Enantioselective synthesis of tertiary alcohols through a zirconium-catalyzed Friedel-Crafts alkylation of pyrroles with α-ketoesters

Article abstract of DOI:10.1021/jo2010704

Chiral complexes of 1,1′-bi-2-naphthol-based ligands with zirconium tert-butoxide catalyze the Friedel-Crafts alkylation of pyrroles with α-ketoesters to afford tertiary alcohols in good yields and ee up to 98%. The reaction is also of application to 4,7-dihydroindole to give C2-alkylated indoles after oxidation with p-benzoquinone.

Full text of DOI:10.1021/jo2010704

ARTICLE
pubs.acs.org/joc
Enantioselective Synthesis of Tertiary Alcohols through a
Zirconium-Catalyzed FriedelꢀCrafts Alkylation of Pyrroles
with r-Ketoesters
Gonzalo Blay,† Isabel Fernꢀandez,† M. Carmen Mu~noz,‡ Josꢀe R. Pedro,*,† Alejandro Recuenco,† and
Carlos Vila†
†Departament de Química Orgꢁanica, Facultat de Química, Universitat de Valꢁencia, C/Dr. Moliner 50,
E-46100 Burjassot (Valꢁencia), Spain
‡Departament de Física Aplicada, Universitat Politꢁecnica de Valꢁencia, Camino de Vera s/n, 46022 Valꢁencia, Spain
S Supporting Information
b
ABSTRACT: Chiral complexes of 1,10-bi-2-naphthol-based ligands with
zirconium tert-butoxide catalyze the FriedelꢀCrafts alkylation of pyrroles
with R-ketoesters to afford tertiary alcohols in good yields and ee up to 98%.
The reaction is also of application to 4,7-dihydroindole to give C2-alkylated
indoles after oxidation with p-benzoquinone.
Scheme 1. Racemization of r-Pyrrolyl Alcohols through
Azafulvenium Ions
’ INTRODUCTION
The catalytic enantioselective construction of stereogenic
tetrasubstituted carbon centers is a very challenging goal in
organic chemistry. The addition of carbon nucleophiles to ketones
appears as an attractive procedure for this purpose, affording
chiral tertiary alcohols which are versatile synthetic precursors for
natural products and pharmaceutical drugs.1
The electron-rich nature of the indole and pyrrole rings allows
enantioselective FriedelꢀCrafts (FꢀC) reactions with prochiral
electrophiles to give enantiomerically enriched indole and pyr-
role derivatives.2 However, despite the prevalence of the pyrrole
ring in biologically active compounds, the FꢀC reaction with
pyrroles has been less explored, compared with the FꢀC reaction
with indoles.3 This is probably due to the tendency of pyrrole to
undergo dialkylation at both the 2- and 5-positions and to its
instability toward acids, which make the development of en-
antioselective FꢀC alkylations with pyrroles more challenging.
Several enantioselective FꢀC alkylations of pyrroles through the
1,4-addition to R,β-unsaturated carbonyl compounds have been
reported.4 However, the asymmetric FꢀC alkylation of pyrroles
involving the 1,2-addition to carbonyl compounds, which would lead
to pyrroles bearing a substituent with a chiral tertiary alcohol in the
R-position, is more troublesome because of the tendency of this
moiety to undergo racemization through azafulvenium intermediates
(Scheme 1).5
hand, our group has carried out the first enantioselective FꢀC
alkylation of pyrrole with 2,2,2-trifluoroacetophenones using a
zirconium-based Lewis acid catalyst (zirconium 3,30-dibromo-
1,10-bi-2-naphthol).7 In both cases the presence of the strong
electron-withdrawing CF3 group (and an additional ethyl car-
boxylate for the copper-catalyzed reaction) attached to the
stereogenic carbon seems to destabilize the azafulvenium cation
intermediate, precluding the loss of stereochemical integrity at
the stereogenic center.8 As a part of our research on the asymmetric
FꢀC reaction, we report herein the first enantioselective FꢀC
reaction of pyrroles with R-ketoesters to give tertiary alcohols. To
the best of our knowledge, this is the first example of synthesis of this
kind of pyrrole-substituted tertiary alcohols (via an FꢀC alkylation
of pyrroles) in which the stereochemical integrity of the quaternary
stereogenic center is not guaranteed by a CF3 group.
’ RESULTS AND DISCUSSION
In fact, only two methods for the enantioselective FꢀC
alkylation of pyrroles with carbonyl compounds have been
reported to date. Jørgensen described the first catalytic FꢀC
reaction of pyrroles with ethyl trifluoropyruvate catalyzed by a
bisoxazolineꢀcopper(II) complex as a Lewis acid.6 On the other
Our investigation began with an examination of the reaction
between pyrrole (1a) and ethyl phenyloxoacetate (2a) (Scheme 2)
Received: May 25, 2011
Published: June 18, 2011
r
2011 American Chemical Society
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Scheme 2. Enantioselective FꢀC Reaction between Pyrrole
(entry 8), the reaction product was obtained with good enantios-
electivity (97% ee), although with a lower yield (58%) than with
Zr(OtBu)4.
(1a) and Ketoester 2a and Ligands Used in This Study
The use of dichloromethane as the solvent resulted in a lower
yield and enantioselectivity (entry 9). Decreasing the catalyst
loading to 10 mol % resulted in a lower yield, although the
enantioselectivity was still kept high (entries 10 and 11). Finally,
lowering the temperature to 0 °C improved the enantioselec-
tivity to 99% ee with a minor detriment to the yield (73%) of
product 3aa (entry 12).
With these optimized conditions, we next investigated the
influence of the ester group in substrates 2 (Table 2, entries
1ꢀ6). The best results in terms of enantioselectivity and yield
were obtained with ethyl and trichloroethyl esters, while other
esters (methyl, isopropyl, or benzyl) gave the expected prod-
ucts with high ee (97ꢀ98%) but lower yields. Therefore, ethyl
ketoesters were established as the best substrates for this
reaction.
To explore the scope of the reaction, various substituted
R-ketoesters 2gꢀm were reacted with pyrrole (1a). In all the
cases, the reaction provided the expected products 3agꢀ3am
with good to high enantiomeric excesses (up to 98%). The
reaction with ethyl R-ketoesters containing weak electron-donat-
ing (ꢀMe) or electron-withdrawing (ꢀCl) groups on the aro-
matic ring gave better results in terms of yields and enantios-
electivities than those containing strong electron-donating
(ꢀOMe) or electron-withdrawing (ꢀCNꢀ or ꢀNO2) groups
on the aromatic ring (entries 7 and 10 vs entries 9 and 11 and 12).
The ortho substitution on the aromatic ring of the ethyl
R-ketoester lowered the reaction rate, and the yield of the alkyl-
ation product dropped to 13% (65% ee), indicating the existence
of a steric effect caused by the ortho substituent. In addition, the
2-naphthyl R-ketoester (2n) and heteroaromatic R-ketoesters
2o and 2p could also serve as substrates for this reaction, giving
the corresponding alkylated pyrroles in acceptable yields and
high enantioselectivities (entries 14 and 15). Finally, ethyl (3,5-
difluorophenyl)oxoacetate (2m), bearing two additional substit-
uents on the aromatic ring, gave the corresponding alkylated
pyrrole 3am with a good yield and enantioselectivity (entry 13).
Unfortunately, the reaction with the aliphatic R-ketoester 2q
(entry 17) took place with a poor yield (30%) and enantioselec-
tivity (46% ee).
