil (76%, 58 mg) with
51% ee determined by HPLC analysis [CHIRALPAK IA column
250 ¥ 4.6 (L ¥ I.D.) 5 mm, hexane/2-propanol (v/v: 85/15) at
0.7 mL min-1, 254 nm, 20 ◦C]: 11.92 min (minor), 14.55 min
(major). [a]2D0 -3.7 (c 0.44, CHCl3). 1H NMR (CDCl3, 250 MHz)
d 8.04 (brs, 1H, NH), 7.85 (d, J = 7.7 Hz, 1H, Ar), 7.38–7.04 (m,
3H, Ar), 4.62–4.23 (m, 2H, CH2), 4.06 (s, 1H, OH), 2.53 (s, 3H,
Me), 1.38 (t, J = 7.2 Hz, 3H, Me of CO2Et). 13C NMR (CDCl3, 63
MHz) d 169.4 (CO), 135.3 (Ar), 134.6 (Ar), 126.8 (Ar), 123.9 (q,
J = 283.2 Hz, CF3), 121.6 (CH, Ar), 120.5 (CH, Ar), 120.2 (CH,
Ar), 110.4 (CH, Ar), 103.9 (Ar), 77.5 (q, J = 31.1 Hz, C–OH),
63.6 (CH2), 14.1 (Me), 13.9 (Me of CO2Et). HRMS (ESI+) Calcd
for C14H14F3NNaO3 (M+Na): 324.0818; found: 324.0810.
7 A. Abdel-Magid, K. G. Garson, B. D. Harris, C. A. Maryanoff and
R. D. Shah, J. Org. Chem., 1996, 61, 3849.
8 (a) M. Lamblin, A. Couture, E. Deniau and P. Grandclaudon,
Tetrahedron: Asymmetry, 2008, 19, 111; (b) H. Yamada, T. Kawate,
A. Nishida and M. Nakagawa, J. Org. Chem., 1999, 64, 8821; (c) G.
Alvaro, G. Martelli and D. Savoia, J. Chem. Soc., Perkin Trans. 1,
1998, 775; (d) D. Delorme, C. Berthelette, R. Lavoie and E. Roberts,
Tetrahedron: Asymmetry, 1998, 9, 3963; (e) D. Enders and U. Reinhold,
Tetrahedron: Asymmetry, 1997, 8, 1895; (f) G. Alvaro, D. Savoia and
M. Valentinetti, Tetrahedron, 1996, 52, 12571; (g) K. Higashiyama, H.
Inoue, T. Yamauchi and H. Takahashi, J. Chem. Soc., Perkin Trans. 1,
1995, 111.
9 H. Brunner, B. Reiter and G. Riepl, Chem. Ber., 1984, 117,
1330.
10 M. B. Eleveld, H. Hogeveen and E. P. Schudde, J. Org. Chem., 1986,
51, 3635.
Methyl 3,3,3-trifluoro-2-hydroxy-2-(1-methyl-1H-indol-3-yl)-
propanoate 3d6c. The reaction was performed according
to procedure
B with 42.9 mg (0.275 mmol) of methyl
trifluoropyruvate and 32.8 mg (0.25 mmol) of N-methylindole.
The crude product was purified by preparative TLC, using
pentane/diethyl ether (7/3) as eluent, to afford 3d as a white
solid (81%, 58 mg) with 79% ee determined by HPLC analysis
[CHIRALPAK IA column 250 ¥ 4.6 (L ¥ I.D.) 5 mm, hexane/2-
propanol (v/v: 85/15) at 0.7 mL min-1, 254 nm, 20 ◦C]: 10.98 min
(major), 12.08 min (minor). [a]2D0 +24.1 (c 0.5, CHCl3). 1H NMR
(CDCl3, 300 MHz) d 7.87 (d, J = 8.1 Hz, 1H, Ar), 7.41–7.24 (m,
3H, Ar), 7.19 (ddd, J = 8.1, 6.8, 1.4 Hz, 1H, Ar), 4.35 (s, 1H, OH),
3.97 (s, 3H, Me), 3.82 (s, 3H, N–Me).
11 The palladium complex was obtained according to: V. Terrasson, D.
Prim and J. Marrot, Eur. J. Inorg. Chem., 2008, 2739. Single crystals
suitable for X-ray analysis were obtained by slow evaporation of a
CH2Cl2–petroleum ether (1/1) solution of the palladium complex.
12 Crystal data†: C20 H20 N2 Cl2 Pd, Mw = 465.68, hexagonal, space
˚
˚
group P61; dimensions: a = b = 18.7436(5) A, c = 13.3951(4) A, V =
3
-1
˚
4075.5(2) A ; Z = 6; m = 0.88 mm ; 26919 reflections measured at
room temperature; independent reflections: 6978 [6054 Fo > 4s (Fo)];
data were collected up to a 2Hmax value of 59.94◦ (99.2% coverage).
Number of variables: 227; R1 = 0.0447, wR2 = 0.1229, S = 1.109; Flack
parameter = 0.08(4); highest residual electron density 0.549/-0.428
Acknowledgements
-3
˚
e.A (all data R1 = 0.0523, wR2 = 0.1294). Several disordered solvent
molecules were initially modelled as discrete molecules but they were
The authors gratefully thank the PRES UniverSud Paris for
a research grant (GG). The Centre National de la Recherche
Scientifique (CNRS) is acknowledged for financial support. RG
and AD thank the RDR2 CNRS network entitled « Aller vers
une chimie e´co-compatible » for extra financial support. Aurelia
Dinut thanks the Ministe`re de l¢Enseignement Supe´rieur et de la
Recherche (MESR) for a PhD grant.
ultimately removed from the structure. The data set was corrected for
a disordered solvent with the program PLATON/SQUEEZE. CCDC
767347.
13 C. Cimarelli and G. Palmieri, Tetrahedron: Asymmetry, 2000, 11,
2555.
14 See experimental part.
15 It is worth noting that in contrast with recent literature (see ref. 6c)
similar ee’s were observed for the alkylation of N-methylindole or
indole.
16 F. Fringuelli, F. Pizzo, S. Tortoioli and L. Vaccaro, J. Org. Chem., 2004,
Notes and references
69, 7745.
17 Y. Wu, H. Yun, Y. Wu, K. Ding and Y. Zhou, Tetrahedron: Asymmetry,
2000, 11, 3543.
1 For recent reviews on asymmetric F–C alkylations, see: (a) M.
Bandini and A. Umani-Ronchi, Catalytic Asymmetric Friedel–Crafts
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