Novel prolinamide-camphor-containing organocatalysts for direct asymmetric michael addition of unmodified aldehydes to nitroalkenes

Article abstract of DOI:10.1002/chem.200901254

A new prolinamide-derived organocatalysts 4a-c that contain a structural rigid bicyclic camphor scaffold were used for the first time in organocatalysis. The aldehyde was added to a mixture of catalyst 4b and the corresponding nitroalkene in CHCl₃

Full text of DOI:10.1002/chem.200901254

DOI: 10.1002/chem.200901254
Novel Prolinamide–Camphor-Containing Organocatalysts for Direct
Asymmetric Michael Addition of Unmodified Aldehydes to ACTHNUTRGENUGNN itroalkenes
Raju Jannapu Reddy, Hsuan-Hao Kuan, Tsai-Yung Chou, and Kwunmin Chen*[a]
The Michael reaction is generally regarded as one of the
most efficient, atom-economical and powerful carbon–
carbon bond-forming reactions in organic chemistry.[1] The
development of organocatalytic asymmetric Michael reac-
tions has been a significant research focus for several
years.[2] The direct asymmetric Michael addition of carbonyl
compounds with nitroalkenes to produce enantiomerically
enriched nitroalkanes has been described.[3,4] Among these
reactions, the Michael addition of unmodified aldehydes to
nitroalkenes is of particular interest because of the valuable
synthetic intermediates that are generated.[4] Betancort and
Barbas originally reported the organocatalytic asymmetric
Michael addition of unmodified aldehydes to nitroalkenes
with moderate to good enantioselectivities.[4a] Recently 3,3’-
bimorpholine derivatives,[4b] a chiral primary amine/thiourea
catalyst[4c] and l-prolinol[4d] organocatalysts have been devel-
oped for the Michael addition of aldehydes to nitroolefins.
Highly diastereo- and enantioselective conjugate additions
that involve aldehydes were independently reported by the
research groups of Wang,[4e] Hayashi,[4f] and Palomo[4g] using
pyrrolidine sulfonamide (1), diphenylprolinol silyl ether (2)
and trans-4-hydroxyprolylamide (3) respectively. However,
some of these reactions required a large excess of donor
source (up to 10 equiv of aldehyde) and high catalyst load-
ings (between 10 and 20 mol%). Despite the excellent re-
sults achieved from previous studies, the development of an
efficient organocatalyst for direct asymmetric Michael addi-
tion of aldehydes to various aryl- and alkylnitroalkenes with
low catalyst loading remains challenging in asymmetric syn-
thesis.
tention in recent years. Organocatalysts are usually highly
efficient and selective, stable under aerobic and aqueous re-
action conditions, nontoxic, environmentally friendly, and
thus highly desirable as catalysts/catalytic systems.[5,6] In
light of this, we have recently developed a series of cam-
phor-based pyrrolidinyl organocatalysts that have proven
their efficacy as catalysts in asymmetric synthesis.[7] In con-
tinuation of our research interest in organocatalysis, we de-
signed and synthesized a new prolinamide–camphor organo-
catalysts and have shown it to be efficient catalysts for
direct asymmetric Michael reaction. Herein, we wish to
report an excellent diastereo- and enantioselective direct
Michael addition of aldehydes with nitroalkenes catalyzed
by bifunctional organocatalysts 4a–c. The desired Michael
products were obtained with high chemical yields (up to
94%) and excellent stereoselectivities (up to 99:1 d.r. and
>99% ee) with 5 mol% of organocatalyst 4b.
In asymmetric organocatalysis there is a strong demand
for the design and synthesis of highly stereoselective, readily
accessible, and tunable catalysts. The synthesis of novel pro-
linamide–camphor organocatalysts 4a–c begins with the
Boc-protected l-proline and trans-4-hydroxy l-proline.
Treatment of Boc l-proline and trans-4-hydroxy l-proline
The metal-free, small, privileged organic molecules that
catalyze enantioselective reactions have attracted much at-
[a] Dr. R. J. Reddy, H.-H. Kuan, T.-Y. Chou, Prof. K. Chen
Department of Chemistry
with 1-amino-7,7-dimethylbicycloACTHNUTRGNEUNG
[2.2.1]heptan-2-one (5)[8]
National Taiwan Normal University
Taipei 116 (Taiwan)
Fax : (+886)2-29324249
under standard coupling conditions (ethyl chloroformate
and Et3N in CHCl3) to give the corresponding amides (6a
and 6b) in 85 and 88% isolated yields, respectively
(Scheme 1). Sodium borohydride reduction of 6a and 6b to
E-mail: kchen@ntnu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901254.
