Recoverable Cinchona ammonium salts as organocatalysts in the enantioselective Michael addition of β-keto esters

Article abstract of DOI:10.1016/j.tetasy.2010.11.016

Several dimeric Cinchona-alkaloid anthracenyldimethyl-derived ammonium salts, are used as organocatalysts in the enantioselective Michael addition reaction of cyclic β-keto esters to α,β-unsaturated carbonyl compounds, in the presence of diisopropylethylamine as a base (30 mol %), for the generation of enantiomerically enriched adducts bearing quaternary stereocenters. Quinine and quinidine-derived dimeric ammonium salts (1-10 mol %) afford the opposite and higher enantioselectivities of the corresponding adducts (up to 94% ee) in good yields (up to 98%). Substituted 2-alkoxycarbonyl-1-indanones are used as nucleophile precursors, as well as ethyl 2-oxocyclopentanecarboxylate and tert-butyl 2,5-dioxo-1-phenylpyrrolidine- 3-carboxylate. These organocatalysts can be recovered at the end of the reaction by precipitation in ether and reused without any loss of activity.

Full text of DOI:10.1016/j.tetasy.2010.11.016

Tetrahedron: Asymmetry 21 (2010) 2872–2878
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Recoverable Cinchona ammonium salts as organocatalysts
in the enantioselective Michael addition of b-keto esters
⇑
⇑
Silvia Tarí, Rafael Chinchilla , Carmen Nájera
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Several dimeric Cinchona-alkaloid anthracenyldimethyl-derived ammonium salts, are used as organocat-
Received 8 November 2010
Accepted 22 November 2010
Available online 20 December 2010
alysts in the enantioselective Michael addition reaction of cyclic b-keto esters to
a,b-unsaturated car-
bonyl compounds, in the presence of diisopropylethylamine as a base (30 mol %), for the generation of
enantiomerically enriched adducts bearing quaternary stereocenters. Quinine and quinidine-derived
dimeric ammonium salts (1–10 mol %) afford the opposite and higher enantioselectivities of the corre-
sponding adducts (up to 94% ee) in good yields (up to 98%). Substituted 2-alkoxycarbonyl-1-indanones
are used as nucleophile precursors, as well as ethyl 2-oxocyclopentanecarboxylate and tert-butyl 2,5-
dioxo-1-phenylpyrrolidine-3-carboxylate. These organocatalysts can be recovered at the end of the reac-
tion by precipitation in ether and reused without any loss of activity.
Dedicated to the memory of Professor Rafael
Suan
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
enantioselective Michael addition of cyclic b-keto esters, affording
enantioselectivities only up to 28%.8b,11
Enantioselective organocatalysis is one of the most fast growing
topics in organic chemistry, with many organic reactions per-
formed enantioselectively by the use of chiral organocatalysts.1
For instance, the Michael addition reaction, one of the most basic
organic transformations,2 has been studied intensively in its enan-
tioselective version when using organocatalysts.3 However, these
studies have been much less frequent with regards to its use in
the enantioselective generation of a quaternary stereogenic center,
probably one of the most challenging tasks for a synthetic organic
chemist.4
In the few last years, we have been working on developing
recoverable unsupported12–14 and supported15 Cinchona alkaloid-
derived ammonium salts for their use in organocatalyzed enantio-
selective reactions. The recovery of the organocatalyst is very often
a problem when scaling up a synthetic procedure and the use of an
easily recyclable organocatalyst always adds an extra value to the
methodology. Of particularly interest has been the preparation of a
series of dimeric anthracenyldimethyl-derived ammonium salts
from Cinchona alkaloids, which have been employed as recoverable
organocatalysts in enantioselective transformations, such as asym-
metric alkylation12 and Michael addition13 reactions of glycinate
Non-organocatalytic enantioselective Michael reactions using
a-substituted b-keto esters leading to quaternary stereocenters
Schiff bases for the enantioselective synthesis of a-amino acids.
have been performed using metal-derived chiral catalysts,3a,5,6
although many of them suffer from typical drawbacks associated
with metal complexes, such as air and moisture sensitivity, thus
hampering large scale implementation. Thus, more convenient
metal-free organocatalytic procedures for the enantioselective
Michael addition of cyclic b-keto esters leading to quaternary
stereocenters have been based mainly on the use of the very pop-
ular Cinchona alkaloids7 as organocatalytic chiral tertiary bases.3,8,9
However, despite the fact that Cinchona alkaloid-derived ammo-
nium salts are frequently used as chiral organocatalysts, especially
when dealing with phase-transfer processes,7,10 they have scarcely
been used in this transformation. Quinine and cinchonidine-derived
ammonium salts have been used as organocatalysts in the
Recently, they have also been employed in the enantioselective
cyanoformylation of aldehydes.14 Herein, we report the use of
these dimeric ammonium salts as recoverable organocatalysts in
the conjugate addition of cyclic b-keto esters and related sub-
strates to Michael acceptors for the enantioselective generation
of quaternary stereocenters.16
2. Results and discussion
For the first screening reactions, we used the dimeric
cinchonidine-derived ammonium salt 1a12,13 as the organocatalyst
(5 mol %), 2-tert-butoxycarbonyl-1-indanone 3a as the model cyclic
b-keto ester, and methyl vinyl ketone (3 equiv) as the Michael
acceptor (Table 1). When diisopropylethylamine was used as the
base(30 mol %)anddichloromethaneasthesolventatroomtemper-
ature, the corresponding Michael reaction took place in excellent
⇑
Corresponding authors. Tel.: +34 96 5903728; fax: +34 96 5903549.
