Activation of nitroaldol reactions by diethylzinc and amino alcohols or diamines as promoters

Article abstract of DOI:10.1016/S0040-4039(02)01768-9

Henry reactions of nitroalkanes can be initiated with diethylzinc in the presence of catalytic amounts of 1,2-aminoethanol or 1,2-diaminoethane.

Full text of DOI:10.1016/S0040-4039(02)01768-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7503–7506
Activation of nitroaldol reactions by diethylzinc and amino
alcohols or diamines as promoters
Gu¨nter Klein, Subramaniam Pandiaraju and Oliver Reiser*
Institut fu¨r Organische Chemie der Universita¨t, Universita¨tsstraße 31, 93053 Regensburg, Germany
Received 21 August 2002; accepted 23 August 2002
Abstract—Henry reactions of nitroalkanes can be initiated with diethylzinc in the presence of catalytic amounts of 1,2-
aminoethanol or 1,2-diaminoethane. © 2002 Elsevier Science Ltd. All rights reserved.
The nitroaldol reaction (Henry reaction) is one of the
classical CꢀC bond forming reactions, which has been
of great interest due to the possibility of chemo- and
regioselective chain elongation in natural products syn-
thesis with tuneable functionalities.
ity due to the structure of the promoter were observed.
First, it was verified that in the absence of any pro-
moter benzaldehyde neither underwent a reaction with
diethylzinc nor with nitromethane (entry 1). Also,
ethyleneglycol as an additive (entry 2) does not initiate
any reaction. Amino alcohols were able to activate the
reaction mixture, although—depending on their struc-
ture—in quite a different way. While N,N-dimethyl-1,2-
aminoethanol gave rise to a 1:1 mixture of 2a and 3a
(entry 3), 1,2-aminoethanol itself promoted exclusively
the nitroaldol reaction, giving rise to 2a in 88% yield
The most commonly applied protocols to form 2-
nitroalcohols from nitroalkanes and carbonyl deriva-
tives require the use of a base like KOH, NaOH,
Al(OR)3, CO32−, HCO3 , F−, TBAF, amines and Al2O3,
−
etc.1
Until recently, the only protocol which made use of
Lewis acid catalysts was developed by Shibasaki2 with
the introduction of bimetallic lanthanum catalysts,
thereby opening the way to enantioselective nitroaldol
reactions.
Table 1. Nitroaldol reactions in the presence of promoters
In a preliminary disclosure3 we described that the use of
Et2Zn in the presence of diamines or amino alcohols as
promoters, a well known protocol for the alkylation of
aldehydes,4 can be applied to nitroaldol reactions. The
very recent reports of the Trost group,5 introducing in
a spectacular and most elegant way a bimetallic zinc
catalyst for enantioselective nitroaldol reactions now
prompts us to fully disclose our results.
Entry
Promoter
None
Ratio 2a/3a
2a Yield (%)
1
2
–
–
0
0
3
50:50
26
Taking the substrate mixture of benzaldehyde,
nitromethane and diethylzinc as our model system, we
investigated the influence of several bifunctional pro-
moters on the course of the reaction (Table 1). In
principle, the formation of the nitroaldol adduct 2, as
well as the addition adduct of diethylzinc to benzalde-
hyde 3 could occur. Indeed, great differences in reactiv-
4
5
100:0
100:0
88
83
6
7
100:0
85:15
78
62
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01768-9