Table 1. Enantioselective FꢀC Reaction between Pyrrole
(1a) and R-Ketoester 2a Catalyzed by Zr(IV)ꢀBINOL
Complexes: Optimization of the Reaction Conditionsa
M(OR)4
entry L(concn, mol %) (concn, mol %) t (h) yieldb (%) eec (%)
1
2
L1 (20)
L2 (20)
L3 (20)
L4 (20)
L5 (20)
L6 (20)
L6 (20)
L6 (20)
L6 (20)
L6 (10)
L6 (10)
L6 (20)
Zr(OtBu)4 (20)
Zr(OtBu)4 (20)
Zr(OtBu)4 (20)
Zr(OtBu)4 (20)
Zr(OtBu)4 (20)
Zr(OtBu)4 (20)
Ti(OiPr)4 (20)
Hf(OtBu)4 (20)
Zr(OtBu)4 (20)
Zr(OtBu)4 (10)
Zr(OtBu)4 (20)
Zr(OtBu)4 (20)
19
19
21
20
20
7
48
52
78
27
39
79
20
58
64
58
56
73
3
ꢀ4
ꢀ54
1
3
4
5
ꢀ9
98
6
7
24
8
5
8
97
9d
10
11
12e
16
8
95
92
9
96
24
99
a All reactions performed with pyrrole (1a; 0.625 mmol) and ketoester
2a (0.125 mmol) in toluene (1 mL) at rt unless otherwise stated. b Yield
after flash chromatography. c Determined by HPLC on a chiral sta-
tionary-phase column. d Dichloromethane was used as the solvent. e The
reaction temperature was 0 °C.
The effects of pyrrole substitution were also evaluated.
2-Ethylpyrrole (1b) and 2-(30-oxobutyl)pyrrole (1c) led to the
C5 alkylation products with good yields (62ꢀ82%) and excellent
enantioselectivities (up to 96%).
under the original optimized catalytic conditions described by
our group for the FꢀC reaction of pyrrole with 2,2,2-trifluoro-
acetophenones.7 However, when compound 2a was reacted with
pyrrole under those conditions, using L3ꢀZr(OtBu)4 as the
catalyst in toluene (instead of benzene), conversion to the FꢀC
adduct 3aa occurred in good yield, although with moderate
enantiomeric excess (Table 1, entry 3). Next we screened other
1,10-bi-2-naphthol (BINOL)-type ligands which contained elec-
tron-withdrawing groups at the 6,60-positions or a tetrahydroge-
nated ring (L1, L2, L4, L5), as well as the highly hindered 3,30-
diaryl-BINOL ligand L6. The best result was obtained with
ligand L6, which allowed compound 3aa to be obtained in
79% yield and 98% ee. The use of other group IV metal alkoxides
was also tested. Performing the reaction with Ti(OiPr)4 and
ligand L6 resulted in a slow reaction rate, and product 3aa was
obtained with very low yield (entry 7). Also, by using Hf(OtBu)4
Interestingly, 4,7-dihydroindole (4), which can be considered
as a disubstituted pyrrole, reacted with different aromatic and
heteroaromatic R-ketoesters 2 to give the C2-alkylated indoles 5
with good yields and enantioselectivities (up to 92%) after
oxidation with p-benzoquinone (Table 3).9
To determine the absolute stereochemistry of the FꢀC products,
we subjected compound 3aj to oxidative cleavage of the pyrrole ring
with ozone followed by reductive treatment with Ph3P, which
provided imide 6 (Scheme 3). For this compound, we could obtain
suitable crystals for X-ray analysis (see the Supporting Informa-
tion),10 which allowed determination of the absolute configuration
of the stereogenic center in compound 6, and hence in compound
3aj, to be R. For the rest of the products 3 and 5, it was assigned as R
on the assumption of a uniform reaction mechanism.
To gain insight into the nature of the chiral zirconium catalyst,
several 1H NMR experiments were carried out. Equimolar mixtures
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Table 2. Enantioselective FꢀC Reaction between Pyrroles 1 and R-Ketoesters 2 Catalyzed by L6ꢀZr(OtBu)4: Substrate Scopea
entry
1
R1
2
R2
R3
t (h)
3
yieldb (%)
eec (%)
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
Et
Et
2a
2b
2c
2d
2e
2f
Ph
Ph
Ph
Ph
Ph
Ph
Et
7
7
3aa
3ab
3ac
3ad
3ae
3af
79
55
58
33
49
79
56
13
35
69
62
77
72
63
68
43
30
82
62
67
71
98
97
98
90
97
97
97
65
98
96
81
60
77
98
95
90
46
92
93
83
96
Me
iPr
tBu
Bn
CH2Cl3
Et
3
7
4
7
5
8
6
5
7
2g
2h
2i
4-MeC6H4
2-MeC6H4
4-MeOC6H4
4-ClC6H4
4-CNC6H4
4-NO2C6H4
3,5-F2C6H3
2-naphthyl
2-thiophene-yl
2-furanyl
18
22
22
17
17
8
3ag
3ah
3ai
8
Et
9
Et
10
11
12
13
14
15
16
17
18
19
20
21
2j
Et
3aj
2k
2l
Et
3ak
3al
Et
2m
2n
2o
2p
2q
2a
2g
2j
Et
20
22
18
18
7
3am
3an
3ao
3ap
3aq
3ba
3bg
3bj
3ca
Et
Et
Et
PhCH2CH2
Ph
Et
Et
20
19
18
16
4-MeC6H4
4-ClC6H4
Ph
Et
Et
CH3COCH2CH2
2a
Et
a All reactions performed with pyrroles 1 (0.625 mmol), ketoester 2 (0.125 mmol), L6 (0.025 mmol), and Zr(OtBu)4 (0.025 mmol) in toluene (1 mL) at
rt. b Yield after flash chromatography. c Determined by HPLC on chiral stationary-phase columns.
Table 3. Enantioselective FꢀC Reaction between 4,7-Dihy-
droindole (4) and R-Ketoesters 2 Catalyzed by
Scheme 3. Ozonolysis of Compound 3aj
L6ꢀZr(OtBu)4
a
1H NMR spectra of the formed complexes showed a single set of
signals for the BINOLate ligands; that is, only five signals for the
binaphthoxy moiety and two signals for the 3,30-bis[3,5-bis-
(trifluoromethyl)phenyl] substituents were observed (Table 4).
These simple spectra support the formation of a C2-symmetrical
species and, hence, the monomeric nature of the zirconium complex
(Figure 1), as has been previously reported for a related zirconium
complex.11
The observed absolute stereochemistry of products 3 indicates
the preference of the pyrrole to approach the R-ketoester from
the re face of the ketone carbonyl group. Our working model to
account for this stereoselectivity is shown in Figure 2. An
octahedrical complex would result from the coordination of
the ketoester to the initial monomeric complex in a bidentante
fashion, with the ketone carbonyl group occupying one of the
apical positions.12 In this situation, the si face of the ketone
carbonyl would be shielded by one of the substituted naphthyl
moieties of ligand L6 and the preferred attack of the pyrrole
would take place on the re face oriented to the outer part of the
complex to give compounds with an R configuration at the newly
entry
2
R2
t (h)
5
yieldb (%)
eec (ee)
1
2
3
4
5
2a
2g
2j
Ph
18
18
18
18
18
5a
5g
5j
76
66
85
74
51
91
92
83
90
84
4-MeC6H4
4-ClC6H4
2n
2o
2-naphthyl
2-thiophene-yl
5n
5o
a All reactions performed with 4,7-dihydroindole (4; 0.15 mmol),
ketoester 2 (0.125 mmol), L6 (0.025 mmol), and Zr(OtBu)4 (0.025 mmol)
in toluene (1.6 mL) at rt. b Yield after flash chromatography. c Determined by
HPLC on chiral stationary-phase columns.
of Zr(OtBu)4 and ligand L6 in toluene-d8 were stirred at room
temperature for 1 h, and 1H NMR spectra of the formed
complexes were then measured. We also prepared the same
catalyst in dichloromethane-d2 since the enantioselectivities of
the FꢀC reaction in both solvents were very similar (98% ee in
toluene vs 95% ee in dichloromethane). In both solvents, the
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Table 4. Assignment of the 1H NMR Spectral Signals for
Ligand L6 and Its Zr(IV) Complexes
δ (toluene-d8)
Zr(OtBu)4ꢀL6
δ (dichloromethane-d2)
signal
L6
L6
Zr(OtBu)4ꢀL6
H100
H300
H4
8.36
8.08
7.85
7.80
7.37
7.23
7.28
5.03
8.56
8.04
7.87
7.86
7.28
7.07
7.32
8.30
7.98
8.18
8.05
7.51
7.44
7.25
5.50
8.32
7.91
7.86
7.85
7.24
7.11
6.87
H5
H6
H7
H8
OH
tBuOH
tBuO
1.04
1.04
1.00
1.00
Figure 2. Working model for the FriedelꢀCrafts reaction of pyrroles
with R-ketoesters catalyzed by L6ꢀZr(OtBu)4.
that are commercially available in both enantiomeric forms (hence
providing access to both enantiomeric products) and a simple
experimental procedure at room temperature constitute addi-
tional advantages of this method. Furthermore, the avoidance
of using N-protecting groups in this pyrrole alkylation also
enhances the efficiency by which substituted pyrroles can be
synthesized.
