Polymer-supported enantioselective bifunctional catalysts for nitro-Michael addition of ketones and aldehydes

Article abstract of DOI:10.1002/chem.201102474

Introduction of an L-amino acid as a spacer and a urea-forming moiety in a polymer-supported bifunctional urea-primary amine catalyst, based on (1R, 2R)-(+)-1,2-diphenylethylenediamine, significantly improves the catalyst's activity and stereoselectivity in the asymmetric addition of ketones and aldehydes to nitroolefins. Yields and enantioselectivities, unprecedented for immobilized catalysts, were obtained with such challenging donors as acetone, cyclopentanone, and α,α-disubstituted aldehydes, which usually perform inadequately in this reaction (particularly when a secondary-amine-based catalyst is used). Remarkably, though in the examined catalysts the D-amino acids as spacers were significantly inferior to the L isomers, for the chosen configuration of the diamine (match-mismatch pairs) the size of the side chain of the amino acid hardly influenced the enantioselectivity of the catalyst. These results, combined with the reactivity profile of the catalysts with substrates bearing two electron-withdrawing groups and the behavior of the catalysts' analogues based on tertiary (rather than primary) amine, suggest an enamine-involving addition mechanism and a particular ordered C-C bond-forming transition state as being responsible for the catalytic reactions with high enantioselectivity. Copyright

Full text of DOI:10.1002/chem.201102474

DOI: 10.1002/chem.201102474
Polymer-Supported Enantioselective Bifunctional Catalysts for Nitro-
Michael Addition of Ketones and Aldehydes
Lital Tuchman-Shukron,[a] Scott J. Miller,[b] and Moshe Portnoy*[a]
Abstract: Introduction of an l-amino
acid as a spacer and a urea-forming
moiety in a polymer-supported bifunc-
tional urea–primary amine catalyst,
based on (1R, 2R)-(+)-1,2-diphenyl-
ally perform inadequately in this reac-
tion (particularly when a secondary-
amine-based catalyst is used). Remark-
ably, though in the examined catalysts
the d-amino acids as spacers were sig-
nificantly inferior to the l isomers, for
the chosen configuration of the di-
of the side chain of the amino acid
hardly influenced the enantioselectivity
of the catalyst. These results, combined
with the reactivity profile of the cata-
lysts with substrates bearing two elec-
tron-withdrawing groups and the be-
havior of the catalystsꢀ analogues based
on tertiary (rather than primary)
amine, suggest an enamine-involving
addition mechanism and a particular
ACHTUNGTRENNUNGethylenediamine, significantly improves
the catalystꢀs activity and stereoselec-
tivity in the asymmetric addition of ke-
tones and aldehydes to nitroolefins.
Yields and enantioselectivities, unpre-
cedented for immobilized catalysts,
were obtained with such challenging
donors as acetone, cyclopentanone, and
a,a-disubstituted aldehydes, which usu-
AHCTUNGTRENNUNG
·
À
ordered C C bond-forming transition
bifunctional catalysis · immobiliza-
tion · nitro-Michael addition · orga-
nocatalysis
state as being responsible for the cata-
lytic reactions with high enantioselec-
tivity.
Introduction
homogeneous catalytic systems, whereas only a few reports
describing catalysts immobilized on insoluble supports have
been published recently.[4] In the overwhelming majority of
the reports, which deal with soluble as well as insoluble cat-
alysts, the benchmark test reaction was that of cyclohexa-
none with b-nitrostyrene.[5] Outstanding yields and stereose-
lectivities are usually reported for this process, but changing
the nucleophilic substrate from cyclohexanone to an acyclic
ketone (e.g., acetone), sterically hindered ketone or alde-
hyde (e.g., isobutyraldehyde), or even to cyclopentanone
frequently brings a dramatic decline in the catalyst perform-
ance.[4a–g,5b–d,6] Accordingly, we focused our study of support-
ed organocatalysis of the nitro-Michael addition on the
model reaction between acetone and b-nitrostyrene, and re-
cently communicated our preliminary findings (Scheme 1)
describing a polystyrene-supported bifunctional aminocarba-
mate catalyst 1.[7]
The revival of interest in enantioselective catalysis by small
metal-free organic molecules (organocatalysts) has led to a
reality wherein tens of new organocatalysts are designed
and prepared each year. Although many new single-step
and cascade organocatalyzed reactions are reported annual-
ly, some of the “textbook” organic processes are particularly
suitable for testing new amine-based catalytic systems. Thus,
the Michael addition of ketones and aldehydes to nitroole-
fins has emerged during the past 5 years into one of the
“litmus test” reactions for new organocatalysts.[1,2] Among
the numerous asymmetric carbon–carbon bond-forming re-
actions, this addition constitutes an important and powerful
tool for the introduction of chirality and represents a con-
venient access to g-nitro carbonyl compounds, useful inter-
mediates en route to valuable building blocks.[3] Mostly,
enantioselective nitro-Michael addition was explored with
Herein, we report the extension of these studies to other
substrates, as well as elaboration of the catalyst design to a
more active and stereoselective variant—an improvement
that was achieved through the introduction of a second
chiral center in a remote position.
[a] L. Tuchman-Shukron, Prof. Dr. M. Portnoy
School of Chemistry
Raymond and Beverly Sackler Faculty of Exact Sciences
Tel Aviv University
Tel Aviv 69978 (Israel)
Fax : (+972)3-6409293
E-mail: portnoy@post.tau.ac.il
[b] Prof. Dr. S. J. Miller
Department of Chemistry
Yale University
225 Prospect Street, New Haven, CT 06520-8107 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102474.
Scheme 1. Nitro-Michael addition reaction promoted by catalyst 1.
