Highly efficient ion-tagged catalyst for the enantioselective Michael addition of aldehydes to nitroalkenes

Article abstract of DOI:10.1002/adsc.200900599

The ion-tagged diphenylprolinol silyl ether 6 very efficiently catalyzes the asymmetric Michael addition of aliphatic aldehydes to nitroalkenes with ee of up to > 99.5% at low catalyst loadings (0.25-5 mol%) and using only a slight excess of aldehydes (1.2-2 equiv.). This new organocatalyst can be used with the same outstanding efficiency in a wide variety of solvents and reaction coditions.

Full text of DOI:10.1002/adsc.200900599

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DOI: 10.1002/adsc.200900599
Highly Efficient Ion-Tagged Catalyst for the Enantioselective
Michael Addition of Aldehydes to Nitroalkenes
Marco Lombardo,a,* Michel Chiarucci,a Arianna Quintavalla,a
and Claudio Trombinia
a
Dipartimento di Chimica “G. Ciamician”, Universitꢀ degli Studi di Bologna, via Selmi 2, 40126, Bologna, Italy
Fax : (+39)-051-209-9456; phone: (+39)-051-209-9513; e-mail: marco.lombardo@unibo.it
Received: August 31, 2009; Published online: November 10, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900599.
Abstract: The ion-tagged diphenylprolinol silyl
ether 6 very efficiently catalyzes the asymmetric
Michael addition of aliphatic aldehydes to nitroal-
kenes with ee of up to>99.5% at low catalyst load-
ings (0.25–5 mol%) and using only a slight excess of
aldehydes (1.2–2 equiv.). This new organocatalyst
can be used with the same outstanding efficiency in
a wide variety of solvents and reaction conditions.
Keywords: asymmetric organocatalysis; ion-tagged
diphenylprolinol; Michael addition; nitro com-
pounds; synthetic methods
Figure 1. Selected organocatalysts for the Michael additions
of aliphatic aldehydes to nitroalkenes.
Since the pioneering studies of Barbas on the organo- aldehydes to nitroalkenes using 1 mol% catalyst load-
catalytic asymmetric Michael addition of aliphatic al- ing and 3 equiv. of carbonyl compounds.[10]
dehydes to nitroalkenes,[1] many different catalysts
We recently showed that inserting an ion-tagged
and synthetic protocols have been developed and pro- side chain in the skeleton of known ligands and orga-
posed.[2–5] In particular, O-TMS-protected diphenyl- nocatalysts may result in the production of more effi-
ACTHNUTRGNEUNG
prolinol (1; TMS=trimethylsilyl),[6] pyrrolidinesulfon- cient catalytic species.[11] In particular, the ion-tagged
ACHTUNGTRENNUNG
amide 2 (Tf=trifluoromethanesulfonyl)[7] and trans-4- cis-hydroxyproline derivative 5 [NTf2 =bis(trifluoro-
hydroxyprolylamide 3[8] (Figure 1) act as effective or- methanesulfonyl)imide] (Figure 2) is one of the most
ganocatalysts for this class of reactions, affording efficient organocatalysts so far reported for the enan-
almost complete enantioselectivities.
tioselective cross-aldol reaction of ketones and alde-
The only drawback of the use of these organocata- hydes.[11c] Besides conferring to the molecule well-de-
lysts is the need to employ high catalyst loadings (5– fined solubility profiles, the ion-tagged side chain can
20 mol%) and large excesses of donor aldehydes (up actively participate in the stabilization of charged
to 10 equiv.) to achieve high conversions in reasona-
ble reaction times. This problem was recently ad-
dressed by Ma for long-chain water-insoluble alde-
hydes with a very efficient protocol using 0.5–2 mol%
of 1 and 1.5–2 equiv. of aldehydes, in water as the sol-
vent and in the presence of 5–20 mol% of benzoic
acid as additive.[9] Finally, the tripeptide H-d-Pro-Pro-
Asp-NH2 (4), recently proposed by Wennemers, is
able to efficiently catalyze the Michael additions of
Figure 2. Ion-tagged organocatalysts.
Adv. Synth. Catal. 2009, 351, 2801 – 2806
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Marco Lombardo et al.
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transition states,[12] thus resulting in a faster reac-
tion.[13]
Table 1. Solvent screening in the addition of propanal to
(E)-b-nitrostyrene catalysed by 6 (5 mol%).[a]
Here we wish to report that the ion-tagged organo-
catalyst 6, easily derived from N-benzyldiphenylproli-
nol 7,[14] is a highly efficient organocatalyst for the
enantioselective Michael addition of aldehydes to ni-
troalkenes, giving good yields and excellent enantiose-
lectivities at 1 mol% catalyst loading, using only a
small excess of donor aldehyde (1.2–2 equiv.) and in a
variety of solvents, ranging from water to typical or-
ganic solvents and ionic liquids.