’ EXPERIMENTAL SECTION
General Experimental Methods. All catalytic reactions were
carried out in glassware dried overnight at 120 °C. Reactions were
monitored by TLC analysis using silica gel 60 thin layer plates. Flash
column chromatography was performed on silica gel 60, 0.040ꢀ0.063
mm. Melting points were measured in a microscope instrument. NMR
1
spectra were determined at 300 MHz for H and at 50 MHz for 13C
NMR and referenced to the residual protic solvent as the internal
standard. Chemical shifts are given in δ values (ppm). The carbon
multiplicity was determined by DEPT experiments. Specific optical
rotations were measured using sodium light (D line, 589 nm). Chiral
HPLC analyses were performed in an instrument equipped with a diode-
array detector using chiral stationary columns. Mass spectra (EI) were
run at 70 eV. ESI mass spectra were recorded on a Q-TOF premier mass
spectrometer with an electrospray source. The drying gas as well as the
nebulizing gas was nitrogen. Toluene was freshly distilled from CaH2
under nitrogen. All BINOL-type ligands, ethyl benzoylformate, methyl
benzoylformate, ethyl (4-nitrophenyl)glyoxylate, ethyl (3,5-difluoro-
benzoyl)formate, ethyl (4-cyanobenzoyl)formate, and ethyl (2-oxo-4-
phenyl)butyrate, were obtained from commercial sources and used
without further purification. The remaining ethyl R-ketoesters were
prepared according to known procedures.14 Zr(OtBu)4 (Puratrem,
99.99%) was obtained from a commercial supplier. Pyrrole and N-
methylpyrrole were distilled prior to use. Dihydroindole was prepared
by reduction of indole with Liꢀammonia.9
Figure 1. Structure for the C2-symmetrical monomeric L6ꢀZr(OtBu)4
complex.
formed stereogenic center. On the other hand, we cannot exclude
the possibility that the pyrrole is activated by another zirconium
molecule through the formation of a hydrogen bond. This may
explain a small nonlinear effect observed (see the Supporting
Information) and why N-methylpyrrole reacts with 2a with a
poor yield and enantioselectivity (13% yield, 20% ee).13
’ CONCLUSIONS
In summary, we have demonstrated the use of a zirconium-
(IV)/BINOL catalyst in a FriedelꢀCrafts reaction of unpro-
tected pyrroles with a variety of differently substituted R-ketoesters
to give pyrroles with a chiral substituted tertiary alcohol moiety.
The reaction takes place with high enantioselectivities (up to
98%) and good isolated yields (up to 79%). The conditions are
also of application to 4,7-dihydroindole, which gives C2-alkylated
indoles after oxidation with p-benzoquinone. The use of ligands
General Procedure for the Catalytic Enantioselective Frie-
delꢀCrafts Reaction. Ligand L6 (11.1 mg, 0.025 mmol) was
introduced into a round-bottom flask provided with a septum, and the
flask was purged with nitrogen. Toluene (1 mL) was added via syringe
followed by Zr(OtBu)4 (10 μL, 0.025 mmol), and the solution was
stirred at rt for 1 h. After this time, R-ketoester 2 (0.125 mmol) and
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pyrrole 1a (45 μL, 0.625 mmol) were added, and the mixture was stirred
at rt until reaction completion (TLC). Then the mixture was filtered
through a short pad of silica gel eluting with diethyl ether. After removal
of the solvent, the products 3 were isolated by column chromatography
eluting with hexaneꢀEtOAc (95:5) mixtures.
6.26ꢀ6.23 (m, 1H), 6.18 (q, J = 3.0 Hz, 1H), 5.30 (d, J = 12.3 Hz, 1H),
5.24 (d, J = 12.3 Hz, 1H), 4.26 (s, 1H) ppm; 13C NMR (75.5 MHz,
CDCl3) δ = 173.2 (C), 141.0 (C), 134.7 (C), 130.2 (C), 128.6 (CH),
128.5 (CH), 128.3 (CH), 128.2 (CH), 128.0 (CH), 126.6 (CH), 117.9
(CH), 108.5 (CH), 107.8 (CH), 77.2 (C), 68.5 (CH2) ppm; MS (EI)
m/z (rel intens) 307 [M]+ (10), 172 (100); HRMS m/z calcd for
C19H17NO3 [M]+ 307.1208, found 307.1200.
Racemic FriedelꢀCrafts products for comparison were prepared
following the same procedure by using racemic BINOL (()-L1.
Data for ethyl 2-hydroxy-2-phenyl-2-(1H-pyrrol-2-yl)acetate (3aa):
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 15.8 min,
(ꢀ)minor tR = 13.2 min, ee = 97%.
oil; [R]2D5 +59.8 (c = 1.00 in CHCl3, 98% ee); H NMR (300 MHz,
1
CDCl3) δ = 8.57 (br s, 1H), 7.43ꢀ7.40 (m, 2H), 7.34ꢀ7.30 (m, 3H),
6.77 (m, 1H), 6.31ꢀ6.30 (m, 1H), 6.21 (q, J = 3.0 Hz, 1H), 4.40ꢀ4.21
(m, 3H), 1.28 (d, J = 7.2 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ
= 173.3 (C), 141.2 (C), 130.4 (C), 128.21 (CH), 128.17 (CH), 126.6
(CH), 117.8 (CH), 108.6 (CH), 107.6 (CH), 77.0 (C), 63.4 (CH2),
14.0 (CH3) ppm; MS (EI) m/z (rel intens) 245 [M]+ (4), 198 (33), 172
(100), 154 (85), 105 (84), 94 (43), 77 (46); HRMS m/z calcd for
C14H15NO3 [M]+ 245.1052, found 245.1052.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 10.0 min,
(ꢀ)minor tR = 8.8 min, ee = 98%.
Data for 2,2,2-trichloroethyl 2-hydroxy-2-phenyl-2-(1H-pyrrol-2-
1
yl)acetate (3af): oil; [R]2D5 +48.8 (c = 1.39 in CHCl3, 97% ee); H
NMR (300 MHz, CDCl3) δ = 8.58 (br s, 1H), 7.51ꢀ7.48 (m, 2H),
7.35ꢀ7.32 (m, 3H), 6.79 (td, J = 2.7, 1.5 Hz, 1H), 6.45 (ddd, J = 3.6, 2.7,
1.5 Hz, 1H), 6.23 (q, J = 3.0 Hz, 1H), 4.86 (d, J = 11.7 Hz, 1H), 4.81 (d,
J = 12.0 Hz, 1H), 4.13 (s, 1H) ppm; 13C NMR (75.5 MHz, CDCl3) δ =
171.8 (C), 140.1 (C), 129.4 (C), 128.6 (CH), 128.3 (CH), 126.7 (CH),
118.3 (CH), 108.6 (CH), 108.2 (CH), 93.8 (C), 77.4 (C), 75.5 (CH2)
ppm; MS (EI) m/z (rel intens) 347 [M]+ (1), 198 (63), 172 (59), 154
(100), 127 (21), 105 (29), 77 (22); HRMS m/z calcd for C14H12-
NO3Cl3 [M]+ 346.9883, found 346.9881.
Data for methyl 2-hydroxy-2-phenyl-2-(1H-pyrrol-2-yl)acetate
(3ab): oil; [R]2D5 +10.5 (c = 0.55 in CHCl3, 97% ee); 1H NMR
(300 MHz, CDCl3) δ = 8.57 (br s, 1H), 7.44ꢀ7.40 (m, 2H), 7.36ꢀ
7.32 (m, 3H), 6.79 (td, J = 2.6, 1.6 Hz, 1H), 6.29ꢀ6.26 (m, 1H), 6.22
(q, J = 3.0 Hz, 1H), 4.27 (s, 1H), 3.85 (s, 3H) ppm; 13C NMR
(75.5 MHz, CDCl3) δ = 173.9 (C), 141.0 (C), 130.2 (C), 128.4 (CH),
128.3 (CH), 126.6 (CH), 117.9 (CH), 108.5 (CH), 107.7 (CH), 77.2 (C),
53.8 (CH3) ppm; MS (EI) m/z (rel intens) 231 [M]+ (9), 184 (17), 172
(100), 171 (18), 105 (67), 94 (34), 77 (34); HRMS m/z calcd for
C13H13NO3 [M]+ 231.0895, found 231.0895.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 13.0 min,
(ꢀ)minor tR = 11.0 min, ee = 97%.