2290
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2290 – 2296

FULL PAPER
Results and Discussion
ability of peptides and peptidomimetics to promote enantio-
selective catalysis,[10] as well as by the structure of some of
the highly selective homogeneous thiourea catalysts for the
nitro-Michael addition developed by Tsogoeva et al. and Ja-
cobsen et al.,[8a–c,11] we decided to introduce an amino acid
spacer between the catalyst and the Wang linker of the sup-
port, thus transposing an aminocarbamate catalyst into an
amino-urea catalyst (Scheme 2). Through this design, we
hoped to achieve a cooperative enhancement of the stereo-
selectivity. Remarkably, the incorporation of l-
We recently reported that the bifunctional catalyst 1 incor-
porating a carbamate and primary amine functions, synthe-
sized on a solid support by using a chiral diphenylethylene-
diamine building block, promotes the reaction of acetone
and nitroolefins (Scheme 1) with appreciable enantioselec-
tivity, unmatched by heterogeneous catalysts known at that
time (Table 1, entries 1–3).[7]
Table 1. Asymmetric nitro-Michael addition of ketones to nitroolefins.[a]
valine, as described in Scheme 2, led to catalyst 2
which displayed an enhanced activity and stereo-
selectivity in the reaction of ketones with nitro-
AHCTUNGTREGUNoNN lefins. Thus, the enantiomeric excess (ee) in the
reactions of acetone reached 91–97%, with a con-
current sharp increase in the reaction yield
(Table 1, compare entries 1 and 2 with 8 and 11,
respectively). With benzoic acid as a co-catalyst,
the time required for the quantitative addition of
acetone to nitrostyrene could be reduced to 48 h,
whereas without acid a slightly lower yield was
obtained (Table 1, entries 9 and 10). For cyclic ke-
tones, the yields were also substantially improved,
and for the adducts derived from cyclopentanone,
the ee value of the minor isomer was notably im-
proved, whereas the high ee value of the major
isomer was preserved (Table 1, compare entries 4
and 5 with 12 and 13, respectively). Notably, the
NMR analysis of the crude filtrates of the reac-
tion mixture demonstrated that the presence of
the benzoic acid additive did not lead to any de-
tectable cleavage of the catalyst 2 from the Wang
support during the course of the reaction.
Entry Catalyst Ar
R1, R2
Additive
Yield d.r.
ee
[%][b] (syn/anti)[c] [%][d]
AHCTUNGTERNNUNG
1
2
3
4
5
6
1
1
1
1
1
1
Ph
2-furanyl
2,4-Cl2C6H3 CH3,
Ph
Ph
Ph
CH3,
CH3,
H
H
H
PhCO2H
PhCO2H
PhCO2H
60
30
73
52
82
–
–
–
83
92[e]
82
-(CH2)4- PhCO2H
-(CH2)3- PhCO2H
1.2:1
4:1
–
73, 93
97, 62[e]
81
CH3,
H
(S)-2-phenyl- 52
propionic acid
7
1
Ph
CH3,
H
(R)-2-phenyl- 61
propionic acid
PhCO2H
PhCO2H
–
–
80
8
2
2
2
2
2
2
Ph
Ph
Ph
2-furanyl
Ph
CH3,
CH3,
CH3,
CH3,
H
H
H
H
99
99
89
99
82
99
–
–
–
–
91
91
91
9[f]
10[f]
11
12
13
PhCO2H
97[e]
86, 92
96, 88[e]
-(CH2)4- PhCO2H
-(CH2)3- PhCO2H
2.6:1
4:1
Ph
[a] Reaction conditions: nitroolefin (0.25 mmol), ketone (1.25 mmol), additive
(0.05 mmol),catalyst (0.075 mmol), solvent (2 mL); 4 days, RT. [b] Determined by
NMR spectroscopy. [c] Diastereomeric ratio. [d] Enantiomeric excess (ee) was deter-
mined by HPLC with a Chiralcel OJ column. [e] ee value was determined by HPLC
with a Chiralpak AD column. [f] Reaction time 2 days.
The catalysts 1 and 2 were also tested in the
nitro-Michael addition of aldehydes and nitroole-
This enantioselectivity was, however, still inferior to that
of the best homogeneous systems.[8] Moreover, only a mod-
erate yield could be reached with this catalytic system, even
with prolonged reaction times and with benzoic acid as a co-
catalyst. By using the same catalytic systems cyclic ketones
could be added to nitroolefins (Table 1, entries 4 and 5), but
again with moderate to good yields (although one of the
diastereomers in this case was formed with a very high
enantioselectivity). Surprisingly, the results obtained with cy-
clopentanone were notably better than those with cyclohex-
anone, although frequently the opposite tendency is observ-
ed.[4e–g,5b,c,6b–h,9]
Seeking to improve the reaction outcome, we tried to sub-
stitute the achiral benzoic acid by a chiral carboxylic acid
co-catalyst (Table 1, entries 6 and 7). Although a minor mis-
match effect on the activity was observed for the (S)-2-phe-
nylpropionic acid, the enantioselectivity with both isomers
of the catalyst was practically unchanged.
Our preliminary study implied that the introduction of a
short linear spacer between the polymer core and the cata-
lytic unit improves the reactivity of the catalyst, with only a
minor impairment of its stereoselectivity. Inspired by the
Scheme 2. Synthesis of amino acid-linked catalysts. Reagents and condi-
tions: a) Fmoc-d/l-AA-OH, DIC, DMAP, DMF, RT, 6 h; b) piperidine/
DMF (2:8), RT, 2–3 min; c) p-nitrophenylchloroformate, DIPEA, THF,
RT, 2 h; d) (1R,2R)-(+)-1,2-diphenylethylenediamine, DMF, 508C, 24 h.
Fmoc=9-fluorenylmethoxycarbonyl, AA=amino acid, DIC=diisopro-
pylcarbodiimide, DMAP=4-dimethylaminopyridine, DIPEA=N,N-diiso-
propylethylamine.
