Dual hydrogen-bond/enamine catalysis enables a direct enantioselective three-component domino reaction

Article abstract of DOI:10.1002/anie.201101835

It takes two to tango: A dual catalyst system, composed of a highly enantioselective enamine catalyst and a multiple-hydrogen-bond catalyst, enabled the chemoselective union of two aldehydes and a nitromethane unit with near-perfect enantioselectivities, excellent diastereoselectivities, and high yields under neutral conditions (see scheme). Copyright

Full text of DOI:10.1002/anie.201101835

DOI: 10.1002/anie.201101835
Organocatalysis
Dual Hydrogen-Bond/Enamine Catalysis Enables a Direct
Enantioselective Three-Component Domino Reaction**
Hasibur Rahaman, ꢀdꢁm Madarꢁsz, Imre Pꢁpai, and Petri M. Pihko*
The nitro group enjoys a privileged position among the
functional groups that can be activated through hydrogen-
bond catalysis.[1] However, the hydrogen-bond-acceptor
capacity of the nitro group is lower than that of the carbonyl
or the imine group.[2] To increase reactivity, the use of
catalysts bearing multiple-hydrogen-bond donor (MHBD)
groups to increase the catalytic activity through possible
formation of several hydrogen bonds represents an attractive
option for enantioselective catalysis.[3,4] Although this
approach has been successfully used in multifunctional
catalysts where all the necessary functionalities are incorpo-
rated in the same catalyst molecule, the use of separate
catalysts for electrophile and nucleophile activation might
allow more opportunities for catalyst and reaction screening
because both catalysts could be optimized separately. As an
example, enantioselective enamine catalysts typically incor-
porate a hydrogen-bond-donor site (Scheme 1, Type A) or
rely on steric control alone (Type B).[5]
three-component reaction sequence (Scheme 2).[7] Both steps
are catalyzed by the MHBD catalyst as well as the amine
catalyst, and two different aldehydes can also be used in a
cross-domino sequence, thus providing the products in
excellent enantioselectivity, diastereoselectivity, and high
yield.[8]
Scheme 2. A domino three-component sequence with activation of the
nitro group by the hydrogen-bond catalyst.
Herein we demonstrate that the use of a dual catalyst
system[6] can lead to significant rate enhancements in enamine
catalysis and describe the successful use of a dual MHBD/
enamine catalyst system for a highly enantioselective domino
Step 1, the condensation of aliphatic aldehydes with
nitromethane to yield nitroolefins (4; Scheme 2), is not as
trivial as it first appears because aliphatic aldehydes readily
undergo self-aldolization and self-condensation reactions
with secondary amine catalysts.[9] Although the preparation
of b-aryl-substituted nitroolefins is relatively straightfor-
ward,[10] the more challenging b-alkyl-substituted nitroolefins
are typically prepared through a two-step sequence.[11] Step 2
of the sequence, the conjugate addition of aldehydes to
nitroolefins, has been intensively studied.[12] The most active
catalyst systems typically include either extra hydrogen-bond
donors in the enamine catalyst[13] or employ acids,[14] phe-
nols,[15] or water[16] as additives, thus allowing lower catalyst
concentrations and/or better aldehyde/nitroolefin stoichiom-
etry. Nevertheless, an excess of the donor aldehyde, up to
10 equivalents, is typically used to boost the reaction rates,
and long reaction times (12–48 h) are often required with
aliphatic aldehydes.
Scheme 1. Activation modes in enamine catalysis.