Data for ethyl 2-hydroxy-2-(1H-pyrrol-2-yl)-2-p-tolylacetate (3ag):
oil; [R]2D5 +51.7 (c = 0.67 in CHCl3, 97% ee); H NMR (300 MHz,
1
CDCl3) δ = 8.56 (br s, 1H), 7.29 (d, J = 8.1 Hz,2H), 7.13 (d, J = 7.8 Hz,
2H), 6.77 (td, J = 2.6, 1.6 Hz,1H), 6.29 (ddd, J = 3.3, 2.4, 1.5 Hz, 1H),
6.21 (q, J = 3.0 Hz, 1H), 4.41ꢀ4.21 (m, 3H), 2.34 (s, 3H), 1.30 (t, J =
7.2 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ = 173.5 (C), 138.4
(C), 138.0 (C), 130.6 (C), 128.9 (CH), 126.5 (CH), 117.7 (CH), 108.4
(CH), 107.5 (CH), 76.9 (C), 63.1 (CH2), 21.2 (CH3), 14.0 (CH3)
ppm; MS (EI) m/z (rel intens) 259 [M]+ (4), 186 (100), 168 (28), 119
(70), 94 (55), 91 (35); HRMS m/z calcd for C15H17NO3 [M]+
259.1208, found 259.1221.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 12.4 min,
(ꢀ)minor tR = 11.0 min, ee = 97%.
Data for isopropyl 2-hydroxy-2-phenyl-2-(1H-pyrrol-2-yl)acetate
(3ac): oil; [R]2D5 +55.8 (c = 0.74 in CHCl3, 98% ee); 1H NMR
(300 MHz, CDCl3) δ = 8.59 (br s, 1H), 7.42ꢀ7.40 (m, 2H), 7.32ꢀ
7.30 (m, 3H), 6.77 (td, J = 2.7, 1.5 Hz, 1H), 6.33ꢀ6.31 (m, 1H), 6.21
(q, J = 3.0 Hz, 1H), 5.14 (sept, J = 6.3 Hz, 1H), 4.38 (s, 1H), 1.32 (d, J =
6.3 Hz, 3H), 1.20 (d, J = 6.3 Hz, 3H) ppm; 13C NMR (75.5 MHz,
CDCl3) δ = 172.8 (C), 141.4 (C), 130.5 (C), 128.2 (CH), 128.1 (CH),
126.5 (CH), 117.7 (CH), 108.4 (CH), 107.5 (CH), 76.9 (C), 71.3
(CH), 21.5 (CH3), 21.4 (CH3) ppm; MS (EI) m/z (rel intens) 259
[M]+ (5), 172 (100), 105 (74), 94 (37), 77 (40); HRMS m/z calcd for
C15H17NO3 [M]+ 259.1208, found 259.1204.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 18.2 min,
(ꢀ)minor tR = 19.6 min, ee = 97%.
Data for ethyl 2-hydroxy-2-(1H-pyrrol-2-yl)-2-o-tolylacetate (3ah):
oil; [R]2D5 +11.5 (c = 0.23 in CHCl3, 65% ee); 1H NMR (300 MHz,
CDCl3) δ = 8.67 (br s, 1H), 7.24ꢀ7.15 (m, 2H), 7.06 (dd, J = 7.4,
1.6 Hz, 1H), 6.84 (td, J = 2.6, 1.7 Hz, 1H), 6.78 (td, J = 8.0, 1.1 Hz,
1H), 6.25ꢀ6.22 (m, 2H), 4.46ꢀ4.24 (m, 2H), 4.09 (s, 1H), 2.31
(s, 3H), 1.31 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3)
δ = 174.0 (C), 139.4 (C), 137.1 (C), 131.6 (CH), 130.3 (C), 128.6
(CH), 128.5 (CH), 125.6 (CH), 117.7 (CH), 108.8 (CH), 107.5
(CH), 78.1 (C), 63.1 (CH2), 29.7 (CH3), 14.0 (CH3) ppm; MS (EI)
m/z (rel intens) 259 [M]+ (10), 186 (100), 168 (34), 119 (67),
94 (45), 91 (30); HRMS m/z calcd for C15H17NO3 [M]+ 259.1208,
found 259.1216.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 8.7 min,
(ꢀ)minor tR = 7.5 min, ee = 98%.
Data for tert-butyl 2-hydroxy-2-phenyl-2-(1H-pyrrol-2-yl)acetate
(3ad): oil; [R]2D5 +62.6 (c = 0.35 in CHCl3, 90% ee); 1H RMN
(300 MHz, CDCl3) δ = 8.57 (br s, 1H), 7.42ꢀ7.39 (m, 2H), 7.31ꢀ
7.29 (m, 3H), 6.77 (td, J = 2.6, 1.5 Hz, 1H), 6.34ꢀ6.32 (m, 1H), 6.22 (q,
J = 3.0 Hz, 1H), 4.42 (s, 1H), 1.46 (s, 9H) ppm; 13C RMN (75.5 MHz,
CDCl3) δ = 172.2 (C), 141.8 (C), 130.7 (C), 128.0 (CH), 127.9 (CH),
126.5 (CH), 117.5 (CH), 108.4 (CH), 107.3 (CH), 84.1 (C), 77.0 (C),
27.7 (CH3) ppm; MS (EI) m/z (rel intens) 273 [M]+ (12), 173 (12),
172 (100), 105 (15); HRMS m/z calcd for C16H19NO3 [M]+ 273.1365,
found 273.1361.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 12.5 min,
(ꢀ)minor tR = 9.4 min, ee = 65%.
Data for ethyl 2-hydroxy-2-(4-methoxyphenyl)-2-(1H-pyrrol-2-
1
yl)acetate (3ai): oil; [R]2D5 +55.6 (c = 0.47 in CHCl3, 98% ee); H
NMR (300 MHz, CDCl3) δ = 8.57 (br s, 1H), 7.32 (d, J = 9.0 Hz, 2H),
6.84 (d, J = 9.0 Hz, 2H), 6.77 (td, J = 2.6, 1.6 Hz, 1H), 6.29 (ddd, J = 3.6,
2.7, 1.8 Hz, 1H), 6.21 (q, J = 2.9 Hz, 1H), 4.40ꢀ4.21 (m, 3H), 3.79 (s,
3H), 1.29 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ =
173.6 (C), 159.4 (C), 133.5 (C), 130.7 (C), 127.9 (CH), 117.7 (CH),
113.5 (CH), 108.4 (CH), 107.4 (CH), 76.7 (C), 63.1 (CH2), 55.3
(CH3), 14.0 (CH3) ppm; MS (EI) m/z (rel intens) 275 [M]+ (1), 228
(17), 202 (18), 184 (62), 135 (100), 94 (14); HRMS m/z calcd for
C15H17NO4 [M]+ 275.1158, found 275.1149.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 7.0 min,
(ꢀ)minor tR = 6.2 min, ee = 90%.
Data for benzyl 2-hydroxy-2-phenyl-2-(1H-pyrrol-2-yl)acetate
(3ae): oil; [R]2D5 +50.6 (c = 0.77 in CHCl3, 97% ee); 1H NMR
(300 MHz, CDCl3) δ = 8.53 (br s, 1H), 7.42ꢀ7.38 (m, 2H), 7.34ꢀ
7.30 (m, 6H), 7.23ꢀ7.20 (m, 2H), 6.76 (td, J = 2.6, 1.7 Hz, 1H),
6290
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ARTICLE
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 12.3 min,
(ꢀ)minor tR = 13.8 min, ee = 98%.