Chem. Eur. J. 2012, 18, 2290 – 2296
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2291

M. Portnoy et al.
fins (Table 2).[12] The reaction exhibited a very good chemo-
selectivity, producing the conjugate addition product only,
without formation of the homoaldol or other byproducts in
any substantial amount. In the reactions of the a-branched
Table 3. Influence of the side chains of different amino acids on the
asymmetric nitro-Michael addition of acetone to trans-b-nitrostyrene.[a]
Table 2. Asymmetric nitro-Michael addition of aldehydes to nitro-
ACHTUNGTRENNUNG
olefins.[a]
Entry
Catalyst
R
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
3
4
2
5
CH3
CH2Ph
87
92
99
99
37
62
89
89
91
91
89
CH
(CH3)3
CH3
CH(CH3)2
A
CR
3-d[b]
2-d[b]
6
80[e]
77[e]
86
Entry Catalyst Ar
R1, R2
Yield d.r.
ee
AHCTUNGTRENNUNG
[%][b]
ACHTUNGTRENNUNG
H
1
2
3
4
5
6
7
8
1
2
1
2
1
2
1
2
1
2
1
2
Ph
Ph
Me, Me
Me, Me
60
70
84
93
12
42
32
57
–
–
–
–
–
–
–
–
99
99
99
99
[a] Reaction conditions: nitroolefins (0.25 mmol), acetone (1.25 mmol),
PhCO2H (0.05 mmol), catalyst (0.075 mmol), solvent (2 mL); 4 days, RT.
[b] Isomer d of the amino acid. [c] Determined by NMR spectroscopy.
[d] ee value was determined by HPLC with a Chiralcel OJ column.
[e] The opposite enantiomer is predominantly formed.
2-furanyl Me, Me
2-furanyl Me, Me
Ph
T
12[d]
55[d]
99[d]
99[d]
82[d,f]
81[d,f]
40[e,f]
38[e,f]
Ph
E
2-furanyl
2-furanyl
Ph
Ph
Ph
E
E
amino acid chiral center led, however, to catalysts with re-
duced enantioselectivity and significantly reduced yield
(Table 3, entries 5 and 6). The catalyst 6 based on Gly still
exhibits a reasonable yield and only a slightly reduced selec-
tivity. In all cases, the configuration of the favored stereoiso-
mer of the adduct was dictated by the chiral centers of the
diamine component, rather than by that of the amino acid.
The intriguing dependence of the catalyst selectivity on
the configuration of the a-carbon of the amino acid, but not
on the steric size of its side chain, must be a consequence of
the reaction mechanism and particularly the transition state.
A number of experiments conducted in our group, though
less impressive than the aforementioned reactions in terms
of enantioselectivity, may shed light on the mechanism of
the addition of ketones and aldehydes to nitroolefins with
our catalytic systems.
Thus, pronucleophiles stabilized by two electron-with-
drawing functionalities can be divided into two groups,
based on their reactivity towards nitroolefins promoted by 1
or 2 (Table 4). Substrates including the ketone group (i.e.,
acetylacetone and acetoacetates; Table 4, entries 1–4) react
with moderate to excellent yields, while exhibiting apprecia-
ble enantioselectivity.[13] On the other hand, pronucleophiles
lacking the ketone (i.e., malonates; Table 4, entries 5 and 6)
exhibited low reactivity toward nitroolefins when our cata-
lytic systems were applied, and formed racemic or almost
racemic products.
9
G
3:1
10
11
12
T
99:1
2:1
2:1
Me, H
Me, H
47
71
Ph
[a] Reaction conditions: nitroolefins (0.25 mmol), aldehyde (0.5 mmol),
PhCO2H (0.05 mmol), catalyst (0.075 mmol), solvent (2 mL); 4 days, RT.
[b] Determined by NMR spectroscopy. [c] ee value was determined by
HPLC with a Chiralcel OD column. [d] ee value was determined by
HPLC with a Chiralpak AD column. [e] ee was determined by HPLC
with a Chiralcel OJ column. [f] ee value for major diastereomer.
isobutyraldehyde and cyclohexylcarboxaldehyde the yields
were notably better for catalyst 2, and in most cases near-
perfect enantioselectivity was demonstrated. In the case of
cyclohexylcarboxaldehyde and b-nitrostyrene, the surprising-
ly low enantioselectivity reached by catalyst 1 was markedly
improved for catalyst 2. Replacement of catalyst 1 by 2 also
led to a slight yield and substantial diastereoselectivity im-
provement in the reaction of the b-branched isovaleralde-
hyde, while the enantioselectivity was preserved. Improve-
ment in yield along with the preservation of diastereo- and
enantioselectivity was also observed for the comparison of 2
and 1 in the reaction of a linear propionaldehyde. Notably,
it seems that, in aldehydes, substitution at the a position
does not lead, by itself, to a reduced reactivity in the reac-
tion, whereas substitution at the b-carbon atoms has a
strong inhibiting effect on the reaction.
We prepared a series of analogues of catalyst 2 to assess
the importance of the second chiral center in the molecule
and the influence of the adjacent substituents (the side
chain of the amino acid). Remarkably, in the reaction of ni-
trostyrene with acetone all l-amino acid-based catalysts ex-
hibited similar enantioselectivity (ca. 90% ee, Table 3, en-
tries 1–4), whereas only a moderate influence of the steric
size of the amino acid side chain on the yield is notable.
Thus, the yield achieved under the indicated conditions in-
creases from 87% for 3 based on l-Ala to >99% for 5
based on l-Tle. The inversion of the stereochemistry at the
Our results, in combination with a vast array of data
found in the literature, provide a number of insights into the
design of organocatalysts for different variants of the nitro-
Michael addition and into the mechanism of the catalysis.
