1294
Chemistry Letters Vol.37, No.12 (2008)
Aqua-aminoorganoboron Catalyst: Engineering Single Water Molecule
to Act as an Acid Catalyst in Nitro Aldol Reaction
Junichi Yoshimoto,1 Christian A. Sandoval,2 and Susumu Saitoꢀ1;3
1Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602
2State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China
3Institute for Advanced Research, Nagoya University, Chikusa-ku, Nagoya 464-8601
(Received September 24, 2008; CL-080915; E-mail: saito.susumu@f.mbox.nagoya-u.ac.jp)
Table 1. Catalyst screening in the reaction of CH3NO2 with PhCHOa
We have disclosed the catalytic potential hidden behind a
series of aqua-aminoorganoboron compounds in the formation
and reaction of nitronate species. The pivotal role of a single-
coordinated water molecule in the catalyst was demonstrated by
comparison with the D2O-analogue. The present results provide
a new strategy for the design of metal-free catalysts which function
via elaborative hydrogen-bonding networks involving water.
catalyst (1 mol%)
CH3NO2+
(3 equiv)
PhCH(OH)CH2NO2
PhCHO
(1 equiv)
additive
THF, 25 °C, 8.5 h
4a
Additive
(mol %)
Yieldb
/%
Entry
Catalyst
1
2
3
4
5
6
7
8
9
1a
1b
1c
2
2
BPh3
BPh3
—
—
—
—
—
90 (93)c
80
0
0
Et3N (1)
Et3N (3)
Et3N (3), H2O (10)
Et3N (1)
Me2NBn (3)
29
29
26
11
<5
Naturally occurring enzymes frequently contain water in
their catalytic active sites, where the water plays a crucial role
in the catalysis.1 In contrast, attempts to impose catalytic func-
tion onto a water molecule represents a challenge in the develop-
ment of artificial molecular catalysts.2 We herein report that
aqua-aminoorganoboron compounds3 exhibit unique catalytic
activities in the nitro aldol reaction.4 The reaction pathways
involve subtle interplay between the multiple functions of the
catalyst.
—
aUnless otherwise specified, reaction was performed using 1 mol % of
catalyst with respect to the amount of PhCHO in anhydrous THF at
25 ꢂC for 8.5 h. bOf isolated, purified product. cWith 70 mg/mL of
MS4A, which was dried at 150 ꢂC under vacuum (1 mmHg) for 12 h.
A series of aqua-aminoorganoboron compounds 1a–1c
(Figure 1) were readily prepared according to literature proce-
dure3 with small modification. Single-crystal X-ray diffraction
analyses of 1a,3 1c,5 and 25 identified a single water molecule
as a common feature. The boron-coordinated water bridges
two of the three nitrogens via formation of two hydrogen bonds
(Figure 1), with the third amine remaining free from any detect-
able interactions. In contrast, the solution structures of 1a–1c
Et3N (1:3) catalyst neither improved the yield of 4a under anhy-
drous conditions nor in the presence of water (Entries 6 and 7).
Et3N (1 mol %) or N,N-dimethylbenzylamine (3 mol %) alone
showed scant catalytic activity under otherwise identical condi-
tions (Entries 8 and 9). The use of 1b, which differs in steric size
at the nitrogen-residue, was also effective, while the extremely
bulky diisopropylamine derivative 1c abolished the reactivity
(Entries 2 and 3). These experiments clearly demonstrate that
the three amino-residues worked in a cooperative fashion and
were critical for generating catalytic activity within some steric
restraints. Other examples listed in Tables 2 and 3 indicate the
versatile nature of catalyst 1a under protic or aprotic conditions.
Solvent-free conditions (R1CHO:CH3NO2 = 1:3) were benefi-
cial resulting in significant rate acceleration (Table 2, Entry 1),
although alcoholic solvents were the best choice for rate optimi-
zation (Table 3, Entries 2–5). The reaction showed substrate
generality with respect to both nitroalkane and aldehyde compo-
nents. Various functional groups were tolerated and self-dimeri-
zation of aldehydes was prevented owing to the mild (almost
neutral pH) reaction conditions (Tables 2 and 3). The optimal
results afforded aldol adducts in more than 90% yields in many
cases and turnover numbers (TON) of up to 800 (generally 70–
100).
1
exhibited dynamic behavior in corresponding H NMR spectra,
consistent with intramolecular NꢁꢁꢁH(OH) exchange. According-
ly, this rapid positional exchange of the NꢁꢁꢁHOHꢁꢁꢁN bridge
makes the three nitrogens indistinguishable on the NMR time
scale.5
Treatment of a 1:3 mixture of PhCHO and CH3NO2 in THF
with a 1 mol % of 1a at 25 ꢂC for 8.5 h gave nitro aldol product
4a in 90% yield (Entry 1, Table 1). In contrast, compound 2, hav-
ing a structure similar to 1a but lacking one of the three amino-
residues, showed no catalytic activity (Entry 4). When a 1:1 mix-
ture of 2 and Et3N was used instead of 1a (Entry 5), the reaction
proceeded although at a significantly slower rate. The BPh3/
R
Me
Me
Me
N
R
N
Me
N
Me
N
R
Me
N
R
H
H
N
H
D
R
H
D
Me
Me
O
B
O
B
O
B
The presence of a water molecule in the catalyst is pivotal
for catalytic activity. Kinetic studies with the D2O-derivative 3
(deuterium content: 75–80%) using CD3NO2 and hexanal in
THF at 27 ꢂC showed that the initial reaction rate (kobs) is rough-
ly 35 times faster than that with Et3N alone (no water).6 The
reaction proceeded with pseudo-first-order dependence on
[hexanal]. Examination of reaction kinetic isotope effects
Me
Me
Me
N
N
R
Me
2
3
1a : R = Me
1b : R−R = (CH2)4
1c : R = i-Pr
Figure 1. Aqua aminoorganoboron compounds.
Copyright Ó 2008 The Chemical Society of Japan
Yoshimoto, Junichi
