Enantioselective synthesis of substituted indoles through zirconium(IV)-catalyzed Friedel-Crafts alkylation

Article abstract of DOI:10.1055/s-0032-1317161

The chiral complex of (R)-3,3-BrBINOL and zirconium tert-butoxide catalyzes the Friedel-Crafts alkylation of indoles with enones bearing an alkyl or fluorinated group at the β-position to give indoles having a side chain at the C3 position with a tertiary

Full text of DOI:10.1055/s-0032-1317161

3590▌
PRACTICAL SYNTHETIC PROCEDURES
pEranctiacanl styinothesteiclperoccetdiuvrees Synthesis of Substituted Indoles Through Zirconium(IV)-
Catalyzed Friedel–Crafts Alkylation
Zr(IV)-Catalyzed Friedel–Crafts Alkylation
Gonzalo Blay, Isabel Fernández, José R. Pedro,* Carlos Vila
Departament de Química Orgànica, Facultat de Química, Universitat de València, C/Dr. Moliner 50,
46100 Burjassot (València), Spain
Fax +34(963)544328; E-mail: jose.r.pedro@uv.es
PSP
Received: 01.06.2012; Accepted after revision: 02.08.2012
No238
Abstract: The chiral complex of (R)-3,3′-Br2-BINOL and zirconium tert-butoxide catalyzes the Friedel–Crafts alkylation of indoles with
enones bearing an alkyl or fluorinated group at the β-position to give indoles having a side chain at the C3 position with a tertiary stereogenic
center in good yields and with excellent enantioselectivities.
Key words: asymmetric catalysis, fluorine, enones, heterocycles, indoles, Michael addition, zirconium
Br
R
R'
O
R5
R5
OH
OH
L-Zr(Ot-Bu)4
L
O
+
R
R'
CH2Cl2, r.t.
N
N
H
H
Br
1
2
3
Scheme 1 Zirconium(IV)-catalyzed asymmetric alkylation of indoles with β-substituted α,β-unsaturated ketones
The indole nucleus is widely distributed in biological sys- enantiomers of a same compound can show, control of the
tems and biologically active natural products such as alka- enantioselectivity in these kinds of reactions is crucial.4 In
loids. Besides, medicinal chemists have identified the recent years, many procedures for the enantioselective al-
indole scaffold as a privileged pharmacophore, which has kylation of indoles with unsaturated carbonyl compounds
been applied to the discovery of several successful drugs. have been developed, most of them using chelating car-
Furthermore, the indole motif also appears in many signif- bonyl substrates and nitroalkenes.5 However, the use of
icant products across the entire chemical industry.1 Driven simple nonchelating α,β-unsaturated carbonyl compounds
by the important applications and significance of indoles as electrophiles represents a considerable synthetic chal-
of both natural and synthetic origin, the synthesis of in- lenge and has been more restricted.6
dole derivatives has been an active field of chemical re-
It is known that the introduction of a fluorine atom into an
organic structure can greatly modify its physicochemical
search for well over a century.2
There are a wide variety of methods for introduction of properties and consequently its biological activity.7 For
carbon substituents at C3 of indoles. Since this is the pre- this reason, the preparation of fluorinated organic com-
ferred site for electrophilic substitution on indoles, direct pounds has become one of the most useful approaches in
alkylation (Friedel–Crafts) procedures are often effec- the modern design of pharmaceuticals and agrochemicals.
tive.3 Thus, 3-alkylation can be accomplished even with In particular, the introduction of fluorinated substituents
mild electrophiles such as alkenes with electron-with- into the privileged indole pharmacophore is doubly ap-
drawing groups under acidic catalysis. However, since the pealing.8
indole ring is quite reactive against protic and Lewis ac-
As a part of our research on asymmetric catalysis we be-
ids, only procedures which generate electrophilic species
came interested in the development of new enantioselec-
under relatively mild conditions are likely to produce
tive Friedel–Crafts reactions catalyzed by group IV
good yields.
