Enantioselective Michael addition of malonate esters to nitroolefins organocatalyzed by diaryl-2-pyrrolidinemethanols

Article abstract of DOI:10.1016/j.tetasy.2006.02.024

Bis-(3,5-dimethylphenyl)((S)-pyrrolidin-2-yl)methanol, easily prepared from l-proline, was found to be an efficient bifunctional organocatalyst, amongst the different 2-pyrrolidinemethanols tested, for the enantioselective Michael addition of malonate est

Full text of DOI:10.1016/j.tetasy.2006.02.024

Tetrahedron: Asymmetry 17 (2006) 837–841
Enantioselective Michael addition of malonate esters to nitroolefins
organocatalyzed by diaryl-2-pyrrolidinemethanols
Alessandra Lattanzi*
`
Dipartimento di Chimica, Universita di Salerno, Via S. Allende, 84081 Baronissi, Salerno, Italy
Received 25 January 2006; accepted 24 February 2006
Available online 23 March 2006
Abstract—Bis-(3,5-dimethylphenyl)((S)-pyrrolidin-2-yl)methanol, easily prepared from L-proline, was found to be an efficient bifunc-
tional organocatalyst, amongst the different 2-pyrrolidinemethanols tested, for the enantioselective Michael addition of malonate esters
to nitroolefins. The products were isolated in good to high yields and with up to 56% ee.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
ate chiral molecular scaffold, which direct the approach of
the nucleophile onto the nitroolefin.
Among the enantioselective C–C bond-forming reactions,
the Michael addition of carbon nucleophiles to nitroalk-
enes has received great attention.1 The highly functional-
ized building blocks which are obtained, can be readily
transformed into a variety of important biologically active
compounds and pharmaceuticals, thanks to the ease of
transformation of the nitro group.2 Several asymmetric
metal-catalyzed protocols3 have been proposed for this
reaction and more recently, metal-free organocatalyzed
versions have been developed, which afforded the nitro
compounds in good to high enantioselectivities. Most of
the methodologies have been focused on the employment
of aldehydes and ketones as donors using L-proline deriva-
tives.4 The activation of the donors and control of asym-
metric induction most likely occur through the formation
of enamine intermediates.4,5 Important results have been
achieved with malonate esters and ketoesters when using
enantiomerically pure bifunctional organocatalysts based
on thioureas6 and chincona derivatives.7 This type of cata-
lyst activates carbon nucleophiles by the basic tertiary
amino group and the olefins through hydrogen bonding
interaction of the nitro group with the Brønsted acid func-
tionality of the promoter (thiourea or hydroxyl moieties).
The asymmetric induction achieved is related to the spatial
positions of the two functionalities, placed in an appropri-
We have recently reported the nucleophilic asymmetric
epoxidation of a,b-unsaturated ketones using (S)-diaryl-
2-pyrrolidinemethanols and t-butyl hydroperoxide as oxi-
dant.8 The epoxides have been isolated in high yield and
enantioselectivity (up to 94% ee). We proposed that the
amino alcohol played the role of a bifunctional catalyst
through deprotonation of the t-butyl hydroperoxide by
the amino group and activation of the enone via hydrogen
bonding between the hydroxyl group of the promoter and
the carbonyl oxygen atom. We envisaged that the double
activation mechanism could be further exploited in C–C
bond forming reaction such as the Michael addition of
carbon nucleophiles to nitroolefins using readily available
2-pyrrolidinemethanols. The secondary amine should
activate the malonate ester and the hydroxyl group the
nitroolefin, through hydrogen bonding interactions orien-
tating the reagents in close proximity (Fig. 1).
R
R
N
O
H
H
H
O
O
O
O
N
R1O
OR1
R2
Figure 1. Proposed bifunctional mode of action of 2-pyrrolidenemetha-
*
nols in Michael addition of malonates to nitroolefins.
Tel.: +39 089 965370; fax: +39 089 965296; e-mail: lattanzi@unisa.it
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.02.024