Entry Solvent
t
Yield
ee
syn/
[min] [%][b]
[%][c] anti[d]
1
2
N
[NTf2][e] 15
95
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
85:15
85:15
84:16
72:28
88:12
86:14
80:20
77:23
84:16
85:15
82:18
85:15
84:16
92:8
G
95
96
96
94
97
98
99
98
97
96
99
99
98
97
98
3
4
5
CH2Cl2
CHCl3
H2O
15
15
15
30
30
45
45
45
45
45
90
90
90
90
The synthesis of 6 proceeded in high yields using
operationally simple procedures (Scheme 1).
6
neat
7
8
9
10
11
12
13
14
15
16
CH3CN
n-hexane
c-hexane
Et2O
THF
t-BuOMe
EtOAc
MeOH
EtOH
84:16
86:14
acetone
[a]
Reaction conditions: nitrostyrene (0.5 mmol), propanal
(5 mmol), 5 mol% 6, 0.5 mL of solvent, 258C for the
specified time.
[b]
[c]
Yield of isolated product.
The ee was determined by HPLC analysis (Chiralpak IC
column). The absolute configuration was assigned by
comparison of the optical rotation with that of the
known products.
Determined by HPLC on crude reaction mixture.
bmim=1-butyl-3-methyl imidazolium.
[d]
[e]
[f]
Scheme 1. Synthesis of ion-tagged catalyst 6.
bmpy=1-butyl-1-methyl pyrrolidinium.
The choice of Tf2N as counter-ion was dictated by
Excellent levels of reaction efficiency and enantio-
its stability towards hydrolysis, a property not shared selectivity were obtained in all conditions tested. In
by the commonly use BF4 or PF6 anions. The latter almost every case, decreasing the reaction tempera-
produce traces amounts of fluoride anions in the pres- ture from 258C to 08C had a negligible impact on
ence of water,[15] that catalyze the desilylation of 6.
enantioselectivity and only a small effect on the dia-
With organocatalyst 6 in our hands, we started test- stereomeric ratio, but the reaction times needed to
ing the simple addition of propanal to nitrostyrene as achieve complete conversion became notably longer
the model reaction in different solvents, using 5 mol% (entries 1, 3, 5 and 7).
catalyst loading in the presence of 10 equiv. of alde-
We were delighted to observe that catalyst loading
hyde (Table 1). The catalytic system displayed an out- can be decreased to 1 mol% in the presence of only
standing activity in all the solvents examined, but es- 1.2 equiv. of aldehyde to achieve a quantitative con-
pecially in ionic liquids (entries 1 and 2), in halogenat- version to the desired product in only 1.5 h (entry 8);
ed solvents (entries 3 and 4) and in water (entry 5), the same reaction was also scaled up to 5 mmol, main-
where reactions were complete after 15 min. More- taining the same level of efficiency and enantiocontrol
over, in all the solvents examined, enantioselectivities (entry 9). Decreasing the reaction temperature from
were invariably high (99% ee) and good diastereose- 258C to 08C had in this last case a beneficial effect
lectivities in favour of syn isomers were obtained. On both on enantioselectivity (>99% ee) and on diaste-
the basis of the results obtained in Table 1, we chose reoselectivity (syn/anti 93:7, entry 10). To confirm the
CH2Cl2 and water as benchmark solvents. Using efficiency of 6, we performed some more reactions
CH2Cl2 we optimized the reaction conditions in terms lowering further the catalyst loading (entries 11–13).
of catalyst loading and excess of aldehyde (Table 2).
In these cases, the presence of 10 equiv. of benzoic
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Highly Efficient Ion-Tagged Catalyst for the Enantioselective Michael Addition
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Table 2. Screening of reaction conditions in the addition of
propanal to (E)-b-nitrostyrene catalysed by 6 in CH2Cl2.[a]
Table 3. Addition of propanal to (E)-b-nitrostyrene cata-
lysed by 6 (1 mol%) in water, with and without benzoic
acid.[a]
Entry Propanal
[equiv.]