metals and BINOL-type ligands. From the different metal
Friedel–Crafts alkylation of indoles with α,β-unsaturated alkoxides and BINOL-type ligands tested we discovered
carbonyl compounds bearing a β-substituent can give rise that the complex formed from Zr(Ot-Bu)4 and (R)-3,3′-
to the formation of a new stereogenic center. Given the Br2-BINOL provided the best catalyst for the enantiose-
dramatic differences in the biological activities that both lective alkylation of indoles 1 with a number of nonche-
lating α,β-unsaturated ketones 29 and β-perfluorinated
α,β-unsaturated ketones 4.10
SYNTHESIS 2012, 44, 3590–3594
Advanced online publication: 23.08.2012
DOI: 10.1055/s-0032-1317161; Art ID: SS-2012-Z0488-PSP
© Georg Thieme Verlag Stuttgart · New York
In a typical procedure, a mixture of the indole 1 (0.15
mmol) and the enone 2 or 4 (0.125 mmol) in CH2Cl2 (1
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

PRACTICAL SYNTHETIC PROCEDURES
Zr(IV)-Catalyzed Friedel–Crafts Alkylation
3591
mL) was added all at once to a solution of the complex lowered the reaction rate and the enantiomeric excess of
prepared from Zr(Ot-Bu)4 (0.025 mmol) and (R)-3,3′-Br2- the alkylation product dropped to 72% (entry 7). On the
BINOL (L, 0.025 mmol) in CH2Cl2 (1 mL) at room tem- other hand, enones substituted with a 2-naphthyl or a 2-
perature under nitrogen, and the mixture was stirred until thienyl group were also adequate substrates, giving the
completion of the reaction. A reduction of the catalyst corresponding alkylated indoles in excellent yields and
load to 10 mol% decreased the yield as well as the enan- high enantioselectivities (entries 11 and 12). Unfortunate-
tiomeric excess of the product.
ly, the reaction is limited to enones where the R′ is either
an aromatic or heteroaromatic group. Aliphatic enones
(R′ = Me), reacted very slowly with indole under the cat-
alytic conditions.
Both the indole and the enone were amenable to modifi-
cation (Scheme 1, Table 1). Thus, alkyl groups of differ-
ent size (R = Me, Et, Pr) were allowed at the β-position of
the enone providing the expected products in good yields We have also tested the reaction of enone 2a with indoles
and with high enantiomeric excesses, although in the case substituted at the 5-position with either electron-donating
of chalcone (R = Ph) a diminished reactivity was ob- (Me, MeO) or electron-withdrawing (Cl) groups. High en-
served (Table 1, entry 4). The group R′ attached to the car- antioselectivities were obtained in all the cases although
bonyl moiety can be an aromatic or heteroaromatic unit. 5-chloroindole reacted more slowly (entries 13–15).
Good yields and enantioselectivities were obtained with
1-aryl ketones regardless of the electronic features of the
substituent on the phenyl group (entries 5–10), although
the existence of ortho-substitution on the phenyl group
The (R)-3,3′-Br2-BINOL/Zr(Ot-Bu)4 catalytic system
could be also applied to the Friedel–Crafts alkylation of
indoles 1 with α,β-unsaturated ketones 4 bearing perfluo-
rinated groups at the β-position (Scheme 2).10 In this case
a
Table 1 Enantioselective Alkylation of Indoles with α,β-Unsaturated Ketones Catalyzed by (R)-3,3′-Br2-BINOL/Zr(Ot-Bu)4
Entry
1
R5
2
R
R′
Time (h)
3
Yield (%)b ee (%)c
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
H
2a
2b
2c
2d
2e
2f
Me
Et
Ph
3
20
24
96
20
4
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
87
87
82
25
91
84
73
54
92
95
89
87
97
95
74
97
94
97
96
95
92
72
95
96
97
98
96
95
97
95
H
Ph
3
H
Pr
Ph
4
H
Ph
Ph
5
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
4-FC6H4
4-BrC6H4
2-naphthyl
2-thienyl
Ph
6
H
7
H
2g
2h
2i
22
18
2
8
H
9
H
10
11
12
13
14
15
H
2j
2
3aj
3ak
3al
H
2k
2l
2
H
20
4
Me
OMe
Cl
2a
2a
2a
3ba
3ca
3da
Ph
4
Ph
30
a (R)-3,3′-Br2-BINOL (20 mol%) and Zr(Ot-Bu)4 (20 mol%) were used.
b Isolated yield.
c Determined by HPLC analysis using chiral stationary phases.