[*] Dr. H. Rahaman, Prof. Dr. P. M. Pihko
Nanoscience Center and Department of Chemistry
University of Jyvꢀskylꢀ
P.O.B. 35, 40014 JYU (Finland)
Fax: (+358)14-260-2501
E-mail: petri.pihko@jyu.fi
We reasoned that significant improvement could be
achieved in one stroke if the most enantioselective enamine
catalyst of Step 2 reported to date, the diphenylprolinol
derivative 3 disclosed by Hayashi et al. in 2005,[12c] would be
boosted with a MHBD co-catalyst. In Step 1, 3 would function
as an iminium catalyst, thus promoting a one-pot condensa-
tion process between aldehyde 2 and nitromethane 1.[17] This
step would require assistance of a MHBD co-catalyst because
3 does not promote the condensation process alone.[8] The
MHBD catalyst would then activate the newly generated b-
substituted nitroolefin 4 towards conjugate addition with the
second aldehyde 5, activated by 3 that now functions as an
Homepage: http://tinyurl.com/pihkogroup
Dr. ꢁ. Madarꢂsz, Dr. I. Pꢂpai
Chemical Research Center of HAS
P.O. Box 17, 1525 Budapest (Hungary)
[**] We thank Reijo Kauppinen and Mirja Lahtiperꢀ for assistance with
the NMR and HRMS measurements, respectively. This work was
supported by the Academy of Finland (projects 217221 and
217224), and OTKA (Hungary, grant no. NN-82955).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101835.
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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enamine catalyst. If the catalyst is successful in activating the
catalysts bearing two or three hydrogen-bond-donor sites
afforded very slow conversions and relatively high amounts of
self-aldol product 18 (Table 1, entries 2, 5, and 7). However,
with more lipophilic hybrid BINOL-(thio)urea catalysts 15
and 17, a rapid and highly selective conversion to the desired
domino product was observed (Table 1, entries 10 and 12).
Notably, the double thiourea catalyst 13 or the triol
catalyst 12 were not significantly more active than the
standard thiourea catalysts 8 or 9. In addition, the importance
of neutral conditions is illustrated by the fact that undistilled
propionaldehyde (containing propionic acid) afforded sig-
nificant amounts of side products 18 and 19, even with the
best catalyst system. These side reactions could be completely
suppressed when freshly distilled propionaldehyde was used.
The presence of a buffer solution boosted the rates somewhat
but the chemoselectivity and enantioselectivity were also
maintained without buffer solution (Table 1, entry 13).
A range of aldehydes with different polarities and
functionalities was then subjected to the reaction sequence.
To preserve the stereochemical integrity of the products and
to facilitate the reliable analysis of the enantiomeric purity,
the aldehydes were further processed with phosphorane 20 to
afford the enoates 21. As summarized in Table 2, several
different aliphatic aldehydes readily participated in the
reaction sequence, without limitations in the size or hydro-
phobicity of the aldehyde partner. In all cases, the products
were obtained in excellent yields, diastereoselectivities, and
near-perfect enantioselectivities.[19]
nitro component in both steps, the entire sequence from 1 to 6
could be completed in a domino fashion, while avoiding
aldehyde–aldehyde condensations or the conjugate addition
of nitromethane to 4.
We initiated our screen with a domino reaction of
propionaldehyde 2a with nitromethane. A biphasic mixture
of CHCl3 and aqueous buffer at pH 7 generally offered the
fastest rates, but the reactions could also be performed
without added buffer.[18] As summarized in Table 1, most
Table 1: Screening of hydrogen-bond-donor co-catalyst.
To demonstrate that the MHBD catalyst 17 does indeed
promote Step 2 (conjugate addition, Scheme 2), control
Table 2: Domino sequence catalyzed by MHBD and enamine starting
with a range of aliphatic and arylaliphatic aldehydes.[a]
Entry Hydrogen- Conv.
Conv.
into
Conv.