E-mail addresses: chinchilla@ua.es (R. Chinchilla), cnajera@ua.es (C. Nájera).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.016

S. Tarí et al. / Tetrahedron: Asymmetry 21 (2010) 2872–2878
2873
Table 1
Screening and optimization of the reaction conditions for the enantioselective Michael addition
O
O
COMe
CO2tBu
cat., base
CO2tBu
*
solvent, T
COMe
3a
4aa
Entry
Cat. (mol %)
Base
Solvent
T (°C)
t (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a (5)
1b (5)
1c (5)
1c (5)
1c (5)
1c (5)
1c (5)
1c (5)
1c (5)
1c (5)
1c (5)
1d (5)
1e (5)
2 (5)
iPr2EtN
iPr2EtN
iPr2EtN
Et3N
PhCO2K
K2CO3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe/CHCl3
PhMe/CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
25
25
25
25
25
25
25
0
À20
À40
À40
À40
À40
À40
8
9
9
16
45
2
94
85
98
98
98
85
72
67
70
59
98
75
98
98
87
36 (S)
5 (S)
52 (S)
36 (S)
16 (S)
32 (S)
26 (S)
21 (S)
50 (S)
64 (S)
68 (S)
33 (S)
2 (S)
K2CO3
2
PhCO2K
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
43
16
16
20
4
2
8
14
73 (R)
73 (R)
2 (1)
a
Determined by 1H NMR (300 MHz) using diphenylmethane as the internal standard.
The enantioselectivities and absolute stereochemistry were determined by chiral HPLC (see Section 4).
b
yield, but the corresponding adduct 4a was obtained as the (S)-enan-
tiomer in only 36% ee (Table 1, entry 1). The use of an O-allylated
cinchonidine-derived ammonium salt 1b12,13 led to a considerable
decrease in the enantioselectivity (Table 1, entry 2), but when the
O-free quinine-derived dimeric ammonium salt 1c16 was employed,
the enantioselectivity for (S)-4a increased up to 52% in excellent
chemical yield in 9 h reaction time (Table 1, entry 3).
tained (Table 1, entry 11). Decreasing the reaction temperature fur-
ther, did not improve the enantioselectivity, only giving rise to
much larger reaction times.
Changing the counteranion from a chloride 1c to a tetrafluoro-
borate 1d or hexafluorophosphate 1e16 in the quinine-derived
organocatalyst, something that was usually beneficial for enantio-
induction by strong ion-pair interactions using dimeric ammonium
salts,12b decreased the enantioselectivity for (S)-4aa (Table 1,
entries 12 and 13).
With the aim of obtaining an opposite enantioselection, we per-
formed this enantioselective Michael reaction using the quinidine-
derived dimeric ammonium salt 2, which can be considered a
pseudoenantiomer of the quinine-derived counterpart 1c.16 This
was confirmed by the isolation of the corresponding opposite
Michael adduct (R)-4aa in an excellent yield and with an even
higher enantioselection (73% ee) (Table 1, entry 14). We also ex-
plored the possibility of lowering the catalyst loading and per-
formed the reaction with only 1 mol % of 2, obtaining (R)-4aa
with the same enantioselectivity when using 5 mol %, although a
longer reaction time was required (Table 1, entry 15).
R1
2 X-
N
+
R1
N
OR2
+N
N
R2O
1a, R1 = H, R2 = H, X = Cl
1b, R1 = H, R2 = allyl, X = Br
, R1 = OMe, R2 = H, X = Cl
1c
1d
, R1 = OMe, R2 = H, X = BF4
1e, R1 = OMe, R2 = H, X = PF6
2 Cl-
OMe
Attempts to improve the enantioselectivity by changing the
base to triethylamine (Table 1, entry 4), potassium benzoate
(Table 1, entry 5) or potassium carbonate (Table 1, entry 6) in
dichloromethane as the solvent were unsuccessful, and lower
enantioselectivities for (S)-4aa were observed. Changing the sol-
vent from dichloromethane to a mixture of toluene/chloroform
(7:3 v/v), which is usually effective in enantioselective phase-
transfer reactions involving these dimeric ammonium salts,12
was not effective when potassium benzoate or potassium carbon-
ate was used as the base (Table 1, entries 7 and 8).
Lowering the reaction temperature was next explored. When
the quinine-derived ammonium salt 1c was used as the organocat-
alyst and diisopropylethylamine as the base in dichloromethane as
the solvent, a reaction temperature of 0 °C did not produce any
improvement in the enantioselectivity of the reaction compared
to when working at 25 °C (Table 1, compare entries 3 and 9). How-
ever, when the reaction temperature was lowered to À20 °C, the
Michael adduct (S)-4aa was obtained in 64% ee (Table 1, entry
10); when at À40 °C, 68% ee in excellent chemical yield was ob-
+
N
OMe
N
HO
N+
N
OH
2
With the most appropriate ammonium salt 2 and convenient
reaction conditions (diisopropylethylamine as base, dichlorometh-
ane as solvent, À40 °C reaction temperature) established, we pro-
ceeded to extend the procedure to other b-keto esters and other
Michael acceptors (Table 2). We decided to use the lowest amount
of organocatalyst (1 mol %) possible unless we observed too slow
reaction rates.
Changing the 2-tert-butyloxycarbonyl on 1-indanone 3 to a
2-methyloxycarbonyl group 3b gave (R)-4ba in excellent yield
in the reaction with methyl vinyl ketone, although with a lower

2874
S. Tarí et al. / Tetrahedron: Asymmetry 21 (2010) 2872–2878
Table 2
Enantioselective Michael addition reaction organocatalyzed by quinidine-derived dimeric ammonium salt 2a
Entry
Keto ester
No.
Olefin
2 (mol %)
t (d)
Product
No.