(q, J = 3.0 Hz, 1H), 4.42ꢀ4.23 (m, 3H), 1.29 (t, J = 7.1 Hz, 3H) ppm; 13
C
NMR (75.5 MHz, CDCl3) δ= 173.3 (C), 138.6 (C), 133.1 (C), 132.9 (C),
130.4 (C), 128.5 (CH), 128.0 (CH), 127.5 (CH), 126.4 (CH), 126.2
(CH), 125.7 (CH), 124.6 (CH), 117.9 (CH), 108.6 (CH), 107.7 (CH),
77.2 (C), 63.2 (CH2), 14.0 (CH3) ppm; MS (EI) m/z (rel intens) 295
[M]+ (5), 277 (24), 222 (100), 204 (80), 155 (53), 127 (47), 94 (96);
HRMS m/z calcd for C18H17N1O3 [M]+ 295.1208, found 295.1209.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 11.7 min,
(ꢀ)minor tR = 12.9 min, ee = 98%.
Data for ethyl 2-(4-chlorophenyl)-2-hydroxy-2-(1H-pyrrol-2-yl)acetate
(3aj): oil; [R]2D5 +67.6 (c = 0.70 in CHCl3, 96% ee); 1H NMR
(300 MHz, CDCl3) δ = 8.56 (br s, 1H), 7.38 (d, J = 8.7, 2H), 7.29
(d, J = 9.0 Hz, 2H), 6.78 (td, J = 2.7, 1.5 Hz, 1H), 6.30ꢀ6.27 (m, 1H),
6.21 (q, J = 3.0 Hz, 1H), 4.41ꢀ4.21 (m, 3H), 1.29 (t, J = 7.1 Hz, 3H) ppm;
13C NMR (75.5 MHz, CDCl3) δ = 172.9 (C), 140.0 (C), 134.2 (C),
130.0 (C), 128.3 (CH), 128.1 (CH), 118.0 (CH), 108.6 (CH), 107.6
(CH), 76.5 (C), 63.3 (CH2), 14.0 (CH3) ppm; MS (EI) m/z (rel intens)
279 [M]+ (9), 226 (16), 208 (34), 206 (100), 190 (48), 188 (24),
139 (28), 99 (19), 97 (20), 85 (35), 83 (19), 71 (42), 69 (26), 57 (56),
55 (24); HRMS m/z calcd for C14H14NO3Cl [M]+ 279.0662, found
279.0664.
Data for ethyl 2-hydroxy-2-(1H-pyrrol-2-yl)-2-(thiophene-2-yl)acetate
(3ao): oil; [R]2D5 +6.7 (c = 0.21 in CHCl3, 95% ee); 1H NMR (300 MHz,
CDCl3) δ = 8.61 (br s, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.07 (dd, J = 3.6,
1.2 Hz, 1H), 6.96 (dd, J = 5.1, 3.6 Hz, 1H), 6.76 (td, J = 2.6, 1.5 Hz, 1H),
6.33ꢀ6.31 (m, 1H), 6.19 (q, J = 3.0 Hz, 1H), 4.50 (s, 1H), 4.34 (dq, J =
7.1, 1.1 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75.5 MHz,
CDCl3) δ = 172.4 (C), 145.7 (C), 130.5 (C), 126.8 (CH), 125.9 (CH),
125.8 (CH), 117.8 (CH), 108.7 (CH), 107.1 (CH), 74.8 (C), 63.5
(CH2), 14.0 (CH3) ppm; MS (EI) m/z (rel intens) 251 [M]+ (7), 178
(100), 160 (20), 110 (76), 94 (34); HRMS m/z calcd for C12H13NO3S
[M]+ 251.0616, found 251.0610.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralpack AD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 16.5 min,
(ꢀ)minor tR = 17.8 min, ee = 96%.
Data for ethyl 2-(4-cyanophenyl)-2-hydroxy-2-(1H-pyrrol-2-yl)acetate
(3ak): oil; [R]2D5 +56.6 (c = 0.78 in CHCl3, 81% ee); H NMR (300
1
MHz, CDCl3) δ = 8.59 (br s, 1H), 7.63ꢀ7.57 (m, 4H), 6.79 (td, J = 2.7,
1.5 Hz, 1H), 6.30 (ddd, J = 3.6, 2.7, 1.5 Hz, 1H), 6.21 (q, J = 2.9 Hz, 1H),
4.44 (s, 1H), 4.42ꢀ4.21 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H) ppm; 13C
NMR (75.5 MHz, CDCl3) δ = 172.1 (C), 146.0 (C), 131.9 (CH), 129.3
(C), 127.5 (CH), 118.6 (C), 118.4 (CH), 112.0 (C), 108.7 (CH), 107.7
(CH), 76.6 (C), 63.6 (CH2), 13.9 (CH3) ppm; MS (EI) m/z (rel intens)
270 [M]+ (16), 197 (100), 130 (23). HRMS m/z calcd for C15H14N2O3
[M]+ 270.1004, found 270.1006.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 16.5 min,
(ꢀ)minor tR = 15.3 min, ee = 81%.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 12.0 min,
(ꢀ)minor tR = 10.5 min, ee = 90%.
Data for ethyl 2-(furan-2-yl)-2-hydroxy-2-(1H-pyrrol-2-yl)acetate
(3ap): oil; [R]2D5 +11.5 (c = 0.30 in CHCl3, 90% ee); 1H NMR
(300 MHz, CDCl3) δ = 8.74 (br s, 1H), 7.40 (dd, J = 1.8, 0.9 Hz,
1H), 6.80 (td, J = 2.6, 1.4 Hz, 1H), 6.34ꢀ6.31 (m, 2H), 6.25ꢀ6.20
(m, 2H), 4.36ꢀ4.29 (m, 3H), 1.29 (t, J = 7.2 Hz, 3H) ppm; 13C NMR
(75.5 MHz, CDCl3) δ = 171.6 (C), 153.7 (C), 143.1 (CH), 127.8 (C),
117.7 (CH), 110.2 (CH), 109.2 (CH), 108.9 (CH), 107.3 (CH), 72.8 (C),
63.4 (CH2), 14.0 (CH3) ppm; MS (EI) m/z(rel intens) 235 [M]+ (3), 162
(74), 97 (39), 95 (60), 83 (43), 71 (54), 57 (100); HRMS m/z calcd for
C12H13NO4 [M]+ 235.0846, found 235.0843.
Data for ethyl 2-hydroxy-2-(4-nitrophenyl)-2-(1H-pyrrol-2-yl)acetate
(3al): oil; [R]2D5 +39.3 (c = 1.27 in CHCl3, 60% ee); 1H NMR (300 MHz,
CDCl3) δ = 8.60 (br s, 1H), 8.16 (d, J = 9.0 Hz, 2H), 7.66 (d, J = 9.0 Hz,
2H), 6.80 (td, J = 2.6, 1.7 Hz, 1H), 6.33ꢀ6.30 (m, 1H), 6.23 (q, J =
3.0 Hz, 1H), 4.47 (s, 1H), 4.43ꢀ4.22 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H)
ppm; 13C NMR (75.5 MHz, CDCl3) δ = 172.0 (C), 147.8 (C), 147.6
(C), 129.3 (C), 127.8 (CH), 123.3 (CH), 118.5 (CH), 108.8 (CH),
107.8 (CH), 76.5 (C), 63.7 (CH2), 13.9 (CH3) ppm; MS (EI) m/z
(rel intens) 290 [M]+ (5), 217 (100), 150 (58), 104 (27), 94 (26);
HRMS m/z calcd for C14H14N2O5 [M]+ 290.0903, found 290.0902.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 17.2 min,
(ꢀ)minor tR = 15.7 min, ee = 60%.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 15.4 min,
(ꢀ)minor tR = 11.6 min, ee = 90%.