838
A. Lattanzi / Tetrahedron: Asymmetry 17 (2006) 837–841
2. Results and discussion
respect to 1a (entry 6). Electron-rich and sterically hindered
catalyst 1h was found to be the most active and the enantio-
selectivity significantly improved (entry 7). The impor-
tance of hydrogen bond donor capability on catalyst
activity was ascertained by performing the reaction using
compound 1i in which the hydroxyl group was removed
(entry 8). In this case, both the activity and the enantio-
selectivity dropped dramatically, which supported the
hypothesis of the bifunctional catalysis provided by 2-pyr-
rolidenemethanols. The reaction was carried out under sol-
vent-free conditions, using an excess of dimethyl malonate,
and although it proceeded faster, it furnished the product
in lower ee (entry 9). When using diethyl malonate as the
donor, a significant improvement in enantioselectivity
was observed (entry 10). With di-t-butyl malonate, almost
no product was recovered under the same conditions (entry
11).
Commercially available a,a-diphenyl-L-prolinol 1a was
first employed in the dimethyl malonate addition to
trans-b-nitrostyrene 3a at room temperature (Table 1).
We were pleased to observe that compound 1a promoted
the addition in different solvents.
Predictably, the enantioselectivity was markedly affected
by the nature of solvent. Polar, protic or coordinating media
(entries 1 and 2), which have a strong effect on hydrogen
bonding interactions, can destroy the templated structure,
made of catalyst, malonate and nitroolefin to afford a race-
mic product. In apolar solvents, the reaction showed a cer-
tain degree of enantiocontrol (entries 3–6) and in p-xylene
the (S)-product was obtained in moderate 39% ee (entry 6).
Under more concentrated conditions (entry 7), 4a was
recovered in better yield and slightly reduced ee.
To study the scope and limitations of the reaction, a vari-
ety of nitroolefins were screened using catalyst 1h and
diethyl malonate at room temperature in p-xylene (Table
3). When trans-b-nitrostyrene was reacted at lower temper-
ature of 4 °C (entry 2), the reaction rate decreased and the
asymmetric induction only improved slightly (compare
with entry 1). Nitroolefins, which had electron-donating
or electron-withdrawing groups on the phenyl ring (entries
3–5), were converted into the corresponding products in
high yields and comparable ees. A nitroolefin bearing the
1-naphthyl group furnished the best result (entry 6). The
less reactive heteroaromatic derivative furnished the prod-
uct in lower ee (entry 7). The alkyl substituted nitroolefin
proved to be unreactive (entry 8). Finally, when the a-
methyl dimethyl malonate was reacted with 3a, the product
was obtained in moderate yield and lower ee (entry 9).
Interestingly, the reaction of a-methyl ethyl acetoacetate
with 3a gave the adduct in high yield and appreciable
diastereoselectivity, although in a comparable level of ee
(entry 10).
Employing these conditions (Table 1, entry 7), commer-
cially or readily available amino alcohols from L-proline
(Fig. 2) were screened in the malonate addition to 3a
(Table 2).
L-Proline was found to be a completely inactive catalyst for
the addition reaction (entry 1). Simple prolinol 1c was
more active than 1a, but 4a was isolated in almost racemic
form (entry 2). Catalyst 1d having a tertiary amino group,
was considerably less reactive and the product was
obtained as the opposite enantiomer in low ee (entry 3).
Since catalyst 1a proved to be the most efficient in terms of
asymmetric induction, we then screened different aryl
substituted 2-pyrrolidinemethanols.9 Catalysts with elec-
tron-donating substituents on the phenyl ring 1e,f were
shown to be more active than 1a (entries 4 and 5)10 and
the enantioselectivity was only slightly reduced. More steri-
cally demanding 1g afforded a comparable result with
Table 1. Michael addition of dimethyl malonate to 3a using catalyst 1a in different solventsa
OH
Ph
Ph
N
H
O
Ph
1a
O
O
(30 mol%)
NO2
+
NO2
MeO
Ph
MeO
OMe
rt
CO2Me
2a
3a
4a
Entry
Solvent
Time (h)
Yield 4ab (%)
ee 4ac (%)
1
2
3
4
5
6
7d
THF
CH3OH
CHCl3
Hexane
Toluene
p-Xylene
p-Xylene
67
63
91
97
71
69
64
63
66
62
85
42
50
62
1
0
22
22
35
39
35
a Conditions: 0.2 mmol 3a, 0.06 mmol 1a, 0.32 mmol 2a, 340 lL solvent.
b Isolated products after flash chromatography.
c Determined by HPLC analysis using Chiralpak AD column. In all cases absolute configuration for the main enantiomer was found to be S.
d In this case 170 lL of solvent was used.