Yieldb (%)
eec (%)
73
O
O
O
O
CO2tBu
COMe
CO2tBu
CO2Me
CO2tBu
COMe
1
3a
1
0.6
(R)-4aa
87
O
O
CO2Me
COMe
2
3
4
3b
3a
1
1
1
1
(R)-4ba
(R)-4ab
(R)-4ac
98
98
86
51
77
79
CO2tBu
COEt
COEt
CHO
7
O
O
CO2tBu
CHO
0.2
CO2tBu
CO2Me
CO2Me
5
10
5
7
7
(R)-4ad
(R)-4ae
55
40
94
83
O
O
CO2tBu
6d
CO2Et
CO2Et
CO2tBu
7
8
5
5
3
3
(R)-4af
(R)-4ag
98
87
71
75
O
O
O
O
O
O
CO2tBu
S
S
O
O
CO2tBu
9d
10
11
10
1
6
(R)-4ah
(R)-4ca
(R)-4da
98
98
98
51
78
83
CN
CN
O
O
CO2tBu
CO2tBu
COMe
COMe
CHO
3c
4
Me
Me
COMe
CO2tBu
COMe
CO2tBu
CHO
O
O
O
CO2tBu
3d
5
3.5
MeO
MeO
MeO
12
5
2
7
(R)-4dc
(R)-4dd
98
68
85
82
13d
10

S. Tarí et al. / Tetrahedron: Asymmetry 21 (2010) 2872–2878
2875
Table 2 (continued)
Entry
Keto ester
No.
Olefin
2 (mol %)
t (d)
Product
No.
Yieldb (%)
eec (%)
O
O
CO2tBu
CO2Me
MeO
CO2Me
O
MeO
MeO
MeO
MeO
CO2tBu
CO2tBu
CO2tBu
CO2tBu
COMe
14
15
16
17
18
19
3e
3f
5
1
7
(R)-4ea
(R)-4fa
(R)-4ga
(S)-4ha
(R)-4ia
(R)-4id
92
98
98
98
98
27
81
66
68
45
70
40
COMe
O
O
O
O
CO2tBu
1
Cl
Cl
COMe
CO2tBu
COMe
3g
3h
3i
1
0.7
Br
O
Br
O
CO2Et
CO2Et
5
5
COMe
O
O
PhN
O
PhN
O
CO2tBu
COMe
CO2tBu
5
0.3
O
PhN
O
CO2tBu
CO2Me
CO2Me
10
7
a
b
c
Reaction conditions: catalyst 2 (5 mol %), iPr2EtN (30 mol %), CH2Cl2, À40 °C.
Determined by 1H NMR (300 MHz) using diphenylmethane as the internal standard.
The enantioselectivities and absolute stereochemistry were determined by chiral HPLC (see Section 4).
The reaction was performed at 25 °C.
d
enantioselection (51% ee) (Table 2, entry 2). Therefore, the tert-butyl
group was the alkyl group of choice in the 2-alkyloxycarbonyl-1-
indanones employed.
entry 10), whereas the 5-methoxy group on 3d with the same
acceptor gave a slightly higher enantioinduction for the corre-
sponding (R)-4da (83%). Other acceptors such as acrolein and
methyl acrylate gave similar enantioselectivities for the final
Michael adducts (R)-4dc and (R)-4dc when reacting with the
b-keto ester 3d (Table 2, entries 12 and 13). In addition, the use
of 5,6-dimethoxy-substituted indanone carboxylate 3e gave rise
to an 81% ee of the corresponding adduct (R)-4ea when reacting
with methyl vinyl ketone (Table 2, entry 14).
The influence of the presence of halogen atoms on the indanone
carboxylate 3 was also explored. Thus, 5-chloro- or 5-bromo-
substituted indanone carboxylates 3f and 3g, respectively, gave
rise to lower enantioselections for the corresponding adducts
(R)-4fa and (R)-4ga with methyl vinyl ketone than when elec-
tron-releasing groups were present (Table 2, entries 15 and 16).
The absence of an aryl group on the b-keto ester was shown to
lower the enantioinduction. Thus, when ethyl 3-methyl-2-oxocyc-
lopentanecarboxylate 3h was used as a nucleophile precursor in
the reaction with methyl vinyl ketone, the Michael adduct (S)-
4fa (same enantioinduction, with just CIP rules in effect) was ob-
tained in excellent 98% yield but in only 45% ee (Table 2, entry 17).
We also studied the performance of tert-butyl 2,5-dioxo-1-phe-
nylpyrrolidine-3-carboxylate 3i as a ‘related’ b-keto ester in this
enantioselective reaction. Thus, the Michael reaction of 3i with
The reaction of 2-tert-butoxycarbonyl-1-indanone 3a with
other Michael acceptors gave higher enantioselectivities of the cor-
responding Michael adducts. Thus, the ethyl vinyl ketone gave the
corresponding (R)-4ab in 77% ee (Table 2, entry 3), whereas the
more reactive acrolein gave adduct (R)-4ac in 79% ee (Table 2,
entry 4). The use of methyl acrylate as the Michael acceptor gave
an excellent enantioselection for (R)-4ad (94%), although it was
necessary to increase the amount of organocatalyst 2 to 10 mol % in
order to achieve a reasonable reaction rate (Table 2, entry 5). Other
acrylates employed, such as ethyl acrylate or naphthalen-1-yl acry-
late, afforded lower enantioselectivities for the corresponding
Michael adducts (R)-4ae and (R)-4af (83 and 71% ee, respectively)
(Table 2, entries 6 and 7). A thioacrylate, such as (S)-naphthalen-1-
yl prop-2-enethioate, was also used as a Michael acceptor, afford-
ing (R)-4ag in 75% ee (Table 2, entry 8). In the case of acrylonitrile,
(R)-4ah was obtained in 98% yield but with a moderate 51% ee
(Table 2, entry 9).