Rf
Br
R'
O
R5
R6
R5
R6
L-Zr(Ot-Bu)4
O
R2
OH
OH
R2
Rf
R'
+
L
CH2Cl2, r.t.
N
R1
N
R1
R7
R7
1
4
5
Br
Scheme 2 Zirconium(IV)-catalyzed asymmetric alkylation of indoles with β-perfluoroalkyl-substituted α,β-unsaturated ketones
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3590–3594

3592
G. Blay et al.
PRACTICAL SYNTHETIC PROCEDURES
the reaction gives functionalized indoles 5 having an high enantioselectivities (entries 7 and 8). Enones bearing
asymmetric tertiary carbon center attached to a fluorinat- a bulkier CF3CF2 group at the β-position reacted slowly
ed group (CF3 or CF3CF2) without any heteroatom substit- and gave the expected products in low yields (entries 9,
uent. Molecules having these structural features are 10) but still with high enantioselectivities (92–93% ee).
challenging synthetic targets.
Substituted indoles can also be used in this reaction (en-
Table 2 shows the results of the catalyzed reaction be- tries 11–17). The presence of either electron-donating
tween a number of indoles and β-trifluoromethyl enones. (Me, MeO) or electron-withdrawing (Br) groups at the 5-
In general, the fluoroalkylated indoles 5 were obtained in position of the indole nucleus did not affect the enantiose-
excellent yields and with high enantioselectivities. The re- lectivity of the reaction but, again, the reaction rate was
action with fluorinated enones 4 followed similar trends diminished in the case of 5-bromoindole. Also, the pres-
as the reaction with the nonfluorinated enones 2. Thus, tri- ence of a methyl substituent at the 2- or 7-position pro-
fluoromethyl enones bearing phenyl or substituted aro- duced a decrease of the yields and enantioselectivities
matic groups attached to the carbonyl group were proper were somewhat lower (entries 14 and 15). Finally, 1-
substrates for the reaction (Table 2, entries 1–8). Electron- methylindole having a substituted nitrogen atom, gave the
donating or electron-withdrawing groups on the aromatic corresponding fluoroalkylated product in low yield and
ring are tolerated, although the presence of a nitro group with low enantioselectivity (entry 16).
caused a pronounced decrease of enantioselectivity (entry
6). Again the presence of ortho-substituents on this aro-
matic ring brought about a drop of the reaction rate and
isolated yield of the trifluoroalkylation product, although
the ee was still high (entry 3). In addition, the 2-naphthyl
and the heteroaromatic β-trifluoromethyl-α,β-enones can
also serve as substrates in this reaction, giving the corre-
sponding trifluoroalkylated indoles in excellent yields and
In summary, the (R)-3,3′-Br2-BINOL/Zr(Ot-Bu)4 com-
plex effectively catalyzes the Friedel–Crafts alkylation of
indole derivatives with a number of non-chelating β-sub-
stituted and β-trifluoromethyl α,β-unsaturated ketones to
give indoles having a side chain at the C3 with a tertiary
stereogenic center in good yields and with excellent enan-
tioselectivities.