Data for ethyl 2-hydroxy-4-phenyl-2-(1H-pyrrol-2-yl)butanoate
(3aq): oil; [R]2D5 ꢀ12.2 (c = 0.54 in CHCl3, 46% ee); 1H NMR
(300 MHz, CDCl3) δ = 8.64 (br s, 1H), 7.30ꢀ7.25 (m, 2H), 7.20ꢀ
7.16 (m, 3H), 6.73 (q, J = 2.2 Hz, 1H), 6.20ꢀ6.18 (m, 2H), 4.28ꢀ4.17
(m, 2H), 3.94 (s, 1H), 2.78ꢀ2.68 (m, 1H), 2.62ꢀ2.52 (m, 1H), 2.43ꢀ
2.24 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75.5 MHz,
CDCl3) δ = 174.5 (C), 141.4 (C), 131.1 (C), 128.41 (CH), 128.37
(CH), 125.9 (CH), 116.8 (CH), 109.1 (CH), 105.2 (CH), 75.2 (C),
62.8 (CH2), 42.2 (CH2), 29.9 (CH2), 14.1 (CH3) ppm; MS (EI) m/z
(rel intens) 273 [M]+ (10), 200 (96), 105 (48), 91 (100); HRMS m/z
calcd for C16H19NO3 [M]+ 273.1365, found 273.1366.
Data for ethyl 2-(3,5-difluorophenyl)-2-hydroxy-2-(1H-pyrrol-2-
yl)acetate (3am): oil; [R]2D5 +57.6 (c = 1.02 in CHCl3, 77% ee); H
1
NMR (300 MHz, CDCl3) δ = 8.58 (br s, 1H), 7.07ꢀ7.00 (m, 2H), 6.78
(td, J = 2.7, 1.5 Hz, 1H), 6.74 (tt, J = 8.7, 2.4 Hz, 1H), 6.32ꢀ6.29
(m, 1H), 6.21 (q, J = 2.7 Hz, 1H), 4.43ꢀ4.23 (m, 3H), 1.32 (t, J(H,H) =
7.2 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ = 172.2 (C), 162.8
(d, J(C,F) = 246.9 Hz, CF), 162.6 (d, J(C,F) = 246.8 Hz, CF), 145.1 (t,
J(C,F) = 8.6 Hz, C) 129.4 (C), 118.3 (CH), 110.1ꢀ109.8 (m, 2CH),
108.7 (CH), 107.7(CH), 103.6 (t, J(C,F) = 25.2 Hz, CH), 76.29 (t, J(C,
F) = 2.2 Hz, C), 63.6 (CH2), 13.9 (CH3) ppm; MS (EI) m/z (rel intens)
281 [M]+ (10), 208 (100), 141 (58), 113 (16); HRMS m/z calcd for
C14H13N1O3F2 [M]+ 281.0864, found 281.0862.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 9.0 min,
(ꢀ)minor tR = 8.4 min, ee = 90%.
Data for ethyl 2-(5-ethyl-1H-pyrrol-2-yl)-2-hydroxy-2-phenylace-
tate (3ba): oil; [R]2D5 +42.8 (c = 1.33 in CHCl3, 92% ee); H NMR
1
(300 MHz, CDCl3) δ = 8.25 (br s, 1H), 7.48ꢀ7.44 (m, 2H), 7.37ꢀ7.30 (m,
3H), 6.17 (d, J = 3.6 Hz, 1H), 5.89 (d, J = 3.3 Hz, 1H), 4.40ꢀ4.20 (m, 2H),
4.38 (s, 1H), 2.60 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.7
Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ = 173.4 (C), 141.3 (C),
134.5 (C), 128.7 (C), 128.1 (2 ꢁ CH), 126.6 (CH), 107.6 (CH), 104.9
(CH), 77.2 (C), 63.0 (CH2), 20.8 (CH2), 14.0 (CH3), 13.4 (CH3) ppm;MS
(EI) m/z (rel intens) 273 [M]+ (10), 255 (26), 200 (100), 154 (85), 105
(29); HRMS m/z calcd for C16H19NO3 [M]+ 273.1365, found 273.1355.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralpack AS-
H, 10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 10.2 min,
(ꢀ)minor tR = 14.5 min, ee = 92%.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralpack AD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 10.3 min,
(ꢀ)minor tR = 11.2 min, ee = 77%.
Data for ethyl 2-hydroxy-2-(naphthalen-2-yl)-2-(1H-pyrrol-2-
yl)acetate (3an): oil; [R]2D5 +49.3 (c = 1.15 in CHCl3, 98% ee); H
1
NMR (300 MHz, CDCl3) δ = 8.59 (br s, 1H), 7.87 (d, J = 1.8 Hz, 1H),
7.82ꢀ7.79 (m, 3H), 7.54 (dd, J = 8.7, 1.8 Hz, 1H), 7.49ꢀ7.46 (m, 2H),
6.81 (td, J = 2.7, 1.5 Hz, 1H), 6.37 (ddd, J = 3.9, 2.7, 1.8 Hz, 1H), 6.25
6291
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ARTICLE
Data for ethyl 2-(5-ethyl-1H-pyrrol-2-yl)-2-hydroxy-2-p-tolylace-
105 (49), 77 (12); HRMS m/z calcd for C18H17NO3 [M]+ 295.1208,
found 295.1215.
tate (3bg): oil; [R]2D5 +28.2 (c = 0.87 in CHCl3, 93% ee); H NMR
1
(300 MHz, CDCl3) δ = 8.21 (br s, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.13
(d, J = 8.1 Hz, 2H), 6.15 (t, J = 3.0 Hz, 1H), 5.88 (t, J = 3.0 Hz, 1H),
4.40ꢀ4.15 (m, 3H), 2.59 (q, J = 7.6 Hz, 2H), 2.34 (s, 3H), 1.29 (t, J =
7.2 Hz, 3H), 1.22 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (75.5 MHz,
CDCl3) δ = 173.5 (C), 138.5 (C), 137.9 (C), 134.4 (C), 129.3 (C),
128.8 (CH), 126.6 (CH), 107.5 (CH), 104.3 (CH), 76.9 (C), 63.0
(CH2), 21.1 (CH3), 20.8 (CH2), 14.0 (CH3), 13.4 (CH3) ppm; MS
(EI) m/z (rel intens) 287 [M]+ (3), 269 (44), 214 (47), 196 (74), 119
(44), 91 (25), 71 (52), 69 (48), 57 (100); HRMS m/z calcd for
C17H21NO3 [M]+ 287.152, found 287.1514.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 13.6 min,
(ꢀ)minor tR = 17.6 min, ee = 91%.
Data for ethyl 2-hydroxy-2-(1H-indol-2-yl)-2-p-tolylacetate (5g):
oil; [R]2D5 +40.5 (c = 1.05 in CHCl3, 92% ee); H NMR (300 MHz,
1
CDCl3) δ = 8.51 (br s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.36ꢀ7.32
(m, 3H), 7.19 (td, J = 7.6, 1.3 Hz, 1H), 7.15ꢀ7.09 (m, 3H), 6.64 (dd, J =
2.1, 0.9 Hz, 1H), 4.43ꢀ4.30 (m, 3H), 2.34 (s, 3H),1.34 (t, J = 7.2 Hz,
3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ = 173.0 (C), 138.3 (C),
137.7 (C), 137.4 (C), 135.7 (C), 129.0 (CH), 128.0 (C), 126.5 (CH),
122.3 (CH), 120.8 (CH), 120.0 (CH), 111.1 (CH), 101.8 (CH), 77.2 (C),
63.4 (CH2), 21.1 (CH3), 14.1 (CH3) ppm; MS (EI) m/z (rel intens)
309 [M]+ (47), 237 (18), 236 (100), 119 (47); HRMS m/z calcd for
C19H19NO3 [M]+ 309.1365, found 309.1354.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralpack AS-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 9.0 min,
(ꢀ)minor tR = 11.3 min, ee = 93%.
Data for ethyl 2-(4-chlorophenyl)-2-(5-ethyl-1H-pyrrol-2-yl)-2-hy-
droxyacetate (3bj): oil; [R]2D5 +26.0 (c = 1.25 in CHCl3, 83% ee); 1H
NMR (300 MHz, CDCl3) δ = 8.17 (br s, 1H), 7.41 (d, J = 8.7 Hz, 2H),
7.29 (d, J = 8.7 Hz, 2H), 6.14 (t, J = 3.0 Hz, 1H), 5.88 (t, J = 3.2 Hz, 1H),
4.39ꢀ4.19 (m, 3H), 2.59 (q, J = 7.5 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H),
1.22 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ = 173.0
(C), 139.7 (C), 134.8 (C), 134.1 (C), 128.4 (C), 128.22 (CH), 128.21
(CH), 107.6 (CH), 104.5 (CH), 77.2 (C), 63.0 (CH2), 20.8 (CH2), 14.0
(CH3), 13.4 (CH3) ppm; HRMS (ESI) m/z calcd for C16H18ClNO3Na
[M + Na]+ 330.0873, found 330.0879.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 11.8 min,
(ꢀ)minor tR = 16.1 min, ee = 92%.