We also explored the use of substituted 2-tert-butoxycarbonyl-
1-indanones as nucleophile precursors. Thus, the use of indanone
3c bearing a 5-methyl group gave the corresponding adduct
(R)-4da in 78% ee when reacting with methyl vinyl ketone (Table 2,

2876
S. Tarí et al. / Tetrahedron: Asymmetry 21 (2010) 2872–2878
O
O
in the case of compound 4ha, it was assigned by the specific rotation
according to its positive sign.6b The absolute configurations of the
other adducts were assigned by analogy.
CO2tBu
DL-Pro (1 eq.)
DMF/H2O (1:1)
reflux, 4d
CO2tBu
COMe
4.2. Typical procedure for the enantioselective Michael reaction
5, 90%, 73% ee
(R)-4aa, 73% ee
Scheme 1.
To a stirred solution of 3a (232 mg, 1 mmol), methyl vinyl ke-
tone (250
lL, 3 mmol) and 2 (9 mg, 0.01 mmol) in CH2Cl2 (6 mL)
at À40 °C was added diisopropylethylamine (50
l
L, 0.3 mmol).
The mixture was stirred vigorously at the same temperature and
after completion (TLC), the solvent was evaporated (15 Torr). The
addition of diethyl ether (6 mL) allowed 2 to precipitate and was
recovered by filtration. The filtrate was diluted with water
(20 mL) and extracted with ethyl acetate (3 Â 5 mL). The combined
organics were dried with MgSO4, filtered, and evaporated in vacuo
(15 Torr) to afford 4aa.
methyl vinyl ketone gave the corresponding adduct (R)-4ia in
almost quantitative yield and in 70% ee. When methyl acrylate
was used as a Michael acceptor, (R)-4id was isolated in poor yield
and in 40% ee even when using 10 mol % of organocatalyst 2
(Table 2, entries 18 and 19).
It is noteworthy that the ammonium salt 2 can be recovered in
95% yield once the reaction is complete after the evaporation of the
dichloromethane, the addition of diethyl ether, and filtration of the
precipitate. The recovered ammonium salt was reused up to three
times in the model reaction (Table 2, entry 1), giving almost iden-
tical yields and enantioselectivities.
Analytical and spectroscopic data for adducts 4aa,ba,ad6a 4ab,9a
4ac,9b 4af,ag,9c and 4ha6b have been reported. Data for the other
obtained adducts follow.
The Michael adducts obtained can be employed in further
transformations. Thus, enantiomerically enriched Michael adduct
(R)-4aa was employed in an intramolecular aldol condensation
reaction promoted by DL-proline to obtain tetrahydro-1H-fluo-
rene-9a-carboxylate 5 in 90% yield and without observing any loss
of enantiointegrity being observed (Scheme 1). The use of inor-
ganic bases for this cyclization reaction resulted in partial or total
racemization.
4.2.1. (R)-tert-Butyl 2-(3-ethoxy-3-oxopropyl)-1-oxo-2,3-
dihydro-1H-indene-2-carboxylate 4ae
Pale yellow oil; IR (film):
m
1739, 1702, 1254, 1154 cmÀ1
;
1H
3
NMR: dH 7.76 (d, 3JH,H = 7.7 Hz, 1H, C(7)-H), 7.62 (td, JH,H = 7.7 Hz,
4JH,H = 1.1 Hz, 1H, C(5)-H), 7.47 (d, JH,H = 7.7 Hz, 1H, C(4)-H), 7.39
3
(t, 3JH,H = 7.7 Hz, 1H, C(6)-H), 4.10 (q, 3JH,H = 7.1 Hz, 2H, COOCH2CH3),
2
2
3.64 (d, JH,H = 17.2 Hz, 1H, C(3)-HA), 3.04 (d, JH,H = 17.4 Hz, 1H,
C(3)-HB), 2.50–2.14 (m, 4H, CH2CH2COOCH2CH3), 1.40 (s, 9H,
3
C(CH3)3), 1.23 (t, JH,H = 7.2 Hz, 3H, COOCH2CH3); 13C NMR: dC
202.3, 172.8, 169.8, 152.7, 135.2, 135.2, 127.7, 126.3, 124.7, 82.0,
60.4, 60.2, 37.2, 29.9, 29.6, 27.8, 14.1; MS (EI): m/z (%) 276
(M+ÀC4H8, 14), 131 (100); HRMS (EI): m/z calcd for C15H16O5
(M+ÀC4H8) 276.0998, found 276.1016; HPLC: Chiralcel AD, k =
210 nm, n-hexane/2-propanol, 95:5, 1.0 mL/min, tR (minor) = 11 .2
min, tR (major) = 12.4 min.
3. Conclusions
It can be concluded that quaternary stereocenters can be cre-
ated enantioselectively by a conjugate addition reaction between
cyclic b-keto esters, or related systems and Michael acceptors,
using Cinchona-derived dimeric ammonium species as chiral
organocatalysts. The corresponding quinine-derived ammonium
salt gave opposite enantioselectivity to that of its pseudoenantio-
mer from quinidine, which afforded the higher enantioselectivities.
These organocatalysts can be easily separated from the reaction
medium by precipitation from ether and filtration and reused
without a loss in activity.