The substantial activity of the catalysts with ketone- or alde-
hyde-containing nucleophiles, versus the low efficiency of
catalysis and lack of enantioselectivity with such substrates
as dimethyl malonate, point to the enamine-involving mech-
anism of activation of the nucleophile in the case of the
former substrates (Scheme 3). In the case of the malonate
and similar highly activated pronucleophiles, the deprotona-
2292
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2290 – 2296

Bifunctional Catalysts for Nitro-Michael Addition
FULL PAPER
Table 4. Asymmetric nitro-Michael addition of nucleophiles with two
electron-withdrawing groups to nitroolefins.[a]
Entry
Catalyst
R1
R2, R3
Yield
[%][b]
d.r.
ee
[%][c]
1
2
2
2
2
1
2
Ph
Ph
Ph
Ph
Ph
Ph
CH3CO, CH3CO
CH3CO, CH3CO
CH3CO, CO2CH3
CH3CO, CO2C2H5
CO2CH3, CO2CH3
CO2CH3, CO2CH3
25
79
99
99
15
14
–
–
63[e]
47[e]
nd
nd
rac
27
2[d]
3
1:1
1:1.2
–
4
5
6
–
[a] Reaction
conditions:
nitroolefins
(0.25 mmol),
nucleophile
(1.25 mmol), PhCO2H (0.05 mmol), catalyst (30 mol%), solvent (2 mL);
4 days, RT. [b] Determined by NMR spectroscopy. [c] ee value was deter-
mined by HPLC with a Chiralcel OJ column. [d] Reaction temperature
758C. [e] ee value was determined by HPLC with a Chiralpak AD
column. nd=not determined.
Scheme 4. Deprotonation-based mechanism.
AHCTUNGTREGaNNUN mine (Scheme 5). These new catalysts 7 and 8 promoted
the nitro-Michael addition of dimethyl malonate to nitro-
Scheme 5. Synthesis of urea–tertiary amine catalysts. Reagents and condi-
tions: a) Fmoc-Val-OH, DIC, DMAP, DMF, RT, 6 h; b) piperidine/DMF
(2:8), RT, 2–3 min; c) p-nitrophenylchloroformate, DIPEA, THF, RT,
2 h; d) (S)-(À)-3-aminoquinuclidine·2HCl, DIPEA, DMF, 508C, 24 h.
Scheme 3. Enamine-based mechanism.
tion-based mechanism may be active (Scheme 4), but it
must be inefficient due to the relatively low basicity of the
primary amine. The somewhat reduced ee value in the case
of diketones and ketoesters, as compared to simple ketones,
may originate from both mechanistic pathways being active,
whereas the deprotonation-based mechanism acts as a “non-
selective bypass”.
The above explanation is further strengthened by the ex-
perimental results that we obtained with the analogues of
catalysts 1 and 2 that incorporate tertiary rather than pri-
mary amine. These catalysts were prepared by a synthesis
similar to that of 1 and 2, but using the chiral building block
of 3-aminoquinuclidine rather than 1,2-diphenylethylenedi-
styrene with the lack of any enantioselectivity, but with
yields that are substantially higher than those achieved with
1 or 2 (presumably because the tertiary quinuclidine amine
is much more basic than the primary amine in 1 or 2). Al-
though similarly designed catalysts (thiourea-based as well
as urea-based) reported by Takemoto et al. performed the
addition of malonates and b-ketoesters to nitroolefins with
high enantioselectivity,[14] presumably through a deprotona-
tion-involving mechanism, this did not happen with our
polymer-supported catalysts.
Since the enamine-based mechanism of the addition of
ketones seems highly likely in the case of catalyst 2 and re-
lated catalysts incorporating other l-amino acids, we consid-
Chem. Eur. J. 2012, 18, 2290 – 2296
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2293

M. Portnoy et al.
er the transition state depicted in Figure 1 as “responsible”
for the lack of influence of the steric size of the amino acid
side chain on the enantioselectivity of the reaction (at least
dary amines, primarily pyrrolidine (e.g., proline and prolinol
derivatives). Along with the excellent results (in terms of
yield, and diastereo- and enantioselectivity) that many of
these systems exhibited in the addition of six-membered
cyclic ketones or linear aldehydes to nitroolefins,[17–19] the
outcome in the case of five-membered cyclic ketones, acyclic
ketones, and a-branched sterically hindered aldehydes was
less impressive.[20–24]
On the other hand, the catalytic systems based on primary
amines, though significantly less abundant and explored,
induce outstanding reactivity and enantioselectivity in the
case of the sterically hindered aldehyde addition to nitroole-
fins.[11,12e,25] Moreover, the only systems capable of inducing
higher than 90% ee in the acetone addition to nitroolefins
are those few based on primary amines.[8b–e,26] The use of pri-
mary amine-derived catalysts in the reaction of cyclopenta-
none with nitroolefins, though entirely unexplored,[27] can
lead to a very good catalytic outcome, as revealed by our re-
sults.
Moreover, the results of our current study demonstrate
that the differences between the catalytic systems based on
secondary versus primary amines are even more pronounced
and significant in heterogeneous catalysis of the nitro-Mi-
chael reaction. Thus, although for the reaction of nitrostyr-
ene with a “classical” cyclohexanone substrate the previous-
ly reported polystyrene- and silica-supported secondary
amine-based catalysts outperform our systems,[4b–i] for the re-
action of this nitroolefin with acetone, cyclopentanone or
isobutyraldehyde the catalyst 2, which is based on a primary
amine, provided outstanding yields and enantioselectivities.
These parameters are remarkably better for our catalysts
than for all systems immobilized on insoluble supports that
have previously been reported.