into
d.r.[b] e.r.[c]
Entry R1
t [h] Yield of 21 [%][b] d.r.[c] e.r.[d]
bond
donor
into
6a [%][a] 18 [%][a] 19 [%][a]
1
CH3
CH3
CH3
nPr
3.0 89 (21a)
3.8 78 (21a)
3.0 88 (21a)
3.3 96 (21b)
3.7 91 (21c)
3.3 89 (21d)
3.8 95 (21e)
4.3 85 (21 f)
4.2 95 (21g)
7.0 81 (21h)
10.0 72 (21i)
6.5 78 (21j)
93:07 >99.5:<0.5
93:07 >99.5:<0.5
94:06 <0.5:>99.5
2[e]
3[f]
4
1
2
3
4
5
6
7
8
none
7
8
<1
<1
<1
<1
<1
4
<1
<1
<1
67
<1
10
9
5
3
8
4
9
<1
8
<1
<1
<1
<1
<1
<1
<1
<1
<1
1
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
95:05 >99.5:<0.5
98:02 >99.5:<0.5
98:02 >99.5:<0.5
96:04 >99.5:<0.5
98:02 >99.5:<0.5
97:03 >99.5:<0.5
95:05 >99.5:<0.5
94:06 >99.5:<0.5
96:04 >99.5:<0.5
97:03 >99.5:<0.5
9
5
nBu
10
11
12
13
14
15
16
17
6
7
8
9
10
11
12
13
(CH2)4CH3
(CH2)5CH3
(CH2)7CH3
(CH2)9CH3
Bn
9
10
11
12
95:5 >99.5:<0.5
3-ClBn
PMB
<1
91
70
<1
6
6
4
3
5
–
–
94:6 >99.5:<0.5
93:7 >99.5:<0.5
(CH2)2OTBDPS 5.5 94 (21k)
13[d] 17
[a] Conditions: 3 + 17 (10 mol% +20 mol%), 1 (120 mol%) and
aldehyde 2 (200 mol%), CHCl3,/pH 7 buffer, 108C; then add 20
(200 mol%). [b] Yield of isolated product. [c] Diastereoselectivity was
[a] Conversion into 6a, 18, and 19 was determined by 1H NMR analysis
of the crude reaction mixture. [b] Diastereoselectivity was determined by
1H NMR analysis. [c] Enantioselectivity was determined by HPLC on a
chiral stationary phase after conversion into the corresponding enoate
21a (see Table 2). [d] Without buffer. Bn=benzyl, MOM=methoxy-
methyl.
1
determined by H NMR analysis. [d] Enantioselectivity was determined
by HPLC on a chiral stationary phase (see the Supporting Information for
details). [e] With urea catalyst 15. [f] With enantiomeric (R)-3. PMB=
para-methoxybenzyl, TBDPS=tert-butyldiphenylsilyl.
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Angew. Chem. Int. Ed. 2011, 50, 6123 –6127

Table 4: Crossed three-component sequence catalyzed by MHBD cata-
lyst 17 and chiral amine catalyst 3.[a]
experiments were carried out with separately formed nitro-
olefins. Both aliphatic and aromatic nitroolefins afforded the
products at a rapid rate and with excellent enantio- and
diastereoselectivity (Table 3). Importantly, the amount of
catalyst could be lowered to 1 mol% (for the enamine catalyst
3) and 2 mol% (for the MHBD catalyst) while maintaining
useful levels of reaction rate, diastereoselectivity, and enan-
tioselectivity. We also tested the activity of simpler MHBD
catalysts 22a and 22b because 22a is known to bind very
strongly to carboxylate anions,[20] but these catalysts were
inactive (Table 3, entries 7 and 8).
Finally, two different aldehydes can readily be used in the
domino reaction sequence. In this case, the aldehyde 2 is first
added to generate the nitroolefin at slightly higher temper-
ature, followed by the addition of the second aldehyde 5 at
108C.[21] In this manner, crossed reaction products can be
readily accessed (Table 4). Importantly, the sequence can also
be carried out without aqueous buffer (Table 4, entry 7), with
only a slight decrease in yield, thus demonstrating that the
dual catalyst system operates also under truly homogenous
conditions, without the need of phase separation of different
catalyst or reaction components.
Entry R1
R2
t [h][b] Yield of
21 [%][c]
d.r.[d] e.r.[e]
1
2
3
4
Ph
Ph
Ph
3-
CH3
nBu
0.5 91 (21o)
0.5 87 (21n)
95:5 >99.5:<0.5
99:1 >99.5:<0.5
99:1 >99.5:<0.5
97:3 >99.5:<0.5
(CH2)2OTBDPS 0.5 92 (21p)
nBu
1.3 63 (21q)
FC6H4
Cy
Cy
5
nBu
9
71 (21r)
76 (21s)
96:4 >99.5:<0.5
97:3 >99.5:<0.5
99:1 >99.5:<0.5
6
(CH2)2OTBDPS 12
nBu
7[f]
Ph
0.8 78 (21n)
[a] Conditions: Step 1:
3
+
17 (10 mol% + 20 mol% +), 1
(120 mol%) and aldehyde 2 (200 mol%), CHCl3, 408C, 12 h. Step 2: 5
(100 mol%) + (optional) buffer (pH 7), 108C, then add 20 (300 mol%).