4.2.2. (R)-tert-Butyl 2-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-
indene-2-carboxylate 4ah
Greenish oil; IR (film):
m 2248, 1734, 1712, 1284, 1254,
3
1154 cmÀ1
;
1H NMR: dH 7.78 (d, JH,H = 7.6 Hz, 1H, C(7)-H), 7.65
3
4
3
(td, JH,H = 7.8 Hz, JH,H = 1.1 Hz, 1H, C(5)-H), 7.50 (d, JH,H = 7.7 Hz,
1H, C(4)-H), 7.43 (t, JH,H = 7.2 Hz, 1H, C(6)-H), 3.65 (d,
3
2JH,H = 17.3 Hz, 1H, C(3)-HA), 3.11 (d, JH,H = 17.4 Hz, 1H, C(3)-HB),
2
4. Experimental
4.1. General
2.60–2.54 (m, 2H, CH2CH2CN), 2.35–2.25 (m, 2H, CH2CH2CN), 1.38
(s, 9H, C(CH3)3); 13C NMR: dC 201.6, 169.2, 152.4, 135.7, 134.8,
128.1, 126.4, 124.9, 119.3, 82.8, 59.7, 37.6, 30.2, 27.7, 13.1; MS
(EI): m/z (%) 229 (M+ÀC4H8, 56), 184 (100); HRMS (EI): m/z calcd
for C13H11NO3 (M+ÀC4H8) 229.0739, found 229.0740; HPLC: Chiral-
cel AD, k = 210 nm, n-hexane/2-propanol, 98:2, 1.0 mL/min, tR
(minor) = 17.0 min, tR (major) = 18.5 min.
All the reagents and solvents employed were of the best grade
available and were used without further purification. Melting
points are uncorrected. IR data were collected on a Nicolet Impact
400D-FT spectrometer. The 1H and 13C NMR spectra were recorded
at 25 °C on a Bruker AC-300 at 300 MHz and 75 MHz, respectively,
using CDCl3 as solvent and TMS as the internal standard. MS (EI,
70 eV) were performed on a HP MS-GC-5973A. HRMS analyses
were carried out on a Finnigan MAT 95S. Enantioselectivities were
determined by chiral HPLC using Chiralcel columns and n-hexane/
2-propanol mixtures as eluent. Reference racemic samples of ad-
ducts 4 were obtained by performing the enantioselective Michael
reaction in the absence of organocatalysts.
4.2.3. (R)-tert-Butyl 5-methyl-1-oxo-2-(3-oxobutyl)-2,3-
dihydro-1H-indene-2-carboxylate 4ca
Pale yellow oil; IR (film):
m
1733, 1712, 1155 cmÀ1; 1H NMR: dH
3
7.64 (d, JH,H = 7.8 Hz, 1H, C(7)-H), 7.26 (br s, 1H, C(4)-H), 7.20 (d,
3JH,H = 7.9 Hz, 1H, C(6)-H), 3.55 (d, JH,H = 17.3 Hz, 1H, C(3)-HA),
2
2
2.94 (d, JH,H = 17.3 Hz, 1H, C(3)-HB), 2.70–2.44 (m, 2H,
CH2CH2COCH3), 2.45 (s, 3H, C(5)-CH3), 2.23–2.12 (m, 2H,
CH2CH2COCH3), 2.12 (s, 3H, CH2CH2COCH3), 1.39 (s, 9H, C(CH3)3);
13C NMR: dC 207.8, 202.1, 170.2, 153.1, 146.5, 132.9, 129.0, 126.6,
124.4, 81.8, 60.0, 38.8, 37.6, 29.8, 28.3, 27.7, 22.0; MS (EI): m/z
(%) 260 (M+ÀC4H8, 27), 190 (100); HRMS (EI): m/z calcd for
Ammonium salts 1a,14b 1b,12a 1c-e16 and 216 have been prepared
followingreported procedures. Compounds 3a,17 3b,18 and 3c–i,17 as
well as the Michael acceptors naphthalen-1-yl acrylate19 and
(S)-naphthalen-1-yl prop-2-enethioate19 were prepared according
to the literature. The absolute configurations for the adducts 4aa,
ba,ad,6a 4ac9b and 4af,ag9c were determined according to the de-
scribed order of elution of their enantiomers in chiral HPLC, whereas
C
15H16O4 (M+ÀC4H8) 260.1049, found 260.1090; HPLC: Chiralcel
AD-H, k = 210 nm, n-hexane/2-propanol, 90:10, 1.0 mL/min, tR
(minor) = 10.7 min, tR (major) = 16.0 min.

S. Tarí et al. / Tetrahedron: Asymmetry 21 (2010) 2872–2878
2877
4.2.4. (R)-tert-Butyl 5-methoxy-1-oxo-2-(3-oxobutyl)-2,3-
dihydro-1H-indene-2-carboxylate 4da
CH2CH2COCH3), 1.39 (s, 9H, C(CH3)3); 13C NMR: dC = 207.4, 201.1,
169.6, 154.0, 141.7, 133.6, 128.5, 126.4, 125.6, 82.2, 60.0, 38.6,
37.4, 29.8, 28.2, 27.7; MS (EI): m/z (%) 280 (M+ÀC4H8, 28), 210
(100); HRMS (EI): m/z calcd for C14H13ClO4 (M+ÀC4H8) 280.0502,
found 280.0487; HPLC: Chiralcel AD-H, k = 210 nm, n-hexane/2-
propanol, 90:10, 1.0 mL/min, tR (minor) = 9.0 min, tR (major) =
12.2 min.