Figure 1. Proposed transition state and the influence of the configuration
of the a-carbon atom of the amino acid component of the catalyst.
Atoms marked in red are aligned in a coplanar manner with the carbonyl
group to reduce the allylic strain.
in the tested case of acetone addition). The conformation of
the catalyst–substrates complex is based on the minimization
of the allylic strain of the amide bonds,[15] thus placing the
hydrogen atoms marked in red coplanar with the urea car-
bonyl group. The presumed double hydrogen-bond activa-
tion of the nitroolefin through a single oxygen atom of the
nitro group was proposed and supported by calculations of
Tsogoeva et al.[8a] When the nitroolefin approaches the en-
amine with its other face, a less favorable alignment of the
hydrogen bonds must result in the substantially lower activa-
tion of the electrophile and slower reaction; hence, it is the
source of the enantioselectivity. Inversion at the amino acid
chiral center of the catalyst puts the side chain in the prox-
imity of the nitro group, possibly forcing the nitroolefin out
of the most favorable hydrogen-bond alignment, and conse-
quently lowering the degree of its activation, the reaction
rate toward the dominant enantiomer of the product and, as
a result, the yield and the enantioselectivity.
In our preliminary report, we showed that in the case of
acetone addition to b-nitrostyrene the catalyst can be recy-
cled a number of times without a significant decrease in the
reaction yield and with perfect reproducibility of the ee
value.[7] In parallel experiments carried out with isobutyral-
dehyde and nitrostyrene (Table 5), the excellent enantiose-
Table 5. Attempted recycling of catalyst 1 in the asymmetric nitro-Mi-
chael addition of isobutyraldehyde to trans-b-nitrostyrene.[a]
Cycle
Yield [%][b]
ee [%][c]
1
2
3
63
30
15
99
99
99
[a] Reaction conditions: trans-b-nitrostyrene (0.25 mmol), acetone
(1.25 mmol), PhCO2H (0.05 mmol), catalyst (0.075 mmol), toluene
(2 mL); 4 days, RT. [b] Determined by NMR spectroscopy. [c] ee value
was determined by HPLC with a Chiralpak OJ column.
The results of our study are aligned with the trends and
conclusions that one is able to deduce from a careful survey
of the outcome observed for various catalytic systems in the
nitro-Michael addition of aldehydes and ketones. According
to the recent analyses in the literature,[1–2,16] the majority of
catalytic systems for this reaction are derived from secon-
lectivity is, once again, preserved, but the activity of the cat-
alyst diminishes steeply. Despite the fact that we are pres-
ently unable to prove this, it appears likely that some irre-
versible side reaction of the catalyst with aldehyde, or alde-
hyde and nitrostyrene, causes this outcome.
2294
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2290 – 2296

Bifunctional Catalysts for Nitro-Michael Addition
FULL PAPER
132.4, 131.1, 130.2, 129.9, 129.6, 127.8,127.4, 62.7, 59.8, 59.6, 31.3, 18.8,
17.2 ppm.
The irreversible formation of a cyclobutane side product 9
À
following the C C bond-forming step of the catalysis, as was
General procedure for the catalytic asymmetric nitro-Michael addition:
The appropriate Michael donor (0.5 mmol for aldehydes or 1.25 mmol
for other donors) and benzoic acid (0.025 mmol) were added to a mixture
of catalyst (0.075 mmol of the catalytic unit) and nitroolefin (0.25 mmol)
in toluene (2 mL). The suspension was stirred at room temperature for
4 days. After the reaction, the mixture was filtered and the catalyst was
washed with AcOEt (3ꢂ10 mL) and dried for reuse. The organic layer
was evaporated and the residue was analyzed by 1H NMR spectroscopy,
and then purified by flash column chromatography on silica gel (hexane/
AcOEt) to afford the Michael adduct. The ee value of the product was
determined by chiral HPLC analysis with Chiralcel OJ, Chiralcel OD, or
Chiralpak AD columns. The majority of the products are known and
were characterized by comparison of their NMR spectra to the corre-
sponding data in the literature.[8c,9c,17b,20f,21e,24g–i,30] Characterization of new
compounds is provided in the Supporting Information.
suggested by Jacobsen et al., can be one plausible explana-
tion for the catalyst deactivation in this type of catalytic re-
action.[11] However, the recently demonstrated reversibility
of such cyclobutane formation
under the reaction conditions
and, consequently, its postulated
role as the resting state of the
catalyst in the amine-catalyzed
nitro-Michael addition suggests
that other modes of catalyst de-
activation may also be possi-
ble.[28]
To the best of our knowledge, effective recycling of a sup-
ported catalyst in the addition of an aldehyde to nitroolefin
still remains a challenge. Most catalysts rapidly lose activity
upon recycling or require regenerating treatment between
the cycles.[4a] Only the peptide catalyst, recently reported by
Wennemers et al., could be reused numerous times without
loss of activity.[29]
Acknowledgements
This research was supported by Grant No. 2008193 from the United
States–Israel Binational Science Foundation (BSF) and Grant No. 960/06
from the Israel Science Foundation.
Conclusion
[1] a) R. Rios, A. Moyano in Catalytic Asymmetric Conjugate Reactions,
(Ed.: A. Cordova), Wiley-VCH, Weinheim, 2010, pp. 191–218;
b) H. Pellissier, Recent Development in Asymmetric Organocatalysis,
RSC Publishing, Cambridge, 2010, pp. 1–76.
[2] a) S. Sulzer-Mossꢃ, A. Alexakis, Chem. Commun. 2007, 3123–3135;
b) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701–1716; c) J. Vicario,
D. Badꢄa, L. Carrillo, Synthesis 2007, 2065–2092; d) D. Almas¸i,
D. A. Alonso, C. Nꢅjera, Tetrahedron: Asymmetry 2007, 18, 299–
365.