[b] Time of Step 2. [c] Yield of isolated product. [d] Diastereoselectivity
was determined by 1H NMR analysis. [e] Enantioselectivity was deter-
mined by HPLC on a chiral stationary phase (see the Supporting
Information for details). [f] Without added buffer. Cy=cyclohexyl.
Mechanistically, we believe that in the first step, the role
of catalyst 17 is to activate nitromethane 1 as a hydrogen-
bonded nitromethane anion towards a Knoevenagel-type
condensation with iminium ion derived from
aldehyde 2 and catalyst 3.[22] Support for the
Table 3: Demonstration of the catalytic efficiency of the MHBD catalyst 17 in the
conjugate addition step.[a]
proposed role of 17 is provided by the chemo-
selectivity of the reaction sequence: in the absence
of 17 but in the presence of the amine catalyst 3,
the reaction affords mainly aldol and aldol-type
products, thereby bypassing nitromethane alto-
gether.
In Step 2, catalyst 17 would then activate the
newly formed nitro olefin 4 as an electrophile
towards the enamine derived from aldehyde 5.
Evidence for the role of 17 in the second step is
provided by the experiments in Table 3, where
Step 2 is studied separately. Importantly, without
17, the reaction is either very sluggish (Table 3,
entry 2) or does not proceed at all (Table 3,
entry 10). In addition, kinetic experiments per-
formed without buffer revealed that Step 2 is first
order in 3 and 0.4th order in 17,[23,24] thus
demonstrating that both catalyst components con-
tribute to the activation of reaction components in
the same phase. Although several dual catalyst
systems are known,[6] the kinetic contributions of
the two catalysts has not usually been verified. The
simplest explanation for these results, assuming
Entry Cat.
[mol%][b]
R1
R2
t [min] Yield of
21 [%][c]
d.r.[d] e.r.[e]
1
2
3
4
5
6
7
8
20:10
0:10
20:10
20:10
10:5
2:1
C11H23 nBu
C11H23 nBu
C11H23 (CH2)2OTBDPS 30
40
40
92 (21l)
19 (21l)
99:1 >99.5:<0.5
[h]
–
–
90 (21m) 99:1 >99.5:<0.5
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
nBu
nBu
nBu
CH3
CH3
CH3
CH3
CH3
7
20
95 (21n)
91 (21n)
99:1 >99.5:<0.5
99:1 >99.5:<0.5
98:2 >98.5:<1.5
90
90
90
390
90
95 (21n)
20:10[f]
20:10[g]
2:1
<3 (21o) [h]
<6 (21o) [h]
86 (21o)
–
–
–
–
9
98:2 >99.5:<0.5
À
that the C C bond formation is rate limiting, is
10
0:1
2:1
<1 (21o)
90 (21o)
–
–
that 17 activates selectively the nitro olefin 4 and 3
activates the aldehyde component (2).
11[i]
240
98:2 >99.5:<0.5
[a] Conditions: See the Supporting Information for details. [b] Catalyst loading in the
order 17/3. [c] Yield of isolated product. [d] Diastereoselectivity was determined by
1H NMR analysis. [e] Enantioselectivity was determined by HPLC on a chiral stationary
phase (see the Supporting Information for details). [f] Urea catalyst 22a instead of 17
(catalyst ratio for 22a/3). [g] Thiourea catalyst 22b instead of 17 (catalyst ratio for 22b/
17). [h] Conversion (determined by 1H NMR analysis). [i] Without added buffer.