White solid; mp 93–95 °C; IR (KBr):
m 1731, 1717, 1697, 1267,
3
1155, 1107 cmÀ1
;
1H NMR: dH 7.68 (d, JH,H = 8.4 Hz, 1H, C(7)-H),
3
6.92 (d, JH,H = 8.4 Hz, 1H, C(6)-H), 6.90 (br s, 1H, C(4)-H), 3.90 (s,
2
3H, C(5)-OCH3), 3.56 (d, JH,H = 17.3 Hz, 1H, C(3)-HA), 2.94 (d,
2JH,H = 17.3 Hz, 1H, C(3)-HB), 2.69–2.43 (m, 2H, CH2CH2COCH3),
2.26–2.10 (m, 2H, CH2CH2COCH3), 2.13 (s, 3H, CH2CH2COCH3),
1.40 (s, 9H, C(CH3)3); 13C NMR: dC 207.7, 200.6, 170.3, 165.7,
155.6, 128.4, 126.2, 115.8, 109.3, 81.8, 60.1, 55.6, 38.8, 37.6, 29.8,
28.4, 27.7; MS (EI): m/z (%) 276 (M+ÀC4H8, 23), 56 (100); HRMS
4.2.9. (R)-tert-Butyl 5-bromo-1-oxo-2-(3-oxobutyl)-2,3-
dihydro-1H-indene-2-carboxylate 4ga
Greenish oil; IR (film):
m
1739, 1715, 1256, 1154 cmÀ1; 1H NMR:
3
(EI): m/z calcd for
276.0744; HPLC: Chiralcel AD-H, k = 210 nm, n-hexane/2-propanol,
80:20, 1.0 mL/min, tR (minor) = 7.9 min, tR (major) = 12.0 min.
C
15H16O5 (M+ÀC4H8) 276.0998, found
dH 7.65 (br s, 1H, C(4)-H), 7.61 (d, JH,H = 8.0 Hz, 1H, C(7)-H), 7.54
3
2
(d, JH,H = 8.0 Hz, 1H, C(6)-H), 3.59 (d, JH,H = 17.4 Hz, 1H, C(3)-HA),
2
2.99 (d, JH,H = 17.6 Hz, 1H, C(3)-HB), 2.70–2.45 (m, 2H,
CH2CH2COCH3), 2.29–2.11 (m, 2H, CH2CH2COCH3), 2.13 (s, 3H,
CH2CH2COCH3), 1.39 (s, 9H, C(CH3)3); 13C NMR: dC 207.2, 201.3,
169.5, 154.0, 134.0, 131.3, 130.5, 129.5, 125.7, 82.1, 60.0, 38.6,
37.4, 29.7, 28.1, 27.6; MS (EI): m/z (%) 324 (M+ÀC4H8, 26), 254
(100); HRMS (EI): m/z calcd for C14H13BrO4 (M+ÀC4H8) 323.9997,
found323.9978;HPLC:ChiralcelAD-H, k = 210 nm, n-hexane/2-pro-
panol, 90:10, 1.0 mL/min, tR (minor) = 9.2 min, tR (major) = 13.2 min.
4.2.5. (R)-tert-Butyl 5-methoxy-1-oxo-2-(3-oxopropyl)-2,3-
dihydro-1H-indene-2-carboxylate 4dc
Pale yellow oil; IR (film):
m
1725, 1699, 1256, 1148 cmÀ1
;
1H
3
NMR: dH 9.75 (s, 1H, CHO), 7.69 (d, JH,H = 8.4 Hz, 1H, C(7)-H),
3
6.93 (d, JH,H = 8.8 Hz, 1H, C(6)-H), 6.91 (br s, 1H, C(4)-H), 3.90 (s,
2
3H, C(5)-OCH3), 3.58 (d, JH,H = 17.4 Hz, 1H, C(3)-HA), 2.94 (d,
2JH,H = 17.2 Hz, 1H, C(3)-HB), 2.65–2.46 (m, 2H, CH2CH2CHO),
2.33–2.14 (m, 2H, CH2CH2CHO), 1.40 (s, 9H, C(CH3)3); 13C NMR:
dC 201.1, 200.4, 170.0, 165.7, 155.6, 128.2, 126.3, 115.8, 109.3,
81.9, 60.0, 55.6, 39.4, 37.4, 27.7, 26.6; MS (EI): m/z (%) 262
(M+ÀC4H8, 16), 162 (100); HRMS (EI): m/z calcd for C14H14O5
(M+ÀC4H8) 262.0841, found 262.1174; HPLC: Chiralcel AD-H,
k = 210 nm, n-hexane/2-propanol, 90:10, 1.0 mL/min, tR (minor) =
12.4 min, tR (major) = 21.9 min.
4.2.10. (R)-tert-Butyl 2,5-dioxo-3-(3-oxobutyl)-1-
phenylpyrrolidine-3-carboxylate 4ia
White solid; mp 128–129 °C; IR (KBr):
m 1735, 1714, 1389,
1372, 1197, 1151 cmÀ1 1H NMR: dH 7.51–7.47 (m, 2H, ArH),
;
7.43–7.40 (m, 1H, ArH), 7.28–7.26 (m, 2H, ArH), 3.17 (d,
2JH,H = 18.3 Hz, 1H, C(4)-HA), 2.89–2.81 (m, 1H, CH2CHAHBCOCH3),
2
2.76 (d, JH,H = 18.1 Hz, 1H, C(4)-HB), 2.62–2.54 (m, 1H, CH2CHAHB
COCH3), 2.34–2.30 (m, 2H, CH2CH2COCH3), 2.18 (s, 3H,
CH2CH2COCH3), 1.48 (s, 9H, C(CH3)3); 13C NMR: dC 207.0, 174.8,
173.8, 168.2, 131.6, 129.3, 128.9, 126.3, 83.7, 54.3, 39.5, 38.6,
30.0, 27.8, 27.4; MS (EI): m/z (%) 245 (M+ÀCO2C4H8, 7), 193
4.2.6. (R)-tert-Butyl 5-methoxy-2-(3-methoxy-3-oxopropyl)-1-
oxo-2,3-dihydro-1H-indene-2-carboxylate 4dd
Pale yellow solid; mp 97–99 °C; IR (KBr):
m
1740, 1726, 1597,
3
1268, 1152 cmÀ1
;
1H NMR: dH 7.68 (d, JH,H = 8.4 Hz, 1H, C(7)-H),
(100); HRMS (EI): m/z calcd for
C
14H15NO3 (M+ÀCO2C4H8)
6.94–6.90 (m, 2H, C(4)-H, C(6)-H), 3.89 (s, 3H, C(5)-OCH3), 3.65
245.1052, found 245.1059; HPLC: Chiralcel AS-H, k = 210 nm, n-
hexane/2-propanol, 95:5, 1.0 mL/min, tR (major) = 38.4 min, tR
(minor) = 43.5 min.
