Highly asymmetric Henry reaction catalyzed by chiral copper(II) complexes

Article abstract of DOI:10.1016/j.tetlet.2012.11.053

Two chiral pyridinylmethyl diphenylprolinolsilyl ether derivatives have been synthesized from N-alkylation of (S)-diphenylprolinolsilyl ether in a single step. They were successfully applied as ligands in the Cu(II)-catalyzed enantioselective Henry reacti

Full text of DOI:10.1016/j.tetlet.2012.11.053

Tetrahedron Letters 54 (2013) 462–465
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly asymmetric Henry reaction catalyzed by chiral copper(II) complexes
⇑
Bukuo Ni , Junpeng He
Department of Chemistry, Texas A&M University-Commerce, Commerce, TX 75429-3011, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Two chiral pyridinylmethyl diphenylprolinolsilyl ether derivatives have been synthesized from N-alkyl-
ation of (S)-diphenylprolinolsilyl ether in a single step. They were successfully applied as ligands in the
Cu(II)-catalyzed enantioselective Henry reaction between aldehydes and nitromethane in ethanol at
room temperature. A variety of chiral Henry products b-nitroalcohols were obtained in good to high
yields (up to 94%) with high to excellent enantioselectivities (up to 94% ee) under the optimized reaction
conditions. The results indicate that the bulky substituent diphenylprolinolsilyl ether of ligand 2 plays an
important role to induce the high stereoselectivity of the process.
Received 23 October 2012
Revised 6 November 2012
Accepted 12 November 2012
Available online 23 November 2012
Keywords:
Asymmetric catalysis
Henry reaction
Amino alcohols
Copper
Ó 2012 Elsevier Ltd. All rights reserved.
Enantioselectivity
The asymmetric Henry or nitroaldol reaction is without ques-
tion one of the most useful methods for the formation of C–C bonds
in organic synthesis.1 The resulting optically active b-nitroalcohols
are versatile building blocks for further transformations into, for
task and limited success has been achieved to date. Herein, we re-
port the synthesis of a new and novel diamine and its chiral copper
(II) complex as catalyst to promote highly asymmetric Henry reac-
tions of nitromethane to aldehydes in ethanol at room tempera-
ture. High yields (up to 94%) and ee values (up to 94%) were
achieved for a wide range of aldehydes.
example, chiral b-amino alcohols, 1,2-diamines,
a-hydroxy acids,
or other invaluable precursors of biologically active compounds.2
Thus, it is not surprising that the development of efficient asym-
metric catalytic protocols for this cornerstone reaction has re-
ceived much attention.3 Since the pioneering work by Shibasaki
and co-workers in 1992,4 a great deal of effort has been devoted
to the development of more selective and catalytic systems for this
transformation, and significant progress has been made in recent
years.3 Both organocatalysts and metal-containing catalyst com-
plexes for this reaction have been described to give good to excel-
lent enantioselectivities.5,6 Among those that have been
successfully applied, copper complexes with chiral ligands (e.g.
aminoalcohols, diamines, and Schiff bases) are, in particular, highly
efficient catalysts for the asymmetric Henry reaction, and in some
cases providing b-nitroalcohols with excellent enantioselectivi-
ties.7 Despite significant advances in this field, there are some cat-
alytic systems that show critical shortcomings, these include
substrate specificity limitation, anhydrous reaction conditions,
low reaction temperatures, high catalyst loading, and some of the
reactions require the use of activated silyl nitronates and tetrabu-
tylammonium triphenylsilyldifluorosilicate (TBAT).8 Therefore, the
design and development of new chiral ligands aimed at overcom-
ing these limitations have proven to be a significant challenging
According to the analogous procedure reported in the litera-
ture,7k the ligand 2 was readily prepared by a single step from both
commercially available (S)-diphenylprolinolsilyl ether 1 and 2-
(bromomethyl)pyridine hydrobromide using K2CO3 and KI in etha-
nol (Scheme 1, eq. 1). Ligand 2 was conceived based on an intuition
that the diphenylsiloxymethyl group would act as an effective ste-
ric controller due to these bulky groups near the catalytic site of
the catalyst. Similarly, chiral ligand 3 was prepared from 1 and
2,6-bis(bromomethyl)pyridine in 74% yield (Scheme 1, eq. 2).
With the chiral ligands 2–3 in hand, we examined their asym-
metric induction abilities in the Cu catalyzed enantioselective
Henry reaction between nitromethane and benzaldehyde, and
the results are summarized in Table 1. Initially, 5 mol % of Cu(OAc)2
was used as catalyst and 5 mol % of chiral diamine 2 was used as
ligand. When toluene was used as solvent, the reaction resulted
in low yield (entry 1). Using THF as solvent, the reaction gave the
desired Henry product 4a in 68% yield with 84% ee (entry 2). When
the protic solvents such as i-PrOH, EtOH, and MeOH were used as
solvents, all the reactions proceeded smoothly to afford the desired
product 4a in good yields (65–75%) and high enantioselectivities
(up to 87% ee) (entry 3–5). However, the use of triamine 3 as chiral
ligand gave product 4a with only 47% ee (entry 6). Other catalysts
Cu(OTf)2 and CuCl2 were tested and only resulted in either low ee
value or no reaction (entries 7 and 8). From these results, it was
⇑
Corresponding author. Fax: +1 903 468 6020.
E-mail address: Bukuo.Ni@tamuc.edu (B. Ni).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.053

