A highly effective bis(Sulfonamide)-diamine ligand: A unique chiral skeleton for the enantioselective Cu-catalyzed Henry reaction

Article abstract of DOI:10.1002/chem.201000964

(Figure Presented) A skeleton in the closet! As a unique chiral skeleton, the newly developed bis(sulfonamide)-diamine, which contains both diamine and bis(sulfonamide) moieties, was a highly effective ligand for the asymmetric Cu(OAc)₂-catalyz

Full text of DOI:10.1002/chem.201000964

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DOI: 10.1002/chem.201000964
A Highly Effective Bis(sulfonamide)–Diamine Ligand: A Unique Chiral
Skeleton for the Enantioselective Cu-Catalyzed Henry Reaction
Wei Jin, Xincheng Li, Yongbo Huang, Fan Wu, and Boshun Wan*[a]
The nitroaldol (Henry) reaction constitutes an atom-eco-
nomic approach to b-hydroxynitroalkanes[1] that provides ef-
ficient access to valuable bifunctional compounds, such as
1,2-amino alcohols and a-hydroxy carboxylic acids.[2] Since
the pioneering work on a BINOL-derived heterometallic
complex (BINOL=1,1’-bi-2-naphthol) was disclosed by Shi-
basaki in 1992[3] for the Henry reaction, various types of cat-
alyst systems, containing chiral ligands with metal atoms
(such as Zn,[4] Co,[5] Cu,[6] Mg,[7] or Cr[8]), and organocata-
lysts[9] have been studied. However, most of these methods
suffer from some limitations, such as relatively high catalyst
loading, low reaction temperatures, multistep synthetic pro-
cedures for ligand preparation, or demanding the use of ad-
ditives, for example molecular sieves. To solve the problem
of reacting aliphatic aldehydes, one of the key strategies is
to develop new chiral ligands, since ligand design has played
a pivotal role in the development of efficient metal-cata-
lyzed asymmetric reactions.
Scheme 1. Ligand design.
performance, providing up to 99% ee for the synthesis of b-
hydroxynitroalkanes with aliphatic aldehydes.
The bis(sulfonamide)–diamines were easily prepared from
commercially available chiral a-amino alcohols and di-
AHCTUNGTREGaNNUN mines in two steps (Scheme 2). Initially, a-amino alcohols 1
were cyclized by sulfonylation to generate the corresponding
aziridines 2 in high yields.[12] Aziridines 2 were then treated
with a 1,2-diamine to form compounds 3 and 4 in satisfacto-
ry yields.
In the past few decades, a large number of chiral di-
amines[10] and chiral sulfonamides[11] have been used as lig-
ACHTUNGTRENNUNGands for numerous enantioselective reactions. However,
there is no precedent for the combination of both diamine
and bis(sulfonamide) moieties in a single chiral ligand for
the Henry reaction. The objective of this work is to explore
the viability of integrating diamine and sulfonamide frag-
ments into a unique bis(sulfonamide)–diamine chiral ligand
for the asymmetric Henry reaction of aliphatic aldehydes
(Scheme 1). Herein, we report our preliminary results on
the development of this bis(sulfonamide)–diamine-type
ligand for the Cu-catalyzed asymmetric Henry reaction. The
catalyst system that we developed demonstrates excellent
Scheme 2. Synthesis of the bis(sulfonamide)-diamines.
[a] W. Jin, X. Li, Y. Huang, F. Wu, Prof. B. Wan
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
The efficiency of ligands 3 and 4 was then evaluated by
the use of a CuACTHNUGTRNEUNG(OAc)2·H2O-catalyzed asymmetric Henry re-
457 Zhongshan Road, Dalian 116023 (China)
Fax : (+86)411-8437-9223
action between hexanal (5a) and nitromethane (6); the re-
sults are summarized in Table 1. The reaction was carried
out at room temperature, in the presence of a low catalyst
E-mail: bswan@dicp.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000964.
Chem. Eur. J. 2010, 16, 8259 – 8261
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8259