2
(s, 3H, COOCH3), 3.59 (d, JH,H = 17.3 Hz, 1H, C(3)-HA), 2.96 (d,
2JH,H = 17.3 Hz, 1H, C(3)-HB), 2.48–2.14 (m, 4H, CH2CH2COOCH3),
1.40 (s, 9H, C(CH3)3); 13C NMR: dH 200.2, 173.3, 169.9, 165.7,
155.7, 128.3, 126.3, 115.8, 109.3, 81.8, 60.4, 55.6, 51.6, 37.1, 29.6,
29.5, 27.7; MS (EI): m/z (%) 292 (M+ÀC4H8, 53), 175 (100); HRMS
(EI): m/z calcd for C15H16O6 (M+ÀC4H8) 292.0947, found
292.0945; HPLC: Chiralcel AD-H, k = 210 nm, n-hexane/2-propanol,
90:10, 1.0 mL/min, tR (minor) = 12.5 min, tR (major) = 19.7 min.
4.2.11. (R)-tert-Butyl 3-(3-methoxy-3-oxopropyl)-2,5-dioxo-1-
phenylpyrrolidine-3-carboxylate 4id
Colorless oil; IR (film):
m 1741, 1716, 1387, 1371, 1255, 1195,
1150 cmÀ1
;
1H NMR: dH 7.51–7.39 (m, 3H, ArH), 7.28–7.26 (m,
2
2H, ArH), 3.69 (s, 3H, COOCH3), 3.19 (d, JH,H = 18.2 Hz, 1H, C(4)-
2
HA), 2.79 (d, JH,H = 18.2 Hz, 1H, C(4)-HB), 2.69–2.56 (m, 1H,
4.2.7. (R)-tert-Butyl 5,6-dimethoxy-1-oxo-2-(3-oxobutyl)-2,3-
dihydro-1H-indene-2-carboxylate 4ea
CH2CHAHBCOOCH3), 2.50–2.36 (m, 3H, CH2CHAHBCOOCH3), 1.49
(s, 9H, C(CH3)3); 13C NMR: dC 174.5, 173.7, 172.7, 167.8, 131.6,
129.2, 128.8, 126.2, 83.8, 54.6, 51.9, 38.6, 29.3, 28.3, 27.7; MS
(EI): m/z (%) 261 (M+ÀCO2C4H8, 60), 188 (100); HRMS (EI): m/z
calcd for C14H15NO4 (M+ÀCO2C4H8) 261.1001, found 261.0966;
HPLC: Chiralcel AD-H, k = 210 nm, n-hexane/2-propanol, 95:5,
1.0 mL/min, tR (minor) = 22.3 min, tR (major) = 24.9 min.
Pale brown solid; mp 160–161 °C; IR (KBr):
m 1721, 1700, 1503,
1320, 1274, 1157 cmÀ1 1H NMR: dH 7.16 (s, 1H, C(7)-H), 6.89 (s,
;
1H, C(4)-H), 3.98 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.51 (d,
2
2JH,H = 17.0 Hz, 1H, C(3)-HA), 2.90 (d, JH,H = 17.0 Hz, 1H, C(3)-HB),
2.65–2.42 (m, 2H, CH2CH2COCH3), 2.26–2.13 (m, 2H,
CH2CH2COCH3), 2.13 (s, 3H, CH2CH2COCH3), 1.41 (s, 9H, C(CH3)3);
13C NMR: dC 207.7, 201.1, 170.3, 155.8, 149.6, 148.0, 127.8, 107.0,
104.7, 81.7, 60.1, 56.2, 55.9, 38.8, 37.4, 29.8, 28.3, 27.7; MS (EI):
m/z (%) 262 (M+ÀCO2C4H8, 45), 205 (100); HRMS (EI): m/z calcd
for C15H18O4 (M+ÀCO2C4H8) 262.1205, found 262.1202; HPLC: Chi-
ralcel AD-H, k = 210 nm, n-hexane/2-propanol, 90:10, 1.0 mL/min,
tR (minor) = 14.3 min, tR (major) = 25.6 min.
4.3. Experimental procedure for the intramolecular aldol
condensation
To a stirred solution of (R)-tert-butyl 1-oxo-2-(3-oxobutyl)-2,3-
dihydro-1H-indene-2-carboxylate (R)-4aa, (73% ee) (64 mg, 0.21
mmol) in a mixture of DMF/H2O (1:1) (1 mL) was added DL-proline
(24 mg, 0.21 mmol). The mixture was stirred vigorously at reflux
(100 °C) until the total consumption of the substrate (TLC, 4 days)
took place. The mixture was allowed to cool down at room temper-
ature and water (20 mL) was added. The mixture was extracted with
ethyl acetate (3 Â 5 mL). The combined organic layers were dried
over MgSO4, filtered, and evaporated in vacuo (15 Torr) to afford
the crude product, which was purified by crystallization from a
mixture of hexane/EtOAc.
4.2.8. (R)-tert-Butyl 5-chloro-1-oxo-2-(3-oxobutyl)-2,3-dihydro-
1H-indene-2-carboxylate 4fa
Dark green oil; IR (film): m
1735, 1708, 1599, 1253, 1150 cmÀ1; 1H
NMR: dH 7.69 (d, 3JH,H = 8.2 Hz, 1H, C(7)-H), 7.47 (br s, 1H, C(4)-H),
7.38 (d, 3JH,H = 8.5 Hz, 1H, C(6)-H), 3.59 (d, 2JH,H = 17.4 Hz, 1H, C(3)-
2
HA), 2.99 (d, JH,H = 17.5 Hz, 1H, C(3)-HB), 2.73–2.44 (m, 2H,
CH2CH2COCH3), 2.26–2.10 (m, 2H, CH2CH2COCH3), 2.14 (s, 3H,

2878
S. Tarí et al. / Tetrahedron: Asymmetry 21 (2010) 2872–2878
4. Review: Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969–
5994.