B. Ni, J. He / Tetrahedron Letters 54 (2013) 462–465
463
Ph
Ph
OTMS
Ph
Ph
OTMS
K2CO3/KI
N
eq. 1
+
EtOH, rt
87%
N
N
H
N
1
Br
2
Ph
Ph
OTMS
N
K2CO3/KI
TMSO
Ph
Ph
OTMS
Ph
Ph
eq. 2
N
N
+
N
EtOH, rt
74%
N
H
Br
Br
1
3
Scheme 1. The synthesis of chiral ligands 2 and 3.
Table 1
Table 2 (continued)
Optimization of the Henry reaction condition
Entry
7
Product
Yielda (%)
70
eeb (%)
O
OH
catalyst (5 mol%)
ligand (5 mol%)
OH
NO2
H
CH3NO2
+
NO2
solvent, rt, 36 h
87
89
4a
4g
OH
F
Entry
Ligand
Catalyst
Solvent
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
2
2
2
2
2
3
2
2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
CuCl2
Toluene
THF
i-PrOH
EtOH
MeOH
EtOH
<10
68
65
75
72
65
66
—
—
NO2
84
75
87
73
47
25
—
8
94
4h
F3C
CF3 OH
NO2
OH
EtOH
EtOH
9
85
80
92
87
4i
a
Isolated yield.
Determined by chiral HPLC of the product.
b
NO2
10
4j
HO
NO2
11
75
50
93
80
Table 2
4k
OH
Scope of aldehydes in the catalytic enantioselective Henry reaction
O
OH
NO2
12
catalyst (5 mol%)
NO2
ligand (5 mol%)
4l
H
CH3NO2
+
solvent, rt, 36 h
a
4a
Isolated yield.
Determined by chiral HPLC of the product.
b
Entry
1
Product
Yielda (%)
75
eeb (%)
87
OH
NO2
demonstrated that ligand 2 in combination with Cu(OAc)2 in EtOH,
is the optimal reaction condition to give the product 4a in 75%
yield and 87% ee (entry 4).
4a
OH
Encouraged by these results, we next investigated the scope of
the reaction with nitromethane and a variety of aldehydes (Table
2). All reactions were conducted in denatured EtOH at room tem-
perature in the presence of 5 mol % of chiral ligand 2 and Cu(OAc)2.
In each case, a smooth reaction occurred to generate desired Henry
products 4a–l in good to high yields (50–94%) and high enantiose-
lectivities (80–94% ee). The results in Table 2 also show that the
nature of substituents on aryl groups influences the yields and
enantioselectivities. For benzaldehydes substituted with electron-
donating groups, the reactions afforded the Henry products 4b–c
in lower yields than 4a (entries 2–4 vs entry 1). Conversely, benz-
aldehydes with electron-withdrawing substituents resulted in
higher yields (entries 5–9 vs entries 1–4). Although the electronic
nature of the substituents on the aromatic ring affected the yields,
they had little influence on the enantioselectivity. Next, the effect
of steric hindrance of the aromatic ring was also investigated. It
was found that the aromatic aldehydes with ortho substituents
(entries 3, 6, and 9) showed better enantioselectivity than those
NO2
2
3
66
65
89
94
4b
OH
NO2
4c
OH
NO2
NO2
4
62
90
4d
MeO
OH
5
6
85
88
87
92
4e
Br
Br
OH
NO2
4f

