Asymmetric organocatalytic Henry reaction

Article abstract of DOI:10.1002/anie.200503724

(Chemical Equation Presented) The nitroaldol (Henry) reaction between aromatic aldehydes and nitromethane can be carried out in high yields and enantiomeric excess by using a novel Cinchona-derived thiourea catalyst. Hydrogen-bond donors at the C6′ position in these organocatalysts are shown to induce preferential formation of one enantiomer.

Full text of DOI:10.1002/anie.200503724

Angewandte
Chemie
Cinchona Alkaloids
scope and enantioselectivities were modest, but we proved
that a hydrogen-bond donor at the C6’ position of an
appropriate Cinchona derivative is required to induce pref-
erential formation of one enantiomer. Because the phenol
moiety and the basic quinuclidine nitrogen atom can be in
reasonable proximity in solution, the enantioselectivity could
arise from a double activation of both the nucleophile and
electrophile.[15] We envisaged that replacement of the phenol
moiety with a better hydrogen-bond donor could result in a
more powerful and more enantioselective catalyst.[16] Trig-
gered by a recent report by Soos and co-workers on the
introduction of an activated thiourea at the C9 position of the
DOI: 10.1002/anie.200503724
Asymmetric Organocatalytic Henry Reaction**
Tommaso Marcelli, Richard N. S. van der Haas,
Jan H. van Maarseveen, and Henk Hiemstra*
Dedicated to Professor Goffredo Rosini
on the occasion of his 65th birthday
The reaction between a carbonyl compound and a nitro-
alkane, known as the Henry (or nitroaldol) reaction, is a
powerful synthetic tool for the construction of complex
molecules.[1] In recent years, several efficient catalytic enan-
tioselective methods to perform this reaction have been
described.[2] Typically, an aldehyde[3–7] (or an activated
ketone)[8,9] is treated with a nitroalkane (mainly nitromethane
or nitroethane) in the presence of a chiral metal complex and
other additives, such as tertiary amines or molecular sieves, to
obtain nitroalcohols with good to excellent optical purities. In
the last decade, asymmetric organocatalysis has proven to be
a robust and valid alternative to traditional metal-based
catalysis for a number of reactions.[10] High enantiomeric
excesses have been achieved in the reaction between nitro-
alkanes and imines (aza-Henry reaction) using chiral, enan-
tiopure organic catalysts. Remarkable results were obtained
in particular by Takemoto and co-workers[11] and Yoon and
Jacobsen,[12] who employed thioureas 2a and 2b, respectively.
To date, the use of metal-free catalysts in the parent nitroaldol
reaction has never resulted in enantioselectivities exceeding
54% ee.[13]
We recently reported the use of Cinchona derivatives as
asymmetric catalysts for the reaction between activated
aromatic aldehydes and nitromethane (Scheme 1).[14] The
Scheme 2. Thiourea catalysts. 2a: Takemoto and co-workers[11]; 2b:
Yoon and Jacobsen[12]; 2c: Soos and co-workers.[17]
Cinchona scaffold 2c,[17] we decided to
functionalize 1 with the same moiety
(Scheme 2). Catalyst 3, a bench-stable
crystalline solid, was synthesized on a
multigram scale by a reliable and high-
yielding sequence (see Supporting
Information).
Scheme 1. Reaction between activated aromatic aldehydes and nitromethane. EWG=electron-
withdrawing group.
Our initial experiments were per-
formed using benzaldehyde (4a) as a
model substrate with 10 equivalents of
[*] T. Marcelli, R. N. S. van der Haas, Dr. J. H. van Maarseveen,
Prof. Dr. H. Hiemstra
nitromethane and 20% of 3 (Table 1). We were delighted to
observe that reaction of 4a in dimethylformamide (DMF) at
room temperature afforded the corresponding nitroalcohol
5a after 6 h in 67% ee (Table 1, entry 4). The use of solvents
other than DMF or THF mostly led to products with
surprisingly low optical purity. Reaction in methanol afforded
5a in a noteworthy 49% ee, whereas reaction in nitrome-
thane, dichloromethane, and toluene essentially gave the
racemic product. These results were somewhat puzzling
because methanol is generally considered a poor solvent in
Van’t Hoff Institute of Molecular Sciences
University of Amsterdam, Nieuwe Achtergracht 129
1018 WS Amsterdam (Netherlands)
Fax: (+31)20-525-5670
E-mail: hiemstra@science.uva.nl
[**] This research was financially supported by the National Research
School Combination Catalysis (NRSC-C).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 929 –931
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Communications
Table 1: Optimization of the reaction conditions.[a]
Table 2: Substrate scope.[a]
Entry
1
Substrate
R
t [h]
Yield [%][b]
90
ee [%][c]
Entry
Solvent
T [8C]
t [h]
Conversion [%][b]
ee [%][c]
4a
48
92
1
2
3
4
5
6
7
8
9
THF
25
25
25
25
25
25
25
25
6
6
6
6
6
6
6
6
48
48
90
97
99
96
92
91
99
83
90
99
62
6
42
67
7
49
30
5
82
89
CH2Cl2
MeCN
DMF
MeNO2
MeOH
2
3
4
5
4b
4c
4d
4e
96
168
24
97
94
99
91
91
89
85
86
[d]
E O
t
2
toluene
DMF
THF
À20
10
À20
[a] Reactions were carried out with 4a (0.1 mmol), MeNO2 (1.0 mmol),
and 3 (0.02 mmol) in 100 mL of solvent. [b] Determined by 1H NMR
spectroscopic analysis. [c] Determined by HPLC analysis using
4
a