[3] a) N. Ono, The Nitro Group in Organic Synthesis Wiley-VCH, New
York, 2001, p; b) O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org.
Chem. 2002, 1877–1894; c) R. Ballini, M. Petrini, Tetrahedron 2004,
60, 1017–1047.
[4] a) E. Alza, M. A. Pericas, Adv. Synth. Catal. 2009, 351, 3051–3056;
b) T. Miao, L. Wang, Tetrahedron Lett. 2008, 49, 2173–2176; c) E.
Alza, X. C. Cambeiro, C. Jimeno, M. A. Pericas, Org. Lett. 2007, 9,
3717–3720; d) P. Li, L. Wang, M. Wang, Y. Zhang, Eur. J. Org.
Chem. 2008, 2008, 1157–1160; e) P. Li, L. Wang, Y. Zhang, G.
Wang, Tetrahedron 2008, 64, 7633–7638; f) Y.-B. Zhao, L.-W.
Zhang, L.-Y. Wu, X. Zhong, R. Li, J.-T. Ma, Tetrahedron: Asymme-
try 2008, 19, 1352–1355; g) S. Luo, J. Li, L. Zhang, H. Xu, J. P.
Cheng, Chem. Eur. J. 2008, 14, 1273–1281; h) J. Liu, P. Li, Y. Zhang,
K. Ren, L. Wang, G. Wang, Chirality 2010, 22, 432–441; i) Y. Chuan,
G. Chen, Y. Peng, Tetrahedron Lett. 2009, 50, 3054–3058; j) M. C.
Varela, S. M. Dixon, K. S. Lam, N. E. Schore, Tetrahedron 2008, 64,
10087–10090.
[5] For multiple examples, see: a) refs. [4b–i]; b) C. L. Cao, M. C. Ye,
X. L. Sun, Y. Tang, Org. Lett. 2006, 8, 2901–2904; c) S. V. Pansare,
K. Pandya, J. Am. Chem. Soc. 2006, 128, 9624–9625; d) H. Chen, Y.
Wang, S. Wei, J. Sun, Tetrahedron: Asymmetry 2007, 18, 1308–1312;
e) F. Y. Liu, S. W. Wang, N. Wang, Y. G. Peng, Synlett 2007, 2415–
2419; f) G. L. Puleo, A. Iuliano, Tetrahedron: Asymmetry 2008, 19,
2045–2050; g) A. P. Carley, S. Dixon, J. D. Kilburn, Synthesis 2009,
2509–2516; h) A. D. Lu, P. Gao, Y. Wu, Y. M. Wang, Z. H. Zhou,
C. C. Tang, Org. Biomol. Chem. 2009, 7, 3141–3147; i) S. V. Pansare,
R. L. Kirby, Tetrahedron 2009, 65, 4557–4561.
We have prepared, for the first time, polymer-supported bi-
functional catalysts incorporating a primary amine, for the
enantioselective nitro-Michael addition of aldehydes and ke-
tones. Introduction of simple l-a-amino acid spacers in the
structures of the “first-generation” catalyst that we prelimi-
narily communicated led to a substantially more active and
stereoselective catalytic system. The profiles of reactivity
and selectivity, which the new catalysts exhibit in the nitro-
Michael reaction of various ketones and aldehydes, empha-
sized the differences between the primary and secondary
amine-based catalysts.
Experimental Section
General procedure for the preparation of amino-urea catalysts: p-Nitro-
phenyl chloroformate (10 equiv per amino unit), DIPEA (20 equiv per
amino unit), and a catalytic amount of pyridine (0.1 equiv) were added to
a suspension of amine-terminated resin (1 equiv) in THF (10 mL per 1 g
resin). The suspension was stirred at room temperature for 2 h. The resin
was washed with water, THF/water, THF, and dichloromethane, and then
dried under vacuum. The resin was stirred in DMF (10 mL per 1 g resin)
and the appropriate chiral diamine (7 equiv per carbonate unit) was
added. The suspension was heated to 508C overnight. The resin was
washed with DMF/water, DMF, THF/water, THF, and dichloromethane,
and then dried under vacuum.
Catalyst 2: Starting materials: Wang-Val-NH2 resin (0.97 mmolgÀ1, pre-
loaded Fmoc-Val on Wang resin (ChemImpex), subjected to deprotec-
tion) and (1R, 2R)-(+)-1,2-diphenylethylenediamine. Yield >99%, load-
ing 0.78 mmolgÀ1. Following trifluoroacetic acid (TFA)-induced cleavage:
1H NMR (400 MHz, CDCl3/TFA 1:1): d=7.55 (brs, 3H), 7.35–7.37 (m,
4H), 7.25–7.34 (m, 4H), 7.15–7.17 (m, 4H), 5.43 (d, J=11.2 Hz, 1H),
4.81–4.82 (m, 1H), 4.37 (m, 1H), 2.29–2.31 (m, 1H), 0.98 ppm (d, J=
7.1 Hz, 6H); partial 13C NMR (100 MHz, CDCl3/TFA 1:1): d=135.7,
[6] a) L. Gu, Y. Wu, Y. Zhang, G. Zhao, J. Mol. Catal. A: Chem 2007,
263, 186–194; b) B. K. Ni, Q. Y. Zhang, K. Dhungana, A. D. Head-
ley, Org. Lett. 2009, 11, 1037–1040; c) G. Lv, R. Jin, W. Mai, L. Gao,
Tetrahedron: Asymmetry 2008, 19, 2568–2572; d) N. Mase, K. Wata-
nabe, H. Yoda, K. Takabe, F. Tanaka, C. F. Barbas, J. Am. Chem.
Chem. Eur. J. 2012, 18, 2290 – 2296
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2295

M. Portnoy et al.
Soc. 2006, 128, 4966–4967; e) C. F. Barbas III, J. M. Betancort, K.