6
T
t
Yield ee
anti/
[mol%] [8C] [h] [%][b] [%][c] syn[d]
Entry Benzoic acid
[mol%]
t
Yield
ee
syn/
[h] [%][b]
[%][c] anti[d]
1
2
3
4
5
6
7
8
10
2
2
10
10
2
5
5
5
1
1
1
1
1
1
1
0.5
0.25
0.1
0
1.5 97
25 0.5 98
97
25 1.5 98
99
99
99
99
99
99
99
99
99
92:8
88:12
90:10
86:14
90:10
86:14
90:10
86:14
89:11
1
2
0
10
2
1
98
97
99
99
93:7
90:10
0
3
[a]
Reaction conditions: nitrostyrene (0.5 mmol), propanal
(1 mmol), 1 mol% 6, 1 mL of H2O, benzoic acid (0-
0.05 mmol), 258C for the specified time.
Yield of isolated product.
The ee was determined by HPLC analysis (Chiralpak IC
column).
0
25
0
8
1
4
96
98
94
2
[b]
[c]
1.2
1.2
1.2
2
2
2
25 1.5 98
25 1.5 97
0
25 1.5 99
25
25
9[e]
10
11[f,g]
12[f,g]
13[f,h]
6
99
>99 93:7
>99 95:5
>99.5 96:4
>99.5 96:4
[d]
Determined by HPLC on crude reaction mixture
4
6
88
35
[a]
Reaction conditions: nitrostyrene (0.5 mmol), propanal
(0.6–5 mmol), 0.1–5 mol% 6, 0.5 mL of CH2Cl2, 08C or
room temperature for the specified time.
Yield of isolated product.
The ee was determined by HPLC analysis (Chiralpak IC
column).
Determined by HPLC on crude reaction mixture.
The reaction was carried out on a 5 mmol scale.
Reaction with 10 equiv. of benzoic acid with respect to 6.
The reaction was carried out on a 1 mmol scale.
The reaction was carried out on a 2.5 mmol scale.
less reactive aliphatic nitroalkenes or longer chain al-
dehydes are used (entries 3–14). This behaviour can
be ascribed to the rapid solubility decrease of alde-
hydes in water when the molecular weight increases.
Indeed, at 208C the solubility of propanal in water is
much higher (22.9 mass%) compared to butanal
(7.44), 2-methylpropanal (5.62), 4-methylpentanal
(2.02) and pentanal (1.43).[16] These values possibly
represent the ability of aldehydes to generate with
water liquid-liquid biphasic systems, where faster re-
actions occur in a highly concentrated organic phase.
Second, when sterically hindered nitroalkenes or alde-
[b]
[c]
[d]
[e]
[f]
[g]
[h]
acid with respect to 6 allowed us to achieve good con- hydes are used (entries 3, 8, 12–14), the presence of
versions in reasonable reaction times.[9] Astonishing an acid additive is necessary to ensure high conver-
results were obtained when the catalyst was used at sions. Moreover, the use of water and addition of ben-
0.5 and 0.25 mol%, with excellent conversions and en- zoic acid generally afforded better enantio- and dia-
hanced selectivities after a few hours. When the cata- stereomeric ratios. Finally, an increased catalyst load-
lyst was used at 0.1 mol% a 35% yield was obtained ing was necessary for the less reactive aliphatic nitro-
after 6 h, with improved values of enantio- and diaste- alkene (entries 3, 8 and 12) and 2-methylpropanal
reoselectivity. These are, to the best of our knowl- (entry 14). This last reaction proved once more the
edge, the smallest catalyst loadings ever employed great efficiency of 6, since a quantitative yield of
successfully for this Michael reaction.
product was recovered after 22 h using 5 mol% of cat-
Finally, the model reaction was also examined using alyst and without the addition of benzoic acid. Albeit
water as the solvent (Table 3). With 1 mol% of 6 and with moderate enantioselectivity, these are to date the
2 equiv, of aldehyde a slower reaction occurred with mildest reaction conditions used for the synthesis of
respect to CH2Cl2, but the use of water slightly im- this Michael adduct.
proved the diastereomeric ratio. The reaction became
much faster in the presence of benzoic acid, while ion-tagged organocatalyst for the asymmetric Michael
maintaining a high level of stereoselectivity. addition of aldehydes to nitroalkenes, which displays
In summary, we have developed a new efficient
CH2Cl2 and H2O as solvents were selected also for remarkable features. Not only does it give excellent
expanding the scope of the reaction. As depicted in enantioselectivities and very good diastereoselectivi-
Table 4, excellent results were obtained for a wide ties in a wide range of reaction media, ranging from
range of aliphatic aldehydes and different substituted water to organic solvents, but it displays enhanced re-
nitroalkenes.
activity compared to the known organocatalysts re-
By inspection of Table 4, some general trends can ported for this Michael reaction, also when used at
be derived. First of all, CH2Cl2 is a much better sol- 0.25–1 mol% and in the presence of only a slight
vent compared to water for reactions of propanal excess of donor aldehyde (1.2–2 equiv.). Further stud-
with aromatic nitroalkenes (entries 1 and 2). On the ies to expand the catalyst scope and to elucidate reac-
other hand, water is a better reaction medium when tion mechanism are in progress.