9294
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Chem. Eur. J. 2009, 15, 9294 – 9298

COMMUNICATION
Table 1. Optimization of enantioselective Michael addition of propion-
AHCTUNGTRENNUNG
aldehyde to trans-b-nitrostyrene catalyzed by 4a–c.[a]
4a–c
solvent or
T
t
Yield[b] d.r.[c] ee[d]
A
[oC] [h] [%]
[%]
78:22 80
93:7 36
61:39 76
90:10 91
1
2
3
4
5
6
7
8
9
4a (20)
4a (20)
4a (20)
4b (20)
4b (20)
4b (20)
4b (20)
4b (20)
4b (20)
CHCl3
MeOH
hexanes
CHCl3
MeOH
hexanes
toluene
neat
RT 48 85
RT 36 94
RT 48 76
RT 24 89
RT 12 97
RT 24 92
RT 24 94
RT 12 94
RT 12 92
RT 24 89
92:8
66
Scheme 1. Synthesis of prolinamide–camphor organocatalysts 4a–c.
77:23 69
87:13 89
88:12 71
brine
water
92:8
70
provide the corresponding exo-alcohols 7a and 7b as a
single diastereomer, which was treated with trifluoroacetic
acid (TFA) in CH2Cl2 to generate the desired organocata-
lysts 4a and 4b without incident.
10 4b (20)
11 4a (20)
12 4b (20)
13 4b (10)
14 4b (5)
15 4b (2)
16 4c (20)
17 4b (10)
18 4b (5)
19 4b (10)
73:27 74
76:24 76
CHCl3/MeOH (9:1) RT 36 87
CHCl3/MeOH (9:1) RT 12 92
CHCl3/MeOH (9:1) RT 15 92
CHCl3/MeOH (9:1) RT 24 90
CHCl3/MeOH (9:1) RT 48 78
CHCl3/MeOH (9:1) RT 72 80
CHCl3/MeOH (9:1)
CHCl3/MeOH (9:1)
CHCl3/MeOH (9:1) À20 72 30
91:9
93:7
94:6
95:5
90
92
92
90
On the other hand, the trans-4-hydroxy group in 6b (R=
OH) was protected as its TBDPS ether derivative, and sub-
sequent NaBH4 reduction to give the corresponding exo-al-
cohol 7c. The exo-alcohol (7c) was treated with TFA in
CH2Cl2 to yield organocatalyst 4c. The synthetic route is
quite straightforward and can be easily scaled up to gram
quantities (2.0 g). The structures of organocatalysts 4a–c
85:15 77
0
0
48 92
96 85
95:5
95:5
96:4
94
93
90
[a] Unless otherwise specified, all reactions were carried out using pro-
pionaldehyde (0.6 mmol), trans-b-nitrostyrene (0.2 mmol) and 5-
20 mol% catalysts 4a–c in the solvent (0.2 mL) indicated. [b] Isolated
yield. [c] Determined by 1H NMR and HPLC analysis. [d] ee of the syn
product was determined by chiral HPLC analysis (see Supporting Infor-
mation).