Sakthivel, R. Thayumanavan, F. Tanaka, Synthesis 2004, 2004, 1509–
1521; f) J. Wang, H. Li, B. Lou, L. Zu, H. Guo, W. Wang, Chem.
Eur. J. 2006, 12, 4321–4332; g) Vishnumaya, V. K. Singh, Org. Lett.
2007, 9, 1117–1119; h) L.-Y. Wu, Z.-Y. Yan, Y.-X. Xie, Y.-N. Niu,
Y.-M. Liang, Tetrahedron: Asymmetry 2007, 18, 2086–2090; i) B. Ni,
Q. Zhang, A. D. Headley, Tetrahedron Lett. 2008, 49, 1249–1252;
j) D. Diez, M. Jose Gil, R. F. Moro, I. S. Marcos, P. Garcꢄa, P.
Basabe, N. M. Garrido, H. B. Broughton, J. G. Urones, Tetrahedron
2007, 63, 740–747; k) S. Mossꢃ, M. Laars, K. Kriis, T. Kanger, A.
Alexakis, Org. Lett. 2006, 8, 2559–2562; l) M. T. Barros, A. M.
Faꢄsca Phillips, Eur. J. Org. Chem. 2007, 2007, 178–185.
[18] For linear aldehydes in solution see, for instance: a) refs. [12c],
[12d]; b) Y. Hayashi, H. Gotoh, T. Hayashi, M. Shoji, Angew. Chem.
2005, 117, 4284–4287; Angew. Chem. Int. Ed. 2005, 44, 4212–4215;
c) C. Palomo, S. Vera, A. Mielgo, E. Gomez-Bengoa, Angew. Chem.
2006, 118, 6130–6133; Angew. Chem. Int. Ed. 2006, 45, 5984–5987;
d) J. B. Wu, B. K. Ni, A. D. Headley, Org. Lett. 2009, 11, 3354–3356.
[19] On solid supports, see refs. [4a–f], [4h], and [4i].
[20] For many examples of low to moderate yield, diastereoselectivity,
and/or enantioselectivity in the reaction of cyclopentanone with ni-
trostyrene, see: a) refs. [4d–g]; b) refs. [5b–c]; c) refs. [6b–h]; d) refs.
[9b–c]; e) ref. [17g]; f) A. Alexakis, O. Andrey, Org. Lett. 2002, 4,
3611–3614.
[7] L. Tuchman-Shukron, M. Portnoy, Adv. Synth. Catal. 2009, 351,
541–546.
[21] For the rare cases of high ee value with cyclopentanone by pyrroli-
dine catalysts, see: a) ref. [4h]; b) ref. [8d]; c) ref. [17f]; d) ref. [17h];
e) A. Lu, R. Wu, Y. Wang, Z. Zhou, G. Wu, J. Fang, C. Tang, Eur. J.
Org. Chem. 2010, 2010, 2057–2061; f) A. Lu, R. Wu, Y. Wang, Z.
Zhou, G. Wu, J. Fang, C. Tang, Eur. J. Org. Chem. 2011, 2011, 122–
127.
[22] For many examples of low to moderate selectivity in the addition of
acetone to nitroolefins, see: a) refs. [4c–h]; b) refs. [5b], [5d]; c) refs.
[6a–e]; d) refs. [6g–j]; e) ref. [9b]; f) refs. [17g], [17i]; g) ref. [20f];
h) B. List, P. Pojarliev, H. J. Martin, Org. Lett. 2001, 3, 2423–2425;
i) D. Enders, A. Seki, Synlett 2002, 26–28; j) O. Andrey, A. Alexakis,
A. Tomassini, G. Bernardinelli, Adv. Synth. Catal. 2004, 346, 1147–
1168; k) A. J. Cobb, D. A. Longbottom, D. M. Shaw, S. V. Ley,
Chem. Commun. 2004, 1808–1809.
[8] a) D. A. Yalalov, S. B. Tsogoeva, S. Schmatz, Adv. Synth. Catal.
2006, 348, 826–832; b) S. B. Tsogoeva, S. Wei, Chem. Commun.
2006, 1451–1453; c) H. B. Huang, E. N. Jacobsen, J. Am. Chem. Soc.
2006, 128, 7170–7171; d) T. Mandal, C.-G. Zhao, Angew. Chem.
2008, 120, 7828–7831; Angew. Chem. Int. Ed. 2008, 47, 7714–7717;
e) Z. Yang, J. Liu, X. Liu, Z. Wang, X. Feng, Z. Su, C. Hu, Adv.
Synth. Catal. 2008, 350, 2001–2006.
[9] a) Y. Xu, W. Zou, H. Sundꢃn, I. Ibrahem, A. Cꢆrdova, Adv. Synth.
Catal. 2006, 348, 418–424; b) S. Luo, X. Mi, L. Zhang, S. Liu, H.
Xu, J. P. Cheng, Angew. Chem. 2006, 118, 3165–3169; Angew. Chem.
Int. Ed. 2006, 45, 3093–3097; c) S. Z. Luo, H. Xu, X. L. Mi, J. Y. Li,
X. X. Zheng, J.-P. Cheng, J. Org. Chem. 2006, 71, 9244–9247.
[10] a) E. A. C. Davie, S. M. Mennen, Y. J. Xu, S. J. Miller, Chem. Rev.
2007, 107, 5759–5812; b) M. Wiesner, M. Neuburger, H. Wennem-
ers, Chem. Eur. J. 2009, 15, 10103–10109.
[23] For the only two cases with ee values exceeding 80% in the addition
of acetone to nitroolefins with catalysts based on secondary amines,
see: a) ref. [4i]; b) ref. [8d].