A. Lattanzi / Tetrahedron: Asymmetry 17 (2006) 837–841
839
t
-Bu
OMe
OH
t
-Bu
OH
OMe
CO2H
N
N
N
H
N
H
1f
OH
N
H
OH
H
Ph
1b
1c
1d
1e
Me
Me
Me
N
H
N
OH
N
H
OH
Me
H
1g
1i
1h
Figure 2. Structures of the catalysts used in this study.
Table 2. Michael addition of malonate esters to 3a using different catalysts under various conditions
O
Ph
1
(30 mol%)
O
O
NO2
RO
+
NO2
Ph
RO
OR
CO2R
rt, p-xylene
2
3a
4
Entry
1
2
Time (h)
Yield 4b (%)
ee 4c (%)
1
2
3
4
5
6
7
8
9d
10
11
1b
1ca
1d
1e
1f
R = Me 2a
R = Me 2a
R = Me 2a
R = Me 2a
R = Me 2a
R = Me 2a
R = Me 2a
R = Me 2a
R = Me 2a
R = Et 2b
78
65
96
71
73
52
71
90
48
68
70
<5
62
34
82
86
65
93
7
—
4(S)
7(R)
31(S)
32(S)
36(S)
44(S)
4(S)
20(S)
53(S)
—
1g
1h
1i
1h
1h
1h
97
60
<5
R = t-Bu 2c
a 20 mol % of catalyst was used.
b Isolated products after flash chromatography.
c Determined by HPLC analysis using Chiralpak AD column. The absolute configuration of the prevalent enantiomer was determined by comparison of
the HPLC retention times with those reported in the literature.3,4
d The reaction was carried out in the absence of a solvent using 10 equiv of 2a with respect to 3a.
It is worth noting that the level of asymmetric induction
observed in Table 3, although moderate, is encouraging
taking into account that it is achieved by using a structu-
rally simple chiral catalyst and most of all noncovalent
bonds are involved in the activation of the reagents by
the promoter.
line derivatives for C–C bond forming reactions.11 Hence,
this additional mode of activation can be employed in
asymmetric organocatalysis, apart from the well-known
strategies based on the formation of enamine or iminium
intermediates.12 We are currently investigating potentially
more efficient L-proline derived bifunctional organocata-
lysts and expanding their utility in other asymmetric
transformations.
3. Conclusion
In conclusion, we have reported a user-friendly organocat-
alytic methodology for the Michael addition of malonate
esters to b-aryl nitroolefins, which furnished the products
in good yield and moderate enantioselectivity. To the best
of our knowledge, the transformation is the first example of
enantioselective bifunctional catalysis mediated by L-pro-
4. Typical experimental procedure
To a solution of nitroolefin (0.2 mmol) and catalyst 1h
(0.06 mmol, 18.4 mg) in p-xylene (220 lL) at rt was added
2b (0.4 mmol, 60 lL). After completion of the reaction,
monitored by TLC, the crude reaction mixture was directly

840
A. Lattanzi / Tetrahedron: Asymmetry 17 (2006) 837–841
Table 3. Scope of the Michael addition of 2 to 3 using catalyst 1ha
O
R23
O
O
(30 mol%)
1h
NO2
R
NO2
+
R2
R3
R1
COR1
R
rt, p-xylene
R2
2
3
4
Entry
3
2
Time (h)
4
Yield 4%b
ee 4%c
1
2d
3
4
5
6
7
8
9
Ph
Ph
2b
114
144
125
88
92
90
119
190
167
93
b
b
c
d
e
f
88
60
75
96
95
97
77
<5
52
81
52(S)
56(S)
45(S)
52(S)
50(S)
54(nd)e
23(S)
—
2b
2b
2b
2b
2b
2b
2b
p-CH3–C6H4
p-F–C6H4
p-Br–C6H4
1-Naphthyl
2-Furyl
n-Pentyl
Ph
g
h
i
R = R1 = OMe, R2 = Me
R = Me, R1 = OEt, R2 = Me
21(S)
26(S,S)f,g
10
Ph
j
a Conditions: 0.2 mmol 3, 0.06 mmol 1h, 0.4 mmol 2, 220 lL solvent.
b Isolated products after flash chromatography.
c Determined by HPLC analysis using chiral columns. The absolute configuration of the prevalent enantiomer was determined by comparison of the
HPLC retention times or specific rotations with those reported in the literature.3,4
d The reaction was carried out at 4 °C.
e Not determined.
f The diastereoisomeric ratio of 70/30 for 4j was determined by 1H NMR analysis (400 MHz) of the crude reaction mixture.6b
g ee and absolute configuration for the prevalent enantiomer of the major diastereoisomer.
3, 3737; (c) Enders, D.; Seki, A. Synlett 2002, 26; (d) Andrey,
O.; Alexakis, A.; Belardinelli, G. Org. Lett. 2003, 5, 2559; (e)
Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III.
Org. Lett. 2004, 6, 2527; (f) Ishii, T.; Fujioka, S.; Sekiguchi,
Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558; (g) Cobb,
A. J. A.; Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem.
Commun. 2004, 1808; (h) Bentacort, J. M.; Sakthivel, K.;
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purified by flash column chromatography on silica gel elut-
ing with petroleum ether/ethyl acetate mixtures (98/2–90/
10) to give the final product 4. Spectroscopic and analytical
data of compounds 4 matched those reported in the
literature.3,4,6b
Acknowledgements
We acknowledge financial support from Ministero dell’-
`
Istruzione, Universita e Ricerca Scientifica (MIUR). We
thank the referees for useful suggestions, which helped to
improve the manuscript.
5. Blarer, S. J.; Seebach, D. Chem. Ber. 1983, 116, 2250.
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A. Lattanzi / Tetrahedron: Asymmetry 17 (2006) 837–841
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