Table 2 Enantioselective Friedel–Crafts Reaction of Indoles with α,β-Unsaturated Ketones Bearing a β-Perfluoroalkylated Group Catalyzed
a,b
by (R)-3,3′-Br2-BINOL/Zr(Ot-Bu)4
Entry
1
R1
R2
R5
R6
R7
4
Rf
R′
Time (h)
5
Yield (%)c ee (%)d
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
4a
4b
4c
4d
4e
4f
CF3
Ph
3.5 (4.5) 5aa
87 (80)
95 (98)
30
96 (99)
97 (95)
94
H
CF3
4-MeC6H4
2-MeC6H4
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
2-naphthyl
2-thienyl
Ph
2 (5)
22
5ab
5ac
5ad
5ae
5af
5ag
5ah
5ai
3
H
CF3
4
H
CF3
7 (23)
1.5 (3)
1.2 (4)
6 (22)
5 (23)
93 (99)
89 (85)
97 (88)
97 (82)
93 (90)
44
91 (97)
93 (81)
64 (66)
76 (92)
96 (98)
92
5
H
CF3
6
H
CF3
7
H
4g
4h
4i
CF3
8
H
CF3
9
H
CF2CF3
CF2CF3
CF3
48
31
5.5 (23)
4 (22)
27
10
11
12
13
14
15
16
17
H
4j
4-MeC6H4
Ph
5aj
5ba
5ca
5da
5ea
5fa
5ga
5ha
46
93
Me
OMe
Br
H
4a
4a
4a
4a
4a
4a
4a
95 (69)
99 (76)
89
90 (94)
85 (82)
94
CF3
Ph
CF3
Ph
CF3
Ph
27
22
22
5
76
82
H
CF3
Ph
64
70
1g
1h
H
CF3
Ph
34
24
H
CF3
Ph
90
90
a (R)-3,3′-Br2-BINOL (20 mol%) and Zr(Ot-Bu)4 (20 mol%) were used.
b Data for the reaction carried out at 0 °C are given in parentheses.
c Isolated yield.
d Determined by HPLC analysis using chiral stationary phases.
Synthesis 2012, 44, 3590–3594
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Zr(IV)-Catalyzed Friedel–Crafts Alkylation
3593
All glassware were oven-dried overnight at 120 °C. Reactions were
monitored by TLC analysis using Merck Silica Gel 60 F-254 thin
layer plates. Flash column chromatography was performed on
Merck silica gel 60, 0.040–0.063 mm. NMR spectra were run in a
Bruker Avance 300 spectrometer, using residual nondeuterated sol-
vent as internal standard. Specific optical rotations were measured
in a PerkinElmer polarimeter using sodium light (D line 589 nm).
Mass spectra (EI) were recorded on a Fisons Instruments VG Auto-
spec GC 8000 series at 70 eV. Chiral HPLC analyses were per-
formed in a Hitachi Elite Lachrom instrument equipped with a
Hitachi UV diode-array L-4500 detector, using chiral stationary col-
umns from Daicel. CH2Cl2 was dried over CaH2 prior to use. Zr(Ot-
Bu)4 was purchased from Fluka. BINOL-type ligand L and all in-
doles 1 were commercially available and used as purchased without
further purification. Enones 211 and fluorinated enones 412 were pre-
pared according to literature procedures.
pound 5aa (34.5 mg, 87%); white solid; mp 117–120 °C (CH2Cl2–
hexane); [α]D25 +55.8 (c 0.74, CHCl3); 96% ee.
HPLC analysis: Chiralcel OD-H, 10% i-PrOH–90% hexane, flow
1.0 mL/min, (R)major tR = 14.9 min, (S)minor tR = 13.9 min.
1H NMR (300 MHz, CDCl3): δ = 8.14 (br s, 1 H, NH), 7.92 (dd,
3JH,H = 7.2, 1.2 Hz, 2 Harom), 7.76 (dd, 3JH,H = 6.9, 1.2 Hz, 1 Harom),
3
3
7.56 (tt, JH,H = 7.4, 1.5 Hz, 1 Harom), 7.44 (t, JH,H = 7.4 Hz, 2 H),
7.35 (dd, 3JH,H = 6.9, 2.4 Hz, 1 H), 7.24–7.15 (m, 3 Harom), 4.70–4.56
(m, 1 H, CH), 3.75 (dd, 2JH,H = 17.5 Hz, 3JH,H = 8.3 Hz, 1 H, CHH),
3.66 (dd, 2JH,H = 17.4 Hz, 3JH,H = 4.8 Hz, 1 H, CHH).
13C NMR (75.5 MHz, CDCl3): δ = 195.9 (C=O), 136.3 (Cquat),
136.0 (Cquat), 133.5 (CHarom), 128.7 (CHarom), 128.0 (CHarom), 127.4
1
(q, JC,F = 277.5 Hz, CF3), 126.5 (Cquat), 123.4 (CHarom), 122.4
(CHarom), 120.1 (CHarom), 119.2 (CHarom), 111.4 (CHarom), 109.7 (q,
3
3JC,F = 2.3 Hz, Cquat), 38.3 (q, JC,F = 1.5 Hz, CH2), 36.7 (q,
2JC,F = 28.8 Hz, CH).