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G. Klein et al. / Tetrahedron Letters 43 (2002) 7503–7506
Table 2. Nitroaldol reactions with aromatic or aliphatic
aldehydes in the presence of promoters 4 or 5
(entries 1–10). However, it was somewhat surprising to
note that electron donors in the arene (entries 3 and 4)
proved to be advantageous compared to electron accep-
tors (entries 5–10) for the reactivity with nitromethane.
For aliphatic aldehydes, 1,2-diaminoethane seems to be
advantageous over 1,2-aminoethanol (cf. entries 11–18).
Nitroaldol reactions with a-chiral aldehydes (Table 3)
yielded in all cases the Felkin–Anh adducts7 as the
major diastereomers (75:25 to 85:15). This was espe-
cially true with a-amino and a-alkoxyaldehydes, indi-
cating that no chelation between the amino or alkoxy
group, the aldehyde group and zinc occurs in contrast
to proposals for diethylzinc additions with N,N-diben-
zylaminoaldehydes.8 Moreover, no change in the
diastereoselectivity with regard to the promoter
employed was observed.
Entry
R in 1
Promoter
Yield (%) of 2
1
2
3
Ph
4
5
4
88
83
78
Finally, other nitroalkanes can be applied in this proto-
col as well, although the reactivity in such reactions is
decreased and higher amounts of the promoter are
necessary. The products 8 are formed as a 1:1 mixture
of diastereomers in all cases (Table 4).
4
5
4
5
4
5
4
5
83
56
64
51
57
50
52
5
6
Since there are a great number of chiral 1,2-amino
alcohols and 1,2-diamines available, the protocol ade-
7
8
9
Table 3. Nitroaldol reaction with a-chiral aldehydes in the
presence of promoters 4 or 5
10
11
12
13
14
15
16
Et
4
5
4
5
4
5
49
67
58
91
49
56
n-Bu
n-Hex
17
18
4
5
63
76
(entry 4).6 Likewise, with 1,2-aminoethane and N,N%-
dimethyl-1,2-diaminoethane only 2a was formed,
although in slightly diminished yields (entries 5 and 6).
N,N%-Tetramethyl-1,2-diamine still favors the nitroaldol
reaction, but alkylation of benzaldehyde to 3a also
occurred to a significant extent (entry 7).
Entry
Aldehyde
Promoter
Ratio
syn/anti
Yield (%)
Having
identified
1,2-aminoethanol
and
1,2-
diaminoethane as the most active promoters in combi-
nation with diethylzinc, we explored these protocols for
a variety of aliphatic and aromatic aldehydes in their
reaction with nitromethane (Table 2).
1
2
3
4
5
6
7
8
6a
6a
6b
6b
6c
6d
6e
6f
4
5
4
5
4
5
4
4
80:20
80:20
80:20
80:20
80:20
85:15
73:27
75:25
75
75
72
71
73
67
77
68
In no case any alkylation products were observed, and
good yields of the nitroalcohols 2 were obtained. Aro-
matic aldehydes reacted in the presence of both pro-
moters 4 or 5 with approximately the same results

G. Klein et al. / Tetrahedron Letters 43 (2002) 7503–7506
7505
Table 4. Nitroaldol reaction with nitroalkanes in the pres-
ence of 1,2-aminoethanol (4)
intermediate of type 11 is decisive in the catalytic cycle
for the high enantioselectivities obtained (Fig. 1). Con-
sequently, this ligand was a promising choice for the
nitroaldol protocol discussed here, especially in light of
the ligands recently introduced by Trost,5 which also
coordinate to two zinc atoms as depicted in 12.
Interestingly, in the reaction of nitromethane with benz-
aldehyde (1a) in the presence of 10, the nitroaldol
product 2a and the alkylated product 3a were obtained
in a ratio of 1:1. While 2a was obtained racemically, 3a
was isolated with 90–92% ee. Obviously, the arrange-
ment of the substrates is very different in the nitroaldol
and in the ethyl transfer to benzaldehyde.
Entry
1
Aldehyde R
Nitroalkane R1
Et
Yield (%)
52a
In conclusion, we have demonstrated that 1,2-
aminoethanol or 1,2-diaminoethane efficiently promote
nitroaldol reactions with nitromethane.
2
3
Et
Pr
43
40
Acknowledgements
a 50 mol% of 4 were employed.
This work was supported by the Deutsche Forschungs-
gemeinschaft (Re 948/3-2) and the Fonds der Chemis-
chen Industrie. S.P. is grateful to the Humboldt
foundation for a fellowship.
scribed here should open up the possibility to find new
catalysts for asymmetric nitroaldol reactions. Indeed,
initial investigations with chiral amino alcohols show
that this process can be rendered asymmetric, although
the selectivities obtained so far are not satisfactory
(Scheme 1). Nevertheless, the results with t-butyl-leucin
as promoter both, in nitroaldol reactions with a prochi-
ral aldehyde 1a as well as in a kinetic resolution of the
racemic amino aldehdyde 6a clearly show that the
reaction takes place in a chiral environment.
Moreover, we had recently introduced bis(oxazoline)
ligands 10 with hydroxymethylene side chains as
efficient chiral promoters for the addition of diethylzinc
to aldehydes9 and concluded, that a bimetallic zinc
Figure 1. Bimetallic zinc complexes for diethylzinc additions
(11) and nitroaldol reactions (12).
Scheme 1. Nitroaldol reactions with t-Bu-leucin as promoter.

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G. Klein et al. / Tetrahedron Letters 43 (2002) 7503–7506
6. Typical procedure: To a precooled (0°C) solution of
References
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continued for 48 h. Aqueous ammoniumchloride solution
was added, and the aqueous layer was extracted with
dichloromethane (3 times 15 ml). The combined organic
layers were dried and concentrated, and the crude product
was purified on silica to yield 2-nitro-1-phenylethanol
(88% yield).
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