Table 1. Ligand evaluation in the Henry reaction.[a]
Table 2. Aldehyde scope of the CuACTHNGUTERNNUG
(OAc)2/4d system.[a]
ee [%][b]
Entry
Ligand
Yield [%]
ee [%][b]
Entry
R
Product
t [h]
Yield [%]
1
2
3
4
5
3
9
85
14
45
99
35
95
65
84
97
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
CH
CH
CH
G
7a
7b
7c
7d
7e
7 f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
48
48
48
48
48
48
48
24
30
86
24
96
48
60
60
60
48
60
99
99
99
91
89
98
99
99
74
99
99
99
76
87
99
88
81
95
97 (R)
97 (R)
97 (R)
99 (R)
98 (R)
98 (R)
98 (R)
95 (R)
94 (R)
96 (R)
92 (R)
95 (R)
97 (R)
96 (R)
96 (R)
96 (R)
96 (R)
97 (R)
4a
4b
4c
4d
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a] Reactions were carried out with hexanal (0.5 mmol), CH3NO2
(5.0 mmol), Cu(OAc)2·H2O (2.5 mol%), and ligand (2.5 mol%) in etha-
nol (1.0 mL) at room temperature for 48 h. [b] Enantiomeric excesses
were determined by HPLC on a Chiral OD-H column.
ACHTUNGTRENNUNG
PhCH=CH
Ph
4-NO2C6H4
2-MeOC6H4
4-PhC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2-naphthyl
2-furyl
loading of CuACHTUNGTRENNUNG(OAc)2·H2O (2.5 mol%) and of the ligand (2.5
mol%) in ethanol. The ligand screening results showed that
the reactivity and enantioselectivity are dependent upon
both the chiral diamine fragment and the substituents of the
side chain which were derived from the a-amino alcohol
(R2). In comparison with 3, 4a provided a better yield and
higher enantioselectivity. Replacing the R2 substituents with
methyl or benzyl (Bn) groups did not improve the enantio-
selectivity. Compared with ligand 4a, with a cyclohexyl frag-
ment, ligand 4d, containing a 1,2-diphenylethylenediamine
backbone, gave a better enantioselectivity (97% ee). More-
over, since all diamine ligands only provide racemic prod-
ucts (see the Supporting Information), this proves the validi-
ty of the bis(sulfonamide)–diamine ligand design. The bis-
(sulfonamide)–diamine ligands have significant advantages
over the traditional chiral diamines and sulfonamides used
for the Henry reaction.
[a] Reactions were carried out with aldehyde (0.5 mmol), CH3NO2
(5.0 mmol), Cu(OAc)2·H2O (2.5 mol%), and ligand 4d (2.5 mol%) in
ethanol (1.0 mL) at room temperature. [b] Enantiomeric excesses were
determined by HPLC and the absolute configurations (R) were estab-
lished by comparison to literature data.
Scheme 3. An application of a nitroaldol adduct.
Under the optimized conditions, the aliphatic aldehyde
substrate scope of the Henry reaction was explored
(Table 2). To our surprise, the reactions proceeded very
well; excellent yields accompanied with excellent enantiose-
lectivities were achieved in most cases. It is notable that nei-
ther the length of the carbon chain, nor its steric bulk has
an obvious effect on the enantioselectivity. Importantly, a-
branched aliphatic aldehydes, such as isobutyraldehyde, piv-
alaldehyde, and cyclohexanecarboxaldehyde, resulted in the
formation of the b-nitroalcohol with excellent enantioselec-
tivities of up to 99% ee (Table 1, entries 4–7). Furthermore,
the optimized catalyst was also used for the Henry reaction
of aromatic aldehydes (Table 2, entries 9–18). In general, all
of the investigated aromatic aldehydes provided the corre-
sponding adducts in excellent enantioselectivities. The aro-
matic substrates containing electron-donating groups tended
to afford better results than those with electron-withdrawing
groups (Table 2, entries 11–16). Even for the bulkier 2-naph-
thaldehyde and 2-furylaldehyde, high enantioselectivities
still remained (Table 2, entries 17–18).
generate the corresponding aziridine 9 without any loss of
stereochemical information. Aziridines constitute the funda-
mental synthetic tool for the generation of some N-contain-
ing natural products and also serve as chiral building blocks,
auxiliaries, and ligands in organic synthesis.[14] They are also
a key intermediate in the synthesis of our bis(sulfonamide)–
diamine ligand.
The bis(sulfonamide)–diamine ligands were also prelimi-
narily examined in Henry reactions in which other nitroal-
kanes were used. We found that the catalyst system of
ligand 4a with CuBr was highly effective for the Henry reac-
tion between 1-nitropropane and cyclohexanecarboxalde-
hyde (Scheme 4). Excellent stereocontrol and the apparently
favorable formation of the syn diastereomer were observed
in this reaction. The ratio of the syn to anti isomers was de-
termined to be 97:3. The syn diastereoisomer was produced
To further demonstrate the applicability of the new bis-
(sulfonamide)–diamine ligand, the transformation of the ni-
troaldol adduct 7d was performed as shown in Scheme 3. In-
itially, 7d was reduced to furnish (R)-(À)-3-methyl-1-amino-
butan-2-ol (8).[13] Then, 8 was cyclized by sulfonylation to
Scheme 4. A Henry reaction of 1-nitropropane.
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A Bis(sulfonamide)–Diamine Ligand
COMMUNICATION
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In summary, a unique chiral skeleton, the bis(sulfona-
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mide) moieties has been developed. This new type of ligand
has been demonstrated to be highly effective for the asym-
metric Cu-catalyzed Henry reaction of both aliphatic and ar-
omatic aldehydes with low catalyst loading, at room temper-
ature. Both aliphatic and aromatic aldehydes gave excellent
enantioselectivities of up to 99% ee. Since the bis(sulfona-
mide)–diamine ligands have significant advantages over the
traditional chiral diamines and sulfonamides, they are ex-
pected to be further investigated in the near future, for in-
stance, by replacing the Ts with acyl, aryl, alkyl, and so
forth. These features may allow this chiral skeleton to ach-
ieve extensive application in other asymmetric catalysis re-
actions. The reaction mechanism of the bis(sulfonamide)–di-
amine ligands will be the subject of future investigations in
our group.
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Acknowledgements
We are grateful for financial support from the National Basic Research
Program of China (2010CB833300).
Keywords: asymmetric catalysis · copper · N ligands ·
sulfonamides · Henry reaction
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Received: April 15, 2010
Published online: June 16, 2010
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8261