Asymmetric Friedel–Crafts Reaction of Indole (1a) with Enone
2a; (3R)-3-(1H-Indol-3-yl)-1-phenylbutan-1-one (3aa); Typical
Procedure
19F NMR (282 MHz, CDCl3): δ = –70.59 (s, CF3).
MS (EI): m/z (%) = 297 (81, [M+]), 297 (34), 212 (58), 198 (55),
(R)-3,3′-Br2-BINOL (L; 11.1 mg, 0.025 mmol) was introduced in a
25 mL round-bottomed flask provided with a rubber septum and
two stopcocks, one of them connected to a bubbler in the N2 line.
The flask was filled with N2 by sequential application of vacuum
and flushing with N2 (3 times) and was kept under a positive N2
pressure. Anhyd CH2Cl2 (0.8 mL) was added via syringe followed
by fast injection of Zr(Ot-Bu)4 (10 μL, 0.025 mmol) via a microsy-
ringe. The mixture was stirred at r.t. for 1 h. Indole (1a; 17.6 mg,
0.15 mmol) and enone 2a (18.3 mg, 0.125 mmol) were weighed in
a vial and dissolved together in anhyd CH2Cl2 (0.8 mL) and added
to the reaction flask via a syringe. The reaction progress was moni-
tored by TLC (hexane–EtOAc, 8:2) until the starting material had
completely reacted. H2O (10 mL) was added and the mixture was
extracted with EtOAc (3 × 20 mL). The combined organic layers
were washed with brine (10 mL) and dried (MgSO4). Removal of
the solvent under reduced pressure followed by column chromato-
graphy eluting with hexane–EtOAc (95:5) gave compound 3aa
(28.6 mg, 87%); white solid; mp 103–105 °C (CH2Cl2–hexane);
[α]D25 +24.2 (c 0.36, CHCl3); 97% ee.
105 (100), 77 (32).
HRMS:
m/z
calcd
for
C18H14F3NO
[M+]: 317.1027;
found: 317.1019.
Acknowledgment
Financial support from the Ministerio de Ciencia e Innovación and
FEDER (CTQ2009-13083) and from Generalitat Valenciana
(ACOMP/2012/212 and ISIC/2012/001) is acknowledged. C. V.
thanks the Generalitat Valenciana for a predoctoral grant (FPI).
References
(1) (a) Wu, Y.-J. New Indole-Containing Medicinal
Compounds, In Topics in Heterocyclic Chemistry; Vol. 26;
Maes, B. U. W.; Gribble, G. W., Eds.; Springer: Heidelberg,
2010, 1. (b) Barden, T. C. Indoles: Industrial, Agricultural
and Over-the-Counter Uses, In Topics in Heterocyclic
Chemistry; Vol. 26; Maes, B. U. W.; Gribble, G. W., Eds.;
Springer: Heidelberg, 2010, 31.
(2) Sundberg, R. J. Indoles; Elsevier: Amsterdam, 1996.
(3) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S.
Comprehensive Organic Synthesis; Vol. 3; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991, 293.
(4) For reviews on enantioselective Friedel–Crafts reactions,
see: (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew.
Chem. Int. Ed. 2004, 43, 550. (b) Jørgensen, K. A. Synthesis
2003, 1117. (c) Bandini, M.; Melloni, A.; Tommasi, S.;
Umani-Ronchi, A. Synlett 2005, 1199. (d) Poulsen, T. B.;
Jorgensen, K. A. Chem. Rev. 2008, 108, 2903. (e) Catalytic
Asymmetric Friedel–Crafts Alkylations; Bandini, M.;
Umani-Ronchi, A., Eds.; Wiley-VCH: Weinheim, 2009.
(f) Marques-Lopez, E.; Diez-Martinez, A.; Merino, P.;
Herrera, R. P. Curr. Org. Chem. 2009, 13, 1585.