464
B. Ni, J. He / Tetrahedron Letters 54 (2013) 462–465
O
OH
OH
Cu(OAc)2 (5 mol%)
R
3 (5 mol%)
S
H
R
R
+
CH3CH2NO2
+
NO2
NO2
EtOH, rt, 48h, 71%
syn-5
anti-5
anti: syn = 3:1
ee (anti) : 47%
ee (syn) : 45%
Scheme 2. The Henry reaction of 2-methylbenzaldehyde and nitroethane.
OAc
N
Experimental section
OAc
N
Typical procedure for the asymmetric Henry reaction
N
N
Cu
Cu
Ph
Ph
Ph
Ph
O
O
O
O
O
O
OTMS
R
To a 10 mL vial was added ligand 2 (10.4 mg, 0.025 mmol),
Cu(OAc)2 (4.5 mg, 0.025 mmol), and 96% denatured EtOH
(0.5 mL), the mixture was stirred for 1 h at room temperature.
Then the aldehyde (0.5 mmol) and nitromethane (2.5 mmol) were
added and the resulting mixture was stirred at room temperature
for 24–48 h (monitored by TLC plate). After completion, the solvent
was removed and the resulting residue was purified by column
chromatography on silica gel to give the Henry product 4.
OTMS
H
N
N
H
R
OH
OH
NO2
NO2
R
R
(S)
(R)
Re-face favored
Si-face unfavored
Figure 1. A plausible transition state model.
Acknowledgments
This research was supported by start-up funds from the College
of Science, Engineering & Agriculture, Texas A&M University-Com-
merce and National Science Foundation (CHE-1213287). We thank
Professor Allan D. Headley for making critical editorial comments
about the manuscript.
with para substituents (entries 2, 5, and 8). Other aromatic alde-
hydes, 2-naphthaldehyde and 1-naphthaldehydes, were also suit-
able substrates, the reaction afforded the desired Henry products
4j–k in high yields (75–80%) and enantioselectivities (87–93% ee)
(entries 10–11). Under the same reaction conditions, the reaction
of aliphatic aldehyde pentanal with nitromethane afforded the
Henry product 4l in relative low yield (50%) and enantioselectivity
(80% ee) (entry 12).
Supplementary data
The reaction of 2-methylbenzaldehyde and nitroethane was
also examined under standard reaction conditions and gave the de-
sired product 5 in 71% yield with moderate diastereoselectivity
(anti:syn = 3:1) and enantioselectivities (47% and 45% ee for the
anti- and syn-isomers, respectively) (Scheme 2).7m
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.11.
053.
References and notes
On the basis of the reported mechanistic studies on the asym-
metric Henry reaction catalyzed by Cu–diamine complexes,7g the
high enantioselectivity can be rationalized by the transition model
as shown in Figure 1. The reaction would involve Cu(II) complex
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2 sterically
shielded one side. The aldehyde molecule coordinates to the cop-
per ion with the bulky R group oriented away from the diphenyl-
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