1
were fully characterized by IR, H, and 13C NMR spectros-
copy and HRMS, and the absolute stereochemistry of orga-
nocatalysts 4a and 4b were further confirmed by single-crys-
tal X-ray analyses (see the Supporting Information).[9]
The Michael reaction of propionaldehyde and trans-b-ni-
trostyrene was selected as model substrates in the presence
of catalytic quantities of organocatalysts 4a–c. We initially
focused on solvent effects in the Michael reactions at ambi-
ent temperature. Organocatalyst 4a was first examined and
led to high reactivities and good stereoselectivities in CHCl3
(Table 1, entry 1). High chemical yield (94%) and diastereo-
selectivity (93:7), but poor enantioselectivity (36% ee) was
observed in MeOH catalyzed by 4a (Table 1, entry 2). A
modest result was achieved when the reaction was per-
formed in hexanes (Table 1, entry 3). Substantial improve-
ment in stereoselectivity (91% ee) was observed when the
reaction was carried out in CHCl3 and catalyzed by 4b at
ambient temperature (Table 1, entry 4). Although the reac-
tivity was improved, unsatisfactory stereoselectivity was ob-
served when the reaction was carried out with very polar
protic solvents (Table 1, entry 5). The desired Michael prod-
uct 8a was obtained with high chemical yields and moderate
enantioselectivties in hexanes and toluene (Table 1, entries 6
and 7). The progress of the reaction was fast under solvent-
free conditions and good diastereo- and enantioselectivities
were observed (Table 1, entry 8). When we performed the
reaction in brine using organocatalyst 4b to generate 8a,
high chemical yield (92%) was achieved with high syn-dia-
stereoselectivity, but only 70% ee (Table 1, entry 9). Reason-
ably, good results were achieved when H2O was used as the
reaction medium (Table 1, entry 10). Reactivity was dramat-
ically improved and high levels of stereoselectivity evolved
when 20 mol% of catalysts 4b was used in solvent system
CHCl3/MeOH (9:1) (Table 1, entry 12). Lowering the con-
centration of 4b to 10 mol% resulted in slightly improved
selectivity (Table 1, entry 13). To our surprise, the 5 mol%
catalyst loading also efficiently catalysed the Michael reac-
tion in a variety of solvent systems, such as CHCl3/MeOH,
CHCl3/IPA, CHCl3/EtOH, and CH2Cl2/MeOH.[10] However,
the best results were achieved in CHCl3/MeOH (9:1) to
afford the desired product with excellent stereoselectivity
(syn/anti ratio 94:6 and 92% ee; Table 1, entry 14). Al-
though the stereoselectivity retained, the reactivity dropped
significantly when 2 mol% catalyst was used (Table 1,
entry 15). Interestingly, the reactivity and stereoselectivity
significantly decreased when we performed the reaction
with 20 mol% of organocatalyst 4c (Table 1, entry 16). The
diastereo- and enantioselectivities were improved when the
reaction was carried out at 08C with 10 mol% of organoca-
talyst 4b (Table 1, entry 17). The rate of the reaction de-
creased in the presence of 5 mol% catalyst 4b at 08C with
the same level of stereoselectivity (Table 1, entry 18). The
reactivity dropped significantly when the reaction was car-
ried out at À208C with retention of stereoselectivity
(Table 1, entry 19). As indicated from Table 1, both catalysts
4a and 4c performed poorly in the reaction between pro-
AHCTUNGTREGpNNUN ionaldehyde and trans-b-nitrostyrene (Table 1, entries 11
and 16 vs. entry 14), indicating that the hydroxyl group in
4b must play some role in determining the stereochemical
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K. Chen et al.
Table 2. Enantioselective Michael addition of propionaldehyde to trans-
b-nitroalkene catalyzed by 4b.[a]
outcomes of the reaction. Similar phenomena have been
previously observed.[4g]
Encouraged by these results, we further optimized cataly-
sis conditions in the presence of 5 mol% of various acid ad-
ditives. No significant improvement was achieved in either
reactivity or selectivity in the presence of various organic
acids (benzoic acid, acetic acid, 3,5-dinitrobenzoic acid, and
TFA). The protonation of the amine catalyst may subse-
quently hinder the enamine formation. To verify this, orga-
nocatalyst 4b was treated with TFA in CHCl3. Upon slow
evaporation of CHCl3, it was clearly demonstrated that or-
ganocatalyst 4b had crystallized as a TFA salt. The chemical
structure of this salt was established by single-crystal data
analysis (see Supporting Information).[9] The absolute con-
figuration of the resulted adduct was determined by compar-
ison of the value of the optical rotation with that of previ-
ously described[4a,e–g,m] and was found to be (R,S). It is worth
mentioning that three equivalents of propionaldehyde was
used as a donor for b-nitrostyrene in this catalytical process.
With the optimal reaction conditions realized, we further
proceeded to examine a variety of nitroalkenes reacting
with propionaldehyde to establish the general utility of this
asymmetric transformation (Table 2). All reactions were per-
formed in a CHCl3/MeOH (9:1) solvent system in the pres-
ence of 5 to 10 mol% of catalyst 4b either at ambient tem-
perature or at 08C. Various aromatic substituted nitroal-
kenes reacted well with propionaldehyde donor to give the
desired Michael products (8a–i) with 75–92% yields and
high to excellent diastereo- and enantioselectivities (Table 2,
entries 1–9). In the case of heteroaromatic nitroalkenes, the
corresponding Michael adducts (8j and 8k) were obtained
with high to excellent diastereo- and enantioselectivities
(Table 2, entries 10 and 11). The aliphatic nitroalkene was
also an excellent Michael acceptor for this catalytic system.