Chiral HPLC analysis: Chiralpak OD-H, 10% i-PrOH–90% hexane,
1.0 mL/min, (R)major tR = 32.1 min, (S)minor tR = 21.3 min.
1H NMR (300 MHz, CDCl3): δ = 7.96–7.94 (m, 3 Harom), 7.68 (d,
3JH,H = 7.8 Hz, 1 Harom), 7.54 (tt, 3JH,H = 7.5, 1.6 Hz, 1 Harom), 7.44
(t, 3JH,H = 7.8 Hz, 2 Harom), 7.36 (d, 3JH,H = 8.1 Hz, 1 Harom), 7.17 (td,
3JH,H = 6.9, 1.2 Hz, 1 Harom), 7.11 (td, 3JH,H = 7.2, 1.2 Hz, 1 Harom),
3
7.04 (d, JH,H = 2.1 Hz, 1 Harom), 3.83 (m, 1 H, CH), 3.48 (dd,
2JH,H = 16.3 Hz, 3JH,H = 4.8 Hz, 1 H, CHH), 3.24 (dd, 2JH,H = 16.3,
3JH,H = 8.9 Hz, 1 H, CHH), 1.45 (d, 3JH,H = 6.9 Hz, 3 H, CH3).
13C NMR (75.5 MHz, CDCl3): δ = 199.7 (C=O), 137.3 (Cquat), 136.5
(Cquat), 132.9 (CHarom), 128.5 (CHarom), 128.1 (CHarom), 126.3
(Cquat), 122.0 (CHarom), 121.5 (Cquat), 120.2 (CHarom), 119.26
(CHarom), 119.23 (CHarom), 111.2 (CHarom), 46.4 (CH2), 27.1 (CH),
21.0 (CH3).
MS (EI): m/z (%) = 263 (68, [M+]), 158 (25), 144 (100).
HRMS: m/z calcd for C18H17NO [M+]: 263.1310; found: 263.1299.
(g) Campbell, J. A. Asymmetric Friedel–Crafts Reactions:
Past to Present, In Name Reactions for Carbocyclic Ring
Formations; Li, J. J., Ed.; Wiley: New York, 2010, 600.
(h) Rueping, M.; Nachtsheim, B. J. Beilstein J. Org. Chem.
2010, 6, No.6. (i) Terrasson, V.; Marcia de Figueiredo, R.;
Campagne, J. M. Eur. J. Org. Chem. 2010, 2635. (j) Zeng,
M.; You, S.-L. Synlett 2010, 1289. For some recent
examples involving 1,2-addition of indoles, see also:
(k) Chauhan, P.; Chimni, S. S. Chem. Eur. J. 2010, 16, 7709.
(l) Xu, F.-X.; Huang, D.; Han, C.; Shen, W.; Lin, X.-F.;
Wang, Y.-G. J. Org. Chem. 2010, 75, 8677. (m) Wolf, C.;
Zhang, P. Adv. Synth. Catal. 2011, 353, 760. (n) Liu, L.;
Zhao, Q.; Du, F.; Chen, H.; Qin, Z.; Fu, B. Tetrahedron:
Asymmetric Friedel–Crafts Reaction of Indole (1a) with Triflu-
oromethyl Enone 4a; (3R)-4,4,4-Trifluoromethyl-3-(1H-indol-
3-yl)-1-phenylbutan-1-one (5aa); Typical Procedure
The catalytic complex was prepared as described above for the
preparation of 3aa. A solution of indole (1a; 17.6 mg, 0.15 mmol)
and enone 4a (25.0 mg, 0.125 mmol) in anhyd CH2Cl2 (1 mL) was
added and the mixture stirred at r.t. After completion of the reaction
(TLC, hexane–EtOAc, 8:2), the mixture was filtered through a short
pad of silica gel eluting with Et2O (50 mL). The solvents were re-
moved under reduced pressure, and flash chromatography of the
residue on silica gel eluting with hexane–EtOAc (95:5) gave com-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3590–3594

3594
G. Blay et al.
PRACTICAL SYNTHETIC PROCEDURES
Asymmetry 2011, 22, 1874. (o) Rueping, M.; Bootwicha, T.;
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