To explain the activity of 17, the complexation
of 1-nitropropene 4t and 17 was studied by
computational methods. The structures of hydro-
gen-bonded complexes were generated with a
Monte Carlo simulation using various force
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Communications
fields, and the lowest energy structures thus obtained were
further refined by accurate quantum chemical calculations.[23]
The most stable structure of the 17···4t complex is charac-
terized by multiple hydrogen bonds formed between the NO2
group of the substrate and the catalyst, but involving only two
hydrogen-bond-donor functionalities (see Figure 1). How-
ever, other types of secondary interactions were found to
contribute to the binding as well. Namely, p-stacking with the
naphthyl ring and anion-p interaction with the electron-
deficient aromatic ring provide notable stabilization for
complex formation, which is borne out by the relatively
large binding energy (DE = À15.7 kcalmolÀ1).[25] These
results lend further support to our hypothesis of the role of
17 as the activator of the nitroolefin 4.[26]
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Figure 1. Optimized structure of the most stable form of the 17···4t
complex; F purple, N blue, O red, S yellow. Selected distances charac-
terizing the key hydrogen bonds (dashed) and secondary interactions
(dotted) are given in ꢃ.
[6] For examples of dual catalyst systems with two separate
catalysts, see: organocatalytic systems: a) H. Jiang, P. Elsner,
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13628 – 13630.
In summary, we have identified a dual catalyst combina-
tion that achieves the three-component enantioselective
aldehyde–nitroalkene–aldehyde domino reaction with excel-
lent enantio- and diastereoselectivities using either two
similar or two different aldehydes. The separate activation
of the nitro reaction component with a multiple-hydrogen-
bond catalyst allows the chemoselective union of the compo-
nents with a minimal competition from the side reactions such
as aldol additions and aldol condensations. The obtained
enantioselectivities are generally superior (or at least equal)
to those reported previously for separately prepared nitro-
olefins, and the overall reaction times are short due to the
dual activation of the reaction components with two chemo-
selective catalysts. We believe the dual catalysis concept using
the MHBD catalyst could readily be extended to other dual
catalysis modes.
Received: March 15, 2011
Published online: May 23, 2011
Keywords: domino reactions · enamine catalysis ·
.
hydrogen-bond catalysis · nitroolefins · organocatalysis
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Angew. Chem. Int. Ed. 2011, 50, 6123 –6127

[8] A related domino sequence restricted to water-miscible aliphatic
aldehydes as the first aldehyde component has been disclosed:
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122, 2443 – 2446; Angew. Chem. Int. Ed. 2010, 49, 2393 – 2396; at
the time of submission of this manuscript, Yoshida and co-
workers reported a one-pot synthesis of g-nitroaldehydes with
modest yields/stereoselectivities: b) M. Yoshida, N. Kitamikado,
H. Ikehara, S. Hara, J. Org. Chem. 2011, 76, 2305 – 2309.
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c) A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
124, 6798 – 6799.
[10] For examples, see: a) B. S. Furniss, A. J. Hannaford, P. W. G.
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X.-Z. Shu, K.-G. Ji, Y.-F. Yang, A. Shaukat, X.-Y. Liu, Y.-M.
Liang, J. Org. Chem. 2010, 75, 2893 – 2902.
[15] Phenols: a) see Ref. [13c].; b) See also: K. Patora-Komisarska,
M. Benohoud, H. Ishikawa, D. Seebach, Y. Hayashi, Helv. Chim.
Acta 2011, 94, 719 – 745.
[16] For recent examples, see: a) J. Wu, B. Ni, A. D. Headley, Org.
Lett. 2009, 11, 3354 – 3356; see also Ref. [14].
[17] For kinetic evidence of the involvement of iminium intermedi-
ates in pyrrolidine-catalyzed aldehyde condensation reactions,
see Ref. [9b].
[18] For a full description of the solvents and alternative amine
catalysts screened, see the Supporting Information.