Data for ethyl 2-(4-chlorophenyl)-2-hydroxy-2-(1H-indol-2-yl)acetate
(5j): oil; [R]2D5 +50.2 (c = 1.41 in CHCl3, 83% ee); 1H NMR (300 MHz,
CDCl3) δ = 8.52 (br s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 8.7 Hz,
2H), 7.34 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.21 (td, J = 7.6,
1.2 Hz, 1H), 7.14 (td, J = 7.4, 1.0 Hz, 1H), 6.64 (d, J = 1.5 Hz, 1H), 4.51
(s, 1H), 4.46ꢀ4.28 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H) ppm; 13C NMR
(75.5 MHz, CDCl3) δ = 172.5 (C), 138.9 (C), 136.7 (C), 135.7 (C),
134.4 (C), 128.4 (CH), 128.1 (CH), 127.9 (C), 122.6 (CH), 120.8
(CH), 120.1 (CH), 111.1 (CH), 101.8 (CH), 76.8 (C), 63.7 (CH2),
14.0 (CH3) ppm; MS (EI) m/z (rel intens) 329 [M]+ (44), 258 (33),
257 (19), 256 (100), 140 (17), 138 (52); HRMS m/z calcd for
C18H16NO3Cl [M]+ 329.0819, found 329.0811.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralpack AD-
H, 10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 10.2 min,
(ꢀ)minor tR = 9.4 min, ee = 83%.
Data for ethyl 2-hydroxy-2-(5-(3-oxobutyl)-1H-pyrrol-2-yl)-2-phe-
nylacetate (3da): oil; [R]D25 +26.5 (c = 1.2 in CHCl3, 96% ee); 1H NMR
(300 MHz, CDCl3) δ = 8.60 (br s, 1H), 7.45ꢀ7.42 (m, 2H), 7.35ꢀ7.28
(m, 3H), 6.12 (t, J = 3.0 Hz, 1H), 5.84 (t, J = 3.0 Hz, 1H), 4.39ꢀ4.23
(m, 3H), 4.22 (1H, s), 2.84ꢀ2.73 (m, 4H), 2.13 (s, 3H), 1.29 (t, J =
7.2 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ = 208.7 (C), 173.4
(C), 141.3 (C), 131.6 (C), 129.5 (C), 128.1 (2 ꢁ CH), 126.6 (CH),
107.4 (CH), 105.5 (CH), 77.2 (C), 63.0 (CH2), 43.7 (CH2), 30.0
(CH3), 21.5 (CH2), 14.0 (CH3) ppm; HRMS (ESI) m/z calcd for
C18H21NO4Na [M + Na]+ 338.1368, found 338.1365.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 13.4 min,
(ꢀ)minor tR = 21.0 min, ee = 83%.
Data for ethyl 2-hydroxy-2-(1H-indol-2-yl)-2-(naphthalen-2-yl)acetate
(5n): oil; [R]2D5 +68.5 (c = 1.43 in CHCl3, 90% ee); 1H NMR (300 MHz,
CDCl3) δ = 8.60 (br s, 1H), 7.94 (d, J = 1.5 Hz, 1H), 7.85ꢀ7.78
(m, 3H), 7.67 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.7, 1.8 Hz, 1H),
7.51ꢀ7.48 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.22 (td, J = 7.5, 1.4 Hz,
1H), 7.16 (td, J = 7.4, 1.2 Hz, 1H), 6.73 (dd, J = 2.1, 0.9 Hz, 1H), 4.60
(s, 1H), 4.48ꢀ4.30 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H) ppm; 13C NMR
(75.5 MHz, CDCl3) δ = 172.9 (C), 137.8 (C), 137.1 (C), 135.8 (C),
133.1 (C), 132.8 (C), 128.4 (CH), 128.1 (CH), 128.0 (C), 127.5 (CH),
126.6 (CH), 126.3 (CH), 125.8 (CH), 124.5 (CH), 122.4 (CH), 120.8
(CH), 120.0 (CH), 111.1 (CH), 102.0 (CH), 77.5 (C), 63.5 (CH2),
14.0 (CH3) ppm; MS (EI) m/z (rel intens) 345 [M]+ (50), 327 (57),
272 (100), 254 (54), 155 (22) ppm; HRMS m/z calcd for C22H19NO3
[M]+ 345.1365, found 345.1352.
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 17.8 min,
(ꢀ)minor tR = 12.7 min, ee = 96%.
General Procedure for the Catalytic Enantioselective Frie-
delꢀCrafts Reaction with Dihydroindole. Zr(OtBu)4 (10 μL,
0.025 mmol) was added via syringe to a solution of ligand L6 (18.7 mg,
0.025 mmol) in toluene (1.0 mL) under a nitrogen atmosphere at rt.
After 1 h, a solution of R-ketoester 2 (0.125 mmol) and 4,7-dihydroin-
dole (4; 0.15 mmol) in toluene (0.8 mL) was added, stirring was
continued until completion of the reaction (TLC), and p-benzoquinone
(40 mg, 0.375 mmol) was added. After 2 h, the reaction mixture was
diluted with diethyl ether (30 mL), washed with 0.5 M aqueous sodium
thiosulfate (25 mL), 2 M aqueous NaOH (2 ꢁ 20 mL), and brine, and
dried over MgSO4. After removal of the solvents under reduced
pressure, product 5 was obtained by column chromatography eluting
with hexaneꢀEtOAc (9:1).
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 17.6 min,
(ꢀ)minor tR = 24.6 min, ee = 90%.
Data for ethyl 2-hydroxy-2-(1H-indol-2-yl)-2-(thiophene-2-yl)acetate
(5o): oil; [R]2D5 +16.7 (c = 0.5 in CHCl3, 84% ee); 1H NMR (300 MHz,
CDCl3) δ = 8.56 (br s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 8.1,
0.9 Hz, 1H), 7.30 (dd, J = 5.1, 1.5 Hz, 1H), 7.19 (td, J = 7.6, 1.3 Hz, 1H),
7.15 (dd, J = 3.6, 1.2 Hz, 1H), 7.11 (td, J = 7.4, 1.2 Hz, 1H), 6.97 (dd, J =
5.0, 3.8 Hz, 1H), 6.65 (dd, J = 2.1, 0.9 Hz, 1H), 4.65 (s, 1H), 4.38 (qd, J =
7.2, 0.5 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75.5 MHz,
CDCl3) δ = 172.0 (C), 144.8 (C), 137.2 (C), 135.6 (C), 128.0 (C),
126.8 (CH), 126.2 (CH), 126.1 (CH), 122.5 (CH), 120.9 (CH), 120.0
(CH), 111.1 (CH), 101.4 (CH), 75.0 (C), 63.8 (CH2), 14.0 (CH3)
ppm; MS (EI) m/z (rel intens) 301 [M]+ (14), 283 (29), 228 (69), 212
(43), 210 (50), 110 (100), 71 (48); HRMS m/z calcd for C16H15NO3S
[M]+ 301.0773, found 301.0775.
Data for ethyl 2-hydroxy-2-(1H-indol-2-yl)-2-phenylacetate (5a):
oil; [R]2D5 +46.3 (c = 1.19 in CHCl3, 91% ee); H NMR (300 MHz,
1
CDCl3) δ = 8.54 (br s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.50ꢀ7.47
(m, 2H), 7.35ꢀ7.33 (m, 4H), 7.21 (td, J = 7.5, 1.2 Hz, 1H), 7.13 (td, J =
7.5, 1.1 Hz, 1H), 6.66 (dd, J = 2.1, 0.9 Hz, 1H), 4.48 (s, 1H), 4.34ꢀ4.31
(m, 2H), 1.34 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3)
δ = 172.9 (C), 140.5 (C), 137.2 (C), 135.7 (C), 128.5 (CH), 128.3
(CH), 127.9 (C), 126.6 (CH), 122.4 (CH), 120.7 (CH), 120.0 (CH),
111.1 (CH), 101.8 (CH), 77.3 (C), 63.5 (CH2), 14.0 (CH3) ppm;
MS (EI) m/z (rel intens) 295 [M]+ (53), 223 (18), 222 (100), 206 (30),
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ARTICLE
Assay of enantiomeric excess: chiral HPLC analysis (Chiralcel OD-H,
10% 2-propanolꢀ90% hexane, 1.0 mL/min) (+)major tR = 14.4 min,
(ꢀ)minor tR = 18.4 min, ee = 84%.