[11] M. P. Lalonde, Y. Chen, E. N. Jacobsen, Angew. Chem. 2006, 118,
6514–6518; Angew. Chem. Int. Ed. 2006, 45, 6366–6370.
[24] For the nitro-Michael addition of a-branched aldehydes promoted
by secondary amine-derived catalysts, see: a) refs. [4a], [4d]; b) ref.
[5b]; c) refs. [6d], [6k], [6l]; d) ref. [9b]; e) ref. [18b], d; f) ref. [20f];
g) Q. Tao, G. Tang, K. Lin, Y. F. Zhao, Chirality 2008, 20, 833–838;
h) N. Mase, R. Thayumanavan, F. Tanaka, C. F. Barbas III, Org.
Lett. 2004, 6, 2527–2530; i) L. S. Zu, J. Wang, H. Li, W. Wang, Org.
Lett. 2006, 8, 3077–3079.
[25] X. J. Zhang, S. P. Liu, X. M. Li, M. Yan, A. S. Chan, Chem.
Commun. 2009, 833–835.
[26] a) C. G. Kokotos, G. Kokotos, Adv. Synth. Catal. 2009, 351, 1355–
1362; b) B.-L. Li, Y.-F. Wang, S.-P. Luo, A.-G. Zhong, Z.-B. Li, X.-
H. Du, D.-Q. Xu, Eur. J. Org. Chem. 2010, 2010, 656–662; c) Q. Gu,
X.-T. Guo, X.-Y. Wu, Tetrahedron 2009, 65, 5265–5270.
[12] For examples of this reaction, see: a) ref. [10b]; b) ref. [11]; c) M.
Wiesner, J. D. Revell, H. Wennemers, Angew. Chem. 2008, 120,
1897–1900; Angew. Chem. Int. Ed. 2008, 47, 1871–1874; d) L. Zu,
H. Li, J. Wang, X. Yu, W. Wang, Tetrahedron Lett. 2006, 47, 5131–
5134; e) J.-R. Chen, Y.-Q. Zou, L. Fu, F. Ren, F. Tan, W.-J. Xiao,
Tetrahedron 2010, 66, 5367–5372.
[13] The exact ee value could not be determined for the reaction of the
acetoacetate esters, because we failed to sufficiently separate the
diastereomeric products, the qualitative estimation point to moder-
ate enantioselectivity.
[14] a) T. Okino, Y. Hoashi, T. Furukawa, X. N. Xu, Y. Takemoto, J. Am.
Chem. Soc. 2005, 127, 119–125; b) T. Okino, Y. Hoashi, Y. Takemo-
to, J. Am. Chem. Soc. 2003, 125, 12672–12673.
[15] a) R. W. Hoffmann, Chem. Rev. 1989, 89, 1841–1860; b) J. Quick, C.
Mondello, M. Humora, T. Brennan, J. Org. Chem. 1978, 43, 2705–
2708.
[27] For the only reported attempt that we are aware of, see ref. [9a].
[28] a) J. Bures, A. Armstrong, D. G. Blackmond, J. Am. Chem. Soc.
2011, 133, 8822–8825; b) K. Patora-Komisarska, M. Benohoud, H.
Ishikawa, D. Seebach, Y. Hayashi, Helv. Chim. Acta 2011, 94, 719–
745.
[16] a) A. Berkessel, H. Grçger, Asymmetric Organocatalysis, Wiley-
VCH, Weinheim, 2005, pp. 45–84; b) C. Bressy, P. I. Dalko in Enan-
tioselective Organocatalysis, (Ed. P. I. Dalko), Wiley-VCH, Wein-
heim, 2007, pp. 77–94.
[29] Y. Arakawa, M. Wiesner, H. Wennemers, Adv. Synth. Catal. 2011,
353, 1201–1206.
[30] a) X.-Y. Cao, J.-C. Zheng, Y.-X. Li, Z.-C. Shu, X.-L. Sun, B.-Q.
Wang, Y. Tang, Tetrahedron 2010, 66, 9703–9707; b) D. A. Evans, S.
Mito, D. Seidel, J. Am. Chem. Soc. 2007, 129, 11583–11592; c) E.
Juaristi, A. K. Beck, J. Hansen, T. Matt, T. Mukhopadhyay, M.
Simson, D. Seebach, Synthesis 1993, 1271–1290; d) J. Wang, H. Li,
W. Duan, L. Zu, W. Wang, Org. Lett. 2005, 7, 4713–4716; e) F. Xue,
S. Zhang, W. Duan, W. Wang, Adv. Synth. Catal. 2008, 350, 2194–
2198.
[17] For six-membered cyclic ketones in solution see, for instance:
a) refs. [5c–e]; b) refs. [6d–i]; c) ref. [9b]; d) T. Ishii, S. Fujioka, Y.
Sekiguchi, H. Kotsuki, J. Am. Chem. Soc. 2004, 126, 9558–9559;
e) S. Luo, X. Mi, S. Liu, H. Xu, J. P. Cheng, Chem. Commun. 2006,
3687–3689; f) T. Mandal, C. G. Zhao, Tetrahedron Lett. 2007, 48,
5803–5806; g) C. Wang, C. Yu, C. Liu, Y. Peng, Tetrahedron Lett.
2009, 50, 2363–2366; h) D.-Q. Xu, L.-P. Wang, S.-P. Luo, Y.-F. Wang,
S. Zhang, Z.-Y. Xu, Eur. J. Org. Chem. 2008, 2008, 1049–1053;
i) D. Q. Xu, H. D. Yue, S. P. Luo, A. B. Xia, S. Zhang, Z. Y. Xu, Org.
Biomol. Chem. 2008, 6, 2054–2057.
Received: August 9, 2011
Revised: November 1, 2011
Published online: January 16, 2012
2296
www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2290 – 2296