[19] As the enantiomeric ratios have not been calibrated, ratios
higher than 200:1 are reported as > 99.5: < 0.5. The actual
observed ratios were: for Table 2, entry 1 (with (S)-3):
99.90:0.10, and for Table 2, entry 3 (with (R)-3): 0.02:99.98. In
addition, we have also prepared ent-17 ((S)-17), which gives
99.98:0.02 e.r. with (S)-3). These are, to the best of our
knowledge, the highest enantioselectivities reported for these
conjugate addition processes. These results also indicate that
catalyst 3 appears to be almost solely responsible for the sense of
enantioinduction. Although 17 is chiral, the results indicate that
achiral versions of 17 could also be conceived.
[11] a) H. Ishikawa, T. Suzuki, Y. Hayashi, Angew. Chem. 2009, 121,
1330 – 1333; Angew. Chem. Int. Ed. 2009, 48, 1304 – 1307; b) H.
Ohta, K. Ozaki, G.-i. Tshuchihashi, Chem. Lett. 1987, 191 – 192;
c) N. J. A. Martin, L. Ozores, B. List, J. Am. Chem. Soc. 2007,
129, 8976 – 8977.
[20] S. J. Brooks, P. A. Gale, M. E. Light, Chem. Commun. 2005,
4696 – 4698.
[12] For selected examples, see: a) R. Husmann, M. Jꢆrres, G. Raabe,
C. Bolm, Chem. Eur. J. 2010, 16, 12549 – 12552; b) M. Wiesner,
M. Neuburger, H. Wennemers, Chem. Eur. J. 2009, 15, 10103 –
10109, and references therein; c) Y. Hayashi, H. Gotoh, T.
Hayashi, M. Shoji, Angew. Chem. 2005, 117, 4284 – 4287; Angew.
Chem. Int. Ed. 2005, 44, 4212 – 4215; for a pioneering study, see:
d) J. M. Betancort, C. F. Barbas III, Org. Lett. 2001, 3, 3737 –
3740; for a full list of references, see the Supporting Information;
for the discovery of the catalyst family 3, see also: e) M. Marigo,
T. C. Wabnitz, D. Fielenbach, K. A. Jørgensen, Angew. Chem.
2005, 117, 804 – 807; Angew. Chem. Int. Ed. 2005, 44, 794 – 797.
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2006, 118, 6130 – 6133; Angew. Chem. Int. Ed. 2006, 45, 5984 –
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He, F.-S. Han, C.-Q. Kang, Z.-L. Ning, L.-X. Gao, Tetrahedron:
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Chang, R. J. Reddy, D. R. Magar, K. Chen, Chem. Eur. J. 2010,
16, 7030 – 7038.
[21] Step 1 (formation of 4) proceeds faster with unbranched
aliphatic aldehydes than with branched aliphatic or aromatic
aldehydes, thus precluding the addition of all three components
at once.
[22] For a review of iminium catalysis, including a discussion of the
mechanism of iminium-catalyzed Knoevenagel condensations,
see: A. Erkkilꢄ, I. Majander, P. M. Pihko, Chem. Rev. 2007, 107,
5416 – 5470.
[23] For details, see the Supporting Information.
[24] Wennemers and co-workers determined an order of 0.4 for the
nitro olefin component for this reaction. See Ref. [13b].
[25] Several other structures with binding energies ranging between
À14 and À10 kcalmolÀ1 have also been identified and they are
presented in the Supporting Information. The reported binding
energies were obtained from the gas-phase electronic energies.
[26] In preliminary binding studies, the complexation of nitroolefin
=
4g ((E)-nC9H19-CH CHNO2) and 17 was also studied by
1H NMR analysis. A slight upfield shift for the vinylic protons
of 4g (Dd = À0.017 ppm for the a and À0.020 ppm for the
b proton) was observed in presence of 17 (see the Supporting
Information). Further binding studies are in progress.
[14] Acids: a) Z. Zheng, B. L. Perkins, B. Ni, J. Am. Chem. Soc. 2010,
132, 50 – 51; b) S. K. Ghosh, Z. Zheng, B. Ni, Adv. Synth. Catal.
2010, 352, 2378 – 2382; c) M. Lombardo, M. Chiarucci, A.
Quintavalla, C. Trombini, Adv. Synth. Catal. 2009, 351, 2801 –
2806.
Angew. Chem. Int. Ed. 2011, 50, 6123 –6127
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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