’ ACKNOWLEDGMENT
We thank the Ministerio de Ciencia e Innovaciꢀon and FEDER
(Grant CTQ2009-13083) and the Generalitat Valenciana (Grant
ACOMP/2011/267) for financial support. C.V. thanks the
Generalitat Valenciana for a predoctoral grant.
Determination of the Absolute Stereochemistry of Com-
pound 3aj. (R)-Ethyl 2-(Formylcarbamoyl)-2-(4-chlorophenyl)-
2-hydroxyacetate (6). Ozone-enriched oxygen was bubbled through
a precooled solution of compound 3aj (84 mg, 0.3 mmol) in dichlor-
omethane (6 mL) at ꢀ78 °C until complete reaction of the starting
material (TLC). The excess ozone was removed by bubbling nitrogen
through the solution. Then triphenylphosphine (87 mg, 0.33 mmol) was
added, and the mixture was allowed to reach room temperature and
diluted with dichloromethane. The solution was washed with brine
and dried over anhydrous MgSO4. The solvent was removed under
reduced pressure, and the concentrated sample was chromato-
graphed on silica gel eluting with hexaneꢀEtOAc (90:10 to 60:40)
to afford product 6 (11.4 mg, 40%). Product 6 was recrystallized from
hexaneꢀdichloromethane to give suitable crystals for X-ray analysis.
Data for 6: 1H NMR (300 MHz, CDCl3) δ = 9.25 (br d, J = 9.9 Hz,
1H), 9.08 (d, J = 9.9 Hz, 1H), 7.70 (d, J = 9.0 Hz, 2H), 7.37 (d, J =
9.0 Hz, 2H), 4.81 (s, OH), 4.38 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H) ppm;
13C NMR (75.5 MHz, CDCl3) δ = 169.1 (C), 168.6(C), 161.4 (CH),
135.5 (C), 133.4 (C), 128.7 (CH), 127.5 (CH), 79.0 (C), 64.8 (CH2),
13.9 (CH3) ppm.
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Characterization of the Chiral Zirconium Catalyst. Data for
(R)-3,30-bis(3,5-bis(trifluoromethyl)phenyl)-1,10-binaphthyl-2,20-diol
(L6): 1H NMR (400 MHz, CD2Cl2) δ = 8.30 (s, 4H), 8.18 (s, 2H), 8.05
(d, J = 8.0 Hz, 2H), 7.98 (s, 2H), 7.51 (ddd, J = 8.1, 6.9, 1.2 Hz, 2H), 7.44
(ddd, J = 8.3, 6.9, 1.4 Hz, 2H), 7.25 (dd, J = 8.4, 0.4 Hz, 2H), 5.50 (s, 2H,
OH) ppm; 1H NMR (400 MHz, toluene-d8) δ = 8.36 (s, 4H), 8.08 (s,
2H), 7.85 (s, 2H), 7.80 (d, J = 8.1 Hz, 2H), 7.37 (ddd, J = 8.1, 6.7, 1.4 Hz,
2H), 7.28 (dd, J = 7.8, 0.6 Hz, 2H), 7.23 (ddd, J = 8.1, 6.7, 1.2 Hz, 2H),
5.03 (s, 2H, OH) ppm; 13C NMR (100.1 MHz, CD2Cl2) δ = 150.8 (C),
140.6 (C), 134.2 (C), 133.2 (CH), 132.1 (q, J(C,F) = 33.2 Hz, C), 130.7
(CH), 130.3 (C), 129.6 (CH), 129.2 (CH), 128.5 (C), 125.8 (CH),
124.7 (CH), 125.4 (q, J(C,F) = 271.3 Hz, CF3). 122.0 (C), 112.6
(CH) ppm.
Zr(OtBu)2-[(R)-3,30-(3,5-bis(trifluoromethyl)phenyl)2-BINOL]. Zr-
(OtBu)4 (10 μL, 0.025 mmol) was added via syringe to a solution of
ligand L6 (18.7 mg, 0.025 mmol) in CD2Cl2 or toluene-d8 (0.5 mL)
under a nitrogen atmosphere at rt. Data for the title compound:
1H NMR (400 MHz, CD2Cl2) δ = 8.32 (s, 4H), 7.91 (s, 2H), 7.86
(s, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.24 (ddd, J = 8.0, 6.8, 1.2 Hz, 2H),
7.11 (ddd, J = 8.2, 6.8, 1.2 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 1.00
(s, 18H) ppm; 1H NMR (400 MHz, toluene-d8) δ = 8.56 (s, 4H), 8.04 (s,
2H), 7.87 (s, 2H), 7.86 (d, J = 6.8 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.28 (t,
J = 7.2 Hz, 2H), 7.07 (t, J = 7.4 Hz, 2H), 1.04 (s, 18H) ppm; 13C NMR
(100.1 MHz, CD2Cl2) δ = 157.0 (C), 144.6 (C), 136.6 (C), 132.5 (q, J(C,
F) = 32.6 Hz, C), 132.0 (C), 130.7 (CH), 130.4 (CH), 129.0 (C), 128.7
(CH), 126.7 (CH), 126.6 (CH), 124.4 (q, J(C,F) = 271.1 Hz, CF3), 123.1
(CH), 121.2 (CH), 120.2 (C), 75.6 (C), 31.6 (CH3) ppm.
(5) Abell, A. D.; Nabss, B. K.; Battersby, A. R. J. Am. Chem. Soc. 1998,
129, 1741–1746.
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48, 6731–6734.
)
)
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of NMR spectra for
b
(10) Flack parameter 0.04(7). Crystallographic data: refined formula
C12H12ClNO5, formula weight Mr 285.68, crystal dimensions 0.02 ꢁ
0.04 ꢁ 0.06 mm, crystal system monoclinic, space group P21, unit-cell
dimensions a = 8.6560(4) Å, b = 5.9190(2) Å, c = 13.1680(5) Å, and β =
104.521(2)°, volume 653.11(4) Å, number of formula units in the unit
cell (Z) 2, calculated density (Fcalcd) 1.453, linear absorption coefficient
(μ) 0.308, radiation wavelength 0.71073 Å, temperature of measure-
ment 293 K, 2θmax = 27.53, nnumber of measured and independent
reflections 3005, Rint = 0.0104, R = 0.0347, Rw = 0.0970, residual electron
density 0.189, ꢀ0.243. Diffraction data were collected with an Enraf-
Nonius Kappa-CCD single-crystal diffractometer using Mo KR radiation.
compounds 3, 5, and 6, and ligand L6 and its Zr(IV) complexes,
X-ray plot and CIF file for compound 6, NLE plot, and chiral
HPLC chromatograms for compounds 3 and 5. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: jose.r.pedro@uv.es. Fax: + 34 963544328. Phone:
+34963544329.
6293
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The Journal of Organic Chemistry
ARTICLE
The structure was solved by direct methods using SHELXS-97 and
refined by full-matrix least-squares on F2 using SHELXL-97. CCDC
812138 contains the supplementary crystallographic data for compound
6. Copies of the data can be obtained free of charge on application to the
CCDC, 12 Union Rd., Cambridge CB2 1EZ, U.K. Fax.: +441223/336-
033. E-mail: deposit@ccdc.cam.ac.uk.
(11) Kobayashi, S.; Kusakabe, K.-I.; Komiyama, S.; Ishitani, H. J. Org.
Chem. 1999, 64, 4220–4221.
(12) Corey, E. J.; Barnes-Seeman, D.; Lee, T. W.; Goodman, S. N.
Tetrahedron Lett. 1997, 38, 6513ꢀ6516 and references therein.
(13) We thank one of the reviewers who suggested this possibility
and proposed NLE studies to check it out.
(14) Creary, X. J. Org. Chem. 1987, 52, 5026–5030.
6294
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