Adv. Synth. Catal. 2009, 351, 2801 – 2806
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Marco Lombardo et al.
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Table 4. Scope of the Michael addition of aliphatic aldehydes to nitroalkenes catalysed by 6.[a]
Entry
Product
Reaction conditions
t [h]
Yield [%][b]
ee [%][c]
syn/anti[d]
A
C
1
4
97
98
99
99
86:14
92:8
1
A
C
1
4
96
96
99
99
87:13
91:9
2
A
B
C
24
22
24
28
66
89
98
99
99
78:22
89:11
78:22
3[e]
A
C
D
D[f]
A
C
5
4
2
3.5
8
94
90
94
84
92
86
>99
>99
>99.5
>99.5
99
87:13
92:8
94:6
93:7
90:10
95:5
4
4
>99
5
6
7
A
C
8
4
96
94
>99
>99
88:12
96:4
A
C
12
4
87
92
99
99
80:20
92:8
A
B
C
D
A
C
D
22
22
22
22
6
48
65
50
81
94
99
98
97
95
95
97
>99
>99.5
>99.5
90:10
85:15
89:11
79:21
85:15
95:5
8[e]
4
2
9
96:4
A
C
6
4
95
99
>99
>99.5
81:19
95:5
10
11
A
C
10
4
92
98
>99.5
>99.5
83:17
93:7
A
B
C
D
B
D
24
24
24
9
24
7
43
98
54
99
42
65
>99
>99.5
>99
>99.5
>99
>99
91:9
95:5
91:9
92:8
92:8
98:2
12[e]
13
A
C
53
22
49
99
58
76
–
–
14[g]
[a]
Reaction conditions: nitroalkene (0.25 mmol), aldehyde (0.5 mmol), 1 mol% 6 at room temperature for the specified
time. A: 0.25 mL of CH2Cl2; B: benzoic acid (0.025 mmol), 0.25 mL of CH2Cl2; C: 0.5 mL of H2O; D: benzoic acid
(0.025 mmol), 0.5 mL of H2O.
Yield of isolated product.
[b]
[c]
Determined by chiral HPLC analysis (Chiralpak IC column). The absolute configuration was assigned by comparison of
the optical rotation with that of the known products.
Determined by HPLC on crude reaction mixture.
2 mol% of 6.
The reaction was carried out on a 4-mmol scale using 1.2 equiv. of butanal.
5 mol% of 6.
[d]
[e]
[f]
[g]
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Highly Efficient Ion-Tagged Catalyst for the Enantioselective Michael Addition
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Experimental Section
Reaction in CH2Cl2 – Typical Procedure
The aldehyde (1.2–2 equiv.) was slowly added at 258C or at
08C to a solution of nitroalkene (0.25–5 mmol) and catalyst
6 (0.25–5 mol%) in CH2Cl2 (0.25–5 mL) in a screw-capped
vial and the reaction mixture was stirred at the desired tem-
perture until thin-layer chromatography (TLC) showed the
disappearance of the starting nitroalkene. The solvent was
evaporated at reduced pressure and the residue was purified
by flash chromatography on silica eluting with cyclohexane/
ethyl acetate, 9:1. The enantiometric excess was determined
on the crude reaction mixture by high-performance liquid
chromatography (HPLC) using a Chiralpak IC column.
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Reaction in H2O – Typical Procedure
The aldehyde (1.2–2 equiv.) was slowly added at room tem-
perature to a suspension of nitroalkene (0.25–4 mmol) and
catalyst 6 (1–5 mol%) in H2O (0.5–8 mL) in a screw-capped
vial and the reaction mixture was vigorously stirred at room
temperature until thin-layer chromatography (TLC) showed
the disappearance of the starting nitroalkene. The aqueous
phase was extracted with CH2Cl2, the combined organic
layers were dried (Na2SO4) and evaporated at reduced pres-
sure. The residue was further purified by flash chromatogra-
phy on silica eluting with cyclohexane/ethyl acetate 9:1. The
enantiometric excess was determined on the crude reaction
mixture by high-performance liquid chromatography
(HPLC) using a Chiralpak IC column.
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Acknowledgements
Financial support was provided by MIUR (Rome) and Uni-
versity of Bologna. “Fondazione del Monte di Bologna e
Ravenna” is gratefully acknowledged for its contribution.
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Adv. Synth. Catal. 2009, 351, 2801 – 2806
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Adv. Synth. Catal. 2009, 351, 2801 – 2806