Chiralcel OD-H column. [d] MeNO2 (100 mL) was used as the solvent/
reactant.
6
4 f
48
99
92
hydrogen-bond-controlled organocatalysis. On the other
hand, Wittkopp and Schreiner demonstrated that a similar
thiourea can retain its catalytic activity in protic solvents.[18]
Lowering the temperature provided synthetically useful
levels of asymmetric induction at a still reasonable reaction
rate (Table 1, entry 10). Further optimization revealed that
these reactions could be carried out on a 1-mmol scale with
only 10% catalyst: under these conditions 5a was obtained
after 48 h in 90% yield of isolated product and with 92% ee.
Unfortunately, these condi-
7
8
4g
4h
24
24
91
95
86
91
[a] Reactions were carried out with 4 (1.0 mmol), MeNO2 (10.0 mmol),
and 3 (0.1 mmol) in 1.0 mL of solvent at À208C. [b] Yield of isolated
product. [c] Determined by HPLC analysis using a Chiralcel OD-H
column. Boc=tert-butoxycarbonyl.
tions did not prove suitable
for the reaction of aliphatic
aldehydes:
cyclohexanecar-
boxaldehyde and isobutyralde-
hyde were not completely con-
verted into the corresponding
nitroalcohols after 1 week and
the enantiomeric excess of the
products was disappointingly
low (< 20% ee). Nevertheless,
a variety of aromatic alde-
hydes could be transformed
into nitroalcohols 5b–h in con-
sistently high yields and enan-
tiomeric excess (Table 2).
Unactivated aromatic alde-
Scheme 3. The use of quinine-derived catalyst 6 (the pseudo-enantiomer of 3) to prepare nitroalcohols
with the opposite configuration.
hydes required long reaction times but the reactions were
clean, and we did not observe dehydration to the correspond-
ing nitroalkenes (Table 2, entries 2 and 3). Not surprisingly,
activated aldehydes typically furnished the nitroaldol product
in one day or less (Table 2, entries 4 and 5). The protocol
proved to be also compatible with heterocyclic aldehydes
(Table 2, entries 7 and 8). Quinine-derived catalyst 6 (the
pseudo enantiomer of 3) gave access to nitroalcohols with the
opposite configuration and comparable enantiomeric excess,
as shown by three examples in Scheme 3.
Although the reasons for the observed enantioselectivity
are still not clear, we believe that the aldehyde is activated by
the thiourea moiety through double hydrogen bonding,[16]
while the nitromethane is activated by the basic quinuclidine
nitrogen atom (Scheme 4). Besides providing control over the
stereochemical outcome of the reaction, this behavior may
also serve to increase the reactivity (catalyst 3 yields faster
conversion than 1 under the same conditions). We also believe
that the observed solvent dependency of the enantioselectiv-
ity may be because of the high conformational freedom of
930
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[10] For comprehensive reviews about asymmetric organocatalysis,
see: P. I. Dalko, L. Moisan, Angew. Chem. 2001, 113, 3840 – 3864;
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[14] T. Marcelli, R. N. S. van der Haas, J. H. van Maarseveen, H.
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3,[19] because our results cannot be rationalized on the basis of
the polarity of the reaction medium.
[15] Selected applications of this concept to asymmetric organo-
catalysis: a) Y. Iwabuchi, M. Nakatani, N. Yokoyama, S.
Hatakeyama, J. Am. Chem. Soc. 1999, 121, 10219 – 10220;
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[17] a) B. Vakulya, S. Varga, A. Csampai, T. Soos, Org. Lett. 2005, 7,
1967 – 1969; during the preparation of this communication,
others reported enantioselective organocatalytic reactions
using an analogous catalyst: b) S. H. McCooey, S. J. Connon,
Angew. Chem. 2005, 117, 6525 – 6528; Angew. Chem. Int. Ed.
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[18] A. Wittkopp, P. R. Schreiner, Chem. Eur. J. 2003, 9, 407 – 414.
[19] In solution, Cinchona alkaloids exist as a mixture of conformers
mainly arising from rotation along the C8–C9 and C4’–C9 bonds:
G. D. H. Dijkstra, R. M. Kellogg, H. Wynberg, J. S. Svendsen, I.
Marko, K. B. Sharpless, J. Am. Chem. Soc. 1989, 111, 8069 –
8076; moreover, the flexible thiourea moiety adds further
conformational complexity to the molecule.
In conclusion, we have developed a new organocatalyst
capable of promoting the direct enantioselective nitroaldol
reaction of aromatic and heteroaromatic aldehydes with
nitromethane in high yields and enantiomeric excess. To the
best of our knowledge, this is the first example of a highly
enantioselective organocatalytic Henry reaction of aromatic
aldehydes.[20] Although not general, we believe that our
protocol constitutes an important step forward in this field. A
study aimed at the understanding of the mechanism and the
reasons for the observed enantioselectivity is currently
underway. We envision that this will allow us to design new
catalysts and widen the scope of this transformation.
Received: October 20, 2005
Keywords: alkaloids · asymmetric catalysis · Henry reaction ·
.
hydrogen bonds · organocatalysis
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Angew. Chem. Int. Ed. 2006, 45, 929 –931
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