4.3.1. (R)-tert-Butyl 6-oxo-7,8,8a,9-tetrahydro-6H-fluorene-8a-
carboxylate 5
5. Review: Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688–1690.
6. Recent examples: (a) Nakajima, M.; Yamamoto, S.; Yamaguchi, Y.; Nakamura,
S.; Hashimoto, S. Tetrahedron 2003, 59, 7307–7313; (b) Kumaraswamy, G.;
Jena, N.; Sastry, M. N. V.; Padmaja, M.; Markondaiah, B. Adv. Synth. Catal.
2005, 347, 867–871; (c) Hamashima, Y.; Hotta, D.; Umebayashi, N.;
Tsuchiya, Y.; Suzuki, T.; Sodeoka, M. Adv. Synth. Catal. 2005, 347, 1576–
1586; (d) Ogawa, C.; Kizu, K.; Shimizu, H.; Takeuchi, M.; Kobayashi, S.
Chem. Asian J. 2006, 1–2, 121–124; (e) Furutachi, M.; Chen, Z.; Matsugana,
S.; Shibasaki, M. Molecules 2010, 15, 532–544; (f) Liu, Z.; Shi, M.
Organometallics 2010, 29, 2831–2834.
White solid; mp 80–82 °C; IR (KBr):
m
1721, 1659, 1145,
3
766 cmÀ1
;
1H NMR: dH 7.59 (d, JH,H = 7.3 Hz, 1H, C(4)-H), 7.39–
7.37 (m, 1H, C(2)-H), 7.33–7.30 (m, 2H, C(1)-H, C(3)-H), 6.35 (s, 1H,
C = CH), 3.49 (d, 2JH,H = 16.4 Hz, 1H, C(9)-HA), 3.00 (d, 2JH,H = 16.4 Hz,
1H, C(9)-HB), 2.77–2.70 (m, 1H, C(7)-HA), 2.60–2.53 (m, 2H, C(7)-HB,
C(8)-HA), 2.17–2.06 (m, 1H, C(8)-HB), 1.31 (s, 9H, C(CH3)3); 13C NMR:
dC 198.9, 172.2, 165.3, 145.9, 138.4, 131.7, 127.6, 125.2, 122.7, 118.5,
82.0, 55.2, 43.2, 35.2, 32.7, 27.7; MS (EI): m/z (%) 284 (M+, 3), 57
(100); HRMS (EI): m/z calcd for C18H20O3 (M+) 284.1412, found
284.1431; HPLC: Chiralcel AD-H, k = 210 nm, n-hexane/2-propanol,
97:3, 1 mL/min, tR (major) = 12.8 min, tR (minor) = 20.7 min.
7. Cinchona Alkaloids in Synthesis
& Catalysis; Song, C. E., Ed.; Wiley-VCH:
Weinheim, 2009.
8. (a) Wynberg, H.; Helder, R. Tetrahedron Lett. 1975, 4057–4060; (b) Hermann, K.;
Wynberg, H. J. Org. Chem. 1979, 44, 2238–2244; (c) Sera, A.; Takagi, K.;
Katayama, H.; Yamada, H. J. Org. Chem. 1988, 53, 1157–1161; (d) Szöllösi, G.;
Bartók, M. Chirality 2001, 13, 614–618.
9. (a) Wu, F.; Li, H.; Hong, R.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 947–950; (b)
Wu, F.; Hong, R.; Khan, J.; Liu, X.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 4301–
4305; (c) Rigby, C. L.; Dixon, D. J. Chem. Commun. 2008, 3798–3800.
10. Asymmetric Phase-transfer Catalysis; Maruoka, K., Ed.; Wiley-VCH: Weinheim,
2008.
11. Díez-Barra, E.; de la Hoz, A.; Merino, S.; Rodríguez, A.; Sánchez-Verdú, P.
Tetrahedron 1998, 54, 1835–1844.
12. (a) Chinchilla, R.; Mazón, P.; Nájera, C. Tetrahedron: Asymmetry 2002, 13, 927–
931; (b) Chinchilla, R.; Mazón, P.; Nájera, C.; Ortega, F. J. Tetrahedron:
Asymmetry 2004, 15, 2603–2607.
Acknowledgments
We are thankful for the financial support from the Spanish
Ministerio de Ciencia e Innovación (projects CTQ2007-62771/BQU
and Consolider Ingenio 2010, CSD2007-00006), the Generalitat
Valenciana (Prometeo/2009/039), FEDER and the University of
Alicante. S.T. thanks the Generalitat Valenciana for a pre-doctoral
fellowship.
13. Chinchilla, R.; Mazón, P.; Nájera, C.; Ortega, F. J.; Yus, M. ARKIVOC 2005, vi, 222–
232.
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268; (b) Chinchilla, R.; Nájera, C.; Ortega, F. J.; Tarí, S. Tetrahedron: Asymmetry
2009, 20, 2279–2286.
15. (a) Chinchilla, R.; Mazón, P.; Nájera, C. Tetrahedron: Asymmetry 2000, 11, 3277–
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Chinchilla, R.; Mazón, P.; Nájera, C. Adv. Synth. Catal. 2004, 346, 1186–1194.
16. Preliminary communication: Tarí, S.; Chinchilla, R.; Nájera, C. Tetrahedron:
Asymmetry 2009, 20, 2651–2654.
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10077.
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