Treatment of (4-nitro-but-3-enyl)benzene and 4-methyl-1-
nitro-pent-1-ene with propanal under the optimum reaction
conditions to give the desired products (8l and 8m) with ex-
cellent stereoselectivities (Table 2, entries 12 and 13). In ad-
dition to propionaldehyde, other linear aldehydes, such as
butyraldehyde and valeraldehyde, or branched aldehydes,
such as isovaleraldehyde, can be employed successfully as
the Michael donors with trans-b-nitrostyrene to give the Mi-
chael adducts (8n–p; Table 3, entries 1–3). These donors
were then used to react with both electron-rich and elec-
tron-deficient nitroalkenes. To our satisfaction, these reac-
tions proceeded smoothly and the desired Michael products
(8q–v) were obtained with high levels of chemical yields
(80–90%) and stereoselectivities (Table 3, entries 4–9). The
heteroaromatic Michael acceptor reacted smoothly with iso-
valeraldehyde to provide the 8w with reasonable good
chemical yield and stereoselectivity (Table 3, entry 10). In-
terestingly, the alkyl-substituted nitroalkenes, such as, (4-
nitro-but-3-enyl)benzene and 4-methyl-1-nitro-pent-1-ene,
are also excellent Michael acceptors to give the desired Mi-
chael products (8x and 8y) in moderate yields with high ste-
reoselectivities (Table 3, entries 11 and 12). Unfortunately,
the acetaldehyde reacts sluggishly with trans-b-nitrostyrene
Product
Cat. 4b
T
t
Yield[b] d.r.[c]
ee[d]
[%]
A
1
2
3
4
5
6
7
5
10
RT
0
1.0 90
2.0 92
94:6
95:5
92
94
5
10
RT
0
2.0 84
3.0 88
96:4
98:2
94
96
5
10
RT
0
1.0 92
1.5 89
93:7
95:5
90
89
5
10
RT
0
2.0 89
2.5 88
95:5
95:5
94
96
5
10
RT
0
1.5 83
2.5 88
83:17
91:9
90
97
5
10
RT
0
2.5 89
5.0 83
93:7
95:5
90
96
5
10
RT
0
1.5 80
2.5 75
93:7
97:3
91
94
8
9
5
10
RT
0
2.0 89
4.0 84
92:8
98:2
94
96
5
10
RT
0
2.0 82
3.0 76
93:7
97:3
94
96
10
5
10
RT
0
2.0 80
4.0 74
97:3
98:2
98
>99
11
5
10
RT
0
2.0 89
3.0 94
90:10
91:9
94
97
12
13
10
10
0
0
4.0 64
4.0 46
99:1
95
99
89:11
[a] Unless otherwise specified, all reactions were carried out using pro-
pionaldehyde (0.6 mmol), nitroalkenes (0.2 mmol) and 5 or 10 mol% cat-
alyst 4b in CHCl3/MeOH. [b] Isolated yield. [c] syn/anti ratio was deter-
1
mined by H NMR and HPLC analysis. [d] ee of the syn product was de-
termined by chiral HPLC analysis (see: Supporting Information).
in the presence of organocatalyst 4b under the optimum re-
action condition. Only trace amount of desired Michael
product formation was observed by the crude 1H NMR anal-
ysis.
The utility of this approach is illustrated in the reaction of
propionaldehyde with b-nitrostyrene on a 10 mmol scale,
which produced 8a with an 85% isolated yield and high
level of diastereo- and enantioselectivity (syn/anti 88:12;
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Asymmetric Organocatalysis
COMMUNICATION
Table 3. Enantioselective Michael addition of unmodified aldehydes to
nitroalkenes catalyzed by 4b.[a]
Product
Cat. 4b
T
t
Yield[b] d.r.[c] ee[d]
A
[%]
[%]
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
10
0
4.0 86
5.0 78
3.5 85
4.0 84
3.5 82
5.0 88
3.0 90
5.0 80
5.0 84
98:2
99:1
91:9
97:3
93:7
98:2
95:5
99:1
95:5
96
0
91
84
93
93
92
90
89
87
RT
0
Scheme 2. Synthesis of triazole derivative (10) from Michael adduct 8a.
chemistry and find various applications in both material sci-
ence and pharmaceutical research.[12]
Though further studies are needed to elucidate the mech-
anism of the Michael addition, the reaction is believed to
proceed through an enamine process and the stereochemical
induction can be explained as follows. The bifunctional or-
ganocatalyst (4b) pyrrolidine moiety reacts with the un-
modified aldehyde to form nucleophilic enamine and the 4-
hydroxy functionality activated
0
0
RT
0
the nitro group through hydro-
gen bonding to organize a fa-
vourable transition model (Fig-
ure 1).[4f,g] The neighboring rigid
0
bicyclic camphor structural
scaffold can serve as an effi-
cient stereocontrolling element.
Approach of the nitro olefin
Figure 1. Proposed transition-
state model for the Michael re-
10
11
12
10
10
10
RT
0
5.0 76
5.0 60
5.0 42
93:7
95:5
99:1
79
96
89
action catalyzed by 4b.
from the less-hindered si face
of the enamine would produce
the observed stereochemistry.
In summary, new prolinamide-derived organocatalysts
4a–c that contain a structural rigid bicyclic camphor scaffold
were used for the first time in organocatalysis. We have
demonstrated a practical application of organocatalysts 4a–c
in the Michael addition of aldehydes with nitroalkenes to
generate corresponding products with high chemical yields
and high to excellent levels of diastereo- and enantioselec-
tivities. This represents an attractive alternative method of
organocatalytic asymmetric Michael addition. Further stud-
ies of the catalysts used in organocatalysis are currently un-
derway.
0
[a] Unless otherwise specified, all reactions were carried out using vari-
ous aldehydes (0.6 mmol), nitroalkenes (0.2 mmol) and 10 mol% catalyst
4b in CHCl3/MeOH. [b] Isolated yield. [c] syn/anti ratio was determined
by 1H NMR and HPLC analysis. [d] ee of the syn product was determined
by chiral HPLC analysis (see: Supporting Information).
91% ee; Scheme 2). As shown in Scheme 2, the Michael
product 8a was converted into corresponding d-nitro alcohol
followed by tosylation with TsCl in the presence of pyridine.
The tosylated product 9 was treated with sodium azide and
subsequent “click” chemistry[11] in the presence copper-cata-
lyzed cycloaddition to afford enantiomerically enriched tria-
zole derivative (10). The stereochemistry of the 1,4-triazole
derivative was retained during the reaction process. The tri-
Experimental Section
General procedure for the asymmetric Michael reaction: The aldehyde
(0.6 mmol) was added to a mixture of catalyst 4b (2.7 mg, 0.01 mmol)
and the corresponding nitroalkene (0.2 mmol) in CHCl3/MeOH (9:1,
0.2 mL). The reaction mixture was stirred at either ambient temperature
or 08C for the requisite times as indicated in Tables 1–3. After the nitro-
alkene was consumed, as seen by TLC analysis, the reaction mixture was
subject to flash column chromatography on silica gel (ethyl acetate/hex-
ACHTUNGTRENNUNGazole derivatives are important building blocks in medicinal
Chem. Eur. J. 2009, 15, 9294 – 9298
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9297

K. Chen et al.
anes=1:5) to give a pure Michael product. The enantiomeric excess of
Michael products was determined by chiral HPLC analysis. (2R, 3S)-2-
Methyl-4-nitro-3-phenyl-butanal (8a): The enantiomeric purity was deter-
mined by using Chiralcel OD-H (iPrOH/hexanes, 10:90, flow rate
1.0 mLminÀ1, l=254 nm); tR =31.7 min (minor); tR =46.7 min (major).
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Acknowledgements
We thank the National Science Council of the Republic of China (NSC
96-2113M-003-005-MY3) for financial support of this work. Our gratitude
extends to the Academic Paper Editing Clinic at NTNU, and to the Na-
tional Center for High-Performance Computing for providing us with
computer time and facilities.
[5] For selected reviews on organocatalysis, see: a) B. List, Tetrahedron
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[6] Special issues on organocatalysis, see: a) Chem. Rev. 2007, 107;
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[7] a) Z.-H. Tzeng, H.-Y. Chen, C.-T. Huang, K. Chen, Tetrahedron
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Keywords: asymmetric catalysis
addition · nitroalkenes · organocatalysis · triazoles
· camphor · Michael
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[10] Further optimization of the Michael reaction at room temperature
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CH2Cl2/MeOH (9:1): 95:5 d.r.; 89% ee (36 h, 86% yield); CHCl3/
IPA (9:1): 91:9 d.r.; 92% ee (36 h, 82% yield); CHCl3/EtOH (9:1):
80:20 d.r.; 92% ee (36 h, 78% yield); CHCl3/MeOH (8:2):
89:11 d.r.; 86% ee (24 h, 88% yield); CHCl3/MeOH (1:1): 96:4 d.r.;
82% ee (24 h, 88% yield).
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Received: May 12, 2009
Published online: August 13, 2009
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